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      Is melatonin associated with pro-inflammatory cytokine activity and liver fibrosis in non-alcoholic fatty liver disease (NAFLD) patients?

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          Abstract

          Aim:

          The associations between serum levels of melatonin and concentrations of tumor necrosis factor (TNF)-a and interleukin (IL)-6 were assessed among patients with different degrees of non-alcoholic fatty liver disease.

          Background:

          Non-alcoholic fatty liver disease (NAFLD) has become a very common worldwide disease.

          Methods:

          In this cross-sectional study, adult patients diagnosed with fatty liver disease by Fibroscan evaluation were included if they met the inclusion/exclusion criteria for NAFLD. The participants were categorized into the three following groups: 1) fibrosis> 9.1KP and steatosis >290 dbm; 2) fibrosis: 6-9.0 KP and steatosis 240-285; and 3) fibrosis < 5.8 KP and steatosis<240 dbm. Post-fasting, 5 ml of venous blood was collected for laboratory assessment, and a questionnaire including demographic, anthropometric, laboratories and clinical data was completed.

          Results:

          A total of 97 participants were included. The mean age was 42.21±11 years, and 59 patients (60.0%) were female. Melatonin levels as well as pro-inflammatory cytokines levels were correlated with advancing fibrosis and steatosis in univariate analysis. A significant association was observed between these cytokines and advancing fibrosis, severe steatosis levels, and melatonin concentrations. Furthermore, in the multiple linear regression model, melatonin levels showed a significant association with these cytokines.

          Conclusion:

          Melatonin may have protective effects on tissue injury during advancing liver fibrosis via cytokines modulation. Therefore, it can be considered as a potential therapeutic management strategy for NAFLD.

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          Most cited references44

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          Mechanisms of NAFLD development and therapeutic strategies

          There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.
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            • Article: found

            The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).

            Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis.
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              Melatonin as an antioxidant: under promises but over delivers.

              Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals, which are involved in the Fenton/Haber-Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its antiradical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high-safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule.

                Author and article information

                Journal
                Gastroenterol Hepatol Bed Bench
                Gastroenterol Hepatol Bed Bench
                GHFBB
                Gastroenterology and Hepatology From Bed to Bench
                Shaheed Beheshti University of Medical Sciences (Tehran, Iran )
                2008-2258
                2008-4234
                Summer 2021
                : 14
                : 3
                : 229-236
                Affiliations
                [1 ] GastroIntestinal and liver Diseases Research Center (GILDRC) , Iran University of Medical sciences, Tehran, Iran
                [2 ] Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran 
                [3 ] Department of Epidemiology & Biostatistics, School of Public Health, Neyshabur University of Medical Sciences, Neyshabur, Iran
                [4 ] Iranian Institute Pasture, Tehran, Iran
                Author notes
                Reprint or Correspondence: Hossein Keyvani& Mohsen Nasiri Toosi, MD. GILDRC ,Firoozgar Hospital ,Behafarin Ave ,Valiasr sq. Tehran & Liver transplantation Research Center. Imam Khomeini Hospital, Tehran –Iran. E-mail: m.keyvanihossein94@gmail.com & nasirimohsen@gmail.com , ORCID ID: 0000-0002-6528-7861& 0000-0002-6106-4265
                Article
                GHFBB-14-229
                8245841
                34221262
                36605eab-2f27-4f79-9453-e1fbe8aca10a
                ©2021 RIGLD, Research Institute for Gastroenterology and Liver Diseases

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 February 2021
                : 22 April 2021
                Categories
                Original Article

                fatty liver,cytokine,melatonin,inflammation
                fatty liver, cytokine, melatonin, inflammation

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