C型肝炎病毒(Hepatitis C Virus; HCV)感染會造成慢性肝發炎，進而造成肝硬化及肝癌。登革熱病毒(dengue virus; DENV)感染導致急性自身的登革熱甚至造成威脅生命的出血性登革熱及登革休克症候群。本論文的目的是從海洋天然物中找尋抗病毒藥物，並且探討細胞內因子對於登革病毒複製之影響。為了找到具有潛力的抗病毒藥物，我們發現從海茄冬萃取出的betulinic acid (BA)及acteoside (AM-4)能夠抑制HCV複製，BA抑制HCV病毒複製的機轉是透過降低NF-κB及MAPK-ERK1/2所調控的第二型環氧合酶(cyclooxygenase-2, COX-2)；AM-4抑制HCV病毒感染是透過阻擋病毒進入細胞及病毒透過細胞與細胞之間的感染。更進一步，我們發現從軟珊瑚萃取出的lobohedleolide能夠透過降低HCV誘導的COX-2表現而抑制病毒複製，藉由數個刪除COX-2啟動子的luciferase冷光報導載體，我們首先發現CCAAT/enhancer-binding protein (C/EBP)對lobohedleolide降低COX-2表現是一個重要的轉錄因子，而lobohedleolide抑制HCV誘導的C/EBP表現是透過降低JNK及c-Jun磷酸化所造成的。值得注意的是，我們發現BA、AM-4及lobohedleolide在與臨床治療HCV的藥物進行合併治療能夠以加成反應方式抑制HCV複製，這結果指出這三個天然物具有高的生物醫學潛力成為控制HCV的輔助藥物。此外，我們發現BA及lobohedleolide亦具有抑制登革病毒複製的活性。為了從細胞基因中尋找抗DENV的治療標靶，我們從臨床登革病人檢體中我們發現COX-2表現量較健康者高，接著在DENV感染的ICR乳鼠中觀察到COX-2表現量提升，而當COX-2基因靜默或活性受到抑制時DENV複製就受到抑制，在ICR乳鼠模式中，我們發現COX-2抑制劑NS398能夠保護乳鼠免於危及生命的DENV感染，這些結果顯示針對COX-2是一個很好的方式去控制DENV感染。更進一步，我們從臨床登革病人檢體中發現絲氨酸蛋白水解酶prostasin表現量較健康者低，而當我們大量表現prostasin基因時能夠降低ICR乳鼠受到DENV感染造成的生存率下降並且能夠抑制DENV複製，我們更進一步發現prostasin抑制DENV複製是透過蛋白質水解切割表皮生長因子受體(epithelial growth factor receptor, EGFR)，而prostasin水解切割活性是依賴著matriptase及hepatocyte growth factor activator inhibitor type 2 (HAI-2)表現量。這些結果指出COX-2及prostasin有高度成為抗登革病毒的標靶基因的潛力。

Hepatitis C virus (HCV) infection causes chronic inflammation of liver, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Infection of dengue virus (DENV) caused diseases ranging from acute self-limiting febrile illness to life-threatening dengue hemorrhagic fever and dengue shock syndrome. The purposes of present dissertation are to discover the anti-viral agents from marine natural products and to investigate the impact of cellular factors on DENV replication. For finding the potential antivirals, we found that betulinic acid (BA) and acteoside (AM-4) extracted from Avicennia marina could reduce HCV replication. The mechanism study demonstrated that BA reduced HCV replication through decreasing the NF-κB- and ERK1/2-mediated cyclooxygenase-2 (COX-2) expression. The AM-4 suppressed HCV infection by blocking viral entry into cells and cell-to-cell spread of HCV. In addition, we identified that lobohedleolide extracted from soft coral exhibited anti-HCV activity by suppression of HCV-induced COX-2 expression. Using various COX-2 promoter deletion constructs linked to luciferase reporter gene, we first identified CCAAT/enhancer-binding protein (C/EBP) as a key transcription factor for the down-regulation of COX-2 by lobohedleolide, and then demonstrated that the HCV-induced C/EBP expression could be suppressed by lobohedleolide through inhibiting the phosphorylation of JNK and c-Jun. Notably, combination treatment of BA, AM-4 and lobohedleolide with several clinically used HCV drugs synergistically inhibited HCV RNA replication, indicating that these three natural products exhibited a high biomedical potential to be used as a supplementary agent for control of HCV infection. Besides, BA and lobohedleolide also exhibited anti-DENV activity. For finding the therapeutic targets from cellular gene against DENV, we observed an increased level of COX-2 in patients with dengue fever compared with healthy individuals. Then, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. Using ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection, revealing targeting COX-2 is a promising strategy to control DENV infection. In addition, we found that the expression of prostasin, a serine protease, is lower in patients with dengue fever than in healthy individuals. Exogenous expression of prostasin could protect ICR suckling mice from life-threatening DENV-2 infection and reduce DENV-2 propagation in Huh-7 cells. We further revealed that prostasin reduced DENV replication through proteolytic cleavage of epithelial growth factor receptor (EGFR). The activity of proteolytic cleavage of prostasin is dependent on the expression of matriptase and hepatocyte growth factor activator inhibitor type 2 (HAI-2). Collectively, COX-2 and prostasin exhibited highly potential to serve as therapeutic targets against DENV replication.

論文審定書 i
論文公開授權書 ii
致謝 iii
中文摘要 iv
Abstract vi
Catalogue viii
Objective 1
Chapter 1. Background 2
1-1. The virology of hepatitis C virus 2
1-2. Process of HCV entry 2
1-3. Current therapy of HCV 3
1-4. The virology of dengue virus (DENV) 4
1-5. The epidemiology of DENV 4
1-6. Pathogenesis and current therapy of DENV 5
1-7. The introduction of cyclooxygenase-2 (COX-2) and the relationship between HCV and COX-2 5
1-8. The relationship between DENV and COX-2 6
1-9. The introduction of Prostasin 6
1-10. The role of EGFR signaling on viral infection 7
1-11. The introduction of betulinic acid (BA) extracted from Avicennia marina (Fork) Vierh. 8
1-12. The introduction of three phenylethanoid glycosides extracted from Avicennia marina (Fork) Vierh. 9
1-13. The introduction of Lobohedleolide extracted from soft coral Lobophytum crassum. 9
Chapter 2. Material and Method 11
2-1. Ethics statement 11
2-2. COX-2, PEG2, and prostasin level in healthy donors and DENV patients 11
2-3. Cell Culture 12
2-4. Reagents 12
2-5. Preparation of BA 13
2-6. Preparation of lobohedleolide. 14
2-7. HCV particle preparation and infection assay. 14
2-8. DENV preparation and infection assay 14
2-9. Western blotting. 15
2-10. Real-time quantitative PCR (RT-qPCR) assay. 16
2-11. Cytotoxicity assay. 16
2-12. Transfection and luciferase activity assay. 16
2-13. PGE2 assay 17
2-14. Preparation of cytoplasmic and nuclear fractions 17
2-15. Analysis of the drug synergism. 18
2-16. Plaque assay 19
2-17. Anti-DENV-2-induced lethality of NS398 in an ICR suckling mouse model 19
2-18. Anti-DENV-2-induced lethality of prostasin in an ICR suckling mouse model 20
2-19. DENV-infection in AG129 mice 20
2-20. Statistical analysis 21
Chapter 3. Results 22
Development of antiviral drug from marine natural products 22
3-1. Betulinic acid (BA) bioactivity on HCV replication 22
3-1-1. BA inhibits HCV replication in the HCV replicon, HCV JFH-1-infected Huh7.5 cells and primary human hepatocytes 22
3-1-2. BA down-regulates COX-2 expression in HCV replicon, HCV JFH-1-infected Huh7.5 cells and primary human hepatocytes 23
3-1-3. BA inhibits HCV replication by suppressing COX-2 expression 24
3-1-4. BA-induced down-regulation of COX-2 expression correlates with blocking NF-κB signaling and the activation of MAPK-ERK1/2 25
3-1-5. BA synergistically inhibits HCV replication in combination treatment with various HCV inhibitors 26
3-2. Bioactivity of similar structure compounds of BA on DENV replication 27
3-3. Lobohedleolide bioactivity on HCV replication 27
3-3-1. Lobohedleolide reduces HCV replication in both HCV replicon and infectious system 27
3-3-2. Lobohedleolide suppresses HCV replication through inhibiting HCV-induced COX-2 expression and its activity 28
3-3-3. Lobohedleolide inhibits C/EBP transcription factor activity 30
3-3-4. Lobohedleolide reduces HCV-induced C/EBP expression, c-Jun phosphorylation, and the activation of JNK 31
3-3-5. Combination treatment of Lobohedleolide with various HCV inhibitors synergistically reduces HCV replication 32
3-4. Lobohedleolide bioactivity on DENV replication 33
3-4-1. Lobohedleolide reduced DENV protein expression and RNA replication. 33
3-4-2. Lobohedleolide delayed lethality from life-threatening DENV-2 infection in ICR suckling mice 33
3-5. Acteoside (AM-4) bioactivity on HCV entry 34
3-5-1. AM-4 reduced HCV infection through blocking virus entry but not replication 34
3-5-2. AM-4 blocked HCV entry but not RNA replication and viral assembly 34
3-5-3. AM-4 inhibited the early attachment step of HCV entry 35
3-5-4. AM-4 blocked cell-to-cell spread of HCV 36
3-5-5. AM-4 did not downregulate HCV binding receptors 37
3-5-6. Combination treatment of AM-4 with other antiviral agents promoted better viral clearance 37
Investigation of drug targeting genes against virus 38
3-6. Cyclooxygenase-2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents 38
3-6-1. COX-2 levels are elevated in patients with DF 38
3-6-2. DENV infection induces COX-2 expression in ICR suckling mice 38
3-6-3. DENV infection induces COX-2 expression and PGE2 production in hepatoma cells 39
3-6-4. COX-2 overexpression and the addition of PGE2 enhance DENV replication 39
3-6-5. DENV-2-elevated COX-2 expression and PGE2 production are required for DENV-2 replication 41
3-6-6. NS398 delays lethality from life-threatening DENV-2 infection in ICR suckling mice 44
3-6-7. DENV-2 elevates COX-2 promoter activation through mediation of NF-κB and C/EBP binding elements 45
3-6-8. NF-κB and MAPK/JNK-mediated C/EBP are responsible for DENV-2-induced COX-2 expression and viral replication 46
3-7. Prostasin impairs activation of epithelial growth factor receptor to suppress dengue virus propagation 48
3-7-1. Prostasin expression decreased in DENV-infected patients, mice, and hepatoma cell line 48
3-7-2. Postasin Overexpression decreases the mortality rate of DENV-infected ICR mice 49
3-7-3. Prostasin overexpression attenuates DENV propagation in Huh-7 cells 50
3-7-4. Prostasin overexpression suppresses DENV replication by reducing the COX-2 expression 51
3-7-5. Prostasin attenuates the EGFR-mediated COX-2 signaling pathway against DENV replication 52
3-7-6. Matriptase and HAI-2 regulate prostasin-mediated EGFR suppression to inhibit DENV replication 54
Chapter 4. Discussion 57
4-1. Alternative mechanism of BA on HCV replication 57
4-2. Alternative mechanism of lobohedleolide on HCV replication 57
4-3. The possible of BA and Lobohedleolide as a treatment against HCV 59
4-4. The importance and possible mechanism of COX-2 on DENV replication 60
4-5. The possible of COX-2 as a therapeutic target against DENV 60
4-6. The possible role of COX-2 in the pathogenesis of DHF 61
4-7. The possibility role of prostasin-mediated EGFR involved in DENV replication 62
Chapter 5. Conclusion 64
References 66
Figures catalogue
Figures and legends 80
Figure 1. The inhibition effect of betulinic acid (BA) on HCV replication. 80
Figure 2. Inhibitory effect of BA on HCV-induced COX-2 expression. 82
Figure 3. Restoration of HCV replication by exogenous COX-2 expression in BA-treated Ava5 cells. 84
Figure 4. Reduction effect of BA on HCV-induced NF-κB signaling pathway. 86
Figure 5. The reduction effect of BA on the phosphorylation of ERK1/2. 87
Figure 6. Proposed model of BA against HCV replication. 88
Figure 7. The suppression effect of BA, betulin and betulonic acid on DENV replication. 89
Figure 8. The inhibition effect of lobohedleolide on HCV replication. 90
Figure 9. Inhibition effect of lobohedleolide on HCV-induced COX-2 expression in protein and transcription levels. 92
Figure 10. Concentration-dependent restoration of HCV replication by exogenous COX-2 expression in lobohedleolide-treated Ava5 cells. 94
Figure 11. Effect of lobohedleolide on the transcriptional factor activity on COX-2 promoter. 95
Figure 12. Reduction effect of lobohedleolide on C/EBP transcription factor activity. 96
Figure 13. Mutagenized C/EBP on COX-2 promoter attenuated the inhibition effect of lobohedleolide on COX-2 promoter activity. 97
Figure 14. Reduction effect of lobohedleolide on C/EBP expression, c-Jun phosphorylation, and JNK phosphorylation. 98
Figure 15. Lobohedleolide did not affect the activation of NF-κB, ERK and p38. 99
Figure 16. Proposed model of lobohedleolide against HCV replication. 100
Figure 17. Lobohedleolide reduced DENV replication and protected ICR mice from life-threaten DENV infection. 101
Figure 18. AM-4 reduced HCV RNA replication by blocking viral entry. 103
Figure 19. AM-4 blocked HCV entry but not affect viral RNA replication and particle release. 105
Figure 20. Kinetic of inhibition of AM-4 on HCV entry. 107
Figure 21. AM-4 inhibited HCV cell-to-cell spread. 109
Figure 22. AM-4 did not affect the expression of HCV binding receptor. 111
Figure 23. Combination treatment of AM-4 with clinical used drugs additive reduced HCV replication. 112
Figure 24. Proposed model of AM-4 against HCV infection. 113
Figure 25. DENV induces COX-2 expression and PGE2 production in DF patients, DENV-infected mice, and human hepatoma cells. 114
Figure 26. DENV-2 induced COX-2 expression and PGE2 production in a concentration-dependent manner. 116
Figure 28. The growth curve of infectious DENV-2, and COX-2 overexpression and PGE2 addition induced DENV-2 propagation at early time point. 120
Figure 29. PGE2 did not affect the DENV-2 protease activity. 121
Figure 31. NS398 reduced DENV-2-elevated PGE2 production without cell cytotoxicity and DENV-2 propagation at early time point. 124
Figure 32. COX-2 expression is required for viral replication. 126
Figure 34. DENV-2 elevates COX-2 promoter activation through mediation of NF-κB and C/EBP binding elements. 130
Figure 35. NF-κB and MAPK/JNK-mediated C/EBP are responsible for DENV-2-induced COX-2 expression and viral replication. 132
Figure 36. MAPK/ERK and p38 are not responsible for DENV-2-induced COX-2 expression. 135
Figure 37. The inhibitors of MAPK/ERK and p38 did not suppress DENV-2 replication. 136
Figure 38. Proposed model to illustrate the mechanism of increased COX-2 expression and PGE2 production during DENV infection. 137
Figure 39. DENV infection decreases prostasin expression in DF patients, DENV-infected mice, and human hepatoma cells. 138
Figure 40. Prostasin overexpression protects mice from life-threatening DENV infection. 140
Figure 41. Prostatin overexpression decreases DENV replication and propagation. 142
Figure 42. Prostasin reduces DENV replication by decreasing COX-2 expression. 144
Figure 43. Prostasin knocks down EGFR to suppress DENV replication. 146
Figure 44. DENV replication requires the activation of Akt/COX-2 signaling. 148
Figure 45. C-Raf inhibitor did not reduce DENV-elevated COX-2 expression and DENV replication. 150
Figure 46. Prostasin-reduced EGFR expression is dependent on matriptase expression but is attenuated by HAI-2. 152
Figure 47. DENV infection and overexpression of HAI-2 facilitated the formation of prostasin-HAI-2 complex. 154
Figure 48. Model for the mechanism of prostasin-mediated EGFR expression against DENV-2 replication. 155
Table catalogue
Tables 156
Table1. The synergistic effect of BA when combined with various HCV inhibitors on the suppression of HCV RNA replication 156
Table2. The synergistic reduction effect of lobohedleolide with IFN-α, telaprevir, or sofosbuvir on HCV replication. 157
Appendix 158

1.Lindenbach, B.D. and C.M. Rice, Unravelling hepatitis C virus replication from genome to function. Nature, 2005. 436(7053): p. 933-8.
2.Mukhopadhyay, S., R.J. Kuhn, and M.G. Rossmann, A structural perspective of the flavivirus life cycle. Nat Rev Microbiol, 2005. 3(1): p. 13-22.
3.Penin, F., J. Dubuisson, F.A. Rey, D. Moradpour, and J.M. Pawlotsky, Structural biology of hepatitis C virus. Hepatology, 2004. 39(1): p. 5-19.
4.Feng, S., M. Li, J. Zhang, S. Liu, Q. Wang, M. Quan, M. Zhang, and J. Cheng, Regulation of HepG2 cell apoptosis by hepatitis C virus (HCV) core protein via the sirt1-p53-bax pathway. Virus Genes, 2015. 51(3): p. 338-46.
5.Lu, L., L. Wei, G. Peng, Y. Mu, K. Wu, L. Kang, X. Yan, Y. Zhu, and J. Wu, NS3 protein of hepatitis C virus regulates cyclooxygenase-2 expression through multiple signaling pathways. Virology, 2008. 371(1): p. 61-70.
6.Chung, Y.L., M.L. Sheu, and S.H. Yen, Hepatitis C virus NS5A as a potential viral Bcl-2 homologue interacts with Bax and inhibits apoptosis in hepatocellular carcinoma. Int J Cancer, 2003. 107(1): p. 65-73.
7.Basu, A., T. Kanda, A. Beyene, K. Saito, K. Meyer, and R. Ray, Sulfated homologues of heparin inhibit hepatitis C virus entry into mammalian cells. J Virol, 2007. 81(8): p. 3933-41.
8.Germi, R., J.M. Crance, D. Garin, J. Guimet, H. Lortat-Jacob, R.W. Ruigrok, J.P. Zarski, and E. Drouet, Cellular glycosaminoglycans and low density lipoprotein receptor are involved in hepatitis C virus adsorption. J Med Virol, 2002. 68(2): p. 206-15.
9.Lavillette, D., A.W. Tarr, C. Voisset, P. Donot, B. Bartosch, C. Bain, A.H. Patel, J. Dubuisson, J.K. Ball, and F.L. Cosset, Characterization of host-range and cell entry properties of the major genotypes and subtypes of hepatitis C virus. Hepatology, 2005. 41(2): p. 265-74.
10.Dreux, M., V.L. Dao Thi, J. Fresquet, M. Guerin, Z. Julia, G. Verney, D. Durantel, F. Zoulim, D. Lavillette, F.L. Cosset, and B. Bartosch, Receptor complementation and mutagenesis reveal SR-BI as an essential HCV entry factor and functionally imply its intra- and extra-cellular domains. PLoS Pathog, 2009. 5(2): p. e1000310.
11.Ploss, A., M.J. Evans, V.A. Gaysinskaya, M. Panis, H. You, Y.P. de Jong, and C.M. Rice, Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature, 2009. 457(7231): p. 882-6.
12.Andre, P., F. Komurian-Pradel, S. Deforges, M. Perret, J.L. Berland, M. Sodoyer, S. Pol, C. Brechot, G. Paranhos-Baccala, and V. Lotteau, Characterization of low- and very-low-density hepatitis C virus RNA-containing particles. J Virol, 2002. 76(14): p. 6919-28.
13.Zeisel, M.B., G. Koutsoudakis, E.K. Schnober, A. Haberstroh, H.E. Blum, F.L. Cosset, T. Wakita, D. Jaeck, M. Doffoel, C. Royer, E. Soulier, E. Schvoerer, C. Schuster, F. Stoll-Keller, R. Bartenschlager, T. Pietschmann, H. Barth, and T.F. Baumert, Scavenger receptor class B type I is a key host factor for hepatitis C virus infection required for an entry step closely linked to CD81. Hepatology, 2007. 46(6): p. 1722-31.
14.Ascione, A., M. De Luca, M.T. Tartaglione, F. Lampasi, G.G. Di Costanzo, A.G. Lanza, F.P. Picciotto, G. Marino-Marsilia, L. Fontanella, and G. Leandro, Peginterferon alfa-2a plus ribavirin is more effective than peginterferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection. Gastroenterology, 2010. 138(1): p. 116-22.
15.Thomas, E., J.J. Feld, Q. Li, Z. Hu, M.W. Fried, and T.J. Liang, Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models. Hepatology, 2011. 53(1): p. 32-41.
16.Schlutter, J., Therapeutics: new drugs hit the target. Nature, 2011. 474(7350): p. S5-7.
17.Lam, A.M., C. Espiritu, S. Bansal, H.M. Micolochick Steuer, C. Niu, V. Zennou, M. Keilman, Y. Zhu, S. Lan, M.J. Otto, and P.A. Furman, Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother, 2012. 56(6): p. 3359-68.
18.Gebhard, L.G., C.V. Filomatori, and A.V. Gamarnik, Functional RNA elements in the dengue virus genome. Viruses, 2011. 3(9): p. 1739-56.
19.Qi, R.F., L. Zhang, and C.W. Chi, Biological characteristics of dengue virus and potential targets for drug design. Acta Biochim Biophys Sin (Shanghai), 2008. 40(2): p. 91-101.
20.Halstead, S.B., Dengue. Lancet, 2007. 370(9599): p. 1644-52.
21.Murrell, S., S.C. Wu, and M. Butler, Review of dengue virus and the development of a vaccine. Biotechnol Adv, 2011. 29(2): p. 239-47.
22.Martina, B.E., P. Koraka, and A.D. Osterhaus, Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev, 2009. 22(4): p. 564-81.
23.McBride, W.J. and H. Bielefeldt-Ohmann, Dengue viral infections; pathogenesis and epidemiology. Microbes Infect, 2000. 2(9): p. 1041-50.
24.Liu, P., M. Woda, F.A. Ennis, and D.H. Libraty, Dengue virus infection differentially regulates endothelial barrier function over time through type I interferon effects. J Infect Dis, 2009. 200(2): p. 191-201.
25.Azizan, A., J. Sweat, C. Espino, J. Gemmer, L. Stark, and D. Kazanis, Differential proinflammatory and angiogenesis-specific cytokine production in human pulmonary endothelial cells, HPMEC-ST1.6R infected with dengue-2 and dengue-3 virus. J Virol Methods, 2006. 138(1-2): p. 211-7.
26.Beatty, P.R., H. Puerta-Guardo, S.S. Killingbeck, D.R. Glasner, K. Hopkins, and E. Harris, Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Sci Transl Med, 2015. 7(304): p. 304ra141.
27.Gee, J., I.L. Lee, H.B. Grossman, and A.L. Sabichi, Forced COX-2 expression induces PGE(2) and invasion in immortalized urothelial cells. Urol Oncol, 2008. 26(6): p. 641-5.
28.Nunez, O., A. Fernandez-Martinez, P.L. Majano, A. Apolinario, M. Gomez-Gonzalo, I. Benedicto, M. Lopez-Cabrera, L. Bosca, G. Clemente, C. Garcia-Monzon, and P. Martin-Sanz, Increased intrahepatic cyclooxygenase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 expression is associated with progressive liver disease in chronic hepatitis C virus infection: role of viral core and NS5A proteins. Gut, 2004. 53(11): p. 1665-72.
29.Waris, G. and A. Siddiqui, Hepatitis C virus stimulates the expression of cyclooxygenase-2 via oxidative stress: role of prostaglandin E2 in RNA replication. J Virol, 2005. 79(15): p. 9725-34.
30.Lin, Y.T., Y.H. Wu, C.K. Tseng, C.K. Lin, W.C. Chen, Y.C. Hsu, and J.C. Lee, Green tea phenolic epicatechins inhibit hepatitis C virus replication via cycloxygenase-2 and attenuate virus-induced inflammation. PLoS One, 2013. 8(1): p. e54466.
31.Wu, W.L., L.J. Ho, D.M. Chang, C.H. Chen, and J.H. Lai, Triggering of DC migration by dengue virus stimulation of COX-2-dependent signaling cascades in vitro highlights the significance of these cascades beyond inflammation. Eur J Immunol, 2009. 39(12): p. 3413-22.
32.Liou, J.T., Z.Y. Chen, L.J. Ho, S.P. Yang, D.M. Chang, C.C. Liang, and J.H. Lai, Differential effects of triptolide and tetrandrine on activation of COX-2, NF-kappaB, and AP-1 and virus production in dengue virus-infected human lung cells. Eur J Pharmacol, 2008. 589(1-3): p. 288-98.
33.Yu, J.X., L. Chao, D.C. Ward, and J. Chao, Structure and chromosomal localization of the human prostasin (PRSS8) gene. Genomics, 1996. 32(3): p. 334-40.
34.Yu, J.X., L. Chao, and J. Chao, Prostasin is a novel human serine proteinase from seminal fluid. Purification, tissue distribution, and localization in prostate gland. J Biol Chem, 1994. 269(29): p. 18843-8.
35.Friis, S., K. Uzzun Sales, S. Godiksen, D.E. Peters, C.Y. Lin, L.K. Vogel, and T.H. Bugge, A matriptase-prostasin reciprocal zymogen activation complex with unique features: prostasin as a non-enzymatic co-factor for matriptase activation. J Biol Chem, 2013. 288(26): p. 19028-39.
36.Shipway, A., H. Danahay, J.A. Williams, D.C. Tully, B.J. Backes, and J.L. Harris, Biochemical characterization of prostasin, a channel activating protease. Biochem Biophys Res Commun, 2004. 324(2): p. 953-63.
37.Chen, Y.W., J.K. Wang, F.P. Chou, C.Y. Chen, E.A. Rorke, L.M. Chen, K.X. Chai, R.L. Eckert, M.D. Johnson, and C.Y. Lin, Regulation of the matriptase-prostasin cell surface proteolytic cascade by hepatocyte growth factor activator inhibitor-1 during epidermal differentiation. J Biol Chem, 2010. 285(41): p. 31755-62.
38.Kawaguchi, T., L. Qin, T. Shimomura, J. Kondo, K. Matsumoto, K. Denda, and N. Kitamura, Purification and cloning of hepatocyte growth factor activator inhibitor type 2, a Kunitz-type serine protease inhibitor. J Biol Chem, 1997. 272(44): p. 27558-64.
39.Shimomura, T., K. Denda, A. Kitamura, T. Kawaguchi, M. Kito, J. Kondo, S. Kagaya, L. Qin, H. Takata, K. Miyazawa, and N. Kitamura, Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor. J Biol Chem, 1997. 272(10): p. 6370-6.
40.Chen, L.M., C. Wang, M. Chen, M.R. Marcello, J. Chao, L. Chao, and K.X. Chai, Prostasin attenuates inducible nitric oxide synthase expression in lipopolysaccharide-induced urinary bladder inflammation. Am J Physiol Renal Physiol, 2006. 291(3): p. F567-77.
41.Bao, Y., K. Li, Y. Guo, Q. Wang, Z. Li, Y. Yang, Z. Chen, J. Wang, W. Zhao, H. Zhang, J. Chen, H. Dong, K. Shen, A.M. Diamond, and W. Yang, Tumor suppressor PRSS8 targets Sphk1/S1P/Stat3/Akt signaling in colorectal cancer. Oncotarget, 2016. 7(18): p. 26780-92.
42.Chen, M., Y.Y. Fu, C.Y. Lin, L.M. Chen, and K.X. Chai, Prostasin induces protease-dependent and independent molecular changes in the human prostate carcinoma cell line PC-3. Biochim Biophys Acta, 2007. 1773(7): p. 1133-40.
43.de Larco, J.E. and G.J. Todaro, Epithelioid and fibroblastic rat kidney cell clones: epidermal growth factor (EGF) receptors and the effect of mouse sarcoma virus transformation. J Cell Physiol, 1978. 94(3): p. 335-42.
44.Yarden, Y., The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer, 2001. 37 Suppl 4: p. S3-8.
45.Tung, W.H., H.L. Hsieh, I.T. Lee, and C.M. Yang, Enterovirus 71 modulates a COX-2/PGE2/cAMP-dependent viral replication in human neuroblastoma cells: role of the c-Src/EGFR/p42/p44 MAPK/CREB signaling pathway. J Cell Biochem, 2011. 112(2): p. 559-70.
46.Diao, J., H. Pantua, H. Ngu, L. Komuves, L. Diehl, G. Schaefer, and S.B. Kapadia, Hepatitis C virus induces epidermal growth factor receptor activation via CD81 binding for viral internalization and entry. J Virol, 2012. 86(20): p. 10935-49.
47.Lupberger, J., M.B. Zeisel, F. Xiao, C. Thumann, I. Fofana, L. Zona, C. Davis, C.J. Mee, M. Turek, S. Gorke, C. Royer, B. Fischer, M.N. Zahid, D. Lavillette, J. Fresquet, F.L. Cosset, S.M. Rothenberg, T. Pietschmann, A.H. Patel, P. Pessaux, M. Doffoel, W. Raffelsberger, O. Poch, J.A. McKeating, L. Brino, and T.F. Baumert, EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med, 2011. 17(5): p. 589-95.
48.Chen, C.J., S.L. Raung, M.D. Kuo, and Y.M. Wang, Suppression of Japanese encephalitis virus infection by non-steroidal anti-inflammatory drugs. J Gen Virol, 2002. 83(Pt 8): p. 1897-905.
49.Lin, C.K., C.K. Tseng, Y.H. Wu, C.C. Liaw, C.Y. Lin, C.H. Huang, Y.H. Chen, and J.C. Lee, Cyclooxygenase-2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents. Sci Rep, 2017. 7: p. 44701.
50.Chen, L.M., M.L. Hatfield, Y.Y. Fu, and K.X. Chai, Prostasin regulates iNOS and cyclin D1 expression by modulating protease-activated receptor-2 signaling in prostate epithelial cells. Prostate, 2009. 69(16): p. 1790-801.
51.Feng, Y., X.M. Li, X.J. Duan, and B.G. Wang, Iridoid glucosides and flavones from the aerial parts of Avicennia marina. Chem Biodivers, 2006. 3(7): p. 799-806.
52.Jain, R., O. Monthakantirat, P. Tengamnuay, and W. De-Eknamkul, Avicequinone C isolated from Avicennia marina exhibits 5alpha-reductase-type 1 inhibitory activity using an androgenic alopecia relevant cell-based assay system. Molecules, 2014. 19(5): p. 6809-21.
53.Sharaf, M., M.A. El-Ansari, and N.A. Saleh, New flavonoids from Avicennia marina. Fitoterapia, 2000. 71(3): p. 274-7.
54.Pisha, E., H. Chai, I.S. Lee, T.E. Chagwedera, N.R. Farnsworth, G.A. Cordell, C.W. Beecher, H.H. Fong, A.D. Kinghorn, D.M. Brown, and et al., Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med, 1995. 1(10): p. 1046-51.
55.Yogeeswari, P. and D. Sriram, Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem, 2005. 12(6): p. 657-66.
56.Hsu, Y.C., N.C. Chen, P.C. Chen, C.C. Wang, W.C. Cheng, and H.N. Wu, Identification of a small-molecule inhibitor of dengue virus using a replicon system. Arch Virol, 2012. 157(4): p. 681-8.
57.Rashid, M.A., K.R. Gustafson, and M.R. Boyd, HIV-inhibitory cembrane derivatives from a Philippines collection of the soft coral Lobophytum species. J Nat Prod, 2000. 63(4): p. 531-3.
58.Cheng, S.Y., S.K. Wang, and C.Y. Duh, Secocrassumol, a seco-cembranoid from the Dongsha Atoll soft coral Lobophytum crassum. Mar Drugs, 2014. 12(12): p. 6028-37.
59.Chao, C.H., Z.H. Wen, Y.C. Wu, H.C. Yeh, and J.H. Sheu, Cytotoxic and anti-inflammatory cembranoids from the soft coral Lobophytum crassum. J Nat Prod, 2008. 71(11): p. 1819-24.
60.W.H.O. 2009: Geneva.
61.Blight, K.J., A.A. Kolykhalov, and C.M. Rice, Efficient initiation of HCV RNA replication in cell culture. Science, 2000. 290(5498): p. 1972-4.
62.Lee, J.C., C.K. Tseng, Y.H. Wu, N. Kaushik-Basu, C.K. Lin, W.C. Chen, and H.N. Wu, Characterization of the activity of 2''-C-methylcytidine against dengue virus replication. Antiviral Res, 2015. 116: p. 1-9.
63.Speir, E., Z.X. Yu, V.J. Ferrans, E.S. Huang, and S.E. Epstein, Aspirin attenuates cytomegalovirus infectivity and gene expression mediated by cyclooxygenase-2 in coronary artery smooth muscle cells. Circ Res, 1998. 83(2): p. 210-6.
64.Natarajan, K., S. Singh, T.R. Burke, Jr., D. Grunberger, and B.B. Aggarwal, Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci U S A, 1996. 93(17): p. 9090-5.
65.Khaliq, S., F.J. Volk, and A.W. Frahm, Phytochemical investigation of Perovskia abrotanoides. Planta Med, 2007. 73(1): p. 77-83.
66.Anjaneyulu, A.S.R., Y.L.N. Murthy, V. Lakshman Rao, and K. Sreedhar, Chemical examination of the mangrove plant Avicennia officinalis. Indian Journal of Chemistry, Sect. B: Organic Chemistry including Medicinal Chemistry 2003. 42B(12): p. 3117-3119.
67.Kato, T., T. Date, A. Murayama, K. Morikawa, D. Akazawa, and T. Wakita, Cell culture and infection system for hepatitis C virus. Nat Protoc, 2006. 1(5): p. 2334-9.
68.Chou, T.C. and P. Talalay, Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur J Biochem, 1981. 115(1): p. 207-16.
69.Chou, T.C. and P. Talalay, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul, 1984. 22: p. 27-55.
70.Lee, Y.R., H.Y. Hu, S.H. Kuo, H.Y. Lei, Y.S. Lin, T.M. Yeh, C.C. Liu, and H.S. Liu, Dengue virus infection induces autophagy: an in vivo study. J Biomed Sci, 2013. 20: p. 65.
71.Kim, A.R., M.S. Lee, T.S. Shin, H. Hua, B.C. Jang, J.S. Choi, D.S. Byun, T. Utsuki, D. Ingram, and H.R. Kim, Phlorofucofuroeckol A inhibits the LPS-stimulated iNOS and COX-2 expressions in macrophages via inhibition of NF-kappaB, Akt, and p38 MAPK. Toxicol In Vitro, 2011. 25(8): p. 1789-95.
72.Trujillo-Murillo, K., A.R. Rincon-Sanchez, H. Martinez-Rodriguez, F. Bosques-Padilla, J. Ramos-Jimenez, H.A. Barrera-Saldana, M. Rojkind, and A.M. Rivas-Estilla, Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways. Hepatology, 2008. 47(5): p. 1462-72.
73.Chen, K.J., C.K. Tseng, F.R. Chang, J.I. Yang, C.C. Yeh, W.C. Chen, S.F. Wu, H.W. Chang, and J.C. Lee, Aqueous extract of the edible Gracilaria tenuistipitata inhibits hepatitis C viral replication via cyclooxygenase-2 suppression and reduces virus-induced inflammation. PLoS One, 2013. 8(2): p. e57704.
74.Gong, G., G. Waris, R. Tanveer, and A. Siddiqui, Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B. Proc Natl Acad Sci U S A, 2001. 98(17): p. 9599-604.
75.Hou, D.X., S. Masuzaki, F. Hashimoto, T. Uto, S. Tanigawa, M. Fujii, and Y. Sakata, Green tea proanthocyanidins inhibit cyclooxygenase-2 expression in LPS-activated mouse macrophages: molecular mechanisms and structure-activity relationship. Arch Biochem Biophys, 2007. 460(1): p. 67-74.
76.Lin, C.K., C.K. Tseng, K.H. Chen, S.H. Wu, C.C. Liaw, and J.C. Lee, Betulinic acid exerts anti-hepatitis C virus activity via the suppression of NF-kappaB- and MAPK-ERK1/2-mediated COX-2 expression. Br J Pharmacol, 2015.
77.Prescott, S.M. and F.A. Fitzpatrick, Cyclooxygenase-2 and carcinogenesis. Biochim Biophys Acta, 2000. 1470(2): p. M69-78.
78.Healy, Z.R., F. Zhu, J.D. Stull, and K. Konstantopoulos, Elucidation of the signaling network of COX-2 induction in sheared chondrocytes: COX-2 is induced via a Rac/MEKK1/MKK7/JNK2/c-Jun-C/EBPbeta-dependent pathway. Am J Physiol Cell Physiol, 2008. 294(5): p. C1146-57.
79.Johnson, G.L. and K. Nakamura, The c-jun kinase/stress-activated pathway: regulation, function and role in human disease. Biochim Biophys Acta, 2007. 1773(8): p. 1341-8.
80.Timpe, J.M., Z. Stamataki, A. Jennings, K. Hu, M.J. Farquhar, H.J. Harris, A. Schwarz, I. Desombere, G.L. Roels, P. Balfe, and J.A. McKeating, Hepatitis C virus cell-cell transmission in hepatoma cells in the presence of neutralizing antibodies. Hepatology, 2008. 47(1): p. 17-24.
81.Witteveldt, J., M.J. Evans, J. Bitzegeio, G. Koutsoudakis, A.M. Owsianka, A.G. Angus, Z.Y. Keck, S.K. Foung, T. Pietschmann, C.M. Rice, and A.H. Patel, CD81 is dispensable for hepatitis C virus cell-to-cell transmission in hepatoma cells. J Gen Virol, 2009. 90(Pt 1): p. 48-58.
82.Lee, A.K., S.H. Sung, Y.C. Kim, and S.G. Kim, Inhibition of lipopolysaccharide-inducible nitric oxide synthase, TNF-alpha and COX-2 expression by sauchinone effects on I-kappaBalpha phosphorylation, C/EBP and AP-1 activation. Br J Pharmacol, 2003. 139(1): p. 11-20.
83.De La Guardia, C. and R. Lleonart, Progress in the identification of dengue virus entry/fusion inhibitors. Biomed Res Int, 2014. 2014: p. 825039.
84.Hilgard, P. and R. Stockert, Heparan sulfate proteoglycans initiate dengue virus infection of hepatocytes. Hepatology, 2000. 32(5): p. 1069-77.
85.Samanta, J. and V. Sharma, Dengue and its effects on liver. World J Clin Cases, 2015. 3(2): p. 125-31.
86.Hu, H., T. Han, M. Zhuo, L.L. Wu, C. Yuan, L. Wu, W. Lei, F. Jiao, and L.W. Wang, Elevated COX-2 Expression Promotes Angiogenesis Through EGFR/p38-MAPK/Sp1-Dependent Signalling in Pancreatic Cancer. Sci Rep, 2017. 7(1): p. 470.
87.Chen, L.M. and K.X. Chai, Proteolytic cleavages in the extracellular domain of receptor tyrosine kinases by membrane-associated serine proteases. Oncotarget, 2017.
88.Chen, M., L.M. Chen, C.Y. Lin, and K.X. Chai, The epidermal growth factor receptor (EGFR) is proteolytically modified by the Matriptase-Prostasin serine protease cascade in cultured epithelial cells. Biochim Biophys Acta, 2008. 1783(5): p. 896-903.
89.Lai, C.H., Y.J. Lai, F.P. Chou, H.H. Chang, C.C. Tseng, M.D. Johnson, J.K. Wang, and C.Y. Lin, Matriptase Complexes and Prostasin Complexes with HAI-1 and HAI-2 in Human Milk: Significant Proteolysis in Lactation. PLoS One, 2016. 11(4): p. e0152904.
90.Shiao, F., L.O. Liu, N. Huang, Y.J. Lai, R.J. Barndt, C.C. Tseng, J.K. Wang, B. Jia, M.D. Johnson, and C.Y. Lin, Selective Inhibition of Prostasin in Human Enterocytes by the Integral Membrane Kunitz-Type Serine Protease Inhibitor HAI-2. PLoS One, 2017. 12(1): p. e0170944.
91.Waris, G., J. Turkson, T. Hassanein, and A. Siddiqui, Hepatitis C virus (HCV) constitutively activates STAT-3 via oxidative stress: role of STAT-3 in HCV replication. J Virol, 2005. 79(3): p. 1569-80.
92.Roulston, A., R.C. Marcellus, and P.E. Branton, Viruses and apoptosis. Annu Rev Microbiol, 1999. 53: p. 577-628.
93.Viji, V., A. Helen, and V.R. Luxmi, Betulinic acid inhibits endotoxin-stimulated phosphorylation cascade and pro-inflammatory prostaglandin E(2) production in human peripheral blood mononuclear cells. Br J Pharmacol, 2011. 162(6): p. 1291-303.
94.Szuster-Ciesielska, A., K. Plewka, J. Daniluk, and M. Kandefer-Szerszen, Betulin and betulinic acid attenuate ethanol-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS), cytokine (TNF-alpha, TGF-beta) production and by influencing intracellular signaling. Toxicology, 2011. 280(3): p. 152-63.
95.Wang, W., A. Bergh, and J.E. Damber, Increased expression of CCAAT/enhancer-binding protein beta in proliferative inflammatory atrophy of the prostate: relation with the expression of COX-2, the androgen receptor, and presence of focal chronic inflammation. Prostate, 2007. 67(11): p. 1238-46.
96.Wadleigh, D.J., S.T. Reddy, E. Kopp, S. Ghosh, and H.R. Herschman, Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. J Biol Chem, 2000. 275(9): p. 6259-66.
97.Zhu, Y., M.A. Saunders, H. Yeh, W.G. Deng, and K.K. Wu, Dynamic regulation of cyclooxygenase-2 promoter activity by isoforms of CCAAT/enhancer-binding proteins. J Biol Chem, 2002. 277(9): p. 6923-8.
98.Xu, G., Y. Zhang, L. Zhang, A.I. Roberts, and Y. Shi, C/EBPbeta mediates synergistic upregulation of gene expression by interferon-gamma and tumor necrosis factor-alpha in bone marrow-derived mesenchymal stem cells. Stem Cells, 2009. 27(4): p. 942-8.
99.Lu, X.L., S.X. He, M.D. Ren, Y.L. Wang, Y.X. Zhang, and E.Q. Liu, Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: involvement of CCAAT/enhancer binding protein beta and cyclooxygenase-2. Mol Med Rep, 2012. 5(3): p. 637-44.
100.Kasprzak, A., M. Zabel, W. Biczysko, J. Wysocki, A. Adamek, R. Spachacz, and J. Surdyk-Zasada, Expression of cytokines (TNF-alpha, IL-1alpha, and IL-2) in chronic hepatitis C: comparative hybridocytochemical and immunocytochemical study in children and adult patients. J Histochem Cytochem, 2004. 52(1): p. 29-38.
101.Mukherjee, A., S. Shrivastava, J. Bhanja Chowdhury, R. Ray, and R.B. Ray, Transcriptional suppression of miR-181c by hepatitis C virus enhances homeobox A1 expression. J Virol, 2014. 88(14): p. 7929-40.
102.Zeng, C., R. Wang, D. Li, X.J. Lin, Q.K. Wei, Y. Yuan, Q. Wang, W. Chen, and S.M. Zhuang, A novel GSK-3 beta-C/EBP alpha-miR-122-insulin-like growth factor 1 receptor regulatory circuitry in human hepatocellular carcinoma. Hepatology, 2010. 52(5): p. 1702-12.
103.Chun, K.S. and Y.J. Surh, Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. Biochem Pharmacol, 2004. 68(6): p. 1089-100.
104.Dixit, U., A.K. Pandey, Z. Liu, S. Kumar, M.B. Neiditch, K.M. Klein, and V.N. Pandey, FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53. J Virol, 2015. 89(15): p. 7905-21.
105.Leng, J., C. Han, A.J. Demetris, G.K. Michalopoulos, and T. Wu, Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through Akt activation: evidence for Akt inhibition in celecoxib-induced apoptosis. Hepatology, 2003. 38(3): p. 756-68.
106.Kawamori, T., C.V. Rao, K. Seibert, and B.S. Reddy, Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res, 1998. 58(3): p. 409-12.
107.Tseng, C.K., C.K. Lin, H.W. Chang, Y.H. Wu, F.L. Yen, F.R. Chang, W.C. Chen, C.C. Yeh, and J.C. Lee, Aqueous extract of Gracilaria tenuistipitata suppresses LPS-induced NF-kappaB and MAPK activation in RAW 264.7 and rat peritoneal macrophages and exerts hepatoprotective effects on carbon tetrachloride-treated rat. PLoS One, 2014. 9(1): p. e86557.
108.Lin, H.M., J.C. Wang, H.S. Hu, P.S. Wu, W.H. Wang, S.Y. Wu, C.C. Yang, T.K. Yeh, T.A. Hsu, W.T. Jiaang, Y.S. Chao, J.H. Chern, and A. Yueh, Resistance studies of a dithiazol analogue, DBPR110, as a potential hepatitis C virus NS5A inhibitor in replicon systems. Antimicrob Agents Chemother, 2013. 57(2): p. 723-33.
109.Saxena, V. and N. Terrault, Hepatitis C virus treatment and liver transplantation in the era of new antiviral therapies. Curr Opin Organ Transplant, 2012. 17(3): p. 216-24.
110.Sarrazin, C., C. Hezode, S. Zeuzem, and J.M. Pawlotsky, Antiviral strategies in hepatitis C virus infection. J Hepatol, 2012. 56 Suppl 1: p. S88-100.
111.Halfon, P. and C. Sarrazin, Future treatment of chronic hepatitis C with direct acting antivirals: is resistance important? Liver Int, 2012. 32 Suppl 1: p. 79-87.
112.Wohlfarth, C. and T. Efferth, Natural products as promising drug candidates for the treatment of hepatitis B and C. Acta Pharmacol Sin, 2009. 30(1): p. 25-30.
113.Duffy, S., L.A. Shackelton, and E.C. Holmes, Rates of evolutionary change in viruses: patterns and determinants. Nat Rev Genet, 2008. 9(4): p. 267-76.
114.Lurain, N.S., K.D. Thompson, E.W. Holmes, and G.S. Read, Point mutations in the DNA polymerase gene of human cytomegalovirus that result in resistance to antiviral agents. J Virol, 1992. 66(12): p. 7146-52.
115.Prussia, A., P. Thepchatri, J.P. Snyder, and R.K. Plemper, Systematic approaches towards the development of host-directed antiviral therapeutics. Int J Mol Sci, 2011. 12(6): p. 4027-52.
116.Fink, J., F. Gu, L. Ling, T. Tolfvenstam, F. Olfat, K.C. Chin, P. Aw, J. George, V.A. Kuznetsov, M. Schreiber, S.G. Vasudevan, and M.L. Hibberd, Host gene expression profiling of dengue virus infection in cell lines and patients. PLoS Negl Trop Dis, 2007. 1(2): p. e86.
117.Lim, S.P., Q.Y. Wang, C.G. Noble, Y.L. Chen, H. Dong, B. Zou, F. Yokokawa, S. Nilar, P. Smith, D. Beer, J. Lescar, and P.Y. Shi, Ten years of dengue drug discovery: progress and prospects. Antiviral Res, 2013. 100(2): p. 500-19.
118.Chuang, Y.C., Y.S. Lin, C.C. Liu, H.S. Liu, S.H. Liao, M.D. Shi, H.Y. Lei, and T.M. Yeh, Factors contributing to the disturbance of coagulation and fibrinolysis in dengue virus infection. J Formos Med Assoc, 2013. 112(1): p. 12-7.
119.Carvalho, D.M., F.G. Garcia, A.P. Terra, A.C. Lopes Tosta, A. Silva Lde, L.R. Castellano, and D.N. Silva Teixeira, Elevated dengue virus nonstructural protein 1 serum levels and altered toll-like receptor 4 expression, nitric oxide, and tumor necrosis factor alpha production in dengue hemorrhagic Fever patients. J Trop Med, 2014. 2014: p. 901276.
120.Fernandez-Mestre, M.T., K. Gendzekhadze, P. Rivas-Vetencourt, and Z. Layrisse, TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens, 2004. 64(4): p. 469-72.
121.Zhang, Y.P., X.Q. Hao, L.M. Zhang, and Y.T. Tian, Enhanced cyclooxygenase-2 activity leads to intestinal dysmotility following hemorrhagic shock. Acta Cir Bras, 2015. 30(12): p. 838-43.
122.Shah, A.A., B. Thjodleifsson, F.E. Murray, E. Kay, M. Barry, G. Sigthorsson, H. Gudjonsson, E. Oddsson, A.B. Price, D.J. Fitzgerald, and I. Bjarnason, Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen. Gut, 2001. 48(3): p. 339-46.
123.Shi, S.S., H.B. Zhang, C.H. Wang, W.Z. Yang, R.S. Liang, Y. Chen, and X.K. Tu, Propofol Attenuates Early Brain Injury After Subarachnoid Hemorrhage in Rats. J Mol Neurosci, 2015. 57(4): p. 538-45.
124.Kim, S.H., I.C. Lee, J.W. Ko, C. Moon, S.H. Kim, I.S. Shin, Y.W. Seo, H.C. Kim, and J.C. Kim, Diallyl Disulfide Prevents Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats through the Inhibition of Oxidative Damage, MAPKs, and NF-kappaB Pathways. Biomol Ther (Seoul), 2015. 23(2): p. 180-8.
125.Chu, J.J. and P.L. Yang, c-Src protein kinase inhibitors block assembly and maturation of dengue virus. Proc Natl Acad Sci U S A, 2007. 104(9): p. 3520-5.
126.Kumar, R., T. Agrawal, N.A. Khan, Y. Nakayama, and G.R. Medigeshi, Identification and characterization of the role of c-terminal Src kinase in dengue virus replication. Sci Rep, 2016. 6: p. 30490.
127.Limjindaporn, T., J. Panaampon, S. Malakar, S. Noisakran, and P.T. Yenchitsomanus, Tyrosine kinase/phosphatase inhibitors decrease dengue virus production in HepG2 cells. Biochem Biophys Res Commun, 2017. 483(1): p. 58-63.
128.Brindley, M.A., C.L. Hunt, A.S. Kondratowicz, J. Bowman, P.L. Sinn, P.B. McCray, Jr., K. Quinn, M.L. Weller, J.A. Chiorini, and W. Maury, Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein. Virology, 2011. 415(2): p. 83-94.
129.Dahlmann, F., N. Biedenkopf, A. Babler, W. Jahnen-Dechent, C.B. Karsten, K. Gnirss, H. Schneider, F. Wrensch, C.A. O''Callaghan, S. Bertram, G. Herrler, S. Becker, S. Pohlmann, and H. Hofmann-Winkler, Analysis of Ebola Virus Entry Into Macrophages. J Infect Dis, 2015. 212 Suppl 2: p. S247-57.
130.Eierhoff, T., E.R. Hrincius, U. Rescher, S. Ludwig, and C. Ehrhardt, The epidermal growth factor receptor (EGFR) promotes uptake of influenza A viruses (IAV) into host cells. PLoS Pathog, 2010. 6(9): p. e1001099.
131.Matsumoto, M., K. Funami, M. Tanabe, H. Oshiumi, M. Shingai, Y. Seto, A. Yamamoto, and T. Seya, Subcellular localization of Toll-like receptor 3 in human dendritic cells. J Immunol, 2003. 171(6): p. 3154-62.
132.Samuel, C.E., Antiviral actions of interferons. Clin Microbiol Rev, 2001. 14(4): p. 778-809, table of contents.
133.Simon-Loriere, E., R.J. Lin, S.M. Kalayanarooj, A. Chuansumrit, I. Casademont, S.Y. Lin, H.P. Yu, W. Lert-Itthiporn, W. Chaiyaratana, N. Tangthawornchaikul, K. Tangnararatchakit, S. Vasanawathana, B.L. Chang, P. Suriyaphol, S. Yoksan, P. Malasit, P. Despres, R. Paul, Y.L. Lin, and A. Sakuntabhai, High Anti-Dengue Virus Activity of the OAS Gene Family Is Associated With Increased Severity of Dengue. J Infect Dis, 2015. 212(12): p. 2011-20.
134.Diwaker, D., K.P. Mishra, L. Ganju, and S.B. Singh, Rhodiola inhibits dengue virus multiplication by inducing innate immune response genes RIG-I, MDA5 and ISG in human monocytes. Arch Virol, 2014. 159(8): p. 1975-86.
135.Perelygin, A.A., S.V. Scherbik, I.B. Zhulin, B.M. Stockman, Y. Li, and M.A. Brinton, Positional cloning of the murine flavivirus resistance gene. Proc Natl Acad Sci U S A, 2002. 99(14): p. 9322-7.
136.Castillo Ramirez, J.A. and S. Urcuqui-Inchima, Dengue Virus Control of Type I IFN Responses: A History of Manipulation and Control. J Interferon Cytokine Res, 2015. 35(6): p. 421-30.
137.Lupberger, J., F.H. Duong, I. Fofana, L. Zona, F. Xiao, C. Thumann, S.C. Durand, P. Pessaux, M.B. Zeisel, M.H. Heim, and T.F. Baumert, Epidermal growth factor receptor signaling impairs the antiviral activity of interferon-alpha. Hepatology, 2013. 58(4): p. 1225-35.