Browsing by Author "Wu, Yu-Hsuan"

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Cyclooxygenase-2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents
(2017-03-20)
Lin, Chun-Kuang
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Tseng, Chin-Kai
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Wu, Yu-Hsuan
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Liaw, Chih-Chuang
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Lin, Chun-Yu
Cyclooxygenase-2 (COX-2) is one of the important mediators of inflammation in response to viral infection, and it contributes to viral replication, for example, cytomegalovirus or hepatitis C virus replication. The role of COX-2 in dengue virus (DENV) replication remains unclear. In the present study, we observed an increased level of COX-2 in patients with dengue fever compared with healthy donors. Consistent with the clinical data, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. Using cell-based experiments, we revealed that DENV-2 infection significantly induced COX-2 expression and prostaglandin E-2 (PGE(2)) production in human hepatoma Huh-7 cells. The exogenous expression of COX-2 or PGE2 treatment dose-dependently enhanced DENV-2 replication. In contrast, COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. In an ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection. By using COX-2 promoter-based analysis and specific inhibitors against signaling molecules, we identified that NF-kappa B and MAPK/JNK are critical factors for DENV-2-induced COX-2 expression and viral replication. Altogether, our results reveal that COX-2 is an important factor for DENV replication and can serve as a potential target for developing therapeutic agents against DENV infection.
Human heme oxygenase 1 is a potential host cell factor against dengue virus replication
(2016-08-24)
Tseng, Chin-Kai
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Lin, Chun-Kuang
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Wu, Yu-Hsuan
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Chen, Yen-Hsu
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Chen, Wei-Chun
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.
Lucidone suppresses dengue viral replication through the induction of heme oxygenase-1
(2018-01-01)
Chen, Wei-Chun
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Tseng, Chin-Kai
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Lin, Chun-Kuang
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Wang, Shen-Nien
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Wang, Wen-Hung
Dengue virus (DENV) infection causes life-threatening diseases such as dengue hemorrhagic fever and dengue shock syndrome. Currently, there is no effective therapeutic agent or vaccine against DENV infection; hence, there is an urgent need to discover anti-DENV agents. The potential therapeutic efficacy of lucidone was first evaluated in vivo using a DENV-infected Institute of Cancer Research (ICR) suckling mouse model by monitoring body weight, clinical score, survival rate, and viral titer. We found that lucidone effectively protected mice from DENV infection by sustaining survival rate and reducing viral titers in DENV-infected ICR suckling mice. Then, the anti-DENV activity of lucidone was confirmed by western blotting and quantitative-reverse-transcription-polymerase chain reaction analysis, with an EC50 value of 25 +/- 3 mu M. Lucidone significantly induced heme oxygenase-1 (HO-1) production against DENV replication by inhibiting DENV NS2B/3 protease activity to induce the DENV-suppressed antiviral interferon response. The inhibitory effect of lucidone on DENV replication was attenuated by silencing of HO-1 gene expression or blocking HO-1 activity. In addition, lucidone-stimulated nuclear factor erythroid 2-related factor 2 (Nrf2), which is involved in transactivation of HO-1 expression for its anti-DENV activity. Taken together, the mechanistic investigations revealed that lucidone exhibits significant anti-DENV activity in in vivo and in vitro by inducing Nrf2-mediated HO-1 expression, leading to blockage of viral protease activity to induce the anti-viral interferon (IFN) response. These results suggest that lucidone is a promising candidate for drug development.
Optimizing influenza vaccine policies for controlling 2009-like pandemics and regular outbreaks
(2019-01-28)
Chen, Sheng-I
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Wu, Chia-Yuan
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Wu, Yu-Hsuan
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Hsieh, Min-Wei
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工業工程與管理學系
Background. This study examined the effectiveness of various vaccine policies against influenza. The transmission rate was calculated by use of the time-series influenza-like illness case during the year of 2009 and recent epidemics in Taiwan. Methods. We developed a stochastic compartmental model to analyze the transmission of influenza, where the population was stratified by location and age group, and the vaccine distribution was considered using the current policy. The simulation study compared the previous vaccine policy and a new policy with expanded coverage and various lengths of the vaccination campaign. The sensitivity analysis investigated different levels of vaccine efficacy to confirm the robustness of the recommended policies. Results. Doubling vaccine coverage can decrease the number of infections effectively in the regular epidemic scenario. However, a peak of infections occurs if the duration of implementing vaccination is too long. In the 2009-like pandemic scenario, both increasing vaccine doses and reducing the program's duration can mitigate infections, although the early outbreak restricts the effectiveness of vaccination programs. Conclusions. The finding indicates that only increasing vaccine coverage can reduce influenza infections. To avoid the peak of infections, it is also necessary to execute the vaccination activity immediately. Vaccine efficacy significantly impacts the vaccination policy's performance. When vaccine efficacy is low, neither increasing vaccination doses nor reducing vaccination timeframe prevents infections. Therefore, the variation in vaccine efficacy should be taken into account when making immunization policies against influenza.
Properties of organosilicate low-k films with 1,3-and 1,3,5-benzene bridges between Si atoms
(2020-07-01)
Liu, Chunhui
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Lv, Chunguang
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Kohler, Nicole
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Wang, Xuesong
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Lin, Hongxiao
Organosilicate (OSG) low dielectric constant films containing different concentrations of 1,3- and 1,3,5-benzene bridges between Si atoms are fabricated using 1,3,5-tribromobenzene via spin-on deposition and evaporation induced self-assembling. Chemical composition, pore structure, mechanical, dielectric and hydrophobic properties of as-prepared benzene bridged OSG thin films are studied using nuclear magnetic resonance, Fourier-transform infrared spectroscopy, ellipsometric porosimetry, nanoindentation, CV measurements and water contact angle. The precursors were synthesized by using two methods with the goal of understanding the effect of 1,3,5-benzene concentration on the films properties. It is shown that the films have very small pore size that does not change with porosity. No significant change in mechanical properties was observed at two different ratios of 1,3- and 1,3,5-benzene bridged films. (C) 2020 The Japan Society of Applied Physics
Prostasin Impairs Epithelial Growth Factor Receptor Activation to Suppress Dengue Virus Propagation
(2019-05-01)
Lin, Chun-Kuang
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Tseng, Chin-Kai
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Wu, Yu-Hsuan
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Lin, Chun-Yu
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Huang, Chung-Hao
Background. Dengue virus (DENV), a common and widely spread arbovirus, causes life-threatening diseases, such as dengue hemorrhagic fever or dengue shock syndrome. There is currently no effective therapeutic or preventive treatment for DENV infection. Methods. Next-generation sequencing analysis revealed that prostasin expression was decreased upon DENV infection. Prostasin expression levels were confirmed by real-time quantitative polymerase chain reaction in patients with dengue fever and a DENV-infected mice model. Short hairpin RNA against EGFR and LY294002 were used to investigate the molecular mechanism. Results. Based on clinical studies, we first found relatively low expression of prostasin, a glycosylphosphatidyl inositol-anchored membrane protease, in blood samples from patients with dengue fever compared with healthy individuals and a high correlation of prostasin expression and DENV-2 RNA copy number. DENV infection significantly decreased prostasin RNA levels of in vivo and in vitro models. By contrast, exogenous expression of prostasin could protect ICR suckling mice from life-threatening DENV-2 infection. Mechanistic studies showed that inhibition of DENV propagation by prostasin was due to reducing expression of epithelial growth factor receptor, leading to suppression of the Akt/NF-kappa B-mediated cyclooxygenase-2 signaling pathway. Conclusion. Our results demonstrate that prostasin expression is a noteworthy clinical feature and a potential therapeutic target against DENV infection.