title: Possible involvement of Nrf2 and PPARγ up-regulation in the protective effect of umbelliferone against cyclophosphamide-induced hepatotoxicity.
abstract: Umbelliferone (UMB) is a coumarin derivative with promising hepatoprotective effects. In this study, we examined the possible protective effects of UMB against cyclophosphamide (CP)-induced hepatotoxicity, addressing the question of the possible role of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator activated receptor gamma (PPARγ). Wistar rats were orally administered UMB at doses 50 and 100mg/kg two weeks prior to CP injection. Five days after CP administration, the rats were sacrificed and samples were collected for analyses. CP induced a significant increase in circulating liver marker enzymes and pro-inflammatory cytokines. Hepatic lipid peroxidation and nitric oxide levels, and nuclear factor-kappaB (NF-κB) and inducible nitric oxide synthase (iNOS) expression were significantly increased following CP administration. UMB supplementation attenuated CP-induced inflammation and oxidative stress as assessed by restoration of the activity and expression of the antioxidant defenses, and suppression of pro-inflammatory cytokines. Histological examination also showed that UMB could significantly reduce CP-induced alterations. CP-induced rats showed significant down-regulation of Nrf2, HO-1 and PPARγ, an effect that was markedly reversed by UMB. In conclusion, the hepatoprotective effects of UMB appear to depend on co-activation of PPARγ and Nrf2, and subsequent suppression of oxidative stress and inflammation.
authors.affiliation: Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Egypt. Electronic address: ayman.mahmoud@science.bsu.edu.eg.
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Mahmoud
authors.affiliation: Biology Department, Faculty of Science, Aljouf University, Saudi Arabia.
authors.forename: Mousa O
authors.initials: MO
authors.lastname: Germoush
authors.affiliation: Department of Physiology, College of Medicine, King Saud University, Saudi Arabia.
authors.forename: Mohammed F
authors.initials: MF
authors.lastname: Alotaibi
authors.affiliation: Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Egypt.
authors.forename: Omnia E
authors.initials: OE
authors.lastname: Hussein
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D020011:Protective Agents / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014468:Umbelliferones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D047495:PPAR gamma; D020011:Protective Agents; D014468:Umbelliferones; D003520:Cyclophosphamide
keywords: 7-Hydroxycoumarin; Cyclophosphamide; Hepatotoxicity; Nrf2; Oxidative stress; PPARγ