Movatterモバイル変換

Abstract

Background: Diabetic cardiotoxicity is commonly associated with oxidative injury, inflammation,and endothelial dysfunction. L-ergothioneine (L-egt), a diet-derived amino acid, hasbeen reported to decrease mortality and risk of cardiovascular injury, provides cytoprotection to tissuesexposed to oxidative damage, and prevents diabetes-induced perturbation.

Objective: This study investigated the cardioprotective effects of L-egt on diabetes-induced cardiovascularinjuries and its probable mechanism of action.

Methods: Twenty-four male Sprague-Dawley rats were divided into non-diabetic (n = 6) and diabeticgroups (n = 18). Six weeks after the induction of diabetes, the diabetic rats were divided intothree groups (n = 6) and administered distilled water, L-egt (35mg/kg), and losartan (20mg/kg) byoral gavage for six weeks. Blood glucose and mean arterial pressure (MAP) were recorded pre-andpost-treatment, while biochemical, ELISA, and RT-qPCR analyses were conducted to determine inflammatory,injury-related and antioxidant biomarkers in cardiac tissue after euthanasia. Also, anin-silico study, including docking and molecular dynamic simulations of L-egt toward the Keap1-Nrf2 protein complex, was done to provide a basis for the molecular antioxidant mechanism of Legt.

Results: Administration of L-egt to diabetic animals reduced serum triglyceride, water intake,MAP, biomarkers of cardiac injury (CK-MB, CRP), lipid peroxidation, and inflammation. Also, Legtincreased body weight, antioxidant enzymes, upregulated Nrf2, HO-1, NQO1 expression, anddecreased Keap1 expression. The in-silico study showed that L-egt inhibits the Keap1-Nrf2 complexby binding to the active site of Nrf2 protein, thereby preventing its degradation.

Conclusion: L-egt protects against diabetes-induced cardiovascular injury via the upregulation ofthe Keap1-Nrf2 pathway and its downstream cytoprotective antioxidants.

Keywords:Cardio-protection, diabetes, L-ergothioneine, molecular docking, molecular dynamics, cardiovascular disease (CVD).

« Previous Next »

Graphical Abstract

[1]

Faselis, C.; Katsimardou, A.; Imprialos, K.; Deligkaris, P.; Kallistratos, M.; Dimitriadis, K. Microvascular complications of type 2 diabetes mellitus.Curr. Vasc. Pharmacol.,2020,18(2), 117-124.
[http://dx.doi.org/10.2174/1570161117666190502103733] [PMID:31057114]

[2]

Viigimaa, M.; Sachinidis, A.; Toumpourleka, M.; Koutsampasopoulos, K.; Alliksoo, S.; Titma, T. Macrovascular complications of type 2 diabetes mellitus.Curr. Vasc. Pharmacol.,2020,18(2), 110-116.
[http://dx.doi.org/10.2174/1570161117666190405165151] [PMID:30961498]

[3]

Jia, G.; Hill, M.A.; Sowers, J.R. Diabetic Cardiomyopathy.Circ. Res.,2018,122(4), 624-638.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.311586] [PMID:29449364]

[4]

Mc Namara, K.; Alzubaidi, H.; Jackson, J.K. Cardiovascular disease as a leading cause of death: how are pharmacists getting involved?Integr. Pharm. Res. Pract.,2019,8, 1-11.
[http://dx.doi.org/10.2147/IPRP.S133088] [PMID:30788283]

[5]

Einarson, T.R.; Acs, A.; Ludwig, C.; Panton, U.H. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017.Cardiovasc. Diabetol.,2018,17(1), 83.
[http://dx.doi.org/10.1186/s12933-018-0728-6] [PMID:29884191]

[6]

Schmidt, A.M. Diabetes mellitus and cardiovascular disease.Arterioscler. Thromb. Vasc. Biol.,2019,39(4), 558-568.
[http://dx.doi.org/10.1161/ATVBAHA.119.310961] [PMID:30786741]

[7]

Aronson, D.; Edelman, E.R. Coronary artery disease and diabetes mellitus.Cardiol. Clin.,2014,32(3), 439-455.
[http://dx.doi.org/10.1016/j.ccl.2014.04.001] [PMID:25091969]

[8]

Rodriguez-Araujo, G.; Nakagami, H. Pathophysiology of cardiovascular disease in diabetes mellitus.Cardiovasc. Endocrinol. Metab.,2018,7(1), 4-9.
[http://dx.doi.org/10.1097/XCE.0000000000000141] [PMID:31646271]

[9]

Yan, B.; Ren, J.; Zhang, Q.; Gao, R.; Zhao, F.; Wu, J.; Yang, J. Antioxidative effects of natural products on diabetic cardiomyopathy.J. Diabetes Res.,2017,2017, 2070178.
[http://dx.doi.org/10.1155/2017/2070178] [PMID:29181412]

[10]

Hill, M.F. Emerging role for antioxidant therapy in protection against diabetic cardiac complications: experimental and clinical evidence for utilization of classic and new antioxidants.Curr. Cardiol. Rev.,2008,4(4), 259-268.
[http://dx.doi.org/10.2174/157340308786349453] [PMID:20066133]

[11]

Adelusi, T.I.; Du, L.; Hao, M.; Zhou, X.; Xuan, Q.; Apu, C.; Sun, Y.; Lu, Q.; Yin, X. Keap1/Nrf2/ARE signaling unfolds therapeutic targets for redox imbalanced-mediated diseases and diabetic nephropathy.Biomed. Pharmacother.,2020,123, 109732.
[http://dx.doi.org/10.1016/j.biopha.2019.109732] [PMID:31945695]

[12]

Jiang, Z.; Fu, L.; Xu, Y.; Hu, X.; Yang, H.; Zhang, Y.; Luo, H.; Gan, S.; Tao, L.; Liang, G.; Shen, X. Cyclovirobuxine D protects against diabetic cardiomyopathy by activating Nrf2-mediated antioxidant responses.Sci. Rep.,2020,10(1), 6427.
[http://dx.doi.org/10.1038/s41598-020-63498-3] [PMID:32286474]

[13]

Ying, Y.; Jin, J.; Ye, L.; Sun, P.; Wang, H.; Wang, X. Phloretin prevents diabetic cardiomyopathy by dissociating keap1/nrf2 complex and inhibiting oxidative stress.Front. Endocrinol. (Lausanne),2018,9(774), 774.
[http://dx.doi.org/10.3389/fendo.2018.00774] [PMID:30619098]

[14]

David, J.A.; Rifkin, W.J.; Rabbani, P.S.; Ceradini, D.J. The Nrf2/Keap1/ARE pathway and oxidative stress as a therapeutic target in type II diabetes mellitus.J. Diabetes Res.,2017,2017, 4826724.
[http://dx.doi.org/10.1155/2017/4826724] [PMID:28913364]

[15]

Li, B.; Liu, S.; Miao, L.; Cai, L. Prevention of diabetic complications by activation of Nrf2: diabetic cardiomyopathy and nephropathy.Exp. Diabetes Res.,2012,2012, 216512.
[http://dx.doi.org/10.1155/2012/216512] [PMID:22645602]

[16]

Tkachev, V.O.; Menshchikova, E.B.; Zenkov, N.K. Mechanism of the Nrf2/Keap1/ARE signaling system.Biochemistry (Mosc.),2011,76(4), 407-422.
[http://dx.doi.org/10.1134/S0006297911040031] [PMID:21585316]

[17]

Turck, D.; Bresson, J-L.; Burlingame, B.; Dean, T.; Fairweather- Tait, S.; Heinonen, M.; Hirsch-Ernst, K.I.; Mangelsdorf, I.; McArdle, H.J.; Naska, A.; Neuhäuser-Berthold, M.; Nowicka, G.; Pentieva, K.; Sanz, Y.; Siani, A.; Sjödin, A.; Stern, M.; Tomé, D.; Vinceti, M.; Willatts, P.; Engel, K.H.; Marchelli, R.; Pöting, A.; Poulsen, M.; Schlatter, J.R.; Ackerl, R.; van Loveren, H. Statement on the safety of synthetic l-ergothioneine as a novel food - supplementary dietary exposure and safety assessment for infants and young children, pregnant and breastfeeding women.EFSA J.,2017,15(11), e05060.
[PMID:32625352]

[18]

Ey, J.; Schömig, E.; Taubert, D. Dietary sources and antioxidant effects of ergothioneine.J. Agric. Food Chem.,2007,55(16), 6466-6474.
[http://dx.doi.org/10.1021/jf071328f] [PMID:17616140]

[19]

Williamson, R.D.; McCarthy, F.P.; Manna, S.; Groarke, E.; Kell, D.B.; Kenny, L.C.; McCarthy, C.M. L-(+)-Ergothioneine significantly improves the clinical characteristics of preeclampsia in the reduced uterine perfusion pressure rat model.Hypertension,2020,75(2), 561-568.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13929] [PMID:31865793]

[20]

Feng, L.; Cheah, I.K.; Ng, M.M.; Li, J.; Chan, S.M.; Lim, S.L.; Mahendran, R.; Kua, E.H.; Halliwell, B. The association between mushroom consumption and mild cognitive impairment: a community-based cross-sectional study in singapore.J. Alzheimers Dis.,2019,68(1), 197-203.
[http://dx.doi.org/10.3233/JAD-180959] [PMID:30775990]

[21]

Guijarro, M.V.; Indart, A.; Aruoma, O.I.; viana, M.; Bonet, B. Effects of ergothioneine on diabetic embryopathy in pregnant rats.Food Chem. Toxicol.,2002,40(12), 1751-1755.
[http://dx.doi.org/10.1016/S0278-6915(02)00177-1] [PMID:12419688]

[22]

D’Onofrio, N.; Servillo, L.; Giovane, A.; Casale, R.; Vitiello, M.; Marfella, R.; Paolisso, G.; Balestrieri, M.L. Ergothioneine oxidation in the protection against high-glucose induced endothelial senescence: Involvement of SIRT1 and SIRT6.Free Radic. Biol. Med.,2016,96, 211-222.
[http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.013] [PMID:27101740]

[23]

Martin, K.R. The bioactive agent ergothioneine, a key component of dietary mushrooms, inhibits monocyte binding to endothelial cells characteristic of early cardiovascular disease.J. Med. Food,2010,13(6), 1340-1346.
[http://dx.doi.org/10.1089/jmf.2009.0194] [PMID:21091247]

[24]

Sakrak, O.; Kerem, M.; Bedirli, A.; Pasaoglu, H.; Akyurek, N.; Ofluoglu, E.; Gültekin, F.A. Ergothioneine modulates proinflammatory cytokines and heat shock protein 70 in mesenteric ischemia and reperfusion injury.J. Surg. Res.,2008,144(1), 36-42.
[http://dx.doi.org/10.1016/j.jss.2007.04.020] [PMID:17603080]

[25]

Gokce, G.; Arun, M.Z. Ergothioneine produces relaxation in isolated rat aorta by inactivating superoxide anion.Eur. Rev. Med. Pharmacol. Sci.,2014,18(21), 3339-3345.
[PMID:25487948]

[26]

Li, R.W.; Yang, C.; Sit, A.S.; Kwan, Y.W.; Lee, S.M.; Hoi, M.P.; Chan, S.W.; Hausman, M.; Vanhoutte, P.M.; Leung, G.P. Uptake and protective effects of ergothioneine in human endothelial cells.J. Pharmacol. Exp. Ther.,2014,350(3), 691-700.
[http://dx.doi.org/10.1124/jpet.114.214049] [PMID:25022513]

[27]

Smith, E.; Ottosson, F.; Hellstrand, S.; Ericson, U.; Orho-Melander, M.; Fernandez, C.; Melander, O. Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease.Heart,2020,106(9), 691-697.
[http://dx.doi.org/10.1136/heartjnl-2019-315485] [PMID:31672783]

[28]

Wilson, R.D.; Islam, M.S. Fructose-fed streptozotocin-injected rat: an alternative model for type 2 diabetes.Pharmacol. Rep.,2012,64(1), 129-139.
[http://dx.doi.org/10.1016/S1734-1140(12)70739-9] [PMID:22580529]

[29]

Srinivasan, K.; Viswanad, B.; Asrat, L.; Kaul, C.L.; Ramarao, P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening.Pharmacol. Res.,2005,52(4), 313-320.
[http://dx.doi.org/10.1016/j.phrs.2005.05.004] [PMID:15979893]

[30]

Tang, R.M.Y.; Cheah, I.K-M.; Yew, T.S.K.; Halliwell, B. Distribution and accumulation of dietary ergothioneine and its metabolites in mouse tissues.Sci. Rep.,2018,8(1), 1601.
[http://dx.doi.org/10.1038/s41598-018-20021-z] [PMID:29371632]

[31]

Koszegi, S.; Molnar, A.; Lenart, L.; Hodrea, J.; Balogh, D.B.; Lakat, T.; Szkibinszkij, E.; Hosszu, A.; Sparding, N.; Genovese, F.; Wagner, L.; Vannay, A.; Szabo, A.J.; Fekete, A. RAAS inhibitors directly reduce diabetes-induced renal fibrosisvia growth factor inhibition.J. Physiol.,2019,597(1), 193-209.
[http://dx.doi.org/10.1113/JP277002] [PMID:30324679]

[32]

Lodovici, M.; Bigagli, E.; Tarantini, F.; Di Serio, C.; Raimondi, L. Losartan reduces oxidative damage to renal DNA and conserves plasma antioxidant capacity in diabetic rats.Exp. Biol. Med. (Maywood),2015,240(11), 1500-1504.
[http://dx.doi.org/10.1177/1535370215570826] [PMID:25710927]

[33]

Ellman, G.L. Tissue sulfhydryl groups.Arch. Biochem. Biophys.,1959,82(1), 70-77.
[http://dx.doi.org/10.1016/0003-9861(59)90090-6] [PMID:13650640]

[34]

Marklund, S. Pyrogallol auto-oxidation. In: Greenwald R, editor. Handbook of methods for oxygen radical research. Boca Raton, FL: CRC Press;198. pp. 243-7.

[35]

Aebi, H. Catalasein vitro.Methods Enzymol.,1984,105, 121-126.
[http://dx.doi.org/10.1016/S0076-6879(84)05016-3] [PMID:6727660]

[36]

Madlala, HP; Van Heerden, FR; Mubagwa, K; Musabayane, CT Changes in renal function and oxidative status associated with the hypotensive effects of oleanolic acid and related synthetic derivatives in experimental animals.PloS one,2015,10(6), e0128192.
[http://dx.doi.org/10.1371/journal.pone.0128192]

[37]

Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.Methods,2001,25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID:11846609]

[38]

Jnoff, E.; Albrecht, C.; Barker, J.J.; Barker, O.; Beaumont, E.; Bromidge, S.; Brookfield, F.; Brooks, M.; Bubert, C.; Ceska, T.; Corden, V.; Dawson, G.; Duclos, S.; Fryatt, T.; Genicot, C.; Jigorel, E.; Kwong, J.; Maghames, R.; Mushi, I.; Pike, R.; Sands, Z.A.; Smith, M.A.; Stimson, C.C.; Courade, J.P. Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex.ChemMedChem,2014,9(4), 699-705.
[http://dx.doi.org/10.1002/cmdc.201300525] [PMID:24504667]

[39]

Webb, B.; Sali, A. Protein structure modeling with MODELLER.Methods Mol. Biol.,2014,1137, 1-15.
[http://dx.doi.org/10.1007/978-1-4939-0366-5_1] [PMID:24573470]

[40]

Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera-a visualization system for exploratory research and analysis.J. Comput. Chem.,2004,25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID:15264254]

[41]

Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.J. Comput. Chem.,2010,31(2), 455-461.
[PMID:19499576]

[42]

Mittal, R.R.; Harris, L.; McKinnon, R.A.; Sorich, M.J. Partial charge calculation method affects CoMFA QSAR prediction accuracy.J. Chem. Inf. Model.,2009,49(3), 704-709.
[http://dx.doi.org/10.1021/ci800390m] [PMID:19239274]

[43]

Sanner, M.F. The Python interpreter as a framework for integrating scientific computing software-components.Scripps. Res. Inst.,2008,26(1), 1-12.

[44]

Hospital, A.; Goñi, J.R.; Orozco, M.; Gelpí, J.L. Molecular dynamics simulations: advances and applications.Adv. Appl. Bioinform. Chem.,2015,8, 37-47.
[PMID:26604800]

[45]

Lee, T-S.; Cerutti, D.S.; Mermelstein, D.; Lin, C.; LeGrand, S.; Giese, T.J.; Roitberg, A.; Case, D.A.; Walker, R.C.; York, D.M. GPU-accelerated molecular dynamics and free energy methods in Amber18: performance enhancements and new features.J. Chem. Inf. Model.,2018,58(10), 2043-2050.
[http://dx.doi.org/10.1021/acs.jcim.8b00462] [PMID:30199633]

[46]

Wang, J.; Wang, W.; Kollman, P.A.; Case, D.A. Automatic atom type and bond type perception in molecular mechanical calculations.J. Mol. Graph. Model.,2006,25(2), 247-260.
[http://dx.doi.org/10.1016/j.jmgm.2005.12.005] [PMID:16458552]

[47]

Berendsen, H.J. Postma Jv, van Gunsteren WF, DiNola A, Haak J. Molecular dynamics with coupling to an external bath.J. Chem. Phys.,1984,81(8), 3684-3690.
[http://dx.doi.org/10.1063/1.448118]

[48]

Roe, D.R.; Cheatham, T.E., III PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data.J. Chem. Theory Comput.,2013,9(7), 3084-3095.
[http://dx.doi.org/10.1021/ct400341p] [PMID:26583988]

[49]

Seifert, E. OriginPro 9.1: scientific data analysis and graphing software-software review.J. Chem. Inf. Model.,2014,54(5), 1552.
[http://dx.doi.org/10.1021/ci500161d] [PMID:24702057]

[50]

Genheden, S.; Ryde, U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities.Expert Opin. Drug Discov.,2015,10(5), 449-461.
[http://dx.doi.org/10.1517/17460441.2015.1032936] [PMID:25835573]

[51]

Drissi, M.; Benhalima, N.; Megrouss, Y.; Rachida, R.; Chouaih, A.; Hamzaoui, F. Theoretical and experimental electrostatic potential around the m-nitrophenol molecule.Molecules,2015,20(3), 4042-4054.
[http://dx.doi.org/10.3390/molecules20034042] [PMID:25741898]

[52]

Hayes, JM; Archontis, G. SA calculations of protein-ligand binding free energies.Molecular Dynamics-Studies of Synthetic and Biological Macromolecules. Wang L. Ed.; IntechOpen. Carbondale.2012; pp. 8285.,

[53]

Hou, T.; Wang, J.; Li, Y.; Wang, W. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations.J. Chem. Inf. Model.,2011,51(1), 69-82.
[http://dx.doi.org/10.1021/ci100275a] [PMID:21117705]

[54]

Sitkoff, D.; Sharp, K.A.; Honig, B. Accurate calculation of hydration free energies using macroscopic solvent models.J. Phys. Chem.,1994,98(7), 1978-1988.
[http://dx.doi.org/10.1021/j100058a043]

[55]

Machaba, K.E.; Mhlongo, N.N.; Soliman, M.E.S. Induced mutation proves a potential target for TB therapy: A molecular dynamics study on LprG.Cell Biochem. Biophys.,2018,76(3), 345-356.
[http://dx.doi.org/10.1007/s12013-018-0852-7] [PMID:30073572]

[56]

Melville, D.B.; Horner, W.H.; Lubschez, R. Tissue ergothioneine.J. Biol. Chem.,1954,206(1), 221-228.
[http://dx.doi.org/10.1016/S0021-9258(18)71313-6] [PMID:13130544]

[57]

Cheah, I.K.; Tang, R.; Ye, P.; Yew, T.S.; Lim, K.H.; Halliwell, B. Liver ergothioneine accumulation in a guinea pig model of non-alcoholic fatty liver disease. A possible mechanism of defence?Free Radic. Res.,2016,50(1), 14-25.
[http://dx.doi.org/10.3109/10715762.2015.1099642] [PMID:26634964]

[58]

Halliwell, B.; Cheah, I.K.; Drum, C.L. Ergothioneine, an adaptive antioxidant for the protection of injured tissues? A hypothesis.Biochem. Biophys. Res. Commun.,2016,470(2), 245-250.
[http://dx.doi.org/10.1016/j.bbrc.2015.12.124] [PMID:26772879]

[59]

Wang, L.; Li, J.; Li, D. Losartan reduces myocardial interstitial fibrosis in diabetic cardiomyopathy rats by inhibiting JAK/STAT signaling pathway.Int. J. Clin. Exp. Pathol.,2015,8(1), 466-473.
[PMID:25755735]

[60]

Chua, S.; Sheu, J.J.; Chang, L.T.; Lee, F.Y.; Wu, C.J.; Sun, C.K.; Yip, H.K. Comparison of losartan and carvedilol on attenuating inflammatory and oxidative response and preserving energy transcription factors and left ventricular function in dilated cardiomyopathy rats.Int. Heart J.,2008,49(5), 605-619.
[http://dx.doi.org/10.1536/ihj.49.605] [PMID:18971572]

[61]

Roongpisuthipong, C.; Kantawan, R.; Roongpisuthipong, W. Reduction of adipose tissue and body weight: effect of water soluble calcium hydroxycitrate in Garcinia atroviridis on the short term treatment of obese women in Thailand.Asia Pac. J. Clin. Nutr.,2007,16(1), 25-29.
[PMID:17215177]

[62]

Matthaei, S.; Stumvoll, M.; Kellerer, M.; Häring, H.U. Pathophysiology and pharmacological treatment of insulin resistance.Endocr. Rev.,2000,21(6), 585-618.
[http://dx.doi.org/10.1210/er.21.6.585] [PMID:11133066]

[63]

Pasquel, F.J.; Umpierrez, G.E. Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment.Diabetes Care,2014,37(11), 3124-3131.
[http://dx.doi.org/10.2337/dc14-0984] [PMID:25342831]

[64]

Zografou, I.; Strachan, M.; McKnight, J. Delay in starting insulin after failure of other treatments in patients with type 2 diabetes mellitus.Hippokratia,2014,18(4), 306-309.
[PMID:26052195]

[65]

Zaidun, N.H.; Sahema, Z.C.T.; Mardiana, A.A.; Santhana, R.L.; Latiff, A.A.; Syed Ahmad Fuad, S.B. Effects of naringenin on vascular changes in prolonged hyperglycaemia in fructose-STZ diabetic rat model.Drug Discov. Ther.,2019,13(4), 212-221.
[http://dx.doi.org/10.5582/ddt.2019.01034] [PMID:31534073]

[66]

Sniderman, A.D.; Couture, P.; Martin, S.S.; DeGraaf, J.; Lawler, P.R.; Cromwell, W.C.; Wilkins, J.T.; Thanassoulis, G. Hypertriglyceridemia and cardiovascular risk: A cautionary note about metabolic confounding.J. Lipid Res.,2018,59(7), 1266-1275.
[http://dx.doi.org/10.1194/jlr.R082271] [PMID:29769239]

[67]

Lê, K.A.; Faeh, D.; Stettler, R.; Ith, M.; Kreis, R.; Vermathen, P.; Boesch, C.; Ravussin, E.; Tappy, L. A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans.Am. J. Clin. Nutr.,2006,84(6), 1374-1379.
[http://dx.doi.org/10.1093/ajcn/84.6.1374] [PMID:17158419]

[68]

Huang, D.W.; Chang, W.C.; Yang, H.J.; Wu, J.S.; Shen, S.C. Gallic acid alleviates hypertriglyceridemia and fat accumulationvia modulating glycolysis and lipolysis pathways in perirenal adipose tissues of rats fed a high-fructose diet.Int. J. Mol. Sci.,2018,19(1), E254.
[http://dx.doi.org/10.3390/ijms19010254] [PMID:29342975]

[69]

Softic, S.; Cohen, D.E.; Kahn, C.R. Role of Dietary Fructose and HepaticDe Novo Lipogenesis in Fatty Liver Disease.Dig. Dis. Sci.,2016,61(5), 1282-1293.
[http://dx.doi.org/10.1007/s10620-016-4054-0] [PMID:26856717]

[70]

Gökçe, G.; Arun, M.Z.; Ertuna, E. Ergothioneine prevents endothelial dysfunction induced by mercury chloride.Exp. Ther. Med.,2018,15(6), 4697-4702.
[PMID:29805489]

[71]

Shah, R; Emin, M; Thoma, T; Sampogna, R; Berger, JS; Jelic, S Direct evidence of endothelial inflammation and reduced nitric oxide bioavailability after sleep restriction in women.Arterioscl Throm Vasc Biol,2017,136((suppl_1))

[72]

Bayorh, M.A.; Ganafa, A.A.; Eatman, D.; Walton, M.; Feuerstein, G.Z. Simvastatin and losartan enhance nitric oxide and reduce oxidative stress in salt-induced hypertension.Am. J. Hypertens.,2005,18(11), 1496-1502.
[http://dx.doi.org/10.1016/j.amjhyper.2005.05.022] [PMID:16280288]

[73]

Sosa-Canache, B.; Hernández-Hernández, R.; Armas-Padilla, M.C.; Armas-Hernández, M.J.; Cammarata-Segura, R.; Pacheco, B.; Guerrero, J.; Israili, Z.H.; Valasco, M. Effect of losartan therapy on endothelial function in hypertensive patients.Am. J. Ther.,2007,14(2), 166-171.
[http://dx.doi.org/10.1097/01.pap.0000249919.44604.e1] [PMID:17414585]

[74]

Soinio, M.; Marniemi, J.; Laakso, M.; Lehto, S.; Rönnemaa, T. High-sensitivity C-reactive protein and coronary heart disease mortality in patients with type 2 diabetes: a 7-year follow-up study.Diabetes Care,2006,29(2), 329-333.
[http://dx.doi.org/10.2337/diacare.29.02.06.dc05-1700] [PMID:16443882]

[75]

Anwar, A.; Akbar Khan, H.; Hafeez, S.; Firdous, K. A comparative study of Creatine Kinase-MB and Troponin levels among diabetic and non diabetic patients with Acute MI.P J M H S.,2016,10(1), 296-298.

[76]

Paul, B.D.; Snyder, S.H. The unusual amino acid L-ergothioneine is a physiologic cytoprotectant.Cell Death Differ.,2010,17(7), 1134-1140.
[http://dx.doi.org/10.1038/cdd.2009.163] [PMID:19911007]

[77]

Colognato, R.; Laurenza, I.; Fontana, I.; Coppedé, F.; Siciliano, G.; Coecke, S.; Aruoma, O.I.; Benzi, L.; Migliore, L. Modulation of hydrogen peroxide-induced DNA damage, MAPKs activation and cell death in PC12 by ergothioneine.Clin. Nutr.,2006,25(1), 135-145.
[http://dx.doi.org/10.1016/j.clnu.2005.10.005] [PMID:16314005]

[78]

Jang, J.H.; Aruoma, O.I.; Jen, L.S.; Chung, H.Y.; Surh, Y.J. Ergothioneine rescues PC12 cells from beta-amyloid-induced apoptotic death.Free Radic. Biol. Med.,2004,36(3), 288-299.
[http://dx.doi.org/10.1016/j.freeradbiomed.2003.11.005] [PMID:15036348]

[79]

Hamburg, R.J.; Friedman, D.L.; Perryman, M.B. Metabolic and diagnostic significance of creatine kinase isoenzymes.Trends Cardiovasc. Med.,1991,1(5), 195-200.
[http://dx.doi.org/10.1016/1050-1738(91)90037-F] [PMID:21239310]

[80]

Yaribeygi, H.; Atkin, S.L.; Sahebkar, A. A review of the molecular mechanisms of hyperglycemia-induced free radical generation leading to oxidative stress.J. Cell. Physiol.,2019,234(2), 1300-1312.
[http://dx.doi.org/10.1002/jcp.27164] [PMID:30146696]

[81]

Hurrle, S.; Hsu, W.H. The etiology of oxidative stress in insulin resistance.Biomed. J.,2017,40(5), 257-262.
[http://dx.doi.org/10.1016/j.bj.2017.06.007] [PMID:29179880]

[82]

Fiorentino, T.V.; Prioletta, A.; Zuo, P.; Folli, F. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases.Curr. Pharm. Des.,2013,19(32), 5695-5703.
[http://dx.doi.org/10.2174/1381612811319320005] [PMID:23448484]

[83]

Halliwell, B.; Cheah, I.K.; Tang, R.M.Y. Ergothioneine - a diet-derived antioxidant with therapeutic potential.FEBS Lett.,2018,592(20), 3357-3366.
[http://dx.doi.org/10.1002/1873-3468.13123] [PMID:29851075]

[84]

Servillo, L.; DʼOnofrio, N.; Balestrieri, M.L. Ergothioneine antioxidant function: From chemistry to cardiovascular therapeutic potential.J. Cardiovasc. Pharmacol.,2017,69(4), 183-191.
[http://dx.doi.org/10.1097/FJC.0000000000000464] [PMID:28375902]

[85]

Borodina, I.; Kenny, L.C.; McCarthy, C.M.; Paramasivan, K.; Pretorius, E.; Roberts, T.J.; van der Hoek, S.A.; Kell, D.B. The biology of ergothioneine, an antioxidant nutraceutical.Nutr. Res. Rev.,2020,33(2), 190-217.
[http://dx.doi.org/10.1017/S0954422419000301] [PMID:32051057]

[86]

Lamhonwah, A.M.; Tein, I. Novel localization of OCTN1, an organic cation/carnitine transporter, to mammalian mitochondria.Biochem. Biophys. Res. Commun.,2006,345(4), 1315-1325.
[http://dx.doi.org/10.1016/j.bbrc.2006.05.026] [PMID:16729965]

[87]

Kawano, H.; Otani, M.; Takeyama, K.; Kawai, Y.; Mayumi, T.; Hama, T. Studies on ergothioneine. VI. Distribution and fluctuations of ergothioneine in rats.Chem. Pharm. Bull. (Tokyo),1982,30(5), 1760-1765.
[http://dx.doi.org/10.1248/cpb.30.1760] [PMID:7116510]

[88]

Khattab, M.; Ahmad, M.; Al-Shabanah, O.A.; Raza, M. Effects of losartan on blood pressure, oxidative stress, and nitrate/nitrite levels in the nitric oxide deficient hypertensive rats.Receptors Channels,2004,10(5-6), 147-157.
[http://dx.doi.org/10.3109/10606820490936141] [PMID:15989079]

[89]

Hseu, Y.C.; Lo, H.W.; Korivi, M.; Tsai, Y.C.; Tang, M.J.; Yang, H.L. Dermato-protective properties of ergothioneine through induction of Nrf2/ARE-mediated antioxidant genes in UVA-irradiated Human keratinocytes.Free Radic. Biol. Med.,2015,86, 102-117.
[http://dx.doi.org/10.1016/j.freeradbiomed.2015.05.026] [PMID:26021820]

[90]

Hseu, Y-C.; Vudhya Gowrisankar, Y.; Chen, X-Z.; Yang, Y-C.; Yang, H-L. The antiaging activity of ergothioneine in uva-irradiated human dermal fibroblastsvia the inhibition of the AP-1 pathway and the activation of Nrf2-mediated antioxidant genes.Oxid. Med. Cell. Longev.,2020,2020, 2576823.
[http://dx.doi.org/10.1155/2020/2576823] [PMID:32104530]

[91]

Chen, J.; Zhang, Z.; Cai, L. Diabetic cardiomyopathy and its prevention by nrf2: current status.Diabetes Metab. J.,2014,38(5), 337-345.
[http://dx.doi.org/10.4093/dmj.2014.38.5.337] [PMID:25349820]

[92]

Frati, G.; Schirone, L.; Chimenti, I.; Yee, D.; Biondi-Zoccai, G.; Volpe, M.; Sciarretta, S. An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy.Cardiovasc. Res.,2017,113(4), 378-388.
[http://dx.doi.org/10.1093/cvr/cvx011] [PMID:28395009]

[93]

Haffner, S.M. Pre-diabetes, insulin resistance, inflammation and CVD risk.Diabetes Res. Clin. Pract.,2003,61(Suppl. 1), S9-S18.
[http://dx.doi.org/10.1016/S0168-8227(03)00122-0] [PMID:12880690]

[94]

Asahi, T.; Wu, X.; Shimoda, H.; Hisaka, S.; Harada, E.; Kanno, T.; Nakamura, Y.; Kato, Y.; Osawa, T. A mushroom-derived amino acid, ergothioneine, is a potential inhibitor of inflammation-related DNA halogenation.Biosci. Biotechnol. Biochem.,2016,80(2), 313-317.
[http://dx.doi.org/10.1080/09168451.2015.1083396] [PMID:26338495]

[95]

Repine, JE; Elkins, ND Effect of ergothioneine on acute lung injury and inflammation in cytokine insufflated rats.Prev Med,2012,54, 79-82.
[http://dx.doi.org/10.1016/j.ypmed.2011.12.006]

[96]

Song, T-Y.; Yang, N-C.; Chen, C-L.; Thi, T.L.V. Protective effects and possible mechanisms of ergothioneine and hispidin against methylglyoxal-induced injuries in rat pheochromocytoma Cells.Oxid. Med. Cell. Longev.,2017,2017, 4824371.
[http://dx.doi.org/10.1155/2017/4824371] [PMID:29181125]

[97]

Salama, S.A.; Omar, H.A. Modulating nf-κb, mapk, and pi3k/akt signaling by ergothioneine attenuates iron overload-induced hepatocellular injury in rats.J. Biochem. Mol. Toxicol.,2021,35(5), e22729.
[http://dx.doi.org/10.1002/jbt.22729] [PMID:33580994]

[98]

Guo, Z.X.; Qiu, M.C. Losartan downregulates the expression of transforming growth factor beta type I and type II receptors in kidney of diabetic rat.Zhonghua Nei Ke Za Zhi,2003,42(6), 403-408.
[PMID:12895325]

[99]

Wang, G.; Song, X.; Zhao, L.; Li, Z.; Liu, B. Resveratrol prevents diabetic cardiomyopathy by increasing nrf2 expression and transcriptional activity.BioMed Res. Int.,2018,2018, 2150218.
[http://dx.doi.org/10.1155/2018/2150218] [PMID:29721501]

[100]

Trzhtsinskaya, B.V.; Abramova, N.D. Imidazole-2-thiones: Synthesis, structure, properties.Sulfur Reports.,1991,10(4), 389-421.
[http://dx.doi.org/10.1080/01961779108048760]

Rights & Permissions Print Cite

Call for Papers in Thematic Issues

Submission closes on : 31 December, 2025

Medicinal Plants with Beneficial Properties on Diabetes and Hypertension

Diabetes and hypertension are real scourges of the 21st century. It is imperative to act in order to find innovative solutions to this problem. Taking medications such as hypoglycemic and antihypertensive drugs may aggravate certain underlying comorbidities, such as chronic kidney disease and cardiovascular disease. This significant drawback therefore requires ...read more

Guest Editor(s): Mohamed Eddouks

Related Journals

Anti-Cancer Agents in Medicinal Chemistry

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

Current Bioactive Compounds

Current Cancer Drug Targets

Combinatorial Chemistry & High Throughput Screening

Current Cancer Therapy Reviews

Current Diabetes Reviews

Current Drug Safety

Current Drug Targets

Current Drug Therapy

Related Books

Therapeutic Plants: Recent Advances in the Use of Herbs as Alternative Medications

Quality Assurance of Ethno-Herbals: Cultivating Confidence in Alternative Medicine

Traditional Medicine in North East Africa: Research on Traditional Healer Preparations and Herbs

Andrographolide and its Analogs: Botanical Sources, Phytochemistry, Pharmacology, and Biotechnology

Anthocyanins: Pharmacology and Nutraceutical Importance

The Roles and Responsibilities of Clinical Pharmacists in Hospital Settings

Bioactive Compounds from Medicinal Plants for Cancer Therapy and Chemoprevention

Drug Addiction Mechanisms in the Brain

Software and Programming Tools in Pharmaceutical Research

Objective Pharmaceutics: A Comprehensive Compilation of Questions and Answers for Pharmaceutics Exam Prep

Article Metrics

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

The Neuroprotective Effect of Ginkgo biloba Leaf Extract and its Possible Mechanism
Central Nervous System Agents in Medicinal Chemistry

Role of Tyrosine Kinases and their Inhibitors in Cancer Therapy: AComprehensive Review
Current Medicinal Chemistry

Adenosine and ATP Receptors in the Brain
Current Topics in Medicinal Chemistry

Phosphonate Analogues of 1α, 25 Dihydroxyvitamin D<sub>3</sub> are Promising Candidates for Antitumoural Therapies
Current Topics in Medicinal Chemistry

Colony-Stimulating Factor-1 Receptor Inhibitors for the Treatment of Cancer and Inflammatory Disease
Current Topics in Medicinal Chemistry

Effects of Elicitors, Viticultural Factors, and Enological Practices on Resveratrol and Stilbenes in Grapevine and Wine
Mini-Reviews in Medicinal Chemistry

Specificity of Binding in Protein Kinases
Current Enzyme Inhibition

GABAergic Contributions to the Pathophysiology of Depression and the Mechanism of Antidepressant Action
CNS & Neurological Disorders - Drug Targets

Maternal Dyslipidaemia in Pregnancy with Gestational Diabetes Mellitus: Possible Impact on Foetoplacental Vascular Function and Lipoproteins in the Neonatal Circulation
Current Vascular Pharmacology

Oxindole Derivatives: Synthesis and Antiglycation Activity
Medicinal Chemistry

Modifications of Cell Signalling and Redox Balance by Targeting Protein Acetylation Using Natural and Engineered Molecules: Implications in Cancer Therapy
Current Topics in Medicinal Chemistry

Energy Balance and Carcinogenesis: Underlying Pathways and Targets for Intervention
Current Cancer Drug Targets

Aldose Reductase: A Novel Target for Cardioprotective Interventions
Current Drug Targets

Angiotensin-(1-7): Blood, Heart, and Blood Vessels
Current Medicinal Chemistry - Cardiovascular & Hematological Agents

Ubiquitin and ubiquitin-like proteins in cardiac disease and protection
Current Drug Targets

Synergistic Antiproliferative and Antiangiogenic Effects of EGFR and mTOR Inhibitors
Current Pharmaceutical Design

Diagnostic Value of 3D Optical Coherence Tomography Multimode Images inthe Diagnosis of Acute Central Serous Chorioretinopathy
Current Medical Imaging

Nucleic Acids Delivery Systems: A Challenge for Pharmaceutical Technologists
Current Drug Metabolism

Antiangiogenics and Hypoxic Response: Role of Fatty Acid Synthase Inhibitors
Current Drug Targets

Design, Synthesis, and Bioactivity of Pyrazole Acid Derivatives as Endothelin Receptor Antagonists
Medicinal Chemistry

DOI https://dx.doi.org/10.2174/1871525719666210809122541	Print ISSN 1871-5257
Publisher Name Bentham Science Publisher	Online ISSN 1875-6182

Movatterモバイル変換

Login

About

Journals

Books

Submission for General Articles

Submit to Thematic Issues

Call for Conference Speakers

Special Open Access APC Discount

Marketing Opportunities

Articles By Disease

For Librarians

For Authors & Editors

Cardiovascular & Hematological Agents in Medicinal Chemistry

Cardioprotective Effects andin-silico Antioxidant Mechanism of L-Ergothioneine in Experimental Type-2 Diabetic Rats