Melatonin prevents oxidative stress, inflammatory activity, and DNA damage in cirrhotic rats

Colares, Josieli Raskopf; Hartmann, Renata Minuzzo; Schemitt, Elizângela Gonçalves; Fonseca, Sandielly Rebeca Benitez da; Brasil, Marilda S; Picada, Jaqueline Nascimento; Dias, Alexandre Simões; Bueno, Aline; Marroni, Cláudio Augusto; Marroni, Norma Possa

doi:10.3748/wjg.v28.i3.348

Cited by 19 publications

(24 citation statements)

References 50 publications

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“…DNA damage in blood was also observed in NASH mice, showing that the in ammation processes elicited in NASH might affect other tissues besides liver, although no increase in MNPCE in the NASH group was observed, showing that the bone marrow cells were not affected by the systemic injuries triggered by the disease. Conversely, in our previous studies, cirrhotic rats have not shown an increase in DNA damage in blood cells, but the MNPCE frequency increased [23][24][25]. These ndings suggest that in the course of progression from NASH to cirrhosis the damaged blood cells could be removed or repaired, however the higher liver injuries in cirrhotic rats in comparison to NASH lead to systemic repercussions able to increase the genomic instability detected using the micronucleus test.…”

Section: Discussioncontrasting

confidence: 53%

“…Similarly, diseases involving an in ammatory process might increase the genomic instability detectable using the micronucleus test [21,59,60]. As already mentioned, no genomic instability was detected in the NASH model induced-MCD diet under conditions of the present study using micronucleus test in bone marrow, differently from other liver injury models such as cirrhosis induced by secondary bile duct ligation model [23][24][25], suggesting that genomic instability increases according to the progression of liver disease stages.…”

Section: Discussionsupporting

confidence: 51%

“…This is the rst study showing the ability of MLT to avoid DNA strand breaks in blood and liver cells of mice with NASH. In cirrhotic rats, MLT also decreased DNA damage in liver [23,54]. Other compounds such as quercetin and simvastatin have shown similar responses in mice with NASH induced by the MCD diet, decreasing DNA damage in liver [20,26].…”

Section: Discussionmentioning

confidence: 99%

“…In this sense, diseases associated with in ammatory processes might induce DNA damage in target tissues, leading to genomic instability which increases with the progression of these diseases [21,22]. It is known that cirrhotic rats have shown increased micronucleus frequency in bone marrow, which is a marker to assess genomic stability [23][24][25], but in the NASH model induced by MCD this biomarker remains to be analyzed.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2022

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Nonalcoholic steatohepatitis (NASH) is a disease with a high incidence worldwide, but its diagnosis and treatment are poorly managed. In this study, NASH pathophysiology and DNA damage biomarkers were investigated in mice with NASH treated and untreated with melatonin (MLT). C57BL/6 mice were fed a methionine-and choline-de cient (MCD) diet for four weeks to develop NASH. Melatonin was administered at 20 mg/kg during the last two weeks. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured, and hepatic tissue was dissected for histological analysis, evaluation of lipoperoxidation, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as nuclear factor-erythroid 2 (Nrf2), tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), and tumor necrosis factor alpha (TGF-β) expression by immunohistochemistry.DNA damage was evaluated using Comet assay, while a micronucleus test in bone marrow was performed to assess the genomic instability associated with the disease. Melatonin decreased AST and ALT, liver in ammatory processes, balloonization and brosis in mice with NASH, decreasing TNF-α, iNOS, and TGF-β, as well as oxidative stress, shown by reducing lipoperoxidation, and intensifying Nrf2 expression. The SOD and GPx activities were increased while CAT was decreased by treatment with MLT.Although the micronucleus frequency was not increased in mice with NASH, a protective effect on DNA was observed with MLT treatment in blood and liver tissues using Comet assay. As conclusions, MLT slows down the progression of NASH, reducing hepatic oxidative stress and in ammatory processes, inhibiting DNA damage via anti-in ammatory and antioxidant actions.

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Section: Discussioncontrasting

confidence: 53%

Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2022

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“…Moreover, melatonin will activate the antioxidant transcription factor (Fernández-Palanca et al 2021 ; Colares et al 2022 ), NRF2, which itself will start the ROS scavenging cascade. So according to our first findings, melatonin appears to act as an anti-drug resistance agent, recover the bad side effects of chemotherapy, could sensitize the cells for anti-tumor drugs, and could be administrated individually, or in combination, or post-chemotherapies as a promising supplementary component that will reduce, and minimize the side-effects of anticancer drugs.…”

Section: Discussionmentioning

confidence: 99%

Anti-drug resistance, anti-inflammation, and anti-proliferation activities mediated by melatonin in doxorubicin-resistant hepatocellular carcinoma: in vitro investigations

Hamed

Yahya

Nabih

2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Hepatocellular carcinoma (HCC) is the major life-threatening primary liver malignancy in both sexes all over the world. Unfortunately, the majority of patients are diagnosed at later stages because HCC does not elicit obvious symptoms during its early incidence. Consequently, most individuals escape the first-line HCC treatments and are treated with chemotherapy. Regrettably, the therapeutic outcomes for those patients are usually poor because of the development of multidrug resistance phenomena. Furthermore, most anti-HCC therapies cause severe undesired side effects that notably interfere with the life quality of such patients. Accordingly, there is an important need to search for an alternative therapeutic drug or adjuvant which is more efficient with safe or even minimal side effects for HCC treatment. Melatonin was recently reported to exert intrinsic antitumor activity in different cancers. However, the regulatory pathways underlying the antitumor activity of melatonin are poorly understood in resistant liver cells. Furthermore, a limited number of studies have addressed the therapeutic role of melatonin in HCC cells resistant to doxorubicin chemotherapy. In this study, we investigated the antitumor effects of melatonin in doxorubicin-resistant HepG2 cells and explored the regulatory pivotal targets underlying these effects. To achieve our aim, an MTT assay was used to calculate the 50% inhibitory concentration of melatonin and evaluate its antiproliferative effect on resistant cells. Additionally, qRT-PCR was used to quantify genes having a role in drug resistance phenotype (ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2); apoptosis (caspases-3, and -7, Bcl2, Bax, and p53); anti-oxidation (NRF2); expression of melatonin receptors (MT1, MT2, and MT3); besides, programmed death receptor PD-1 gene. The active form of the caspase-3 enzyme was estimated by ELISA. A human inflammatory antibody membrane array was employed to quantify forty inflammatory factors expressed in treated cells. We observed that melatonin inhibited the proliferation of doxorubicin-resistant HepG2 cells in a dose-dependent manner after 24-h incubation time with a calculated IC50 greater than 10 mM (13.4 mM), the expression levels of genes involved in drug resistance response (ABCB1, ABCC1, ABCC5, and ABCG2) were downregulated. Also, the expression of caspase-3, Caspase-7, NRF2, and p53 genes were expressed at higher levels as compared to control (DMSO-treated cells). An active form of caspase-3 was confirmed by ELISA. Moreover, the anti-inflammatory effect of melatonin was detected through the calculated fold change to control which was reduced for various mediators that have a role in the inflammation pathway. The current findings introduce melatonin as a promising anti-cancer treatment for human-resistant HCC which could be used in combination with current chemotherapeutic regimens to improve the outcome and reduce the developed multidrug resistance.

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Depleted uranium causes renal mitochondrial dysfunction through the ETHE1/Nrf2 pathway

Liu

Wang

Zhao

et al. 2023

Chemico-Biological Interactions

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Melatonin prevents oxidative stress, inflammatory activity, and DNA damage in cirrhotic rats

Cited by 19 publications

References 50 publications

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

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

Anti-drug resistance, anti-inflammation, and anti-proliferation activities mediated by melatonin in doxorubicin-resistant hepatocellular carcinoma: in vitro investigations

Depleted uranium causes renal mitochondrial dysfunction through the ETHE1/Nrf2 pathway

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