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Jani CT, Mouchati C, Abdallah N, Jani R, Kakoullis L, Chen LH. Do Statins Affect Viral Infections Encountered by International Travelers? Trop Med Infect Dis 2025; 10:73. [PMID: 40137827 PMCID: PMC11946866 DOI: 10.3390/tropicalmed10030073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 03/06/2025] [Accepted: 03/08/2025] [Indexed: 03/29/2025] Open
Abstract
Statins are among the most frequently prescribed medications. In addition to their well-established effectiveness in lowering total cholesterol, LDL, and triglycerides, statins have been described to have immunomodulatory and anti-inflammatory properties and have been associated with improved endothelial functions. Given the common use of statins, we sought to evaluate the effect of statins on some viral infections encountered by residents in tropical areas or by international travelers. A literature search was performed in PubMED/MEDLINE focusing on keywords that included statins and the viruses of interest, including SARS-CoV-2, influenza, yellow fever, dengue, Zika, tick-borne encephalitis, hemorrhagic fever viruses, hepatitis A, norovirus, hepatitis B, hepatitis C, measles, and herpesviruses; findings were synthesized for each virus into a summary. The effects of statins on viral infections vary depending on the specific virus. While some studies indicate potential benefits in chronic HBV and HCV infections, evidence regarding SARS-CoV-2 and influenza remains inconclusive due to mixed findings from observational studies and randomized controlled trials. The role of statins in other viral infections is largely unexplored, with preclinical data available for only a few viruses. Given the conflicting evidence, further prospective studies and randomized controlled trials are warranted to elucidate statins' role in viral infections, particularly in modulating inflammation, endothelial dysfunction, and immune responses. Future research should aim to define the optimal patient populations, target viruses, statin types, and treatment durations that may confer benefits in specific viral infections.
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Affiliation(s)
- Chinmay T. Jani
- Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA;
| | - Christian Mouchati
- Division of Neurology, University of Connecticut, Farmington, CT 06030, USA;
| | - Nour Abdallah
- Department of Medicine, University of Connecticut, Farmington, CT 06030, USA;
| | - Ruchi Jani
- Department of Medicine, Smt NHL Municipal Medical College, Ahmedabad 380006, Gujarat, India;
| | - Loukas Kakoullis
- Department of Medicine, Mount Auburn Hospital, Cambridge, MA 02138, USA;
- Harvard Medical School, Boston, MA 02115, USA
| | - Lin H. Chen
- Department of Medicine, Mount Auburn Hospital, Cambridge, MA 02138, USA;
- Harvard Medical School, Boston, MA 02115, USA
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2
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Gonzalez-Aldaco K, Torres-Reyes LA, Ojeda-Granados C, Leal-Mercado L, Roman S, Panduro A. Metabolic Dysfunction-Associated Steatotic Liver Disease in Chronic Hepatitis C Virus Infection: From Basics to Clinical and Nutritional Management. Clin Pract 2024; 14:2542-2558. [PMID: 39585028 PMCID: PMC11587073 DOI: 10.3390/clinpract14060200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 11/26/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with obesity and other cardiometabolic risk factors. MASLD has rapidly become the most common cause of liver disease worldwide, currently affecting 38% of the global population. Excess weight causes chronic inflammation and the activation of different pathways involved in liver damage. MASLD can progress from simple steatosis to steatohepatitis, giving way to its inflammatory component, metabolic dysfunction-associated steatohepatitis (MASH), previously recognized as non-alcoholic steatosis hepatitis (NASH). Chronic hepatitis C virus (HCV) infection remains a significant challenge to liver health as it triggers hepatic inflammation, metabolic disruption, and hepatic steatosis. The convergence of MASLD and chronic HCV infection can significantly alter the course of liver disease and accelerate the progression to severe liver damage. Currently, HCV treatment has a high cure rate. However, in patients who achieve a sustained virological response after treatment with direct-acting antivirals, weight gain, and excessive calorie intake may contribute to increased liver steatosis and a higher risk of liver disease progression. Therefore, the effective clinical and nutritional management of HCV patients, both before and after viral eradication, is crucial to reducing the risk of death from hepatocellular carcinoma. Understanding the complex interactions between MASLD and HCV infection is crucial for managing these patients appropriately. Herein, host and viral mechanisms inducing liver damage during the coexistence of MASLD and HCV infection are described, and their therapeutic and dietary management are discussed.
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Affiliation(s)
- Karina Gonzalez-Aldaco
- Centro Universitario de los Valles, Universidad de Guadalajara, Carretera Guadalajara-Ameca Km. 45.5, Ameca 46600, Jalisco, Mexico;
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico; (L.L.-M.); (S.R.); (A.P.)
| | - Luis A. Torres-Reyes
- Centro Universitario de los Valles, Universidad de Guadalajara, Carretera Guadalajara-Ameca Km. 45.5, Ameca 46600, Jalisco, Mexico;
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico; (L.L.-M.); (S.R.); (A.P.)
| | - Claudia Ojeda-Granados
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, 95123 Catania, Italy;
| | - Leonardo Leal-Mercado
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico; (L.L.-M.); (S.R.); (A.P.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico; (L.L.-M.); (S.R.); (A.P.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Panduro
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico; (L.L.-M.); (S.R.); (A.P.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
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3
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Aoki-Utsubo C, Kameoka M, Deng L, Hanafi M, Dewi BE, Sudarmono P, Wakita T, Hotta H. Statins enhance extracellular release of hepatitis C virus particles through ERK5 activation. Microbiol Immunol 2024; 68:359-370. [PMID: 39073705 DOI: 10.1111/1348-0421.13166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/13/2024] [Accepted: 07/09/2024] [Indexed: 07/30/2024]
Abstract
Statins, such as lovastatin, have been known to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins were reported to moderately suppress hepatitis C virus (HCV) replication in cultured cells harboring HCV RNA replicons. We report here using an HCV cell culture (HCVcc) system that high concentrations of lovastatin (5-20 μg/mL) markedly enhanced the release of HCV infectious particles (virion) in the culture supernatants by up to 40 times, without enhancing HCV RNA replication, HCV protein synthesis, or HCV virion assembly in the cells. We also found that lovastatin increased the phosphorylation (activation) level of extracellular-signal-regulated kinase 5 (ERK5) in both the infected and uninfected cells in a dose-dependent manner. The lovastatin-mediated increase of HCV virion release was partially reversed by selective ERK5 inhibitors, BIX02189 and XMD8-92, or by ERK5 knockdown using small interfering RNA (siRNA). Moreover, we demonstrated that other cholesterol-lowering statins, but not dehydrolovastatin that is incapable of inhibiting HMG-CoA reductase and activating ERK5, enhanced HCV virion release to the same extent as observed with lovastatin. These results collectively suggest that statins markedly enhance HCV virion release from infected cells through HMG-CoA reductase inhibition and ERK5 activation.
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Affiliation(s)
- Chie Aoki-Utsubo
- Department of Public Health, Graduate School of Health Sciences, Kobe University, Kobe, Japan
| | - Masanori Kameoka
- Department of Public Health, Graduate School of Health Sciences, Kobe University, Kobe, Japan
| | - Lin Deng
- Division of Infectious Disease Control, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Muhammad Hanafi
- Research Center for Chemistry, National Research and Innovation Agency (BRIN), Serpong, Indonesia
| | - Beti Ernawati Dewi
- Department of Microbiology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Pratiwi Sudarmono
- Department of Microbiology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Takaji Wakita
- National Institute of Infectious Diseases, Tokyo, Japan
| | - Hak Hotta
- Department of Public Health, Graduate School of Health Sciences, Kobe University, Kobe, Japan
- Faculty of Clinical Nutrition and Dietetics, Konan Women's University, Kobe, Japan
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4
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Schöbel A, Pinho Dos Reis V, Burkhard R, Hehner J, Schneider L, Schauflinger M, Vieyres G, Herker E. Inhibition of sterol O-acyltransferase 1 blocks Zika virus infection in cell lines and cerebral organoids. Commun Biol 2024; 7:1089. [PMID: 39237833 PMCID: PMC11377701 DOI: 10.1038/s42003-024-06776-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 08/23/2024] [Indexed: 09/07/2024] Open
Abstract
Viruses depend on host metabolic pathways and flaviviruses are specifically linked to lipid metabolism. During dengue virus infection lipid droplets are degraded to fuel replication and Zika virus (ZIKV) infection depends on triglyceride biosynthesis. Here, we systematically investigated the neutral lipid-synthesizing enzymes diacylglycerol O-acyltransferases (DGAT) and the sterol O-acyltransferase (SOAT) 1 in orthoflavivirus infection. Downregulation of DGAT1 and SOAT1 compromises ZIKV infection in hepatoma cells but only SOAT1 and not DGAT inhibitor treatment reduces ZIKV infection. DGAT1 interacts with the ZIKV capsid protein, indicating that protein interaction might be required for ZIKV replication. Importantly, inhibition of SOAT1 severely impairs ZIKV infection in neural cell culture models and cerebral organoids. SOAT1 inhibitor treatment decreases extracellular viral RNA and E protein level and lowers the specific infectivity of virions, indicating that ZIKV morphogenesis is compromised, likely due to accumulation of free cholesterol. Our findings provide insights into the importance of cholesterol and cholesterol ester balance for efficient ZIKV replication and implicate SOAT1 as an antiviral target.
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Affiliation(s)
- Anja Schöbel
- Institute of Virology, Philipps-University Marburg, Marburg, Germany
| | | | - Rabea Burkhard
- Institute of Virology, Philipps-University Marburg, Marburg, Germany
| | - Julia Hehner
- Institute of Virology, Philipps-University Marburg, Marburg, Germany
| | - Laura Schneider
- Institute of Virology, Philipps-University Marburg, Marburg, Germany
| | | | - Gabrielle Vieyres
- Institute of Virology and Cell Biology, University of Lübeck, Lübeck, Germany
| | - Eva Herker
- Institute of Virology, Philipps-University Marburg, Marburg, Germany.
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Stancheva VG, Sanyal S. Positive-strand RNA virus replication organelles at a glance. J Cell Sci 2024; 137:jcs262164. [PMID: 39254430 PMCID: PMC11423815 DOI: 10.1242/jcs.262164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/11/2024] Open
Abstract
Membrane-bound replication organelles (ROs) are a unifying feature among diverse positive-strand RNA viruses. These compartments, formed as alterations of various host organelles, provide a protective niche for viral genome replication. Some ROs are characterised by a membrane-spanning pore formed by viral proteins. The RO membrane separates the interior from immune sensors in the cytoplasm. Recent advances in imaging techniques have revealed striking diversity in RO morphology and origin across virus families. Nevertheless, ROs share core features such as interactions with host proteins for their biogenesis and for lipid and energy transfer. The restructuring of host membranes for RO biogenesis and maintenance requires coordinated action of viral and host factors, including membrane-bending proteins, lipid-modifying enzymes and tethers for interorganellar contacts. In this Cell Science at a Glance article and the accompanying poster, we highlight ROs as a universal feature of positive-strand RNA viruses reliant on virus-host interplay, and we discuss ROs in the context of extensive research focusing on their potential as promising targets for antiviral therapies and their role as models for understanding fundamental principles of cell biology.
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Affiliation(s)
- Viktoriya G. Stancheva
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Sumana Sanyal
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
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6
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Pham N, Benhammou JN. Statins in Chronic Liver Disease: Review of the Literature and Future Role. Semin Liver Dis 2024; 44:191-208. [PMID: 38701856 DOI: 10.1055/a-2319-0694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Chronic liver disease (CLD) is a major contributor to global mortality, morbidity, and healthcare burden. Progress in pharmacotherapeutic for CLD management is lagging given its impact on the global population. While statins are indicated for the management of dyslipidemia and cardiovascular disease, their role in CLD prevention and treatment is emerging. Beyond their lipid-lowering effects, their liver-related mechanisms of action are multifactorial and include anti-inflammatory, antiproliferative, and immune-protective effects. In this review, we highlight what is known about the clinical benefits of statins in viral and nonviral etiologies of CLD and hepatocellular carcinoma (HCC), and explore key mechanisms and pathways targeted by statins. While their benefits may span the spectrum of CLD and potentially HCC treatment, their role in CLD chemoprevention is likely to have the largest impact. As emerging data suggest that genetic variants may impact their benefits, the role of statins in precision hepatology will need to be further explored.
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Affiliation(s)
- Nguyen Pham
- Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Jihane N Benhammou
- Department of Medicine, University of California, Los Angeles, Los Angeles, California
- Veterans Affairs Greater Los Angeles, Los Angeles, California
- Comprehensive Liver Research Center at University of California, Los Angeles, Los Angeles, California
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7
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Wang Y, Gao L. Cholesterol: A friend to viruses. Int Rev Immunol 2024; 43:248-262. [PMID: 38372266 DOI: 10.1080/08830185.2024.2314577] [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] [Received: 09/17/2023] [Accepted: 01/28/2024] [Indexed: 02/20/2024]
Abstract
Cholesterol is a key life-sustaining molecule which regulates membrane fluidity and serves as a signaling mediator. Cholesterol homeostasis is closely related to various pathological conditions including tumor, obesity, atherosclerosis, Alzheimer's disease and viral infection. Viral infection disrupts host cholesterol homeostasis, facilitating their own survival. Meanwhile, the host cells strive to reduce cholesterol accessibility to limit viral infection. This review focuses on the regulation of cholesterol metabolism and the role of cholesterol in viral infection, specifically providing an overview of cholesterol as a friend to promote viral entry, replication, assembly, release and immune evasion, which might inspire valuable thinking for pathogenesis and intervention of viral infection.
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Affiliation(s)
- Yingchun Wang
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity, and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity, and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
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8
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Fernandez CJ, Alkhalifah M, Afsar H, Pappachan JM. Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Viral Hepatitis: The Interlink. Pathogens 2024; 13:68. [PMID: 38251375 PMCID: PMC10821334 DOI: 10.3390/pathogens13010068] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/23/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one-third of the global population and has become the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) remain significant challenges to liver health even in the 21st century. The co-existence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. A thorough understanding of the pathobiological interactions between MAFLD and these two chronic viral infections is crucial for appropriately managing these patients. In this comprehensive clinical review, we discuss the various mechanisms of chronic viral hepatitis-mediated metabolic dysfunction and the impact of MAFLD on the progression of liver disease.
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Affiliation(s)
- Cornelius J. Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, UK;
| | - Mohammed Alkhalifah
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Department of Family Medicine and Polyclinics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia
- University Diabetes Center, King Saud University Medical City, King Saud University, Riyadh 11411, Saudi Arabia
| | - Hafsa Afsar
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
| | - Joseph M. Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, UK
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, UK
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Gong Z, Yan Z, Liu W, Luo B. Oncogenic viruses and host lipid metabolism: a new perspective. J Gen Virol 2023; 104. [PMID: 37279154 DOI: 10.1099/jgv.0.001861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023] Open
Abstract
As noncellular organisms, viruses do not have their own metabolism and rely on the metabolism of host cells to provide energy and metabolic substances for their life cycles. Increasing evidence suggests that host cells infected with oncogenic viruses have dramatically altered metabolic requirements and that oncogenic viruses produce substances used for viral replication and virion production by altering host cell metabolism. We focused on the processes by which oncogenic viruses manipulate host lipid metabolism and the lipid metabolism disorders that occur in oncogenic virus-associated diseases. A deeper understanding of viral infections that cause changes in host lipid metabolism could help with the development of new antiviral agents as well as potential new therapeutic targets.
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Affiliation(s)
- Zhiyuan Gong
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Zhiyong Yan
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Wen Liu
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
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10
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Lu MC, Chen CC, Lu MY, Lin KJ, Chiu CC, Yang TY, Fang YA, Jian W, Chen MY, Hsu MH, Lai YH, Yang TL, Hao WR, Liu JC. The Association between Statins and Liver Cancer Risk in Patients with Heart Failure: A Nationwide Population-Based Cohort Study. Cancers (Basel) 2023; 15:cancers15112959. [PMID: 37296921 DOI: 10.3390/cancers15112959] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/25/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Heart failure (HF) and cancer have similar risk factors. HMG-CoA reductase inhibitors, also known as statins, are chemoprotective agents against carcinogenesis. We aimed to evaluate the chemoprotective effects of statins against liver cancer in patients with HF. This cohort study enrolled patients with HF aged ≥20 years between 1 January 2001 and 31 December 2012 from the National Health Insurance Research Database in Taiwan. Each patient was followed to assess liver cancer risk. A total of 25,853 patients with HF were followed for a 12-year period; 7364 patients used statins and 18,489 did not. The liver cancer risk decreased in statin users versus non-users (adjusted hazard ratio (aHR) = 0.26, 95% confidence interval (CI): 0.20-0.33) in the entire cohort in the multivariate regression analysis. In addition, both lipophilic and hydrophilic statins reduced the liver cancer risk in patients with HF (aHR 0.34, 95% CI: 0.26-0.44 and aHR 0.42, 95% CI: 0.28-0.54, respectively). In the sensitivity analysis, statin users in all dose-stratified subgroups had a reduced liver cancer risk regardless of age, sex, comorbidity, or other concomitant drug use. In conclusion, statins may decrease liver cancer risk in patients with HF.
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Affiliation(s)
- Meng-Chuan Lu
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Chun-Chao Chen
- Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Meng-Ying Lu
- Division of Cardiology, Department of Internal Medicine, Taitung MacKay Memorial Hospital, Taitung 95054, Taiwan
| | - Kuan-Jie Lin
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiovascular Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
| | - Chun-Chih Chiu
- Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - Tsung-Yeh Yang
- Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Ann Fang
- Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - William Jian
- Department of Emergency, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Ming-Yao Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Min-Huei Hsu
- Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei 11031, Taiwan
- Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
| | - Yu-Hsin Lai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Tsung-Lin Yang
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology, Department of Internal Medicine and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan
| | - Wen-Rui Hao
- Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Ju-Chi Liu
- Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
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11
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Abomughaid M, Tay ESE, Pickford R, Malladi C, Read SA, Coorssen JR, Gloss BS, George J, Douglas MW. PEMT Mediates Hepatitis C Virus-Induced Steatosis, Explains Genotype-Specific Phenotypes and Supports Virus Replication. Int J Mol Sci 2023; 24:ijms24108781. [PMID: 37240132 DOI: 10.3390/ijms24108781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/05/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
The hepatitis C virus (HCV) relies on cellular lipid pathways for virus replication and also induces liver steatosis, but the mechanisms involved are not clear. We performed a quantitative lipidomics analysis of virus-infected cells by combining high-performance thin-layer chromatography (HPTLC) and mass spectrometry, using an established HCV cell culture model and subcellular fractionation. Neutral lipid and phospholipids were increased in the HCV-infected cells; in the endoplasmic reticulum there was an ~four-fold increase in free cholesterol and an ~three-fold increase in phosphatidyl choline (p < 0.05). The increase in phosphatidyl choline was due to the induction of a non-canonical synthesis pathway involving phosphatidyl ethanolamine transferase (PEMT). An HCV infection induced expression of PEMT while knocking down PEMT with siRNA inhibited virus replication. As well as supporting virus replication, PEMT mediates steatosis. Consistently, HCV induced the expression of the pro-lipogenic genes SREBP 1c and DGAT1 while inhibiting the expression of MTP, promoting lipid accumulation. Knocking down PEMT reversed these changes and reduced the lipid content in virus-infected cells. Interestingly, PEMT expression was over 50% higher in liver biopsies from people infected with the HCV genotype 3 than 1, and three times higher than in people with chronic hepatitis B, suggesting that this may account for genotype-dependent differences in the prevalence of hepatic steatosis. PEMT is a key enzyme for promoting the accumulation of lipids in HCV-infected cells and supports virus replication. The induction of PEMT may account for virus genotype specific differences in hepatic steatosis.
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Affiliation(s)
- Mosleh Abomughaid
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW 2145, Australia
| | - Enoch S E Tay
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW 2145, Australia
| | - Russell Pickford
- Bioanalytical Mass Spectrometry Facility, Mark Wainright Analytical Centre, University of New South Wales, Sydney, NSW 2052, Australia
| | - Chandra Malladi
- Department of Molecular Physiology, School of Medicine, Western Sydney University, Sydney, NSW 2751, Australia
| | - Scott A Read
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW 2145, Australia
- Blacktown Clinical School, Western Sydney University and Blacktown Hospital, Sydney, NSW 2751, Australia
| | - Jens R Coorssen
- Department of Molecular Physiology, School of Medicine, Western Sydney University, Sydney, NSW 2751, Australia
- Department of Biological Sciences, Faculty of Mathematics and Science, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Brian S Gloss
- Westmead Research Hub, Westmead Institute for Medical Research, Sydney, NSW 2145, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW 2145, Australia
| | - Mark W Douglas
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW 2145, Australia
- Centre for Infectious Diseases and Microbiology, Sydney Infectious Diseases Institute, The University of Sydney at Westmead Hospital, Sydney, NSW 2145, Australia
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12
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Lin D, Chen Y, Koksal AR, Dash S, Aydin Y. Targeting ER stress/PKA/GSK-3β/β-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients. Cell Commun Signal 2023; 21:102. [PMID: 37158967 PMCID: PMC10165818 DOI: 10.1186/s12964-023-01081-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 02/13/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). The HCC risk, while decreased compared with active HCV infection, persists in HCV-cured patients by direct-acting antiviral agents (DAA). We previously demonstrated that Wnt/β-catenin signaling remained activated after DAA-mediated HCV eradication. Developing therapeutic strategies to both eradicate HCV and reverse Wnt/β-catenin signaling is needed. METHODS Cell-based HCV long term infection was established. Chronically HCV infected cells were treated with DAA, protein kinase A (PKA) inhibitor H89 and endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Western blotting analysis and fluorescence microscopy were performed to determine HCV levels and component levels involved in ER stress/PKA/glycogen synthase kinase-3β (GSK-3β)/β-catenin pathway. Meanwhile, the effects of H89 and TUDCA were determined on HCV infection. RESULTS Both chronic HCV infection and replicon-induced Wnt/β-catenin signaling remained activated after HCV and replicon eradication by DAA. HCV infection activated PKA activity and PKA/GSK-3β-mediated Wnt/β-catenin signaling. Inhibition of PKA with H89 both repressed HCV and replicon replication and reversed PKA/GSK-3β-mediated Wnt/β-catenin signaling in both chronic HCV infection and replicon. Both chronic HCV infection and replicon induced ER stress. Inhibition of ER stress with TUDCA both repressed HCV and replicon replication and reversed ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling. Inhibition of either PKA or ER stress both inhibited extracellular HCV infection. CONCLUSION Targeting ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling with PKA inhibitor could be a novel therapeutic strategy for HCV-infected patients to overcomes the issue of remaining activated Wnt/β-catenin signaling by DAA treatment. Video Abstract.
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Affiliation(s)
- Dong Lin
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
| | - Yijia Chen
- The College of Liberal Arts and Sciences, Arizona State University, Tempe, AZ, 85281, USA
| | - Ali Riza Koksal
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
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13
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Surendran A, Jamalkhah M, Poutou J, Birtch R, Lawson C, Dave J, Crupi MJF, Mayer J, Taylor V, Petryk J, de Souza CT, Moodie N, Billingsley JL, Austin B, Cormack N, Blamey N, Rezaei R, McCloskey CW, Fekete EEF, Birdi HK, Neault S, Jamieson TR, Wylie B, Tucker S, Azad T, Vanderhyden B, Tai LH, Bell JC, Ilkow CS. Fatty acid transport protein inhibition sensitizes breast and ovarian cancers to oncolytic virus therapy via lipid modulation of the tumor microenvironment. Front Immunol 2023; 14:1099459. [PMID: 36969187 PMCID: PMC10036842 DOI: 10.3389/fimmu.2023.1099459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 02/13/2023] [Indexed: 03/12/2023] Open
Abstract
IntroductionAdipocytes in the tumour microenvironment are highly dynamic cells that have an established role in tumour progression, but their impact on anti-cancer therapy resistance is becoming increasingly difficult to overlook.MethodsWe investigated the role of adipose tissue and adipocytes in response to oncolytic virus (OV) therapy in adipose-rich tumours such as breast and ovarian neoplasms.ResultsWe show that secreted products in adipocyte-conditioned medium significantly impairs productive virus infection and OV-driven cell death. This effect was not due to the direct neutralization of virions or inhibition of OV entry into host cells. Instead, further investigation of adipocyte secreted factors demonstrated that adipocyte-mediated OV resistance is primarily a lipid-driven phenomenon. When lipid moieties are depleted from the adipocyte-conditioned medium, cancer cells are re-sensitized to OV-mediated destruction. We further demonstrated that blocking fatty acid uptake by cancer cells, in a combinatorial strategy with virotherapy, has clinical translational potential to overcome adipocyte-mediated OV resistance.DiscussionOur findings indicate that while adipocyte secreted factors can impede OV infection, the impairment of OV treatment efficacy can be overcome by modulating lipid flux in the tumour milieu.
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Affiliation(s)
- Abera Surendran
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Monire Jamalkhah
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Joanna Poutou
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Rayanna Birtch
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Christine Lawson
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Jaahnavi Dave
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Mathieu J. F. Crupi
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Justin Mayer
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Victoria Taylor
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Julia Petryk
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | | | - Neil Moodie
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | | | - Bradley Austin
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Nicole Cormack
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Natalie Blamey
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Reza Rezaei
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Curtis W. McCloskey
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Emily E. F. Fekete
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Harsimrat K. Birdi
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Serge Neault
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Taylor R. Jamieson
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Brenna Wylie
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Sarah Tucker
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Taha Azad
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Barbara Vanderhyden
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Lee-Hwa Tai
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - John C. Bell
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Carolina S. Ilkow
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- *Correspondence: Carolina S. Ilkow,
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14
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Plasma-Like Culture Medium for the Study of Viruses. mBio 2023; 14:e0203522. [PMID: 36515528 PMCID: PMC9973327 DOI: 10.1128/mbio.02035-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Viral infections attract more and more attention, especially after the emergence of novel zoonotic coronaviruses and the monkeypox virus over the last 2 decades. Research on viruses is based to a great extent on mammalian cell lines that are permissive to the respective viruses. These cell lines are usually cultivated according to the protocols established in the 1950s to 1970s, although it is clear that classical media have a significant imprint on cell growth, phenotype, and especially metabolism. So, recently in the field of biochemistry and metabolomics novel culture media have been developed that resemble human blood plasma. As perturbations in metabolic and redox pathways during infection are considered significant factors of viral pathogenesis, these novel medium formulations should be adapted by the virology field. So far, there are only scarce data available on viral propagation efficiencies in cells cultivated in plasma-like media. But several groups have presented convincing data on the use of such media for cultivation of uninfected cells. The aim of the present review is to summarize the current state of research in the field of plasma-resembling culture media and to point out the influence of media on various cellular processes in uninfected cells that may play important roles in viral replication and pathogenesis in order to sensitize virology research to the use of such media.
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15
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Islam KU, Anwar S, Patel AA, Mirdad MT, Mirdad MT, Azmi MI, Ahmad T, Fatima Z, Iqbal J. Global Lipidome Profiling Revealed Multifaceted Role of Lipid Species in Hepatitis C Virus Replication, Assembly, and Host Antiviral Response. Viruses 2023; 15:v15020464. [PMID: 36851679 PMCID: PMC9965260 DOI: 10.3390/v15020464] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/29/2023] [Accepted: 02/01/2023] [Indexed: 02/11/2023] Open
Abstract
Hepatitis C virus (HCV) is a major human pathogen that requires a better understanding of its interaction with host cells. There is a close association of HCV life cycle with host lipid metabolism. Lipid droplets (LDs) have been found to be crucial organelles that support HCV replication and virion assembly. In addition to their role in replication, LDs also have protein-mediated antiviral properties that are activated during HCV infection. Studies have shown that HCV replicates well in cholesterol and sphingolipid-rich membranes, but the ways in which HCV alters host cell lipid dynamics are not yet known. In this study, we performed a kinetic study to check the enrichment of LDs at different time points of HCV infection. Based on the LD enrichment results, we selected early and later time points of HCV infection for global lipidomic study. Early infection represents the window period for HCV sensing and host immune response while later infection represents the establishment of viral RNA replication, virion assembly, and egress. We identified the dynamic profile of lipid species at early and later time points of HCV infection by global lipidomic study using mass spectrometry. At early HCV infection, phosphatidylinositol phospholipids (PIPs), lysophosphatidic acid (LPA), triacyl glycerols (TAG), phosphatidylcholine (PC), and trihexosylceramides (Hex3Cer) were observed to be enriched. Similarly, free fatty acids (FFA), phosphatidylethanolamine (PE), N-acylphosphatidylethanolamines (NAPE), and tri acylglycerols were enriched at later time points of HCV infection. Lipids enriched at early time of infection may have role in HCV sensing, viral attachment, and immune response as LPA and PIPs are important for immune response and viral attachment, respectively. Moreover, lipid species observed at later infection may contribute to HCV replication and virion assembly as PE, FFA, and triacylglycerols are known for the similar function. In conclusion, we identified lipid species that exhibited dynamic profile across early and later time points of HCV infection compared to mock cells, which could be therapeutically relevant in the design of more specific and effective anti-viral therapies.
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Affiliation(s)
- Khursheed Ul Islam
- Multidisciplinary Center for Advanced Research and Studies, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Saleem Anwar
- Multidisciplinary Center for Advanced Research and Studies, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Ayyub A. Patel
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
| | | | | | - Md Iqbal Azmi
- Multidisciplinary Center for Advanced Research and Studies, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Tanveer Ahmad
- Multidisciplinary Center for Advanced Research and Studies, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Zeeshan Fatima
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia
- Amity Institute of Biotechnology, Amity University Haryana, Manesar, Gurugram 122413, India
- Correspondence: (Z.F.); (J.I.)
| | - Jawed Iqbal
- Multidisciplinary Center for Advanced Research and Studies, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
- Correspondence: (Z.F.); (J.I.)
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16
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Evers P, Pezacki JP. Unraveling Complex MicroRNA Signaling Pathways with Activity‐Based Protein Profiling to Guide Therapeutic Discovery**. Isr J Chem 2023. [DOI: 10.1002/ijch.202200088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Parrish Evers
- Department of Chemistry and Biomolecular Sciences University of Ottawa 150 Louis-Pasteur Pvt. K1N 6N5 Ottawa Canada
| | - John Paul Pezacki
- Department of Chemistry and Biomolecular Sciences University of Ottawa 150 Louis-Pasteur Pvt. K1N 6N5 Ottawa Canada
- Department of Biochemistry Microbiology, and Immunology University of Ottawa 451 Smyth Rd. K1H 8M5 Ottawa Canada
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Hepatitis C Virus-Lipid Interplay: Pathogenesis and Clinical Impact. Biomedicines 2023; 11:biomedicines11020271. [PMID: 36830808 PMCID: PMC9953247 DOI: 10.3390/biomedicines11020271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Hepatitis C virus (HCV) infection represents the major cause of chronic liver disease, leading to a wide range of hepatic diseases, including cirrhosis and hepatocellular carcinoma. It is the leading indication for liver transplantation worldwide. In addition, there is a growing body of evidence concerning the role of HCV in extrahepatic manifestations, including immune-related disorders and metabolic abnormalities, such as insulin resistance and steatosis. HCV depends on its host cells to propagate successfully, and every aspect of the HCV life cycle is closely related to human lipid metabolism. The virus circulates as a lipid-rich particle, entering the hepatocyte via lipoprotein cell receptors. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation (steatosis) and circulating hypocholesterolemia. Patients with chronic HCV are at increased risk for hepatic steatosis, dyslipidemia, and cardiovascular disease, including accelerated atherosclerosis. This review aims to describe different aspects of the HCV viral life cycle as it impacts host lipoproteins and lipid metabolism. It then discusses the mechanisms of HCV-related hepatic steatosis, hypocholesterolemia, and accelerated atherosclerosis.
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18
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Impact of eradication of hepatitis C virus on liver-related and -unrelated diseases: morbidity and mortality of chronic hepatitis C after SVR. J Gastroenterol 2022; 58:299-310. [PMID: 36585501 DOI: 10.1007/s00535-022-01940-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/05/2022] [Indexed: 12/31/2022]
Abstract
Hepatitis C virus infection is characterized by chronic liver inflammation and fibrogenesis, leading to end-stage liver failure and hepatocellular carcinoma over the course of 20 to 30 years. It seems not only the chronicity of hepatitis C but also the presence of the virus in non-hepatic tissues creates a favorable environment for the potential development of pathogenic impacts on extrahepatic systems and organs. Numerous extra-hepatic manifestations have been reported in association with HCV infection, all of which can substantially affect morbidity, mortality, and quality of life. With the recent development of DAAs, antiviral treatment can cure almost all patients with HCV infection, even those intolerant of or unresponsive to IFN treatment, and several large multicenter studies have confirmed the association of DAA-induced SVR with reductions in liver-related and liver-unrelated complications, such as cardiovascular events, end stage renal disease, and so on. Because, in addition to liver-related diseases, extrahepatic lesions are threatening for patients, it is important to eradicate the virus before these progress and affect life prognosis; in other words, patients should be treated before reaching the point of no return. Tailored surveillance with biomarkers such as M2BPGi and Ang-2, which can be used to identify patients with an elevated risk of EHM, and early prevention or treatment for these patients could improve the morbidity, mortality and QOL. Advancement of both basic and clinical research in this field including the development of more precise biomarkers is highly anticipated.
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Zou X, Yang Y, Lin F, Chen J, Zhang H, Li L, Ouyang H, Pang D, Ren L, Tang X. Lactate facilitates classical swine fever virus replication by enhancing cholesterol biosynthesis. iScience 2022; 25:105353. [PMID: 36339254 PMCID: PMC9626675 DOI: 10.1016/j.isci.2022.105353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 09/14/2022] [Accepted: 10/11/2022] [Indexed: 11/29/2022] Open
Abstract
An emerging topic in virology is that viral replication is closely linked with the metabolic reprogramming of host cells. Understanding the effects of reprogramming host cell metabolism due to classical swine fever virus (CSFV) infection and the underling mechanisms would facilitate controlling the spread of classical swine fever (CSF). In the current study, we found that CSFV infection enhanced aerobic glycolysis in PK-15 cells. Blocking glycolysis with 2-deoxy-d-glycose or disrupting the enzymes PFKL and LDHA decreased CSFV replication. Lactate was identified as an important molecule in CSFV replication, independent of the pentose phosphate pathway and tricarboxylic acid cycle. Further analysis demonstrated that the accumulated lactate in cells promoted cholesterol biosynthesis, which facilitated CSFV replication and disrupted the type I interferon response during CSFV replication, and the disruption of cholesterol synthesis abolished the lactate effects on CSFV replication. The results provided more insights into the complex pathological mechanisms of CSFV.
Aerobic glycolysis plays an important role in CSFV replication Intracellular lactate maintains CSFV replication as an effector of glycolysis Lactate promotes cholesterol biosynthesis to maintain CSFV replication Enhanced cholesterol biosynthesis inhibited the response of IFNs during CSFV replication
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Affiliation(s)
- Xiaodong Zou
- College of Animal Sciences, Jilin University, Changchun, China
| | - Yang Yang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Feng Lin
- College of Animal Sciences, Jilin University, Changchun, China
| | - Jiahuan Chen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Huanyu Zhang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Linquan Li
- College of Animal Sciences, Jilin University, Changchun, China
| | - Hongsheng Ouyang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
| | - Daxin Pang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
| | - Linzhu Ren
- College of Animal Sciences, Jilin University, Changchun, China
- Corresponding author
| | - Xiaochun Tang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
- Corresponding author
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20
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Kim M, Kim M, Salloum S, Qian T, Wong LP, Xu M, Lee Y, Shroff SG, Sadreyev RI, Corey KE, Baumert TF, Hoshida Y, Chung RT. Atorvastatin favorably modulates a clinical hepatocellular carcinoma risk gene signature. Hepatol Commun 2022; 6:2581-2593. [PMID: 35712812 PMCID: PMC9426409 DOI: 10.1002/hep4.1991] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 04/11/2022] [Accepted: 04/15/2022] [Indexed: 11/22/2022] Open
Abstract
Lipophilic but not hydrophilic statins have been shown to be associated with reduced risk for hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis. We investigated differential actions of lipophilic and hydrophilic statins and their ability to modulate a clinical prognostic liver signature (PLS) predicting HCC risk in patients with liver disease. Hepatitis C virus (HCV)-infected Huh7.5.1 cells, recently developed as a model to screen HCC chemopreventive agents, were treated with lipophilic statins (atorvastatin and simvastatin) and hydrophilic statins (rosuvastatin and pravastatin), and then analyzed by RNA sequencing and PLS. Lipophilic statins, particularly atorvastatin, more significantly suppressed the HCV-induced high-risk pattern of PLS and genes in YAP and AKT pathway implicated in fibrogenesis and carcinogenesis, compared with the hydrophilic statins. While atorvastatin inhibited YAP activation through the mevalonate pathway, the distinctive AKT inhibition of atorvastatin was mediated by stabilizing truncated retinoid X receptor alpha, which has been known to enhance AKT activation, representing a target for HCC chemoprevention. In addition, atorvastatin modulated the high-risk PLS in an in vitro model of nonalcoholic fatty liver disease (NAFLD). Conclusion: Atorvastatin distinctively inhibits YAP and AKT activation, which are biologically implicated in HCC development, and attenuates a high-risk PLS in an in vitro model of HCV infection and NAFLD. These findings suggest that atorvastatin is the most potent statin to reduce HCC risk in patients with viral and metabolic liver diseases.
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Affiliation(s)
- Myung‐Ho Kim
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
| | - Mi‐Young Kim
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
- Department of GastroenterologyCHA Bundang Medical CenterCHA University School of MedicineSeongnamSouth Korea
- Department of Gastroenterology, Chaum Life CenterCHA University School of MedicineSeoulSouth Korea
| | - Shadi Salloum
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
| | - Tongqi Qian
- Liver Tumor Translational Research ProgramSimmons Comprehensive Cancer CenterDivision of Digestive and Liver DiseasesDepartment of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Lai Ping Wong
- Department of Molecular BiologyMassachusetts General HospitalBostonMassachusettsUSA
- Department of GeneticsHarvard Medical SchoolBostonMassachusettsUSA
| | - Min Xu
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
| | - Yoojin Lee
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
| | - Stuti G. Shroff
- Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Ruslan I. Sadreyev
- Department of Molecular BiologyMassachusetts General HospitalBostonMassachusettsUSA
- Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Kathleen E. Corey
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
| | - Thomas F. Baumert
- Institut National de la Santé et de la Recherche MédicaleU1110Institut de Recherche sur les Maladies Virales et HépatiquesStrasbourgFrance
- Pole Hepato‐digestif, IHUStrasbourg University HospitalsStrasbourgFrance
| | - Yujin Hoshida
- Liver Tumor Translational Research ProgramSimmons Comprehensive Cancer CenterDivision of Digestive and Liver DiseasesDepartment of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Raymond T. Chung
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
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21
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Zou X, Lin F, Yang Y, Chen J, Zhang H, Li L, Ouyang H, Pang D, Tang X. Cholesterol Biosynthesis Modulates CSFV Replication. Viruses 2022; 14:v14071450. [PMID: 35891429 PMCID: PMC9316236 DOI: 10.3390/v14071450] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 12/13/2022] Open
Abstract
Classical swine fever (CSF) caused by the classical swine fever virus (CSFV) has resulted in severe losses to the pig industry worldwide. It has been proposed that lipid synthesis is essential for viral replication, and lipids are involved in viral protein maturation and envelope production. However, the specific crosstalk between CSFV and host cell lipid metabolism is still unknown. In this study, we found that CSFV infection increased intracellular cholesterol levels in PK-15 cells. Further analysis demonstrated that CSFV infection upregulated PCSK9 expression to block the uptake of exogenous cholesterol by LDLR and enhanced the cholesterol biosynthesis pathway, which disrupted the type I IFN response in PK-15 cells. Our findings provide new insight into the mechanisms underpinning the pathogenesis of CSFV and hint at methods for controlling the disease.
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Affiliation(s)
- Xiaodong Zou
- College of Animal Sciences, Jilin University, Changchun 130062, China; (X.Z.); (F.L.); (Y.Y.); (J.C.); (H.Z.); (L.L.); (H.O.); (D.P.)
| | - Feng Lin
- College of Animal Sciences, Jilin University, Changchun 130062, China; (X.Z.); (F.L.); (Y.Y.); (J.C.); (H.Z.); (L.L.); (H.O.); (D.P.)
| | - Yang Yang
- College of Animal Sciences, Jilin University, Changchun 130062, China; (X.Z.); (F.L.); (Y.Y.); (J.C.); (H.Z.); (L.L.); (H.O.); (D.P.)
| | - Jiahuan Chen
- College of Animal Sciences, Jilin University, Changchun 130062, China; (X.Z.); (F.L.); (Y.Y.); (J.C.); (H.Z.); (L.L.); (H.O.); (D.P.)
| | - Huanyu Zhang
- College of Animal Sciences, Jilin University, Changchun 130062, China; (X.Z.); (F.L.); (Y.Y.); (J.C.); (H.Z.); (L.L.); (H.O.); (D.P.)
| | - Linquan Li
- College of Animal Sciences, Jilin University, Changchun 130062, China; (X.Z.); (F.L.); (Y.Y.); (J.C.); (H.Z.); (L.L.); (H.O.); (D.P.)
| | - Hongsheng Ouyang
- College of Animal Sciences, Jilin University, Changchun 130062, China; (X.Z.); (F.L.); (Y.Y.); (J.C.); (H.Z.); (L.L.); (H.O.); (D.P.)
- Chongqing Research Institute, Jilin University, Chongqing 401120, China
| | - Daxin Pang
- College of Animal Sciences, Jilin University, Changchun 130062, China; (X.Z.); (F.L.); (Y.Y.); (J.C.); (H.Z.); (L.L.); (H.O.); (D.P.)
- Chongqing Research Institute, Jilin University, Chongqing 401120, China
| | - Xiaochun Tang
- College of Animal Sciences, Jilin University, Changchun 130062, China; (X.Z.); (F.L.); (Y.Y.); (J.C.); (H.Z.); (L.L.); (H.O.); (D.P.)
- Chongqing Research Institute, Jilin University, Chongqing 401120, China
- Correspondence:
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22
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Chen D, Zhao YG, Zhang H. Endomembrane remodeling in SARS-CoV-2 infection. CELL INSIGHT 2022; 1:100031. [PMID: 37193051 PMCID: PMC9112566 DOI: 10.1016/j.cellin.2022.100031] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/09/2022] [Accepted: 05/09/2022] [Indexed: 12/18/2022]
Abstract
During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the viral proteins intimately interact with host factors to remodel the endomembrane system at various steps of the viral lifecycle. The entry of SARS-CoV-2 can be mediated by endocytosis-mediated internalization. Virus-containing endosomes then fuse with lysosomes, in which the viral S protein is cleaved to trigger membrane fusion. Double-membrane vesicles generated from the ER serve as platforms for viral replication and transcription. Virions are assembled at the ER-Golgi intermediate compartment and released through the secretory pathway and/or lysosome-mediated exocytosis. In this review, we will focus on how SARS-CoV-2 viral proteins collaborate with host factors to remodel the endomembrane system for viral entry, replication, assembly and egress. We will also describe how viral proteins hijack the host cell surveillance system-the autophagic degradation pathway-to evade destruction and benefit virus production. Finally, potential antiviral therapies targeting the host cell endomembrane system will be discussed.
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Affiliation(s)
- Di Chen
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yan G. Zhao
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Hong Zhang
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
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23
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Liou JW, Mani H, Yen JH. Viral Hepatitis, Cholesterol Metabolism, and Cholesterol-Lowering Natural Compounds. Int J Mol Sci 2022; 23:ijms23073897. [PMID: 35409259 PMCID: PMC8999150 DOI: 10.3390/ijms23073897] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/27/2022] [Accepted: 03/30/2022] [Indexed: 11/24/2022] Open
Abstract
Hepatitis is defined as inflammation of the liver; it can be acute or chronic. In chronic cases, the prolonged inflammation gradually damages the liver, resulting in liver fibrosis, cirrhosis, and sometimes liver failure or cancer. Hepatitis is often caused by viral infections. The most common causes of viral hepatitis are the five hepatitis viruses—hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). While HAV and HEV rarely (or do not) cause chronic hepatitis, a considerable proportion of acute hepatitis cases caused by HBV (sometimes co-infected with HDV) and HCV infections become chronic. Thus, many medical researchers have focused on the treatment of HBV and HCV. It has been documented that host lipid metabolism, particularly cholesterol metabolism, is required for the hepatitis viral infection and life cycle. Thus, manipulating host cholesterol metabolism-related genes and proteins is a strategy used in fighting the viral infections. Efforts have been made to evaluate the efficacy of cholesterol-lowering drugs, particularly 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in the treatment of hepatitis viral infections; promising results have been obtained. This review provides information on the relationships between hepatitis viruses and host cholesterol metabolism/homeostasis, as well as the discovery/development of cholesterol-lowering natural phytochemicals that could potentially be applied in the treatment of viral hepatitis.
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Affiliation(s)
- Je-Wen Liou
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
| | - Hemalatha Mani
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
| | - Jui-Hung Yen
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan
- Correspondence: or ; Tel.: +886-3-856-5301 (ext. 2683)
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24
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Marascio N, Rotundo S, Quirino A, Matera G, Liberto MC, Costa C, Russo A, Trecarichi EM, Torti C. Similarities, differences, and possible interactions between hepatitis E and hepatitis C viruses: Relevance for research and clinical practice. World J Gastroenterol 2022; 28:1226-1238. [PMID: 35431515 PMCID: PMC8968488 DOI: 10.3748/wjg.v28.i12.1226] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/06/2022] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV) and hepatitis C virus (HCV) are both RNA viruses with a tropism for liver parenchyma but are also capable of extrahepatic manifestations. Hepatitis E is usually a viral acute fecal-oral transmitted and self-limiting disease presenting with malaise, jaundice, nausea and vomiting. Rarely, HEV causes a chronic infection in immunocompromised persons and severe fulminant hepatitis in pregnant women. Parenteral HCV infection is typically asymptomatic for decades until chronic complications, such as cirrhosis and cancer, occur. Despite being two very different viruses in terms of phylogenetic and clinical presentations, HEV and HCV show many similarities regarding possible transmission through organ transplantation and blood transfusion, pathogenesis (production of antinuclear antibodies and cryoglobulins) and response to treatment with some direct-acting antiviral drugs. Although both HEV and HCV are well studied individually, there is a lack of knowledge about coinfection and its consequences. The aim of this review is to analyze current literature by evaluating original articles and case reports and to hypothesize some interactions that can be useful for research and clinical practice.
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Affiliation(s)
- Nadia Marascio
- Department of Health Sciences, Unit of Microbiology, University “Magna Graecia” of Catanzaro, Catanzaro 88100, Italy
| | - Salvatore Rotundo
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, "Magna Graecia" University of Catanzaro, Catanzaro 88100, Italy
| | - Angela Quirino
- Department of Health Sciences, Unit of Microbiology, University “Magna Graecia” of Catanzaro, Catanzaro 88100, Italy
| | - Giovanni Matera
- Department of Health Sciences, Unit of Microbiology, University “Magna Graecia” of Catanzaro, Catanzaro 88100, Italy
| | - Maria Carla Liberto
- Department of Health Sciences, Unit of Microbiology, University “Magna Graecia” of Catanzaro, Catanzaro 88100, Italy
| | - Chiara Costa
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, "Magna Graecia" University of Catanzaro, Catanzaro 88100, Italy
| | - Alessandro Russo
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, "Magna Graecia" University of Catanzaro, Catanzaro 88100, Italy
| | - Enrico Maria Trecarichi
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, "Magna Graecia" University of Catanzaro, Catanzaro 88100, Italy
| | - Carlo Torti
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, "Magna Graecia" University of Catanzaro, Catanzaro 88100, Italy
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25
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Proulx J, Ghaly M, Park IW, Borgmann K. HIV-1-Mediated Acceleration of Oncovirus-Related Non-AIDS-Defining Cancers. Biomedicines 2022; 10:biomedicines10040768. [PMID: 35453518 PMCID: PMC9024568 DOI: 10.3390/biomedicines10040768] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/22/2022] [Accepted: 03/22/2022] [Indexed: 11/25/2022] Open
Abstract
With the advent of combination antiretroviral therapy (cART), overall survival has been improved, and the incidence of acquired immunodeficiency syndrome (AIDS)-defining cancers has also been remarkably reduced. However, non-AIDS-defining cancers among human immunodeficiency virus-1 (HIV-1)-associated malignancies have increased significantly so that cancer is the leading cause of death in people living with HIV in certain highly developed countries, such as France. However, it is currently unknown how HIV-1 infection raises oncogenic virus-mediated cancer risks in the HIV-1 and oncogenic virus co-infected patients, and thus elucidation of the molecular mechanisms for how HIV-1 expedites the oncogenic viruses-triggered tumorigenesis in the co-infected hosts is imperative for developing therapeutics to cure or impede the carcinogenesis. Hence, this review is focused on HIV-1 and oncogenic virus co-infection-mediated molecular processes in the acceleration of non-AIDS-defining cancers.
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26
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Allen CNS, Arjona SP, Santerre M, Sawaya BE. Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis. Viruses 2022; 14:602. [PMID: 35337009 PMCID: PMC8955778 DOI: 10.3390/v14030602] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 02/07/2023] Open
Abstract
Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways. Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals.
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Affiliation(s)
- Charles N. S. Allen
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
| | - Sterling P. Arjona
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
| | - Maryline Santerre
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
| | - Bassel E. Sawaya
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
- Departments of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Cancer and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
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27
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Wang X, Xie Q. Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD) and Viral Hepatitis. J Clin Transl Hepatol 2022; 10:128-133. [PMID: 35233381 PMCID: PMC8845159 DOI: 10.14218/jcth.2021.00200] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 08/19/2021] [Accepted: 09/07/2021] [Indexed: 12/04/2022] Open
Abstract
A new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed in 2020. The change from nonalcoholic fatty liver disease (NAFLD) to MAFLD highlights the metabolic abnormalities that accompany fatty liver. The diagnosis of MAFLD does not require exclusion of secondary causes of liver diseases and alcohol consumption. Thus, MAFLD may coexist with other types of liver diseases, such as viral hepatitis, a disease that remains the most common cause of liver disease-related death. With the increasing prevalence of MAFLD, patients with coincidental MAFLD and viral hepatitis are frequently encountered in clinical practice. In this review, we mainly summarize the mutual relationship between hepatitis B/C and systematic metabolism dysfunction related to MAFLD. We discuss the impact of MAFLD on progression of viral hepatitis and the therapies. Some unaddressed clinical problems related to concomitant MAFLD and viral hepatitis are also identified.
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Affiliation(s)
- Xiaolin Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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28
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Gauthier T, Chen W. Modulation of Macrophage Immunometabolism: A New Approach to Fight Infections. Front Immunol 2022; 13:780839. [PMID: 35154105 PMCID: PMC8825490 DOI: 10.3389/fimmu.2022.780839] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 01/07/2022] [Indexed: 12/13/2022] Open
Abstract
Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection.
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Affiliation(s)
- Thierry Gauthier
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Wanjun Chen
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, United States
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29
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Moretti R, Giuffrè M, Merli N, Caruso P, Di Bella S, Tiribelli C, Crocè LS. Hepatitis C Virus-Related Central and Peripheral Nervous System Disorders. Brain Sci 2021; 11:1569. [PMID: 34942871 PMCID: PMC8699483 DOI: 10.3390/brainsci11121569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C Virus (HCV), despite being a hepatotropic virus, is the causative agent of many systemic disorders, such as vasculitis, autoimmune diseases, lymphoproliferative disorders, and a broad spectrum of neurological and psychiatric manifestations. Although symptoms have been misdiagnosed or underdiagnosed, only recently, evidence of direct (inflammatory) or indirect (immune-mediated) HCV-dependent cerebral effects has been established. HCV infection can promote acute inflammatory response, pro-coagulative status and ischemic disorders, and neurodegeneration. These effects rely on cerebral HCV replication, possibly mediated by blood-brain barrier alterations. Further study is needed to better understand the HCV-related mechanisms of brain damage.
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Affiliation(s)
- Rita Moretti
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Mauro Giuffrè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Nicola Merli
- Department Neurological Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Paola Caruso
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Stefano Di Bella
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | | | - Lory Saveria Crocè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
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30
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Huang J, Wang J, He H, Huang Z, Wu S, Chen C, Liu W, Xie L, Tao Y, Cong L, Jiang Y. Close interactions between lncRNAs, lipid metabolism and ferroptosis in cancer. Int J Biol Sci 2021; 17:4493-4513. [PMID: 34803512 PMCID: PMC8579446 DOI: 10.7150/ijbs.66181] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/01/2021] [Indexed: 12/19/2022] Open
Abstract
Abnormal lipid metabolism including synthesis, uptake, modification, degradation and transport has been considered a hallmark of malignant tumors and contributes to the supply of substances and energy for rapid cell growth. Meanwhile, abnormal lipid metabolism is also associated with lipid peroxidation, which plays an important role in a newly discovered type of regulated cell death termed ferroptosis. Long noncoding RNAs (lncRNAs) have been proven to be associated with the occurrence and progression of cancer. Growing evidence indicates that lncRNAs are key regulators of abnormal lipid metabolism and ferroptosis in cancer. In this review, we mainly summarized the mechanism by which lncRNAs regulate aberrant lipid metabolism in cancer, illustrated that lipid metabolism can also influence the expression of lncRNAs, and discussed the mechanism by which lncRNAs affect ferroptosis. A comprehensive understanding of the interactions between lncRNAs, lipid metabolism and ferroptosis could help us to develop novel strategies for precise cancer treatment in the future.
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Affiliation(s)
- Jingjing Huang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Jin Wang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210013 Jiangsu, China
| | - Hua He
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Zichen Huang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210013 Jiangsu, China
| | - Sufang Wu
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Chao Chen
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210013 Jiangsu, China
| | - Wenbing Liu
- Department of Head and Neck Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013 Hunan, P.R. China
| | - Li Xie
- Department of Head and Neck Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013 Hunan, P.R. China
| | - Yongguang Tao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, Changsha, 410078 Hunan, China
| | - Li Cong
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Yiqun Jiang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
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31
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ORP4L is a prerequisite for the induction of T-cell leukemogenesis associated with human T-cell leukemia virus 1. Blood 2021; 139:1052-1065. [PMID: 34797912 PMCID: PMC8854678 DOI: 10.1182/blood.2021013579] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 11/09/2021] [Indexed: 11/20/2022] Open
Abstract
ORP4L deletion blocks Tax-induced T-cell leukemia, whereas engineering ORP4L expression in T cells results in T-cell leukemia in mice. Loss of miR-31 induced by Tax releases ORP4L expression, which initiates T-cell deterioration, but ORP4L inhibition eliminates ATL in PDX mice. Human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL), but the mechanism underlying its initiation remains elusive. In this study, ORP4L was expressed in ATL cells but not in normal T-cells. ORP4L ablation completely blocked T-cell leukemogenesis induced by the HTLV-1 oncoprotein Tax in mice, whereas engineering ORP4L expression in T-cells resulted in T-cell leukemia in mice, suggesting the oncogenic properties and prerequisite of ORP4L promote the initiation of T-cell leukemogenesis. For molecular insight, we found that loss of miR-31 caused by HTLV-1 induced ORP4L expression in T-cells. ORP4L interacts with PI3Kδ to promote PI(3,4,5)P3 generation, contributing to AKT hyperactivation; NF-κB–dependent, p53 inactivation-induced pro-oncogene expression; and T-cell leukemogenesis. Consistently, ORP4L ablation eliminates human ATL cells in patient-derived xenograft ATL models. These results reveal a plausible mechanism of T-cell deterioration by HTLV-1 that can be therapeutically targeted.
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32
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Vitner EB, Avraham R, Politi B, Melamed S, Israely T. Elevation in sphingolipid upon SARS-CoV-2 infection: possible implications for COVID-19 pathology. Life Sci Alliance 2021; 5:5/1/e202101168. [PMID: 34764206 PMCID: PMC8605327 DOI: 10.26508/lsa.202101168] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/25/2021] [Accepted: 10/26/2021] [Indexed: 12/14/2022] Open
Abstract
SARS-CoV-2 infection alters the levels of sphingolipids early post infection. This phenomenon is reflected by increased levels of sphingolipids, including gangliosides, in infected cells, as well as in serum in a SARS-CoV-2 murine model. Understanding pathways that might impact coronavirus disease 2019 (COVID-19) manifestations and disease outcomes is necessary for better disease management and for therapeutic development. Here, we analyzed alterations in sphingolipid (SL) levels upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection induced elevation of SL levels in both cells and sera of infected mice. A significant increase in glycosphingolipid levels was induced early post SARS-CoV-2 infection, which was essential for viral replication. This elevation could be reversed by treatment with glucosylceramide synthase inhibitors. Levels of sphinganine, sphingosine, GA1, and GM3 were significantly increased in both cells and the murine model upon SARS-CoV-2 infection. The potential involvement of SLs in COVID-19 pathology is discussed.
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Affiliation(s)
- Einat B Vitner
- Departments of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona, Israel
| | - Roy Avraham
- Departments of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona, Israel
| | - Boaz Politi
- Departments of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona, Israel
| | - Sharon Melamed
- Departments of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona, Israel
| | - Tomer Israely
- Departments of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona, Israel
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33
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Shi S, Wang L, van der Laan LJW, Pan Q, Verstegen MMA. Mitochondrial Dysfunction and Oxidative Stress in Liver Transplantation and Underlying Diseases: New Insights and Therapeutics. Transplantation 2021; 105:2362-2373. [PMID: 33577251 PMCID: PMC9005104 DOI: 10.1097/tp.0000000000003691] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 01/09/2021] [Accepted: 01/16/2021] [Indexed: 12/06/2022]
Abstract
Mitochondria are essential organelles for cellular energy and metabolism. Like with any organ, the liver highly depends on the function of these cellular powerhouses. Hepatotoxic insults often lead to an impairment of mitochondrial activity and an increase in oxidative stress, thereby compromising the metabolic and synthetic functions. Mitochondria play a critical role in ATP synthesis and the production or scavenging of free radicals. Mitochondria orchestrate many cellular signaling pathways involved in the regulation of cell death, metabolism, cell division, and progenitor cell differentiation. Mitochondrial dysfunction and oxidative stress are closely associated with ischemia-reperfusion injury during organ transplantation and with different liver diseases, including cholestasis, steatosis, viral hepatitis, and drug-induced liver injury. To develop novel mitochondria-targeting therapies or interventions, a better understanding of mitochondrial dysfunction and oxidative stress in hepatic pathogenesis is very much needed. Therapies targeting mitochondria impairment and oxidative imbalance in liver diseases have been extensively studied in preclinical and clinical research. In this review, we provide an overview of how oxidative stress and mitochondrial dysfunction affect liver diseases and liver transplantation. Furthermore, we summarize recent developments of antioxidant and mitochondria-targeted interventions.
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Affiliation(s)
- Shaojun Shi
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Ling Wang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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34
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Girdhar K, Powis A, Raisingani A, Chrudinová M, Huang R, Tran T, Sevgi K, Dogus Dogru Y, Altindis E. Viruses and Metabolism: The Effects of Viral Infections and Viral Insulins on Host Metabolism. Annu Rev Virol 2021; 8:373-391. [PMID: 34586876 PMCID: PMC9175272 DOI: 10.1146/annurev-virology-091919-102416] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Over the past decades, there have been tremendous efforts to understand the cross-talk between viruses and host metabolism. Several studies have elucidated the mechanisms through which viral infections manipulate metabolic pathways including glucose, fatty acid, protein, and nucleotide metabolism. These pathways are evolutionarily conserved across the tree of life and extremely important for the host's nutrient utilization and energy production. In this review, we focus on host glucose, glutamine, and fatty acid metabolism and highlight the pathways manipulated by the different classes of viruses to increase their replication. We also explore a new system of viral hormones in which viruses mimic host hormones to manipulate the host endocrine system. We discuss viral insulin/IGF-1-like peptides and their potential effects on host metabolism. Together, these pathogenesis mechanisms targeting cellular signaling pathways create a multidimensional network of interactions between host and viral proteins. Defining and better understanding these mechanisms will help us to develop new therapeutic tools to prevent and treat viral infections.
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Affiliation(s)
- Khyati Girdhar
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Amaya Powis
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Amol Raisingani
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Martina Chrudinová
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Ruixu Huang
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Tu Tran
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Kaan Sevgi
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Yusuf Dogus Dogru
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
| | - Emrah Altindis
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA;
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Adherence to a Fish-Rich Dietary Pattern Is Associated with Chronic Hepatitis C Patients Showing Low Viral Load: Implications for Nutritional Management. Nutrients 2021; 13:nu13103337. [PMID: 34684338 PMCID: PMC8541240 DOI: 10.3390/nu13103337] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 01/04/2023] Open
Abstract
Hepatitis C virus (HCV) infection is influenced by genetic (e.g., APOE polymorphisms) and environmental factors between the virus and the host. HCV modulates the host’s lipid metabolism but dietary components influence lipids and in vitro HCV RNA replication. Few data exist on the role of dietary features or patterns (DPs) in HCV infection. Herein, we aimed to evaluate the nutritional profiles of chronic HCV (CHC) and spontaneous clearance (SC) Mexican patients in the context of APOE alleles and their correlation with HCV-related variables. The fibrosis-related APOEε3 allele prevailed in CHC and SC patients, who had four DPs (“meat and soft drinks”, DP1; “processed animal and fried foods”, DP2; “Mexican-healthy”, DP3; and “fish-rich”, DP4). In CHC subjects, polyunsaturated fatty acid intake (PUFA ≥ 4.9%) was negatively associated, and fiber intake (≥21.5 g/day) was positively associated with a high viral load (p < 0.036). High adherence to fish-rich DP4 was associated with a higher frequency of CHC individuals consuming PUFA ≥ 4.9% (p = 0.004) and low viral load (p = 0.036), but a lower frequency of CHC individuals consuming fiber ≥21.5 g/day (p = 0.038). In SC and CHC individuals, modifying unhealthy DPs and targeting HCV-interacting nutrients, respectively, could be part of a nutritional management strategy to prevent further liver damage.
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Fatty Acid Synthase Is Involved in Classical Swine Fever Virus Replication by Interaction with NS4B. J Virol 2021; 95:e0078121. [PMID: 34132567 DOI: 10.1128/jvi.00781-21] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Classical swine fever virus (CSFV), a member of the genus Pestivirus of the family Flaviviridae, relies on host machinery to complete its life cycle. Previous studies have shown a close connection between virus infection and fatty acid biosynthesis, mainly regulated by fatty acid synthase (FASN). However, the molecular action of how FASN participates in CSFV replication remains to be elucidated. In this study, two chemical inhibitors of the fatty acid synthesis pathway [5-(tetradecyloxy)-2-furoic acid (TOFA) and tetrahydro-4-methylene-2R-octyl-5-oxo-3S-furancarboxylic acid (C75)] significantly impaired the late stage of viral propagation, suggesting CSFV replication required fatty acid synthesis. We next found that CSFV infection stimulated the expression of FASN, whereas knockdown of FASN inhibited CSFV replication. Furthermore, confocal microscopy showed that FASN participated in the formation of replication complex (RC), which was associated with the endoplasmic reticulum (ER). Interestingly, CSFV NS4B interacted with FASN and promoted overexpression of FASN, which is regulated by functional Rab18. Moreover, we found that FASN regulated the formation of lipid droplets (LDs) upon CSFV infection, promoting virus proliferation. Taken together, our work provides mechanistic insight into the role of FASN in the viral life of CSFV, and it highlights the potential antiviral target for the development of therapeutics against pestiviruses. IMPORTANCE Classical swine fever, caused by classical swine fever virus (CSFV), is one of the notifiable diseases by the World Organization for Animal Health (OIE) and causes significant financial losses to the pig industry globally. CSFV, like other (+)-strand RNA viruses, requires lipid and sterol biosynthesis for efficient replication. However, the role of lipid metabolism in CSFV replication remains unknown. Here, we found that fatty acid synthase (FASN) was involved in viral propagation. Moreover, FASN is recruited to CSFV replication sites in the endoplasmic reticulum (ER) and interacts with NS4B to regulate CSFV replication that requires Rab18. Furthermore, we speculated that lipid droplet (LD) biosynthesis, indirectly regulated by FASN, ultimately promotes CSFV replication. Our results highlight a critical role for de novo fatty acid synthesis in CSFV infection, which might help control this devastating virus.
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Li HC, Yang CH, Lo SY. Cellular factors involved in the hepatitis C virus life cycle. World J Gastroenterol 2021; 27:4555-4581. [PMID: 34366623 PMCID: PMC8326260 DOI: 10.3748/wjg.v27.i28.4555] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/04/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV), an obligatory intracellular pathogen, highly depends on its host cells to propagate successfully. The HCV life cycle can be simply divided into several stages including viral entry, protein translation, RNA replication, viral assembly and release. Hundreds of cellular factors involved in the HCV life cycle have been identified over more than thirty years of research. Characterization of these cellular factors has provided extensive insight into HCV replication strategies. Some of these cellular factors are targets for anti-HCV therapies. In this review, we summarize the well-characterized and recently identified cellular factors functioning at each stage of the HCV life cycle.
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Affiliation(s)
- Hui-Chun Li
- Department of Biochemistry, Tzu Chi University, Hualien 970, Taiwan
| | - Chee-Hing Yang
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien 970, Taiwan
| | - Shih-Yen Lo
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien 970, Taiwan
- Department of Laboratory Medicine, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan
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38
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Inhibition of Orbivirus Replication by Fluvastatin and Identification of the Key Elements of the Mevalonate Pathway Involved. Viruses 2021; 13:v13081437. [PMID: 34452303 PMCID: PMC8402872 DOI: 10.3390/v13081437] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/16/2021] [Accepted: 07/20/2021] [Indexed: 01/21/2023] Open
Abstract
Statin derivatives can inhibit the replication of a range of viruses, including hepatitis C virus (HCV, Hepacivirus), dengue virus (Flavivirus), African swine fever virus (Asfarviridae) and poliovirus (Picornaviridae). We assess the antiviral effect of fluvastatin in cells infected with orbiviruses (bluetongue virus (BTV) and Great Island virus (GIV)). The synthesis of orbivirus outer-capsid protein VP2 (detected by confocal immunofluorescence imaging) was used to assess levels of virus replication, showing a reduction in fluvastatin-treated cells. A reduction in virus titres of ~1.7 log (98%) in fluvastatin-treated cells was detected by a plaque assay. We have previously identified a fourth non-structural protein (NS4) of BTV and GIV, showing that it interacts with lipid droplets in infected cells. Fluvastatin, which inhibits 3-hydroxy 3-methyl glutaryl CoA reductase in the mevalonic acid pathway, disrupts these NS4 interactions. These findings highlight the role of the lipid pathways in orbivirus replication and suggest a greater role for the membrane-enveloped orbivirus particles than previously recognised. Chemical intermediates of the mevalonic acid pathway were used to assess their potential to rescue orbivirus replication. Pre-treatment of IFNAR(−/−) mice with fluvastatin promoted their survival upon challenge with live BTV, although only limited protection was observed.
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Khatun M, Sur S, Steele R, Ray R, Ray RB. Inhibition of Long Noncoding RNA Linc-Pint by Hepatitis C Virus in Infected Hepatocytes Enhances Lipogenesis. Hepatology 2021; 74:41-54. [PMID: 33236406 PMCID: PMC8141542 DOI: 10.1002/hep.31656] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/11/2020] [Accepted: 11/08/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS HCV often causes chronic infection in liver, cirrhosis, and, in some instances, HCC. HCV encodes several factors' those impair host genes for establishment of chronic infection. The long noncoding RNAs (lncRNAs) display diverse effects on biological regulations. However, their role in virus replication and underlying diseases is poorly understood. In this study, we have shown that HCV exploits lncRNA long intergenic nonprotein-coding RNA, p53 induced transcript (Linc-Pint) in hepatocytes for enhancement of lipogenesis. APPROACH AND RESULTS We identified a lncRNA, Linc-Pint, which is significantly down-regulated in HCV-replicating hepatocytes and liver specimens from HCV infected patients. Using RNA pull-down proteomics, we identified serine/arginine protein specific kinase 2 (SRPK2) as an interacting partner of Linc-Pint. A subsequent study demonstrated that overexpression of Linc-Pint inhibits the expression of lipogenesis-related genes, such as fatty acid synthase and ATP-citrate lyase. We also observed that Linc-Pint significantly inhibits HCV replication. Furthermore, HCV-mediated enhanced lipogenesis can be controlled by exogenous Linc-Pint expression. Together, our results suggested that HCV-mediated down-regulation of Linc-Pint enhances lipogenesis favoring virus replication and liver disease progression. CONCLUSIONS We have shown that SRPK2 is a direct target of Linc-Pint and that depletion of SRPK2 inhibits lipogenesis. Our study contributes to the mechanistic understanding of the role of Linc-Pint in HCV-associated liver pathogenesis.
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Affiliation(s)
- Mousumi Khatun
- Department of Pathology, Saint Louis University, Missouri, USA
| | - Subhayan Sur
- Department of Pathology, Saint Louis University, Missouri, USA
| | - Robert Steele
- Department of Pathology, Saint Louis University, Missouri, USA
| | - Ranjit Ray
- Department of Internal Medicine, Saint Louis University, Missouri, USA
| | - Ratna B. Ray
- Department of Pathology, Saint Louis University, Missouri, USA
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40
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Hepatitis C Virus Uses Host Lipids to Its Own Advantage. Metabolites 2021; 11:metabo11050273. [PMID: 33925362 PMCID: PMC8145847 DOI: 10.3390/metabo11050273] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/11/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Lipids and lipoproteins constitute indispensable components for living not only for humans. In the case of hepatitis C virus (HCV), the option of using the products of our lipid metabolism is “to be, or not to be”. On the other hand, HCV infection, which is the main cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma, exerts a profound influence on lipid and lipoprotein metabolism of the host. The consequences of this alternation are frequently observed as hypolipidemia and hepatic steatosis in chronic hepatitis C (CHC) patients. The clinical relevance of these changes reflects the fact that lipids and lipoprotein play a crucial role in all steps of the life cycle of HCV. The virus circulates in the bloodstream as a highly lipidated lipo-viral particle (LVP) that defines HCV hepatotropism. Thus, strict relationships between lipids/lipoproteins and HCV are indispensable for the mechanism of viral entry into hepatocytes, viral replication, viral particles assembly and secretion. The purpose of this review is to summarize the tricks thanks to which HCV utilizes host lipid metabolism to its own advantage.
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Li HC, Yang CH, Lo SY. Hepatitis C Viral Replication Complex. Viruses 2021; 13:v13030520. [PMID: 33809897 PMCID: PMC8004249 DOI: 10.3390/v13030520] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/18/2021] [Accepted: 03/19/2021] [Indexed: 12/16/2022] Open
Abstract
The life cycle of the hepatitis C virus (HCV) can be divided into several stages, including viral entry, protein translation, RNA replication, viral assembly, and release. HCV genomic RNA replication occurs in the replication organelles (RO) and is tightly linked to ER membrane alterations containing replication complexes (proteins NS3 to NS5B). The amplification of HCV genomic RNA could be regulated by the RO biogenesis, the viral RNA structure (i.e., cis-acting replication elements), and both viral and cellular proteins. Studies on HCV replication have led to the development of direct-acting antivirals (DAAs) targeting the replication complex. This review article summarizes the viral and cellular factors involved in regulating HCV genomic RNA replication and the DAAs that inhibit HCV replication.
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Affiliation(s)
- Hui-Chun Li
- Department of Biochemistry, Tzu Chi University, Hualien 97004, Taiwan;
| | - Chee-Hing Yang
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien 97004, Taiwan;
| | - Shih-Yen Lo
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien 97004, Taiwan;
- Department of Laboratory Medicine, Buddhist Tzu Chi General Hospital, Hualien 97004, Taiwan
- Correspondence: ; Tel.: +886-3-8565301 (ext. 2322)
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Seo DJ, Choi C. Antiviral Bioactive Compounds of Mushrooms and Their Antiviral Mechanisms: A Review. Viruses 2021; 13:350. [PMID: 33672228 PMCID: PMC7926341 DOI: 10.3390/v13020350] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/15/2021] [Accepted: 02/20/2021] [Indexed: 12/03/2022] Open
Abstract
Mushrooms are used in their natural form as a food supplement and food additive. In addition, several bioactive compounds beneficial for human health have been derived from mushrooms. Among them, polysaccharides, carbohydrate-binding protein, peptides, proteins, enzymes, polyphenols, triterpenes, triterpenoids, and several other compounds exert antiviral activity against DNA and RNA viruses. Their antiviral targets were mostly virus entry, viral genome replication, viral proteins, and cellular proteins and influenced immune modulation, which was evaluated through pre-, simultaneous-, co-, and post-treatment in vitro and in vivo studies. In particular, they treated and relieved the viral diseases caused by herpes simplex virus, influenza virus, and human immunodeficiency virus (HIV). Some mushroom compounds that act against HIV, influenza A virus, and hepatitis C virus showed antiviral effects comparable to those of antiviral drugs. Therefore, bioactive compounds from mushrooms could be candidates for treating viral infections.
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Affiliation(s)
- Dong Joo Seo
- Department of Food Science and Nutrition, College of Health and Welfare and Education, Gwangju University 277 Hyodeok-ro, Nam-gu, Gwangju 61743, Korea;
| | - Changsun Choi
- Department of Food and Nutrition, School of Food Science and Technology, College of Biotechnology and Natural Resources, Chung-Ang University, 4726 Seodongdaero, Daeduck-myun, Anseong-si, Gyeonggi-do 17546, Korea
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43
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Sumbria D, Berber E, Mathayan M, Rouse BT. Virus Infections and Host Metabolism-Can We Manage the Interactions? Front Immunol 2021; 11:594963. [PMID: 33613518 PMCID: PMC7887310 DOI: 10.3389/fimmu.2020.594963] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/16/2020] [Indexed: 01/08/2023] Open
Abstract
When viruses infect cells, they almost invariably cause metabolic changes in the infected cell as well as in several host cell types that react to the infection. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Several examples are discussed in this review, which include effects on energy metabolism, glutaminolysis and fatty acid metabolism. The response of the immune system also involves metabolic changes and manipulating these may change the outcome of infection. This could include changing the status of herpesviruses infections from productive to latency. The consequences of viral infections which include coronavirus disease 2019 (COVID-19), may also differ in patients with metabolic problems, such as diabetes mellitus (DM), obesity, and endocrine diseases. Nutrition status may also affect the pattern of events following viral infection and examples that impact on the pattern of human and experimental animal viral diseases and the mechanisms involved are discussed. Finally, we discuss the so far few published reports that have manipulated metabolic events in-vivo to change the outcome of virus infection. The topic is expected to expand in relevance as an approach used alone or in combination with other therapies to shape the nature of virus induced diseases.
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Affiliation(s)
- Deepak Sumbria
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, United States
| | - Engin Berber
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, United States.,Department of Virology, Faculty of Veterinary Medicine, Erciyes University, Kayseri, Turkey
| | - Manikannan Mathayan
- Center for Drug Discovery and Development, Sathyabama Institute of Science and Technology, Chennai, India
| | - Barry T Rouse
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, United States
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Filip R, Desrochers GF, Lefebvre DM, Reed A, Singaravelu R, Cravatt BF, Pezacki JP. Profiling of MicroRNA Targets Using Activity-Based Protein Profiling: Linking Enzyme Activity to MicroRNA-185 Function. Cell Chem Biol 2021; 28:202-212.e6. [PMID: 33450181 DOI: 10.1016/j.chembiol.2020.12.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 11/06/2020] [Accepted: 12/18/2020] [Indexed: 02/08/2023]
Abstract
MicroRNAs (miRNAs) act as cellular signal transducers through repression of protein translation. Elucidating targets using bioinformatics and traditional quantitation methods is often insufficient to uncover global miRNA function. Herein, alteration of protein function caused by miRNA-185 (miR-185), an immunometabolic miRNA, was determined using activity-based protein profiling, transcriptomics, and lipidomics. Fluorophosphonate-based activity-based protein profiling of miR-185-induced changes to human liver cells revealed that exclusively metabolic serine hydrolase enzymes were regulated in activity, some with roles in lipid and endocannabinoid metabolism. Lipidomic analysis linked enzymatic changes to levels of cellular lipid species, such as components of very-low-density lipoprotein particles. Additionally, inhibition of one miR-185 target, monoglyceride lipase, led to decreased hepatitis C virus levels in an infectious model. Overall, the approaches used here were able to identify key functional changes in serine hydrolases caused by miR-185 that are targetable pharmacologically, such that a small molecule inhibitor can recapitulate the miRNA phenotype.
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Affiliation(s)
- Roxana Filip
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada
| | - Geneviève F Desrochers
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada
| | - David M Lefebvre
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada
| | - Alex Reed
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Ragunath Singaravelu
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada
| | - Benjamin F Cravatt
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - John Paul Pezacki
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada.
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Simon TG, Chan AT. Lifestyle and Environmental Approaches for the Primary Prevention of Hepatocellular Carcinoma. Clin Liver Dis 2020; 24:549-576. [PMID: 33012445 PMCID: PMC7536356 DOI: 10.1016/j.cld.2020.06.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Patients with chronic liver disease are at increased risk of developing hepatocellular carcinoma (HCC). Most patients diagnosed with HCC have limited treatment options and a poor overall prognosis, with a 5-year survival less than 15%. Preventing the development of HCC represents the most important strategy. However, current guidelines lack specific recommendations for primary prevention. Lifestyle factors may be central in the pathogenesis of HCC, and primary prevention strategies focused on lifestyle modification could represent an important approach to the prevention of HCC. Both experimental and epidemiologic studies have identified promising chemopreventive agents for the primary prevention of HCC.
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Affiliation(s)
- Tracey G. Simon
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA
| | - Andrew T. Chan
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston MA,Broad Institute, Boston MA,Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston MA
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46
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Thyrsted J, Holm CK. Virus-induced metabolic reprogramming and innate sensing hereof by the infected host. Curr Opin Biotechnol 2020; 68:44-50. [PMID: 33113498 DOI: 10.1016/j.copbio.2020.10.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/29/2020] [Accepted: 10/07/2020] [Indexed: 12/20/2022]
Abstract
To make new infectious particles, all viruses must manipulate host cell metabolism to secure sufficient availability of biomolecules and energy-a phenomenon now known as metabolic reprogramming. Numerous observations of this has already been made for a range of viruses with each type of virus seemingly applying its own unique tactics to accomplish this unifying goal. In this light, metabolic reprogramming of the infected cell is largely beneficial to the virus and not to the host. On the other hand, virus-induced metabolic reprogramming represents a transformed self with distorted cellular and extracellular levels of distinct metabolites and metabolic by-products. This review briefly outlines current knowledge of virus-induced metabolic reprogramming, discusses how this could be sensed by the infected host to initiate anti-viral programs, and presents examples of innate anti-viral mechanisms of the host that target the availability of biomolecules to block viral replication.
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Affiliation(s)
- Jacob Thyrsted
- Infection and Inflammation, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
| | - Christian Kanstrup Holm
- Infection and Inflammation, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
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47
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Weill P, Plissonneau C, Legrand P, Rioux V, Thibault R. May omega-3 fatty acid dietary supplementation help reduce severe complications in Covid-19 patients? Biochimie 2020; 179:275-280. [PMID: 32920170 PMCID: PMC7481803 DOI: 10.1016/j.biochi.2020.09.003] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/03/2020] [Accepted: 09/08/2020] [Indexed: 12/14/2022]
Abstract
In around 10% of SARS-CoV-2 infected patients, coronavirus disease-2019 (Covid-19) symptoms are complicated with a severe lung damage called Acute Respiratory Distress Syndrome (ARDS), which is often lethal. ARDS is mainly associated with an uncontrolled overproduction of immune cells and cytokines, called "cytokine storm syndrome"; it appears 7-15 days following the onset of symptoms, leading to systemic inflammation and multiple organ failure. Because they are well-known metabolic precursors of specialized pro-resolving lipid mediators (SPMs), omega-3 long-chain polyunsaturated fatty acids (omega-3 LC-PUFAs) could help improve the resolution of the inflammatory balance, limiting therefore the level and duration of the critical inflammatory period. Omega-3 LC-PUFAs may also interact at different stages of the viral infection, notably on the virus entry and replication. In the absence of demonstrated treatment and while waiting for vaccine possibility, the use of omega-3 LC-PUFAs deserve therefore to be considered, based on previous clinical studies suggesting that omega-3 supplementation could improve clinical outcomes of critically ill patients at the acute phase of ARDS. In this context, it is crucial to remind that the omega-3 PUFA dietary intake levels in Western countries remains largely below the current recommendations, considering both the omega-3 precursor α-linolenic acid (ALA) and long chain derivatives such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). An optimized omega-3 PUFAs status could be helpful to prevent infectious diseases, including Covid-19.
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Affiliation(s)
- Pierre Weill
- Bleu-Blanc-Cœur Association - Univ Rennes, France
| | - Claire Plissonneau
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), 63001, Clermont-Ferrand, France; Université Clermont Auvergne, Laboratoire des Adaptations Métaboliques à l'Exercice en Conditions Physiologiques et Pathologiques (AME2P), EA 3533, 63171, Clermont-Ferrand, France
| | - Philippe Legrand
- Laboratoire de Biochimie et Nutrition Humaine, Institut Agro, Rennes, France; INRAE, INSERM, Univ Rennes, Nutrition Métabolismes et Cancer, NuMeCan, Rennes, France
| | - Vincent Rioux
- Laboratoire de Biochimie et Nutrition Humaine, Institut Agro, Rennes, France; INRAE, INSERM, Univ Rennes, Nutrition Métabolismes et Cancer, NuMeCan, Rennes, France
| | - Ronan Thibault
- INRAE, INSERM, Univ Rennes, Nutrition Métabolismes et Cancer, NuMeCan, Rennes, France; Unité de Nutrition, CHU Rennes, Rennes, France.
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Abstract
Despite increasing evidence suggesting that antibiotic heteroresistance can lead to treatment failure, the significance of this phenomena in the clinic is not well understood, because many clinical antibiotic susceptibility testing approaches lack the resolution needed to reliably classify heteroresistant strains. Here we present G0790, a new globomycin analog and potent inhibitor of the Escherichia coli type II signal peptidase LspA. We demonstrate that in addition to previously known mechanisms of resistance to LspA inhibitors, unstable genomic amplifications containing lspA can lead to modest yet biologically significant increases in LspA protein levels that confer a heteroresistance phenotype. Clinical development of antibiotics with novel mechanisms of action to kill pathogenic bacteria is challenging, in part, due to the inevitable emergence of resistance. A phenomenon of potential clinical importance that is broadly overlooked in preclinical development is heteroresistance, an often-unstable phenotype in which subpopulations of bacterial cells show decreased antibiotic susceptibility relative to the dominant population. Here, we describe a new globomycin analog, G0790, with potent activity against the Escherichia coli type II signal peptidase LspA and uncover two novel resistance mechanisms to G0790 in the clinical uropathogenic E. coli strain CFT073. Building on the previous finding that complete deletion of Lpp, the major Gram-negative outer membrane lipoprotein, leads to globomycin resistance, we also find that an unexpectedly modest decrease in Lpp levels mediated by insertion-based disruption of regulatory elements is sufficient to confer G0790 resistance and increase sensitivity to serum killing. In addition, we describe a heteroresistance phenotype mediated by genomic amplifications of lspA that result in increased LspA levels sufficient to overcome inhibition by G0790 in culture. These genomic amplifications are highly unstable and are lost after as few as two subcultures in the absence of G0790, which places amplification-containing resistant strains at high risk of being misclassified as susceptible by routine antimicrobial susceptibility testing. In summary, our study uncovers two vastly different mechanisms of resistance to LspA inhibitors in E. coli and emphasizes the importance of considering the potential impact of unstable and heterogenous phenotypes when developing antibiotics for clinical use.
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Hsu CS, Liu WL, Li Q, Lowey B, Hertz L, Chao YC, Liang TJ, Chen DS, Kao JH. Hepatitis C virus genotypes 1-3 infections regulate lipogenic signaling and suppress cholesterol biosynthesis in hepatocytes. J Formos Med Assoc 2020; 119:1382-1395. [PMID: 32284164 PMCID: PMC11492201 DOI: 10.1016/j.jfma.2020.03.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/18/2020] [Accepted: 03/23/2020] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Patients with different hepatitis C virus (HCV) genotype infections are associated with varying metabolic disorders. Although alteration of lipid metabolism has been confirmed as a virus-induced metabolic derangement in chronic hepatitis C patients, the impact of various HCV genotypes on hepatic cholesterol metabolism remains elusive. In this study, we thus investigated the HCV genotype-specific lipogenic and cholesterol metabolism profiles in an in vitro cell culture system. METHODS We first conducted HCV cell culture system (HCVcc) assays by infecting Huh7.5.1 cells with multiple infection-competent HCV strains, including the genotype 2a JFH1 and JFH1-based intergenotypic recombinants 1b and 3a. We then examined the expression levels of various lipid and cholesterol-related genes. RESULTS The data showed that infection with individual HCV genotypes exerted unique gene expression regulatory effects on lipoproteins and cholesterol metabolism genes. Of note, all HCV strains suppressed cholesterol biosynthesis in hepatocytes through downregulating the expression of HMG-CoA reductase (HMGCR) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1) - two essential enzymes for cholesterol biosynthesis. These HCV-mediated inhibitory effects could be reversed by treatment with sofosbuvir, a pangenotypic NS5B inhibitor. In addition, overexpression of HCV genotype 1b, 2a or 3a core protein significantly suppressed HMGCR mRNA transcription and translation, thus diminished cellular cholesterol biosynthesis. Nonetheless, the core protein had no effect on FDFT1 expression. CONCLUSION Although HCV infection regulates host lipid metabolism in a genotype-specific manner, its inhibition on hepatocellular cholesterogenic gene expression and total cholesterol biosynthesis is a common effect among HCV genotype 1b, 2a and 3a.
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Affiliation(s)
- Ching-Sheng Hsu
- Liver Diseases Research Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan; School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - Wei-Liang Liu
- National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Miaoli, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Qisheng Li
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Brianna Lowey
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Laura Hertz
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - You-Chen Chao
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Nankang, 11549, Taiwan
| | - Jia-Horng Kao
- National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Miaoli, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.
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Clinical effects of simvastatin in chronic hepatitis C patients receiving sofosbuvir/daclatasvir combination. A randomized, placebo-controlled, double-blinded study. Clin Exp Hepatol 2020; 6:99-105. [PMID: 32728626 PMCID: PMC7380473 DOI: 10.5114/ceh.2020.95566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 02/17/2020] [Indexed: 11/17/2022] Open
Abstract
Aim of the study Chronic hepatitis C (CHC) affects more than 71 million people worldwide. Many therapies containing different direct-acting antivirals (DAAs) are now used. However, lipid profile is considered an important outcome with DAAs. So, this study aimed to assess clinical effects of statins in CHC patients. Material and methods One hundred patients were recruited from Kobri El koba Armed Forces Hospital and randomly assigned to: the drug group (D;n = 50) receiving simvastatin 10 mg plus sofosbuvir 400 mg/daclatasvir 60 mg (SOF/DAC) daily for 12 weeks; and the placebo group (P; n = 50), receiving placebo plus the same (SOF/DAC) regimen. Sustained virological response at 12 weeks after treatment (SVR12), lipid profile, C-reactive protein (CRP) and fibrosis stage were assessed. Results One hundred treatment-naïve CHC patients completed 12 weeks of the protocol with no clinically significant side effects. There was an increase in SVR failure rate in P (10%) compared to D (only 2%) but not reaching statistical significant difference; SVR12 (p > 0.05). Logistic regression analysis showed that high baseline CRP, low baseline hemoglobin level and non-statin usage had an independent effect on increasing the probability of SVR failure in both groups; p = 0.03, p = 0.0028, p = 0.02, respectively. Conclusions Statins could have an irreplaceable role in successful treatment of CHC patients receiving sofosbuvir/daclatasvir.
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