Effects of a Ganoderma lucidum Proteoglycan on Type 2 Diabetic Rats and the Recovery of Rat Pancreatic IsletsClick to copy article linkArticle link copied!
- Fanzhen YuFanzhen YuState Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, ChinaMore by Fanzhen Yu
- Yilong TengYilong TengState Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, ChinaMore by Yilong Teng
- Jiaqi LiJiaqi LiState Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, ChinaMore by Jiaqi Li
- Shutong Yang
- Zeng ZhangZeng ZhangYueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. ChinaMore by Zeng Zhang
- Yanming HeYanming HeYueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. ChinaMore by Yanming He
- Hongjie Yang*Hongjie Yang*Email: [email protected]Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. ChinaMore by Hongjie Yang
- Chuan-Fan Ding*Chuan-Fan Ding*Email: [email protected]Zhejiang Provincial Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis, Institute of Mass Spectrometry, School of Material Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang 315211, ChinaMore by Chuan-Fan Ding
- Ping Zhou*Ping Zhou*Email: [email protected]. Phone: (+86) 21-31244038. Fax: (+86) 21-31244038.State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, ChinaMore by Ping Zhou
Abstract
Type 2 diabetes (T2D) results from both insulin resistance and pancreatic β-cell dysfunction. A natural proteoglycan extracted from Ganoderma lucidum, namely, FYGL, has been demonstrated to be capable of ameliorating insulin resistance in previous work. In this work, a T2D rat model induced by streptozocin (STZ) and a high-fat diet was used to investigate the effects of FYGL on pancreatic functions, and the transcriptomics of the rat pancreas was used to investigate the biological processes (BP) and signal pathways influenced by FYGL on the gene basis. Furthermore, the results of transcriptomics were verified both by histopathological analyses and protein expression. The studies showed that FYGL positively regulated T2D-related BP and signaling pathways and recovered the pancreatic function, therefore ameliorating hyperglycemia and hyperlipidemia in vivo. Importantly, the recovery of the pancreatic function suggested a crucial strategy to radically treat T2D.
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Introduction
Figure 1
Figure 1. Structures of the polysaccharide components of (A) FYGL-1, (B) FYGL-2, and (C) FYGL-3 characterized by chemical analysis and NMR spectrum and the simulated structures of the protein moiety of (D) FYGL-2 and (E) FYGL-3. (17−21) p: pyranose; f: furanose; Thr: threonine; Ser: serine. The acidic amino acids Asp and Glu are marked in green and purple, respectively.
Results and Discussion
Symptoms of T2D Rats Ameliorated by FYGL
Figure 2
Figure 2. (A) FBG, (B) water intake, (C) food intake, and (D) BW of T2D rats and the influence of FYGL, where normal: normal group, model: model group, metformin: 200 mg/kg metformin group as the positive drug group, FYGL-L/M/H: FYGL groups with dosages of 225(low)/450(middle)/900(high) mg/kg, similarly hereinafter. (E) Effects of FYGL on the OGTT and (F) the area under the curves (AUC) of OGTT of T2D rats. ###p < 0.001 vs the normal group; *p < 0.05, **p < 0.01, ***p < 0.001 vs the model group (n = 14).
Effects of FYGL on Differentially Expressed Genes of the T2D Rat Pancreas
Figure 3
Figure 3. (A) DEG number statistics of each group compared with the model group. DEGs statistics between the model group and (B) normal, (C) metformin, (D) low-dose FYGL (FYGL-L), (E) middle-dose FYGL (FYGL-M), and (F) high-dose FYGL (FYGL-H) groups, respectively, displayed by the volcano plot. Red dots represented up-regulated genes, blue dots represented down-regulated genes, and gray points were not-significant genes. DESeq2 p-value < 0.05, |log2FoldChange| > 1. (25,26)
T2D-Related Biological Processes Positively Regulated by FYGL
Figure 4
Figure 4. GO enrichment analysis of the T2D rat pancreas transcriptome. (A) Top ten MF, CC, and BP according to the DEGs between the model and the FYGL-H group. The lower padj value indicated a higher geostatistical significance of differences. The count number referred to the extent of DEGs related to the MF/CC/BP. (B) DEG heatmap of preferentially enriched BP related to T2D and the effects of high doses of FYGL. DEGs with a red color were strongly expressed, and DEGs with a blue color were weakly expressed.
Pathways Positively Regulated by FYGL on KEGG Analysis
Figure 5
Figure 5. KEGG pathway enrichment analysis of the T2D rat pancreas transcriptome. (A) Top 20 pathways affected by a high dose of FYGL. The lower padj value indicated the higher geostatistical significance of differences. The count number referred to the extent of DEGs related to the pathway. (B) DEG heatmap of some preferentially enriched pathways related to T2D and the effects of FYGL. (C)DEG heatmap of the cell cycle and apoptosis pathways related to T2D and the effects of FYGL. DEGs in red color were strongly expressed, and DEGs in blue color were weakly expressed.
Decrease of Lipids and Glycosylated Hemoglobin (HbA1c) in Blood by FYGL
Figure 6
Figure 6. (A) Plasma of rats in different groups. (B) Concentration of TG in rat plasma. (C) Concentration of TC in rat plasma. (D) Percentage of glycosylated hemoglobin (HbA1c)/Hb in the whole blood of rats. ###p < 0.001 vs the normal model group; *p < 0.05, **p < 0.01, ***p < 0.001 vs the model group (n = 14).
Recovery of Damaged Islets in T2D Rats Affected by FYGL
Figure 7
Figure 7. Histopathology of pancreatic islets stained by hematoxylin&eosin (H&E) staining.
Figure 8
Figure 8. (A) Insulin immunohistochemistry in rat pancreatic islets. (B) Relative insulin level in islets. (C) Concentration of insulin in rat serum. ###p < 0.001 vs the normal group; *p < 0.05, **p < 0.01, ***p < 0.001 vs the model group (n = 4).
Activation of PPARγ Signaling in the T2D Rat Pancreas by FYGL
Figure 9
Figure 9. Relative expressions of (A) PPARγ, (B) Bcl-2, and (C) Pdx-1 in the rat pancreas, referred to the normal group. ##p < 0.01, ###p < 0.001 vs the normal group; *p < 0.05, **p < 0.01 vs the model group (n = 4).
Figure 10
Figure 10. Summary scheme of FYGL effects on T2D rats.
Conclusions
Materials and Methods
Materials
Animal Experiments
Oral Glucose Tolerance
Transcriptomics Analysis
Blood and Histological Examinations
Protein Relative Expression Measured by Elisa
Statistical Analysis
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c02200.
Extraction of FYGL from Ganoderma lucidum (G. lucidum) (PDF)
Terms & Conditions
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (nos. 21374022 and 81374032), the National Health Commission of the People’s Republic of China (no. 2017ZX09301006), the Science and Technology Commission of Shanghai Municipality (no. 17401902700), and the Shanghai Collaborative Innovation Center of Industrial Transformation of Hospital TCM Preparation.
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M.; Pemberton, N. T.; Prineas, R.; Rautaharju, F. S. R.; Zhang, Z.; Mayer-Davis, E. J.; Costacou, T.; Martin, M.; Sparks, K. L.; O'Leary, D. H.; Funk, L. R. C.; O'Leary, K. A.; Polak, J. F.; Stamm, E. R.; Scherzinger, A. L.; Wing, R. R.; Gillis, B. P.; Huffmyer, C.; Kriska, A. M.; Venditti, E. M.; Walker, E. A.; Harroun, T.; Ganiats, T. G.; Groessl, E. J.; Beerman, P. R.; David, K. M.; Kaplan, R. M.; Sieber, W. J.; Genuth, S. M.; Cahill, G. F.; Ferris, F. L., III; Gavin, J. R., III; Halter, J. B.; Wittes, J.; Henry, R. R.; Haffner, S. M.; Rubin, R. R.; Montgomery, B. K.; Ratner, R. E.; Herman, W. H.; Kahn, S. E.; Santiago, J. V.; Olefsky, J.; Wing, R. R.; Saudek, C.; Montez, M.; Kramer, K.; Hamman, R. F.; Knowler, W. C.; Goldberg, R. B.; Fujimoto, W. Y.; Charleston, J.; Nathan, D. M.New England Journal of Medicine (2002), 346 (6), 393-403CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Type 2 diabetes affects approx. 8 % of adults in the United States. Some risk factors - elevated plasma glucose concns. in the fasting state and after an oral glucose load, over-wt., and a sedentary lifestyle - are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concns. to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 % wt. loss and at least 150 min of phys. activity per wk. The mean age of the participants was 51 yr, and the mean body-mass index (the wt. in kilograms divided by the square of the height in meters) was 34.0; 68 % were women, and 45 % were members of minority groups. The av. follow-up was 2.8 yr. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and life-style groups, resp. The lifestyle intervention reduced the incidence by 58 % (95 % confidence interval, 48 to 66 %) and metformin by 31 % (95 % confidence interval, 17 to 43 %), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.
- 4Sanyal, A. J.; Chalasani, N.; Kowdley, K. V.; McCullough, A.; Diehl, A. M.; Bass, N. M.; Neuschwander-Tetri, B. A.; Lavine, J. E.; Tonascia, J.; Unalp, A.; Van Natta, M.; Clark, J.; Brunt, E. M.; Kleiner, D. E.; Hoofnagle, J. H.; Robuck, P. R.; Crn, N. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N. Engl. J. Med. 2010, 362, 1675– 1685, DOI: 10.1056/nejmoa0907929Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXls1Oltr4%253D&md5=f439009e1d05196c7a9f94ca7cbc11cbPioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitisSanyal, Arun J.; Chalasani, Naga; Kowdley, Kris V.; McCullough, Arthur; Diehi, Anna Mae; Bass, Nathan M.; Neuschwander-Tetri, Brent A.; Lavine, Joel E.; Tonascia, James; Unalp, Aynur; Van Natta, Mark; Clark, Jeanne; Brunt, Elizabeth M.; Kleiner, David E.; Hoofnagle, Jay H.; Robuck, Patricia R.New England Journal of Medicine (2010), 362 (18), 1675-1685CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Background: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. Methods: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 wk. The primary outcome was an improvement in histol. features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Results: Vitamin E therapy, as compared with placebo, was assocd. with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P = 0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, resp.; P = 0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P < 0.001 for both comparisons), and both agents were assocd. with redns. in hepatic steatosis (P = 0.005 for vitamin E and P < 0.001 for pioglitazone) and lobular inflammation (P = 0.02 for vitamin E and P = 0.004 for pioglitazone) but not with improvement in fibrosis scores (P = 0.24 for vitamin E and P = 0.12 for pioglitazone). Subjects who received pioglitazone gained more wt. than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Conclusions: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were obsd. for some of the secondary outcomes.
- 5Chiasson, J. L.; Josse, R. G.; Gomis, R.; Hanefeld, M.; Karasik, A.; Laakso, M.; Grp, S.-N. T. R. Acarbose for prevention of type 2 diabetes mellitus: the STOPNIDDM randomised trial. Lancet 2002, 359, 2072– 2077, DOI: 10.1016/s0140-6736(02)08905-5Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XkslGhs7g%253D&md5=973c014555356fea844b393fa3ed311aAcarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trialChiasson, Jean-Louis; Josse, Robert G.; Gomis, Ramon; Hanefeld, Markolf; Karasik, Avraham; Laakso, MarkkuLancet (2002), 359 (9323), 2072-2077CODEN: LANCAO; ISSN:0140-6736. (Lancet Publishing Group)The worldwide increase in type 2 diabetes mellitus is becoming a major health concern. We aimed to assess the effect of acarbose in preventing or delaying conversion of impaired glucose tolerance to type 2 diabetes. In a multicenter, placebo-controlled randomized trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat. We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no post-randomization data. Of 682 patients in the acarbose group 211 (31%), and of 686 on placebo 130 (19%), discontinued treatment early. Of patients randomized to acarbose 221 (32%), and of patients randomized to placebo 285 (42%), developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0·0001). At the end of the study, treatment with placebo for 3 mo was assocd. with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhea. Thus, acarbose could be used, either as an alternative or in addn. to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance.
- 6Turner, R.; Holman, R. R.; Cull, C. A.; Stratton, I. M.; Matthews, D. R.; Frighi, V.; Manley, S. E.; Neil, A.; McElroy, K.; Wright, D.; Kohner, E.; Fox, C.; Hadden, D.; Mehta, Z.; Smith, A.; Nugent, Z.; Peto, R.; Adlel, A. I.; Mann, J. I.; Bassett, P. A.; Oakes, S. F.; Dornan, T. L.; Aldington, S.; Lipinski, H.; Collum, R.; Harrison, K.; MacIntyre, C.; Skinner, S.; Mortemore, A.; Nelson, D.; Cockley, S.; Levien, S.; Bodsworth, L.; Willox, R.; Biggs, T.; Dove, S.; Beattie, E.; Gradwell, M.; Staples, S.; Lam, R.; Taylor, F.; Leung, L.; Carter, R. D.; Brownlee, S. M.; Fisher, K. E.; Islam, K.; Jelfs, R.; Williams, P. A.; Williams, F. A.; Sutton, P. J.; Ayres, A.; Logie, L. J.; Lovatt, C.; Evans, M. A.; Stowell, L. A.; Ross, I.; Kennedy, I. A.; Croft, D.; Keen, A. H.; Rose, C.; Raikou, M.; Fletcher, A. E.; Bulpitt, C.; Battersby, C.; Yudkin, J. S.; Stevens, R.; Stearn, M. R.; Palmer, S. L.; Hammersley, M. S.; Franklin, S. L.; Spivey, R. S.; Levy, J. C.; Tidy, C. R.; Bell, N. J.; Steemson, J.; Barrow, B. A.; Coster, R.; Waring, K.; Nolan, L.; Truscott, E.; Walravens, N.; Cook, L.; Lampard, H.; Merle, C.; Parker, P.; McVittie, J.; Draisey, I.; Murchison, L. E.; Brunt, A. H. E.; Williams, M. J.; Pearson, D. W.; Petrie, X. M. P.; Lean, M. E. J.; Walmsley, D.; Lyall, F.; Christie, E.; Church, J.; Thomson, E.; Farrow, A.; Stowers, J. M.; Stowers, M.; McHardy, K.; Patterson, N.; Wright, A. D.; Levi, N. A.; Shearer, A. C. I.; Thompson, R. J. W.; Taylor, G.; Rayton, S.; Bradbury, M.; Glover, A.; Smyth-Osbourne, A.; Parkes, C.; Graham, J.; England, P.; Gyde, S.; Eagle, C.; Chakrabarti, B.; Smith, J.; Sherwell, J.; Oakley, N. W.; Whitehead, M. A.; Hollier, G. P.; Pilkington, T.; Simpson, J.; Anderson, M.; Martin, S.; Kean, J.; Rice, B.; Rolland, A.; Nisbet, J.; Kohner, E. M.; Dornhorst, A.; Doddridge, M. C.; Dumskyij, M.; Walji, S.; Sharp, P.; Sleightholm, M.; Vanterpool, G.; Frost, G.; Roseblade, M.; Elliott, S.; Forrester, S.; Foster, M.; Myers, K.; Chapman, R.; Hayes, J. R.; Henry, R. W.; Featherston, M. S.; Archbold, G. P. R.; Copeland, M.; Harper, R.; Richardson, I.; Davison, H. A.; Alexander, L.; Scarpello, J. H. B.; Shiers, D. E.; Tucker, R. J.; Worthington, J. R. H.; Angris, S.; Bates, A.; Walton, J.; Teasdale, M.; Browne, J.; Stanley, S.; Davis, B. A.; Strange, R. C.; Hadden, D. R.; Kennedy, L.; Atkinson, A. B.; Bell, P. M.; McCance, D. R.; Rutherford, J.; Culbert, A. M.; Hegan, C.; Tennet, H.; Webb, N.; Robinson, I.; Holmes, J.; Nesbitt, S.; Spathis, A. S.; Hyer, S.; Nanson, M. E.; James, L. M.; Tyrell, J. M.; Davis, C.; Strugnell, P.; Booth, M.; Petrie, H.; Clark, D.; Hulland, S.; Barron, J. L.; Gould, B. C.; Singer, J.; Badenoch, A.; McGregor, M.; Isenberg, L.; Eckert, M.; Alibhai, K.; Marriot, E.; Cox, C.; Price, R.; Fernandez, M.; Ryle, A.; Clarke, S.; Wallace, G.; Mehmed, E.; Lankester, J. A.; Howard, E.; Waite, A.; MacFarlane, S.; Greenwood, R. H.; Wilson, J.; Denholm, M. J.; Temple, R. C.; Whitfield, K.; Johnson, F.; Munroe, C.; Gorick, S.; Duckworth, E.; Fatman, M.; Rainbow, S.; Borthwick, L.; Wheatcroft, D. J.; Seaman, R. J.; Christie, R. A.; Wheatcroft, W.; Musk, P.; White, J.; McDougal, S.; Bond, M.; Raniga, P.; Day, J. L.; Doshi, M. J.; Wilson, J. G.; Howard-Williams, J. R.; Humphreys, H.; Graham, A.; Hicks, K.; Hexman, S.; Bayliss, P.; Pledger, D.; Newton, R. W.; Jung, R. T.; Roxburgh, C.; Kilgallon, B.; Dick, L.; Waugh, N.; Kilby, S.; Ellingford, A.; Burns, J.; Fox, C. V.; Holloway, M. C.; Coghill, H. M.; Hein, N.; Fox, A.; Cowan, W.; Richard, M.; Quested, K.; Evans, S. J.; Paisey, R. B.; Brown, N. P. R.; Tucker, A. J.; Paisey, R.; Garrett, F.; Hogg, J.; Park, P.; Williams, K.; Harvey, P.; Wilcocks, R.; Mason, S.; Frost, J.; Warren, C.; Rocket, P.; Bower, L.; Roland, J. M.; Brown, D. J.; Youens, J.; Stanton-King, K.; Mungall, H.; Ball, V.; Maddison, W.; Donnelly, D.; King, S.; Griffin, P.; Smith, S.; Church, S.; Dunn, G.; Wilson, A.; Palmer, K.; Brown, P. M.; Humphriss, D.; Davidson, A. J. M.; Rose, R.; Armistead, L.; Townsend, S.; Poon, P.; Peacock, I. D. A.; Culverwell, N. J. C.; Charlton, M. H.; Connolly, B. P. S.; Peacock, J.; Barrett, J.; Wain, J.; Beeston, W.; King, G.; Hill, P. G.; Boulton, A. J. M.; Robertson, A. M.; Katoulis, V.; Olukoga, A.; McDonald, H.; Kumar, S.; Abouaesha, F.; Abuaisha, B.; Knowles, E. A.; Higgins, S.; Booker, J.; Sunter, J.; Breislin, K.; Parker, R.; Raval, P.; Curwell, J.; Davenport, H.; Shawcross, G.; Prest, A.; Grey, J.; Cole, H.; Sereviratne, C.; Young, R. J.; Clyne, J. R.; Gibson, M.; O’Connell, I.; Wong, L. M.; Wilson, S. J.; Wright, K. L.; Wallace, C.; McDowell, D.; Burden, A. C.; Sellen, E. M.; Gregory, R.; Roshan, M.; Vaghela, N.; Burden, M.; Sherriff, C.; Mansingh, S.; Clarke, J.; Grenfell, J.; Tooke, J. E.; MacLeod, K.; Seamark, C.; Rammell, M.; Pym, C.; Stockman, J.; Yeo, C.; Piper, J.; Leighton, L.; Green, E.; Hoyle, M.; Jones, K.; Hudson, A.; James, A. J.; Shore, A.; Higham, A.; Martin, B.; Neil, H. A. W.; Butterfield, W. J. H.; Doll, W. R. S.; Eastman, R.; Ferris, F. R.; Kurinij, N.; McPherson, K.; Mahler, R. F.; Meade, T. W.; Shafer, G.; Watkins, P. J.; Keen, H.; Siegel, D.; Wright, A. D.; Betteridge, D. J.; Cohen, R. D.; Currie, D.; Darbyshire, J.; Forrester, J. V.; Guppy, T.; Johnston, D. G.; McGuire, A.; Murphy, M.; el-Nahas, A. M.; Pentecost, B.; Spiegelhalter, D.; Alberti, K. G. M. M.; Denton, R.; Home, P. D.; Howell, S.; Jarrett, J. R.; Marks, V.; Marmot, M.; Ward, J. D.; Grp, U. P. D. S. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998, 352, 837– 853, DOI: 10.1016/S0140-6736(98)07019-6Google ScholarThere is no corresponding record for this reference.
- 7Olvera-Roldan, E. O.; Cristobal-Luna, J. M.; Garcia-Martinez, Y.; Mojica-Villegas, M. A.; Perez-Pasten-Borja, R.; Gutierrez-Salmean, G.; Perez-Gutierrez, S.; Garcia-Rodriguez, R. V.; Madrigal-Santillan, E.; Morales-Gonzalez, J. A.; Chamorro-Cevallos, G. Effects of Spirulina maxima on a Model of Sexual Dysfunction in Streptozotocin-Induced Diabetic Male Rats. Plants 2023, 12, 722, DOI: 10.3390/plants12040722Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXkslWhsr0%253D&md5=e10ff814448fd0ac22b760e8e1826d9dEffects of Spirulina maxima on a Model of Sexual Dysfunction in Streptozotocin-Induced Diabetic Male RatsOlvera-Roldan, Eduardo Osel; Cristobal-Luna, Jose Melesio; Garcia-Martinez, Yuliana; Mojica-Villegas, Maria Angelica; Perez-Pasten-Borja, Ricardo; Gutierrez-Salmean, Gabriela; Perez-Gutierrez, Salud; Garcia-Rodriguez, Rosa Virginia; Madrigal-Santillan, Eduardo; Morales-Gonzalez, Jose A.; Chamorro-Cevallos, GermanPlants (2023), 12 (4), 722CODEN: PLANCD; ISSN:2223-7747. (MDPI AG)Arthrospira (Spirulina) maxima (SM) is a cyanobacterium that has a long history of being used as human food. In recent years, several investigations have shown its beneficial biol. effects, among which its antioxidant capacity has been highlighted. The purpose of this study was to evaluate the effects of SM on body wt., glycemia, sexual behavior, sperm quality, testosterone levels, sex organ wts., and the activity of antioxidant enzymes in diabetic male rats (a disease characterized by an increase in reactive oxygen species). The expt. consisted of six groups of sexually expert adult males (n = 6): (1) control (vehicle); (2) streptozotocin (STZ)-65 mg/kg; (3) SM-400 mg/kg; (4) STZ + SM-100 mg/kg; (5) STZ + SM-200 mg/kg; and (6) STZ + SM-400 mg/kg. Sexual behavior tests were performed during the first 3 h of the dark period under dim red illumination. Our results showed that SM significantly improved sexual behavior and sperm quality vs. diabetic animals. Likewise, while the enzymic activities of SOD and GPx increased, TBARS lipoperoxidn. decreased and testosterone levels increased. In view of the findings, it is suggested that SM may potentially be used as a nutraceutical for the treatment of diabetic male sexual dysfunction due to its antioxidant property.
- 8Hsu, Y. C.; Chang, C. C.; Hsieh, C. C.; Shih, Y. H.; Chang, H. C.; Lin, C. L. Therapeutic Potential of Extracts from Macaranga tanarius (MTE) in Diabetic Nephropathy. Plants 2023, 12, 656, DOI: 10.3390/plants12030656Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXjsF2jsrc%253D&md5=e176b266f9f7e26bbe1f04a3e5bdc2b3Therapeutic Potential of Extracts from Macaranga tanarius (MTE) in Diabetic NephropathyHsu, Yung-Chien; Chang, Cheng-Chih; Hsieh, Ching-Chuan; Shih, Ya-Hsueh; Chang, Hsiu-Ching; Lin, Chun-LiangPlants (2023), 12 (3), 656CODEN: PLANCD; ISSN:2223-7747. (MDPI AG)Diabetic nephropathy is a complication of diabetes that leads to end-stage kidney disease and is a major health burden worldwide. Prenylflavonoid compds. extd. from Macaranga tanarius (MTE) exhibit anti-inflammation, anti-oxidant, and anti-bacterial properties. However, the effects of these compds. on diabetic nephropathy remain unclear. The effects of MTE on diabetic nephropathy were investigated in vitro by using mouse renal mesangial cells and in vivo by using a db/db knockout mouse model. No overt alteration in proliferation was obsd. in mouse renal mesangial cells treated with 0-1 μg/mL MTE. Western blot anal. indicated that MTE dose-dependently attenuated the expression of fibronectin, α-smooth muscle actin, and collagen IV. Administration of MTE ameliorated renal albumin loss in db/db mice. Immunohistochem. staining revealed that MTE mitigated diabetes-induced fibronectin and collagen IV expression. Periodic acid-Schiff (PAS) and trichrome staining also showed that administration of MTE reduced the renal fibrosis phenomenon. MTE significantly ameliorated diabetes-induced nephropathy.
- 9Belaabed, S.; Khalfaoui, A.; Parisi, V.; Santoro, V.; Russo, D.; Ponticelli, M.; Monne, M.; Rebbas, K.; Milella, L.; Donadio, G. Rhanteriol, a New Rhanterium suaveolens Desf. Lignan with Pharmacological Potential as an Inhibitor of Enzymes Involved in Neurodegeneration and Type 2 Diabetes. Plants 2023, 12, 301, DOI: 10.3390/plants12020301Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXivFSnsb4%253D&md5=7dc57806544c1193011f0456b13d5f6dRhanteriol, a New Rhanterium suaveolens Desf. Lignan with Pharmacological Potential as an Inhibitor of Enzymes Involved in Neurodegeneration and Type 2 DiabetesBelaabed, Soumia; Khalfaoui, Ayoub; Parisi, Valentina; Santoro, Valentina; Russo, Daniela; Ponticelli, Maria; Monne, Magnus; Rebbas, Khellaf; Milella, Luigi; Donadio, GiulianaPlants (2023), 12 (2), 301CODEN: PLANCD; ISSN:2223-7747. (MDPI AG)Several specialized plant metabolites are reported to be enzyme inhibitors. In this investigation, the phytochem. compn. and the biol. activity of Rhanterium suaveolens Desf. were studied. One new lignan (rhanteriol 1) and seven known secondary metabolites were isolated from the aerial parts of R. suaveolens by using different chromatog. procedures. The biol. properties of the R. suaveolens exts. and the new compd. were evaluated by measuring their ability to inhibit the cholinesterase and carbohydrate-hydrolyzing enzymes, using cell-free in vitro methods. The new lignan, rhanteriol, was shown to inhibit α-amylase and α-glucosidase (IC50 = 46.42 ± 3.25 μM and 26.76 ± 3.29 μM, resp.), as well as butyrylcholinesterase (IC50 = 10.41 ± 0.03 μM), with an effect comparable to that of the resp. stds., acarbose and galantamine. Furthermore, docking studies were performed suggesting the interaction mode of rhanteriol with the active sites of the investigated enzymes. The obtained data demonstrated that the aerial part of R. suaveolens could represent a source of active mols., such as rhanteriol, usable in the development of treatments for preventing or treating type 2 diabetes mellitus and neurodegeneration.
- 10Chukiatsiri, S.; Wongsrangsap, N.; Ratanabunyong, S.; Choowongkomon, K. In Vitro Evaluation of Antidiabetic Potential of Cleistocalyx nervosum var. paniala Fruit Extract. Plants 2022, 12, 112, DOI: 10.3390/plants12010112Google ScholarThere is no corresponding record for this reference.
- 11Hassan, H. M.; Mahran, Y. F.; Ghanim, A. M. H. Ganoderma lucidum ameliorates the diabetic nephropathy via down-regulatory effect on TGFbeta-1 and TLR-4/NFkappaB signalling pathways. J. Pharm. Pharmacol. 2021, 73, 1250– 1261, DOI: 10.1093/jpp/rgab058Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3sbgt1Oltg%253D%253D&md5=3d3e5b20cf8399060151df5ca5379306Ganoderma lucidum ameliorates the diabetic nephropathy via down-regulatory effect on TGFβ-1 and TLR-4/NFκB signalling pathwaysHassan Hanan M; Mahran Yasmen F; Mahran Yasmen F; Ghanim Amal M HThe Journal of pharmacy and pharmacology (2021), 73 (9), 1250-1261 ISSN:.OBJECTIVES: Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus and it is considered as a principal cause for end-stage renal failure. Ganoderma lucidum (GL) has been studied for its reno-protective effect against different kidney injury models. The aim of our study is to investigate the mechanisms by which GL can improve kidney injury and consequent renal inflammation and fibrosis. METHODS: GL either in a low dose (250 mg/kg, i.p.) or high dose (500 mg/kg, i.p.) was administered to DN rat model, and nephropathy indices were investigated. KEY FINDINGS: GL treatment significantly down-regulated kidney injury molecule-1 (KIM-1) gene expression and inhibited TLR-4 (Toll-like receptor-4)/NFκB (nuclear factor kappa B) signalling pathway. As well, GL treatment significantly decreased the pro-inflammatory mediator; IL-1β (interleukin-1 beta) level and fibrosis-associated growth factors; FGF-23 (fibroblast growth factor-23) and TGFβ-1 (transforming growth factor beta-1) levels. In addition, GL remarkably inhibited (Bax) the pro-apoptotic protein and induced (Bcl-2) the anti-apoptotic protein expression in kidneys. Moreover, GL treatment significantly alleviates kidney injury indicated by correcting the deteriorated kidney function and improving oxidative stress status in DN rats. CONCLUSIONS: GL significantly improved renal function indices through dose-dependent kidney function restoration, oxidative stress reduction, down-regulation of gene expression of KIM-1 and TLR4/NFκB signalling pathway blockage with subsequent alleviation of renal inflammation and fibrosis.
- 12Sun, J.; He, H.; Xie, B. J. Novel antioxidant peptides from fermented mushroom Ganoderma lucidum. J. Agric. Food Chem. 2004, 52, 6646– 6652, DOI: 10.1021/jf0495136Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXns1Wit70%253D&md5=91c7391dfc158852e6f85e93b62d851bNovel Antioxidant Peptides from Fermented Mushroom Ganoderma lucidumSun, Jie; He, Hui; Xie, Bi JunJournal of Agricultural and Food Chemistry (2004), 52 (21), 6646-6652CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Oxidative stress has been linked with the pathogenesis of many human diseases including cancer, aging, and atherosclerosis. The present study investigates the antioxidant activities of peptides isolated from the medicinal mushroom, Ganoderma lucidum. G. Lucidum has been shown to possess potent antioxidant activity with little or no side effects. Polysaccharide, polysaccharide-peptide complex, and phenolic components of G. Lucidum have been proposed to be responsible for this antioxidant effect. However, research has shown that the G. Lucidum peptides (GLP) is the major antioxidant component of G. lucidum. The objective of this study was to evaluate the antioxidant activity of these peptides using different oxidn. systems. GLP showed potent antioxidant activities in both lightproof soybean oil and lard systems, assessed by lipid peroxidant value. Compared to butylated hydroxytoluene, GLP showed a higher antioxidant activity in the soybean oil system. Soybean lipoxygenase activity was blocked by GLP in a dose-dependent manner with an IC50 value of 27.1 μg/mL. GLP showed scavenging activity toward hydroxyl radicals produced in a deoxyribose system with an IC50 value of 25 μg/mL, and GLP effectively quenched superoxide radical anion produced by pyrogallol autoxidn. in a dose-dependent manner. Malondialdehyde level has been used as the oxidn. index in many biol. systems. GLP showed substantial antioxidant activity in the rat liver tissue homogenates and mitochondrial membrane peroxidn. systems. The auto-hemolysis of rat red blood cells was also blocked by GLP in a dose-dependent manner. On the basis of these results, it is concluded that GLP is the major constituent responsible for the antioxidant activity of G. lucidum. GLP could play an important role in the inhibition of lipid peroxidn. in biol. systems through its antioxidant, metal chelating, and free radical scavenging activities.
- 13van der Hem, L. G.; van der Vliet, J. A.; Bocken, C. F.; Kino, K.; Hoitsma, A. J.; Tax, W. J. Ling Zhi-8: studies of a new immunomodulating agent. Transplantation 1995, 60, 438– 443, DOI: 10.1097/00007890-199509000-00006Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXovVWrt7w%253D&md5=fd0b29ddb505c57c6b564c4323f384a4Ling ZHI-8: studies of a new immunomodulating agentvan der Hem, Lieuwe G.; van der Vliet, J. Adam; Bocken, C. Frans M.; Kino, Kohsuke; Hoitsma, Andries J.; Tax, Wil J.M.Transplantation (1995), 60 (5), 438-43CODEN: TRPLAU; ISSN:0041-1337. (Williams & Wilkins)Ling ZHI-8 (LZ-8) is a protein derived from the fungus Ganoderma lucidum and has immunomodulatory capacities. It was shown to be mitogenic toward mouse splenocytes in vitro and immunosuppressive in vivo by reducing antigen-induced antibody formation and by preventing completely the incidence of autoimmune diabetes in nonobese diabetic mice. In this study, the mitogenic effects of LZ-8 on human mononuclear cells are reported. In accordance to its mitogenic effect on mouse splenocytes, LZ-8 proved to be mitogenic for human PBMC. This mitogenic effect of LZ-8 apparently required the presence of monocytes. The authors also demonstrated it to be immunosuppressive in vitro in a human MLC performed in the absence of monocytes, using purified T cells and EBV-transformed allogeneic B cells. Furthermore, the authors tested LZ-8 for its possible suppressive effects in 2 different models of allogeneic tissue transplantation. LZ-8 proved to have a significant effect on cellular immunity, since its administration in an allografted mouse skin model resulted in an increased survival time. In a model of transplanted allogeneic pancreatic rat islets, LZ-8 was effective in delaying the rejection process of allografted islets. More frequent or continuous administration resulted in a further prolongation of survival time. No serious side effects of LZ-8 could be discerned in these expts.
- 14Thomford, N. E.; Senthebane, D. A.; Rowe, A.; Munro, D.; Seele, P.; Maroyi, A.; Dzobo, K. Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery. Int. J. Mol. Sci. 2018, 19, 1578, DOI: 10.3390/ijms19061578Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVGrt7nO&md5=75122cc3e54f8cdeec7d42043405629aNatural products for drug discovery in the 21st century: innovations for novel drug discoveryThomford, Nicholas Ekow; Senthebane, Dimakatso Alice; Rowe, Arielle; Munro, Daniella; Seele, Palesa; Maroyi, Alfred; Dzobo, KevinInternational Journal of Molecular Sciences (2018), 19 (6), 1578/1-1578/29CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)The therapeutic properties of plants have been recognized since time immemorial. Many pathol. conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concd. plant exts. without isolation of active compds. Modern medicine however, requires the isolation and purifn. of one or two active compds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of "active compd." hasmade the compd. ineffective. Drug discovery is amultidimensional problemrequiring several parameters of both natural and synthetic compds. such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of 'organ-on chip' and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compds. while allowing novel ways of drug design and synthesis based on natural compds. Recent advances in anal. and computational techniques have opened new avenues to process complex natural products and to use their structures to derive newand innovative drugs. Indeed, we are in the era of computational mol. design, as applied to natural products. Predictive computational softwares have contributed to the discovery of mol. targets of natural products and their derivs. In future the use of quantum computing, computational softwares and databases in modeling mol. interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false pos. leads in drug development. This review discusses plant-based natural product drug discovery and how innovative technologies play a role in next-generation drug discovery.
- 15Xu, S.; Dou, Y.; Ye, B.; Wu, Q.; Wang, Y.; Hu, M.; Ma, F.; Rong, X.; Guo, J. Ganoderma lucidum polysaccharides improve insulin sensitivity by regulating inflammatory cytokines and gut microbiota composition in mice. J. Funct. Foods 2017, 38, 545– 552, DOI: 10.1016/j.jff.2017.09.032Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1SitbvI&md5=138b0a8934aa61132534934cdc32ae94Ganoderma lucidum polysaccharides improve insulin sensitivity by regulating inflammatory cytokines and gut microbiota composition in miceXu, S.; Dou, Y.; Ye, B.; Wu, Q.; Wang, Y.; Hu, M.; Ma, F.; Rong, X.; Guo, J.Journal of Functional Foods (2017), 38 (Part_A), 545-552CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)Ectopic lipid accumulation and low-grade chronic inflammation are crit. pathogenesis of insulin resistance development. Ganoderma lucidum is a traditional Chinese herb for balancing energy homeostasis. In this research, we detd. the effects of G. lucidum polysaccharides (GLP) on high-fat diet (HFD)-induced insulin resistant mice. We obsd. that GLP treatment decreased plasma insulin concn. and reversed HFD-induced systemic insulin resistance. Meanwhile, GLP ameliorated low-grade chronic inflammation, inducing lipolysis in adipose tissues. GLP decreased plasma triglyceride and non-esterified fatty acid outflux by suppressing mRNA expressions of hormone-sensitive lipase, fatty acid binding protein 4, tumor necrosis factor-α, and interleukin-6 in epididymal fat. Finally, GLP treatment suppressed ectopic lipid accumulation in peripheral tissues and hepatic insulin-regulated lipogenesis. GLP also regulated compn. of gut microbiota implicated in type 2 diabetes mellitus development.
- 16Teng, B. S.; Wang, C. D.; Yang, H. J.; Wu, J. S.; Zhang, D.; Zheng, M.; Fan, Z. H.; Pan, D.; Zhou, P. A protein tyrosine phosphatase 1B activity inhibitor from the fruiting bodies of Ganoderma lucidum (Fr.) Karst and its hypoglycemic potency on streptozotocin-induced type 2 diabetic mice. J. Agric. Food Chem. 2011, 59, 6492– 6500, DOI: 10.1021/jf200527yGoogle Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvFSltrk%253D&md5=51bc78266138c7765cef7d1f6b76e82aA Protein Tyrosine Phosphatase 1B Activity Inhibitor from the Fruiting Bodies of Ganoderma lucidum (Fr.) Karst and Its Hypoglycemic Potency on Streptozotocin-Induced Type 2 Diabetic MiceTeng, Bao-Song; Wang, Chen-Dong; Yang, Hong-Jie; Wu, Jia-Sheng; Zhang, Dan; Zheng, Min; Fan, Zhao-Hua; Pan, Deng; Zhou, PingJournal of Agricultural and Food Chemistry (2011), 59 (12), 6492-6500CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Inhibition of protein tyrosine phosphatase 1B (PTP1B) activity has been considered to be a promising therapy approach to treat type 2 diabetes. A novel PTP1B activity inhibitor, named FYGL (Fudan-Yueyang-G. lucidum), was screened from the fruiting bodies of Ganoderma lucidum and showed an efficient PTP1B inhibitory potency with IC50 = 5.12±0.05 μg/mL. FYGL is a water-sol. macromol. proteoglycan with a protein to polysaccharide ratio of 17:77 and a viscosity-av. mol. wt. (Mη) of 2.6 × 105. The type 2 diabetic mice treated orally by FYGL showed an obvious decrease in plasma glucose level compared with the diabetic controls without drug treatment, comparable with that of diabetic mice treated with metformin, a clin. drug. The toxicity of FYGL is very low. The results indicate that FYGL may serve as a drug candidate or a health-care food for diabetic therapy or protection.
- 17Pan, D.; Wang, L.; Chen, C.; Hu, B.; Zhou, P. Isolation and characterization of a hyperbranched proteoglycan from Ganoderma lucidum for anti-diabetes. Carbohydr. Polym. 2015, 117, 106– 114, DOI: 10.1016/j.carbpol.2014.09.051Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Kgu73F&md5=f823762d3d9d4f3ac66b26bdf657ab27Isolation and characterization of a hyperbranched proteoglycan from Ganoderma lucidum for anti-diabetesPan, Deng; Wang, Linqiang; Chen, Congheng; Hu, Bingwen; Zhou, PingCarbohydrate Polymers (2015), 117 (), 106-114CODEN: CAPOD8; ISSN:0144-8617. (Elsevier Ltd.)An efficient protein tyrosine phosphatase 1B (PTP1B) inhibitor, named FYGL-n, was isolated from Ganoderma lucidum and characterized for its structure and bioactivity. The structure and chain conformation of FYGL-n based on both chem. and spectroscopic anal. showed that FYGL-n was a hyperbranched heteropolysaccharide bonded with protein via both serine and threonine residues by O-type glycoside, and showed a sphere obsd. by AFM. FYGL-n consisted of D-arabinose, D-galactose, L-rhamnose and D-glucose in a mole ratio of 0.08:0.21:0.24:0.47, with a mol. mass of 72.9 kDa. Anal. of amino acids in FYGL-n indicated that there were 16 common amino acids, among which aspartic acid, glycine, serine, alanine, glutamic acid and threonine were the dominant components. FYGL-n could inhibit the PTP1B activity via a competitive mechanism in vitro.
- 18Pan, D.; Wang, L.; Hu, B.; Zhou, P. Structural characterization and bioactivity evaluation of an acidic proteoglycan extract from Ganoderma lucidum fruiting bodies for PTP1B inhibition and anti-diabetes. Biopolymers 2014, 101, 613– 623, DOI: 10.1002/bip.22426Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvVGrs7s%253D&md5=2b7e3991226cf2f900ec0f3c63e881f0Structural characterization and bioactivity evaluation of an acidic proteoglycan extract from Ganoderma lucidum fruiting bodies for PTP1B inhibition and anti-diabetesPan, Deng; Wang, Linqiang; Hu, Bingwen; Zhou, PingBiopolymers (2014), 101 (6), 613-623CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)A water-sol. PTP1B inhibitor, named FYGL-a, was fractionated for structure investigation and bioactivity evaluation. FYGL-a is an ingredient of a reported antihyperglycemia ext. from Ganoderma Lucidum fruiting bodies. Compn. anal. indicated that FYGL-a was a 100.2 kDa acidic proteoglycan, consisting of 85 ± 2% heteropolysaccharide chain with rhamnose, galactose, glucose, and glucuronic acid residues in a mole ratio of 1.0:3.7:3.9:2.0, and the 15 ± 2% protein moiety of FYGL-a was covalently bonded to the polysaccharide chain in O-linkage type via threonine residues. The complete sequence of FYGL-a was characterized systematically by periodate oxidn., Smith degrdn., methylation anal., 1H & 13C 1D NMR, and 2D NMR (HSQC, HMBC, NOESY, COSY, & TOCSY). The chem. structure of FYGL-a was detd. as following, which may play special role in the competitive inhibition of PTP1B and antihyperglycemia potency. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 613-623, 2014.
- 19Pan, D.; Wang, L.; Chen, C.; Teng, B.; Wang, C.; Xu, Z.; Hu, B.; Zhou, P. Structure characterization of a novel neutral polysaccharide isolated from Ganoderma lucidum fruiting bodies. Food Chem. 2012, 135, 1097– 1103, DOI: 10.1016/j.foodchem.2012.05.071Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlSmurjF&md5=2ca616283a5d3410ceba607e3a6d6f10Structure characterization of a novel neutral polysaccharide isolated from Ganoderma lucidum fruiting bodiesPan, Deng; Wang, Linqiang; Chen, Congheng; Teng, Baosong; Wang, Chendong; Xu, Zhixue; Hu, Bingwen; Zhou, PingFood Chemistry (2012), 135 (3), 1097-1103CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)Ganoderma lucidum (G. lucidum) is a mushroom which has been used for health promotion for a long time in China. In the present work a neutral hetero-polysaccharide, named FYGL-1, was isolated from FYGL which was reported previously capable of antihyperglycemia in vivo for further detailed chem. structure investigation. The results of monosaccharide compn. and GPC anal. indicated that FYGL-1 consisted of galactose, rhamnose and glucose in mole ratio of 1.00:1.15:3.22 with a mol. wt. of 78 kDa. The detailed structure of FYGL-1 was characterized by periodate oxidn., Smith degrdn., methylation anal., along with FT-IR, GC, GC-MS, 1D 1H and 13C NMR and 2D NMR (HSQC, COSY, NOESY and TOCSY). Based on the anal. of the results, the structure of the repeating unit of FYGL-1 was established as:.
- 20Pan, D.; Zhang, D.; Wu, J.; Chen, C.; Xu, Z.; Yang, H.; Zhou, P. Antidiabetic, antihyperlipidemic and antioxidant activities of a novel proteoglycan from ganoderma lucidum fruiting bodies on db/db mice and the possible mechanism. PLoS One 2013, 8, e68332 DOI: 10.1371/journal.pone.0068332Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFymtrzF&md5=f924b1921c7d59242fee324ea29a57c2Antidiabetic, antihyperlipidemic and antioxidant activities of a novel proteoglycan from Ganoderma Lucidum fruiting bodies on db/db mice and the possible mechanismPan, Deng; Zhang, Dang; Wu, Jiasheng; Chen, Congheng; Xu, Zhixue; Yang, Hongjie; Zhou, PingPLoS One (2013), 8 (7), e68332CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Previously, we screened a proteoglycan for anti-hyperglycemic, named FYGL, from Ganoderma Lucidum. For further research of the antidiabetic mechanisms of FYGL in vivo, the glucose homeostasis, activities of insulin-sensitive enzymes, glucose transporter expression and pancreatic function were analyzed using db/db mice as diabetic models in the present work. FYGL not only lead to a redn. in glycated Hb level, but also an increase in insulin and C-peptide level, whereas a decrease in glucagons level and showed a potential for the remediation of pancreatic islets. FYGL also increased the glucokinase activities and simultaneously lowered the phosphoenol pyruvate carboxykinase activities, accompanied by a redn. in the expression of hepatic glucose transporter protein 2, while the expression of adipose and skeletal glucose transporter protein 4 was increased. Moreover, the antioxidant enzyme activities were also increased by FYGL treatment. Thus, FYGL was an effective antidiabetic agent by enhancing insulin secretion and decreasing hepatic glucose output along with increase of adipose and skeletal muscle glucose disposal in the late stage of diabetes. Furthermore, FYGL is beneficial against oxidative stress, thereby being helpful in preventing the diabetic complications.
- 21Yu, F. Z.; Teng, Y. L.; Yang, S. T.; He, Y. M.; Zhang, Z.; Yang, H. J.; Ding, C. F.; Zhou, P. The thermodynamic and kinetic mechanisms of a Ganoderma lucidum proteoglycan inhibiting hIAPP amyloidosis. Biophys. Chem. 2022, 280, 106702, DOI: 10.1016/j.bpc.2021.106702Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVamsLnF&md5=c84b39e8b76038e943cbf2e2010f3dc6The thermodynamic and kinetic mechanisms of a Ganoderma lucidum proteoglycan inhibiting hIAPP amyloidosisYu, Fanzhen; Teng, Yilong; Yang, Shutong; He, Yanming; Zhang, Zeng; Yang, Hongjie; Ding, Chuan-Fan; Zhou, PingBiophysical Chemistry (2022), 280 (), 106702CODEN: BICIAZ; ISSN:0301-4622. (Elsevier B.V.)Ganoderma lucidum is a valuable medicinal herbal which has been reported to prevent type 2 diabetes (T2D). A natural hyperbranched proteoglycan extd. from Ganoderma lucidum, namely, FYGL, has been demonstrated to inhibit the amyloidosis of human islet amyloid polypeptide (hIAPP) previously by our lab. However, the effective active components and the mechanisms of FYGL in inhibiting hIAPP amyloidosis are unknown. To identify the effective active components, different components from FYGL were isolated: the polysaccharide FYGL-1, the proteoglycans of FYGL-2 and FYGL-3. We further sepd. and sequenced the protein moieties of FYGL-2 and FYGL-3, namely, FYGL-2-P and FYGL-3-P, resp., and compared their abilities to inhibit hIAPP amyloidosis, and systematically explored the inhibitory mechanisms by spectroscopy, microscopy and mol. dynamic simulation methods. Results showed that the protein moieties of FYGL played essential roles in inhibiting hIAPP amyloidosis. The strong, specific, and enthalpy-driven interaction by π-π stacking and electrostatic forces between hIAPP and FYGL-3-P dramatically inhibited hIAPP amyloidosis. These results suggested that FYGL-3-P had enormous potential to prevent hIAPP misfolding-induced diabetes and structurally helped researchers to seek or design inhibitors against polypeptide amyloidosis.
- 22Pan, D.; Zhang, D.; Wu, J.; Chen, C.; Xu, Z.; Yang, H.; Zhou, P. A novel proteoglycan from Ganoderma lucidum fruiting bodies protects kidney function and ameliorates diabetic nephropathy via its antioxidant activity in C57BL/6 db/db mice. Food Chem. Toxicol. 2014, 63, 111– 118, DOI: 10.1016/j.fct.2013.10.046Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFyls7bF&md5=ff590f82015be7cdb29dbab653a7b6d8A novel proteoglycan from Ganoderma lucidum fruiting bodies protects kidney function and ameliorates diabetic nephropathy via its antioxidant activity in C57BL/6 db/db micePan, Deng; Zhang, Dan; Wu, Jiasheng; Chen, Congheng; Xu, Zhixue; Yang, Hongjie; Zhou, PingFood and Chemical Toxicology (2014), 63 (), 111-118CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)Diabetic nephropathy (DN) is the major cause of morbidity among diabetic patients. Thus, antidiabetic drugs with protection potential in the kidneys would have a higher therapeutic value. The effects of a novel proteoglycan, named FYGL, isolated from G. lucidum fruiting bodies, on the kidney function were investigated systematically in present work. FYGL (250 mg/kg) not only dosedependently reduced the blood glucose concn. (23.5%, p < 0.05), kidney/body wt. ratio (23.6%, p < 0.01), serum creatinine (33.1%, p < 0.01), urea nitrogen (24.1%, p < 0.01),urea acid contents (35.9%, p < 0.01) and albuminuria (30.7%, p < 0.01)of DN mice compared to the untreated DN mice but also increased the renal superoxide dismutase (75.3%, p < 0.01), glutathione peroxidase (35.0%, p < 0.01) and catalase activities (58.5%, p < 0.01) compared to the untreated DN mice. The decreasing of renal malondialdehyde content (34.3%, p < 0.01) and 8-hydroxy-2'-deoxyguanosine expression (2.5-fold, p < 0.01) were also obsd. in FYGL-treated DN mice compared to the untreated DN mice, along with an amelioration of renal morphol. abnormalities. We conclude that FYGL confers protection against the renal functional and morphol. injuries by increasing activities of antioxidants and inhibiting accumulation of oxidn., suggesting a potential nutritional supplement for the prevention and therapy of DN.
- 23Yang, Z.; Wu, F.; He, Y.; Zhang, Q.; Zhang, Y.; Zhou, G.; Yang, H.; Zhou, P. A novel PTP1B inhibitor extracted from Ganoderma lucidum ameliorates insulin resistance by regulating IRS1-GLUT4 cascades in the insulin signaling pathway. Food Funct. 2018, 9, 397– 406, DOI: 10.1039/c7fo01489aGoogle Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVKhur7E&md5=6c8be3a7ed6c6c4bfea6932dd3808b74A novel PTP1B inhibitor extracted from Ganoderma lucidum ameliorates insulin resistance by regulating IRS1-GLUT4 cascades in the insulin signaling pathwayYang, Zhou; Wu, Fan; He, Yanming; Zhang, Qiang; Zhang, Yuan; Zhou, Guangrong; Yang, Hongjie; Zhou, PingFood & Function (2018), 9 (1), 397-406CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)Insulin resistance caused by the overexpression of protein tyrosine phosphatase 1 B (PTP1B) as well as the dephosphorylation of its target is one of the main causes of type 2 diabetes (T2D). A newly discovered proteoglycan, Fudan-Yueyang Ganoderma lucidum (FYGL) extd. from Ganoderma lucidum, was first reported to be capable of competitively inhibiting PTP1B activity in vitro in our previous work. In the present study, we sought to reveal the mechanism of PTP1B inhibition by FYGL at the animal and cellular levels. We found that FYGL can decrease blood glucose, reduce body wt. and ameliorate insulin resistance in ob/ob mice. Decrease of PTP1B expression and increase of the phosphorylation of PTP1B targets in the insulin signaling pathway of skeletal muscles were obsd. In order to clearly reveal the underlying mechanism of the hypoglycemic effect caused by FYGL, we further investigated the effects of FYGL on the PTP1B-involved insulin signaling pathway in rat myoblast L6 cells. We demonstrated that FYGL had excellent cell permeability by using a confocal laser scanning microscope and a flow cytometer. We found that FYGL had a pos. effect on insulin-stimulated glucose uptake by using the 2-deoxyglucose (2-DG) method. FYGL could inhibit PTP1B expression at the mRNA level, phosphorylating insulin receptor substrate-1 (IRS1), as well as activating phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt). Finally, FYGL increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and consequently up-regulated the expression of glucose transporter type 4 (GLUT4), promoting GLUT4 transportation to the plasma membrane in PTP1B-transfected L6 cells. Our study provides theor. evidence for FYGL to be potentially used in T2D management.
- 24Weng, Y. J.; Zhang, M.; Wang, J.; Zhang, Y. Q. Significantly hypoglycemic effect of a novel functional bread rich in mulberry bark and improving the related functions of liver, pancreas, and kidney, on T2D mice. Food Sci. Nutr. 2021, 9, 2468– 2482, DOI: 10.1002/fsn3.2189Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsFyis7%252FP&md5=9eda06c8c2f1b186e2b5391d9d5c86b1Significantly hypoglycemic effect of a novel functional bread rich in mulberry bark and improving the related functions of liver, pancreas, and kidney, on T2D miceWeng, Yu-Jie; Zhang, Meng; Wang, Jiang; Zhang, Yu-QingFood Science & Nutrition (Hoboken, NJ, United States) (2021), 9 (5), 2468-2482CODEN: FSNHBW; ISSN:2048-7177. (John Wiley & Sons, Inc.)To develop a novel functional food with lowering blood glucose for diabetics, the mixed bread contg. mulberry branch bark powder (MBBP) was used for the oral administration of the type 2 diabetic (T2D) mice induced by streptozocin (STZ), high-fat and high-sugar diet for 7 wk. 5%, 10%, and 15% MBBP bread diets had a significatively pos. influence on the biochem. indicators, histol. examn., and immunohistochem. observations in T2D mice. The 15% MBBP-rich bread diet evidently retarded loss wt. of T2D mice, and decreased in FBG by about 55% and in glycosylated Hb (HbA1c) levels by about 30%. Its glucose tolerance and serum insulin levels were very close to normal level. The abnormal lipid metab. and insulin-related index of T2D mice in both the 10% and 15% MBBP bread diet groups were partly reversed. The Western blotting results showed that the expression levels of key proteins in PI3K/AKT signaling pathway were decreased and expression levels of immunoproteins PPARγ, TNF-α, P65, and IL6 were increased. In general, oral MBBP bread diets effectively restored some functions and repaired damage to the pancreas, liver, and kidney in T2D mice. Therefore, MBBP is potential to develop into a novel functional food additive with significantly hypoglycemic effect.
- 25Love, M. I.; Huber, W.; Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014, 15, 550, DOI: 10.1186/s13059-014-0550-8Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtVCrsL8%253D&md5=e1052687faf6b297cdf615a14676c5b0Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2Love, Michael I.; Huber, Wolfgang; Anders, SimonGenome Biology (2014), 15 (12), 550/1-550/21, 21 pp.CODEN: GNBLFW; ISSN:1474-760X. (BioMed Central Ltd.)In comparative high-throughput sequencing assays, a fundamental task is the anal. of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across exptl. conditions. Small replicate nos., discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential anal. of count data, using shrinkage estn. for dispersions and fold changes to improve stability and interpretability of ests. This enables a more quant. anal. focused on the strength rather than the mere presence of differential expression.
- 26Wang, H.; Niu, L.; Jiang, S.; Zhai, J.; Wang, P.; Kong, F.; Jin, X. Comprehensive analysis of aberrantly expressed profiles of lncRNAs and miRNAs with associated ceRNA network in muscle-invasive bladder cancer. Oncotarget 2016, 7, 86174– 86185, DOI: 10.18632/oncotarget.13363Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2snotVaksw%253D%253D&md5=7a216f91848c32ca29798a3dd0859c7aComprehensive analysis of aberrantly expressed profiles of lncRNAs and miRNAs with associated ceRNA network in muscle-invasive bladder cancerWang Hanbo; Jiang Shaobo; Jin Xunbo; Niu Leilei; Zhai Jing; Wang Ping; Kong FengOncotarget (2016), 7 (52), 86174-86185 ISSN:.Although initially thought to be transcriptional noise, long noncoding RNAs (lncRNAs) are gaining increased attention in human cancers as its diversity function. At present, lncRNAs are regarded as the main part of competing endogenous RNA (ceRNA) network due to its regulation on protein-coding gene expression by acting as miRNA sponges. However, functional roles of lncRNA-mediated ceRNAs in muscle-invasive bladder cancer remain unclear. To clarify relevant potential mechanisms, here we comprehensively compared the expression profiles of mRNAs, lncRNAs and miRNAs between 322 muscle-invasive bladder cancer tissues and 19 non-tumor bladder tissues, based on the Cancer Genome Atlas (TCGA). A total of 22 lncRNAs were identified as aberrantly expressed and had correlations with tumorigenesis and/or progression of muscle-invasive bladder cancer ( log2FoldChange > 1.5, corrected P value < 0.01). 6 out of the 22 dysregulated lncRNAs functioned as prognostic biomarkers for patients with muscle-invasive bladder cancer according to the overall survival analysis (P value < 0.05). Finally, a dysregulated lncRNA-associated ceRNA network was successfully constructed, which inculdes five muscle-invasive bladder cancer-specific lncRNAs, nine miRNAs and 32 mRNAs. In summary, our study identified novel lncRNAs as candidate prognostic biomarkers and potential therapeutic targets for muscle-invasive bladder cancer, based on large-scale sample size. More importantly, the newly identified ceRNA network will be beneficial for improving the understanding of lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of muscle-invasive bladder cancer.
- 27Benjamini, Y.; Hochberg, Y. Controlling the False Discovery Rate - a Practical and Powerful Approach to Multiple Testing. J. R. Stat. Soc., B: Stat. Methodol. 1995, 57, 289– 300, DOI: 10.1111/j.2517-6161.1995.tb02031.xGoogle ScholarThere is no corresponding record for this reference.
- 28Kakumanu, A.; Ambavaram, M. M.; Klumas, C.; Krishnan, A.; Batlang, U.; Myers, E.; Grene, R.; Pereira, A. Effects of drought on gene expression in maize reproductive and leaf meristem tissue revealed by RNA-Seq. Plant Physiol. 2012, 160, 846– 867, DOI: 10.1104/pp.112.200444Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFaksbbN&md5=b239d3bfa139ef6728f751f642414255Effects of drought on gene expression in maize reproductive and leaf meristem tissue revealed by RNA-seqKakumanu, Akshay; Ambavaram, Madana M. R.; Klumas, Curtis; Krishnan, Arjun; Batlang, Utlwang; Myers, Elijah; Grene, Ruth; Pereira, AndyPlant Physiology (2012), 160 (2), 846-867CODEN: PLPHAY; ISSN:0032-0889. (American Society of Plant Biologists)Drought stress affects cereals esp. during the reproductive stage. The maize (Zea mays) drought transcriptome was studied using RNA-Seq anal. to compare drought-treated and well-watered fertilized ovary and basal leaf meristem tissue. More drought-responsive genes responded in the ovary compared with the leaf meristem. Gene Ontol. enrichment anal. revealed a massive decrease in transcript abundance of cell division and cell cycle genes in the drought-stressed ovary only. Among Gene Ontol. categories related to carbohydrate metab., changes in starch and Suc metab.-related genes occurred in the ovary, consistent with a decrease in starch levels, and in Suc transporter function, with no comparable changes occurring in the leaf meristem. Abscisic acid (ABA)-related processes responded pos., but only in the ovaries. Related responses suggested the operation of low glucose sensing in drought-stressed ovaries. The data are discussed in the context of the susceptibility of maize kernel to drought stress leading to embryo abortion and the relative robustness of dividing vegetative tissue taken at the same time from the same plant subjected to the same conditions. Our working hypothesis involves signaling events assocd. with increased ABA levels, decreased glucose levels, disruption of ABA/sugar signaling, activation of programmed cell death/senescence through repression of a phospholipase C-mediated signaling pathway, and arrest of the cell cycle in the stressed ovary at 1 d after pollination. Increased invertase levels in the stressed leaf meristem, on the other hand, resulted in that tissue maintaining hexose levels at an "unstressed" level, and at lower ABA levels, which was correlated with successful resistance to drought stress.
- 29Der, E.; Suryawanshi, H.; Morozov, P.; Kustagi, M.; Goilav, B.; Ranabothu, S.; Izmirly, P.; Clancy, R.; Belmont, H. M.; Koenigsberg, M.; Mokrzycki, M.; Rominieki, H.; Graham, J. A.; Rocca, J. P.; Bornkamp, N.; Jordan, N.; Schulte, E.; Wu, M.; Pullman, J.; Slowikowski, K.; Raychaudhuri, S.; Guthridge, J.; James, J.; Buyon, J.; Tuschl, T.; Putterman, C. Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Nat. Immunol. 2019, 20, 915– 927, DOI: 10.1038/s41590-019-0386-1Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvFeht7g%253D&md5=e349214c3f4ec3bf22eb3c36a7802a16Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathwaysDer, Evan; Suryawanshi, Hemant; Morozov, Pavel; Kustagi, Manjunath; Goilav, Beatrice; Ranabathou, Saritha; Izmirly, Peter; Clancy, Robert; Belmont, H. Michael; Koenigsberg, Mordecai; Mokrzycki, Michele; Rominieki, Helen; Graham, Jay A.; Rocca, Juan P.; Bornkamp, Nicole; Jordan, Nicole; Schulte, Emma; Wu, Ming; Pullman, James; Slowikowski, Kamil; Raychaudhuri, Soumya; Guthridge, Joel; James, Judith; Buyon, Jill; Tuschl, Thomas; Putterman, Chaim; the Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus ConsNature Immunology (2019), 20 (7), 915-927CODEN: NIAMCZ; ISSN:1529-2908. (Nature Research)The mol. and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each assocd. with failure to respond to treatment. Anal. of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histol. differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.
- 30De Felice, F. G.; Ferreira, S. T. Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease. Diabetes 2014, 63, 2262– 2272, DOI: 10.2337/db13-1954Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfisV2ntw%253D%253D&md5=9379bc211cc092b3547394abbe283288Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer diseaseDe Felice Fernanda G; Ferreira Sergio TDiabetes (2014), 63 (7), 2262-72 ISSN:.A growing body of evidence supports an intriguing clinical/epidemiological connection between Alzheimer disease (AD) and type 2 diabetes (T2D). T2D patients have significantly increased risk of developing AD and vice versa. Recent studies have begun to reveal common pathogenic mechanisms shared by AD and metabolic disorders, notably obesity and T2D. In T2D and obesity, low-grade chronic inflammation is a key mechanism leading to peripheral insulin resistance, which progressively causes tissue deterioration and overall health decline. In the brain, proinflammatory signaling was recently found to mediate impaired neuronal insulin signaling, synapse deterioration, and memory loss. Here, we review evidence indicating that inflammation, insulin resistance, and mitochondrial dysfunction are common features in AD and T2D. We further propose the hypothesis that dementia and its underlying neuronal dysfunction are exacerbated or driven by peripheral inflammation. Identification of central and peripheral inflammation as potential mediators of brain dysfunction in AD may lead to the development of effective treatments for this devastating disease.
- 31Turner, N.; Cooney, G. J.; Kraegen, E. W.; Bruce, C. R. Fatty acid metabolism, energy expenditure and insulin resistance in muscle. J. Endocrinol. 2014, 220, T61– T79, DOI: 10.1530/joe-13-0397Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtlSls7g%253D&md5=6eda9e2cabfa379bb1d159a2058a4decFatty acid metabolism, energy expenditure and insulin resistance in muscleTurner, Nigel; Cooney, Gregory J.; Kraegen, Edward W.; Bruce, Clinton R.Journal of Endocrinology (2014), 220 (2), T61-T79CODEN: JOENAK; ISSN:0022-0795. (BioScientifica Ltd.)A review. Fatty acids (FAs) are essential elements of all cells and have significant roles as energy substrates, components of cellular structure and signaling mols. The storage of excess energy intake as fat in adipose tissue is an evolutionary advantage aimed at protecting against starvation, but in much of today's world, humans are faced with an unlimited availability of food, and the excessive accumulation of fat is now a major risk for human health, esp. the development of type 2 diabetes (T2D). Since the first recognition of the assocn. between fat accumulation, reduced insulin action and increased risk of T2D, several mechanisms have been proposed to link excess FA availability to reduced insulin action, with some of them being competing or contradictory. This review summarizes the evidence for these mechanisms in the context of excess dietary FAs generating insulin resistance in muscle, the major tissue involved in insulin-stimulated disposal of blood glucose. It also outlines potential problems with models and measurements that may hinder as well as help improve our understanding of the links between FAs and insulin action.
- 32Kraegen, E. W.; Clark, P. W.; Jenkins, A. B.; Daley, E. A.; Chisholm, D. J.; Storlien, L. H. Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats. Diabetes 1991, 40, 1397– 1403, DOI: 10.2337/diab.40.11.1397Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XltF2ltQ%253D%253D&md5=23b75219b968712bd6649370d3817d80Development of muscle insulin resistance after liver insulin resistance in high-fat-fed ratsKraegen, Edward W.; Clark, Peter W.; Jenkins, Arthur B.; Daley, Eugene A.; Chisholm, Donald J.; Storlien, Leonard H.Diabetes (1991), 40 (11), 1397-403CODEN: DIAEAZ; ISSN:0012-1797.Progressive changes in the development of high-fat-diet-induced insulin resistance in liver, adipose tissue, and muscle of the adult male Wistar rat were studied. In vivo insulin action was compared 3 days and 3 wk after isocaloric synthetic high-fat or high-starch feeding (59 and 10% cal as fat, resp.). Basal and insulin-stimulated glucose metab. were assessed in the conscious 5- to 7-h fasted state with the euglycemic clamp (600 pM insulin) with a [3-3H]glucose infusion. Fat feeding reduced suppressibility of hepatic glucose output by insulin after both 3 days and 3 wk of diet. However, a significant impairment of insulin-mediated peripheral glucose disposal was only present after 3 wk of diet. Further in vivo [3H]2-deoxyglucose uptake studies supported this finding and demonstrated adipose but not muscle insulin resistance after 3 days of high-fat feeding. Muscle triglyceride accumulation due to fat feeding was not significant at 3 days but had doubled by 3 wk in red muscle compared with starch-fed controls. By 3 wk, high-fat-fed animals had developed significant glucose intolerance. Apparently, fat feeding induces insulin resistance in liver and adipose tissue before skeletal muscle with early metabolic changes favoring an oversupply of energy substrate to skeletal muscle relative to metabolic needs. This may generate later muscle insulin resistance.
- 33Storlien, L. H.; Kraegen, E. W.; Chisholm, D. J.; Ford, G. L.; Bruce, D. G.; Pascoe, W. S. Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science 1987, 237, 885– 888, DOI: 10.1126/science.3303333Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s3pt1WitQ%253D%253D&md5=fc2719cd20769d3ff09edb84efeaf0baFish oil prevents insulin resistance induced by high-fat feeding in ratsStorlien L H; Kraegen E W; Chisholm D J; Ford G L; Bruce D G; Pascoe W SScience (New York, N.Y.) (1987), 237 (4817), 885-8 ISSN:0036-8075.Non-insulin-dependent diabetes mellitus is an increasingly prevalent disease in Western and developing societies. A major metabolic abnormality of non-insulin-dependent diabetes is impaired insulin action (insulin resistance). Diets high in fat from vegetable and nonaquatic animal sources (rich in linoleic acid, an omega-6 fatty acid, and saturated fats) lead to insulin resistance. In rats fed high-fat diets, replacement of only 6 percent of the linoleic omega-6 fatty acids from safflower oil with long-chain polyunsaturated omega-3 fatty acids from fish oil prevented the development of insulin resistance. The effect was most pronounced in the liver and skeletal muscle, which have important roles in glucose supply and demand. The results may be important for therapy or prevention of non-insulin-dependent diabetes mellitus.
- 34Ranganathan, S.; Nagaraj, S. H.; Hu, M.; Strube, C.; Schnieder, T.; Gasser, R. B. A transcriptomic analysis of the adult stage of the bovine lungworm, Dictyocaulus viviparus. BMC Genomics 2007, 8, 311, DOI: 10.1186/1471-2164-8-311Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sjjsFehug%253D%253D&md5=11a89a83dd8559e3ea3192e0def2deb4A transcriptomic analysis of the adult stage of the bovine lungworm, Dictyocaulus viviparusRanganathan Shoba; Nagaraj Shivashankar H; Hu Min; Strube Christina; Schnieder Thomas; Gasser Robin BBMC genomics (2007), 8 (), 311 ISSN:.BACKGROUND: Lungworms of the genus Dictyocaulus (family Dictyocaulidae) are parasitic nematodes of major economic importance. They cause pathological effects and clinical disease in various ruminant hosts, particularly in young animals. Dictyocaulus viviparus, called the bovine lungworm, is a major pathogen of cattle, with severe infections being fatal. In this study, we provide first insights into the transcriptome of the adult stage of D. viviparus through the analysis of expressed sequence tags (ESTs). RESULTS: Using our EST analysis pipeline, we estimate that the present dataset of 4436 ESTs is derived from 2258 genes based on cluster and comparative genomic analyses of the ESTs. Of the 2258 representative ESTs, 1159 (51.3%) had homologues in the free-living nematode C. elegans, 1174 (51.9%) in parasitic nematodes, 827 (36.6%) in organisms other than nematodes, and 863 (38%) had no significant match to any sequence in the current databases. Of the C. elegans homologues, 569 had observed 'non-wildtype' RNAi phenotypes, including embryonic lethality, maternal sterility, sterility in progeny, larval arrest and slow growth. We could functionally classify 776 (35%) sequences using the Gene Ontologies (GO) and established pathway associations to 696 (31%) sequences in Kyoto Encyclopedia of Genes and Genomes (KEGG). In addition, we predicted 85 secreted proteins which could represent potential candidates for developing novel anthelmintics or vaccines. CONCLUSION: The bioinformatic analyses of ESTs data for D. viviparus has elucidated sets of relatively conserved and potentially novel genes. The genes discovered in this study should assist research toward a better understanding of the basic molecular biology of D. viviparus, which could lead, in the longer term, to novel intervention strategies. The characterization of the D. viviparus transcriptome also provides a foundation for whole genome sequence analysis and future comparative transcriptomic analyses.
- 35Ahmadian, M.; Suh, J. M.; Hah, N.; Liddle, C.; Atkins, A. R.; Downes, M.; Evans, R. M. PPAR gamma signaling and metabolism: the good, the bad and the future. Nat. Med. 2013, 19, 557– 566, DOI: 10.1038/nm.3159Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntF2kurs%253D&md5=78ee5d0f4ce5dc5192cd010bb7519ce4PPARγ signaling and metabolism: the good, the bad and the futureAhmadian, Maryam; Suh, Jae Myoung; Hah, Nasun; Liddle, Christopher; Atkins, Annette R.; Downes, Michael; Evans, Ronald M.Nature Medicine (New York, NY, United States) (2013), 19 (5), 557-566CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)A review. Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, wt. gain, bone loss, and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARγ-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiol. and therapeutic relevance of the PPARγ pathway also provide opportunities to develop newer classes of mols. that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.
- 36Jeon, S. M. Regulation and function of AMPK in physiology and diseases. Exp. Mol. Med. 2016, 48, e245 DOI: 10.1038/emm.2016.81Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtV2iu7nK&md5=ddcf6d926d097f657c231dec63d89ba0Regulation and function of AMPK in physiology and diseasesJeon, Sang-MinExperimental & Molecular Medicine (2016), 48 (7), e245CODEN: EMMEF3; ISSN:2092-6413. (NPG Nature Asia-Pacific)5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that was originally identified as the key player in maintaining cellular energy homeostasis. Intensive research over the last decade has identified diverse mol. mechanisms and physiol. conditions that regulate the AMPK activity. AMPK regulates diverse metabolic and physiol. processes and is dysregulated in major chronic diseases, such as obesity, inflammation, diabetes and cancer. On the basis of its crit. roles in physiol. and pathol., AMPK is emerging as one of the most promising targets for both the prevention and treatment of these diseases. In this review, we discuss the current understanding of the mol. and physiol. regulation of AMPK and its metabolic and physiol. functions. In addn., we discuss the mechanisms underlying the versatile roles of AMPK in diabetes and cancer.
- 37Gupta, D.; Jetton, T. L.; Mortensen, R. M.; Duan, S. Z.; Peshavaria, M.; Leahy, J. L. In vivo and in vitro studies of a functional peroxisome proliferator-activated receptor gamma response element in the mouse pdx-1 promoter. J. Biol. Chem. 2008, 283, 32462– 32470, DOI: 10.1074/jbc.m801813200Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlOjtL3O&md5=9acd245573710b479d27340bd653f814In Vivo and in Vitro Studies of a Functional Peroxisome Proliferator-activated Receptor γ Response Element in the Mouse pdx-1 PromoterGupta, Dhananjay; Jetton, Thomas L.; Mortensen, Richard M.; Duan, Sheng Zhong; Peshavaria, Mina; Leahy, Jack L.Journal of Biological Chemistry (2008), 283 (47), 32462-32470CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The authors reported that peroxisome proliferator-activated receptor γ (PPARγ) transcriptionally regulates the β-cell differentiation factor pancreatic duodenal homeobox (PDX)-1 based on in vitro RNA interference studies. The authors have now studied mice depleted of PPARγ within the pancreas (PANC PPARγ-/-) created by a Cre/loxP recombinase system, with Cre driven by the pdx-1 promoter. Male PANC PPARγ-/- mice were hyperglycemic at 8 wk of age (8.1 ± 0.2 mM vs. 6.4 ± 0.3 mM, p = 0.009) with islet cytoarchitecture and pancreatic mass of islet β-cells that were indistinguishable from the controls. Islet PDX-1 mRNA (p = 0.001) and protein levels (p = 0.003) were lowered 60 and 40%, resp., in tandem with impaired glucose-induced insulin secretion and loss of thiazolidinedione-induced increase in PDX-1 expression. The authors next identified a putative PPAR-response element (PPRE) in the mouse pdx-1 promoter with substantial homol. to the corresponding region of the human PDX-1 promoter. Electrophoretic mobility supershift assays with nuclear exts. from β-cell lines and mouse islets, also in vitro translated PPARγ and retinoid X receptor, and chromatin immunopptn. anal. demonstrated specific binding of PPARγ and retinoid X receptor to the human and mouse pdx-1 x PPREs. Transient transfection assays of β-cells with reporter constructs of mutated PPREs showed dramatically reduced pdx-1 promoter activity. In summary, the authors have presented in vivo and in vitro evidence showing PPARγ regulation of pdx-1 transcription in β-cells, plus these results support an important regulatory role for PPARγ in β-cell physiol. and thiazolidinedione pharmacol. of type 2 diabetes.
- 38Tremblay, K.; Methot, J.; Brisson, D.; Gaudet, D. Etiology and risk of lactescent plasma and severe hypertriglyceridemia. J. Clin. Lipidol. 2011, 5, 37– 44, DOI: 10.1016/j.jacl.2010.11.004Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M7ktVCnsw%253D%253D&md5=68eb67a0d4ce32502d0a8896fabdb40cEtiology and risk of lactescent plasma and severe hypertriglyceridemiaTremblay Karine; Methot Julie; Brisson Diane; Gaudet DanielJournal of clinical lipidology (2011), 5 (1), 37-44 ISSN:1933-2874.BACKGROUND: Plasma lactescence is a clinical sign of severe hypertriglyceridemia (hyperTG; TG >10 mmol/L), which is likely to be observed more frequently in the next decades because of the growing prevalence of obesity and diabetes worldwide. OBJECTIVE: The objective of this study was to describe the clinical expression of plasma lactescence. METHODS: A total of 354 subjects with lactescent plasma hyperTG (mean TG ± SD: 17.1 ± 1.8 mmol/L) were classified according to blood appearance, etiology, and biochemical characteristics. The resulting phenotypes were compared with those of 364 normolipidemic controls (TG ≤2 mmol/L) and 487 clear plasma hyperTG subjects (5 < TG ≤9 mmol/L). The association of lactescent plasma with clinical covariates (obesity, coronary artery disease, peripheral artery disease, hypertension, diabetes, glucose intolerance, pancreatitis, and response to TG-lowering drugs) was performed by the use of multiple regression models. RESULTS: The risk of pancreatitis increased as a function of the plasma creamy white collar and was the greatest among nonobese individuals with early-onset lactescence not responding to current TG-lowering drugs (familial hyperchylomicronemia). Patients with lactescent plasma and yellowish palmar xanthomas (dysbetalipoproteinemia) responded significantly better to fibrates than the other severe hyperTG phenotypes but were at greater risk of peripheral atherosclerosis. Overweight and obese patients with a creamy supernatant and a cloudy, cream of tomato, infranatant caused by hyper apolipoprotein B showed the most deleterious cardiometabolic risk profile, followed by the severe hyperTG-normal apolipoprotein B phenotype, the most frequent cause of lactescent plasma. CONCLUSION: Lactescent plasma hyperTG represents a clinically heterogeneous group of high-risk patients.
- 39Zhou, Q.; Melton, D. A. Pancreas regeneration. Nature 2018, 557, 351– 358, DOI: 10.1038/s41586-018-0088-0Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVSgurs%253D&md5=c3a510413f8d81a778110c18dc290eafPancreas regenerationZhou, Qiao; Melton, Douglas A.Nature (London, United Kingdom) (2018), 557 (7705), 351-358CODEN: NATUAS; ISSN:0028-0836. (Nature Research)A review. The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.
- 40Yang, J. PPAR-gamma silencing inhibits the apoptosis of A549 cells by upregulating Bcl-2. Zhongguo Feiai Zazhi 2013, 16, 125– 130, DOI: 10.3779/j.issn.1009-3419.2013.03.02Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitVSitrrK&md5=629be0071984ed064d0ef64b52bf9d4fRole of PPAR-γ silencing in inhibiting the apoptosis of A549 cells by upregulating the expression of Bcl-2Yang, JingyuZhongguo Feiai Zazhi (2013), 16 (3), 125-130CODEN: ZFZHAG; ISSN:1009-3419. (Zhongguo Feiai Zazhi Bianji Weiyuanhui)Drug resistance is one of primary causes of death in patients with lung cancer, and PPAR-γ could induce the apoptosis and reverse drug resistance. The aim of this study is to investigate the influence of down-regulated expression of PPAR-γ on cisplatin sensitivity and apoptosis response of human lung cancer cell line A549. SiRNA silencing of PPAR-γ in A549 cells (A549/PPAR-γ(-)) is constructed. MTT assay was used to det. the effect of cisplatin on the proliferation of A549/PPAR-γ(-), flow cytometry was used to det. the effect of cisplatin on the cell apoptosis, and Western blot was used to det. the change of phosphorylation of Akt, caspase-3 and expression of bcl-2/bax. Finally, RT-PCR was used to det. the transcriptional level of bcl-2. Two PPAR-γ silencing A549 cell clones were established successfully, and the expression of PPAR-γ was downregulated significantly, which was confirmed by RT-PCR and Western blot. After PPAR-γ silencing, the resistance of these two A549 cell clones to cisplatin was increased by 1.29 times and 1.60 times resp. Flow cytometry showed that the apoptosis rate was decreased, and Western Blot showed that the phosphorylation of Akt and expression of bcl-2/bax were upregulated, and caspase-3 was downregulated. Finally, RT-PCR showed that the transcriptional level of bcl-2 was upregulated as well. Downregulation of PPAR-γ in A549 cells led to the increase of cisplatin resistance. One of the mechanisms was upregulation of phosphorylation of Akt and expression of bcl-2, which inhibited the apoptosis of cells. The downregulation of PPAR-γ is a possible mechanism that leads to the clin. drug resistance of cancer.
- 41Liu, J.; Lang, G.; Shi, J. Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus. Diabetes, Metab. Syndr. Obes.: Targets Ther. 2021, 14, 431– 442, DOI: 10.2147/dmso.s291932Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3snitVCksw%253D%253D&md5=8e3bea314909291371f98cf5510b4ceeEpigenetic Regulation of PDX-1 in Type 2 Diabetes MellitusLiu Jiangman; Lang Guangping; Shi JingshanDiabetes, metabolic syndrome and obesity : targets and therapy (2021), 14 (), 431-442 ISSN:1178-7007.Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia which is caused by insufficient insulin secretion or insulin resistance. Interaction of genetic, epigenetic and environmental factors plays a significant role in the development of T2DM. Several environmental factors including diet and lifestyle, as well as age have been associated with an increased risk for T2DM. It has been demonstrated that these environmental factors may affect global epigenetic status, and alter the expression of susceptible genes, thereby contributing to the pathogenesis of T2DM. In recent years, a growing body of molecular and genetic studies in diabetes have been focused on the ways to restore the numbers or function of β-cells in order to reverse a range of metabolic consequences of insulin deficiency. The pancreatic duodenal homeobox 1 (PDX-1) is a transcriptional factor that is essential for the development and function of islet cells. A number of studies have shown that there is a significant increase in the level of DNA methylation of PDX-1 resulting in reduced activity in T2DM islets. The decrease in PDX-1 activity may be a critical mediator causing dysregulation of pancreatic β cells in T2DM. This article reviews the epigenetic mechanisms of PDX-1 involved in T2DM, focusing on diabetes and DNA methylation, and discusses some potential strategies for the application of PDX-1 in the treatment of diabetes.
- 42Wang, C.; Li, J.; Lv, X.; Zhang, M.; Song, Y.; Chen, L.; Liu, Y. Ameliorative effect of berberine on endothelial dysfunction in diabetic rats induced by high-fat diet and streptozotocin. Eur. J. Pharmacol. 2009, 620, 131– 137, DOI: 10.1016/j.ejphar.2009.07.027Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFGlt73M&md5=67ecb615f94e7f22dbed9a658076a030Ameliorative effect of berberine on endothelial dysfunction in diabetic rats induced by high-fat diet and streptozotocinWang, Chunmei; Li, Jing; Lv, Xiaoyan; Zhang, Ming; Song, Yanfang; Chen, Li; Liu, YanjunEuropean Journal of Pharmacology (2009), 620 (1-3), 131-137CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Berberine can improve insulin resistance, lower blood glucose, and regulate lipid metab. disorders which cause endothelial dysfunction, leading to vascular complications of type 2 diabetes mellitus. The aim of the present study was to investigate the effects of berberine on endothelial dysfunction of aortas in type 2 diabetes mellitus rats and its mechanism. Wistar rats were randomly divided into four groups: diabetic rats, control rats, diabetic rats treated with berberine (100 mg/kg), and control rats treated with berberine. The serum fasting blood glucose, insulin, total cholesterol, triglyceride and nitric oxide (NO) levels were tested. Acetylcholine-induced endothelium-dependent relaxation and sodium nitroprusside induced endothelium-independent relaxation were measured in aortas for estg. endothelial function. The expression of endothelial nitric oxide synthase (eNOS) mRNA was measured by RT-PCR, and the protein expressions of eNOS and NADPH oxidase (NOX4) were analyzed by western blot. The results showed that berberine significantly decreased fasting blood glucose, and triglyceride levels in diabetic rats. Berberine also improved endothelium-dependent vasorelaxation impaired in aorta. The expressions of eNOS mRNA and protein were significantly increased, while NOX4 protein expression was decreased in aortas from diabetic rats with berberine treatment. Moreover, serum NO levels were elevated after berberine treatment. In conclusion, berberine restores diabetic endothelial dysfunction through enhanced NO bioavailability by up-regulating eNOS expression and down-regulating expression of NADPH oxidase.
- 43Moreira-Teixeira, L.; Tabone, O.; Graham, C. M.; Singhania, A.; Stavropoulos, E.; Redford, P. S.; Chakravarty, P.; Priestnall, S. L.; Suarez-Bonnet, A.; Herbert, E.; Mayer-Barber, K. D.; Sher, A.; Fonseca, K. L.; Sousa, J.; Ca, B.; Verma, R.; Haldar, P.; Saraiva, M.; O’Garra, A. Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis. Nat. Immunol. 2020, 21, 464– 476, DOI: 10.1038/s41590-020-0610-zGoogle Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXltVSisbg%253D&md5=3831f9159c28491baede1c8501d733d9Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosisMoreira-Teixeira, Lucia; Tabone, Olivier; Graham, Christine M.; Singhania, Akul; Stavropoulos, Evangelos; Redford, Paul S.; Chakravarty, Probir; Priestnall, Simon L.; Suarez-Bonnet, Alejandro; Herbert, Eleanor; Mayer-Barber, Katrin D.; Sher, Alan; Fonseca, Kaori L.; Sousa, Jeremy; Ca, Baltazar; Verma, Raman; Haldar, Pranabashis; Saraiva, Margarida; O'Garra, AnneNature Immunology (2020), 21 (4), 464-476CODEN: NIAMCZ; ISSN:1529-2908. (Nature Research)Abstr.: Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human tuberculosis (TB) resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clin. isolate of M. tuberculosis resembles that of active human TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addn., resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.
- 44Lee, J. H.; Kwak, H. J.; Shin, D.; Seo, H. J.; Park, S. J.; Hong, B. H.; Shin, M. S.; Kim, S. H.; Kang, K. S. Mitigation of Gastric Damage Using Cinnamomum cassia Extract: Network Pharmacological Analysis of Active Compounds and Protection Effects in Rats. Plants 2022, 11, 716, DOI: 10.3390/plants11060716Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhtVShsLnO&md5=35e5d6b5d76d86fc21790c9f2d031383Mitigation of Gastric Damage Using Cinnamomum cassia Extract: Network Pharmacological Analysis of Active Compounds and Protection Effects in RatsLee, Ji Hwan; Kwak, Hee Jae; Shin, Dongchul; Seo, Hye Jin; Park, Shin Jung; Hong, Bo-Hee; Shin, Myoung-Sook; Kim, Seung Hyun; Kang, Ki SungPlants (2022), 11 (6), 716CODEN: PLANCD; ISSN:2223-7747. (MDPI AG)Gastritis is a common disease worldwide that is caused by various causes such as eating habits, smoking, severe stress, and heavy drinking, as well as Helicobacter pylori infections and non-steroidal anti-inflammatory drugs. Cinnamomum cassia is a tropical arom. evergreen tree commonly used as a natural medicine in Asia and as a functional food ingredient. Studies have reported this species' anti-obesity, anti-diabetic, and cardiovascular disease suppression effects. We evaluated the potential effects of C. cassia using non-steroidal anti-inflammatory drugs (NSAIDs), ethanol (EtOH), and ethanol/hydrochloric acid (HCl)-induced gastric mucosal injury models. C. cassia exts. reduced the area of gastric mucosa injury caused by indomethacin, NSAID, EtOH, and EtOH/HCl. We also applied a network pharmacol.-based approach to identify the active compds., potential targets, and pharmacol. mechanisms of C. cassia against gastritis. Through a network pharmacol. anal., 10 key components were predicted as anti-gastritis effect-related compds. of C. cassia among 51 expected active compds. The NF-κB signaling pathway, a widely known inflammatory response mechanism, comprised a major signaling pathway within the network pharmacol. anal. These results suggest that the anti-gastritis activities of C. cassia may be induced via the anti-inflammatory effects of key components, which suppress the inflammation-related genes and signaling pathways identified in this study.
- 45Pintana, H.; Lietzau, G.; Augestad, I. L.; Chiazza, F.; Nystrom, T.; Patrone, C.; Darsalia, V. Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons. Clin. Sci. 2019, 133, 1367– 1386, DOI: 10.1042/cs20190180Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVOlu7%252FI&md5=ebb4faa5a3a198bf68c29a5a6ba2d7c0Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneuronsPintana, Hiranya; Lietzau, Grazyna; Augestad, Ingrid Lovise; Chiazza, Fausto; Nystrom, Thomas; Patrone, Cesare; Darsalia, VladimerClinical Science (2019), 133 (13), 1367-1386CODEN: CSCIAE; ISSN:1470-8736. (Portland Press Ltd.)Type 2 diabetes (T2D) hampers stroke recovery though largely undetd. mechanisms. Few preclin. studies have investigated the effect of genetic/toxin-induced diabetes on long-term stroke recovery. However, the effects of obesity-induced T2D are mostly unknown. We aimed to investigate whether obesity-induced T2D worsens long-term stroke recovery through the impairment of brain's self-repair mechanisms - stroke-induced neurogenesis and parvalbumin (PV)+ interneurons-mediated neuroplasticity. To mimic obesity-induced T2D in the middle-age, C57bl/6j mice were fed 12 mo with high-fat diet (HFD) and subjected to transient middle cerebral artery occlusion (tMCAO). We evaluated neurol. recovery by upper-limb grip strength at 1 and 6 wk after tMCAO. Gray and white matter damage, stroke-induced neurogenesis, and survival and potential atrophy of PV-interneurons were quantitated by immunohistochem. (IHC) at 2 and 6 wk after tMCAO. Obesity/T2D impaired neurol. function without exacerbating brain damage. Moreover, obesity/T2D diminished stroke-induced neural stem cell (NSC) proliferation and neuroblast formation in striatum and hippocampus at 2 wk after tMCAO and abolished stroke-induced neurogenesis in hippocampus at 6 wk. Finally, stroke resulted in the atrophy of surviving PV-interneurons 2 wk after stroke in both non-diabetic and obese/T2D mice. However, after 6 wk, this effect selectively persisted in obese/T2D mice. We show in a preclin. setting of clin. relevance that obesity/T2D impairs neurol. functions in the stroke recovery phase in correlation with reduced neurogenesis and persistent atrophy of PV-interneurons, suggesting impaired neuroplasticity. These findings shed light on the mechanisms behind impaired stroke recovery in T2D and could facilitate the development of new stroke rehabilitative strategies for obese/T2D patients.
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Abstract
Figure 1
Figure 1. Structures of the polysaccharide components of (A) FYGL-1, (B) FYGL-2, and (C) FYGL-3 characterized by chemical analysis and NMR spectrum and the simulated structures of the protein moiety of (D) FYGL-2 and (E) FYGL-3. (17−21) p: pyranose; f: furanose; Thr: threonine; Ser: serine. The acidic amino acids Asp and Glu are marked in green and purple, respectively.
Figure 2
Figure 2. (A) FBG, (B) water intake, (C) food intake, and (D) BW of T2D rats and the influence of FYGL, where normal: normal group, model: model group, metformin: 200 mg/kg metformin group as the positive drug group, FYGL-L/M/H: FYGL groups with dosages of 225(low)/450(middle)/900(high) mg/kg, similarly hereinafter. (E) Effects of FYGL on the OGTT and (F) the area under the curves (AUC) of OGTT of T2D rats. ###p < 0.001 vs the normal group; *p < 0.05, **p < 0.01, ***p < 0.001 vs the model group (n = 14).
Figure 3
Figure 3. (A) DEG number statistics of each group compared with the model group. DEGs statistics between the model group and (B) normal, (C) metformin, (D) low-dose FYGL (FYGL-L), (E) middle-dose FYGL (FYGL-M), and (F) high-dose FYGL (FYGL-H) groups, respectively, displayed by the volcano plot. Red dots represented up-regulated genes, blue dots represented down-regulated genes, and gray points were not-significant genes. DESeq2 p-value < 0.05, |log2FoldChange| > 1. (25,26)
Figure 4
Figure 4. GO enrichment analysis of the T2D rat pancreas transcriptome. (A) Top ten MF, CC, and BP according to the DEGs between the model and the FYGL-H group. The lower padj value indicated a higher geostatistical significance of differences. The count number referred to the extent of DEGs related to the MF/CC/BP. (B) DEG heatmap of preferentially enriched BP related to T2D and the effects of high doses of FYGL. DEGs with a red color were strongly expressed, and DEGs with a blue color were weakly expressed.
Figure 5
Figure 5. KEGG pathway enrichment analysis of the T2D rat pancreas transcriptome. (A) Top 20 pathways affected by a high dose of FYGL. The lower padj value indicated the higher geostatistical significance of differences. The count number referred to the extent of DEGs related to the pathway. (B) DEG heatmap of some preferentially enriched pathways related to T2D and the effects of FYGL. (C)DEG heatmap of the cell cycle and apoptosis pathways related to T2D and the effects of FYGL. DEGs in red color were strongly expressed, and DEGs in blue color were weakly expressed.
Figure 6
Figure 6. (A) Plasma of rats in different groups. (B) Concentration of TG in rat plasma. (C) Concentration of TC in rat plasma. (D) Percentage of glycosylated hemoglobin (HbA1c)/Hb in the whole blood of rats. ###p < 0.001 vs the normal model group; *p < 0.05, **p < 0.01, ***p < 0.001 vs the model group (n = 14).
Figure 7
Figure 7. Histopathology of pancreatic islets stained by hematoxylin&eosin (H&E) staining.
Figure 8
Figure 8. (A) Insulin immunohistochemistry in rat pancreatic islets. (B) Relative insulin level in islets. (C) Concentration of insulin in rat serum. ###p < 0.001 vs the normal group; *p < 0.05, **p < 0.01, ***p < 0.001 vs the model group (n = 4).
Figure 9
Figure 9. Relative expressions of (A) PPARγ, (B) Bcl-2, and (C) Pdx-1 in the rat pancreas, referred to the normal group. ##p < 0.01, ###p < 0.001 vs the normal group; *p < 0.05, **p < 0.01 vs the model group (n = 4).
Figure 10
Figure 10. Summary scheme of FYGL effects on T2D rats.
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- 3Knowler, W. C.; Barrett-Connor, E.; Fowler, S. E.; Hamman, R. F.; Lachin, J. M.; Walker, E. A.; Nathan, D. M.; Diabetes Prevention Program Research, G. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 2002, 346, 393– 403, DOI: 10.1056/NEJMoa0125123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhtVWqurc%253D&md5=fe29c42a032eda9166ffa65f0094eba2Reduction in the incidence of type 2 diabetes with lifestyle intervention or metforminKnowler, William C.; Barrett-Connor, Elizabeth; Fowler, Sarah E.; Hamman, Richard F.; Lachin, John M.; Walker, Elizabeth A.; Nathan, David M.; Bray, G. A.; Culbert, I. W.; Champagne, C. M.; Crow, M. D.; Dawson, L.; Eberhardt, B.; Greenway, F. L.; Guillory, F. G.; Herbert, A. A.; Jeffirs, M. L.; Joyce, K.; Kennedy, B. M.; Lovejoy, J. C.; Mancuso, S.; Melancon, L. E.; Morris, L. H.; Reed, L.; Perault, J.; Rau, K.; Ryan, D. H.; Sanford, D. A.; Smith, K. G.; Smith, L. L.; Smith, S. R.; St. Amant, J. A.; Terry, M.; Tucker, E.; Tulley, R. T.; Vicknair, P. C.; Williamson, D.; Zachwieja, J. J.; Ehrmann, D. A.; Matulik, M. J.; Clark, B.; Collins, D. A.; Czech, K. B.; DeSandre, C.; Geiger, G.; Frief, S.; Harding-Clay, B.; Hilbrich, R. M.; Le Grange, D.; McCormick, M. R.; McNabb, W. L.; Polonsky, K. S.; Sauter, N. P.; Semenske, A. R.; Stepp, K. A.; Tobian, J. A.; Watson, P. G.; Mendoza, J. T.; Smith, K. A.; Caro, J.; Goldstein, B.; Lark, C.; Menefee, L.; Murphy, L.; Pepe, C.; Spandorfer, J. M.; Goldberg, R. B.; Rowe, P.; Calles, J.; Casanova, P.; Donahue, R. P.; Florez, H. J.; Giannella, A.; Larreal, G.; McLymont, V.; Mendez, J.; O'Hara, P.; Ojito, J.; Prineas, R.; Saab, P. G.; Haffner, S. M.; Montez, M. G.; Lorenzo, C.; Miettinen, H.; Mobley, C. M.; Mykkanen, L. A.; Rozek, M. M.; Hamman, R. F.; Nash, P. V.; Testaverde, L.; Anderson, D. R.; Ballonoff, L. B.; Bouffard, A.; Calonge, B. N.; Farago, M.; Georgitis, W. J.; Hill, J. O.; Hoyer, S. R.; Jortberg, B. T.; Merenich, J. A.; Miller, M.; Regensteiner, J. G.; Seagle, H. M.; Smith, C. M.; Steinke, S. C.; Van Dorsten, B.; Horton, E. S.; Lawton, K. E.; Arky, R. A.; Bryant, M.; Burke, J. P.; Caballero, E.; Callaghan, K. M.; Devlin, D.; Franklin, T.; Ganda, O. P.; Goebel-Fabbri, A. E.; Harris, M.; Jackson, S. D.; Jacobsen, A. M.; Kula, L. M.; Kocal, M.; Ledbury, S.; Malloy, M. A.; Mullooly, C.; Nicosia, M.; Oldmixon, C. F.; Pan, J.; Pomposelli, C.; Quitongan, M.; Rubtchinsky, S.; Schweizer, D.; Seely, E. W.; Simonson, D.; Smith, F.; Solomon, C. G.; Tyson, J.; Warram, J.; Kahn, S. E.; Montgomery, B. K.; Alger, M.; Allen, E.; Barrett, T.; Bhanji, D.; Cowan, J.; Cullen, J.; Fujimoto, W. Y.; Katz, B.; Knopp, R. H.; Lipkin, E. W.; Marr, M.; McCann, B. S.; Palmer, J. P.; Schwartz, R. S.; Uyema, D.; Kitabachi, A. E.; Murphy, M. E.; Applegate, W. B.; Bryer-Ash, M.; Coble, J. H.; Crisler, A.; Cunningham, G.; Franklin, A. W.; Frieson, S. L.; Green, D. L.; Imseis, R.; Kennedy, C. L.; Lambeth, H. C.; Latif, K. A.; Lichtermann, L. C.; McIntyre, M. D.; Nault, J. D.; Oktaei, H.; O'Toole, M. L.; Ricks, H.; Rutledge, L. M. K.; Schussler, S. C.; Sherman, A. R.; Smith, C. M.; Soberman, J. E.; Stewart, K. J.; Van Brunt, D. L.; Williams-Cleaves, B. J.; Johnson, M. K.; Behrends, C.; Cook, M. L.; Fitzgibbon, M.; Giles, M. M.; Heard, D.; Johnson, C.; Larsen, D.; Lowe, A.; Lyman, M.; McPherson, D.; Molitch, M. E.; Pitts, T.; Reinhart, R.; Roston, S.; Schinleber, P. A.; Nathan, D. M.; McKitrick, C.; Abbott, K.; Anderson, E.; Bissett, L.; Cagliero, E.; Crowell, S.; Delahanty, L.; Fritz, S.; Hayward, K.; Levina, E.; Michel, T.; Norman, D.; O'Keefe, J.; Poulos, A.; Ronan, L.; Rosal, M.; Salerno, M.; Schneider, M.; Shagensky, C.; Steiner, B.; Turgeon, H.; Young, A.; Olefsky, J. M.; Carrion-Petersen, M. L.; Barrett-Connor, E.; Beltran, M.; Caenepeel-Mills, K.; Edelman, S. V.; Ford, R. O.; Garcia, J.; Hagerty, M.; Henry, R. R.; Hill, M.; Horne, J.; Leos, D.; Matney, J.; Mudaliar, S.; Petersen, G.; Pollard, A.; Polonsky, W.; Szerdi, S.; Torio-Hurley, J.; Vejvoda, K.; Pi-Sunyer, F. X.; Lee, J. E.; Allison, D. B.; Agharanya, N.; Aronoff, N. J.; Baldo, M.; Foo, S. T.; Hagamen, S.; Pal, C.; Parkes, K.; Pena, M.; Van Wye, G. E. H.; Marrero, D. G.; Kukman-Kelly, M. S.; Dorson, Y. F.; Fineberg, S. E.; Guare, J. C.; Hadden, A.; Hills, B.; Ignaut, J. M.; Jackson, M. A.; Kirkman, M. S.; Mather, K.; McAree, G.; Porter, B. D.; Prince, M. J.; Wheeler, M. L.; Ratner, R. E.; Youssef, G.; Shapiro, S.; Bonar, A.; Bronsord, M.; Brown, E.; Cheatham, W. W.; Cola, S.; Comfort, A.; Boggs, G.; Eagle, C.; Evans, C.; Gorman, E.; Johnson, R.; Levetan, C.; Kellum, T.; Lagarda, M.; Nair, A. K.; Passaro, M. D.; Phillips, W.; Saad, M. F.; Budgett, M.; Fahmi, S.; Jinagouda, S. D.; Bernaba, B.; Bodkin, S. L.; Ciobanu, V.; Commisso, R.; Cosenza, C.; Dinh, T.; Gonzalez, M.; Khan, A.; Kumar, D.; Lui, G.; Mehra, V.; Sharma, A.; Soukiazian, S.; Szamos, K.; Tramanian, A.; Vargas, A.; Zambrana, N.; White, N. H.; Santiago, A. S.; Das, S.; Brown, A. L.; Dagogo-Jack, S.; Fisher, E. B.; Hurt, E.; Jones, T.; Kerr, M.; Ryder, L.; Santiago, J. V.; Wernimont, C.; Saudek, C. D.; Bradley, V. L.; Fowlkes, T.; Joseph, H.; Brancati, F. L.; Charleston, J. B.; Clark, J. M.; Horak, K.; Jiggetts, D.; Mosley, H.; Rubin, R. R.; Samuels, A.; Stewart, K. J.; Thomas, L.; Williamson, P.; Schade, D. S.; Adams, K. S.; Atler, L. F.; Bland, A.; Bowling, D. A.; Boyle, P. J.; Burge, M. R.; Butler, L.; Canady, J. L.; Chai, L.; Colleran, K. M.; Guillen, M.; Gonzales, Y.; Gutierrez, M.; Hornbeck, D.; Johannes, C.; Karz, P.; King, C.; Libby, E. N., III; McCalman, R.; Montoya, D. A.; Rassam, A.; Rubinchik, S.; Senter, W.; Shamoon, H.; Brown, J. O.; Adames, J.; Blanco, E.; Cox, L.; Crandall, J. P.; Duffy, H.; Engel, S.; Friedler, A.; Harroun, T.; Howard-Century, C. J.; Kloiber, S.; Longchamp, N.; Pompi, D.; Violino, E.; Walker, E. A.; Wylie-Rosett, J.; Zimmerman, E.; Zonszein, J.; Wing, R. R.; Kramer, M. K.; Barr, S.; Boraz, M. A.; Clifford, L.; Culyba, R.; Frazier, M.; Gilligan, R.; Harris, L.; Harrier, S.; Henderson, W.; Jeffreis, S.; Koenning, G.; Kriska, A. M.; Maholic, K.; Manjoo, Q.; Mullen, M.; Noel, A.; Orchard, T. J.; Orro, A.; Semler, L. N.; Smith, C.; Smith, M.; Stapinski, V.; Viteri, J.; Wilson, T.; Williams, K. V.; Zgibor, J.; Arakaki, R. F.; Latimer, R. W.; Baker-Ladao, N. K.; Beddow, R. M.; Braginsky, R.; Calizar, M.; Dias, L. M.; Durham, N.; Dupont, D. A.; Fukuhara, L. L.; Inouye, J.; Mau, M, K.; Mikami, K.; Mohideen, P.; Odom, S. K.; Sinkuie-Kam, B.; Tokunaga, J. S.; Twiggs, R. U.; Wang, C. Y.; Vita, J.; Knowler, W. C.; Cooeyate, N. J.; Hoskin, M. A.; Percy, C. A.; Acton, K. J.; Andre, V. L.; Antone, S.; Baptisto, N. M.; Barber, R.; Segay, S.; Bennett, P. H.; Benson, M. B.; Beyale, S.; Bird, E. C.; Broussard, B. A.; Chavez, M.; Daeawyma, T. S.; Doughty, M. S.; Duncan, R.; Edgerton, C.; Ghahate, J. M.; Glass, M.; Gohdes, D.; Grant, W.; Hanson, R. L.; Horse, E.; Hughte, G.; Ingraham, L. E.; Jackson, M. C.; Jay, P. A.; Kaskalla, R. S.; Kessler, D.; Kobus, K. M.; Krakoff, J.; Manus, C.; Morgan, T.; Nashboo, Y.; Nelson, J.; Pauk, G. L.; Poirier, S.; Polczynski, E.; Reidy, M.; Roumain, J.; Rowse, D. H.; Roy, R. J.; Sangster, S.; Sewemaenewa, J.; Tonemah, D.; Wilson, C.; Yazzie, M.; Fowler, S.; Brenneman, T.; Abebe, S.; Bain, R.; Bamdad, J.; Callaghan, J.; Edelstein, S. L.; Gao, Y.; Grimes, K. L.; Grover, N.; Hirst, K.; Jones, S.; Jones, T. L.; Katz, R. J.; Lachin, J. M.; Orlosky, R.; Stimpson, C. E.; Suiter, C.; Temprosa, M. G.; Walker-Murray, F. E. M.; Garfield, S.; Eastman, R.; Fradkin, J.; Andres, R.; Engelgau, M. M.; Venkat Narayan, K. M.; Williamson, D. F.; Herman, W. H.; Marcovina, S. M.; Aldrich, A.; Chandler, W. L.; Rautaharju, P. M.; Pemberton, N. T.; Prineas, R.; Rautaharju, F. S. R.; Zhang, Z.; Mayer-Davis, E. J.; Costacou, T.; Martin, M.; Sparks, K. L.; O'Leary, D. H.; Funk, L. R. C.; O'Leary, K. A.; Polak, J. F.; Stamm, E. R.; Scherzinger, A. L.; Wing, R. R.; Gillis, B. P.; Huffmyer, C.; Kriska, A. M.; Venditti, E. M.; Walker, E. A.; Harroun, T.; Ganiats, T. G.; Groessl, E. J.; Beerman, P. R.; David, K. M.; Kaplan, R. M.; Sieber, W. J.; Genuth, S. M.; Cahill, G. F.; Ferris, F. L., III; Gavin, J. R., III; Halter, J. B.; Wittes, J.; Henry, R. R.; Haffner, S. M.; Rubin, R. R.; Montgomery, B. K.; Ratner, R. E.; Herman, W. H.; Kahn, S. E.; Santiago, J. V.; Olefsky, J.; Wing, R. R.; Saudek, C.; Montez, M.; Kramer, K.; Hamman, R. F.; Knowler, W. C.; Goldberg, R. B.; Fujimoto, W. Y.; Charleston, J.; Nathan, D. M.New England Journal of Medicine (2002), 346 (6), 393-403CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Type 2 diabetes affects approx. 8 % of adults in the United States. Some risk factors - elevated plasma glucose concns. in the fasting state and after an oral glucose load, over-wt., and a sedentary lifestyle - are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concns. to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 % wt. loss and at least 150 min of phys. activity per wk. The mean age of the participants was 51 yr, and the mean body-mass index (the wt. in kilograms divided by the square of the height in meters) was 34.0; 68 % were women, and 45 % were members of minority groups. The av. follow-up was 2.8 yr. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and life-style groups, resp. The lifestyle intervention reduced the incidence by 58 % (95 % confidence interval, 48 to 66 %) and metformin by 31 % (95 % confidence interval, 17 to 43 %), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.
- 4Sanyal, A. J.; Chalasani, N.; Kowdley, K. V.; McCullough, A.; Diehl, A. M.; Bass, N. M.; Neuschwander-Tetri, B. A.; Lavine, J. E.; Tonascia, J.; Unalp, A.; Van Natta, M.; Clark, J.; Brunt, E. M.; Kleiner, D. E.; Hoofnagle, J. H.; Robuck, P. R.; Crn, N. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N. Engl. J. Med. 2010, 362, 1675– 1685, DOI: 10.1056/nejmoa09079294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXls1Oltr4%253D&md5=f439009e1d05196c7a9f94ca7cbc11cbPioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitisSanyal, Arun J.; Chalasani, Naga; Kowdley, Kris V.; McCullough, Arthur; Diehi, Anna Mae; Bass, Nathan M.; Neuschwander-Tetri, Brent A.; Lavine, Joel E.; Tonascia, James; Unalp, Aynur; Van Natta, Mark; Clark, Jeanne; Brunt, Elizabeth M.; Kleiner, David E.; Hoofnagle, Jay H.; Robuck, Patricia R.New England Journal of Medicine (2010), 362 (18), 1675-1685CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Background: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. Methods: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 wk. The primary outcome was an improvement in histol. features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Results: Vitamin E therapy, as compared with placebo, was assocd. with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P = 0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, resp.; P = 0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P < 0.001 for both comparisons), and both agents were assocd. with redns. in hepatic steatosis (P = 0.005 for vitamin E and P < 0.001 for pioglitazone) and lobular inflammation (P = 0.02 for vitamin E and P = 0.004 for pioglitazone) but not with improvement in fibrosis scores (P = 0.24 for vitamin E and P = 0.12 for pioglitazone). Subjects who received pioglitazone gained more wt. than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Conclusions: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were obsd. for some of the secondary outcomes.
- 5Chiasson, J. L.; Josse, R. G.; Gomis, R.; Hanefeld, M.; Karasik, A.; Laakso, M.; Grp, S.-N. T. R. Acarbose for prevention of type 2 diabetes mellitus: the STOPNIDDM randomised trial. Lancet 2002, 359, 2072– 2077, DOI: 10.1016/s0140-6736(02)08905-55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XkslGhs7g%253D&md5=973c014555356fea844b393fa3ed311aAcarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trialChiasson, Jean-Louis; Josse, Robert G.; Gomis, Ramon; Hanefeld, Markolf; Karasik, Avraham; Laakso, MarkkuLancet (2002), 359 (9323), 2072-2077CODEN: LANCAO; ISSN:0140-6736. (Lancet Publishing Group)The worldwide increase in type 2 diabetes mellitus is becoming a major health concern. We aimed to assess the effect of acarbose in preventing or delaying conversion of impaired glucose tolerance to type 2 diabetes. In a multicenter, placebo-controlled randomized trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat. We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no post-randomization data. Of 682 patients in the acarbose group 211 (31%), and of 686 on placebo 130 (19%), discontinued treatment early. Of patients randomized to acarbose 221 (32%), and of patients randomized to placebo 285 (42%), developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0·0001). At the end of the study, treatment with placebo for 3 mo was assocd. with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhea. Thus, acarbose could be used, either as an alternative or in addn. to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance.
- 6Turner, R.; Holman, R. R.; Cull, C. A.; Stratton, I. M.; Matthews, D. R.; Frighi, V.; Manley, S. E.; Neil, A.; McElroy, K.; Wright, D.; Kohner, E.; Fox, C.; Hadden, D.; Mehta, Z.; Smith, A.; Nugent, Z.; Peto, R.; Adlel, A. I.; Mann, J. I.; Bassett, P. A.; Oakes, S. F.; Dornan, T. L.; Aldington, S.; Lipinski, H.; Collum, R.; Harrison, K.; MacIntyre, C.; Skinner, S.; Mortemore, A.; Nelson, D.; Cockley, S.; Levien, S.; Bodsworth, L.; Willox, R.; Biggs, T.; Dove, S.; Beattie, E.; Gradwell, M.; Staples, S.; Lam, R.; Taylor, F.; Leung, L.; Carter, R. D.; Brownlee, S. M.; Fisher, K. E.; Islam, K.; Jelfs, R.; Williams, P. A.; Williams, F. A.; Sutton, P. J.; Ayres, A.; Logie, L. J.; Lovatt, C.; Evans, M. A.; Stowell, L. A.; Ross, I.; Kennedy, I. A.; Croft, D.; Keen, A. H.; Rose, C.; Raikou, M.; Fletcher, A. E.; Bulpitt, C.; Battersby, C.; Yudkin, J. S.; Stevens, R.; Stearn, M. R.; Palmer, S. L.; Hammersley, M. S.; Franklin, S. L.; Spivey, R. S.; Levy, J. C.; Tidy, C. R.; Bell, N. J.; Steemson, J.; Barrow, B. A.; Coster, R.; Waring, K.; Nolan, L.; Truscott, E.; Walravens, N.; Cook, L.; Lampard, H.; Merle, C.; Parker, P.; McVittie, J.; Draisey, I.; Murchison, L. E.; Brunt, A. H. E.; Williams, M. J.; Pearson, D. W.; Petrie, X. M. P.; Lean, M. E. J.; Walmsley, D.; Lyall, F.; Christie, E.; Church, J.; Thomson, E.; Farrow, A.; Stowers, J. M.; Stowers, M.; McHardy, K.; Patterson, N.; Wright, A. D.; Levi, N. A.; Shearer, A. C. I.; Thompson, R. J. W.; Taylor, G.; Rayton, S.; Bradbury, M.; Glover, A.; Smyth-Osbourne, A.; Parkes, C.; Graham, J.; England, P.; Gyde, S.; Eagle, C.; Chakrabarti, B.; Smith, J.; Sherwell, J.; Oakley, N. W.; Whitehead, M. A.; Hollier, G. P.; Pilkington, T.; Simpson, J.; Anderson, M.; Martin, S.; Kean, J.; Rice, B.; Rolland, A.; Nisbet, J.; Kohner, E. M.; Dornhorst, A.; Doddridge, M. C.; Dumskyij, M.; Walji, S.; Sharp, P.; Sleightholm, M.; Vanterpool, G.; Frost, G.; Roseblade, M.; Elliott, S.; Forrester, S.; Foster, M.; Myers, K.; Chapman, R.; Hayes, J. R.; Henry, R. W.; Featherston, M. S.; Archbold, G. P. R.; Copeland, M.; Harper, R.; Richardson, I.; Davison, H. A.; Alexander, L.; Scarpello, J. H. B.; Shiers, D. E.; Tucker, R. J.; Worthington, J. R. H.; Angris, S.; Bates, A.; Walton, J.; Teasdale, M.; Browne, J.; Stanley, S.; Davis, B. A.; Strange, R. C.; Hadden, D. R.; Kennedy, L.; Atkinson, A. B.; Bell, P. M.; McCance, D. R.; Rutherford, J.; Culbert, A. M.; Hegan, C.; Tennet, H.; Webb, N.; Robinson, I.; Holmes, J.; Nesbitt, S.; Spathis, A. S.; Hyer, S.; Nanson, M. E.; James, L. M.; Tyrell, J. M.; Davis, C.; Strugnell, P.; Booth, M.; Petrie, H.; Clark, D.; Hulland, S.; Barron, J. L.; Gould, B. C.; Singer, J.; Badenoch, A.; McGregor, M.; Isenberg, L.; Eckert, M.; Alibhai, K.; Marriot, E.; Cox, C.; Price, R.; Fernandez, M.; Ryle, A.; Clarke, S.; Wallace, G.; Mehmed, E.; Lankester, J. A.; Howard, E.; Waite, A.; MacFarlane, S.; Greenwood, R. H.; Wilson, J.; Denholm, M. J.; Temple, R. C.; Whitfield, K.; Johnson, F.; Munroe, C.; Gorick, S.; Duckworth, E.; Fatman, M.; Rainbow, S.; Borthwick, L.; Wheatcroft, D. J.; Seaman, R. J.; Christie, R. A.; Wheatcroft, W.; Musk, P.; White, J.; McDougal, S.; Bond, M.; Raniga, P.; Day, J. L.; Doshi, M. J.; Wilson, J. G.; Howard-Williams, J. R.; Humphreys, H.; Graham, A.; Hicks, K.; Hexman, S.; Bayliss, P.; Pledger, D.; Newton, R. W.; Jung, R. T.; Roxburgh, C.; Kilgallon, B.; Dick, L.; Waugh, N.; Kilby, S.; Ellingford, A.; Burns, J.; Fox, C. V.; Holloway, M. C.; Coghill, H. M.; Hein, N.; Fox, A.; Cowan, W.; Richard, M.; Quested, K.; Evans, S. J.; Paisey, R. B.; Brown, N. P. R.; Tucker, A. J.; Paisey, R.; Garrett, F.; Hogg, J.; Park, P.; Williams, K.; Harvey, P.; Wilcocks, R.; Mason, S.; Frost, J.; Warren, C.; Rocket, P.; Bower, L.; Roland, J. M.; Brown, D. J.; Youens, J.; Stanton-King, K.; Mungall, H.; Ball, V.; Maddison, W.; Donnelly, D.; King, S.; Griffin, P.; Smith, S.; Church, S.; Dunn, G.; Wilson, A.; Palmer, K.; Brown, P. M.; Humphriss, D.; Davidson, A. J. M.; Rose, R.; Armistead, L.; Townsend, S.; Poon, P.; Peacock, I. D. A.; Culverwell, N. J. C.; Charlton, M. H.; Connolly, B. P. S.; Peacock, J.; Barrett, J.; Wain, J.; Beeston, W.; King, G.; Hill, P. G.; Boulton, A. J. M.; Robertson, A. M.; Katoulis, V.; Olukoga, A.; McDonald, H.; Kumar, S.; Abouaesha, F.; Abuaisha, B.; Knowles, E. A.; Higgins, S.; Booker, J.; Sunter, J.; Breislin, K.; Parker, R.; Raval, P.; Curwell, J.; Davenport, H.; Shawcross, G.; Prest, A.; Grey, J.; Cole, H.; Sereviratne, C.; Young, R. J.; Clyne, J. R.; Gibson, M.; O’Connell, I.; Wong, L. M.; Wilson, S. J.; Wright, K. L.; Wallace, C.; McDowell, D.; Burden, A. C.; Sellen, E. M.; Gregory, R.; Roshan, M.; Vaghela, N.; Burden, M.; Sherriff, C.; Mansingh, S.; Clarke, J.; Grenfell, J.; Tooke, J. E.; MacLeod, K.; Seamark, C.; Rammell, M.; Pym, C.; Stockman, J.; Yeo, C.; Piper, J.; Leighton, L.; Green, E.; Hoyle, M.; Jones, K.; Hudson, A.; James, A. J.; Shore, A.; Higham, A.; Martin, B.; Neil, H. A. W.; Butterfield, W. J. H.; Doll, W. R. S.; Eastman, R.; Ferris, F. R.; Kurinij, N.; McPherson, K.; Mahler, R. F.; Meade, T. W.; Shafer, G.; Watkins, P. J.; Keen, H.; Siegel, D.; Wright, A. D.; Betteridge, D. J.; Cohen, R. D.; Currie, D.; Darbyshire, J.; Forrester, J. V.; Guppy, T.; Johnston, D. G.; McGuire, A.; Murphy, M.; el-Nahas, A. M.; Pentecost, B.; Spiegelhalter, D.; Alberti, K. G. M. M.; Denton, R.; Home, P. D.; Howell, S.; Jarrett, J. R.; Marks, V.; Marmot, M.; Ward, J. D.; Grp, U. P. D. S. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998, 352, 837– 853, DOI: 10.1016/S0140-6736(98)07019-6There is no corresponding record for this reference.
- 7Olvera-Roldan, E. O.; Cristobal-Luna, J. M.; Garcia-Martinez, Y.; Mojica-Villegas, M. A.; Perez-Pasten-Borja, R.; Gutierrez-Salmean, G.; Perez-Gutierrez, S.; Garcia-Rodriguez, R. V.; Madrigal-Santillan, E.; Morales-Gonzalez, J. A.; Chamorro-Cevallos, G. Effects of Spirulina maxima on a Model of Sexual Dysfunction in Streptozotocin-Induced Diabetic Male Rats. Plants 2023, 12, 722, DOI: 10.3390/plants120407227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXkslWhsr0%253D&md5=e10ff814448fd0ac22b760e8e1826d9dEffects of Spirulina maxima on a Model of Sexual Dysfunction in Streptozotocin-Induced Diabetic Male RatsOlvera-Roldan, Eduardo Osel; Cristobal-Luna, Jose Melesio; Garcia-Martinez, Yuliana; Mojica-Villegas, Maria Angelica; Perez-Pasten-Borja, Ricardo; Gutierrez-Salmean, Gabriela; Perez-Gutierrez, Salud; Garcia-Rodriguez, Rosa Virginia; Madrigal-Santillan, Eduardo; Morales-Gonzalez, Jose A.; Chamorro-Cevallos, GermanPlants (2023), 12 (4), 722CODEN: PLANCD; ISSN:2223-7747. (MDPI AG)Arthrospira (Spirulina) maxima (SM) is a cyanobacterium that has a long history of being used as human food. In recent years, several investigations have shown its beneficial biol. effects, among which its antioxidant capacity has been highlighted. The purpose of this study was to evaluate the effects of SM on body wt., glycemia, sexual behavior, sperm quality, testosterone levels, sex organ wts., and the activity of antioxidant enzymes in diabetic male rats (a disease characterized by an increase in reactive oxygen species). The expt. consisted of six groups of sexually expert adult males (n = 6): (1) control (vehicle); (2) streptozotocin (STZ)-65 mg/kg; (3) SM-400 mg/kg; (4) STZ + SM-100 mg/kg; (5) STZ + SM-200 mg/kg; and (6) STZ + SM-400 mg/kg. Sexual behavior tests were performed during the first 3 h of the dark period under dim red illumination. Our results showed that SM significantly improved sexual behavior and sperm quality vs. diabetic animals. Likewise, while the enzymic activities of SOD and GPx increased, TBARS lipoperoxidn. decreased and testosterone levels increased. In view of the findings, it is suggested that SM may potentially be used as a nutraceutical for the treatment of diabetic male sexual dysfunction due to its antioxidant property.
- 8Hsu, Y. C.; Chang, C. C.; Hsieh, C. C.; Shih, Y. H.; Chang, H. C.; Lin, C. L. Therapeutic Potential of Extracts from Macaranga tanarius (MTE) in Diabetic Nephropathy. Plants 2023, 12, 656, DOI: 10.3390/plants120306568https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXjsF2jsrc%253D&md5=e176b266f9f7e26bbe1f04a3e5bdc2b3Therapeutic Potential of Extracts from Macaranga tanarius (MTE) in Diabetic NephropathyHsu, Yung-Chien; Chang, Cheng-Chih; Hsieh, Ching-Chuan; Shih, Ya-Hsueh; Chang, Hsiu-Ching; Lin, Chun-LiangPlants (2023), 12 (3), 656CODEN: PLANCD; ISSN:2223-7747. (MDPI AG)Diabetic nephropathy is a complication of diabetes that leads to end-stage kidney disease and is a major health burden worldwide. Prenylflavonoid compds. extd. from Macaranga tanarius (MTE) exhibit anti-inflammation, anti-oxidant, and anti-bacterial properties. However, the effects of these compds. on diabetic nephropathy remain unclear. The effects of MTE on diabetic nephropathy were investigated in vitro by using mouse renal mesangial cells and in vivo by using a db/db knockout mouse model. No overt alteration in proliferation was obsd. in mouse renal mesangial cells treated with 0-1 μg/mL MTE. Western blot anal. indicated that MTE dose-dependently attenuated the expression of fibronectin, α-smooth muscle actin, and collagen IV. Administration of MTE ameliorated renal albumin loss in db/db mice. Immunohistochem. staining revealed that MTE mitigated diabetes-induced fibronectin and collagen IV expression. Periodic acid-Schiff (PAS) and trichrome staining also showed that administration of MTE reduced the renal fibrosis phenomenon. MTE significantly ameliorated diabetes-induced nephropathy.
- 9Belaabed, S.; Khalfaoui, A.; Parisi, V.; Santoro, V.; Russo, D.; Ponticelli, M.; Monne, M.; Rebbas, K.; Milella, L.; Donadio, G. Rhanteriol, a New Rhanterium suaveolens Desf. Lignan with Pharmacological Potential as an Inhibitor of Enzymes Involved in Neurodegeneration and Type 2 Diabetes. Plants 2023, 12, 301, DOI: 10.3390/plants120203019https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXivFSnsb4%253D&md5=7dc57806544c1193011f0456b13d5f6dRhanteriol, a New Rhanterium suaveolens Desf. Lignan with Pharmacological Potential as an Inhibitor of Enzymes Involved in Neurodegeneration and Type 2 DiabetesBelaabed, Soumia; Khalfaoui, Ayoub; Parisi, Valentina; Santoro, Valentina; Russo, Daniela; Ponticelli, Maria; Monne, Magnus; Rebbas, Khellaf; Milella, Luigi; Donadio, GiulianaPlants (2023), 12 (2), 301CODEN: PLANCD; ISSN:2223-7747. (MDPI AG)Several specialized plant metabolites are reported to be enzyme inhibitors. In this investigation, the phytochem. compn. and the biol. activity of Rhanterium suaveolens Desf. were studied. One new lignan (rhanteriol 1) and seven known secondary metabolites were isolated from the aerial parts of R. suaveolens by using different chromatog. procedures. The biol. properties of the R. suaveolens exts. and the new compd. were evaluated by measuring their ability to inhibit the cholinesterase and carbohydrate-hydrolyzing enzymes, using cell-free in vitro methods. The new lignan, rhanteriol, was shown to inhibit α-amylase and α-glucosidase (IC50 = 46.42 ± 3.25 μM and 26.76 ± 3.29 μM, resp.), as well as butyrylcholinesterase (IC50 = 10.41 ± 0.03 μM), with an effect comparable to that of the resp. stds., acarbose and galantamine. Furthermore, docking studies were performed suggesting the interaction mode of rhanteriol with the active sites of the investigated enzymes. The obtained data demonstrated that the aerial part of R. suaveolens could represent a source of active mols., such as rhanteriol, usable in the development of treatments for preventing or treating type 2 diabetes mellitus and neurodegeneration.
- 10Chukiatsiri, S.; Wongsrangsap, N.; Ratanabunyong, S.; Choowongkomon, K. In Vitro Evaluation of Antidiabetic Potential of Cleistocalyx nervosum var. paniala Fruit Extract. Plants 2022, 12, 112, DOI: 10.3390/plants12010112There is no corresponding record for this reference.
- 11Hassan, H. M.; Mahran, Y. F.; Ghanim, A. M. H. Ganoderma lucidum ameliorates the diabetic nephropathy via down-regulatory effect on TGFbeta-1 and TLR-4/NFkappaB signalling pathways. J. Pharm. Pharmacol. 2021, 73, 1250– 1261, DOI: 10.1093/jpp/rgab05811https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3sbgt1Oltg%253D%253D&md5=3d3e5b20cf8399060151df5ca5379306Ganoderma lucidum ameliorates the diabetic nephropathy via down-regulatory effect on TGFβ-1 and TLR-4/NFκB signalling pathwaysHassan Hanan M; Mahran Yasmen F; Mahran Yasmen F; Ghanim Amal M HThe Journal of pharmacy and pharmacology (2021), 73 (9), 1250-1261 ISSN:.OBJECTIVES: Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus and it is considered as a principal cause for end-stage renal failure. Ganoderma lucidum (GL) has been studied for its reno-protective effect against different kidney injury models. The aim of our study is to investigate the mechanisms by which GL can improve kidney injury and consequent renal inflammation and fibrosis. METHODS: GL either in a low dose (250 mg/kg, i.p.) or high dose (500 mg/kg, i.p.) was administered to DN rat model, and nephropathy indices were investigated. KEY FINDINGS: GL treatment significantly down-regulated kidney injury molecule-1 (KIM-1) gene expression and inhibited TLR-4 (Toll-like receptor-4)/NFκB (nuclear factor kappa B) signalling pathway. As well, GL treatment significantly decreased the pro-inflammatory mediator; IL-1β (interleukin-1 beta) level and fibrosis-associated growth factors; FGF-23 (fibroblast growth factor-23) and TGFβ-1 (transforming growth factor beta-1) levels. In addition, GL remarkably inhibited (Bax) the pro-apoptotic protein and induced (Bcl-2) the anti-apoptotic protein expression in kidneys. Moreover, GL treatment significantly alleviates kidney injury indicated by correcting the deteriorated kidney function and improving oxidative stress status in DN rats. CONCLUSIONS: GL significantly improved renal function indices through dose-dependent kidney function restoration, oxidative stress reduction, down-regulation of gene expression of KIM-1 and TLR4/NFκB signalling pathway blockage with subsequent alleviation of renal inflammation and fibrosis.
- 12Sun, J.; He, H.; Xie, B. J. Novel antioxidant peptides from fermented mushroom Ganoderma lucidum. J. Agric. Food Chem. 2004, 52, 6646– 6652, DOI: 10.1021/jf049513612https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXns1Wit70%253D&md5=91c7391dfc158852e6f85e93b62d851bNovel Antioxidant Peptides from Fermented Mushroom Ganoderma lucidumSun, Jie; He, Hui; Xie, Bi JunJournal of Agricultural and Food Chemistry (2004), 52 (21), 6646-6652CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Oxidative stress has been linked with the pathogenesis of many human diseases including cancer, aging, and atherosclerosis. The present study investigates the antioxidant activities of peptides isolated from the medicinal mushroom, Ganoderma lucidum. G. Lucidum has been shown to possess potent antioxidant activity with little or no side effects. Polysaccharide, polysaccharide-peptide complex, and phenolic components of G. Lucidum have been proposed to be responsible for this antioxidant effect. However, research has shown that the G. Lucidum peptides (GLP) is the major antioxidant component of G. lucidum. The objective of this study was to evaluate the antioxidant activity of these peptides using different oxidn. systems. GLP showed potent antioxidant activities in both lightproof soybean oil and lard systems, assessed by lipid peroxidant value. Compared to butylated hydroxytoluene, GLP showed a higher antioxidant activity in the soybean oil system. Soybean lipoxygenase activity was blocked by GLP in a dose-dependent manner with an IC50 value of 27.1 μg/mL. GLP showed scavenging activity toward hydroxyl radicals produced in a deoxyribose system with an IC50 value of 25 μg/mL, and GLP effectively quenched superoxide radical anion produced by pyrogallol autoxidn. in a dose-dependent manner. Malondialdehyde level has been used as the oxidn. index in many biol. systems. GLP showed substantial antioxidant activity in the rat liver tissue homogenates and mitochondrial membrane peroxidn. systems. The auto-hemolysis of rat red blood cells was also blocked by GLP in a dose-dependent manner. On the basis of these results, it is concluded that GLP is the major constituent responsible for the antioxidant activity of G. lucidum. GLP could play an important role in the inhibition of lipid peroxidn. in biol. systems through its antioxidant, metal chelating, and free radical scavenging activities.
- 13van der Hem, L. G.; van der Vliet, J. A.; Bocken, C. F.; Kino, K.; Hoitsma, A. J.; Tax, W. J. Ling Zhi-8: studies of a new immunomodulating agent. Transplantation 1995, 60, 438– 443, DOI: 10.1097/00007890-199509000-0000613https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXovVWrt7w%253D&md5=fd0b29ddb505c57c6b564c4323f384a4Ling ZHI-8: studies of a new immunomodulating agentvan der Hem, Lieuwe G.; van der Vliet, J. Adam; Bocken, C. Frans M.; Kino, Kohsuke; Hoitsma, Andries J.; Tax, Wil J.M.Transplantation (1995), 60 (5), 438-43CODEN: TRPLAU; ISSN:0041-1337. (Williams & Wilkins)Ling ZHI-8 (LZ-8) is a protein derived from the fungus Ganoderma lucidum and has immunomodulatory capacities. It was shown to be mitogenic toward mouse splenocytes in vitro and immunosuppressive in vivo by reducing antigen-induced antibody formation and by preventing completely the incidence of autoimmune diabetes in nonobese diabetic mice. In this study, the mitogenic effects of LZ-8 on human mononuclear cells are reported. In accordance to its mitogenic effect on mouse splenocytes, LZ-8 proved to be mitogenic for human PBMC. This mitogenic effect of LZ-8 apparently required the presence of monocytes. The authors also demonstrated it to be immunosuppressive in vitro in a human MLC performed in the absence of monocytes, using purified T cells and EBV-transformed allogeneic B cells. Furthermore, the authors tested LZ-8 for its possible suppressive effects in 2 different models of allogeneic tissue transplantation. LZ-8 proved to have a significant effect on cellular immunity, since its administration in an allografted mouse skin model resulted in an increased survival time. In a model of transplanted allogeneic pancreatic rat islets, LZ-8 was effective in delaying the rejection process of allografted islets. More frequent or continuous administration resulted in a further prolongation of survival time. No serious side effects of LZ-8 could be discerned in these expts.
- 14Thomford, N. E.; Senthebane, D. A.; Rowe, A.; Munro, D.; Seele, P.; Maroyi, A.; Dzobo, K. Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery. Int. J. Mol. Sci. 2018, 19, 1578, DOI: 10.3390/ijms1906157814https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVGrt7nO&md5=75122cc3e54f8cdeec7d42043405629aNatural products for drug discovery in the 21st century: innovations for novel drug discoveryThomford, Nicholas Ekow; Senthebane, Dimakatso Alice; Rowe, Arielle; Munro, Daniella; Seele, Palesa; Maroyi, Alfred; Dzobo, KevinInternational Journal of Molecular Sciences (2018), 19 (6), 1578/1-1578/29CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)The therapeutic properties of plants have been recognized since time immemorial. Many pathol. conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concd. plant exts. without isolation of active compds. Modern medicine however, requires the isolation and purifn. of one or two active compds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of "active compd." hasmade the compd. ineffective. Drug discovery is amultidimensional problemrequiring several parameters of both natural and synthetic compds. such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of 'organ-on chip' and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compds. while allowing novel ways of drug design and synthesis based on natural compds. Recent advances in anal. and computational techniques have opened new avenues to process complex natural products and to use their structures to derive newand innovative drugs. Indeed, we are in the era of computational mol. design, as applied to natural products. Predictive computational softwares have contributed to the discovery of mol. targets of natural products and their derivs. In future the use of quantum computing, computational softwares and databases in modeling mol. interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false pos. leads in drug development. This review discusses plant-based natural product drug discovery and how innovative technologies play a role in next-generation drug discovery.
- 15Xu, S.; Dou, Y.; Ye, B.; Wu, Q.; Wang, Y.; Hu, M.; Ma, F.; Rong, X.; Guo, J. Ganoderma lucidum polysaccharides improve insulin sensitivity by regulating inflammatory cytokines and gut microbiota composition in mice. J. Funct. Foods 2017, 38, 545– 552, DOI: 10.1016/j.jff.2017.09.03215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1SitbvI&md5=138b0a8934aa61132534934cdc32ae94Ganoderma lucidum polysaccharides improve insulin sensitivity by regulating inflammatory cytokines and gut microbiota composition in miceXu, S.; Dou, Y.; Ye, B.; Wu, Q.; Wang, Y.; Hu, M.; Ma, F.; Rong, X.; Guo, J.Journal of Functional Foods (2017), 38 (Part_A), 545-552CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)Ectopic lipid accumulation and low-grade chronic inflammation are crit. pathogenesis of insulin resistance development. Ganoderma lucidum is a traditional Chinese herb for balancing energy homeostasis. In this research, we detd. the effects of G. lucidum polysaccharides (GLP) on high-fat diet (HFD)-induced insulin resistant mice. We obsd. that GLP treatment decreased plasma insulin concn. and reversed HFD-induced systemic insulin resistance. Meanwhile, GLP ameliorated low-grade chronic inflammation, inducing lipolysis in adipose tissues. GLP decreased plasma triglyceride and non-esterified fatty acid outflux by suppressing mRNA expressions of hormone-sensitive lipase, fatty acid binding protein 4, tumor necrosis factor-α, and interleukin-6 in epididymal fat. Finally, GLP treatment suppressed ectopic lipid accumulation in peripheral tissues and hepatic insulin-regulated lipogenesis. GLP also regulated compn. of gut microbiota implicated in type 2 diabetes mellitus development.
- 16Teng, B. S.; Wang, C. D.; Yang, H. J.; Wu, J. S.; Zhang, D.; Zheng, M.; Fan, Z. H.; Pan, D.; Zhou, P. A protein tyrosine phosphatase 1B activity inhibitor from the fruiting bodies of Ganoderma lucidum (Fr.) Karst and its hypoglycemic potency on streptozotocin-induced type 2 diabetic mice. J. Agric. Food Chem. 2011, 59, 6492– 6500, DOI: 10.1021/jf200527y16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvFSltrk%253D&md5=51bc78266138c7765cef7d1f6b76e82aA Protein Tyrosine Phosphatase 1B Activity Inhibitor from the Fruiting Bodies of Ganoderma lucidum (Fr.) Karst and Its Hypoglycemic Potency on Streptozotocin-Induced Type 2 Diabetic MiceTeng, Bao-Song; Wang, Chen-Dong; Yang, Hong-Jie; Wu, Jia-Sheng; Zhang, Dan; Zheng, Min; Fan, Zhao-Hua; Pan, Deng; Zhou, PingJournal of Agricultural and Food Chemistry (2011), 59 (12), 6492-6500CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Inhibition of protein tyrosine phosphatase 1B (PTP1B) activity has been considered to be a promising therapy approach to treat type 2 diabetes. A novel PTP1B activity inhibitor, named FYGL (Fudan-Yueyang-G. lucidum), was screened from the fruiting bodies of Ganoderma lucidum and showed an efficient PTP1B inhibitory potency with IC50 = 5.12±0.05 μg/mL. FYGL is a water-sol. macromol. proteoglycan with a protein to polysaccharide ratio of 17:77 and a viscosity-av. mol. wt. (Mη) of 2.6 × 105. The type 2 diabetic mice treated orally by FYGL showed an obvious decrease in plasma glucose level compared with the diabetic controls without drug treatment, comparable with that of diabetic mice treated with metformin, a clin. drug. The toxicity of FYGL is very low. The results indicate that FYGL may serve as a drug candidate or a health-care food for diabetic therapy or protection.
- 17Pan, D.; Wang, L.; Chen, C.; Hu, B.; Zhou, P. Isolation and characterization of a hyperbranched proteoglycan from Ganoderma lucidum for anti-diabetes. Carbohydr. Polym. 2015, 117, 106– 114, DOI: 10.1016/j.carbpol.2014.09.05117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Kgu73F&md5=f823762d3d9d4f3ac66b26bdf657ab27Isolation and characterization of a hyperbranched proteoglycan from Ganoderma lucidum for anti-diabetesPan, Deng; Wang, Linqiang; Chen, Congheng; Hu, Bingwen; Zhou, PingCarbohydrate Polymers (2015), 117 (), 106-114CODEN: CAPOD8; ISSN:0144-8617. (Elsevier Ltd.)An efficient protein tyrosine phosphatase 1B (PTP1B) inhibitor, named FYGL-n, was isolated from Ganoderma lucidum and characterized for its structure and bioactivity. The structure and chain conformation of FYGL-n based on both chem. and spectroscopic anal. showed that FYGL-n was a hyperbranched heteropolysaccharide bonded with protein via both serine and threonine residues by O-type glycoside, and showed a sphere obsd. by AFM. FYGL-n consisted of D-arabinose, D-galactose, L-rhamnose and D-glucose in a mole ratio of 0.08:0.21:0.24:0.47, with a mol. mass of 72.9 kDa. Anal. of amino acids in FYGL-n indicated that there were 16 common amino acids, among which aspartic acid, glycine, serine, alanine, glutamic acid and threonine were the dominant components. FYGL-n could inhibit the PTP1B activity via a competitive mechanism in vitro.
- 18Pan, D.; Wang, L.; Hu, B.; Zhou, P. Structural characterization and bioactivity evaluation of an acidic proteoglycan extract from Ganoderma lucidum fruiting bodies for PTP1B inhibition and anti-diabetes. Biopolymers 2014, 101, 613– 623, DOI: 10.1002/bip.2242618https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvVGrs7s%253D&md5=2b7e3991226cf2f900ec0f3c63e881f0Structural characterization and bioactivity evaluation of an acidic proteoglycan extract from Ganoderma lucidum fruiting bodies for PTP1B inhibition and anti-diabetesPan, Deng; Wang, Linqiang; Hu, Bingwen; Zhou, PingBiopolymers (2014), 101 (6), 613-623CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)A water-sol. PTP1B inhibitor, named FYGL-a, was fractionated for structure investigation and bioactivity evaluation. FYGL-a is an ingredient of a reported antihyperglycemia ext. from Ganoderma Lucidum fruiting bodies. Compn. anal. indicated that FYGL-a was a 100.2 kDa acidic proteoglycan, consisting of 85 ± 2% heteropolysaccharide chain with rhamnose, galactose, glucose, and glucuronic acid residues in a mole ratio of 1.0:3.7:3.9:2.0, and the 15 ± 2% protein moiety of FYGL-a was covalently bonded to the polysaccharide chain in O-linkage type via threonine residues. The complete sequence of FYGL-a was characterized systematically by periodate oxidn., Smith degrdn., methylation anal., 1H & 13C 1D NMR, and 2D NMR (HSQC, HMBC, NOESY, COSY, & TOCSY). The chem. structure of FYGL-a was detd. as following, which may play special role in the competitive inhibition of PTP1B and antihyperglycemia potency. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 613-623, 2014.
- 19Pan, D.; Wang, L.; Chen, C.; Teng, B.; Wang, C.; Xu, Z.; Hu, B.; Zhou, P. Structure characterization of a novel neutral polysaccharide isolated from Ganoderma lucidum fruiting bodies. Food Chem. 2012, 135, 1097– 1103, DOI: 10.1016/j.foodchem.2012.05.07119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlSmurjF&md5=2ca616283a5d3410ceba607e3a6d6f10Structure characterization of a novel neutral polysaccharide isolated from Ganoderma lucidum fruiting bodiesPan, Deng; Wang, Linqiang; Chen, Congheng; Teng, Baosong; Wang, Chendong; Xu, Zhixue; Hu, Bingwen; Zhou, PingFood Chemistry (2012), 135 (3), 1097-1103CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)Ganoderma lucidum (G. lucidum) is a mushroom which has been used for health promotion for a long time in China. In the present work a neutral hetero-polysaccharide, named FYGL-1, was isolated from FYGL which was reported previously capable of antihyperglycemia in vivo for further detailed chem. structure investigation. The results of monosaccharide compn. and GPC anal. indicated that FYGL-1 consisted of galactose, rhamnose and glucose in mole ratio of 1.00:1.15:3.22 with a mol. wt. of 78 kDa. The detailed structure of FYGL-1 was characterized by periodate oxidn., Smith degrdn., methylation anal., along with FT-IR, GC, GC-MS, 1D 1H and 13C NMR and 2D NMR (HSQC, COSY, NOESY and TOCSY). Based on the anal. of the results, the structure of the repeating unit of FYGL-1 was established as:.
- 20Pan, D.; Zhang, D.; Wu, J.; Chen, C.; Xu, Z.; Yang, H.; Zhou, P. Antidiabetic, antihyperlipidemic and antioxidant activities of a novel proteoglycan from ganoderma lucidum fruiting bodies on db/db mice and the possible mechanism. PLoS One 2013, 8, e68332 DOI: 10.1371/journal.pone.006833220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFymtrzF&md5=f924b1921c7d59242fee324ea29a57c2Antidiabetic, antihyperlipidemic and antioxidant activities of a novel proteoglycan from Ganoderma Lucidum fruiting bodies on db/db mice and the possible mechanismPan, Deng; Zhang, Dang; Wu, Jiasheng; Chen, Congheng; Xu, Zhixue; Yang, Hongjie; Zhou, PingPLoS One (2013), 8 (7), e68332CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Previously, we screened a proteoglycan for anti-hyperglycemic, named FYGL, from Ganoderma Lucidum. For further research of the antidiabetic mechanisms of FYGL in vivo, the glucose homeostasis, activities of insulin-sensitive enzymes, glucose transporter expression and pancreatic function were analyzed using db/db mice as diabetic models in the present work. FYGL not only lead to a redn. in glycated Hb level, but also an increase in insulin and C-peptide level, whereas a decrease in glucagons level and showed a potential for the remediation of pancreatic islets. FYGL also increased the glucokinase activities and simultaneously lowered the phosphoenol pyruvate carboxykinase activities, accompanied by a redn. in the expression of hepatic glucose transporter protein 2, while the expression of adipose and skeletal glucose transporter protein 4 was increased. Moreover, the antioxidant enzyme activities were also increased by FYGL treatment. Thus, FYGL was an effective antidiabetic agent by enhancing insulin secretion and decreasing hepatic glucose output along with increase of adipose and skeletal muscle glucose disposal in the late stage of diabetes. Furthermore, FYGL is beneficial against oxidative stress, thereby being helpful in preventing the diabetic complications.
- 21Yu, F. Z.; Teng, Y. L.; Yang, S. T.; He, Y. M.; Zhang, Z.; Yang, H. J.; Ding, C. F.; Zhou, P. The thermodynamic and kinetic mechanisms of a Ganoderma lucidum proteoglycan inhibiting hIAPP amyloidosis. Biophys. Chem. 2022, 280, 106702, DOI: 10.1016/j.bpc.2021.10670221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVamsLnF&md5=c84b39e8b76038e943cbf2e2010f3dc6The thermodynamic and kinetic mechanisms of a Ganoderma lucidum proteoglycan inhibiting hIAPP amyloidosisYu, Fanzhen; Teng, Yilong; Yang, Shutong; He, Yanming; Zhang, Zeng; Yang, Hongjie; Ding, Chuan-Fan; Zhou, PingBiophysical Chemistry (2022), 280 (), 106702CODEN: BICIAZ; ISSN:0301-4622. (Elsevier B.V.)Ganoderma lucidum is a valuable medicinal herbal which has been reported to prevent type 2 diabetes (T2D). A natural hyperbranched proteoglycan extd. from Ganoderma lucidum, namely, FYGL, has been demonstrated to inhibit the amyloidosis of human islet amyloid polypeptide (hIAPP) previously by our lab. However, the effective active components and the mechanisms of FYGL in inhibiting hIAPP amyloidosis are unknown. To identify the effective active components, different components from FYGL were isolated: the polysaccharide FYGL-1, the proteoglycans of FYGL-2 and FYGL-3. We further sepd. and sequenced the protein moieties of FYGL-2 and FYGL-3, namely, FYGL-2-P and FYGL-3-P, resp., and compared their abilities to inhibit hIAPP amyloidosis, and systematically explored the inhibitory mechanisms by spectroscopy, microscopy and mol. dynamic simulation methods. Results showed that the protein moieties of FYGL played essential roles in inhibiting hIAPP amyloidosis. The strong, specific, and enthalpy-driven interaction by π-π stacking and electrostatic forces between hIAPP and FYGL-3-P dramatically inhibited hIAPP amyloidosis. These results suggested that FYGL-3-P had enormous potential to prevent hIAPP misfolding-induced diabetes and structurally helped researchers to seek or design inhibitors against polypeptide amyloidosis.
- 22Pan, D.; Zhang, D.; Wu, J.; Chen, C.; Xu, Z.; Yang, H.; Zhou, P. A novel proteoglycan from Ganoderma lucidum fruiting bodies protects kidney function and ameliorates diabetic nephropathy via its antioxidant activity in C57BL/6 db/db mice. Food Chem. Toxicol. 2014, 63, 111– 118, DOI: 10.1016/j.fct.2013.10.04622https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFyls7bF&md5=ff590f82015be7cdb29dbab653a7b6d8A novel proteoglycan from Ganoderma lucidum fruiting bodies protects kidney function and ameliorates diabetic nephropathy via its antioxidant activity in C57BL/6 db/db micePan, Deng; Zhang, Dan; Wu, Jiasheng; Chen, Congheng; Xu, Zhixue; Yang, Hongjie; Zhou, PingFood and Chemical Toxicology (2014), 63 (), 111-118CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)Diabetic nephropathy (DN) is the major cause of morbidity among diabetic patients. Thus, antidiabetic drugs with protection potential in the kidneys would have a higher therapeutic value. The effects of a novel proteoglycan, named FYGL, isolated from G. lucidum fruiting bodies, on the kidney function were investigated systematically in present work. FYGL (250 mg/kg) not only dosedependently reduced the blood glucose concn. (23.5%, p < 0.05), kidney/body wt. ratio (23.6%, p < 0.01), serum creatinine (33.1%, p < 0.01), urea nitrogen (24.1%, p < 0.01),urea acid contents (35.9%, p < 0.01) and albuminuria (30.7%, p < 0.01)of DN mice compared to the untreated DN mice but also increased the renal superoxide dismutase (75.3%, p < 0.01), glutathione peroxidase (35.0%, p < 0.01) and catalase activities (58.5%, p < 0.01) compared to the untreated DN mice. The decreasing of renal malondialdehyde content (34.3%, p < 0.01) and 8-hydroxy-2'-deoxyguanosine expression (2.5-fold, p < 0.01) were also obsd. in FYGL-treated DN mice compared to the untreated DN mice, along with an amelioration of renal morphol. abnormalities. We conclude that FYGL confers protection against the renal functional and morphol. injuries by increasing activities of antioxidants and inhibiting accumulation of oxidn., suggesting a potential nutritional supplement for the prevention and therapy of DN.
- 23Yang, Z.; Wu, F.; He, Y.; Zhang, Q.; Zhang, Y.; Zhou, G.; Yang, H.; Zhou, P. A novel PTP1B inhibitor extracted from Ganoderma lucidum ameliorates insulin resistance by regulating IRS1-GLUT4 cascades in the insulin signaling pathway. Food Funct. 2018, 9, 397– 406, DOI: 10.1039/c7fo01489a23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVKhur7E&md5=6c8be3a7ed6c6c4bfea6932dd3808b74A novel PTP1B inhibitor extracted from Ganoderma lucidum ameliorates insulin resistance by regulating IRS1-GLUT4 cascades in the insulin signaling pathwayYang, Zhou; Wu, Fan; He, Yanming; Zhang, Qiang; Zhang, Yuan; Zhou, Guangrong; Yang, Hongjie; Zhou, PingFood & Function (2018), 9 (1), 397-406CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)Insulin resistance caused by the overexpression of protein tyrosine phosphatase 1 B (PTP1B) as well as the dephosphorylation of its target is one of the main causes of type 2 diabetes (T2D). A newly discovered proteoglycan, Fudan-Yueyang Ganoderma lucidum (FYGL) extd. from Ganoderma lucidum, was first reported to be capable of competitively inhibiting PTP1B activity in vitro in our previous work. In the present study, we sought to reveal the mechanism of PTP1B inhibition by FYGL at the animal and cellular levels. We found that FYGL can decrease blood glucose, reduce body wt. and ameliorate insulin resistance in ob/ob mice. Decrease of PTP1B expression and increase of the phosphorylation of PTP1B targets in the insulin signaling pathway of skeletal muscles were obsd. In order to clearly reveal the underlying mechanism of the hypoglycemic effect caused by FYGL, we further investigated the effects of FYGL on the PTP1B-involved insulin signaling pathway in rat myoblast L6 cells. We demonstrated that FYGL had excellent cell permeability by using a confocal laser scanning microscope and a flow cytometer. We found that FYGL had a pos. effect on insulin-stimulated glucose uptake by using the 2-deoxyglucose (2-DG) method. FYGL could inhibit PTP1B expression at the mRNA level, phosphorylating insulin receptor substrate-1 (IRS1), as well as activating phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt). Finally, FYGL increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and consequently up-regulated the expression of glucose transporter type 4 (GLUT4), promoting GLUT4 transportation to the plasma membrane in PTP1B-transfected L6 cells. Our study provides theor. evidence for FYGL to be potentially used in T2D management.
- 24Weng, Y. J.; Zhang, M.; Wang, J.; Zhang, Y. Q. Significantly hypoglycemic effect of a novel functional bread rich in mulberry bark and improving the related functions of liver, pancreas, and kidney, on T2D mice. Food Sci. Nutr. 2021, 9, 2468– 2482, DOI: 10.1002/fsn3.218924https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsFyis7%252FP&md5=9eda06c8c2f1b186e2b5391d9d5c86b1Significantly hypoglycemic effect of a novel functional bread rich in mulberry bark and improving the related functions of liver, pancreas, and kidney, on T2D miceWeng, Yu-Jie; Zhang, Meng; Wang, Jiang; Zhang, Yu-QingFood Science & Nutrition (Hoboken, NJ, United States) (2021), 9 (5), 2468-2482CODEN: FSNHBW; ISSN:2048-7177. (John Wiley & Sons, Inc.)To develop a novel functional food with lowering blood glucose for diabetics, the mixed bread contg. mulberry branch bark powder (MBBP) was used for the oral administration of the type 2 diabetic (T2D) mice induced by streptozocin (STZ), high-fat and high-sugar diet for 7 wk. 5%, 10%, and 15% MBBP bread diets had a significatively pos. influence on the biochem. indicators, histol. examn., and immunohistochem. observations in T2D mice. The 15% MBBP-rich bread diet evidently retarded loss wt. of T2D mice, and decreased in FBG by about 55% and in glycosylated Hb (HbA1c) levels by about 30%. Its glucose tolerance and serum insulin levels were very close to normal level. The abnormal lipid metab. and insulin-related index of T2D mice in both the 10% and 15% MBBP bread diet groups were partly reversed. The Western blotting results showed that the expression levels of key proteins in PI3K/AKT signaling pathway were decreased and expression levels of immunoproteins PPARγ, TNF-α, P65, and IL6 were increased. In general, oral MBBP bread diets effectively restored some functions and repaired damage to the pancreas, liver, and kidney in T2D mice. Therefore, MBBP is potential to develop into a novel functional food additive with significantly hypoglycemic effect.
- 25Love, M. I.; Huber, W.; Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014, 15, 550, DOI: 10.1186/s13059-014-0550-825https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtVCrsL8%253D&md5=e1052687faf6b297cdf615a14676c5b0Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2Love, Michael I.; Huber, Wolfgang; Anders, SimonGenome Biology (2014), 15 (12), 550/1-550/21, 21 pp.CODEN: GNBLFW; ISSN:1474-760X. (BioMed Central Ltd.)In comparative high-throughput sequencing assays, a fundamental task is the anal. of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across exptl. conditions. Small replicate nos., discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential anal. of count data, using shrinkage estn. for dispersions and fold changes to improve stability and interpretability of ests. This enables a more quant. anal. focused on the strength rather than the mere presence of differential expression.
- 26Wang, H.; Niu, L.; Jiang, S.; Zhai, J.; Wang, P.; Kong, F.; Jin, X. Comprehensive analysis of aberrantly expressed profiles of lncRNAs and miRNAs with associated ceRNA network in muscle-invasive bladder cancer. Oncotarget 2016, 7, 86174– 86185, DOI: 10.18632/oncotarget.1336326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2snotVaksw%253D%253D&md5=7a216f91848c32ca29798a3dd0859c7aComprehensive analysis of aberrantly expressed profiles of lncRNAs and miRNAs with associated ceRNA network in muscle-invasive bladder cancerWang Hanbo; Jiang Shaobo; Jin Xunbo; Niu Leilei; Zhai Jing; Wang Ping; Kong FengOncotarget (2016), 7 (52), 86174-86185 ISSN:.Although initially thought to be transcriptional noise, long noncoding RNAs (lncRNAs) are gaining increased attention in human cancers as its diversity function. At present, lncRNAs are regarded as the main part of competing endogenous RNA (ceRNA) network due to its regulation on protein-coding gene expression by acting as miRNA sponges. However, functional roles of lncRNA-mediated ceRNAs in muscle-invasive bladder cancer remain unclear. To clarify relevant potential mechanisms, here we comprehensively compared the expression profiles of mRNAs, lncRNAs and miRNAs between 322 muscle-invasive bladder cancer tissues and 19 non-tumor bladder tissues, based on the Cancer Genome Atlas (TCGA). A total of 22 lncRNAs were identified as aberrantly expressed and had correlations with tumorigenesis and/or progression of muscle-invasive bladder cancer ( log2FoldChange > 1.5, corrected P value < 0.01). 6 out of the 22 dysregulated lncRNAs functioned as prognostic biomarkers for patients with muscle-invasive bladder cancer according to the overall survival analysis (P value < 0.05). Finally, a dysregulated lncRNA-associated ceRNA network was successfully constructed, which inculdes five muscle-invasive bladder cancer-specific lncRNAs, nine miRNAs and 32 mRNAs. In summary, our study identified novel lncRNAs as candidate prognostic biomarkers and potential therapeutic targets for muscle-invasive bladder cancer, based on large-scale sample size. More importantly, the newly identified ceRNA network will be beneficial for improving the understanding of lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of muscle-invasive bladder cancer.
- 27Benjamini, Y.; Hochberg, Y. Controlling the False Discovery Rate - a Practical and Powerful Approach to Multiple Testing. J. R. Stat. Soc., B: Stat. Methodol. 1995, 57, 289– 300, DOI: 10.1111/j.2517-6161.1995.tb02031.xThere is no corresponding record for this reference.
- 28Kakumanu, A.; Ambavaram, M. M.; Klumas, C.; Krishnan, A.; Batlang, U.; Myers, E.; Grene, R.; Pereira, A. Effects of drought on gene expression in maize reproductive and leaf meristem tissue revealed by RNA-Seq. Plant Physiol. 2012, 160, 846– 867, DOI: 10.1104/pp.112.20044428https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFaksbbN&md5=b239d3bfa139ef6728f751f642414255Effects of drought on gene expression in maize reproductive and leaf meristem tissue revealed by RNA-seqKakumanu, Akshay; Ambavaram, Madana M. R.; Klumas, Curtis; Krishnan, Arjun; Batlang, Utlwang; Myers, Elijah; Grene, Ruth; Pereira, AndyPlant Physiology (2012), 160 (2), 846-867CODEN: PLPHAY; ISSN:0032-0889. (American Society of Plant Biologists)Drought stress affects cereals esp. during the reproductive stage. The maize (Zea mays) drought transcriptome was studied using RNA-Seq anal. to compare drought-treated and well-watered fertilized ovary and basal leaf meristem tissue. More drought-responsive genes responded in the ovary compared with the leaf meristem. Gene Ontol. enrichment anal. revealed a massive decrease in transcript abundance of cell division and cell cycle genes in the drought-stressed ovary only. Among Gene Ontol. categories related to carbohydrate metab., changes in starch and Suc metab.-related genes occurred in the ovary, consistent with a decrease in starch levels, and in Suc transporter function, with no comparable changes occurring in the leaf meristem. Abscisic acid (ABA)-related processes responded pos., but only in the ovaries. Related responses suggested the operation of low glucose sensing in drought-stressed ovaries. The data are discussed in the context of the susceptibility of maize kernel to drought stress leading to embryo abortion and the relative robustness of dividing vegetative tissue taken at the same time from the same plant subjected to the same conditions. Our working hypothesis involves signaling events assocd. with increased ABA levels, decreased glucose levels, disruption of ABA/sugar signaling, activation of programmed cell death/senescence through repression of a phospholipase C-mediated signaling pathway, and arrest of the cell cycle in the stressed ovary at 1 d after pollination. Increased invertase levels in the stressed leaf meristem, on the other hand, resulted in that tissue maintaining hexose levels at an "unstressed" level, and at lower ABA levels, which was correlated with successful resistance to drought stress.
- 29Der, E.; Suryawanshi, H.; Morozov, P.; Kustagi, M.; Goilav, B.; Ranabothu, S.; Izmirly, P.; Clancy, R.; Belmont, H. M.; Koenigsberg, M.; Mokrzycki, M.; Rominieki, H.; Graham, J. A.; Rocca, J. P.; Bornkamp, N.; Jordan, N.; Schulte, E.; Wu, M.; Pullman, J.; Slowikowski, K.; Raychaudhuri, S.; Guthridge, J.; James, J.; Buyon, J.; Tuschl, T.; Putterman, C. Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Nat. Immunol. 2019, 20, 915– 927, DOI: 10.1038/s41590-019-0386-129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvFeht7g%253D&md5=e349214c3f4ec3bf22eb3c36a7802a16Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathwaysDer, Evan; Suryawanshi, Hemant; Morozov, Pavel; Kustagi, Manjunath; Goilav, Beatrice; Ranabathou, Saritha; Izmirly, Peter; Clancy, Robert; Belmont, H. Michael; Koenigsberg, Mordecai; Mokrzycki, Michele; Rominieki, Helen; Graham, Jay A.; Rocca, Juan P.; Bornkamp, Nicole; Jordan, Nicole; Schulte, Emma; Wu, Ming; Pullman, James; Slowikowski, Kamil; Raychaudhuri, Soumya; Guthridge, Joel; James, Judith; Buyon, Jill; Tuschl, Thomas; Putterman, Chaim; the Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus ConsNature Immunology (2019), 20 (7), 915-927CODEN: NIAMCZ; ISSN:1529-2908. (Nature Research)The mol. and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each assocd. with failure to respond to treatment. Anal. of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histol. differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.
- 30De Felice, F. G.; Ferreira, S. T. Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease. Diabetes 2014, 63, 2262– 2272, DOI: 10.2337/db13-195430https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfisV2ntw%253D%253D&md5=9379bc211cc092b3547394abbe283288Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer diseaseDe Felice Fernanda G; Ferreira Sergio TDiabetes (2014), 63 (7), 2262-72 ISSN:.A growing body of evidence supports an intriguing clinical/epidemiological connection between Alzheimer disease (AD) and type 2 diabetes (T2D). T2D patients have significantly increased risk of developing AD and vice versa. Recent studies have begun to reveal common pathogenic mechanisms shared by AD and metabolic disorders, notably obesity and T2D. In T2D and obesity, low-grade chronic inflammation is a key mechanism leading to peripheral insulin resistance, which progressively causes tissue deterioration and overall health decline. In the brain, proinflammatory signaling was recently found to mediate impaired neuronal insulin signaling, synapse deterioration, and memory loss. Here, we review evidence indicating that inflammation, insulin resistance, and mitochondrial dysfunction are common features in AD and T2D. We further propose the hypothesis that dementia and its underlying neuronal dysfunction are exacerbated or driven by peripheral inflammation. Identification of central and peripheral inflammation as potential mediators of brain dysfunction in AD may lead to the development of effective treatments for this devastating disease.
- 31Turner, N.; Cooney, G. J.; Kraegen, E. W.; Bruce, C. R. Fatty acid metabolism, energy expenditure and insulin resistance in muscle. J. Endocrinol. 2014, 220, T61– T79, DOI: 10.1530/joe-13-039731https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtlSls7g%253D&md5=6eda9e2cabfa379bb1d159a2058a4decFatty acid metabolism, energy expenditure and insulin resistance in muscleTurner, Nigel; Cooney, Gregory J.; Kraegen, Edward W.; Bruce, Clinton R.Journal of Endocrinology (2014), 220 (2), T61-T79CODEN: JOENAK; ISSN:0022-0795. (BioScientifica Ltd.)A review. Fatty acids (FAs) are essential elements of all cells and have significant roles as energy substrates, components of cellular structure and signaling mols. The storage of excess energy intake as fat in adipose tissue is an evolutionary advantage aimed at protecting against starvation, but in much of today's world, humans are faced with an unlimited availability of food, and the excessive accumulation of fat is now a major risk for human health, esp. the development of type 2 diabetes (T2D). Since the first recognition of the assocn. between fat accumulation, reduced insulin action and increased risk of T2D, several mechanisms have been proposed to link excess FA availability to reduced insulin action, with some of them being competing or contradictory. This review summarizes the evidence for these mechanisms in the context of excess dietary FAs generating insulin resistance in muscle, the major tissue involved in insulin-stimulated disposal of blood glucose. It also outlines potential problems with models and measurements that may hinder as well as help improve our understanding of the links between FAs and insulin action.
- 32Kraegen, E. W.; Clark, P. W.; Jenkins, A. B.; Daley, E. A.; Chisholm, D. J.; Storlien, L. H. Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats. Diabetes 1991, 40, 1397– 1403, DOI: 10.2337/diab.40.11.139732https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XltF2ltQ%253D%253D&md5=23b75219b968712bd6649370d3817d80Development of muscle insulin resistance after liver insulin resistance in high-fat-fed ratsKraegen, Edward W.; Clark, Peter W.; Jenkins, Arthur B.; Daley, Eugene A.; Chisholm, Donald J.; Storlien, Leonard H.Diabetes (1991), 40 (11), 1397-403CODEN: DIAEAZ; ISSN:0012-1797.Progressive changes in the development of high-fat-diet-induced insulin resistance in liver, adipose tissue, and muscle of the adult male Wistar rat were studied. In vivo insulin action was compared 3 days and 3 wk after isocaloric synthetic high-fat or high-starch feeding (59 and 10% cal as fat, resp.). Basal and insulin-stimulated glucose metab. were assessed in the conscious 5- to 7-h fasted state with the euglycemic clamp (600 pM insulin) with a [3-3H]glucose infusion. Fat feeding reduced suppressibility of hepatic glucose output by insulin after both 3 days and 3 wk of diet. However, a significant impairment of insulin-mediated peripheral glucose disposal was only present after 3 wk of diet. Further in vivo [3H]2-deoxyglucose uptake studies supported this finding and demonstrated adipose but not muscle insulin resistance after 3 days of high-fat feeding. Muscle triglyceride accumulation due to fat feeding was not significant at 3 days but had doubled by 3 wk in red muscle compared with starch-fed controls. By 3 wk, high-fat-fed animals had developed significant glucose intolerance. Apparently, fat feeding induces insulin resistance in liver and adipose tissue before skeletal muscle with early metabolic changes favoring an oversupply of energy substrate to skeletal muscle relative to metabolic needs. This may generate later muscle insulin resistance.
- 33Storlien, L. H.; Kraegen, E. W.; Chisholm, D. J.; Ford, G. L.; Bruce, D. G.; Pascoe, W. S. Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science 1987, 237, 885– 888, DOI: 10.1126/science.330333333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s3pt1WitQ%253D%253D&md5=fc2719cd20769d3ff09edb84efeaf0baFish oil prevents insulin resistance induced by high-fat feeding in ratsStorlien L H; Kraegen E W; Chisholm D J; Ford G L; Bruce D G; Pascoe W SScience (New York, N.Y.) (1987), 237 (4817), 885-8 ISSN:0036-8075.Non-insulin-dependent diabetes mellitus is an increasingly prevalent disease in Western and developing societies. A major metabolic abnormality of non-insulin-dependent diabetes is impaired insulin action (insulin resistance). Diets high in fat from vegetable and nonaquatic animal sources (rich in linoleic acid, an omega-6 fatty acid, and saturated fats) lead to insulin resistance. In rats fed high-fat diets, replacement of only 6 percent of the linoleic omega-6 fatty acids from safflower oil with long-chain polyunsaturated omega-3 fatty acids from fish oil prevented the development of insulin resistance. The effect was most pronounced in the liver and skeletal muscle, which have important roles in glucose supply and demand. The results may be important for therapy or prevention of non-insulin-dependent diabetes mellitus.
- 34Ranganathan, S.; Nagaraj, S. H.; Hu, M.; Strube, C.; Schnieder, T.; Gasser, R. B. A transcriptomic analysis of the adult stage of the bovine lungworm, Dictyocaulus viviparus. BMC Genomics 2007, 8, 311, DOI: 10.1186/1471-2164-8-31134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sjjsFehug%253D%253D&md5=11a89a83dd8559e3ea3192e0def2deb4A transcriptomic analysis of the adult stage of the bovine lungworm, Dictyocaulus viviparusRanganathan Shoba; Nagaraj Shivashankar H; Hu Min; Strube Christina; Schnieder Thomas; Gasser Robin BBMC genomics (2007), 8 (), 311 ISSN:.BACKGROUND: Lungworms of the genus Dictyocaulus (family Dictyocaulidae) are parasitic nematodes of major economic importance. They cause pathological effects and clinical disease in various ruminant hosts, particularly in young animals. Dictyocaulus viviparus, called the bovine lungworm, is a major pathogen of cattle, with severe infections being fatal. In this study, we provide first insights into the transcriptome of the adult stage of D. viviparus through the analysis of expressed sequence tags (ESTs). RESULTS: Using our EST analysis pipeline, we estimate that the present dataset of 4436 ESTs is derived from 2258 genes based on cluster and comparative genomic analyses of the ESTs. Of the 2258 representative ESTs, 1159 (51.3%) had homologues in the free-living nematode C. elegans, 1174 (51.9%) in parasitic nematodes, 827 (36.6%) in organisms other than nematodes, and 863 (38%) had no significant match to any sequence in the current databases. Of the C. elegans homologues, 569 had observed 'non-wildtype' RNAi phenotypes, including embryonic lethality, maternal sterility, sterility in progeny, larval arrest and slow growth. We could functionally classify 776 (35%) sequences using the Gene Ontologies (GO) and established pathway associations to 696 (31%) sequences in Kyoto Encyclopedia of Genes and Genomes (KEGG). In addition, we predicted 85 secreted proteins which could represent potential candidates for developing novel anthelmintics or vaccines. CONCLUSION: The bioinformatic analyses of ESTs data for D. viviparus has elucidated sets of relatively conserved and potentially novel genes. The genes discovered in this study should assist research toward a better understanding of the basic molecular biology of D. viviparus, which could lead, in the longer term, to novel intervention strategies. The characterization of the D. viviparus transcriptome also provides a foundation for whole genome sequence analysis and future comparative transcriptomic analyses.
- 35Ahmadian, M.; Suh, J. M.; Hah, N.; Liddle, C.; Atkins, A. R.; Downes, M.; Evans, R. M. PPAR gamma signaling and metabolism: the good, the bad and the future. Nat. Med. 2013, 19, 557– 566, DOI: 10.1038/nm.315935https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntF2kurs%253D&md5=78ee5d0f4ce5dc5192cd010bb7519ce4PPARγ signaling and metabolism: the good, the bad and the futureAhmadian, Maryam; Suh, Jae Myoung; Hah, Nasun; Liddle, Christopher; Atkins, Annette R.; Downes, Michael; Evans, Ronald M.Nature Medicine (New York, NY, United States) (2013), 19 (5), 557-566CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)A review. Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, wt. gain, bone loss, and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARγ-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiol. and therapeutic relevance of the PPARγ pathway also provide opportunities to develop newer classes of mols. that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.
- 36Jeon, S. M. Regulation and function of AMPK in physiology and diseases. Exp. Mol. Med. 2016, 48, e245 DOI: 10.1038/emm.2016.8136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtV2iu7nK&md5=ddcf6d926d097f657c231dec63d89ba0Regulation and function of AMPK in physiology and diseasesJeon, Sang-MinExperimental & Molecular Medicine (2016), 48 (7), e245CODEN: EMMEF3; ISSN:2092-6413. (NPG Nature Asia-Pacific)5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that was originally identified as the key player in maintaining cellular energy homeostasis. Intensive research over the last decade has identified diverse mol. mechanisms and physiol. conditions that regulate the AMPK activity. AMPK regulates diverse metabolic and physiol. processes and is dysregulated in major chronic diseases, such as obesity, inflammation, diabetes and cancer. On the basis of its crit. roles in physiol. and pathol., AMPK is emerging as one of the most promising targets for both the prevention and treatment of these diseases. In this review, we discuss the current understanding of the mol. and physiol. regulation of AMPK and its metabolic and physiol. functions. In addn., we discuss the mechanisms underlying the versatile roles of AMPK in diabetes and cancer.
- 37Gupta, D.; Jetton, T. L.; Mortensen, R. M.; Duan, S. Z.; Peshavaria, M.; Leahy, J. L. In vivo and in vitro studies of a functional peroxisome proliferator-activated receptor gamma response element in the mouse pdx-1 promoter. J. Biol. Chem. 2008, 283, 32462– 32470, DOI: 10.1074/jbc.m80181320037https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlOjtL3O&md5=9acd245573710b479d27340bd653f814In Vivo and in Vitro Studies of a Functional Peroxisome Proliferator-activated Receptor γ Response Element in the Mouse pdx-1 PromoterGupta, Dhananjay; Jetton, Thomas L.; Mortensen, Richard M.; Duan, Sheng Zhong; Peshavaria, Mina; Leahy, Jack L.Journal of Biological Chemistry (2008), 283 (47), 32462-32470CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The authors reported that peroxisome proliferator-activated receptor γ (PPARγ) transcriptionally regulates the β-cell differentiation factor pancreatic duodenal homeobox (PDX)-1 based on in vitro RNA interference studies. The authors have now studied mice depleted of PPARγ within the pancreas (PANC PPARγ-/-) created by a Cre/loxP recombinase system, with Cre driven by the pdx-1 promoter. Male PANC PPARγ-/- mice were hyperglycemic at 8 wk of age (8.1 ± 0.2 mM vs. 6.4 ± 0.3 mM, p = 0.009) with islet cytoarchitecture and pancreatic mass of islet β-cells that were indistinguishable from the controls. Islet PDX-1 mRNA (p = 0.001) and protein levels (p = 0.003) were lowered 60 and 40%, resp., in tandem with impaired glucose-induced insulin secretion and loss of thiazolidinedione-induced increase in PDX-1 expression. The authors next identified a putative PPAR-response element (PPRE) in the mouse pdx-1 promoter with substantial homol. to the corresponding region of the human PDX-1 promoter. Electrophoretic mobility supershift assays with nuclear exts. from β-cell lines and mouse islets, also in vitro translated PPARγ and retinoid X receptor, and chromatin immunopptn. anal. demonstrated specific binding of PPARγ and retinoid X receptor to the human and mouse pdx-1 x PPREs. Transient transfection assays of β-cells with reporter constructs of mutated PPREs showed dramatically reduced pdx-1 promoter activity. In summary, the authors have presented in vivo and in vitro evidence showing PPARγ regulation of pdx-1 transcription in β-cells, plus these results support an important regulatory role for PPARγ in β-cell physiol. and thiazolidinedione pharmacol. of type 2 diabetes.
- 38Tremblay, K.; Methot, J.; Brisson, D.; Gaudet, D. Etiology and risk of lactescent plasma and severe hypertriglyceridemia. J. Clin. Lipidol. 2011, 5, 37– 44, DOI: 10.1016/j.jacl.2010.11.00438https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M7ktVCnsw%253D%253D&md5=68eb67a0d4ce32502d0a8896fabdb40cEtiology and risk of lactescent plasma and severe hypertriglyceridemiaTremblay Karine; Methot Julie; Brisson Diane; Gaudet DanielJournal of clinical lipidology (2011), 5 (1), 37-44 ISSN:1933-2874.BACKGROUND: Plasma lactescence is a clinical sign of severe hypertriglyceridemia (hyperTG; TG >10 mmol/L), which is likely to be observed more frequently in the next decades because of the growing prevalence of obesity and diabetes worldwide. OBJECTIVE: The objective of this study was to describe the clinical expression of plasma lactescence. METHODS: A total of 354 subjects with lactescent plasma hyperTG (mean TG ± SD: 17.1 ± 1.8 mmol/L) were classified according to blood appearance, etiology, and biochemical characteristics. The resulting phenotypes were compared with those of 364 normolipidemic controls (TG ≤2 mmol/L) and 487 clear plasma hyperTG subjects (5 < TG ≤9 mmol/L). The association of lactescent plasma with clinical covariates (obesity, coronary artery disease, peripheral artery disease, hypertension, diabetes, glucose intolerance, pancreatitis, and response to TG-lowering drugs) was performed by the use of multiple regression models. RESULTS: The risk of pancreatitis increased as a function of the plasma creamy white collar and was the greatest among nonobese individuals with early-onset lactescence not responding to current TG-lowering drugs (familial hyperchylomicronemia). Patients with lactescent plasma and yellowish palmar xanthomas (dysbetalipoproteinemia) responded significantly better to fibrates than the other severe hyperTG phenotypes but were at greater risk of peripheral atherosclerosis. Overweight and obese patients with a creamy supernatant and a cloudy, cream of tomato, infranatant caused by hyper apolipoprotein B showed the most deleterious cardiometabolic risk profile, followed by the severe hyperTG-normal apolipoprotein B phenotype, the most frequent cause of lactescent plasma. CONCLUSION: Lactescent plasma hyperTG represents a clinically heterogeneous group of high-risk patients.
- 39Zhou, Q.; Melton, D. A. Pancreas regeneration. Nature 2018, 557, 351– 358, DOI: 10.1038/s41586-018-0088-039https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVSgurs%253D&md5=c3a510413f8d81a778110c18dc290eafPancreas regenerationZhou, Qiao; Melton, Douglas A.Nature (London, United Kingdom) (2018), 557 (7705), 351-358CODEN: NATUAS; ISSN:0028-0836. (Nature Research)A review. The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.
- 40Yang, J. PPAR-gamma silencing inhibits the apoptosis of A549 cells by upregulating Bcl-2. Zhongguo Feiai Zazhi 2013, 16, 125– 130, DOI: 10.3779/j.issn.1009-3419.2013.03.0240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitVSitrrK&md5=629be0071984ed064d0ef64b52bf9d4fRole of PPAR-γ silencing in inhibiting the apoptosis of A549 cells by upregulating the expression of Bcl-2Yang, JingyuZhongguo Feiai Zazhi (2013), 16 (3), 125-130CODEN: ZFZHAG; ISSN:1009-3419. (Zhongguo Feiai Zazhi Bianji Weiyuanhui)Drug resistance is one of primary causes of death in patients with lung cancer, and PPAR-γ could induce the apoptosis and reverse drug resistance. The aim of this study is to investigate the influence of down-regulated expression of PPAR-γ on cisplatin sensitivity and apoptosis response of human lung cancer cell line A549. SiRNA silencing of PPAR-γ in A549 cells (A549/PPAR-γ(-)) is constructed. MTT assay was used to det. the effect of cisplatin on the proliferation of A549/PPAR-γ(-), flow cytometry was used to det. the effect of cisplatin on the cell apoptosis, and Western blot was used to det. the change of phosphorylation of Akt, caspase-3 and expression of bcl-2/bax. Finally, RT-PCR was used to det. the transcriptional level of bcl-2. Two PPAR-γ silencing A549 cell clones were established successfully, and the expression of PPAR-γ was downregulated significantly, which was confirmed by RT-PCR and Western blot. After PPAR-γ silencing, the resistance of these two A549 cell clones to cisplatin was increased by 1.29 times and 1.60 times resp. Flow cytometry showed that the apoptosis rate was decreased, and Western Blot showed that the phosphorylation of Akt and expression of bcl-2/bax were upregulated, and caspase-3 was downregulated. Finally, RT-PCR showed that the transcriptional level of bcl-2 was upregulated as well. Downregulation of PPAR-γ in A549 cells led to the increase of cisplatin resistance. One of the mechanisms was upregulation of phosphorylation of Akt and expression of bcl-2, which inhibited the apoptosis of cells. The downregulation of PPAR-γ is a possible mechanism that leads to the clin. drug resistance of cancer.
- 41Liu, J.; Lang, G.; Shi, J. Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus. Diabetes, Metab. Syndr. Obes.: Targets Ther. 2021, 14, 431– 442, DOI: 10.2147/dmso.s29193241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3snitVCksw%253D%253D&md5=8e3bea314909291371f98cf5510b4ceeEpigenetic Regulation of PDX-1 in Type 2 Diabetes MellitusLiu Jiangman; Lang Guangping; Shi JingshanDiabetes, metabolic syndrome and obesity : targets and therapy (2021), 14 (), 431-442 ISSN:1178-7007.Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia which is caused by insufficient insulin secretion or insulin resistance. Interaction of genetic, epigenetic and environmental factors plays a significant role in the development of T2DM. Several environmental factors including diet and lifestyle, as well as age have been associated with an increased risk for T2DM. It has been demonstrated that these environmental factors may affect global epigenetic status, and alter the expression of susceptible genes, thereby contributing to the pathogenesis of T2DM. In recent years, a growing body of molecular and genetic studies in diabetes have been focused on the ways to restore the numbers or function of β-cells in order to reverse a range of metabolic consequences of insulin deficiency. The pancreatic duodenal homeobox 1 (PDX-1) is a transcriptional factor that is essential for the development and function of islet cells. A number of studies have shown that there is a significant increase in the level of DNA methylation of PDX-1 resulting in reduced activity in T2DM islets. The decrease in PDX-1 activity may be a critical mediator causing dysregulation of pancreatic β cells in T2DM. This article reviews the epigenetic mechanisms of PDX-1 involved in T2DM, focusing on diabetes and DNA methylation, and discusses some potential strategies for the application of PDX-1 in the treatment of diabetes.
- 42Wang, C.; Li, J.; Lv, X.; Zhang, M.; Song, Y.; Chen, L.; Liu, Y. Ameliorative effect of berberine on endothelial dysfunction in diabetic rats induced by high-fat diet and streptozotocin. Eur. J. Pharmacol. 2009, 620, 131– 137, DOI: 10.1016/j.ejphar.2009.07.02742https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFGlt73M&md5=67ecb615f94e7f22dbed9a658076a030Ameliorative effect of berberine on endothelial dysfunction in diabetic rats induced by high-fat diet and streptozotocinWang, Chunmei; Li, Jing; Lv, Xiaoyan; Zhang, Ming; Song, Yanfang; Chen, Li; Liu, YanjunEuropean Journal of Pharmacology (2009), 620 (1-3), 131-137CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Berberine can improve insulin resistance, lower blood glucose, and regulate lipid metab. disorders which cause endothelial dysfunction, leading to vascular complications of type 2 diabetes mellitus. The aim of the present study was to investigate the effects of berberine on endothelial dysfunction of aortas in type 2 diabetes mellitus rats and its mechanism. Wistar rats were randomly divided into four groups: diabetic rats, control rats, diabetic rats treated with berberine (100 mg/kg), and control rats treated with berberine. The serum fasting blood glucose, insulin, total cholesterol, triglyceride and nitric oxide (NO) levels were tested. Acetylcholine-induced endothelium-dependent relaxation and sodium nitroprusside induced endothelium-independent relaxation were measured in aortas for estg. endothelial function. The expression of endothelial nitric oxide synthase (eNOS) mRNA was measured by RT-PCR, and the protein expressions of eNOS and NADPH oxidase (NOX4) were analyzed by western blot. The results showed that berberine significantly decreased fasting blood glucose, and triglyceride levels in diabetic rats. Berberine also improved endothelium-dependent vasorelaxation impaired in aorta. The expressions of eNOS mRNA and protein were significantly increased, while NOX4 protein expression was decreased in aortas from diabetic rats with berberine treatment. Moreover, serum NO levels were elevated after berberine treatment. In conclusion, berberine restores diabetic endothelial dysfunction through enhanced NO bioavailability by up-regulating eNOS expression and down-regulating expression of NADPH oxidase.
- 43Moreira-Teixeira, L.; Tabone, O.; Graham, C. M.; Singhania, A.; Stavropoulos, E.; Redford, P. S.; Chakravarty, P.; Priestnall, S. L.; Suarez-Bonnet, A.; Herbert, E.; Mayer-Barber, K. D.; Sher, A.; Fonseca, K. L.; Sousa, J.; Ca, B.; Verma, R.; Haldar, P.; Saraiva, M.; O’Garra, A. Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis. Nat. Immunol. 2020, 21, 464– 476, DOI: 10.1038/s41590-020-0610-z43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXltVSisbg%253D&md5=3831f9159c28491baede1c8501d733d9Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosisMoreira-Teixeira, Lucia; Tabone, Olivier; Graham, Christine M.; Singhania, Akul; Stavropoulos, Evangelos; Redford, Paul S.; Chakravarty, Probir; Priestnall, Simon L.; Suarez-Bonnet, Alejandro; Herbert, Eleanor; Mayer-Barber, Katrin D.; Sher, Alan; Fonseca, Kaori L.; Sousa, Jeremy; Ca, Baltazar; Verma, Raman; Haldar, Pranabashis; Saraiva, Margarida; O'Garra, AnneNature Immunology (2020), 21 (4), 464-476CODEN: NIAMCZ; ISSN:1529-2908. (Nature Research)Abstr.: Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human tuberculosis (TB) resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clin. isolate of M. tuberculosis resembles that of active human TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addn., resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.
- 44Lee, J. H.; Kwak, H. J.; Shin, D.; Seo, H. J.; Park, S. J.; Hong, B. H.; Shin, M. S.; Kim, S. H.; Kang, K. S. Mitigation of Gastric Damage Using Cinnamomum cassia Extract: Network Pharmacological Analysis of Active Compounds and Protection Effects in Rats. Plants 2022, 11, 716, DOI: 10.3390/plants1106071644https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhtVShsLnO&md5=35e5d6b5d76d86fc21790c9f2d031383Mitigation of Gastric Damage Using Cinnamomum cassia Extract: Network Pharmacological Analysis of Active Compounds and Protection Effects in RatsLee, Ji Hwan; Kwak, Hee Jae; Shin, Dongchul; Seo, Hye Jin; Park, Shin Jung; Hong, Bo-Hee; Shin, Myoung-Sook; Kim, Seung Hyun; Kang, Ki SungPlants (2022), 11 (6), 716CODEN: PLANCD; ISSN:2223-7747. (MDPI AG)Gastritis is a common disease worldwide that is caused by various causes such as eating habits, smoking, severe stress, and heavy drinking, as well as Helicobacter pylori infections and non-steroidal anti-inflammatory drugs. Cinnamomum cassia is a tropical arom. evergreen tree commonly used as a natural medicine in Asia and as a functional food ingredient. Studies have reported this species' anti-obesity, anti-diabetic, and cardiovascular disease suppression effects. We evaluated the potential effects of C. cassia using non-steroidal anti-inflammatory drugs (NSAIDs), ethanol (EtOH), and ethanol/hydrochloric acid (HCl)-induced gastric mucosal injury models. C. cassia exts. reduced the area of gastric mucosa injury caused by indomethacin, NSAID, EtOH, and EtOH/HCl. We also applied a network pharmacol.-based approach to identify the active compds., potential targets, and pharmacol. mechanisms of C. cassia against gastritis. Through a network pharmacol. anal., 10 key components were predicted as anti-gastritis effect-related compds. of C. cassia among 51 expected active compds. The NF-κB signaling pathway, a widely known inflammatory response mechanism, comprised a major signaling pathway within the network pharmacol. anal. These results suggest that the anti-gastritis activities of C. cassia may be induced via the anti-inflammatory effects of key components, which suppress the inflammation-related genes and signaling pathways identified in this study.
- 45Pintana, H.; Lietzau, G.; Augestad, I. L.; Chiazza, F.; Nystrom, T.; Patrone, C.; Darsalia, V. Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons. Clin. Sci. 2019, 133, 1367– 1386, DOI: 10.1042/cs2019018045https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVOlu7%252FI&md5=ebb4faa5a3a198bf68c29a5a6ba2d7c0Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneuronsPintana, Hiranya; Lietzau, Grazyna; Augestad, Ingrid Lovise; Chiazza, Fausto; Nystrom, Thomas; Patrone, Cesare; Darsalia, VladimerClinical Science (2019), 133 (13), 1367-1386CODEN: CSCIAE; ISSN:1470-8736. (Portland Press Ltd.)Type 2 diabetes (T2D) hampers stroke recovery though largely undetd. mechanisms. Few preclin. studies have investigated the effect of genetic/toxin-induced diabetes on long-term stroke recovery. However, the effects of obesity-induced T2D are mostly unknown. We aimed to investigate whether obesity-induced T2D worsens long-term stroke recovery through the impairment of brain's self-repair mechanisms - stroke-induced neurogenesis and parvalbumin (PV)+ interneurons-mediated neuroplasticity. To mimic obesity-induced T2D in the middle-age, C57bl/6j mice were fed 12 mo with high-fat diet (HFD) and subjected to transient middle cerebral artery occlusion (tMCAO). We evaluated neurol. recovery by upper-limb grip strength at 1 and 6 wk after tMCAO. Gray and white matter damage, stroke-induced neurogenesis, and survival and potential atrophy of PV-interneurons were quantitated by immunohistochem. (IHC) at 2 and 6 wk after tMCAO. Obesity/T2D impaired neurol. function without exacerbating brain damage. Moreover, obesity/T2D diminished stroke-induced neural stem cell (NSC) proliferation and neuroblast formation in striatum and hippocampus at 2 wk after tMCAO and abolished stroke-induced neurogenesis in hippocampus at 6 wk. Finally, stroke resulted in the atrophy of surviving PV-interneurons 2 wk after stroke in both non-diabetic and obese/T2D mice. However, after 6 wk, this effect selectively persisted in obese/T2D mice. We show in a preclin. setting of clin. relevance that obesity/T2D impairs neurol. functions in the stroke recovery phase in correlation with reduced neurogenesis and persistent atrophy of PV-interneurons, suggesting impaired neuroplasticity. These findings shed light on the mechanisms behind impaired stroke recovery in T2D and could facilitate the development of new stroke rehabilitative strategies for obese/T2D patients.
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