A network pharmacology approach: Inhibition of the NF-κB signaling pathway contributes to the NASH preventative effect of an Oroxylum indicum seed extract in oleic acid-stimulated HepG2 cells and high-fat diet-fed rats
A network pharmacology approach: Inhibition of the NF-κB signaling pathway contributes to the NASH preventative effect of an Oroxylum indicum seed extract in oleic acid-stimulated HepG2 cells and high-fat diet-fed rats
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网络药理学方法：抑制 NF-kappa B 信号通路有助于木蝴蝶种子提取物对油酸刺激的 HepG2 细胞和高脂饮食喂养的大鼠的 NASH 预防作用
DOI：
10.1016/j.phymed.2021.153498
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发表时间：
2021-06-15
期刊：
影响因子：
7.9
通讯作者：
Li, Jingda
中科院分区：
文献类型：
--
作者：
Sun, Wenlong;Liu, Panpan;Li, Jingda
背景：非酒精性脂肪性肝病(NAFLD)，尤其是非酒精性脂肪性肝炎(NASH)的发病率近年来显著上升，已成为一个重要的公共卫生问题。然而，目前还没有美国食品和药物管理局(FDA)批准的一线药物可用于治疗NAFLD和NASH；因此，新药的研究目前是一个热门话题。花椒Oroxitalininum(Linn.)库尔茨植物广泛分布于南亚、中国和南亚，具有多种生物活性。目的：研究野牡丹种子提取物(OISE)在单纯性非酒精性脂肪肝(NAFL)向非酒精性脂肪肝(NASH)转化过程中的抗炎作用及其机制。方法：构建网络药理学方法构建NASH中成分-靶点网络和蛋白质-蛋白质相互作用(PPI)网络，进行拓扑分析和枢纽-靶点筛选。进行了浓缩分析，以确定关键的生物学过程和信号通路。同时，在体外和体内实验中，通过生化指标检测、荧光素酶报告、病理染色和免疫印迹等方法，研究了噪声对油酸刺激的HepG2细胞和高脂饲料喂养的大鼠炎症反应的影响及其机制。结果：网络药理学结果表明，噪声通过多种途径和靶点阻止NAFL向NASH的发展和进展，黄芩素和白杨素调控的核因子核因子-kappa B(NF-kappa B)通路在NASH的治疗中起重要作用。在体外实验中，我们进一步证明Oise及其成分黄芩素和白杨素均能改善油酸刺激的HepG2细胞的炎症状态，抑制核转录活性，提高核转录因子-kappaB水平，降低核因子-kappaB的磷酸化水平。此外，在高脂饮食诱导的大鼠NASH模型中，结论：OISE通过抑制NF-kappaB的核转录活性，抑制炎症反应，阻止NAFL向NASH的发展和进展。结论：OISE可通过提高胰岛素敏感性、减少肝脏脂质积聚、抑制炎症反应和清除自由基等多种作用来治疗NAFLD。
Background: The incidence of nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), has significantly increased in recent years and has become an important public health issue. However, no U.S. Food and Drug Administration (FDA)-approved first-line drug is currently available for the treatment of NAFLD and NASH; therefore, research on new drugs is currently a hot topic. Oroxylum indicum (Linn.) Kurz is extensively distributed in South China and South Asia and has many biological activities. However, its effects on NAFLD or even NASH and the corresponding mechanisms are still not clear.Purpose: To investigate the effect and mechanism of O. indicum seed extract (OISE) on preventing anti-inflammatory action in the progression from simple nonalcoholic fatty liver (NAFL) to NASH.Methods: A network pharmacology method to construct ingredient-target networks and the protein-protein interaction (PPI) network of OISE in NASH were constructed for topological analyses and hub-target screening. Enrichment analyses were performed to identify the critical biological processes and signaling pathways. Simultaneously, in vitro and in vivo experiments investigated the effect and mechanism of OISE, baicalein, and chrysin on inflammation by biochemical indicator detection, luciferase reporters, pathological staining, and immunoblotting in oleic acid-stimulated HepG2 cells or in high-fat diet-fed rats.Results: The network pharmacology showed that OISE prevented the development and progression of NAFL into NASH through various pathways and targets and that the nuclear factor NF-kappa B (NF-kappa B) pathway regulated by baicalein and chrysin played an important role in the treatment of NASH. In in vitro experiments, we further showed that OISE and its ingredients, namely, baicalein and chrysin, all improved the inflammatory status in oleic acid-stimulated HepG2 cells, inhibited the nuclear transcriptional activities of NF-kappa B, increased the I kappa B level, and decreased the phosphorylation level of NF-kappa B. Furthermore, in a high-fat diet-induced NASH model in rats, we also showed that OISE prevented the development and progression of NASH by inhibiting the nuclear transcriptional activity of NF-kappa B.Conclusion: OISE suppressed inflammatory responses and prevented the development and progression of NAFL into NASH through inhibition of the nuclear transcriptional activity of NF-kappa B. OISE may be used to treat NAFLD through many functions, including an increase in insulin sensitivity, a decrease in lipid accumulation in the liver, suppression of inflammation, and clearance of free radicals.