Possible involvement of Nrf2 and PPARγ up-regulation in the protective effect of umbelliferone against cyclophosphamide-induced hepatotoxicity

详细信息    查看全文

• 作者：Ayman M. Mahmoud^a ; ^{ayman.mahmoud@science.bsu.edu.eg} ; Mousa O. Germoush^b ; Mohammed F. Alotaibi^c ; Omnia E. Hussein^a
• 关键词：UMB ; umbelliferone ; PPARγ ; peroxisome proliferator activated receptor gamma ; CP ; cyclophosphamide ; Nrf2 ; nuclear factor erythroid 2-related factor 2 ; iNOS ; inducible nitric oxide synthase ; NF-κB ; nuclear factor-kappa B ; HO-1 ; heme oxygenase 1 ; ROS ; Reactive oxygen species ; Keap 1 ; Kelch-like ECH2-associated protein ; RXR ; retinoid X receptor ; ARE ; antioxidant response element ; ALP ; alkaline phosphatase ; ALT ; alanine aminotransferase ; AST ; aspartate aminotransferase ; MDA ; malondialdehyde ; NO ; nitr
• 刊名：Biomedicine & Pharmacotherapy
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：86
• 期：Complete
• 页码：297-306
• 全文大小：3092 K
• 卷排序：86

文摘

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 100 mg/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.