牛樟芝是具有高價值性的藥用菇類，在傳統醫學上常用來治療癌症、高血壓和發炎性疾病。樟芝酸A是牛樟芝的主要藥理活性化合物之一。目前，牛樟芝或樟芝酸A的作用機制尚未完全闡明。 Toll-like receptor 4 (TLR4)是細胞膜上的受體，與它的輔助蛋白myeloid differentiation factor-2 (MD-2)，常用於細菌感染的治療靶標。我們利用X-score與HotLig建模方法分析了人類TLR4/MD-2複合體與樟芝酸A接觸的結構；與兩種不同的MD-2抗體來確認MD-2與樟芝酸A之間的交互作用；以及小鼠體內先給予樟芝酸A再注射脂多糖的方式來進行發炎反應和存活率的監測。建模結果顯示樟芝酸A藉由特異分子辨識也就是疏水性的接觸力可與MD-2的疏水口袋進行結合。樟芝酸A與MD-2結合可以減少MD-2抗體的辨識與脂多糖和MD-2的結合效果是相似的。此外，樟芝酸A提前給予顯著改善小鼠體內脂多糖誘導的內毒素血症和沙門氏菌引起的腹瀉。此研究結果表明，樟芝酸A可與脂多糖競爭結合到MD-2疏水口袋，可作為TLR4/MD-2拮抗劑，是具有潛力可用來治療革蘭氏陰性細菌感染。 Janus kinase 2 (JAK2)激酶在造血系統的發展扮演重要角色，它的活化參與細胞激素的訊息傳遞。因此JAK2可被用來作為發炎性疾病治療靶標。在此研究中，HotLig建模方法被應用來分析JAK2與樟芝酸A的結合模型；刀豆素引起的小鼠急性肝發炎被用來評估樟芝酸A對肝損傷的保護效果。建模方法結果顯示樟芝酸A可藉由氫鍵和JAK2的ATP結合口袋進行結合。樟芝酸A與JAK2結合亦可以減少JAK2抗體對JAK2蛋白的辨識。再者，樟芝酸A可以減少JAK2的磷酸化與下游分子的訊息傳遞，來抑制interferon (IFN)-γ/signal transducer and activator of transcription (STAT) 1/ interferon regulatory factor (IRF)-1的傳導路徑。提前給予樟芝酸A顯著地改善刀豆素引起的小鼠急性肝損傷。因此，樟芝酸A在小鼠急性肝發炎時期是可以因抑制JAK2磷酸化而達到防止肝損傷，所以對於發炎性疾病的治療是具有潛力的藥物。

Taiwanofungus camphoratus is highly valued as a medicinal mushroom for cancer, hypertension, and inflammation in traditional medicine. Zhankuic acid A (ZAA) is the major pharmacologically active compound of T. camphoratus. The mechanism of action of T. camphoratus or ZAA has not been fully elucidated. TLR4, a membrane receptor that functions in complex with its accessory protein myeloid differentiation factor-2 (MD-2), is a therapeutic target for bacterial infections. We analyzed the structure of human TLR4/MD-2 complex with ZAA by X-score and HotLig modeling approaches. Two antibodies against MD-2 were used to verify the MD-2/ZAA interaction. The inflammation and survival of the mice pretreated with ZAA and injected with LPS were monitored. The modeling structure shows that ZAA binds the MD-2 hydrophobic pocket exclusively via specific molecular recognition; the contact interface is dominated by hydrophobic interactions. Binding of ZAA to MD-2 reduced antibody recognition to native MD-2, similar to the effect of lipopolysaccharide (LPS) binding. Furthermore, ZAA significantly ameliorated LPS-induced endotoxemia and Salmonella-induced diarrhea in mice. Our results suggest that ZAA, which can compete with LPS for binding to MD-2 as a TLR4/MD-2 antagonist, may be a potential therapeutic agent for gram-negative bacterial infections. Janus kinase 2 (JAK2), whose activation is involved in cytokine signaling, plays critical roles in the development and biology of the hematopoietic system. JAK2 has been implicated as a therapeutic target in inflammatory diseases. The HotLig modeling approach was used to generate the binding model for ZAA with JAK2, showing that ZAA could bind to the ATP-binding pocket of JAK2 exclusively via the H-bond. The interaction between ZAA and JAK2 was verified by antibody competition assay. Binding of ZAA to JAK2 reduced antibody recognition of native JAK2. The expressions of phosphorylated JAK2 and STATs were analyzed by immunoblotting. ZAA reduced the phosphorylation and downstream signaling of JAK2, and inhibited the interferon (IFN)-γ/signal transducer and activator of transcription (STAT) 1/ interferon regulatory factor (IRF)-1 pathway. The protective effect of ZAA on liver injury was evaluated in mice by Con-A-induced acute hepatitis. Pretreatment with ZAA also significantly ameliorated acute liver injury in mice. Therefore, ZAA can inhibit JAK2 phosphorylation and protect against liver injury during acute hepatitis in mice. In this study, we present data that ZAA exerts anti-inflammatory effects through the JAK2 signaling pathway. Therefore, ZAA may be a potential therapeutic agent for the treatment of inflammatory diseases.

Chinese Abstract…………I
Abstract……………II
List of figures and tables…………VIII
Abbreviations…………XI
Introduction……………1
Anti-inflammatory activities in fruiting body of T. camphoratus…………1
Anti-cancer activities in fruiting body of T. camphoratus……….1
The bioactivities of zhankuic acid A (ZAA)……………2
Lipopolysaccharide (LPS)-induced inflammation………………2
Salmonella choleraesuis-induced endotoxemia and diarrhea as animal study…….….3
Janus tyrosine kinase 2 (JAK2) signaling in inflammation……………3
JAK2 and hepatitis………………4
Concanavalin A (Con A)-induced hepatitis………………4
Material and methods………………5
Reagents and kits………………5
Antibodies and recombinant proteins……………6
Plasmids…………………8
Primers……………………8
Equipment and software……………………9
Cells, bacteria, and mice…………………10
Extraction and isolation of fungal compounds………………11
Assay of anti-inflammatory molecules………………11
Cell viability assay………………………11
Mixed lymphocyte reaction assay…………………11
Reverse transcription-polymerase chain reaction (RT-PCR)……11
Immunoblot analysis……………………12
Reporter assay…………………….12
Molecular docking…………………….13
Native PAGE……………………13
ELISA for cytokine expression……………………13
Mouse models of LPS- or S. choleraesuis-induced inflammatory responses and diarrhea……………………14
LPS-induced sepsis model………………14
Luciferase-based noninvasive bioluminescence imaging………………14
Con A-induced hepatitis and drug administration……….…15
Immunohistochemistry…………………15
Analysis of plasma transaminase activities………………15
Statistical analysis…………………15
Results……………………16
Part I: Zhankuic acid A isolated from T. camphoratus is a novel selective TLR4/MD-2 antagonist with anti-inflammatory properties
ZAA dose-dependently inhibits the production of iNOS, COX2, and NO……..16
ZAA blocks LPS-induced NF-κB, MAPK, and Akt signaling pathways………16
ZAA interacts with the hydrophobic pocket of MD-2 to block LPS actions…...16
ZAA reduces LPS- and S. choleraesuis-induced pro-inflammatory cytokine production………………18
ZAA attenuates LPS-induced lung and renal injury and lethality……………18
ZAA ameliorates clinical symptoms of mice infected with S. choleraesuis….19
Part II: Zhankuic acid A as a novel JAK2 inhibitor for the treatment of Concanavalin A-induced hepatitis
Effects of ZAA on splenic T-cell proliferation in vitro………………20
ZAA induces apoptosis in Jurkat and activated CD4+-T cells in vitro………20
ZAA pretreatment effectively attenuates Con A-induced liver injury……....20
Prediction of ZAA-binding targets…………………………21
ZAA interacts with the hydrophobic pocket of JAK2 to block tyrosine kinase phosphorylation…………………………21
ZAA inhibits the phosphorylation of JAK2 and downstream signaling…………………………23
Effects of ZAA on hepatic cells in vitro…………………………23
High levels of IFN-γ and IL-6 overcome ZAA inhibition of JAK2/STAT1 signaling…………………………24
Discussion……………………………25
ZAA is an anti-inflammatory small-molecule compound…………25
ZAA competes for entry into the MD-2 pocket…....25
ZAA protects S. choleraesuis-induced pathogenesis…………………26
Anti-inflammatory and anti-cancer mechanisms of ZAA………………26
ZAA competes for interaction with the JH1 domain of JAK2……………26
ZAA inhibits LPS- and JAK2-associated inflammation……………27
ZAA treats IFN-γ/STAT1-activated inflammatory disorders………….27
Figures…………28
Tables……………58
Conclusion ………………61
References…………………62
Appendixes…………………70

References
Akashi-Takamura, S., Furuta, T., Takahashi, K., Tanimura, N., Kusumoto, Y., Kobayashi, T., Saitoh, S., Adachi, Y., Doi, T., and Miyake, K. (2006). Agonistic antibody to TLR4/MD-2 protects mice from acute lethal hepatitis induced by TNF-α. J Immunol 176, 4244-4251.
Arpaia, N., Godec, J., Lau, L., Sivick, K.E., McLaughlin, L.M., Jones, M.B., Dracheva, T., Peterson, S.N., Monack, D.M., and Barton, G.M. (2011). TLR signaling is required for Salmonella typhimurium virulence. Cell 144, 675-688.
Barochia, A., Solomon, S., Cui, X., Natanson, C., and Eichacker, P.Q. (2011). Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Expert Opin Drug Metab Toxicol 7, 479-494.
Bos, M.P., Robert, V., and Tommassen, J. (2007). Biogenesis of the gram-negative bacterial outer membrane. Annu Rev Microbiol 61, 191-214.
Bryant, C.E., Spring, D.R., Gangloff, M., and Gay, N.J. (2010). The molecular basis of the host response to lipopolysaccharide. Nat Rev Microbiol 8, 8-14.
Burns, C.J., Bourke, D.G., Andrau, L., Bu, X., Charman, S.A., Donohue, A.C., Fantino, E., Farrugia, M., Feutrill, J.T., Joffe, M., et al. (2009). Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs). Bioorg Med Chem Lett 19, 5887-5892.
Butturini, E., Cavalieri, E., de Prati, A.C., Darra, E., Rigo, A., Shoji, K., Murayama, N., Yamazaki, H., Watanabe, Y., Suzuki, H., et al. (2011). Two naturally occurring terpenes, dehydrocostuslactone and costunolide, decrease intracellular GSH content and inhibit STAT3 activation. PLoS One 6, e20174.
Chen, C.H., Yang, S.W., and Shen, Y.C. (1995). New steroid acids from Antrodia cinnamomea, a fungal parasite of Cinnamomum micranthum. J Nat Prod 58, 1655-1661.
Chen, Y.F., Shiau, A.L., Wang, S.H., Yang, J.S., Chang, S.J., Wu, C.L., and Wu, T.S. (2014). Zhankuic Acid A Isolated from Taiwanofungus camphoratus Is a Novel Selective TLR4/MD-2 Antagonist with Anti-Inflammatory Properties. J Immunol 192, 2778-2786.
Chen, Y.Y., Chou, P.Y., Chien, Y.C., Wu, C.H., Wu, T.S., and Sheu, M.J. (2012). Ethanol extracts of fruiting bodies of Antrodia cinnamomea exhibit anti-migration action in human adenocarcinoma CL1-0 cells through the MAPK and PI3K/AKT signaling pathways. Phytomedicine : international journal of phytotherapy and phytopharmacology 19, 768-778.
Cheng, T., Li, X., Li, Y., Liu, Z., and Wang, R. (2009). Comparative assessment of scoring functions on a diverse test set. J Chem Inf Model 49, 1079-1093.
Chiu, C.H., Su, L.H., and Chu, C. (2004). Salmonella enterica serotype Choleraesuis: epidemiology, pathogenesis, clinical disease, and treatment. Clin microbiol rev 17, 311-322. Crowley, L.V. (1967). The Reitman-Frankel colorimetric transaminase procedure in suspected myocardial infarction. Clin Chem 13, 482-487.
Darnell, J.E., Jr., Kerr, I.M., and Stark, G.R. (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415-1421.
Daubeuf, B., Mathison, J., Spiller, S., Hugues, S., Herren, S., Ferlin, W., Kosco-Vilbois, M., Wagner, H., Kirschning, C.J., Ulevitch, R., et al. (2007). TLR4/MD-2 monoclonal antibody therapy affords protection in experimental models of septic shock. J Immunol 179, 6107-6114.
Dawson, M.A., Bannister, A.J., Gottgens, B., Foster, S.D., Bartke, T., Green, A.R., and Kouzarides, T. (2009). JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin. Nature 461, 819-822.
Delhommeau, F., Pisani, D.F., James, C., Casadevall, N., Constantinescu, S., and Vainchenker, W. (2006). Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci 63, 2939-2953.
Digicaylioglu, M., and Lipton, S.A. (2001). Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-κB signalling cascades. Nature 412, 641-647.
Dong, Y., Lu, B., Zhang, X., Zhang, J., Lai, L., Li, D., Wu, Y., Song, Y., Luo, J., Pang, X., et al. (2010). Cucurbitacin E, a tetracyclic triterpenes compound from Chinese medicine, inhibits tumor angiogenesis through VEGFR2-mediated Jak2-STAT3 signaling pathway. Carcinogenesis 31, 2097-2104.
Doyle, S.L., and O'Neill, L.A. (2006). Toll-like receptors: from the discovery of NFκB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol 72, 1102-1113.
Du, Y.C., Chang, F.R., Wu, T.Y., Hsu, Y.M., El-Shazly, M., Chen, C.F., Sung, P.J., Lin, Y.Y., Lin, Y.H., Wu, Y.C., et al. (2012a). Antileukemia component, dehydroeburicoic acid from Antrodia camphorata induces DNA damage and apoptosis in vitro and in vivo models. Phytomedicine 19, 788-796.
Du, Y.C., Wu, T.Y., Chang, F.R., Lin, W.Y., Hsu, Y.M., Cheng, F.T., Lu, C.Y., Yen, M.H., Tsui, Y.T., Chen, H.L., et al. (2012b). Chemical profiling of the cytotoxic triterpenoid-concentrating fraction and characterization of ergostane stereo-isomer ingredients from Antrodia camphorata. J Pharm Biomed Anal 58, 182-192.
Emoto, M., Nishimura, H., Sakai, T., Hiromatsu, K., Gomi, H., Itohara, S., and Yoshikai, Y. (1995). Mice deficient in γδ T cells are resistant to lethal infection with Salmonella choleraesuis. Infect Immun 63, 3736-3738.
Fang, J., and Silverman, R.B. (2009). A cellular model for screening neuronal nitric oxide synthase inhibitors. Anal Biochem 390, 74-78.
Forsyth, T., Kearney, P.C., Kim, B.G., Johnson, H.W.B., Aay, N., Arcalas, A., Brown, D.S., Chan, V., Chen, J., Du, H.W., et al. (2012). SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors. Bioorg Med Chem Lett 22, 7653-7658.
Freitas, M.C.S., Uchida, Y., Zhao, D., Ke, B., Busuttil, R.W., and Kupiec-Weglinski, J.W. (2010). Blockade of Janus Kinase-2 Signaling Ameliorates Mouse Liver Damage Due to Ischemia and Reperfusion. Liver Transplant 16, 600-610.
Friedbichler, K., Themanns, M., Mueller, K.M., Schlederer, M., Kornfeld, J.W., Terracciano, L.M., Kozlov, A.V., Haindl, S., Kenner, L., Kolbe, T., et al. (2012). Growth-hormone-induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer. Hepatology 55, 941-952.
Gao, B., Wang, H., Lafdil, F., and Feng, D. (2012). STAT proteins - key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver. J Hepatol 57, 430-441.
Ghoreschi, K., Laurence, A., and O'Shea, J.J. (2009). Janus kinases in immune cell signaling. Immunol Rev 228, 273-287.
Gioannini, T.L., Teghanemt, A., Zhang, D., Coussens, N.P., Dockstader, W., Ramaswamy, S., and Weiss, J.P. (2004). Isolation of an endotoxin-MD-2 complex that produces Toll-like receptor 4-dependent cell activation at picomolar concentrations. Proc Natl Acad Sci U S A 101, 4186-4191.
Gioannini, T.L., Teghanemt, A., Zhang, D., Levis, E.N., and Weiss, J.P. (2005). Monomeric endotoxin: protein complexes are essential for TLR4-dependent cell activation. J Endotoxin Res 11, 117-123.
Guha, M., and Mackman, N. (2001). LPS induction of gene expression in human monocytes. Cell Signal 13, 85-94.
Guha, R., Howard, M.T., Hutchison, G.R., Murray-Rust, P., Rzepa, H., Steinbeck, C., Wegner, J., and Willighagen, E.L. (2006). The Blue Obelisk-interoperability in chemical informatics. J Chem Inf Model 46, 991-998.
Guillot, L., Medjane, S., Le-Barillec, K., Balloy, V., Danel, C., Chignard, M., and Si-Tahar, M. (2004). Response of human pulmonary epithelial cells to lipopolysaccharide involves Toll-like receptor 4 (TLR4)-dependent signaling pathways: evidence for an intracellular compartmentalization of TLR4. J Biol Chem 279, 2712-2718.
Hapfelmeier, S., and Hardt, W.D. (2005). A mouse model for S. typhimurium-induced enterocolitis. Trends Microbiol 13, 497-503.
Hseu, Y.C., Yang, H.L., Lai, Y.C., Lin, J.G., Chen, G.W., and Chang, Y.H. (2004). Induction of apoptosis by Antrodia camphorata in human premyelocytic leukemia HL-60 cells. Nutr Cancer 48, 189-197.
Hsu, Y.L., Kuo, Y.C., Kuo, P.L., Ng, L.T., Kuo, Y.H., and Lin, C.C. (2005). Apoptotic effects of extract from Antrodia camphorata fruiting bodies in human hepatocellular carcinoma cell lines. Cancer Lett 221, 77-89.
Jaruga, B., Hong, F., Kim, W.H., and Gao, B. (2004). IFN-γ/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1. Am J Physiol Gastrointest Liver Physiol 287, G1044-1052.
Kawahara, K., Haraguchi, Y., Tsuchimoto, M., Terakado, N., and Danbara, H. (1988). Evidence of correlation between 50-kilobase plasmid of Salmonella choleraesuis and its virulence. Microb Pathog 4, 155-163.
Kim, W.H., Hong, F., Radaeva, S., Jaruga, B., Fan, S., and Gao, B. (2003). STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury. Am J Physiol Gastrointest Liver Physiol 285, G761-768.
Kisseleva, T., Bhattacharya, S., Braunstein, J., and Schindler, C.W. (2002). Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285, 1-24.
Kiu, H., and Nicholson, S.E. (2012). Biology and significance of the JAK/STAT signalling pathways. Growth Factors 30, 88-106.
Kuo, P.L., Hsu, Y.L., Cho, C.Y., Ng, L.T., Kuo, Y.H., and Lin, C.C. (2006). Apoptotic effects of Antrodia cinnamomea fruiting bodies extract are mediated through calcium and calpain-dependent pathways in Hep 3B cells. Food Chem Toxicol 44, 1316-1326.
Levine, R.L., Pardanani, A., Tefferi, A., and Gilliland, D.G. (2007). Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 7, 673-683.
Liby, K.T., and Sporn, M.B. (2012). Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev 64, 972-1003.
Liu, D.Z., Liang, H.J., Chen, C.H., Su, C.H., Lee, T.H., Huang, C.T., Hou, W.C., Lin, S.Y., Zhong, W.B., Lin, P.J., et al. (2007). Comparative anti-inflammatory characterization of wild fruiting body, liquid-state fermentation, and solid-state culture of Taiwanofungus camphoratus in microglia and the mechanism of its action. J Ethnopharmacol 113, 45-53.
Liu, F.C., Lai, M.T., Chen, Y.Y., Lin, W.H., Chang, S.J., Sheu, M.J., and Wu, C.H. (2013a). Elucidating the inhibitory mechanisms of the ethanolic extract of the fruiting body of the mushroom Antrodia cinnamomea on the proliferation and migration of murine leukemia WEHI-3 cells and their tumorigenicity in a BALB/c allograft tumor model. Phytomedicine 20, 874-882.
Liu, Y.Y., Zheng, Q., Fang, B., Wang, W., Ma, F.Y., Roshan, S., Banafa, A., Chen, M.J., Chang, J.L., Deng, X.M., et al. (2013b). Germacrone induces apoptosis in human hepatoma HepG2 cells through inhibition of the JAK2/STAT3 signalling pathway. J Huazhong Univ Sci Technolog Med Sci 33, 339-345.
Lu, M.C., Du, Y.C., Chuu, J.J., Hwang, S.L., Hsieh, P.C., Hung, C.S., Chang, F.R., and Wu, Y.C. (2009). Active extracts of wild fruiting bodies of Antrodia camphorata (EEAC) induce leukemia HL 60 cells apoptosis partially through histone hypoacetylation and synergistically promote anticancer effect of trichostatin A. Arch Toxicol 83, 121-129.
Melgar, S., Karlsson, A., and Michaelsson, E. (2005). Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: correlation between symptoms and inflammation. Am J Physiol Gastrointest Liver Physiol 288, G1328-1338.
Moustakas, D.T., Lang, P.T., Pegg, S., Pettersen, E., Kuntz, I.D., Brooijmans, N., and Rizzo, R.C. (2006). Development and validation of a modular, extensible docking program: DOCK 5. J Comput Aided Mol Des 20, 601-619.
O'Shea, J.J., Laurence, A., and McInnes, I.B. (2013). Back to the future: oral targeted therapy for RA and other autoimmune diseases. Nat Rev Rheumatol 9, 173-182.
O'Sullivan, L.A., Liongue, C., Lewis, R.S., Stephenson, S.E., and Ward, A.C. (2007). Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol 44, 2497-2506.
Opal, S.M., Laterre, P.F., Francois, B., LaRosa, S.P., Angus, D.C., Mira, J.P., Wittebole, X., Dugernier, T., Perrotin, D., Tidswell, M., et al. (2013). Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309, 1154-1162.
Ostojic, A., Vrhovac, R., and Verstovsek, S. (2011). Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Future Oncol 7, 1035-1043.
Park, S.H., Kim, N.D., Jung, J.K., Lee, C.K., Han, S.B., and Kim, Y. (2012). Myeloid differentiation 2 as a therapeutic target of inflammatory disorders. Pharmacol Ther 133, 291-298.
Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., and Ferrin, T.E. (2004). UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 25, 1605-1612.
Rahmouni, S., Delacroix, L., Liu, W.H., and Tautz, L. (2013). Evaluating effects of tyrosine phosphatase inhibitors on T cell receptor signaling. Methods Mol Biol 1053, 241-270.
Rao, Y.K., Fang, S.H., and Tzeng, Y.M. (2007). Evaluation of the anti-inflammatory and anti-proliferation tumoral cells activities of Antrodia camphorata, Cordyceps sinensis, and Cinnamomum osmophloeum bark extracts. J Ethnopharmacol 114, 78-85.
Re, F., and Strominger, J.L. (2002). Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness. J Biol Chem 277, 23427-23432.
Rocchia, W., Alexov, E., and Honig, B. (2001). Extending the applicability of the nonlinear Poisson-Boltzmann equation: Multiple dielectric constants and multivalent ions. J Phys Chem B 105, 6507-6514.
Rossol, M., Heine, H., Meusch, U., Quandt, D., Klein, C., Sweet, M.J., and Hauschildt, S. (2011). LPS-induced cytokine production in human monocytes and macrophages. Crit Rev Immunol 31, 379-446.
Senaldi, G., Shaklee, C.L., Guo, J., Martin, L., Boone, T., Mak, T.W., and Ulich, T.R. (1999). Protection against the mortality associated with disease models mediated by TNF and IFN-γ in mice lacking IFN regulatory factor-1. J Immunol 163, 6820-6826.
Shen, Y.C., Wang, Y.H., Chou, Y.C., Chen, C.F., Lin, L.C., Chang, T.T., Tien, J.H., and Chou, C.J. (2004). Evaluation of the anti-inflammatory activity of zhankuic acids isolated from the fruiting bodies of Antrodia camphorata. Planta Med 70, 310-314.
Shi, L.S., Chao, C.H., Shen, D.Y., Chan, H.H., Chen, C.H., Liao, Y.R., Wu, S.J., Leu, Y.L., Shen, Y.C., Kuo, Y.H., et al. (2011). Biologically active constituents from the fruiting body of Taiwanofungus camphoratus. Bioorg Med Chem 19, 677-683.
Siebler, J., Wirtz, S., Klein, S., Protschka, M., Blessing, M., Galle, P.R., and Neurath, M.F. (2003). A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation. Hepatology 38, 1573-1580.
Song, D.H., and Lee, J.O. (2012). Sensing of microbial molecular patterns by Toll-like receptors. Immunol Rev 250, 216-229.
Tagawa, Y., Sekikawa, K., and Iwakura, Y. (1997). Suppression of concanavalin A-induced hepatitis in IFN-γ (-/-) mice, but not in TNF-α (-/-) mice: role for IFN-γ in activating apoptosis of hepatocytes. J Immunol 159, 1418-1428.
Talbot, S., Totemeyer, S., Yamamoto, M., Akira, S., Hughes, K., Gray, D., Barr, T., Mastroeni, P., Maskell, D.J., and Bryant, C.E. (2009). Toll-like receptor 4 signalling through MyD88 is essential to control Salmonella enterica serovar typhimurium infection, but not for the initiation of bacterial clearance. Immunology 128, 472-483.
Tiegs, G., Hentschel, J., and Wendel, A. (1992). A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest 90, 196-203.
Vainchenker, W., and Constantinescu, S.N. (2013). JAK/STAT signaling in hematological malignancies. Oncogene 32, 2601-2613.
Vainio, M.J., and Johnson, M.S. (2007). Generating conformer ensembles using a multiobjective genetic algorithm. J Chem Inf Model 47, 2462-2474.
Vandewalle, A. (2008). Toll-like receptors and renal bacterial infections. Chang Gung Med J 31, 525-537.
Verstovsek, S. (2013). Ruxolitinib: an oral Janus kinase 1 and Janus kinase 2 inhibitor in the management of myelofibrosis. Postgrad Med 125, 128-135.
Vichai, V., and Kirtikara, K. (2006). Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1, 1112-1116.
Visintin, A., Halmen, K.A., Latz, E., Monks, B.G., and Golenbock, D.T. (2005). Pharmacological inhibition of endotoxin responses is achieved by targeting the TLR4 coreceptor, MD-2. J Immunol 175, 6465-6472.
Wang, H., Lafdil, F., Kong, X.N., and Gao, B. (2011). Signal Transducer and Activator of Transcription 3 in Liver Diseases: A Novel Therapeutic Target. Int J Biol Sci 7, 536-550.
Wang, R., Lu, Y., and Wang, S. (2003). Comparative evaluation of 11 scoring functions for molecular docking. J Med Chem 46, 2287-2303.
Wang, S.H., Wu, Y.T., Kuo, S.C., and Yu, J. (2013). HotLig: A Molecular Surface-Directed Approach to Scoring Protein-Ligand Interactions. J Chem Inf Model 53, 2181-2195.
Weiss, D.S., Raupach, B., Takeda, K., Akira, S., and Zychlinsky, A. (2004). Toll-like receptors are temporally involved in host defense. J Immunol 172, 4463-4469.
Wu, S.J., Leu, Y.L., Chen, C.H., Chao, C.H., Shen, D.Y., Chan, H.H., Lee, E.J., Wu, T.S., Wang, Y.H., Shen, Y.C., et al. (2010). Camphoratins A-J, potent cytotoxic and anti-inflammatory triterpenoids from the fruiting body of Taiwanofungus camphoratus. J Nat Prod 73, 1756-1762.
Yu, Z., Zhang, W., and Kone, B.C. (2002). Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor κB. Biochem J 367, 97-105.
Zhou, T., Georgeon, S., Moser, R., Moore, D.J., Caflisch, A., and Hantschel, O. (2013). Specificity and mechanism-of-action of the JAK2 tyrosine kinase inhibitors ruxolitinib and SAR302503 (TG101348). Leukemia.