Quantum Dot Nanomedicine Formulations Dramatically Improve Pharmacological Properties and Alter Uptake Pathways of Metformin and Nicotinamide Mononucleotide in Aging MiceClick to copy article linkArticle link copied!
- Nicholas J. HuntNicholas J. HuntAgeing and Alzheimers Institute, Centre for Education & Research on Ageing, Concord Repatriation General Hospital, ANZAC Research Institute, Concord, NSW 2139, AustraliaFaculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaCharles Perkins Centre, The University of Sydney, Sydney, NSW 2006, AustraliaSydney Nano Institute, The University of Sydney, Sydney, NSW 2006, AustraliaMore by Nicholas J. Hunt
- Glen P. LockwoodGlen P. LockwoodAgeing and Alzheimers Institute, Centre for Education & Research on Ageing, Concord Repatriation General Hospital, ANZAC Research Institute, Concord, NSW 2139, AustraliaFaculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaMore by Glen P. Lockwood
- Sun W. S. KangSun W. S. KangAgeing and Alzheimers Institute, Centre for Education & Research on Ageing, Concord Repatriation General Hospital, ANZAC Research Institute, Concord, NSW 2139, AustraliaCell Biology and Imaging Section, Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United StatesMore by Sun W. S. Kang
- Lara J. WestwoodLara J. WestwoodFaculty of Science, University of Technology Sydney, Sydney, NSW 2000, AustraliaMore by Lara J. Westwood
- Christina LimantoroChristina LimantoroSydney Nano Institute, The University of Sydney, Sydney, NSW 2006, AustraliaSydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaMore by Christina Limantoro
- Wojciech ChrzanowskiWojciech ChrzanowskiSydney Nano Institute, The University of Sydney, Sydney, NSW 2006, AustraliaSydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaMore by Wojciech Chrzanowski
- Peter A. G. McCourtPeter A. G. McCourtCharles Perkins Centre, The University of Sydney, Sydney, NSW 2006, AustraliaDepartment of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø 9037, NorwayMore by Peter A. G. McCourt
- Zdenka KuncicZdenka KuncicCharles Perkins Centre, The University of Sydney, Sydney, NSW 2006, AustraliaSydney Nano Institute, The University of Sydney, Sydney, NSW 2006, AustraliaSchool of Physics, The University of Sydney, Sydney, NSW 2006, AustraliaMore by Zdenka Kuncic
- David G. Le CouteurDavid G. Le CouteurAgeing and Alzheimers Institute, Centre for Education & Research on Ageing, Concord Repatriation General Hospital, ANZAC Research Institute, Concord, NSW 2139, AustraliaFaculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaCharles Perkins Centre, The University of Sydney, Sydney, NSW 2006, AustraliaMore by David G. Le Couteur
- Victoria C. Cogger*Victoria C. Cogger*Email: [email protected]Ageing and Alzheimers Institute, Centre for Education & Research on Ageing, Concord Repatriation General Hospital, ANZAC Research Institute, Concord, NSW 2139, AustraliaFaculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaCharles Perkins Centre, The University of Sydney, Sydney, NSW 2006, AustraliaMore by Victoria C. Cogger
Abstract
Orally administered Ag2S quantum dots (QDs) rapidly cross the small intestine and are taken up by the liver. Metformin and nicotinamide mononucleotide (NMN) target metabolic and aging processes within the liver. This study examined the pharmacology and toxicology of QD-based nanomedicines as carriers of metformin and NMN in young and old mice, determining if their therapeutic potency and reduced effects associated with aging could be improved. Pharmacokinetic studies demonstrated that QD-conjugated metformin and NMN have greater bioavailability, with selective accumulation in the liver following oral administration compared to unconjugated formulations. Pharmacodynamic data showed that the QD-conjugated medicines had increased physiological, metabolic, and cellular potency compared to unconjugated formulations (25× metformin; 100× NMN) and highlighted a shift in the peak induction of, and greater metabolic response to, glucose tolerance testing. Two weeks of treatment with low-dose QD-NMN (0.8 mg/kg/day) improved glucose tolerance tests in young (3 months) mice, whereas old (18 and 24 months) mice demonstrated improved fasting and fed insulin levels and insulin resistance. High-dose unconjugated NMN (80 mg/kg/day) demonstrated improvements in young mice but not in old mice. After 100 days of QD (320 μg/kg/day) treatment, there was no evidence of cellular necrosis, fibrosis, inflammation, or accumulation. Ag2S QD nanomedicines improved the pharmacokinetic and pharmacodynamic properties of metformin and NMN by increasing their therapeutic potency, bypassing classical cellular uptake pathways, and demonstrated efficacy when drug alone was ineffective in aging mice.
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Results and Discussion
Synthesis and Characterization of Drug Loading on Ag2S QDs
Figure 1
Figure 1. Conjugation and characterization of Ag2S quantum dots (QDs) with metformin and nicotinamide mononucleotide (NMN). (A) Water-soluble QDs with a hydrophilic external layer of carboxylic acid molecules on their surface (as shown using Fourier transform infrared (FTIR) microscopy spectral analysis) are conjugated with metformin or NMN using EDC/NHS chemical coupling. Repeat FTIR spectra analysis demonstrates an external layer of drug conjugate on these QDs. (B) QDs (gray) with/without drug attachment (QD-metformin (red) and QD-NMN (blue)) demonstrated similar sizing when dried for visualization under transmission electron microscopy. Examination in solution showed drug attachment increases the hydrodynamic diameter (C) and shifts zeta-potential toward 0 (D). The loading efficiency was measured using a low (E) and high (F) concentration (concn) of QDs. The amount of drug retained following conjugation and 24 h at pH 7 under dialysis was 100% when a greater ratio of QDs to drug was used. When greater concentration of drug compared to QDs was used, loading efficiency shifted toward 10%. A maximal drug attachment ratio was observed for metformin (90 mM/1 mM) and NMN (150 mM/1 mM) (G).
Biodistribution and Pharmacokinetics of QD-Metformin
Figure 2
Figure 2. Pharmacokinetic and biodistribution data of (3H)QDs (gray), (14C)metformin (black), and QD-(14C)metformin (red) following oral administration. Following ingestion, QDs, metformin, and QD-metformin accumulate in various organs. (A) Metformin uptake peaks in the liver 8 h after administration; attachment to QDs leads to an earlier peak at 2 h. After 8 h, QDs show faster liver clearance than the attached metformin, indicating detachment of drug from QDs. Over a 24 h period, a greater concentration of metformin is in the liver when it is conjugated to QDs, as shown by the greater area under the curve (AUC). (B) Persistence in the small intestinal lumen is reduced when metformin is attached to QDs; without attachment, 50% of metformin is localized to the intestine after 8 h compared to 25% of QD-metformin; this contributes to a greater AUC for metformin compared to that for QD-metformin. (C) Similar fecal clearance of metformin and QD-metformin was observed. (D) Blood concentration of metformin and QD-metformin demonstrated similar shifts; attachment to QDs allows for faster passage into blood; concentration is reduced by 8 h followed by re-entry into the blood. Comparison to QD clearance from blood suggests detachment of metformin from QDs similar to that observed in liver. (E) Kidney and (F) spleen demonstrate small accumulations of drug and QDs. Following 24 h, less than 5% of materials remain in these organs with no differences in AUC between QD or metformin alone. Data show mean ± SD (n = 3 per group, compared with Kruskal–Wallis test and post-hoc Dunn’s method; α = 0.05).
Pharmacodynamic Properties of QD-Metformin and QD-NMN
Figure 3
Figure 3. In vivo pharmacodynamics and PK/PD of metformin and NMN with and without attachment to QDs. (A) Metformin (black) and (B) QD-metformin (red) given by oral gavage 2 h prior to an oral glucose tolerance test (oGTT) demonstrated a dose-dependent reduction in the time taken to clear glucose from the blood and AUC. (C) Comparison between dosage of metformin alone and QD-metformin and the percentage of reduction in oGTT AUC demonstrates QD-metformin induces the same effect as drug alone at 1% of the dosage given. (D) Comparison of the effects of the same dosage of metformin with/without conjugation to QDs on the reduction in oGTT AUC. oGTTs were performed 0.5, 2, 4, 8, or 24 h following gavage. (E) NMN (greenh) and (F) QD-NMN (blue) given by oral gavage 2 h prior to an oGTT demonstrated a dose-dependent reduction in the time taken to clear glucose from the blood and AUC. (G) Comparison in the concentration of drug given between NMN alone and QD-NMN and the percentage of reduction in oGTT AUC demonstrates QD-NMN induces the same effect as drug alone at 0.1% of the dosage given. (D) Comparison of the effects of the same dosage of NMN with/without conjugation to QDs on the reduction in oGTT AUC. oGTTs were performed 0.5, 2, 4, 8, or 24 h following gavage. Data show mean ± SD (n = 3 per group). Statistical test: Kruskal–Wallis tests with a post-hoc Dunn’s method; α = 0.05.
Mechanisms for the Uptake and Activity of QD-Metformin and QD-NMN
Figure 4
Figure 4. In vivo molecular pathways promoted by QD-drug treatment compared to drug alone. Mice received an oral gavage of water (white), QDs (gray), QD-metformin (red), metformin (black), QD-NMN (blue) or NMN (green) (dosages are given per figure) 2 h prior to liver tissue collection and hepatocyte and liver endothelial cell isolations. (A) p-AMPK/AMPK and (B) SIRT1 were analyzed by Western blots and normalized to β-tubulin expression, percentage changes relative to untreated controls are compared between groups. (C) cGMP by a commercial ELISA, and (D) NAD total, NAD+ and NADH by a commercial NAD/NADH assay. Westernblot images are provided in Supplementary Figure 2. ELISA and assay protein measurements are relative to mg of liver tissue or protein from isolated cells. Data show mean ± SD (A,B: n = 5, C–D: n = 3 per group). Statistical test: (A,B) one-way-ANOVA with post-hoc Bonferroni test; (C,D) Kruskal–Wallis tests with a post-hoc Dunn’s method; α = 0.05.
Figure 5
Figure 5. In vitro drug/QD-drug treatment on isolated hepatocyte endocytosis/activation and LSEC fenestrations. Hepatocytes were isolated from young 3 months old mice (A) and old 18 months old mice (B). Hepatocytes were nonpretreated control (CNTR) or pretreated for 0.5 h with sucrose (0.5 M) to block clathrin-mediated endocytosis and micropinocytosis or omeprazole (10 μM) to block endocytosis via protein pumps. Cells were then treated for 2 h with radiolabeled (14C)metformin (black) or QD(14C)metformin (red). (C) Young and (D) old hepatocytes were isolated and either nonpretreated or pretreated with sucrose (stripes) or cytidine 5-monophosphate (CMP) (spots) an inhibitor of dephosphorylation of NMN. Cells were then treated with QD-NMN (blue) or NMN (green) for 2 h. Cells were then lysed and NAD+ measured by NAD/NADH assay. (E) Young hepatocytes were isolated and incubated for 2 h with increasing concentration of QDs (1 nM to 10 mM). Cell viability was measured with an MTT assay. Data show mean ± SD (n = 3 per group, compared with Kruskal–Wallis tests and post-hoc Dunn’s method; α = 0.05).
Effects of 2 Weeks of Treatment with QD-NMN versus NMN in Young and Old Mice
Figure 6
Figure 6. Overview of 2-week in vivo treatment with QD-NMN (blue) and NMN (green) in 3, 18, and 24 month old mice on metabolic parameters and toxicity. (A) schematic of experimental treatments and ages of intervention. (B–D) Effects of treatment in 3 month (B), 18 month (C), and 24 month (D) old mice. Data show liver NAD+, blood AST, and ALT; before and after treatment: oral glucose tolerance test area under the curve (AUC), fasting and fed insulin and HOMA-IR. Comprehensive data shown in Supplementary Figures 3–6. Data show mean ± SD (n = 5 per group). Statistical test: one-way-ANOVA with post-hoc Bonferroni test; α = 0.05.
Short- and Long-Term Toxicity of QDs and QD Drug Treatments
Figure 7
Figure 7. Effects of 100 day in vivo treatment with QDs (320 μg/kg/day). (A) Body weight of mice was collected every 7 days with control (CNTR) collected at day 0 and 100. (B) AST and ALT were not significantly influenced by treatment. (C) No changes in plasma IL-6, MIP-2 (mouse homologue of IL-8), or IFN-γ were observed. (D) H&E staining of the liver demonstrated sparse immune cell infiltration in QD-treated mice with no other pathohistological features. (E) TNFα staining did not show differences between CNTR and QD-treated mice, positive and negative control section from the spleen of control tissue. (F) Sirius Red staining of the liver and kidney (G) did not show differences between groups with low minimal fibrosis of the portal vein nor were differences observed in the METAVIR fibrosis score. In the kidney, no enlargement of the Bowman’s capsules in the kidney was observed, and no change in plasma creatinine was shown. Data show mean ± SD (n = 5 per group compared with one-way-ANOVA and post-hoc Bonferroni test); α = 0.05.
Figure 8
Figure 8. Autometallography staining of the liver and small intestine and inductively coupled plasma mass spectrometry. (A) Autometallography is a measure of silver distribution and involves adding additional silver to aggregate to silver ions in tissue sections. Liver panels show untreated negative control, 250 μg/kg treated, and 250 μg/kg treated with a 3 day wash out prior to tissue collection. Staining of the endothelium is absent in the 3 day wash out compared to the treated sample. Fourteen day (250 μg/kg/day) and 100 day (320 μg/kg/day) treated mice demonstrate staining in the sinusoids of the liver and of the bile ducts. The 7500 μg/kg (toxic dosage) shows silver staining in all tissue compartments with aggregates in hepatocytes. Small intestine panels show silver staining in the blood vessel underlining the villi. (B) ICP-MS was performed was performed on liver tissue samples to analysis the concentration of Ag+. No differences were observed between groups, one 100 day sample demonstrated elevated Ag+ content with data shown with and without outlier (statistical test: one-way ANOVA with post-hoc Bonferroni test); α = 0.05. Cells were then incubated with Alexa Fluor 488 goat anti-rabbit, 1% goat serum in PBS for 30 min at 4 °C. Cells were again centrifuged, washed in PBS twice with centrifugation between washes.
Clinical Relevance
Future Directions
Conclusion
Experimental Procedures
Ethics
Materials
Synthesis of Water-Soluble Ag2S QDs
Drug Attachment
Fourier Transform Infrared Microscopy
High-Voltage Transmission Electron Microscopy
Zetasizer Characterization
Mice
Radiolabeling
Tritium:
Carbon-14:
Tissue Collection
Sample Preparation and Radiolabeled Activity Analysis
Hepatocyte and LSEC Isolation
Flow Cytometry
Western B lots
Assays for Hepatocyte Metabolites
Assays for Toxicity and Immune Response
Cell Culture
In Vitro Hepatocyte Endocytosis and NAD Generation
LSEC Fenestration Ultrastructure Imaging
Oral Glucose Tolerance Testing and Insulin Levels
Administration of Drugs in Drinking Water
Histology and Immunofluorescence
Autometallography Staining
Inductively Coupled Plasma Mass Spectrometry
Statistics
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.0c09278. The raw data are available upon request to the corresponding author.
Expanded DLS data, Western blot images, expanded 2 week treatment and histology, fenestration data and cell culture purity data (PDF)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Acknowledgments
NHMRC project Grant No. 1141234; Sydney Medical School Foundation McKnight Bequest, The University of Sydney DVCR Research Equity Fellowship, The University of Sydney Seed Grant and the University of Tromsø Faculty of Health Sciences travel grant to P.M. Australian Centre for Microscopy and Microanalysis and the Sydney Analytical Vibrational Spectrometry Facility, the University of Sydney. The Microscopy and Flow Cytometry Core Facility, ANZAC Research Institute. Concord RG Hospital Electron Microscopy Unit.
References
This article references 72 other publications.
- 1Zrazhevskiy, P.; Gao, X. Multifunctional Quantum Dots for Personalized Medicine. Nano Today 2009, 4 (5), 414– 428, DOI: 10.1016/j.nantod.2009.07.004Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltFGmsb0%253D&md5=9bb17a953e9f4b516a96378d04bd0dd7Multifunctional quantum dots for personalized medicineZrazhevskiy, Pavei; Gao, XiaohuNano Today (2009), 4 (5), 414-428CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)A review. Successes in biomedical research and state-of-the-art medicine have undoubtedly improved the quality of life. However, a no. of diseases, such as cancer, immunodeficiencies, and neurol. disorders, still evade conventional diagnostic and therapeutic approaches. A transformation towards personalized medicine may help to combat these diseases. For this, identification of disease mol. fingerprints and their assocn. with prognosis and targeted therapy must become available. Quantum dots (QDs), semiconductor nanocrystals with unique photo-phys. properties, represent a novel class of fluorescence probes to address many of the needs of personalized medicine. This review outlines the properties of QDs that make them a suitable platform for advancing personalized medicine, examines several proof-of-concept studies showing utility of QDs for clin. relevant applications, and discusses current challenges in introducing QDs into clin. practice.
- 2Wagner, A. M.; Knipe, J. M.; Orive, G.; Peppas, N. A. Quantum Dots in Biomedical Applications. Acta Biomater. 2019, 94, 44– 63, DOI: 10.1016/j.actbio.2019.05.022Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFGqu7fF&md5=c0ac69d4024fd8714c58b45d420be870Quantum dots in biomedical applicationsWagner, Angela M.; Knipe, Jennifer M.; Orive, Gorka; Peppas, Nicholas A.Acta Biomaterialia (2019), 94 (), 44-63CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)A review. Semiconducting nanoparticles, more commonly known as quantum dots, possess unique size and shape dependent optoelectronic properties. In recent years, these unique properties have attracted much attention in the biomedical field to enable real-time tissue imaging (bioimaging), diagnostics, single mol. probes, and drug delivery, among many other areas. The optical properties of quantum dots can be tuned by size and compn., and their high brightness, resistance to photobleaching, multiplexing capacity, and high surface-to-vol. ratio make them excellent candidates for intracellular tracking, diagnostics, in vivo imaging, and therapeutic delivery. We discuss recent advances and challenges in the mol. design of quantum dots are discussed, along with applications of quantum dots as drug delivery vehicles, theranostic agents, single mol. probes, and real-time in vivo deep tissue imaging agents. We present a detailed discussion of the biodistribution and toxicity of quantum dots, and highlight recent advances to improve long-term stability in biol. buffers, increase quantum yield following bioconjugation, and improve clearance from the body. Last, we present an outlook on future challenges and strategies to further advance translation to clin. application. Semiconducting nanoparticles, commonly known as quantum dots, possess unique size and shape dependent elec. and optical properties. In recent years, they have attracted much attention in biomedical imaging to enable diagnostics, single mol. probes, and real-time imaging of tumors. This review discusses recent advances and challenges in the design of quantum dots, and highlights how these strategies can further advance translation to clin. applications.
- 3Pelaz, B.; Alexiou, C.; Alvarez-Puebla, R. A.; Alves, F.; Andrews, A. M.; Ashraf, S.; Balogh, L. P.; Ballerini, L.; Bestetti, A.; Brendel, C.; Bosi, S.; Carril, M.; Chan, W. C. W.; Chen, C.; Chen, X.; Chen, X.; Cheng, Z.; Cui, D.; Du, J.; Dullin, C. Diverse Applications of Nanomedicine. ACS Nano 2017, 11 (3), 2313– 2381, DOI: 10.1021/acsnano.6b06040Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXktV2isLg%253D&md5=3441feba35a8ea371b661906e1d0813bDiverse Applications of NanomedicinePelaz, Beatriz; Alexiou, Christoph; Alvarez-Puebla, Ramon A.; Alves, Frauke; Andrews, Anne M.; Ashraf, Sumaira; Balogh, Lajos P.; Ballerini, Laura; Bestetti, Alessandra; Brendel, Cornelia; Bosi, Susanna; Carril, Monica; Chan, Warren C. W.; Chen, Chunying; Chen, Xiaodong; Chen, Xiaoyuan; Cheng, Zhen; Cui, Daxiang; Du, Jianzhong; Dullin, Christian; Escudero, Alberto; Feliu, Neus; Gao, Mingyuan; George, Michael; Gogotsi, Yury; Gruenweller, Arnold; Gu, Zhongwei; Halas, Naomi J.; Hampp, Norbert; Hartmann, Roland K.; Hersam, Mark C.; Hunziker, Patrick; Jian, Ji; Jiang, Xingyu; Jungebluth, Philipp; Kadhiresan, Pranav; Kataoka, Kazunori; Khademhosseini, Ali; Kopecek, Jindrich; Kotov, Nicholas A.; Krug, Harald F.; Lee, Dong Soo; Lehr, Claus-Michael; Leong, Kam W.; Liang, Xing-Jie; Ling Lim, Mei; Liz-Marzan, Luis M.; Ma, Xiaowei; Macchiarini, Paolo; Meng, Huan; Moehwald, Helmuth; Mulvaney, Paul; Nel, Andre E.; Nie, Shuming; Nordlander, Peter; Okano, Teruo; Oliveira, Jose; Park, Tai Hyun; Penner, Reginald M.; Prato, Maurizio; Puntes, Victor; Rotello, Vincent M.; Samarakoon, Amila; Schaak, Raymond E.; Shen, Youqing; Sjoeqvist, Sebastian; Skirtach, Andre G.; Soliman, Mahmoud G.; Stevens, Molly M.; Sung, Hsing-Wen; Tang, Ben Zhong; Tietze, Rainer; Udugama, Buddhisha N.; VanEpps, J. Scott; Weil, Tanja; Weiss, Paul S.; Willner, Itamar; Wu, Yuzhou; Yang, Lily; Yue, Zhao; Zhang, Qian; Zhang, Qiang; Zhang, Xian-En; Zhao, Yuliang; Zhou, Xin; Parak, Wolfgang J.ACS Nano (2017), 11 (3), 2313-2381CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biol., nonbiol., biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clin. products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.
- 4Hassan, S.; Prakash, G.; Bal Ozturk, A.; Saghazadeh, S.; Farhan Sohail, M.; Seo, J.; Remzi Dokmeci, M.; Zhang, Y. S.; Khademhosseini, A. Evolution and Clinical Translation of Drug Delivery Nanomaterials. Nano Today 2017, 15, 91– 106, DOI: 10.1016/j.nantod.2017.06.008Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlCqtrzJ&md5=3f7b9d21e3ff0a6192d2ee592395d895Review on Evolution and clinical translation of drug delivery nanomaterialsHassan, Shabir; Prakasha, Gyan; Bal Ozturk, Ayca; Saghazadeh, Saghi; Farhan Sohail, Muhammad; Seo, Jungmok; Remzi Dokmeci, Mehmet; Zhang, Yu Shrike; Khademhosseini, AliNano Today (2017), 15 (), 91-106CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)A review. With the advent of technol., the role of nanomaterials in medicine has grown exponentially in the last few decades. The main advantage of such materials has been exploited in drug delivery applications, due to their effective targeting that in turn reduces systemic toxicity compared to the conventional routes of drug administration. While therapeutically improved and safe materials have been introduced in nanomedicine platforms, issues related to their degrdn. rate and bio-distribution still exist, thus making their successful translation to clin. application very challenging. Researchers are constantly improving upon novel nanomaterials that are safer and more effective not only as therapeutic agents but as diagnostic tools as well, making the research in the field of nanomedicine ever more fascinating. In this review stress has been made on the evolution of nanomaterials that are under different stages of clin. trials or have been approved by the United States Food and Drug Administration (FDA).
- 5Tsoi, K. M.; MacParland, S. A.; Ma, X.-Z.; Spetzler, V. N.; Echeverri, J.; Ouyang, B.; Fadel, S. M.; Sykes, E. A.; Goldaracena, N.; Kaths, J. M.; Conneely, J. B.; Alman, B. A.; Selzner, M.; Ostrowski, M. A.; Adeyi, O. A.; Zilman, A.; McGilvray, I. D.; Chan, W. C. W. Mechanism of Hard-Nanomaterial Clearance by the Liver. Nat. Mater. 2016, 15 (11), 1212– 1221, DOI: 10.1038/nmat4718Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlCitb%252FF&md5=18e6822d496d5a3a2813c14f245bbf5bMechanism of hard-nanomaterial clearance by the liverTsoi, Kim M.; MacParland, Sonya A.; Ma, Xue-Zhong; Spetzler, Vinzent N.; Echeverri, Juan; Ouyang, Ben; Fadel, Saleh M.; Sykes, Edward A.; Goldaracena, Nicolas; Kaths, Johann M.; Conneely, John B.; Alman, Benjamin A.; Selzner, Markus; Ostrowski, Mario A.; Adeyi, Oyedele A.; Zilman, Anton; McGilvray, Ian D.; Chan, Warren C. W.Nature Materials (2016), 15 (11), 1212-1221CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)The liver and spleen are major biol. barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examd. the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 ± 6.4%), hepatic B cells (81.5 ± 9.3%) and liver sinusoidal endothelial cells (64.6 ± 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 ± 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.
- 6Kermanizadeh, A.; Powell, L. G.; Stone, V. A Review of Hepatic Nanotoxicology - Summation of Recent Findings and Considerations for the Next Generation of Study Designs. J. Toxicol. Environ. Health, Part B 2020, 23 (4), 137– 176, DOI: 10.1080/10937404.2020.1751756Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnslWgt7Y%253D&md5=c19ec7e18cd1e22e78204e0523d4e5a1A review of hepatic nanotoxicology - summation of recent findings and considerations for the next generation of study designsKermanizadeh, Ali; Powell, Leagh G.; Stone, VickiJournal of Toxicology and Environmental Health, Part B: Critical Reviews (2020), 23 (4), 137-176CODEN: JTECFR; ISSN:1093-7404. (Taylor & Francis, Inc.)The liver is one of the most important multi-functional organs in the human body. Amongst various crucial functions, it is the main detoxification center and predominantly implicated in the clearance of xenobiotics potentially including particulates that reach this organ. It is now well established that a significant quantity of injected, ingested or inhaled nanomaterials (NMs) translocate from primary exposure sites and accumulate in liver. This review aimed to summarize and discuss the progress made in the field of hepatic nanotoxicol., and crucially highlight knowledge gaps that still exist. Key considerations include In vivo studies clearly demonstrate that low-soly. NMs predominantly accumulate in the liver macrophages the Kupffer cells (KC), rather than hepatocytes. KCs lining the liver sinusoids are the first cell type that comes in contact with NMs in vivo. Further, these macrophages govern overall inflammatory responses in a healthy liver. Therefore, interaction with of NM with KCs in vitro appears to be very important. Many acute in vivo studies demonstrated signs of toxicity induced by a variety of NMs. However, acute studies may not be that meaningful due to liver's unique and unparalleled ability to regenerate. In almost all investigations where a recovery period was included, the healthy liver was able to recover from NM challenge. This organ's ability to regenerate cannot be reproduced in vitro. However, recommendations and evidence is offered for the design of more physiol. relevant in vitro models. Models of hepatic disease enhance the NM-induced hepatotoxicity. The review offers a no. of important suggestions for the future of hepatic nanotoxicol. study design. This is of great significance as its findings are highly relevant due to the development of more advanced in vitro, and in silico models aiming to improve physiol. relevant toxicol. testing strategies and bridging the gap between in vitro and in vivo experimentation.
- 7Kim, H. J.; Kim, A.; Miyata, K.; Kataoka, K. Recent Progress in Development of siRNA Delivery Vehicles for Cancer Therapy. Adv. Drug Delivery Rev. 2016, 104, 61– 77, DOI: 10.1016/j.addr.2016.06.011Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFSgt7fP&md5=e5ac0b415079dce255fb4b0012ad70c5Recent progress in development of siRNA delivery vehicles for cancer therapyKim, Hyun Jin; Kim, Ahram; Miyata, Kanjiro; Kataoka, KazunoriAdvanced Drug Delivery Reviews (2016), 104 (), 61-77CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)Recent progress in RNA biol. has broadened the scope of therapeutic targets of RNA drugs for cancer therapy. However, RNA drugs, typically small interfering RNAs (siRNAs), are rapidly degraded by RNases and filtrated in the kidney, thereby requiring a delivery vehicle for efficient transport to the target cells. To date, various delivery formulations have been developed from cationic lipids, polymers, and/or inorg. nanoparticles for systemic delivery of siRNA to solid tumors. This review describes the current status of clin. trials related to siRNA-based cancer therapy, as well as the remaining issues that need to be overcome to establish a successful therapy. It, then introduces various promising design strategies of delivery vehicles for stable and targeted siRNA delivery, including the prospects for future design.
- 8Murakami, M.; Nishina, K.; Watanabe, C.; Yoshida-Tanaka, K.; Piao, W.; Kuwahara, H.; Horikiri, Y.; Miyata, K.; Nishiyama, N.; Kataoka, K.; Yoshida, M.; Mizusawa, H.; Yokota, T. Enteral siRNA Delivery Technique for Therapeutic Gene Silencing in the Liver via the Lymphatic Route. Sci. Rep. 2015, 5 (1), 17035, DOI: 10.1038/srep17035Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFensbfJ&md5=60a7d99d585ff3ef6c0fa28d8f670f8dEnteral siRNA delivery technique for therapeutic gene silencing in the liver via the lymphatic routeMurakami, Masahiro; Nishina, Kazutaka; Watanabe, Chie; Yoshida-Tanaka, Kie; Piao, Wenying; Kuwahara, Hiroya; Horikiri, Yuji; Miyata, Kanjiro; Nishiyama, Nobuhiro; Kataoka, Kazunori; Yoshida, Masayuki; Mizusawa, Hidehiro; Yokota, TakanoriScientific Reports (2015), 5 (), 17035CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)An efficient targeting delivery technol. is needed for functional oligonucleotides to exert their potential effect on the target gene without an adverse effect in vivo. Development of enteral delivery systems for nucleic acids is a major challenge because of their large mol. size and instability. Here, we describe a new enteral delivery technique that enables small interfering RNA (siRNA) selectively delivered to the liver to silence its target Apolipoprotein B gene expression. A nuclease-resistant synthetic siRNA was conjugated with α-tochopherol and administered as lipid nanoparticle to the large intestine of the mice in a postprandial state. The selective transport into the liver, effective gene silence, and consequently significant redn. in serum low d. lipoprotein-cholesterol level, were demonstrated. The chylomicron-mediated pathway via the lymphatic route was suggested as major mechanism. This unique approach may provide a basis for developing oral and rectal delivery systems for nucleic acids targeting liver.
- 9Hunt, N. J.; McCourt, P. A. G.; Le Couteur, D. G.; Cogger, V. C. Novel Targets for Delaying Aging: The Importance of the Liver and Advances in Drug Delivery. Adv. Drug Delivery Rev. 2018, 135, 39– 49, DOI: 10.1016/j.addr.2018.09.006Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVygsr3L&md5=c2c6016b989d8495d5be00e08b9fd64dNovel targets for delaying aging: The importance of the liver and advances in drug deliveryHunt, Nicholas J.; McCourt, Peter A. G.; Le Couteur, David G.; Cogger, Victoria C.Advanced Drug Delivery Reviews (2018), 135 (), 39-49CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Age-related changes in liver function have a significant impact on systemic aging and susceptibility to age-related diseases. Nutrient sensing pathways have emerged as important targets for the development of drugs that delay aging and the onset age-related diseases. This supports a central role for the hepatic regulation of metab. in the assocn. between nutrition and aging. Recently, a role for liver sinusoidal endothelial cells (LSECs) in the relationship between aging and metab. has also been proposed. Age-related loss of fenestrations within LSECs impairs the transfer of substrates (such as lipoproteins and insulin) between sinusoidal blood and hepatocytes, resulting in post-prandial hyperlipidemia and insulin resistance. Targeted drug delivery methods such as nanoparticles and quantum dots will facilitate the direct delivery of drugs that regulate fenestrations in LSECs, providing an innovative approach to ameliorating age-related diseases and increasing healthspan.
- 10Hunt, N. J.; Lockwood, G. P.; Le Couteur, F. H.; McCourt, P. A. G.; Singla, N.; Kang, S. W. S.; Burgess, A.; Kuncic, Z.; Le Couteur, D. G.; Cogger, V. C. Rapid Intestinal Uptake and Targeted Delivery to the Liver Endothelium Using Orally Administered Silver Sulfide Quantum Dots. ACS Nano 2020, 14 (2), 1492– 1507, DOI: 10.1021/acsnano.9b06071Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFyltr8%253D&md5=f2a40cb7208013a42a2424e45af109d9Rapid Intestinal Uptake and Targeted Delivery to the Liver Endothelium Using Orally Administered Silver Sulfide Quantum DotsHunt, Nicholas J.; Lockwood, Glen P.; Le Couteur, Frank H.; McCourt, Peter A. G.; Singla, Nidhi; Kang, Sun Woo Sophie; Burgess, Andrew; Kuncic, Zdenka; Le Couteur, David G.; Cogger, Victoria C.ACS Nano (2020), 14 (2), 1492-1507CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Quantum dots (QDs) are used for imaging and transport of therapeutics. Here we demonstrate rapid absorption across the small intestine and targeted delivery of QDs with bound materials to the liver sinusoidal endothelial cells (LSECs) or hepatocytes in vitro and in vivo following oral administration. QDs were radiolabeled with 3H-oleic acid, with a fluorescent tag or 14C-metformin placed within a drug binding site. Three different biopolymer shell coatings were compared (formaldehyde-treated serum albumin (FSA), gelatin, heparin). Passage across the small intestine into mesenteric veins is mediated by clathrin endocytosis and micropinocytosis. 60% of an oral dose of QDs was rapidly distributed to the liver within 30 min, and this increased to 85% with FSA biopolymer coating. Uptake into LSECs also increased 3-fold with FSA coating, while uptake into hepatocytes was increased from 40% to 85% with gelatin biopolymer coating. Localization of QDs to LSECs was confirmed with immunofluorescence and transmission electron microscopy. 85% of QDs were cleared within 24 h of administration. The bioavailability of 14C-metformin 2 h post-ingestion was increased 5-fold by conjugation with QD-FSA, while uptake of metformin into LSECs was improved 50-fold by using these QDs. Endocytosis of QDs by SK-Hep1 cells (an LSEC immortal cell line) was via clathrin- and caveolae-mediated pathways with QDs taken up into lysosomes. In conclusion, we have shown high specificity targeting of the LSEC or hepatocytes after oral administration of QDs coated with a biopolymer layer of FSA or gelatin, which improved the bioavailability and delivery of metformin to LSECs.
- 11Hunt, N. J.; Kang, S. W.; Lockwood, G. P.; Le Couteur, D. G.; Cogger, V. C. Hallmarks of Aging in the Liver. Comput. Struct. Biotechnol. J. 2019, 17, 1151– 1161, DOI: 10.1016/j.csbj.2019.07.021Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1art7zO&md5=7252f235fddde7dcd16f75c66c66217bHallmarks of Aging in the LiverHunt, Nicholas J.; Kang, Sun Woo; Lockwood, Glen P.; Le Couteur, David G.; Cogger, Victoria C.Computational and Structural Biotechnology Journal (2019), 17 (), 1151-1161CODEN: CSBJAC; ISSN:2001-0370. (Elsevier B.V.)While the liver demonstrates remarkable resilience during aging, there is growing evidence that it undergoes all the cellular hallmarks of aging, which increases the risk of liver and systemic disease. The aging process in the liver is driven by alterations of the genome and epigenome that contribute to dysregulation of mitochondrial function and nutrient sensing pathways, leading to cellular senescence and low-grade inflammation. These changes promote multiple phenotypic changes in all liver cells (hepatocytes, liver sinusoidal endothelial, hepatic stellate and Kupffer cells) and impairment of hepatic function. In particular, age-related changes in the liver sinusoidal endothelial cells are a significant but under-recognized risk factor for the development of age-related cardiometabolic disease.
- 12Alfaras, I.; Mitchell, S. J.; Mora, H.; Lugo, D. R.; Warren, A.; Navas-Enamorado, I.; Hoffmann, V.; Hine, C.; Mitchell, J. R.; Le Couteur, D. G.; Cogger, V. C.; Bernier, M.; de Cabo, R. Health Benefits of Late-Onset Metformin Treatment Every Other Week in Mice. npj Aging Mech Dis 2017, 3 (1), 16, DOI: 10.1038/s41514-017-0018-7Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M3kt1SmsQ%253D%253D&md5=83d6345c013ceb7fb6076c9b7011fc64Health benefits of late-onset metformin treatment every other week in miceAlfaras Irene; Mitchell Sarah J; Mora Hector; Lugo Darisbeth Rosario; Navas-Enamorado Ignacio; Bernier Michel; de Cabo Rafael; Warren Alessandra; Le Couteur David G; Cogger Victoria C; Hoffmann Vickie; Hine Christopher; Mitchell James R; Le Couteur David G; Cogger Victoria CNPJ aging and mechanisms of disease (2017), 3 (), 16 ISSN:2056-3973.Chronic 1% metformin treatment is nephrotoxic in mice, but this dose may nonetheless confer health benefits if given intermittently rather than continuously. Here, we examined the effects of 1% metformin given every-other week (EOW) or two consecutive weeks per month (2WM) on survival of 2-year-old male mice fed standard chow. EOW and 2WM mice had comparable life span compared with control mice. A significant reduction in body weight within the first few weeks of metformin treatment was observed without impact on food consumption and energy expenditure. Moreover, there were differences in the action of metformin on metabolic markers between the EOW and 2WM groups, with EOW metformin conferring greater benefits. Age-associated kidney lesions became more pronounced with metformin, although without pathological consequences. In the liver, metformin treatment led to an overall reduction in steatosis and was accompanied by distinct transcriptomic and metabolomic signatures in response to EOW versus 2WM regimens. Thus, the absence of adverse outcomes associated with chronic, intermittent use of 1% metformin in old mice has clinical translatability into the biology of aging in humans.
- 13Katsyuba, E.; Romani, M.; Hofer, D.; Auwerx, J. NAD+ Homeostasis in Health and Disease. Nat. Metab 2020, 2, 9, DOI: 10.1038/s42255-019-0161-5Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXks1Krsrg%253D&md5=8c165c237d9ef8f9b757e422ad9c29d1NAD+ homeostasis in health and diseaseKatsyuba, Elena; Romani, Mario; Hofer, Dina; Auwerx, JohanNature Metabolism (2020), 2 (1), 9-31CODEN: NMAED6; ISSN:2522-5812. (Springer International Publishing AG)A review. Abstr.: The conceptual evolution of NAD (NAD+) from being seen as a simple metabolic cofactor to a pivotal cosubstrate for proteins regulating metab. and longevity, including the sirtuin family of protein deacylases, has led to a new wave of scientific interest in NAD+. NAD+ levels decline during ageing, and alterations in NAD+ homeostasis can be found in virtually all age-related diseases, including neurodegeneration, diabetes and cancer. In preclin. settings, various strategies to increase NAD+ levels have shown beneficial effects, thus starting a competitive race to discover marketable NAD+ boosters to improve healthspan and lifespan. Here, we review the basics of NAD+ biochem. and metab., and its roles in health and disease, and we discuss current challenges and the future translational potential of NAD+ research.
- 14Mills, K. F.; Yoshida, S.; Stein, L. R.; Grozio, A.; Kubota, S.; Sasaki, Y.; Redpath, P.; Migaud, M. E.; Apte, R. S.; Uchida, K.; Yoshino, J.; Imai, S.-i. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016, 24 (6), 795– 806, DOI: 10.1016/j.cmet.2016.09.013Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKmsLvF&md5=1c523f308481ab9749bf6a9f93c05ab5Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in MiceMills, Kathryn F.; Yoshida, Shohei; Stein, Liana R.; Grozio, Alessia; Kubota, Shunsuke; Sasaki, Yo; Redpath, Philip; Migaud, Marie E.; Apte, Rajendra S.; Uchida, Koji; Yoshino, Jun; Imai, Shin-ichiroCell Metabolism (2016), 24 (6), 795-806CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)NAD+ availability decreases with age and in certain disease conditions. NMN (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12-mo-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-assocd. physiol. decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-assocd. body wt. gain, enhanced energy metab., promoted phys. activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-assocd. gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metab. and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.
- 15Yoshino, J.; Mills, K. F.; Yoon, M. J.; Imai, S.-I. Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet-and Age-Induced Diabetes in Mice. Cell Metab. 2011, 14 (4), 528– 536, DOI: 10.1016/j.cmet.2011.08.014Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht12rtLvK&md5=a33f288cd823d4f85fd7201623e842d4Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in MiceYoshino, Jun; Mills, Kathryn F.; Yoon, Myeong Jin; Imai, Shin-ichiroCell Metabolism (2011), 14 (4), 528-536CODEN: CMEEB5; ISSN:1550-4131. (Cell Press)Type 2 diabetes (T2D) has become epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here, we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, NMN (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide crit. insights into a potential nutriceutical intervention against diet- and age-induced T2D.
- 16Hunt, N. J.; Lockwood, G. P.; Kang, S. W.; Pulpitel, T.; Clark, X.; Mao, H.; McCourt, P. A.; Cooney, G. J.; Wali, J. A.; Le Couteur, F. H. The Effects of Metformin on Age-Related Changes in the Liver Sinusoidal Endothelial Cell. J. Gerontol A Biol. Sci. 2020, 75 (2), 278– 285, DOI: 10.1093/gerona/glz153Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M3mslarsg%253D%253D&md5=f1e88b4fdaac277f862e321b9fa70c89The Effects of Metformin on Age-Related Changes in the Liver Sinusoidal Endothelial CellHunt Nicholas J; Lockwood Glen P; Kang Sun Woo Sophie; Le Couteur Frank H; Le Couteur David G; Cogger Victoria C; Hunt Nicholas J; Lockwood Glen P; Kang Sun Woo Sophie; Wali Jibran A; Le Couteur David G; Cogger Victoria C; Hunt Nicholas J; Le Couteur David G; Cogger Victoria C; Hunt Nicholas J; Lockwood Glen P; Kang Sun Woo Sophie; Pulpitel Tamara; Clark Ximonie; McCourt Peter A G; Cooney Gregory J; Wali Jibran A; Le Couteur David G; Cogger Victoria C; Mao Hong; McCourt Peter A G; Wali Jibran AThe journals of gerontology. Series A, Biological sciences and medical sciences (2020), 75 (2), 278-285 ISSN:.Age-related changes in the liver sinusoidal endothelium, particularly the reduction in fenestrations, contribute to insulin resistance in old age. Metformin impacts on the aging process and improves insulin resistance. Therefore, the effects of metformin on the liver sinusoidal endothelium were studied. Metformin increased fenestrations in liver sinusoidal endothelial cells isolated from both young and old mice. Mice administered metformin in the diet for 12 months had increased fenestrations and this was associated with lower insulin levels. The effect of metformin on fenestrations was blocked by inhibitors of AMP-activated protein kinase (AMPK), endothelial nitric oxide synthase, and myosin light chain kinase phosphorylation. Metformin led to increased transgelin expression and structural changes in the actin cytoskeleton but had no effect on lactate production. Metformin also generated fenestration-like structures in SK-Hep1 cells, a liver endothelial cell line, and this was associated with increased ATP, cGMP, and mitochondrial activity. In conclusion, metformin ameliorates age-related changes in the liver sinusoidal endothelial cell via AMPK and endothelial nitric oxide pathways, which might promote insulin sensitivity in the liver, particularly in old age.
- 17Hunt, N. J.; Lockwood, G. P.; Warren, A.; Mao, H.; McCourt, P. A.; Le Couteur, D. G.; Cogger, V. C. Manipulating Fenestrations in Young and Old Liver Sinusoidal Endothelial Cells. Am. J. Physiol Gastrointest Liver Physiol 2019, 316 (1), G144– G154, DOI: 10.1152/ajpgi.00179.2018Google ScholarThere is no corresponding record for this reference.
- 18Patiño-Herrera, R.; Louvier-Hernández, J. F.; Escamilla-Silva, E. M.; Chaumel, J.; Escobedo, A. G. P.; Pérez, E. Prolonged Release of Metformin by SiO2 Nanoparticles Pellets for Type II Diabetes Control. Eur. J. Pharm. Sci. 2019, 131, 1– 8, DOI: 10.1016/j.ejps.2019.02.003Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivVWks7o%253D&md5=3befef0cbbd369dce3463af62aea45aeProlonged release of metformin by SiO2 nanoparticles pellets for type II diabetes controlPatino-Herrera, Rosalba; Louvier-Hernandez, Jose Francisco; Escamilla-Silva, Eleazar M.; Chaumel, Julie; Escobedo, Alma Gabriela Palestino; Perez, EliasEuropean Journal of Pharmaceutical Sciences (2019), 131 (), 1-8CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)Mesoporous silica nanoparticles (MSNPs) were synthesized and loaded with metformin hydrochloride (Metf), its adsorption has studied at different concns. and pHs, optimal adsorption conditions were detd. Hybrid MSNPs-Metf were mixed with chitosan to compress them and form quasi-spherical pellets, were coated with five chitosan layers as a barrier to prolong metformin release. It showed that this pellet is useful for metformin controlled release since drug over time was significantly delayed by the chitosan coating and then, as metformin is electrostatically linked to MSNPs, it also controls the release of drug, releasing 170 mg after 17 h of exposure at pH 1.2. When pH is >1.2, metformin release was significantly prolonged. Since 170 mg is 21% of a 850-mg metformin dose and previous studies report that 90% of metformin is recovered as unchanged drug in urine after 12 h of metformin intakes. These results suggest that MSNPs-Metf pellets, coated with chitosan, are an option to avoid excessive metformin ingest.
- 19Xu, H.; Jiang, Q.; Reddy, N.; Yang, Y. Hollow Nanoparticles from Zein for Potential Medical Applications. J. Mater. Chem. 2011, 21 (45), 18227– 18235, DOI: 10.1039/c1jm11163aGoogle Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVehsrbO&md5=20acaad239a57445cd69fa50e691e9e3Hollow nanoparticles from zein for potential medical applicationsXu, Helan; Jiang, Qiuran; Reddy, Narendra; Yang, YiqiJournal of Materials Chemistry (2011), 21 (45), 18227-18235CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)Hollow nanoparticles from corn storage protein zein, with av. diams. as small as 65 nm and capable of loading a large amt. of drug and penetrating into the cell cytoplasm, have been developed for potential drug delivery applications. As an important protein co-product of corn-based ethanol, zein is biocompatible and has been proved to be useful for medical applications through in vitro and in vivo evaluations. Zein can overcome the limitations of inorg. or metal nanoparticles that tend to accumulate in the organs and tissues and is therefore preferable for drug delivery applications. However, it has been obsd. that only small proteins and peptides are able to penetrate into cells and zein with a mol. wt. of 14-44 kDa may not be able to enter into the cells. In this research, hollow zein nanoparticles have been developed and the potential of the hollow zein nanoparticles to load drugs and enter the cell cytoplasm was investigated. Hollow zein nanoparticles developed in this research were capable of loading as high as 369 mg g-1 of the drug metformin at an equil. concn. of 3 g L-1. Metformin in hollow zein nanoparticles showed a more sustained and controlled release profile than that in solid zein nanoparticles. Hollow zein nanoparticles were found to be able to enter the fibroblast cells 1 h after incubation. The biocompatibility, nano-scale diams., potential for loading a large amt. of drugs and the ability to penetrate into cells make hollow zein nanoparticles ideal candidates for carrying various payloads for intracellular drug delivery.
- 20Pereira, A.; Brito, G.; Lima, M.; Silva Junior, A.; Silva, E.; de Rezende, A.; Bortolin, R.; Galvan, M.; Pirih, F.; Araujo Junior, R.; Medeiros, C.; Guerra, G.; Araujo, A. Metformin Hydrochloride-Loaded PLGA Nanoparticle in Periodontal Disease Experimental Model Using Diabetic Rats. Int. J. Mol. Sci. 2018, 19 (11), 3488, DOI: 10.3390/ijms19113488Google ScholarThere is no corresponding record for this reference.
- 21Panda, B. P.; Krishnamoorthy, R.; Shivashekaregowda, N. K. H.; Patnaik, S. Influence of Poloxamer- 188 on Design and Development of Second Generation PLGA Nanocrystals of Metformin Hydrochloride. Nano Biomed. Eng. 2018, 10 (4), 334– 343, DOI: 10.5101/nbe.v10i4.p334-343Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVCjsL3K&md5=bc80a231a0bcc6049c287919d8df553dInfluence of poloxamer 188 on design and development of second generation PLGA nanocrystals of metformin hydrochloridePanda, Bibhu Prasad; Krishnamoorthy, Rachna; Shivashekaregowda, Naveen Kumar Hawala; Patnaik, SujataNano Biomedicine and Engineering (2018), 10 (4), 334-343CODEN: NBEAA2; ISSN:2150-5578. (Nano Biomedicine and Engineering)The poly(D,L-lactide-co-glycolide) (PLGA) based second-generation nanocrystals prepd. by modified nanopptn. method, is the method of choice for encapsulation of both lipophilic and hydrophilic drugs. In this study, nanopptn. technique was adopted to develop second generation nanocrystals of PLGA loaded with metformin HCl (MHc). Poloxamer 188 with three different concns. (0.5, 0.75, 1% w/v) in combination with PLGA at 1, 2, 3% concns. (w/v) successfully produced MHc loaded PLGA second generation nanocrystals. The effects of poloxamer 188, amphiphilic triblock copolymer on carrier particle size, surface morphol., polydispersity index, zeta potential, drug entrapment efficiency and drug release of nanoformulation were investigated. The optimized formulation of second-generation nanocrystals with concns. 0.75% w/v poloxamer 188 and 2% w/v PLGA, could produce particle size of 114.6 nm, entrapment efficiency of 63.48% and drug release 80.23% at 12 h. A blank formulation with the same compn. as optimized formulation without addn. of poloxamer188 compared with optimized formulation, exhibited nanoparticles of larger mean particle size of 212.9 nm with entrapment efficiency of 68.47% and 50.5% drug release at 12 h. Transmission electron microscopy (TEM) anal. of the nanoformulations revealed that poloxamer188 greatly contributed to smooth, spherical morphol. of nanosize polymeric nanoparticles. Further Fourier-transform IR spectroscopy (FTIR) and differential scanning calorimetry (DSC) studies on nanoformulation emphasized the significance of poloxamer188 in formulation and development of optimized MHc loaded PLGA nanosuspensions of second generation nanocrystals. In conclusion, the study emphasizes that poloxamer 188 was a versatile excipient, which played a pivotal role in producing nanosize carrier with high drug release profile of MHc loaded PLGA nanosuspensions of second generation nanocrystals.
- 22Kumar, S.; Bhanjana, G.; Verma, R. K.; Dhingra, D.; Dilbaghi, N.; Kim, K. H. Metformin-Loaded Alginate Nanoparticles as an Effective Antidiabetic Agent for Controlled Drug Release. J. Pharm. Pharmacol. 2017, 69 (2), 143– 150, DOI: 10.1111/jphp.12672Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjtFCq&md5=c355fc189bdd1cd7df0d8d4708af93a2Metformin-loaded alginate nanoparticles as an effective antidiabetic agent for controlled drug releaseKumar, Sandeep; Bhanjana, Gaurav; Verma, Ritesh Kumar; Dhingra, Dinesh; Dilbaghi, Neeraj; Kim, Ki-HyunJournal of Pharmacy and Pharmacology (2017), 69 (2), 143-150CODEN: JPPMAB; ISSN:0022-3573. (John Wiley & Sons Ltd.)Objectives : Present modalities for the diagnosis and treatment of diabetes still suffer from certain limitations such as erratic absorption, need of high dose, poor sensitivity or specificity, resistance, substantial morbidity and mortality, long-term complications, and patient-to-patient variability with lifetime treatment. Methods : This study focused on the development of a water-in-oil-in-water metformin nanoemulsion as an effective method in diabetes treatment. As a Biopharmaceutics Classification System (BCS) class III drug, metformin is hydrophilic in nature with high soly. and poor absorption characteristics. To simultaneously facilitate gastrointestinal absorption and intestinal permeability, metformin was loaded into alginate nanocapsules prepd. by an emulsion crosslinking technol. Key findings : These prepd. metformin-loaded alginate nanoparticles (MLANs) were characterized using transmission electron microscopy (TEM), Fourier transform IR (FTIR) spectroscopy, and photon correlation spectroscopy (PCS)-based particle size anal. Conclusions : The drug loading and encapsulation efficiency in MLANs were 3.12 mg (the amt. of metformin added in 100 mg of nanoparticles) and 78%, resp. The results of in-vitro drug release studies and in-vivo efficacy tests (using animal models) demonstrated enhanced efficiency and response of MLANs relative to pure metformin. The efficacy of MLANs (46.8 mg/kg) was overall about three times higher than that of pure metformin 150 mg/kg.
- 23Chinnaiyan, S. K.; Karthikeyan, D.; Gadela, V. R. Development and Characterization of Metformin Loaded Pectin Nanoparticles for T2 Diabetes Mellitus. Pharm. Nanotechnol. 2019, 6 (4), 253– 263, DOI: 10.2174/2211738507666181221142406Google ScholarThere is no corresponding record for this reference.
- 24Jose, P.; Sundar, K.; Anjali, C.; Ravindran, A. Metformin-Loaded Bsa Nanoparticles in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug. Cell Biochem. Biophys. 2015, 71 (2), 627– 636, DOI: 10.1007/s12013-014-0242-8Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFagtbzK&md5=f76778cdf9ecad24644d8523833a630bMetformin-Loaded BSA Nanoparticles in Cancer Therapy: A New Perspective for an Old Antidiabetic DrugJose, Pinkybel; Sundar, K.; Anjali, C. H.; Ravindran, AswathyCell Biochemistry and Biophysics (2015), 71 (2), 627-636CODEN: CBBIFV; ISSN:1085-9195. (Springer)Clin. and exptl. data suggest that there is a strong assocn. between type II diabetic mellitus and pancreatic cancer. The present study focuses on exploring the anticancer and antidiabetic properties of metformin-loaded bovine serum albumin nanoparticles (BSA NPs) on (MiaPaCa-2) pancreatic carcinoma cell lines. Albumin nanoparticles were synthesized using coacervation method and the av. size of the particles was found to be 97 nm. The particles were stable and showed a spherical morphol. with narrow size distribution. We investigated the impact of two stages characterized in type II diabetes mellitus (hyperglycemia and hyperinsulinemia) on the proliferation of MiaPaCa-2 cells and compared the inhibitory effects of bare metformin to that of MET-BSA NPs. Further, different concns. of insulin and glucose were added along with bare metformin, bare BSA, and metformin encapsulated BSA carrier on MiaPaCa-2 cells to check the strong assocn. between type II diabetes and pancreatic cancer. The results revealed that MET-BSA NPs showed more toxicity when compared with drug and carrier individually.
- 25Choi, Y. H.; Han, H.-K. Nanomedicines: Current Status and Future Perspectives in Aspect of Drug Delivery and Pharmacokinetics. J. Pharm. Invest. 2018, 48 (1), 43– 60, DOI: 10.1007/s40005-017-0370-4Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFekt7fM&md5=890427cf846ce15df8af7d01b5230011Nanomedicines: current status and future perspectives in aspect of drug delivery and pharmacokineticsChoi, Young Hee; Han, Hyo-KyungJournal of Pharmaceutical Investigation (2018), 48 (1), 43-60CODEN: JPIOBH; ISSN:2093-5552. (Springer)A Review. Nanomedicines have evolved into various forms including dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles since their first launch in the market. Widely highlighted benefits of nanomedicines over conventional medicines include superior efficacy, safety, physicochem. properties, and pharmacokinetic/pharmacodynamic profiles of pharmaceutical ingredients. Esp., various kinetic characteristics of nanomedicines in body are further influenced by their formulations. This review provides an updated understanding of nanomedicines with respect to delivery and pharmacokinetics. It describes the process and advantages of the nanomedicines approved by FDA and EMA. New FDA and EMA guidelines will also be discussed. Based on the anal. of recent guidelines and approved nanomedicines, key issues in the future development of nanomedicines will be addressed.
- 26Sambol, N. C.; Chiang, J.; O’Conner, M.; Liu, C. Y.; Lin, E. T.; Goodman, A. M.; Benet, L. Z.; Karam, J. H. Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Subjects and Patients with Noninsulin-Dependent Diabetes Mellitus. J. Clin. Pharmacol. 1996, 36 (11), 1012– 1021, DOI: 10.1177/009127009603601105Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXkvVamtw%253D%253D&md5=3db573b4ac6380eb74fee3c00fecc950Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitusSambol, Nancy C.; Chiang, Janie; O'Conner, Michael; Liu, Chui Y.; Lin, Emil T.; Goodman, Anita M.; Benet, Leslie Z.; Karam, John H.Journal of Clinical Pharmacology (1996), 36 (11), 1012-1021CODEN: JCPCBR; ISSN:0091-2700. (Lippincott-Raven)This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose-dependent pharmacokinetics. The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed. Nine patients with NIDDM and 9 healthy subjects received 4 single-blind single-dose treatments of metformin HCl (850 mg, 1,700 mg, 2,550 mg, and placebo) and a multiple-dose treatment of 850 mg metformin HCl (3 times daily for 19 doses). After each single-dose treatment and the final dose of the multiple-dose phase, multiple plasma and urine samples were collected for 48 h and assayed for metformin levels. Plasma samples were also assayed for glucose and insulin levels. There were no significant differences in metformin kinetics in patients with NIDDM compared with healthy subjects, in men compared with women, or during multiple-dose treatment vs. single-dose treatment. Plasma concns. of metformin increase less than proportionally to dose, most likely due to a decrease in percent absorbed. In patients with NIDDM, single doses of 1,700-mg or higher of metformin significantly decrease postprandial, but not preprandial, glucose concns. and do not influence insulin concns. With multiple doses, both preprandial and postprandial glucose concns. and preprandial insulin concns. were significantly lower than with placebo. The effect of metformin on glucose level is correlated with the av. fasting plasma glucose level without drug. In healthy subjects, single and multiple doses of metformin showed no effect on plasma glucose, but significantly attenuated the rise in immediate postprandial insulin levels.
- 27Padwal, R. S.; Gabr, R. Q.; Sharma, A. M.; Langkaas, L.-A.; Birch, D. W.; Karmali, S.; Brocks, D. R. Effect of Gastric Bypass Surgery on the Absorption and Bioavailability of Metformin. Diabetes Care 2011, 34 (6), 1295– 1300, DOI: 10.2337/dc10-2140Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXos1KmsLo%253D&md5=97266ca74d83ab42f4bde51cdf5b989bEffect of gastric bypass surgery on the absorption and bioavailability of metforminPadwal, Raj S.; Gabr, Ranlah Q.; Sharma, Arya M.; Langkaas, Lee-Ann; Birch, Dan W.; Karmali, Shahzeer; Brocks, Dion R.Diabetes Care (2011), 34 (6), 1295-1300CODEN: DICAD2; ISSN:0149-5992. (American Diabetes Association, Inc.)Use of gastric bypass surgery is common and increasing. Over 40% of patients in diabetes remission after gastric bypass surgery may redevelop diabetes within 5 years. Metformin, the first-line drug for diabetes, has low bioavailability and slow, incomplete gastrointestinal absorption. We hypothesized that gastric bypass would further reduce the absorption and bioavailability of metformin. In a nonblinded, single-dose pharmacokinetic study, 16 nondiabetic post-gastric bypass patients and 16 sex- and BMI-matched control subjects (mean age 40 years and BMI 39.2 kg/m2) were administered two 500-mg metformin tablets. Plasma metformin levels were sampled at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 h. Metformin absorption, estd. by the area under the curve (AUC) of the plasma drug concns. from time 0 to infinity (AUC0-∞), was the primary outcome, and metformin bioavailability, assessed by measuring 24-h urine metformin levels, was a secondary outcome. Compared with control subjects, metformin AUC0-∞ was increased in gastric bypass subjects by 21% (13.7 vs. 11.4 μg/mL/h; mean difference 2.3 [95% CI -1.3 to 5.9]) and bioavailability was increased by 50% (41.8 vs. 27.8%; 14.0 [4.1-23.9]). Gastric bypass patients had significantly lower AUC glucose levels over 8 h compared with control subjects (35.8 vs. 41.7 μg/mL/h; 5.9 [3.1-8.8]), but this was likely a result of differences in baseline fasting glucose and not metformin absorption. Metformin absorption and bioavailability seem to be higher after gastric bypass, and this may have implications on dosing and toxicity risk. Studies are needed to confirm these findings and delineate potential mechanisms.
- 28Isin, E. M.; Guengerich, F. P. Complex Reactions Catalyzed by Cytochrome P450 Enzymes. Biochim. Biophys. Acta, Gen. Subj. 2007, 1770 (3), 314– 329, DOI: 10.1016/j.bbagen.2006.07.003Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpvVyqsQ%253D%253D&md5=05b988e6536ea1e8725799d3cf395005Complex reactions catalyzed by cytochrome P 450 enzymesIsin, Emre M.; Guengerich, F. PeterBiochimica et Biophysica Acta, General Subjects (2007), 1770 (3), 314-329CODEN: BBGSB3; ISSN:0304-4165. (Elsevier Ltd.)A review. Cytochrome P 450 (P 450) isoforms are some of the most versatile redox proteins known. The basic P 450 reactions include C-hydroxylation, heteroatom oxygenation, heteroatom release (dealkylation), and epoxide formation. Mechanistic explanations for these reactions have been advanced. A no. of more complex P 450 reactions also occur, and these can be understood largely in the context of the basic chem. mechanisms and subsequent rearrangements. The list discussed here updates a 2001 review and includes Cl oxygenation, arom. dehalogenation, formation of diindole products, dimer formation via Diels-Alder reactions of products, ring coupling and also ring formation, reductive activation (e.g., aristolochic acid), ring contraction (piperidine nitroxide radical), oxidn. of troglitazone, cleavage of amino oxazoles and a 1,2,4-oxadiazole ring, bioactivation of a dihydrobenzoxathiin, and oxidative aryl migration.
- 29Bobo, D.; Robinson, K. J.; Islam, J.; Thurecht, K. J.; Corrie, S. R. Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date. Pharm. Res. 2016, 33 (10), 2373– 2387, DOI: 10.1007/s11095-016-1958-5Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xpslyrsbk%253D&md5=e1babf0ad4e9b4ecc4c36874c04108f2Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to DateBobo, Daniel; Robinson, Kye J.; Islam, Jiaul; Thurecht, Kristofer J.; Corrie, Simon R.Pharmaceutical Research (2016), 33 (10), 2373-2387CODEN: PHREEB; ISSN:0724-8741. (Springer)A review. In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clin. trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biol. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clin. trials, with ∼40% of trials listed in clin. trials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorg. and metallic particles in clin. trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clin. trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials ("theranostics") and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what addnl. testing (e.g. safety and toxicity) is required before products become available.
- 30Boles, M. A.; Ling, D.; Hyeon, T.; Talapin, D. V. The Surface Science of Nanocrystals. Nat. Mater. 2016, 15 (2), 141– 153, DOI: 10.1038/nmat4526Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1Cksrs%253D&md5=74fad72ab2b0a439dff7f7c49711d695The surface science of nanocrystalsBoles, Michael A.; Ling, Daishun; Hyeon, Taeghwan; Talapin, Dmitri V.Nature Materials (2016), 15 (2), 141-153CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)A review. All nanomaterials share a common feature of large surface-to-vol. ratio, making their surfaces the dominant player in many phys. and chem. processes. Surface ligands - mols. that bind to the surface - are an essential component of nanomaterial synthesis, processing and application. Understanding the structure and properties of nanoscale interfaces requires an intricate mix of concepts and techniques borrowed from surface science and coordination chem. This Review elaborates these connections and discusses the bonding, electronic structure and chem. transformations at nanomaterial surfaces. The authors specifically focus on the role of surface ligands in tuning and rationally designing properties of functional nanomaterials. Given their importance for biomedical (imaging, diagnostics and therapeutics) and optoelectronic (light-emitting devices, transistors, solar cells) applications, the authors end with an assessment of application-targeted surface engineering.
- 31Gao, L.; Liu, G.; Ma, J.; Wang, X.; Zhou, L.; Li, X. Drug Nanocrystals: In Vivo Performances. J. Controlled Release 2012, 160 (3), 418– 430, DOI: 10.1016/j.jconrel.2012.03.013Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XltVKmur0%253D&md5=20a5165e2b2998089a073f41848742b8Drug nanocrystals: In vivo performancesGao, Lei; Liu, Guiyang; Ma, Jianli; Wang, Xiaoqing; Zhou, Liang; Li, XiangJournal of Controlled Release (2012), 160 (3), 418-430CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Over the past few decades, there was a considerable research interest in drug nanocrystal system as a pharmaceutical approach for poorly sol. drugs. At the beginning lots of works were done to study various technologies assocd. with prodn. of drug nanocrystals and their in vitro phys. and chem. properties, such as morphol., formulation compn., stabilities, cryst. structure and enhanced soly. and dissoln. velocity. Recently, in vivo behaviors of the nanocrystals were generally studied in animals (including human), and the results proved that drug nanocrystals could be used as a versatile formulation to alter and improve the pharmacokinetic, pharmacodynamic and targeting properties of poorly sol. drugs. In this paper, in vivo performances of drug nanocrystals exhibited in animals in different administration route were reviewed, and the advantages of drug nanocrystals in the aspect of safety, pharmacodynamics, pharmacokinetics and targeting delivery were discussed in detail.
- 32Szunerits, S.; Melinte, S.; Barras, A.; Pagneux, Q.; Voronova, A.; Abderrahmani, A.; Boukherroub, R. The Impact of Chemical Engineering and Technological Advances on Managing Diabetes: Present and Future Concepts. Chem. Soc. Rev. 2020, DOI: 10.1039/C9CS00886AGoogle ScholarThere is no corresponding record for this reference.
- 33Patel, S.; Kim, J.; Herrera, M.; Mukherjee, A.; Kabanov, A. V.; Sahay, G. Brief Update on Endocytosis of Nanomedicines. Adv. Drug Delivery Rev. 2019, 144, 90– 111, DOI: 10.1016/j.addr.2019.08.004Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1ent73P&md5=c39a50133726ef18fefd07291e79d064Brief update on endocytosis of nanomedicinesPatel, Siddharth; Kim, Jeonghwan; Herrera, Marco; Mukherjee, Anindit; Kabanov, Alexander V.; Sahay, GauravAdvanced Drug Delivery Reviews (2019), 144 (), 90-111CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. As such, significant effort has been devoted to advancing our understanding of the biophys. interactions of the myriad nanoparticles. Endocytosis of nanomedicine has drawn tremendous interest in the last decade. Here, we highlight the ever-present barriers to efficient intracellular delivery of nanoparticles as well as the current advances and strategies deployed to breach these barriers. We also introduce new barriers that have been largely overlooked such as the glycocalyx and macromol. crowding. Addnl., we draw attention to the potential complications arising from the disruption of the newly discovered functions of the lysosomes. Novel strategies of exploiting the inherent intracellular defects in disease states to enhance delivery and the use of exosomes for bioanalytics and drug delivery are explored. Furthermore, we discuss the advances in imaging techniques like electron microscopy, super resoln. fluorescence microscopy, and single particle tracking which have been instrumental in our growing understanding of intracellular pathways and nanoparticle trafficking. Finally, we advocate for the push towards more intravital anal. of nanoparticle transport phenomena using the multitude of techniques available to us. Unraveling the underlying mechanisms governing the cellular barriers to delivery and biol. interactions of nanoparticles will guide the innovations capable of breaching these barriers.
- 34Behzadi, S.; Serpooshan, V.; Tao, W.; Hamaly, M. A.; Alkawareek, M. Y.; Dreaden, E. C.; Brown, D.; Alkilany, A. M.; Farokhzad, O. C.; Mahmoudi, M. Cellular Uptake of Nanoparticles: Journey inside the Cell. Chem. Soc. Rev. 2017, 46 (14), 4218– 4244, DOI: 10.1039/C6CS00636AGoogle Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1yhtLw%253D&md5=938d2f8aa9d3b017cf728a93c62bec42Cellular uptake of nanoparticles: journey inside the cellBehzadi, Shahed; Serpooshan, Vahid; Tao, Wei; Hamaly, Majd A.; Alkawareek, Mahmoud Y.; Dreaden, Erik C.; Brown, Dennis; Alkilany, Alaaldin M.; Farokhzad, Omid C.; Mahmoudi, MortezaChemical Society Reviews (2017), 46 (14), 4218-4244CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)Nanoscale materials are increasingly found in consumer goods, electronics, and pharmaceuticals. While these particles interact with the body in myriad ways, their beneficial and/or deleterious effects ultimately arise from interactions at the cellular and subcellular level. Nanoparticles (NPs) can modulate cell fate, induce or prevent mutations, initiate cell-cell communication, and modulate cell structure in a manner dictated largely by phenomena at the nano-bio interface. Recent advances in chem. synthesis have yielded new nanoscale materials with precisely defined biochem. features, and emerging anal. techniques have shed light on nuanced and context-dependent nano-bio interactions within cells. In this review, we provide an objective and comprehensive account of our current understanding of the cellular uptake of NPs and the underlying parameters controlling the nano-cellular interactions, along with the available anal. techniques to follow and track these processes.
- 35Rosario, D.; Benfeitas, R.; Bidkhori, G.; Zhang, C.; Uhlen, M.; Shoaie, S.; Mardinoglu, A. Understanding the Representative Gut Microbiota Dysbiosis in Metformin-Treated Type 2 Diabetes Patients Using Genome-Scale Metabolic Modeling. Front Physiol 2018, 9, 775, DOI: 10.3389/fphys.2018.00775Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FmtlyltA%253D%253D&md5=60b8643aac89e111f0298b9d19cc907cUnderstanding the Representative Gut Microbiota Dysbiosis in Metformin-Treated Type 2 Diabetes Patients Using Genome-Scale Metabolic ModelingRosario Dorines; Benfeitas Rui; Bidkhori Gholamreza; Zhang Cheng; Uhlen Mathias; Mardinoglu Adil; Shoaie Saeed; Shoaie Saeed; Mardinoglu AdilFrontiers in physiology (2018), 9 (), 775 ISSN:1664-042X.Dysbiosis in the gut microbiome composition may be promoted by therapeutic drugs such as metformin, the world's most prescribed antidiabetic drug. Under metformin treatment, disturbances of the intestinal microbes lead to increased abundance of Escherichia spp., Akkermansia muciniphila, Subdoligranulum variabile and decreased abundance of Intestinibacter bartlettii. This alteration may potentially lead to adverse effects on the host metabolism, with the depletion of butyrate producer genus. However, an increased production of butyrate and propionate was verified in metformin-treated Type 2 diabetes (T2D) patients. The mechanisms underlying these nutritional alterations and their relation with gut microbiota dysbiosis remain unclear. Here, we used Genome-scale Metabolic Models of the representative gut bacteria Escherichia spp., I. bartlettii, A. muciniphila, and S. variabile to elucidate their bacterial metabolism and its effect on intestinal nutrient pool, including macronutrients (e.g., amino acids and short chain fatty acids), minerals and chemical elements (e.g., iron and oxygen). We applied flux balance analysis (FBA) coupled with synthetic lethality analysis interactions to identify combinations of reactions and extracellular nutrients whose absence prevents growth. Our analyses suggest that Escherichia sp. is the bacteria least vulnerable to nutrient availability. We have also examined bacterial contribution to extracellular nutrients including short chain fatty acids, amino acids, and gasses. For instance, Escherichia sp. and S. variabile may contribute to the production of important short chain fatty acids (e.g., acetate and butyrate, respectively) involved in the host physiology under aerobic and anaerobic conditions. We have also identified pathway susceptibility to nutrient availability and reaction changes among the four bacteria using both FBA and flux variability analysis. For instance, lipopolysaccharide synthesis, nucleotide sugar metabolism, and amino acid metabolism are pathways susceptible to changes in Escherichia sp. and A. muciniphila. Our observations highlight important commensal and competing behavior, and their association with cellular metabolism for prevalent gut microbes. The results of our analysis have potential important implications for development of new therapeutic approaches in T2D patients through the development of prebiotics, probiotics, or postbiotics.
- 36Nies, A. T.; Hofmann, U.; Resch, C.; Schaeffeler, E.; Rius, M.; Schwab, M. Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs). PLoS One 2011, 6 (7), e22163, DOI: 10.1371/journal.pone.0022163Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVSlt77J&md5=5d8eaa6bd39db4c374151741f8e11d77Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs)Nies, Anne T.; Hofmann, Ute; Resch, Claudia; Schaeffeler, Elke; Rius, Maria; Schwab, MatthiasPLoS One (2011), 6 (7), e22163CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Metformin, an oral insulin-sensitizing drug, is actively transported into cells by org. cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metab., drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concn.-dependent manner. Half-maximal inhibitory concn. values (IC50) were in the low micromolar range (3-36 μM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clin. relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy.
- 37Dong, S.; Cho, H. J.; Lee, Y. W.; Roman, M. Synthesis and Cellular Uptake of Folic Acid-Conjugated Cellulose Nanocrystals for Cancer Targeting. Biomacromolecules 2014, 15 (5), 1560– 1567, DOI: 10.1021/bm401593nGoogle Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvVCrsro%253D&md5=a3350e98074027fe0806ae4155d7b86bSynthesis and Cellular Uptake of Folic Acid-Conjugated Cellulose Nanocrystals for Cancer TargetingDong, Shuping; Cho, Hyung Joon; Lee, Yong Woo; Roman, MarenBiomacromolecules (2014), 15 (5), 1560-1567CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)Elongated nanoparticles have recently been shown to have distinct advantages over spherical ones in targeted drug delivery applications. In addn. to their oblong geometry, their lack of cytotoxicity and numerous surface hydroxyl groups make cellulose nanocrystals (CNCs) promising drug delivery vectors. Herein we report the synthesis of folic acid-conjugated CNCs for the targeted delivery of chemotherapeutic agents to folate receptor-pos. cancer cells. Folate receptor-mediated cellular binding/uptake of the conjugate was demonstrated on human (DBTRG-05MG, H4) and rat (C6) brain tumor cells. Folate receptor expression of the cells was verified by immunofluorescence staining. Cellular binding/uptake of the conjugate by DBTRG-05MG, H4, and C6 cells was 1452, 975, and 46 times higher, resp., than that of nontargeted CNCs. The uptake mechanism was detd. by preincubation of the cells with the uptake inhibitors chlorpromazine or genistein. DBTRG-05MG and C6 cells internalized the conjugate primarily via caveolae-mediated endocytosis, whereas H4 cells internalized the conjugate primarily via clathrin-mediated endocytosis.
- 38Anas, A.; Okuda, T.; Kawashima, N.; Nakayama, K.; Itoh, T.; Ishikawa, M.; Biju, V. Clathrin-Mediated Endocytosis of Quantum Dot- Peptide Conjugates in Living Cells. ACS Nano 2009, 3 (8), 2419– 2429, DOI: 10.1021/nn900663rGoogle Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpsFSjs7w%253D&md5=14b3cc5a3d684f65bee7e36d560d837dClathrin-Mediated Endocytosis of Quantum Dot-Peptide Conjugates in Living CellsAnas, Abdulaziz; Okuda, Tetsuya; Kawashima, Nagako; Nakayama, Kenichi; Itoh, Tamitake; Ishikawa, Mitsuru; Biju, VasudevanpillaiACS Nano (2009), 3 (8), 2419-2429CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Efficient intracellular delivery of quantum dots (QDs) and unravelling the mechanism underlying the intracellular delivery are essential for advancing the applications of QDs toward in vivo imaging and therapeutic interventions. Here, we show that clathrin-mediated endocytosis is the most important pathway for the intracellular delivery of peptide-conjugated QDs. We selected an insect neuropeptide, namely, allatostatin (AST1, APSGAQRLYG FGL-NH2), conjugated it with CdSe-ZnS QDs, and investigated the intracellular delivery of the conjugate in living cells such as human epidermoid ovarian carcinoma cells (A431) and mouse embryonic fibroblast cells (3T3). We selected AST1 to investigate the intracellular delivery of QDs because we recently found it to be efficient for delivering QDs in living mammalian cells. Also, the receptors of AST1 in insects show functional and sequence similarity to G-protein-coupled galanin receptors in mammals. We employed flow cytometry and fluorescence microscopy and investigated the contributions of clathrin-mediated endocytosis, receptor-mediated endocytosis, and charge-based cell penetration or transduction to the intracellular delivery of QD-AST1 conjugates. Interestingly, the intracellular delivery was suppressed by ∼57% when we inhibited the regulatory enzyme phosphoinositide 3-kinase (PI3K) with wortmannin and blocked the formation of clathrin-coated vesicles. In parallel, we investigated clathrin-mediated endocytosis by colocalizing QD560-labeled clathrin heavy-chain antibody and QD605-AST1. We also estd. galanin receptor-mediated endocytosis of QD-AST1 at <10% by blocking the cells with a galanin antagonist and transduction at <30% by both removing the charge of the peptide due to arginine and suppressing the cell-surface charge due to glycosaminoglycan. In short, the current work shows that multiple pathways are involved in the intracellular delivery of peptide-conjugated QDs, among which clathrin-mediated endocytosis is the most important.
- 39Hua, S.; de Matos, M. B. C.; Metselaar, J. M.; Storm, G. Current Trends and Challenges in the Clinical Translation of Nanoparticulate Nanomedicines: Pathways for Translational Development and Commercialization. Front Pharmacol 2018, 9, 790, DOI: 10.3389/fphar.2018.00790Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXis1ert7c%253D&md5=cb5739d5b68c67add2a5baded94fa973Current trends and challenges in the clinical translation of nanoparticulate nanomedicines: pathways for translational development and commercializationHua, Susan; de Matos, Maria B. C.; Metselaar, Josbert M.; Storm, GertFrontiers in Pharmacology (2018), 9 (), 790/1-790/14CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)A review. The use of nanotechnol. in medicine has the potential to have a major impact on human health for the prevention, diagnosis, and treatment of diseases. One particular aspect of the nanomedicine field which has received a great deal of attention is the design and development of nanoparticulate nanomedicines (NNMs) for drug delivery (i.e., drug-contg. nanoparticles). NNMs are intended to deliver drugs via various mechanisms: solubilization, passive targeting, active targeting, and triggered release. The NNM approach aims to increase therapeutic efficacy, decrease the therapeutically ED, and/or reduce the risk of systemic side effects. In order to move a NNM from the bench to the bedside, several exptl. challenges need to be addressed. This review will discuss the current trends and challenges in the clin. translation of NNMs as well as the potential pathways for translational development and commercialization. Key issues related to the clin. development of NNMs will be covered, including biol. challenges, large-scale manufg., biocompatibility and safety, intellectual property (IP), government regulations, and overall cost-effectiveness in comparison to current therapies. These factors can impose significant hurdles limiting the appearance of NNMs on the market, irrelevant of whether they are therapeutically beneficial or not.
- 40Ratajczak, J.; Joffraud, M.; Trammell, S. A. J.; Ras, R.; Canela, N.; Boutant, M.; Kulkarni, S. S.; Rodrigues, M.; Redpath, P.; Migaud, M. E.; Auwerx, J.; Yanes, O.; Brenner, C.; Canto, C. Nrk1 Controls Nicotinamide Mononucleotide and Nicotinamide Riboside Metabolism in Mammalian Cells. Nat. Commun. 2016, 7 (1), 13103, DOI: 10.1038/ncomms13103Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1GnurnN&md5=9c26093d3ba216924341ecf507a03455NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cellsRatajczak, Joanna; Joffraud, Magali; Trammell, Samuel A. J.; Ras, Rosa; Canela, Nuria; Boutant, Marie; Kulkarni, Sameer S.; Rodrigues, Marcelo; Redpath, Philip; Migaud, Marie E.; Auwerx, Johan; Yanes, Oscar; Brenner, Charles; Canto, CarlesNature Communications (2016), 7 (), 13103CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)NAD+ is a vital redox cofactor and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Supplementation with NAD+ precursors, such as NMN (NMN) or nicotinamide riboside (NR), protects against metabolic disease, neurodegenerative disorders and age-related physiol. decline in mammals. Here we show that nicotinamide riboside kinase 1 (NRK1) is necessary and rate-limiting for the use of exogenous NR and NMN for NAD+ synthesis. Using genetic gain- and loss-of-function models, we further demonstrate that the role of NRK1 in driving NAD+ synthesis from other NAD+ precursors, such as nicotinamide or nicotinic acid, is dispensable. Using stable isotope-labeled compds., we confirm NMN is metabolized extracellularly to NR that is then taken up by the cell and converted into NAD+. Our results indicate that mammalian cells require conversion of extracellular NMN to NR for cellular uptake and NAD+ synthesis, explaining the overlapping metabolic effects obsd. with the two compds.
- 41McReynolds, M. R.; Chellappa, K.; Baur, J. A. Age-Related NAD+ Decline. Exp. Gerontol. 2020, 134, 110888, DOI: 10.1016/j.exger.2020.110888Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXks1Gmt78%253D&md5=d88e2638f943d89208c56096dc86aa82Age-related NAD+ declineMcReynolds, Melanie R.; Chellappa, Karthikeyani; Baur, Joseph A.Experimental Gerontology (2020), 134 (), 110888CODEN: EXGEAB; ISSN:0531-5565. (Elsevier)NAD (NAD+) is an essential metabolite that is reported to decline in concn. in tissues of aged animals. Strategies to increase NAD+ availability have shown promise in treating many conditions in rodents, including age-related degeneration, which has in turn driven intense interest in the effects of supplements on human health. However, many aspects of NAD+ metab. remain poorly understood, and human data are limited. Here, we discuss the state of the evidence for an age-related decline in NAD+, along with potential mechanistic explanations, including increased consumption or decreased synthesis of NAD+ and changes in the compn. of cells or tissues with age. Key challenges for the field involve the development of better tools to resolve information on the NAD+ content of specific cells and subcellular compartments as well as detg. the threshold levels at which NAD+ depletion triggers physiol. consequences in different tissues. Understanding how NAD+ metab. changes with age in humans may ultimately allow the design of more targeted strategies to maintain its availability, such as inhibition of key consumers in specific tissues or direct delivery of precursors to sites of deficiency. In the meantime, human clin. trials with oral supplements are poised to provide some of the first direct evidence as to whether increasing NAD+ availability can impact human physiol. Thus, it is an exciting time for NAD+ research, with much remaining to be learned in terms of both basic biol. and potential therapeutic applications.
- 42Yoshino, J.; Baur, J. A.; Imai, S.-I. NAD+ Intermediates: The Biology and Therapeutic Potential of Nmn and Nr. Cell Metab. 2018, 27 (3), 513– 528, DOI: 10.1016/j.cmet.2017.11.002Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvF2js7%252FP&md5=7cf208aa6b5442fb0a23981b72a42d57NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NRYoshino, Jun; Baur, Joseph A.; Imai, Shin-ichiroCell Metabolism (2018), 27 (3), 513-528CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)Research on the biol. of NAD+ has been gaining momentum, providing many crit. insights into the pathogenesis of age-assocd. functional decline and diseases. In particular, two key NAD+ intermediates, nicotinamide riboside (NR) and NMN (NMN), have been extensively studied over the past several years. Supplementing these NAD+ intermediates has shown preventive and therapeutic effects, ameliorating age-assocd. pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD+ intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD+ metab. to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclin. results can be translated to improve human health.
- 43Cogger, V. C.; Hunt, N. J.; Le Couteur, D. G. Fenestrations in the Liver Sinusoidal Endothelial Cell. In The Liver: Biology and Pathobiology, 6th ed.; Arias, I. M., Alter, H. J., Boyer, J. L., Cohen, D. E., Shafritz, D. A., Thorgeirsson, S. S., Wolkoff, A. W., Eds.; Wiley-Blackwell: Hoboken, NJ, 2020; pp 435– 443.Google ScholarThere is no corresponding record for this reference.
- 44Mohamad, M.; Mitchell, S. J.; Wu, L. E.; White, M. Y.; Cordwell, S. J.; Mach, J.; Solon-Biet, S. M.; Boyer, D.; Nines, D.; Das, A.; Catherine Li, S.-Y.; Warren, A.; Hilmer, S. N.; Fraser, R.; Sinclair, D. A.; Simpson, S. J.; Cabo, R.; Le Couteur, D. G.; Cogger, V. C. Ultrastructure of the Liver Microcirculation Influences Hepatic and Systemic Insulin Activity and Provides a Mechanism for Age-Related Insulin Resistance. Aging Cell 2016, 15 (4), 706– 715, DOI: 10.1111/acel.12481Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmtlSitb0%253D&md5=c749cd7bbfb4cbaa44d5cf0284be60f4Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistanceMohamad, Mashani; Mitchell, Sarah Jayne; Wu, Lindsay Edward; White, Melanie Yvonne; Cordwell, Stuart James; Mach, John; Solon-Biet, Samantha Marie; Boyer, Dawn; Nines, Dawn; Das, Abhirup; Catherine Li, Shi-Yun; Warren, Alessandra; Hilmer, Sarah Nicole; Fraser, Robin; Sinclair, David Andrew; Simpson, Stephen James; de Cabo, Rafael; Le Couteur, David George; Cogger, Victoria CarrollAging Cell (2016), 15 (4), 706-715CODEN: ACGECQ; ISSN:1474-9718. (Wiley-Blackwell)Summary : While age-related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole-body insulin handling and its role in age-related changes in insulin homeostasis is largely unknown. Here, we show that patent pores called 'fenestrations' are essential for insulin transfer across the liver sinusoidal endothelium and that age-related loss of fenestrations causes an impaired insulin clearance and hyperinsulinemia, induces hepatic insulin resistance, impairs hepatic insulin signaling, and deranges glucose homeostasis. To further define the role of fenestrations in hepatic insulin signaling without any of the long-term adaptive responses that occur with aging, we induced acute defenestration using poloxamer 407 (P407), and this replicated many of the age-related changes in hepatic glucose and insulin handling. Loss of fenestrations in the liver sinusoidal endothelium is a hallmark of aging that has previously been shown to cause deficits in hepatic drug and lipoprotein metab. and now insulin. Liver defenestration thus provides a new mechanism that potentially contributes to age-related insulin resistance.
- 45Fraser, J. A.; Kemp, S.; Young, L.; Ross, M.; Prach, M.; Hutchison, G. R.; Malone, E. Silver Nanoparticles Promote the Emergence of Heterogeneic Human Neutrophil Sub-Populations. Sci. Rep 2018, 8 (1), 7506– 14, DOI: 10.1038/s41598-018-25854-2Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MfjtFyntQ%253D%253D&md5=be4d9d6cac0bc9995326c79e2c03da13Silver nanoparticles promote the emergence of heterogeneic human neutrophil sub-populationsFraser Jennifer A; Kemp Sadie; Young Lesley; Ross Mark; Prach Morag; Hutchison Gary R; Malone EvaScientific reports (2018), 8 (1), 7506 ISSN:.Neutrophil surveillance is central to nanoparticle clearance. Silver nanoparticles (AgNP) have numerous uses, however conflicting evidence exists as to their impact on neutrophils and whether they trigger damaging inflammation. Neutrophil's importance in innate defence and regulating immune networks mean it's essential we understand AgNP's impact on neutrophil function. Human neutrophil viability following AgNP or Ag Bulk treatment was analysed by flow cytometry and AnV/PI staining. Whilst AgNP exposure did not increase the total number of apoptotic neutrophils, the number of late apoptotic neutrophils was increased, suggesting AgNP increase transit through apoptosis. Mature (CD16(bright)/CD62L(bright)), immature (CD16(dim)/CD62L(bright)) and apoptotic (CD16(dim)/CD62L(dim)) neutrophil populations were evident within isolated neutrophil preparations. AgNP exposure significantly reduced CD62L staining of CD16(bright)/CD62L(bright) neutrophils, and increased CD16 staining of CD16(dim)/CD62L(bright) populations, suggesting AgNPs trigger neutrophil activation and maturation, respectively. AgNP exposure dramatically increased IL-8, yet not classical pro-inflammatory cytokine release, suggesting AgNP triggers neutrophil activation, without pro-inflammation or damaging, necrotic cell death. For the first time, we show AgNPs differentially affect distinct sub-populations of circulating human neutrophils; activating mature neutrophils with the emergence of CD16(bright)/CD62L(dim) neutrophils. This may stimulate particle clearance without harmful inflammation, challenging previous assumptions that silver nanomaterials induce neutrophil toxicity and damaging inflammatory responses.
- 46Friedman, S. L. Liver Fibrosis - From Bench to Bedside. J. Hepatol. 2003, 38, 38– 53, DOI: 10.1016/S0168-8278(02)00429-4Google ScholarThere is no corresponding record for this reference.
- 47Poynard, T.; Bedossa, P.; Opolon, P. Natural History of Liver Fibrosis Progression in Patients with Chronic Hepatitis C. Lancet 1997, 349 (9055), 825– 832, DOI: 10.1016/S0140-6736(96)07642-8Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3js1ymug%253D%253D&md5=90ead48b73f318e22310622fa7e710d5Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groupsPoynard T; Bedossa P; Opolon PLancet (London, England) (1997), 349 (9055), 825-32 ISSN:0140-6736.BACKGROUND: Our aim was to assess the natural history of liver fibrosis progression in hepatitis C and the factors associated with this progression. METHODS: We recruited 2235 patients from the Observatoire de l'Hepatite C (OBSVIRC) population, the Cohorte Hepatite C Pitie-Salpetriere (DOSVIRC) population, and the original METAVIR population. All the patients had a biopsy sample compatible with chronic hepatitis C as assessed by the METAVIR scoring system (grades the stage of fibrosis on a five-point scale, F0 = no fibrosis, F4 = cirrhosis, and histological activity on a four-point scale, A0 = no activity, A3 = severe activity). No patient had received interferon treatment before the liver biopsy sample was obtained. We assessed the effect of nine factors on fibrosis progression: age at biopsy; estimated duration of infection; sex; age at infection; alcohol consumption; hepatitis C virus C (HCV) genotype; HCV viraemia; cause of infection; and histological activity grade. We defined fibrosis progression per year as the ratio between fibrosis stage in METAVIR units and the duration of infection (1 unit = one stage, 4 units = cirrhosis). FINDINGS: The median rate of fibrosis progression per year was 0.133 fibrosis unit (95% CI 0.125-0.143), which was similar to the estimates from previous studies (0.146 to 0.154). Three independent factors were associated with an increased rate of fibrosis progression: age at infection older than 40 years, daily alcohol consumption of 50 g or more, and male sex. There was no association between fibrosis progression and HCV genotype. The median estimated duration of infection for progression to cirrhosis was 30 years (28-32), ranging from 13 years in men infected after the age of 40 to 42 years in women who did not drink alcohol and were infected before the age of 40. Without treatment, 377 (33%) patients had an expected median time to cirrhosis of less than 20 years, and 356 (31%) will never progress to cirrhosis or will not progress for at least 50 years. INTERPRETATION: The host factors of ageing, alcohol consumption, and male sex have a stronger association with fibrosis progression than virological factors in HCV infection.
- 48Desmoulière, A.; Darby, I. A.; Gabbiani, G. Normal and Pathologic Soft Tissue Remodeling: Role of the Myofibroblast, with Special Emphasis on Liver and Kidney Fibrosis. Lab. Invest. 2003, 83 (12), 1689– 1707, DOI: 10.1097/01.LAB.0000101911.53973.90Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3sngvVKnsw%253D%253D&md5=fbe4824d102001f9e540929c20a38897Normal and pathologic soft tissue remodeling: role of the myofibroblast, with special emphasis on liver and kidney fibrosisDesmouliere Alexis; Darby Ian A; Gabbiani GiulioLaboratory investigation; a journal of technical methods and pathology (2003), 83 (12), 1689-707 ISSN:0023-6837.There is no expanded citation for this reference.
- 49Glancy, D.; Zhang, Y.; Wu, J. L. Y.; Ouyang, B.; Ohta, S.; Chan, W. C. W. Characterizing the Protein Corona of Sub-10 Nm Nanoparticles. J. Controlled Release 2019, 304, 102– 110, DOI: 10.1016/j.jconrel.2019.04.023Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpsVyntL0%253D&md5=a07fab0169aaa31fc95c1778a252c9a9Characterizing the protein corona of sub-10 nm nanoparticlesGlancy, Dylan; Zhang, Yuwei; Wu, Jamie L. Y.; Ouyang, Ben; Ohta, Seiichi; Chan, Warren C. W.Journal of Controlled Release (2019), 304 (), 102-110CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)Studies into the interactions of serum proteins with nanoparticles are typically performed using nanoparticles that are larger than the size of proteins. Due to this size discrepancy, adsorbed proteins are commonly depicted as a globular structure surrounding a nanoparticle. Here, we asked how we should view nanoparticle-protein complexes when the nanoparticles are of similar size or smaller than the proteins with which they interact. We showed that nanoparticles can serve as a cargo on a protein rather than as a carrier of the protein in a size-dependent manner. This can occur when nanoparticles are below 10 nm in diam. We discovered that when the nanoparticle is a cargo on the protein, the binding of the protein to the receptor target is minimally affected in contrast to the nanoparticle serving as a carrier. Our study should change how we view and describe nanoparticle-protein complexes when the nanoparticles involved are equal in size or smaller than proteins.
- 50Lundqvist, M.; Stigler, J.; Elia, G.; Lynch, I.; Cedervall, T.; Dawson, K. A. Nanoparticle Size and Surface Properties Determine the Protein Corona with Possible Implications for Biological Impacts. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (38), 14265– 14270, DOI: 10.1073/pnas.0805135105Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1SgtrvJ&md5=a1bb38c51fdbdb83a3c0addf245d4280Nanoparticle size and surface properties determine the protein corona with possible implications for biological impactsLundqvist, Martin; Stigler, Johannes; Elia, Giuliano; Lynch, Iseult; Cedervall, Tommy; Dawson, Kenneth A.Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (38), 14265-14270,S14265/1-S14265/11CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Nanoparticles in a biol. fluid (plasma, or otherwise) assoc. with a range of biopolymers, esp. proteins, organized into the "protein corona" that is assocd. with the nanoparticle and continuously exchanging with the proteins in the environment. Methodologies to det. the corona and to understand its dependence on nanomaterial properties are likely to become important in bionanoscience. Here, we study the long-lived ("hard") protein corona formed from human plasma for a range of nanoparticles that differ in surface properties and size. Six different polystyrene nanoparticles were studied: three different surface chemistries (plain PS, carboxyl-modified, and amine-modified) and two sizes of each (50 and 100 nm), enabling us to perform systematic studies of the effect of surface properties and size on the detailed protein coronas. Proteins in the corona that are conserved and unique across the nanoparticle types were identified and classified according to the protein functional properties. Remarkably, both size and surface properties were found to play a very significant role in detg. the nanoparticle coronas on the different particles of identical materials. We comment on the future need for scientific understanding, characterization, and possibly some addnl. emphasis on stds. for the surfaces of nanoparticles.
- 51Walkey, C. D.; Olsen, J. B.; Guo, H.; Emili, A.; Chan, W. C. W. Nanoparticle Size and Surface Chemistry Determine Serum Protein Adsorption and Macrophage Uptake. J. Am. Chem. Soc. 2012, 134 (4), 2139– 2147, DOI: 10.1021/ja2084338Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1Gls7vN&md5=99fda4a9a3d7af67b0d6de0b83e526cfNanoparticle Size and Surface Chemistry Determine Serum Protein Adsorption and Macrophage UptakeWalkey, Carl D.; Olsen, Jonathan B.; Guo, Hongbo; Emili, Andrew; Chan, Warren C. W.Journal of the American Chemical Society (2012), 134 (4), 2139-2147CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Delivery and toxicity are crit. issues facing nanomedicine research. Currently, there is limited understanding and connection between the physicochem. properties of a nanomaterial and its interactions with a physiol. system. As a result, it remains unclear how to optimally synthesize and chem. modify nanomaterials for in vivo applications. It has been suggested that the physicochem. properties of a nanomaterial after synthesis, known as its "synthetic identity", are not what a cell encounters in vivo. Adsorption of blood components and interactions with phagocytes can modify the size, aggregation state, and interfacial compn. of a nanomaterial, giving it a distinct "biol. identity". Here, we investigate the role of size and surface chem. in mediating serum protein adsorption to gold nanoparticles and their subsequent uptake by macrophages. Using label-free liq. chromatog. tandem mass spectrometry, we find that over 70 different serum proteins are heterogeneously adsorbed to the surface of gold nanoparticles. The relative d. of each of these adsorbed proteins depends on nanoparticle size and poly(ethylene glycol) grafting d. Variations in serum protein adsorption correlate with differences in the mechanism and efficiency of nanoparticle uptake by a macrophage cell line. Macrophages contribute to the poor efficiency of nanomaterial delivery into diseased tissues, redistribution of nanomaterials within the body, and potential toxicity. This study establishes principles for the rational design of clin. useful nanomaterials.
- 52Fischer, H. C.; Liu, L.; Pang, K. S.; Chan, W. C. W. Pharmacokinetics of Nanoscale Quantum Dots: InVivo Distribution, Sequestration, and Clearance in the Rat. Adv. Funct. Mater. 2006, 16 (10), 1299– 1305, DOI: 10.1002/adfm.200500529Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XntFGnurw%253D&md5=e5735bcaeeef5c5d01579dbb4c755be0Pharmacokinetics of nanoscale quantum dots: in vivo distribution, sequestration, and clearance in the ratFischer, Hans C.; Liu, Lichuan; Pang, K. Sandy; Chan, Warren C. W.Advanced Functional Materials (2006), 16 (10), 1299-1305CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)Advances in nanotechnol. research on quantum dots (QDs)-water sol. ZnS-capped, CdSe fluorescent semiconductor nanocrystals-for in vivo biomedical applications have prompted a close scrutiny of the behavior of nanostructures in vivo. Data pertaining to pharmacokinetics and toxicity will undoubtedly assist in designing better in vivo nanostructure contrast agents or therapies. In vivo kinetics, clearance, and metab. of semiconductor QDs are characterized following their i.v. dosing in Sprague-Dawley rats. The QDs coated with the org. mol. mercaptoundecanoic acid and crosslinked with lysine (denoted as QD-LM) are cleared from plasma with a clearance of 0.59±0.16 mL min-1 kg-1. A higher clearance (1.23±0.22 mL min-1 kg-1) exists when the QDs are conjugated to bovine serum albumin (QD-BSA, P <.05). The biodistribution between these two QDs is also different. The liver takes up 40% of the QD-LM dose and 99% of QD-BSA dose after 90 min. Small amts. of both QDs appear in the spleen, kidney, and bone marrow. However, QDs are not detected in feces or urine for up to ten days after i.v. dosing.
- 53Poon, W.; Zhang, Y.-N.; Ouyang, B.; Kingston, B. R.; Wu, J. L. Y.; Wilhelm, S.; Chan, W. C. W. Elimination Pathways of Nanoparticles. ACS Nano 2019, 13 (5), 5785– 5798, DOI: 10.1021/acsnano.9b01383Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnsV2rtb4%253D&md5=c0d48a288db0048614df3db0e59ceaf9Elimination Pathways of NanoparticlesPoon, Wilson; Zhang, Yi-Nan; Ouyang, Ben; Kingston, Benjamin R.; Wu, Jamie L. Y.; Wilhelm, Stefan; Chan, Warren C. W.ACS Nano (2019), 13 (5), 5785-5798CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Understanding how nanoparticles are eliminated from the body is required for their successful clin. translation. Many promising nanoparticle formulations for in vivo medical applications are large (>5.5 nm) and nonbiodegradable, so they cannot be eliminated renally. A proposed pathway for these nanoparticles is hepatobiliary elimination, but their transport has not been well-studied. Here, we explored the barriers that detd. the elimination of nanoparticles through the hepatobiliary route. The route of hepatobiliary elimination is usually through the following pathway: (1) liver sinusoid, (2) space of Disse, (3) hepatocytes, (4) bile ducts, (5) intestines, and (6) out of the body. We discovered that the interaction of nanoparticles with liver nonparenchymal cells (e.g., Kupffer cells and liver sinusoidal endothelial cells) dets. the elimination fate. Each step in the route contains cells that can sequester and chem. or phys. alter the nanoparticles, which influences their fecal elimination. We showed that the removal of Kupffer cells increased fecal elimination by >10 times. Combining our results with those of prior studies, we can start to build a systematic view of nanoparticle elimination pathways as it relates to particle size and other design parameters. This is crit. to engineering medically useful and translatable nanotechnologies.
- 54Loeschner, K.; Hadrup, N.; Qvortrup, K.; Larsen, A.; Gao, X.; Vogel, U.; Mortensen, A.; Lam, H. R.; Larsen, E. H. Distribution of Silver in Rats Following 28 Days of Repeated Oral Exposure to Silver Nanoparticles or Silver Acetate. Part. Fibre Toxicol. 2011, 8 (1), 18, DOI: 10.1186/1743-8977-8-18Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpt1Grsbg%253D&md5=1eb34e198f982a93858b44c8e0e97ee2Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetateLoeschner, Katrin; Hadrup, Niels; Qvortrup, Klaus; Larsen, Agnete; Gao, Xueyun; Vogel, Ulla; Mortensen, Alicja; Lam, Henrik Rye; Larsen, Erik H.Particle and Fibre Toxicology (2011), 8 (), 18CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)Background: The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs) and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food and food contact materials. Results: AgNPs were synthesized with a size distribution of 14 ± 4 nm in diam. (90% of the nanoparticle vol.) and stabilized in aq. suspension by the polymer polyvinylpyrrolidone (PVP). The AgNPs remained stable throughout the duration of the 28-day oral toxicity study in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the abs. silver concns. in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of AgNPs. Besides the intestinal system, the largest silver concns. were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallog. (AMG) staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or AgAc. Using transmission electron microscopy (TEM), nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy it was shown that the granules in lysosomes consisted of silver, selenium, and sulfur for both AgNP and AgAc exposed rats. The diam. of the deposited granules was in the same size range as that of the administered AgNPs. No silver granules were detected by TEM in the liver. Conclusions: The results of the present study demonstrate that the organ distribution of silver was similar when AgNPs or AgAc were administered orally to rats. The presence of silver granules contg. selenium and sulfur in the intestinal wall of rats exposed to either of the silver forms suggests a common mechanism of their formation. Addnl. studies however, are needed to gain further insight into the underlying mechanisms of the granule formation, and to clarify whether AgNPs dissolve in the gastrointestinal system and/or become absorbed and translocate as intact nanoparticles to organs and tissues.
- 55Barzilai, N.; Crandall, J. P.; Kritchevsky, S. B.; Espeland, M. A. Metformin as a Tool to Target Aging. Cell Metab. 2016, 23 (6), 1060– 1065, DOI: 10.1016/j.cmet.2016.05.011Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xpt1ens7w%253D&md5=ca94d0e30dadc25aa3a45109b0442669Metformin as a Tool to Target AgingBarzilai, Nir; Crandall, Jill P.; Kritchevsky, Stephen B.; Espeland, Mark A.Cell Metabolism (2016), 23 (6), 1060-1065CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)Aging has been targeted by genetic and dietary manipulation and by drugs in order to increase lifespan and health span in numerous models. Metformin, which has demonstrated protective effects against several age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial, as the initial step in the development of increasingly effective next-generation drugs.
- 56Knowler, W. C.; Barrett-Connor, E.; Fowler, S. E.; Hamman, R. F.; Lachin, J. M.; Walker, E. A.; Nathan, D. M. Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin. N. Engl. J. Med. 2002, 346 (6), 393– 403, DOI: 10.1056/NEJMoa012512Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhtVWqurc%253D&md5=fe29c42a032eda9166ffa65f0094eba2Reduction in the incidence of type 2 diabetes with lifestyle intervention or metforminKnowler, William C.; Barrett-Connor, Elizabeth; Fowler, Sarah E.; Hamman, Richard F.; Lachin, John M.; Walker, Elizabeth A.; Nathan, David M.; Bray, G. A.; Culbert, I. W.; Champagne, C. M.; Crow, M. D.; Dawson, L.; Eberhardt, B.; Greenway, F. L.; Guillory, F. G.; Herbert, A. A.; Jeffirs, M. L.; Joyce, K.; Kennedy, B. M.; Lovejoy, J. C.; Mancuso, S.; Melancon, L. E.; Morris, L. H.; Reed, L.; Perault, J.; Rau, K.; Ryan, D. H.; Sanford, D. A.; Smith, K. G.; Smith, L. L.; Smith, S. R.; St. Amant, J. A.; Terry, M.; Tucker, E.; Tulley, R. T.; Vicknair, P. C.; Williamson, D.; Zachwieja, J. J.; Ehrmann, D. A.; Matulik, M. J.; Clark, B.; Collins, D. A.; Czech, K. B.; DeSandre, C.; Geiger, G.; Frief, S.; Harding-Clay, B.; Hilbrich, R. M.; Le Grange, D.; McCormick, M. R.; McNabb, W. L.; Polonsky, K. S.; Sauter, N. P.; Semenske, A. R.; Stepp, K. A.; Tobian, J. A.; Watson, P. G.; Mendoza, J. T.; Smith, K. A.; Caro, J.; Goldstein, B.; Lark, C.; Menefee, L.; Murphy, L.; Pepe, C.; Spandorfer, J. M.; Goldberg, R. B.; Rowe, P.; Calles, J.; Casanova, P.; Donahue, R. P.; Florez, H. J.; Giannella, A.; Larreal, G.; McLymont, V.; Mendez, J.; O'Hara, P.; Ojito, J.; Prineas, R.; Saab, P. G.; Haffner, S. M.; Montez, M. G.; Lorenzo, C.; Miettinen, H.; Mobley, C. M.; Mykkanen, L. A.; Rozek, M. M.; Hamman, R. F.; Nash, P. V.; Testaverde, L.; Anderson, D. R.; Ballonoff, L. B.; Bouffard, A.; Calonge, B. N.; Farago, M.; Georgitis, W. J.; Hill, J. O.; Hoyer, S. R.; Jortberg, B. T.; Merenich, J. A.; Miller, M.; Regensteiner, J. G.; Seagle, H. M.; Smith, C. M.; Steinke, S. C.; Van Dorsten, B.; Horton, E. S.; Lawton, K. E.; Arky, R. A.; Bryant, M.; Burke, J. P.; Caballero, E.; Callaghan, K. M.; Devlin, D.; Franklin, T.; Ganda, O. P.; Goebel-Fabbri, A. E.; Harris, M.; Jackson, S. D.; Jacobsen, A. M.; Kula, L. M.; Kocal, M.; Ledbury, S.; Malloy, M. A.; Mullooly, C.; Nicosia, M.; Oldmixon, C. F.; Pan, J.; Pomposelli, C.; Quitongan, M.; Rubtchinsky, S.; Schweizer, D.; Seely, E. W.; Simonson, D.; Smith, F.; Solomon, C. G.; Tyson, J.; Warram, J.; Kahn, S. E.; Montgomery, B. K.; Alger, M.; Allen, E.; Barrett, T.; Bhanji, D.; Cowan, J.; Cullen, J.; Fujimoto, W. Y.; Katz, B.; Knopp, R. H.; Lipkin, E. W.; Marr, M.; McCann, B. S.; Palmer, J. P.; Schwartz, R. S.; Uyema, D.; Kitabachi, A. E.; Murphy, M. E.; Applegate, W. B.; Bryer-Ash, M.; Coble, J. H.; Crisler, A.; Cunningham, G.; Franklin, A. W.; Frieson, S. L.; Green, D. L.; Imseis, R.; Kennedy, C. L.; Lambeth, H. C.; Latif, K. A.; Lichtermann, L. C.; McIntyre, M. D.; Nault, J. D.; Oktaei, H.; O'Toole, M. L.; Ricks, H.; Rutledge, L. M. K.; Schussler, S. C.; Sherman, A. R.; Smith, C. M.; Soberman, J. E.; Stewart, K. J.; Van Brunt, D. L.; Williams-Cleaves, B. J.; Johnson, M. K.; Behrends, C.; Cook, M. L.; Fitzgibbon, M.; Giles, M. M.; Heard, D.; Johnson, C.; Larsen, D.; Lowe, A.; Lyman, M.; McPherson, D.; Molitch, M. E.; Pitts, T.; Reinhart, R.; Roston, S.; Schinleber, P. A.; Nathan, D. M.; McKitrick, C.; Abbott, K.; Anderson, E.; Bissett, L.; Cagliero, E.; Crowell, S.; Delahanty, L.; Fritz, S.; Hayward, K.; Levina, E.; Michel, T.; Norman, D.; O'Keefe, J.; Poulos, A.; Ronan, L.; Rosal, M.; Salerno, M.; Schneider, M.; Shagensky, C.; Steiner, B.; Turgeon, H.; Young, A.; Olefsky, J. M.; Carrion-Petersen, M. L.; Barrett-Connor, E.; Beltran, M.; Caenepeel-Mills, K.; Edelman, S. V.; Ford, R. O.; Garcia, J.; Hagerty, M.; Henry, R. R.; Hill, M.; Horne, J.; Leos, D.; Matney, J.; Mudaliar, S.; Petersen, G.; Pollard, A.; Polonsky, W.; Szerdi, S.; Torio-Hurley, J.; Vejvoda, K.; Pi-Sunyer, F. X.; Lee, J. E.; Allison, D. B.; Agharanya, N.; Aronoff, N. J.; Baldo, M.; Foo, S. T.; Hagamen, S.; Pal, C.; Parkes, K.; Pena, M.; Van Wye, G. E. H.; Marrero, D. G.; Kukman-Kelly, M. S.; Dorson, Y. F.; Fineberg, S. E.; Guare, J. C.; Hadden, A.; Hills, B.; Ignaut, J. M.; Jackson, M. A.; Kirkman, M. S.; Mather, K.; McAree, G.; Porter, B. D.; Prince, M. J.; Wheeler, M. L.; Ratner, R. E.; Youssef, G.; Shapiro, S.; Bonar, A.; Bronsord, M.; Brown, E.; Cheatham, W. W.; Cola, S.; Comfort, A.; Boggs, G.; Eagle, C.; Evans, C.; Gorman, E.; Johnson, R.; Levetan, C.; Kellum, T.; Lagarda, M.; Nair, A. K.; Passaro, M. D.; Phillips, W.; Saad, M. F.; Budgett, M.; Fahmi, S.; Jinagouda, S. D.; Bernaba, B.; Bodkin, S. L.; Ciobanu, V.; Commisso, R.; Cosenza, C.; Dinh, T.; Gonzalez, M.; Khan, A.; Kumar, D.; Lui, G.; Mehra, V.; Sharma, A.; Soukiazian, S.; Szamos, K.; Tramanian, A.; Vargas, A.; Zambrana, N.; White, N. H.; Santiago, A. S.; Das, S.; Brown, A. L.; Dagogo-Jack, S.; Fisher, E. B.; Hurt, E.; Jones, T.; Kerr, M.; Ryder, L.; Santiago, J. V.; Wernimont, C.; Saudek, C. D.; Bradley, V. L.; Fowlkes, T.; Joseph, H.; Brancati, F. L.; Charleston, J. B.; Clark, J. M.; Horak, K.; Jiggetts, D.; Mosley, H.; Rubin, R. R.; Samuels, A.; Stewart, K. J.; Thomas, L.; Williamson, P.; Schade, D. S.; Adams, K. S.; Atler, L. F.; Bland, A.; Bowling, D. A.; Boyle, P. J.; Burge, M. R.; Butler, L.; Canady, J. L.; Chai, L.; Colleran, K. M.; Guillen, M.; Gonzales, Y.; Gutierrez, M.; Hornbeck, D.; Johannes, C.; Karz, P.; King, C.; Libby, E. N., III; McCalman, R.; Montoya, D. A.; Rassam, A.; Rubinchik, S.; Senter, W.; Shamoon, H.; Brown, J. O.; Adames, J.; Blanco, E.; Cox, L.; Crandall, J. P.; Duffy, H.; Engel, S.; Friedler, A.; Harroun, T.; Howard-Century, C. J.; Kloiber, S.; Longchamp, N.; Pompi, D.; Violino, E.; Walker, E. A.; Wylie-Rosett, J.; Zimmerman, E.; Zonszein, J.; Wing, R. R.; Kramer, M. K.; Barr, S.; Boraz, M. A.; Clifford, L.; Culyba, R.; Frazier, M.; Gilligan, R.; Harris, L.; Harrier, S.; Henderson, W.; Jeffreis, S.; Koenning, G.; Kriska, A. M.; Maholic, K.; Manjoo, Q.; Mullen, M.; Noel, A.; Orchard, T. J.; Orro, A.; Semler, L. N.; Smith, C.; Smith, M.; Stapinski, V.; Viteri, J.; Wilson, T.; Williams, K. V.; Zgibor, J.; Arakaki, R. F.; Latimer, R. W.; Baker-Ladao, N. K.; Beddow, R. M.; Braginsky, R.; Calizar, M.; Dias, L. M.; Durham, N.; Dupont, D. A.; Fukuhara, L. L.; Inouye, J.; Mau, M, K.; Mikami, K.; Mohideen, P.; Odom, S. K.; Sinkuie-Kam, B.; Tokunaga, J. S.; Twiggs, R. U.; Wang, C. Y.; Vita, J.; Knowler, W. C.; Cooeyate, N. J.; Hoskin, M. A.; Percy, C. A.; Acton, K. J.; Andre, V. L.; Antone, S.; Baptisto, N. M.; Barber, R.; Segay, S.; Bennett, P. H.; Benson, M. B.; Beyale, S.; Bird, E. C.; Broussard, B. A.; Chavez, M.; Daeawyma, T. S.; Doughty, M. S.; Duncan, R.; Edgerton, C.; Ghahate, J. M.; Glass, M.; Gohdes, D.; Grant, W.; Hanson, R. L.; Horse, E.; Hughte, G.; Ingraham, L. E.; Jackson, M. C.; Jay, P. A.; Kaskalla, R. S.; Kessler, D.; Kobus, K. M.; Krakoff, J.; Manus, C.; Morgan, T.; Nashboo, Y.; Nelson, J.; Pauk, G. L.; Poirier, S.; Polczynski, E.; Reidy, M.; Roumain, J.; Rowse, D. H.; Roy, R. J.; Sangster, S.; Sewemaenewa, J.; Tonemah, D.; Wilson, C.; Yazzie, M.; Fowler, S.; Brenneman, T.; Abebe, S.; Bain, R.; Bamdad, J.; Callaghan, J.; Edelstein, S. L.; Gao, Y.; Grimes, K. L.; Grover, N.; Hirst, K.; Jones, S.; Jones, T. L.; Katz, R. J.; Lachin, J. M.; Orlosky, R.; Stimpson, C. E.; Suiter, C.; Temprosa, M. G.; Walker-Murray, F. E. M.; Garfield, S.; Eastman, R.; Fradkin, J.; Andres, R.; Engelgau, M. M.; Venkat Narayan, K. M.; Williamson, D. F.; Herman, W. H.; Marcovina, S. M.; Aldrich, A.; Chandler, W. L.; Rautaharju, P. M.; Pemberton, N. T.; Prineas, R.; Rautaharju, F. S. R.; Zhang, Z.; Mayer-Davis, E. J.; Costacou, T.; Martin, M.; Sparks, K. L.; O'Leary, D. H.; Funk, L. R. C.; O'Leary, K. A.; Polak, J. F.; Stamm, E. R.; Scherzinger, A. L.; Wing, R. R.; Gillis, B. P.; Huffmyer, C.; Kriska, A. M.; Venditti, E. M.; Walker, E. A.; Harroun, T.; Ganiats, T. G.; Groessl, E. J.; Beerman, P. R.; David, K. M.; Kaplan, R. M.; Sieber, W. J.; Genuth, S. M.; Cahill, G. F.; Ferris, F. L., III; Gavin, J. R., III; Halter, J. B.; Wittes, J.; Henry, R. R.; Haffner, S. M.; Rubin, R. R.; Montgomery, B. K.; Ratner, R. E.; Herman, W. H.; Kahn, S. E.; Santiago, J. V.; Olefsky, J.; Wing, R. R.; Saudek, C.; Montez, M.; Kramer, K.; Hamman, R. F.; Knowler, W. C.; Goldberg, R. B.; Fujimoto, W. Y.; Charleston, J.; Nathan, D. M.New England Journal of Medicine (2002), 346 (6), 393-403CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Type 2 diabetes affects approx. 8 % of adults in the United States. Some risk factors - elevated plasma glucose concns. in the fasting state and after an oral glucose load, over-wt., and a sedentary lifestyle - are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concns. to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 % wt. loss and at least 150 min of phys. activity per wk. The mean age of the participants was 51 yr, and the mean body-mass index (the wt. in kilograms divided by the square of the height in meters) was 34.0; 68 % were women, and 45 % were members of minority groups. The av. follow-up was 2.8 yr. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and life-style groups, resp. The lifestyle intervention reduced the incidence by 58 % (95 % confidence interval, 48 to 66 %) and metformin by 31 % (95 % confidence interval, 17 to 43 %), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.
- 57Schlender, L.; Martinez, Y. V.; Adeniji, C.; Reeves, D.; Faller, B.; Sommerauer, C.; Al Qur’an, T.; Woodham, A.; Kunnamo, I.; Sönnichsen, A.; Renom-Guiteras, A. Efficacy and Safety of Metformin in the Management of Type 2 Diabetes Mellitus in Older Adults: A Systematic Review for the Development of Recommendations to Reduce Potentially Inappropriate Prescribing. BMC Geriatr. 2017, 17 (S1), 227, DOI: 10.1186/s12877-017-0574-5Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7it1alsQ%253D%253D&md5=e3bc89eff696a895485c158e6bd11de5Efficacy and safety of metformin in the management of type 2 diabetes mellitus in older adults: a systematic review for the development of recommendations to reduce potentially inappropriate prescribingSchlender Lisa; Faller Barbara; Sommerauer Christina; Al Qur'an Thekraiat; Sonnichsen Andreas; Renom-Guiteras Anna; Martinez Yolanda V; Adeniji Charles; Reeves David; Woodham Adrine; Al Qur'an Thekraiat; Kunnamo Ilkka; Renom-Guiteras AnnaBMC geriatrics (2017), 17 (Suppl 1), 227 ISSN:.BACKGROUND: Metformin is usually prescribed as first line therapy for type 2 diabetes mellitus (DM2). However, the benefits and risks of metformin may be different for older people. This systematic review examined the available evidence on the safety and efficacy of metformin in the management of DM2 in older adults. The findings were used to develop recommendations for the electronic decision support tool of the European project PRIMA-eDS. METHODS: The systematic review followed a staged approach, initially searching for systematic reviews and meta-analyses first, and then individual studies when prior searches were inconclusive. The target population was older people (≥65 years old) with DM2. Studies were included if they reported safety or efficacy outcomes with metformin (alone or in combination) for the management of DM2 compared to placebo, usual or no treatment, or other antidiabetics. Using the evidence identified, recommendations were developed using GRADE methodology. RESULTS: Fifteen studies were included (4 intervention and 11 observational studies). In ten studies at least 80% of participants were 65 years or older and 5 studies reported subgroup analyses by age. Comorbidities were reported by 9 studies, cognitive status was reported by 4 studies and functional status by 1 study. In general, metformin showed similar or better safety and efficacy than other specific or non-specific active treatments. However, these findings were mainly based on retrospective observational studies. Four recommendations were developed suggesting to discontinue the use of metformin for the management of DM2 in older adults with risk factors such as age > 80, gastrointestinal complaints during the last year and/or GFR ≤60 ml/min. CONCLUSIONS: On the evidence available, the safety and efficacy profiles of metformin appear to be better, and certainly no worse, than other treatments for the management of DM2 in older adults. However, the quality and quantity of the evidence is low, with scarce data on adverse events such as gastrointestinal complaints or renal failure. Further studies are needed to more reliably assess the benefits and risks of metformin in very old (>80), cognitively and functionally impaired older people.
- 58Dujic, T.; Zhou, K.; Donnelly, L. A.; Tavendale, R.; Palmer, C. N. A.; Pearson, E. R. Association of Organic Cation Transporter 1 with Intolerance to Metformin in Type 2 Diabetes: A Godarts Study. Diabetes 2015, 64 (5), 1786– 1793, DOI: 10.2337/db14-1388Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotFKrs7g%253D&md5=acbe0c4bf9ceab2b10dc22609f248488Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS studyDujic, Tanja; Zhou, Kaixin; Donnelly, Louise A.; Tavendale, Roger; Palmer, Colin N. A.; Pearson, Ewan R.Diabetes (2015), 64 (5), 1786-1793CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)Metformin is the most widely prescribed medication for the treatment of type 2 diabetes (T2D). However, gastrointestinal (GI) side effects develop in ∼25% of patients treated with metformin, leading to the discontinuation of therapy in ∼5% of cases. We hypothesized that reduced transport of metformin via org. cation transporter 1 (OCT1) could increase metformin concn. in the intestine, leading to increased risk of severe GI side effects and drug discontinuation. We compared the phenotype, carriage of reduced-function OCT1 variants, and concomitant prescribing of drugs known to inhibit OCT1 transport in 251 intolerant and 1,915 fully metformin-tolerant T2D patients. We showed that women and older people were more likely to be intolerant to metformin. Concomitant use of medications, known to inhibit OCT1 activity, was assocd. with intolerance (odds ratio [OR] 1.63 [95% CI 1.22-2.17], P = 0.001) as was carriage of two reduced-function OCT1 alleles compared with carriage of one or no deficient allele (OR 2.41 [95% CI 1.48-3.93], P < 0.001). Intolerance was over four times more likely to develop (OR 4.13 [95% CI 2.09-8.16], P < 0.001) in individuals with two reduced-function OCT1 alleles who were treated with OCT1 inhibitors. Our results suggest that reduced OCT1 transport is an important determinant of metformin intolerance.
- 59McCreight, L. J.; Bailey, C. J.; Pearson, E. R. Metformin and the Gastrointestinal Tract. Diabetologia 2016, 59 (3), 426– 435, DOI: 10.1007/s00125-015-3844-9Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFSjs7w%253D&md5=95ff2e424c18b64790ccec3af7ea4adbMetformin and the gastrointestinal tractMcCreight, Laura J.; Bailey, Clifford J.; Pearson, Ewan R.Diabetologia (2016), 59 (3), 426-435CODEN: DBTGAJ; ISSN:0012-186X. (Springer)Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognized as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a no. of actions within the gut. It increases intestinal glucose uptake and lactate prodn., increases GLP-1 concns. and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release prepn. of metformin has recently been shown to improve glycemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects assocd. with metformin intolerance.
- 60Grozio, A.; Mills, K. F.; Yoshino, J.; Bruzzone, S.; Sociali, G.; Tokizane, K.; Lei, H. C.; Cunningham, R.; Sasaki, Y.; Migaud, M. E.; Imai, S.-I. Slc12a8 Is a Nicotinamide Mononucleotide Transporter. Nat. Metab 2019, 1 (1), 47– 57, DOI: 10.1038/s42255-018-0009-4Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXltlOnsL0%253D&md5=ebc0e129508e787bf3d6e5c41684c0bbSlc12a8 is a nicotinamide mononucleotide transporterGrozio, Alessia; Mills, Kathryn F.; Yoshino, Jun; Bruzzone, Santina; Sociali, Giovanna; Tokizane, Kyohei; Lei, Hanyue Cecilia; Cunningham, Richard; Sasaki, Yo; Migaud, Marie E.; Imai, Shin-ichiroNature Metabolism (2019), 1 (1), 47-57CODEN: NMAED6; ISSN:2522-5812. (Springer International Publishing AG)Abstr.: NMN (NMN) is a biosynthetic precursor of NAD (NAD+) known to promote cellular NAD+ prodn. and counteract age-assocd. pathologies assocd. with a decline in tissue NAD+ levels. How NMN is taken up into cells has not been entirely clear. Here we show that the Slc12a8 gene encodes a specific NMN transporter. We find that Slc12a8 is highly expressed and regulated by NAD+ in the mouse small intestine. Slc12a8 knockdown abrogates the uptake of NMN in vitro and in vivo. We further show that Slc12a8 specifically transports NMN, but not nicotinamide riboside, and that NMN transport depends on the presence of sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, which is assocd. with reduced NMN uptake as traced by doubly labeled isotopic NMN. Finally, we observe that Slc12a8 expression is upregulated in the aged mouse ileum, which contributes to the maintenance of ileal NAD+ levels. Our work identifies a specific NMN transporter and demonstrates that Slc12a8 has a crit. role in regulating intestinal NAD+ metab.
- 61Poisson, J.; Lemoinne, S.; Boulanger, C.; Durand, F.; Moreau, R.; Valla, D.; Rautou, P.-E. Liver Sinusoidal Endothelial Cells: Physiology and Role in Liver Diseases. J. Hepatol. 2017, 66 (1), 212– 227, DOI: 10.1016/j.jhep.2016.07.009Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslehtbzO&md5=cc989b389724edba17a7d931e3c7151aLiver sinusoidal endothelial cells: Physiology and role in liver diseasesPoisson, Johanne; Lemoinne, Sara; Boulanger, Chantal; Durand, Francois; Moreau, Richard; Valla, Dominique; Rautou, Pierre-EmmanuelJournal of Hepatology (2017), 66 (1), 212-227CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells representing the interface between blood cells on the one side and hepatocytes and hepatic stellate cells on the other side. LSECs represent a permeable barrier. Indeed, the assocn. of 'fenestrae', absence of diaphragm and lack of basement membrane make them the most permeable endothelial cells of the mammalian body. They also have the highest endocytosis capacity of human cells. In physiol. conditions, LSECs regulate hepatic vascular tone contributing to the maintenance of a low portal pressure despite the major changes in hepatic blood flow occurring during digestion. LSECs maintain hepatic stellate cell quiescence, thus inhibiting intrahepatic vasoconstriction and fibrosis development. In pathol. conditions, LSECs play a key role in the initiation and progression of chronic liver diseases. Indeed, they become capillarized and lose their protective properties, and they promote angiogenesis and vasoconstriction. LSECs are implicated in liver regeneration following acute liver injury or partial hepatectomy since they renew from LSECs and/or LSEC progenitors, they sense changes in shear stress resulting from surgery, and they interact with platelets and inflammatory cells. LSECs also play a role in hepatocellular carcinoma development and progression, in ageing, and in liver lesions related to inflammation and infection. This review also presents a detailed anal. of the tech. aspects relevant for LSEC anal. including the markers these cells express, the available cell lines and the transgenic mouse models. Finally, this review provides an overview of the strategies available for a specific targeting of LSECs.
- 62Park, K. The Beginning of the End of the Nanomedicine Hype. J. Controlled Release 2019, 305, 221– 222, DOI: 10.1016/j.jconrel.2019.05.044Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFClu73N&md5=020e62d1a9228f6f84fb0053b4f3b2c7The beginning of the end of the nanomedicine hypePark, KinamJournal of Controlled Release (2019), 305 (), 221-222CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)There is no expanded citation for this reference.
- 63Dai, Q.; Wilhelm, S.; Ding, D.; Syed, A. M.; Sindhwani, S.; Zhang, Y.; Chen, Y. Y.; MacMillan, P.; Chan, W. C. Quantifying the Ligand-Coated Nanoparticle Delivery to Cancer Cells in Solid Tumors. ACS Nano 2018, 12 (8), 8423– 8435, DOI: 10.1021/acsnano.8b03900Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlaku7zM&md5=98fd65b49025397a7607a2940164e10eQuantifying the Ligand-Coated Nanoparticle Delivery to Cancer Cells in Solid TumorsDai, Qin; Wilhelm, Stefan; Ding, Ding; Syed, Abdullah Muhammad; Sindhwani, Shrey; Zhang, Yuwei; Chen, Yih Yang; MacMillan, Presley; Chan, Warren C. W.ACS Nano (2018), 12 (8), 8423-8435CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Coating the nanoparticle surface with cancer cell recognizing ligands is expected to facilitate specific delivery of nanoparticles to diseased cells in vivo. While this targeting strategy is appealing, no nanoparticle-based active targeting formulation for solid tumor treatment had made it past phase III clin. trials. Here, we quantified the cancer cell-targeting efficiencies of Trastuzumab (Herceptin) and folic acid coated gold and silica nanoparticles in multiple mouse tumor models. Surprisingly, we showed that less than 14 out of 1 million (0.0014% injected dose) i.v. administrated nanoparticles were delivered to targeted cancer cells, and that only 2 out of 100 cancer cells interacted with the nanoparticles. The majority of the intratumoral nanoparticles were either trapped in the extracellular matrix or taken up by perivascular tumor assocd. macrophages. The low cancer cell targeting efficiency and significant uptake by noncancer cells suggest the need to re-evaluate the active targeting process and therapeutic mechanisms using quant. methods. This will be important for developing strategies to deliver emerging therapeutics such as genome editing, nucleic acid therapy, and immunotherapy for cancer treatment using nanocarriers.
- 64Lammers, T.; Ferrari, M. The Success of Nanomedicine. Nano Today 2020, 31, 100853, DOI: 10.1016/j.nantod.2020.100853Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsl2lsbg%253D&md5=d64b8eb6ea263157348d01fa5cc8a5c0The success of nanomedicineLammers, Twan; Ferrari, MauroNano Today (2020), 31 (), 100853CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)In recent years, the promise and prospects of nanomedicine have been controversially discussed. We here argue that nanomedicine has undeniably been successful, not only academically and preclinically, but also industrially and clin. To ensure that we keep on making progress, we have to move away from over-focusing on nano and on materials, towards more holistic approaches that address real medical problems, in a realistic manner.
- 65Ortega-Ribera, M.; Hunt, N. J.; Gracia-Sancho, J.; Cogger, V. C. The Hepatic Sinusoid in Aging and Disease: Update and Advances from the 20th Liver Sinusoid Meeting. Hepatol Commun. 2020, 4 (7), 1087– 1098, DOI: 10.1002/hep4.1517Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38noslWlsg%253D%253D&md5=d5c7bf8141c354ef65a43d302567288fThe Hepatic Sinusoid in Aging and Disease: Update and Advances From the 20th Liver Sinusoid MeetingOrtega-Ribera Marti; Gracia-Sancho Jordi; Hunt Nicholas J; Cogger Victoria C; Hunt Nicholas J; Cogger Victoria C; Gracia-Sancho JordiHepatology communications (2020), 4 (7), 1087-1098 ISSN:.This is a meeting report of the 2019 Liver Sinusoid Meeting, 20th International Symposium on Cells of the Hepatic Sinusoid, held in Sydney, Australia, in September 2019. The meeting, which was organized by the International Society for Hepatic Sinusoidal Research, provided an update on the recent advances in the field of hepatic sinusoid cells in relation to cell biology, aging, and liver disease, with particular focus on the molecular and cellular targets involved in hepatic fibrosis, nonalcoholic hepatic steatohepatitis, alcoholic liver disease, hepatocellular carcinoma, and cirrhosis. In addition, the meeting highlighted the recent advances in regenerative medicine, targeted nanotechnologies, therapeutics, and novel methodologies.
- 66Wong, X. Y.; Sena-Torralba, A.; Álvarez-Diduk, R.; Muthoosamy, K.; Merkoçi, A. Nanomaterials for Nanotheranostics: Tuning Their Properties According to Disease Needs. ACS Nano 2020, 14 (3), 2585– 2627, DOI: 10.1021/acsnano.9b08133Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFKrtbo%253D&md5=4e9c710bb2d91696150b0c530e49a01aNanomaterials for Nanotheranostics: Tuning Their Properties According to Disease NeedsWong, Xin Yi; Sena-Torralba, Amadeo; Alvarez-Diduk, Ruslan; Muthoosamy, Kasturi; Merkoci, ArbenACS Nano (2020), 14 (3), 2585-2627CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)A review. Nanotheranostics is one of the biggest scientific breakthroughs in nanomedicine. Most of the currently available diagnosis and therapies are invasive, time-consuming, and assocd. with severe toxic side effects. Nanotheranostics, on the other hand, has the potential to bridge this gap by harnessing the capabilities of nanotechnol. and nanomaterials for combined therapeutics and diagnostics with markedly enhanced efficacy. However, nanomaterial applications in nanotheranostics are still in its infancy. This is due to the fact that each disease has a particular microenvironment with well-defined characteristics, which promotes deeper selection criteria of nanomaterials to meet the disease needs. In this review, we have outlined how nanomaterials are designed and tailored for nanotheranostics of cancer and other diseases such as neurodegenerative, autoimmune (particularly on rheumatoid arthritis), and cardiovascular diseases. The penetrability and retention of a nanomaterial in the biol. system, the therapeutic strategy used, and the imaging mode selected are some of the aspects discussed for each disease. The specific properties of the nanomaterials in terms of feasibility, physicochem. challenges, progress in clin. trials, its toxicity, and their future application on translational medicine are addressed. Our review meticulously and critically examines the applications of nanotheranostics with various nanomaterials, including graphene, across several diseases, offering a broader perspective of this emerging field.
- 67Tang, R.; Xue, J.; Xu, B.; Shen, D.; Sudlow, G. P.; Achilefu, S. Tunable Ultrasmall Visible-to-Extended Near-Infrared Emitting Silver Sulfide Quantum Dots for Integrin-Targeted Cancer Imaging. ACS Nano 2015, 9 (1), 220– 230, DOI: 10.1021/nn5071183Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXks1Omug%253D%253D&md5=40fcd3571d93e27106349d3739d5258eTunable Ultrasmall Visible-to-Extended Near-Infrared Emitting Silver Sulfide Quantum Dots for Integrin-Targeted Cancer ImagingTang, Rui; Xue, Jianpeng; Xu, Baogang; Shen, Duanwen; Sudlow, Gail P.; Achilefu, SamuelACS Nano (2015), 9 (1), 220-230CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)The large size of many near-IR (NIR) fluorescent nanoparticles prevents rapid extravasation from blood vessels and subsequent diffusion to tumors. This confines in vivo uptake to the peritumoral space and results in high liver retention. The authors developed a viscosity modulated approach to synthesize ultrasmall silver sulfide quantum dots (QDs) with distinct tunable light emission from 500 to 1200 nm and a QD core diam. between 1.5 and 9 nm. Conjugation of a tumor-avid cyclic pentapeptide (Arg-Gly-Asp-DPhe-Lys) resulted in monodisperse, water-sol. QDs (hydrodynamic diam. < 10 nm) without loss of the peptide's high binding affinity to tumor-assocd. integrins (KI = 1.8 nM/peptide). Fluorescence and electron microscopy showed that selective integrin-mediated internalization was obsd. only in cancer cells treated with the peptide-labeled QDs, demonstrating that the unlabeled hydrophilic nanoparticles exhibit characteristics of neg. charged fluorescent dye mols., which typically do not internalize in cells. The biodistribution profiles of i.v. administered QDs in different mouse models of cancer reveal an exceptionally high tumor-to-liver uptake ratio, suggesting that the small sized QDs evaded conventional opsonization and subsequent high uptake in the liver and spleen. The seamless tunability of the QDs over a wide spectral range with only a small increase in size, as well as the ease of labeling the bright and noncytotoxic QDs with biomols., provides a platform for multiplexing information, tracking the trafficking of single mols. in cells, and selectively targeting disease biomarkers in living organisms without premature QD opsonization in circulating blood.
- 68Cogger, V. C.; O’Reilly, J. N.; Warren, A.; Le Couteur, D. G. A Standardized Method for the Analysis of Liver Sinusoidal Endothelial Cells and Their Fenestrations by Scanning Electron Microscopy. JoVE 2015, (98), e52698 DOI: 10.3791/52698Google ScholarThere is no corresponding record for this reference.
- 69Kang, S. W. S.; Cogger, V. C.; Le Couteur, D. G.; Fu, D. Multiple Cellular Pathways Regulate Lipid Droplet Homeostasis for the Establishment of Polarity in Collagen Sandwich-Cultured Hepatocytes. Am. J. Physiol Cell Physiol 2019, 317 (5), C942– C952, DOI: 10.1152/ajpcell.00051.2019Google ScholarThere is no corresponding record for this reference.
- 70Warren, A.; Bertolino, P.; Cogger, V. C.; McLean, A. J.; Fraser, R.; Le Couteur, D. G. Hepatic Pseudocapillarization in Aged Mice. Exp. Gerontol. 2005, 40 (10), 807– 812, DOI: 10.1016/j.exger.2005.06.012Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MrjvVegsQ%253D%253D&md5=775f25282e84bd6f14805d34324908afHepatic pseudocapillarization in aged miceWarren Alessandra; Bertolino Patrick; Cogger Victoria C; McLean Allan J; Fraser Robin; Le Couteur David GExperimental gerontology (2005), 40 (10), 807-12 ISSN:0531-5565.Age-related changes in the hepatic sinusoid of the rat, human and baboons called pseudocapillarization have been discovered and are important because they are considered to be implicated in the pathogenesis of some age-related diseases. In this study, we investigated whether similar changes occur in the livers of old mice. Livers of young (3-4 months) and old (20-24 months) mice were perfusion-fixed and studied using electron microscopy and immunohistochemistry. The thickness of the sinusoidal endothelium was increased in old mice (154+/-4 versus 244+/-8 nm, P<0.001). There was a reduction in fenestrations within the endothelium (porosity decreased from 4.1+/-0.3 to 2.2+/-0.2%, P<0.001). There was perisinusoidal staining with Sirius red in old mice, however, expression of laminin and von Willebrands factor was similar in young and old mice. Novel perisinusoidal fat-engorged stellate cells were found extensively in the old mice. This study confirmed that pseudocapillarization is a widespread aging change in the liver, now documented in several species including the mouse. Mice are an appropriate animal model for studying aging and the hepatic sinusoid.
- 71Miller, D. L.; Yu, I. J.; Genter, M. B. Use of Autometallography in Studies of Nanosilver Distribution and Toxicity. Int. J. Toxicol. 2016, 35 (1), 47– 51, DOI: 10.1177/1091581815616602Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvV2jt74%253D&md5=36218bf136e8b4de1bc24d91b49c9d17Use of autometallography in studies of nanosilver distribution and toxicityMiller, David L.; Je, Yu; Genter, Mary BethInternational Journal of Toxicology (2016), 35 (1), 47-51CODEN: IJTOFN; ISSN:1091-5818. (Sage Publications)With the increasing use of and interest in nanoparticles in medicine and technol., the tissue and cell-specific localization of the particles are important considerations when the nanomaterials find their way into biol. systems. This brief communication shows the utility of autometallog. in detg. the location of metal deposition at the light microscopic level. Although primarily focusing on studies of the toxicity and deposition of silver nanoparticles, use of autometallog. to localize zinc and other metals at the tissue and subcellular localization is also recognized.
- 72Zhang, Y.; Hedo, R.; Rivera, A.; Rull, R.; Richardson, S.; Tu, X. M. Post Hoc Power Analysis: Is It an Informative and Meaningful Analysis?. Gen Psychiatry 2019, 32 (4), e100069 DOI: 10.1136/gpsych-2019-100069Google ScholarThere is no corresponding record for this reference.
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(12)
, 734-747. https://doi.org/10.1080/03639045.2023.2282990
- Christoph Hieber, Stephan Grabbe, Matthias Bros. Counteracting Immunosenescence—Which Therapeutic Strategies Are Promising?. Biomolecules 2023, 13
(7)
, 1085. https://doi.org/10.3390/biom13071085
- Jeladhara Sobhanan, Jose V. Rival, Abdulaziz Anas, Edakkattuparambil Sidharth Shibu, Yuta Takano, Vasudevanpillai Biju. Luminescent quantum dots: Synthesis, optical properties, bioimaging and toxicity. Advanced Drug Delivery Reviews 2023, 197 , 114830. https://doi.org/10.1016/j.addr.2023.114830
- Xiaolan Liang, Liping Shi, Run Zhang, Mingying Zhang. Pectin mediated green synthesis of CuO nanoparticles: evaluation of its cytotoxicity, antioxidant and anti-human cervical cancer properties. Journal of Experimental Nanoscience 2022, 17
(1)
, 315-325. https://doi.org/10.1080/17458080.2021.2013470
- Nicholas J. Hunt, Devin Wahl, Lara J. Westwood, Glen P. Lockwood, David G. Le Couteur, Victoria C. Cogger. Targeting the liver in dementia and cognitive impairment: Dietary macronutrients and diabetic therapeutics. Advanced Drug Delivery Reviews 2022, 190 , 114537. https://doi.org/10.1016/j.addr.2022.114537
- Luan F. Diniz, Paulo S. Carvalho, José E. Gonçalves, Renata Diniz, Christian Fernandes. Solid-state landscape and biopharmaceutical implications of novel metformin-based salts. New Journal of Chemistry 2022, 46
(28)
, 13725-13737. https://doi.org/10.1039/D2NJ00453D
- Nicholas J. Hunt, Peter A. G. McCourt, Zdenka Kuncic, David G. Le Couteur, Victoria C. Cogger. Opportunities and Challenges for Nanotherapeutics for the Aging Population. Frontiers in Nanotechnology 2022, 4 https://doi.org/10.3389/fnano.2022.832524
- K. Szafranska, C.F. Holte, L.D. Kruse, H. Mao, C.I. Øie, M. Szymonski, B. Zapotoczny, P.A.G. McCourt. Quantitative analysis methods for studying fenestrations in liver sinusoidal endothelial cells. A comparative study. Micron 2021, 150 , 103121. https://doi.org/10.1016/j.micron.2021.103121
- Zisong Wei, Hua Chai, Yan Chen, Yue Cheng, Xiaojing Liu. Nicotinamide mononucleotide: An emerging nutraceutical against cardiac aging?. Current Opinion in Pharmacology 2021, 60 , 291-297. https://doi.org/10.1016/j.coph.2021.08.006
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Abstract
Figure 1
Figure 1. Conjugation and characterization of Ag2S quantum dots (QDs) with metformin and nicotinamide mononucleotide (NMN). (A) Water-soluble QDs with a hydrophilic external layer of carboxylic acid molecules on their surface (as shown using Fourier transform infrared (FTIR) microscopy spectral analysis) are conjugated with metformin or NMN using EDC/NHS chemical coupling. Repeat FTIR spectra analysis demonstrates an external layer of drug conjugate on these QDs. (B) QDs (gray) with/without drug attachment (QD-metformin (red) and QD-NMN (blue)) demonstrated similar sizing when dried for visualization under transmission electron microscopy. Examination in solution showed drug attachment increases the hydrodynamic diameter (C) and shifts zeta-potential toward 0 (D). The loading efficiency was measured using a low (E) and high (F) concentration (concn) of QDs. The amount of drug retained following conjugation and 24 h at pH 7 under dialysis was 100% when a greater ratio of QDs to drug was used. When greater concentration of drug compared to QDs was used, loading efficiency shifted toward 10%. A maximal drug attachment ratio was observed for metformin (90 mM/1 mM) and NMN (150 mM/1 mM) (G).
Figure 2
Figure 2. Pharmacokinetic and biodistribution data of (3H)QDs (gray), (14C)metformin (black), and QD-(14C)metformin (red) following oral administration. Following ingestion, QDs, metformin, and QD-metformin accumulate in various organs. (A) Metformin uptake peaks in the liver 8 h after administration; attachment to QDs leads to an earlier peak at 2 h. After 8 h, QDs show faster liver clearance than the attached metformin, indicating detachment of drug from QDs. Over a 24 h period, a greater concentration of metformin is in the liver when it is conjugated to QDs, as shown by the greater area under the curve (AUC). (B) Persistence in the small intestinal lumen is reduced when metformin is attached to QDs; without attachment, 50% of metformin is localized to the intestine after 8 h compared to 25% of QD-metformin; this contributes to a greater AUC for metformin compared to that for QD-metformin. (C) Similar fecal clearance of metformin and QD-metformin was observed. (D) Blood concentration of metformin and QD-metformin demonstrated similar shifts; attachment to QDs allows for faster passage into blood; concentration is reduced by 8 h followed by re-entry into the blood. Comparison to QD clearance from blood suggests detachment of metformin from QDs similar to that observed in liver. (E) Kidney and (F) spleen demonstrate small accumulations of drug and QDs. Following 24 h, less than 5% of materials remain in these organs with no differences in AUC between QD or metformin alone. Data show mean ± SD (n = 3 per group, compared with Kruskal–Wallis test and post-hoc Dunn’s method; α = 0.05).
Figure 3
Figure 3. In vivo pharmacodynamics and PK/PD of metformin and NMN with and without attachment to QDs. (A) Metformin (black) and (B) QD-metformin (red) given by oral gavage 2 h prior to an oral glucose tolerance test (oGTT) demonstrated a dose-dependent reduction in the time taken to clear glucose from the blood and AUC. (C) Comparison between dosage of metformin alone and QD-metformin and the percentage of reduction in oGTT AUC demonstrates QD-metformin induces the same effect as drug alone at 1% of the dosage given. (D) Comparison of the effects of the same dosage of metformin with/without conjugation to QDs on the reduction in oGTT AUC. oGTTs were performed 0.5, 2, 4, 8, or 24 h following gavage. (E) NMN (greenh) and (F) QD-NMN (blue) given by oral gavage 2 h prior to an oGTT demonstrated a dose-dependent reduction in the time taken to clear glucose from the blood and AUC. (G) Comparison in the concentration of drug given between NMN alone and QD-NMN and the percentage of reduction in oGTT AUC demonstrates QD-NMN induces the same effect as drug alone at 0.1% of the dosage given. (D) Comparison of the effects of the same dosage of NMN with/without conjugation to QDs on the reduction in oGTT AUC. oGTTs were performed 0.5, 2, 4, 8, or 24 h following gavage. Data show mean ± SD (n = 3 per group). Statistical test: Kruskal–Wallis tests with a post-hoc Dunn’s method; α = 0.05.
Figure 4
Figure 4. In vivo molecular pathways promoted by QD-drug treatment compared to drug alone. Mice received an oral gavage of water (white), QDs (gray), QD-metformin (red), metformin (black), QD-NMN (blue) or NMN (green) (dosages are given per figure) 2 h prior to liver tissue collection and hepatocyte and liver endothelial cell isolations. (A) p-AMPK/AMPK and (B) SIRT1 were analyzed by Western blots and normalized to β-tubulin expression, percentage changes relative to untreated controls are compared between groups. (C) cGMP by a commercial ELISA, and (D) NAD total, NAD+ and NADH by a commercial NAD/NADH assay. Westernblot images are provided in Supplementary Figure 2. ELISA and assay protein measurements are relative to mg of liver tissue or protein from isolated cells. Data show mean ± SD (A,B: n = 5, C–D: n = 3 per group). Statistical test: (A,B) one-way-ANOVA with post-hoc Bonferroni test; (C,D) Kruskal–Wallis tests with a post-hoc Dunn’s method; α = 0.05.
Figure 5
Figure 5. In vitro drug/QD-drug treatment on isolated hepatocyte endocytosis/activation and LSEC fenestrations. Hepatocytes were isolated from young 3 months old mice (A) and old 18 months old mice (B). Hepatocytes were nonpretreated control (CNTR) or pretreated for 0.5 h with sucrose (0.5 M) to block clathrin-mediated endocytosis and micropinocytosis or omeprazole (10 μM) to block endocytosis via protein pumps. Cells were then treated for 2 h with radiolabeled (14C)metformin (black) or QD(14C)metformin (red). (C) Young and (D) old hepatocytes were isolated and either nonpretreated or pretreated with sucrose (stripes) or cytidine 5-monophosphate (CMP) (spots) an inhibitor of dephosphorylation of NMN. Cells were then treated with QD-NMN (blue) or NMN (green) for 2 h. Cells were then lysed and NAD+ measured by NAD/NADH assay. (E) Young hepatocytes were isolated and incubated for 2 h with increasing concentration of QDs (1 nM to 10 mM). Cell viability was measured with an MTT assay. Data show mean ± SD (n = 3 per group, compared with Kruskal–Wallis tests and post-hoc Dunn’s method; α = 0.05).
Figure 6
Figure 6. Overview of 2-week in vivo treatment with QD-NMN (blue) and NMN (green) in 3, 18, and 24 month old mice on metabolic parameters and toxicity. (A) schematic of experimental treatments and ages of intervention. (B–D) Effects of treatment in 3 month (B), 18 month (C), and 24 month (D) old mice. Data show liver NAD+, blood AST, and ALT; before and after treatment: oral glucose tolerance test area under the curve (AUC), fasting and fed insulin and HOMA-IR. Comprehensive data shown in Supplementary Figures 3–6. Data show mean ± SD (n = 5 per group). Statistical test: one-way-ANOVA with post-hoc Bonferroni test; α = 0.05.
Figure 7
Figure 7. Effects of 100 day in vivo treatment with QDs (320 μg/kg/day). (A) Body weight of mice was collected every 7 days with control (CNTR) collected at day 0 and 100. (B) AST and ALT were not significantly influenced by treatment. (C) No changes in plasma IL-6, MIP-2 (mouse homologue of IL-8), or IFN-γ were observed. (D) H&E staining of the liver demonstrated sparse immune cell infiltration in QD-treated mice with no other pathohistological features. (E) TNFα staining did not show differences between CNTR and QD-treated mice, positive and negative control section from the spleen of control tissue. (F) Sirius Red staining of the liver and kidney (G) did not show differences between groups with low minimal fibrosis of the portal vein nor were differences observed in the METAVIR fibrosis score. In the kidney, no enlargement of the Bowman’s capsules in the kidney was observed, and no change in plasma creatinine was shown. Data show mean ± SD (n = 5 per group compared with one-way-ANOVA and post-hoc Bonferroni test); α = 0.05.
Figure 8
Figure 8. Autometallography staining of the liver and small intestine and inductively coupled plasma mass spectrometry. (A) Autometallography is a measure of silver distribution and involves adding additional silver to aggregate to silver ions in tissue sections. Liver panels show untreated negative control, 250 μg/kg treated, and 250 μg/kg treated with a 3 day wash out prior to tissue collection. Staining of the endothelium is absent in the 3 day wash out compared to the treated sample. Fourteen day (250 μg/kg/day) and 100 day (320 μg/kg/day) treated mice demonstrate staining in the sinusoids of the liver and of the bile ducts. The 7500 μg/kg (toxic dosage) shows silver staining in all tissue compartments with aggregates in hepatocytes. Small intestine panels show silver staining in the blood vessel underlining the villi. (B) ICP-MS was performed was performed on liver tissue samples to analysis the concentration of Ag+. No differences were observed between groups, one 100 day sample demonstrated elevated Ag+ content with data shown with and without outlier (statistical test: one-way ANOVA with post-hoc Bonferroni test); α = 0.05. Cells were then incubated with Alexa Fluor 488 goat anti-rabbit, 1% goat serum in PBS for 30 min at 4 °C. Cells were again centrifuged, washed in PBS twice with centrifugation between washes.
References
This article references 72 other publications.
- 1Zrazhevskiy, P.; Gao, X. Multifunctional Quantum Dots for Personalized Medicine. Nano Today 2009, 4 (5), 414– 428, DOI: 10.1016/j.nantod.2009.07.0041https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltFGmsb0%253D&md5=9bb17a953e9f4b516a96378d04bd0dd7Multifunctional quantum dots for personalized medicineZrazhevskiy, Pavei; Gao, XiaohuNano Today (2009), 4 (5), 414-428CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)A review. Successes in biomedical research and state-of-the-art medicine have undoubtedly improved the quality of life. However, a no. of diseases, such as cancer, immunodeficiencies, and neurol. disorders, still evade conventional diagnostic and therapeutic approaches. A transformation towards personalized medicine may help to combat these diseases. For this, identification of disease mol. fingerprints and their assocn. with prognosis and targeted therapy must become available. Quantum dots (QDs), semiconductor nanocrystals with unique photo-phys. properties, represent a novel class of fluorescence probes to address many of the needs of personalized medicine. This review outlines the properties of QDs that make them a suitable platform for advancing personalized medicine, examines several proof-of-concept studies showing utility of QDs for clin. relevant applications, and discusses current challenges in introducing QDs into clin. practice.
- 2Wagner, A. M.; Knipe, J. M.; Orive, G.; Peppas, N. A. Quantum Dots in Biomedical Applications. Acta Biomater. 2019, 94, 44– 63, DOI: 10.1016/j.actbio.2019.05.0222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFGqu7fF&md5=c0ac69d4024fd8714c58b45d420be870Quantum dots in biomedical applicationsWagner, Angela M.; Knipe, Jennifer M.; Orive, Gorka; Peppas, Nicholas A.Acta Biomaterialia (2019), 94 (), 44-63CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)A review. Semiconducting nanoparticles, more commonly known as quantum dots, possess unique size and shape dependent optoelectronic properties. In recent years, these unique properties have attracted much attention in the biomedical field to enable real-time tissue imaging (bioimaging), diagnostics, single mol. probes, and drug delivery, among many other areas. The optical properties of quantum dots can be tuned by size and compn., and their high brightness, resistance to photobleaching, multiplexing capacity, and high surface-to-vol. ratio make them excellent candidates for intracellular tracking, diagnostics, in vivo imaging, and therapeutic delivery. We discuss recent advances and challenges in the mol. design of quantum dots are discussed, along with applications of quantum dots as drug delivery vehicles, theranostic agents, single mol. probes, and real-time in vivo deep tissue imaging agents. We present a detailed discussion of the biodistribution and toxicity of quantum dots, and highlight recent advances to improve long-term stability in biol. buffers, increase quantum yield following bioconjugation, and improve clearance from the body. Last, we present an outlook on future challenges and strategies to further advance translation to clin. application. Semiconducting nanoparticles, commonly known as quantum dots, possess unique size and shape dependent elec. and optical properties. In recent years, they have attracted much attention in biomedical imaging to enable diagnostics, single mol. probes, and real-time imaging of tumors. This review discusses recent advances and challenges in the design of quantum dots, and highlights how these strategies can further advance translation to clin. applications.
- 3Pelaz, B.; Alexiou, C.; Alvarez-Puebla, R. A.; Alves, F.; Andrews, A. M.; Ashraf, S.; Balogh, L. P.; Ballerini, L.; Bestetti, A.; Brendel, C.; Bosi, S.; Carril, M.; Chan, W. C. W.; Chen, C.; Chen, X.; Chen, X.; Cheng, Z.; Cui, D.; Du, J.; Dullin, C. Diverse Applications of Nanomedicine. ACS Nano 2017, 11 (3), 2313– 2381, DOI: 10.1021/acsnano.6b060403https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXktV2isLg%253D&md5=3441feba35a8ea371b661906e1d0813bDiverse Applications of NanomedicinePelaz, Beatriz; Alexiou, Christoph; Alvarez-Puebla, Ramon A.; Alves, Frauke; Andrews, Anne M.; Ashraf, Sumaira; Balogh, Lajos P.; Ballerini, Laura; Bestetti, Alessandra; Brendel, Cornelia; Bosi, Susanna; Carril, Monica; Chan, Warren C. W.; Chen, Chunying; Chen, Xiaodong; Chen, Xiaoyuan; Cheng, Zhen; Cui, Daxiang; Du, Jianzhong; Dullin, Christian; Escudero, Alberto; Feliu, Neus; Gao, Mingyuan; George, Michael; Gogotsi, Yury; Gruenweller, Arnold; Gu, Zhongwei; Halas, Naomi J.; Hampp, Norbert; Hartmann, Roland K.; Hersam, Mark C.; Hunziker, Patrick; Jian, Ji; Jiang, Xingyu; Jungebluth, Philipp; Kadhiresan, Pranav; Kataoka, Kazunori; Khademhosseini, Ali; Kopecek, Jindrich; Kotov, Nicholas A.; Krug, Harald F.; Lee, Dong Soo; Lehr, Claus-Michael; Leong, Kam W.; Liang, Xing-Jie; Ling Lim, Mei; Liz-Marzan, Luis M.; Ma, Xiaowei; Macchiarini, Paolo; Meng, Huan; Moehwald, Helmuth; Mulvaney, Paul; Nel, Andre E.; Nie, Shuming; Nordlander, Peter; Okano, Teruo; Oliveira, Jose; Park, Tai Hyun; Penner, Reginald M.; Prato, Maurizio; Puntes, Victor; Rotello, Vincent M.; Samarakoon, Amila; Schaak, Raymond E.; Shen, Youqing; Sjoeqvist, Sebastian; Skirtach, Andre G.; Soliman, Mahmoud G.; Stevens, Molly M.; Sung, Hsing-Wen; Tang, Ben Zhong; Tietze, Rainer; Udugama, Buddhisha N.; VanEpps, J. Scott; Weil, Tanja; Weiss, Paul S.; Willner, Itamar; Wu, Yuzhou; Yang, Lily; Yue, Zhao; Zhang, Qian; Zhang, Qiang; Zhang, Xian-En; Zhao, Yuliang; Zhou, Xin; Parak, Wolfgang J.ACS Nano (2017), 11 (3), 2313-2381CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biol., nonbiol., biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clin. products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.
- 4Hassan, S.; Prakash, G.; Bal Ozturk, A.; Saghazadeh, S.; Farhan Sohail, M.; Seo, J.; Remzi Dokmeci, M.; Zhang, Y. S.; Khademhosseini, A. Evolution and Clinical Translation of Drug Delivery Nanomaterials. Nano Today 2017, 15, 91– 106, DOI: 10.1016/j.nantod.2017.06.0084https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlCqtrzJ&md5=3f7b9d21e3ff0a6192d2ee592395d895Review on Evolution and clinical translation of drug delivery nanomaterialsHassan, Shabir; Prakasha, Gyan; Bal Ozturk, Ayca; Saghazadeh, Saghi; Farhan Sohail, Muhammad; Seo, Jungmok; Remzi Dokmeci, Mehmet; Zhang, Yu Shrike; Khademhosseini, AliNano Today (2017), 15 (), 91-106CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)A review. With the advent of technol., the role of nanomaterials in medicine has grown exponentially in the last few decades. The main advantage of such materials has been exploited in drug delivery applications, due to their effective targeting that in turn reduces systemic toxicity compared to the conventional routes of drug administration. While therapeutically improved and safe materials have been introduced in nanomedicine platforms, issues related to their degrdn. rate and bio-distribution still exist, thus making their successful translation to clin. application very challenging. Researchers are constantly improving upon novel nanomaterials that are safer and more effective not only as therapeutic agents but as diagnostic tools as well, making the research in the field of nanomedicine ever more fascinating. In this review stress has been made on the evolution of nanomaterials that are under different stages of clin. trials or have been approved by the United States Food and Drug Administration (FDA).
- 5Tsoi, K. M.; MacParland, S. A.; Ma, X.-Z.; Spetzler, V. N.; Echeverri, J.; Ouyang, B.; Fadel, S. M.; Sykes, E. A.; Goldaracena, N.; Kaths, J. M.; Conneely, J. B.; Alman, B. A.; Selzner, M.; Ostrowski, M. A.; Adeyi, O. A.; Zilman, A.; McGilvray, I. D.; Chan, W. C. W. Mechanism of Hard-Nanomaterial Clearance by the Liver. Nat. Mater. 2016, 15 (11), 1212– 1221, DOI: 10.1038/nmat47185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlCitb%252FF&md5=18e6822d496d5a3a2813c14f245bbf5bMechanism of hard-nanomaterial clearance by the liverTsoi, Kim M.; MacParland, Sonya A.; Ma, Xue-Zhong; Spetzler, Vinzent N.; Echeverri, Juan; Ouyang, Ben; Fadel, Saleh M.; Sykes, Edward A.; Goldaracena, Nicolas; Kaths, Johann M.; Conneely, John B.; Alman, Benjamin A.; Selzner, Markus; Ostrowski, Mario A.; Adeyi, Oyedele A.; Zilman, Anton; McGilvray, Ian D.; Chan, Warren C. W.Nature Materials (2016), 15 (11), 1212-1221CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)The liver and spleen are major biol. barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examd. the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 ± 6.4%), hepatic B cells (81.5 ± 9.3%) and liver sinusoidal endothelial cells (64.6 ± 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 ± 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.
- 6Kermanizadeh, A.; Powell, L. G.; Stone, V. A Review of Hepatic Nanotoxicology - Summation of Recent Findings and Considerations for the Next Generation of Study Designs. J. Toxicol. Environ. Health, Part B 2020, 23 (4), 137– 176, DOI: 10.1080/10937404.2020.17517566https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnslWgt7Y%253D&md5=c19ec7e18cd1e22e78204e0523d4e5a1A review of hepatic nanotoxicology - summation of recent findings and considerations for the next generation of study designsKermanizadeh, Ali; Powell, Leagh G.; Stone, VickiJournal of Toxicology and Environmental Health, Part B: Critical Reviews (2020), 23 (4), 137-176CODEN: JTECFR; ISSN:1093-7404. (Taylor & Francis, Inc.)The liver is one of the most important multi-functional organs in the human body. Amongst various crucial functions, it is the main detoxification center and predominantly implicated in the clearance of xenobiotics potentially including particulates that reach this organ. It is now well established that a significant quantity of injected, ingested or inhaled nanomaterials (NMs) translocate from primary exposure sites and accumulate in liver. This review aimed to summarize and discuss the progress made in the field of hepatic nanotoxicol., and crucially highlight knowledge gaps that still exist. Key considerations include In vivo studies clearly demonstrate that low-soly. NMs predominantly accumulate in the liver macrophages the Kupffer cells (KC), rather than hepatocytes. KCs lining the liver sinusoids are the first cell type that comes in contact with NMs in vivo. Further, these macrophages govern overall inflammatory responses in a healthy liver. Therefore, interaction with of NM with KCs in vitro appears to be very important. Many acute in vivo studies demonstrated signs of toxicity induced by a variety of NMs. However, acute studies may not be that meaningful due to liver's unique and unparalleled ability to regenerate. In almost all investigations where a recovery period was included, the healthy liver was able to recover from NM challenge. This organ's ability to regenerate cannot be reproduced in vitro. However, recommendations and evidence is offered for the design of more physiol. relevant in vitro models. Models of hepatic disease enhance the NM-induced hepatotoxicity. The review offers a no. of important suggestions for the future of hepatic nanotoxicol. study design. This is of great significance as its findings are highly relevant due to the development of more advanced in vitro, and in silico models aiming to improve physiol. relevant toxicol. testing strategies and bridging the gap between in vitro and in vivo experimentation.
- 7Kim, H. J.; Kim, A.; Miyata, K.; Kataoka, K. Recent Progress in Development of siRNA Delivery Vehicles for Cancer Therapy. Adv. Drug Delivery Rev. 2016, 104, 61– 77, DOI: 10.1016/j.addr.2016.06.0117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFSgt7fP&md5=e5ac0b415079dce255fb4b0012ad70c5Recent progress in development of siRNA delivery vehicles for cancer therapyKim, Hyun Jin; Kim, Ahram; Miyata, Kanjiro; Kataoka, KazunoriAdvanced Drug Delivery Reviews (2016), 104 (), 61-77CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)Recent progress in RNA biol. has broadened the scope of therapeutic targets of RNA drugs for cancer therapy. However, RNA drugs, typically small interfering RNAs (siRNAs), are rapidly degraded by RNases and filtrated in the kidney, thereby requiring a delivery vehicle for efficient transport to the target cells. To date, various delivery formulations have been developed from cationic lipids, polymers, and/or inorg. nanoparticles for systemic delivery of siRNA to solid tumors. This review describes the current status of clin. trials related to siRNA-based cancer therapy, as well as the remaining issues that need to be overcome to establish a successful therapy. It, then introduces various promising design strategies of delivery vehicles for stable and targeted siRNA delivery, including the prospects for future design.
- 8Murakami, M.; Nishina, K.; Watanabe, C.; Yoshida-Tanaka, K.; Piao, W.; Kuwahara, H.; Horikiri, Y.; Miyata, K.; Nishiyama, N.; Kataoka, K.; Yoshida, M.; Mizusawa, H.; Yokota, T. Enteral siRNA Delivery Technique for Therapeutic Gene Silencing in the Liver via the Lymphatic Route. Sci. Rep. 2015, 5 (1), 17035, DOI: 10.1038/srep170358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFensbfJ&md5=60a7d99d585ff3ef6c0fa28d8f670f8dEnteral siRNA delivery technique for therapeutic gene silencing in the liver via the lymphatic routeMurakami, Masahiro; Nishina, Kazutaka; Watanabe, Chie; Yoshida-Tanaka, Kie; Piao, Wenying; Kuwahara, Hiroya; Horikiri, Yuji; Miyata, Kanjiro; Nishiyama, Nobuhiro; Kataoka, Kazunori; Yoshida, Masayuki; Mizusawa, Hidehiro; Yokota, TakanoriScientific Reports (2015), 5 (), 17035CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)An efficient targeting delivery technol. is needed for functional oligonucleotides to exert their potential effect on the target gene without an adverse effect in vivo. Development of enteral delivery systems for nucleic acids is a major challenge because of their large mol. size and instability. Here, we describe a new enteral delivery technique that enables small interfering RNA (siRNA) selectively delivered to the liver to silence its target Apolipoprotein B gene expression. A nuclease-resistant synthetic siRNA was conjugated with α-tochopherol and administered as lipid nanoparticle to the large intestine of the mice in a postprandial state. The selective transport into the liver, effective gene silence, and consequently significant redn. in serum low d. lipoprotein-cholesterol level, were demonstrated. The chylomicron-mediated pathway via the lymphatic route was suggested as major mechanism. This unique approach may provide a basis for developing oral and rectal delivery systems for nucleic acids targeting liver.
- 9Hunt, N. J.; McCourt, P. A. G.; Le Couteur, D. G.; Cogger, V. C. Novel Targets for Delaying Aging: The Importance of the Liver and Advances in Drug Delivery. Adv. Drug Delivery Rev. 2018, 135, 39– 49, DOI: 10.1016/j.addr.2018.09.0069https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVygsr3L&md5=c2c6016b989d8495d5be00e08b9fd64dNovel targets for delaying aging: The importance of the liver and advances in drug deliveryHunt, Nicholas J.; McCourt, Peter A. G.; Le Couteur, David G.; Cogger, Victoria C.Advanced Drug Delivery Reviews (2018), 135 (), 39-49CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Age-related changes in liver function have a significant impact on systemic aging and susceptibility to age-related diseases. Nutrient sensing pathways have emerged as important targets for the development of drugs that delay aging and the onset age-related diseases. This supports a central role for the hepatic regulation of metab. in the assocn. between nutrition and aging. Recently, a role for liver sinusoidal endothelial cells (LSECs) in the relationship between aging and metab. has also been proposed. Age-related loss of fenestrations within LSECs impairs the transfer of substrates (such as lipoproteins and insulin) between sinusoidal blood and hepatocytes, resulting in post-prandial hyperlipidemia and insulin resistance. Targeted drug delivery methods such as nanoparticles and quantum dots will facilitate the direct delivery of drugs that regulate fenestrations in LSECs, providing an innovative approach to ameliorating age-related diseases and increasing healthspan.
- 10Hunt, N. J.; Lockwood, G. P.; Le Couteur, F. H.; McCourt, P. A. G.; Singla, N.; Kang, S. W. S.; Burgess, A.; Kuncic, Z.; Le Couteur, D. G.; Cogger, V. C. Rapid Intestinal Uptake and Targeted Delivery to the Liver Endothelium Using Orally Administered Silver Sulfide Quantum Dots. ACS Nano 2020, 14 (2), 1492– 1507, DOI: 10.1021/acsnano.9b0607110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFyltr8%253D&md5=f2a40cb7208013a42a2424e45af109d9Rapid Intestinal Uptake and Targeted Delivery to the Liver Endothelium Using Orally Administered Silver Sulfide Quantum DotsHunt, Nicholas J.; Lockwood, Glen P.; Le Couteur, Frank H.; McCourt, Peter A. G.; Singla, Nidhi; Kang, Sun Woo Sophie; Burgess, Andrew; Kuncic, Zdenka; Le Couteur, David G.; Cogger, Victoria C.ACS Nano (2020), 14 (2), 1492-1507CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Quantum dots (QDs) are used for imaging and transport of therapeutics. Here we demonstrate rapid absorption across the small intestine and targeted delivery of QDs with bound materials to the liver sinusoidal endothelial cells (LSECs) or hepatocytes in vitro and in vivo following oral administration. QDs were radiolabeled with 3H-oleic acid, with a fluorescent tag or 14C-metformin placed within a drug binding site. Three different biopolymer shell coatings were compared (formaldehyde-treated serum albumin (FSA), gelatin, heparin). Passage across the small intestine into mesenteric veins is mediated by clathrin endocytosis and micropinocytosis. 60% of an oral dose of QDs was rapidly distributed to the liver within 30 min, and this increased to 85% with FSA biopolymer coating. Uptake into LSECs also increased 3-fold with FSA coating, while uptake into hepatocytes was increased from 40% to 85% with gelatin biopolymer coating. Localization of QDs to LSECs was confirmed with immunofluorescence and transmission electron microscopy. 85% of QDs were cleared within 24 h of administration. The bioavailability of 14C-metformin 2 h post-ingestion was increased 5-fold by conjugation with QD-FSA, while uptake of metformin into LSECs was improved 50-fold by using these QDs. Endocytosis of QDs by SK-Hep1 cells (an LSEC immortal cell line) was via clathrin- and caveolae-mediated pathways with QDs taken up into lysosomes. In conclusion, we have shown high specificity targeting of the LSEC or hepatocytes after oral administration of QDs coated with a biopolymer layer of FSA or gelatin, which improved the bioavailability and delivery of metformin to LSECs.
- 11Hunt, N. J.; Kang, S. W.; Lockwood, G. P.; Le Couteur, D. G.; Cogger, V. C. Hallmarks of Aging in the Liver. Comput. Struct. Biotechnol. J. 2019, 17, 1151– 1161, DOI: 10.1016/j.csbj.2019.07.02111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1art7zO&md5=7252f235fddde7dcd16f75c66c66217bHallmarks of Aging in the LiverHunt, Nicholas J.; Kang, Sun Woo; Lockwood, Glen P.; Le Couteur, David G.; Cogger, Victoria C.Computational and Structural Biotechnology Journal (2019), 17 (), 1151-1161CODEN: CSBJAC; ISSN:2001-0370. (Elsevier B.V.)While the liver demonstrates remarkable resilience during aging, there is growing evidence that it undergoes all the cellular hallmarks of aging, which increases the risk of liver and systemic disease. The aging process in the liver is driven by alterations of the genome and epigenome that contribute to dysregulation of mitochondrial function and nutrient sensing pathways, leading to cellular senescence and low-grade inflammation. These changes promote multiple phenotypic changes in all liver cells (hepatocytes, liver sinusoidal endothelial, hepatic stellate and Kupffer cells) and impairment of hepatic function. In particular, age-related changes in the liver sinusoidal endothelial cells are a significant but under-recognized risk factor for the development of age-related cardiometabolic disease.
- 12Alfaras, I.; Mitchell, S. J.; Mora, H.; Lugo, D. R.; Warren, A.; Navas-Enamorado, I.; Hoffmann, V.; Hine, C.; Mitchell, J. R.; Le Couteur, D. G.; Cogger, V. C.; Bernier, M.; de Cabo, R. Health Benefits of Late-Onset Metformin Treatment Every Other Week in Mice. npj Aging Mech Dis 2017, 3 (1), 16, DOI: 10.1038/s41514-017-0018-712https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M3kt1SmsQ%253D%253D&md5=83d6345c013ceb7fb6076c9b7011fc64Health benefits of late-onset metformin treatment every other week in miceAlfaras Irene; Mitchell Sarah J; Mora Hector; Lugo Darisbeth Rosario; Navas-Enamorado Ignacio; Bernier Michel; de Cabo Rafael; Warren Alessandra; Le Couteur David G; Cogger Victoria C; Hoffmann Vickie; Hine Christopher; Mitchell James R; Le Couteur David G; Cogger Victoria CNPJ aging and mechanisms of disease (2017), 3 (), 16 ISSN:2056-3973.Chronic 1% metformin treatment is nephrotoxic in mice, but this dose may nonetheless confer health benefits if given intermittently rather than continuously. Here, we examined the effects of 1% metformin given every-other week (EOW) or two consecutive weeks per month (2WM) on survival of 2-year-old male mice fed standard chow. EOW and 2WM mice had comparable life span compared with control mice. A significant reduction in body weight within the first few weeks of metformin treatment was observed without impact on food consumption and energy expenditure. Moreover, there were differences in the action of metformin on metabolic markers between the EOW and 2WM groups, with EOW metformin conferring greater benefits. Age-associated kidney lesions became more pronounced with metformin, although without pathological consequences. In the liver, metformin treatment led to an overall reduction in steatosis and was accompanied by distinct transcriptomic and metabolomic signatures in response to EOW versus 2WM regimens. Thus, the absence of adverse outcomes associated with chronic, intermittent use of 1% metformin in old mice has clinical translatability into the biology of aging in humans.
- 13Katsyuba, E.; Romani, M.; Hofer, D.; Auwerx, J. NAD+ Homeostasis in Health and Disease. Nat. Metab 2020, 2, 9, DOI: 10.1038/s42255-019-0161-513https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXks1Krsrg%253D&md5=8c165c237d9ef8f9b757e422ad9c29d1NAD+ homeostasis in health and diseaseKatsyuba, Elena; Romani, Mario; Hofer, Dina; Auwerx, JohanNature Metabolism (2020), 2 (1), 9-31CODEN: NMAED6; ISSN:2522-5812. (Springer International Publishing AG)A review. Abstr.: The conceptual evolution of NAD (NAD+) from being seen as a simple metabolic cofactor to a pivotal cosubstrate for proteins regulating metab. and longevity, including the sirtuin family of protein deacylases, has led to a new wave of scientific interest in NAD+. NAD+ levels decline during ageing, and alterations in NAD+ homeostasis can be found in virtually all age-related diseases, including neurodegeneration, diabetes and cancer. In preclin. settings, various strategies to increase NAD+ levels have shown beneficial effects, thus starting a competitive race to discover marketable NAD+ boosters to improve healthspan and lifespan. Here, we review the basics of NAD+ biochem. and metab., and its roles in health and disease, and we discuss current challenges and the future translational potential of NAD+ research.
- 14Mills, K. F.; Yoshida, S.; Stein, L. R.; Grozio, A.; Kubota, S.; Sasaki, Y.; Redpath, P.; Migaud, M. E.; Apte, R. S.; Uchida, K.; Yoshino, J.; Imai, S.-i. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016, 24 (6), 795– 806, DOI: 10.1016/j.cmet.2016.09.01314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKmsLvF&md5=1c523f308481ab9749bf6a9f93c05ab5Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in MiceMills, Kathryn F.; Yoshida, Shohei; Stein, Liana R.; Grozio, Alessia; Kubota, Shunsuke; Sasaki, Yo; Redpath, Philip; Migaud, Marie E.; Apte, Rajendra S.; Uchida, Koji; Yoshino, Jun; Imai, Shin-ichiroCell Metabolism (2016), 24 (6), 795-806CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)NAD+ availability decreases with age and in certain disease conditions. NMN (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12-mo-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-assocd. physiol. decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-assocd. body wt. gain, enhanced energy metab., promoted phys. activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-assocd. gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metab. and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.
- 15Yoshino, J.; Mills, K. F.; Yoon, M. J.; Imai, S.-I. Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet-and Age-Induced Diabetes in Mice. Cell Metab. 2011, 14 (4), 528– 536, DOI: 10.1016/j.cmet.2011.08.01415https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht12rtLvK&md5=a33f288cd823d4f85fd7201623e842d4Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in MiceYoshino, Jun; Mills, Kathryn F.; Yoon, Myeong Jin; Imai, Shin-ichiroCell Metabolism (2011), 14 (4), 528-536CODEN: CMEEB5; ISSN:1550-4131. (Cell Press)Type 2 diabetes (T2D) has become epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here, we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, NMN (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide crit. insights into a potential nutriceutical intervention against diet- and age-induced T2D.
- 16Hunt, N. J.; Lockwood, G. P.; Kang, S. W.; Pulpitel, T.; Clark, X.; Mao, H.; McCourt, P. A.; Cooney, G. J.; Wali, J. A.; Le Couteur, F. H. The Effects of Metformin on Age-Related Changes in the Liver Sinusoidal Endothelial Cell. J. Gerontol A Biol. Sci. 2020, 75 (2), 278– 285, DOI: 10.1093/gerona/glz15316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M3mslarsg%253D%253D&md5=f1e88b4fdaac277f862e321b9fa70c89The Effects of Metformin on Age-Related Changes in the Liver Sinusoidal Endothelial CellHunt Nicholas J; Lockwood Glen P; Kang Sun Woo Sophie; Le Couteur Frank H; Le Couteur David G; Cogger Victoria C; Hunt Nicholas J; Lockwood Glen P; Kang Sun Woo Sophie; Wali Jibran A; Le Couteur David G; Cogger Victoria C; Hunt Nicholas J; Le Couteur David G; Cogger Victoria C; Hunt Nicholas J; Lockwood Glen P; Kang Sun Woo Sophie; Pulpitel Tamara; Clark Ximonie; McCourt Peter A G; Cooney Gregory J; Wali Jibran A; Le Couteur David G; Cogger Victoria C; Mao Hong; McCourt Peter A G; Wali Jibran AThe journals of gerontology. Series A, Biological sciences and medical sciences (2020), 75 (2), 278-285 ISSN:.Age-related changes in the liver sinusoidal endothelium, particularly the reduction in fenestrations, contribute to insulin resistance in old age. Metformin impacts on the aging process and improves insulin resistance. Therefore, the effects of metformin on the liver sinusoidal endothelium were studied. Metformin increased fenestrations in liver sinusoidal endothelial cells isolated from both young and old mice. Mice administered metformin in the diet for 12 months had increased fenestrations and this was associated with lower insulin levels. The effect of metformin on fenestrations was blocked by inhibitors of AMP-activated protein kinase (AMPK), endothelial nitric oxide synthase, and myosin light chain kinase phosphorylation. Metformin led to increased transgelin expression and structural changes in the actin cytoskeleton but had no effect on lactate production. Metformin also generated fenestration-like structures in SK-Hep1 cells, a liver endothelial cell line, and this was associated with increased ATP, cGMP, and mitochondrial activity. In conclusion, metformin ameliorates age-related changes in the liver sinusoidal endothelial cell via AMPK and endothelial nitric oxide pathways, which might promote insulin sensitivity in the liver, particularly in old age.
- 17Hunt, N. J.; Lockwood, G. P.; Warren, A.; Mao, H.; McCourt, P. A.; Le Couteur, D. G.; Cogger, V. C. Manipulating Fenestrations in Young and Old Liver Sinusoidal Endothelial Cells. Am. J. Physiol Gastrointest Liver Physiol 2019, 316 (1), G144– G154, DOI: 10.1152/ajpgi.00179.2018There is no corresponding record for this reference.
- 18Patiño-Herrera, R.; Louvier-Hernández, J. F.; Escamilla-Silva, E. M.; Chaumel, J.; Escobedo, A. G. P.; Pérez, E. Prolonged Release of Metformin by SiO2 Nanoparticles Pellets for Type II Diabetes Control. Eur. J. Pharm. Sci. 2019, 131, 1– 8, DOI: 10.1016/j.ejps.2019.02.00318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivVWks7o%253D&md5=3befef0cbbd369dce3463af62aea45aeProlonged release of metformin by SiO2 nanoparticles pellets for type II diabetes controlPatino-Herrera, Rosalba; Louvier-Hernandez, Jose Francisco; Escamilla-Silva, Eleazar M.; Chaumel, Julie; Escobedo, Alma Gabriela Palestino; Perez, EliasEuropean Journal of Pharmaceutical Sciences (2019), 131 (), 1-8CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)Mesoporous silica nanoparticles (MSNPs) were synthesized and loaded with metformin hydrochloride (Metf), its adsorption has studied at different concns. and pHs, optimal adsorption conditions were detd. Hybrid MSNPs-Metf were mixed with chitosan to compress them and form quasi-spherical pellets, were coated with five chitosan layers as a barrier to prolong metformin release. It showed that this pellet is useful for metformin controlled release since drug over time was significantly delayed by the chitosan coating and then, as metformin is electrostatically linked to MSNPs, it also controls the release of drug, releasing 170 mg after 17 h of exposure at pH 1.2. When pH is >1.2, metformin release was significantly prolonged. Since 170 mg is 21% of a 850-mg metformin dose and previous studies report that 90% of metformin is recovered as unchanged drug in urine after 12 h of metformin intakes. These results suggest that MSNPs-Metf pellets, coated with chitosan, are an option to avoid excessive metformin ingest.
- 19Xu, H.; Jiang, Q.; Reddy, N.; Yang, Y. Hollow Nanoparticles from Zein for Potential Medical Applications. J. Mater. Chem. 2011, 21 (45), 18227– 18235, DOI: 10.1039/c1jm11163a19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVehsrbO&md5=20acaad239a57445cd69fa50e691e9e3Hollow nanoparticles from zein for potential medical applicationsXu, Helan; Jiang, Qiuran; Reddy, Narendra; Yang, YiqiJournal of Materials Chemistry (2011), 21 (45), 18227-18235CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)Hollow nanoparticles from corn storage protein zein, with av. diams. as small as 65 nm and capable of loading a large amt. of drug and penetrating into the cell cytoplasm, have been developed for potential drug delivery applications. As an important protein co-product of corn-based ethanol, zein is biocompatible and has been proved to be useful for medical applications through in vitro and in vivo evaluations. Zein can overcome the limitations of inorg. or metal nanoparticles that tend to accumulate in the organs and tissues and is therefore preferable for drug delivery applications. However, it has been obsd. that only small proteins and peptides are able to penetrate into cells and zein with a mol. wt. of 14-44 kDa may not be able to enter into the cells. In this research, hollow zein nanoparticles have been developed and the potential of the hollow zein nanoparticles to load drugs and enter the cell cytoplasm was investigated. Hollow zein nanoparticles developed in this research were capable of loading as high as 369 mg g-1 of the drug metformin at an equil. concn. of 3 g L-1. Metformin in hollow zein nanoparticles showed a more sustained and controlled release profile than that in solid zein nanoparticles. Hollow zein nanoparticles were found to be able to enter the fibroblast cells 1 h after incubation. The biocompatibility, nano-scale diams., potential for loading a large amt. of drugs and the ability to penetrate into cells make hollow zein nanoparticles ideal candidates for carrying various payloads for intracellular drug delivery.
- 20Pereira, A.; Brito, G.; Lima, M.; Silva Junior, A.; Silva, E.; de Rezende, A.; Bortolin, R.; Galvan, M.; Pirih, F.; Araujo Junior, R.; Medeiros, C.; Guerra, G.; Araujo, A. Metformin Hydrochloride-Loaded PLGA Nanoparticle in Periodontal Disease Experimental Model Using Diabetic Rats. Int. J. Mol. Sci. 2018, 19 (11), 3488, DOI: 10.3390/ijms19113488There is no corresponding record for this reference.
- 21Panda, B. P.; Krishnamoorthy, R.; Shivashekaregowda, N. K. H.; Patnaik, S. Influence of Poloxamer- 188 on Design and Development of Second Generation PLGA Nanocrystals of Metformin Hydrochloride. Nano Biomed. Eng. 2018, 10 (4), 334– 343, DOI: 10.5101/nbe.v10i4.p334-34321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVCjsL3K&md5=bc80a231a0bcc6049c287919d8df553dInfluence of poloxamer 188 on design and development of second generation PLGA nanocrystals of metformin hydrochloridePanda, Bibhu Prasad; Krishnamoorthy, Rachna; Shivashekaregowda, Naveen Kumar Hawala; Patnaik, SujataNano Biomedicine and Engineering (2018), 10 (4), 334-343CODEN: NBEAA2; ISSN:2150-5578. (Nano Biomedicine and Engineering)The poly(D,L-lactide-co-glycolide) (PLGA) based second-generation nanocrystals prepd. by modified nanopptn. method, is the method of choice for encapsulation of both lipophilic and hydrophilic drugs. In this study, nanopptn. technique was adopted to develop second generation nanocrystals of PLGA loaded with metformin HCl (MHc). Poloxamer 188 with three different concns. (0.5, 0.75, 1% w/v) in combination with PLGA at 1, 2, 3% concns. (w/v) successfully produced MHc loaded PLGA second generation nanocrystals. The effects of poloxamer 188, amphiphilic triblock copolymer on carrier particle size, surface morphol., polydispersity index, zeta potential, drug entrapment efficiency and drug release of nanoformulation were investigated. The optimized formulation of second-generation nanocrystals with concns. 0.75% w/v poloxamer 188 and 2% w/v PLGA, could produce particle size of 114.6 nm, entrapment efficiency of 63.48% and drug release 80.23% at 12 h. A blank formulation with the same compn. as optimized formulation without addn. of poloxamer188 compared with optimized formulation, exhibited nanoparticles of larger mean particle size of 212.9 nm with entrapment efficiency of 68.47% and 50.5% drug release at 12 h. Transmission electron microscopy (TEM) anal. of the nanoformulations revealed that poloxamer188 greatly contributed to smooth, spherical morphol. of nanosize polymeric nanoparticles. Further Fourier-transform IR spectroscopy (FTIR) and differential scanning calorimetry (DSC) studies on nanoformulation emphasized the significance of poloxamer188 in formulation and development of optimized MHc loaded PLGA nanosuspensions of second generation nanocrystals. In conclusion, the study emphasizes that poloxamer 188 was a versatile excipient, which played a pivotal role in producing nanosize carrier with high drug release profile of MHc loaded PLGA nanosuspensions of second generation nanocrystals.
- 22Kumar, S.; Bhanjana, G.; Verma, R. K.; Dhingra, D.; Dilbaghi, N.; Kim, K. H. Metformin-Loaded Alginate Nanoparticles as an Effective Antidiabetic Agent for Controlled Drug Release. J. Pharm. Pharmacol. 2017, 69 (2), 143– 150, DOI: 10.1111/jphp.1267222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjtFCq&md5=c355fc189bdd1cd7df0d8d4708af93a2Metformin-loaded alginate nanoparticles as an effective antidiabetic agent for controlled drug releaseKumar, Sandeep; Bhanjana, Gaurav; Verma, Ritesh Kumar; Dhingra, Dinesh; Dilbaghi, Neeraj; Kim, Ki-HyunJournal of Pharmacy and Pharmacology (2017), 69 (2), 143-150CODEN: JPPMAB; ISSN:0022-3573. (John Wiley & Sons Ltd.)Objectives : Present modalities for the diagnosis and treatment of diabetes still suffer from certain limitations such as erratic absorption, need of high dose, poor sensitivity or specificity, resistance, substantial morbidity and mortality, long-term complications, and patient-to-patient variability with lifetime treatment. Methods : This study focused on the development of a water-in-oil-in-water metformin nanoemulsion as an effective method in diabetes treatment. As a Biopharmaceutics Classification System (BCS) class III drug, metformin is hydrophilic in nature with high soly. and poor absorption characteristics. To simultaneously facilitate gastrointestinal absorption and intestinal permeability, metformin was loaded into alginate nanocapsules prepd. by an emulsion crosslinking technol. Key findings : These prepd. metformin-loaded alginate nanoparticles (MLANs) were characterized using transmission electron microscopy (TEM), Fourier transform IR (FTIR) spectroscopy, and photon correlation spectroscopy (PCS)-based particle size anal. Conclusions : The drug loading and encapsulation efficiency in MLANs were 3.12 mg (the amt. of metformin added in 100 mg of nanoparticles) and 78%, resp. The results of in-vitro drug release studies and in-vivo efficacy tests (using animal models) demonstrated enhanced efficiency and response of MLANs relative to pure metformin. The efficacy of MLANs (46.8 mg/kg) was overall about three times higher than that of pure metformin 150 mg/kg.
- 23Chinnaiyan, S. K.; Karthikeyan, D.; Gadela, V. R. Development and Characterization of Metformin Loaded Pectin Nanoparticles for T2 Diabetes Mellitus. Pharm. Nanotechnol. 2019, 6 (4), 253– 263, DOI: 10.2174/2211738507666181221142406There is no corresponding record for this reference.
- 24Jose, P.; Sundar, K.; Anjali, C.; Ravindran, A. Metformin-Loaded Bsa Nanoparticles in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug. Cell Biochem. Biophys. 2015, 71 (2), 627– 636, DOI: 10.1007/s12013-014-0242-824https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFagtbzK&md5=f76778cdf9ecad24644d8523833a630bMetformin-Loaded BSA Nanoparticles in Cancer Therapy: A New Perspective for an Old Antidiabetic DrugJose, Pinkybel; Sundar, K.; Anjali, C. H.; Ravindran, AswathyCell Biochemistry and Biophysics (2015), 71 (2), 627-636CODEN: CBBIFV; ISSN:1085-9195. (Springer)Clin. and exptl. data suggest that there is a strong assocn. between type II diabetic mellitus and pancreatic cancer. The present study focuses on exploring the anticancer and antidiabetic properties of metformin-loaded bovine serum albumin nanoparticles (BSA NPs) on (MiaPaCa-2) pancreatic carcinoma cell lines. Albumin nanoparticles were synthesized using coacervation method and the av. size of the particles was found to be 97 nm. The particles were stable and showed a spherical morphol. with narrow size distribution. We investigated the impact of two stages characterized in type II diabetes mellitus (hyperglycemia and hyperinsulinemia) on the proliferation of MiaPaCa-2 cells and compared the inhibitory effects of bare metformin to that of MET-BSA NPs. Further, different concns. of insulin and glucose were added along with bare metformin, bare BSA, and metformin encapsulated BSA carrier on MiaPaCa-2 cells to check the strong assocn. between type II diabetes and pancreatic cancer. The results revealed that MET-BSA NPs showed more toxicity when compared with drug and carrier individually.
- 25Choi, Y. H.; Han, H.-K. Nanomedicines: Current Status and Future Perspectives in Aspect of Drug Delivery and Pharmacokinetics. J. Pharm. Invest. 2018, 48 (1), 43– 60, DOI: 10.1007/s40005-017-0370-425https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFekt7fM&md5=890427cf846ce15df8af7d01b5230011Nanomedicines: current status and future perspectives in aspect of drug delivery and pharmacokineticsChoi, Young Hee; Han, Hyo-KyungJournal of Pharmaceutical Investigation (2018), 48 (1), 43-60CODEN: JPIOBH; ISSN:2093-5552. (Springer)A Review. Nanomedicines have evolved into various forms including dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles since their first launch in the market. Widely highlighted benefits of nanomedicines over conventional medicines include superior efficacy, safety, physicochem. properties, and pharmacokinetic/pharmacodynamic profiles of pharmaceutical ingredients. Esp., various kinetic characteristics of nanomedicines in body are further influenced by their formulations. This review provides an updated understanding of nanomedicines with respect to delivery and pharmacokinetics. It describes the process and advantages of the nanomedicines approved by FDA and EMA. New FDA and EMA guidelines will also be discussed. Based on the anal. of recent guidelines and approved nanomedicines, key issues in the future development of nanomedicines will be addressed.
- 26Sambol, N. C.; Chiang, J.; O’Conner, M.; Liu, C. Y.; Lin, E. T.; Goodman, A. M.; Benet, L. Z.; Karam, J. H. Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Subjects and Patients with Noninsulin-Dependent Diabetes Mellitus. J. Clin. Pharmacol. 1996, 36 (11), 1012– 1021, DOI: 10.1177/00912700960360110526https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXkvVamtw%253D%253D&md5=3db573b4ac6380eb74fee3c00fecc950Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitusSambol, Nancy C.; Chiang, Janie; O'Conner, Michael; Liu, Chui Y.; Lin, Emil T.; Goodman, Anita M.; Benet, Leslie Z.; Karam, John H.Journal of Clinical Pharmacology (1996), 36 (11), 1012-1021CODEN: JCPCBR; ISSN:0091-2700. (Lippincott-Raven)This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose-dependent pharmacokinetics. The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed. Nine patients with NIDDM and 9 healthy subjects received 4 single-blind single-dose treatments of metformin HCl (850 mg, 1,700 mg, 2,550 mg, and placebo) and a multiple-dose treatment of 850 mg metformin HCl (3 times daily for 19 doses). After each single-dose treatment and the final dose of the multiple-dose phase, multiple plasma and urine samples were collected for 48 h and assayed for metformin levels. Plasma samples were also assayed for glucose and insulin levels. There were no significant differences in metformin kinetics in patients with NIDDM compared with healthy subjects, in men compared with women, or during multiple-dose treatment vs. single-dose treatment. Plasma concns. of metformin increase less than proportionally to dose, most likely due to a decrease in percent absorbed. In patients with NIDDM, single doses of 1,700-mg or higher of metformin significantly decrease postprandial, but not preprandial, glucose concns. and do not influence insulin concns. With multiple doses, both preprandial and postprandial glucose concns. and preprandial insulin concns. were significantly lower than with placebo. The effect of metformin on glucose level is correlated with the av. fasting plasma glucose level without drug. In healthy subjects, single and multiple doses of metformin showed no effect on plasma glucose, but significantly attenuated the rise in immediate postprandial insulin levels.
- 27Padwal, R. S.; Gabr, R. Q.; Sharma, A. M.; Langkaas, L.-A.; Birch, D. W.; Karmali, S.; Brocks, D. R. Effect of Gastric Bypass Surgery on the Absorption and Bioavailability of Metformin. Diabetes Care 2011, 34 (6), 1295– 1300, DOI: 10.2337/dc10-214027https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXos1KmsLo%253D&md5=97266ca74d83ab42f4bde51cdf5b989bEffect of gastric bypass surgery on the absorption and bioavailability of metforminPadwal, Raj S.; Gabr, Ranlah Q.; Sharma, Arya M.; Langkaas, Lee-Ann; Birch, Dan W.; Karmali, Shahzeer; Brocks, Dion R.Diabetes Care (2011), 34 (6), 1295-1300CODEN: DICAD2; ISSN:0149-5992. (American Diabetes Association, Inc.)Use of gastric bypass surgery is common and increasing. Over 40% of patients in diabetes remission after gastric bypass surgery may redevelop diabetes within 5 years. Metformin, the first-line drug for diabetes, has low bioavailability and slow, incomplete gastrointestinal absorption. We hypothesized that gastric bypass would further reduce the absorption and bioavailability of metformin. In a nonblinded, single-dose pharmacokinetic study, 16 nondiabetic post-gastric bypass patients and 16 sex- and BMI-matched control subjects (mean age 40 years and BMI 39.2 kg/m2) were administered two 500-mg metformin tablets. Plasma metformin levels were sampled at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 h. Metformin absorption, estd. by the area under the curve (AUC) of the plasma drug concns. from time 0 to infinity (AUC0-∞), was the primary outcome, and metformin bioavailability, assessed by measuring 24-h urine metformin levels, was a secondary outcome. Compared with control subjects, metformin AUC0-∞ was increased in gastric bypass subjects by 21% (13.7 vs. 11.4 μg/mL/h; mean difference 2.3 [95% CI -1.3 to 5.9]) and bioavailability was increased by 50% (41.8 vs. 27.8%; 14.0 [4.1-23.9]). Gastric bypass patients had significantly lower AUC glucose levels over 8 h compared with control subjects (35.8 vs. 41.7 μg/mL/h; 5.9 [3.1-8.8]), but this was likely a result of differences in baseline fasting glucose and not metformin absorption. Metformin absorption and bioavailability seem to be higher after gastric bypass, and this may have implications on dosing and toxicity risk. Studies are needed to confirm these findings and delineate potential mechanisms.
- 28Isin, E. M.; Guengerich, F. P. Complex Reactions Catalyzed by Cytochrome P450 Enzymes. Biochim. Biophys. Acta, Gen. Subj. 2007, 1770 (3), 314– 329, DOI: 10.1016/j.bbagen.2006.07.00328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpvVyqsQ%253D%253D&md5=05b988e6536ea1e8725799d3cf395005Complex reactions catalyzed by cytochrome P 450 enzymesIsin, Emre M.; Guengerich, F. PeterBiochimica et Biophysica Acta, General Subjects (2007), 1770 (3), 314-329CODEN: BBGSB3; ISSN:0304-4165. (Elsevier Ltd.)A review. Cytochrome P 450 (P 450) isoforms are some of the most versatile redox proteins known. The basic P 450 reactions include C-hydroxylation, heteroatom oxygenation, heteroatom release (dealkylation), and epoxide formation. Mechanistic explanations for these reactions have been advanced. A no. of more complex P 450 reactions also occur, and these can be understood largely in the context of the basic chem. mechanisms and subsequent rearrangements. The list discussed here updates a 2001 review and includes Cl oxygenation, arom. dehalogenation, formation of diindole products, dimer formation via Diels-Alder reactions of products, ring coupling and also ring formation, reductive activation (e.g., aristolochic acid), ring contraction (piperidine nitroxide radical), oxidn. of troglitazone, cleavage of amino oxazoles and a 1,2,4-oxadiazole ring, bioactivation of a dihydrobenzoxathiin, and oxidative aryl migration.
- 29Bobo, D.; Robinson, K. J.; Islam, J.; Thurecht, K. J.; Corrie, S. R. Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date. Pharm. Res. 2016, 33 (10), 2373– 2387, DOI: 10.1007/s11095-016-1958-529https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xpslyrsbk%253D&md5=e1babf0ad4e9b4ecc4c36874c04108f2Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to DateBobo, Daniel; Robinson, Kye J.; Islam, Jiaul; Thurecht, Kristofer J.; Corrie, Simon R.Pharmaceutical Research (2016), 33 (10), 2373-2387CODEN: PHREEB; ISSN:0724-8741. (Springer)A review. In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clin. trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biol. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clin. trials, with ∼40% of trials listed in clin. trials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorg. and metallic particles in clin. trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clin. trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials ("theranostics") and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what addnl. testing (e.g. safety and toxicity) is required before products become available.
- 30Boles, M. A.; Ling, D.; Hyeon, T.; Talapin, D. V. The Surface Science of Nanocrystals. Nat. Mater. 2016, 15 (2), 141– 153, DOI: 10.1038/nmat452630https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1Cksrs%253D&md5=74fad72ab2b0a439dff7f7c49711d695The surface science of nanocrystalsBoles, Michael A.; Ling, Daishun; Hyeon, Taeghwan; Talapin, Dmitri V.Nature Materials (2016), 15 (2), 141-153CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)A review. All nanomaterials share a common feature of large surface-to-vol. ratio, making their surfaces the dominant player in many phys. and chem. processes. Surface ligands - mols. that bind to the surface - are an essential component of nanomaterial synthesis, processing and application. Understanding the structure and properties of nanoscale interfaces requires an intricate mix of concepts and techniques borrowed from surface science and coordination chem. This Review elaborates these connections and discusses the bonding, electronic structure and chem. transformations at nanomaterial surfaces. The authors specifically focus on the role of surface ligands in tuning and rationally designing properties of functional nanomaterials. Given their importance for biomedical (imaging, diagnostics and therapeutics) and optoelectronic (light-emitting devices, transistors, solar cells) applications, the authors end with an assessment of application-targeted surface engineering.
- 31Gao, L.; Liu, G.; Ma, J.; Wang, X.; Zhou, L.; Li, X. Drug Nanocrystals: In Vivo Performances. J. Controlled Release 2012, 160 (3), 418– 430, DOI: 10.1016/j.jconrel.2012.03.01331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XltVKmur0%253D&md5=20a5165e2b2998089a073f41848742b8Drug nanocrystals: In vivo performancesGao, Lei; Liu, Guiyang; Ma, Jianli; Wang, Xiaoqing; Zhou, Liang; Li, XiangJournal of Controlled Release (2012), 160 (3), 418-430CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Over the past few decades, there was a considerable research interest in drug nanocrystal system as a pharmaceutical approach for poorly sol. drugs. At the beginning lots of works were done to study various technologies assocd. with prodn. of drug nanocrystals and their in vitro phys. and chem. properties, such as morphol., formulation compn., stabilities, cryst. structure and enhanced soly. and dissoln. velocity. Recently, in vivo behaviors of the nanocrystals were generally studied in animals (including human), and the results proved that drug nanocrystals could be used as a versatile formulation to alter and improve the pharmacokinetic, pharmacodynamic and targeting properties of poorly sol. drugs. In this paper, in vivo performances of drug nanocrystals exhibited in animals in different administration route were reviewed, and the advantages of drug nanocrystals in the aspect of safety, pharmacodynamics, pharmacokinetics and targeting delivery were discussed in detail.
- 32Szunerits, S.; Melinte, S.; Barras, A.; Pagneux, Q.; Voronova, A.; Abderrahmani, A.; Boukherroub, R. The Impact of Chemical Engineering and Technological Advances on Managing Diabetes: Present and Future Concepts. Chem. Soc. Rev. 2020, DOI: 10.1039/C9CS00886AThere is no corresponding record for this reference.
- 33Patel, S.; Kim, J.; Herrera, M.; Mukherjee, A.; Kabanov, A. V.; Sahay, G. Brief Update on Endocytosis of Nanomedicines. Adv. Drug Delivery Rev. 2019, 144, 90– 111, DOI: 10.1016/j.addr.2019.08.00433https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1ent73P&md5=c39a50133726ef18fefd07291e79d064Brief update on endocytosis of nanomedicinesPatel, Siddharth; Kim, Jeonghwan; Herrera, Marco; Mukherjee, Anindit; Kabanov, Alexander V.; Sahay, GauravAdvanced Drug Delivery Reviews (2019), 144 (), 90-111CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. As such, significant effort has been devoted to advancing our understanding of the biophys. interactions of the myriad nanoparticles. Endocytosis of nanomedicine has drawn tremendous interest in the last decade. Here, we highlight the ever-present barriers to efficient intracellular delivery of nanoparticles as well as the current advances and strategies deployed to breach these barriers. We also introduce new barriers that have been largely overlooked such as the glycocalyx and macromol. crowding. Addnl., we draw attention to the potential complications arising from the disruption of the newly discovered functions of the lysosomes. Novel strategies of exploiting the inherent intracellular defects in disease states to enhance delivery and the use of exosomes for bioanalytics and drug delivery are explored. Furthermore, we discuss the advances in imaging techniques like electron microscopy, super resoln. fluorescence microscopy, and single particle tracking which have been instrumental in our growing understanding of intracellular pathways and nanoparticle trafficking. Finally, we advocate for the push towards more intravital anal. of nanoparticle transport phenomena using the multitude of techniques available to us. Unraveling the underlying mechanisms governing the cellular barriers to delivery and biol. interactions of nanoparticles will guide the innovations capable of breaching these barriers.
- 34Behzadi, S.; Serpooshan, V.; Tao, W.; Hamaly, M. A.; Alkawareek, M. Y.; Dreaden, E. C.; Brown, D.; Alkilany, A. M.; Farokhzad, O. C.; Mahmoudi, M. Cellular Uptake of Nanoparticles: Journey inside the Cell. Chem. Soc. Rev. 2017, 46 (14), 4218– 4244, DOI: 10.1039/C6CS00636A34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1yhtLw%253D&md5=938d2f8aa9d3b017cf728a93c62bec42Cellular uptake of nanoparticles: journey inside the cellBehzadi, Shahed; Serpooshan, Vahid; Tao, Wei; Hamaly, Majd A.; Alkawareek, Mahmoud Y.; Dreaden, Erik C.; Brown, Dennis; Alkilany, Alaaldin M.; Farokhzad, Omid C.; Mahmoudi, MortezaChemical Society Reviews (2017), 46 (14), 4218-4244CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)Nanoscale materials are increasingly found in consumer goods, electronics, and pharmaceuticals. While these particles interact with the body in myriad ways, their beneficial and/or deleterious effects ultimately arise from interactions at the cellular and subcellular level. Nanoparticles (NPs) can modulate cell fate, induce or prevent mutations, initiate cell-cell communication, and modulate cell structure in a manner dictated largely by phenomena at the nano-bio interface. Recent advances in chem. synthesis have yielded new nanoscale materials with precisely defined biochem. features, and emerging anal. techniques have shed light on nuanced and context-dependent nano-bio interactions within cells. In this review, we provide an objective and comprehensive account of our current understanding of the cellular uptake of NPs and the underlying parameters controlling the nano-cellular interactions, along with the available anal. techniques to follow and track these processes.
- 35Rosario, D.; Benfeitas, R.; Bidkhori, G.; Zhang, C.; Uhlen, M.; Shoaie, S.; Mardinoglu, A. Understanding the Representative Gut Microbiota Dysbiosis in Metformin-Treated Type 2 Diabetes Patients Using Genome-Scale Metabolic Modeling. Front Physiol 2018, 9, 775, DOI: 10.3389/fphys.2018.0077535https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FmtlyltA%253D%253D&md5=60b8643aac89e111f0298b9d19cc907cUnderstanding the Representative Gut Microbiota Dysbiosis in Metformin-Treated Type 2 Diabetes Patients Using Genome-Scale Metabolic ModelingRosario Dorines; Benfeitas Rui; Bidkhori Gholamreza; Zhang Cheng; Uhlen Mathias; Mardinoglu Adil; Shoaie Saeed; Shoaie Saeed; Mardinoglu AdilFrontiers in physiology (2018), 9 (), 775 ISSN:1664-042X.Dysbiosis in the gut microbiome composition may be promoted by therapeutic drugs such as metformin, the world's most prescribed antidiabetic drug. Under metformin treatment, disturbances of the intestinal microbes lead to increased abundance of Escherichia spp., Akkermansia muciniphila, Subdoligranulum variabile and decreased abundance of Intestinibacter bartlettii. This alteration may potentially lead to adverse effects on the host metabolism, with the depletion of butyrate producer genus. However, an increased production of butyrate and propionate was verified in metformin-treated Type 2 diabetes (T2D) patients. The mechanisms underlying these nutritional alterations and their relation with gut microbiota dysbiosis remain unclear. Here, we used Genome-scale Metabolic Models of the representative gut bacteria Escherichia spp., I. bartlettii, A. muciniphila, and S. variabile to elucidate their bacterial metabolism and its effect on intestinal nutrient pool, including macronutrients (e.g., amino acids and short chain fatty acids), minerals and chemical elements (e.g., iron and oxygen). We applied flux balance analysis (FBA) coupled with synthetic lethality analysis interactions to identify combinations of reactions and extracellular nutrients whose absence prevents growth. Our analyses suggest that Escherichia sp. is the bacteria least vulnerable to nutrient availability. We have also examined bacterial contribution to extracellular nutrients including short chain fatty acids, amino acids, and gasses. For instance, Escherichia sp. and S. variabile may contribute to the production of important short chain fatty acids (e.g., acetate and butyrate, respectively) involved in the host physiology under aerobic and anaerobic conditions. We have also identified pathway susceptibility to nutrient availability and reaction changes among the four bacteria using both FBA and flux variability analysis. For instance, lipopolysaccharide synthesis, nucleotide sugar metabolism, and amino acid metabolism are pathways susceptible to changes in Escherichia sp. and A. muciniphila. Our observations highlight important commensal and competing behavior, and their association with cellular metabolism for prevalent gut microbes. The results of our analysis have potential important implications for development of new therapeutic approaches in T2D patients through the development of prebiotics, probiotics, or postbiotics.
- 36Nies, A. T.; Hofmann, U.; Resch, C.; Schaeffeler, E.; Rius, M.; Schwab, M. Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs). PLoS One 2011, 6 (7), e22163, DOI: 10.1371/journal.pone.002216336https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVSlt77J&md5=5d8eaa6bd39db4c374151741f8e11d77Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs)Nies, Anne T.; Hofmann, Ute; Resch, Claudia; Schaeffeler, Elke; Rius, Maria; Schwab, MatthiasPLoS One (2011), 6 (7), e22163CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Metformin, an oral insulin-sensitizing drug, is actively transported into cells by org. cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metab., drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concn.-dependent manner. Half-maximal inhibitory concn. values (IC50) were in the low micromolar range (3-36 μM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clin. relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy.
- 37Dong, S.; Cho, H. J.; Lee, Y. W.; Roman, M. Synthesis and Cellular Uptake of Folic Acid-Conjugated Cellulose Nanocrystals for Cancer Targeting. Biomacromolecules 2014, 15 (5), 1560– 1567, DOI: 10.1021/bm401593n37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvVCrsro%253D&md5=a3350e98074027fe0806ae4155d7b86bSynthesis and Cellular Uptake of Folic Acid-Conjugated Cellulose Nanocrystals for Cancer TargetingDong, Shuping; Cho, Hyung Joon; Lee, Yong Woo; Roman, MarenBiomacromolecules (2014), 15 (5), 1560-1567CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)Elongated nanoparticles have recently been shown to have distinct advantages over spherical ones in targeted drug delivery applications. In addn. to their oblong geometry, their lack of cytotoxicity and numerous surface hydroxyl groups make cellulose nanocrystals (CNCs) promising drug delivery vectors. Herein we report the synthesis of folic acid-conjugated CNCs for the targeted delivery of chemotherapeutic agents to folate receptor-pos. cancer cells. Folate receptor-mediated cellular binding/uptake of the conjugate was demonstrated on human (DBTRG-05MG, H4) and rat (C6) brain tumor cells. Folate receptor expression of the cells was verified by immunofluorescence staining. Cellular binding/uptake of the conjugate by DBTRG-05MG, H4, and C6 cells was 1452, 975, and 46 times higher, resp., than that of nontargeted CNCs. The uptake mechanism was detd. by preincubation of the cells with the uptake inhibitors chlorpromazine or genistein. DBTRG-05MG and C6 cells internalized the conjugate primarily via caveolae-mediated endocytosis, whereas H4 cells internalized the conjugate primarily via clathrin-mediated endocytosis.
- 38Anas, A.; Okuda, T.; Kawashima, N.; Nakayama, K.; Itoh, T.; Ishikawa, M.; Biju, V. Clathrin-Mediated Endocytosis of Quantum Dot- Peptide Conjugates in Living Cells. ACS Nano 2009, 3 (8), 2419– 2429, DOI: 10.1021/nn900663r38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpsFSjs7w%253D&md5=14b3cc5a3d684f65bee7e36d560d837dClathrin-Mediated Endocytosis of Quantum Dot-Peptide Conjugates in Living CellsAnas, Abdulaziz; Okuda, Tetsuya; Kawashima, Nagako; Nakayama, Kenichi; Itoh, Tamitake; Ishikawa, Mitsuru; Biju, VasudevanpillaiACS Nano (2009), 3 (8), 2419-2429CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Efficient intracellular delivery of quantum dots (QDs) and unravelling the mechanism underlying the intracellular delivery are essential for advancing the applications of QDs toward in vivo imaging and therapeutic interventions. Here, we show that clathrin-mediated endocytosis is the most important pathway for the intracellular delivery of peptide-conjugated QDs. We selected an insect neuropeptide, namely, allatostatin (AST1, APSGAQRLYG FGL-NH2), conjugated it with CdSe-ZnS QDs, and investigated the intracellular delivery of the conjugate in living cells such as human epidermoid ovarian carcinoma cells (A431) and mouse embryonic fibroblast cells (3T3). We selected AST1 to investigate the intracellular delivery of QDs because we recently found it to be efficient for delivering QDs in living mammalian cells. Also, the receptors of AST1 in insects show functional and sequence similarity to G-protein-coupled galanin receptors in mammals. We employed flow cytometry and fluorescence microscopy and investigated the contributions of clathrin-mediated endocytosis, receptor-mediated endocytosis, and charge-based cell penetration or transduction to the intracellular delivery of QD-AST1 conjugates. Interestingly, the intracellular delivery was suppressed by ∼57% when we inhibited the regulatory enzyme phosphoinositide 3-kinase (PI3K) with wortmannin and blocked the formation of clathrin-coated vesicles. In parallel, we investigated clathrin-mediated endocytosis by colocalizing QD560-labeled clathrin heavy-chain antibody and QD605-AST1. We also estd. galanin receptor-mediated endocytosis of QD-AST1 at <10% by blocking the cells with a galanin antagonist and transduction at <30% by both removing the charge of the peptide due to arginine and suppressing the cell-surface charge due to glycosaminoglycan. In short, the current work shows that multiple pathways are involved in the intracellular delivery of peptide-conjugated QDs, among which clathrin-mediated endocytosis is the most important.
- 39Hua, S.; de Matos, M. B. C.; Metselaar, J. M.; Storm, G. Current Trends and Challenges in the Clinical Translation of Nanoparticulate Nanomedicines: Pathways for Translational Development and Commercialization. Front Pharmacol 2018, 9, 790, DOI: 10.3389/fphar.2018.0079039https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXis1ert7c%253D&md5=cb5739d5b68c67add2a5baded94fa973Current trends and challenges in the clinical translation of nanoparticulate nanomedicines: pathways for translational development and commercializationHua, Susan; de Matos, Maria B. C.; Metselaar, Josbert M.; Storm, GertFrontiers in Pharmacology (2018), 9 (), 790/1-790/14CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)A review. The use of nanotechnol. in medicine has the potential to have a major impact on human health for the prevention, diagnosis, and treatment of diseases. One particular aspect of the nanomedicine field which has received a great deal of attention is the design and development of nanoparticulate nanomedicines (NNMs) for drug delivery (i.e., drug-contg. nanoparticles). NNMs are intended to deliver drugs via various mechanisms: solubilization, passive targeting, active targeting, and triggered release. The NNM approach aims to increase therapeutic efficacy, decrease the therapeutically ED, and/or reduce the risk of systemic side effects. In order to move a NNM from the bench to the bedside, several exptl. challenges need to be addressed. This review will discuss the current trends and challenges in the clin. translation of NNMs as well as the potential pathways for translational development and commercialization. Key issues related to the clin. development of NNMs will be covered, including biol. challenges, large-scale manufg., biocompatibility and safety, intellectual property (IP), government regulations, and overall cost-effectiveness in comparison to current therapies. These factors can impose significant hurdles limiting the appearance of NNMs on the market, irrelevant of whether they are therapeutically beneficial or not.
- 40Ratajczak, J.; Joffraud, M.; Trammell, S. A. J.; Ras, R.; Canela, N.; Boutant, M.; Kulkarni, S. S.; Rodrigues, M.; Redpath, P.; Migaud, M. E.; Auwerx, J.; Yanes, O.; Brenner, C.; Canto, C. Nrk1 Controls Nicotinamide Mononucleotide and Nicotinamide Riboside Metabolism in Mammalian Cells. Nat. Commun. 2016, 7 (1), 13103, DOI: 10.1038/ncomms1310340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1GnurnN&md5=9c26093d3ba216924341ecf507a03455NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cellsRatajczak, Joanna; Joffraud, Magali; Trammell, Samuel A. J.; Ras, Rosa; Canela, Nuria; Boutant, Marie; Kulkarni, Sameer S.; Rodrigues, Marcelo; Redpath, Philip; Migaud, Marie E.; Auwerx, Johan; Yanes, Oscar; Brenner, Charles; Canto, CarlesNature Communications (2016), 7 (), 13103CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)NAD+ is a vital redox cofactor and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Supplementation with NAD+ precursors, such as NMN (NMN) or nicotinamide riboside (NR), protects against metabolic disease, neurodegenerative disorders and age-related physiol. decline in mammals. Here we show that nicotinamide riboside kinase 1 (NRK1) is necessary and rate-limiting for the use of exogenous NR and NMN for NAD+ synthesis. Using genetic gain- and loss-of-function models, we further demonstrate that the role of NRK1 in driving NAD+ synthesis from other NAD+ precursors, such as nicotinamide or nicotinic acid, is dispensable. Using stable isotope-labeled compds., we confirm NMN is metabolized extracellularly to NR that is then taken up by the cell and converted into NAD+. Our results indicate that mammalian cells require conversion of extracellular NMN to NR for cellular uptake and NAD+ synthesis, explaining the overlapping metabolic effects obsd. with the two compds.
- 41McReynolds, M. R.; Chellappa, K.; Baur, J. A. Age-Related NAD+ Decline. Exp. Gerontol. 2020, 134, 110888, DOI: 10.1016/j.exger.2020.11088841https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXks1Gmt78%253D&md5=d88e2638f943d89208c56096dc86aa82Age-related NAD+ declineMcReynolds, Melanie R.; Chellappa, Karthikeyani; Baur, Joseph A.Experimental Gerontology (2020), 134 (), 110888CODEN: EXGEAB; ISSN:0531-5565. (Elsevier)NAD (NAD+) is an essential metabolite that is reported to decline in concn. in tissues of aged animals. Strategies to increase NAD+ availability have shown promise in treating many conditions in rodents, including age-related degeneration, which has in turn driven intense interest in the effects of supplements on human health. However, many aspects of NAD+ metab. remain poorly understood, and human data are limited. Here, we discuss the state of the evidence for an age-related decline in NAD+, along with potential mechanistic explanations, including increased consumption or decreased synthesis of NAD+ and changes in the compn. of cells or tissues with age. Key challenges for the field involve the development of better tools to resolve information on the NAD+ content of specific cells and subcellular compartments as well as detg. the threshold levels at which NAD+ depletion triggers physiol. consequences in different tissues. Understanding how NAD+ metab. changes with age in humans may ultimately allow the design of more targeted strategies to maintain its availability, such as inhibition of key consumers in specific tissues or direct delivery of precursors to sites of deficiency. In the meantime, human clin. trials with oral supplements are poised to provide some of the first direct evidence as to whether increasing NAD+ availability can impact human physiol. Thus, it is an exciting time for NAD+ research, with much remaining to be learned in terms of both basic biol. and potential therapeutic applications.
- 42Yoshino, J.; Baur, J. A.; Imai, S.-I. NAD+ Intermediates: The Biology and Therapeutic Potential of Nmn and Nr. Cell Metab. 2018, 27 (3), 513– 528, DOI: 10.1016/j.cmet.2017.11.00242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvF2js7%252FP&md5=7cf208aa6b5442fb0a23981b72a42d57NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NRYoshino, Jun; Baur, Joseph A.; Imai, Shin-ichiroCell Metabolism (2018), 27 (3), 513-528CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)Research on the biol. of NAD+ has been gaining momentum, providing many crit. insights into the pathogenesis of age-assocd. functional decline and diseases. In particular, two key NAD+ intermediates, nicotinamide riboside (NR) and NMN (NMN), have been extensively studied over the past several years. Supplementing these NAD+ intermediates has shown preventive and therapeutic effects, ameliorating age-assocd. pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD+ intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD+ metab. to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclin. results can be translated to improve human health.
- 43Cogger, V. C.; Hunt, N. J.; Le Couteur, D. G. Fenestrations in the Liver Sinusoidal Endothelial Cell. In The Liver: Biology and Pathobiology, 6th ed.; Arias, I. M., Alter, H. J., Boyer, J. L., Cohen, D. E., Shafritz, D. A., Thorgeirsson, S. S., Wolkoff, A. W., Eds.; Wiley-Blackwell: Hoboken, NJ, 2020; pp 435– 443.There is no corresponding record for this reference.
- 44Mohamad, M.; Mitchell, S. J.; Wu, L. E.; White, M. Y.; Cordwell, S. J.; Mach, J.; Solon-Biet, S. M.; Boyer, D.; Nines, D.; Das, A.; Catherine Li, S.-Y.; Warren, A.; Hilmer, S. N.; Fraser, R.; Sinclair, D. A.; Simpson, S. J.; Cabo, R.; Le Couteur, D. G.; Cogger, V. C. Ultrastructure of the Liver Microcirculation Influences Hepatic and Systemic Insulin Activity and Provides a Mechanism for Age-Related Insulin Resistance. Aging Cell 2016, 15 (4), 706– 715, DOI: 10.1111/acel.1248144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmtlSitb0%253D&md5=c749cd7bbfb4cbaa44d5cf0284be60f4Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistanceMohamad, Mashani; Mitchell, Sarah Jayne; Wu, Lindsay Edward; White, Melanie Yvonne; Cordwell, Stuart James; Mach, John; Solon-Biet, Samantha Marie; Boyer, Dawn; Nines, Dawn; Das, Abhirup; Catherine Li, Shi-Yun; Warren, Alessandra; Hilmer, Sarah Nicole; Fraser, Robin; Sinclair, David Andrew; Simpson, Stephen James; de Cabo, Rafael; Le Couteur, David George; Cogger, Victoria CarrollAging Cell (2016), 15 (4), 706-715CODEN: ACGECQ; ISSN:1474-9718. (Wiley-Blackwell)Summary : While age-related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole-body insulin handling and its role in age-related changes in insulin homeostasis is largely unknown. Here, we show that patent pores called 'fenestrations' are essential for insulin transfer across the liver sinusoidal endothelium and that age-related loss of fenestrations causes an impaired insulin clearance and hyperinsulinemia, induces hepatic insulin resistance, impairs hepatic insulin signaling, and deranges glucose homeostasis. To further define the role of fenestrations in hepatic insulin signaling without any of the long-term adaptive responses that occur with aging, we induced acute defenestration using poloxamer 407 (P407), and this replicated many of the age-related changes in hepatic glucose and insulin handling. Loss of fenestrations in the liver sinusoidal endothelium is a hallmark of aging that has previously been shown to cause deficits in hepatic drug and lipoprotein metab. and now insulin. Liver defenestration thus provides a new mechanism that potentially contributes to age-related insulin resistance.
- 45Fraser, J. A.; Kemp, S.; Young, L.; Ross, M.; Prach, M.; Hutchison, G. R.; Malone, E. Silver Nanoparticles Promote the Emergence of Heterogeneic Human Neutrophil Sub-Populations. Sci. Rep 2018, 8 (1), 7506– 14, DOI: 10.1038/s41598-018-25854-245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MfjtFyntQ%253D%253D&md5=be4d9d6cac0bc9995326c79e2c03da13Silver nanoparticles promote the emergence of heterogeneic human neutrophil sub-populationsFraser Jennifer A; Kemp Sadie; Young Lesley; Ross Mark; Prach Morag; Hutchison Gary R; Malone EvaScientific reports (2018), 8 (1), 7506 ISSN:.Neutrophil surveillance is central to nanoparticle clearance. Silver nanoparticles (AgNP) have numerous uses, however conflicting evidence exists as to their impact on neutrophils and whether they trigger damaging inflammation. Neutrophil's importance in innate defence and regulating immune networks mean it's essential we understand AgNP's impact on neutrophil function. Human neutrophil viability following AgNP or Ag Bulk treatment was analysed by flow cytometry and AnV/PI staining. Whilst AgNP exposure did not increase the total number of apoptotic neutrophils, the number of late apoptotic neutrophils was increased, suggesting AgNP increase transit through apoptosis. Mature (CD16(bright)/CD62L(bright)), immature (CD16(dim)/CD62L(bright)) and apoptotic (CD16(dim)/CD62L(dim)) neutrophil populations were evident within isolated neutrophil preparations. AgNP exposure significantly reduced CD62L staining of CD16(bright)/CD62L(bright) neutrophils, and increased CD16 staining of CD16(dim)/CD62L(bright) populations, suggesting AgNPs trigger neutrophil activation and maturation, respectively. AgNP exposure dramatically increased IL-8, yet not classical pro-inflammatory cytokine release, suggesting AgNP triggers neutrophil activation, without pro-inflammation or damaging, necrotic cell death. For the first time, we show AgNPs differentially affect distinct sub-populations of circulating human neutrophils; activating mature neutrophils with the emergence of CD16(bright)/CD62L(dim) neutrophils. This may stimulate particle clearance without harmful inflammation, challenging previous assumptions that silver nanomaterials induce neutrophil toxicity and damaging inflammatory responses.
- 46Friedman, S. L. Liver Fibrosis - From Bench to Bedside. J. Hepatol. 2003, 38, 38– 53, DOI: 10.1016/S0168-8278(02)00429-4There is no corresponding record for this reference.
- 47Poynard, T.; Bedossa, P.; Opolon, P. Natural History of Liver Fibrosis Progression in Patients with Chronic Hepatitis C. Lancet 1997, 349 (9055), 825– 832, DOI: 10.1016/S0140-6736(96)07642-847https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3js1ymug%253D%253D&md5=90ead48b73f318e22310622fa7e710d5Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groupsPoynard T; Bedossa P; Opolon PLancet (London, England) (1997), 349 (9055), 825-32 ISSN:0140-6736.BACKGROUND: Our aim was to assess the natural history of liver fibrosis progression in hepatitis C and the factors associated with this progression. METHODS: We recruited 2235 patients from the Observatoire de l'Hepatite C (OBSVIRC) population, the Cohorte Hepatite C Pitie-Salpetriere (DOSVIRC) population, and the original METAVIR population. All the patients had a biopsy sample compatible with chronic hepatitis C as assessed by the METAVIR scoring system (grades the stage of fibrosis on a five-point scale, F0 = no fibrosis, F4 = cirrhosis, and histological activity on a four-point scale, A0 = no activity, A3 = severe activity). No patient had received interferon treatment before the liver biopsy sample was obtained. We assessed the effect of nine factors on fibrosis progression: age at biopsy; estimated duration of infection; sex; age at infection; alcohol consumption; hepatitis C virus C (HCV) genotype; HCV viraemia; cause of infection; and histological activity grade. We defined fibrosis progression per year as the ratio between fibrosis stage in METAVIR units and the duration of infection (1 unit = one stage, 4 units = cirrhosis). FINDINGS: The median rate of fibrosis progression per year was 0.133 fibrosis unit (95% CI 0.125-0.143), which was similar to the estimates from previous studies (0.146 to 0.154). Three independent factors were associated with an increased rate of fibrosis progression: age at infection older than 40 years, daily alcohol consumption of 50 g or more, and male sex. There was no association between fibrosis progression and HCV genotype. The median estimated duration of infection for progression to cirrhosis was 30 years (28-32), ranging from 13 years in men infected after the age of 40 to 42 years in women who did not drink alcohol and were infected before the age of 40. Without treatment, 377 (33%) patients had an expected median time to cirrhosis of less than 20 years, and 356 (31%) will never progress to cirrhosis or will not progress for at least 50 years. INTERPRETATION: The host factors of ageing, alcohol consumption, and male sex have a stronger association with fibrosis progression than virological factors in HCV infection.
- 48Desmoulière, A.; Darby, I. A.; Gabbiani, G. Normal and Pathologic Soft Tissue Remodeling: Role of the Myofibroblast, with Special Emphasis on Liver and Kidney Fibrosis. Lab. Invest. 2003, 83 (12), 1689– 1707, DOI: 10.1097/01.LAB.0000101911.53973.9048https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3sngvVKnsw%253D%253D&md5=fbe4824d102001f9e540929c20a38897Normal and pathologic soft tissue remodeling: role of the myofibroblast, with special emphasis on liver and kidney fibrosisDesmouliere Alexis; Darby Ian A; Gabbiani GiulioLaboratory investigation; a journal of technical methods and pathology (2003), 83 (12), 1689-707 ISSN:0023-6837.There is no expanded citation for this reference.
- 49Glancy, D.; Zhang, Y.; Wu, J. L. Y.; Ouyang, B.; Ohta, S.; Chan, W. C. W. Characterizing the Protein Corona of Sub-10 Nm Nanoparticles. J. Controlled Release 2019, 304, 102– 110, DOI: 10.1016/j.jconrel.2019.04.02349https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpsVyntL0%253D&md5=a07fab0169aaa31fc95c1778a252c9a9Characterizing the protein corona of sub-10 nm nanoparticlesGlancy, Dylan; Zhang, Yuwei; Wu, Jamie L. Y.; Ouyang, Ben; Ohta, Seiichi; Chan, Warren C. W.Journal of Controlled Release (2019), 304 (), 102-110CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)Studies into the interactions of serum proteins with nanoparticles are typically performed using nanoparticles that are larger than the size of proteins. Due to this size discrepancy, adsorbed proteins are commonly depicted as a globular structure surrounding a nanoparticle. Here, we asked how we should view nanoparticle-protein complexes when the nanoparticles are of similar size or smaller than the proteins with which they interact. We showed that nanoparticles can serve as a cargo on a protein rather than as a carrier of the protein in a size-dependent manner. This can occur when nanoparticles are below 10 nm in diam. We discovered that when the nanoparticle is a cargo on the protein, the binding of the protein to the receptor target is minimally affected in contrast to the nanoparticle serving as a carrier. Our study should change how we view and describe nanoparticle-protein complexes when the nanoparticles involved are equal in size or smaller than proteins.
- 50Lundqvist, M.; Stigler, J.; Elia, G.; Lynch, I.; Cedervall, T.; Dawson, K. A. Nanoparticle Size and Surface Properties Determine the Protein Corona with Possible Implications for Biological Impacts. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (38), 14265– 14270, DOI: 10.1073/pnas.080513510550https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1SgtrvJ&md5=a1bb38c51fdbdb83a3c0addf245d4280Nanoparticle size and surface properties determine the protein corona with possible implications for biological impactsLundqvist, Martin; Stigler, Johannes; Elia, Giuliano; Lynch, Iseult; Cedervall, Tommy; Dawson, Kenneth A.Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (38), 14265-14270,S14265/1-S14265/11CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Nanoparticles in a biol. fluid (plasma, or otherwise) assoc. with a range of biopolymers, esp. proteins, organized into the "protein corona" that is assocd. with the nanoparticle and continuously exchanging with the proteins in the environment. Methodologies to det. the corona and to understand its dependence on nanomaterial properties are likely to become important in bionanoscience. Here, we study the long-lived ("hard") protein corona formed from human plasma for a range of nanoparticles that differ in surface properties and size. Six different polystyrene nanoparticles were studied: three different surface chemistries (plain PS, carboxyl-modified, and amine-modified) and two sizes of each (50 and 100 nm), enabling us to perform systematic studies of the effect of surface properties and size on the detailed protein coronas. Proteins in the corona that are conserved and unique across the nanoparticle types were identified and classified according to the protein functional properties. Remarkably, both size and surface properties were found to play a very significant role in detg. the nanoparticle coronas on the different particles of identical materials. We comment on the future need for scientific understanding, characterization, and possibly some addnl. emphasis on stds. for the surfaces of nanoparticles.
- 51Walkey, C. D.; Olsen, J. B.; Guo, H.; Emili, A.; Chan, W. C. W. Nanoparticle Size and Surface Chemistry Determine Serum Protein Adsorption and Macrophage Uptake. J. Am. Chem. Soc. 2012, 134 (4), 2139– 2147, DOI: 10.1021/ja208433851https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1Gls7vN&md5=99fda4a9a3d7af67b0d6de0b83e526cfNanoparticle Size and Surface Chemistry Determine Serum Protein Adsorption and Macrophage UptakeWalkey, Carl D.; Olsen, Jonathan B.; Guo, Hongbo; Emili, Andrew; Chan, Warren C. W.Journal of the American Chemical Society (2012), 134 (4), 2139-2147CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Delivery and toxicity are crit. issues facing nanomedicine research. Currently, there is limited understanding and connection between the physicochem. properties of a nanomaterial and its interactions with a physiol. system. As a result, it remains unclear how to optimally synthesize and chem. modify nanomaterials for in vivo applications. It has been suggested that the physicochem. properties of a nanomaterial after synthesis, known as its "synthetic identity", are not what a cell encounters in vivo. Adsorption of blood components and interactions with phagocytes can modify the size, aggregation state, and interfacial compn. of a nanomaterial, giving it a distinct "biol. identity". Here, we investigate the role of size and surface chem. in mediating serum protein adsorption to gold nanoparticles and their subsequent uptake by macrophages. Using label-free liq. chromatog. tandem mass spectrometry, we find that over 70 different serum proteins are heterogeneously adsorbed to the surface of gold nanoparticles. The relative d. of each of these adsorbed proteins depends on nanoparticle size and poly(ethylene glycol) grafting d. Variations in serum protein adsorption correlate with differences in the mechanism and efficiency of nanoparticle uptake by a macrophage cell line. Macrophages contribute to the poor efficiency of nanomaterial delivery into diseased tissues, redistribution of nanomaterials within the body, and potential toxicity. This study establishes principles for the rational design of clin. useful nanomaterials.
- 52Fischer, H. C.; Liu, L.; Pang, K. S.; Chan, W. C. W. Pharmacokinetics of Nanoscale Quantum Dots: InVivo Distribution, Sequestration, and Clearance in the Rat. Adv. Funct. Mater. 2006, 16 (10), 1299– 1305, DOI: 10.1002/adfm.20050052952https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XntFGnurw%253D&md5=e5735bcaeeef5c5d01579dbb4c755be0Pharmacokinetics of nanoscale quantum dots: in vivo distribution, sequestration, and clearance in the ratFischer, Hans C.; Liu, Lichuan; Pang, K. Sandy; Chan, Warren C. W.Advanced Functional Materials (2006), 16 (10), 1299-1305CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)Advances in nanotechnol. research on quantum dots (QDs)-water sol. ZnS-capped, CdSe fluorescent semiconductor nanocrystals-for in vivo biomedical applications have prompted a close scrutiny of the behavior of nanostructures in vivo. Data pertaining to pharmacokinetics and toxicity will undoubtedly assist in designing better in vivo nanostructure contrast agents or therapies. In vivo kinetics, clearance, and metab. of semiconductor QDs are characterized following their i.v. dosing in Sprague-Dawley rats. The QDs coated with the org. mol. mercaptoundecanoic acid and crosslinked with lysine (denoted as QD-LM) are cleared from plasma with a clearance of 0.59±0.16 mL min-1 kg-1. A higher clearance (1.23±0.22 mL min-1 kg-1) exists when the QDs are conjugated to bovine serum albumin (QD-BSA, P <.05). The biodistribution between these two QDs is also different. The liver takes up 40% of the QD-LM dose and 99% of QD-BSA dose after 90 min. Small amts. of both QDs appear in the spleen, kidney, and bone marrow. However, QDs are not detected in feces or urine for up to ten days after i.v. dosing.
- 53Poon, W.; Zhang, Y.-N.; Ouyang, B.; Kingston, B. R.; Wu, J. L. Y.; Wilhelm, S.; Chan, W. C. W. Elimination Pathways of Nanoparticles. ACS Nano 2019, 13 (5), 5785– 5798, DOI: 10.1021/acsnano.9b0138353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnsV2rtb4%253D&md5=c0d48a288db0048614df3db0e59ceaf9Elimination Pathways of NanoparticlesPoon, Wilson; Zhang, Yi-Nan; Ouyang, Ben; Kingston, Benjamin R.; Wu, Jamie L. Y.; Wilhelm, Stefan; Chan, Warren C. W.ACS Nano (2019), 13 (5), 5785-5798CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Understanding how nanoparticles are eliminated from the body is required for their successful clin. translation. Many promising nanoparticle formulations for in vivo medical applications are large (>5.5 nm) and nonbiodegradable, so they cannot be eliminated renally. A proposed pathway for these nanoparticles is hepatobiliary elimination, but their transport has not been well-studied. Here, we explored the barriers that detd. the elimination of nanoparticles through the hepatobiliary route. The route of hepatobiliary elimination is usually through the following pathway: (1) liver sinusoid, (2) space of Disse, (3) hepatocytes, (4) bile ducts, (5) intestines, and (6) out of the body. We discovered that the interaction of nanoparticles with liver nonparenchymal cells (e.g., Kupffer cells and liver sinusoidal endothelial cells) dets. the elimination fate. Each step in the route contains cells that can sequester and chem. or phys. alter the nanoparticles, which influences their fecal elimination. We showed that the removal of Kupffer cells increased fecal elimination by >10 times. Combining our results with those of prior studies, we can start to build a systematic view of nanoparticle elimination pathways as it relates to particle size and other design parameters. This is crit. to engineering medically useful and translatable nanotechnologies.
- 54Loeschner, K.; Hadrup, N.; Qvortrup, K.; Larsen, A.; Gao, X.; Vogel, U.; Mortensen, A.; Lam, H. R.; Larsen, E. H. Distribution of Silver in Rats Following 28 Days of Repeated Oral Exposure to Silver Nanoparticles or Silver Acetate. Part. Fibre Toxicol. 2011, 8 (1), 18, DOI: 10.1186/1743-8977-8-1854https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpt1Grsbg%253D&md5=1eb34e198f982a93858b44c8e0e97ee2Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetateLoeschner, Katrin; Hadrup, Niels; Qvortrup, Klaus; Larsen, Agnete; Gao, Xueyun; Vogel, Ulla; Mortensen, Alicja; Lam, Henrik Rye; Larsen, Erik H.Particle and Fibre Toxicology (2011), 8 (), 18CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)Background: The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs) and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food and food contact materials. Results: AgNPs were synthesized with a size distribution of 14 ± 4 nm in diam. (90% of the nanoparticle vol.) and stabilized in aq. suspension by the polymer polyvinylpyrrolidone (PVP). The AgNPs remained stable throughout the duration of the 28-day oral toxicity study in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the abs. silver concns. in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of AgNPs. Besides the intestinal system, the largest silver concns. were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallog. (AMG) staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or AgAc. Using transmission electron microscopy (TEM), nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy it was shown that the granules in lysosomes consisted of silver, selenium, and sulfur for both AgNP and AgAc exposed rats. The diam. of the deposited granules was in the same size range as that of the administered AgNPs. No silver granules were detected by TEM in the liver. Conclusions: The results of the present study demonstrate that the organ distribution of silver was similar when AgNPs or AgAc were administered orally to rats. The presence of silver granules contg. selenium and sulfur in the intestinal wall of rats exposed to either of the silver forms suggests a common mechanism of their formation. Addnl. studies however, are needed to gain further insight into the underlying mechanisms of the granule formation, and to clarify whether AgNPs dissolve in the gastrointestinal system and/or become absorbed and translocate as intact nanoparticles to organs and tissues.
- 55Barzilai, N.; Crandall, J. P.; Kritchevsky, S. B.; Espeland, M. A. Metformin as a Tool to Target Aging. Cell Metab. 2016, 23 (6), 1060– 1065, DOI: 10.1016/j.cmet.2016.05.01155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xpt1ens7w%253D&md5=ca94d0e30dadc25aa3a45109b0442669Metformin as a Tool to Target AgingBarzilai, Nir; Crandall, Jill P.; Kritchevsky, Stephen B.; Espeland, Mark A.Cell Metabolism (2016), 23 (6), 1060-1065CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)Aging has been targeted by genetic and dietary manipulation and by drugs in order to increase lifespan and health span in numerous models. Metformin, which has demonstrated protective effects against several age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial, as the initial step in the development of increasingly effective next-generation drugs.
- 56Knowler, W. C.; Barrett-Connor, E.; Fowler, S. E.; Hamman, R. F.; Lachin, J. M.; Walker, E. A.; Nathan, D. M. Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin. N. Engl. J. Med. 2002, 346 (6), 393– 403, DOI: 10.1056/NEJMoa01251256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhtVWqurc%253D&md5=fe29c42a032eda9166ffa65f0094eba2Reduction in the incidence of type 2 diabetes with lifestyle intervention or metforminKnowler, William C.; Barrett-Connor, Elizabeth; Fowler, Sarah E.; Hamman, Richard F.; Lachin, John M.; Walker, Elizabeth A.; Nathan, David M.; Bray, G. A.; Culbert, I. W.; Champagne, C. M.; Crow, M. D.; Dawson, L.; Eberhardt, B.; Greenway, F. L.; Guillory, F. G.; Herbert, A. A.; Jeffirs, M. L.; Joyce, K.; Kennedy, B. M.; Lovejoy, J. C.; Mancuso, S.; Melancon, L. E.; Morris, L. H.; Reed, L.; Perault, J.; Rau, K.; Ryan, D. H.; Sanford, D. A.; Smith, K. G.; Smith, L. L.; Smith, S. R.; St. Amant, J. A.; Terry, M.; Tucker, E.; Tulley, R. T.; Vicknair, P. C.; Williamson, D.; Zachwieja, J. J.; Ehrmann, D. A.; Matulik, M. J.; Clark, B.; Collins, D. A.; Czech, K. B.; DeSandre, C.; Geiger, G.; Frief, S.; Harding-Clay, B.; Hilbrich, R. M.; Le Grange, D.; McCormick, M. R.; McNabb, W. L.; Polonsky, K. S.; Sauter, N. P.; Semenske, A. R.; Stepp, K. A.; Tobian, J. A.; Watson, P. G.; Mendoza, J. T.; Smith, K. A.; Caro, J.; Goldstein, B.; Lark, C.; Menefee, L.; Murphy, L.; Pepe, C.; Spandorfer, J. M.; Goldberg, R. B.; Rowe, P.; Calles, J.; Casanova, P.; Donahue, R. P.; Florez, H. J.; Giannella, A.; Larreal, G.; McLymont, V.; Mendez, J.; O'Hara, P.; Ojito, J.; Prineas, R.; Saab, P. G.; Haffner, S. M.; Montez, M. G.; Lorenzo, C.; Miettinen, H.; Mobley, C. M.; Mykkanen, L. A.; Rozek, M. M.; Hamman, R. F.; Nash, P. V.; Testaverde, L.; Anderson, D. R.; Ballonoff, L. B.; Bouffard, A.; Calonge, B. N.; Farago, M.; Georgitis, W. J.; Hill, J. O.; Hoyer, S. R.; Jortberg, B. T.; Merenich, J. A.; Miller, M.; Regensteiner, J. G.; Seagle, H. M.; Smith, C. M.; Steinke, S. C.; Van Dorsten, B.; Horton, E. S.; Lawton, K. E.; Arky, R. A.; Bryant, M.; Burke, J. P.; Caballero, E.; Callaghan, K. M.; Devlin, D.; Franklin, T.; Ganda, O. P.; Goebel-Fabbri, A. E.; Harris, M.; Jackson, S. D.; Jacobsen, A. M.; Kula, L. M.; Kocal, M.; Ledbury, S.; Malloy, M. A.; Mullooly, C.; Nicosia, M.; Oldmixon, C. F.; Pan, J.; Pomposelli, C.; Quitongan, M.; Rubtchinsky, S.; Schweizer, D.; Seely, E. W.; Simonson, D.; Smith, F.; Solomon, C. G.; Tyson, J.; Warram, J.; Kahn, S. E.; Montgomery, B. K.; Alger, M.; Allen, E.; Barrett, T.; Bhanji, D.; Cowan, J.; Cullen, J.; Fujimoto, W. Y.; Katz, B.; Knopp, R. H.; Lipkin, E. W.; Marr, M.; McCann, B. S.; Palmer, J. P.; Schwartz, R. S.; Uyema, D.; Kitabachi, A. E.; Murphy, M. E.; Applegate, W. B.; Bryer-Ash, M.; Coble, J. H.; Crisler, A.; Cunningham, G.; Franklin, A. W.; Frieson, S. L.; Green, D. L.; Imseis, R.; Kennedy, C. L.; Lambeth, H. C.; Latif, K. A.; Lichtermann, L. C.; McIntyre, M. D.; Nault, J. D.; Oktaei, H.; O'Toole, M. L.; Ricks, H.; Rutledge, L. M. K.; Schussler, S. C.; Sherman, A. R.; Smith, C. M.; Soberman, J. E.; Stewart, K. J.; Van Brunt, D. L.; Williams-Cleaves, B. J.; Johnson, M. K.; Behrends, C.; Cook, M. L.; Fitzgibbon, M.; Giles, M. M.; Heard, D.; Johnson, C.; Larsen, D.; Lowe, A.; Lyman, M.; McPherson, D.; Molitch, M. E.; Pitts, T.; Reinhart, R.; Roston, S.; Schinleber, P. A.; Nathan, D. M.; McKitrick, C.; Abbott, K.; Anderson, E.; Bissett, L.; Cagliero, E.; Crowell, S.; Delahanty, L.; Fritz, S.; Hayward, K.; Levina, E.; Michel, T.; Norman, D.; O'Keefe, J.; Poulos, A.; Ronan, L.; Rosal, M.; Salerno, M.; Schneider, M.; Shagensky, C.; Steiner, B.; Turgeon, H.; Young, A.; Olefsky, J. M.; Carrion-Petersen, M. L.; Barrett-Connor, E.; Beltran, M.; Caenepeel-Mills, K.; Edelman, S. V.; Ford, R. O.; Garcia, J.; Hagerty, M.; Henry, R. R.; Hill, M.; Horne, J.; Leos, D.; Matney, J.; Mudaliar, S.; Petersen, G.; Pollard, A.; Polonsky, W.; Szerdi, S.; Torio-Hurley, J.; Vejvoda, K.; Pi-Sunyer, F. X.; Lee, J. E.; Allison, D. B.; Agharanya, N.; Aronoff, N. J.; Baldo, M.; Foo, S. T.; Hagamen, S.; Pal, C.; Parkes, K.; Pena, M.; Van Wye, G. E. H.; Marrero, D. G.; Kukman-Kelly, M. S.; Dorson, Y. F.; Fineberg, S. E.; Guare, J. C.; Hadden, A.; Hills, B.; Ignaut, J. M.; Jackson, M. A.; Kirkman, M. S.; Mather, K.; McAree, G.; Porter, B. D.; Prince, M. J.; Wheeler, M. L.; Ratner, R. E.; Youssef, G.; Shapiro, S.; Bonar, A.; Bronsord, M.; Brown, E.; Cheatham, W. W.; Cola, S.; Comfort, A.; Boggs, G.; Eagle, C.; Evans, C.; Gorman, E.; Johnson, R.; Levetan, C.; Kellum, T.; Lagarda, M.; Nair, A. K.; Passaro, M. D.; Phillips, W.; Saad, M. F.; Budgett, M.; Fahmi, S.; Jinagouda, S. D.; Bernaba, B.; Bodkin, S. L.; Ciobanu, V.; Commisso, R.; Cosenza, C.; Dinh, T.; Gonzalez, M.; Khan, A.; Kumar, D.; Lui, G.; Mehra, V.; Sharma, A.; Soukiazian, S.; Szamos, K.; Tramanian, A.; Vargas, A.; Zambrana, N.; White, N. H.; Santiago, A. S.; Das, S.; Brown, A. L.; Dagogo-Jack, S.; Fisher, E. B.; Hurt, E.; Jones, T.; Kerr, M.; Ryder, L.; Santiago, J. V.; Wernimont, C.; Saudek, C. D.; Bradley, V. L.; Fowlkes, T.; Joseph, H.; Brancati, F. L.; Charleston, J. B.; Clark, J. M.; Horak, K.; Jiggetts, D.; Mosley, H.; Rubin, R. R.; Samuels, A.; Stewart, K. J.; Thomas, L.; Williamson, P.; Schade, D. S.; Adams, K. S.; Atler, L. F.; Bland, A.; Bowling, D. A.; Boyle, P. J.; Burge, M. R.; Butler, L.; Canady, J. L.; Chai, L.; Colleran, K. M.; Guillen, M.; Gonzales, Y.; Gutierrez, M.; Hornbeck, D.; Johannes, C.; Karz, P.; King, C.; Libby, E. N., III; McCalman, R.; Montoya, D. A.; Rassam, A.; Rubinchik, S.; Senter, W.; Shamoon, H.; Brown, J. O.; Adames, J.; Blanco, E.; Cox, L.; Crandall, J. P.; Duffy, H.; Engel, S.; Friedler, A.; Harroun, T.; Howard-Century, C. J.; Kloiber, S.; Longchamp, N.; Pompi, D.; Violino, E.; Walker, E. A.; Wylie-Rosett, J.; Zimmerman, E.; Zonszein, J.; Wing, R. R.; Kramer, M. K.; Barr, S.; Boraz, M. A.; Clifford, L.; Culyba, R.; Frazier, M.; Gilligan, R.; Harris, L.; Harrier, S.; Henderson, W.; Jeffreis, S.; Koenning, G.; Kriska, A. M.; Maholic, K.; Manjoo, Q.; Mullen, M.; Noel, A.; Orchard, T. J.; Orro, A.; Semler, L. N.; Smith, C.; Smith, M.; Stapinski, V.; Viteri, J.; Wilson, T.; Williams, K. V.; Zgibor, J.; Arakaki, R. F.; Latimer, R. W.; Baker-Ladao, N. K.; Beddow, R. M.; Braginsky, R.; Calizar, M.; Dias, L. M.; Durham, N.; Dupont, D. A.; Fukuhara, L. L.; Inouye, J.; Mau, M, K.; Mikami, K.; Mohideen, P.; Odom, S. K.; Sinkuie-Kam, B.; Tokunaga, J. S.; Twiggs, R. U.; Wang, C. Y.; Vita, J.; Knowler, W. C.; Cooeyate, N. J.; Hoskin, M. A.; Percy, C. A.; Acton, K. J.; Andre, V. L.; Antone, S.; Baptisto, N. M.; Barber, R.; Segay, S.; Bennett, P. H.; Benson, M. B.; Beyale, S.; Bird, E. C.; Broussard, B. A.; Chavez, M.; Daeawyma, T. S.; Doughty, M. S.; Duncan, R.; Edgerton, C.; Ghahate, J. M.; Glass, M.; Gohdes, D.; Grant, W.; Hanson, R. L.; Horse, E.; Hughte, G.; Ingraham, L. E.; Jackson, M. C.; Jay, P. A.; Kaskalla, R. S.; Kessler, D.; Kobus, K. M.; Krakoff, J.; Manus, C.; Morgan, T.; Nashboo, Y.; Nelson, J.; Pauk, G. L.; Poirier, S.; Polczynski, E.; Reidy, M.; Roumain, J.; Rowse, D. H.; Roy, R. J.; Sangster, S.; Sewemaenewa, J.; Tonemah, D.; Wilson, C.; Yazzie, M.; Fowler, S.; Brenneman, T.; Abebe, S.; Bain, R.; Bamdad, J.; Callaghan, J.; Edelstein, S. L.; Gao, Y.; Grimes, K. L.; Grover, N.; Hirst, K.; Jones, S.; Jones, T. L.; Katz, R. J.; Lachin, J. M.; Orlosky, R.; Stimpson, C. E.; Suiter, C.; Temprosa, M. G.; Walker-Murray, F. E. M.; Garfield, S.; Eastman, R.; Fradkin, J.; Andres, R.; Engelgau, M. M.; Venkat Narayan, K. M.; Williamson, D. F.; Herman, W. H.; Marcovina, S. M.; Aldrich, A.; Chandler, W. L.; Rautaharju, P. M.; Pemberton, N. T.; Prineas, R.; Rautaharju, F. S. R.; Zhang, Z.; Mayer-Davis, E. J.; Costacou, T.; Martin, M.; Sparks, K. L.; O'Leary, D. H.; Funk, L. R. C.; O'Leary, K. A.; Polak, J. F.; Stamm, E. R.; Scherzinger, A. L.; Wing, R. R.; Gillis, B. P.; Huffmyer, C.; Kriska, A. M.; Venditti, E. M.; Walker, E. A.; Harroun, T.; Ganiats, T. G.; Groessl, E. J.; Beerman, P. R.; David, K. M.; Kaplan, R. M.; Sieber, W. J.; Genuth, S. M.; Cahill, G. F.; Ferris, F. L., III; Gavin, J. R., III; Halter, J. B.; Wittes, J.; Henry, R. R.; Haffner, S. M.; Rubin, R. R.; Montgomery, B. K.; Ratner, R. E.; Herman, W. H.; Kahn, S. E.; Santiago, J. V.; Olefsky, J.; Wing, R. R.; Saudek, C.; Montez, M.; Kramer, K.; Hamman, R. F.; Knowler, W. C.; Goldberg, R. B.; Fujimoto, W. Y.; Charleston, J.; Nathan, D. M.New England Journal of Medicine (2002), 346 (6), 393-403CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Type 2 diabetes affects approx. 8 % of adults in the United States. Some risk factors - elevated plasma glucose concns. in the fasting state and after an oral glucose load, over-wt., and a sedentary lifestyle - are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concns. to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 % wt. loss and at least 150 min of phys. activity per wk. The mean age of the participants was 51 yr, and the mean body-mass index (the wt. in kilograms divided by the square of the height in meters) was 34.0; 68 % were women, and 45 % were members of minority groups. The av. follow-up was 2.8 yr. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and life-style groups, resp. The lifestyle intervention reduced the incidence by 58 % (95 % confidence interval, 48 to 66 %) and metformin by 31 % (95 % confidence interval, 17 to 43 %), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.
- 57Schlender, L.; Martinez, Y. V.; Adeniji, C.; Reeves, D.; Faller, B.; Sommerauer, C.; Al Qur’an, T.; Woodham, A.; Kunnamo, I.; Sönnichsen, A.; Renom-Guiteras, A. Efficacy and Safety of Metformin in the Management of Type 2 Diabetes Mellitus in Older Adults: A Systematic Review for the Development of Recommendations to Reduce Potentially Inappropriate Prescribing. BMC Geriatr. 2017, 17 (S1), 227, DOI: 10.1186/s12877-017-0574-557https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7it1alsQ%253D%253D&md5=e3bc89eff696a895485c158e6bd11de5Efficacy and safety of metformin in the management of type 2 diabetes mellitus in older adults: a systematic review for the development of recommendations to reduce potentially inappropriate prescribingSchlender Lisa; Faller Barbara; Sommerauer Christina; Al Qur'an Thekraiat; Sonnichsen Andreas; Renom-Guiteras Anna; Martinez Yolanda V; Adeniji Charles; Reeves David; Woodham Adrine; Al Qur'an Thekraiat; Kunnamo Ilkka; Renom-Guiteras AnnaBMC geriatrics (2017), 17 (Suppl 1), 227 ISSN:.BACKGROUND: Metformin is usually prescribed as first line therapy for type 2 diabetes mellitus (DM2). However, the benefits and risks of metformin may be different for older people. This systematic review examined the available evidence on the safety and efficacy of metformin in the management of DM2 in older adults. The findings were used to develop recommendations for the electronic decision support tool of the European project PRIMA-eDS. METHODS: The systematic review followed a staged approach, initially searching for systematic reviews and meta-analyses first, and then individual studies when prior searches were inconclusive. The target population was older people (≥65 years old) with DM2. Studies were included if they reported safety or efficacy outcomes with metformin (alone or in combination) for the management of DM2 compared to placebo, usual or no treatment, or other antidiabetics. Using the evidence identified, recommendations were developed using GRADE methodology. RESULTS: Fifteen studies were included (4 intervention and 11 observational studies). In ten studies at least 80% of participants were 65 years or older and 5 studies reported subgroup analyses by age. Comorbidities were reported by 9 studies, cognitive status was reported by 4 studies and functional status by 1 study. In general, metformin showed similar or better safety and efficacy than other specific or non-specific active treatments. However, these findings were mainly based on retrospective observational studies. Four recommendations were developed suggesting to discontinue the use of metformin for the management of DM2 in older adults with risk factors such as age > 80, gastrointestinal complaints during the last year and/or GFR ≤60 ml/min. CONCLUSIONS: On the evidence available, the safety and efficacy profiles of metformin appear to be better, and certainly no worse, than other treatments for the management of DM2 in older adults. However, the quality and quantity of the evidence is low, with scarce data on adverse events such as gastrointestinal complaints or renal failure. Further studies are needed to more reliably assess the benefits and risks of metformin in very old (>80), cognitively and functionally impaired older people.
- 58Dujic, T.; Zhou, K.; Donnelly, L. A.; Tavendale, R.; Palmer, C. N. A.; Pearson, E. R. Association of Organic Cation Transporter 1 with Intolerance to Metformin in Type 2 Diabetes: A Godarts Study. Diabetes 2015, 64 (5), 1786– 1793, DOI: 10.2337/db14-138858https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotFKrs7g%253D&md5=acbe0c4bf9ceab2b10dc22609f248488Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS studyDujic, Tanja; Zhou, Kaixin; Donnelly, Louise A.; Tavendale, Roger; Palmer, Colin N. A.; Pearson, Ewan R.Diabetes (2015), 64 (5), 1786-1793CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)Metformin is the most widely prescribed medication for the treatment of type 2 diabetes (T2D). However, gastrointestinal (GI) side effects develop in ∼25% of patients treated with metformin, leading to the discontinuation of therapy in ∼5% of cases. We hypothesized that reduced transport of metformin via org. cation transporter 1 (OCT1) could increase metformin concn. in the intestine, leading to increased risk of severe GI side effects and drug discontinuation. We compared the phenotype, carriage of reduced-function OCT1 variants, and concomitant prescribing of drugs known to inhibit OCT1 transport in 251 intolerant and 1,915 fully metformin-tolerant T2D patients. We showed that women and older people were more likely to be intolerant to metformin. Concomitant use of medications, known to inhibit OCT1 activity, was assocd. with intolerance (odds ratio [OR] 1.63 [95% CI 1.22-2.17], P = 0.001) as was carriage of two reduced-function OCT1 alleles compared with carriage of one or no deficient allele (OR 2.41 [95% CI 1.48-3.93], P < 0.001). Intolerance was over four times more likely to develop (OR 4.13 [95% CI 2.09-8.16], P < 0.001) in individuals with two reduced-function OCT1 alleles who were treated with OCT1 inhibitors. Our results suggest that reduced OCT1 transport is an important determinant of metformin intolerance.
- 59McCreight, L. J.; Bailey, C. J.; Pearson, E. R. Metformin and the Gastrointestinal Tract. Diabetologia 2016, 59 (3), 426– 435, DOI: 10.1007/s00125-015-3844-959https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFSjs7w%253D&md5=95ff2e424c18b64790ccec3af7ea4adbMetformin and the gastrointestinal tractMcCreight, Laura J.; Bailey, Clifford J.; Pearson, Ewan R.Diabetologia (2016), 59 (3), 426-435CODEN: DBTGAJ; ISSN:0012-186X. (Springer)Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognized as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a no. of actions within the gut. It increases intestinal glucose uptake and lactate prodn., increases GLP-1 concns. and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release prepn. of metformin has recently been shown to improve glycemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects assocd. with metformin intolerance.
- 60Grozio, A.; Mills, K. F.; Yoshino, J.; Bruzzone, S.; Sociali, G.; Tokizane, K.; Lei, H. C.; Cunningham, R.; Sasaki, Y.; Migaud, M. E.; Imai, S.-I. Slc12a8 Is a Nicotinamide Mononucleotide Transporter. Nat. Metab 2019, 1 (1), 47– 57, DOI: 10.1038/s42255-018-0009-460https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXltlOnsL0%253D&md5=ebc0e129508e787bf3d6e5c41684c0bbSlc12a8 is a nicotinamide mononucleotide transporterGrozio, Alessia; Mills, Kathryn F.; Yoshino, Jun; Bruzzone, Santina; Sociali, Giovanna; Tokizane, Kyohei; Lei, Hanyue Cecilia; Cunningham, Richard; Sasaki, Yo; Migaud, Marie E.; Imai, Shin-ichiroNature Metabolism (2019), 1 (1), 47-57CODEN: NMAED6; ISSN:2522-5812. (Springer International Publishing AG)Abstr.: NMN (NMN) is a biosynthetic precursor of NAD (NAD+) known to promote cellular NAD+ prodn. and counteract age-assocd. pathologies assocd. with a decline in tissue NAD+ levels. How NMN is taken up into cells has not been entirely clear. Here we show that the Slc12a8 gene encodes a specific NMN transporter. We find that Slc12a8 is highly expressed and regulated by NAD+ in the mouse small intestine. Slc12a8 knockdown abrogates the uptake of NMN in vitro and in vivo. We further show that Slc12a8 specifically transports NMN, but not nicotinamide riboside, and that NMN transport depends on the presence of sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, which is assocd. with reduced NMN uptake as traced by doubly labeled isotopic NMN. Finally, we observe that Slc12a8 expression is upregulated in the aged mouse ileum, which contributes to the maintenance of ileal NAD+ levels. Our work identifies a specific NMN transporter and demonstrates that Slc12a8 has a crit. role in regulating intestinal NAD+ metab.
- 61Poisson, J.; Lemoinne, S.; Boulanger, C.; Durand, F.; Moreau, R.; Valla, D.; Rautou, P.-E. Liver Sinusoidal Endothelial Cells: Physiology and Role in Liver Diseases. J. Hepatol. 2017, 66 (1), 212– 227, DOI: 10.1016/j.jhep.2016.07.00961https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslehtbzO&md5=cc989b389724edba17a7d931e3c7151aLiver sinusoidal endothelial cells: Physiology and role in liver diseasesPoisson, Johanne; Lemoinne, Sara; Boulanger, Chantal; Durand, Francois; Moreau, Richard; Valla, Dominique; Rautou, Pierre-EmmanuelJournal of Hepatology (2017), 66 (1), 212-227CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells representing the interface between blood cells on the one side and hepatocytes and hepatic stellate cells on the other side. LSECs represent a permeable barrier. Indeed, the assocn. of 'fenestrae', absence of diaphragm and lack of basement membrane make them the most permeable endothelial cells of the mammalian body. They also have the highest endocytosis capacity of human cells. In physiol. conditions, LSECs regulate hepatic vascular tone contributing to the maintenance of a low portal pressure despite the major changes in hepatic blood flow occurring during digestion. LSECs maintain hepatic stellate cell quiescence, thus inhibiting intrahepatic vasoconstriction and fibrosis development. In pathol. conditions, LSECs play a key role in the initiation and progression of chronic liver diseases. Indeed, they become capillarized and lose their protective properties, and they promote angiogenesis and vasoconstriction. LSECs are implicated in liver regeneration following acute liver injury or partial hepatectomy since they renew from LSECs and/or LSEC progenitors, they sense changes in shear stress resulting from surgery, and they interact with platelets and inflammatory cells. LSECs also play a role in hepatocellular carcinoma development and progression, in ageing, and in liver lesions related to inflammation and infection. This review also presents a detailed anal. of the tech. aspects relevant for LSEC anal. including the markers these cells express, the available cell lines and the transgenic mouse models. Finally, this review provides an overview of the strategies available for a specific targeting of LSECs.
- 62Park, K. The Beginning of the End of the Nanomedicine Hype. J. Controlled Release 2019, 305, 221– 222, DOI: 10.1016/j.jconrel.2019.05.04462https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFClu73N&md5=020e62d1a9228f6f84fb0053b4f3b2c7The beginning of the end of the nanomedicine hypePark, KinamJournal of Controlled Release (2019), 305 (), 221-222CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)There is no expanded citation for this reference.
- 63Dai, Q.; Wilhelm, S.; Ding, D.; Syed, A. M.; Sindhwani, S.; Zhang, Y.; Chen, Y. Y.; MacMillan, P.; Chan, W. C. Quantifying the Ligand-Coated Nanoparticle Delivery to Cancer Cells in Solid Tumors. ACS Nano 2018, 12 (8), 8423– 8435, DOI: 10.1021/acsnano.8b0390063https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlaku7zM&md5=98fd65b49025397a7607a2940164e10eQuantifying the Ligand-Coated Nanoparticle Delivery to Cancer Cells in Solid TumorsDai, Qin; Wilhelm, Stefan; Ding, Ding; Syed, Abdullah Muhammad; Sindhwani, Shrey; Zhang, Yuwei; Chen, Yih Yang; MacMillan, Presley; Chan, Warren C. W.ACS Nano (2018), 12 (8), 8423-8435CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Coating the nanoparticle surface with cancer cell recognizing ligands is expected to facilitate specific delivery of nanoparticles to diseased cells in vivo. While this targeting strategy is appealing, no nanoparticle-based active targeting formulation for solid tumor treatment had made it past phase III clin. trials. Here, we quantified the cancer cell-targeting efficiencies of Trastuzumab (Herceptin) and folic acid coated gold and silica nanoparticles in multiple mouse tumor models. Surprisingly, we showed that less than 14 out of 1 million (0.0014% injected dose) i.v. administrated nanoparticles were delivered to targeted cancer cells, and that only 2 out of 100 cancer cells interacted with the nanoparticles. The majority of the intratumoral nanoparticles were either trapped in the extracellular matrix or taken up by perivascular tumor assocd. macrophages. The low cancer cell targeting efficiency and significant uptake by noncancer cells suggest the need to re-evaluate the active targeting process and therapeutic mechanisms using quant. methods. This will be important for developing strategies to deliver emerging therapeutics such as genome editing, nucleic acid therapy, and immunotherapy for cancer treatment using nanocarriers.
- 64Lammers, T.; Ferrari, M. The Success of Nanomedicine. Nano Today 2020, 31, 100853, DOI: 10.1016/j.nantod.2020.10085364https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsl2lsbg%253D&md5=d64b8eb6ea263157348d01fa5cc8a5c0The success of nanomedicineLammers, Twan; Ferrari, MauroNano Today (2020), 31 (), 100853CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)In recent years, the promise and prospects of nanomedicine have been controversially discussed. We here argue that nanomedicine has undeniably been successful, not only academically and preclinically, but also industrially and clin. To ensure that we keep on making progress, we have to move away from over-focusing on nano and on materials, towards more holistic approaches that address real medical problems, in a realistic manner.
- 65Ortega-Ribera, M.; Hunt, N. J.; Gracia-Sancho, J.; Cogger, V. C. The Hepatic Sinusoid in Aging and Disease: Update and Advances from the 20th Liver Sinusoid Meeting. Hepatol Commun. 2020, 4 (7), 1087– 1098, DOI: 10.1002/hep4.151765https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38noslWlsg%253D%253D&md5=d5c7bf8141c354ef65a43d302567288fThe Hepatic Sinusoid in Aging and Disease: Update and Advances From the 20th Liver Sinusoid MeetingOrtega-Ribera Marti; Gracia-Sancho Jordi; Hunt Nicholas J; Cogger Victoria C; Hunt Nicholas J; Cogger Victoria C; Gracia-Sancho JordiHepatology communications (2020), 4 (7), 1087-1098 ISSN:.This is a meeting report of the 2019 Liver Sinusoid Meeting, 20th International Symposium on Cells of the Hepatic Sinusoid, held in Sydney, Australia, in September 2019. The meeting, which was organized by the International Society for Hepatic Sinusoidal Research, provided an update on the recent advances in the field of hepatic sinusoid cells in relation to cell biology, aging, and liver disease, with particular focus on the molecular and cellular targets involved in hepatic fibrosis, nonalcoholic hepatic steatohepatitis, alcoholic liver disease, hepatocellular carcinoma, and cirrhosis. In addition, the meeting highlighted the recent advances in regenerative medicine, targeted nanotechnologies, therapeutics, and novel methodologies.
- 66Wong, X. Y.; Sena-Torralba, A.; Álvarez-Diduk, R.; Muthoosamy, K.; Merkoçi, A. Nanomaterials for Nanotheranostics: Tuning Their Properties According to Disease Needs. ACS Nano 2020, 14 (3), 2585– 2627, DOI: 10.1021/acsnano.9b0813366https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFKrtbo%253D&md5=4e9c710bb2d91696150b0c530e49a01aNanomaterials for Nanotheranostics: Tuning Their Properties According to Disease NeedsWong, Xin Yi; Sena-Torralba, Amadeo; Alvarez-Diduk, Ruslan; Muthoosamy, Kasturi; Merkoci, ArbenACS Nano (2020), 14 (3), 2585-2627CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)A review. Nanotheranostics is one of the biggest scientific breakthroughs in nanomedicine. Most of the currently available diagnosis and therapies are invasive, time-consuming, and assocd. with severe toxic side effects. Nanotheranostics, on the other hand, has the potential to bridge this gap by harnessing the capabilities of nanotechnol. and nanomaterials for combined therapeutics and diagnostics with markedly enhanced efficacy. However, nanomaterial applications in nanotheranostics are still in its infancy. This is due to the fact that each disease has a particular microenvironment with well-defined characteristics, which promotes deeper selection criteria of nanomaterials to meet the disease needs. In this review, we have outlined how nanomaterials are designed and tailored for nanotheranostics of cancer and other diseases such as neurodegenerative, autoimmune (particularly on rheumatoid arthritis), and cardiovascular diseases. The penetrability and retention of a nanomaterial in the biol. system, the therapeutic strategy used, and the imaging mode selected are some of the aspects discussed for each disease. The specific properties of the nanomaterials in terms of feasibility, physicochem. challenges, progress in clin. trials, its toxicity, and their future application on translational medicine are addressed. Our review meticulously and critically examines the applications of nanotheranostics with various nanomaterials, including graphene, across several diseases, offering a broader perspective of this emerging field.
- 67Tang, R.; Xue, J.; Xu, B.; Shen, D.; Sudlow, G. P.; Achilefu, S. Tunable Ultrasmall Visible-to-Extended Near-Infrared Emitting Silver Sulfide Quantum Dots for Integrin-Targeted Cancer Imaging. ACS Nano 2015, 9 (1), 220– 230, DOI: 10.1021/nn507118367https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXks1Omug%253D%253D&md5=40fcd3571d93e27106349d3739d5258eTunable Ultrasmall Visible-to-Extended Near-Infrared Emitting Silver Sulfide Quantum Dots for Integrin-Targeted Cancer ImagingTang, Rui; Xue, Jianpeng; Xu, Baogang; Shen, Duanwen; Sudlow, Gail P.; Achilefu, SamuelACS Nano (2015), 9 (1), 220-230CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)The large size of many near-IR (NIR) fluorescent nanoparticles prevents rapid extravasation from blood vessels and subsequent diffusion to tumors. This confines in vivo uptake to the peritumoral space and results in high liver retention. The authors developed a viscosity modulated approach to synthesize ultrasmall silver sulfide quantum dots (QDs) with distinct tunable light emission from 500 to 1200 nm and a QD core diam. between 1.5 and 9 nm. Conjugation of a tumor-avid cyclic pentapeptide (Arg-Gly-Asp-DPhe-Lys) resulted in monodisperse, water-sol. QDs (hydrodynamic diam. < 10 nm) without loss of the peptide's high binding affinity to tumor-assocd. integrins (KI = 1.8 nM/peptide). Fluorescence and electron microscopy showed that selective integrin-mediated internalization was obsd. only in cancer cells treated with the peptide-labeled QDs, demonstrating that the unlabeled hydrophilic nanoparticles exhibit characteristics of neg. charged fluorescent dye mols., which typically do not internalize in cells. The biodistribution profiles of i.v. administered QDs in different mouse models of cancer reveal an exceptionally high tumor-to-liver uptake ratio, suggesting that the small sized QDs evaded conventional opsonization and subsequent high uptake in the liver and spleen. The seamless tunability of the QDs over a wide spectral range with only a small increase in size, as well as the ease of labeling the bright and noncytotoxic QDs with biomols., provides a platform for multiplexing information, tracking the trafficking of single mols. in cells, and selectively targeting disease biomarkers in living organisms without premature QD opsonization in circulating blood.
- 68Cogger, V. C.; O’Reilly, J. N.; Warren, A.; Le Couteur, D. G. A Standardized Method for the Analysis of Liver Sinusoidal Endothelial Cells and Their Fenestrations by Scanning Electron Microscopy. JoVE 2015, (98), e52698 DOI: 10.3791/52698There is no corresponding record for this reference.
- 69Kang, S. W. S.; Cogger, V. C.; Le Couteur, D. G.; Fu, D. Multiple Cellular Pathways Regulate Lipid Droplet Homeostasis for the Establishment of Polarity in Collagen Sandwich-Cultured Hepatocytes. Am. J. Physiol Cell Physiol 2019, 317 (5), C942– C952, DOI: 10.1152/ajpcell.00051.2019There is no corresponding record for this reference.
- 70Warren, A.; Bertolino, P.; Cogger, V. C.; McLean, A. J.; Fraser, R.; Le Couteur, D. G. Hepatic Pseudocapillarization in Aged Mice. Exp. Gerontol. 2005, 40 (10), 807– 812, DOI: 10.1016/j.exger.2005.06.01270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MrjvVegsQ%253D%253D&md5=775f25282e84bd6f14805d34324908afHepatic pseudocapillarization in aged miceWarren Alessandra; Bertolino Patrick; Cogger Victoria C; McLean Allan J; Fraser Robin; Le Couteur David GExperimental gerontology (2005), 40 (10), 807-12 ISSN:0531-5565.Age-related changes in the hepatic sinusoid of the rat, human and baboons called pseudocapillarization have been discovered and are important because they are considered to be implicated in the pathogenesis of some age-related diseases. In this study, we investigated whether similar changes occur in the livers of old mice. Livers of young (3-4 months) and old (20-24 months) mice were perfusion-fixed and studied using electron microscopy and immunohistochemistry. The thickness of the sinusoidal endothelium was increased in old mice (154+/-4 versus 244+/-8 nm, P<0.001). There was a reduction in fenestrations within the endothelium (porosity decreased from 4.1+/-0.3 to 2.2+/-0.2%, P<0.001). There was perisinusoidal staining with Sirius red in old mice, however, expression of laminin and von Willebrands factor was similar in young and old mice. Novel perisinusoidal fat-engorged stellate cells were found extensively in the old mice. This study confirmed that pseudocapillarization is a widespread aging change in the liver, now documented in several species including the mouse. Mice are an appropriate animal model for studying aging and the hepatic sinusoid.
- 71Miller, D. L.; Yu, I. J.; Genter, M. B. Use of Autometallography in Studies of Nanosilver Distribution and Toxicity. Int. J. Toxicol. 2016, 35 (1), 47– 51, DOI: 10.1177/109158181561660271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvV2jt74%253D&md5=36218bf136e8b4de1bc24d91b49c9d17Use of autometallography in studies of nanosilver distribution and toxicityMiller, David L.; Je, Yu; Genter, Mary BethInternational Journal of Toxicology (2016), 35 (1), 47-51CODEN: IJTOFN; ISSN:1091-5818. (Sage Publications)With the increasing use of and interest in nanoparticles in medicine and technol., the tissue and cell-specific localization of the particles are important considerations when the nanomaterials find their way into biol. systems. This brief communication shows the utility of autometallog. in detg. the location of metal deposition at the light microscopic level. Although primarily focusing on studies of the toxicity and deposition of silver nanoparticles, use of autometallog. to localize zinc and other metals at the tissue and subcellular localization is also recognized.
- 72Zhang, Y.; Hedo, R.; Rivera, A.; Rull, R.; Richardson, S.; Tu, X. M. Post Hoc Power Analysis: Is It an Informative and Meaningful Analysis?. Gen Psychiatry 2019, 32 (4), e100069 DOI: 10.1136/gpsych-2019-100069There is no corresponding record for this reference.
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.0c09278. The raw data are available upon request to the corresponding author.
Expanded DLS data, Western blot images, expanded 2 week treatment and histology, fenestration data and cell culture purity data (PDF)
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