title: Antiviral activity of aloe-emodin against influenza A virus via galectin-3 up-regulation.
abstract: Novel influenza A H7N9 virus, which emerged in 2013, and highly pathogenic H5N1 virus, identified since 2003, pose challenges to public health and necessitate quest for new anti-influenza compounds. Anthraquinone derivatives like aloe-emodin, emodin and chrysophanol, reportedly exhibit antiviral activity. This study probes their inhibitory mechanism and effect against influenza A virus. Of three anthraquinone derivatives, aloe-emodin, with a lower cytotoxicity showed concentration-dependently reducing virus-induced cytopathic effect and inhibiting replication of influenza A in MDCK cells. 50% inhibitory concentration value of aloe-emodin on virus yield was less than 0.05 μg/ml. Proteomics and Western blot of MDCK cells indicated aloe-emodin up-regulating galectin-3, and thioredoxin as well as down-regulating nucleoside diphosphate kinase A. Western blot and quantitative PCR confirmed aloe-emodin up-regulating galectin-3 expression; recombinant galectin-3 augmented expression of antiviral genes IFN-β, IFN-γ, PKR and 2'5',-OAS in infected cells, agreeing with expression pattern of those treated with aloe-emodin. Galectin-3 also inhibited influenza A virus replication. Proteomic analysis of treated cells indicated galectin-3 up-regulation as one anti-influenza A virus action by aloe-emodin. Since galectin-3 exhibited cytokine-like regulatory actions via JAK/STAT pathways, aloe-emodin also restored NS1-inhibited STAT1-mediated antiviral responses in transfected cells: e.g., STAT1 phosphorylation of interferon (IFN) stimulation response element (ISRE)-driven promoter, RNA-dependent protein kinase (PKR) and 2'5',-oligoadenylate synthetase (2'5',-OAS) expression. Treatment with aloe-emodin could control influenza infection in humans.
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan.
authors.forename: Shih-Wen
authors.initials: SW
authors.lastname: Li
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming University, Taipei, Taiwan.
authors.forename: Tsuey-Ching
authors.initials: TC
authors.lastname: Yang
authors.affiliation: Institute of Molecular Biology, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Chien-Chen
authors.initials: CC
authors.lastname: Lai
authors.affiliation: Department of Biotechnology and Bioinformatics, Asia University, Taichung 413, Taiwan.
authors.forename: Su-Hua
authors.initials: SH
authors.lastname: Huang
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan.
authors.forename: Jun-Ming
authors.initials: JM
authors.lastname: Liao
authors.affiliation: Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Lei
authors.initials: L
authors.lastname: Wan
authors.affiliation: Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan; Department of Biotechnology and Bioinformatics, Asia University, Taichung 413, Taiwan. Electronic address: cwlin@mail.cmu.edu.tw.
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Lin
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D004285:Dogs; D037502:Galectin 3 / Q000235:genetics*; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000502:physiology; D007370:Interferon Type I / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D040901:Proteomics; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000880:Anthraquinones; D000998:Antiviral Agents; D037502:Galectin 3; C085820:INS1 protein, influenza virus; D007370:Interferon Type I; D050791:STAT Transcription Factors; D017361:Viral Nonstructural Proteins; C518327:aloe emodin; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Aloe-emodin; Anthraquinone; Galectin-3; Influenza A virus