Metabolism of N-nitrosodimethylamine, methylation of macromolecules, and development of hepatic fibrosis in rodent model
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REVIEW
Metabolism of N-nitrosodimethylamine, methylation of macromolecules, and development of hepatic fibrosis in rodent models Joseph George 1
&
Mutsumi Tsuchishima 1 & Mikihiro Tsutsumi 1
Received: 4 March 2020 / Revised: 4 July 2020 / Accepted: 9 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Hepatic fibrosis and cirrhosis are chronic diseases affecting liver and a major health problem throughout the world. The hallmark of fibrosis and cirrhosis is inordinate synthesis and deposition of fibril forming collagens in the extracellular matrix of the liver leading to nodule formation and loss of normal architecture. Hepatic stellate cells play a crucial role in the pathogenesis and progression of liver fibrosis through secretion of several potent fibrogenic factors that trigger hepatocytes, portal fibrocytes, and bone marrow–derived fibroblasts to synthesize and deposit several connective tissue proteins, especially collagens between hepatocytes and space of Disse. Regulation of various events involved in the activation and transformation of hepatic stellate cells seems to be an appropriate strategy for the arrest of hepatic fibrosis and liver cirrhosis. In order to unravel the molecular mechanisms involved in the pathogenesis and progression of hepatic fibrosis, to determine proper and potent targets to arrest fibrosis, and to discover powerful therapeutic agents, a quick and reproducible animal model of hepatic fibrosis and liver cirrhosis that display all decompensating features of human condition is required. This review thoroughly evaluates the biochemical, histological, and pathological features of N-nitrosodimethylamine-induced model of liver injury, hepatic fibrosis, and early cirrhosis in rodents. Keywords Hepatic fibrosis . Liver cirrhosis . Rodent model . N-Nitrosodimethylamine . NDMA . Dimethylnitrosamine
Introduction Hepatic fibrosis is the result of a pathological response of most chronic liver injury and a serious health problem worldwide. Hepatic fibrogenesis is a physiological process that converts into a pathological situation due to contour stimulus from the causative agent. Various types of chronic liver injury could lead to fibrosis that gradually develops into liver cirrhosis and may result in liver cancer [1, 2]. The hallmark of hepatic fibrosis is an excessive synthesis and abnormal deposition of connective tissue components, especially interstitial collagens in the extracellular matrix of the liver [3–7]. It is the result of an abnormal and repeated wound healing response generated as a result of chronic liver injury from various factors, such as drugs, alcohol,
* Joseph George [email protected] 1
Department of Hepatology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan
non-alcoholic steatohepatitis (NASH), hepatitis B and C viral (HBV & HCV) infections, autoimmune hepatitis, and cholestatic liver diseases [8, 9]. The pathogenesis of hepatic fibrosis triggers from oxidative stress caused from elevated levels of r
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