School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Biofactors. 2023 Nov-Dec;49(6):1189-1204. doi: 10.1002/biof.1987. Epub 2023 Jul 4.
Nonalcoholic steatohepatitis (NASH) and hepatic fibrosis are leading causes of cirrhosis with rising morbidity and mortality worldwide. Currently, there is no appropriate treatment for NASH and hepatic fibrosis. Many studies have shown that oxidative stress is a main factor inducing NASH. Nomilin (NML) and obacunone (OBA) are limonoid compounds naturally occurring in citrus fruits with various biological properties. However, whether OBA and NML have beneficial effects on NASH remains unclear. Here, we demonstrated that OBA and NML inhibited hepatic tissue necrosis, inflammatory infiltration and liver fibrosis progression in methionine and choline-deficient (MCD) diet, carbon tetrachloride (CCl )-treated and bile duct ligation (BDL) NASH and hepatic fibrosis mouse models. Mechanistic studies showed that NML and OBA enhanced anti-oxidative effects, including reduction of malondialdehyde (MDA) level, increase of catalase (CAT) activity and the gene expression of glutathione S-transferases (GSTs) and Nrf2-keap1 signaling. Additional, NML and OBA inhibited the expression of inflammatory gene interleukin 6 (Il-6), and regulated the bile acid metabolism genes Cyp3a11, Cyp7a1, multidrug resistance-associated protein 3 (Mrp3). Overall, these findings indicate that NML and OBA may alleviate NASH and liver fibrosis in mice via enhancing antioxidant and anti-inflammation capacity. Our study proposed that NML and OBA may be potential strategies for NASH treatment.
非酒精性脂肪性肝炎（NASH）和肝纤维化是导致全球发病率和死亡率上升的肝硬化的主要原因。目前，尚无针对 NASH 和肝纤维化的适当治疗方法。许多研究表明，氧化应激是导致 NASH 的主要因素。诺米林（NML）和奥巴醌（OBA）是柑橘类水果中天然存在的具有多种生物学特性的柠檬苦素类化合物。然而，OBA 和 NML 是否对 NASH 有有益作用尚不清楚。在这里，我们证明 OBA 和 NML 抑制了蛋氨酸和胆碱缺乏（MCD）饮食、四氯化碳（CCl）处理和胆管结扎（BDL）NASH 和肝纤维化小鼠模型中的肝组织坏死、炎症浸润和肝纤维化进展。机制研究表明，NML 和 OBA 增强了抗氧化作用，包括降低丙二醛（MDA）水平、增加过氧化氢酶（CAT）活性以及谷胱甘肽 S-转移酶（GSTs）和 Nrf2-keap1 信号的基因表达。此外，NML 和 OBA 抑制了炎症基因白细胞介素 6（Il-6）的表达，并调节了胆汁酸代谢基因 Cyp3a11、Cyp7a1、多药耐药相关蛋白 3（Mrp3）。总的来说，这些发现表明，NML 和 OBA 可能通过增强抗氧化和抗炎能力来缓解小鼠的 NASH 和肝纤维化。我们的研究表明，NML 和 OBA 可能是 NASH 治疗的潜在策略。
