期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 96, 期 -, 页码 347-361出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2016.04.021
关键词
Rupestonic acid derivative; Influenza virus; Heme oxygenase-1; Type I interferon
资金
- Science Fund for Creative Research Groups of the National Natural Science Foundation of China [81321004]
- Open Subject of the Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences [2008DP173091-2012-01]
- Xinjiang High-Tech RD Program [201317101]
- Doctorial Innovation Fund of Peking Union Medical College [2013-1007-08]
Given the limitation of available antiviral drugs and vaccines, there remains to be a pressing need for novel anti-influenza drugs. Rupestonic acid derivatives were reported to have an anti-influenza virus activity, but their mechanism remains to be elucidated. Herein, we aim to evaluate the antiviral activity of YZH-106, a rupestonic acid derivative, against a broad-spectrum of influenza viruses and to dissect its antiviral mechanisms. Our results demonstrated that YZH-106 exhibited a broad-spectrum antiviral activity against influenza viruses, including drug-resistant strains in vitro. Furthermore, YZH-106 provided partial protection of the mice to Influenza A virus (IAV) infection, as judged by decreased viral load in lungs, improved lung pathology, reduced body weight loss and partial survival benefits. Mechanistically, YZH-106 induced p38 MAPK and ERK1/2 phosphorylation, which led to the activation of erythroid 2-related factor 2 (Nrf2) that up-regulated heme oxygenase-1 (HO-1) expression in addition to other genes. HO-1 inhibited IAV replication by activation of type I IFN expression and subsequent induction of IFN-stimulated genes (ISGs), possibly in a HO-1 enzymatic activity independent manner. These results suggest that YZH-106 inhibits IAV by up-regulating HO-1-mediated IFN response. HO-1 is thus a promising host target for antiviral therapeutics against influenza and other viral infectious diseases. (C) 2016 Elsevier Inc. All rights reserved.
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