Effects of Melatonin on Liver Injuries and Diseases

Zhang, Jiao Jiao; Meng, Xiao; Li, Ya; Zhou, Yue; Xu, Danyan; Li, Sha; Li, Hua Bin

doi:10.3390/ijms18040673

Cited by 102 publications

(73 citation statements)

References 168 publications

(196 reference statements)

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“…Melatonin has protective effects against oxidative stress followed by inflammation caused by reactive oxygen species (ROS) or reactive nitrogen species . Therefore, melatonin administration shows therapeutic effects in various disorders including liver diseases . Melatonin has potentials for novel treatments of liver diseases by decreasing oxidative stress or restoring circadian rhythms and functions.…”

Section: Introductionmentioning

confidence: 99%

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress‐induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.

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Section: Introductionmentioning

confidence: 99%

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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“…Melatonin has been shown to be associated with the severity of liver insufficiency in patients with liver cirrhosis (7). Several studies have shown that melatonin has protective effects in several diseases, including cholestatic liver injury, alcohol-induced liver injury, nonalcoholic fatty liver disease, liver fibrosis and cirrhosis, and hepatocarcinoma (8)(9)(10)(11). We have shown that prolonged exposure to dark reduces biliary hyperplasia and liver fibrosis in bile-ductligated (BDL) rats by enhanced melatonin synthesis and down-regulation of selected clock genes (8).…”

mentioning

confidence: 99%

Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR‐200b down‐regulation

Meng

Zhou

et al. 2017

FASEB j.

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Melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in bile-duct-ligated (BDL) rats; however, no information exists in primary sclerosing cholangitis (PSC). Thus, we aimed to determine the therapeutic effects of prolonged dark therapy or melatonin administration on hepatic fibrosis in the multidrug resistance gene 2-knockout (Mdr2) mouse model of PSC. Melatonin levels, biliary mass, liver fibrosis, angiogenesis and miR-200b expression were evaluated in wild-type and Mdr2 mice exposed to darkness or melatonin treatment or in male patients with PSC and healthy controls. Mdr2 mice were also treated with miR-200b inhibitor or control before evaluating biliary mass, liver fibrosis, and angiogenesis. After overexpression of arylalkylamine -acetyltransferase (AANAT; the enzyme regulating melatonin synthesis) or inhibition of miR-200b in cholangiocytes and hepatic stellate cells, we evaluated angiogenesis and fibrosis gene expression. After exposure to darkness or administration of melatonin, Mdr2 mice show elevated serum melatonin levels and inhibition of biliary mass, along with reduction of liver fibrosis and angiogenesis. MicroRNA PCR analysis demonstrated that miR-200b expression increased in Mdr2 mice and patients with PSC compared with controls and decreased in Mdr2 mice subjected to dark exposure or melatonin treatment. Inhibition of miR-200b in Mdr2 ablates biliary proliferation, liver fibrosis, and angiogenesis. , overexpression of AANAT or inhibition of miR-200b in cholangiocytes and hepatic stellate cells decreased the expression of miR-200b, angiogenesis, and fibrosis genes. Dark therapy or targeting melatonin/miR-200b axis may be important in the management of biliary damage and liver fibrosis in cholangiopathies including PSC.-Wu, N., Meng, F., Zhou, T., Han, Y., Kennedy, L., Venter, J., Francis, H., DeMorrow, S., Onori, P., Invernizzi, P., Bernuzzi, F., Mancinelli, R., Gaudio, E., Franchitto, A., Glaser, S., Alpini G. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation.

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“…It protects various tissues from persistently produced free radicals and significant anti‐inflammatory and immunomodulatory activity, as well as oncostatic properties . Preliminary tests in human subjects have shown the beneficial effect of exogenous MLT in preventing ulcerative colitis, colon cancer, nonalcoholic fatty liver disease, and complications associated with partial liver resection …”

Section: Introductionmentioning

confidence: 99%

“…Chronic liver diseases cause progressive destruction of the liver parenchyma and accumulation of the extracellular matrix (ECM), increased collagen synthesis, and inability to promote ECM degradation, resulting in fibrosis and subsequent liver cirrhosis, which is the 10th leading cause of death in the Western world. 1,2 Liver fibrogenesis is triggered by increased reactive oxygen species (ROS), 3 leading to an inflammatory process by activating profibrogenic mediators, such as transforming growth factor beta (TGF-β). TGF-β induces the activation of hepatic stellate cells (HSC) to differentiate into myofibroblasts, thus increasing the expression of cytokines and proteins involved in matrix remodeling.…”

Section: Introductionmentioning

confidence: 99%

“…5 Preliminary tests in human subjects have shown the beneficial effect of exogenous MLT in preventing ulcerative colitis, colon cancer, nonalcoholic fatty liver disease, and complications associated with partial liver resection. 2,15 Liver cirrhosis is associated with high risk of mortality, and liver transplantation is not always available in a timely manner. The inhibition of fibrogenic mechanisms represents an important molecular target of therapeutic action, contributing to a temporary support for patients awaiting liver transplantation.…”

Section: Introductionmentioning

confidence: 99%

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Antifibrogenic effect of melatonin in rats with experimental liver cirrhosis induced by carbon tetrachloride

et al. 2018

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Background and AimLiver diseases are a major public health problem, accounting for a significant number of hospital visits and admissions and an increasing mortality rate. Melatonin (MLT) is a powerful antioxidant molecule that has been shown to be beneficial under various conditions. The objective was to evaluate the effect of MLT on experimental liver cirrhosis induced by carbon tetrachloride (CCl4) in rats.MethodsTwenty male Wistar rats (230–250 g) were divided into four groups. I: control group (CO); II: CO + MLT; III: CCl4; and IV: CCl4 + MLT. CCl4 was administered intraperitoneally (i.p.) as follows: 10 doses every 5 days, 10 doses every 4 days, and 7 doses every 3 days. MLT was administered i.p. at a dose of 20 mg/kg from the 10th week to the end of the experiment (16th week).ResultsIn the CCl4 + MLT group, we found that MLT caused a decrease in the level of F2‐isoprostanes and NQO1 expression. We also found that MLT reduced the inflammatory process as shown by decreased expressions of NF‐KB/p65 and inducible nitric oxide synthase (iNOS) and a smaller amount of inflammatory infiltrate. MLT reduced the expression of transforming growth factor beta1 (TGF‐β1), alpha‐smooth muscle actin (α‐SMA), and vascular endothelial growth factor (VEGF). Picrosirius staining showed that MLT decreases fibrosis.ConclusionMLT has a potent antifibrogenic effect, modulating the parameters of oxidative stress, angiogenesis, and inflammation.

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Effects of Melatonin on Liver Injuries and Diseases

Cited by 102 publications

References 168 publications

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR‐200b down‐regulation

Antifibrogenic effect of melatonin in rats with experimental liver cirrhosis induced by carbon tetrachloride

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