©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pharmacol Ther. Mar 5, 2022; 13(2): 11-22
Published online Mar 5, 2022. doi: 10.4292/wjgpt.v13.i2.11
Melatonin restores zinc levels, activates the Keap1/Nrf2 pathway, and modulates endoplasmic reticular stress and HSP in rats with chronic hepatotoxicity
Silvia Bona, Sabrina Alves Fernandes, Andrea C Janz Moreira, Graziella Rodrigues, Elizângela G Schemitt, Fabio Cangeri Di Naso, Cláudio A Marroni, Norma P Marroni
Silvia Bona, Graziella Rodrigues, Elizângela G Schemitt, Norma P Marroni, Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
Sabrina Alves Fernandes, Cláudio A Marroni, Posgraduate Program in Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre 90040-001, Rio Grande do Sul, Brazil
Andrea C Janz Moreira, Biological Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
Fabio Cangeri Di Naso, Postgraduate Program in Pneumological Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90000-000, Rio Grande do Sul, Brazil
Author contributions: Marroni NP contributed to conceptualization; Bona S, Rodrigues G, and Moreira AJ contributed to data collection and review of the formal analysis of the databases; Di Naso F, Fernandes SA, Schemitt EG, and Marroni CA contributed to original preparation of the manuscript; Marroni NP, Bona S, Rodrigues G, Moreira AJ, Di Naso F, Fernandes SA, Schemitt EG, and Marroni CA have read and agreed to the published version of the manuscript.
Supported by the FIPE/Hospital de Clínicas of Porto Alegre.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee on the use of animals of the Research and Graduate Group of the Hospital de Clínicas de Porto Alegre.
Institutional animal care and use committee statement: The project was approved in its ethical and methodological aspects in accordance with established procedures for the scientific use of animals (Letter of approval nº 100316-Ethical Committee on the Use of Animals [CEUA] of the Hospital de Clínicas of Porto Alegre [HCPA], RS, Brazil).
Conflict-of-interest statement: The authors declare that they have no conflicts of interest to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Corresponding author: Norma P Marroni, PhD, Doctor, Full Professor, Research Scientist, Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Rua José Kanan Aranha 102, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
nmarroni@terra.com.br
Received: July 7, 2021
Peer-review started: July 7, 2021
First decision: October 3, 2021
Revised: October 18, 2021
Accepted: January 19, 2022
Article in press: January 19, 2022
Published online: March 5, 2022
Processing time: 237 Days and 9.4 Hours
BACKGROUND
Melatonin (MLT) is a potent antioxidant molecule that is shown to have a beneficial effect in various pathological situations, due to its action against free radicals.
AIM
To evaluate the effect of MLT on carbon tetrachloride (CCl4) induced liver injury in rats in terms of oxidative stress, reticular stress, and cell damage.
METHODS
Twenty male Wistar rats (230-250 g) were divided into four groups: Control rats, rats treated with MLT alone, rats treated with CCl4 alone, and rats treated with CCl4 plus MLT. CCl4 was administered as follows: Ten doses every 5 d, ten every 4 d, and seven every 3 d. MLT was administered intraperitoneally at a dose of 20 mg/kg from the 10th wk to the end of the experiment (16th wk).
RESULTS
MLT was able to reduce the release of liver enzymes in the bloodstream and to decrease oxidative stress in CCl4 treated rats by decreasing the level of thiobarbituric acid reactive substances and increasing superoxide dismutase activity, with a lower reduction in serum zinc levels, guaranteeing a reduction in liver damage; additionally, it increased the expression of nuclear factor (erythroid-derived 2)-like 2 and decreased the expression of Kelch-like ECH-associated protein 1. MLT also decreased the expression of the proteins associated with endoplasmic reticulum stress, i.e., glucose-regulated protein 78 and activating transcription factor 6, as well as of heat shock factor 1 and heat shock protein 70.
CONCLUSION
MLT has a hepatoprotective effect in an experimental model of CCl4-induced liver injury, since it reduces oxidative stress, restores zinc levels, and modulates endoplasmic reticulum stress.
Core Tip: Liver cirrhosis is a chronic condition of the liver that is characterized by inflammation, steatosis, and formation of fibrotic tissue that impair liver function. Several studies have demonstrated the relationship between oxidative stress and the development of different diseases. As oxidative stress can damage lipids, proteins, and DNA, causing changes in cell homeostasis, it is important to study therapeutic substances that can minimize or delay the effects of the disease. Hepatotoxic drugs are commonly used as an experimental model to assess different stages of liver disease. Melatonin was used in this work as a therapeutic strategy and showed hepatoprotective action in a chronic hepatotoxicity model.
