Basic Study
Copyright ©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.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
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
ARTICLE HIGHLIGHTS
Research background

Chronic liver diseases are characterized by a multistep process that involves several molecules and cellular events to transform a normal parenchyma into a parenchyma with steatosis, increased collagen deposition, fibrosis, and cirrhosis. 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.

Research motivation

To reduce the generation of reactive oxygen species would be a way to slow the progression of cell damage observed in liver diseases.

Research objectives

To study the effects of MLT on biochemical analysis, on serum zinc levels, and on oxidative stress in rats exposed to carbon tetrachloride (CCl4), and to evaluate the expression of proteins involved in cell damage, endoplasmic reticular stress, and unfolded protein response in animals with liver injury induced by CCl4 and treated with MLT.

Research 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 7 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).

Research results

Administration of CCl4 caused an increase in liver enzyme levels, a reduction in serum zinc levels, and greater oxidative stress and ER stress. MLT treatment was able to reverse the changes promoted by the toxic agent CCl4.

Research conclusions

We conclude that MLT acts as a potent antioxidant, promoting activation of the nuclear factor Nrf2, which allows the reduction in oxidative stress. Concomitantly, we observed the restoration of serum zinc levels, which contributes to numerous hepatic cytoprotective processes. With the reduction of oxidative stress, it is possible to attenuate the ER stress and the unfolded protein response, as well as the cell damage caused by the toxic agent CCl4.

Research perspectives

MLT may offer a promising therapeutic approach to liver diseases, given its effectiveness in the attenuation of oxidative stress. A major limitation in the application of MLT is that most of the studies were designed especially on rats. More research is needed in clinical trials to approve the potentials of this indolamine in humans.