Anti-influenza A virus activity of rhein through regulating oxidative stress, TLR4, Akt, MAPK, and NF-κB signal pathways

• Published in: PloS one Vol. 13; no. 1; p. e0191793
• Main Authors: Wang, Qian-Wen, Su, Yun, Sheng, Jiang-Tao, Gu, Li-Ming, Zhao, Ying, Chen, Xiao-Xuan, Chen, Cheng, Li, Wei-Zhong, Li, Kang-Sheng, Dai, Jian-Ping
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2018; Public Library of Science (PLoS)
• Subjects: A549 Cells; Adsorption; AKT protein; Animals; Anthraquinone; Anthraquinones - pharmacology; Antioxidants; Antiviral Agents - pharmacology; Assaying; Biology and life sciences; Cytokines; Cytokines - biosynthesis; Cytotoxicity; Dogs; Drugs; Enzyme-linked immunosorbent assay; Female; Herbal medicine; Humans; Hydrogen peroxide; Immunology; In vivo methods and tests; Infections; Inflammation; Influenza; Influenza A; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H1N1 Subtype - pathogenicity; Influenza A Virus, H1N1 Subtype - physiology; JNK protein; Lung - drug effects; Lung - pathology; Lungs; Madin Darby Canine Kidney Cells; Male; MAP kinase; MAP Kinase Signaling System - drug effects; Matrix metalloproteinases; Matrix Metalloproteinases - biosynthesis; Medicine and health sciences; Mice; Mice, Inbred C57BL; NF-kappa B - metabolism; NF-κB protein; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - metabolism; Orthomyxoviridae Infections - virology; Oxidative stress; Oxidative Stress - drug effects; Pandemics; Physical Sciences; Pneumonia, Viral - drug therapy; Pneumonia, Viral - pathology; Pneumonia, Viral - physiopathology; Proto-Oncogene Proteins c-akt - metabolism; Replication; Rodents; Signal Transduction - drug effects; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Virus Attachment - drug effects; Virus Replication - drug effects; Viruses; Western blotting; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0191793

Rhein, an anthraquinone compound existing in many traditional herbal medicines, has anti-inflammatory, antioxidant, antitumor, antiviral, hepatoprotective, and nephroprotective activities, but its anti-influenza A virus (IAV) activity is ambiguous. In the present study, through plaque inhibition assay, time-of-addition assay, antioxidant assay, qRT-PCR, ELISA, and western blotting assays, we investigated the anti-IAV effect and mechanism of action of rhein in vitro and in vivo. The results showed that rhein could significantly inhibit IAV adsorption and replication, decrease IAV-induced oxidative stress, activations of TLR4, Akt, p38, JNK MAPK, and NF-κB pathways, and production of inflammatory cytokines and matrix metalloproteinases in vitro. Oxidant H2O2 and agonists of TLR4, Akt, p38/JNK and IKK/NF-κB could significantly antagonize the inhibitory effects of rhein on IAV-induced cytopathic effect (CPE) and IAV replication. Through an in vivo test in mice, we also found that rhein could significantly improve the survival rate, lung index, pulmonary cytokines, and pulmonary histopathological changes. Rhein also significantly decreased pulmonary viral load at a high dose. In conclusion, rhein can inhibit IAV adsorption and replication, and the mechanism of action to inhibit IAV replication may be due to its ability to suppress IAV-induced oxidative stress and activations of TLR4, Akt, p38, JNK MAPK, and NF-κB signal pathways.