Potent Antifungal Activity of Penta-O-galloyl-β-d-Glucose against Drug-Resistant Candida albicans, Candida auris, and Other Non-albicans Candida SpeciesClick to copy article linkArticle link copied!
- Lewis MarquezLewis MarquezMolecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, Georgia 30322, United StatesJones Center at Ichauway, Newton, Georgia 39870, United StatesMore by Lewis Marquez
- Yunjin LeeYunjin LeeDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, CanadaMore by Yunjin Lee
- Dustin DuncanDustin DuncanDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, CanadaDepartment of Chemistry, Brock University, St. Catharines, Ontario L2S 3A1, CanadaMore by Dustin Duncan
- Luke WhitesellLuke WhitesellDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, CanadaMore by Luke Whitesell
- Leah E. CowenLeah E. CowenDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, CanadaMore by Leah E. Cowen
- Cassandra Quave*Cassandra Quave*Email: [email protected]Center for the Study of Human Health, Emory University, Atlanta, Georgia 30322, United StatesDepartment of Dermatology, Emory University, Atlanta, Georgia 30322, United StatesMore by Cassandra Quave
Abstract
![](/cms/10.1021/acsinfecdis.3c00113/asset/images/medium/id3c00113_0007.gif)
Among fungal pathogens, infections by drug-resistant Candida species continue to pose a major challenge to healthcare. This study aimed to evaluate the activity of the bioactive natural product, penta-O-galloyl-β-d-glucose (PGG) against multidrug-resistant (MDR) Candida albicans, MDR Candida auris, and other MDR non-albicans Candida species. Here, we show that PGG has a minimum inhibitory concentration (MIC) of 0.25–8 μg mL–1 (0.265–8.5 μM) against three clinical strains of C. auris and a MIC of 0.25–4 μg mL–1 (0.265–4.25 μM) against a panel of other MDR Candida species. Our cytotoxicity studies found that PGG was well tolerated by human kidney, liver, and epithelial cells with an IC50 > 256 μg mL–1 (>272 μM). We also show that PGG is a high-capacity iron chelator and that deletion of key iron homeostasis genes in C. albicans rendered strains hypersensitive to PGG. In conclusion, PGG displayed potent anti-Candida activity with minimal cytotoxicity for human cells. We also found that the antifungal activity of PGG is mediated through an iron-chelating mechanism, suggesting that the compound could prove useful as a topical treatment for superficial Candida infections.
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License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
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License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
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Special Issue
Published as part of the ACS Infectious Diseases virtual special issue “Drug Resistance in Infectious Diseases and Beyond”.
target | IC50/EC50 | mode of action | refs |
---|---|---|---|
Antibacterial | |||
Staphylococcus aureus (various strains) | 16–32 μg/mL | possibly iron chelation | (19) |
MRSA (various strains) | 16–32 μg/mL | possibly iron chelation | (19) |
Acinetobacter baumannii (various strains) | 16–64 μg/mL | possibly iron chelation | (18) |
Anticancer (Liver Cancer) | |||
SK-HEP-1 cells | 25–50 μM | inhibition of proliferation (inactivation of NF-κB) | (20) |
Anticancer (Colorectal Cancer) | |||
HCT-116 cells | 1.61 μM | inhibition of proliferation (induction of the p53 gene) | (21,22) |
HT-29 cells | 4.46 μM | inhibition of proliferation (induction of the p53 gene) | (21,22) |
Anticancer (Breast Cancer) | |||
MDA-MB-231 | 50.23 μM | induction of apoptosis | (23) |
MDA-MB-468 | 35.72 μM | induction of apoptosis | (23) |
Antiviral | |||
influenza A | 5.3 μg/mL | interference with viral replication | (24) |
IC50 (μg/mL) | MIC (μg/mL) | MIC (μg/mL) | |||||
---|---|---|---|---|---|---|---|
species | strain ID | antibiogram | PGG | PGG | AMB | FLC | KTC |
Candida albicans | ATCC 90028 | AfgS, CasS, FlcS, ItcS, MfgS, VrcS | 0.5 | 1 | 1 | 0.25 | <0.0039 |
Candida albicans | MH12 | AfgS, CasS, FlcR, ItcS, MfgS, VrcS | 0.25 | 0.5 | 1 | >8 | 1 |
Candida parapsilosis | AR Bank #0335 | AfgI, CasS, FlcR, MfgS, VrcR | 1 | 4 | 1 | >8 | 4 |
Candida parapsilosis | AR Bank #0337 | AfgS, CasS, FlcR, MfgS, VrcR | 0.5 | 0.5 | 1 | >8 | 2 |
Candida parapsilosis | AR Bank #0338 | AfgS, CasS, FlcR, MfgS | 0.25 | 0.5 | 1 | >8 | 0.5 |
Candida parapsilosis | AR Bank #0339 | AfgS, CasS, FlcR, MfgS | 0.5 | 1 | 2 | >8 | 0.25 |
Candida glabrata | AR Bank #0325 | AfgR, CasR, FlcR, MfgR | 0.25 | 0.5 | 1 | >8 | 4 |
Candida glabrata | AR Bank #0326 | AfgS, CasS, FlcSDD, MfgS, | 0.125 | 0.25 | 1 | 4 | 0.25 |
Candida aurisa | AR Bank #0381 | AfgS, AmbS, CasS, FlcS, MfgS | ─ | 0.25 | 1 | 4 | <0.0039 |
Candida aurisa | AR Bank #0387 | AfgS, AmbS, CasS, FlcI, MfgS | 0.5 | 1 | 0.5 | 1 | <0.0039 |
Candida aurisa | AR Bank #0390 | AfgS, AmbR, CasS, FlcR, MfgS | 4 | 8 | 2 | >8 | 0.5 |
There are currently no established C. auris antifungal breakpoints; as outlined by the CDC, (25) breakpoints from closely related Candida sp. were used to determine the antibiogram profile. Abbreviations used are amphotericin B (Amb), anidulafungin (Afg), caspofungin (Cas), itraconazole (Itc), fluconazole (Flu), micafungin (Mfg), voriconazole (Vrc), and ketoconazole (Ktc). Superscripts used: S, susceptible; SDD, susceptible dose-dependent; I, intermediate; and R, resistant.
Results
Anti-Candida Activity of Penta-O-galloyl-β-d-glucose
Figure 1
![](/cms/10.1021/acsinfecdis.3c00113/asset/images/medium/id3c00113_0002.gif)
Figure 1. Chemical structure of penta-O-galloyl-β-d-glucose, PGG.
Figure 2
![](/cms/10.1021/acsinfecdis.3c00113/asset/images/medium/id3c00113_0003.gif)
Figure 2. Penta-O-galloyl-β-d-glucose displays broad spectrum anti-Candida activity. Growth inhibition of PGG against (A) C. albicans, (B) C. glabrata, (C) C. parapsilosis, and (D) C. auris. Solid lines represent PGG. Dashed lines represent the positive control fluconazole. The data are plotted as the mean % growth inhibition ± SD as compared to the DMSO vehicle from two independent experiments. The horizontal dotted line represents 90% growth inhibition. See Supplemental Figures S8–S11 for expanded graphs including additional positive controls. See Table 2 for strain details.
Cytotoxicity
PGG Sensitivity of C. albicans Is Not Modulated by Major Efflux Pumps
Figure 3
![](/cms/10.1021/acsinfecdis.3c00113/asset/images/medium/id3c00113_0004.gif)
Figure 3. PGG sensitivity in C. albicans is not modulated by efflux pumps. The cdr1Δ/Δ, cdr2Δ/Δ, mdr1Δ/Δ, flu1Δ/Δ, and wild-type strains were grown overnight in YPD and subject to dose–response assays in RPMI-1640 medium with twofold dilution gradients of PGG. Fluconazole was included as a positive control. Growth (OD600nm) was measured after 72 h of incubation at 30 °C, averaged between technical duplicates, and normalized to the drug-free wild-type control. Results are presented in a heat-map format with a scale bar provided at the bottom of the figure. All assays were performed in biological duplicates.
PGG Does Not Bind to Fungal Ergosterol
PGG’s Anti-Candida Activity Is Tied to Iron Chelation
Figure 4
![](/cms/10.1021/acsinfecdis.3c00113/asset/images/medium/id3c00113_0005.gif)
Figure 4. Growth inhibition of PGG against multiple Candida species is abrogated by iron supplementation, and PGG binds multiple iron ions. (A) C. albicans 90028, (B) C. glabrata CDC325, and (C) C. auris CDC381 were treated with PGG or Amphotericin B at varying concentrations (4, 8, and 16 μg/mL) and media was supplemented with a 10 mM solution of ferrous sulfate (Fe2+) or ferric sulfate (Fe3+) and % growth inhibition measured after 48 h. The data are plotted as the mean % growth inhibition ± SD as compared to the DMSO vehicle from two independent experiments. The horizontal dotted line represents 90% growth inhibition compared to the vehicle. Statistical analysis was done using two-way ANOVA with multiple comparisons. (D) PGG or EGCG was allowed to react with varying concentrations of iron (III) in solution at pH 2.0. The bipy solution was added to the mixtures and the formation of the [Fe(bipy)3]2+ complex was measured at 520 nm. [PGG]total, [EGCG]total = 10 μM. The data are plotted as the mean absorbance ± SD from two independent experiments.
Figure 5
![](/cms/10.1021/acsinfecdis.3c00113/asset/images/medium/id3c00113_0006.gif)
Figure 5. Iron homeostasis genes are required for PGG tolerance in C. albicans. The ire1Δ/ire1Δ, hap43Δ/hap43Δ, and rim101Δ/rim101Δ strains and their respective wild-type controls were grown overnight in YPD and subject to dose–response assays in RPMI-1640 medium with twofold dilution gradients of PGG. The metal chelator BPS was included as a positive control. After 48 h incubation at 30 °C, the relative viable cell number was assessed. Data were averaged between technical duplicates and normalized to wild-type drug-free control wells. Results are presented in a heat-map format with a color scale bar presented at the bottom of the figure. All assays were performed in biological duplicates.
Discussion
Methods
Cell Lines and Growth Conditions
Growth Inhibition
Method for Concentration-Response Matrixes (Checkerboard Assays)
Method for the Ergosterol Binding Assay
Concentration-Response Assays of C. albicans Efflux and Iron Homeostasis Mutants
2,2′-Bipyridyl Test
Method for Job’s Method
Cell Viability and Cytotoxicity
Chemical-Induced Cytotoxicity
Cell Viability/Proliferation
Statistical Analysis
Data Availability
ChemDraw Professional version 16.0.1.4 (77) was used for chemical structures.
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.3c00113.
Experimental methods for concentration-response matrixes; effects of penta-O-galloyl-β-d-glucose upon human cytotoxicity and cell viability; media supplementation assays; Job’s method spectra; expanded MIC graphs with additional positive controls; and table with the additional Candida albicans strains and genotype (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
This work was supported in part by a grant from the National Institutes of Health, National Center for Complementary and Integrative Health (NCCIH) (R01AT011990 to C.L.Q.) and a graduate student fellowship from The Jones Center at Ichauway to L.M. Y.L. is supported by the CIHR Frederick Banting and Charles Best Canada Graduate Scholarship─Doctoral Awards. L.E.C. is supported by the Canadian Institutes of Health Research Foundation Grant (FDN-154288) and is a Canada Research Chair (Tier 1) in Microbial Genomics & Infectious Disease and co-director of the CIFAR Fungal Kingdom: Threats & Opportunities program.
References
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- 9Cleveland, A. A.; Farley, M. M.; Harrison, L. H.; Stein, B.; Hollick, R.; Lockhart, S. R.; Magill, S. S.; Derado, G.; Park, B. J.; Chiller, T. M. Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011. Clin. Infect. Dis. 2012, 55, 1352– 1361, DOI: 10.1093/cid/cis697Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Srur%252FJ&md5=8adf53f14e51dcd8b8a0b313332b3632Changes in Incidence and Antifungal Drug Resistance in Candidemia: Results From Population-Based Laboratory Surveillance in Atlanta and Baltimore, 2008-2011Cleveland, Angela Ahlquist; Farley, Monica M.; Harrison, Lee H.; Stein, Betsy; Hollick, Rosemary; Lockhart, Shawn R.; Magill, Shelley S.; Derado, Gordana; Park, Benjamin J.; Chiller, Tom M.Clinical Infectious Diseases (2012), 55 (10), 1352-1361CODEN: CIDIEL; ISSN:1058-4838. (Oxford University Press)We describe marked shifts in candidemia epidemiol. over the past 2 decades. Adults aged ≥65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Efforts to det. effective prevention strategies are needed. Background. Candidemia is common and assocd. with high morbidity and mortality; changes in population-based incidence rates have not been reported. Methods. We conducted active, population-based surveillance in metropolitan Atlanta, Georgia, and Baltimore City/County, Maryland (combined population 5.2 million), during 2008-2011. We calcd. candidemia incidence and antifungal drug resistance compared with prior surveillance (Atlanta, 1992-1993; Baltimore, 1998-2000). Results. We identified 2675 cases of candidemia with 2329 isolates during 3 years of surveillance. Mean annual crude incidence per 100 000 person-years was 13.3 in Atlanta and 26.2 in Baltimore. Rates were highest among adults aged ≥65 years (Atlanta, 59.1; Baltimore, 72.4) and infants (aged <1 yr; Atlanta, 34.3; Baltimore, 46.2). In both locations compared with prior surveillance, adjusted incidence significantly declined for infants of both black and white race (Atlanta: black risk ratio [RR], 0.26 [95% confidence interval {CI}, .17-.38]; white RR: 0.19 [95% CI, .12-.29]; Baltimore: black RR, 0.38 [95% CI, .22-.64]; white RR: 0.51 [95% CI: .29-.90]). Prevalence of fluconazole resistance (7%) was unchanged compared with prior surveillance; 32 (1%) isolates were echinocandin-resistant, and 9 (8 Candida glabrata) were multidrug resistant to both fluconazole and an echinocandin. Conclusions. We describe marked shifts in candidemia epidemiol. over the past 2 decades. Adults aged ≥65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Use of antifungal prophylaxis, improvements in infection control, or changes in catheter insertion practices may be contributing to these declines. Further surveillance for antifungal resistance and efforts to det. effective prevention strategies are needed.
- 10Kreusch, A.; Karstaedt, A. S. Candidemia among adults in Soweto, South Africa, 1990-2007. Int. J. Infect. Dis. 2013, 17, e621– 3, DOI: 10.1016/j.ijid.2013.02.010Google ScholarThere is no corresponding record for this reference.
- 11Doi, A. M.; Pignatari, A. C. C.; Edmond, M. B.; Marra, A. R.; Camargo, L. F. A.; Siqueira, R. A.; da Mota, V. P.; Colombo, A. L. Epidemiology and Microbiologic Characterization of Nosocomial Candidemia from a Brazilian National Surveillance Program. PLoS One 2016, 11, e0146909, DOI: 10.1371/journal.pone.0146909Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVWrtbjI&md5=d185c63a744317e55cdf7fe0bd1240fbEpidemiology and microbiologic characterization of nosocomial candidemia from a brazilian national surveillance programDoi, Andre Mario; Pignatari, Antonio Carlos Campos; Edmond, Michael B.; Marra, Alexandre Rodrigues; Camargo, Luis Fernando Aranha; Siqueira, Ricardo Andreotti; Pereira da Mota, Vivian; Colombo, Arnaldo LopesPLoS One (2016), 11 (1), e0146909/1-e0146909/9CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Candidemia is a growing problemin hospitals all over the world. Despite advances in the medical support of critically ill patients, candidiasis leads to prolonged hospitalization, and has a crude mortality rate around 50%.We conducted a multicenter surveillance study in 16 hospitals distributed across five regions of Brazil to assess the incidence, species distribution, antifungal susceptibility, and risk factors for bloodstreaminfections due to Candida species. From June 2007 to March 2010, we studied a total of 2,563 nosocomial bloodstream infection (nBSI) episodes. Candida spp. was the 7th most prevalent agent. Most of the patients were male, with a median age of 56 years. A total of 64 patients (46.7%) were in the ICU when candidemia occurred. Malignancies were the most common underlying condition (32%). The crude mortality rate of candidemia during the hospital admission was 72.2%. Non-albicans species of Candida accounted for 65.7%of the 137 yeast isolates. C. albicans (34.3%), Candida parapsilosis (24.1%), Candida tropicalis (15.3%) and Candida glabrata (10.2%) were the most prevalent species. Only 47 out of 137 Candida isolates were sent to the ref. lab. for antifungal susceptibility testing. All C. albicans, C. tropicalis and C. parapsilosis isolates were susceptible to the 5 antifungal drugs tested. Among 11 C. glabrata isolates, 36% were resistant to fluconazole, and 64%SDD. All of them were susceptible to anidulafungin and amphotericin B.We obsd. that C. glabrata is emerging as a major player among non-albicans Candida spp. and fluconazole resistance was primarily confined to C. glabrata and C. krusei strains. Candida resistance to echinocandins and amphotericin B remains rare in Brazil. Mortality rates remain increasingly higher than that obsd. in the Northern Hemisphere countries, emphasizing the need for improving local practices of clin. management of candidemia, including early diagnosis, source control and precise antifungal therapy.
- 12Chowdhary, A.; Anil Kumar, V.; Sharma, C.; Prakash, A.; Agarwal, K.; Babu, R.; Dinesh, K. R.; Karim, S.; Singh, S. K.; Hagen, F.; Meis, J. F. Multidrug-resistant endemic clonal strain of Candida auris in India. Eur. J. Clin. Microbiol. Infect. Dis. 2014, 33, 919– 926, DOI: 10.1007/s10096-013-2027-1Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOis73K&md5=2817ac62702eb203503530f823c7b4d9Multidrug-resistant endemic clonal strain of Candida auris in IndiaChowdhary, A.; Anil Kumar, V.; Sharma, C.; Prakash, A.; Agarwal, K.; Babu, R.; Dinesh, K. R.; Karim, S.; Singh, S. K.; Hagen, F.; Meis, J. F.European Journal of Clinical Microbiology & Infectious Diseases (2014), 33 (6), 919-926CODEN: EJCDEU; ISSN:0934-9723. (Springer)Candida auris is a recently described rare agent of fungemia. It is notable for its antifungal resistance. A total of 15 C. auris isolates, originating from seven cases of fungemia, three cases of diabetic gangrenous foot, and one case of bronchopneumonia from a tertiary care hospital in south India, were studied. All of the 15 isolates were identified by sequencing and 14 of these along with 12 C. auris isolates previously reported from two hospitals in Delhi, north India, two each from Japan and Korea were genotyped by amplified fragment length polymorphism (AFLP). In vitro antifungal susceptibility testing (AFST) was done by the Clin. and Lab. Stds. Institute (CLSI) broth microdilution method. Candida auris isolates were misidentified as Candida haemulonii by VITEK. All were resistant to fluconazole [geometric mean min. inhibitory concn. (MIC) 64 μg/mL] and 11 isolates were resistant to voriconazole (MIC ≥1 μg/mL). Forty-seven percent of the C. auris isolates were resistant to flucytosine (MIC ≥64 μg/mL) and 40% had high MIC (≥1 μg/mL) of caspofungin. Breakthrough fungemia developed in 28.6% of patients and therapeutic failure in 4 (66.7%) patients. The 26 Indian C. auris isolates from north and south India were clonal and phenotypically and genotypically distinct from Korean and Japanese isolates. C. auris is a potential emerging pathogen that can cause a wide spectrum of human mycotic infections. The prevalence of a C. auris endemic clonal strain resistant to azoles and other antifungals in Indian hospitals with high rates of therapeutic failure in cases of fungemia is worrisome.
- 13Morales-López, S. E.; Parra-Giraldo, C. M.; Ceballos-Garzon, A.; Martinez, H. P.; Rodriguez, G. J.; Alvarez-Moreno, C. A.; Rodriguez, J. Y. Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia. Emerg. Infect. Dis. 2017, 23, 162– 164, DOI: 10.3201/eid2301.161497Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c%252FlsVSisA%253D%253D&md5=99bc0cef9e5a1d0715f6098dc06b66c0Invasive Infections with Multidrug-Resistant Yeast Candida auris, ColombiaMorales-Lopez Soraya E; Parra-Giraldo Claudia M; Ceballos-Garzon Andres; Martinez Heidys P; Rodriguez Gerson J; Alvarez-Moreno Carlos A; Rodriguez Jose YEmerging infectious diseases (2017), 23 (1), 162-164 ISSN:.Candida auris is an emerging multidrug-resistant fungus that causes a wide range of symptoms. We report finding 17 cases of C. auris infection that were originally misclassified but correctly identified 27.5 days later on average. Patients with a delayed diagnosis of C. auris had a 30-day mortality rate of 35.2%.
- 14Sayeed, M. A.; Farooqi, J.; Jabeen, K.; Awan, S.; Mahmood, S. F. Clinical spectrum and factors impacting outcome of Candida auris: a single center study from Pakistan. BMC Infect. Dis. 2019, 19, 384, DOI: 10.1186/s12879-019-3999-yGoogle Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7ivFKisw%253D%253D&md5=769e11d5029dec6652a45cbb5479f3cdClinical spectrum and factors impacting outcome of Candida auris: a single center study from PakistanSayeed Muneeba Ahsan; Farooqi Joveria; Jabeen Kausar; Awan Safia; Mahmood Syed FaisalBMC infectious diseases (2019), 19 (1), 384 ISSN:.BACKGROUND: An outbreak of Candida auris began globally in 2014 including Pakistan and since then it has emerged as a nosocomial multi-drug resistant pathogen. The aim of this study was to assess the clinical spectrum and outcome of patients, from a single center in Pakistan, in whom C. auris was isolated. METHODS: A retrospective study was conducted on 92 patients; ≥16 years with at least one culture positive for C. auris, at the Aga Khan University Hospital Karachi, Pakistan from Sept 2014-Mar 2017.Demographics, clinical history, management and outcome were studied. A logistic regression model was used to identify the risk factors for mortality. RESULTS: We identified 92 patients with C. auris (193 isolates), of whom 52.2% were males. Mean age was 54.14 ± 20.4 years. Positive cultures were obtained after a median hospital stay of 14 days. Most patients had a history of surgery (57.6%), antibiotic use (95.6%), ICU stay (44.6%), indwelling lines (88.04%) and isolation of another multi-resistant organism (52.2%).Most patients were symptomatic (70.7%). Amongst these, 38 had candidemia while 27 had non-candidemia infections. Sites of infection included central lines (35), urinary tract (19), peritonitis (4), nosocomial ventriculitis (1), empyema (1), fungal keratitis (1) otitis externa (1) and surgical site (1). Fluconazole resistance was 100% while 28.5 and 7.9% were Voriconazole and Amphotericin resistant respectively. Overall crude mortality was 42.4% while 14-day mortality was 31.5%. Both infected and colonized cases shared similar mortality (46.2% vs 33.3%; p-value = 0.25). Among infected cases mortality was high in candidemia compared to non-candidemia (60.5% vs 25.9%) in which deaths related to C. auris were 34.2% vs 22.2% respectively. On multivariate analysis candidemia (AOR 4.2, 95% CI: 1.09-16.49; p-value = 0.037) was associated with greater mortality with source control being the only protective factor for mortality (AOR 0.22, 95% CI: 0.05-0.92; p-value0.038] while ICU stay, rapidity of blood culture clearance, DM, malignancy and MDR co-infection had no impact. CONCLUSION: Patients with C.auris from a single center in Pakistan have a wide clinical spectrum with line associated infection being the predominant site of infection. Candidemia leads to high mortality while source control improves outcome.
- 15Al-Siyabi, T.; Al Busaidi, I.; Balkhair, A.; Al-Muharrmi, Z.; Al-Salti, M.; Al’Adawi, B. First report of Candida auris in Oman: Clinical and microbiological description of five candidemia cases. J. Infect. 2017, 75, 373– 376, DOI: 10.1016/j.jinf.2017.05.016Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnkslGntg%253D%253D&md5=3ce0424632cac9d79fc576c94c8391ebFirst report of Candida auris in Oman: Clinical and microbiological description of five candidemia casesAl-Siyabi Turkiya; Al-Muharrmi Zakariya; Al-Salti Maya; Al'Adawi Badriya; Al Busaidi Ibrahim; Balkhair AbdullahThe Journal of infection (2017), 75 (4), 373-376 ISSN:.There is no expanded citation for this reference.
- 16CDC Tracking Candida auris. https://www.cdc.gov/fungal/candida-auris/tracking-c-auris.html (accessed August 12, 2021).Google ScholarThere is no corresponding record for this reference.
- 17Morton, J. F. Brazilian pepper─Its impact on people, animals and the environment. Econ Bot 1978, 32, 353– 359, DOI: 10.1007/BF02907927Google ScholarThere is no corresponding record for this reference.
- 18Dettweiler, M.; Marquez, L.; Lin, M.; Sweeney-Jones, A. M.; Chhetri, B. K.; Zurawski, D. V.; Kubanek, J.; Quave, C. L. Pentagalloyl glucose from Schinus terebinthifolia inhibits growth of carbapenem-resistant Acinetobacter baumannii. Sci. Rep. 2020, 10, 15340 DOI: 10.1038/s41598-020-72331-wGoogle Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFSis7rE&md5=08cab11f957b41a6999e5e9c3e717a51Pentagalloyl glucose from Schinus terebinthifolia inhibits growth of carbapenem-resistant Acinetobacter baumanniiDettweiler, Micah; Marquez, Lewis; Lin, Michelle; Sweeney-Jones, Anne M.; Chhetri, Bhuwan Khatri; Zurawski, Daniel V.; Kubanek, Julia; Quave, Cassandra L.Scientific Reports (2020), 10 (1), 15340CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)Abstr.: The rise of antibiotic resistance has necessitated a search for new antimicrobials with potent activity against multidrug-resistant gram-neg. pathogens, such as carbapenem-resistant Acinetobacter baumannii (CRAB). In this study, a library of botanical exts. generated from plants used to treat infections in traditional medicine was screened for growth inhibition of CRAB. A crude ext. of Schinus terebinthifolia leaves exhibited 80% inhibition at 256 μg/mL and underwent bioassay-guided fractionation, leading to the isolation of pentagalloyl glucose (PGG), a bioactive gallotannin. PGG inhibited growth of both CRAB and susceptible A. baumannii (MIC 64-256 μg/mL), and also exhibited activity against Pseudomonas aeruginosa (MIC 16 μg/mL) and Staphylococcus aureus (MIC 64 μg/mL). A mammalian cytotoxicity assay with human keratinocytes (HaCaTs) yielded an IC50 for PGG of 256 μg/mL. Mechanistic expts. revealed iron chelation as a possible mode of action for PGG's activity against CRAB. Passaging assays for resistance did not produce any resistant mutants over a period of 21 days. In conclusion, PGG exhibits antimicrobial activity against CRAB, but due to known pharmacol. restrictions in delivery, translation as a therapeutic may be limited to topical applications such as wound rinses and dressings.
- 19Cho, J.-Y.; Sohn, M.-J.; Lee, J.; Kim, W.-G. Isolation and identification of pentagalloylglucose with broad-spectrum antibacterial activity from Rhus trichocarpa Miquel. Food Chem. 2010, 123, 501– 506, DOI: 10.1016/j.foodchem.2010.04.072Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnt12mu7c%253D&md5=ef1a52c87e8a4ee719978a8d3390af82Isolation and identification of pentagalloylglucose with broad-spectrum antibacterial activity from Rhus trichocarpa MiquelCho, Jun-Young; Sohn, Mi-Jin; Lee, Joongku; Kim, Won-GonFood Chemistry (2010), 123 (2), 501-506CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)Rhus trichocarpa Miquel has been utilized both as a food and for medicinal purposes. In this study, we detd. that the methanol exts. of the stem and leaf portions of R. trichocarpa inhibited the growth of both Gram-neg. and Gram-pos. bacteria. The active constituent was isolated, and identified via mass spectrometry and NMR as 1,2,3,4,6-penta-O-galloyl-β-D-glucose. The compd. also evidenced a broad spectrum of antibacterial activity against both Gram-neg. and Gram-pos. bacteria including Staphylococcus aureus (both methicillin-resistant S. aureus and quinolone-resistant S. aureus), Bacillus subtilis, Streptococcus mutans, Escherichia coli, Salmonella typhimurium, and Pseudomonas aeruginosa with MRC values of 16-32 μg/mL, whereas gallate failed to inhibit the growth of Gram-neg. bacteria, even at a concn. of 128 μg/mL. The antibacterial activity of penta-O-galloylglucose was restored by the addn. of Fe2+, whereas gallate was not, thereby indicating that its antibacterial activity could be attributable to the chelation of iron. The results of the time-kill study against S. aureus and E. coli revealed that penta-O-galloylglucose exhibited bacteriostatic activity. These findings indicate that the exts. of R. trichocarpa as well as its active component, penta-O-galloylglucose, may have profound potential for the control of both Gram-pos. and neg. pathogens.
- 20Oh, G.-S.; Pae, H.-O.; Oh, H.; Hong, S.-G.; Kim, I.-K.; Chai, K.-Y.; Yun, Y.-G.; Kwon, T.-O.; Chung, H.-T. In vitro anti-proliferative effect of 1,2,3,4,6-penta-O-galloyl-beta-d-glucose on human hepatocellular carcinoma cell line, SK-HEP-1 cells. Cancer Lett. 2001, 174, 17– 24, DOI: 10.1016/S0304-3835(01)00680-2Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnslCjtbw%253D&md5=4e1f604f99f29bdb9c33d616e60c3bd2In vitro anti-proliferative effect of 1,2,3,4,6-penta-O-galloyl-beta-d-glucose on human hepatocellular carcinoma cell line, SK-HEP-1 cellsOh, Gi-Su; Pae, Hyun-Ock; Oh, Hyuncheol; Hong, Seong-Gak; Kim, Il-Kwang; Chai, Kyu-Yun; Yun, Young-Gab; Kwon, Tae-Oh; Chung, Hun-TaegCancer Letters (Shannon, Ireland) (2001), 174 (1), 17-24CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Science Ireland Ltd.)The root of Paeonia suffruticosa ANDREWS is an important Chinese crude drug used in many traditional prescriptions; 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG), a major component of this crude drug, was found to exhibit in vitro growth-inhibiting effect on human hepatocellular carcinoma cell line, SK-HEP-1 cells. The growth-inhibitory effect was related to the ability of PGG not only to cause a G0/G1 phase arrest but also to suppress the activation of nuclear factor-kappa B. Neither apoptosis nor necrosis was obsd. in the cells treated with PGG. These findings suggest that PGG could be a candidate for developing a low-toxic anticancer agent.
- 21Shaikh, Q.-u.-a.; Yang, M.; Memon, K. H.; Lateef, M.; Na, D.; Wan, S.; Eric, D.; Zhang, L.; Jiang, T. 1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) analogs: design, synthesis, anti-tumor and anti-oxidant activities. Carbohydr. Res. 2016, 430, 72– 81, DOI: 10.1016/j.carres.2016.04.021Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntFGgtLc%253D&md5=ebba3a41cbdc3dbd6ece6f90a870a0d11,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) analogs: design, synthesis, antitumor and antioxidant activitiesShaikh, Qurat-ul-ain; Yang, Meiting; Memon, Khadim Hussain; Lateef, Mehreen; Na, Du; Wan, Shengbiao; Eric, Deslandes; Zhang, Lijuan; Jiang, TaoCarbohydrate Research (2016), 430 (), 72-81CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) has been reported for its antioxidant activities, where the free OH groups in PGG seem to be crit. for activities. To explore PGG-based compds. as chemotherapeutic agents and to analyze the contribution of specific OH groups in PGG for anti-cancer activities, we designed and synthesized a series of 27 benzoic and cinnamic acid analogs of PGG. These analogs were tested for cytotoxicities against two human lung (A549 and H1299) and two human colon (HCT116 and HT29) cancer cell lines. PGG had highest cytotoxicities against HCT116 and A549 cells with IC50 of 1.61 μM and 3.02 μM, resp. In contrast, 1,2,3,4,6-pentakis[-O-(4-hydroxy-3-methoxybenzoyl)]-α,β-D-glucopyranose (PVG) was most effective at killing HT29 and H1299 cells with IC50 of 1.76 μM and 3.65 μM, resp., indicating the mutual contribution of m-methoxy and p-hydroxy groups to the obsd. cytotoxicities. Moreover, cinnamic acid analogs were less active than the benzoic acid analogs evidenced by higher IC50 values. Furthermore, in cinnamic acid analogs the hydrogenation of double bond to satd. 2-C side chain enhance the cytotoxicities in all four cell lines. Compds. also possess good antioxidant and reducing activities. PPG show the highest antioxidant and reducing activities.
- 22Kawk, S. H.; Kang, Y. R.; Kim, Y. H. 1,2,3,4,6-Penta-O-galloyl-β-d-glucose suppresses colon cancer through induction of tumor suppressor. Bioorg. Med. Chem. Lett. 2018, 28, 2117– 2123, DOI: 10.1016/j.bmcl.2018.05.028Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVKjurw%253D&md5=22e90123fe718b2b0b58b2dda4c076f91,2,3,4,6-Penta-O-galloyl-β-D-glucose suppresses colon cancer through induction of tumor suppressorKawk, Sang Hee; Kang, Ye Rim; Kim, Yoon HeeBioorganic & Medicinal Chemistry Letters (2018), 28 (12), 2117-2123CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Colon cancer is the third most common malignancy in both sexes of Korea. Here, we investigated anti-colorectal cancer effects of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG), a gallotannin from Galla rhois, and its possible mechanisms. PGG induced cytotoxicity and decreased proliferation of colon cancer cells without affecting normal colon fibroblasts. PGG inhibited clonogenic ability and induced apoptosis in cancer cells. One of the underlying mechanisms of the anti-cancer effect exerted by PGG, was owing to the induction p53 expression, a well-known tumor suppressor, and increased in P21, the representative target gene of p53. PGG affected cell-cycle- or apoptosis-related proteins such as cyclin E, CDK2, and Bcl-2, cleaved caspase-3. Also, PGG induced caspase-3/7 activity. These data suggest that PGG exerts anti-colorectal cancer effects.
- 23Mendonca, P.; Alghamdi, S.; Messeha, S.; Soliman, K. F. A. Pentagalloyl glucose inhibits TNF-α-activated CXCL1/GRO-α expression and induces apoptosis-related genes in triple-negative breast cancer cells. Sci. Rep. 2021, 11, 5649 DOI: 10.1038/s41598-021-85090-zGoogle Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXmslGqsbc%253D&md5=5c0041ef9feaaf431ddc1b5d7b5e787bPentagalloyl glucose inhibits TNF-α-activated CXCL1/GRO-α expression and induces apoptosis-related genes in triple-negative breast cancer cellsMendonca, Patricia; Alghamdi, Sumaih; Messeha, Samia; Soliman, Karam F. A.Scientific Reports (2021), 11 (1), 5649CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)In triple-neg. breast cancer (TNBC), the tumor microenvironment is assocd. with increased proliferation, suppressing apoptotic mechanisms, an altered immune response, and drug resistance. The current investigation was designed to examine the natural compd. pentagalloyl glucose (PGG) effects on TNF-α activated TNBC cell lines, MDA-MB-231 and MDA-MB-468. The results obtained showed that PGG reduced the expression of the cytokine GRO-α/CXCL1. PGG also inhibited IBKE and MAPK1 genes and the protein expression of IBKE and MAPK, indicating that GRO-α downregulation is possibly through NFB and MAPK signaling pathway. PGG also inhibited cell proliferation in both cell lines. Moreover, PGG induced apoptosis, modulating caspases, and TNF superfamily receptor genes. It also augmented mRNA of receptors DR4 and DR5 expression, which binds to TNF-related apoptosis-induced ligand, a potent and specific stimulator of apoptosis in tumors. Remarkably, PGG induced a 154-fold increase in TNF expression in MDA-MB-468 compared to a 14.6-fold increase in MDA-MB-231 cells. These findings indicate PGG anti-cancer ability in inhibiting tumor cell proliferation and GRO-α release and inducing apoptosis by increasing TNF and TNF family receptors expression. Thus, PGG use may be recommended as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.
- 24Joo, Y.-H.; Lee, Y.-G.; Lim, Y.; Jeon, H.; Kim, E. H.; Choi, J.; Hong, W.; Jeon, H.; Ahrweiler, M.; Kim, H.; Kang, S. C.; Seo, Y.-J. Potent antiviral activity of the extract of Elaeocarpus sylvestris against influenza A virus in vitro and in vivo. Phytomedicine 2022, 97, 153892 DOI: 10.1016/j.phymed.2021.153892Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhtV2itbfK&md5=01144d525471b4a0123b9364efdec293Potent antiviral activity of the extract of Elaeocarpus sylvestris against influenza A virus in vitro and in vivoJoo, Yong-Hyun; Lee, Yeong-Geun; Lim, Younghyun; Jeon, Hoyeon; Kim, Eui Ho; Choi, Joongyeon; Hong, Woojae; Jeon, Hyelin; Ahrweiler, Michael; Kim, Hyunggun; Kang, Se Chan; Seo, Young-JinPhytomedicine (2022), 97 (), 153892CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)Elaeocarpus sylvestris (Lour.) Poir. (Elaeocarpaceae) belongs to a genus of tropical and semitropical evergreen trees, which has known biol. activities such as antiviral and immunomodulatory activities. However, its antiviral potential against influenza virus infection remains unknown. In this study, we investigated the antiviral activity of the 50% aq. ethanolic ext. of E. sylvestris (ESE) against influenza A virus (IAV) infection, which could lead to the development of novel phytomedicine to treat influenza virus infection. To investigate the in vitro antiviral activity of ESE and its main ingredients, 1, 2, 3, 4, 6- penta- O- galloyl-β-D-glucose (PGG) and geraniin (GE), the levels of viral RNAs, proteins, and infectious viral particles in IAV-infected MDCK cells were analyzed. Mol. docking anal. was performed to det. the binding energy of PGG and GE for IAV proteins. To investigate in vivo antiviral activity, IAV-infected mice were treated intranasally or intragastrically with ESE, PGG, or GE. ESE and its gallate main ingredients (PGG and GE) strongly inhibited the prodn. of viral RNAs, viral proteins, and infectious viral particles in vitro. Also through the viral attachment on cells, polymerase activity, signaling pathway, we revealed the ESE, PGG, and GE inhibit multiple steps of IAV replication. Mol. docking anal. revealed that PGG and GE could interact with 12 key viral proteins (M1, NP, NS1 effector domain (ED), NS1 RNA-binding domain (RBD), HA pocket A, HA receptor-binding domain (RBD), NA, PA, PB1, PB2 C-terminal domain, PB2 middle domain, and PB2 cap-binding domain) of IAV proteins with stable binding energy. Furthermore, intranasal administration of ESE, PGG, or GE protected mice from IAV-induced mortality and morbidity. Importantly, oral administration of ESE suppressed IAV replication and the expression of inflammatory cytokines such as IFN-γ, TNF-α, and IL-6 in the lungs to a large extent. ESE and its major components (PGG and PE) exhibited strong antiviral activity in multiple steps against IAV infection in silico, in vivo, and in vitro. Therefore, ESE could be used as a novel natural product derived therapeutic agent to treat influenza virus infection.
- 25CDC Candida Auris: Antifungal Susceptibility Testing and Interpretation. https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html, (accessed November 20, 2022).Google ScholarThere is no corresponding record for this reference.
- 26Calabrese, D.; Bille, J.; Sanglard, D. A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole. Microbiology 2000, 146, 2743– 2754, DOI: 10.1099/00221287-146-11-2743Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXotlWltb8%253D&md5=d3ab7cec62fe7e5d1881f13ab1307f12A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazoleCalabrese, David; Bille, Jacques; Sanglard, DominiqueMicrobiology (Reading, United Kingdom) (2000), 146 (11), 2743-2754CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)Azole resistance in Candida albicans can be mediated by several resistance mechanisms. Among these, alterations of the azole target enzyme and the overexpression of multidrug efflux transporter genes are the most frequent. To identify addnl. putative azole resistance genes in C. albicans, a genomic library from this organism was screened for complementation of fluconazole hypersusceptibility in Saccharomyces cerevisiae YKKB-13 lacking the ABC (ATP-binding cassette) transporter gene PDR5. Among the C. albicans genes obtained, a new gene was isolated and named FLU1 (fluconazole resistance). The deduced amino acid sequence of FLU1 showed similarity to CaMDR1 (formerly BENr), a member of the major facilitator superfamily of multidrug efflux transporters. The expression of FLU1 in YKKB-13 mediated not only resistance to fluconazole but also to cycloheximide among the different drugs tested. The disruption of FLU1 in C. albicans had only a slight effect on fluconazole susceptibility; however, it resulted in hypersusceptibility to mycophenolic acid, thus suggesting that this compd. could be a substrate for the protein encoded by FLU1. Disruption of FLU1 in a background of C. albicans mutants with deletions in several multidrug efflux transporter genes, including CDR1, CDR2 and CaMDR1, resulted in enhanced susceptibility to several azole derivs. FLU1 expression did not vary significantly between several pairs of azole-susceptible and azole-resistant C. albicans clin. isolates. Therefore, FLU1 seems not to be required for the development of azole resistance in clin. isolates.
- 27Ryan, P.; Hynes, M. J. The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron(III). J. Inorg. Biochem. 2007, 101, 585– 593, DOI: 10.1016/j.jinorgbio.2006.12.001Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXislKjsrs%253D&md5=1827f1f85fe54d749ac1a07bb598d326The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron(III)Ryan, Paul; Hynes, Michael J.Journal of Inorganic Biochemistry (2007), 101 (4), 585-593CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier B.V.)(-)-Epigallocatechin-gallate ((-)-EGCg) and (-)-epicatechin-gallate ((-)-ECG) are important antioxidants which are found in green tea. The kinetics and mechanisms of the reactions of a pseudo-first order excess of iron(III) with EGCg and ECG have been investigated in aq. soln. at 25 °C and an ionic strength of 0.5 M NaClO4. Mechanisms have been proposed which account satisfactorily for the kinetic data. These are consistent with a mechanism in which the 2:1 metal:ligand complex initially formed on reaction of iron(III) with the ligand subsequently decomps. in an electron transfer step. Complex formation takes place at two sep. binding sites via coupled reactions. Rate consts. of 4.28(±0.06) × 106 M-2 s-1 and 2.83(±0.04) × 106 M-2 s-1 have been evaluated for the reaction of monohydroxy Fe(OH)2+ species with EGCg and ECG, resp. while rate consts. for of 2.94(±0.4) × 104 M-2 s-1 and 2.41(±0.25) × 104 M-2 s-1 have been evaluated for the reaction of Fe3+ species with EGCg and ECG, resp. The iron(III) assisted decompn. of the initial iron(III) complex formed was also investigated and the rate consts. evaluated. Both the complex formation and subsequent electron transfer reactions of iron(III) with EGCg and ECG were monitored using UV-visible spectrophotometry. All of the suggested mechanisms and calcd. rate consts. are supported by calcns. carried out using global anal. of time dependant spectra. The results obtained show that one mol. of either EGCg or EGC is capable of reducing up to four iron(III) species, a fact which is consistent with the powerful antioxidant properties of the ligands.
- 28Jones, M. M.; Innes, K. K. Restrictions on the Use of Job’s Method. J. Phys. Chem. A 1958, 62, 1005– 1008, DOI: 10.1021/j150566a031Google ScholarThere is no corresponding record for this reference.
- 29Vosburgh, W. C.; Cooper, G. R. Complex Ions. I. The Identification of Complex Ions in Solution by Spectrophotometric Measurements. J. Am. Chem. Soc. 1941, 63, 437– 442, DOI: 10.1021/ja01847a025Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaH3MXhtlWntQ%253D%253D&md5=2017957810966438cd9d5b808d771282Complex ions. I. The identification of complex ions in solution by spectrophotometric measurementsVosburgh, Warren C.; Cooper, Gerald R.Journal of the American Chemical Society (1941), 63 (), 437-42CODEN: JACSAT; ISSN:0002-7863.This paper reports a study of the method of continuous variations (cf. Job, C. A. 22, 2120) for the detn. of the character of complex ions in soln. Data are given for the absorption spectra of solns. of chromate and dichromate, NiSO4 and o-phenanthroline, NiSO4 and ethylenediamine, CuSO4 and (NH4)2SO4. The absorption of monochromatic light was measured in each case. When only a single compd. is formed, the results are independent of the wave length of the light used. When more than one compd. is formed, the results obtained depend on the wave length of the light, and for useful conclusions the wave lengths used must be carefully selected. Both o-phenanthroline and ethylenediamine unite with Ni ion in the proportions of one, two and three mols. to one Ni ion. Cu ion and NH3 form a complex ion with two mols. of NH3 per atom of Cu as well as the one with four.
- 30Baek, Y. U.; Li, M.; Davis, D. A. Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factors. Eukaryot Cell 2008, 7, 1168– 1179, DOI: 10.1128/EC.00108-08Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXovFeqtbg%253D&md5=63de0e81463360ef06550d7dc4d0b188Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factorsBaek, Yong-Un; Li, Mingchun; Davis, Dana A.Eukaryotic Cell (2008), 7 (7), 1168-1179CODEN: ECUEA2; ISSN:1535-9786. (American Society for Microbiology)Iron is an essential nutrient that is severely limited in the mammalian host. Candida albicans encodes a family of 15 putative ferric reductases, which are required for iron acquisition and utilization. Despite the central role of ferric reductases in iron acquisition and mobilization, relatively little is known about the regulatory networks that govern ferric reductase gene expression in C. albicans. Here, the authors have demonstrated the differential regulation of two ferric reductases, FRE2 and FRP1, in response to distinct iron-limited environments. FRE2 and FRP1 are both induced in alk.-pH environments directly by the Rim101 transcription factor. However, FRP1 but not FRE2 is also induced by iron chelation. The authors have identified a CCAAT motif as the crit. regulatory sequence for chelator-mediated induction and have found that the CCAAT binding factor (CBF) is essential for FRP1 expression in iron-limited environments. They found that a hap5Δ/hap5Δ mutant, which disrupts the core DNA binding activity of CBF, is unable to grow under iron-limited conditions. C. albicans encodes three CBF-dependent transcription factors, and we identified the Hap43 protein as the CBF-dependent transcription factor required for iron-limited responses. These studies provide key insights into the regulation of ferric reductase gene expression in the fungal pathogen C. albicans.
- 31Hsu, P. C.; Yang, C. Y.; Lan, C. Y. Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence. Eukaryot Cell 2011, 10, 207– 225, DOI: 10.1128/EC.00158-10Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitVCgsrY%253D&md5=997b04e3b8a70c857959808c68d5a20fCandida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulenceHsu, Po-Chen; Yang, Cheng-Yao; Lan, Chung-YuEukaryotic Cell (2011), 10 (2), 207-225CODEN: ECUEA2; ISSN:1535-9786. (American Society for Microbiology)Candida albicans is an opportunistic fungal pathogen that exists as normal flora in healthy human bodies but causes life-threatening infections in immunocompromised patients. In addn. to innate and adaptive immunities, hosts also resist microbial infections by developing a mechanism of "natural resistance" that maintains a low level of free iron to restrict the growth of invading pathogenes. C. albicans must overcome this iron deprived environment to cause infections. There are three types of iron-responsive transcriptional regulators in fungi; Aft1/Aft2 activators in yeast, GATA-type repressors in many fungi, and HapX/Php4 in Schizosaccharomyces pombe and Aspergillus species. In this study, we characterized the iron-responsive regulator Hap43, which is the C. albicans homolog of HapX/Php4 and is repressed by the GATA-type repressor Sfu1 under iron-sufficient conditions. We provide evidence that Hap43 is essential for the growth of C. albicans under low-iron conditions and for C. albicans virulence in a mouse model of infection. Hap43 was not required for iron acquisition under low-iron conditions. Instead, it was responsible for repression of genes that encode iron-dependent proteins involved in mitochondrial respiration and iron-sulfur cluster assembly. We also demonstrated that Hap43 executes its function by becoming a transcriptional repressor and accumulating in the nucleus in response to iron deprivation. Finally, we found a connection between Hap43 and the global corepressor Tup1 in low-iron-induced flavinogenesis. Taken together, our data suggest a complex interplay among Hap43, Sfu1, and Tup1 to coordinately regulate iron acquisition, iron utilization, and other iron-responsive metabolic activities.
- 32Ramírez-Zavala, B.; Krüger, I.; Dunker, C.; Jacobsen, I. D.; Morschhäuser, J. The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. PLoS Pathog. 2022, 18, e1010283 DOI: 10.1371/journal.ppat.1010283Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XktV2gs7g%253D&md5=4ada8b75742ee157b2977ddfe29a01a7The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicansRamirez-Zavala, Bernardo; Krueger, Ines; Dunker, Christine; Jacobsen, Ilse D.; Morschhaeuser, JoachimPLoS Pathogens (2022), 18 (2), e1010283CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)Protein kinases play central roles in virtually all signaling pathways that enable organisms to adapt to their environment. Microbial pathogens must cope with severely restricted iron availability in mammalian hosts to invade and establish themselves within infected tissues. To uncover protein kinase signaling pathways that are involved in the adaptation of the pathogenic yeast Candida albicans to iron limitation, we generated a comprehensive protein kinase deletion mutant library of a wild-type strain. Screening of this library revealed that the protein kinase Ire1, which has a conserved role in the response of eukaryotic cells to endoplasmic reticulum stress, is essential for growth of C. albicans under iron-limiting conditions. Ire1 was not necessary for the activity of the transcription factor Sef1, which regulates the response of the fungus to iron limitation, and Sef1 target genes that are induced by iron depletion were normally upregulated in ire1Δ mutants. Instead, Ire1 was required for proper localization of the high-affinity iron permease Ftr1 to the cell membrane. Intriguingly, iron limitation did not cause increased endoplasmic reticulum stress, and the transcription factor Hac1, which is activated by Ire1-mediated removal of the non-canonical intron in the HAC1 mRNA, was dispensable for Ftr1 localization to the cell membrane and growth under iron-limiting conditions. Nevertheless, expression of a pre-spliced HAC1 copy in ire1Δ mutants restored Ftr1 localization and rescued the growth defects of the mutants. Both ire1Δ and hac1Δ mutants were avirulent in a mouse model of systemic candidiasis, indicating that an appropriate response to endoplasmic reticulum stress is important for the virulence of C. albicans. However, the specific requirement of Ire1 for the functionality of the high-affinity iron permease Ftr1, a well-established virulence factor, even in the absence of endoplasmic reticulum stress uncovers a novel Hac1-independent essential role of Ire1 in iron acquisition and virulence of C. albicans.
- 33Cryan, L. M.; Bazinet, L.; Habeshian, K. A.; Cao, S.; Clardy, J.; Christensen, K. A.; Rogers, M. S. 1,2,3,4,6-Penta-O-galloyl-beta-D-glucopyranose inhibits angiogenesis via inhibition of capillary morphogenesis gene 2. J. Med. Chem. 2013, 56, 1940– 1945, DOI: 10.1021/jm301558tGoogle Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1GhsLo%253D&md5=8759f46bb593c8eed20bb59965fb41e71,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose Inhibits Angiogenesis via Inhibition of Capillary Morphogenesis Gene 2Cryan, Lorna M.; Bazinet, Lauren; Habeshian, Kaiane A.; Cao, Shugeng; Clardy, Jon; Christensen, Kenneth A.; Rogers, Michael S.Journal of Medicinal Chemistry (2013), 56 (5), 1940-1945CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Capillary morphogenesis gene 2 (CMG2) is a transmembrane extracellular matrix binding protein that is also an anthrax toxin receptor. We have shown that high-affinity CMG2 binders can inhibit angiogenesis and tumor growth. We recently described a high-throughput FRET assay to identify CMG2 inhibitors. We now report the serendipitous discovery that PGG (1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose) is a CMG2 inhibitor with antiangiogenic activity. PGG is a gallotannin produced by a variety of medicinal plants that exhibits a wide variety of antitumor and other activities. We find that PGG inhibits CMG2 with a submicromolar IC50 and it also inhibits the migration of human dermal microvascular endothelial cells at similar concns. in vitro. Finally, oral or i.p. administration of PGG inhibits angiogenesis in the mouse corneal micropocket assay in vivo. Together, these results suggest that a portion of the in vivo antitumor activity of PGG may be the result of antiangiogenic activity mediated by inhibition of CMG2.
- 34Feldman, K. S.; Sahasrabudhe, K.; Lawlor, M. D.; Wilson, S. L.; Lang, C. H.; Scheuchenzuber, W. J. In vitro and In vivo inhibition of LPS-stimulated tumor necrosis factor-alpha secretion by the gallotannin beta-D-pentagalloylglucose. Bioorg. Med. Chem. Lett. 2001, 11, 1813– 1815, DOI: 10.1016/S0960-894X(01)00332-8Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXltFylsr0%253D&md5=2a63a32c4ec14fd0636e469665ac8f01In vitro and In vivo inhibition of LPS-stimulated tumor necrosis factor-α secretion by the gallotannin β-D-pentagalloylglucoseFeldman, K. S.; Sahasrabudhe, K.; Lawlor, M. D.; Wilson, S. L.; Lang, C. H.; Scheuchenzuber, W. J.Bioorganic & Medicinal Chemistry Letters (2001), 11 (14), 1813-1815CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The naturally occurring gallotannin β-d-pentagalloylglucose (β-PGG) decreases tumor necrosis factor-alpha (TNF-α) output from human peripheral blood mononucleocytes exposed to lipopolysaccharide (LPS) by as much as 90% (vs. control) at ∼5 μM concn. A qual. similar but less pronounced effect (∼50% decrease) was obsd. in the serum of rats dosed with both LPS and β-PGG. These results may have relevance to therapies that target disease states characterized by an overprodn. of TNF-α.
- 35Cheng, S. W. K.; Eagleton, M.; Echeverri, S.; Munoz, J. G.; Holden, A. H.; Hill, A. A.; Krievins, D.; Ramaiah, V. A pilot study to evaluate a novel localized treatment to stabilize small- to medium-sized infrarenal abdominal aortic aneurysms. J. Vasc. Surg. 2023, DOI: 10.1016/j.jvs.2023.05.056Google ScholarThere is no corresponding record for this reference.
- 36Jiamboonsri, P.; Pithayanukul, P.; Bavovada, R.; Leanpolchareanchai, J.; Yin, T.; Gao, S.; Hu, M. Factors Influencing Oral Bioavailability of Thai Mango Seed Kernel Extract and Its Key Phenolic Principles. Molecules 2015, 20, 21254– 21273, DOI: 10.3390/molecules201219759Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhslers7c%253D&md5=dfc66ad8c4b9ff3faa2d4db12690aeceFactors influencing oral bioavailability of thai mango seed kernel extract and its key phenolic principlesJiamboonsri, Pimsumon; Pithayanukul, Pimolpan; Bavovada, Rapepol; Leanpolchareanchai, Jiraporn; Yin, Taijun; Gao, Song; Hu, MingMolecules (2015), 20 (12), 21254-21273CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Mango seed kernel ext. (MSKE) and its key components (gallic acid, GA; Me gallate, MG; and pentagalloyl glucopyranose, PGG) have generated interest because of their pharmacol. activities. To develop the potential use of the key components in MSKE as natural therapeutic agents, their pharmacokinetic data are necessary. Therefore, this study was performed to evaluate the factors affecting their oral bioavailability as pure compds. and as components in MSKE. The in vitro chem. stability, biol. stability, and absorption were evaluated in Hanks' Balanced Salt Soln., Caco-2 cell and rat fecal lysates, and the Caco-2 cell model, resp. The in vivo oral pharmacokinetic behavior was elucidated in Sprague-Dawley rats. The key components were unstable under alk. conditions and in Caco-2 cell lysates or rat fecal lysates. The absorptive permeability coeff. followed the order MG > GA > PGG. The in vivo results exhibited similar pharmacokinetic trends to the in vitro studies. Addnl., the co-components in MSKE may affect the pharmacokinetic behaviors of the key components in MSKE. In conclusion, chem. degrdn. under alk. conditions, biol. degrdn. by intestinal cell and colonic microflora enzymes, and low absorptive permeability could be important factors underlying the oral bioavailability of these polyphenols.
- 37Li, L.; Shaik, A. A.; Zhang, J.; Nhkata, K.; Wang, L.; Zhang, Y.; Xing, C.; Kim, S. H.; Lu, J. Preparation of penta-O-galloyl-beta-D-glucose from tannic acid and plasma pharmacokinetic analyses by liquid-liquid extraction and reverse-phase HPLC. J. Pharm. Biomed. Anal. 2011, 54, 545– 550, DOI: 10.1016/j.jpba.2010.09.028Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsValt77K&md5=ff5e6c7a258c5d4bfa0ec06292ab979bPreparation of penta-O-galloyl-β-D-glucose from tannic acid and plasma pharmacokinetic analyses by liquid-liquid extraction and reverse-phase HPLCLi, Li; Shaik, Ahmad Ali; Zhang, Jinhui; Nhkata, Katai; Wang, Lei; Zhang, Yong; Xing, Chengguo; Kim, Sung-Hoon; Lue, JunxuanJournal of Pharmaceutical and Biomedical Analysis (2011), 54 (3), 545-550CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)The gallotannin penta-O-galloyl-beta-d-glucose (PGG) has many biol. activities including in vivo anti-cancer efficacy. We present in this paper a scaled-up protocol for its prepn. in high purity from tannic acid by acidic methanolysis with typical yield of 15%. We also describe a method for the anal. of PGG in mouse plasma by HPLC and its application in preliminary pharmacokinetic studies. A liq.-liq. extn. (LLE) protocol was optimized for the extn. of PGG from mouse plasma. The extn. efficiency for PGG at 1 μg/mL in mouse plasma was 70.0±1.3% (n = 5). The limit of detection (LOD) for PGG was approx. 0.2 μg/mL. Preliminary pharmacokinetic parameters of PGG following a single i.p. injection with 5% ethanol/saline vehicle in mice were established. The peak plasma PGG concns. (Cmax) were approx. 3-4 μM at a dose of 0.5 mg per mouse (∼20 mg/kg) at 2 h post-injection (Tmax).
- 38Ma, C.-x.; Zhao, X.; Wang, P.; Jia, P.; Zhao, X.-f.; Xiao, C.-n.; Zheng, X.-h. Metabolite characterization of Penta-O-galloyl-β-D-glucose in rat biofluids by HPLC-QTOF-MS. Chin. Herb. Med. 2018, 10, 73– 79, DOI: 10.1016/j.chmed.2018.01.002Google ScholarThere is no corresponding record for this reference.
- 39Hatcher, H. C.; Singh, R. N.; Torti, F. M.; Torti, S. V. Synthetic and natural iron chelators: therapeutic potential and clinical use. Future Med. Chem. 2009, 1, 1643– 1670, DOI: 10.4155/fmc.09.121Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtVejuw%253D%253D&md5=d4e0da1164fc51106fa87954c8116777Synthetic and natural iron chelators: therapeutic potential and clinical useHatcher, Heather C.; Singh, Ravi N.; Torti, Frank M.; Torti, Suzy V.Future Medicinal Chemistry (2009), 1 (9), 1643-1670CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)A review. Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the std. for this purpose was deferoxamine. Recently, considerable progress was made in identifying synthetic chelators with improved pharmacol. properties relative to deferoxamine. Most notable are deferasirox (Exjade) and deferiprone (Ferriprox), which are now available clin. In addn. to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases, and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochems., many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochem.
- 40Bairwa, G.; Hee Jung, W.; Kronstad, J. W. Iron acquisition in fungal pathogens of humans. Metallomics 2017, 9, 215– 227, DOI: 10.1039/C6MT00301JGoogle Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXisFShu7o%253D&md5=4ea94263eddbdb5ebb391697eec48840Iron acquisition in fungal pathogens of humansBairwa, Gaurav; Hee Jung, Won; Kronstad, James W.Metallomics (2017), 9 (3), 215-227CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)A review. In recent years, the contributions to virulence of reductive iron uptake, siderophore-mediated uptake and heme acquisition have been identified in the best studied and most life-threatening fungal pathogens: Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. In particular, exciting new work illustrates the importance of iron acquisition from heme and Hb in the virulence of pathogenic yeasts. However, the challenge of establishing how these fungi gain access to Hb in blood and to other sources of heme remains to be fully addressed. Recent studies are also expanding our knowledge of iron uptake in less-well studied fungal pathogens, including dimorphic fungi where new information reveals an integration of iron acquisition with morphogenesis and cell-surface properties for adhesion to host cells. Overall, the accumulating information provides opportunities to exploit iron acquisition for antifungal therapy, and new work highlights the development of specific inhibitors of siderophore biosynthesis and metal chelators for therapeutic use alone or in conjunction with existing antifungal drugs. It is clear that iron-related therapies will need to be customized for specific diseases because the emerging view is that fungal pathogens use different combinations of strategies for iron acquisition in the varied niches of vertebrate hosts.
- 41Gerwien, F.; Skrahina, V.; Kasper, L.; Hube, B.; Brunke, S. Metals in fungal virulence. FEMS Microbiol. Rev. 2018, 42, fux050, DOI: 10.1093/femsre/fux050Google ScholarThere is no corresponding record for this reference.
- 42Fourie, R.; Kuloyo, O. O.; Mochochoko, B. M.; Albertyn, J.; Pohl, C. H. Iron at the Centre of Candida albicans Interactions. Front. Cell. Infect. Microbiol. 2018, 8, 185, DOI: 10.3389/fcimb.2018.00185Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVKlt7bJ&md5=c74e5729d1eb31276caf3588c52f29deIron at the centre of Candida albicans interactionsFourie, Ruan; Kuloyo, Oluwasegun O.; Mochochoko, Bonang M.; Albertyn, Jacobus; Pohl, Carolina H.Frontiers in Cellular and Infection Microbiology (2018), 8 (), 185/1-185/14CODEN: FCIMAB; ISSN:2235-2988. (Frontiers Media S.A.)Iron is an abs. requirement for both the host and most pathogens alike and is needed for normal cellular growth. The acquisition of iron by biol. systems is regulated to circumvent toxicity of iron overload, as well as the growth deficits imposed by iron deficiency. In addn., hosts, such as humans, need to limit the availability of iron to pathogens. However, opportunistic pathogens such as Candida albicans are able to adapt to extremes of iron availability, such as the iron replete environment of the gastrointestinal tract and iron deficiency during systemic infection. C. albicans has developed a complex and effective regulatory circuit for iron acquisition and storage to circumvent iron limitation within the human host. As C. albicans can form complex interactions with both commensal and pathogenic co-inhabitants, it can be speculated that iron may play an important role in these interactions. In this review, we highlight host iron regulation as well as regulation of iron homeostasis in C. albicans. In addn., the review argues for the need for further research into the role of iron in polymicrobial interactions. Lastly, the role of iron in treatment of C. albicans infection is discussed.
- 43Dittmar, W.; Lohaus, G. HOE 296, a new antimycotic compound with a broad antimicrobial spectrum. Laboratory results. Arzneimittelforschung 1973, 23, 670– 674Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE3s7psVCgsA%253D%253D&md5=273934aa56cb9f73fecf1ac31b488a5cHOE 296, a new antimycotic compound with a broad antimicrobial spectrum. Laboratory resultsDittmar W; Lohaus GArzneimittel-Forschung (1973), 23 (5), 670-4 ISSN:0004-4172.There is no expanded citation for this reference.
- 44Subissi, A.; Monti, D.; Togni, G.; Mailland, F. Ciclopirox. Drugs 2010, 70, 2133– 2152, DOI: 10.2165/11538110-000000000-00000Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbht1aktg%253D%253D&md5=bcebda6fa862d4306dac52c100f7778fCiclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agentSubissi Alessandro; Monti Daniela; Togni Giuseppe; Mailland FedericoDrugs (2010), 70 (16), 2133-52 ISSN:.Ciclopirox is a topical antimycotic agent belonging to the chemical class of hydroxypyridones and not related to azoles or any other class of antifungal agents. Its antimicrobial profile includes nearly all of the clinically relevant dermatophytes, yeasts and moulds, and is therefore broader than that of most other antimycotics. It is also active against certain frequently azole-resistant Candida species and against some bacteria. The mechanism of action of ciclopirox is different from that of other topical antifungal drugs, which generally act through ergosterol inhibition. The high affinity of ciclopirox for trivalent metal cations, resulting in inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell, appears to be the major determinant of its antimicrobial activity. This unique and multilevel mechanism of action provides a very low potential for the development of resistance in pathogenic fungi, with cases of resistance rarely reported. Ciclopirox also displays mild anti-inflammatory effects in biochemical and pharmacological models; effects also shown in small clinical studies. Scavenging of reactive oxygen species released from inflammatory cells is a likely contributor to these anti-inflammatory effects. Ciclopirox, and its olamine salt, is available in multiple topical formulations, suitable for administration onto the skin and nails and into the vagina. The pharmaceutical forms most widely investigated are 1% ciclopirox olamine cream and 8% ciclopirox acid nail lacquer, but lotion, spray, shampoo, pessary, solution, gel and douche formulations have also been used. Ciclopirox penetrates into the deep layers of the skin, mucosal membranes and nail keratin, reaching concentrations exceeding the minimal fungicidal concentrations for most medically important fungi. A large number of clinical trials were and are still being performed with ciclopirox, starting in the early 1980s. Ciclopirox was first developed for fungal skin infections and vaginal candidiasis, and is currently well established in these indications. More recently, the drug has been clinically investigated in seborrhoeic dermatitis and onychomycosis, showing good efficacy and excellent tolerability. Emphasis in this review is given to a ciclopirox medicated nail lacquer, which is based on an original technology and has superior properties in terms of its affinity to keratin and nail permeation. It has been found to have superior efficacy and safety to another commercially available formulation in the treatment of onychomycosis. The safety features of ciclopirox are well known. The topical drug is devoid of systemic adverse reactions. Mild local reactions characterized by a burning sensation of the skin, irritation, redness, pain or pruritus, generally in less than 5% of treated patients, can be observed following skin and vaginal application. With nail application, the most common adverse event is the appearance of mild erythema in 5% of the treated population. As a general conclusion, although less effective than some oral antimycotic agents in various indications, ciclopirox compares very well in terms of the benefit/risk ratio due to its excellent tolerability and complete absence of serious adverse effects.
- 45Niewerth, M.; Kunze, D.; Seibold, M.; Schaller, M.; Korting, H. C.; Hube, B. Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors. Antimicrob. Agents Chemother. 2003, 47, 1805– 1817, DOI: 10.1128/AAC.47.6.1805-1817.2003Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktlymt7g%253D&md5=d8991b12cf9c1673b62c4a767fa530a1Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins and drug resistance factorsNiewerth, Markus; Kunze, Donika; Seibold, Michael; Schaller, Martin; Korting, Hans Christian; Hube, BernhardAntimicrobial Agents and Chemotherapy (2003), 47 (6), 1805-1817CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examd. the expression patterns of 47 Candida albicans genes in cells grown in the presence of a subinhibitory concn. (0.6 μg/mL) of ciclopirox olamine by reverse transcription-PCR. In addn., we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such as ACT1 was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up- or down-regulation of genes encoding iron permeases or transporters (FTR1, FTR2, FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addn. of FeCl3 to ciclopirox olamine-treated cells reversed the effect of the drug. Addn. of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1, FTR2). While serum-induced yeast-to-hyphal phase transition of C. albicans was not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-contg. gene products responsible for detoxification. Although the Candida drug resistance genes CDR1 and CDR2 were up-regulated, no change in resistance or increased tolerance could be obsd. even after an incubation period of 6 mo. This was in contrast to control expts. with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 mo. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms caused C. albicans resistance to this drug even after long-term exposure.
- 46Lee, R. E. B.; Liu, T. T.; Barker, K. S.; Lee, R. E.; Rogers, P. D. Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans. J. Antimicrob. Chemother 2005, 55, 655– 662, DOI: 10.1093/jac/dki105Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjvFymu7g%253D&md5=b7ee3367cc8be2231544d36ffd0112f6Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicansLee, Robin E. B.; Liu, Teresa T.; Barker, Katherine S.; Lee, Richard E.; Rogers, P. DavidJournal of Antimicrobial Chemotherapy (2005), 55 (5), 655-662CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)The aim of this study was to identify changes in the gene expression profile of Candida albicans upon exposure to the hydroxypyridone anti-infective agent ciclopirox olamine in an effort to better understand its mechanism of action. C. albicans SC5314 was exposed to either medium alone or ciclopirox olamine at a concn. equiv. to the IC50 (0.24 mg/L) for 3 h. RNA was isolated and gene expression profiles were compared using DNA microarrays. Differential expression of select genes was confirmed by real-time reverse transcription (RT)-PCR. Mutants disrupted for CDR2 and both CDR1 and CDR2, as well as a clin. isolate overexpressing CDR1 and CDR2, were examd. for changes in susceptibility to ciclopirox olamine. A total of 49 genes were found to be responsive to ciclopirox olamine, including 36 up-regulated genes and 13 down-regulated genes. These included genes involved in small mol. transport (HGT11, HXT5, ENA22, PHO84, CDR4), iron uptake (FRE30, FET34, FTR1, FTR2, SIT1) and cell stress (SOD1, SOD22, CDR1, DDR48). Mutants disrupted for CDR2 and both CDR1 and CDR2, as well as a clin. isolate overexpressing CDR1 and CDR2, showed no change in susceptibility to ciclopirox olamine compared with the resp. parent. Consistent with the hypothesis that ciclopirox olamine acts as an iron chelator, it induced changes in expression of many genes involved in iron uptake. Despite induction of the multidrug efflux pump genes CDR1 and, to a lesser extent, CDR2 by ciclopirox olamine, these genes do not affect susceptibility to this agent.
- 47Sigle, H.-C.; Thewes, S.; Niewerth, M.; Korting, H. C.; Schäfer-Korting, M.; Hube, B. Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans. J. Antimicrob. Chemother 2005, 55, 663– 673, DOI: 10.1093/jac/dki089Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjvFymurg%253D&md5=cab6a167d4d90afc810522e24c3343b9Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicansSigle, Hans-Christian; Thewes, Sascha; Niewerth, Markus; Korting, Hans Christian; Schaefer-Korting, Monika; Hube, BernhardJournal of Antimicrobial Chemotherapy (2005), 55 (5), 663-673CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)Ciclopirox is a topical antifungal agent of the hydroxypyridone class whose mode of action is poorly understood. In order to elucidate the mechanism of action of ciclopirox, we analyzed the growth, cellular integrity, biochem. properties, viability and transcriptional profile of the polymorphic yeast Candida albicans following exposure to this antifungal agent. Multiple biochem. assays served to identify factors that were crit. for antifungal activity and to identify proteins whose activities changed in drug-exposed cells. Genome-wide transcriptional profiling was used to identify genes that were up-regulated in response to the cellular effects of the drug. Ciclopirox inhibited growth of C. albicans yeast and hyphal cells in a dose-dependent manner. This effect was reduced (i) by the addn. of iron ions or the metabolic inhibitor 2-deoxy-D-glucose to growth media, (ii) in media that lacked glucose, and (iii) for cells that were pre-incubated with hydrogen peroxide or menadione [which caused induction of proteins involved in detoxification of reactive oxygen species (ROS)]. In contrast, cells pre-cultured under poor oxygen conditions (which had decreased activity of proteins involved in ROS detoxification) were more susceptible to ciclopirox. Treatment with ciclopirox did not directly cause cell membrane damage and did not change intracellular levels of ATP. Finally, the transcriptional profiling pattern of drug-treated cells strongly resembled iron-limited conditions. These data indicate that metabolic activity, oxygen accessibility and iron levels are crit. parameters in the mode of action of ciclopirox olamine.
- 48Linden, T.; Katschinski, D. M.; Eckhardt, K.; Scheid, A.; Pagel, H.; Wenger, R. H. The antimycotic ciclopirox olamine induces HIF-1α stability, VEGF expression, and angiogenesis. FASEB J. 2003, 17, 761– 763, DOI: 10.1096/fj.02-0586fjeGoogle Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXislGlt70%253D&md5=dd39c593d247c43036f591011d5b308aThe antimycotic ciclopirox olamine induces HIF-1α stability, VEGF expression, and angiogenesisLinden, Tobias; Katschinski, Dorthe M.; Eckhardt, Katrin; Scheid, Annette; Pagel, Horst; Wenger, Roland H.FASEB Journal (2003), 17 (6), 761-763, 10.1096/fj.0586fjeCODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)The heterodimeric hypoxia-inducible factor (HIF)-1 is a master regulator of oxygen homeostasis. Protein stability and transactivation function of the a subunit are controlled by iron- and oxygen-dependent hydroxylation of proline and asparagine residues. The anti-mycotic ciclopirox olamine (CPX) is a lipophilic bidentate iron chelator that stabilizes HIF-1α under normoxic conditions at lower concns. than other iron chelators, probably by inhibiting HIF-1α hydroxylation. As shown by the inhibition of iron-dependent quenching of FITC-labeled deferoxamine (DFX) fluorescence, CPX appears to have an even higher affinity for iron than DFX. Initial observations that treatment with 1% CPX, but not with placebo, occasionally caused reddening of wound margins in a mouse skin wound model prompted us to investigate the capability of CPX to induce angiogenesis. CPX-induced HIF-1-mediated reporter gene activity and endogenous HIF-1 target gene expression, including elevation of transcription, mRNA, and protein levels of the vascular endothelial growth factor (VEGF). In the chick chorioallantoic membrane assay, inert polymer disks contg. CPX but not the solvent alone induced angiogenesis. In summary, these results suggest that CPX induces angiogenesis in vivo via HIF-1 and VEGF induction. Therefore, CPX might serve as an alternative to recombinant VEGF treatment or to VEGF gene therapy for therapeutic angiogenesis.
- 49Skrzypek, M. S.; Binkley, J.; Binkley, G.; Miyasato, S. R.; Simison, M.; Sherlock, G. Candida Genome Database: C. albicans HAP43/C1_11210C.. http://www.candidagenome.org/cgi-bin/locus.pl?dbid=CAL0000188360, (accessed 06-27-2023).Google ScholarThere is no corresponding record for this reference.
- 50Zinatizadeh, M. R.; Schock, B.; Chalbatani, G. M.; Zarandi, P. K.; Jalali, S. A.; Miri, S. R. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases. Genes Dis. 2021, 8, 287– 297, DOI: 10.1016/j.gendis.2020.06.005Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFCis7jP&md5=9a6723bc94f65d06e93b0a4f7dc1e26dThe Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseasesZinatizadeh, Mohammad Reza; Schock, Bettina; Chalbatani, Ghanbar Mahmoodi; Zarandi, Peyman Kheirandish; Jalali, Seyed Amir; Miri, Seyed RouhollahGenes and Diseases (2021), 8 (3), 287-297CODEN: GDEIAV; ISSN:2352-3042. (Elsevier B.V.)The nuclear factor kappa B (NF-kB) family of transcription factors plays an essential role as stressors in the cellular environment, and controls the expression of important regulatory genes such as immunity, inflammation, death, and cell proliferation. NF-kB protein is located in the cytoplasm, and can be activated by various cellular stimuli. There are two pathways for NF-kB activation, as the canonical and non-canonical pathways, which require complex mol. interactions with adapter proteins and phosphorylation and ubiquitinase enzymes. Accordingly, this increases NF-kB translocation in the nucleus and regulates gene expression. In this study, the concepts that emerge in different cellular systems allow the design of NF-kB function in humans. This would not only allow the development for rare diseases assocd. with NF-kB, but would also be used as a source of useful information to eliminate widespread consequences such as cancer or inflammatory/immune diseases.
- 51Xiong, S.; She, H.; Takeuchi, H.; Han, B.; Engelhardt, J. F.; Barton, C. H.; Zandi, E.; Giulivi, C.; Tsukamoto, H. Signaling Role of Intracellular Iron in NF-κB Activation*. J. Biol. Chem. 2003, 278, 17646– 17654, DOI: 10.1074/jbc.M210905200Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjs1KisbY%253D&md5=1055d0d77effd87f949ba1dd1c85dadcSignaling Role of Intracellular Iron in NF-κB ActivationXiong, Shigang; She, Hongyun; Takeuchi, Heigo; Han, Bora; Engelhardt, John F.; Barton, C. H.; Zandi, Ebrahim; Giulivi, Cecilia; Tsukamoto, HidekazuJournal of Biological Chemistry (2003), 278 (20), 17646-17654CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Iron chelators inhibit endotoxin-induced NF-κB activation in hepatic macrophages (HMs), suggesting a role for the intracellular chelatable pool of iron in NF-κB activation. The present study tested this hypothesis. Anal. of Fe59-loaded HMs stimulated with lipopolysaccharide (LPS), revealed a previously unreported, transient rise in intracellular low mol. wt. (LMW)·Fe59 complex ([LMW·Fe]i) at ≤2 min returning to the basal level within 15 min. The [LMW·Fe]i response preceded IκB kinase (IKK) (≥15 min) and NF-κB (≥30 min) activation. Iron chelators (1,2-dimethyl-3-hydroxypyridin-4-one and N,N'-bis-2-hydroxybenzylethylenediamine-N,N'-diacetic acid) abrogated the [LMW·Fe]i response and IKK and NF-κB activation. The [LMW·Fe]i response was also obsd. in tumor necrosis factor α (TNFα)-stimulated HMs and RAW264.7 cells treated with LPS and interferon-γ but not in primary rat hepatocytes or myofibroblastic cells exposed to LPS or TNFα. Both [LMW·Fe]i response and IKK activation in LPS-stimulated HMs were inhibited by diphenylene iodonium (nonspecific inhibitor for flavin-contg. oxidases), L-N6-(1-iminoethyl)lysine (selective iNOS inhibitor), and adenoviral-mediated expression of a dominant neg. mutant of Rac1 or Cu,Zn-superoxide dismutase, suggesting the role of NO and O in mediating the iron signaling. In fact, this inhibition was recapitulated by a cell-permeable scavenger of ONOO-, 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinato iron (III) chloride. Conversely, ONOO- alone induced both [LMW·Fe]i response and IKK activation. Finally, direct addn. of ferrous iron to cultured HMs activated IKK and NF-κB. These results support a novel signaling role for [LMW·Fe]i in IKK activation, which appears to be induced by ONOO- and selectively operative in macrophages.
- 52She, H.; Xiong, S.; Lin, M.; Zandi, E.; Giulivi, C.; Tsukamoto, H. Iron activates NF-κB in Kupffer cells. Am. J. Physiol.: Gastrointest. Liver Physiol. 2002, 283, G719– G726, DOI: 10.1152/ajpgi.00108.2002Google ScholarThere is no corresponding record for this reference.
- 53Kim, B. M.; Choi, J. Y.; Kim, Y. J.; Woo, H. D.; Chung, H. W. Desferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage response. Toxicology 2007, 229, 226– 235, DOI: 10.1016/j.tox.2006.10.022Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1arsA%253D%253D&md5=1191002f61a254b33ade9db623c8f77cDesferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage responseKim, Byeong Mo; Choi, Jun Yeol; Kim, Yang Jee; Woo, Hae Dong; Chung, Hai WonToxicology (2007), 229 (3), 226-235CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Ltd.)Desferrioxamine (DFX), which is an iron chelator, mimics hypoxia by enhancing HIF1-α accumulation and upregulating inflammatory mediators. DFX is usually beneficial, with preventive effects related primarily to its ability to scavenge reactive oxygen species. However, toxic effects on skeletal and ocular organs have been reported. The cytokinesis block micronucleus test and alk. single-cell gel (Comet) assay were used to evaluate the genotoxic effects of DFX on human blood lymphocytes. Cultured human lymphocytes treated with 130 μM DFX for various periods of time showed significant differences in the incidence of micronucleated binucleate cells, as well as in the length and moment of the comet tail. Western blot anal. using antibodies to proteins involved in the p53-mediated response to DNA damage revealed that p53 was accumulated and DNA damage checkpoint kinases were activated in lymphocytes treated with DFX. The p53 downstream target proteins p21 and bax were not affected, which indicates that DFX does not promote the transactivational activity of p53. Apoptosis assays demonstrated DFX-induced apoptosis of lymphocytes via the caspase cascade. The obsd. increase in the sub-G1 fraction and enhanced caspase-3 activity indicate that DFX can promote apoptosis in human lymphocytes, and these results were confirmed by protein immunoblot anal. As apoptotic cell death is preceded by the collapse of the mitochondrial membrane potential, we also measured the mitochondrial membrane potential (Δψ m) using DiOC6, which is a fluorescent membrane potential probe. The fluorescence intensity of DiOC6 in lymphocytes was significantly reduced in a time-dependent manner after DFX treatment. Taken together, these results indicate that DFX activates p53-mediated checkpoint signals and induces apoptosis via mitochondrial damage in human peripheral blood lymphocytes.
- 54Liang, S. X.; Richardson, D. R. The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1. Carcinogenesis 2003, 24, 1601– 1614, DOI: 10.1093/carcin/bgg116Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXotVCls7g%253D&md5=f5a5e29c06888ad5792bd0e2c0f69306The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1Liang, S. X.; Richardson, D. R.Carcinogenesis (2003), 24 (10), 1601-1614CODEN: CRNGDP; ISSN:0143-3334. (Oxford University Press)Iron (Fe) chelators induce a G1/S arrest and several of these are undergoing clin. trials as anticancer agents. Despite this, little is known concerning the precise function of Fe in cell cycle progression and the role of p53 in this process. The aim of this study was to assess the effect of Fe chelators on p53 and the mechanism involved in the chelator-mediated increase in mRNA levels of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1. Cells were incubated with the potent Fe chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) and the results compared with those from cells treated with actinomycin D (Act D), which induces p53. Following incubation with 311, a 3- to 5-fold increase in nuclear p53 protein was obsd. in cells with wild-type p53. In addn., 311 increased p53 DNA-binding activity 2-fold, while Act D increased it 3- to 5-fold in cells with native p53. To det. the role of p53 in WAF1 transcription, a reporter construct was used consisting of a WAF1 promoter contg. the p53-binding site. In cells with wild-type p53, chelators had no effect on luciferase activity, while the pos. control, Act D, caused a significant increase. Hence, despite increased p53 protein expression and p53 DNA-binding activity following chelation, these latter results suggested it had no role in up-regulating WAF1 mRNA. Our expts. demonstrated: (i) that the elevated WAF1 mRNA expression after Fe chelation was due to increased transcription and also to a post-transcriptional mechanism that was sensitive to cycloheximide; and (ii) that Fe-chelation increased WAF1 expression through a p53-independent pathway.
- 55Torres-León, C.; Ventura-Sobrevilla, J.; Serna-Cock, L.; Ascacio-Valdés, J. A.; Contreras-Esquivel, J.; Aguilar, C. N. Pentagalloylglucose (PGG): A valuable phenolic compound with functional properties. J. Funct. Foods 2017, 37, 176– 189, DOI: 10.1016/j.jff.2017.07.045Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1OitLjI&md5=6c46f633ad3082101b033433ae7fa655Pentagalloylglucose (PGG): A valuable phenolic compound with functional propertiesTorres-Leon, Cristian; Ventura-Sobrevilla, Janeth; Serna-Cock, Liliana; Ascacio-Valdes, Juan A.; Contreras-Esquivel, Juan; Aguilar, Cristobal N.Journal of Functional Foods (2017), 37 (), 176-189CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)1,2,3,4,6-Penta-O-Galloyl-β-D-Glucose (PGG) is a hydrolysable tannin that belongs to the group of gallotannins but also participates in the formation of ellagitannins. PGG is composed of five galloyl groups with a glucose at its core and has structural characteristics that confer a high biol. power. In this paper, we describe the chem. of PGG, which is analyzed from a crit. point regarding the types of synthesis, new sources of prodn. from plants and byproducts, highlighting the PGG obtaining, and its main functional properties recently reported in scientific literature. PGG has attracted attention because of its therapeutic potential and has shown functional properties as antimicrobial, anti-inflammatory, anti-carcinogenic, antidiabetic and antioxidant. Bioconversion from tannic acid can be potentialized with the use of biotechnol. techniques. PGG can be obtained from natural sources as byproducts. Research should continue to obtain pure mols., in adequate quantity and with great biol. activity.
- 56Lee, Y.; Hossain, S.; MacAlpine, J.; Robbins, N.; Cowen, L. E. Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environments. iScience 2023, 26, 106145 DOI: 10.1016/j.isci.2023.106145Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXjtl2mt7c%253D&md5=f1fcbdc61505a2fe2c6cd9836492c273Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environmentsLee, Yunjin; Hossain, Saif; MacAlpine, Jessie; Robbins, Nicole; Cowen, Leah E.iScience (2023), 26 (3), 106145CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)Candida albicans is a leading cause of mycotic infection. The ability to transition between yeast and filamentous forms is crit. to C. albicans virulence and complex signaling pathways regulate this process. Here, we screened a C. albicans protein kinase mutant library in six environmental conditions to identify regulators of morphogenesis. We identified the uncharacterized gene orf19.3751 as a neg. regulator of filamentation and follow-up investigations implicated a role for orf19.3751 in cell cycle regulation. We also uncovered a dual role for the kinases Ire1 and protein kinase A (Tpk1 and Tpk2) in C. albicans morphogenesis, specifically as neg. regulators of wrinkly colony formation on solid medium but pos. regulators of filamentation in liq. medium. Further analyses suggested Ire1 modulates morphogenesis in both media states in part through the transcription factor Hac1 and in part through independent mechanisms. Overall, this work provides insights into the signaling governing morphogenesis in C. albicans.
- 57Homann, O. R.; Dea, J.; Noble, S. M.; Johnson, A. D. A Phenotypic Profile of the Candida albicans Regulatory Network. PLoS Genet. 2009, 5, e1000783 DOI: 10.1371/journal.pgen.1000783Google ScholarThere is no corresponding record for this reference.
- 58Clinical and Laboratory Standards Institute, Performance standards for antimicrobial susceptibility testing: twenty-third informational supplement ; M100 - S23. CLSI: 2013.Google ScholarThere is no corresponding record for this reference.
- 59Odds, F. C. Synergy, antagonism, and what the chequerboard puts between them. J. Antimicrob. Chemother. 2003, 52, 1, DOI: 10.1093/jac/dkg301Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltVWjsr0%253D&md5=b214be21ff21422856db140f8c4a0fd0Synergy, antagonism, and what the chequerboard puts between themOdds, F. C.Journal of Antimicrobial Chemotherapy (2003), 52 (1), 1CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)There is no expanded citation for this reference.
- 60Leite, M. C. A.; Bezerra, A. P. d. B.; Sousa, J. P. d.; Guerra, F. Q. S.; Lima, E. d. O. Evaluation of antifungal activity and mechanism of action of citral against Candida albicans. J. Evidence-Based Complementary Altern. Med. 2014, 2014, 378280 DOI: 10.1155/2014/378280Google ScholarThere is no corresponding record for this reference.
- 61Singh, S. D.; Robbins, N.; Zaas, A. K.; Schell, W. A.; Perfect, J. R.; Cowen, L. E. Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog. 2009, 5, e1000532 DOI: 10.1371/journal.ppat.1000532Google ScholarThere is no corresponding record for this reference.
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Abstract
Figure 1
Figure 1. Chemical structure of penta-O-galloyl-β-d-glucose, PGG.
Figure 2
Figure 2. Penta-O-galloyl-β-d-glucose displays broad spectrum anti-Candida activity. Growth inhibition of PGG against (A) C. albicans, (B) C. glabrata, (C) C. parapsilosis, and (D) C. auris. Solid lines represent PGG. Dashed lines represent the positive control fluconazole. The data are plotted as the mean % growth inhibition ± SD as compared to the DMSO vehicle from two independent experiments. The horizontal dotted line represents 90% growth inhibition. See Supplemental Figures S8–S11 for expanded graphs including additional positive controls. See Table 2 for strain details.
Figure 3
Figure 3. PGG sensitivity in C. albicans is not modulated by efflux pumps. The cdr1Δ/Δ, cdr2Δ/Δ, mdr1Δ/Δ, flu1Δ/Δ, and wild-type strains were grown overnight in YPD and subject to dose–response assays in RPMI-1640 medium with twofold dilution gradients of PGG. Fluconazole was included as a positive control. Growth (OD600nm) was measured after 72 h of incubation at 30 °C, averaged between technical duplicates, and normalized to the drug-free wild-type control. Results are presented in a heat-map format with a scale bar provided at the bottom of the figure. All assays were performed in biological duplicates.
Figure 4
Figure 4. Growth inhibition of PGG against multiple Candida species is abrogated by iron supplementation, and PGG binds multiple iron ions. (A) C. albicans 90028, (B) C. glabrata CDC325, and (C) C. auris CDC381 were treated with PGG or Amphotericin B at varying concentrations (4, 8, and 16 μg/mL) and media was supplemented with a 10 mM solution of ferrous sulfate (Fe2+) or ferric sulfate (Fe3+) and % growth inhibition measured after 48 h. The data are plotted as the mean % growth inhibition ± SD as compared to the DMSO vehicle from two independent experiments. The horizontal dotted line represents 90% growth inhibition compared to the vehicle. Statistical analysis was done using two-way ANOVA with multiple comparisons. (D) PGG or EGCG was allowed to react with varying concentrations of iron (III) in solution at pH 2.0. The bipy solution was added to the mixtures and the formation of the [Fe(bipy)3]2+ complex was measured at 520 nm. [PGG]total, [EGCG]total = 10 μM. The data are plotted as the mean absorbance ± SD from two independent experiments.
Figure 5
Figure 5. Iron homeostasis genes are required for PGG tolerance in C. albicans. The ire1Δ/ire1Δ, hap43Δ/hap43Δ, and rim101Δ/rim101Δ strains and their respective wild-type controls were grown overnight in YPD and subject to dose–response assays in RPMI-1640 medium with twofold dilution gradients of PGG. The metal chelator BPS was included as a positive control. After 48 h incubation at 30 °C, the relative viable cell number was assessed. Data were averaged between technical duplicates and normalized to wild-type drug-free control wells. Results are presented in a heat-map format with a color scale bar presented at the bottom of the figure. All assays were performed in biological duplicates.
References
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- 1Limon, J. J.; Skalski, J. H.; Underhill, D. M. Commensal Fungi in Health and Disease. Cell Host Microbe 2017, 22, 156– 165, DOI: 10.1016/j.chom.2017.07.0021https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlSgsL3K&md5=9398257c3f22ec7e55ae8ed6644566a3Commensal Fungi in Health and DiseaseLimon, Jose J.; Skalski, Joseph H.; Underhill, David M.Cell Host & Microbe (2017), 22 (2), 156-165CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)Fungi are increasingly being recognized as common members of the microbiomes found on nearly all mucosal surfaces, and interest is growing in understanding how these organisms may contribute to health and disease. In this review, we investigate recent developments in our understanding of the fungal microbiota or "mycobiota" including challenges faced in characterizing it, where these organisms are found, their diversity, and how they interact with host immunity. Growing evidence indicates that, like the bacterial microbiota, the fungal microbiota is often altered in disease states, and increasingly studies are being designed to probe the functional consequences of such fungal dysbiosis on health and disease.
- 2Neville, B. A.; d’Enfert, C.; Bougnoux, M.-E. Candida albicans commensalism in the gastrointestinal tract. FEMS Yeast Res 2015, 15, fov081, DOI: 10.1093/femsyr/fov081There is no corresponding record for this reference.
- 3Bilal, H.; Hou, B.; Shafiq, M.; Chen, X.; Shahid, M. A.; Zeng, Y. Antifungal susceptibility pattern of Candida isolated from cutaneous candidiasis patients in eastern Guangdong region: A retrospective study of the past 10 years. Front. Microbiol. 2022, 13, 981181 DOI: 10.3389/fmicb.2022.9811813https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB28%252FksVClsA%253D%253D&md5=c4c77133a7563baaaa8dc95420d060c9Antifungal susceptibility pattern of Candida isolated from cutaneous candidiasis patients in eastern Guangdong region: A retrospective study of the past 10 yearsBilal Hazrat; Chen Xinyu; Zeng Yuebin; Hou Bing; Shafiq Muhammad; Shahid Muhammad AkbarFrontiers in microbiology (2022), 13 (), 981181 ISSN:1664-302X.Cutaneous candidiasis is one of the most prevalent mycotic infections caused by Candida species. The severity of infection mounts faster when the species shows antifungal resistance. In the current retrospective study, we aimed to analyze the occurrence, causes of cutaneous candidiasis, and antifungal susceptibility pattern of Candida isolates from Skin and Venereal Diseases Prevention and Control Hospital of Shantou, located in eastern Guangdong, China. The laboratory data of all patients (n = 3,113) suffering from various skin and venereal infections during January 2012 to December 2021 was analyzed through Excel and GraphPad prism. Our analysis indicate that cutaneous candidiasis was 22.29% (n = 694), of which 78.53% (n = 554) of patients were males and 21.47% (n = 149) of patients were females. The median age of patients with cutaneous candidiasis was 38-year [interquartile range (30-48)]. Most cases occurred in the adult age group (19-50 years). Regarding the species type, the Candida albicans were prominently detected (n = 664, 95.68%), while non-C. albicans were found only in 30 (4.32%) patients, which were C. glabrata (n = 18), C. krusei (n = 8), C. tropicalis (n = 3), and C. parapsilosis (n = 1). The C. albicans susceptibility rate for terbinafine, miconazole, voriconazole, itraconazole, fluconazole, ketoconazole, nystatin, 5-flucytosine and amphotericin B were 10.83, 29.32, 59.39, 78.53, 85.28, 87.75, 99.59, 99.41, and 100%, respectively. Finally, all C. glabrata isolates were found susceptible to all tested azole drugs with exception to miconazole against which 8.33% of isolates showed resistance. The findings of this study will help healthcare officials to establish better antifungal stewardship in the region.
- 4Khodadadi, H.; Zomorodian, K.; Nouraei, H.; Zareshahrabadi, Z.; Barzegar, S.; Zare, M. R.; Pakshir, K. Prevalence of superficial-cutaneous fungal infections in Shiraz, Iran: A five-year retrospective study (2015–2019). J. Clin. Lab. Anal. 2021, 35, e23850 DOI: 10.1002/jcla.238504https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVOmsLvO&md5=ee1f9e11eed25a4333f9183b9b660663Prevalence of superficial-cutaneous fungal infections in Shiraz, Iran: A five-year retrospective study (2015-2019)Khodadadi, Hossein; Zomorodian, Kamiar; Nouraei, Hasti; Zareshahrabadi, Zahra; Barzegar, Sajjad; Zare, Mohammad Reza; Pakshir, KeyvanJournal of Clinical Laboratory Analysis (2021), 35 (7), e23850CODEN: JCANEM; ISSN:1098-2825. (Wiley-Blackwell)Superficial and cutaneous fungal infections are common in tropical areas. The aim of this study was to provide a basic database of superficial and cutaneous mycoses and the most common etiol. agents among patients. Between 2015 and 2019, a total of 1807 patients suspected of superficial and cutaneous mycosis referring to the mycol. lab. of Shiraz medical school, Fars, Iran were evaluated. Specimens were taken from the patients' affected area, and clin. samples were examd. by direct microscopy and culture. The epidemiol. profile of the patients was collected. A total of 750 patients were confirmed with mycoses. Pos. samples totaled 750 cases consisting of the nail (373/49.7%), skin (323/43%), head (47/6.26%), and mucosal membrane (4/0.5%). The yeasts group included 304 Candida spp. (70.3%), 123 Malassezia spp. (28.47%), and 5 Rhodotorula spp. (1.1%). The filamentous fungi were distributed as 34.8% dermatophytes and 7.5% non-dermatophyte. The clin. types of dermatophytosis were tinea unguium (110/261), tinea capitis (50/261), tinea pedis (48/261), tinea corporis (37/261), and tinea cruris (16/261). Non-dermatophyte molds included A. flavus 17, A. niger 4, Aspergillus spp. 15, Penicillium. 10, Fusarium 6, Mucor 2, Stemphylium 1, and Alternaria 1. This study provides useful data for the study trends of superficial and cutaneous fungal infections in a specific area. The mycol. data confirmed higher incidence of candidiasis (mainly onychomycosis) and dermatophytosis in patients affected by fungal pathogens, which helped to better understand the epidemiol. aspects of these mycoses.
- 5Otašević, S.; Momčilović, S.; Golubović, M.; Ignjatović, A.; Rančić, N.; Đorđević, M.; Ranđelović, M.; Hay, R.; Arsić-Arsenijević, V. Species distribution and epidemiological characteristics of superficial fungal infections in Southeastern Serbia. Mycoses 2019, 62, 458– 465, DOI: 10.1111/myc.129005https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnsV2kt70%253D&md5=9d51a4f6c02f4f1b56dac098492fd1e2Species distribution and epidemiological characteristics of superficial fungal infections in Southeastern SerbiaOtasevic, Suzana; Momcilovic, Stefan; Golubovic, Milan; Ignjatovic, Aleksandra; Rancic, Natasa; Dordevic, Marina; Randelovic, Marina; Hay, Roderick; Arsic-Arsenijevic, ValentinaMycoses (2019), 62 (5), 458-465CODEN: MYCSEU; ISSN:1439-0507. (Wiley-Blackwell)Summary : Background : Superficial fungal infections (SFI), one of the most prevalent diseases in the world, are infections of keratin-rich structures of human body mostly caused by dermatophytes and yeasts. Objectives : The goal of this study was to det. the possible changes in the epidemiol. of SFI on the territory of Southeastern Serbia and to investigate epidemiol. characteristics and the influence of SFI on the patient's quality of life. Methods : From 2012 to the end of 2017, samples of 1643 patients (568 males and 1075 females, mean age 40.32 ± 22.44 years) with suspected SFI from Southeastern Serbia were examd. using the std. mycol. methods. The questionnaires were used to investigate epidemiol. characteristics. Results : Superficial fungal infections were diagnosed in 20.5% (n = 336) of patients. In the group of dermatophytes, the most prevalent was Microsporum canis (63.9%, n = 76) followed by Trichophyton mentagrophytes (21.8%, n = 26). Non-albicans Candida species were dominant etiol. agents of superficial candidosis (62.3%). BMI ≥25 kg/m2 (P = 0.019) was detd. as an independent risk factor for SFI. There was a statistically significant difference in the EQVAS score between the groups of patients and the control group (P < 0.001). Conclusions : Results of conducted study indicate that SFI prevalence has not changed in the previous period. However, increase of Candida-SFI prevalence, esp. Candida onychomycosis, was established.
- 6Pappas, P. G.; Lionakis, M. S.; Arendrup, M. C.; Ostrosky-Zeichner, L.; Kullberg, B. J. Invasive candidiasis. Nat. Rev. Dis. Primers 2018, 4, 18026, DOI: 10.1038/nrdp.2018.266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MfitVymtA%253D%253D&md5=a56107bdcf357205a0f0298c225623e3Invasive candidiasisPappas Peter G; Lionakis Michail S; Arendrup Maiken Cavling; Arendrup Maiken Cavling; Arendrup Maiken Cavling; Ostrosky-Zeichner Luis; Kullberg Bart JanNature reviews. Disease primers (2018), 4 (), 18026 ISSN:.Invasive candidiasis is an important health-care-associated fungal infection that can be caused by several Candida spp.; the most common species is Candida albicans, but the prevalence of these organisms varies considerably depending on geographical location. The spectrum of disease of invasive candidiasis ranges from minimally symptomatic candidaemia to fulminant sepsis with an associated mortality exceeding 70%. Candida spp. are common commensal organisms in the skin and gut microbiota, and disruptions in the cutaneous and gastrointestinal barriers (for example, owing to gastrointestinal perforation) promote invasive disease. A deeper understanding of specific Candida spp. virulence factors, host immune response and host susceptibility at the genetic level has led to key insights into the development of early intervention strategies and vaccine candidates. The early diagnosis of invasive candidiasis is challenging but key to the effective management, and the development of rapid molecular diagnostics could improve the ability to intervene rapidly and potentially reduce mortality. First-line drugs, including echinocandins and azoles, are effective, but the emergence of antifungal resistance, especially among Candida glabrata, is a matter of concern and underscores the need to administer antifungal medications in a judicious manner, avoiding overuse when possible. A newly described pathogen, Candida auris, is an emerging multidrug-resistant organism that poses a global threat.
- 7Tsay, S.; Williams, S.; Mu, Y.; Epson, E.; Johnston, H.; Farley, M. M.; Harrison, L. H.; Vonbank, B.; Shrum, S.; Dumyati, G.; Zhang, A.; Schaffner, W.; Magill, S.; Vallabhaneni, S. 363. National Burden of Candidemia, United States, 2017. Open Forum Infect. Dis. 2018, 5, S142– S143, DOI: 10.1093/ofid/ofy210.374There is no corresponding record for this reference.
- 8Puig-Asensio, M.; Padilla, B.; Garnacho-Montero, J.; Zaragoza, O.; Aguado, J. M.; Zaragoza, R.; Montejo, M.; Muñoz, P.; Ruiz-Camps, I.; Cuenca-Estrella, M.; Almirante, B. Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain. Clin. Microbiol. Infect. 2014, 20, O245– 54, DOI: 10.1111/1469-0691.12380There is no corresponding record for this reference.
- 9Cleveland, A. A.; Farley, M. M.; Harrison, L. H.; Stein, B.; Hollick, R.; Lockhart, S. R.; Magill, S. S.; Derado, G.; Park, B. J.; Chiller, T. M. Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011. Clin. Infect. Dis. 2012, 55, 1352– 1361, DOI: 10.1093/cid/cis6979https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Srur%252FJ&md5=8adf53f14e51dcd8b8a0b313332b3632Changes in Incidence and Antifungal Drug Resistance in Candidemia: Results From Population-Based Laboratory Surveillance in Atlanta and Baltimore, 2008-2011Cleveland, Angela Ahlquist; Farley, Monica M.; Harrison, Lee H.; Stein, Betsy; Hollick, Rosemary; Lockhart, Shawn R.; Magill, Shelley S.; Derado, Gordana; Park, Benjamin J.; Chiller, Tom M.Clinical Infectious Diseases (2012), 55 (10), 1352-1361CODEN: CIDIEL; ISSN:1058-4838. (Oxford University Press)We describe marked shifts in candidemia epidemiol. over the past 2 decades. Adults aged ≥65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Efforts to det. effective prevention strategies are needed. Background. Candidemia is common and assocd. with high morbidity and mortality; changes in population-based incidence rates have not been reported. Methods. We conducted active, population-based surveillance in metropolitan Atlanta, Georgia, and Baltimore City/County, Maryland (combined population 5.2 million), during 2008-2011. We calcd. candidemia incidence and antifungal drug resistance compared with prior surveillance (Atlanta, 1992-1993; Baltimore, 1998-2000). Results. We identified 2675 cases of candidemia with 2329 isolates during 3 years of surveillance. Mean annual crude incidence per 100 000 person-years was 13.3 in Atlanta and 26.2 in Baltimore. Rates were highest among adults aged ≥65 years (Atlanta, 59.1; Baltimore, 72.4) and infants (aged <1 yr; Atlanta, 34.3; Baltimore, 46.2). In both locations compared with prior surveillance, adjusted incidence significantly declined for infants of both black and white race (Atlanta: black risk ratio [RR], 0.26 [95% confidence interval {CI}, .17-.38]; white RR: 0.19 [95% CI, .12-.29]; Baltimore: black RR, 0.38 [95% CI, .22-.64]; white RR: 0.51 [95% CI: .29-.90]). Prevalence of fluconazole resistance (7%) was unchanged compared with prior surveillance; 32 (1%) isolates were echinocandin-resistant, and 9 (8 Candida glabrata) were multidrug resistant to both fluconazole and an echinocandin. Conclusions. We describe marked shifts in candidemia epidemiol. over the past 2 decades. Adults aged ≥65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Use of antifungal prophylaxis, improvements in infection control, or changes in catheter insertion practices may be contributing to these declines. Further surveillance for antifungal resistance and efforts to det. effective prevention strategies are needed.
- 10Kreusch, A.; Karstaedt, A. S. Candidemia among adults in Soweto, South Africa, 1990-2007. Int. J. Infect. Dis. 2013, 17, e621– 3, DOI: 10.1016/j.ijid.2013.02.010There is no corresponding record for this reference.
- 11Doi, A. M.; Pignatari, A. C. C.; Edmond, M. B.; Marra, A. R.; Camargo, L. F. A.; Siqueira, R. A.; da Mota, V. P.; Colombo, A. L. Epidemiology and Microbiologic Characterization of Nosocomial Candidemia from a Brazilian National Surveillance Program. PLoS One 2016, 11, e0146909, DOI: 10.1371/journal.pone.014690911https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVWrtbjI&md5=d185c63a744317e55cdf7fe0bd1240fbEpidemiology and microbiologic characterization of nosocomial candidemia from a brazilian national surveillance programDoi, Andre Mario; Pignatari, Antonio Carlos Campos; Edmond, Michael B.; Marra, Alexandre Rodrigues; Camargo, Luis Fernando Aranha; Siqueira, Ricardo Andreotti; Pereira da Mota, Vivian; Colombo, Arnaldo LopesPLoS One (2016), 11 (1), e0146909/1-e0146909/9CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Candidemia is a growing problemin hospitals all over the world. Despite advances in the medical support of critically ill patients, candidiasis leads to prolonged hospitalization, and has a crude mortality rate around 50%.We conducted a multicenter surveillance study in 16 hospitals distributed across five regions of Brazil to assess the incidence, species distribution, antifungal susceptibility, and risk factors for bloodstreaminfections due to Candida species. From June 2007 to March 2010, we studied a total of 2,563 nosocomial bloodstream infection (nBSI) episodes. Candida spp. was the 7th most prevalent agent. Most of the patients were male, with a median age of 56 years. A total of 64 patients (46.7%) were in the ICU when candidemia occurred. Malignancies were the most common underlying condition (32%). The crude mortality rate of candidemia during the hospital admission was 72.2%. Non-albicans species of Candida accounted for 65.7%of the 137 yeast isolates. C. albicans (34.3%), Candida parapsilosis (24.1%), Candida tropicalis (15.3%) and Candida glabrata (10.2%) were the most prevalent species. Only 47 out of 137 Candida isolates were sent to the ref. lab. for antifungal susceptibility testing. All C. albicans, C. tropicalis and C. parapsilosis isolates were susceptible to the 5 antifungal drugs tested. Among 11 C. glabrata isolates, 36% were resistant to fluconazole, and 64%SDD. All of them were susceptible to anidulafungin and amphotericin B.We obsd. that C. glabrata is emerging as a major player among non-albicans Candida spp. and fluconazole resistance was primarily confined to C. glabrata and C. krusei strains. Candida resistance to echinocandins and amphotericin B remains rare in Brazil. Mortality rates remain increasingly higher than that obsd. in the Northern Hemisphere countries, emphasizing the need for improving local practices of clin. management of candidemia, including early diagnosis, source control and precise antifungal therapy.
- 12Chowdhary, A.; Anil Kumar, V.; Sharma, C.; Prakash, A.; Agarwal, K.; Babu, R.; Dinesh, K. R.; Karim, S.; Singh, S. K.; Hagen, F.; Meis, J. F. Multidrug-resistant endemic clonal strain of Candida auris in India. Eur. J. Clin. Microbiol. Infect. Dis. 2014, 33, 919– 926, DOI: 10.1007/s10096-013-2027-112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOis73K&md5=2817ac62702eb203503530f823c7b4d9Multidrug-resistant endemic clonal strain of Candida auris in IndiaChowdhary, A.; Anil Kumar, V.; Sharma, C.; Prakash, A.; Agarwal, K.; Babu, R.; Dinesh, K. R.; Karim, S.; Singh, S. K.; Hagen, F.; Meis, J. F.European Journal of Clinical Microbiology & Infectious Diseases (2014), 33 (6), 919-926CODEN: EJCDEU; ISSN:0934-9723. (Springer)Candida auris is a recently described rare agent of fungemia. It is notable for its antifungal resistance. A total of 15 C. auris isolates, originating from seven cases of fungemia, three cases of diabetic gangrenous foot, and one case of bronchopneumonia from a tertiary care hospital in south India, were studied. All of the 15 isolates were identified by sequencing and 14 of these along with 12 C. auris isolates previously reported from two hospitals in Delhi, north India, two each from Japan and Korea were genotyped by amplified fragment length polymorphism (AFLP). In vitro antifungal susceptibility testing (AFST) was done by the Clin. and Lab. Stds. Institute (CLSI) broth microdilution method. Candida auris isolates were misidentified as Candida haemulonii by VITEK. All were resistant to fluconazole [geometric mean min. inhibitory concn. (MIC) 64 μg/mL] and 11 isolates were resistant to voriconazole (MIC ≥1 μg/mL). Forty-seven percent of the C. auris isolates were resistant to flucytosine (MIC ≥64 μg/mL) and 40% had high MIC (≥1 μg/mL) of caspofungin. Breakthrough fungemia developed in 28.6% of patients and therapeutic failure in 4 (66.7%) patients. The 26 Indian C. auris isolates from north and south India were clonal and phenotypically and genotypically distinct from Korean and Japanese isolates. C. auris is a potential emerging pathogen that can cause a wide spectrum of human mycotic infections. The prevalence of a C. auris endemic clonal strain resistant to azoles and other antifungals in Indian hospitals with high rates of therapeutic failure in cases of fungemia is worrisome.
- 13Morales-López, S. E.; Parra-Giraldo, C. M.; Ceballos-Garzon, A.; Martinez, H. P.; Rodriguez, G. J.; Alvarez-Moreno, C. A.; Rodriguez, J. Y. Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia. Emerg. Infect. Dis. 2017, 23, 162– 164, DOI: 10.3201/eid2301.16149713https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c%252FlsVSisA%253D%253D&md5=99bc0cef9e5a1d0715f6098dc06b66c0Invasive Infections with Multidrug-Resistant Yeast Candida auris, ColombiaMorales-Lopez Soraya E; Parra-Giraldo Claudia M; Ceballos-Garzon Andres; Martinez Heidys P; Rodriguez Gerson J; Alvarez-Moreno Carlos A; Rodriguez Jose YEmerging infectious diseases (2017), 23 (1), 162-164 ISSN:.Candida auris is an emerging multidrug-resistant fungus that causes a wide range of symptoms. We report finding 17 cases of C. auris infection that were originally misclassified but correctly identified 27.5 days later on average. Patients with a delayed diagnosis of C. auris had a 30-day mortality rate of 35.2%.
- 14Sayeed, M. A.; Farooqi, J.; Jabeen, K.; Awan, S.; Mahmood, S. F. Clinical spectrum and factors impacting outcome of Candida auris: a single center study from Pakistan. BMC Infect. Dis. 2019, 19, 384, DOI: 10.1186/s12879-019-3999-y14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7ivFKisw%253D%253D&md5=769e11d5029dec6652a45cbb5479f3cdClinical spectrum and factors impacting outcome of Candida auris: a single center study from PakistanSayeed Muneeba Ahsan; Farooqi Joveria; Jabeen Kausar; Awan Safia; Mahmood Syed FaisalBMC infectious diseases (2019), 19 (1), 384 ISSN:.BACKGROUND: An outbreak of Candida auris began globally in 2014 including Pakistan and since then it has emerged as a nosocomial multi-drug resistant pathogen. The aim of this study was to assess the clinical spectrum and outcome of patients, from a single center in Pakistan, in whom C. auris was isolated. METHODS: A retrospective study was conducted on 92 patients; ≥16 years with at least one culture positive for C. auris, at the Aga Khan University Hospital Karachi, Pakistan from Sept 2014-Mar 2017.Demographics, clinical history, management and outcome were studied. A logistic regression model was used to identify the risk factors for mortality. RESULTS: We identified 92 patients with C. auris (193 isolates), of whom 52.2% were males. Mean age was 54.14 ± 20.4 years. Positive cultures were obtained after a median hospital stay of 14 days. Most patients had a history of surgery (57.6%), antibiotic use (95.6%), ICU stay (44.6%), indwelling lines (88.04%) and isolation of another multi-resistant organism (52.2%).Most patients were symptomatic (70.7%). Amongst these, 38 had candidemia while 27 had non-candidemia infections. Sites of infection included central lines (35), urinary tract (19), peritonitis (4), nosocomial ventriculitis (1), empyema (1), fungal keratitis (1) otitis externa (1) and surgical site (1). Fluconazole resistance was 100% while 28.5 and 7.9% were Voriconazole and Amphotericin resistant respectively. Overall crude mortality was 42.4% while 14-day mortality was 31.5%. Both infected and colonized cases shared similar mortality (46.2% vs 33.3%; p-value = 0.25). Among infected cases mortality was high in candidemia compared to non-candidemia (60.5% vs 25.9%) in which deaths related to C. auris were 34.2% vs 22.2% respectively. On multivariate analysis candidemia (AOR 4.2, 95% CI: 1.09-16.49; p-value = 0.037) was associated with greater mortality with source control being the only protective factor for mortality (AOR 0.22, 95% CI: 0.05-0.92; p-value0.038] while ICU stay, rapidity of blood culture clearance, DM, malignancy and MDR co-infection had no impact. CONCLUSION: Patients with C.auris from a single center in Pakistan have a wide clinical spectrum with line associated infection being the predominant site of infection. Candidemia leads to high mortality while source control improves outcome.
- 15Al-Siyabi, T.; Al Busaidi, I.; Balkhair, A.; Al-Muharrmi, Z.; Al-Salti, M.; Al’Adawi, B. First report of Candida auris in Oman: Clinical and microbiological description of five candidemia cases. J. Infect. 2017, 75, 373– 376, DOI: 10.1016/j.jinf.2017.05.01615https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnkslGntg%253D%253D&md5=3ce0424632cac9d79fc576c94c8391ebFirst report of Candida auris in Oman: Clinical and microbiological description of five candidemia casesAl-Siyabi Turkiya; Al-Muharrmi Zakariya; Al-Salti Maya; Al'Adawi Badriya; Al Busaidi Ibrahim; Balkhair AbdullahThe Journal of infection (2017), 75 (4), 373-376 ISSN:.There is no expanded citation for this reference.
- 16CDC Tracking Candida auris. https://www.cdc.gov/fungal/candida-auris/tracking-c-auris.html (accessed August 12, 2021).There is no corresponding record for this reference.
- 17Morton, J. F. Brazilian pepper─Its impact on people, animals and the environment. Econ Bot 1978, 32, 353– 359, DOI: 10.1007/BF02907927There is no corresponding record for this reference.
- 18Dettweiler, M.; Marquez, L.; Lin, M.; Sweeney-Jones, A. M.; Chhetri, B. K.; Zurawski, D. V.; Kubanek, J.; Quave, C. L. Pentagalloyl glucose from Schinus terebinthifolia inhibits growth of carbapenem-resistant Acinetobacter baumannii. Sci. Rep. 2020, 10, 15340 DOI: 10.1038/s41598-020-72331-w18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFSis7rE&md5=08cab11f957b41a6999e5e9c3e717a51Pentagalloyl glucose from Schinus terebinthifolia inhibits growth of carbapenem-resistant Acinetobacter baumanniiDettweiler, Micah; Marquez, Lewis; Lin, Michelle; Sweeney-Jones, Anne M.; Chhetri, Bhuwan Khatri; Zurawski, Daniel V.; Kubanek, Julia; Quave, Cassandra L.Scientific Reports (2020), 10 (1), 15340CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)Abstr.: The rise of antibiotic resistance has necessitated a search for new antimicrobials with potent activity against multidrug-resistant gram-neg. pathogens, such as carbapenem-resistant Acinetobacter baumannii (CRAB). In this study, a library of botanical exts. generated from plants used to treat infections in traditional medicine was screened for growth inhibition of CRAB. A crude ext. of Schinus terebinthifolia leaves exhibited 80% inhibition at 256 μg/mL and underwent bioassay-guided fractionation, leading to the isolation of pentagalloyl glucose (PGG), a bioactive gallotannin. PGG inhibited growth of both CRAB and susceptible A. baumannii (MIC 64-256 μg/mL), and also exhibited activity against Pseudomonas aeruginosa (MIC 16 μg/mL) and Staphylococcus aureus (MIC 64 μg/mL). A mammalian cytotoxicity assay with human keratinocytes (HaCaTs) yielded an IC50 for PGG of 256 μg/mL. Mechanistic expts. revealed iron chelation as a possible mode of action for PGG's activity against CRAB. Passaging assays for resistance did not produce any resistant mutants over a period of 21 days. In conclusion, PGG exhibits antimicrobial activity against CRAB, but due to known pharmacol. restrictions in delivery, translation as a therapeutic may be limited to topical applications such as wound rinses and dressings.
- 19Cho, J.-Y.; Sohn, M.-J.; Lee, J.; Kim, W.-G. Isolation and identification of pentagalloylglucose with broad-spectrum antibacterial activity from Rhus trichocarpa Miquel. Food Chem. 2010, 123, 501– 506, DOI: 10.1016/j.foodchem.2010.04.07219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnt12mu7c%253D&md5=ef1a52c87e8a4ee719978a8d3390af82Isolation and identification of pentagalloylglucose with broad-spectrum antibacterial activity from Rhus trichocarpa MiquelCho, Jun-Young; Sohn, Mi-Jin; Lee, Joongku; Kim, Won-GonFood Chemistry (2010), 123 (2), 501-506CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)Rhus trichocarpa Miquel has been utilized both as a food and for medicinal purposes. In this study, we detd. that the methanol exts. of the stem and leaf portions of R. trichocarpa inhibited the growth of both Gram-neg. and Gram-pos. bacteria. The active constituent was isolated, and identified via mass spectrometry and NMR as 1,2,3,4,6-penta-O-galloyl-β-D-glucose. The compd. also evidenced a broad spectrum of antibacterial activity against both Gram-neg. and Gram-pos. bacteria including Staphylococcus aureus (both methicillin-resistant S. aureus and quinolone-resistant S. aureus), Bacillus subtilis, Streptococcus mutans, Escherichia coli, Salmonella typhimurium, and Pseudomonas aeruginosa with MRC values of 16-32 μg/mL, whereas gallate failed to inhibit the growth of Gram-neg. bacteria, even at a concn. of 128 μg/mL. The antibacterial activity of penta-O-galloylglucose was restored by the addn. of Fe2+, whereas gallate was not, thereby indicating that its antibacterial activity could be attributable to the chelation of iron. The results of the time-kill study against S. aureus and E. coli revealed that penta-O-galloylglucose exhibited bacteriostatic activity. These findings indicate that the exts. of R. trichocarpa as well as its active component, penta-O-galloylglucose, may have profound potential for the control of both Gram-pos. and neg. pathogens.
- 20Oh, G.-S.; Pae, H.-O.; Oh, H.; Hong, S.-G.; Kim, I.-K.; Chai, K.-Y.; Yun, Y.-G.; Kwon, T.-O.; Chung, H.-T. In vitro anti-proliferative effect of 1,2,3,4,6-penta-O-galloyl-beta-d-glucose on human hepatocellular carcinoma cell line, SK-HEP-1 cells. Cancer Lett. 2001, 174, 17– 24, DOI: 10.1016/S0304-3835(01)00680-220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnslCjtbw%253D&md5=4e1f604f99f29bdb9c33d616e60c3bd2In vitro anti-proliferative effect of 1,2,3,4,6-penta-O-galloyl-beta-d-glucose on human hepatocellular carcinoma cell line, SK-HEP-1 cellsOh, Gi-Su; Pae, Hyun-Ock; Oh, Hyuncheol; Hong, Seong-Gak; Kim, Il-Kwang; Chai, Kyu-Yun; Yun, Young-Gab; Kwon, Tae-Oh; Chung, Hun-TaegCancer Letters (Shannon, Ireland) (2001), 174 (1), 17-24CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Science Ireland Ltd.)The root of Paeonia suffruticosa ANDREWS is an important Chinese crude drug used in many traditional prescriptions; 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG), a major component of this crude drug, was found to exhibit in vitro growth-inhibiting effect on human hepatocellular carcinoma cell line, SK-HEP-1 cells. The growth-inhibitory effect was related to the ability of PGG not only to cause a G0/G1 phase arrest but also to suppress the activation of nuclear factor-kappa B. Neither apoptosis nor necrosis was obsd. in the cells treated with PGG. These findings suggest that PGG could be a candidate for developing a low-toxic anticancer agent.
- 21Shaikh, Q.-u.-a.; Yang, M.; Memon, K. H.; Lateef, M.; Na, D.; Wan, S.; Eric, D.; Zhang, L.; Jiang, T. 1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) analogs: design, synthesis, anti-tumor and anti-oxidant activities. Carbohydr. Res. 2016, 430, 72– 81, DOI: 10.1016/j.carres.2016.04.02121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntFGgtLc%253D&md5=ebba3a41cbdc3dbd6ece6f90a870a0d11,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) analogs: design, synthesis, antitumor and antioxidant activitiesShaikh, Qurat-ul-ain; Yang, Meiting; Memon, Khadim Hussain; Lateef, Mehreen; Na, Du; Wan, Shengbiao; Eric, Deslandes; Zhang, Lijuan; Jiang, TaoCarbohydrate Research (2016), 430 (), 72-81CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) has been reported for its antioxidant activities, where the free OH groups in PGG seem to be crit. for activities. To explore PGG-based compds. as chemotherapeutic agents and to analyze the contribution of specific OH groups in PGG for anti-cancer activities, we designed and synthesized a series of 27 benzoic and cinnamic acid analogs of PGG. These analogs were tested for cytotoxicities against two human lung (A549 and H1299) and two human colon (HCT116 and HT29) cancer cell lines. PGG had highest cytotoxicities against HCT116 and A549 cells with IC50 of 1.61 μM and 3.02 μM, resp. In contrast, 1,2,3,4,6-pentakis[-O-(4-hydroxy-3-methoxybenzoyl)]-α,β-D-glucopyranose (PVG) was most effective at killing HT29 and H1299 cells with IC50 of 1.76 μM and 3.65 μM, resp., indicating the mutual contribution of m-methoxy and p-hydroxy groups to the obsd. cytotoxicities. Moreover, cinnamic acid analogs were less active than the benzoic acid analogs evidenced by higher IC50 values. Furthermore, in cinnamic acid analogs the hydrogenation of double bond to satd. 2-C side chain enhance the cytotoxicities in all four cell lines. Compds. also possess good antioxidant and reducing activities. PPG show the highest antioxidant and reducing activities.
- 22Kawk, S. H.; Kang, Y. R.; Kim, Y. H. 1,2,3,4,6-Penta-O-galloyl-β-d-glucose suppresses colon cancer through induction of tumor suppressor. Bioorg. Med. Chem. Lett. 2018, 28, 2117– 2123, DOI: 10.1016/j.bmcl.2018.05.02822https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVKjurw%253D&md5=22e90123fe718b2b0b58b2dda4c076f91,2,3,4,6-Penta-O-galloyl-β-D-glucose suppresses colon cancer through induction of tumor suppressorKawk, Sang Hee; Kang, Ye Rim; Kim, Yoon HeeBioorganic & Medicinal Chemistry Letters (2018), 28 (12), 2117-2123CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Colon cancer is the third most common malignancy in both sexes of Korea. Here, we investigated anti-colorectal cancer effects of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG), a gallotannin from Galla rhois, and its possible mechanisms. PGG induced cytotoxicity and decreased proliferation of colon cancer cells without affecting normal colon fibroblasts. PGG inhibited clonogenic ability and induced apoptosis in cancer cells. One of the underlying mechanisms of the anti-cancer effect exerted by PGG, was owing to the induction p53 expression, a well-known tumor suppressor, and increased in P21, the representative target gene of p53. PGG affected cell-cycle- or apoptosis-related proteins such as cyclin E, CDK2, and Bcl-2, cleaved caspase-3. Also, PGG induced caspase-3/7 activity. These data suggest that PGG exerts anti-colorectal cancer effects.
- 23Mendonca, P.; Alghamdi, S.; Messeha, S.; Soliman, K. F. A. Pentagalloyl glucose inhibits TNF-α-activated CXCL1/GRO-α expression and induces apoptosis-related genes in triple-negative breast cancer cells. Sci. Rep. 2021, 11, 5649 DOI: 10.1038/s41598-021-85090-z23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXmslGqsbc%253D&md5=5c0041ef9feaaf431ddc1b5d7b5e787bPentagalloyl glucose inhibits TNF-α-activated CXCL1/GRO-α expression and induces apoptosis-related genes in triple-negative breast cancer cellsMendonca, Patricia; Alghamdi, Sumaih; Messeha, Samia; Soliman, Karam F. A.Scientific Reports (2021), 11 (1), 5649CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)In triple-neg. breast cancer (TNBC), the tumor microenvironment is assocd. with increased proliferation, suppressing apoptotic mechanisms, an altered immune response, and drug resistance. The current investigation was designed to examine the natural compd. pentagalloyl glucose (PGG) effects on TNF-α activated TNBC cell lines, MDA-MB-231 and MDA-MB-468. The results obtained showed that PGG reduced the expression of the cytokine GRO-α/CXCL1. PGG also inhibited IBKE and MAPK1 genes and the protein expression of IBKE and MAPK, indicating that GRO-α downregulation is possibly through NFB and MAPK signaling pathway. PGG also inhibited cell proliferation in both cell lines. Moreover, PGG induced apoptosis, modulating caspases, and TNF superfamily receptor genes. It also augmented mRNA of receptors DR4 and DR5 expression, which binds to TNF-related apoptosis-induced ligand, a potent and specific stimulator of apoptosis in tumors. Remarkably, PGG induced a 154-fold increase in TNF expression in MDA-MB-468 compared to a 14.6-fold increase in MDA-MB-231 cells. These findings indicate PGG anti-cancer ability in inhibiting tumor cell proliferation and GRO-α release and inducing apoptosis by increasing TNF and TNF family receptors expression. Thus, PGG use may be recommended as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.
- 24Joo, Y.-H.; Lee, Y.-G.; Lim, Y.; Jeon, H.; Kim, E. H.; Choi, J.; Hong, W.; Jeon, H.; Ahrweiler, M.; Kim, H.; Kang, S. C.; Seo, Y.-J. Potent antiviral activity of the extract of Elaeocarpus sylvestris against influenza A virus in vitro and in vivo. Phytomedicine 2022, 97, 153892 DOI: 10.1016/j.phymed.2021.15389224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhtV2itbfK&md5=01144d525471b4a0123b9364efdec293Potent antiviral activity of the extract of Elaeocarpus sylvestris against influenza A virus in vitro and in vivoJoo, Yong-Hyun; Lee, Yeong-Geun; Lim, Younghyun; Jeon, Hoyeon; Kim, Eui Ho; Choi, Joongyeon; Hong, Woojae; Jeon, Hyelin; Ahrweiler, Michael; Kim, Hyunggun; Kang, Se Chan; Seo, Young-JinPhytomedicine (2022), 97 (), 153892CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)Elaeocarpus sylvestris (Lour.) Poir. (Elaeocarpaceae) belongs to a genus of tropical and semitropical evergreen trees, which has known biol. activities such as antiviral and immunomodulatory activities. However, its antiviral potential against influenza virus infection remains unknown. In this study, we investigated the antiviral activity of the 50% aq. ethanolic ext. of E. sylvestris (ESE) against influenza A virus (IAV) infection, which could lead to the development of novel phytomedicine to treat influenza virus infection. To investigate the in vitro antiviral activity of ESE and its main ingredients, 1, 2, 3, 4, 6- penta- O- galloyl-β-D-glucose (PGG) and geraniin (GE), the levels of viral RNAs, proteins, and infectious viral particles in IAV-infected MDCK cells were analyzed. Mol. docking anal. was performed to det. the binding energy of PGG and GE for IAV proteins. To investigate in vivo antiviral activity, IAV-infected mice were treated intranasally or intragastrically with ESE, PGG, or GE. ESE and its gallate main ingredients (PGG and GE) strongly inhibited the prodn. of viral RNAs, viral proteins, and infectious viral particles in vitro. Also through the viral attachment on cells, polymerase activity, signaling pathway, we revealed the ESE, PGG, and GE inhibit multiple steps of IAV replication. Mol. docking anal. revealed that PGG and GE could interact with 12 key viral proteins (M1, NP, NS1 effector domain (ED), NS1 RNA-binding domain (RBD), HA pocket A, HA receptor-binding domain (RBD), NA, PA, PB1, PB2 C-terminal domain, PB2 middle domain, and PB2 cap-binding domain) of IAV proteins with stable binding energy. Furthermore, intranasal administration of ESE, PGG, or GE protected mice from IAV-induced mortality and morbidity. Importantly, oral administration of ESE suppressed IAV replication and the expression of inflammatory cytokines such as IFN-γ, TNF-α, and IL-6 in the lungs to a large extent. ESE and its major components (PGG and PE) exhibited strong antiviral activity in multiple steps against IAV infection in silico, in vivo, and in vitro. Therefore, ESE could be used as a novel natural product derived therapeutic agent to treat influenza virus infection.
- 25CDC Candida Auris: Antifungal Susceptibility Testing and Interpretation. https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html, (accessed November 20, 2022).There is no corresponding record for this reference.
- 26Calabrese, D.; Bille, J.; Sanglard, D. A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazole. Microbiology 2000, 146, 2743– 2754, DOI: 10.1099/00221287-146-11-274326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXotlWltb8%253D&md5=d3ab7cec62fe7e5d1881f13ab1307f12A novel multidrug efflux transporter gene of the major facilitator superfamily from Candida albicans (FLU1) conferring resistance to fluconazoleCalabrese, David; Bille, Jacques; Sanglard, DominiqueMicrobiology (Reading, United Kingdom) (2000), 146 (11), 2743-2754CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)Azole resistance in Candida albicans can be mediated by several resistance mechanisms. Among these, alterations of the azole target enzyme and the overexpression of multidrug efflux transporter genes are the most frequent. To identify addnl. putative azole resistance genes in C. albicans, a genomic library from this organism was screened for complementation of fluconazole hypersusceptibility in Saccharomyces cerevisiae YKKB-13 lacking the ABC (ATP-binding cassette) transporter gene PDR5. Among the C. albicans genes obtained, a new gene was isolated and named FLU1 (fluconazole resistance). The deduced amino acid sequence of FLU1 showed similarity to CaMDR1 (formerly BENr), a member of the major facilitator superfamily of multidrug efflux transporters. The expression of FLU1 in YKKB-13 mediated not only resistance to fluconazole but also to cycloheximide among the different drugs tested. The disruption of FLU1 in C. albicans had only a slight effect on fluconazole susceptibility; however, it resulted in hypersusceptibility to mycophenolic acid, thus suggesting that this compd. could be a substrate for the protein encoded by FLU1. Disruption of FLU1 in a background of C. albicans mutants with deletions in several multidrug efflux transporter genes, including CDR1, CDR2 and CaMDR1, resulted in enhanced susceptibility to several azole derivs. FLU1 expression did not vary significantly between several pairs of azole-susceptible and azole-resistant C. albicans clin. isolates. Therefore, FLU1 seems not to be required for the development of azole resistance in clin. isolates.
- 27Ryan, P.; Hynes, M. J. The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron(III). J. Inorg. Biochem. 2007, 101, 585– 593, DOI: 10.1016/j.jinorgbio.2006.12.00127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXislKjsrs%253D&md5=1827f1f85fe54d749ac1a07bb598d326The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron(III)Ryan, Paul; Hynes, Michael J.Journal of Inorganic Biochemistry (2007), 101 (4), 585-593CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier B.V.)(-)-Epigallocatechin-gallate ((-)-EGCg) and (-)-epicatechin-gallate ((-)-ECG) are important antioxidants which are found in green tea. The kinetics and mechanisms of the reactions of a pseudo-first order excess of iron(III) with EGCg and ECG have been investigated in aq. soln. at 25 °C and an ionic strength of 0.5 M NaClO4. Mechanisms have been proposed which account satisfactorily for the kinetic data. These are consistent with a mechanism in which the 2:1 metal:ligand complex initially formed on reaction of iron(III) with the ligand subsequently decomps. in an electron transfer step. Complex formation takes place at two sep. binding sites via coupled reactions. Rate consts. of 4.28(±0.06) × 106 M-2 s-1 and 2.83(±0.04) × 106 M-2 s-1 have been evaluated for the reaction of monohydroxy Fe(OH)2+ species with EGCg and ECG, resp. while rate consts. for of 2.94(±0.4) × 104 M-2 s-1 and 2.41(±0.25) × 104 M-2 s-1 have been evaluated for the reaction of Fe3+ species with EGCg and ECG, resp. The iron(III) assisted decompn. of the initial iron(III) complex formed was also investigated and the rate consts. evaluated. Both the complex formation and subsequent electron transfer reactions of iron(III) with EGCg and ECG were monitored using UV-visible spectrophotometry. All of the suggested mechanisms and calcd. rate consts. are supported by calcns. carried out using global anal. of time dependant spectra. The results obtained show that one mol. of either EGCg or EGC is capable of reducing up to four iron(III) species, a fact which is consistent with the powerful antioxidant properties of the ligands.
- 28Jones, M. M.; Innes, K. K. Restrictions on the Use of Job’s Method. J. Phys. Chem. A 1958, 62, 1005– 1008, DOI: 10.1021/j150566a031There is no corresponding record for this reference.
- 29Vosburgh, W. C.; Cooper, G. R. Complex Ions. I. The Identification of Complex Ions in Solution by Spectrophotometric Measurements. J. Am. Chem. Soc. 1941, 63, 437– 442, DOI: 10.1021/ja01847a02529https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaH3MXhtlWntQ%253D%253D&md5=2017957810966438cd9d5b808d771282Complex ions. I. The identification of complex ions in solution by spectrophotometric measurementsVosburgh, Warren C.; Cooper, Gerald R.Journal of the American Chemical Society (1941), 63 (), 437-42CODEN: JACSAT; ISSN:0002-7863.This paper reports a study of the method of continuous variations (cf. Job, C. A. 22, 2120) for the detn. of the character of complex ions in soln. Data are given for the absorption spectra of solns. of chromate and dichromate, NiSO4 and o-phenanthroline, NiSO4 and ethylenediamine, CuSO4 and (NH4)2SO4. The absorption of monochromatic light was measured in each case. When only a single compd. is formed, the results are independent of the wave length of the light used. When more than one compd. is formed, the results obtained depend on the wave length of the light, and for useful conclusions the wave lengths used must be carefully selected. Both o-phenanthroline and ethylenediamine unite with Ni ion in the proportions of one, two and three mols. to one Ni ion. Cu ion and NH3 form a complex ion with two mols. of NH3 per atom of Cu as well as the one with four.
- 30Baek, Y. U.; Li, M.; Davis, D. A. Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factors. Eukaryot Cell 2008, 7, 1168– 1179, DOI: 10.1128/EC.00108-0830https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXovFeqtbg%253D&md5=63de0e81463360ef06550d7dc4d0b188Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factorsBaek, Yong-Un; Li, Mingchun; Davis, Dana A.Eukaryotic Cell (2008), 7 (7), 1168-1179CODEN: ECUEA2; ISSN:1535-9786. (American Society for Microbiology)Iron is an essential nutrient that is severely limited in the mammalian host. Candida albicans encodes a family of 15 putative ferric reductases, which are required for iron acquisition and utilization. Despite the central role of ferric reductases in iron acquisition and mobilization, relatively little is known about the regulatory networks that govern ferric reductase gene expression in C. albicans. Here, the authors have demonstrated the differential regulation of two ferric reductases, FRE2 and FRP1, in response to distinct iron-limited environments. FRE2 and FRP1 are both induced in alk.-pH environments directly by the Rim101 transcription factor. However, FRP1 but not FRE2 is also induced by iron chelation. The authors have identified a CCAAT motif as the crit. regulatory sequence for chelator-mediated induction and have found that the CCAAT binding factor (CBF) is essential for FRP1 expression in iron-limited environments. They found that a hap5Δ/hap5Δ mutant, which disrupts the core DNA binding activity of CBF, is unable to grow under iron-limited conditions. C. albicans encodes three CBF-dependent transcription factors, and we identified the Hap43 protein as the CBF-dependent transcription factor required for iron-limited responses. These studies provide key insights into the regulation of ferric reductase gene expression in the fungal pathogen C. albicans.
- 31Hsu, P. C.; Yang, C. Y.; Lan, C. Y. Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence. Eukaryot Cell 2011, 10, 207– 225, DOI: 10.1128/EC.00158-1031https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitVCgsrY%253D&md5=997b04e3b8a70c857959808c68d5a20fCandida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulenceHsu, Po-Chen; Yang, Cheng-Yao; Lan, Chung-YuEukaryotic Cell (2011), 10 (2), 207-225CODEN: ECUEA2; ISSN:1535-9786. (American Society for Microbiology)Candida albicans is an opportunistic fungal pathogen that exists as normal flora in healthy human bodies but causes life-threatening infections in immunocompromised patients. In addn. to innate and adaptive immunities, hosts also resist microbial infections by developing a mechanism of "natural resistance" that maintains a low level of free iron to restrict the growth of invading pathogenes. C. albicans must overcome this iron deprived environment to cause infections. There are three types of iron-responsive transcriptional regulators in fungi; Aft1/Aft2 activators in yeast, GATA-type repressors in many fungi, and HapX/Php4 in Schizosaccharomyces pombe and Aspergillus species. In this study, we characterized the iron-responsive regulator Hap43, which is the C. albicans homolog of HapX/Php4 and is repressed by the GATA-type repressor Sfu1 under iron-sufficient conditions. We provide evidence that Hap43 is essential for the growth of C. albicans under low-iron conditions and for C. albicans virulence in a mouse model of infection. Hap43 was not required for iron acquisition under low-iron conditions. Instead, it was responsible for repression of genes that encode iron-dependent proteins involved in mitochondrial respiration and iron-sulfur cluster assembly. We also demonstrated that Hap43 executes its function by becoming a transcriptional repressor and accumulating in the nucleus in response to iron deprivation. Finally, we found a connection between Hap43 and the global corepressor Tup1 in low-iron-induced flavinogenesis. Taken together, our data suggest a complex interplay among Hap43, Sfu1, and Tup1 to coordinately regulate iron acquisition, iron utilization, and other iron-responsive metabolic activities.
- 32Ramírez-Zavala, B.; Krüger, I.; Dunker, C.; Jacobsen, I. D.; Morschhäuser, J. The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicans. PLoS Pathog. 2022, 18, e1010283 DOI: 10.1371/journal.ppat.101028332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XktV2gs7g%253D&md5=4ada8b75742ee157b2977ddfe29a01a7The protein kinase Ire1 has a Hac1-independent essential role in iron uptake and virulence of Candida albicansRamirez-Zavala, Bernardo; Krueger, Ines; Dunker, Christine; Jacobsen, Ilse D.; Morschhaeuser, JoachimPLoS Pathogens (2022), 18 (2), e1010283CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)Protein kinases play central roles in virtually all signaling pathways that enable organisms to adapt to their environment. Microbial pathogens must cope with severely restricted iron availability in mammalian hosts to invade and establish themselves within infected tissues. To uncover protein kinase signaling pathways that are involved in the adaptation of the pathogenic yeast Candida albicans to iron limitation, we generated a comprehensive protein kinase deletion mutant library of a wild-type strain. Screening of this library revealed that the protein kinase Ire1, which has a conserved role in the response of eukaryotic cells to endoplasmic reticulum stress, is essential for growth of C. albicans under iron-limiting conditions. Ire1 was not necessary for the activity of the transcription factor Sef1, which regulates the response of the fungus to iron limitation, and Sef1 target genes that are induced by iron depletion were normally upregulated in ire1Δ mutants. Instead, Ire1 was required for proper localization of the high-affinity iron permease Ftr1 to the cell membrane. Intriguingly, iron limitation did not cause increased endoplasmic reticulum stress, and the transcription factor Hac1, which is activated by Ire1-mediated removal of the non-canonical intron in the HAC1 mRNA, was dispensable for Ftr1 localization to the cell membrane and growth under iron-limiting conditions. Nevertheless, expression of a pre-spliced HAC1 copy in ire1Δ mutants restored Ftr1 localization and rescued the growth defects of the mutants. Both ire1Δ and hac1Δ mutants were avirulent in a mouse model of systemic candidiasis, indicating that an appropriate response to endoplasmic reticulum stress is important for the virulence of C. albicans. However, the specific requirement of Ire1 for the functionality of the high-affinity iron permease Ftr1, a well-established virulence factor, even in the absence of endoplasmic reticulum stress uncovers a novel Hac1-independent essential role of Ire1 in iron acquisition and virulence of C. albicans.
- 33Cryan, L. M.; Bazinet, L.; Habeshian, K. A.; Cao, S.; Clardy, J.; Christensen, K. A.; Rogers, M. S. 1,2,3,4,6-Penta-O-galloyl-beta-D-glucopyranose inhibits angiogenesis via inhibition of capillary morphogenesis gene 2. J. Med. Chem. 2013, 56, 1940– 1945, DOI: 10.1021/jm301558t33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1GhsLo%253D&md5=8759f46bb593c8eed20bb59965fb41e71,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose Inhibits Angiogenesis via Inhibition of Capillary Morphogenesis Gene 2Cryan, Lorna M.; Bazinet, Lauren; Habeshian, Kaiane A.; Cao, Shugeng; Clardy, Jon; Christensen, Kenneth A.; Rogers, Michael S.Journal of Medicinal Chemistry (2013), 56 (5), 1940-1945CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Capillary morphogenesis gene 2 (CMG2) is a transmembrane extracellular matrix binding protein that is also an anthrax toxin receptor. We have shown that high-affinity CMG2 binders can inhibit angiogenesis and tumor growth. We recently described a high-throughput FRET assay to identify CMG2 inhibitors. We now report the serendipitous discovery that PGG (1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose) is a CMG2 inhibitor with antiangiogenic activity. PGG is a gallotannin produced by a variety of medicinal plants that exhibits a wide variety of antitumor and other activities. We find that PGG inhibits CMG2 with a submicromolar IC50 and it also inhibits the migration of human dermal microvascular endothelial cells at similar concns. in vitro. Finally, oral or i.p. administration of PGG inhibits angiogenesis in the mouse corneal micropocket assay in vivo. Together, these results suggest that a portion of the in vivo antitumor activity of PGG may be the result of antiangiogenic activity mediated by inhibition of CMG2.
- 34Feldman, K. S.; Sahasrabudhe, K.; Lawlor, M. D.; Wilson, S. L.; Lang, C. H.; Scheuchenzuber, W. J. In vitro and In vivo inhibition of LPS-stimulated tumor necrosis factor-alpha secretion by the gallotannin beta-D-pentagalloylglucose. Bioorg. Med. Chem. Lett. 2001, 11, 1813– 1815, DOI: 10.1016/S0960-894X(01)00332-834https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXltFylsr0%253D&md5=2a63a32c4ec14fd0636e469665ac8f01In vitro and In vivo inhibition of LPS-stimulated tumor necrosis factor-α secretion by the gallotannin β-D-pentagalloylglucoseFeldman, K. S.; Sahasrabudhe, K.; Lawlor, M. D.; Wilson, S. L.; Lang, C. H.; Scheuchenzuber, W. J.Bioorganic & Medicinal Chemistry Letters (2001), 11 (14), 1813-1815CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The naturally occurring gallotannin β-d-pentagalloylglucose (β-PGG) decreases tumor necrosis factor-alpha (TNF-α) output from human peripheral blood mononucleocytes exposed to lipopolysaccharide (LPS) by as much as 90% (vs. control) at ∼5 μM concn. A qual. similar but less pronounced effect (∼50% decrease) was obsd. in the serum of rats dosed with both LPS and β-PGG. These results may have relevance to therapies that target disease states characterized by an overprodn. of TNF-α.
- 35Cheng, S. W. K.; Eagleton, M.; Echeverri, S.; Munoz, J. G.; Holden, A. H.; Hill, A. A.; Krievins, D.; Ramaiah, V. A pilot study to evaluate a novel localized treatment to stabilize small- to medium-sized infrarenal abdominal aortic aneurysms. J. Vasc. Surg. 2023, DOI: 10.1016/j.jvs.2023.05.056There is no corresponding record for this reference.
- 36Jiamboonsri, P.; Pithayanukul, P.; Bavovada, R.; Leanpolchareanchai, J.; Yin, T.; Gao, S.; Hu, M. Factors Influencing Oral Bioavailability of Thai Mango Seed Kernel Extract and Its Key Phenolic Principles. Molecules 2015, 20, 21254– 21273, DOI: 10.3390/molecules20121975936https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhslers7c%253D&md5=dfc66ad8c4b9ff3faa2d4db12690aeceFactors influencing oral bioavailability of thai mango seed kernel extract and its key phenolic principlesJiamboonsri, Pimsumon; Pithayanukul, Pimolpan; Bavovada, Rapepol; Leanpolchareanchai, Jiraporn; Yin, Taijun; Gao, Song; Hu, MingMolecules (2015), 20 (12), 21254-21273CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Mango seed kernel ext. (MSKE) and its key components (gallic acid, GA; Me gallate, MG; and pentagalloyl glucopyranose, PGG) have generated interest because of their pharmacol. activities. To develop the potential use of the key components in MSKE as natural therapeutic agents, their pharmacokinetic data are necessary. Therefore, this study was performed to evaluate the factors affecting their oral bioavailability as pure compds. and as components in MSKE. The in vitro chem. stability, biol. stability, and absorption were evaluated in Hanks' Balanced Salt Soln., Caco-2 cell and rat fecal lysates, and the Caco-2 cell model, resp. The in vivo oral pharmacokinetic behavior was elucidated in Sprague-Dawley rats. The key components were unstable under alk. conditions and in Caco-2 cell lysates or rat fecal lysates. The absorptive permeability coeff. followed the order MG > GA > PGG. The in vivo results exhibited similar pharmacokinetic trends to the in vitro studies. Addnl., the co-components in MSKE may affect the pharmacokinetic behaviors of the key components in MSKE. In conclusion, chem. degrdn. under alk. conditions, biol. degrdn. by intestinal cell and colonic microflora enzymes, and low absorptive permeability could be important factors underlying the oral bioavailability of these polyphenols.
- 37Li, L.; Shaik, A. A.; Zhang, J.; Nhkata, K.; Wang, L.; Zhang, Y.; Xing, C.; Kim, S. H.; Lu, J. Preparation of penta-O-galloyl-beta-D-glucose from tannic acid and plasma pharmacokinetic analyses by liquid-liquid extraction and reverse-phase HPLC. J. Pharm. Biomed. Anal. 2011, 54, 545– 550, DOI: 10.1016/j.jpba.2010.09.02837https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsValt77K&md5=ff5e6c7a258c5d4bfa0ec06292ab979bPreparation of penta-O-galloyl-β-D-glucose from tannic acid and plasma pharmacokinetic analyses by liquid-liquid extraction and reverse-phase HPLCLi, Li; Shaik, Ahmad Ali; Zhang, Jinhui; Nhkata, Katai; Wang, Lei; Zhang, Yong; Xing, Chengguo; Kim, Sung-Hoon; Lue, JunxuanJournal of Pharmaceutical and Biomedical Analysis (2011), 54 (3), 545-550CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)The gallotannin penta-O-galloyl-beta-d-glucose (PGG) has many biol. activities including in vivo anti-cancer efficacy. We present in this paper a scaled-up protocol for its prepn. in high purity from tannic acid by acidic methanolysis with typical yield of 15%. We also describe a method for the anal. of PGG in mouse plasma by HPLC and its application in preliminary pharmacokinetic studies. A liq.-liq. extn. (LLE) protocol was optimized for the extn. of PGG from mouse plasma. The extn. efficiency for PGG at 1 μg/mL in mouse plasma was 70.0±1.3% (n = 5). The limit of detection (LOD) for PGG was approx. 0.2 μg/mL. Preliminary pharmacokinetic parameters of PGG following a single i.p. injection with 5% ethanol/saline vehicle in mice were established. The peak plasma PGG concns. (Cmax) were approx. 3-4 μM at a dose of 0.5 mg per mouse (∼20 mg/kg) at 2 h post-injection (Tmax).
- 38Ma, C.-x.; Zhao, X.; Wang, P.; Jia, P.; Zhao, X.-f.; Xiao, C.-n.; Zheng, X.-h. Metabolite characterization of Penta-O-galloyl-β-D-glucose in rat biofluids by HPLC-QTOF-MS. Chin. Herb. Med. 2018, 10, 73– 79, DOI: 10.1016/j.chmed.2018.01.002There is no corresponding record for this reference.
- 39Hatcher, H. C.; Singh, R. N.; Torti, F. M.; Torti, S. V. Synthetic and natural iron chelators: therapeutic potential and clinical use. Future Med. Chem. 2009, 1, 1643– 1670, DOI: 10.4155/fmc.09.12139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtVejuw%253D%253D&md5=d4e0da1164fc51106fa87954c8116777Synthetic and natural iron chelators: therapeutic potential and clinical useHatcher, Heather C.; Singh, Ravi N.; Torti, Frank M.; Torti, Suzy V.Future Medicinal Chemistry (2009), 1 (9), 1643-1670CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)A review. Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the std. for this purpose was deferoxamine. Recently, considerable progress was made in identifying synthetic chelators with improved pharmacol. properties relative to deferoxamine. Most notable are deferasirox (Exjade) and deferiprone (Ferriprox), which are now available clin. In addn. to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases, and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochems., many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochem.
- 40Bairwa, G.; Hee Jung, W.; Kronstad, J. W. Iron acquisition in fungal pathogens of humans. Metallomics 2017, 9, 215– 227, DOI: 10.1039/C6MT00301J40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXisFShu7o%253D&md5=4ea94263eddbdb5ebb391697eec48840Iron acquisition in fungal pathogens of humansBairwa, Gaurav; Hee Jung, Won; Kronstad, James W.Metallomics (2017), 9 (3), 215-227CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)A review. In recent years, the contributions to virulence of reductive iron uptake, siderophore-mediated uptake and heme acquisition have been identified in the best studied and most life-threatening fungal pathogens: Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. In particular, exciting new work illustrates the importance of iron acquisition from heme and Hb in the virulence of pathogenic yeasts. However, the challenge of establishing how these fungi gain access to Hb in blood and to other sources of heme remains to be fully addressed. Recent studies are also expanding our knowledge of iron uptake in less-well studied fungal pathogens, including dimorphic fungi where new information reveals an integration of iron acquisition with morphogenesis and cell-surface properties for adhesion to host cells. Overall, the accumulating information provides opportunities to exploit iron acquisition for antifungal therapy, and new work highlights the development of specific inhibitors of siderophore biosynthesis and metal chelators for therapeutic use alone or in conjunction with existing antifungal drugs. It is clear that iron-related therapies will need to be customized for specific diseases because the emerging view is that fungal pathogens use different combinations of strategies for iron acquisition in the varied niches of vertebrate hosts.
- 41Gerwien, F.; Skrahina, V.; Kasper, L.; Hube, B.; Brunke, S. Metals in fungal virulence. FEMS Microbiol. Rev. 2018, 42, fux050, DOI: 10.1093/femsre/fux050There is no corresponding record for this reference.
- 42Fourie, R.; Kuloyo, O. O.; Mochochoko, B. M.; Albertyn, J.; Pohl, C. H. Iron at the Centre of Candida albicans Interactions. Front. Cell. Infect. Microbiol. 2018, 8, 185, DOI: 10.3389/fcimb.2018.0018542https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVKlt7bJ&md5=c74e5729d1eb31276caf3588c52f29deIron at the centre of Candida albicans interactionsFourie, Ruan; Kuloyo, Oluwasegun O.; Mochochoko, Bonang M.; Albertyn, Jacobus; Pohl, Carolina H.Frontiers in Cellular and Infection Microbiology (2018), 8 (), 185/1-185/14CODEN: FCIMAB; ISSN:2235-2988. (Frontiers Media S.A.)Iron is an abs. requirement for both the host and most pathogens alike and is needed for normal cellular growth. The acquisition of iron by biol. systems is regulated to circumvent toxicity of iron overload, as well as the growth deficits imposed by iron deficiency. In addn., hosts, such as humans, need to limit the availability of iron to pathogens. However, opportunistic pathogens such as Candida albicans are able to adapt to extremes of iron availability, such as the iron replete environment of the gastrointestinal tract and iron deficiency during systemic infection. C. albicans has developed a complex and effective regulatory circuit for iron acquisition and storage to circumvent iron limitation within the human host. As C. albicans can form complex interactions with both commensal and pathogenic co-inhabitants, it can be speculated that iron may play an important role in these interactions. In this review, we highlight host iron regulation as well as regulation of iron homeostasis in C. albicans. In addn., the review argues for the need for further research into the role of iron in polymicrobial interactions. Lastly, the role of iron in treatment of C. albicans infection is discussed.
- 43Dittmar, W.; Lohaus, G. HOE 296, a new antimycotic compound with a broad antimicrobial spectrum. Laboratory results. Arzneimittelforschung 1973, 23, 670– 67443https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE3s7psVCgsA%253D%253D&md5=273934aa56cb9f73fecf1ac31b488a5cHOE 296, a new antimycotic compound with a broad antimicrobial spectrum. Laboratory resultsDittmar W; Lohaus GArzneimittel-Forschung (1973), 23 (5), 670-4 ISSN:0004-4172.There is no expanded citation for this reference.
- 44Subissi, A.; Monti, D.; Togni, G.; Mailland, F. Ciclopirox. Drugs 2010, 70, 2133– 2152, DOI: 10.2165/11538110-000000000-0000044https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cbht1aktg%253D%253D&md5=bcebda6fa862d4306dac52c100f7778fCiclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agentSubissi Alessandro; Monti Daniela; Togni Giuseppe; Mailland FedericoDrugs (2010), 70 (16), 2133-52 ISSN:.Ciclopirox is a topical antimycotic agent belonging to the chemical class of hydroxypyridones and not related to azoles or any other class of antifungal agents. Its antimicrobial profile includes nearly all of the clinically relevant dermatophytes, yeasts and moulds, and is therefore broader than that of most other antimycotics. It is also active against certain frequently azole-resistant Candida species and against some bacteria. The mechanism of action of ciclopirox is different from that of other topical antifungal drugs, which generally act through ergosterol inhibition. The high affinity of ciclopirox for trivalent metal cations, resulting in inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell, appears to be the major determinant of its antimicrobial activity. This unique and multilevel mechanism of action provides a very low potential for the development of resistance in pathogenic fungi, with cases of resistance rarely reported. Ciclopirox also displays mild anti-inflammatory effects in biochemical and pharmacological models; effects also shown in small clinical studies. Scavenging of reactive oxygen species released from inflammatory cells is a likely contributor to these anti-inflammatory effects. Ciclopirox, and its olamine salt, is available in multiple topical formulations, suitable for administration onto the skin and nails and into the vagina. The pharmaceutical forms most widely investigated are 1% ciclopirox olamine cream and 8% ciclopirox acid nail lacquer, but lotion, spray, shampoo, pessary, solution, gel and douche formulations have also been used. Ciclopirox penetrates into the deep layers of the skin, mucosal membranes and nail keratin, reaching concentrations exceeding the minimal fungicidal concentrations for most medically important fungi. A large number of clinical trials were and are still being performed with ciclopirox, starting in the early 1980s. Ciclopirox was first developed for fungal skin infections and vaginal candidiasis, and is currently well established in these indications. More recently, the drug has been clinically investigated in seborrhoeic dermatitis and onychomycosis, showing good efficacy and excellent tolerability. Emphasis in this review is given to a ciclopirox medicated nail lacquer, which is based on an original technology and has superior properties in terms of its affinity to keratin and nail permeation. It has been found to have superior efficacy and safety to another commercially available formulation in the treatment of onychomycosis. The safety features of ciclopirox are well known. The topical drug is devoid of systemic adverse reactions. Mild local reactions characterized by a burning sensation of the skin, irritation, redness, pain or pruritus, generally in less than 5% of treated patients, can be observed following skin and vaginal application. With nail application, the most common adverse event is the appearance of mild erythema in 5% of the treated population. As a general conclusion, although less effective than some oral antimycotic agents in various indications, ciclopirox compares very well in terms of the benefit/risk ratio due to its excellent tolerability and complete absence of serious adverse effects.
- 45Niewerth, M.; Kunze, D.; Seibold, M.; Schaller, M.; Korting, H. C.; Hube, B. Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors. Antimicrob. Agents Chemother. 2003, 47, 1805– 1817, DOI: 10.1128/AAC.47.6.1805-1817.200345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktlymt7g%253D&md5=d8991b12cf9c1673b62c4a767fa530a1Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins and drug resistance factorsNiewerth, Markus; Kunze, Donika; Seibold, Michael; Schaller, Martin; Korting, Hans Christian; Hube, BernhardAntimicrobial Agents and Chemotherapy (2003), 47 (6), 1805-1817CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examd. the expression patterns of 47 Candida albicans genes in cells grown in the presence of a subinhibitory concn. (0.6 μg/mL) of ciclopirox olamine by reverse transcription-PCR. In addn., we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such as ACT1 was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up- or down-regulation of genes encoding iron permeases or transporters (FTR1, FTR2, FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addn. of FeCl3 to ciclopirox olamine-treated cells reversed the effect of the drug. Addn. of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1, FTR2). While serum-induced yeast-to-hyphal phase transition of C. albicans was not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-contg. gene products responsible for detoxification. Although the Candida drug resistance genes CDR1 and CDR2 were up-regulated, no change in resistance or increased tolerance could be obsd. even after an incubation period of 6 mo. This was in contrast to control expts. with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 mo. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms caused C. albicans resistance to this drug even after long-term exposure.
- 46Lee, R. E. B.; Liu, T. T.; Barker, K. S.; Lee, R. E.; Rogers, P. D. Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans. J. Antimicrob. Chemother 2005, 55, 655– 662, DOI: 10.1093/jac/dki10546https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjvFymu7g%253D&md5=b7ee3367cc8be2231544d36ffd0112f6Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicansLee, Robin E. B.; Liu, Teresa T.; Barker, Katherine S.; Lee, Richard E.; Rogers, P. DavidJournal of Antimicrobial Chemotherapy (2005), 55 (5), 655-662CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)The aim of this study was to identify changes in the gene expression profile of Candida albicans upon exposure to the hydroxypyridone anti-infective agent ciclopirox olamine in an effort to better understand its mechanism of action. C. albicans SC5314 was exposed to either medium alone or ciclopirox olamine at a concn. equiv. to the IC50 (0.24 mg/L) for 3 h. RNA was isolated and gene expression profiles were compared using DNA microarrays. Differential expression of select genes was confirmed by real-time reverse transcription (RT)-PCR. Mutants disrupted for CDR2 and both CDR1 and CDR2, as well as a clin. isolate overexpressing CDR1 and CDR2, were examd. for changes in susceptibility to ciclopirox olamine. A total of 49 genes were found to be responsive to ciclopirox olamine, including 36 up-regulated genes and 13 down-regulated genes. These included genes involved in small mol. transport (HGT11, HXT5, ENA22, PHO84, CDR4), iron uptake (FRE30, FET34, FTR1, FTR2, SIT1) and cell stress (SOD1, SOD22, CDR1, DDR48). Mutants disrupted for CDR2 and both CDR1 and CDR2, as well as a clin. isolate overexpressing CDR1 and CDR2, showed no change in susceptibility to ciclopirox olamine compared with the resp. parent. Consistent with the hypothesis that ciclopirox olamine acts as an iron chelator, it induced changes in expression of many genes involved in iron uptake. Despite induction of the multidrug efflux pump genes CDR1 and, to a lesser extent, CDR2 by ciclopirox olamine, these genes do not affect susceptibility to this agent.
- 47Sigle, H.-C.; Thewes, S.; Niewerth, M.; Korting, H. C.; Schäfer-Korting, M.; Hube, B. Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans. J. Antimicrob. Chemother 2005, 55, 663– 673, DOI: 10.1093/jac/dki08947https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjvFymurg%253D&md5=cab6a167d4d90afc810522e24c3343b9Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicansSigle, Hans-Christian; Thewes, Sascha; Niewerth, Markus; Korting, Hans Christian; Schaefer-Korting, Monika; Hube, BernhardJournal of Antimicrobial Chemotherapy (2005), 55 (5), 663-673CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)Ciclopirox is a topical antifungal agent of the hydroxypyridone class whose mode of action is poorly understood. In order to elucidate the mechanism of action of ciclopirox, we analyzed the growth, cellular integrity, biochem. properties, viability and transcriptional profile of the polymorphic yeast Candida albicans following exposure to this antifungal agent. Multiple biochem. assays served to identify factors that were crit. for antifungal activity and to identify proteins whose activities changed in drug-exposed cells. Genome-wide transcriptional profiling was used to identify genes that were up-regulated in response to the cellular effects of the drug. Ciclopirox inhibited growth of C. albicans yeast and hyphal cells in a dose-dependent manner. This effect was reduced (i) by the addn. of iron ions or the metabolic inhibitor 2-deoxy-D-glucose to growth media, (ii) in media that lacked glucose, and (iii) for cells that were pre-incubated with hydrogen peroxide or menadione [which caused induction of proteins involved in detoxification of reactive oxygen species (ROS)]. In contrast, cells pre-cultured under poor oxygen conditions (which had decreased activity of proteins involved in ROS detoxification) were more susceptible to ciclopirox. Treatment with ciclopirox did not directly cause cell membrane damage and did not change intracellular levels of ATP. Finally, the transcriptional profiling pattern of drug-treated cells strongly resembled iron-limited conditions. These data indicate that metabolic activity, oxygen accessibility and iron levels are crit. parameters in the mode of action of ciclopirox olamine.
- 48Linden, T.; Katschinski, D. M.; Eckhardt, K.; Scheid, A.; Pagel, H.; Wenger, R. H. The antimycotic ciclopirox olamine induces HIF-1α stability, VEGF expression, and angiogenesis. FASEB J. 2003, 17, 761– 763, DOI: 10.1096/fj.02-0586fje48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXislGlt70%253D&md5=dd39c593d247c43036f591011d5b308aThe antimycotic ciclopirox olamine induces HIF-1α stability, VEGF expression, and angiogenesisLinden, Tobias; Katschinski, Dorthe M.; Eckhardt, Katrin; Scheid, Annette; Pagel, Horst; Wenger, Roland H.FASEB Journal (2003), 17 (6), 761-763, 10.1096/fj.0586fjeCODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)The heterodimeric hypoxia-inducible factor (HIF)-1 is a master regulator of oxygen homeostasis. Protein stability and transactivation function of the a subunit are controlled by iron- and oxygen-dependent hydroxylation of proline and asparagine residues. The anti-mycotic ciclopirox olamine (CPX) is a lipophilic bidentate iron chelator that stabilizes HIF-1α under normoxic conditions at lower concns. than other iron chelators, probably by inhibiting HIF-1α hydroxylation. As shown by the inhibition of iron-dependent quenching of FITC-labeled deferoxamine (DFX) fluorescence, CPX appears to have an even higher affinity for iron than DFX. Initial observations that treatment with 1% CPX, but not with placebo, occasionally caused reddening of wound margins in a mouse skin wound model prompted us to investigate the capability of CPX to induce angiogenesis. CPX-induced HIF-1-mediated reporter gene activity and endogenous HIF-1 target gene expression, including elevation of transcription, mRNA, and protein levels of the vascular endothelial growth factor (VEGF). In the chick chorioallantoic membrane assay, inert polymer disks contg. CPX but not the solvent alone induced angiogenesis. In summary, these results suggest that CPX induces angiogenesis in vivo via HIF-1 and VEGF induction. Therefore, CPX might serve as an alternative to recombinant VEGF treatment or to VEGF gene therapy for therapeutic angiogenesis.
- 49Skrzypek, M. S.; Binkley, J.; Binkley, G.; Miyasato, S. R.; Simison, M.; Sherlock, G. Candida Genome Database: C. albicans HAP43/C1_11210C.. http://www.candidagenome.org/cgi-bin/locus.pl?dbid=CAL0000188360, (accessed 06-27-2023).There is no corresponding record for this reference.
- 50Zinatizadeh, M. R.; Schock, B.; Chalbatani, G. M.; Zarandi, P. K.; Jalali, S. A.; Miri, S. R. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases. Genes Dis. 2021, 8, 287– 297, DOI: 10.1016/j.gendis.2020.06.00550https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFCis7jP&md5=9a6723bc94f65d06e93b0a4f7dc1e26dThe Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseasesZinatizadeh, Mohammad Reza; Schock, Bettina; Chalbatani, Ghanbar Mahmoodi; Zarandi, Peyman Kheirandish; Jalali, Seyed Amir; Miri, Seyed RouhollahGenes and Diseases (2021), 8 (3), 287-297CODEN: GDEIAV; ISSN:2352-3042. (Elsevier B.V.)The nuclear factor kappa B (NF-kB) family of transcription factors plays an essential role as stressors in the cellular environment, and controls the expression of important regulatory genes such as immunity, inflammation, death, and cell proliferation. NF-kB protein is located in the cytoplasm, and can be activated by various cellular stimuli. There are two pathways for NF-kB activation, as the canonical and non-canonical pathways, which require complex mol. interactions with adapter proteins and phosphorylation and ubiquitinase enzymes. Accordingly, this increases NF-kB translocation in the nucleus and regulates gene expression. In this study, the concepts that emerge in different cellular systems allow the design of NF-kB function in humans. This would not only allow the development for rare diseases assocd. with NF-kB, but would also be used as a source of useful information to eliminate widespread consequences such as cancer or inflammatory/immune diseases.
- 51Xiong, S.; She, H.; Takeuchi, H.; Han, B.; Engelhardt, J. F.; Barton, C. H.; Zandi, E.; Giulivi, C.; Tsukamoto, H. Signaling Role of Intracellular Iron in NF-κB Activation*. J. Biol. Chem. 2003, 278, 17646– 17654, DOI: 10.1074/jbc.M21090520051https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjs1KisbY%253D&md5=1055d0d77effd87f949ba1dd1c85dadcSignaling Role of Intracellular Iron in NF-κB ActivationXiong, Shigang; She, Hongyun; Takeuchi, Heigo; Han, Bora; Engelhardt, John F.; Barton, C. H.; Zandi, Ebrahim; Giulivi, Cecilia; Tsukamoto, HidekazuJournal of Biological Chemistry (2003), 278 (20), 17646-17654CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Iron chelators inhibit endotoxin-induced NF-κB activation in hepatic macrophages (HMs), suggesting a role for the intracellular chelatable pool of iron in NF-κB activation. The present study tested this hypothesis. Anal. of Fe59-loaded HMs stimulated with lipopolysaccharide (LPS), revealed a previously unreported, transient rise in intracellular low mol. wt. (LMW)·Fe59 complex ([LMW·Fe]i) at ≤2 min returning to the basal level within 15 min. The [LMW·Fe]i response preceded IκB kinase (IKK) (≥15 min) and NF-κB (≥30 min) activation. Iron chelators (1,2-dimethyl-3-hydroxypyridin-4-one and N,N'-bis-2-hydroxybenzylethylenediamine-N,N'-diacetic acid) abrogated the [LMW·Fe]i response and IKK and NF-κB activation. The [LMW·Fe]i response was also obsd. in tumor necrosis factor α (TNFα)-stimulated HMs and RAW264.7 cells treated with LPS and interferon-γ but not in primary rat hepatocytes or myofibroblastic cells exposed to LPS or TNFα. Both [LMW·Fe]i response and IKK activation in LPS-stimulated HMs were inhibited by diphenylene iodonium (nonspecific inhibitor for flavin-contg. oxidases), L-N6-(1-iminoethyl)lysine (selective iNOS inhibitor), and adenoviral-mediated expression of a dominant neg. mutant of Rac1 or Cu,Zn-superoxide dismutase, suggesting the role of NO and O in mediating the iron signaling. In fact, this inhibition was recapitulated by a cell-permeable scavenger of ONOO-, 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinato iron (III) chloride. Conversely, ONOO- alone induced both [LMW·Fe]i response and IKK activation. Finally, direct addn. of ferrous iron to cultured HMs activated IKK and NF-κB. These results support a novel signaling role for [LMW·Fe]i in IKK activation, which appears to be induced by ONOO- and selectively operative in macrophages.
- 52She, H.; Xiong, S.; Lin, M.; Zandi, E.; Giulivi, C.; Tsukamoto, H. Iron activates NF-κB in Kupffer cells. Am. J. Physiol.: Gastrointest. Liver Physiol. 2002, 283, G719– G726, DOI: 10.1152/ajpgi.00108.2002There is no corresponding record for this reference.
- 53Kim, B. M.; Choi, J. Y.; Kim, Y. J.; Woo, H. D.; Chung, H. W. Desferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage response. Toxicology 2007, 229, 226– 235, DOI: 10.1016/j.tox.2006.10.02253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1arsA%253D%253D&md5=1191002f61a254b33ade9db623c8f77cDesferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage responseKim, Byeong Mo; Choi, Jun Yeol; Kim, Yang Jee; Woo, Hae Dong; Chung, Hai WonToxicology (2007), 229 (3), 226-235CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Ltd.)Desferrioxamine (DFX), which is an iron chelator, mimics hypoxia by enhancing HIF1-α accumulation and upregulating inflammatory mediators. DFX is usually beneficial, with preventive effects related primarily to its ability to scavenge reactive oxygen species. However, toxic effects on skeletal and ocular organs have been reported. The cytokinesis block micronucleus test and alk. single-cell gel (Comet) assay were used to evaluate the genotoxic effects of DFX on human blood lymphocytes. Cultured human lymphocytes treated with 130 μM DFX for various periods of time showed significant differences in the incidence of micronucleated binucleate cells, as well as in the length and moment of the comet tail. Western blot anal. using antibodies to proteins involved in the p53-mediated response to DNA damage revealed that p53 was accumulated and DNA damage checkpoint kinases were activated in lymphocytes treated with DFX. The p53 downstream target proteins p21 and bax were not affected, which indicates that DFX does not promote the transactivational activity of p53. Apoptosis assays demonstrated DFX-induced apoptosis of lymphocytes via the caspase cascade. The obsd. increase in the sub-G1 fraction and enhanced caspase-3 activity indicate that DFX can promote apoptosis in human lymphocytes, and these results were confirmed by protein immunoblot anal. As apoptotic cell death is preceded by the collapse of the mitochondrial membrane potential, we also measured the mitochondrial membrane potential (Δψ m) using DiOC6, which is a fluorescent membrane potential probe. The fluorescence intensity of DiOC6 in lymphocytes was significantly reduced in a time-dependent manner after DFX treatment. Taken together, these results indicate that DFX activates p53-mediated checkpoint signals and induces apoptosis via mitochondrial damage in human peripheral blood lymphocytes.
- 54Liang, S. X.; Richardson, D. R. The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1. Carcinogenesis 2003, 24, 1601– 1614, DOI: 10.1093/carcin/bgg11654https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXotVCls7g%253D&md5=f5a5e29c06888ad5792bd0e2c0f69306The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1Liang, S. X.; Richardson, D. R.Carcinogenesis (2003), 24 (10), 1601-1614CODEN: CRNGDP; ISSN:0143-3334. (Oxford University Press)Iron (Fe) chelators induce a G1/S arrest and several of these are undergoing clin. trials as anticancer agents. Despite this, little is known concerning the precise function of Fe in cell cycle progression and the role of p53 in this process. The aim of this study was to assess the effect of Fe chelators on p53 and the mechanism involved in the chelator-mediated increase in mRNA levels of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1. Cells were incubated with the potent Fe chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) and the results compared with those from cells treated with actinomycin D (Act D), which induces p53. Following incubation with 311, a 3- to 5-fold increase in nuclear p53 protein was obsd. in cells with wild-type p53. In addn., 311 increased p53 DNA-binding activity 2-fold, while Act D increased it 3- to 5-fold in cells with native p53. To det. the role of p53 in WAF1 transcription, a reporter construct was used consisting of a WAF1 promoter contg. the p53-binding site. In cells with wild-type p53, chelators had no effect on luciferase activity, while the pos. control, Act D, caused a significant increase. Hence, despite increased p53 protein expression and p53 DNA-binding activity following chelation, these latter results suggested it had no role in up-regulating WAF1 mRNA. Our expts. demonstrated: (i) that the elevated WAF1 mRNA expression after Fe chelation was due to increased transcription and also to a post-transcriptional mechanism that was sensitive to cycloheximide; and (ii) that Fe-chelation increased WAF1 expression through a p53-independent pathway.
- 55Torres-León, C.; Ventura-Sobrevilla, J.; Serna-Cock, L.; Ascacio-Valdés, J. A.; Contreras-Esquivel, J.; Aguilar, C. N. Pentagalloylglucose (PGG): A valuable phenolic compound with functional properties. J. Funct. Foods 2017, 37, 176– 189, DOI: 10.1016/j.jff.2017.07.04555https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1OitLjI&md5=6c46f633ad3082101b033433ae7fa655Pentagalloylglucose (PGG): A valuable phenolic compound with functional propertiesTorres-Leon, Cristian; Ventura-Sobrevilla, Janeth; Serna-Cock, Liliana; Ascacio-Valdes, Juan A.; Contreras-Esquivel, Juan; Aguilar, Cristobal N.Journal of Functional Foods (2017), 37 (), 176-189CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)1,2,3,4,6-Penta-O-Galloyl-β-D-Glucose (PGG) is a hydrolysable tannin that belongs to the group of gallotannins but also participates in the formation of ellagitannins. PGG is composed of five galloyl groups with a glucose at its core and has structural characteristics that confer a high biol. power. In this paper, we describe the chem. of PGG, which is analyzed from a crit. point regarding the types of synthesis, new sources of prodn. from plants and byproducts, highlighting the PGG obtaining, and its main functional properties recently reported in scientific literature. PGG has attracted attention because of its therapeutic potential and has shown functional properties as antimicrobial, anti-inflammatory, anti-carcinogenic, antidiabetic and antioxidant. Bioconversion from tannic acid can be potentialized with the use of biotechnol. techniques. PGG can be obtained from natural sources as byproducts. Research should continue to obtain pure mols., in adequate quantity and with great biol. activity.
- 56Lee, Y.; Hossain, S.; MacAlpine, J.; Robbins, N.; Cowen, L. E. Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environments. iScience 2023, 26, 106145 DOI: 10.1016/j.isci.2023.10614556https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXjtl2mt7c%253D&md5=f1fcbdc61505a2fe2c6cd9836492c273Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environmentsLee, Yunjin; Hossain, Saif; MacAlpine, Jessie; Robbins, Nicole; Cowen, Leah E.iScience (2023), 26 (3), 106145CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)Candida albicans is a leading cause of mycotic infection. The ability to transition between yeast and filamentous forms is crit. to C. albicans virulence and complex signaling pathways regulate this process. Here, we screened a C. albicans protein kinase mutant library in six environmental conditions to identify regulators of morphogenesis. We identified the uncharacterized gene orf19.3751 as a neg. regulator of filamentation and follow-up investigations implicated a role for orf19.3751 in cell cycle regulation. We also uncovered a dual role for the kinases Ire1 and protein kinase A (Tpk1 and Tpk2) in C. albicans morphogenesis, specifically as neg. regulators of wrinkly colony formation on solid medium but pos. regulators of filamentation in liq. medium. Further analyses suggested Ire1 modulates morphogenesis in both media states in part through the transcription factor Hac1 and in part through independent mechanisms. Overall, this work provides insights into the signaling governing morphogenesis in C. albicans.
- 57Homann, O. R.; Dea, J.; Noble, S. M.; Johnson, A. D. A Phenotypic Profile of the Candida albicans Regulatory Network. PLoS Genet. 2009, 5, e1000783 DOI: 10.1371/journal.pgen.1000783There is no corresponding record for this reference.
- 58Clinical and Laboratory Standards Institute, Performance standards for antimicrobial susceptibility testing: twenty-third informational supplement ; M100 - S23. CLSI: 2013.There is no corresponding record for this reference.
- 59Odds, F. C. Synergy, antagonism, and what the chequerboard puts between them. J. Antimicrob. Chemother. 2003, 52, 1, DOI: 10.1093/jac/dkg30159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltVWjsr0%253D&md5=b214be21ff21422856db140f8c4a0fd0Synergy, antagonism, and what the chequerboard puts between themOdds, F. C.Journal of Antimicrobial Chemotherapy (2003), 52 (1), 1CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)There is no expanded citation for this reference.
- 60Leite, M. C. A.; Bezerra, A. P. d. B.; Sousa, J. P. d.; Guerra, F. Q. S.; Lima, E. d. O. Evaluation of antifungal activity and mechanism of action of citral against Candida albicans. J. Evidence-Based Complementary Altern. Med. 2014, 2014, 378280 DOI: 10.1155/2014/378280There is no corresponding record for this reference.
- 61Singh, S. D.; Robbins, N.; Zaas, A. K.; Schell, W. A.; Perfect, J. R.; Cowen, L. E. Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog. 2009, 5, e1000532 DOI: 10.1371/journal.ppat.1000532There is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.3c00113.
Experimental methods for concentration-response matrixes; effects of penta-O-galloyl-β-d-glucose upon human cytotoxicity and cell viability; media supplementation assays; Job’s method spectra; expanded MIC graphs with additional positive controls; and table with the additional Candida albicans strains and genotype (PDF)
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