臺灣博碩士論文加值系統

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

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