|
1
|
Ghabril M, Vuppalanchi R, Chalasani N. Drug-Induced Liver Injury in Patients With Chronic Liver Disease. Liver Int 2025; 45:e70019. [PMID: 39927421 PMCID: PMC11808633 DOI: 10.1111/liv.70019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 01/05/2025] [Accepted: 01/27/2025] [Indexed: 02/11/2025]
Abstract
OBJECTIVE Drug-induced liver injury (DILI) is a global problem and can develop from exposure to prescription or over-the-counter medications as well as herbal and dietary supplements. The diagnosis of DILI is clinically challenging, and liver injury can be severe leading to liver failure, death, or liver transplantation. Patients with underlying chronic liver diseases (CLD) may be at increased risk for DILI, which is associated with factors related to drug or liver disease. METHODS This review summarises current knowledge on the risk and outcomes of DILI in patients with CLD. RESULTS Patients with CLD may be at an increased risk for DILI. Additionally patients with underlying CLD are at risk for more severe liver injury and worse outcomes after DILI. DISCUSSION The risk for and poor outcomes from DILI are accentuated in patients with CLD and potentially leading to the worst-case scenario of acute-on-chronic liver failure. We highlight the key observations on DILI with a broad range of underlying liver diseases and the high-DILI risk agents implicated in those populations.
Collapse
Affiliation(s)
- Marwan Ghabril
- Gastroenterology and HepatologyIndiana University School of Medicine and Indiana University HealthIndianapolisIndianaUSA
| | - Raj Vuppalanchi
- Gastroenterology and HepatologyIndiana University School of Medicine and Indiana University HealthIndianapolisIndianaUSA
| | - Naga Chalasani
- Gastroenterology and HepatologyIndiana University School of Medicine and Indiana University HealthIndianapolisIndianaUSA
| |
Collapse
|
|
2
|
Damle VG, Wu K, Arouri DJ, Schirhagl R. Detecting free radicals post viral infections. Free Radic Biol Med 2022; 191:8-23. [PMID: 36002131 DOI: 10.1016/j.freeradbiomed.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 08/02/2022] [Accepted: 08/08/2022] [Indexed: 11/18/2022]
Abstract
Free radical generation plays a key role in viral infections. While free radicals have an antimicrobial effect on bacteria or fungi, their interplay with viruses is complicated and varies greatly for different types of viruses as well as different radical species. In some cases, radical generation contributes to the defense against the viruses and thus reduces the viral load. In other cases, radical generation induces mutations or damages the host tissue and can increase the viral load. This has led to antioxidants being used to treat viral infections. Here we discuss the roles that radicals play in virus pathology. Furthermore, we critically review methods that facilitate the detection of free radicals in vivo or in vitro in viral infections.
Collapse
Affiliation(s)
- V G Damle
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - K Wu
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - D J Arouri
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - R Schirhagl
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
| |
Collapse
|
|
3
|
Cheng C, Ma H, Liu G, Deng Y, Jiang J, Feng J, Guo Z. Biochemical, metabolic, and immune responses of mud crab (Scylla paramamosain) after mud crab reovirus infection. FISH & SHELLFISH IMMUNOLOGY 2022; 127:437-445. [PMID: 35779811 DOI: 10.1016/j.fsi.2022.06.058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 06/15/2023]
Abstract
Mud crab reovirus (MCRV) is a serious pathogen that leads to large economic losses in the mud crab farming. However, the molecular mechanism of the immune response after MCRV infection is unclear. In the present study, physiological, transcriptomic, and metabolomic responses after MCRV infection were investigated. The results showed that MCRV infection could increase lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase activities. MCRV infection decreased antioxidant enzyme activity levels, induced oxidative stress, and caused severe histological damage. Transcriptome analysis identified 416 differentially expressed genes, including 354 up-regulated and 62 down-regulated genes. The detoxification, immune response, and metabolic processes-related genes were found. The results showed that two key pathways including phagocytosis and apoptosis played important roles in response to MCRV infection. The combination of transcriptomic and metabolomic analyses showed that related metabolic pathways, such as glycolysis, citrate cycle, lipid, and amino acid metabolism were also significantly disrupted. Moreover, the biosynthesis of unsaturated fatty acids was activated in response to MCRV infection. This study provided a novel insight into the understanding of cellular mechanisms in crustaceans against viral invasion.
Collapse
Affiliation(s)
- ChangHong Cheng
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, PR China
| | - HongLing Ma
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, PR China
| | - GuangXin Liu
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, PR China
| | - YiQing Deng
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, PR China
| | - JianJun Jiang
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, PR China
| | - Juan Feng
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, PR China
| | - ZhiXun Guo
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, PR China.
| |
Collapse
|
|
4
|
Manzoor S, Khalid M, Idrees M. P2X4 receptors mediate induction of antioxidants, fibrogenic cytokines and ECM transcripts; in presence of replicating HCV in in vitro setting: An insight into role of P2X4 in fibrosis. PLoS One 2022; 17:e0259727. [PMID: 35594248 PMCID: PMC9122194 DOI: 10.1371/journal.pone.0259727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/02/2022] [Indexed: 11/19/2022] Open
Abstract
Background & aims
Major HCV infections lead to chronic hepatitis, which results in progressive liver disease including fibrosis, cirrhosis and eventually hepatocellular carcinoma (HCC). P2X4 and P2X7 are most widely distributed receptors on hepatocytes.
Methods
Full length P2X4 (1.7kb) (Rattus norvegicus) was sub cloned in mammalian expression vector pcDNA3.1+. Two stable cell lines 293T/P2X4 (experimental) and 293T/ NV or null vector (control) were established. Both cell lines were inoculated with high viral titers human HCV sera and control human sera. Successfully infected cells harvested on day 5 and day 9 of post infection were used for further studies.
Results
The results revealed a significant increase in gene expression of P2X4 on day 5 and day 9 Post -infection in cells infected with HCV sera compared with cells inoculated with control sera. Quantitative real time PCR analysis revealed that HO-1 was significantly upregulated in presence of P2X4 in HCV infected cells (P2X4/HCV) when compared with control NV/HCV cells. A significant decrease was observed in expression of Cu/ZnSOD in presence of P2X4 in HCV infected cells compared to control NV/HCV cells. However, expression of both antioxidants was observed unaltered in cells harvested on day 9 post infection. Gene expression of angiotensin II significantly increased in HCV infected cells in presence of P2X4 on day 5 and day 9 of post infection when compared with control NV/HCV cells. A significant increase in gene expression of TNF-α and TGF-β was observed in HCV infected cells in presence of P2X4 on day 9 post infection in comparison with control (NV/HCV cells). However, gene expression of adipokine leptin was not affected in both experimental (P2X4/HCV) and control (NV/HCV) groups on day 5 and day 9 of post infection. Extracellular matrix proteins, laminin and elastin genes expression also significantly increased in presence of P2X4 (HCV/P2X4) on day 9 of post-infection compared to control group NV/HCV cells.
Conclusion
In conclusion, these findings constitute the evidence that P2X4 receptors in the presence of HCV play a significant role in the regulation of key antioxidant enzymes (HO-1, Cu/ZnSOD), in the induction of proinflammatory. cytokine (TNF-α), profibrotic cytokine (TGF-β) vasoactive cytokine (angiotensin II). P2X4 also increases the expression of extracellular matrix proteins (laminin and elastin) in the presence of HCV.
Collapse
Affiliation(s)
- Sobia Manzoor
- Center of Excellence in Molecular Biology (CEMB), University of Punjab, Lahore, Pakistan
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST), Islamabad, Pakistan
- * E-mail: ,
| | - Madiha Khalid
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST), Islamabad, Pakistan
| | - Muhammad Idrees
- Center of Excellence in Molecular Biology (CEMB), University of Punjab, Lahore, Pakistan
| |
Collapse
|
|
5
|
Malla RR, Marni R, Chakraborty A. ROS-mediated pathways: potential role in hepatocellular carcinoma biology and therapy. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA, VOLUME 2 2022:321-335. [DOI: 10.1016/b978-0-323-98807-0.00004-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
6
|
Romero‐Cordero S, Noguera‐Julian A, Cardellach F, Fortuny C, Morén C. Mitochondrial changes associated with viral infectious diseases in the paediatric population. Rev Med Virol 2021; 31:e2232. [PMID: 33792105 PMCID: PMC9286481 DOI: 10.1002/rmv.2232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 12/24/2022]
Abstract
Infectious diseases occur worldwide with great frequency in both adults and children, causing 350,000 deaths in 2017, according to the latest World Health Organization reports. Both infections and their treatments trigger mitochondrial interactions at multiple levels: (i) incorporation of damaged or mutated proteins into the complexes of the electron transport chain; (ii) impact on mitochondrial genome (depletion, deletions and point mutations) and mitochondrial dynamics (fusion and fission); (iii) membrane potential impairment; (iv) apoptotic regulation; and (v) generation of reactive oxygen species, among others. Such alterations may result in serious adverse clinical events with considerable impact on the quality of life of the children and could even cause death. Herein, we use a systematic review to explore the association between mitochondrial alterations in paediatric infections including human immunodeficiency virus, cytomegalovirus, herpes viruses, various forms of hepatitis, adenovirus, T-cell lymphotropic virus and influenza. We analyse how these paediatric viral infectious processes may cause mitochondrial deterioration in this especially vulnerable population, with consideration for the principal aspects of research and diagnosis leading to improved disease understanding, management and surveillance.
Collapse
Affiliation(s)
- Sonia Romero‐Cordero
- Faculty of MedicinePompeu Fabra UniversityBarcelonaSpain
- Faculty of MedicineUniversitat Autònoma de BarcelonaBellaterraSpain
| | - Antoni Noguera‐Julian
- Malalties Infeccioses i Resposta Inflamatòria Sistèmica en PediatriaUnitat d´InfeccionsServei de PediatriaInstitut de Recerca Pediàtrica Hospital Sant Joan de DéuBarcelonaSpain
- Departament de PediatriaUniversitat de BarcelonaBarcelonaSpain
- CIBER de Epidemiología y Salud Pública, CIBERESP (ISCIII)MadridSpain
- Red de Investigación Translacional en Infectología PediátricaRITIPMadridSpain
| | - Francesc Cardellach
- Faculty of Medicine and Health SciencesMuscle Research and Mitochondrial Function LaboratoryCellex‐IDIBAPSUniversity of BarcelonaBarcelonaSpain
- CIBER de Enfermedades RarasCIBERER (ISCIII)MadridSpain
- Internal Medicine DepartmentHospital Clínic of Barcelona (HCB)BarcelonaSpain
| | - Clàudia Fortuny
- Malalties Infeccioses i Resposta Inflamatòria Sistèmica en PediatriaUnitat d´InfeccionsServei de PediatriaInstitut de Recerca Pediàtrica Hospital Sant Joan de DéuBarcelonaSpain
- Departament de PediatriaUniversitat de BarcelonaBarcelonaSpain
- CIBER de Epidemiología y Salud Pública, CIBERESP (ISCIII)MadridSpain
- Red de Investigación Translacional en Infectología PediátricaRITIPMadridSpain
| | - Constanza Morén
- Faculty of Medicine and Health SciencesMuscle Research and Mitochondrial Function LaboratoryCellex‐IDIBAPSUniversity of BarcelonaBarcelonaSpain
- CIBER de Enfermedades RarasCIBERER (ISCIII)MadridSpain
- Internal Medicine DepartmentHospital Clínic of Barcelona (HCB)BarcelonaSpain
| |
Collapse
|
|
7
|
Shahid M, Idrees M, Butt AM, Raza SM, Amin I, Rasul A, Afzal S. Blood-based gene expression profile of oxidative stress and antioxidant genes for identifying surrogate markers of liver tissue injury in chronic hepatitis C patients. Arch Virol 2020; 165:809-822. [PMID: 32103340 DOI: 10.1007/s00705-020-04564-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 01/27/2020] [Indexed: 12/16/2022]
Abstract
Oxidative stress is the process by which reactive molecules and free radicals are formed in cells. In this study, we report the blood-based gene expression profile of oxidative stress and antioxidant genes for identifying surrogate markers of liver tissue in chronic hepatitis C (CHC) patients by using real-time PCR. A total of 144 untreated patients diagnosed with CHC having genotype 3a and 20 healthy controls were selected for the present study. Liver biopsy staging and grading of CHC patients were performed using the METAVIR score. Total RNA was extracted from liver tissue and blood samples, followed by cDNA synthesis and real-time PCR. The relative expression of genes was calculated using the ΔΔCt method. The expression profile of 84 genes associated with oxidative stress and antioxidants was determined in liver tissue and blood samples. In liver tissue, 46 differentially expressed genes (upregulated, 27; downregulated, 19) were identified in CHC patients compared to normal samples. In blood, 61 genes (upregulated, 51; downregulated; 10) were significantly expressed in CHC patients. A comparison of gene expression in liver and whole blood showed that 20 genes were expressed in a similar manner in the liver and blood. The expression levels of commonly expressed liver and blood-based genes were also correlated with clinical factors in CHC patients. A receiver operating curve (ROC) analysis of oxidative stress genes (ALB, CAT, DHCR24, GPX7, PRDX5, and MBL2) showed that infections in patients with CHC can be distinguished from healthy controls. In conclusion, blood-based gene expression can reflect the behavior of oxidative stress genes in liver tissue, and this blood-based gene expression study in CHC patients explores new blood-based non-invasive biomarkers that represent liver damage.
Collapse
Affiliation(s)
- Muhammad Shahid
- Divison of Molecular Virology, National Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan.
| | - Muhammad Idrees
- Divison of Molecular Virology, National Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan.,Hazara University, Mansehra, Pakistan
| | - Azeem Mehmood Butt
- Divison of Molecular Virology, National Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan.,Department of Bioscience, COMSATS University Islamabad, Islamabad, Pakistan
| | - Syed Mohsin Raza
- Divison of Molecular Virology, National Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan.,Institute of Biomedical and Allied Health Sciences, University of Health Science, Lahore, Pakistan
| | - Iram Amin
- Divison of Molecular Virology, National Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan
| | - Afza Rasul
- Department of Statistic, Lahore College for Women University, Lahore, Pakistan
| | - Samia Afzal
- Divison of Molecular Virology, National Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan
| |
Collapse
|
|
8
|
Ijaz B, Ahmad W, Das T, Shabbiri K, Husnain T, Hassan S. HCV infection causes cirrhosis in human by step-wise regulation of host genes involved in cellular functioning and defense during fibrosis: Identification of bio-markers. Genes Dis 2019; 6:304-317. [PMID: 32042870 PMCID: PMC6997584 DOI: 10.1016/j.gendis.2019.04.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/25/2019] [Indexed: 12/15/2022] Open
Abstract
Chronic Hepatitis C Viral (HCV) infection is a leading health problem worldwide and resulted in fibrotic scar formation, and finally liver-cirrhosis. Although contemporary therapies can partially reverse this destructive process, the rehabilitation is too slow and unsuitable for all chronic infections. The current study elucidates the mechanism of disease progression from early (F1) to moderate (F2, F3), and to severe fibrosis (F4)/cirrhosis in HCV genotype 3a infected patients to find out new candidates as potential disease progression markers and antiviral therapeutic agents. A total of 550 genes were found differentially regulated in the four fibrosis stages and grouped in 22 classes according to their biological functions. Gene set enrichment (GSEA) and Ingenuity pathway analysis (IPA) were used to identify the regulation of crucial biological functions and pathways involved in HCV progression. HCV differentially regulated the expression of genes involved in apoptosis, cell structure, signal transduction, proliferation, metabolism, cytokine signaling, immune response, cell adhesion and maintenance, and post translational modifications by pathway analysis. There was an increasing trend of proliferative and cell growth related genes and shutting down of immune response as the disease progress mild to moderate to advanced stage cirrhosis. The myriad of changes in gene expression showed more chances of developing liver cancer in patients infected with HCV genotype 3a in a systematic manner. The identified gene set can act as disease markers for prediction, whether the fibrosis lead to cirrhosis and its association with end stage liver disease development.
Collapse
Affiliation(s)
- Bushra Ijaz
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Waqar Ahmad
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.,School of Biological Sciences, The University of Queensland, Australia.,College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
| | - Trina Das
- Division of Transplantation, Department of Surgery, School of Medicine, University of Washington, Seattle, WA, USA
| | - Khadija Shabbiri
- School of Biological Sciences, The University of Queensland, Australia
| | - Tayyab Husnain
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Sajida Hassan
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.,Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
| |
Collapse
|
|
9
|
Hepatitis C Virus Modulates Solute carrier family 3 member 2 for Viral Propagation. Sci Rep 2018; 8:15486. [PMID: 30341327 PMCID: PMC6195511 DOI: 10.1038/s41598-018-33861-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 10/04/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) exploits an extensive network of host proteins to maintain chronic infection. Using RNA-Seq technology, we identified 30 host genes that were differentially expressed in cell culture grown HCV (HCVcc)-infected cells. Of these candidate genes, we selected solute carrier family 3 member 2 (SLC3A2) for further investigation. SLC3A2, also known as CD98hc, is a member of the solute carrier family and encodes a subunit of heterodimeric amino acid transporter. SLC3A2 and LAT1 constitute a heterodimeric transmembrane protein complex that catalyzes amino acid transport. In this study, we showed that HCV upregulated both mRNA and protein expression levels of SLC3A2 and this upregulation occurred through NS3/4A-mediated oxidative stress. HCV also elevated SLC3A2/LAT1 complex level and thus mammalian target of rapamycin complex 1 (mTORC1) signaling was activated. We further showed that L-leucine transport level was significantly increased in Jc1-infected cells as compared with mock-infected cells. Using RNA interference technology, we demonstrated that SLC3A2 was specifically required for the entry step but not for other stages of the HCV life cycle. These data suggest that SLC3A2 plays an important role in regulating HCV entry. Collectively, HCV exploits SLC3A2 for viral propagation and upregulation of SLC3A2 may contribute to HCV-mediated pathogenesis.
Collapse
|
|
10
|
Peng JL, Patel MP, McGee B, Liang T, Chandler K, Tayarachakul S, O'Connor S, Liangpunsakul S. Management of alcohol misuse in patients with liver diseases. J Investig Med 2016; 65:673-680. [PMID: 27940551 DOI: 10.1136/jim-2016-000254] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2016] [Indexed: 12/20/2022]
Abstract
Excessive alcohol use not only causes alcoholic liver disease (ALD) but also increases the risk of liver-related mortality in patients who already have other chronic liver diseases. Screening for alcohol misuse or alcohol use disorder (AUD) among patients with underlying liver disease is essential. This clinical review covers what is known about ALD, the impact of alcohol in patients with underlying liver diseases, current management of alcohol misuse and AUD, and the management of alcohol misuse and AUD specifically in patients with liver diseases. Several treatment options for alcohol misuse and AUD exist such as psychosocial intervention and behavioral and pharmacological therapies. The strategies used in the treatment of alcohol misuse and AUD are still applicable in those who consume alcohol and have underlying liver disease. However, certain medications still need to be carefully used due to potentially worsening already compromised liver function. Screening of ongoing alcohol use in subjects with liver disease is important, and prompt intervention is needed to prevent the associated morbidity and mortality from the detrimental effects of continued alcohol use on underlying liver disease. Considering alcoholism is a complex disease, probably a multidisciplinary approach combining psychotherapy and comprehensive medical care will be the most effective. Future research could focus on identifying additional treatment options for addressing the psychotherapy component since the self-determination and will to quit drinking alcohol can play such a crucial role in promoting abstinence.
Collapse
Affiliation(s)
- Jennifer L Peng
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, USA
| | - Milan Prakash Patel
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, USA
| | - Breann McGee
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, USA
| | - Tiebing Liang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, USA
| | - Kristina Chandler
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, USA
| | - Sucharat Tayarachakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, USA.,Southern Plains Tribal Health Board, Oklahoma Area Tribal Epidemiology Center, Oklahoma City, Oklahoma, USA
| | - Sean O'Connor
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Roudebush Veterans Administration Medical Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, USA.,Roudebush Veterans Administration Medical Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Depertment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| |
Collapse
|
|
11
|
Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016. [PMID: 26819510 DOI: 10.3748/wjg.v22.i4.141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
Collapse
Affiliation(s)
- Ignacio Novo-Veleiro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Lucía Alvela-Suárez
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Antonio-Javier Chamorro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Rogelio González-Sarmiento
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Francisco-Javier Laso
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Miguel Marcos
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| |
Collapse
|
|
12
|
Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016; 22:1411-1420. [PMID: 26819510 PMCID: PMC4721976 DOI: 10.3748/wjg.v22.i4.1411] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/01/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
Collapse
|
|
13
|
Ohkoshi S, Hirono H, Watanabe K, Hasegawa K, Yano M. Contributions of transgenic mouse studies on the research of hepatitis B virus and hepatitis C virus-induced hepatocarcinogenesis. World J Hepatol 2015; 7:2834-2840. [PMID: 26668695 PMCID: PMC4670955 DOI: 10.4254/wjh.v7.i28.2834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 09/28/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
Transgenic mouse technology has enabled the investigation of the pathogenic effects, including those on development, immunological reactions and carcinogenesis, of viral genes directly in living organism in a real-time manner. Although viral hepatocarcinogenesis comprises multiple sequences of pathological events, that is, chronic necroinflammation and the subsequent regeneration of hepatocytes that induces the accumulation of genetic alterations and hepatocellular carcinoma (HCC), the direct action of viral proteins also play significant roles. The pathogenesis of hepatitis B virus X and hepatitis C virus (HCV) core genes has been extensively studied by virtue of their functions as a transactivator and a steatosis inducer, respectively. In particular, the mechanism of steatosis in HCV infection and its possible association with HCC has been well studied using HCV core gene transgenic mouse models. Although transgenic mouse models have remarkable advantages, they are intrinsically accompanied by some drawbacks when used to study human diseases. Therefore, the results obtained from transgenic mouse studies should be carefully interpreted in the context of whether or not they are well associated with human pathogenesis.
Collapse
Affiliation(s)
- Shogo Ohkoshi
- Shogo Ohkoshi, Haruka Hirono, Kazuhiko Watanabe, Katsuhiko Hasegawa, Department of Internal Medicine, School of Life Dentistry at Niigata, the Nippon Dental University, Niigata-city 951-8580, Japan
| | - Haruka Hirono
- Shogo Ohkoshi, Haruka Hirono, Kazuhiko Watanabe, Katsuhiko Hasegawa, Department of Internal Medicine, School of Life Dentistry at Niigata, the Nippon Dental University, Niigata-city 951-8580, Japan
| | - Kazuhiko Watanabe
- Shogo Ohkoshi, Haruka Hirono, Kazuhiko Watanabe, Katsuhiko Hasegawa, Department of Internal Medicine, School of Life Dentistry at Niigata, the Nippon Dental University, Niigata-city 951-8580, Japan
| | - Katsuhiko Hasegawa
- Shogo Ohkoshi, Haruka Hirono, Kazuhiko Watanabe, Katsuhiko Hasegawa, Department of Internal Medicine, School of Life Dentistry at Niigata, the Nippon Dental University, Niigata-city 951-8580, Japan
| | - Masahiko Yano
- Shogo Ohkoshi, Haruka Hirono, Kazuhiko Watanabe, Katsuhiko Hasegawa, Department of Internal Medicine, School of Life Dentistry at Niigata, the Nippon Dental University, Niigata-city 951-8580, Japan
| |
Collapse
|
|
14
|
Ramachandran A, Lebofsky M, Yan HM, Weinman SA, Jaeschke H. Hepatitis C virus structural proteins can exacerbate or ameliorate acetaminophen-induced liver injury in mice. Arch Toxicol 2015; 89:773-83. [PMID: 25743375 PMCID: PMC4398656 DOI: 10.1007/s00204-015-1498-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/26/2015] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis C virus (HCV) infection predisposes patients to develop liver failure after acetaminophen (APAP) overdose. Mechanisms involved in this were explored using transgenic mice expressing the HCV structural proteins core, E1 and E2. Treatment of C57BL/6J mice with 200 mg/kg body weight APAP resulted in significant liver injury at 6 h as indicated by elevated ALT levels, focal centrilobular necrosis and nuclear DNA fragmentation. HCV transgenic mice showed a variable response, with approximately half the animals showing exacerbation of all parameters of liver injury, while the other half was protected. HCV transgenic mice with higher liver injury had lower liver glutathione levels, elevated mitochondrial oxidative stress and enhanced release of apoptosis-inducing factor (AIF) from the mitochondria. This was accompanied by induction of a higher ER stress response and induction of autophagy. Transgenic animals showing protection against liver injury had a robust recovery of liver glutathione content at 6 h when compared to wild-type animals, accompanied by reduction in mitochondrial oxidative stress and AIF release. This was accompanied by an elevation in glutathione S-transferase mRNA levels and activity, which suggests that an efficient clearance of the reactive intermediate may contribute to the protection against APAP hepatotoxicity in these mice. These results demonstrate that while HCV infection could exacerbate APAP-induced liver injury due to induction and amplification of mitochondrial oxidant stress, it could also protect against injury by activation of APAP scavenging mechanisms.
Collapse
Affiliation(s)
- Anup Ramachandran
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Margitta Lebofsky
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Hui-Min Yan
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Steven A. Weinman
- Departments of Internal Medicine and Microbiology & Immunology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| |
Collapse
|
|
15
|
Sekine S, Ito K, Watanabe H, Nakano T, Moriya K, Shintani Y, Fujie H, Tsutsumi T, Miyoshi H, Fujinaga H, Shinzawa S, Koike K, Horie T. Mitochondrial iron accumulation exacerbates hepatic toxicity caused by hepatitis C virus core protein. Toxicol Appl Pharmacol 2014; 282:237-43. [PMID: 25545986 DOI: 10.1016/j.taap.2014.12.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 12/09/2014] [Accepted: 12/16/2014] [Indexed: 01/06/2023]
Abstract
Patients with long-lasting hepatitis C virus (HCV) infection are at major risk of hepatocellular carcinoma (HCC). Iron accumulation in the livers of these patients is thought to exacerbate conditions of oxidative stress. Transgenic mice that express the HCV core protein develop HCC after the steatosis stage and produce an excess of hepatic reactive oxygen species (ROS). The overproduction of ROS in the liver is the net result of HCV core protein-induced dysfunction of the mitochondrial respiratory chain. This study examined the impact of ferric nitrilacetic acid (Fe-NTA)-mediated iron overload on mitochondrial damage and ROS production in HCV core protein-expressing HepG2 (human HCC) cells (Hep39b cells). A decrease in mitochondrial membrane potential and ROS production were observed following Fe-NTA treatment. After continuous exposure to Fe-NTA for six days, cell toxicity was observed in Hep39b cells, but not in mock (vector-transfected) HepG2 cells. Moreover, mitochondrial iron ((59)Fe) uptake was increased in the livers of HCV core protein-expressing transgenic mice. This increase in mitochondrial iron uptake was inhibited by Ru360, a mitochondrial Ca(2+) uniporter inhibitor. Furthermore, the Fe-NTA-induced augmentation of mitochondrial dysfunction, ROS production, and cell toxicity were also inhibited by Ru360 in Hep39b cells. Taken together, these results indicate that Ca(2+) uniporter-mediated mitochondrial accumulation of iron exacerbates hepatocyte toxicity caused by the HCV core protein.
Collapse
Affiliation(s)
- Shuichi Sekine
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Konomi Ito
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Haruna Watanabe
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Takafumi Nakano
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Kyoji Moriya
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yoshizumi Shintani
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Hajime Fujie
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Takeya Tsutsumi
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Hideyuki Miyoshi
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Hidetake Fujinaga
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Seiko Shinzawa
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Kazuhiko Koike
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Toshiharu Horie
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
| |
Collapse
|
|
16
|
Cheng ML, Weng SF, Kuo CH, Ho HY. Enterovirus 71 induces mitochondrial reactive oxygen species generation that is required for efficient replication. PLoS One 2014; 9:e113234. [PMID: 25401329 PMCID: PMC4234665 DOI: 10.1371/journal.pone.0113234] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 10/22/2014] [Indexed: 12/16/2022] Open
Abstract
Redox homeostasis is an important host factor determining the outcome of infectious disease. Enterovirus 71 (EV71) infection has become an important endemic disease in Southeast Asia and China. We have previously shown that oxidative stress promotes viral replication, and progeny virus induces oxidative stress in host cells. The detailed mechanism for reactive oxygen species (ROS) generation in infected cells remains elusive. In the current study, we demonstrate that mitochondria were a major ROS source in EV71-infected cells. Mitochondria in productively infected cells underwent morphologic changes and exhibited functional anomalies, such as a decrease in mitochondrial electrochemical potential ΔΨm and an increase in oligomycin-insensitive oxygen consumption. Respiratory control ratio of mitochondria from infected cells was significantly lower than that of normal cells. The total adenine nucleotide pool and ATP content of EV71-infected cells significantly diminished. However, there appeared to be a compensatory increase in mitochondrial mass. Treatment with mito-TEMPO reduced eIF2α phosphorylation and viral replication, suggesting that mitochondrial ROS act to promote viral replication. It is plausible that EV71 infection induces mitochondrial ROS generation, which is essential to viral replication, at the sacrifice of efficient energy production, and that infected cells up-regulate biogenesis of mitochondria to compensate for their functional defect.
Collapse
Affiliation(s)
- Mei-Ling Cheng
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
- Healthy Aging Research Center, Chang Gung University, Tao-Yuan, Taiwan
- Metabolomics Core Laboratory, Chang Gung University, Tao-Yuan, Taiwan
| | - Shiue-Fen Weng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Chih-Hao Kuo
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Hung-Yao Ho
- Healthy Aging Research Center, Chang Gung University, Tao-Yuan, Taiwan
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
- Office of Research and Development, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
- * E-mail:
| |
Collapse
|
|
17
|
Abstract
Abundant evidence supports the belief of a causal relationship between cirrhosis and hepatocellular carcinoma, but one that differs between high- and low-incidence regions of the tumor. In high-incidence regions, the cirrhosis is of the macronodular variety, is typically asymptomatic, and is caused predominantly by chronic hepatitis B virus infection, whereas in low-incidence regions, the cirrhosis, although usually macronodular, may be micronodular, is commonly symptomatic and of long-standing, and is caused by chronic hepatitis C virus infection, alcohol abuse over many years, the metabolic syndrome, or hereditary hemochromatosis. In a minority of patients, hepatocellular carcinoma develops in the absence of cirrhosis, supporting a direct hepatocarcinogenic effect of some of the causal agents. Cirrhosis is the major risk factor for tumor formation in patients with chronic hepatitis C virus infection. This virus does not integrate into cellular DNA, and malignant transformation results from increased liver cell turnover induced by recurring injury and regeneration of cells in the context of persisting inflammation, oxidative DNA damage, fibrosis, cirrhosis, and changes induced by the virus at a DNA level that have yet to be fully defined. Hepatitis B virus causes malignant transformation by both direct and indirect routes. The direct route results, in part, from integration of the viral DNA into host cellular DNA; transcriptional activation of host growth regulatory genes by hepatitis B virus-encoded proteins; and effects on apoptosis, cell signaling, and DNA repair. The direct route may share some similarities with that of hepatitis C virus infection. The metabolic syndrome may cause malignant transformation by production of oxidative stress and the induction of a variety of mutations, including some in the p53 gene.
Collapse
Affiliation(s)
- Michael C Kew
- Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa,
| |
Collapse
|
|
18
|
Ortiz V, Wands JR. Chronic ethanol diet increases regulatory T-cell activity and inhibits hepatitis C virus core-specific cellular immune responses in mice. Hepatol Res 2014; 44:788-97. [PMID: 23710581 PMCID: PMC3883867 DOI: 10.1111/hepr.12173] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 05/21/2013] [Accepted: 05/22/2013] [Indexed: 12/13/2022]
Abstract
AIM Chronic ethanol consumption is associated with persistent hepatitis C viral (HCV) infection. This study explores the role of the host cellular immune response to HCV core protein in a murine model and how chronic ethanol consumption alters T-cell regulatory (Treg) populations. METHODS BALB/c mice were fed an isocaloric control or ethanol liquid diet. Dendritic cells (DC) were isolated after expansion with a hFl3tL-expression plasmid and subsequently transfected with HCV core protein. Core-containing DC (1 × 10(6) ) were s.c. injected (×3) in mice every 2 weeks. Splenocytes from immunized mice were isolated and stimulated with HCV core protein to measure generation of viral antigen-specific Treg, as well as secretion of interleukin (IL)-2, tumor necrosis factor (TNF)-α and IL-4. Cytotoxicity was measured by lactate dehydrogenase release from HCV core-expressing syngeneic SP2/19 myeloma cells. RESULTS Splenocytes from mice immunized with ethanol-derived and HCV core-loaded DC exhibited significantly lower in vitro cytotoxicity compared to mice immunized with HCV core-loaded DC derived from isocaloric pair-fed controls. Stimulation with HCV core protein triggered higher IL-2, TNF-α and IL-4 release in splenocytes following immunization with core-loaded DC derived from controls as compared to chronic ethanol-fed mice. Splenocytes derived from mice immunized with core-loaded DC isolated from ethanol-fed mice exhibited a significantly higher CD25(+) FOXP3(+) and CD4(+) FOXP3(+) Treg population. CONCLUSION These results suggest that immunization with HCV core-containing DC from ethanol-fed mice induces an increase in the CD25(+) FOXP3(+) and CD4(+) FOXP3(+) Treg population and may suppress HCV core-specific CD4(+) and CD8(+) T-cell immune responses.
Collapse
Affiliation(s)
- Vivian Ortiz
- Department of Medicine; Division of Gastroenterology and Liver Research Center; Warren Alpert Medical School of Brown University; Providence Rhode Island USA
| | - Jack R. Wands
- Department of Medicine; Division of Gastroenterology and Liver Research Center; Warren Alpert Medical School of Brown University; Providence Rhode Island USA
| |
Collapse
|
|
19
|
Higgs MR, Chouteau P, Lerat H. 'Liver let die': oxidative DNA damage and hepatotropic viruses. J Gen Virol 2014; 95:991-1004. [PMID: 24496828 DOI: 10.1099/vir.0.059485-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Chronic infections by the hepatotropic viruses hepatitis B virus (HBV) and hepatitis C virus (HCV) are major risk factors for the development of hepatocellular carcinoma (HCC). It is estimated that more than 700,000 individuals per year die from HCC, and around 80 % of HCC is attributable to HBV or HCV infection. Despite the clear clinical importance of virus-associated HCC, the underlying molecular mechanisms remain largely elusive. Oxidative stress, in particular DNA lesions associated with oxidative damage, play a major contributory role in carcinogenesis, and are strongly linked to the development of many cancers, including HCC. A large body of evidence demonstrates that both HBV and HCV induce hepatic oxidative stress, with increased oxidative DNA damage being observed both in infected individuals and in murine models of infection. Here, we review the impact of HBV and HCV on the incidence and repair of oxidative DNA damage. We begin by giving a brief overview of oxidative stress and the repair of DNA lesions induced by oxidative stress. We then review in detail the evidence surrounding the mechanisms by which both viruses stimulate oxidative stress, before focusing on how the viral proteins themselves may perturb the cellular response to oxidative DNA damage, impacting upon genome stability and thus hepatocarcinogenesis.
Collapse
Affiliation(s)
- Martin R Higgs
- School of Cancer Sciences, University of Birmingham, Birmingham, UK
| | | | - Hervé Lerat
- INSERM U955, Université Paris-Est, Créteil, France
| |
Collapse
|
|
20
|
Han H, Xiong AZ, He CY, Liu Q, Yang L, Wang ZT. Combination of UHPLC/Q-TOF-MS, NMR spectroscopy, and ECD calculation for screening and identification of reactive metabolites of gentiopicroside in humans. Anal Bioanal Chem 2014; 406:1781-93. [PMID: 24408300 DOI: 10.1007/s00216-013-7572-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 12/01/2013] [Accepted: 12/10/2013] [Indexed: 01/09/2023]
Abstract
The metabolic investigation of natural products is a great challenge because of unpredictable metabolic pathways, little knowledge on metabolic effects, and lack of recommended analytical methodology. Herein, a combined strategy based on ultrahigh-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC/Q-TOF-MS), nuclear magnetic resonance (NMR) spectroscopy, and electronic circular dichroism (ECD) calculation was developed and employed for the human metabolism study of gentiopicroside (GPS), a naturally hepato-protective iridoid glycoside. The whole metabolic study consisted of three major procedures. First, an improved UHPLC/Q-TOF-MS method was used to separate and detect a total of 15 GPS metabolites that were obtained from urine samples (0 to 72 h) of 12 healthy male participants after a single 50-mg oral dose of GPS. Second, a developed "MS-NMR-MS" method was applied to accurately identify molecular structures of the observed metabolites. Finally, given that the associated stereochemistry may be a crucial factor of the metabolic activation, the absolute configuration of the reactive metabolites was revealed through chemical calculations. Based on the combined use, a pair of diastereoisomers (G05 and G06) were experimentally addressed as the bioreactive metabolites of GPS, and the stereochemical determination was completed. Whereas several novel metabolic transformations, occurring via oxidation, N-heterocyclization and glucuronidation after deglycosylation, were also observed. The results indicated that GPS has to undergo in vivo metabolism-based activation to generate reactive molecules capable of processing its hepato-protective activity.
Collapse
Affiliation(s)
- Han Han
- The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Traditional Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201210, China
| | | | | | | | | | | |
Collapse
|
|
21
|
Wang T, Weinman SA. Interactions Between Hepatitis C Virus and Mitochondria: Impact on Pathogenesis and Innate Immunity. CURRENT PATHOBIOLOGY REPORTS 2013; 1:179-187. [PMID: 23956955 DOI: 10.1007/s40139-013-0024-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) causes a persistent chronic infection of hepatocytes resulting in progressive fibrosis and carcinogenesis. Abnormalities in mitochondria are prominent features of clinical disease where ultrastructural changes, alterations in electron transport, and excess reactive oxygen species (ROS) production occur. These mitochondrial abnormalities correlate with disease severity and resolve with viral eradication. Multiple viral proteins, particularly core and NS3/4a bind to mitochondria. The core and NS5a proteins primarily cause ER stress, ER Ca2+ release and enhance direct transfer of Ca2+ from ER to mitochondria. This results in electron transport changes, increased ROS production and sensitivity to mitochondrial permeability transition and cell death. The viral protease, NS3/4a, binds to mitochondria as well where it cleaves an important signaling adapter, MAVS, thus preventing viral clearance by endogenous interferon production. This review discusses the mechanisms by which HCV causes mitochondrial changes and consequences of these for disease.
Collapse
Affiliation(s)
- Ting Wang
- Liver Center and Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | | |
Collapse
|
|
22
|
Hepatitis C virus-induced mitochondrial dysfunctions. Viruses 2013; 5:954-80. [PMID: 23518579 PMCID: PMC3705306 DOI: 10.3390/v5030954] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 03/15/2013] [Accepted: 03/20/2013] [Indexed: 12/15/2022] Open
Abstract
Chronic hepatitis C is characterized by metabolic disorders and a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that lead in the long term to hepatocellular carcinoma. Many lines of evidence suggest that mitochondrial dysfunctions, including modification of metabolic fluxes, generation and elimination of oxidative stress, Ca2+ signaling and apoptosis, play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory, probably due to the use of artificial expression and replication systems. In vivo studies are hampered by the fact that innate and adaptive immune responses will overlay mitochondrial dysfunctions induced directly in the hepatocyte by HCV. Thus, the molecular aspects underlying HCV-induced mitochondrial dysfunctions and their roles in viral replication and the associated pathology need yet to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems.
Collapse
|
|
23
|
Stability and antioxidant activity of gossypol derivative immobilized on N-polyvinylpyrrolidone. Int J Biol Macromol 2012; 51:908-14. [DOI: 10.1016/j.ijbiomac.2012.08.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Revised: 07/18/2012] [Accepted: 08/05/2012] [Indexed: 11/20/2022]
|
|
24
|
Uehara T, Kosyk O, Jeannot E, Bradford BU, Tech K, Macdonald JM, Boorman GA, Chatterjee S, Mason RP, Melnyk SB, Tryndyak VP, Pogribny IP, Rusyn I. Acetaminophen-induced acute liver injury in HCV transgenic mice. Toxicol Appl Pharmacol 2012. [PMID: 23200774 DOI: 10.1016/j.taap.2012.11.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility.
Collapse
Affiliation(s)
- Takeki Uehara
- Department of Environmental Sciences & Engineering, University of North Carolina, Chapel Hill, NC 27599, USA
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection. Gastroenterology 2012; 143:1244-1252.e12. [PMID: 22841784 PMCID: PMC3756935 DOI: 10.1053/j.gastro.2012.07.097] [Citation(s) in RCA: 120] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Revised: 07/13/2012] [Accepted: 07/16/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We performed a 2-stage GWA study of liver fibrosis progression related to HCV infection. METHODS We studied well-characterized HCV-infected patients of European descent who underwent liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of METAVIR scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P values <5 × 10(-5) from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance. RESULTS In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients who received blood transfusions) were associated with fibrosis progression (P(combined) = 8.9 × 10(-9) and 1.1 × 10(-9), respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (P(combined) = 5.4 × 10(-7)), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages. CONCLUSIONS Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.
Collapse
|
|
26
|
Abstract
BACKGROUND Chronic hepatitis C (CHC) infection is associated with insulin resistance and with oxidative stress, but the relationship between the two has not been thoroughly examined. PURPOSE To evaluate the association between insulin resistance and oxidative stress in CHC patients. METHOD In 115 CHC patients (68 with genotype 1 and 47 with genotype 3), the relationship between the serum concentration of malondialdehyde (MDA), a marker of oxidative stress and insulin resistance as defined by the homeostasis model (HOMA-IR) was examined. RESULTS There was no significant difference in MDA levels between genotype 1- and genotype 3-infected subjects (12.882 vs. 12.426 ng/mL, p = 0.2). By univariate analysis, factors associated with HOMA-IR in both genotypes were oxidative stress as measured by MDA (p = 0.002), body mass index (BMI), portal activity, and fibrosis. Genotype-specific differences in HOMA-IR association were steatosis and triglycerides (TG) for genotype 1, and age and glutathione (GSH) for genotype 3. In a stepwise multiple linear regression analysis in both genotypes, MDA was a significant and independent predictor of HOMA-IR (p = 0.04). As expected, BMI and fibrosis were likewise independently correlated to HOMA-IR. In addition, MDA levels were higher (p < 0.001) and GSH levels were lower (p = 0.023) in insulin-resistant subjects compared to their insulin-sensitive counterparts. CONCLUSIONS It is concluded that in CHC, oxidative stress is an independent predictor of HOMA-IR, irrespective of virus genotype. Further studies on the role of oxidative stress in the development of insulin resistance in CHC are warranted.
Collapse
|
|
27
|
Ishikawa T. Can zinc enhance response interferon therapy for patients with HCV-related liver disease? World J Gastroenterol 2012; 18:3196-3200. [PMID: 22783042 PMCID: PMC3391755 DOI: 10.3748/wjg.v18.i25.3196] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Revised: 09/24/2011] [Accepted: 10/11/2011] [Indexed: 02/06/2023] Open
Abstract
Patients with liver disease may be at risk of zinc depletion. Zinc supplementation has been shown to contribute to inhibition of liver fibrosis and improvement in hepatic encephalopathy. However, little is known about the anti-inflammatory effect of zinc on hepatitis C virus (HCV)-related chronic liver disease. The standard of care for chronic HCV has improved markedly since the approval of interferon (IFN) therapy more than a decade ago. Over the past 20 years, IFN therapy has improved to more effectively eliminate the virus, progressing from single IFN therapy to combination therapy with ribavirin (RBV) and finally to pegylated IFN (PEG-IFN) therapy. However, even combined therapy with PEG-IFN and RBV for 48 wk is unable to eliminate the virus in some 40% of hepatitis C cases, particularly those with genotype 1b and high viral load. Treatment options for patients who have relapsed or are refractory to treatment with PEG-IFN and RBV therefore need to be critically assessed. This paper overviews the relationship between chronic liver disease and zinc metabolism.
Collapse
|
|
28
|
Quarato G, Scrima R, Agriesti F, Moradpour D, Capitanio N, Piccoli C. Targeting mitochondria in the infection strategy of the hepatitis C virus. Int J Biochem Cell Biol 2012; 45:156-66. [PMID: 22710347 DOI: 10.1016/j.biocel.2012.06.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 05/29/2012] [Accepted: 06/07/2012] [Indexed: 12/23/2022]
Abstract
Hepatitis C virus (HCV) infection induces a state of oxidative stress more pronounced than that observed in many other inflammatory diseases. Here, we propose a temporal sequence of events in the HCV-infected cell whereby the primary alteration consists of a release of Ca(2+) from the endoplasmic reticulum, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen species and a progressive metabolic adaptive response. Evidence is provided for a positive feed-back mechanism between alterations of calcium and redox homeostasis. This likely involves deregulation of the mitochondrial permeability transition and induces progressive dysfunction of cellular bioenergetics. Pathogenetic implications of the model and new opportunities for therapeutic intervention are discussed. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.
Collapse
Affiliation(s)
- Giovanni Quarato
- Department of Biomedical Sciences, University of Foggia, Foggia, Italy
| | | | | | | | | | | |
Collapse
|
|
29
|
Chu VC, Bhattacharya S, Nomoto A, Lin J, Zaidi SK, Oberley TD, Weinman SA, Azhar S, Huang TT. Persistent expression of hepatitis C virus non-structural proteins leads to increased autophagy and mitochondrial injury in human hepatoma cells. PLoS One 2011; 6:e28551. [PMID: 22164304 PMCID: PMC3229600 DOI: 10.1371/journal.pone.0028551] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Accepted: 11/10/2011] [Indexed: 02/07/2023] Open
Abstract
HCV infection is a major cause of chronic liver disease and liver cancer in the United States. To address the pathogenesis caused by HCV infection, recent studies have focused on the direct cytopathic effects of individual HCV proteins, with the objective of identifying their specific roles in the overall pathogenesis. However, this approach precludes examination of the possible interactions between different HCV proteins and organelles. To obtain a better understanding of the various cytopathic effects of and cellular responses to HCV proteins, we used human hepatoma cells constitutively replicating HCV RNA encoding either the full-length polyprotein or the non-structural proteins, or cells constitutively expressing the structural protein core, to model the state of persistent HCV infection and examined the combination of various HCV proteins in cellular pathogenesis. Increased reactive oxygen species (ROS) generation in the mitochondria, mitochondrial injury and degeneration, and increased lipid accumulation were common among all HCV protein-expressing cells regardless of whether they expressed the structural or non-structural proteins. Expression of the non-structural proteins also led to increased oxidative stress in the cytosol, membrane blebbing in the endoplasmic reticulum, and accumulation of autophagocytic vacuoles. Alterations of cellular redox state, on the other hand, significantly changed the level of autophagy, suggesting a direct link between oxidative stress and HCV-mediated activation of autophagy. With the wide-spread cytopathic effects, cells with the full-length HCV polyprotein showed a modest antioxidant response and exhibited a significant increase in population doubling time and a concomitant decrease in cyclin D1. In contrast, cells expressing the non-structural proteins were able to launch a vigorous antioxidant response with up-regulation of antioxidant enzymes. The population doubling time and cyclin D1 level were also comparable to that of control cells. Finally, the cytopathic effects of core protein appeared to focus on the mitochondria without remarkable disturbances in the cytosol.
Collapse
Affiliation(s)
- Victor C. Chu
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, United States of America
| | - Sayanti Bhattacharya
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, United States of America
| | - Ann Nomoto
- Geriatric Research, Education, and Clinical Center (GRECC), VA Palo Alto Health Care System, Palo Alto, California, United States of America
| | - Jiahui Lin
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, United States of America
| | - Syed Kashif Zaidi
- Geriatric Research, Education, and Clinical Center (GRECC), VA Palo Alto Health Care System, Palo Alto, California, United States of America
| | - Terry D. Oberley
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
- William S. Middleton Veterans Administration Hospital, Madison, Wisconsin, United States of America
| | - Steven A. Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Salman Azhar
- Geriatric Research, Education, and Clinical Center (GRECC), VA Palo Alto Health Care System, Palo Alto, California, United States of America
| | - Ting-Ting Huang
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, United States of America
- Geriatric Research, Education, and Clinical Center (GRECC), VA Palo Alto Health Care System, Palo Alto, California, United States of America
- * E-mail:
| |
Collapse
|
|
30
|
Binjawadagi B, Dwivedi V, Manickam C, Torrelles JB, Renukaradhya GJ. Intranasal Delivery of an Adjuvanted Modified Live Porcine Reproductive and Respiratory Syndrome Virus Vaccine Reduces ROS Production. Viral Immunol 2011; 24:475-82. [DOI: 10.1089/vim.2011.0040] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Basavaraj Binjawadagi
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, Ohio
| | - Varun Dwivedi
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, Ohio
| | - Cordelia Manickam
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, Ohio
| | - Jordi B. Torrelles
- Center for Microbial Interface Biology, Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Gourapura J. Renukaradhya
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, Ohio
| |
Collapse
|
|
31
|
Trak-Smayra V, Paradis V, Massart J, Nasser S, Jebara V, Fromenty B. Pathology of the liver in obese and diabetic ob/ob and db/db mice fed a standard or high-calorie diet. Int J Exp Pathol 2011; 92:413-21. [PMID: 22118645 DOI: 10.1111/j.1365-2613.2011.00793.x] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the commonest liver diseases in Western countries. Although leptin deficient ob/ob and db/db mice are frequently used as murine models of NAFLD, an exhaustive characterization of their hepatic lesions has not been reported to date, particularly under calorie overconsumption. Thus, liver lesions were characterized in 78 ob/ob and db/db mice fed either a standard or high-calorie (HC) diet, for one or three months. Steatosis, necroinflammation, apoptosis and fibrosis were assessed and the NAFLD activity score (NAS) was calculated. Steatosis was milder in db/db mice compared to ob/ob mice and was more frequently microvesicular. Although necroinflammation was usually mild in both genotypes, it was aggravated in db/db mice after one month of calorie overconsumption. Apoptosis was observed in db/db mice whereas it was only detected in ob/ob mice after HC feeding. Increased apoptosis was frequently associated with microvesicular steatosis. In db/db mice fed the HC diet for three months, fibrosis was aggravated while steatosis, necroinflammation and apoptosis tended to alleviate. This was associated with increased plasma β-hydroxybutyrate suggesting an adaptive stimulation of hepatic mitochondrial fatty acid oxidation (FAO). Nevertheless, one-third of these db/db mice had steatohepatitis (NAS ≥ 5), whereas none of the ob/ob mice developed non-alcoholic steatohepatitis under the same conditions. Steatosis, necroinflammation, apoptosis and fibrosis are modulated by calorie overconsumption in the context of leptin deficiency. Association between apoptosis and microvesicular steatosis in obese mice suggests common mitochondrial abnormalities. Enhanced hepatic FAO in db/db mice is associated with fibrosis aggravation.
Collapse
|
|
32
|
Abstract
The unfolded protein response (UPR) is an ensemble of signal transduction pathways that respond to perturbations in the oxidative, pro-folding environment of the endoplasmic reticulum. During the past decade, ongoing research implicated these pathways in maintaining homeostasis of cells and organisms exposed to various stresses. Herein, we highlight recent findings regarding the functional role of the UPR in both normal and pathophysiologic processes.
Collapse
Affiliation(s)
- J. Alan Diehl
- The Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Serge Y. Fuchs
- Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Costantinos Koumenis
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
33
|
Osna NA, Thomes PG, Jr TMD. Involvement of autophagy in alcoholic liver injury and hepatitis C pathogenesis. World J Gastroenterol 2011; 17:2507-2514. [PMID: 21633655 PMCID: PMC3103808 DOI: 10.3748/wjg.v17.i20.2507] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Revised: 03/23/2011] [Accepted: 03/30/2011] [Indexed: 02/06/2023] Open
Abstract
This review describes the principal pathways of macroautophagy (i.e. autophagy), microautophagy and chaperone-mediated autophagy as they are currently known to occur in mammalian cells. Because of its crucial role as an accessory digestive organ, the liver has a particularly robust autophagic activity that is sensitive to changes in plasma and dietary components. Ethanol consumption causes major changes in hepatic protein and lipid metabolism and both are regulated by autophagy, which is significantly affected by hepatic ethanol metabolism. Ethanol exposure enhances autophagosome formation in liver cells, but suppresses lysosome function. Excessive ethanol consumption synergizes with hepatitis C virus (HCV) to exacerbate liver injury, as alcohol-consuming HCV patients frequently have a longer course of infection and more severe manifestations of chronic hepatitis than abstinent HCV patients. Alcohol-elicited exacerbation of HCV infection pathogenesis is related to modulation by ethanol metabolism of HCV replication. Additionally, as part of this mechanism, autophagic proteins have been shown to regulate viral (HCV) replication and their intracellular accumulation. Because ethanol induces autophagosome expression, enhanced levels of autophagic proteins may enhance HCV infectivity in liver cells of alcoholics and heavy drinkers.
Collapse
|
|
34
|
Petti S, Rabiei M, De Luca M, Scully C. The magnitude of the association between hepatitis C virus infection and oral lichen planus: meta-analysis and case control study. Odontology 2011; 99:168-78. [PMID: 21505737 DOI: 10.1007/s10266-011-0008-3] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Accepted: 10/31/2010] [Indexed: 12/12/2022]
Abstract
Although hepatitis C virus (HCV) infection is associated with oral lichen planus (OLP), a case-control study and a meta-analysis were designed to investigate the magnitude of such an association. A total of 413 presumptive OLP patients (18-75 years) who referred to a dental clinic in Rasht (Iran) were consecutively selected. OLP was diagnosed clinically (typical forms) and histologically (atypical forms) by a calibrated examiner. A total of 487 adults (20-77 years) attending the same dental clinic were the controls. The two groups were homogeneous in terms of age, gender and occupation. Subjects were tested for anti-HCV antibodies. The odds ratio (OR) for OLP attributable to HCV infection was non-significant [OR 1.2, 95% confidence interval (95CI) 0.3-4.8], suggesting that the association between HCV and OLP was weak in the Iranian context. Meta-analysis of observational studies characteristics of primary studies were that cases were diagnosed clinically (only typical forms) and histologically and exposure was assessed through anti-HCV antibodies. Exposed/unexposed cases/controls were extracted and zero values were appropriately transformed. As much as 44 studies, including the present, were located. Publication bias could not be totally excluded. The pooled OR, estimated using the random-effect model, was 2.8 (95CI 2.4-3.2). Sensitivity analysis confirmed the robustness of results. Subgroup analysis showed non-significant differences between American/European and Asian/African studies. The fraction of global OLP cases associated with HCV (population attributable fraction) was 2.1% (95CI 1.9-2.2%). Although HCV and OLP were significantly associated, the majority of OLP patients were not affected by HCV.
Collapse
Affiliation(s)
- Stefano Petti
- Department of Public Health and Infectious Diseases, Sanarelli Building, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.
| | | | | | | |
Collapse
|
|
35
|
Abstract
Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is one of the most deadly human cancers. The pathogenesis of HCC is frequently linked with continuous hepatocyte death, inflammatory cell infiltration and compensatory liver regeneration. Understanding the molecular signaling pathways driving or mediating these processes during liver tumorigenesis is important for the identification of novel therapeutic targets for this dreadful disease. The classical IKKβ-dependent NF-κB signaling pathway has been shown to promote hepatocyte survival in both developing and adult livers. In addition, it also plays a crucial role in liver inflammatory responses by controlling the expression of an array of growth factors and cytokines. One of these cytokines is IL-6, which is best known for its role in the liver acute phase response. IL-6 exerts many of its functions via activation of STAT3, a transcription factor found to be important for HCC development. This review will focus on recent studies on the roles of NF-κB and STAT3 in liver cancer. Interactions between the two pathways and their potential as therapeutic targets will also be discussed.
Collapse
Affiliation(s)
- Guobin He
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
- Current address: Isis Pharmaceuticals Inc., 1896 Rutherford Road, Carlsbad, CA 92008–7326. E-mail:
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
| |
Collapse
|
|
36
|
Wang T, Campbell RV, Yi MK, Lemon SM, Weinman SA. Role of Hepatitis C virus core protein in viral-induced mitochondrial dysfunction. J Viral Hepat 2010; 17:784-93. [PMID: 20002299 PMCID: PMC2970657 DOI: 10.1111/j.1365-2893.2009.01238.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatitis C virus (HCV) infection results in several changes in mitochondrial function including increased reactive oxygen species (ROS) production and greater sensitivity to oxidant, Ca(2+) and cytokine-induced cell death. Prior studies in protein over-expression systems have shown that this effect can be induced by the core protein, but other viral proteins and replication events may contribute as well. To evaluate the specific role of core protein in the context of viral replication and infection, we compared mitochondrial sensitivity in Huh7-derived HCV replicon bearing cells with or without core protein expression with that of cells infected with the JFH1 virus strain. JFH1 infection increased hydrogen peroxide production and sensitized cells to oxidant-induced loss of mitochondrial membrane potential and cell death. An identical phenomenon occurred in genome-length replicons-bearing cells but not in cells bearing the subgenomic replicons lacking core protein. Both cell death and mitochondrial depolarization were Ca(2+) dependent and could be prevented by Ca(2+) chelation. The difference in the mitochondrial response of the two replicon systems could be demonstrated even in isolated mitochondria derived from the two cell lines with the 'genome-length' mitochondria displaying greater sensitivity to Ca(2+) -induced cytochrome c release. In vitro incubation of 'subgenomic' mitochondria with core protein increased oxidant sensitivity to a level similar to that of mitochondria derived from cells bearing genome-length replicons. These results indicate that increased mitochondrial ROS production and a reduced threshold for Ca(2+) and ROS-induced permeability transition is a characteristic of HCV infection. This phenomenon is a direct consequence of core protein interactions with mitochondria and is present whenever core is expressed, either in infection, full-length replicon-bearing cells, or in over-expression systems.
Collapse
Affiliation(s)
- T. Wang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
| | - R. V. Campbell
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - M. K. Yi
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
| | - S. M. Lemon
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX
| | - S. A. Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| |
Collapse
|
|
37
|
Szabo G, Wands JR, Eken A, Osna NA, Weinman SA, Machida K, Wang HJ. Alcohol and hepatitis C virus--interactions in immune dysfunctions and liver damage. Alcohol Clin Exp Res 2010; 34:1675-86. [PMID: 20608905 PMCID: PMC3253556 DOI: 10.1111/j.1530-0277.2010.01255.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatitis C virus infection affects 170 million people worldwide, and the majority of individuals exposed to HCV develop chronic hepatitis leading to progressive liver damage, cirrhosis, and hepatocellular cancer. The natural history of HCV infection is influenced by genetic and environmental factors of which chronic alcohol use is an independent risk factor for cirrhosis in HCV-infected individuals. Both the hepatitis C virus and alcohol damage the liver and result in immune alterations contributing to both decreased viral clearance and liver injury. This review will capture the major components of the interactions between alcohol and HCV infection to provide better understanding for the molecular basis of the dangerous combination of alcohol use and HCV infection. Common targets of HCV and alcohol involve innate immune recognition and dendritic cells, the critical cell type in antigen presentation and antiviral immunity. In addition, both alcohol and HCV affect intracellular processes critical for hepatocyte and immune cell functions including mitochondrial and proteasomal activation. Finally, both chronic alcohol use and hepatitis C virus infection increase the risk of hepatocellular cancer. The common molecular mechanisms underlying the pathological interactions between alcohol and HCV include the modulation of cytokine production, lipopolysaccharide (LPS)-TLR4 signaling, and reactive oxygen species (ROS) production. LPS-induced chronic inflammation is not only a major cause of progressive liver injury and fibrosis, but it can also contribute to modification of the tissue environment and stem cells to promote hepatocellular cancer development. Alteration of these processes by alcohol and HCV produces an environment of impaired antiviral immune response, greater hepatocellular injury, and activation of cell proliferation and dedifferentiation.
Collapse
Affiliation(s)
- Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | - Jack R. Wands
- The Liver Research Center, Brown Alpert Medical School and Rhode Island Hospital, Providence, RI02903
| | - Ahmet Eken
- The Liver Research Center, Brown Alpert Medical School and Rhode Island Hospital, Providence, RI02903
| | - Natalia A. Osna
- Dept Internal Medicine, University of Nebraska Medical Center and VA Medical Center, Omaha, NE68198
| | - Steven A. Weinman
- Liver Center and Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS66160
| | - Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033
- Departments of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033
| | - H. Joe Wang
- Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD20892
| |
Collapse
|
|
38
|
Interaction of the hepatitis C virus (HCV) core with cellular genes in the development of HCV-induced steatosis. Arch Virol 2010; 155:1735-53. [DOI: 10.1007/s00705-010-0797-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Accepted: 08/31/2010] [Indexed: 12/13/2022]
|
|
39
|
Zhang R, Kang KA, Piao MJ, Kim KC, Kim AD, Chae S, Park JS, Youn UJ, Hyun JW. Cytoprotective effect of the fruits of Lycium chinense Miller against oxidative stress-induced hepatotoxicity. JOURNAL OF ETHNOPHARMACOLOGY 2010; 130:299-306. [PMID: 20546868 DOI: 10.1016/j.jep.2010.05.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2010] [Revised: 04/26/2010] [Accepted: 05/05/2010] [Indexed: 05/29/2023]
Abstract
AIM OF THE STUDY Fruits of Lycium chinense Miller (Solanaceae), distributed in northeast Asia, have gained attraction for their hepatoprotective role in traditional oriental medicine. The excessive production of reactive oxygen species (ROS) is hazardous for living organisms and damage major cellular constituents such as DNA, lipid, and protein. The cytoprotective effect of Lycium chinense fruits (Lycium extract) was assessed against H(2)O(2)-induced Chang liver cell damage. MATERIALS AND METHODS The effect of Lycium extract against H(2)O(2)-induced cell death was determined by the MTT assay. Radical scavenging activity was determined through the assessments of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, intracellular ROS, hydroxyl radicals, and superoxide. The inductions of antioxidant enzymes were determined via their protein expressions and activities. DNA damage was measured using comet assay and expression of phospho-histone H2A.X. Lipid peroxidation was measured using 8-isoprostane level and fluorescent probe. Protein modification was measured using protein carbonyl moiety. RESULTS AND CONCLUSION Lycium extract scavenged the DPPH free radicals, intracellular ROS, hydroxyl radicals, and superoxide. Lycium extract recovered activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) decreased by H(2)O(2). Lycium extract decreased DNA damage, lipid peroxidation and protein carbonyl values increased by H(2)O(2) exposure. In addition, Lycium extract increased the cell viability of Chang liver cells exposed to H(2)O(2) via inhibition of apoptosis. These results show that Lycium extract protected Chang liver cells against oxidative stressed cell damage by H(2)O(2) via scavenging ROS and enhancing antioxidant enzyme activity.
Collapse
Affiliation(s)
- Rui Zhang
- School of Medicine, Jeju National University, Jeju-si, Republic of Korea
| | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Ruggieri A, Barbati C, Malorni W. Cellular and molecular mechanisms involved in hepatocellular carcinoma gender disparity. Int J Cancer 2010; 127:499-504. [PMID: 20201099 DOI: 10.1002/ijc.25298] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and one of the most fatal human cancers. Besides alcoholic liver disease as well as genetic and environmental factors, hepatitis B and C viral infections also represent the most important risk factors for onset and development of the disease. In fact, HCC worldwide prevalence varies widely and mirrors the geographical distribution of chronic viral hepatitis. Interestingly, a gender difference was described for this disease: in almost all populations, a male/female ratio averaging between 2:1 and 4:1 was reported. Here, we analyze the implication of cytokines and sex hormones in this issue. Exploiting the emerging knowledge on the possible differential role of hepatitis viruses B and C, we discuss the role of reactive oxygen species and apoptosis dysregulation in the characterization of the molecular mechanisms of gender disparity in the development of HCC.
Collapse
Affiliation(s)
- Anna Ruggieri
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita', Rome, Italy
| | | | | |
Collapse
|
|
41
|
Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 2010. [PMID: 20227042 DOI: 10.1016/j.ccr.2009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The NF-kappaB activating kinase IKKbeta suppresses early chemically induced liver tumorigenesis by inhibiting hepatocyte death and compensatory proliferation. To study IKKbeta's role in late tumor promotion and progression, we developed a transplant system that allows initiated mouse hepatocytes to form hepatocellular carcinomas (HCC) in host liver after a long latency. Deletion of IKKbeta long after initiation accelerated HCC development and enhanced proliferation of tumor initiating cells. These effects of IKKbeta/NF-kappaB were cell autonomous and correlated with increased accumulation of reactive oxygen species that led to JNK and STAT3 activation. Hepatocyte-specific STAT3 ablation prevented HCC development. The negative crosstalk between NF-kappaB and STAT3, which is also evident in human HCC, is a critical regulator of liver cancer development and progression.
Collapse
|
|
42
|
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Despite recent advances in the diagnosis and treatment of HCC, its prognosis remains dismal. Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major risk factors for HCC. Although both are hepatotropic viral infections, there are important differences between the oncogenic mechanisms of these two viruses. In addition to the oncogenic potential of its viral proteins, HBV, as a DNA virus, can integrate into host DNA and directly transform hepatocytes. In contrast, HCV, an RNA virus, is unable to integrate into the host genome, and viral protein expression has a more critical function in hepatocarcinogenesis. Both HBV and HCV proteins have been implicated in disrupting cellular signal transduction pathways that lead to unchecked cell growth. Most HCC develops in the cirrhotic liver, but the linkage between cirrhosis and HCC is likely multifactorial. In this review, we summarize current knowledge regarding the pathogenetic mechanisms of viral HCC.
Collapse
Affiliation(s)
- W-L Tsai
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - RT Chung
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
43
|
He G, Yu GY, Temkin V, Ogata H, Kuntzen C, Sakurai T, Sieghart W, Peck-Radosavljevic M, Leffert HL, Karin M. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 2010; 17:286-97. [PMID: 20227042 PMCID: PMC2841312 DOI: 10.1016/j.ccr.2009.12.048] [Citation(s) in RCA: 371] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2009] [Revised: 12/17/2009] [Accepted: 02/03/2010] [Indexed: 02/07/2023]
Abstract
The NF-kappaB activating kinase IKKbeta suppresses early chemically induced liver tumorigenesis by inhibiting hepatocyte death and compensatory proliferation. To study IKKbeta's role in late tumor promotion and progression, we developed a transplant system that allows initiated mouse hepatocytes to form hepatocellular carcinomas (HCC) in host liver after a long latency. Deletion of IKKbeta long after initiation accelerated HCC development and enhanced proliferation of tumor initiating cells. These effects of IKKbeta/NF-kappaB were cell autonomous and correlated with increased accumulation of reactive oxygen species that led to JNK and STAT3 activation. Hepatocyte-specific STAT3 ablation prevented HCC development. The negative crosstalk between NF-kappaB and STAT3, which is also evident in human HCC, is a critical regulator of liver cancer development and progression.
Collapse
Affiliation(s)
- Guobin He
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
| | - Guann-Yi Yu
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
| | - Vladislav Temkin
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
| | - Hisanobu Ogata
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
| | - Christian Kuntzen
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
| | - Toshiharu Sakurai
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
- Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Wolfgang Sieghart
- Department of Internal Medicine III, Division of Gastroenterology/Hepatology, Medical University Vienna, Währingergürtel 18–20, 1090 Vienna, Austria
| | - Markus Peck-Radosavljevic
- Department of Internal Medicine III, Division of Gastroenterology/Hepatology, Medical University Vienna, Währingergürtel 18–20, 1090 Vienna, Austria
| | - Hyam L. Leffert
- Hepatocyte Growth Control and Stem Cell Laboratory, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
| |
Collapse
|
|
44
|
Pal S, Polyak SJ, Bano N, Qiu WC, Carithers RL, Shuhart M, Gretch DR, Das A. Hepatitis C virus induces oxidative stress, DNA damage and modulates the DNA repair enzyme NEIL1. J Gastroenterol Hepatol 2010; 25:627-34. [PMID: 20074151 PMCID: PMC3565844 DOI: 10.1111/j.1440-1746.2009.06128.x] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Hepatitis C virus (HCV)-induced chronic inflammation may induce oxidative stress which could compromise the repair of damaged DNA, rendering cells more susceptible to spontaneous or mutagen-induced alterations, the underlying cause of liver cirrhosis and hepatocellular carcinoma. In the current study we examined the induction of reactive oxygen species (ROS) resulting from HCV infection and evaluated its effect on the host DNA damage and repair machinery. METHODS HCV infected human hepatoma cells were analyzed to determine (i) ROS, (ii) 8-oxoG and (iii) DNA glycosylases NEIL1, NEIL2, OGG1. Liver biopsies were analyzed for NEIL1. RESULTS Human hepatoma cells infected with HCV JFH-1 showed 30-60-fold increases in ROS levels compared to uninfected cells. Levels of the oxidatively modified guanosine base 8-oxoguanine (8-oxoG) were significantly increased sixfold in the HCV-infected cells. Because DNA glycosylases are the enzymes that remove oxidized nucleotides, their expression in HCV-infected cells was analyzed. NEIL1 but not OGG1 or NEIL2 gene expression was impaired in HCV-infected cells. In accordance, we found reduced glycosylase (NEIL1-specific) activity in HCV-infected cells. The antioxidant N-acetyl cystein (NAC) efficiently reversed the NEIL1 repression by inhibiting ROS induction by HCV. NEIL1 expression was also partly restored when virus-infected cells were treated with interferon (IFN). HCV core and to a lesser extent NS3-4a and NS5A induced ROS, and downregulated NEIL1 expression. Liver biopsy specimens showed significant impairment of NEIL1 levels in HCV-infected patients with advanced liver disease compared to patients with no disease. CONCLUSION Collectively, the data indicate that HCV induction of ROS and perturbation of NEIL1 expression may be mechanistically involved in progression of liver disease and suggest that antioxidant and antiviral therapies can reverse these deleterious effects of HCV in part by restoring function of the DNA repair enzyme/s.
Collapse
Affiliation(s)
- Sampa Pal
- Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195-7110 USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010. [PMID: 20141834 DOI: 10.1016/j.cell.2009.12.052.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.
Collapse
|
|
46
|
Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Österreicher CH, Takahashi H, Karin M. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140:197-208. [PMID: 20141834 PMCID: PMC2836922 DOI: 10.1016/j.cell.2009.12.052] [Citation(s) in RCA: 1358] [Impact Index Per Article: 90.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2009] [Revised: 11/19/2009] [Accepted: 12/28/2009] [Indexed: 02/07/2023]
Abstract
Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.
Collapse
Affiliation(s)
- Eek Joong Park
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Jun Hee Lee
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Guann-Yi Yu
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Guobin He
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Syed Raza Ali
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Ryan G Holzer
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Christoph H. Österreicher
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Hiroyuki Takahashi
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA
| |
Collapse
|
|
47
|
Georgakilas AG, Mosley WG, Georgakila S, Ziech D, Panayiotidis MI. Viral-induced human carcinogenesis: an oxidative stress perspective. MOLECULAR BIOSYSTEMS 2010; 6:1162-72. [DOI: 10.1039/b923958h] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
48
|
Viral factors influencing the response to the combination therapy of peginterferon plus ribavirin in chronic hepatitis C. J Gastroenterol 2009; 44:1009-15. [PMID: 19756352 DOI: 10.1007/s00535-009-0126-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Accepted: 08/13/2009] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV) is a single-stranded RNA virus known for its high genetic variability owing to the lack of a proofreading mechanism of its RNA dependent RNA polymerase. Until now, numerous studies have been undertaken to clarify the correlation between pretreatment HCV genetic variability and the therapeutic response. Even with the recent combination therapy of peginterferon plus ribavirin for chronic hepatitis C, viral response is variable, and only half of treated patients could clear the virus [sustained viral response (SVR)]. In this review, the contribution of viral genetic variability affecting the treatment outcome is discussed according to each HCV genomic region.
Collapse
|
|
49
|
Ezzikouri S, Feydi AEE, Afifi R, Benazzouz M, Hassar M, Pineau P, Benjelloun S. Polymorphisms in antioxidant defence genes and susceptibility to hepatocellular carcinoma in a Moroccan population. Free Radic Res 2009; 44:208-16. [DOI: 10.3109/10715760903402906] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
|
|
50
|
Marquez-Quiñones A, Čipak A, Žarkovic K, Fattel-Fazenda S, Villa-Treviño S, Waeg G, Žarkovic N, Guéraud F. HNE-protein adducts formation in different pre-carcinogenic stages of hepatitis in LEC rats. Free Radic Res 2009; 44:119-27. [DOI: 10.3109/10715760903338071] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
|