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AR-12通过下调PI3K/AKT和GRP78来抑制登革病毒复制。

AR-12 suppresses dengue virus replication by down-regulation of PI3K/AKT and GRP78.

作者信息

Chen Hsin-Hsin, Chen Chien-Chin, Lin Yee-Shin, Chang Po-Chun, Lu Zi-Yi, Lin Chiou-Feng, Chen Chia-Ling, Chang Chih-Peng

机构信息

Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Department of Pathology, Chia-Yi Christian Hospital, Chiayi 600, Taiwan; Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan 701, Taiwan.

出版信息

Antiviral Res. 2017 Jun;142:158-168. doi: 10.1016/j.antiviral.2017.02.015. Epub 2017 Feb 24.

Abstract

Dengue virus (DENV) infection has become a public health issue of worldwide concern and is a serious health problem in Taiwan, yet there are no approved effective antiviral drugs to treat DENV. The replication of DENV requires both viral and cellular factors. Targeting host factors may provide a potential antiviral strategy. It has been known that up-regulation of PI3K/AKT signaling and GRP78 by DENV infection supports its replication. AR-12, a celecoxib derivative with no inhibiting activity on cyclooxygenase, shows potent inhibitory activities on both PI3K/AKT signaling and GRP78 expression levels, and recently has been found to block the replication of several hemorrhagic fever viruses. However the efficacy of AR-12 in treating DENV infection is still unclear. Here, we provide evidence to show that AR-12 is able to suppress DENV replication before or after virus infection in cell culture and mice. The antiviral activities of AR-12 are positive against infection of the four different DENV serotypes. AR-12 significantly down-regulates the PI3K/AKT activity and GRP78 expression in DENV infected cells whereas AKT and GRP78 rescue are able to attenuate anti-DENV effect of AR-12. Using a DENV-infected suckling mice model, we further demonstrate that treatment of AR-12 before or after DENV infection reduces virus replication and mice mortality. In conclusion, we uncover the potential efficacy of AR-12 as a novel drug for treating dengue.

摘要

登革病毒(DENV)感染已成为全球关注的公共卫生问题,在台湾也是一个严重的健康问题,但目前尚无经批准的有效抗病毒药物来治疗登革病毒。登革病毒的复制需要病毒和细胞因子。靶向宿主因子可能提供一种潜在的抗病毒策略。已知登革病毒感染会导致PI3K/AKT信号通路和GRP78上调,从而支持其复制。AR-12是一种对环氧化酶无抑制活性的塞来昔布衍生物,对PI3K/AKT信号通路和GRP78表达水平均显示出强大的抑制活性,最近发现它能阻断几种出血热病毒的复制。然而,AR-12治疗登革病毒感染的疗效仍不清楚。在此,我们提供证据表明,AR-12能够在细胞培养和小鼠中抑制病毒感染前或感染后的登革病毒复制。AR-12的抗病毒活性对四种不同血清型的登革病毒感染均呈阳性。AR-12显著下调登革病毒感染细胞中的PI3K/AKT活性和GRP78表达,而AKT和GRP78的挽救能够减弱AR-12的抗登革病毒作用。使用登革病毒感染的乳鼠模型,我们进一步证明,在登革病毒感染前或感染后用AR-12治疗可减少病毒复制和小鼠死亡率。总之,我们揭示了AR-12作为一种治疗登革热的新型药物的潜在疗效。

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