|
1
|
Nainu F, Ophinni Y, Shiratsuchi A, Nakanishi Y. Apoptosis and Phagocytosis as Antiviral Mechanisms. Subcell Biochem 2023; 106:77-112. [PMID: 38159224 DOI: 10.1007/978-3-031-40086-5_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
Viruses are infectious entities that make use of the replication machinery of their hosts to produce more progenies, causing disease and sometimes death. To counter viral infection, metazoan hosts are equipped with various defense mechanisms, from the rapid-evoking innate immune responses to the most advanced adaptive immune responses. Previous research demonstrated that cells in fruit flies and mice infected with Drosophila C virus and influenza, respectively, undergo apoptosis, which triggers the engulfment of apoptotic virus-infected cells by phagocytes. This process involves the recognition of eat-me signals on the surface of virus-infected cells by receptors of specialized phagocytes, such as macrophages and neutrophils in mice and hemocytes in fruit flies, to facilitate the phagocytic elimination of virus-infected cells. Inhibition of phagocytosis led to severe pathologies and death in both species, indicating that apoptosis-dependent phagocytosis of virus-infected cells is a conserved antiviral mechanism in multicellular organisms. Indeed, our understanding of the mechanisms underlying apoptosis-dependent phagocytosis of virus-infected cells has shed a new perspective on how hosts defend themselves against viral infection. This chapter explores the mechanisms of this process and its potential for developing new treatments for viral diseases.
Collapse
Affiliation(s)
- Firzan Nainu
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia.
| | - Youdiil Ophinni
- Division of Clinical Virology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
- Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Akiko Shiratsuchi
- Center for Medical Education, Sapporo Medical University, Sapporo, Japan
- Division of Biological Function and Regulation, Graduate School of Medicine, Sapporo Medical University, Sapporo, Japan
| | | |
Collapse
|
|
2
|
Rattanasupar A, Chang A, Prateepchaiboon T, Pungpipattrakul N, Akarapatima K, Songjamrat A, Pakdeejit S, Prachayakul V, Piratvisuth T. Impact of alcohol consumption on treatment outcome of hepatocellular carcinoma patients with viral hepatitis who underwent transarterial chemoembolization. World J Hepatol 2022; 14:1162-1172. [PMID: 35978671 PMCID: PMC9258258 DOI: 10.4254/wjh.v14.i6.1162] [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: 02/04/2022] [Revised: 04/24/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alcohol consumption increases the risk of hepatocellular carcinoma (HCC) in patients with pre-existing liver disease, including viral hepatitis. However, studies on the impact of alcohol consumption on the outcomes of HCC are limited. We hypothesized that alcohol had an additional effect with chronic viral hepatitis infection on treatment outcomes after transarterial chemoembolization (TACE) in patients with intermediate-stage HCC (Barcelona Clinical Liver Cancer [BCLC] -B). AIM To evaluate the additional effect of alcohol on treatment outcomes of TACE among HCC patients with viral hepatitis. METHODS This study, conducted at Hatyai Hospital in Thailand, included HCC patients over 18 years of age with chronic viral hepatitis. Records of HCC patients with viral hepatitis classified as BCLC-B who underwent TACE as the first treatment modality between 2014 and 2019 were retrospectively reviewed. Patients with chronic viral hepatitis only were categorized under group A, and those with chronic viral hepatitis and concurrent alcohol consumption were categorized under group B. Both groups were compared, and the Cox proportional-hazards model was used to identify the survival-influencing variables. RESULTS Of the 69 patients, 53 were categorized in group A and 16 in group B. There were no statistically significant differences in tumor characteristics between the two patient groups. However, Group A had a statistically significantly higher proportion of complete response (24.5% vs 0%, P = 0.030) and a higher median survival rate (26.2 mo vs 8.4 mo; log-rank P = 0.012) compared to group B. Factors associated with decreased survival in the proportional-hazards model included alcohol consumption (hazards ratio [HR], 2.377; 95% confidence interval [CI], 1.109-5.095; P = 0.026), presence of portal hypertension (HR, 2.578; 95%CI, 1.320-5.037; P = 0.006), largest tumor size > 5 cm (HR, 3.558; 95%CI, 1.824-6.939; P < 0.001), and serum alpha-fetoprotein level > 100 ng/mL (HR, 2.536; 95%CI, 1.377-4.670; P = 0.003). CONCLUSION In HCC BCLC B patients with chronic viral hepatitis, alcohol consumption is an independent risk factor for increased mortality and decreases the rate of complete response and survival after TACE.
Collapse
Affiliation(s)
- Attapon Rattanasupar
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Arunchai Chang
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand.
| | | | | | - Keerati Akarapatima
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Apiradee Songjamrat
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Songklod Pakdeejit
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Varayu Prachayakul
- Siriraj Gastrointestinal Endoscopy Center, Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkoknoi 10700, Bangkok, Thailand
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Hatyai 90110, Songkhla, Thailand
| |
Collapse
|
|
3
|
Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
Collapse
Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| |
Collapse
|
|
4
|
Mu LY, Li SQ, Tang LX, Li R. Efficacy and Safety of Emricasan in Liver Cirrhosis and/or Fibrosis. Clinics (Sao Paulo) 2021; 76:e2409. [PMID: 34133478 PMCID: PMC8183342 DOI: 10.6061/clinics/2021/e2409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 01/04/2021] [Indexed: 11/18/2022] Open
Abstract
This study aimed to perform a meta-analysis to determine the efficacy and safety of emricasan. Nine databases were searched for clinical trials investigating the efficacy of emricasan treatment in patients with liver cirrhosis or fibrosis. A manual search was conducted to identify the missing trials. The quality of the included studies was assessed using the revised Cochrane risk of bias tool. Efficacy of emricasan treatment was defined as a positive change in apoptosis-related parameters from baseline to the last follow-up visit. Overall, emricasan treatment is more effective in patients with liver cirrhosis or fibrosis than placebo (standardized mean difference [SMD] [95% confidence intervals (CI)]=0.28 [0.14; 0.41]). No significant change in model for end-stage liver disease (MELD) score between the emricasan and placebo groups was noted (SMD [95% CI]=0.18 [-0.01; 0.36]; p=0.058). A 50 mg dose of emricasan had the highest efficacy rate compared to placebo (SMD [95% CI]=0.28 [0.06; 0.50]; p=0.012), followed by the 5 mg dosing regimen (SMD [95% CI]=0.28 [0.06; 0.50]; p=0.012). Treatment with emricasan resulted in significant reductions in ALT (mean difference (MD) [95% CI]=-5.89 [-10.59; -1.20]; p=0.014) and caspase3/7 levels (MD [95%CI]=-1215.93 [-1238.53; -1193.33]; p<0.001), respectively. No significant increase in the rate of overall adverse events was noted (OR [95% CI]=1.52 [0.97; 2.37]; p=0.069). Treatment with emricasan is more effective in improving liver function and apoptosis parameters compared to placebo, with a well-tolerated safety profile. However, due to the poor quality of the analyzed studies, the small number of trials and patients, and the short follow-up periods, more robust trials are still warranted.
Collapse
Affiliation(s)
- Li-ya Mu
- Department of Gastroenterology, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150030, China
| | - Shu-qin Li
- Department of Gastroenterology, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150030, China
| | - Li-xin Tang
- Department of Gastroenterology, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150030, China
| | - Rui Li
- Department of Gastroenterology, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150030, China
- Corresponding author. E-mail:
| |
Collapse
|
|
5
|
Zhang J, Liu X, Wu J, Zhou W, Tian J, Guo S, Jia SS, Meng Z, Ni M. A bioinformatics investigation into the pharmacological mechanisms of the effect of the Yinchenhao decoction on hepatitis C based on network pharmacology. BMC Complement Med Ther 2020; 20:50. [PMID: 32050950 PMCID: PMC7076901 DOI: 10.1186/s12906-020-2823-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 01/20/2020] [Indexed: 12/29/2022] Open
Abstract
Background Globally, more than 170 million people are infected with hepatitis C virus, a major cause of cirrhosis and hepatocellular carcinoma. The Yinchenhao Decoction (YCHD) is a classic formula comprising three herbal medicines. This decoction have long been used in China for clinically treating acute and chronic infectious hepatitis and other liver and gallbladder damp heat-accumulation disorders. Methods In this study, we identified 32 active ingredients and 200 hepatitis C proteins and established a compound-predicted target network and a hepatitis C protein–protein interaction network by using Cytoscape 3.6.1. Then, we systematically analyzed the potential targets of the YCHD for the treatment of hepatitis C. Finally, molecular docking was applied to verify the key targets. In addition, we analyzed the mechanism of action of the predicted targets by the Kyoto Encyclopedia of Genes and Genomes and gene ontology analyses. Results This study adopted a network pharmacology approach, mainly comprising target prediction, network construction, module detection, functional enrichment analysis, and molecular docking to systematically investigate the mechanisms of action of the YCHD in hepatitis C. The targets of the YCHD in the treatment of hepatitis C mainly involved PIK3CG, CASP3, BCL2, CASP8, and MMP1. The module and pathway enrichment analyses showed that the YCHD had the potential to influence varieties of biological pathways, including the TNF signaling pathway, Ras signaling pathway, PI3K-Akt signaling pathway, FoxO signaling pathway, and pathways in cancer, that play an important role in the pathogenesis of hepatitis C. Conclusion The results of this study preliminarily verified the basic pharmacological effects and related mechanisms of the YCHD in the treatment of hepatitis C.
Collapse
Affiliation(s)
- Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11 of North Three-ring East Road, Chao Yang District, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11 of North Three-ring East Road, Chao Yang District, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11 of North Three-ring East Road, Chao Yang District, Beijing, China.
| | - Wei Zhou
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11 of North Three-ring East Road, Chao Yang District, Beijing, China
| | - Jinhui Tian
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, 222 Tianshui South Road, Lanzhou City, China
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11 of North Three-ring East Road, Chao Yang District, Beijing, China
| | - Shan Shan Jia
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11 of North Three-ring East Road, Chao Yang District, Beijing, China
| | - Ziqi Meng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11 of North Three-ring East Road, Chao Yang District, Beijing, China
| | - Mengwei Ni
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11 of North Three-ring East Road, Chao Yang District, Beijing, China
| |
Collapse
|
|
6
|
Liu W, Jing ZT, Wu SX, He Y, Lin YT, Chen WN, Lin XJ, Lin X. A Novel AKT Activator, SC79, Prevents Acute Hepatic Failure Induced by Fas-Mediated Apoptosis of Hepatocytes. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:1171-1182. [PMID: 29673487 DOI: 10.1016/j.ajpath.2018.01.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 12/16/2017] [Accepted: 01/08/2018] [Indexed: 01/18/2023]
Abstract
Acute liver failure is a serious clinical problem of which the underlying pathogenesis remains unclear and for which effective therapies are lacking. The Fas receptor/ligand system, which is negatively regulated by AKT, is known to play a prominent role in hepatocytic cell death. We hypothesized that AKT activation may represent a strategy to alleviate Fas-induced fulminant liver failure. We report here that a novel AKT activator, SC79, protects hepatocytes from apoptosis induced by agonistic anti-Fas antibody CH11 (for humans) or Jo2 (for mice) and significantly prolongs the survival of mice given a lethal dose of Jo2. Under Fas-signaling stimulation, SC79 inhibited Fas aggregation, prevented the recruitment of the adaptor molecule Fas-associated death domain (FADD) and procaspase-8 [or FADD-like IL-1β-converting enzyme (FLICE)] into the death-inducing signaling complex (DISC), but SC79 enhanced the recruitment of the long and short isoforms of cellular FLICE-inhibitory protein at the DISC. All of the SC79-induced hepatoprotective and DISC-interruptive effects were confirmed to have been reversed by the Akt inhibitor LY294002. These results strongly indicate that SC79 protects hepatocytes from Fas-induced fatal hepatic apoptosis. The potent alleviation of Fas-mediated hepatotoxicity by the relatively safe drug SC79 highlights the potential of our findings for immediate hepatoprotective translation.
Collapse
Affiliation(s)
- Wei Liu
- Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Zhen-Tang Jing
- Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Shu-Xiang Wu
- Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yun He
- Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yan-Ting Lin
- Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Wan-Nan Chen
- Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Xin-Jian Lin
- Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Xu Lin
- Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
| |
Collapse
|
|
7
|
|
|
8
|
Ghare SS, Donde H, Chen WY, Barker DF, Gobejishvilli L, McClain CJ, Barve SS, Joshi-Barve S. Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine. Toxicol In Vitro 2016; 35:66-76. [PMID: 27238871 PMCID: PMC4938746 DOI: 10.1016/j.tiv.2016.05.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/16/2016] [Accepted: 05/25/2016] [Indexed: 10/21/2022]
Abstract
Zidovudine (AZT) remains the mainstay of antiretroviral therapy against HIV in resource-poor countries; however, its use is frequently associated with hepatotoxicity. Not all HIV patients on AZT develop hepatotoxicity, and the determining factors are unclear. Alcohol consumption and cigarette smoking are known risk factors for HIV hepatotoxicity, and both are significant sources of acrolein, a highly reactive and toxic aldehyde. This study examines the potential hepatotoxic interactions between acrolein and AZT. Our data demonstrate that acrolein markedly enhanced AZT-induced transcriptionally permissive histone modifications (H3K9Ac and H3K9Me3) allowing the recruitment of transcription factor NF-kB and RNA polymerase II at the FasL gene promoter, resulting in FasL upregulation and apoptosis in hepatocytes. Notably, the acrolein scavenger, hydralazine prevented these promoter-associated epigenetic changes and inhibited FasL upregulation and apoptosis induced by the combination of AZT and acrolein, as well as AZT alone. Our data strongly suggest that acrolein enhancement of promoter histone modifications and FasL upregulation are major pathogenic mechanisms driving AZT-induced hepatotoxicity. Moreover, these data also indicate the therapeutic potential of hydralazine in mitigating AZT hepatotoxicity.
Collapse
Affiliation(s)
- Smita S Ghare
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Hridgandh Donde
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Wei-Yang Chen
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - David F Barker
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Leila Gobejishvilli
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Craig J McClain
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Shirish S Barve
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Swati Joshi-Barve
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA.
| |
Collapse
|
|
9
|
Abstract
Alcohol consumption is often a comorbid condition in other chronic liver diseases. It has been shown to act in synergy to increase liver injury in viral hepatitis, hereditary hemochromatosis, and nonalcoholic fatty liver disease (NAFLD), leading to an increased risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Data suggest that modest alcohol consumption may be inversely related to the risk of developing NAFLD and lower rates of progression of NAFLD to nonalcoholic steatohepatitis (NASH). This article reviews data on the relationship between alcohol consumption and other chronic liver diseases.
Collapse
Affiliation(s)
- Christine C Hsu
- Division of Gastroenterology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19146, USA
| | - Kris V Kowdley
- Swedish Liver Care Network, Swedish Medical Center, 1124 Columbia Street, Suite 600, Seattle, WA 98104, USA.
| |
Collapse
|
|
10
|
Yao L, Chen W, Han C, Wu T. Microsomal prostaglandin E synthase-1 protects against Fas-induced liver injury. Am J Physiol Gastrointest Liver Physiol 2016; 310:G1071-80. [PMID: 27102561 PMCID: PMC4935489 DOI: 10.1152/ajpgi.00327.2015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 04/17/2016] [Indexed: 01/31/2023]
Abstract
Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme for the synthesis of prostaglandin E2 (PGE2), a proproliferative and antiapoptotic lipid molecule important for tissue regeneration and injury repair. In this study, we developed transgenic (Tg) mice with targeted expression of mPGES-1 in the liver to assess Fas-induced hepatocyte apoptosis and acute liver injury. Compared with wild-type (WT) mice, the mPGES-1 Tg mice showed less liver hemorrhage, lower serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, less hepatic necrosis/apoptosis, and lower level of caspase cascade activation after intraperitoneal injection of the anti-Fas antibody Jo2. Western blotting analysis revealed increased expression and activation of the serine/threonine kinase Akt and associated antiapoptotic molecules in the liver tissues of Jo2-treated mPGES-1 Tg mice. Pretreatment with the mPGES-1 inhibitor (MF63) or the Akt inhibitor (Akt inhibitor V) restored the susceptibility of the mPGES-1 Tg mice to Fas-induced liver injury. Our findings provide novel evidence that mPGES-1 prevents Fas-induced liver injury through activation of Akt and related signaling and suggest that induction of mPGES-1 or treatment with PGE2 may represent important therapeutic strategy for the prevention and treatment of Fas-associated liver injuries.
Collapse
Affiliation(s)
| | | | | | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| |
Collapse
|
|
11
|
Gabr SA, Alghadir AH, Allam AA, Ajarem J, Al-Basher G, Abdel-Maksoud MA, Ghfar AA, Aboud A. Correlation between vitamin D levels and apoptosis in geriatric patients infected with hepatitis C virus genotype 4. Clin Interv Aging 2016; 11:523-33. [PMID: 27217734 PMCID: PMC4862759 DOI: 10.2147/cia.s104599] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Vitamin D levels play a pivotal role in most biological processes and differ according to age. A deficiency of vitamin D in chronic hepatitis C (CHC) patients has been shown to be linked with the severity of liver fibrosis, but little is known about the mechanism of this association. Objective In this study, we evaluate the potential interrelation between vitamin D levels, oxidative stress, and apoptosis, based on liver fibrosis in geriatric patients infected with hepatitis C virus (HCV) genotype 4. Subjects and methods A total of 120 adult individuals aged 30–68 years were recruited in this study. Of these, 20 healthy subjects (15 men and five women) with a mean age of 48.3±6.1 years were selected as controls, and 100 patients with a mean age of 47.8±4.9 years with chronic HCV (CHC) who had undergone liver biopsy (80 men and 20 women) were included in this study. Based on liver radiographic (computed tomography, magnetic resonance imaging) and histological Metavir system analyses, the CHC patients were classified into three groups: asymptomatic CHC carriers (n=30), fibrosis (n=25), and cirrhosis (n=45). HCV RNA, HCV genotypes, inflammatory cytokines AFP and TNFα, 25-hydroxyvitamin D (25[OH]D) levels, apoptotic markers single-stranded DNA (ssDNA) and soluble Fas (sFas), and oxidative stress markers nitric oxide (NO) and total antioxidant capacity (TAC) were estimated by using molecular, immunoassay, and colorimetric techniques. Results Approximately 30% of the study population (n=30) were diagnosed as asymptomatic CHC carriers, and 70% of the study population (n=70) had severe fibrosis; these were classified into fibrosis and cirrhosis. There was a significant reduction in 25(OH)D levels and TAC activity, along with an increase in levels of NO, AFP, TNFα, ssDNA, and sFas in fibrosis and cirrhosis subjects compared with those of asymptomatic CHC carriers and health controls. The deficiency in 25(OH)D levels correlated positively with sFas, ssDNA, AFP, TNFα, NO, and TAC, and negatively with age, sex, liver function, body mass index, homeostatic model assessment – insulin resistance, HCV RNA, and viral load. Significant intercorrelation was reported between serum 25(OH)D concentrations and apoptotic and oxidative markers, which suggested progression of liver pathogenesis and fibrogenesis via oxidative and apoptotic mechanisms. Conclusion The data showed that vitamin D status was significantly correlated with pathogenesis and fibrogenesis of the liver in geriatric patients infected with HCV genotype 4. The deficiency in 25(OH)D levels was shown to have a pivotal role in the pathogenesis of liver via apoptotic, oxidative stress, and inflammatory mechanistic pathways. The data point to adequate vitamin D levels being recommended for a good response to treatment strategies, especially in older CHC patients.
Collapse
Affiliation(s)
- Sami A Gabr
- Rehabilitation Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia; Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmad H Alghadir
- Rehabilitation Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Ahmed A Allam
- Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia; Zoology Department, Faculty of Science, Beni-Suef University, Beni Suef, Egypt
| | - Jamaan Ajarem
- Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Ghada Al-Basher
- Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | | | - Ayman A Ghfar
- Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Alaa Aboud
- Internal Endemic Medicine Department, College of Medicine, Beni-Suef University, Beni Suef, Egypt
| |
Collapse
|
|
12
|
miR-223 Deficiency Protects against Fas-Induced Hepatocyte Apoptosis and Liver Injury through Targeting Insulin-Like Growth Factor 1 Receptor. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 185:3141-51. [PMID: 26598234 DOI: 10.1016/j.ajpath.2015.08.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 07/21/2015] [Accepted: 08/06/2015] [Indexed: 01/26/2023]
Abstract
The biological functions and molecular mechanisms of miR-223 action in liver cells and liver diseases remain unclear. We therefore determined the effect and mechanism of action of miR-233 in Fas-induced hepatocyte apoptosis and liver injury. Wild-type (WT) and miR-223 knockout (KO) mice were treated i.p. with 0.5 μg/g body weight anti-Fas antibody Jo2, and the animals were monitored for survival and the extent of liver injury. Although WT mice died 4 to 6 hours after Jo2 injection (n = 6), all of the miR-223 KO mice (n = 6) survived. In comparison to WT mice, the miR-223 KO mice showed resistance to Fas-induced liver injury, as indicated by less tissue damage under histopathological examination, fewer apoptotic hepatocytes under caspase-3 immunostaining, and less elevation of serum transaminases. miR-223 KO livers showed less caspase-3, caspase-8, and caspase-9 activation and less poly (ADP-ribose) polymerase cleavage compared with WT livers (P < 0.05). Furthermore, tail vein injection of miR-223 lentiviral vector to miR-223 KO mice restored Jo2-induced liver injury. Transfection of miR-223 KO hepatocytes with miR-223 mimic enhanced Jo2-induced activation of caspase-3, caspase-8, and caspase-9, whereas transfection of WT hepatocytes with the miR-223 inhibitor attenuated Jo2-induced apoptosis. These findings demonstrate that miR-223 deficiency protects against Fas-induced hepatocyte apoptosis and liver injury. Further in vitro and in vivo data indicate that miR-223 regulates Fas-induced hepatocyte apoptosis and liver injury by targeting the insulin-like growth factor 1 receptor.
Collapse
|
|
13
|
Komarov AP, Komarova EA, Green K, Novototskaya LR, Baker PS, Eroshkin A, Osterman AL, Chenchick AA, Frangou C, Gudkov AV. Functional genetics-directed identification of novel pharmacological inhibitors of FAS- and TNF-dependent apoptosis that protect mice from acute liver failure. Cell Death Dis 2016; 7:e2145. [PMID: 26986512 PMCID: PMC4823946 DOI: 10.1038/cddis.2016.45] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 01/25/2016] [Accepted: 02/04/2016] [Indexed: 12/12/2022]
Abstract
shRNA-mediated gene-silencing technology paired with cell-based functional readouts reveals potential targets directly, providing an opportunity to identify drugs against the target without knowing the precise role of the target in the pathophysiological processes of interest. By screening a lentiviral shRNA library targeting for major components of human signaling pathways and known drug targets, we identified and validated both canonical as well as 52 novel mediators of FAS and TNF ligand-induced apoptosis. Presence of potential therapeutic targets among these mediators was confirmed by demonstration of in vivo activity of siRNAs against four identified target candidates that protected mice from acute liver failure (ALF), a life-threatening disease with known involvement of death receptor (DR)-mediated apoptosis. Network-based modeling was used to predict small-molecule inhibitors for several candidate apoptosis mediators, including somatostatin receptor 5 (SSTR5) and a regulatory subunit of PP2A phosphatase, PPP2R5A. Remarkably, pharmacological inhibition of either SSTR5 or PPP2R5A reduced apoptosis induced by either FASL or TNF in cultured cells and dramatically improved survival in several mouse models of ALF. These results demonstrate the utility of loss-of-function genetic screens and network-based drug-repositioning methods for expedited identification of targeted drug candidates and revealed pharmacological agents potentially suitable for treatment of DR-mediated pathologies.
Collapse
Affiliation(s)
| | - E A Komarova
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - K Green
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - L R Novototskaya
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - P S Baker
- Buffalo BioLabs, LLC, Buffalo, NY, USA
| | - A Eroshkin
- Infectious and Inflammatory Disease Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - A L Osterman
- Buffalo BioLabs, LLC, Buffalo, NY, USA
- Infectious and Inflammatory Disease Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA
| | | | - C Frangou
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - A V Gudkov
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| |
Collapse
|
|
14
|
Chen W, Han C, Zhang J, Song K, Wang Y, Wu T. Deletion of Mir155 prevents Fas-induced liver injury through up-regulation of Mcl-1. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1033-44. [PMID: 25794705 DOI: 10.1016/j.ajpath.2014.12.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 11/29/2014] [Accepted: 12/09/2014] [Indexed: 12/12/2022]
Abstract
Fas-induced apoptosis is involved in diverse liver diseases. Herein, we investigated the effect of Mir155 deletion on Fas-induced liver injury. Wild-type (WT) mice and Mir155 knockout (KO) mice were i.p. administered with the anti-Fas antibody (Jo2) to determine animal survival and the extent of liver injury. After Jo2 injection, the Mir155 KO mice exhibited prolonged survival versus the WT mice (P < 0.01). The Mir155 KO mice showed lower alanine aminotransferase and aspartate aminotransferase levels, less liver tissue damage, fewer apoptotic hepatocytes, and lower liver tissue caspase 3/7, 8, and 9 activities compared with the WT mice, indicating that Mir155 deletion prevents Fas-induced hepatocyte apoptosis and liver injury. Hepatocytes isolated from Mir155 KO mice also showed resistance to Fas-induced apoptosis, in vitro. Higher protein level of myeloid cell leukemia-1 (Mcl-1) was also observed in Mir155 KO hepatocytes compared to WT hepatocytes. A miR-155 binding site was identified in the 3'-untranslated region of Mcl-1 mRNA; Mcl1 was identified as a direct target of miR-155 in hepatocytes. Consistently, pretreatment with a siRNA specific for Mcl1 reversed Mir155 deletion-mediated protection against Jo2-induced liver tissue damage. Finally, restoration of Mir155 expression in Mir155 KO mice abolished the protection against Fas-induced hepatocyte apoptosis. Taken together, these findings demonstrate that deletion of Mir155 prevents Fas-induced hepatocyte apoptosis and liver injury through the up-regulation of Mcl1.
Collapse
Affiliation(s)
- Weina Chen
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Ying Wang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana; Department of Gastroenterology and Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
| |
Collapse
|
|
15
|
Chen W, Han C, Zhang J, Song K, Wang Y, Wu T. miR-150 Deficiency Protects against FAS-Induced Acute Liver Injury in Mice through Regulation of AKT. PLoS One 2015. [PMID: 26196694 PMCID: PMC4510058 DOI: 10.1371/journal.pone.0132734] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Although miR-150 is implicated in the regulation of immune cell differentiation and activation, it remains unknown whether miR-150 is involved in liver biology and disease. This study was performed to explore the potential role of miR-150 in LPS/D-GalN and Fas-induced liver injuries by using wild type and miR-150 knockout (KO) mice. Whereas knockout of miR-150 did not significantly alter LPS/D-GalN-induced animal death and liver injury, it protected against Fas-induced liver injury and mortality. The Jo2-induced increase in serum transaminases, apoptotic hepatocytes, PARP cleavage, as well as caspase-3/7, caspase-8, and caspase-9 activities were significantly attenuated in miR-150 KO mice. The liver tissues from Jo2-treated miR-150 KO mice expressed higher levels of Akt1, Akt2, total Akt, as well as p-Akt(Ser473) compared to the wild type livers. Pretreatment with the Akt inhibitor V reversed Jo2-induced liver injury in miR-150 KO mice. The primary hepatocytes isolated from miR-150 KO mice also showed protection against Fas-induced apoptosis in vitro (characterized by less prominent PARP cleavage, less nuclear fragmentation and less caspase activation) in comparison to hepatocytes from wild type mice. Luciferase reporter assays in hepatocytes transfected with the Akt1 or Akt2 3’-UTR reporter constructs (with or without mutation of miR-150 binding site) established Akt1 and Akt2 as direct targets of miR-150. Tail vein injection of lentiviral particles containing pre-miR-150 enhanced Jo2-induced liver injury in miR-150 KO mice. These findings demonstrate that miR-150 deficiency prevents Fas-induced hepatocyte apoptosis and liver injury through regulation of the Akt pathway.
Collapse
Affiliation(s)
- Weina Chen
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
| | - Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
| | - Ying Wang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
- Department of Gastroenterology and Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
- * E-mail:
| |
Collapse
|
|
16
|
Abstract
Chronic HCV infection is the leading indication for liver transplantation. However, as a result of HCV recurrence, patient and graft survival after liver transplantation are inferior compared with other indications for transplantation. HCV recurrence after liver transplantation is associated with considerable mortality and morbidity. The development of HCV-related fibrosis is accelerated after liver transplantation, which is influenced by a combination of factors related to the virus, donor, recipient, surgery and immunosuppression. Successful antiviral therapy is the only treatment that can attenuate fibrosis. The advent of direct-acting antiviral agents (DAAs) has changed the therapeutic landscape for the treatment of patients with HCV. DAAs have improved tolerability, and can potentially be used without PEG-IFN for a shorter time than previous therapies, which should result in better outcomes. In this Review, we describe the important risk factors that influence HCV recurrence after liver transplantation, highlighting the mechanisms of fibrosis and the integral role of hepatic stellate cells. Indirect and direct assessment of fibrosis, in addition to new antiviral therapies, are also discussed.
Collapse
|
|
17
|
Lim EJ, El Khobar K, Chin R, Earnest-Silveira L, Angus PW, Bock CT, Nachbur U, Silke J, Torresi J. Hepatitis C virus-induced hepatocyte cell death and protection by inhibition of apoptosis. J Gen Virol 2014; 95:2204-2215. [PMID: 24973240 DOI: 10.1099/vir.0.065862-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection results in progressive liver fibrosis leading to cirrhosis and liver cancer. The mechanism for this remains unclear but hepatocyte apoptosis is thought to play a major role. Hepatocyte apoptosis in human liver tissue was determined by immunohistochemistry for cytokeratin 18 (M30 CytoDEATH) and cleaved poly(ADP-ribose) polymerase (PARP). In vitro studies were performed with replication-defective recombinant adenoviruses expressing HCV proteins (rAdHCV) to study the effects of HCV on cell death in Huh7 cells, primary mouse hepatocytes (PMoHs) and primary human hepatocytes (PHHs). Cell viability and apoptosis were studied using crystal violet assays and Western blots probed for cleaved caspase-3 and cleaved PARP, with and without treatment with the pan-caspase inhibitor Q-VD-OPh and necrostatin-1. Liver tissue of HCV-infected patients expressed elevated levels of apoptotic markers compared with HCV-negative patients. rAdHCV infection reduced cell viability compared with uninfected controls and cells infected with control virus (rAdGFP). Huh7, PMoHs and PHHs infected with rAdHCV showed significantly increased levels of apoptotic markers compared with uninfected controls and rAdGFP-infected cells. In rAdHCV-infected Huh7, treatment with Q-VD-OPh and necrostatin-1 both improved cell viability. Q-VD-Oph also reduced cleaved PARP in rAdHCV-infected Huh7 and PMoHs. Hepatocyte apoptosis is known to be increased in the livers of HCV-infected patients. HCV promoted cell death in primary and immortalized hepatocytes, and this was inhibited by Q-VD-OPh and necrostatin-1. These findings indicate that HCV-induced cell death occurs by both apoptosis and necroptosis, and provide new insights into the mechanisms of HCV-induced liver injury.
Collapse
Affiliation(s)
- Eu Jin Lim
- Department of Gastroenterology and Hepatology, Austin Hospital, Heidelberg, Victoria, Australia
- Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia
| | - Korri El Khobar
- Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia
| | - Ruth Chin
- Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia
| | - Linda Earnest-Silveira
- Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia
| | - Peter W Angus
- Department of Gastroenterology and Hepatology, Austin Hospital, Heidelberg, Victoria, Australia
- Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia
| | - C-Thomas Bock
- Department of Virology, Robert Koch Institute, Berlin, Germany
| | - Ueli Nachbur
- Walter and Eliza Hall Institute, Parkville, Victoria, Australia
| | - John Silke
- Walter and Eliza Hall Institute, Parkville, Victoria, Australia
| | - Joseph Torresi
- Department Infectious Diseases, Austin Hospital, Heidelberg, Victoria, Australia
- Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia
| |
Collapse
|
|
18
|
Urbaczek AC, Ribeiro LCDA, Ximenes VF, Afonso A, Nogueira CT, Generoso WC, Alberice JV, Rudnicki M, Ferrer R, da Fonseca LM, da Costa PI. Inflammatory response of endothelial cells to hepatitis C virus recombinant envelope glycoprotein 2 protein exposure. Mem Inst Oswaldo Cruz 2014; 109:748-56. [PMID: 25317702 PMCID: PMC4238766 DOI: 10.1590/0074-0276140090] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 07/29/2014] [Indexed: 12/12/2022] Open
Abstract
The hepatitis C virus (HCV) encodes approximately 10 different structural and non-structural proteins, including the envelope glycoprotein 2 (E2). HCV proteins, especially the envelope proteins, bind to cell receptors and can damage tissues. Endothelial inflammation is the most important determinant of fibrosis progression and, consequently, cirrhosis. The aim of this study was to evaluate and compare the inflammatory response of endothelial cells to two recombinant forms of the HCV E2 protein produced in different expression systems (Escherichia coli and Pichia pastoris). We observed the induction of cell death and the production of nitric oxide, hydrogen peroxide, interleukin-8 and vascular endothelial growth factor A in human umbilical vein endothelial cells (HUVECs) stimulated by the two recombinant E2 proteins. The E2-induced apoptosis of HUVECs was confirmed using the molecular marker PARP. The apoptosis rescue observed when the antioxidant N-acetylcysteine was used suggests that reactive oxygen species are involved in E2-induced apoptosis. We propose that these proteins are involved in the chronic inflammation caused by HCV.
Collapse
Affiliation(s)
- Ana Carolina Urbaczek
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
| | | | - Valdecir Farias Ximenes
- Departamento de Química, Faculdade de Ciências, Universidade Estadual
Paulista Julio de Mesquita Filho, Bauru, SP, Brasil
| | - Ana Afonso
- Departamento de Parasitologia Médica, Unidade de Parasitologia Médica e
Microbiologia, Instituto de Higiene e Medicina Tropcal, Universidade Nova de Lisboa,
Lisboa, Portugal
- Departamento de Morfologia e Patologia, Universidade Federal de São
Carlos, São Carlos, SP, Brasil
- Grupo de Bioanalítica, Microfabricações e Separações, Departamento de
Química e Física Molecular, Instituto de Química de São Carlos, Universidade de São
Paulo, São Carlos, SP, Brasil
| | - Camila Tita Nogueira
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
| | - Wesley Cardoso Generoso
- Departamento de Genética e Evolução, Universidade Federal de São
Carlos, São Carlos, SP, Brasil
| | - Juliana Vieira Alberice
- Grupo de Bioanalítica, Microfabricações e Separações, Departamento de
Química e Física Molecular, Instituto de Química de São Carlos, Universidade de São
Paulo, São Carlos, SP, Brasil
| | - Martina Rudnicki
- Escola de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo,
SP, Brasil
| | - Renila Ferrer
- Escola de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo,
SP, Brasil
| | - Luiz Marcos da Fonseca
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
| | - Paulo Inácio da Costa
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
| |
Collapse
|
|
19
|
TRAIL enhances apoptosis of human hepatocellular carcinoma cells sensitized by hepatitis C virus infection: therapeutic implications. PLoS One 2014; 9:e98171. [PMID: 24927176 PMCID: PMC4057066 DOI: 10.1371/journal.pone.0098171] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 04/29/2014] [Indexed: 12/20/2022] Open
Abstract
Hepatitis C virus (HCV) infection causes chronic liver diseases leading to hepatocellular carcinoma (HCC) and liver failure. We have previously shown that HCV sensitizes hepatocytes to mitochondrial apoptosis via the TRAIL death receptors DR4 and DR5. Although TRAIL and its receptors are selective targets for cancer therapy, their potential against HCC with chronic HCV infection has not been explored yet. Here we show that HCV induces DR4/DR5-dependent activation of caspase-8 leading to elevation of apoptotic signaling in infected cells and also present TRAIL effect in HCV-induced apoptotic signaling. HCV induced proteolytic cleavage of caspase-9 by stimulating DR4 and DR5, resulting in subsequent cleavage of caspase-3. Further, HCV-induced proteolytic cleavage in caspase-8, caspase-9, and caspase-3 was enhanced in the presence of recombinant TRAIL. HCV-induced cleavage in caspase-9 and increase in caspase-3/7 activity was completely suppressed by silencing of either DR4 or DR5. Perturbing DR4/DR5-caspase-8 signaling complex by silencing DR4 and DR5 or by chemical inhibitor specific to caspase-8 led to decrease of HCV-induced cleavage of poly(ADP-ribose) polymerase (PARP), a substrate for caspase-3 during apoptosis, indicating the functional role of caspase-8 in HCV-induced apoptotic signaling network. Furthermore, TRAIL enhanced PARP cleavage in apoptotic response induced by HCV infection, indicating the effect of TRAIL for the induction of selective apoptosis of HCC cells infected with HCV. Given the importance of apoptosis in HCC development, our data suggest that HCV-induced DR4 and DR5 may be considered as an attractive target for TRAIL therapy against HCC with chronic HCV infection.
Collapse
|
|
20
|
Abstract
Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis.
Collapse
|
|
21
|
Molecular mechanisms of hepatic apoptosis. Cell Death Dis 2014; 5:e996. [PMID: 24434519 PMCID: PMC4040708 DOI: 10.1038/cddis.2013.499] [Citation(s) in RCA: 250] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 11/07/2013] [Accepted: 11/07/2013] [Indexed: 02/07/2023]
Abstract
Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis.
Collapse
|
|
22
|
Altamirano J, Michelena J. Alcohol consumption as a cofactor for other liver diseases. Clin Liver Dis (Hoboken) 2013; 2:72-75. [PMID: 30992828 PMCID: PMC6448625 DOI: 10.1002/cld.197] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 03/15/2013] [Accepted: 03/15/2013] [Indexed: 02/04/2023] Open
Affiliation(s)
- Jose Altamirano
- Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Javier Michelena
- Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| |
Collapse
|
|
23
|
Khattab MA, Eslam M, Aly MM, Shatat M, Hussen A, Moussa YI, Elsaghir G, Abdalhalim H, Aly A, Gaber S, Harrison SA. Association of serum adipocytokines with insulin resistance and liver injury in patients with chronic hepatitis C genotype 4. J Clin Gastroenterol 2012; 46:871-879. [PMID: 22664476 DOI: 10.1097/mcg.0b013e318256b68a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection, especially genotypes 1 and 4, is associated with metabolic dysfunction. We investigated the potential role of adipocytokines in HCV-induced insulin resistance (IR) and modulating the progression of liver disease in patients with HCV-4. METHODS Serum adiponectin, high molecular weight adiponectin, leptin, tumor necrosis factor-α, interluekin-6, homeostasis model for the assessment of insulin resistance, and M30 protein were measured in 147 HCV patients and 89 controls. Liver biopsies were evaluated for steatosis/inflammation/fibrosis, adiponectin mRNA/protein, AdipoR1/-R2 mRNA, and phosphoenolpyruvate carboxykinase gene expression, and adiponectin and CD95 immunoreactivity. RESULTS CD95 immunoreactivity and adiponectin immunoreactivity were detected in all biopsies examined. Hepatic adiponectin immunostaining correlated positively with the intensity of hepatic CD95/Fas immunostaining (r=0.424; P=0.001). Hepatocyte CD95/Fas upregulation correlated with fibrosis, inflammation, and steatosis (r=0.52, P=0.0001; r=0.16, P=0.04; r=0.24, P=0.0001; respectively). Significant correlations of serum adiponectin, its receptors mRNA expression, hepatic adiponectin immunostaining, and mRNA transcription for phosphoenolpyruvate carboxykinase were identified with steatosis. A positive association between adiponectin and hepatic inflammation and fibrosis was identified. This correlation remained significant even after adjusting for age, sex, and body mass index. Among body mass index, age, and sex-matched HCV-negative controls, patients with HCV-4 have higher serum leptin, adiponectin, and high molecular weight adiponectin, and these changes are independently correlated with IR. CONCLUSIONS Our findings in patients with HCV-4 show that adiponectin correlates with IR and with the different stages of liver injury. Steatosis upregulates hepatocyte CD95/Fas and thus increases apoptosis, which facilitates inflammation and fibrosis. These findings may provide potential clues for novel therapeutic intervention.
Collapse
|
|
24
|
Abstract
In addition to directly causing liver disease, alcohol consumption is a common comorbid condition with other chronic liver diseases and may exacerbate liver injury, particularly in nonalcoholic fatty liver disease, chronic viral hepatitis, hereditary hemochromatosis, and autoimmune liver diseases. This synergism can result in increased hepatic inflammation and accelerated rates of fibrosis, with more rapid and earlier development of cirrhosis, and also increase the risk for liver cancer and death from liver disease.
Collapse
Affiliation(s)
- Maximilian Lee
- Liver Center of Excellence, Virginia Mason Medical Center, 1100 Ninth Avenue, Seattle, WA 98101, USA
| | | |
Collapse
|
|
25
|
Bantel H, Schulze-Osthoff K. Mechanisms of cell death in acute liver failure. Front Physiol 2012; 3:79. [PMID: 22485095 PMCID: PMC3317271 DOI: 10.3389/fphys.2012.00079] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 03/16/2012] [Indexed: 12/27/2022] Open
Abstract
Acute liver failure (ALF) can be the consequence of various etiologies, that might vary between different geographic regions. Most frequent are intoxications with acetaminophen, viral hepatitis, or liver damage of unknown origin. ALF occurs when the extent of hepatocyte death exceeds the regenerative capacity of the liver. The mode of liver cell death that is predominantly induced in ALF, i.e., apoptosis or necrosis, is still controversial and presumably determined by the etiology, duration, and magnitude of liver injury. Severe liver damage involves oxidative stress and depletion of ATP resulting in necrosis. In contrast, maintenance of ATP stores is required for the execution of apoptosis. Recent data suggest that necrosis resulting from severe liver damage is associated with poor outcome of ALF patients. Discrimination between apoptosis and necrosis might be therefore useful for the identification of ALF patients requiring liver transplantation. Identification of the molecular cell death mechanisms remains an important issue not only for early prediction of ALF outcome, but also for therapeutic interventions. In view of the pleiotropic functions of critical mediators of cell death and tissue regeneration, a particular challenge will be to reduce hepatocellular death without inhibiting the regenerative capacity of the liver. Here, we review the molecular mechanisms of hepatocyte injury and the pathways leading to apoptosis and necrosis, which might represent potential diagnostic and therapeutic targets in ALF.
Collapse
Affiliation(s)
- Heike Bantel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School Hannover, Germany
| | | |
Collapse
|
|
26
|
Jahan S, Ashfaq UA, Qasim M, Khaliq S, Saleem MJ, Afzal N. Hepatitis C virus to hepatocellular carcinoma. Infect Agent Cancer 2012; 7:2. [PMID: 22289144 PMCID: PMC3293064 DOI: 10.1186/1750-9378-7-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Accepted: 01/30/2012] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus causes acute and chronic hepatitis and can lead to permanent liver damage and hepatocellular carcinoma (HCC) in a significant number of patients via oxidative stress, insulin resistance (IR), fibrosis, liver cirrhosis and HCV induced steatosis. HCV induced steatosis and oxidative stress causes steato-hepatitis and these pathways lead to liver injury or HCC in chronic HCV infection. Steatosis and oxidative stress crosstalk play an important role in liver damage in HCV infection. This Review illustrates viral and host factors which induce Oxidative stress, steatosis and leads toward HCC. It also expresses Molecular cascade which leads oxidative stress and steatosis to HCC.
Collapse
Affiliation(s)
- Shah Jahan
- Department of Immunology, University of Health Sciences, Lahore, Pakistan.
| | | | | | | | | | | |
Collapse
|
|
27
|
Theise ND, Bodenheimer HC, Ferrell LD. Acute and chronic viral hepatitis. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:361-401. [DOI: 10.1016/b978-0-7020-3398-8.00007-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
28
|
Arends JE, Hoepelman AIM, Nanlohy NM, Höppener FJP, Hirsch KR, Park JG, van Baarle D. Low doses of the novel caspase-inhibitor GS-9450 leads to lower caspase-3 and -8 expression on peripheral CD4+ and CD8+ T-cells. Apoptosis 2011; 16:959-66. [PMID: 21667042 PMCID: PMC3152720 DOI: 10.1007/s10495-011-0620-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Chronic hepatitis C virus (HCV) infection is characterized by increased rates of apoptotic hepatocytes and activated caspases have been shown in HCV-infected patients. GS-9450, a novel caspase-inhibitor has demonstrated hepatoprotective activity in fibrosis/apoptosis animal models. This study evaluated the effects of GS-9450 on peripheral T-cell apoptosis in chronic HCV-infected patients. As sub study of the GS-US-227-0102, a double-blind, placebo-controlled phase 2a trial evaluating the safety and tolerability of GS-9450, apoptosis of peripheral CD4+ and CD8+ T-cells was measured using activated caspase-3, activated caspase-8 and CD95 (Fas). Blood samples were drawn at baseline, day 14 after therapy and at 5 weeks off-treatment follow-up in the first cohort of 10 mg. In contrast to the placebo-treated patients, GS-9450 caused a median of 46% decrease in ALT-values from baseline to day 14 in all treated patients (median of 118-64 U/l) rising again to a median of 140 U/l (19%) at 5 weeks off-treatment follow-up. In GS9450-treated patients, during treatment and follow-up, percentages of activated caspase-3+ and caspase-8 expression tended to decrease, in contrast to placebo-treated patients. Interestingly, compared to healthy controls, higher percentages of caspase-3 and caspase-8 positive CD4+ and CD8+ T-cells were demonstrated in HCV-infected patients at baseline. Decreased ALT-values were observed in all HCV-infected patients during treatment with low dose of the caspase-inhibitor GS-9450 accompanied by a lower expression of caspase-3 and -8 on peripheral T-cells. Furthermore, at baseline percentages of activated caspase-3, activated caspase-8 and CD95+ T-cells were higher in chronic HCV-infected patients compared to healthy controls.
Collapse
Affiliation(s)
- J E Arends
- Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht (UMCU), Heidelberglaan, GA, Utrecht, The Netherlands.
| | | | | | | | | | | | | |
Collapse
|
|
29
|
Suh YG, Jeong WI. Hepatic stellate cells and innate immunity in alcoholic liver disease. World J Gastroenterol 2011; 17:2543-51. [PMID: 21633659 PMCID: PMC3103812 DOI: 10.3748/wjg.v17.i20.2543] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Revised: 02/25/2011] [Accepted: 03/04/2011] [Indexed: 02/06/2023] Open
Abstract
Constant alcohol consumption is a major cause of chronic liver disease, and there has been a growing concern regarding the increased mortality rates worldwide. Alcoholic liver diseases (ALDs) range from mild to more severe conditions, such as steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The liver is enriched with innate immune cells (e.g. natural killer cells and Kupffer cells) and hepatic stellate cells (HSCs), and interestingly, emerging evidence suggests that innate immunity contributes to the development of ALDs (e.g. steatohepatitis and liver fibrosis). Indeed, HSCs play a crucial role in alcoholic steatosis via production of endocannabinoid and retinol metabolites. This review describes the roles of the innate immunity and HSCs in the pathogenesis of ALDs, and suggests therapeutic targets and strategies to assist in the reduction of ALD.
Collapse
|
|
30
|
Bergheim I, Eagon PK, Dooley S, Breitkopf-Heinlein K. Alcoholic liver disease and exacerbation by malnutrition and infections: what animal models are currently available? Ann N Y Acad Sci 2010; 1216:41-9. [PMID: 21182534 DOI: 10.1111/j.1749-6632.2010.05833.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Alcoholic liver disease remains a frequent and serious problem for increasing numbers of patients. Research has expanded our molecular understanding of the cellular basis of disease progression; however, translation into therapy is still hampered by a lack of suitable animal models for alcoholic liver disease, as well as from consequences of related liver damage due to malnutrition, hepatitis C virus infection, or abuse of other substances. Many patients with liver disease do not simply consume too much alcohol; they also suffer from comorbidities such as obesity or viral hepatitis, and/or may be addicted to other drugs besides alcohol. This review will summarize the currently available animal models to study liver disease due to either single causes or combinations of liver toxic substances/infections and alcohol.
Collapse
Affiliation(s)
- Ina Bergheim
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | | | | | | |
Collapse
|
|
31
|
Abstract
Hepatocyte injury is ubiquitous in clinical practice, and the mode of cell death associated with this injury is often apoptosis, especially by death receptors. Information from experimental systems demonstrates that hepatocyte apoptosis is sufficient to cause liver hepatic fibrogenesis. The mechanisms linking hepatocyte apoptosis to hepatic fibrosis remain incompletely understood, but likely relate to engulfment of apoptotic bodies by professional phagocytic cells and stellate cells, and release of mediators by cells undergoing apoptosis. Inhibition of apoptosis with caspase inhibitors has demonstrated beneficial effects in murine models of hepatic fibrosis. Recent studies implicating Toll-like receptor 9 in liver injury and fibrosis are also of particular interest. Engulfment of apoptotic bodies is one mechanism by which the TLR9 ligand (CpG DNA motifs) could be delivered to this intracellular receptor. These concepts suggest therapy focused on interrupting the cellular mechanisms linking apoptosis to fibrosis would be useful in human liver diseases.
Collapse
|
|
32
|
Banerjee A, Ray RB, Ray R. Oncogenic potential of hepatitis C virus proteins. Viruses 2010; 2:2108-2133. [PMID: 21994721 PMCID: PMC3185750 DOI: 10.3390/v2092108] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 09/23/2010] [Accepted: 09/24/2010] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major risk factor for liver disease progression, and may lead to cirrhosis and hepatocellular carcinoma (HCC). The HCV genome contains a single-stranded positive sense RNA with a cytoplasmic lifecycle. HCV proteins interact with many host-cell factors and are involved in a wide range of activities, including cell cycle regulation, transcriptional regulation, cell proliferation, apoptosis, lipid metabolism, and cell growth promotion. Increasing experimental evidences suggest that HCV contributes to HCC by modulating pathways that may promote malignant transformation of hepatocytes. At least four of the 10 HCV gene products, namely core, NS3, NS5A and NS5B play roles in several potentially oncogenic pathways. Induction of both endoplasmic reticulum (ER) stress and oxidative stress by HCV proteins may also contribute to hepatocyte growth promotion. The current review identifies important functions of the viral proteins connecting HCV infections and potential for development of HCC. However, most of the putative transforming potentials of the HCV proteins have been defined in artificial cellular systems, and need to be established relevant to infection and disease models. The new insight into the mechanisms for HCV mediated disease progression may offer novel therapeutic targets for one of the most devastating human malignancies in the world today.
Collapse
Affiliation(s)
- Arup Banerjee
- Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA; E-Mail:
| | - Ratna B. Ray
- Department of Pathology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 2nd Floor, St. Louis, MO 63104, USA; E-Mail:
| | - Ranjit Ray
- Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA; E-Mail:
- Molecular Microbiology & Immunology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: 1-314- 977-9034; Fax: 1-314-771-3816
| |
Collapse
|
|
33
|
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]
|
|
34
|
Mas VR, Fassnacht R, Archer KJ, Maluf D. Molecular mechanisms involved in the interaction effects of alcohol and hepatitis C virus in liver cirrhosis. Mol Med 2010; 16:287-97. [PMID: 20386865 DOI: 10.2119/molmed.2009.00165] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2009] [Accepted: 03/25/2010] [Indexed: 12/19/2022] Open
Abstract
The mechanisms by which alcohol consumption accelerates liver disease in patients with chronic hepatitis C virus (HCV) are not well understood. To identify the characteristics of molecular pathways affected by alcohol in HCV patients, we fit probe-set level linear models that included the additive effects as well as the interaction between alcohol and HCV. The study included liver tissue samples from 78 patients, 23 (29.5%) with HCV-cirrhosis, 13 (16.7%) with alcohol-cirrhosis, 23 (29.5%) with HCV/alcohol cirrhosis and 19 (24.4%) with no liver disease (no HCV/no alcohol group). We performed gene-expression profiling by using microarrays. Probe-set expression summaries were calculated by using the robust multiarray average. Probe-set level linear models were fit where probe-set expression was modeled by HCV status, alcohol status, and the interaction between HCV and alcohol. We found that 2172 probe sets (1895 genes) were differentially expressed between HCV cirrhosis versus alcoholic cirrhosis groups. Genes involved in the virus response and the immune response were the more important upregulated genes in HCV cirrhosis. Genes involved in apoptosis regulation were also overexpressed in HCV cirrhosis. Genes of the cytochrome P450 superfamily of enzymes were upregulated in alcoholic cirrhosis, and 1230 probe sets (1051 genes) had a significant interaction estimate. Cell death and cellular growth and proliferation were affected by the interaction between HCV and alcohol. Immune response and response to the virus genes were downregulated in HCV-alcohol interaction (interaction term alcohol*HCV). Alcohol*HCV in the cirrhotic tissues resulted in a strong negative regulation of the apoptosis pattern with concomitant positive regulation of cellular division and proliferation.
Collapse
Affiliation(s)
- Valeria R Mas
- Hume-Lee Transplant Center, Division of Transplant, Department of Surgery, Virginia Commonwealth University Health System, Richmond, Virginia 23298-0057, USA.
| | | | | | | |
Collapse
|
|
35
|
Abstract
Development and testing of antifibrotic agents for the treatment of chronic hepatitis C have generally been targeted toward hepatic stellate cells, transforming growth factor-beta, the inflammatory response, or extracellular matrix accumulation. Although several agents such as interferon-gamma, long-term pegylated interferon, and caspase inhibitors have been studied, none have proved to be effective to date. There is a clear need for drugs that inhibit or reverse hepatic fibrosis as these would be immediately applicable to patients for whom antiviral therapy has failed or who have contraindications to antiviral therapy such as those with decompensated liver disease or renal failure. A major impediment in the development of new drugs in this field has been the inability to identify appropriate histologic or clinical end points within a reasonable period of study. Progress on providing suitable end points to therapy will then promote the development of newer agents.
Collapse
Affiliation(s)
- Paul J Pockros
- Division of Gastroenterology and Hepatology, The Scripps Research Institute, La Jolla, CA 92037, USA.
| |
Collapse
|
|
36
|
Corazza N, Badmann A, Lauer C. Immune cell-mediated liver injury. Semin Immunopathol 2009; 31:267-77. [DOI: 10.1007/s00281-009-0168-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2009] [Accepted: 05/27/2009] [Indexed: 02/07/2023]
|
|
37
|
HCV induces oxidative and ER stress, and sensitizes infected cells to apoptosis in SCID/Alb-uPA mice. PLoS Pathog 2009; 5:e1000291. [PMID: 19242562 PMCID: PMC2647842 DOI: 10.1371/journal.ppat.1000291] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2008] [Accepted: 01/08/2009] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) is a blood-borne pathogen and a major cause of liver disease worldwide. Gene expression profiling was used to characterize the transcriptional response to HCV H77c infection. Evidence is presented for activation of innate antiviral signaling pathways as well as induction of lipid metabolism genes, which may contribute to oxidative stress. We also found that infection of chimeric SCID/Alb-uPA mice by HCV led to signs of hepatocyte damage and apoptosis, which in patients plays a role in activation of stellate cells, recruitment of macrophages, and the subsequent development of fibrosis. Infection of chimeric mice with HCV H77c also led an inflammatory response characterized by infiltration of monocytes and macrophages. There was increased apoptosis in HCV-infected human hepatocytes in H77c-infected mice but not in mice inoculated with a replication incompetent H77c mutant. Moreover, TUNEL reactivity was restricted to HCV-infected hepatocytes, but an increase in FAS expression was not. To gain insight into the factors contributing specific apoptosis of HCV infected cells, immunohistological and confocal microscopy using antibodies for key apoptotic mediators was done. We found that the ER chaperone BiP/GRP78 was increased in HCV-infected cells as was activated BAX, but the activator of ER stress-mediated apoptosis CHOP was not. We found that overall levels of NF-kappaB and BCL-xL were increased by infection; however, within an infected liver, comparison of infected cells to uninfected cells indicated both NF-kappaB and BCL-xL were decreased in HCV-infected cells. We conclude that HCV contributes to hepatocyte damage and apoptosis by inducing stress and pro-apoptotic BAX while preventing the induction of anti-apoptotic NF-kappaB and BCL-xL, thus sensitizing hepatocytes to apoptosis.
Collapse
|
|
38
|
Adiponectin inhibits steatotic CD95/Fas up-regulation by hepatocytes: therapeutic implications for hepatitis C. J Hepatol 2009; 50:140-9. [PMID: 19019483 DOI: 10.1016/j.jhep.2008.08.023] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2008] [Revised: 08/05/2008] [Accepted: 08/27/2008] [Indexed: 12/15/2022]
Abstract
BACKGROUND/AIMS Steatosis may trigger hepatocytes to up-regulate CD95/Fas thereby increasing susceptibility to apoptosis, inflammation and fibrosis. We investigated this concept and potential roles of adiponectin and its receptors (AdipoR1; AdipoR2) in chronically HCV-infected patients. METHODS In 98 HCV+ patients and 20 controls, sera were tested for HCV genotypes, FFAs, adiponectin and the M30 apoptosis indicator, and biopsies were evaluated for steatosis/inflammation/fibrosis, CD95/Fas (mRNA/protein), adiponectin (mRNA/protein), AdipoR1/-R2 (mRNA) and M30 (protein). We also questioned whether adiponectin protects HepG2 hepatoblastoma cells from FFA-triggered CD95/Fas up-regulation and apoptosis. RESULTS Patients [HCV clades 1 (78%), 2 (3%) and 3 (19%)] revealed increased FFA and adiponectin serum levels (p = .005). Hepatocyte CD95/Fas up-regulation correlated with steatosis, inflammation and fibrosis (p = .004). Advanced fibrosis correlated significantly (p = .05) with serum M30. Liver adiponectin correlated with steatosis (p = .016), CD95/Fas (p < .001) and inflammation/fibrosis. Hepatocyte AdipoR2 mRNA specifically correlated with serum adiponectin and steatosis (p = .003), while hepatocyte AdipoR1 mRNA dropped in pronounced fibrosis (p = .060). Finally, adiponectin protected HepG2 cells from FFA-triggered CD95/Fas expression and induction of apoptosis (p = .0396). CONCLUSIONS In chronic HCV infection, steatosis up-regulates hepatocyte CD95/Fas and thus increases apoptosis, which facilitates inflammation and fibrosis. The physiologic countermeasure of adiponectin up-regulation may offer clues for future therapeutic intervention.
Collapse
|
|
39
|
Graf D, Haselow K, Münks I, Bode JG, Häussinger D. Caspase-mediated cleavage of the signal-transducing IL-6 receptor subunit gp130. Arch Biochem Biophys 2008; 477:330-8. [DOI: 10.1016/j.abb.2008.06.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2008] [Revised: 06/09/2008] [Accepted: 06/10/2008] [Indexed: 12/21/2022]
|
|
40
|
Abstract
Derangements in apoptosis of liver cells are mechanistically important in the pathogenesis of end-stage liver disease. Vulnerable hepatocytes can undergo apoptosis via an extrinsic, death receptor-mediated pathway, or alternatively intracellular stress can activate the intrinsic pathway of apoptosis. Both pathways converge on mitochondria, and mitochondrial dysfunction is a prerequisite for hepatocyte apoptosis. Persistent apoptosis is a feature of chronic liver diseases, and massive apoptosis is a feature of acute liver diseases. Fibrogenesis is stimulated by ongoing hepatocyte apoptosis, eventually resulting in cirrhosis of the liver in chronic liver diseases. Endothelial cell apoptosis occurs in ischemia-reperfusion injury. Natural killer and natural killer T cells remove virus-infected hepatocytes by death receptor-mediated fibrosis. Lastly, activated stellate cell apoptosis leads to slowing and resolution of apoptosis. This review summarizes recent cellular and molecular advances in the understanding of the injury mechanisms leading to end-stage liver disease.
Collapse
Affiliation(s)
- Harmeet Malhi
- Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA
| | | |
Collapse
|
|
41
|
Seronello S, Sheikh MY, Choi J. Redox regulation of hepatitis C in nonalcoholic and alcoholic liver. Free Radic Biol Med 2007; 43:869-82. [PMID: 17697932 DOI: 10.1016/j.freeradbiomed.2007.05.036] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2007] [Revised: 05/26/2007] [Accepted: 05/30/2007] [Indexed: 12/19/2022]
Abstract
Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family that is estimated to have infected 170 million people worldwide. HCV can cause serious liver disease in humans, such as cirrhosis, steatosis, and hepatocellular carcinoma. HCV induces a state of oxidative/nitrosative stress in patients through multiple mechanisms, and this redox perturbation has been recognized as a key player in HCV-induced pathogenesis. Studies have shown that alcohol synergizes with HCV in the pathogenesis of liver disease, and part of these effects may be mediated by reactive species that are generated during hepatic metabolism of alcohol. Furthermore, reactive species and alcohol may influence HCV replication and the outcome of interferon therapy. Alcohol consumption has also been associated with increased sequence heterogeneity of the HCV RNA sequences, suggesting multiple modes of interaction between alcohol and HCV. This review summarizes the current understanding of oxidative and nitrosative stress during HCV infection and possible combined effects of HCV, alcohol, and reactive species in the pathogenesis of liver disease.
Collapse
Affiliation(s)
- Scott Seronello
- School of Natural Sciences, University of California at Merced, Merced, CA 95344, USA
| | | | | |
Collapse
|
|
42
|
Pockros PJ, Schiff ER, Shiffman ML, McHutchison JG, Gish RG, Afdhal NH, Makhviladze M, Huyghe M, Hecht D, Oltersdorf T, Shapiro DA. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology 2007; 46:324-9. [PMID: 17654603 DOI: 10.1002/hep.21664] [Citation(s) in RCA: 138] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
UNLABELLED Increased rates of apoptosis (programmed cell death) have been demonstrated in many hepatic diseases including chronic hepatitis C. IDN-6556 is a potent inhibitor of caspases, the proteases that execute apoptosis. In a prior phase 1 study, IDN-6556 lowered aminotransferase activity in a small number of patients with liver impairment. The purpose of this study was to further explore the effect of IDN-6556 in patients with liver disease in a multicenter, double-blind, placebo-controlled, dose-ranging study with a 14-day dosing period. A total of 105 patients were enrolled in the study; 79 received active drug; 80 patients had chronic hepatitis C and 25 had other liver diseases including nonalcoholic steatohepatitis (NASH), hepatitis B, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). IDN-6556 doses ranged from 5 mg to 400 mg daily, given from 1 to 3 times per day. In the HCV patients, all doses of IDN-6556 significantly lowered ALT and AST (P = 0.0041 to P < 0.0001 for various dosing groups in Wilcoxon tests comparing IDN-6556 to placebo), with the exception of the lowest dose. Declines in aminotransferase activity were also seen in patients with NASH but effects were not apparent in the small number of other liver diseases. Adverse experiences were not different between IDN-6556 and placebo. There were no clinically meaningful changes in other laboratory parameters. In particular, mean HCV RNA levels did not show significant changes. CONCLUSION Oral IDN-6556, given for 14 days, significantly lowered aminotransferase activity in HCV patients and appeared to be well tolerated. Longer studies to assess potential effects of IDN-6556 on liver inflammation and fibrosis are merited.
Collapse
Affiliation(s)
- Paul J Pockros
- Division of Gastroenterology and Hepatology, Scripps Clinic, La Jolla, CA 92037, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Abstract
HCV (hepatitis C virus) has a high propensity to persist and to cause chronic hepatitis C, eventually leading to cirrhosis. Since HCV itself is not cytopathic, liver damage in chronic hepatitis C is commonly attributed to immune-mediated mechanisms. HCV proteins interact with several pathways in the host's immune response and disrupt pathogen-associated pattern recognition pathways, interfere with cellular immunoregulation via CD81 binding and subvert the activity of NK (natural killer) cells as well as CD4(+) and CD8(+) T-cells. Finally, HCV-specific T-cells become increasingly unresponsive and apparently disappear, owing to several possible mechanisms, such as escape mutations in critical viral epitopes, lack of sufficient help, clonal anergy or expansion of regulatory T-cells. The role of neutralizing antibodies remains uncertain, although it is still possible that humoral immunity contributes to bystander damage of virally coated cells via antibody-dependent cellular cytotoxicity. Cytotoxic lymphocytes kill HCV-infected cells via the perforin/granzyme pathway, but also release Fas ligand and inflammatory cytokines such as IFNgamma (interferon gamma). Release of soluble effector molecules helps to control HCV infection, but may also destroy uninfected liver cells and can attract further lymphocytes without HCV specificity to invade the liver. Bystander damage of these non-specific inflammatory cells will expand the tissue damage triggered by HCV infection and ultimately activate fibrogenesis. A clear understanding of these processes will eventually help to develop novel treatment strategies for HCV liver disease, independent from direct inhibition of HCV replication.
Collapse
Affiliation(s)
- Ulrich Spengler
- Department of Internal Medicine 1, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany.
| | | |
Collapse
|
|
44
|
Hashmi AZ, Hakim W, Kruglov EA, Watanabe A, Watkins W, Dranoff JA, Mehal WZ. Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2007; 292:G395-401. [PMID: 17053161 PMCID: PMC3224076 DOI: 10.1152/ajpgi.00208.2006] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Adenosine is produced during cellular hypoxia and apoptosis, resulting in elevated tissue levels at sites of injury. Adenosine is also known to regulate a number of cellular responses to injury, but its role in hepatic stellate cell (HSC) biology and liver fibrosis is poorly understood. We tested the effect of adenosine on the cytosolic Ca2+ concentration, chemotaxis, and upregulation of activation markers in HSCs. We showed that adenosine did not induce an increase in the cytosolic Ca2+ concentration in LX-2 cells and, in addition, inhibited increases in the cytosolic Ca2+ concentration in response to ATP and PDGF. Using a Transwell system, we showed that adenosine strongly inhibited PDGF-induced HSC chemotaxis in a dose-dependent manner. This inhibition was mediated via the A(2a) receptor, was reversible, was reproduced by forskolin, and was blocked by the adenylate cyclase inhibitor 2,5-dideoxyadenosine. Adenosine also upregulated the production of TGF-beta and collagen I mRNA. In conclusion, adenosine reversibly inhibits Ca2+ fluxes and chemotaxis of HSCs and upregulates TGF-beta and collagen I mRNA. We propose that adenosine provides 1) a "stop" signal to HSCs when they reach sites of tissue injury with high adenosine concentrations and 2) stimulates transdifferentiation of HSCs by upregulating collagen and TGF-beta production.
Collapse
Affiliation(s)
- Ardeshir Z Hashmi
- Section of Digestive Diseases, Yale Univ., 333 Cedar St., 1080 LMP, PO Box 208019, New Haven, CT 06520-8019, USA
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Lapinski TW, Jaroszewicz J, Wiercinska-Drapalo A. Concentrations of soluble Fas and soluble Fas ligand as indicators of programmed cell death among patients coinfected with Human Immunodeficiency Virus and Hepatitis C Virus. Viral Immunol 2006; 19:570-5. [PMID: 16987075 DOI: 10.1089/vim.2006.19.570] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) coinfections can affect mechanisms of programmed cell death and therefore influence acquired immunodeficiency syndrome (AIDS) development as well as the course of chronic hepatitis C. The aim of the study was to assess soluble Fas (sFas) and soluble Fas ligand (sFasL) concentrations in HIV- and HCV-coinfected patients and, moreover, to establish their relationships with HIV viral load, CD4+ T lymphocyte count, as well as liver function tests. Seventy-eight patients were included in the study, among them 30 coinfected with HIV and HCV, 10 infected only with HIV, and 38 infected only with HCV. HIV infection was confirmed by means of Western blot analysis; HIV viral load was measured by RTPCR; and CD3+, CD4+, and CD8+ T lymphocyte counts were established by means of flow cytometry. HCV infection was confirmed through HCV RNA isolation, using RT-PCR. sFas and sFasL concentrations were measured in duplicate by ELISA. The mean CD4+ T lymphocyte count decreased in HIV- and HCV-coinfected patients versus HIV-infected individuals (429 versus 279/ml). sFasL protein was detectable principally in HIV-infected individuals without HCV infection (90%), whereas in those with HCV infection it occurred only in 11% of cases. The highest sFas concentration was observed in HCV-infected patients (25.9 ng/ml) as well as in HIV- and HCV-coinfected individuals (20.3 ng/ml). This concentration was negatively proportional to sFasL prevalence. The results of our study suggest that HCV infection in HIV-positive individuals may suppress processes of programmed cell death. There was no correlation between sFas, sFasL, and HIV-1 viral load. On the other hand, sFas concentration and the presence of sFasL were related to CD4+ T lymphocyte count.
Collapse
|
|
46
|
Walters KA, Smith MW, Pal S, Thompson JC, Thomas MJ, Yeh MM, Thomas DL, Fitzgibbon M, Proll S, Fausto N, Gretch DR, Carithers RL, Shuhart MC, Katze MG. Identification of a specific gene expression pattern associated with HCV-induced pathogenesis in HCV- and HCV/HIV-infected individuals. Virology 2006; 350:453-64. [PMID: 16574185 DOI: 10.1016/j.virol.2006.02.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2006] [Revised: 01/25/2006] [Accepted: 02/01/2006] [Indexed: 01/27/2023]
Abstract
Gene expression profiling was performed on liver biopsies from 28 patients (12 HCV and 16 HCV/HIV infected) in an attempt to understand the mechanisms of HCV liver disease in the presence and absence of HIV coinfection. The data were compared with clinical observations and a gene expression database obtained for transplant HCV-infected samples. This is the first report of functional genomics being used to compare intrahepatic gene expression profiles of HCV- and HCV/HIV-infected individuals. Significantly, the intrahepatic global gene expression profiles do not differ between HCV- and HCV/HIV-infected individuals. However, a subset of patients was identified who share a specific pattern of gene expression, termed the enhanced gene expression (EGE) pattern. Specifically, the EGE (+) patients show a dramatic decreased expression of multiple genes associated with the FAS-apoptosis pathway and increased expression of lymphocyte adhesion molecules and lymphocyte-specific genes. The EGE (+) patients also have partially impaired Type I and II IFN-mediated antiviral responses, including a lack of induction of the anti-fibrogenic cytokine IFN-gamma. Importantly, the pattern of gene expression observed in EGE (+) patients has similarities to patients who developed fibrosis within 1 year of receiving a liver transplant.
Collapse
Affiliation(s)
- Kathie-Anne Walters
- Department of Microbiology, School of Medicine, University of Washington, Box 358070, Seattle, WA 98195-8070, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Walters KA, Joyce MA, Thompson JC, Smith MW, Yeh MM, Proll S, Zhu LF, Gao TJ, Kneteman NM, Tyrrell DL, Katze MG. Host-specific response to HCV infection in the chimeric SCID-beige/Alb-uPA mouse model: role of the innate antiviral immune response. PLoS Pathog 2006; 2:e59. [PMID: 16789836 PMCID: PMC1480599 DOI: 10.1371/journal.ppat.0020059] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2006] [Accepted: 05/04/2006] [Indexed: 12/14/2022] Open
Abstract
The severe combined immunodeficiency disorder (SCID)-beige/albumin (Alb)-urokinase plasminogen activator (uPA) mouse containing a human-mouse chimeric liver is currently the only small animal model capable of supporting hepatitis C virus (HCV) infection. This model was utilized to characterize the host transcriptional response to HCV infection. The purpose of these studies was to investigate the genetic component of the host response to HCV infection and also to distinguish virus-induced gene expression changes from adaptive HCV-specific immune-mediated effects. Gene expression profiles from HCV-infected mice were also compared to those from HCV-infected patients. Analyses of the gene expression data demonstrate that host factors regulate the response to HCV infection, including the nature of the innate antiviral immune response. They also indicate that HCV mediates gene expression changes, including regulation of lipid metabolism genes, which have the potential to be directly cytopathic, indicating that liver pathology may not be exclusively mediated by HCV-specific adaptive immune responses. This effect appears to be inversely related to the activation of the innate antiviral immune response. In summary, the nature of the initial interferon response to HCV infection may determine the extent of viral-mediated effects on host gene expression.
Collapse
Affiliation(s)
- Kathie-Anne Walters
- Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Chiou HL, Hsieh YS, Hsieh MR, Chen TY. HCV E2 may induce apoptosis of Huh-7 cells via a mitochondrial-related caspase pathway. Biochem Biophys Res Commun 2006; 345:453-8. [PMID: 16681997 DOI: 10.1016/j.bbrc.2006.04.118] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2006] [Accepted: 04/20/2006] [Indexed: 01/29/2023]
Abstract
INTRODUCTION One unusual characteristic of HCV is to establish chronic infection and the precise mechanisms remain unclear. MATERIALS AND METHODS Huh-7 cells were transiently transfected with E2 and subjected to MTT assay, DNA fragmentation assay, and Western blotting to see the impact of E2 protein on apoptosis. RESULTS AND DISCUSSION E2 may inhibit cell proliferation by inducing apoptosis and pro-caspases 3, 8, and 9 were cleaved and activated to result in the presence of active forms in a time-dependent fashion, which suggest that E2-induced apoptosis is caspase-dependent. Furthermore, the cytosolic level of cytochrome c was increased together with a gradually down-regulated Bcl-2 and up-regulated Bax protein expression. The continuing reduction of Bid protein and the gradual increase of tBid protein also indicated that a time-dependent increased turn-over of Bid protein into tBid. Taken together, our data suggested that HCV E2 may induce apoptosis through a mitochondrial damage-mediated caspase pathway.
Collapse
Affiliation(s)
- Hui-Ling Chiou
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan, ROC.
| | | | | | | |
Collapse
|
|
49
|
Purohit V, Brenner DA. Mechanisms of alcohol-induced hepatic fibrosis: a summary of the Ron Thurman Symposium. Hepatology 2006; 43:872-8. [PMID: 16502397 DOI: 10.1002/hep.21107] [Citation(s) in RCA: 130] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
This report is a summary of Ron Thurman Symposium on the Mechanisms of Alcohol-Induced Hepatic Fibrosis which was organized by The National Institutes of Health in Santa Barbara, California, June 25, 2005. The Symposium and this report highlight the unique aspects by which drinking alcoholic beverages may result in hepatic fibrosis. Acetaldehyde, the first metabolite of ethanol, can upregulate transcription of collagen I directly as well as indirectly by upregulating the synthesis of transforming growth factor-beta 1 (TGF-beta1). Reactive oxygen species (ROS) generated in hepatocytes by alcohol metabolism can activate collagen production in hepatic stellate cells (HSCs) in a paracrine manner. Alcohol-induced hepatocyte apoptotic bodies can be phagocytosed by HSCs and Kupffer cells and result in increased expression of TGF-beta1 and subsequent HSC activation. Kupffer cells may contribute to the activation of HSCs by releasing ROS and TGF- beta1. Innate immunity may suppress hepatic fibrosis by killing activated HSCs and blocking TGF-beta1 signaling. In patients infected with hepatitis C virus (HCV), alcohol may promote hepatic fibrosis by suppressing innate immunity. HCV core and non-structural proteins contribute to HCV-induced hepatic fibrosis. Alcohol and HCV together may promote hepatic fibrosis through increased oxidative stress and upregulation of fibrogenic cytokines. The inactive aldehyde dehydrogenase (ALDH2) and the super-active alcohol dehydrogenase (ADH2) alleles may promote hepatic fibrosis through increased accumulation of acetaldehyde in the liver. Hepatic fibrosis can be reversed by inducing selective apoptosis or necrosis of activated HSCs, or by reverse trans-differentiation of activated HSCs into the quiescent phenotype.
Collapse
Affiliation(s)
- Vishnudutt Purohit
- Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
| | | |
Collapse
|
|
50
|
Abstract
Death of hepatocytes and other hepatic cell types is a characteristic feature of liver diseases as diverse as cholestasis, viral hepatitis, ischemia/reperfusion, liver preservation for transplantation and drug/toxicant-induced injury. Cell death typically follows one of two patterns: oncotic necrosis and apoptosis. Necrosis is typically the consequence of acute metabolic perturbation with ATP depletion as occurs in ischemia/reperfusion and acute drug-induced hepatotoxicity. Apoptosis, in contrast, represents the execution of an ATP-dependent death program often initiated by death ligand/death receptor interactions, such as Fas ligand with Fas, which leads to a caspase activation cascade. A common event leading to both apoptosis and necrosis is mitochondrial permeabilization and dysfunction, although the mechanistic basis of mitochondrial injury may vary in different settings. Prevention of these modes of cell death is an important target of therapy, but controversies still exist regarding which mode of cell death predominates in various forms of liver disease and injury. Resolution of these controversies may come with the recognition that apoptosis and necrosis frequently represent alternate outcomes of the same cellular pathways to cell death, especially for cell death mediated by mitochondrial permeabilization. An understanding of processes leading to liver cell death will be important for development of effective interventions to prevent hepatocellular death leading to liver failure and to promote cancer and stellate cell death in malignancy and fibrotic disease.
Collapse
Affiliation(s)
- Harmeet Malhi
- Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | | | | |
Collapse
|