title: Fluoxetine a novel anti-hepatitis C virus agent via ROS-, JNK-, and PPARβ/γ-dependent pathways.
abstract: More than 20% of chronic hepatitis C (CHC) patients receiving interferon-alpha (IFN-α)-based anti-hepatitis C virus (HCV) therapy experienced significant depression, which was relieved by treatment with fluoxetine. However, whether and how fluoxetine affected directly the anti-HCV therapy remained unclear. Here, we demonstrated that fluoxetine inhibited HCV infection and blocked the production of reactive oxygen species (ROS) and lipid accumulation in Huh7.5 cells. Fluoxetine facilitated the IFN-α-mediated antiviral actions via activations of signal transducer and activator of transcription (STAT)-1 and c-Jun amino-terminal kinases (JNK). Alternatively, fluoxetine elevated peroxisome proliferator-activated receptor (PPAR) response element activity under HCV infection. The inhibitory effects of fluoxetine on HCV infection and lipid accumulation, but not production of ROS, were partially reversed by the PPAR-β, -γ, and JNK antagonists. Furthermore, fluoxetine intervention to the IFN-α-2b regimen facilitated to reduce HCV titer and alanine transaminase level for CHC patients. Therefore, fluoxetine intervention to the IFN-α-2b regimen improved the efficacy of anti-HCV treatment, which might be related to blockades of ROS generation and lipid accumulation and activation of host antiviral JNK/STAT-1 and PPARβ/γ signals.
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Kung-Chia
authors.initials: KC
authors.lastname: Young
authors.affiliation: Department of Public Health, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Chyi-Huey
authors.initials: CH
authors.lastname: Bai
authors.affiliation: Department of Pharmacy, Chi-Mei Medical Center, Tainan, Taiwan, ROC.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Su
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Pei-Ju
authors.initials: PJ
authors.lastname: Tsai
authors.affiliation: Department of Public Health, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Pu
authors.affiliation: Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC.
authors.forename: Chao-Sheng
authors.initials: CS
authors.lastname: Liao
authors.affiliation: Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC.
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Lin
authors.affiliation: Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC.
authors.forename: Hsin-Wen
authors.initials: HW
authors.lastname: Lai
authors.affiliation: Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC.
authors.forename: Lee-Won
authors.initials: LW
authors.lastname: Chong
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Yau-Sheng
authors.initials: YS
authors.lastname: Tsai
authors.affiliation: Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan, ROC. Electronic address: tcwhmy@ms58.hinet.net.
authors.forename: Chiung-Wen
authors.initials: CW
authors.lastname: Tsao
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use*; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D048068:PPAR-beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D012367:RNA, Viral / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012189:Retrospective Studies; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D050794:STAT1 Transcription Factor / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047495:PPAR gamma; D048068:PPAR-beta; D012367:RNA, Viral; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D005473:Fluoxetine; D011092:Polyethylene Glycols; D012254:Ribavirin; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases; C417083:peginterferon alfa-2b
keywords: Fluoxetine; Hepatitis C virus; Interferon-α; JNK; PPAR-β/γ; STAT-1