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Cannabinoids and Chronic Liver Diseases. Int J Mol Sci 2022; 23:ijms23169423. [PMID: 36012687 PMCID: PMC9408890 DOI: 10.3390/ijms23169423] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/13/2022] [Accepted: 08/17/2022] [Indexed: 11/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), alcohol-induced liver disease (ALD), and viral hepatitis are the main causes of morbidity and mortality related to chronic liver diseases (CLDs) worldwide. New therapeutic approaches to prevent or reverse these liver disorders are thus emerging. Although their etiologies differ, these CLDs all have in common a significant dysregulation of liver metabolism that is closely linked to the perturbation of the hepatic endocannabinoid system (eCBS) and inflammatory pathways. Therefore, targeting the hepatic eCBS might have promising therapeutic potential to overcome CLDs. Experimental models of CLDs and observational studies in humans suggest that cannabis and its derivatives may exert hepatoprotective effects against CLDs through diverse pathways. However, these promising therapeutic benefits are not yet fully validated, as the few completed clinical trials on phytocannabinoids, which are thought to hold the most promising therapeutic potential (cannabidiol or tetrahydrocannabivarin), remained inconclusive. Therefore, expanding research on less studied phytocannabinoids and their derivatives, with a focus on their mode of action on liver metabolism, might provide promising advances in the development of new and original therapeutics for the management of CLDs, such as NAFLD, ALD, or even hepatitis C-induced liver disorders.
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Rodriguez JL, Lopez JA, Steel JJ. Involvement of the endocannabinoid system in the inhibition of Sindbis virus replication: a preliminary study. J Cannabis Res 2021; 3:10. [PMID: 33892823 PMCID: PMC8066438 DOI: 10.1186/s42238-021-00068-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 04/13/2021] [Indexed: 01/03/2023] Open
Abstract
Background Sindbis virus (Alphaviridae) is a plus-strand RNA virus that is dependent on the host cell for replication. Cannabinoid (CB) receptors are found on most human cells, including virally infected cells. Activation of cannabinoid receptors has been shown to alter normal cellular physiology. This study aimed to assess how agonist (ACEA) or antagonists/inverse agonist (AM251) of the cannabinoid receptors would alter the cellular environment and impact Sindbis virus replication. Methods Human hepatoma (Huh7) cells were used as our model for viral replication. Cells were infected with Sindbis virus (SINV) and then treated with CB agonist (ACEA) (10 μM) or antagonist/inverse agonist (AM-251) (10 μM) and virus replication was monitored. A double subgenomic Sindbis virus containing a green fluorescent protein (GFP) reporter gene inserted into a 3′ subgenomic promoter was utilized for these assays to quickly measure viral replication. GFP fluorescent cells were analyzed using flow cytometry to measure the percentage of cells expressing the viral reporter and also quantify the levels of GFP fluorescence. Result Treatment of SINV-infected Huh7 cells with CB1 receptor antagonist/inverse agonist (AM251, 10 μM) resulted in a significant decrease in viral replication, while infected cells treated with a CB1 receptor agonist (ACEA, 10 μM) resulted in a significant increase of viral infection. The data indicates that activation of CB1 receptor by cannabinoids significantly influences the ability of Sindbis virus to replicate in the host cell. Conclusion Blocking CB1 receptor activity with 10 μM AM251 reduced viral replication, but activating the CB1 receptor with 10 μM ACEA resulted in an increase in viral infection. These results indicate cannabinoids may significantly impact a virus replicating in human liver cells. Future confirmation with other viruses and cell lines will be performed to better understand the impact of cannabinoids on viral infections.
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Affiliation(s)
- Juan L Rodriguez
- Biology Department, Colorado State University-Pueblo, 2200 Bonforte Blvd LS220, Pueblo, CO, 81001, USA.
| | - Joseph A Lopez
- Biology Department, Colorado State University-Pueblo, 2200 Bonforte Blvd LS220, Pueblo, CO, 81001, USA
| | - J Jordan Steel
- Biology Department, Colorado State University-Pueblo, 2200 Bonforte Blvd LS220, Pueblo, CO, 81001, USA.,Department of Biology, US Air Force Academy, 2355 Faculty Dr. DFB, Colorado Springs, CO, USA
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Choi CJ, Weiss SH, Nasir UM, Pyrsopoulos NT. Cannabis use history is associated with increased prevalence of ascites among patients with nonalcoholic fatty liver disease: A nationwide analysis. World J Hepatol 2020; 12:993-1003. [PMID: 33312424 PMCID: PMC7701971 DOI: 10.4254/wjh.v12.i11.993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/27/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent studies have revealed the endocannabinoid system as a potential therapeutic target in the management of nonalcoholic fatty liver disease (NAFLD). Cannabis use is associated with reduced risk for NAFLD, we hypothesized that cannabis use would be associated with less liver-related clinical complications in patients with NAFLD. AIM To assess the effects of cannabis use on liver-related clinical outcomes in hospitalized patients with NAFLD. METHODS We performed a retrospective matched cohort study based on querying the 2014 National Inpatient Sample (NIS) for hospitalizations of adults with a diagnosis of NAFLD. The NIS database is publicly available and the largest all-payer inpatient database in the United States. The patients with cannabis use were selected as cases and those without cannabis were selected as controls. Case-control matching at a ratio of one case to two controls was performed based on sex, age, race, and comorbidities. The liver-related outcomes such as portal hypertension, ascites, varices and variceal bleeding, and cirrhosis were compared between the groups. RESULTS A total of 49911 weighed hospitalizations with a diagnosis of NAFLD were identified. Of these, 3820 cases were selected as the cannabis group, and 7625 non-cannabis cases were matched as controls. Patients with cannabis use had a higher prevalence of ascites (4.5% vs 3.6%), with and without cannabis use, P = 0.03. The prevalence of portal hypertension (2.1% vs 2.2%), varices and variceal bleeding (1.3% vs 1.7%), and cirrhosis (3.7% vs 3.6%) was not different between the groups, with and without cannabis use, all P > 0.05. Hyperlipidemia, race/ethnicity other than White, Black, Asian, Pacific Islander or Native American, and higher comorbidity score were independent risk factors for ascites in the cannabis group. Among non-cannabis users, obesity and hyperlipidemia were independent protective factors against ascites while older age, Native American and higher comorbidity index were independent risk factors for ascites. CONCLUSION Cannabis was associated with higher rates of ascites, but there was no statistical difference in the prevalence of portal hypertension, varices and variceal bleeding, and cirrhosis.
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Affiliation(s)
- Catherine J Choi
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States
| | - Stanley H Weiss
- Department of Medicine, Biostatistics and Epidemiology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Umair M Nasir
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, United States
| | - Nikolaos T Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States.
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Zhang Y, Kim DK, Jung YS, Kim YH, Lee YS, Kim J, Jeong WI, Lee IK, Cho SJ, Dooley S, Lee CH, Choi HS. Inverse agonist of ERRγ reduces cannabinoid receptor type 1-mediated induction of fibrinogen synthesis in mice with a high-fat diet-intoxicated liver. Arch Toxicol 2018; 92:2885-2896. [PMID: 30019168 DOI: 10.1007/s00204-018-2270-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 07/12/2018] [Indexed: 12/12/2022]
Abstract
Upon liver intoxication with malnutrition or high-fat diet feeding, fibrinogen is synthesized by hepatocytes and secreted into the blood in human and mouse. Its primary function is to occlude blood vessels upon damage and thereby stop excessive bleeding. High fibrinogen levels may contribute to the development of pathological thrombosis, which is one mechanism linking fatty liver disease with cardiovascular disease. Our previous results present ERRγ as key regulator of hepatocytic fibrinogen gene expression in human. In a therapeutic approach, we now tested ERRγ inverse agonist GSK5182 as regulator of fibrinogen levels in mouse hyperfibrinogenemia caused by diet-induced obesity and in mouse hepatocytes. ACEA, a CB1R agonist, up-regulated transcription of mouse fibrinogen via induction of ERRγ, whereas knockdown of ERRγ attenuated the effect of ACEA (10 µM) on fibrinogen expression in AML12 mouse hepatocytes. Deletion analyses of the mouse fibrinogen γ (FGG) gene promoter and ChIP assays revealed binding sites for ERRγ on the mouse FGG promoter. ACEA or adenovirus ERRγ injection induced FGA, FGB and FGG mRNA and protein expression in mouse liver, while ERRγ knockdown with Ad-shERRγ attenuated ACEA-mediated induction of fibrinogen gene expression. Moreover, mice maintained on a high-fat diet (HFD) expressed higher levels of fibrinogen, whereas cannabinoid receptor type 1 (CB1R)-KO mice fed an HFD had nearly normal fibrinogen levels. Finally, GSK5182 (40 mg/kg) strongly inhibits the ACEA (10 mg/kg) or HFD-mediated induction of fibrinogen level in mice. Taken together, targeting ERRγ with its inverse agonist GSK5182 represents a promising therapeutic strategy for ameliorating hyperfibrinogenemia.
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Affiliation(s)
- Yaochen Zhang
- National Creative Research Initiatives Center for Nuclear Receptor Signals, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Don-Kyu Kim
- National Creative Research Initiatives Center for Nuclear Receptor Signals, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Yoon Seok Jung
- National Creative Research Initiatives Center for Nuclear Receptor Signals, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Yong-Hoon Kim
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Yong Soo Lee
- National Creative Research Initiatives Center for Nuclear Receptor Signals, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Jina Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea
| | - Won-Il Jeong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - In-Kyu Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.,Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Sung Jin Cho
- Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.,New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea
| | - Steven Dooley
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Chul-Ho Lee
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Hueng-Sik Choi
- National Creative Research Initiatives Center for Nuclear Receptor Signals, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
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Montalbano R, Honrath B, Wissniowski TT, Elxnat M, Roth S, Ocker M, Quint K, Churin Y, Roederfeld M, Schroeder D, Glebe D, Roeb E, Fazio PD. Exogenous hepatitis B virus envelope proteins induce endoplasmic reticulum stress: involvement of cannabinoid axis in liver cancer cells. Oncotarget 2016; 7:20312-20323. [PMID: 26967385 PMCID: PMC4991457 DOI: 10.18632/oncotarget.7950] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 02/13/2016] [Indexed: 02/07/2023] Open
Abstract
HBV represents the most common chronic viral infection and major cause of hepatocellular carcinoma (HCC), although its exact role in liver tumorigenesis is unclear. Massive storage of the small (SHBs), middle (MHBs) and large surface (LHBs) HBV envelope proteins leads to cell stress and sustained inflammatory responses. Cannabinoid (CB) system is involved in the pathogenesis of liver diseases, stimulating acute and chronic inflammation, liver damage and fibrogenesis; it triggers endoplasmic reticulum (ER) stress response. The aim of our work was to investigate the activation of ER stress pathway after ectopic HBV envelope proteins expression, in liver cancer cells, and the role exerted by CB receptors. PCR, immunofluorescence and western blotting showed that exogenous LHBs and MHBs induce a clear ER stress response in Huh-7 cells expressing CB1 receptor. Up-regulation of the chaperone BiP/GRP78 (Binding Immunoglobulin Protein/Glucose-Regulated Protein 78) and of the transcription factor CHOP/GADD153 (C/EBP Homologous Protein/Growth Arrest and DNA Damage inducible gene 153), phosphorylation of PERK (PKR-like ER Kinase) and eIF2α (Eukaryotic Initiation Factor 2α) and splicing of XBP1 (X-box binding protein 1) was observed. CB1-/- HepG2 cells did not show any ER stress activation. Inhibition of CB1 receptor counteracted BiP expression in transfected Huh-7 and in HBV+ PLC/PRF/5 cells; whereas no effect was observed in HBV- HLF cells. These results suggest that HBV envelope proteins are able to induce the ER stress pathway. CB1 expression is directly correlated with ER stress function. Further investigations are needed to clarify the involvement of cannabinoid in HCC progression after HBV infection.
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Affiliation(s)
- Roberta Montalbano
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Birgit Honrath
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | | | - Moritz Elxnat
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Silvia Roth
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
| | - Matthias Ocker
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
- Present address: Department of Gastroenterology CBF, Charité University Medicine Berlin and Bayer Pharma AG, Experimental Medicine Oncology, Berlin, Germany
| | - Karl Quint
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
| | - Yuri Churin
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Martin Roederfeld
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Dirk Schroeder
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, Justus Liebig University, Giessen, Germany
| | - Elke Roeb
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany
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Cooper ME, Regnell SE. The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake. Br J Clin Pharmacol 2015; 77:21-30. [PMID: 23452341 DOI: 10.1111/bcp.12102] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 02/12/2013] [Indexed: 12/11/2022] Open
Abstract
The cannabinoid 1 receptor (CB1R) has a well-established role in appetite regulation. Central CB1R antagonists, notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals, but were discontinued due to psychiatric side-effects. The CB1R is also expressed peripherally, where its effects include promotion of liver fat accumulation, which consumes ATP. Type 2 diabetes in obese subjects is linked to excess liver fat, whilst there is a negative correlation between hepatic ATP content and insulin resistance. A decreased hepatic ATP/AMP ratio increases food intake by signals via the vagus nerve to the brain. The hepatic cannabinoid system is highly upregulated in obesity, and the effects of hepatic CB1R activation include increased activity of lipogenic and gluconeogenic transcription factors. Thus, blockade of hepatic CB1Rs could contribute significantly to the weight-reducing and insulin-sensitizing effects of CB1R antagonists. Additionally, upregulation of the hepatic CB1R may contribute to chronic liver inflammation, fibrosis and cirrhosis from causes including obesity, alcoholism and viral hepatitis. Peripheral CB1R antagonists induce weight loss and metabolic improvements in obese rodents; however, as there is evidence that hepatic CB1Rs are predominately intracellular, due to high intrinsic clearance, many drugs may not effectively block these receptors and therefore have limited efficacy. Hepatoselective CB1R antagonists may be effective at reducing hepatic steatosis, insulin resistance and bodyweight in obese, diabetic patients, with far fewer side-effects than first-generation CB1R antagonists. Additionally, such compounds may be effective in treating inflammatory liver disease, such as non-alcoholic steatohepatitis, reducing the likelihood of disease progression to cirrhosis or cancer.
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Flores-Contreras L, Sandoval-Rodríguez AS, Mena-Enriquez MG, Lucano-Landeros S, Arellano-Olivera I, Álvarez-Álvarez A, Sanchez-Parada MG, Armendáriz-Borunda J. Treatment with pirfenidone for two years decreases fibrosis, cytokine levels and enhances CB2 gene expression in patients with chronic hepatitis C. BMC Gastroenterol 2014; 14:131. [PMID: 25064094 PMCID: PMC4236537 DOI: 10.1186/1471-230x-14-131] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Accepted: 07/14/2014] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The aim of this study was to assess whether two-years treatment with Pirfenidone influences necroinflammation, fibrosis and steatosis, serum levels of TGF-β1, IL-6, TNF-α and CB1 and CB2 gene expression, in patients with chronic hepatitis C (CHC). METHODS Twenty-eight patients out of 34 with CHC virus infection were enrolled in the study and received Pirfenidone (1200 mg/day) for 24 months. Six patients dropped out after 12 months of PFD. Liver biopsies and serum samples were obtained at the beginning and end of treatment. Modified HAI was calculated. CB1 and CB2 gene expression was correlated with fibrosis progression alongside with necroinflammation and steatosis. TGF-β1, IL-6, TNF-α and liver transaminases were measured in serum at two-months intervals. HCV genotype and viral load were also assessed. Quality of life was evaluated by SF36 questionnaires and the prognosis of disease was assessed with Child-Pugh score. The Wilcoxon test matched-pair signed ranks were used to analyze the outcomes. RESULTS Intention to treat analyses were performed for biochemistry and clinical parameters. At the end of treatment, necroinflammation grading was reduced in an average of 3.2 points in 82% of patients (p < 0.05) and Ishak's fibrosis stage decreased 2-points average in 67% of patients (p < 0.05). Steatosis decreased in 61% of patients. IL-6 and TGF-β1 serum levels decreased significantly in 93% and 67% of patients (p < 0.05), respectively, while TNF-α diminished in 47% of patients. ALT and AST tended to normalize in 81% of patients; CB2 mRNA levels increased in 86% and CB1 expression diminished in 29% of patients. Both, quality of life and Child-Pugh score improvements were reported in all patients. CONCLUSIONS Pirfenidone for two years benefits CHC patients and improves inflammation, fibrosis and steatosis in higher number of patients as previously shown for 12-months treatment with PFD. Additionally, PFD improved TGFβ1 and IL-6 levels and diminished liver expression of anti-fibrogenic receptor CB2. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02161952. Protocol Registration Date: 06/11/2014.
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Affiliation(s)
- Lucia Flores-Contreras
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - Ana S Sandoval-Rodríguez
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - Mayra G Mena-Enriquez
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - Silvia Lucano-Landeros
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - Inmaculada Arellano-Olivera
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
- Unidad Médica de Alta Especialidad, Hospital de Especialidades Centro Medico Nacional de Occidente, Guadalajara, Jalisco, Mexico
| | - Arnulfo Álvarez-Álvarez
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - M Guadalupe Sanchez-Parada
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
| | - Juan Armendáriz-Borunda
- Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Universidad de Guadalajara, Sierra Mojada # 950, Guadalajara, Jalisco 44281, Mexico
- INNOVARE, Guadalajara, Jalisco, Mexico
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Pisonero-Vaquero S, García-Mediavilla MV, Jorquera F, Majano PL, Benet M, Jover R, González-Gallego J, Sánchez-Campos S. Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin. J Transl Med 2014; 94:262-74. [PMID: 24492281 DOI: 10.1038/labinvest.2013.156] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 11/28/2013] [Accepted: 12/23/2013] [Indexed: 02/07/2023] Open
Abstract
There is experimental evidence that some antioxidant flavonoids show therapeutic potential in the treatment of hepatitis C through inhibition of hepatitis C virus (HCV) replication. We examined the effect of treatment with the flavonols quercetin and kaempferol, the flavanone taxifolin and the flavone apigenin on HCV replication efficiency in an in vitro model. While all flavonoids studied were able to reduce viral replication at very low concentrations (ranging from 0.1 to 5 μM), quercetin appeared to be the most effective inhibitor of HCV replication, showing a marked anti-HCV activity in replicon-containing cells when combined with interferon (IFN)α. The contribution of oxidative/nitrosative stress and lipogenesis modulation to inhibition of HCV replication by quercetin was also examined. As expected, quercetin decreased HCV-induced reactive oxygen and nitrogen species (ROS/RNS) generation and lipoperoxidation in replicating cells. Quercetin also inhibited liver X receptor (LXR)α-induced lipid accumulation in LXRα-overexpressing and replicon-containing Huh7 cells. The mechanism underlying the LXRα-dependent lipogenesis modulatory effect of quercetin in HCV-replicating cells seems to involve phosphatidylinositol 3-kinase (PI3K)/AKT pathway inactivation. Thus, inhibition of the PI3K pathway by LY294002 attenuated LXRα upregulation and HCV replication mediated by lipid accumulation, showing an additive effect when combined with quercetin. Inactivation of the PI3K pathway by quercetin may contribute to the repression of LXRα-dependent lipogenesis and to the inhibition of viral replication induced by the flavonol. Combined, our data suggest that oxidative/nitrosative stress blockage and subsequent modulation of PI3K-LXRα-mediated lipogenesis might contribute to the inhibitory effect of quercetin on HCV replication.
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Affiliation(s)
| | - María V García-Mediavilla
- 1] Institute of Biomedicine (IBIOMED), University of León, León, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco Jorquera
- 1] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain [2] Department of Gastroenterology, Complejo Asistencial Universitario de León, León, Spain
| | - Pedro L Majano
- 1] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain [2] Molecular Biology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
| | - Marta Benet
- 1] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain [2] Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain
| | - Ramiro Jover
- 1] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain [2] Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain [3] Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain
| | - Javier González-Gallego
- 1] Institute of Biomedicine (IBIOMED), University of León, León, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Sonia Sánchez-Campos
- 1] Institute of Biomedicine (IBIOMED), University of León, León, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Brunet L, Moodie EEM, Rollet K, Cooper C, Walmsley S, Potter M, Klein MB. Marijuana smoking does not accelerate progression of liver disease in HIV-hepatitis C coinfection: a longitudinal cohort analysis. Clin Infect Dis 2013; 57:663-70. [PMID: 23811492 PMCID: PMC3739469 DOI: 10.1093/cid/cit378] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background. Marijuana smoking is common and believed to relieve many symptoms, but daily use has been associated with liver fibrosis in cross-sectional studies. We aimed to estimate the effect of marijuana smoking on liver disease progression in a Canadian prospective multicenter cohort of human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected persons. Methods. Data were analyzed for 690 HCV polymerase chain reaction positive (PCR-positive) individuals without significant fibrosis or end-stage liver disease (ESLD) at baseline. Time-updated Cox Proportional Hazards models were used to assess the association between the average number of joints smoked/week and progression to significant liver fibrosis (APRI ≥ 1.5), cirrhosis (APRI ≥ 2) or ESLD. Results At baseline, 53% had smoked marijuana in the past 6 months, consuming a median of 7 joints/week (IQR, 1–21); 40% smoked daily. There was no evidence that marijuana smoking accelerates progression to significant liver fibrosis (APRI ≥ 1.5) or cirrhosis (APRI ≥ 2; hazard ratio [HR]: 1.02 [0.93–1.12] and 0.99 [0.88–1.12], respectively). Each 10 additional joints/week smoked slightly increased the risk of progression to a clinical diagnosis of cirrhosis and ESLD combined (HR, 1.13 [1.01–1.28]). However, when exposure was lagged to 6–12 months before the diagnosis, marijuana was no longer associated with clinical disease progression (HR, 1.10 [0.95–1.26]). Conclusions In this prospective analysis we found no evidence for an association between marijuana smoking and significant liver fibrosis progression in HIV/HCV coinfection. A slight increase in the hazard of cirrhosis and ESLD with higher intensity of marijuana smoking was attenuated after lagging marijuana exposure, suggesting that reverse causation due to self-medication could explain previous results.
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Affiliation(s)
- Laurence Brunet
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada, H2X 2P4
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