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Metabolism of N-nitrosodimethylamine, methylation of macromolecules, and development of hepatic fibrosis in rodent models

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.

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Funding

This work was partly supported from Japan Society for the Promotion of Science (JSPS) by Grant # 10670515 to M. Tsutsumi.

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Contributions

J. George carried out the major experiments, collected the data, analyzed and interpreted the data, and wrote the manuscript. M. Tsuchishima was involved in the conception and design of the study, provided materials, and evaluated the work. M. Tsutsumi obtained funding and critically evaluated the contents of the manuscript.

Corresponding author

Correspondence to Joseph George.

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All the experimental works stated in the manuscript have been carried out in compliance with ethical standards. All the animals received food and water available ad libitum. All authors have read and approved the final version of the manuscript and tacitly or explicitly share responsibility.

Ethical approval

All the animal experiments stated in this manuscript have been carried out with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 86-23, revised 1996). The animals received humane care as per the criteria outlined in the manual. The protocol was also approved by the Animal Care and Research Committee of Kanazawa Medical University on the Ethics of Animal Experiments.

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The authors declare that they do not have no any conflicts of interest. to declare in connection with this manuscript.

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George, J., Tsuchishima, M. & Tsutsumi, M. Metabolism of N-nitrosodimethylamine, methylation of macromolecules, and development of hepatic fibrosis in rodent models. J Mol Med 98, 1203–1213 (2020). https://doi.org/10.1007/s00109-020-01950-7

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Keywords

  • Hepatic fibrosis
  • Liver cirrhosis
  • Rodent model
  • N-Nitrosodimethylamine
  • NDMA
  • Dimethylnitrosamine