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Chen P, Yao L, Yuan M, Wang Z, Zhang Q, Jiang Y, Li L. Mitochondrial dysfunction: A promising therapeutic target for liver diseases. Genes Dis 2024; 11:101115. [PMID: 38299199 PMCID: PMC10828599 DOI: 10.1016/j.gendis.2023.101115] [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: 04/14/2023] [Revised: 07/15/2023] [Accepted: 08/10/2023] [Indexed: 02/02/2024] Open
Abstract
The liver is an important metabolic and detoxification organ and hence demands a large amount of energy, which is mainly produced by the mitochondria. Liver tissues of patients with alcohol-related or non-alcohol-related liver diseases contain ultrastructural mitochondrial lesions, mitochondrial DNA damage, disturbed mitochondrial dynamics, and compromised ATP production. Overproduction of mitochondrial reactive oxygen species induces oxidative damage to mitochondrial proteins and mitochondrial DNA, decreases mitochondrial membrane potential, triggers hepatocyte inflammation, and promotes programmed cell death, all of which impair liver function. Mitochondrial DNA may be a potential novel non-invasive biomarker of the risk of progression to liver cirrhosis and hepatocellular carcinoma in patients infected with the hepatitis B virus. We herein present a review of the mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases, such as hepatocellular carcinoma, viral hepatitis, drug-induced liver injury, alcoholic liver disease, and non-alcoholic fatty liver disease. This review also discusses mitochondrion-centric therapies for treating liver diseases.
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Affiliation(s)
- Ping Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Zheng Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Qiuling Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Lanjuan Li
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
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Ye Z, Zhao TSY, Li SB, Zhou XL, Luo Q, Qin JK, Liang CQ, Wang P, Ge GB. Synthesis and biological evaluation of esculetin derivatives as potential anti-HBV agents. Med Chem Res 2023; 32:899-909. [PMID: 37056462 PMCID: PMC10030075 DOI: 10.1007/s00044-023-03045-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/07/2023] [Indexed: 03/24/2023]
Abstract
Previous in vivo and in vitro studies revealed that esculetin (Fig. 1) has anti-hepatitis B virus (anti-HBV) activity as well as a protective effect on liver damage caused by duck hepatitis B virus. We designed and synthesized a series of esculetin derivatives, introduced side chains containing various amino groups into site 7 of the parent structure, and synthesized C-4 and C-8 substituted derivatives with the goal of investigating their anti-HBV activities. In vitro anti-HBV activity was performed against HepG2.2.15 cells by using Enzyme-Linked Immunosorbent Assay(ELISA) kit and cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay with lamivudine as the positive control. The results demonstrated that several compounds showed moderate anti-HBV activity, while the introduction of morpholine groups could significantly inhibit the expression of hepatitis B e antigen (HBeAg) and the introduction of the 2-methylimidazole group could significantly inhibit the expression of Hepatitis B surface antigen (HBsAg). Among all tested compounds, compound 4a demonstrated the best anti-HBeAg activity (IC50 = 15.8 ± 4.2 μM), while compound 6d demonstrated the best anti-HBsAg activity (IC50 = 21.4 ± 2.8 μM). Compounds 6b and 6c showed moderate anti-HBV activity and HBsAg inhibition. Compounds 4b showed moderate anti-HBV activity and an inhibitory effect on HBeAg. In addition, compounds 4a, 4c, 4d, 6b, 6c and 6d showed improved metabolic stability. This study provides useful guidance for the discovery of anti-HBV drugs, which merits further investigation.
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Affiliation(s)
- Zhen Ye
- grid.443385.d0000 0004 1798 9548College of Pharmacy, Guilin Medical University, Guilin, 541199 Guangxi China
| | - Tong-Shi-Yao Zhao
- grid.443385.d0000 0004 1798 9548College of Biotechnology, Guilin Medical University, Guilin, 541199 Guangxi China
| | - Shan-Bin Li
- grid.443385.d0000 0004 1798 9548College of Biotechnology, Guilin Medical University, Guilin, 541199 Guangxi China
| | - Xian-Li Zhou
- grid.443385.d0000 0004 1798 9548College of Biotechnology, Guilin Medical University, Guilin, 541199 Guangxi China
| | - Qin Luo
- grid.443385.d0000 0004 1798 9548Science Experiment Center, Guilin Medical University, Guilin, 541199 Guangxi China
| | - Jiang-Ke Qin
- grid.459584.10000 0001 2196 0260State Key Laboratory for the Chemistry and MoLecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004 Guangxi China
| | - Cheng-Qin Liang
- grid.443385.d0000 0004 1798 9548College of Pharmacy, Guilin Medical University, Guilin, 541199 Guangxi China
| | - Ping Wang
- grid.412540.60000 0001 2372 7462Shanghai Frontiers Science Center for Traditional Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China
| | - Guang-Bo Ge
- grid.412540.60000 0001 2372 7462Shanghai Frontiers Science Center for Traditional Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China
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Falco A, Piscitelli P, Vito D, Pacella F, Franco C, Pulimeno M, Ambrosino P, Arias J, Miani A. COVID-19 epidemic spread and green areas Italy and Spain between 2020 and 2021: An observational multi-country retrospective study. ENVIRONMENTAL RESEARCH 2023; 216:114089. [PMID: 36007572 PMCID: PMC9393106 DOI: 10.1016/j.envres.2022.114089] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 08/06/2022] [Accepted: 08/06/2022] [Indexed: 05/19/2023]
Abstract
Several studies have proposed that environmental factors influencing human wellbeing, such as chronic exposures to high levels of particulate matter, could indirectly or even directly affect also the severity of COVID-19 disease in case of infection by novel coronavirus SARS-COV2. This study has investigated the association between COVID-19 infections, hospitalizations or deaths and the extension of public green areas (km2 per 100,000 based on OECD data of 2014), an indicator that has been chosen as independent endpoint variable to test the research hypothesis in 10 Italian and 8 Spanish Provinces with more than 500.000 inhabitants, including capitals (Rome and Madrid) and bigger cities (Bologna, Catania, Florence, Genoa, Milan, Naples, Palermo, Turin and Venice for Italy; Barcelona, Valencia, Seville, Zaragoza, Malaga, Las Palmas and Bilbao for Spain). Two different methodologies have been applied: a bottom-up approach was applied to Spanish institutional data concerning contagions/hospitalizations/deaths and the extent of public green areas for each responder to an official questionnaire in the frame of a nationwide survey (with detailed data granularity per province) containing specific georeferenced information; a top-down approach was used for Italy, starting from the official figures of contagions/hospitalizations/deaths of each province and linking them to the OECD statistics about the extension of public green areas in the different areas. Linear and generalized models were used for statistical analyses including also PM2.5 in a multivariate approach (with annual average concentrations from official air quality monitoring stations) and were able to adjust for the different number inhabitants living in each province, in order to take into account the difference in contagion dynamics related to the different density of population. The results obtained for Spain are consistent with those observed for Italy, as for both countries, it has clearly emerged a statistically significant association between COVID-19 clinical features (contagions, hospitalizations, and deaths) and the extension of public green areas, as well as the annual average concentrations of PM2.5 (with this latter variable loosing statistical significance in some province). Therefore, the extension of public green areas and air pollution seem to have a high correlation with COVID-19 severity.
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Affiliation(s)
- Andrea Falco
- University of Sannio, Benevento, Italy; Italian Society of Environmental Medicine, Milan, Italy.
| | | | - Domenico Vito
- Italian Society of Environmental Medicine, Milan, Italy
| | | | | | | | | | - Javier Arias
- Dean of Medical School, Complutense University, Madrid, Spain
| | - Alessandro Miani
- Italian Society of Environmental Medicine, Milan, Italy; Department of Environmental Sciences and Policy, University of Milan, Italy
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Oxidative Stress in Chronic Hepatitis B—An Update. Microorganisms 2022; 10:microorganisms10071265. [PMID: 35888983 PMCID: PMC9318593 DOI: 10.3390/microorganisms10071265] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/19/2022] [Accepted: 06/20/2022] [Indexed: 02/01/2023] Open
Abstract
In recent years, the role of oxidative stress has been investigated in an increasing number of infections. There is a close link between the inflammation that accompanies infections and oxidative stress. Excessive reactive oxygen species induce harmful effects on cell components, including lipids, proteins, and nucleic acids. A growing body of evidence attests to the role of oxidative stress in the pathogenesis of viral liver infections, especially in hepatitis C virus (HCV) infection. Regarding hepatitis B virus (HBV) infection, the data are limited, but important progress has been achieved in recent years. This review presents the latest advances pertaining to the role of the oxidative stress byproducts in the pathogenesis of chronic hepatitis B, constituting a source of potential new markers for the evaluation and monitoring of patients with chronic hepatitis B.
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He Y, Wang F, Yao N, Wu Y, Zhao Y, Tian Z. Serum superoxide dismutase level is a potential biomarker of disease prognosis in patients with HEV-induced liver failure. BMC Gastroenterol 2022; 22:14. [PMID: 35000581 PMCID: PMC8742945 DOI: 10.1186/s12876-022-02095-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 01/05/2022] [Indexed: 01/11/2024] Open
Abstract
Background Viral hepatitis E clinically ranges from self-limiting hepatitis to lethal liver failure. Oxidative stress has been shown to mediate hepatic inflammation during HBV-induced liver failure. We investigated whether a biomarker of oxidative stress may be helpful in assessing severity and disease outcomes of patients with HEV-induced liver failure. Methods Clinical data were obtained from patients with HEV-induced acute viral hepatitis (AVH, n = 30), acute liver failure (ALF, n = 17), and acute-on-chronic liver failure (ACLF, n = 36), as well as from healthy controls (HC, n = 30). The SOD and HMGB1 levels were measured in serum by ELISA. HL-7702 cells were cultured and stimulated by serum from HEV-infected patients or by HMGB1; oxidative status was investigated by CellROX and apoptosis was investigated by flow cytometry. Results Patients with HEV-induced liver failure (including ALF and ACLF) showed increased SOD levels compared with HEV-AVH patients and healthy controls. SOD levels > 400 U/mL were associated with a significantly higher risk of mortality in HEV-ALF and HEV-ACLF patients. Serum from HEV-infected patients led to ROS accumulation, HMGB1 secretion, and apoptosis in HL-7702 cells. Antioxidant treatment successfully inhibited HEV-induced HMGB1 secretion, and HMGB1 promoted apoptosis in HL-7702 cells. Conclusion HEV increased oxidative stress in the pathogenesis of HEV-induced hepatic diseases. Early testing of serum SOD may serve as a predictor of both HEV-ALF and HEV-ACLF outcomes. Moreover, development of strategies for modulating oxidative stress might be a potential target for treating HEV-induced liver failure patients.
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Affiliation(s)
- Yajuan He
- Department of Ultrasound, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an City, 710061, Shaanxi Province, China
| | - Fei Wang
- Department of Ultrasound, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an City, 710061, Shaanxi Province, China
| | - Naijuan Yao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, China
| | - Yuchao Wu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, China
| | - Yingren Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, China
| | - Zhen Tian
- Department of Ultrasound, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an City, 710061, Shaanxi Province, China. .,Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, China.
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Geng H, Xing Y, Zhang J, Cao K, Ye M, Wang G, Liu C. Association between viral infection other than human papillomavirus and risk of esophageal carcinoma: a comprehensive meta-analysis of epidemiological studies. Arch Virol 2022; 167:1-20. [PMID: 34636955 DOI: 10.1007/s00705-021-05268-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 08/27/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Infection with viruses such as human papillomavirus (HPV) is known to induce carcinomas, including esophageal carcinoma (EC). However, the possible role of viruses other than HPV in EC carcinogenesis is unclear in many studies. Here, we aimed to explore the association between infection with viruses other than HPV and EC risk by integrating existing studies of epidemiology in a meta-analysis. METHODS The PubMed, Web of Science, Cochrane Library and China National Knowledge Infrastructure databases were searched. The Newcastle-Ottawa scale was used to assess the quality of the included studies. Odds ratios (ORs) or relative risks (RRs) (with 95% confidence intervals [CIs]) were pooled to estimate the association between virus infection and risk of EC. RESULTS We included 31 eligible studies involving nine different viruses. Overall, an increased risk of EC was associated with hepatitis B virus (HBV) infection (OR = 1.19, 95%CI 1.01-1.36) and hepatitis C virus (HCV) infection (OR = 1.77, 95%CI 1.17-2.36), but not human immunodeficiency virus (HIV) infection, according to the current evidence. The evidence for an association with Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), JC virus (JCV), cytomegalovirus (CMV), human T-lymphotropic virus 1 (HTLV-1) or Merkel cell polyomavirus (MCPyV) infection was insufficient. CONCLUSIONS We confirmed the relationship between HBV and HCV infection and the risk of EC, but we found no association of EC risk with HIV and EBV infection. The roles of HSV-1, JCV, CMV, HTLV-1, and MCPyV were not clear because of the limited number of studies.
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Affiliation(s)
- Hui Geng
- Department of Preventive Medicine, Shantou University Medical College, No. 22, Xinling Rd., Shantou, 515041, Guangdong, China
| | - Yaqi Xing
- Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China
| | - Jingbing Zhang
- Department of Preventive Medicine, Shantou University Medical College, No. 22, Xinling Rd., Shantou, 515041, Guangdong, China
| | - Kexin Cao
- Department of Preventive Medicine, Shantou University Medical College, No. 22, Xinling Rd., Shantou, 515041, Guangdong, China
| | - Meijie Ye
- Department of Preventive Medicine, Shantou University Medical College, No. 22, Xinling Rd., Shantou, 515041, Guangdong, China
| | - Geng Wang
- Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Caixia Liu
- Department of Preventive Medicine, Shantou University Medical College, No. 22, Xinling Rd., Shantou, 515041, Guangdong, China
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Pomacu MM, Trașcă MD, Pădureanu V, Bugă AM, Andrei AM, Stănciulescu EC, Baniță IM, Rădulescu D, Pisoschi CG. Interrelation of inflammation and oxidative stress in liver cirrhosis. Exp Ther Med 2021; 21:602. [PMID: 33936259 PMCID: PMC8082585 DOI: 10.3892/etm.2021.10034] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 02/22/2021] [Indexed: 12/11/2022] Open
Abstract
Recently, the trend of research has been focused on the role of hematological indicators in assessing the activities of various diseases. The aim of the present study was to determine the usefulness of such hematological indicators for assessment of the relationship between inflammation and oxidative stress in order to provide new predictive tools for a non-invasive investigation of disease outcome for liver cirrhosis patients. A total of 35 subjects with compensated or decompensated liver cirrhosis and 10 age-matched healthy volunteers were included in this study. The patients were divided into two groups: Group 1, patients with toxic metabolic cirrhosis due to ethanol consumption; group 2, patients with liver cirrhosis following hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Using hematological data obtained after the complete counting of peripheral blood cells, the monocyte/lymphocyte (MLR), neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) ratios as well as systemic immune inflammation biomarkers were determined. The erythrocyte sedimentation ratio (ESR), C-reactive protein (CRP), fibrinogen and biochemical parameters related to liver function were also registered. Thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCARB), and total antioxidant capacity (TAC) were also investigated in the peripheral blood samples of healthy subjects and liver cirrhosis patients. The results revealed that NLR, MLR and PLR were significantly increased in group 2. PLR was significantly increased in group 1 compared with that noted in the control group. TBARS and PCARB were increased in patients from group 1 compared to patients from group 2 and the control group. However, no difference in TAC was found between the liver cirrhosis groups and the control. We showed that the pro-inflammatory status of liver cirrhosis patients can be easily appreciated by NLR, MLR but not PLR. However, the increase in these ratios was not significantly associated with a decrease in the antioxidant capacity and an augmentation of oxidative stress markers for the patients diagnosed with cirrhosis included in the two groups of study.
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Affiliation(s)
- Mihnea Marian Pomacu
- Department of Biochemistry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania.,4th Department-Medical Specialties, First Clinic of Internal Medicine, Clinical City Hospital 'Filantropia', University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Maria Diana Trașcă
- 4th Department-Medical Specialties, First Clinic of Internal Medicine, Clinical City Hospital 'Filantropia', University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Vlad Pădureanu
- Department of Internal Medicine, County Hospital of Craiova, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Ana Maria Bugă
- Department of Biochemistry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Ana Marina Andrei
- Department of Biochemistry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | | | - Ileana Monica Baniță
- Department of Histology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dumitru Rădulescu
- Department of General Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Bakadia BM, Boni BOO, Ahmed AAQ, Yang G. The impact of oxidative stress damage induced by the environmental stressors on COVID-19. Life Sci 2021; 264:118653. [PMID: 33115606 PMCID: PMC7586125 DOI: 10.1016/j.lfs.2020.118653] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/21/2020] [Accepted: 10/21/2020] [Indexed: 12/11/2022]
Abstract
The ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a substantial stressor that is greatly impacting environmental sustainability. Besides, the different pre-existing environmental stressors and coronavirus disease-2019 (COVID-19)-related stressors are further worsening the effects of the viral disease by inducing the generation of oxidative stress. The generated oxidative stress results in nucleic acid damage associated with viral mutations, that could potentially reduce the effectiveness of COVID-19 management, including the vaccine approach. The current review is aimed to overview the impact of the oxidative stress damage induced by various environmental stressors on COVID-19. The available data regarding the COVID-19-related stressors and the effects of oxidative stress damage induced by the chronic stress, exposure to free radicals, and malnutrition are also analyzed to showcase the promising options, which could be investigated further for sustainable control of the pandemic.
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Affiliation(s)
- Bianza Moise Bakadia
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Biaou Oscar Ode Boni
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Abeer Ahmed Qaed Ahmed
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Guang Yang
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China.
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Liver Cirrhosis in Chronic Hepatitis B Patients Is Associated with Genetic Variations in DNA Repair Pathway Genes. Cancers (Basel) 2020; 12:cancers12113295. [PMID: 33171788 PMCID: PMC7694950 DOI: 10.3390/cancers12113295] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary As DNA repair enzymes affect dynamics of liver damage and are involved in HBV viral replication, this study focused on the role of genetic variations within genes representing key DNA-repair pathways in HBV-induced liver cirrhosis. The obtained results have demonstrated that SNPs within XRCC1, ERCC2 genes may confer susceptibility to liver cirrhosis in chronic hepatitis B patients. Abstract Liver cirrhosis (LC), contributing to more than 1 million of deaths annually, is a major healthcare concern worldwide. Hepatitis B virus (HBV) is a major LC etiological factor, and 15% of patients with chronic HBV infection (CHB) develop LC within 5 years. Recently, novel host genetic determinants were shown to influence HBV lifecycle and CHB course. DNA repair enzymes can affect dynamics of liver damage and are involved in HBV covalently closed circular DNA (cccDNA) formation, an essential step for viral replication. This study aimed to evaluate the possible role of genes representing key DNA-repair pathways in HBV-induced liver damage. MALDI-TOF MS genotyping platform was applied to evaluate variations within XRCC1, XRCC4, ERCC2, ERCC5, RAD52, Mre11, and NBN genes. Apart from older age (p < 0.001), female sex (p = 0.021), portal hypertension (p < 0.001), thrombocytopenia (p < 0.001), high HBV DNA (p = 0.001), and high aspartate aminotransferase (AST) (p < 0.001), we found that G allele at rs238406 (ERCC2, p = 0.025), T allele at rs25487 (XRCC1, p = 0.012), rs13181 GG genotype (ERCC2, p = 0.034), and C allele at rs2735383 (NBN, p = 0.042) were also LC risk factors. The multivariate logistic regression model showed that rs25487 CC (p = 0.005) and rs238406 TT (p = 0.027) were independently associated with lower risk of LC. This study provides evidence for the impact of functional and potentially functional variations in key DNA-repair genes XRCC1 and ERCC2 in HBV-induced liver damage in a Caucasian population.
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Ganesan M, Eikenberry A, Poluektova LY, Kharbanda KK, Osna NA. Role of alcohol in pathogenesis of hepatitis B virus infection. World J Gastroenterol 2020; 26:883-903. [PMID: 32206001 PMCID: PMC7081008 DOI: 10.3748/wjg.v26.i9.883] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/09/2020] [Accepted: 02/14/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) and alcohol abuse often contribute to the development of end-stage liver disease. Alcohol abuse not only causes rapid progression of liver disease in HBV infected patients but also allows HBV to persist chronically. Importantly, the mechanism by which alcohol promotes the progression of HBV-associated liver disease are not completely understood. Potential mechanisms include a suppressed immune response, oxidative stress, endoplasmic reticulum and Golgi apparatus stresses, and increased HBV replication. Certainly, more research is necessary to gain a better understanding of these mechanisms such that treatment(s) to prevent rapid liver disease progression in alcohol-abusing HBV patients could be developed. In this review, we discuss the aforementioned factors for the higher risk of liver diseases in alcohol-induced HBV pathogenies and suggest the areas for future studies in this field.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Allison Eikenberry
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
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Ma N, Liu W, Zhang X, Gao X, Yu F, Guo W, Meng Y, Gao P, Zhou J, Yuan M, Mi Y, Zhang L, Qi S, Li L, Wang L, Su Q, Yang L, Liu D. Oxidative Stress-Related Gene Polymorphisms Are Associated With Hepatitis B Virus-Induced Liver Disease in the Northern Chinese Han Population. Front Genet 2020; 10:1290. [PMID: 31969899 PMCID: PMC6960262 DOI: 10.3389/fgene.2019.01290] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 11/22/2019] [Indexed: 12/11/2022] Open
Abstract
Oxidative stress is closely related to the occurrence and development of various diseases such as cancer, diabetes, and cardiovascular and infectious diseases. We identified six critical genetic variants related to oxidative stress, and evaluated their main effects and their interaction effects on hepatitis B virus (HBV)-induced liver diseases. We enrolled 3,128 Han Chinese subjects into five groups: healthy controls, chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and natural clearance. We then determined the genotypes in each group for CYBA-rs4673, NCF4-rs1883112, NOX4-rs1836882, rs3017887, SOD2-rs4880, and GCLM-rs41303970, and evaluated the association between these variants and HBV-induced liver diseases. Gene-gene interactions were evaluated using generalized multifactor dimensionality reduction, logistic regression, and four-by-two tables. Significant associations were observed between healthy controls and the CIB group (CHB+LC+HCC). The CYBA-rs4673AG genotype was associated with a 1.356 rate of susceptibility of HBV-induced liver disease compared to the wild type GG genotype. The NCF4-rs1883112G allele occurred more frequently in healthy controls than in the CIB group in all three models (dominant, codominant, and recessive). Nox4-rs1836882 TC showed a protective association, being more frequent in healthy controls compared to the wild type TT genotype. GCLM-rs41303970A was associated with HBV-induced liver disease. The overall best model by multifactor dimensionality reduction was a five factor interaction model that had the highest cross validation consistency (10/10) and test accuracy (0.5669), P= 0.001. Oxidative stress-related gene polymorphisms are likely to be associated with HBV-induced liver disease, suggesting that information on these variations is useful for risk assessment of HBV-induced liver disease.
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Affiliation(s)
- Ning Ma
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Wenxuan Liu
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Xiaolin Zhang
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Xia Gao
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Fengxue Yu
- The Hebei Key Laboratory of Gastroenterology, Division of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Weiheng Guo
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Yanxin Meng
- Antenatal Diagnosis Center, The Fourth Hospital of Shijiazhuang, Shijiazhuang, China
| | - Ping Gao
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Jin Zhou
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Meina Yuan
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Yingjun Mi
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Lei Zhang
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Sufen Qi
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Lu Li
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Luyao Wang
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Qiao Su
- School of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Lei Yang
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Dianwu Liu
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
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Yang J, Xiong Y, Zhou L, Huang Y, Chen W, Wang B. Soluble E-cadherin is associated with oxidative stress in patients with chronic HBV infection. J Med Virol 2019; 92:34-44. [PMID: 31429942 DOI: 10.1002/jmv.25571] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 08/11/2019] [Indexed: 12/11/2022]
Abstract
Mounting evidence indicates that serum soluble E-cadherin (sE-cadherin) serves as an important player in various physiological and pathological processes. However, the crosstalk between serum sE-cadherin and oxidative stress in chronic hepatitis B (CHB) remains to be illustrated. The main purpose of this study is to explore the molecular mechanisms underlying the function of sE-cadherin in CHB virus infection. Levels of serum sE-cadherin, total antioxidant capacity (TAC), glutathione (GSH), superoxide dismutase (SOD), total oxidant activity (TOA), NADPH oxidase 2 (NOX2), and malondialdehyde (MDA), from 51 patients with hepatitis B envelope antigen (HBeAg)-negative CHB, 54 patients with HBeAg-positive CHB, and 109 healthy individuals were detected by enzyme-linked immunosorbent assay. In our study, patients with CHB showed significantly higher serum sE-cadherin levels than healthy individuals (P < .01). Furthermore, we also found that the serum sE-cadherin levels were significantly negatively correlated with TAC, antioxidant enzymes (GSH and SOD) in patients with CHB, and that serum sE-cadherin concentrations were significantly positively correlated with liver enzyme markers (alanine transaminase and aspartate aminotransferase) and oxidative markers (TOA, NOX2, and MDA) in patients with CHB. Therefore, serum sE-cadherin may act as a new candidate biomarker for reflecting inflammation and oxidative stress status in the development and progression of hepatitis B virus infection.
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Affiliation(s)
- Jun Yang
- Department of Laboratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yuan Xiong
- Department of Laboratory Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Lijing Zhou
- Department of Laboratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yong Huang
- Department of Laboratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Weixian Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Bo Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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