期刊
SCIENTIFIC REPORTS
卷 6, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/srep32176
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资金
- Ministry Science and Technology of Taiwan [MOST104-2320-B-037-025-MY3, MOST103-2622-B-037-007-CC3, MOST103-2314-B-037-039-MY3]
- Kaohsiung Medical University [KMU-TP103H12, KMU-TP104H03]
- National Sun Yat-Sen University-KUM Joint Research Project [NSYSU-KMU 105-I003]
- Center for Dengue Fever Control and Research, Kaohsiung Medical University [MOHW104-CDC-C-114-114901]
Dengue virus (DENV) infection and replication induces oxidative stress, which further contributes to the progression and pathogenesis of the DENV infection. Modulation of host antioxidant molecules may be a useful strategy for interfering with DENV replication. In this study, we showed that induction or exogenous overexpression of heme oxygenase-1 (HO-1), an antioxidant enzyme, effectively inhibited DENV replication in DENV-infected Huh-7 cells. This antiviral effect of HO-1 was attenuated by its inhibitor tin protoporphyrin (SnPP), suggesting that HO-1 was an important cellular factor against DENV replication. Biliverdin but not carbon monoxide and ferrous ions, which are products of the HO-1 on heme, mediated the HO-1-induced anti-DENV effect by non-competitively inhibiting DENV protease, with an inhibition constant (Ki) of 8.55 +/- 0.38 mu M. Moreover, HO-1 induction or its exogenous overexpression, rescued DENV-suppressed antiviral interferon response. Moreover, we showed that HO-1 induction by cobalt protoporphyrin (CoPP) and andrographolide, a natural product, as evidenced by a significant delay in the onset of disease and mortality, and virus load in the infected mice's brains. These findings clearly revealed that a drug or therapy that induced the HO-1 signal pathway was a promising strategy for treating DENV infection.
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