Sudhakaran Gokul, Prathap Pandurangan, Guru Ajay, Haridevamuthu B, Murugan Raghul, Almutairi Bader O, Almutairi Mikhlid H, Juliet Annie, Gopinath Pushparathinam, Arockiaraj Jesu
Department of Biotechnology, College of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur 603 203, Chennai, Tamil Nadu, India.
Department of Chemistry, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur 603 203, Chennai, Tamil Nadu, India.
Mol Cell Biochem. 2022 Oct;477(10):2387-2401. doi: 10.1007/s11010-022-04448-7. Epub 2022 May 16.
Alcoholic liver disease is one of the most prominent liver diseases in the world. Lipid accumulation accompanied by oxidative stress and inflammation in the liver is the most important pathogenesis of ALD. This study was designed to investigate the anti-oxidative, fat metabolism-regulating, and anti-inflammatory potential of N2, a seminatural analog of Nimbin. The ethanol exposure was found to induce liver injury on zebrafish larvae, such as liver inflammation, lipid accumulation, oxidative stress, and hepatocytes apoptosis. N2 was subjected to ADMET screening in-silico, and it was observed N2's co-exposure decreased the ROS, apoptosis, lipid peroxidation, and macrophage accumulation in the liver of larval zebrafish. To further study the mechanism behind ethanol hepatotoxicity and the hepatoprotective behavior of N2, gene expression changes were determined in zebrafish. The results of this study revealed that ethanol exposure upregulated mRNA expressions of SREBP1, C/EBP-α, FAS and provoked more severe oxidative stress and hepatitis via upregulation of inflammatory cytokines TNF-α, IL-10, IL-1β, iNOS, COX-2. However, the N2 co-exposure protected the hepatocyte damage and almost reversed the condition by downregulating the mRNA levels. The study suggested that N2 could be an effective therapeutic agent for the treatment of ALD and other inflammatory conditions.
酒精性肝病是世界上最突出的肝脏疾病之一。肝脏中脂质积累伴随氧化应激和炎症是酒精性肝病最重要的发病机制。本研究旨在探究N2（一种印楝宁的半天然类似物）的抗氧化、调节脂肪代谢和抗炎潜力。研究发现乙醇暴露会诱导斑马鱼幼体肝脏损伤，如肝脏炎症、脂质积累、氧化应激和肝细胞凋亡。对N2进行了计算机辅助的药物代谢及毒性预测筛选，观察到N2共同暴露可降低斑马鱼幼体肝脏中的活性氧、凋亡、脂质过氧化和巨噬细胞积累。为进一步研究乙醇肝毒性背后的机制以及N2的肝脏保护作用，测定了斑马鱼的基因表达变化。本研究结果显示，乙醇暴露上调了固醇调节元件结合蛋白1（SREBP1）、CCAAT/增强子结合蛋白α（C/EBP-α）、脂肪酸合酶（FAS）的mRNA表达，并通过上调炎性细胞因子肿瘤坏死因子-α（TNF-α）、白细胞介素-10（IL-10）、白细胞介素-1β（IL-1β）、诱导型一氧化氮合酶（iNOS）、环氧化酶-2（COX-2）引发更严重的氧化应激和肝炎。然而，N2共同暴露通过下调mRNA水平保护了肝细胞损伤并几乎逆转了这种状况。该研究表明N2可能是治疗酒精性肝病和其他炎症性疾病的有效治疗剂。
