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March 14, 2022, 16:41

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There are many studies on the overproduction of reactive oxygen species (ROS) in liver toxicity and chronic liver disease resulting in oxidative stress and endoplasmic reticulum stress. The study of Silvia Bona et al., is among these. The authors have evaluated the damage induced by CCL4 administration to rats and the effect on the liver toxicity of melatonin, the hormone derives from the amino acid tryptophan and is produced by the pineal gland, with a variety of effects on mood, sleep, reproduction, immune system, circadian rhythm, aging and thus modulating antioxidant defense system. The biochemical analysis indicates that the transaminases and alkaline phosphatase were increased in CCL4 –treated animals and Melatonin was able to bring the levels of enzyme activities back to basal. Melatonin also was able to restore the peroxidation markers, LPO and SOD activity as well as the protein markers related to oxidative stress Keap1/Nrf2 pathway. An here comes the more original part of the article of Bona et al., a less common parameter, such as endoplasmic reticulum stress and the protein folding were also taken into account, measuring the markers of ER stress: ATF6 and GRP78/BiP. Redox stress impair the protein synthesis resulting in accumulation of misfolded proteins. The expression of these proteins was increased in CCL4- treated animals and melatonin was able to restore the levels to basal. Unfolded proteins are very toxic due to their capability to aggregate, therefore eukariotic cells have evolved systems able to prevent excessive accumulation of proteins in the endoplasmic reticulum that may give rise to a complex reaction called unfolded protein response (UPR). UPR in turn gives rise to an increased transcription of the specific genes leading to the synthesis of chaperones proteins of ER or they may slow down the synthesis of the new proteins, to keep it low and reduce aggregation. Other parameters very important for cellular proteins to keep low the excessive redox levels and protein folding are Heat Shock Proteins (HSP) and the nuclear Heat Shock Factor 1 (HSF1). Among heat shock proteins, a protein family most conserved in evolution expressed both constitutively and inducibly is the HSP70. Another interesting paramenter studied by Bona et al.,in addition to the biochemical parameters measured is the level of Zinc. Zinc is a very important micronutrient essential for human health starting from protein physiology and function (i.e.insulin) up to oxidative markers and its dysregulation may be an important determinant of several pathologies such as anemia, growth retardation, skin alteration , mental impairment, macular degeneration, blindness. Zinc deficiency impairs situations of oxidative stress and its markers. The zinc levels was dramatically decreased in cytotoxic hepatocytes, but melatonin restored its level to normal control value, confirming once more its efficiency, not only as an antioxidant. Melatonin is probably able to modulate zinc level and its association to circadian rhythm. To summarize, the paper of Bona et al., has a very good consistency since the authors take into account not only the known biochemical parameters, but also zinc levels, a micronutrient essential for human health, and UPR, very important to know how the membrane-bound transcription factors as well as the cell function and structure are regulated.

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Replied on June 01, 2024, 19:55

We are pleased with your criticisms and comments. Thank you for taking your precious time to review the article.

Replied on April 24, 2022, 14:36

Thanks for the opportunity

Replied on April 15, 2022, 15:43

We are very pleased with such recognition of our study. We remain at your disposal for any questions, suggestions and criticisms.