title: The protective role of isorhamnetin on human brain microvascular endothelial cells from cytotoxicity induced by methylglyoxal and oxygen-glucose deprivation.
abstract: As the first target of stroke, cerebral endothelial cells play a key role in brain vascular repair and maintenance, and their function is impeded in diabetes. Methylglyoxal (MGO), a reactive dicarbonyl produced during glucose metabolism, accumulates in diabetic patients. MGO and MGO-induced advanced glycation end-products (AGEs) could ameliorate stroke-induced brain vascular damage, closely related with ECs dysfunction. Using MGO plus oxygen-glucose deprivation (OGD) to mimic diabetic stroke, we reported the protective effect of isorhamnetin on OGD-induced cytotoxicity after MGO treatment on primary human brain microvascular endothelial cells (HBMEC) and explored the underlying mechanisms. Treatment of MGO for 24 h significantly enhanced 3-h OGD-induced HBMEC toxic effect, which was inhibited by pretreatment of isorhamnetin (100 μmol/L). Moreover, the protective effect of isorhamnetin is multiple function dependent, which includes anti-inflammation, anti-oxidative stress and anti-apoptosis effects. Besides its well-known inhibition on the mitochondria-dependent or intrinsic apoptotic pathway, isorhamnetin also reduced activation of the extrinsic apoptotic pathway, as characterized by the decreased expression and activity of caspase 3 and caspase 8. Furthermore, pretreatment with isorhamnetin specifically inhibited FAS/FASL expression and suppressed nuclear factor-kappa B nuclear translocation. Taken together, our results indicated that isorhamnetin protected against OGD-induced cytotoxicity after MGO treatment in cultured HBMEC due to its multiple protective effects and could inhibit Fas-mediated extrinsic apoptosis. Therefore, isorhamnetin is a promising reagent for the treatment of hyperglycemia and ischemia-induced cerebral vascular degeneration. A proposed model of the potential protective mechanism of isorhamnetin, a metabolite of quercetin, on methylglyoxal (MGO) treatment plus oxygen-glucose deprivation (OGD) exposure-induced cytotoxicity in cultured human brain microvascular endothelial cells. Isorhamnetin inhibits FasL-mediated extrinsic apoptosis and neurotrophic factor κB (NF-κB) nuclear translocation, which can induce the cell DNA damage. Therefore, the protective effect of isorhamnetin occurs through multiple functions, including anti-inflammation, anti-oxidative stress and anti-apoptosis. Therefore, isorhamnetin is a promising reagent for the treatment of hyperglycemia and ischemia-induced cerebral vascular degeneration.
authors.affiliation: Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Wenlu
authors.initials: W
authors.lastname: Li
authors.affiliation: Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Cancer Institute, Zhejiang University, Hangzhou, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Cancer Institute, Zhejiang University, Hangzhou, China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Dai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology*; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D053222:Fas Ligand Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology*; D011765:Pyruvaldehyde / Q000633:toxicity*; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D016328:NF-kappa B; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D017472:Receptors, Interleukin-1; C047368:3-methylquercetin; D011765:Pyruvaldehyde; D011794:Quercetin; D020169:Caspases; D005947:Glucose; D010100:Oxygen
keywords: Fas/FasL; isorhamnetin; methylglyoxal; oxygen-glucose deprivation; primary human brain microvascular endothelial cells