DataSheet_2_Magnolol Prevents Acute Alcoholic Liver Damage by Activating PI3K/Nrf2/PPARγ and Inhibiting NLRP3 Signaling Pathway.zip

Alcoholic liver damage (ALD) is a toxic liver damage caused by excessive drinking. Oxidative stress is one of the most crucial pathogenic factors leading to ALD. Magnolol is one of the main active constituents of traditional Chinese medicine Magnolia officinalis, which has been reported to possess many pharmacological effects including anti-inflammatory, anti-oxidant, and anti-tumor. However, the effects of magnolol on ALD remain unclear. In this study, we firstly evaluated the protective effects of magnolol on ALD, and then tried to clarify the mechanism underlying the pharmacological activities. AST, ALT, GSH-Px, and SOD were detected by respective kits. Histopathological changes of liver tissue were analyzed by H&E staining. The activities of PI3K, Nrf2, and NLRP3 signaling pathways activation were detected by western blotting analysis. It was showed that alcohol-induced ALT and AST levels were significantly reduced by magnolol, but the antioxidant enzymes of GSH-Px and SOD levels were significantly increased. Magnolol attenuated alcohol-induced pathologic damage such as decreasing hepatic cord swelling, hepatocyte necrosis, and inflammatory cell infiltration. Furthermore, it was found that magnolol inhibited oxidative stress through up-regulating the activities of HO-1, Nrf2, and PPARγ and the phosphorylation of PI3K and AKT. And magnolol also decreased inflammatory response by inhibiting the activation of NLRP3inflammasome, caspase-1, and caspase-3 signaling pathway. Above results showed that magnolol could prevent alcoholic liver damage, and the underlying mechanism was through activating PI3K/Nrf2/PPARγ signaling pathways as well as inhibiting NLRP3 inflammasome, which also suggested magnolol might be used as a potential drug for ALD.

酒精性肝损伤（Alcoholic liver damage, ALD）是由过量饮酒引发的毒性肝损伤。氧化应激是导致ALD的关键致病因素之一。和厚朴酚（Magnolol）是中药厚朴（Magnolia officinalis）的主要活性成分之一，据报道其具备多种药理活性，包括抗炎、抗氧化及抗肿瘤作用。然而，和厚朴酚对ALD的作用仍不明确。本研究首先评估了和厚朴酚对ALD的保护作用，随后试图阐明其药理活性的潜在机制。研究采用相应试剂盒检测了天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、谷胱甘肽过氧化物酶（GSH-Px）及超氧化物歧化酶（SOD）的水平；通过苏木精-伊红（H&E）染色分析了肝组织的病理组织学变化；通过蛋白质印迹法（western blotting）检测了磷脂酰肌醇3-激酶（PI3K）、核因子E2相关因子2（Nrf2）及NLRP3信号通路的活化水平。结果显示，和厚朴酚可显著降低酒精诱导升高的ALT与AST水平，并显著提升抗氧化酶GSH-Px与SOD的活性。和厚朴酚可减轻酒精诱导的病理性肝损伤，包括缓解肝索肿胀、减少肝细胞坏死及炎性细胞浸润。进一步研究发现，和厚朴酚可通过上调血红素加氧酶1（HO-1）、Nrf2及过氧化物酶体增殖物激活受体γ（PPARγ）的活性，以及增强PI3K与蛋白激酶B（AKT）的磷酸化水平，从而抑制氧化应激。此外，和厚朴酚还可通过抑制NLRP3炎症小体、半胱氨酸天冬氨酸蛋白酶1（caspase-1）及半胱氨酸天冬氨酸蛋白酶3（caspase-3）信号通路的活化，减轻炎症反应。综上，和厚朴酚可对酒精性肝损伤起到预防作用，其潜在机制为激活PI3K/Nrf2/PPARγ信号通路并抑制NLRP3炎症小体，这提示和厚朴酚有望成为治疗ALD的潜在药物。