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Cheng P, Wang X, Wang S, Ren S, Liang Z, Guo K, Qu M, Meng X, Dou Y, Yin X, Sun Y. Class IIa histone deacetylase (HDAC) inhibitor TMP269 suppresses lumpy skin disease virus replication by regulating host lysophosphatidic acid metabolism. J Virol 2025; 99:e0182724. [PMID: 39840984 PMCID: PMC11852836 DOI: 10.1128/jvi.01827-24] [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: 10/28/2024] [Accepted: 12/13/2024] [Indexed: 01/23/2025] Open
Abstract
Lumpy skin disease virus (LSDV) infection poses a significant threat to global cattle farming. Currently, effective therapeutic agents are lacking. TMP269, a small molecule inhibitor of class IIa histone deacetylase inhibitor, plays a vital role in cancer therapy. In this study, we demonstrated that TMP269 treatment inhibits the early-stage replication of LSDV in a dose-dependent manner. RNA sequencing data revealed that metabolism-related signaling pathways were significantly enriched after LSDV infection. Furthermore, untargeted metabolomics analysis revealed that lysophosphatidic acid (LPA), a key metabolite of the glycerophospholipid pathway, was upregulated following LSDV infection and downregulated after TMP269 treatment. In addition, exogenous LPA promotes LSDV replication by activating the mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) signaling pathway and suppressing the host's innate immune response. Furthermore, treatment with the LPA receptor inhibitor Ki16425 suppressed LSDV replication and promoted the host's innate immune response. These findings suggest that LSDV infection can induce LPA expression and aid viral activation of the MEK/ERK signaling pathway and escape of the host's innate immune response, whereas TMP269 treatment can inhibit LPA production and limit its promotion of LSDV replication. These data identified the antiviral mechanism of TMP269 and a novel mechanism by which LSDV inhibits host innate immune responses, providing insights into the development of new preventive or therapeutic strategies targeting altered metabolic pathways.IMPORTANCELumpy skin disease virus (LSDV) poses a significant threat to global cattle farming. Owing to insufficient research on LSDV infection, pathogenesis, and immune escape mechanisms, prevention and control methods against LSDV infection are lacking. Here, we found that TMP269, a class IIa histone deacetylase inhibitor, significantly inhibited LSDV replication. We further demonstrated that TMP269 altered LSDV infection-induced host glycerophospholipid metabolism. In addition, TMP269 decreased the accumulation of lysophosphatidic acid (LPA), a key metabolite in glycerophospholipid metabolism, induced by LSDV infection, and exogenous LPA-promoted LSDV replication by activating the mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) signaling pathway and suppressing the host innate immune response. Our findings identified the antiviral mechanism of TMP269 and a novel mechanism by which LSDV manipulates host signaling pathways to promote its replication, offering insights into the development of novel antiviral agents against LSDV infection.
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Affiliation(s)
- Pengyuan Cheng
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
| | - Xiangwei Wang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
| | - Shasha Wang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
| | - Shanhui Ren
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
| | - Zhengji Liang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
| | - Ke Guo
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
| | - Min Qu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
| | - Xuelian Meng
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
| | - Yongxi Dou
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
| | - Xiangping Yin
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
| | - Yuefeng Sun
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China
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Li Y, Luo H, Pang H, Qin B. Epigenetic Targeting for Controlling Persistent Neurotropic Infections Caused by Borna Virus and HIV. Rev Med Virol 2025; 35:e70000. [PMID: 39643925 DOI: 10.1002/rmv.70000] [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: 08/19/2024] [Revised: 10/09/2024] [Accepted: 10/12/2024] [Indexed: 12/09/2024]
Abstract
Long-lasting persistence within infected cells is a major challenge for viral pathogens, as it necessitates an exact regulation of viral replication to reduce viral cytopathic effects. This is particularly challenging for viruses that persistently infect cells with limited renewal capabilities, such as neurons. Accordingly, neurotropic viruses have evolved various specific mechanisms to promote a long-lasting persistent infection in the host cells without inducing an exacerbated cytopathic effect. Borna disease virus (BDV) and Human immunodeficiency virus (HIV) are two neurotropic RNA viruses that, in contrast to other RNA viruses, can establish long-lasting intranuclear infections within the nervous system. These viruses interact with different cellular processes such as epigenetic modifications to develop a successful persistence infection. Studies show that cellular epigenetic mechanisms play a significant role in the pathogenesis of BDV and HIV and their neurological disorders. Hence, targeting these mechanisms by epigenetic modulator agents can be regarded as a novel therapeutic strategy to manage BDV- and HIV-associated neurological diseases. This review provides an overview of different epigenetic modulator compounds as a potential therapeutic target for controlling persistent neurotropic intranuclear infections caused by BDV and HIV.
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Affiliation(s)
- Yadi Li
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huating Luo
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Pang
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Qin
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Rani A, Stadler JT, Marsche G. HDL-based therapeutics: A promising frontier in combating viral and bacterial infections. Pharmacol Ther 2024; 260:108684. [PMID: 38964560 DOI: 10.1016/j.pharmthera.2024.108684] [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: 02/26/2024] [Revised: 06/03/2024] [Accepted: 07/01/2024] [Indexed: 07/06/2024]
Abstract
Low levels of high-density lipoprotein (HDL) and impaired HDL functionality have been consistently associated with increased susceptibility to infection and its serious consequences. This has been attributed to the critical role of HDL in maintaining cellular lipid homeostasis, which is essential for the proper functioning of immune and structural cells. HDL, a multifunctional particle, exerts pleiotropic effects in host defense against pathogens. It functions as a natural nanoparticle, capable of sequestering and neutralizing potentially harmful substances like bacterial lipopolysaccharides. HDL possesses antiviral activity, preventing viruses from entering or fusing with host cells, thereby halting their replication cycle. Understanding the complex relationship between HDL and the immune system may reveal innovative targets for developing new treatments to combat infectious diseases and improve patient outcomes. This review aims to emphasize the role of HDL in influencing the course of bacterial and viral infections and its and its therapeutic potential.
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Affiliation(s)
- Alankrita Rani
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Styria, Austria
| | - Julia T Stadler
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Styria, Austria
| | - Gunther Marsche
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Styria, Austria; BioTechMed-Graz, Mozartgasse 12/II, 8010 Graz, Styria, Austria.
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Mondal A, Sarkar A, Das D, Sengupta A, Kabiraj A, Mondal P, Nag R, Mukherjee S, Das C. Epigenetic orchestration of the DNA damage response: Insights into the regulatory mechanisms. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 387:99-141. [PMID: 39179350 DOI: 10.1016/bs.ircmb.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2024]
Abstract
The DNA damage response (DDR) is a critical cellular mechanism that safeguards genome integrity and prevents the accumulation of harmful DNA lesions. Increasing evidence highlights the intersection between DDR signaling and epigenetic regulation, offering profound insights into various aspects of cellular function including oncogenesis. This comprehensive review explores the intricate relationship between the epigenetic modifications and DDR activation, with a specific focus on the impact of viral infections. Oncogenic viruses, such as human papillomavirus, hepatitis virus (HBV or HCV), and Epstein-Barr virus have been shown to activate the DDR. Consequently, these DNA damage events trigger a cascade of epigenetic alterations, including changes in DNA methylation patterns, histone modifications and the expression of noncoding RNAs. These epigenetic changes exert profound effects on chromatin structure, gene expression, and maintenance of genome stability. Importantly, elucidation of the viral-induced epigenetic alterations in the context of DDR holds significant implications for comprehending the complexity of cancer and provides potential targets for therapeutic interventions.
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Affiliation(s)
- Atanu Mondal
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | | | - Dipanwita Das
- Virus Unit [NICED-ICMR], ID and BG Hospital, Kolkata, India
| | - Amrita Sengupta
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
| | - Aindrila Kabiraj
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | - Payel Mondal
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | - Rachayita Nag
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | - Shravanti Mukherjee
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
| | - Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India.
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Yin J, Wang S, Ren S, Liang Z, Ge J, Sun Y, Yin X, Wang X. TMP269, a small molecule inhibitor of class IIa HDAC, suppresses RABV replication in vitro. Front Microbiol 2023; 14:1284439. [PMID: 38107853 PMCID: PMC10722228 DOI: 10.3389/fmicb.2023.1284439] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 11/06/2023] [Indexed: 12/19/2023] Open
Abstract
TMP269, a small molecular inhibitor of IIa histone deacetylase, plays a vital role in cancer therapeutic. However, the effect of TMP269 on the regulation of viral replication has not been studied. In the present study, we found that TMP269 treatment significantly inhibited RABV replication at concentrations without significant cytotoxicity in a dose-dependent manner. In addition, TMP269 can reduce the viral titers and protein levels of RABV at an early stage in the viral life cycle. RNA sequencing data revealed that immune-related pathways and autophagy-related genes were significantly downregulated after RABV infection treated with TMP269. Further exploration shows that autophagy enhances RABV replication in HEK-293T cells, while TMP269 can inhibit autophagy to decrease RABV replication. Together, these results provide a novel treatment strategy for rabies.
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Affiliation(s)
- Juanbin Yin
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
| | - Shasha Wang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Shanhui Ren
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Zhengji Liang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Junwei Ge
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
| | - Yuefeng Sun
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Xiangping Yin
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Xiangwei Wang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
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Hua Y, Dai X, Xu Y, Xing G, Liu H, Lu T, Chen Y, Zhang Y. Drug repositioning: Progress and challenges in drug discovery for various diseases. Eur J Med Chem 2022; 234:114239. [PMID: 35290843 PMCID: PMC8883737 DOI: 10.1016/j.ejmech.2022.114239] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 02/20/2022] [Accepted: 02/24/2022] [Indexed: 12/17/2022]
Abstract
Compared with traditional de novo drug discovery, drug repurposing has become an attractive drug discovery strategy due to its low-cost and high efficiency. Through a comprehensive analysis of the candidates that have been identified with drug repositioning potentials, it is found that although some drugs do not show obvious advantages in the original indications, they may exert more obvious effects in other diseases. In addition, some drugs have a synergistic effect to exert better clinical efficacy if used in combination. Particularly, it has been confirmed that drug repositioning has benefits and values on the current public health emergency such as the COVID-19 pandemic, which proved the great potential of drug repositioning. In this review, we systematically reviewed a series of representative drugs that have been repositioned for different diseases and illustrated successful cases in each disease. Especially, the mechanism of action for the representative drugs in new indications were explicitly explored for each disease, we hope this review can provide important insights for follow-up research.
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Affiliation(s)
- Yi Hua
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China
| | - Xiaowen Dai
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China
| | - Yuan Xu
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China
| | - Guomeng Xing
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China
| | - Haichun Liu
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China
| | - Tao Lu
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Yadong Chen
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
| | - Yanmin Zhang
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
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Amilca-Seba K, Sabbah M, Larsen AK, Denis JA. Osteopontin as a Regulator of Colorectal Cancer Progression and Its Clinical Applications. Cancers (Basel) 2021; 13:cancers13153793. [PMID: 34359694 PMCID: PMC8345080 DOI: 10.3390/cancers13153793] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 12/29/2022] Open
Abstract
Simple Summary The mortality of colorectal cancer is principally related to metastatic disease at the time of diagnosis or to the growth of initially undetectable micro-metastasis. Current therapeutic strategies are efficient in patients with locally advanced cancer, but are rarely able to cure patients with metastatic disease. Therapeutic failure is mainly associated with drug resistance and an aggressive phenotype. The identification of new biomarkers for micro-metastasis and tumor progression remains an unmet clinical need that should allow for improved patient stratification for optimal treatment and may lead to the identification of novel therapeutic targets. Osteopontin (OPN), a multifunctional protein, has emerged as a potentially valuable biomarker in several cancer types. This review principally describes the molecular mechanisms of OPN that are associated with colorectal cancer (CRC) progression and metastasis, as well as the use of OPN as a clinical biomarker. This review identifies a role for OPN as a biomarker ready for extended clinical application and discusses its use as a therapeutic target. Abstract A high expression of the phosphoprotein osteopontin (OPN) has been associated with cancer progression in several tumor types, including breast cancer, hepatocarcinoma, ovarian cancer, and colorectal cancer (CRC). Interestingly, OPN is overexpressed in CRC and is associated with a poor prognosis linked to invasion and metastasis. Here, we review the regulation and functions of OPN with an emphasis on CRC. We examine how epigenetic and genetic regulators interact with the key signaling pathways involved in this disease. Then, we describe the role of OPN in cancer progression, including proliferation, survival, migration, invasion, and angiogenesis. Furthermore, we outline the interest of using OPN as a clinical biomarker, and discuss if and how osteopontin can be implemented as a routine assay in clinical laboratories for monitoring CRC patients. Finally, we discuss the use of OPN an attractive, but challenging, therapeutic target.
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Affiliation(s)
- Katyana Amilca-Seba
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France; (K.A.-S.); (M.S.); (A.K.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012 Paris, France
- Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, 75005 Paris, France
| | - Michèle Sabbah
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France; (K.A.-S.); (M.S.); (A.K.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012 Paris, France
- Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, 75005 Paris, France
- Centre National de la Recherche Scientifique (CNRS), 75016 Paris, France
| | - Annette K. Larsen
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France; (K.A.-S.); (M.S.); (A.K.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012 Paris, France
- Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, 75005 Paris, France
- Centre National de la Recherche Scientifique (CNRS), 75016 Paris, France
| | - Jérôme A. Denis
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France; (K.A.-S.); (M.S.); (A.K.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012 Paris, France
- Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, 75005 Paris, France
- Department of Endocrinology and Oncology Biochemistry, Pitié-Salpetrière Hospital, 75013 Paris, France
- Correspondence: ; Tel.: +33-(0)1-42-16-20-39
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Liu Z, Xuan B, Tang S, Qian Z. Histone Deacetylase Inhibitor SAHA Induces Expression of Fatty Acid-Binding Protein 4 and Inhibits Replication of Human Cytomegalovirus. Virol Sin 2021; 36:1352-1362. [PMID: 34156645 DOI: 10.1007/s12250-021-00382-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 03/11/2021] [Indexed: 10/21/2022] Open
Abstract
Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor that shows marked efficacy against many types of cancers and is approved to treat severe metastatic cutaneous T-cell lymphomas. In addition to its anticancer activity, SAHA has significant effects on the growth of many viruses. The effect of SAHA on replication of human cytomegalovirus (HCMV) has not, however, been investigated. Here, we showed that the replication of HCMV was significantly suppressed by treatment with SAHA at concentrations that did not show appreciable cytotoxicity. SAHA reduced transcription and protein levels of HCMV immediate early genes, showing that SAHA acts at an early stage in the viral life-cycle. RNA-sequencing data mining showed that numerous pathways and molecules were affected by SAHA. Interferon-mediated immunity was one of the most relevant pathways in the RNA-sequencing data, and we confirmed that SAHA inhibits HCMV-induced IFN-mediated immune responses using quantitative Real-time PCR (qRT-PCR). Fatty acid-binding protein 4 (FABP4), which plays a role in lipid metabolism, was identified by RNA-sequencing. We found that FABP4 expression was reduced by HCMV infection but increased by treatment with SAHA. We then showed that knockdown of FABP4 partially rescued the effect of SAHA on HCMV replication. Our data suggest that FABP4 contributes to the inhibitory effect of SAHA on HCMV replication.
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Affiliation(s)
- Zhongshun Liu
- CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, 200031, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Baoqin Xuan
- CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, 200031, China
| | - Shubing Tang
- CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, 200031, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhikang Qian
- CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, 200031, China.
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Malikova AZ, Shcherbakova AS, Konduktorov KA, Zemskaya AS, Dalina AA, Popenko VI, Leonova OG, Morozov AV, Kurochkin NN, Smirnova OA, Kochetkov SN, Kozlov MV. Pre-Senescence Induction in Hepatoma Cells Favors Hepatitis C Virus Replication and Can Be Used in Exploring Antiviral Potential of Histone Deacetylase Inhibitors. Int J Mol Sci 2021; 22:4559. [PMID: 33925399 PMCID: PMC8123837 DOI: 10.3390/ijms22094559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/16/2021] [Accepted: 04/22/2021] [Indexed: 12/22/2022] Open
Abstract
Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Importantly, suppression of HCV replication by direct acting antivirals (DAAs) was barely affected by pre-senescence induction, and vice versa, the antiviral activities of host-targeting agents (HTAs), such as inhibitors of human histone deacetylases (HDACi), produced a wide range of reactions-from a dramatic reduction to a noticeable increase. It is very likely that under conditions of the G1 arrest in the cell cycle, HDACi exhibit their actual antiviral potency, since their inherent anticancer activity that complicates the interpretation of test results is minimized.
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Jit BP, Qazi S, Arya R, Srivastava A, Gupta N, Sharma A. An immune epigenetic insight to COVID-19 infection. Epigenomics 2021; 13:465-480. [PMID: 33685230 PMCID: PMC7958646 DOI: 10.2217/epi-2020-0349] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 02/14/2021] [Indexed: 12/14/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 is a positive-sense RNA virus, a causal agent of ongoing COVID-19 pandemic. ACE2R methylation across three CpG sites (cg04013915, cg08559914, cg03536816) determines the host cell's entry. It regulates ACE2 expression by controlling the SIRT1 and KDM5B activity. Further, it regulates Type I and III IFN response by modulating H3K27me3 and H3K4me3 histone mark. SARS-CoV-2 protein with bromodomain and protein E mimics bromodomain histones and evades from host immune response. The 2'-O MTases mimics the host's cap1 structure and plays a vital role in immune evasion through Hsp90-mediated epigenetic process to hijack the infected cells. Although the current review highlighted the critical epigenetic events associated with SARS-CoV-2 immune evasion, the detailed mechanism is yet to be elucidated.
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Affiliation(s)
- Bimal P Jit
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Sahar Qazi
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Rakesh Arya
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Ankit Srivastava
- Regional Institute of Ophthalmology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 220115, India
| | - Nimesh Gupta
- National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Ashok Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
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Abstract
Antiviral drugs have traditionally been developed by directly targeting essential viral components. However, this strategy often fails due to the rapid generation of drug-resistant viruses. Recent genome-wide approaches, such as those employing small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeats (CRISPR) or those using small molecule chemical inhibitors targeting the cellular "kinome," have been used successfully to identify cellular factors that can support virus replication. Since some of these cellular factors are critical for virus replication, but are dispensable for the host, they can serve as novel targets for antiviral drug development. In addition, potentiation of immune responses, regulation of cytokine storms, and modulation of epigenetic changes upon virus infections are also feasible approaches to control infections. Because it is less likely that viruses will mutate to replace missing cellular functions, the chance of generating drug-resistant mutants with host-targeted inhibitor approaches is minimized. However, drug resistance against some host-directed agents can, in fact, occur under certain circumstances, such as long-term selection pressure of a host-directed antiviral agent that can allow the virus the opportunity to adapt to use an alternate host factor or to alter its affinity toward the target that confers resistance. This review describes novel approaches for antiviral drug development with a focus on host-directed therapies and the potential mechanisms that may account for the acquisition of antiviral drug resistance against host-directed agents.
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12
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Nehme Z, Pasquereau S, Herbein G. Targeting histone epigenetics to control viral infections. HISTONE MODIFICATIONS IN THERAPY 2020. [PMCID: PMC7453269 DOI: 10.1016/b978-0-12-816422-8.00011-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
During the past decades, many studies have significantly broadened our understanding of complex virus-host interactions to control chromatin structure and dynamics.1, 2 However, the role and impact of such modifications during viral infections is not fully revealed. Indeed, this type of regulation is bidirectional between the virus and the host. While viral replication and gene expression are significantly impacted by histone modifications on the viral chromatin,3 studies have shown that some viral pathogens dynamically manipulate cellular epigenetic factors to enhance their own survival and pathogenesis, as well as escape the immune system defense lines.4 In this dynamic, histone posttranslational modifications (PTMs) appear to play fundamental roles in the regulation of chromatin structure and recruitment of other factors.5 Genuinely, those PTMs play a vital role in lytic infection, latency reinforcement, or, conversely, viral reactivation.6 In this chapter, we will examine and review the involvement of histone modifications as well as their potential manipulation to control infections during various viral life cycle stages, highlighting their prospective implications in the clinical management of human immunodeficiency virus (HIV), herpes simplex virus (HSV), human cytomegalovirus (HCMV), hepatitis B and C viruses (HBV and HCV, respectively), Epstein–Barr virus (EBV), and other viral diseases. Targeting histone modifications is critical in setting the treatment of chronic viral infections with both lytic and latent stages (HIV, HCMV, HSV, RSV), virus-induced cancers (HBV, HCV, EBV, KSHV, HPV), and epidemic/emerging viruses (e.g. influenza virus, arboviruses).
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13
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Mirzaei H, Ghorbani S, Khanizadeh S, Namdari H, Faghihloo E, Akbari A. Histone deacetylases in virus-associated cancers. Rev Med Virol 2019; 30:e2085. [PMID: 31743548 DOI: 10.1002/rmv.2085] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 08/31/2019] [Accepted: 09/03/2019] [Indexed: 12/24/2022]
Abstract
Oncogenic viruses are one of the most important causes of cancer worldwide. The pathogens contribute to the establishment of human malignancies by affecting various cellular events. Epigenetic mechanisms, such as histone modification methylation/demethylation, are one of the most critical events manipulated by oncogenic viruses to drive tumorigenesis. Histone modifications are mediated by histone acetylation and deacetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Dysregulation of HDACs activity affects viral tumorigenesis in several ways, such as manipulating tumor suppressor and viral gene expression. The present review aims to describe the vital interactions between both cancer-caused/associated viruses and the HDAC machinery, particularly by focusing on those viruses involved in gastrointestinal tumors, as some of the most common viral-mediated cancers.
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Affiliation(s)
- Habibollah Mirzaei
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran.,Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeed Ghorbani
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran.,Department of Virology, Faculty of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Sayyad Khanizadeh
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran.,Department of Virology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Haideh Namdari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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14
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Kozlov MV, Konduktorov KA, Malikova AZ, Kamarova KA, Shcherbakova AS, Solyev PN, Kochetkov SN. Structural isomers of cinnamic hydroxamic acids block HCV replication via different mechanisms. Eur J Med Chem 2019; 183:111723. [PMID: 31557613 DOI: 10.1016/j.ejmech.2019.111723] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 09/19/2019] [Indexed: 02/07/2023]
Abstract
A set of ortho-, meta- and para-substituted cinnamic hydroxamic acids (CHAs) was synthesized. In each series of structural isomers, a phenyl substituent was linked to an aromatic ring of the parent cinnamic acid via a linker of one to four atoms in length. Using a cell test system with the full-length replicon of hepatitis C virus (HCV), we established a relationship between the suppression of HCV replicon propagation and the inhibition of class I/IIb histone deacetylases (HDACs). Anti-HCV activity correlated with the inhibition of HDAC8 in the case of ortho-CHAs, while in the case of meta-CHAs it correlated with the inhibition of HDAC1/2/3 and HDAC6. The antiviral activity of para-CHAs was many times stronger than that of meta-CHAs with about the same efficiency of HDAC1/2/3/6 inhibition, which indicated the existence of an additional cell target that does not belong to the studied group of HDACs.
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Affiliation(s)
- Maxim V Kozlov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia.
| | - Konstantin A Konduktorov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
| | - Alsu Z Malikova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
| | - Kamila A Kamarova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
| | - Anastasia S Shcherbakova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
| | - Pavel N Solyev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
| | - Sergey N Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
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15
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Kozlov MV, Konduktorov KA, Shcherbakova AS, Kochetkov SN. Synthesis of N'-propylhydrazide analogs of hydroxamic inhibitors of histone deacetylases (HDACs) and evaluation of their impact on activities of HDACs and replication of hepatitis C virus (HCV). Bioorg Med Chem Lett 2019; 29:2369-2374. [PMID: 31201063 DOI: 10.1016/j.bmcl.2019.06.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/24/2019] [Accepted: 06/05/2019] [Indexed: 01/22/2023]
Abstract
N'-Propylhydrazide analogs of hydroxamic inhibitors of histone deacetylases (HDACs), including tubastatin A, vorinostat and belinostat, were synthesized. All prepared compounds inhibited HDAC1/2/3, but not HDAC6, except for one hydrazide analog of HDAC4/5/7 inhibitor that was completely inactive. A novel 4-substituted derivative of N'-propylbenzohydrazide with extremely high anti-HCV activity was discovered.
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Affiliation(s)
- Maxim V Kozlov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow 119991, Russia.
| | - Konstantin A Konduktorov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow 119991, Russia
| | - Anastasia S Shcherbakova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow 119991, Russia
| | - Sergey N Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow 119991, Russia
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16
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Nehme Z, Pasquereau S, Herbein G. Control of viral infections by epigenetic-targeted therapy. Clin Epigenetics 2019; 11:55. [PMID: 30917875 PMCID: PMC6437953 DOI: 10.1186/s13148-019-0654-9] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 03/13/2019] [Indexed: 12/13/2022] Open
Abstract
Epigenetics is defined as the science that studies the modifications of gene expression that are not owed to mutations or changes in the genetic sequence. Recently, strong evidences are pinpointing toward a solid interplay between such epigenetic alterations and the outcome of human cytomegalovirus (HCMV) infection. Guided by the previous possibly promising experimental trials of human immunodeficiency virus (HIV) epigenetic reprogramming, the latter is paving the road toward two major approaches to control viral gene expression or latency. Reactivating HCMV from the latent phase ("shock and kill" paradigm) or alternatively repressing the virus lytic and reactivation phases ("block and lock" paradigm) by epigenetic-targeted therapy represent encouraging options to overcome latency and viral shedding or otherwise replication and infectivity, which could lead eventually to control the infection and its complications. Not limited to HIV and HCMV, this concept is similarly studied in the context of hepatitis B and C virus, herpes simplex virus, and Epstein-Barr virus. Therefore, epigenetic manipulations stand as a pioneering research area in modern biology and could constitute a curative methodology by potentially consenting the development of broad-spectrum antivirals to control viral infections in vivo.
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Affiliation(s)
- Zeina Nehme
- Department Pathogens & Inflammation-EPILAB, UPRES EA4266, University of Franche-Comté, University of Bourgogne Franche-Comté, 16 route de Gray, F-25030 Besançon cedex, France
- Université Libanaise, Beirut, Lebanon
| | - Sébastien Pasquereau
- Department Pathogens & Inflammation-EPILAB, UPRES EA4266, University of Franche-Comté, University of Bourgogne Franche-Comté, 16 route de Gray, F-25030 Besançon cedex, France
| | - Georges Herbein
- Department Pathogens & Inflammation-EPILAB, UPRES EA4266, University of Franche-Comté, University of Bourgogne Franche-Comté, 16 route de Gray, F-25030 Besançon cedex, France
- Department of Virology, CHRU Besancon, F-25030 Besançon, France
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Tsilimigras DI, Ntanasis-Stathopoulos I, Moris D, Spartalis E, Pawlik TM. Histone deacetylase inhibitors in hepatocellular carcinoma: A therapeutic perspective. Surg Oncol 2018; 27:611-618. [PMID: 30449480 DOI: 10.1016/j.suronc.2018.07.015] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 07/06/2018] [Accepted: 07/29/2018] [Indexed: 02/07/2023]
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18
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Zhou Y, Wang Q, Yang Q, Tang J, Xu C, Gai D, Chen X, Chen J. Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 Expression. Virol Sin 2018; 33:418-428. [PMID: 30328580 DOI: 10.1007/s12250-018-0057-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Accepted: 08/31/2018] [Indexed: 12/16/2022] Open
Abstract
Histone deacetylase (HDAC) inhibitors show clinical promise for the treatment of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the effect of HDAC inhibitor treatment on hepatitis C virus (HCV) replication in Huh7 human liver cells and in a mouse model of HCV infection. Viral replication was markedly suppressed by the HDAC3 inhibitor at concentrations below 1 mmol/L, with no cellular toxicity. This was accompanied by upregulation of liver-expressed antimicrobial peptide 1(LEAP-1) and downregulation of apolipoprotein-A1 (Apo-A1), as determined by microarray and quantitative RT-PCR analyses. Moreover, HDAC3 was found to modulate the binding of CCAAT-enhancer-binding protein α (C/EBPα), hypoxia-inducible factor 1α (HIF1α), and signal transducer and activator of transcription 3 (STAT3) to the LEAP-1 promoter. HDAC3 inhibitor treatment also blocked HCV replication in a mouse model of HCV infection. These results indicate that epigenetic therapy with HDAC3 inhibitor may be a potential treatment for diseases associated with HCV infection such as HCC.
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Affiliation(s)
- Yuan Zhou
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Qian Wang
- Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China
| | - Qi Yang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Jielin Tang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Chonghui Xu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Dongwei Gai
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Jizheng Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
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19
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Murayama A, Saitoh H, Takeuchi A, Yamada N, Matsumura T, Shiina M, Muramatsu M, Wakita T, Imawari M, Kato T. Vitamin D derivatives inhibit hepatitis C virus production through the suppression of apolipoprotein. Antiviral Res 2018; 160:55-63. [PMID: 30339849 DOI: 10.1016/j.antiviral.2018.10.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 09/21/2018] [Accepted: 10/14/2018] [Indexed: 01/28/2023]
Abstract
Supplementation with vitamin D (VD) has been reported to improve the efficacy of interferon-based therapy for chronic hepatitis C. We found that 25-hydroxyvitamin D3 (25-(OH)D3), one of the metabolites of VD, has antiviral effects by inhibiting the infectious virus production of the hepatitis C virus (HCV). In this study, to clarify the underlying mechanisms of the anti-HCV effects, we searched VD derivatives that have anti-HCV effects and identified the common target molecule in the HCV life cycle by using an HCV cell culture system. After infection of Huh-7.5.1 cells with cell culture-generated HCV, VD derivatives were added to culture media, and the propagation of HCV was assessed by measuring the HCV core antigen levels in culture media and cell lysates. To determine the step in the HCV life cycle affected by these compounds, the single-cycle virus production assay was used with a CD81-negative cell line. Of the 14 structural derivatives of VD, an anti-HCV effect was detected in 9 compounds. Cell viability was not affected by these effective compounds. The 2 representative VD derivatives inhibited the infectious virus production in the single-cycle virus production assay. Treatment with these compounds and 25-(OH)D3 suppressed the expression of apolipoprotein A1 and C3, which are known to be involved in infectious virus production of HCV, and the knockdown of these apolipoproteins reduced infectious virus production. In conclusion, we identified several compounds with anti-HCV activity by screening VD derivatives. These compounds reduce the infectious virus production of HCV by suppressing the expression of apolipoproteins in host cells.
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Affiliation(s)
- Asako Murayama
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroshi Saitoh
- Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Tokyo, Japan
| | - Akiko Takeuchi
- Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Tokyo, Japan
| | - Norie Yamada
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takuya Matsumura
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Masaaki Shiina
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan; Department of Gastroenterology and Hepatology, Shin-Yurigaoka General Hospital, Kawasaki, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Michio Imawari
- Research Institute for Gastrointestinal and Liver Diseases, Shin-Yurigaoka General Hospital, Kawasaki, Japan
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
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20
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Guo H, Zhang J, Wang Y, Bu C, Zhou Y, Fang Q. Comparative Proteomic Analysis of Lysine Acetylation in Fish CIK Cells Infected with Aquareovirus. Int J Mol Sci 2017; 18:E2419. [PMID: 29135940 PMCID: PMC5713387 DOI: 10.3390/ijms18112419] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 11/10/2017] [Accepted: 11/12/2017] [Indexed: 01/06/2023] Open
Abstract
Grass carp (Ctenopharyngodon idellus) is an important worldwide commercial freshwater culture species. However, grass carp reovirus (GCRV) causes serious hemorrhagic disease in fingerlings and yearlings of fishes. To understand the molecular pathogenesis of host cells during GCRV infection, intensive proteomic quantification analysis of lysine acetylation in Ctenopharyngodon idella kidney (CIK) cells was performed. Using dimethylation labeling-based quantitative proteomics, 832 acetylated proteins with 1391 lysine acetylation sites were identified in response to GCRV infection, among which 792 proteins with 1323 sites were quantifiable. Bioinformatics analysis showed that differentially expressed lysine acetylated proteins are involved in diverse cellular processes and associated with multifarious functions, suggesting that extensive intracellular activities were changed upon viral infection. In addition, extensive alterations on host-protein interactions at the lysine acetylation level were also detected. Further biological experiments showed that the histone deacetylases (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) could significantly suppress the GCRV replication. To our knowledge, this is the first to reveal the proteome-wide changes in host cell acetylome with aquatic virus infection. The results provided in this study laid a basis for further understanding the host response to aquareovirus infection in the post-translational modification aspect by regulating cell lysine acetylation conducive to viral replication.
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Affiliation(s)
- Hong Guo
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
| | - Jie Zhang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
| | - Yaping Wang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
| | - Chen Bu
- Jingjie PTM BioLab (Hangzhou) Co., Ltd., Hangzhou 310018, China.
| | - Yanyan Zhou
- Jingjie PTM BioLab (Hangzhou) Co., Ltd., Hangzhou 310018, China.
| | - Qin Fang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
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Crouchet E, Baumert TF, Schuster C. Hepatitis C virus-apolipoprotein interactions: molecular mechanisms and clinical impact. Expert Rev Proteomics 2017; 14:593-606. [PMID: 28625086 PMCID: PMC6138823 DOI: 10.1080/14789450.2017.1344102] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, hepatocellular carcinoma and liver failure. Moreover, chronic HCV infection is associated with liver steatosis and metabolic disorders. With 130-150 million people chronically infected in the world, HCV infection represents a major public health problem. One hallmark on the virus is its close link with hepatic lipid and lipoprotein metabolism. Areas covered: HCV is associated with lipoprotein components such as apolipoproteins. These interactions play a key role in the viral life cycle, viral persistence and pathogenesis of liver disease. This review introduces first the role of apolipoproteins in lipoprotein metabolism, then highlights the molecular mechanisms of HCV-lipoprotein interactions and finally discusses their clinical impact. Expert commentary: While the study of virus-host interactions has resulted in a improvement of the understanding of the viral life cycle and the development of highly efficient therapies, major challenges remain: access to therapy is limited and an urgently needed HCV vaccine remains still elusive. Furthermore, the pathogenesis of disease biology is still only partially understood. The investigation of HCV-lipoproteins interactions offers new perspectives for novel therapeutic approaches, contribute to HCV vaccine design and understand virus-induced liver disease and cancer.
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Affiliation(s)
- Emilie Crouchet
- Inserm, U1110: Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
| | - Thomas F. Baumert
- Inserm, U1110: Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Pôle hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Catherine Schuster
- Inserm, U1110: Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
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Ueki S, Murakami Y, Yamada S, Kimura M, Saito Y, Saito H. microRNA-mediated resistance to hypoglycemia in the HepG2 human hepatoma cell line. BMC Cancer 2016; 16:732. [PMID: 27629773 PMCID: PMC5024426 DOI: 10.1186/s12885-016-2762-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 09/06/2016] [Indexed: 12/20/2022] Open
Abstract
Background It is generally accepted that the energy resources of cancer cells rely on anaerobic metabolism or the glycolytic system, even if they have sufficient oxygen. This is known as the Warburg effect. The cells skillfully survive under hypoglycemic conditions when their circumstances change, which probably at least partly involves microRNA (miRNA)-mediated regulation. Methods To determine how cancer cells exploit miRNA-mediated epigenetic mechanisms to survive in hypoglycemic conditions, we used DNA microarray analysis to comprehensively and simultaneously compare the expression of miRNAs and mRNAs in the HepG2 human hepatoma cell line and in cultured normal human hepatocytes. Results The hypoglycemic condition decreased the expression of miRNA-17-5p and -20a-5p in hepatoma cells and consequently upregulated the expression of their target gene p21. These regulations were also confirmed by using antisense inhibitors of these miRNAs. In addition to this change, the hypoglycemic condition led to upregulated expression of heat shock proteins and increased resistance to caspase-3-induced apoptosis. However, we could not identify miRNA-mediated regulations, despite using comprehensive detection. Several interesting genes were also found to be upregulated in the hypoglycemic condition by the microarray analysis, probably because of responding to this cellular stress. Conclusion These results suggest that cancer cells skillfully survive in hypoglycemic conditions, which frequently occur in malignancies, and that some of the gene regulation of this process is manipulated by miRNAs. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2762-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Satomi Ueki
- Department of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 1058512, Japan
| | - Yuko Murakami
- Department of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 1058512, Japan
| | - Shoji Yamada
- Department of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 1058512, Japan
| | - Masaki Kimura
- Department of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 1058512, Japan
| | - Yoshimasa Saito
- Department of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 1058512, Japan
| | - Hidetsugu Saito
- Department of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, 1058512, Japan.
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Kozlov MV, Kleymenova AA, Konduktorov KA, Malikova AZ, Kamarova KA, Novikov RA, Kochetkov SN. Synthesis of (Z)-N-hydroxy-3-methoxy-3-phenylacrylamide as new selective inhibitor of hepatitis C virus replication. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2016. [DOI: 10.1134/s1068162016010076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Grassi G, Di Caprio G, Fimia GM, Ippolito G, Tripodi M, Alonzi T. Hepatitis C virus relies on lipoproteins for its life cycle. World J Gastroenterol 2016; 22:1953-1965. [PMID: 26877603 PMCID: PMC4726671 DOI: 10.3748/wjg.v22.i6.1953] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 10/19/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infects over 150 million people worldwide. In most cases, HCV infection becomes chronic causing liver disease ranging from fibrosis to cirrhosis and hepatocellular carcinoma. Viral persistence and pathogenesis are due to the ability of HCV to deregulate specific host processes, mainly lipid metabolism and innate immunity. In particular, HCV exploits the lipoprotein machineries for almost all steps of its life cycle. The aim of this review is to summarize current knowledge concerning the interplay between HCV and lipoprotein metabolism. We discuss the role played by members of lipoproteins in HCV entry, replication and virion production.
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25
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Sippl SP, White PB, Fry CG, Volk SE, Ye L, Schenck HL. Kinetic and thermodynamic characterization of C-N bond rotation by N-methylacetohydroxamic acid in aqueous media. MAGNETIC RESONANCE IN CHEMISTRY : MRC 2016; 54:46-50. [PMID: 26477862 DOI: 10.1002/mrc.4318] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 07/15/2015] [Accepted: 07/22/2015] [Indexed: 06/05/2023]
Abstract
Hydroxamic acids (HAs) perform tasks in medicine and industry that require bidentate metal binding. The two favored conformations of HAs are related by rotation around the C(=O)-N bond. The conformations are unequal in stability. Recently, we reported that the most stable conformation of a small secondary HA in water places the oxygen atoms anti to one another. The barrier to C-N bond rotation may therefore modulate metal binding by secondary HAs in aqueous media. We have now determined the activation barrier to C-N rotation from major to minor conformation of a small secondary HA in D2O to be 67.3 kJ/mol. The HA rotational barrier scales with solvent polarity, as is observed in amides, although the HA barrier is less than that of a comparable tertiary amide in aqueous solution. Successful design of new secondary HAs to perform specific tasks requires solid understanding of rules governing HA structural behavior. Results from this work provide a more complete foundation for HA design efforts.
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Affiliation(s)
- Stefanie P Sippl
- Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, La Crosse, WI, USA
| | - Paul B White
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Charles G Fry
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Sarah E Volk
- Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, La Crosse, WI, USA
| | - Lingxiao Ye
- Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, La Crosse, WI, USA
| | - Heather L Schenck
- Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, La Crosse, WI, USA
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26
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Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection. Viruses 2015; 7:5659-85. [PMID: 26540069 PMCID: PMC4664971 DOI: 10.3390/v7112898] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 09/25/2015] [Accepted: 10/19/2015] [Indexed: 12/13/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.
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Alizadeh E, Eslaminejad MB, Akbarzadeh A, Sadeghi Z, Abasi M, Herizchi R, Zarghami N. Upregulation of MiR-122 via Trichostatin A Treatments in Hepatocyte-like Cells Derived from Mesenchymal Stem Cells. Chem Biol Drug Des 2015; 87:296-305. [PMID: 26360933 DOI: 10.1111/cbdd.12664] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Revised: 08/29/2015] [Accepted: 08/31/2015] [Indexed: 12/13/2022]
Abstract
The miR-122 is a tissue-specific miRNA; its expression is abundant in liver. MiR-122 upregulation is crucial for differentiation, functionality, and maintenance of differentiated phenotype in hepatocytes. The improving effects of trichostatin A (TSA) on hepatic differentiation have been reported previously. The aim of this study was to determine whether TSA can affect the expression of miR-122 in hepatocyte-like cells (HLCs) generated from human adipose tissue-derived mesenchymal stem cells (hAT-MSCs). The hepatic differentiation of hAT-MSCs induced by a mixture of growth factors and cytokines either with or without TSA treatments. The functionality of HLCs generated with or without TSA and the expression levels of miR-122 were studied. The expression levels of miR-122 in TSA-treated HLCs was significantly (p < 0.05) higher than those generated by growth factors and cytokines, only. The downregulation of a-fetoprotein (AFP) levels but enhanced albumin synthesis (p < 0.05) and upregulation of liver-enriched transcription factors (LETFs) HNF4α (hepatocyte nuclear factor 4α) and HNF6 (hepatocyte nuclear factor 6) were observed in TSA-treated HLCs (p < 0.05). In conclusion, administration of TSA in hepatogenic differentiation of hAT-MSCs resulted in higher expression levels of miR-122, facilitation of differentiation, and subsequently attenuation of AFP levels.
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Affiliation(s)
- Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Ave., Tabriz 3137851656, I.R. Iran
| | - MohamadReza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology at Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Royan Institute, Tehran, I.R. Iran
| | - Abolfazl Akbarzadeh
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Ave., Tabriz 3137851656, I.R. Iran
| | - Zohre Sadeghi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Ave., Tabriz 3137851656, I.R. Iran
| | - Mozghan Abasi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Ave., Tabriz 3137851656, I.R. Iran
| | - Roya Herizchi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Ave., Tabriz 3137851656, I.R. Iran
| | - Nosratollah Zarghami
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Golgasht Ave., Tabriz 3137851656, I.R. Iran.,The Umbilical Cord Stem Cell Research Center (UCSRC), Tabriz University of Medical Sciences, Golgasht Ave., Tabriz 3137851656, I.R. Iran
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Kanda T, Sasaki R, Nakamoto S, Haga Y, Nakamura M, Shirasawa H, Okamoto H, Yokosuka O. The sirtuin inhibitor sirtinol inhibits hepatitis A virus (HAV) replication by inhibiting HAV internal ribosomal entry site activity. Biochem Biophys Res Commun 2015; 466:567-71. [PMID: 26388050 DOI: 10.1016/j.bbrc.2015.09.083] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 09/14/2015] [Indexed: 12/14/2022]
Abstract
Epigenetics plays a role in the regulation of gene expression. Epigenetic changes control gene expression at the transcriptional level. Our previous study suggested that the La protein, which is mainly localized in the nucleus, was associated with hepatitis A virus (HAV) internal ribosomal entry site (IRES)-mediated translation and HAV replication. The aim of this study was to investigate whether epigenetic compounds have effects on HAV IRES-mediated translation and HAV replication. Sirtinol, a sirtuin inhibitor, inhibited HAV IRES-mediated translation in COS7-HAV-IRES cells. Treatment with 10 μM sirtinol resulted in a significant reduction in the intracellular RNA levels of HAV HA11-1299 genotype IIIA in Huh7 cells. Epigenetic treatment with a sirtuin inhibitor may represent a new treatment option for HAV infection. In conclusion, epigenetic control was involved in HAV IRES-dependent translation and HAV replication. Special attention should also be paid to underlying viral diseases in the clinical use of epigenetic treatments for malignancies.
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Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Reina Sasaki
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Yuki Haga
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Masato Nakamura
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Hiroshi Shirasawa
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
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Inhibition of Histone Deacetylase Activity Aggravates Coxsackievirus B3-Induced Myocarditis by Promoting Viral Replication and Myocardial Apoptosis. J Virol 2015; 89:10512-23. [PMID: 26269170 PMCID: PMC4580191 DOI: 10.1128/jvi.01028-15] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 07/28/2015] [Indexed: 01/09/2023] Open
Abstract
Viral myocarditis, which is most prevalently caused by coxsackievirus B3 (CVB3), is a serious clinical condition characterized by excessive myocardial inflammation. Recent studies suggest that regulation of protein acetylation levels by inhibiting histone deacetylase (HDAC) activity modulates inflammatory response and shows promise as a therapy for several inflammatory diseases. However, the role of HDAC activity in viral myocarditis is still not fully understood. Here, we aim to investigate the role of HDAC activity in viral myocarditis and its underlying mechanism. CVB3-infected BALB/c mice were treated with the HDAC inhibitor (HDACI) suberoylanilide hydroxamic acid (SAHA) or trichostatin A (TSA). We found inhibition of HDAC activity aggravated rather than ameliorated the severity of CVB3-induced myocarditis, which was contrary to our expectations. The aggravated myocarditis by HDACI treatment seemed not to be caused by an elevated inflammatory response but by the increased CVB3 replication. Further, it was revealed that the increased CVB3 replication was closely associated with the HDACI-enhanced autophagosome formation. Inhibition of autophagosome formation by wortmannin or ATG5 short hairpin RNA dramatically suppressed the HDACI-increased CVB3 replication. The increased viral replication subsequently elevated CVB3-induced myocardial apoptosis. Conversely, inhibition of CVB3 replication and ensuing myocardial apoptosis by the antiviral drug ribavirin significantly reversed the HDACI-aggravated viral myocarditis. In conclusion, we elucidate that the inhibition of HDAC activity increases CVB3 replication and ensuing myocardial apoptosis, resulting in aggravated viral myocarditis. Possible adverse consequences of administering HDACI should be considered in patients infected (or coinfected) with CVB3. IMPORTANCE Viral myocarditis, which is most prevalently caused by CVB3, is characterized by excessive myocardial inflammation. Inhibition of HDAC activity was originally identified as a powerful anti-cancer therapeutic strategy and was recently found to be implicated in the regulation of inflammatory response. HDACI has been demonstrated to be efficacious in animal models of several inflammatory diseases. Thus, we hypothesize that inhibition of HDAC activity also protects against CVB3-induced viral myocarditis. Surprisingly, we found inhibition of HDAC activity enhanced myocardial autophagosome formation, which led to the elevated CVB3 viral replication and ensuing increased myocardial apoptosis. Viral myocarditis was eventually aggravated rather than ameliorated by HDAC inhibition. In conclusion, we elucidate the role of HDAC activity in viral myocarditis. Moreover, given the importance of HDACI in preclinical and clinical treatments, the possible unfavorable effect of HDACI should be carefully evaluated in patients infected with viruses, including CVB3.
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Repurposing of HDAC inhibitors toward anti-hepatitis C virus drug discovery: teaching an old dog new tricks. Future Med Chem 2015; 7:1367-71. [DOI: 10.4155/fmc.15.76] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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31
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Chu PS, Ebinuma H, Nakamoto N, Sugiyama K, Usui S, Wakayama Y, Taniki N, Yamaguchi A, Shiba S, Yamagishi Y, Wakita T, Hibi T, Saito H, Kanai T. Genotype-Associated Differential NKG2D Expression on CD56+CD3+ Lymphocytes Predicts Response to Pegylated-Interferon/Ribavirin Therapy in Chronic Hepatitis C. PLoS One 2015; 10:e0125664. [PMID: 25965701 PMCID: PMC4428701 DOI: 10.1371/journal.pone.0125664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Accepted: 03/16/2015] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) genotype 1 infections are significantly more difficult to eradicate with PEG-IFN/ribavirin therapy, compared to HCV genotype 2. The aim of this work is to investigate the difference of immunological impairments underlying this phenomenon. Pre-treatment NKG2D expression on peripheral CD56+CD3+ lymphocytes and CD56+CD3- NK cells from cases of chronic hepatitis C were analyzed and assessed by treatment effect. Two strains of HCV were used to co-incubate with immune cells in vitro. NKG2D expression on peripheral CD56+CD3+ lymphocytes, but not NK cells, was significantly impaired in genotype 1 infection, compared to genotype 2. When peripheral blood mononuclear cells from healthy donors were co-incubated with TNS2J1, a genotype 1b/2a chimera strain, or with JFH1, a genotype 2a strain, genotype-specific decrease of NKG2D on CD56+CD3+ lymphocytes, but not NK cells, was observed. Pre-treatment NKG2D expression on peripheral CD56+CD3+ lymphocytes significantly correlated with reduction in serum HCV RNA levels from week 0 to week 4, and predicted treatment response. Ex vivo stimulation of peripheral CD56+CD3+ lymphocytes showed NKG2D expression-correlated IFN-γ production. In conclusion, Decreased NKG2D expression on CD56+CD3+ lymphocytes in chronic HCV genotype 1 infection predicts inferior treatment response to PEG-IFN/ribavirin therapy compared to genotype 2.
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Affiliation(s)
- Po-sung Chu
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Hirotoshi Ebinuma
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Nobuhiro Nakamoto
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Kazuo Sugiyama
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Shingo Usui
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Yuko Wakayama
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Nobuhito Taniki
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Akihiro Yamaguchi
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Shunsuke Shiba
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Yoshiyuki Yamagishi
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
| | - Hidetsugu Saito
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
- Division of Pharmacotherapeutics, School of Pharmacy, Keio University, Tokyo, Japan
| | - Takanori Kanai
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
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Kozlov MV, Kleymenova AA, Konduktorov KA, Malikova AZ, Kochetkov SN. Selective inhibitor of histone deacetylase 6 (tubastatin A) suppresses proliferation of hepatitis C virus replicon in culture of human hepatocytes. BIOCHEMISTRY (MOSCOW) 2015; 79:637-42. [PMID: 25108326 DOI: 10.1134/s0006297914070050] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Acetylation of α-tubulin was studied in cultures of human hepatocytes under the influence of selective inhibitors of histone deacetylases HDAC6 and SIRT-2 - tubastatin A and 2-(3-phenethoxyphenylamino)benzamide, respectively. It was found that in hepatocyte cell line HepG2 acetylated α-tubulin is accumulated preferentially on inhibition of HDAC6 but not of SIRT-2. Under the same conditions, no acetylation of α-tubulin was observed in hepatocyte cell line Huh7. However, the inhibition of HDAC6 with tubastatin A led to hyperacetylation of α-tubulin and simultaneously to decrease in viral RNA concentration in hepatocyte cell line Huh7-luc/neo, which supports propagation of the full genome replicon of hepatitis C virus. The correlation between these two processes points to HDAC6 as a promising cellular target for therapy of hepatitis C.
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Affiliation(s)
- M V Kozlov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
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Ai T, Xu Y, Qiu L, Geraghty RJ, Chen L. Hydroxamic Acids Block Replication of Hepatitis C Virus. J Med Chem 2014; 58:785-800. [DOI: 10.1021/jm501330g] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Teng Ai
- Center for Drug Design, Academic
Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, Minnesota 55455, United States
| | - Yanli Xu
- Center for Drug Design, Academic
Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, Minnesota 55455, United States
| | - Li Qiu
- Center for Drug Design, Academic
Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, Minnesota 55455, United States
| | - Robert J. Geraghty
- Center for Drug Design, Academic
Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, Minnesota 55455, United States
| | - Liqiang Chen
- Center for Drug Design, Academic
Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, Minnesota 55455, United States
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Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells. Oncogenesis 2014; 3:e104. [PMID: 24861464 PMCID: PMC4035694 DOI: 10.1038/oncsis.2014.17] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 03/28/2014] [Accepted: 04/10/2014] [Indexed: 12/14/2022] Open
Abstract
Enhancer of zeste homolog 2 (EZH2) enhances tumorigenesis and is commonly overexpressed in several types of cancer. To investigate the anticancer effects of EZH2 inhibitors, microRNA (miRNA) expression profiles were examined in gastric and liver cancer cells treated with suberoylanilide hydroxamic acid (SAHA) and 3-deazaneplanocin A (DZNep). We confirmed that SAHA and DZNep suppressed EZH2 expression in AGS and HepG2 cells and inhibited their proliferation. The results of microarray analyses demonstrated that miR-1246 was commonly upregulated in cancer cells by treatment with SAHA and DZNep. MiR-302a and miR-4448 were markedly upregulated by treatment with SAHA and DZNep, respectively. DYRK1A, CDK2, BMI-1 and Girdin, which are targets of miR-1246, miR-302a and miR-4448, were suppressed by treatment with SAHA and DZNep, leading to apoptosis, cell cycle arrest and reduced migration of AGS and HepG2 cells. ChIP assay revealed that SAHA and DZNep inhibited the binding of EZH2 to the promoter regions of miR-1246, miR-302a and miR-4448. These findings suggest that EZH2 inhibitors such as SAHA and DZNep exert multiple anticancer effects through activation of tumor-suppressor miRNAs.
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Saito Y, Hibino S, Saito H. Alterations of epigenetics and microRNA in hepatocellular carcinoma. Hepatol Res 2014; 44:31-42. [PMID: 23617364 DOI: 10.1111/hepr.12147] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 04/12/2013] [Accepted: 04/21/2013] [Indexed: 01/05/2023]
Abstract
Studies have shown that alterations of epigenetics and microRNA (miRNA) play critical roles in the initiation and progression of hepatocellular carcinoma (HCC). Epigenetic silencing of tumor suppressor genes in HCC is generally mediated by DNA hypermethylation of CpG island promoters and histone modifications such as histone deacetylation, methylation of histone H3 lysine 9 (H3K9) and tri-methylation of H3K27. Chromatin-modifying drugs such as DNA methylation inhibitors and histone deacetylase inhibitors have shown clinical promise for cancer therapy. miRNA are small non-coding RNA that regulate expression of various target genes. Specific miRNA are aberrantly expressed and play roles as tumor suppressors or oncogenes during hepatocarcinogenesis. We and other groups have demonstrated that important tumor suppressor miRNA are silenced by epigenetic alterations, resulting in activation of target oncogenes in human malignancies including HCC. Restoring the expression of tumor suppressor miRNA by inhibitors of DNA methylation and histone deacetylase may be a promising therapeutic strategy for HCC.
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Affiliation(s)
- Yoshimasa Saito
- Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
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Li MR, Lu LG, Bu P. Advances in research of epigenetic regulation in liver fibrosis. Shijie Huaren Xiaohua Zazhi 2013; 21:3499-3504. [DOI: 10.11569/wcjd.v21.i32.3499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a pathological repair process in response to chronic injury caused by various etiologies in the liver. Imbalance between the expression of pro-fibrosis genes and anti-fibrosis genes play a pivotal role in hepatic fibrosis. The important path of reversing liver fibrosis is the early diagnosis and effective treatment. Epigenetic modifications have been considered an initial event in the development of hepatic fibrosis. Epigenetic regulatory mechanisms in liver fibrosis are intricate, including DNA methylation, histone modification, and microRNAs (miRNAs). Recently, many researchers have studied the effect of fibrosis-related gene expression at the epigenetic level on hepatic stellate cell activation and myofibroblast differentiation in hepatic fibrosis. This review discusses the epigenetic regulation in liver fibrosis, with an aim to provide new insights into the early non-invasive diagnosis, condition assessment and targeted therapy of this disease.
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