Melatonin alleviates cholestatic liver injury through modulating gut microbiota and activating the NRF2/HO-1 antioxidant pathway

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-09-06 DOI:10.1016/j.tice.2025.103131

Shijing Dong , Jiangpeng Liu , Chenyang Xuan , Simin Zhou , Zongze Han, Chenhui Zhu, Nian Chen, Ruiyun Liu, Weirong Wang, Hongyu Chu, Xue Zhang, Hui Yang, Man Liu, Liping Guo, Lu Zhou

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引用次数: 0

Abstract

Cholestasis is a pathological state characterized by the dysfunction of bile acid flow, which could lead to liver fibrosis, cirrhosis, and even liver failure, but its therapeutic agents are limited. The aim of this study was to investigate the therapeutic potential and underlying mechanism of melatonin on cholestatic liver injury. C57BL/6 J mice were fed with 0.05 % 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine (DDC) diet to induce cholestatic liver injury, with or without daily intraperitoneal injection of 20 mg/kg melatonin. The supplementation of melatonin alleviated cholestatic liver injury through improving liver histopathology and abnormal serum indicators reflecting liver function. Meanwhile, melatonin treatment inhibited the hepatic inflammatory infiltration and release of pro-inflammatory cytokines. Moreover, liver fibrosis caused by cholestasis was mitigated by melatonin via reducing collagen deposition and pro-fibrogenic factors. Furthermore, the gut microbiota dysbiosis and impaired intestinal barrier induced by DDC were mitigated after melatonin treatment. Notably, melatonin activated the cholangiocyte nuclear factor erythroid 2-related factor 2 (NRF2) / heme oxygenase-1 (HO-1) signalling pathway through melatonin receptor 1 A (MTNR1A) to protect the liver from oxidative stress damage. In conclusion, melatonin is a potential therapeutic agent for cholestatic liver injury, possibly acting by modulating gut microbiota and activating the NRF2/HO1 pathway.

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褪黑素通过调节肠道菌群和激活NRF2/HO-1抗氧化途径减轻胆汁淤积性肝损伤

胆汁淤积是一种以胆汁酸流动功能障碍为特征的病理状态，可导致肝纤维化、肝硬化甚至肝功能衰竭，但其治疗药物有限。本研究旨在探讨褪黑素对胆汁淤积性肝损伤的治疗潜力及其机制。C57BL/6 J小鼠分别饲喂0.05 % 3,5-二氧羰基-1,4-二氢-2,4,6-碰撞碱（DDC）饲粮诱导胆汁淤积性肝损伤，并每日腹腔注射20 mg/kg褪黑素。补充褪黑素可通过改善肝脏组织病理学和反映肝功能的异常血清指标减轻胆汁淤积性肝损伤。同时，褪黑素治疗抑制肝脏炎症浸润和促炎细胞因子的释放。此外，褪黑素通过减少胶原沉积和促纤维化因子减轻胆汁淤积引起的肝纤维化。此外，褪黑激素治疗后，DDC引起的肠道微生物群失调和肠道屏障受损得到缓解。值得注意的是，褪黑素通过褪黑素受体1 A （MTNR1A）激活胆管细胞核因子-红细胞2相关因子2 (NRF2) /血红素加氧酶-1 （HO-1）信号通路，保护肝脏免受氧化应激损伤。综上所述，褪黑素是一种潜在的治疗胆汁淤积性肝损伤的药物，可能通过调节肠道微生物群和激活NRF2/HO1途径起作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.