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      The Hepatoprotective Effect of Taurisolo, a Nutraceutical Enriched in Resveratrol and Polyphenols, Involves Activation of Mitochondrial Metabolism in Mice Liver

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          Abstract

          Liver diseases affect millions of people worldwide. In most of the cases, severe hepatic dysfunction and liver cancer stem from mild and common clinical signs including hepatic steatosis, insulin resistance, liver inflammation, and oxidative stress, all together referred to as Nonalcoholic Fatty Liver Disease (NAFLD). Nutraceuticals endowed with antioxidant activity have been shown to reduce NAFLD risk factors and exert hepatoprotective effects. Here, we test the protective effect exerted on liver by the antioxidant Taurisolo, a nutraceutical formulation produced by grape pomace and enriched in Resveratrol and Polyphenols. We analyze the effect of Taurisolo on liver cells by profiling the metabolome of in vitro cultured hepatic HuH7 cells and of C57BL-6J mice fed a High Fat Diet and treated with the nutraceutical. Both in vitro and in vivo, we provide evidence that Taurisolo reduces risk factor markers associated with NAFLD. Taurisolo stimulates glucose uptake and reduces hepatic cholesterol and serum triglycerides. Furthermore, we give new insights into the mechanism of action of Taurisolo. The nutraceutical increases mitochondrial activity and promotes respiration and ATP production, fostering catabolic reactions like fatty acid β-oxidation and amino acid catabolism. On the contrary, Taurisolo reduces anabolic reactions like biosynthesis of cholesterol, bile acids, and plasma membrane lipids.

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          Most cited references32

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          Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine

          Chronic fibrotic liver disease caused by viral or metabolic etiologies is a high-risk condition for developing hepatocellular carcinoma (HCC). Even after complete HCC tumor resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumors, which progress into incurable, advanced-stage disease in the majority of patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, practice guideline-recommended “one-size-fits-all” HCC screening for early tumor detection is utilized in less than 20% of the target population, and performance of screening modalities, i.e., ultrasound and alpha-fetoprotein is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations such as chronic hepatitis C after viral cure and non-cirrhotic non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailored HCC screening for individual patients to maximize its cost-effectiveness and optimize allocation of limited medical resources. Several etiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalized chemoprevention targeting high-risk patients to achieve precision HCC prevention and substantially improve the dismal prognosis of HCC.
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            Risk of Hepatocellular Cancer in Patients with Non-alcoholic Fatty Liver Disease

            Background There are limited data on the risk of hepatocellular cancer (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to estimate the risk of incident HCC among patients with NAFLD. Methods We conducted a retrospective cohort study from a total of 130 facilities in the Veterans Health Administration. Patients with NAFLD diagnosed between 1/1/2004 and 12/31/2008 were included and followed until HCC diagnosis, death or 12/31/2015. We also identified a gender and age-matched control cohort without NAFLD. We ascertained all new HCC cases from the Central Cancer Registry and manual chart reviews. We calculated incidence rates for HCC by NAFLD status as well as in subgroups of NAFLD patients. We used competing risk models to compare the risk of HCC in patients with vs . those without NAFLD. We reviewed electronic medical records of all HCC cases that developed in NAFLD patients without cirrhosis. Results We compared 296,707 NAFLD patients with 296,707 matched controls. During 2,382,289 person-years [PY] of follow-up, 490 NAFLD patients developed HCC (0.21/1000 PY). HCC incidence was significantly higher among NAFLD patients vs. controls (0.02/1000 PY; hazard ratio, 7.62, 95% confidence interval=5.76–10.09). Among patients with NAFLD, those with cirrhosis had the highest annual incidence of HCC (10.6 /1000 PY). Among patients with NAFLD cirrhosis, HCC risk ranged from 1.6 to 23.7 per 1000 PY based on other demographic characteristics; the risk of HCC was the highest in older Hispanics with cirrhosis. In medical record reviews, 20% of NAFLD patients with HCC had no evidence of cirrhosis. Conclusions Risk of HCC was higher in NAFLD patients than that observed in general clinical population. Most HCC cases in NAFLD developed in patients with cirrhosis. The absolute risk of HCC was higher than the accepted thresholds for HCC surveillance for most patients with NAFLD cirrhosis.
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              Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet.

              Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here, we tested the effect of a 2-year resveratrol administration on proinflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Resveratrol supplementation (80 and 480 mg/day for the first and second year, respectively) decreased adipocyte size, increased sirtuin 1 expression, decreased NF-κB activation, and improved insulin sensitivity in visceral, but not subcutaneous, WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS ± resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Antioxidants (Basel)
                Antioxidants (Basel)
                antioxidants
                Antioxidants
                MDPI
                2076-3921
                11 May 2020
                May 2020
                : 9
                : 5
                : 410
                Affiliations
                [1 ]Department of Pharmacy, University of Naples Federico II, Via Montesano 49, 80131 Naples, Italy; nadia.badolati@ 123456unina.it (N.B.); raffaello.masselli@ 123456unina.it (R.M.); alessandro.diminno@ 123456unina.it (A.D.M.); giancarlo.tenore@ 123456unina.it (G.C.T.); ettore.novellino@ 123456unina.it (E.N.)
                [2 ]Department of Pharmacy, School of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, SA, Italy; esommella@ 123456unisa.it (E.S.); esalviati@ 123456unisa.it (E.S.); pcampiglia@ 123456unisa.it (P.C.)
                [3 ]Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Pansini 5, 80149 Naples, Italy; serena.sagliocchi@ 123456unina.it (S.S.); monica.dentice@ 123456unina.it (M.D.)
                [4 ]PhD Program in Drug Discovery and Development, University of Salerno, I-84084 Fisciano, SA, Italy
                Author notes
                [* ]Correspondence: mariano.stornaiuolo@ 123456unina.it ; Tel.: +39-081-678-117
                [†]

                These authors equally contributed to the manuscript.

                Author information
                https://orcid.org/0000-0002-1622-6384
                https://orcid.org/0000-0003-4408-283X
                https://orcid.org/0000-0001-8084-9976
                https://orcid.org/0000-0003-2867-2784
                https://orcid.org/0000-0002-1069-2181
                https://orcid.org/0000-0002-9977-3761
                https://orcid.org/0000-0002-0251-9936
                https://orcid.org/0000-0003-2200-5083
                Article
                antioxidants-09-00410
                10.3390/antiox9050410
                7278674
                32403305
                70b81217-bc5c-4f07-8c37-e44926657e67
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 04 April 2020
                : 08 May 2020
                Categories
                Article

                antioxidants,resveratrol,polyphenols,nutraceuticals,mitochondria,liver

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