Melatonin Attenuates Inflammation, Oxidative Stress, and DNA Damage in Mice with Nonalcoholic Steatohepatitis Induced by a Methionine- and Choline-Deficient Diet

Miguel, Fabiano Moraes; Picada, Jaqueline Nascimento; Silva, Juliana Bondan da; Schemitt, Elizângela Gonçalves; Colares, Josieli Raskopf; Hartmann, Renata Minuzzo; Marroni, Cláudio Augusto; Marroni, Norma Possa

doi:10.1007/s10753-022-01667-4

Cited by 6 publications

(1 citation statement)

References 65 publications

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“…In contrast to the majority of studies that approved melatonin as an anti-oxidant agent that can induce the expression of NRF2 30,36,37 . Our data reported NRF2 to be expressed at lower levels after the treatment of cells by melatonin.…”

Section: Discussionmentioning

confidence: 89%

Anti-proliferative effect of melatonin in human hepatoma HepG2 cells occurs mainly through cell cycle arrest and inflammation inhibition

Nabih

Hamed

Yahya

2023

Sci Rep

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Hepatocellular carcinoma (HCC) is the major lethal primary liver malignant worldwide. Although, melatonin has various antitumor bioactivities; there is a requirement for more investigations to elucidate the not discussed effects, and the controversial responses of the treatment with melatonin on targets mediated in HCC. To achieve the aim of the present study, HCC-HepG2 cells were treated with different concentrations of melatonin at various time intervals. The selected minimal proliferation inhibition doses of melatonin were then incubated with cells to examine the arresting effect of melatonin on dividing cells using flow cytometry. Furthermore, the molecular patterns of genes that contributed to apoptosis, drug resistance development, antioxidation, and melatonin crossing were quantified by qRT-PCR. Additionally, the Human inflammation antibody array membrane (40 targets) was used to check the anti-inflammatory effect of melatonin. Our results validated that, melatonin shows anti-proliferative action through preserving cells in G0/G1 phase (P < 0.001) that is associated with a highly significant increase in the expression level of the P53 gene (P < 0.01). On contrary, as a novelty, our data recorded decreases in expression levels of genes involved in the pro-apoptotic pathway; with a significant increase (P < 0.05) in the expression level of an anti-apoptotic gene, Bcl2. Interestingly, we detected observed increases in the expression levels of genes responsible for conferring drug resistance including ABCB1, ABCC1, and ABCC5. Our study proved the anti-inflammatory activity of 1 mM melatonin in HCC-HepG2 cells. Accordingly, we can conclude that melatonin facilitates the anti-proliferation of cells at doses of 1 mM, and 2.5 mM after 24 h. This action is initiated through cell cycle arrest at G0/G1 phase via increasing the expression of P53, but independently on apoptosis. Collectively, melatonin is an effective anti-inflammatory and anti-proliferative promising therapy for the treatment of HCC. However, its consumption should be cautious to avoid the development of drug resistance and provide a better treatment strategy.

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Section: Discussionmentioning

confidence: 89%

Anti-proliferative effect of melatonin in human hepatoma HepG2 cells occurs mainly through cell cycle arrest and inflammation inhibition

Nabih

Hamed

Yahya

2023

Sci Rep

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A step forward on the in vitro and in vivo assessment of a novel nanomedicine against melanoma

Pinho

Matias

Godinho‐Santos

et al. 2023

International Journal of Pharmaceutics

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Melatonin alleviates diet-induced steatohepatitis by targeting multiple cell types in the liver to suppress inflammation and fibrosis

Zhang

et al. 2023

Journal of Molecular Endocrinology

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The pathogenesis of nonalcoholic steatohepatitis (NASH), a severe stage of nonalcoholic fatty liver disease, is complex and implicates multiple cell interactions. However, therapies for NASH that target multiple cell interactions are still lacking. Melatonin (MEL) alleviates NASH with mechanisms not yet fully understood. Thus, we herein investigate the effects of MEL on key cell types involved in NASH, including hepatocytes, macrophages, and stellate cells. In a mouse NASH model with feeding of a methionine and choline-deficient (MCD) diet, MEL administration suppressed lipid accumulation and peroxidation, improved insulin sensitivity, attenuated inflammation and fibrogenesis in the liver. Specifically, MEL reduced proinflammatory cytokines expression and inflammatory signal activation and attenuated CD11C+CD206- M1-like macrophage polarization in the liver of NASH mice. The reduction of proinflammatory response by MEL was also observed in the lipopolysaccharide-stimulated Raw264.7 cells. Additionally, MEL increased liver fatty acid β-oxidation, leading to reduced lipid accumulation, and restored the oleate-loaded primary hepatocytes. Finally, MEL attenuated hepatic stellate cell activation and fibrogenesis in the liver of MCD-fed mice and in LX-2 human hepatic stellate cells. In conclusion, MEL acts on multiple cell types in the liver to mitigate NASH-associated phenotypes, supporting MEL or its analog as potential treatment for NASH.

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Melatonin Attenuates Inflammation, Oxidative Stress, and DNA Damage in Mice with Nonalcoholic Steatohepatitis Induced by a Methionine- and Choline-Deficient Diet

Cited by 6 publications

References 65 publications

Anti-proliferative effect of melatonin in human hepatoma HepG2 cells occurs mainly through cell cycle arrest and inflammation inhibition

Anti-proliferative effect of melatonin in human hepatoma HepG2 cells occurs mainly through cell cycle arrest and inflammation inhibition

A step forward on the in vitro and in vivo assessment of a novel nanomedicine against melanoma

Melatonin alleviates diet-induced steatohepatitis by targeting multiple cell types in the liver to suppress inflammation and fibrosis

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