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Fu Y, Jiang C, Li Z, Shi X, Lv P, Zhang J. Association between the composite dietary antioxidant index and non-alcoholic fatty liver disease: evidence from National Health and Nutrition Examination Survey 2005-2016. Front Nutr 2025; 12:1473487. [PMID: 39917746 PMCID: PMC11798779 DOI: 10.3389/fnut.2025.1473487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 01/06/2025] [Indexed: 02/09/2025] Open
Abstract
Importance Oxidative stress contributes to the progression of non-alcoholic fatty liver disease (NAFLD). Antioxidants from food can reduce NAFLD incidence, and the Composite Dietary Antioxidant Index (CDAI) measures total antioxidant capacity (TAC). However, the relationship between CDAI and NAFLD in the US adult population remains unclear. Objective To assess whether CDAI is associated with NAFLD in US adults. Design setting and participants This population-based cross-sectional study used data on US adults from the National Health and Nutrition Examination Survey (NHANES) 2005-2016 cycles. Data were analyzed from January to February 2024. Exposures CDAI obtained from the dietary intake questionnaire. Main outcomes and measures The main outcome was NAFLD which defined by the US fatty liver score (USFLI) ≥30. Sampling weights were calculated according to NHANES guidelines. Results Among 9,746 adults included in this study [mean age, 48.3 years; 4,662 (47.6%) males], 3,324 (33.0%) were classified as having NAFLD using USFLI. In the fully adjusted of multivariable logistic regression, CDAI was negatively associated with NAFLD (odds ratio [OR], 0.95; 95% CI, 0.93-0.98). Furthermore, individuals in the highest quartile of CDAI were 34% less likely to have NAFLD compared to those in the lowest quartile (OR, 0.66; 95% CI, 0.52-0.85). In subgroup analyses, CDAI was inversely associated with NAFLD among participants with a BMI <25 (OR, 0.89; 95% CI, 0.83-0.95) and without metabolic syndrome (OR, 0.93; 95% CI, 0.91-0.96). The interaction tests revealed significant differences in these subgroups (P for interaction = 0.04 for BMI and 0.003 for metabolic syndrome). Sensitivity analyses confirmed this association using the hepatic steatosis index (HSI) to define NAFLD, applying unweighted logistic regression, adjusting for physical activity or after excluding non-Hispanic Black participants, and after excluding medications known for their potential hepatotoxic effects. Conclusions and relevance In this cross-sectional study based on six cycles (2005-2016) of the NHANES, CDAI was negatively associated with NAFLD in US adult population. This association highlights the potential for dietary interventions to reduce NAFLD incidence and underscores the need for future research, including clinical trials and mechanistic studies, to further explore the role of dietary antioxidants in NAFLD prevention and management.
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Affiliation(s)
- Yidian Fu
- Graduate School of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Chao Jiang
- Department of Psychosomatic Medicine, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Zonglin Li
- Department of Medical Laboratory, Liaocheng Hospital of Traditional Chinese Medicine, Liaocheng, Shandong, China
| | - Xiangyun Shi
- College of Geography and Resources, Sichuan Normal University, Chengdu, China
| | - Peiyuan Lv
- Graduate School of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Jingbo Zhang
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Himoto T, Fujita K, Mimura S, Tani J, Morishita A, Kubota S, Masaki T. Involvement of essential trace elements in the pathogenesis of hepatitis C virus‑related chronic liver disease and nonalcoholic steatohepatitis. Exp Ther Med 2024; 27:19. [PMID: 38223320 PMCID: PMC10785032 DOI: 10.3892/etm.2023.12307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 08/24/2023] [Indexed: 01/16/2024] Open
Abstract
Essential trace elements are involved in the pathogenesis of chronic liver disease (CLD), which causes hepatic inflammation, steatosis and fibrosis. The present study investigated the roles of essential trace elements in the pathogenesis of hepatitis C virus-related CLD (CLD-C) and nonalcoholic steatohepatitis (NASH), and compared the levels of these trace elements between the two groups. Serum zinc (Zn), selenium (Se), copper (Cu) and ferritin levels were measured in patients with CLD-C (n=66) and NASH (n=26). Subsequently, the correlations between the levels of these essential trace elements in patient sera and the biochemical or pathological parameters of patients with CLD-C and NASH were determined. The results demonstrated that the serum ferritin levels were significantly correlated with serum alanine aminotransferase levels in both the CLD-C and NASH groups. In both groups, the serum Zn and Se levels were significantly associated with serum albumin levels, and inversely associated with the stages of hepatic fibrosis. Furthermore, serum ferritin levels were positively associated, and serum Zn levels were inversely correlated with the grades of hepatic steatosis in patients with CLD-C, whereas serum Se levels were closely associated with the grades of hepatic steatosis only in patients with NASH. In both groups, serum ferritin levels were positively correlated, and serum Zn levels were inversely correlated with homeostasis model for the assessment of insulin resistance (HOMA-IR) values, and serum Se was negatively correlated with the HOMA-IR values in patients with CLD-C only. In conclusion, these results indicated that the involvement of essential trace elements in insulin resistance and hepatic steatosis may differ slightly between patients with CLD-C and those with NASH.
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Affiliation(s)
- Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761-0123, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Miki-cho, Kagawa 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Miki-cho, Kagawa 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Miki-cho, Kagawa 761-0793, Japan
| | - Asashiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Miki-cho, Kagawa 761-0793, Japan
| | | | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Miki-cho, Kagawa 761-0793, Japan
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Charaya A, Sahu C, Singla S, Jena G. Zinc Deficiency Exacerbates Bisphenol A-Induced Hepatic and Renal Damage: Delineation of Molecular Mechanisms. Biol Trace Elem Res 2023; 201:2879-2894. [PMID: 36076144 DOI: 10.1007/s12011-022-03392-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 08/12/2022] [Indexed: 11/02/2022]
Abstract
Zinc (Zn) plays an important role in the maintenance of redox status in the biological system. Zn deficiency has been found to be associated with negative effects on the functioning of many organ systems, including hepatic and renal systems. Bisphenol A (BPA) can alter Zn homeostasis and perturb the physiological system by provoking oxidative stress, which can lead to damage of different organs such as reproductive, immune, neuroendocrine, hepatic and renal systems. The present study aims to investigate the toxicity of BPA in Zn deficient condition in the liver and kidney of rat and to correlate its synergistic actions. Zn deficiency was induced by feeding Zn-deficient diet (ZDD), and BPA was administered orally (100 mg/kg/d). Male Sprague-Dawley rats were divided into four groups: NPD + Vehicle (normal feed and water), NPD + BPA (100 mg/kg/d), ZDD + Vehicle (fed with Zn-deficient diet only) and ZDD + BPA (Zn-deficient diet + BPA; 100 mg/kg/d) for 8 weeks. Biochemical, histopathological, TUNEL assay and protein expression profiles were determined to decipher the oxidative damage induced by ZDD and the toxicant BPA. Expression profile of nuclear factor erythroid 2-related factor 2, proliferating cell nuclear antigen, kelch-like ECH-associated protein 1, superoxide dismutase-1, metallothionein and apoptosis incidence showed that ZDD and BPA have a synergistic exacerbation effect on the liver and kidney of rat.
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Affiliation(s)
- Aarzoo Charaya
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Sahibzada Ajit Singh Nagar, Punjab, India, 160062
| | - Chittaranjan Sahu
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Sahibzada Ajit Singh Nagar, Punjab, India, 160062
| | - Shivani Singla
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Sahibzada Ajit Singh Nagar, Punjab, India, 160062
| | - Gopabandhu Jena
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Sahibzada Ajit Singh Nagar, Punjab, India, 160062.
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Coni P, Pichiri G, Lachowicz JI, Ravarino A, Ledda F, Fanni D, Gerosa C, Piras M, Coghe F, Gibo Y, Cau F, Castagnola M, Van Eyken P, Saba L, Piludu M, Faa G. Zinc as a Drug for Wilson's Disease, Non-Alcoholic Liver Disease and COVID-19-Related Liver Injury. Molecules 2021; 26:6614. [PMID: 34771023 PMCID: PMC8587580 DOI: 10.3390/molecules26216614] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 10/29/2021] [Indexed: 02/07/2023] Open
Abstract
Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson's disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson's disease. On the basis of the similarities, at histological level, between Wilson's disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.
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Affiliation(s)
- Pierpaolo Coni
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
| | - Giuseppina Pichiri
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
| | - Joanna Izabela Lachowicz
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
| | - Alberto Ravarino
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
| | - Francesca Ledda
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
| | - Daniela Fanni
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
| | - Clara Gerosa
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
| | - Monica Piras
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
| | - Ferdinando Coghe
- Dipartimento Servizi di Diagnosi e Cura, Azienda Ospedaliero-Universitaria di Cagliari (A.O.U.), University of Cagliari, 09024 Cagliari, Italy;
| | - Yukio Gibo
- Hepatology Clinic, 1-34-20 Muraimachiminami, Matsumoto, Nagano 399-0036, Japan;
| | - Flaviana Cau
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
| | - Massimo Castagnola
- Laboratorio di Proteomica e Metabonomica-Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00013 Rome, Italy;
| | - Peter Van Eyken
- Department of Pathology, Genk Regional Ziekenhuis, 3600 Genk, Belgium;
| | - Luca Saba
- Department of Radiology, Azienda Ospedaliero Universitaria (A.O.U.), di Cagliari—Polo di Monserrato s.s. 554, 09045 Monserrato, Italy;
| | - Marco Piludu
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy;
| | - Gavino Faa
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
- UOC Anatomia Patologica, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy
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Fathi M, Alavinejad P, Haidari Z, Amani R. The Effect of Zinc Supplementation on Steatosis Severity and Liver Function Enzymes in Overweight/Obese Patients with Mild to Moderate Non-alcoholic Fatty Liver Following Calorie-Restricted Diet: a Double-Blind, Randomized Placebo-Controlled Trial. Biol Trace Elem Res 2020; 197:394-404. [PMID: 32020523 DOI: 10.1007/s12011-019-02015-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 12/13/2019] [Indexed: 12/17/2022]
Abstract
The role of zinc is known in balancing the oxidant/antioxidant system and also in improving insulin resistance in many diseases. Recently, in vivo and in vitro studies revealed roles of zinc on lipophagy and suppressing hepatic lipid deposition. The present study is the first double-blind randomized clinical trial that investigated the effect of zinc supplement on clinical manifestations and anthropometric parameters of overweight/obese non-alcoholic fatty liver patients following calorie-restricted diet. Fifty-six overweight/obese subjects with confirmed non-alcoholic fatty liver disease (NAFLD) using ultrasonography were randomized to treatment (calorie-restricted diet plus 30 mg/day zinc supplement) or placebo (calorie-restricted diet and placebo) groups. Serum liver enzymes and liver steatosis were measured at the baseline and 12 weeks post-intervention. Anthropometric measurements and food recalls were collected at the beginning, weeks 6 and 12. Zinc supplementation significantly elevated serum zinc concentrations in the treatment group (p < 0.001). Treatment also reduced alanine aminotransferase and γ-glutamyl transpeptidase enzymes in the treatment group (p < 0.05). Waist circumference was also significantly lowered in the zinc group (p < 0.05). Liver steatosis and fatty liver index changes were not significant between the groups. Overall, beneficial effects of zinc supplementation were shown on serum levels of zinc and liver enzymes in overweight/obese NAFLD patients.
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Affiliation(s)
- Mojdeh Fathi
- Department of Clinical Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Isfahan Province, Iran
| | - Pezhman Alavinejad
- Alimentary Tract Research Center, Ahvaz Imam Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan Province, Iran
| | - Zahra Haidari
- Department of Biostatistics and Epidemiology, School of Health, Isfahan University of Medical Sciences, Isfahan, Isfahan Province, Iran
| | - Reza Amani
- Department of Clinical Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Isfahan Province, Iran.
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Himoto T, Masaki T. Current Trends of Essential Trace Elements in Patients with Chronic Liver Diseases. Nutrients 2020; 12:nu12072084. [PMID: 32674425 PMCID: PMC7400835 DOI: 10.3390/nu12072084] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/16/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Essential trace elements play crucial roles in the maintenance of health, since they are involved in many metabolic pathways. A deficiency or an excess of some trace elements, including zinc, selenium, iron, and copper, frequently causes these metabolic disorders such as impaired glucose tolerance and dyslipidemia. The liver largely regulates most of the metabolism of trace elements, and accordingly, an impairment of liver functions can result in numerous metabolic disorders. The administration or depletion of these trace elements can improve such metabolic disorders and liver dysfunction. Recent advances in molecular biological techniques have helped to elucidate the putative mechanisms by which liver disorders evoke metabolic abnormalities that are due to deficiencies or excesses of these trace elements. A genome-wide association study revealed that a genetic polymorphism affected the metabolism of a specific trace element. Gut dysbiosis was also responsible for impairment of the metabolism of a trace element. This review focuses on the current trends of four trace elements in chronic liver diseases, including chronic hepatitis, liver cirrhosis, nonalcoholic fatty liver disease, and autoimmune liver diseases. The novel mechanisms by which the trace elements participated in the pathogenesis of the chronic liver diseases are also mentioned.
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Affiliation(s)
- Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Hara, Mure-Cho, Takamatsu, Kagawa 761-0123, Japan
- Correspondence: ; Tel.: +81-87-870-1240; Fax: +81-87-870-1202
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0123, Japan;
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Bertol FS, Araujo B, Jorge BB, Rinaldi N, De Carli LA, Tovo CV. Role of micronutrients in staging of nonalcoholic fatty liver disease: A retrospective cross-sectional study. World J Gastrointest Surg 2020; 12:269-276. [PMID: 32774765 PMCID: PMC7385512 DOI: 10.4240/wjgs.v12.i6.269] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 04/10/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) presents high incidence throughout the world and has been progressively increasing in prevalence. This disease has a heterogeneous natural history, including simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. The factors that determine its evolution to more severe forms of the disease are still poorly understood, and micronutrients with antioxidant potential may be involved in the pathophysiology of the disease.
AIM To evaluate the relationship between serum levels of micronutrients and the severity of NAFLD.
METHODS A retrospective, observational and cross-sectional study was conducted. This study included all patients undergoing bariatric surgery who experienced liver biopsy during the procedure, and had serum levels of micronutrients (vitamin D, vitamin B12, zinc, iron, and magnesium), which was assessed in a preoperative evaluation conducted at a reference center in southern Brazil.
RESULTS A total of 614 patients were analyzed, of which 93% had steatosis, 70.7% had NASH, and 49.3% had some degree of fibrosis. Serum levels of vitamin D were negatively correlated with the severity of steatosis and NASH, and serum levels of vitamin B12 were positively correlated with the severity of steatosis and fibrosis. The other micronutrients showed no association with NAFLD staging.
CONCLUSION Serum levels of vitamin D are inversely related to the severity of steatosis and NASH, and serum levels of vitamin B12 are higher in more advanced stages of simple steatosis and liver fibrosis. Serum levels of zinc, iron, and magnesium were not associated with NAFLD severity.
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Affiliation(s)
- Franciele Sabadin Bertol
- Graduate Program of Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS 90430080, Brazil
| | - Bruna Araujo
- Graduate Program of Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS 90430080, Brazil
| | - Brunno Brochado Jorge
- Graduate Program of Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS 90430080, Brazil
| | - Natalino Rinaldi
- Graduate Program of Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS 90430080, Brazil
| | - Luiz Alberto De Carli
- Graduate Program of Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS 90430080, Brazil
| | - Cristiane Valle Tovo
- Graduate Program of Medicine, Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS 90430080, Brazil
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Sisnande T, Lima CK, da Silva DC, Beninatto TM, Alves NL, Amaral MJ, Miranda-Alves L, Lima LMTR. Dietary zinc restriction promotes degeneration of the endocrine pancreas in mice. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165675. [PMID: 31927001 DOI: 10.1016/j.bbadis.2020.165675] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 01/03/2020] [Accepted: 01/06/2020] [Indexed: 12/25/2022]
Abstract
Zinc is a key component of several proteins, interacting with the pancreatic hormones insulin and amylin. The role of zinc in insulin oligomerization and crystallinity is well established, although the effects of dietary zinc restriction on both energetic metabolism and β-pancreatic hormonemia and morphology remain unexplored. Here we report the effects of dietary zinc restriction on the endocrine pancreas and metabolic phenotype of mice. Nontransgenic male Swiss mice were fed a low-zinc or control diet for 4 weeks after weanling. Growth, glycemia, insulinemia and amylinemia were lower and pancreatic islets were smaller in the intervention group despite the preserved insulin crystallinity in secretory granules. We found strong immunostaining for insulin, amylin and oligomers in apoptotic pancreatic islet. High production of β-pancreatic hormones in zinc-restricted animals counteracted the reduced islet size caused by apoptosis. These data suggest that zinc deficiency is sufficient to promote islet β-cell hormonal disruption and degeneration.
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Affiliation(s)
- Tháyna Sisnande
- Laboratory for Pharmaceutical Biotechnology - pbiotech, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
| | - Cleverton K Lima
- Laboratory for Pharmaceutical Biotechnology - pbiotech, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Dayana Cabral da Silva
- Laboratory for Pharmaceutical Biotechnology - pbiotech, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Thayana Moulin Beninatto
- Laboratory for Pharmaceutical Biotechnology - pbiotech, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Natália Leão Alves
- Laboratory for Pharmaceutical Biotechnology - pbiotech, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Mariana J Amaral
- Hospital Universitário Clementino Fraga Filho, Federal University of Rio de Janeiro - UFRJ, CCS, Ilha do Fundão, 21941-902 Rio de Janeiro, RJ, Brazil.
| | - Leandro Miranda-Alves
- Laboratory of Experimental Endocrinology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
| | - Luís Maurício T R Lima
- Laboratory for Pharmaceutical Biotechnology - pbiotech, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil; Laboratory for Macromolecules (LAMAC-DIMAV), National Institute of Metrology, Quality and Technology - INMETRO, Avenida Nossa Senhora das Graças, 50 - Xerém, Duque de Caxias, Rio de Janeiro 25250-020, RJ, Brazil.
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Sevastianos VA, Voulgaris TA, Dourakis SP. Hepatitis C, systemic inflammation and oxidative stress: correlations with metabolic diseases. Expert Rev Gastroenterol Hepatol 2020; 14:27-37. [PMID: 31868062 DOI: 10.1080/17474124.2020.1708191] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Hepatitis C chronic infection has long been correlated with numerous systemic diseases, such as diabetes mellitus and hepatic steatosis. Recent studies have also revealed an association with atherosclerosis.Areas covered: An analysis is presented on the mechanisms through which the hepatitis C viral infection can lead to a systemic increase in pro-inflammatory markers, especially tumor necrosis factor-a and interleukin-6. The immunological imbalance created may, through different mechanisms, act on the metabolic pathways that contribute to the development of insulin resistance, the accumulation of lipids in the liver, and even the formation of atherosclerotic plaques. Moreover, an additional contributing factor to the above-mentioned metabolic derangements is the unopposed oxidative stress observed in chronic hepatitis C viral infection. The virus itself contributes to the formation of oxidative stress, through alterations in the trace metal homeostasis and its effect on pro-inflammatory cytokines, such as tumor necrosis factor-a.Expert opinion: The scope of this review is to emphasize the importance of the metabolic manifestations of hepatitis C viral infection and to elucidate the pathophysiological mechanisms behind their emergence.
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Affiliation(s)
- Vassilios A Sevastianos
- Department of Internal Medicine and Liver Outpatient Clinic, "Evangelismos" General Hospital, Athens, Greece
| | - Theodoros A Voulgaris
- Department of Internal Medicine and Liver Outpatient Clinic, "Evangelismos" General Hospital, Athens, Greece
| | - Spyros P Dourakis
- Department of Internal Μedicine, Medical School, National and Kapodistrian University of Athens, General Hospital of Athens Ippokrateio, Athens, Greece
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Shakibzadeh A, Sarvari J, Sabahi F, Ravanshad M. Antiviral activity and possible site of action of zinc against Hepatitis C virus in vitro. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2019. [DOI: 10.23736/s0393-3660.18.03964-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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11
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The relationship between zinc and hepatic steatosis. JOURNAL OF SURGERY AND MEDICINE 2019. [DOI: 10.28982/josam.608618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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12
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Thoen RU, Barther NN, Schemitt E, Bona S, Fernandes S, Coral G, Marroni NP, Tovo C, Guedes RP, Porawski M. Zinc supplementation reduces diet-induced obesity and improves insulin sensitivity in rats. Appl Physiol Nutr Metab 2019; 44:580-586. [PMID: 30339765 DOI: 10.1139/apnm-2018-0519] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Rates of obesity have been growing at alarming rates, compromising the health of the world population. Thus, the search for interventions that address the metabolic repercussions of obesity are necessary. Here we evaluated the metabolic and antioxidant effects of zinc and branched-chain amino acids (BCAA) supplementation on obese rats. Male Wistar rats were fed either a high-fat/high-fructose diet (HFD) or a standard diet (SD) for 19 weeks. From the fifteenth week until the end of the experiment, HFD- and SD-fed rats received zinc (6 mg/kg) or BCAA (750 mg/kg) supplementation. Body weight, abdominal fat, lipid profile, blood glucose, insulin, leptin, and hepatic transaminases were evaluated. In the liver, superoxide dismutase and catalase activities and lipid peroxidation were also analyzed. HFD-fed animals showed increased weight gain, abdominal fat pad, plasma insulin, leptin, and triglycerides levels in comparison with SD-fed rats. Zinc supplementation reduced all these parameters, suggesting a beneficial role for the treatment of obesity. BCAA, on the other hand, did not show any beneficial effect. Liver antioxidant enzymes and hepatic transaminases plasma levels did not change among groups. Lipid peroxidation was higher in HFD-fed rats and was not reverted by zinc or BCAA supplementation. In conclusion, zinc supplementation may be a useful strategy for the treatment of the metabolic dysfunction associated with obesity.
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Affiliation(s)
- Rutiane Ullmann Thoen
- a Postgraduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS 90050-170, Brazil
| | - Nathaniele Nebel Barther
- a Postgraduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS 90050-170, Brazil
| | - Elizângela Schemitt
- b Postgraduate Program in Medical Sciences, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS 90035-007, Brazil
| | - Sílvia Bona
- b Postgraduate Program in Medical Sciences, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS 90035-007, Brazil
| | - Sabrina Fernandes
- a Postgraduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS 90050-170, Brazil
| | - Gabriela Coral
- a Postgraduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS 90050-170, Brazil
| | - Norma Possa Marroni
- b Postgraduate Program in Medical Sciences, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS 90035-007, Brazil
| | - Cristiane Tovo
- a Postgraduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS 90050-170, Brazil
| | - Renata Padilha Guedes
- c Postgraduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre, RS 90050-170, Brazil
- d Postgraduate Program in Biosciences, UFCSPA, Porto Alegre, RS 90050-170, Brazil
| | - Marilene Porawski
- a Postgraduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS 90050-170, Brazil
- d Postgraduate Program in Biosciences, UFCSPA, Porto Alegre, RS 90050-170, Brazil
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13
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Himoto T, Fujita K, Sakamoto T, Nomura T, Morishita A, Yoneyama H, Haba R, Masaki T. Clinical efficacy of free androgen index, a surrogate hallmark of circulating free testosterone level, in male patients with HCV-related chronic liver disease. J Clin Biochem Nutr 2018; 63:238-245. [PMID: 30487676 PMCID: PMC6252299 DOI: 10.3164/jcbn.18-30] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 03/28/2018] [Indexed: 12/15/2022] Open
Abstract
The role of free testosterone, that not bound to sex hormone-binding globulin, in male patients with HCV infection remains uncertain. We investigated whether free testosterone is involved in the progression to hepatic fibrosis/steatosis or insulin resistance in male patients with HCV-related chronic liver disease or not. Free androgen indices, which reflect circulating free testosterone levels, were calculated as 100 × total testosterone levels/sex hormone-binding globulin levels in 30 male patients with HCV-related chronic liver disease. Degrees of hepatic fibrosis and steatosis were evaluated by the New Inuyama Classification and the classification proposed by Brunt and colleagues, respectively. Insulin resistance was estimated by HOMA-IR values. Serum total testosterone levels were independent of hepatic fibrosis staging in the enrolled patients. However, circulating sex hormone-binding globulin levels were significantly increased in proportion to the severity of hepatic fibrosis. Therefore, free androgen indices were inversely correlated with the severity of hepatic fibrosis. Moreover, free androgen indices were inversely correlated with the grades of hepatic steatosis and HOMA-IR values in those patients. Our data suggest that lower circulating free testosterone levels may be recognized as the risk factor for more advanced hepatic fibrosis, steatosis and/or higher insulin resistance in male patients with HCV-related chronic liver disease.
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Affiliation(s)
- Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1 Hara, Mure-Cho, Takamatsu, Kagawa 761-0123, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Reiji Haba
- Department of Diagnosis Pathology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
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14
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Liang X, Zheng S, Cui J, Yu D, Yang G, Zhou L, Wang B, Cai L, Li W. Alterations of MicroRNA Expression in the Liver, Heart, and Testis of Mice Upon Exposure to Repeated Low-Dose Radiation. Dose Response 2018; 16:1559325818799561. [PMID: 30263020 PMCID: PMC6153535 DOI: 10.1177/1559325818799561] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/30/2018] [Accepted: 08/07/2018] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRs), which regulate target gene expression at the post-transcriptional level, play a crucial role in inducing biological effects upon high-dose ionizing radiation. Yet, the miR expression profiles in response to repeated low-dose radiation (LDR) in vivo have not been elucidated. This study investigated the response profiles of 11 miRs with functions involved in metabolism, DNA damage and repair, inflammation, and fibrosis in mouse liver, heart, and testis upon repeated LDR exposure for 4 months. The expression profiles were evaluated using stem-loop quantitative reverse transcription polymerase chain reaction immediately and at 2 months after LDR exposure. The expression profiles varied significantly at both time points. At the organ level, the heart was the most affected, followed by the liver and testis, in which significant miR upregulation related to DNA damage response was found. Metabolism-related miRs decreased in the liver and increased in the testis. The current results showed immediate and long-lasting alterations in the miR expression profiles in response to repeated LDR in different organs.
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Affiliation(s)
- Xinyue Liang
- Cancer Center, The First Hospital of Jilin University, Changchun,
China
- Pediatric Research Institute, Department of Pediatrics of the
University of Louisville, Louisville, KY, USA
| | - Shirong Zheng
- Pediatric Research Institute, Department of Pediatrics of the
University of Louisville, Louisville, KY, USA
| | - Jiuwei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun,
China
| | - Dehai Yu
- Cancer Center, The First Hospital of Jilin University, Changchun,
China
| | - Guozi Yang
- Cancer Center, The First Hospital of Jilin University, Changchun,
China
| | - Lei Zhou
- Cancer Center, The First Hospital of Jilin University, Changchun,
China
| | - Brain Wang
- Department of Radiation Oncology, The University of Louisville,
Louisville, KY, USA
| | - Lu Cai
- Pediatric Research Institute, Department of Pediatrics of the
University of Louisville, Louisville, KY, USA
- Department of Radiation Oncology, The University of Louisville,
Louisville, KY, USA
| | - Wei Li
- Cancer Center, The First Hospital of Jilin University, Changchun,
China
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15
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Himoto T, Masaki T. Associations between Zinc Deficiency and Metabolic Abnormalities in Patients with Chronic Liver Disease. Nutrients 2018; 10:nu10010088. [PMID: 29342898 PMCID: PMC5793316 DOI: 10.3390/nu10010088] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 01/04/2018] [Accepted: 01/05/2018] [Indexed: 02/06/2023] Open
Abstract
Zinc (Zn) is an essential trace element which has favorable antioxidant, anti-inflammatory, and apoptotic effects. The liver mainly plays a crucial role in maintaining systemic Zn homeostasis. Therefore, the occurrence of chronic liver diseases, such as chronic hepatitis, liver cirrhosis, or fatty liver, results in the impairment of Zn metabolism, and subsequently Zn deficiency. Zn deficiency causes plenty of metabolic abnormalities, including insulin resistance, hepatic steatosis and hepatic encephalopathy. Inversely, metabolic abnormalities like hypoalbuminemia in patients with liver cirrhosis often result in Zn deficiency. Recent studies have revealed the putative mechanisms by which Zn deficiency evokes a variety of metabolic abnormalities in chronic liver disease. Zn supplementation has shown beneficial effects on such metabolic abnormalities in experimental models and actual patients with chronic liver disease. This review summarizes the pathogenesis of metabolic abnormalities deriving from Zn deficiency and the favorable effects of Zn administration in patients with chronic liver disease. In addition, we also highlight the interactions between Zn and other trace elements, vitamins, amino acids, or hormones in such patients.
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Affiliation(s)
- Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Hara, Mure-Cho, Takamatsu, Kagawa 761-0123, Japan.
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0123, Japan.
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16
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Recent Advances in the Pathogenesis of Hepatitis C Virus-Related Non-Alcoholic Fatty Liver Disease and Its Impact on Patients Cured of Hepatitis C. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s11901-017-0370-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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17
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Zhang JJ, Hao JJ, Zhang YR, Wang YL, Li MY, Miao HL, Zou XJ, Liang B. Zinc mediates the SREBP-SCD axis to regulate lipid metabolism in Caenorhabditis elegans. J Lipid Res 2017; 58:1845-1854. [PMID: 28710073 DOI: 10.1194/jlr.m077198] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 07/12/2017] [Indexed: 12/15/2022] Open
Abstract
Maintenance of lipid homeostasis is crucial for cells in response to lipid requirements or surplus. The SREBP transcription factors play essential roles in regulating lipid metabolism and are associated with many metabolic diseases. However, SREBP regulation of lipid metabolism is still not completely understood. Here, we showed that reduction of SBP-1, the only homolog of SREBPs in Caenorhabditis elegans, surprisingly led to a high level of zinc. On the contrary, zinc reduction by mutation of sur-7, encoding a member of the cation diffusion facilitator (CDF) family, restored the fat accumulation and fatty acid profile of the sbp-1(ep79) mutant. Zinc reduction resulted in iron overload, which thereby directly activated the conversion activity of stearoyl-CoA desaturase (SCD), a main target of SREBP, to promote lipid biosynthesis and accumulation. However, zinc reduction reversely repressed SBP-1 nuclear translocation and further downregulated the transcription expression of SCD for compensation. Collectively, we revealed zinc-mediated regulation of the SREBP-SCD axis in lipid metabolism, distinct from the negative regulation of SREBP-1 or SREBP-2 by phosphatidylcholine or cholesterol, respectively, thereby providing novel insights into the regulation of lipid homeostasis.
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Affiliation(s)
- Jing-Jing Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.,Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Jun-Jun Hao
- State Key Laboratory of Genetic Resources and Evolutionary and Functional Genomics, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Yu-Ru Zhang
- College of Fisheries, Henan Normal University, Xinxiang, Henan 453007, China
| | - Yan-Li Wang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Ming-Yi Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Hui-Lai Miao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Xiao-Ju Zou
- Department of Life Science and Biotechnology, Key Laboratory of Special Biological Resource Development and Utilization of University in Yunnan Province, Kunming University, Kunming 650214, China
| | - Bin Liang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China .,Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
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18
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Himoto T, Fujita K, Nomura T, Tani J, Morishita A, Yoneyama H, Haba R, Masaki T. Verification of B-lymphocyte activating factor's involvement in the exacerbation of insulin resistance as well as an autoimmune response in patients with nonalcoholic steatohepatitis and patients with HCV-related chronic liver disease. Diabetol Metab Syndr 2017; 9:45. [PMID: 28630652 PMCID: PMC5470186 DOI: 10.1186/s13098-017-0243-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 05/30/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Ten to forty percent of nonalcoholic steatohepatitis (NASH) and HCV-related chronic liver disease (CLD-C) patients have antinuclear antibodies (ANAs). However, the relationship between autoimmune response and insulin resistance remains uncertain among those patients. The primary purpose of this study was to investigate whether or not ANA status was associated with the development of insulin resistance and obesity in NASH and CLD-C patients. METHODS Degrees of hepatic fibrosis and steatosis were evaluated by the classification proposed by Brunt et al. Obesity and insulin resistance were estimated by calculating body mass index and the value of homeostasis model of for assessment of insulin resistance (HOMA-IR), respectively. A revised scoring system was applied to the diagnosis of autoimmune hepatitis (AIH). Serum B-lymphocyte activating factor (BAFF) levels were determined, using an ELISA technique. RESULTS Ten of 25 (40%) NASH patients and 9 of 22 (41%) CLD-C patients had ANAs, though the titers were weak in most patients. Only one NASH patient met the category of "definite" AIH among the enrolled patients. Serum IgG levels were significantly higher in NASH and CLD-C patients with ANAs than in those without ANAs, and NASH and CLD-C patients with ANAs had significantly higher HOMA-IR values than those without ANAs (6.81 ± 3.36 vs. 4.00 ± 2.57, p = 0.0305, 3.01 ± 1.31 vs. 1.28 ± 0.50, p = 0.0011). CLD-C patients with ANAs had more advanced hepatic fibrosis and steatosis than those without ANAs, while ANA status was not associated with hepatic fibrosis or steatosis in NASH patients. Obesity was independent of ANA status in both subjects. Serum BAFF levels were significantly higher in CLD-C patients with ANAs than those in CLD-C patients without ANAs (1303 ± 268 vs. 714 ± 143 pg/ml, p = 0.0036). A close correlation between serum BAFF level and the HOMA-IR value was observed in CLD-C patients (r = 0.467, p = 0.0485). CONCLUSION Our data suggest that NASH and CLD-C patients with ANAs have more severe insulin resistance than those without ANAs. More advanced insulin resistance deriving from excessive BAFF production may result in severe hepatic fibrosis and steatosis in CLD-C patients with ANAs.
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Affiliation(s)
- Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Hara, Mure-Cho, Takamatsu, Kagawa 761-0123 Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Takamatsu, Kagawa Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Takamatsu, Kagawa Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Takamatsu, Kagawa Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Takamatsu, Kagawa Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Takamatsu, Kagawa Japan
| | - Reiji Haba
- Department of Diagnosis Pathology, Kagawa University School of Medicine, Takamatsu, Kagawa Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Takamatsu, Kagawa Japan
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19
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Martinez SS, Campa A, Li Y, Fleetwood C, Stewart T, Ramamoorthy V, Baum MK. Low Plasma Zinc Is Associated with Higher Mitochondrial Oxidative Stress and Faster Liver Fibrosis Development in the Miami Adult Studies in HIV Cohort. J Nutr 2017; 147:556-562. [PMID: 28228506 PMCID: PMC5368586 DOI: 10.3945/jn.116.243832] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 12/02/2016] [Accepted: 01/31/2017] [Indexed: 12/23/2022] Open
Abstract
Background: Oxidative stress and reduced antioxidants may be a trigger for liver fibrogenesis. Reducing oxidative stress through higher antioxidant concentration may be a potential antifibrotic target.Objective: We aimed to investigate longitudinally whether plasma zinc, an antioxidant, is related to mitochondrial oxidative stress and the progression of liver fibrosis in the Miami Adult Studies in HIV (MASH) cohort.Methods: A prospective observational cohort study was conducted in 487 predominantly African American HIV-monoinfected and HIV/hepatitis C virus (HCV)-coinfected adults with a mean ± SD age of 47.08 ± 7.67 y from the MASH cohort and followed for a median of 34 mo. Blood was collected for plasma zinc and measures were used to calculate the fibrosis-4 (FIB-4) score (aspartate amino transferase, alanine aminotransferase, and platelets). Plasma zinc deficiency was defined as <0.75 mg/L. Total DNA was extracted from peripheral blood mononuclear cells and mitochondrial DNA (mtDNA) 8-hydroxyguanosine (8-oxo-dG) was determined. Adjusted mixed models were used to assess the relations between zinc, stage of liver disease, and oxidative stress over time and compared between HIV and HIV/HCV groups.Results: Zinc concentrations (β: -0.368, SE = 0.172; P = 0.033) and deficiency were associated with lower FIB-4 scores over time (β: 0.381, SE = 0.118; P = 0.001). Compared with those who were not zinc deficient, zinc-deficient participants had an increased risk of having more-progressed liver disease (OR: 1.91; 95% CI: 1.15, 3.16; P = 0.012). Higher mtDNA 8-oxo-dG was associated with zinc deficiency (β: 0.049, SE = 0.024; P = 0.044) and higher FIB-4 scores over time (β: 0.597, SE = 0.168, P < 0.001).Conclusions: Lower plasma zinc concentrations were associated with liver fibrosis progression and mitochondrial oxidative stress in the HIV and HIV/HCV groups. Zinc may play a role in the impact of liver disease outcomes.
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Affiliation(s)
- Sabrina S Martinez
- Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL
| | - Adriana Campa
- Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL
| | - Yinghui Li
- Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL
| | | | - Tiffanie Stewart
- Center for Nanoscience and Technology, University of Notre Dame, Notre Dame, IN; and
| | | | - Marianna K Baum
- Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL;
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20
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Zhu L, Chen X, Kong X, Cai YD. Investigation of the roles of trace elements during hepatitis C virus infection using protein-protein interactions and a shortest path algorithm. Biochim Biophys Acta Gen Subj 2016; 1860:2756-68. [PMID: 27208424 DOI: 10.1016/j.bbagen.2016.05.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 05/05/2016] [Accepted: 05/13/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis is a type of infectious disease that induces inflammation of the liver without pinpointing a particular pathogen or pathogenesis. Type C hepatitis, as a type of hepatitis, has been reported to induce cirrhosis and hepatocellular carcinoma within a very short amount of time. It is a great threat to human health. Some studies have revealed that trace elements are associated with infection with and immune rejection against hepatitis C virus (HCV). However, the mechanism underlying this phenomenon is still unclear. METHODS In this study, we aimed to expand our knowledge of this phenomenon by designing a computational method to identify genes that may be related to both HCV and trace element metabolic processes. The searching procedure included three stages. First, a shortest path algorithm was applied to a large network, constructed by protein-protein interactions, to identify potential genes of interest. Second, a permutation test was executed to exclude false discoveries. Finally, some rules based on the betweenness and associations between candidate genes and HCV and trace elements were built to select core genes among the remaining genes. RESULTS 12 lists of genes, corresponding to 12 types of trace elements, were obtained. These genes are deemed to be associated with HCV infection and trace elements metabolism. CONCLUSIONS The analyses indicate that some genes may be related to both HCV and trace element metabolic processes, further confirming the associations between HCV and trace elements. The method was further tested on another set of HCV genes, the results indicate that this method is quite robustness. GENERAL SIGNIFICANCE The newly found genes may partially reveal unknown mechanisms between HCV infection and trace element metabolism. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.
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Affiliation(s)
- LiuCun Zhu
- School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China
| | - XiJia Chen
- School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China
| | - Xiangyin Kong
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, People's Republic of China
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China.
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21
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Klaren WD, Gibson-Corley KN, Wels B, Simmons DL, McCormick ML, Spitz DR, Robertson LW. Assessment of the Mitigative Capacity of Dietary Zinc on PCB126 Hepatotoxicity and the Contribution of Zinc to Toxicity. Chem Res Toxicol 2016; 29:851-9. [PMID: 26967026 DOI: 10.1021/acs.chemrestox.6b00022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatic levels of the essential micronutrient, zinc, are diminished by several hepatotoxicants, and the dietary supplementation of zinc has proven protective in those cases. 3,3',4,4',5-Pentachlorobiphenyl (PCB126), a liver toxicant, alters hepatic nutrient homeostasis and lowers hepatic zinc levels. The current study was designed to determine the mitigative potential of dietary zinc in the toxicity associated with PCB126 and the role of zinc in that toxicity. Male Sprague-Dawley rats were divided into three dietary groups and fed diets deficient in zinc (7 ppm Zn), adequate in zinc (30 ppm Zn), and supplemented in zinc (300 ppm). The animals were maintained for 3 weeks on these diets, then given a single IP injection of vehicle or 1 or 5 μmol/kg PCB126. After 2 weeks, the animals were euthanized. Dietary zinc increased the level of ROS, the activity of CuZnSOD, and the expression of metallothionein but decreased the levels of hepatic manganese. PCB126 exposed rats exhibited classic signs of exposure, including hepatomegaly, increased hepatic lipids, increased ROS and CYP induction. Liver histology suggests some mild ameliorative properties of both zinc deficiency and zinc supplementation. Other metrics of toxicity (relative liver and thymus weights, hepatic lipids, and hepatic ROS) did not support this trend. Interestingly, the zinc supplemented high dose PCB126 group had mildly improved histology and less efficacious induction of investigated genes than did the low dose PCB126 group. Overall, decreases in zinc caused by PCB126 likely contribute little to the ongoing toxicity, and the mitigative/preventive capacity of zinc against PCB126 exposure seems limited.
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Affiliation(s)
- William D Klaren
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa , Iowa City, Iowa 52242, United States.,Department of Occupational and Environmental Health, College of Public Health, University of Iowa , Iowa City, Iowa 52242, United States
| | | | - Brian Wels
- State Hygienic Laboratory, University of Iowa , Ankeny, Iowa 50023, United States
| | - Donald L Simmons
- State Hygienic Laboratory, University of Iowa , Ankeny, Iowa 50023, United States
| | - Michael L McCormick
- Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, United States
| | - Douglas R Spitz
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa , Iowa City, Iowa 52242, United States.,Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, United States
| | - Larry W Robertson
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa , Iowa City, Iowa 52242, United States.,Department of Occupational and Environmental Health, College of Public Health, University of Iowa , Iowa City, Iowa 52242, United States
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22
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Liang X, Gu J, Yu D, Wang G, Zhou L, Zhang X, Zhao Y, Chen X, Zheng S, Liu Q, Cai L, Cui J, Li W. Low-Dose Radiation Induces Cell Proliferation in Human Embryonic Lung Fibroblasts but not in Lung Cancer Cells: Importance of ERK1/2 and AKT Signaling Pathways. Dose Response 2016; 14:1559325815622174. [PMID: 26788032 PMCID: PMC4710120 DOI: 10.1177/1559325815622174] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Hormesis and adaptive responses are 2 important biological effects of low-dose ionizing radiation (LDR). In normal tissue, LDR induces hormesis as evinced by increased cell proliferation; however, whether LDR also increases tumor cell proliferation needs to be investigated. In this study, cell proliferation was assayed by total cell numbers and the Cell Counting Kit 8 assay. Mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3' -kinase(PI3K)-Akt (PI3K/AKT) phosphorylation were determined by Western blot analysis. Human embryonic lung fibroblast 2BS and lung cancer NCI-H446 cell lines were irradiated with LDR at different doses (20-100 mGy). In response to 20 to 75 mGy X-rays, cell proliferation was significantly increased in 2BS but not in NCI-H446 cells. In 2BS cells, LDR at 20 to 75 mGy also stimulated phosphorylation of MAPK/ERK pathway proteins including ERK, MEK, and Raf and of the PI3K/AKT pathway protein AKT. To test whether ERK1/2 and AKT pathway activation was involved in the stimulation of cell proliferation in 2BS cells, the MAPK/ERK and PI3K/AKT pathways were inhibited using their specific inhibitors, U0126 and LY294002. U0126 decreased the phosphorylation of ERK1/2, and LY294002 decreased the phosphorylation of AKT; each could significantly inhibit LDR-induced 2BS cell proliferation. However, LDR did not stimulate these kinases, and kinase inhibitors also did not affect cell proliferation in the NCI-H446 cells. These results suggest that LDR stimulates cell proliferation via the activation of both MAPK/ERK and PI3K/AKT signaling pathways in 2BS but not in NCI-H446 cells. This finding implies the potential for applying LDR to protect normal tissues from radiotherapy without diminishing the efficacy of tumor therapy.
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Affiliation(s)
- Xinyue Liang
- Cancer Center, the First Hospital of Jilin University, Changchun, China
- Department of Pediatrics, Kosair Children’s Hospital Research Institute, University of Louisville, Louisville, KY, USA
| | - Junlian Gu
- Department of Pediatrics, Kosair Children’s Hospital Research Institute, University of Louisville, Louisville, KY, USA
| | - Dehai Yu
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Guanjun Wang
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Lei Zhou
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Xiaoying Zhang
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Yuguang Zhao
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Xiao Chen
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Shirong Zheng
- Department of Pediatrics, Kosair Children’s Hospital Research Institute, University of Louisville, Louisville, KY, USA
| | - Qiang Liu
- Tianjin Key Lab of Radiation and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Lu Cai
- Department of Pediatrics, Kosair Children’s Hospital Research Institute, University of Louisville, Louisville, KY, USA
| | - Jiuwei Cui
- Cancer Center, the First Hospital of Jilin University, Changchun, China
| | - Wei Li
- Cancer Center, the First Hospital of Jilin University, Changchun, China
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