臺灣博碩士論文加值系統

小豆蔻明 (cardamonin) 屬於類黃酮分類底下的查耳酮，許多文獻指出具有抗發炎和抗氧化特性。退化性關節炎是一種常發生在關節的退化性疾病，會造成軟骨破壞並使病患出現行動障礙，而乙型第一介白素 (IL-1β)是表現在退化性關節炎病人關節腔內的強效細胞介質之一，並誘發後續軟骨的分解代謝效應。痛風性關節炎是由關節中沉積的尿酸結晶引起之急性發炎反應，巨噬細胞吞噬尿酸結晶後活化NLRP3發炎小體，進而分泌出IL-1β，誘發其他發炎細胞聚集，而退化性關節炎和痛風性關節炎最終都會導致關節破壞和疼痛。本研究的目的在於探討cardamonin對退化性關節炎和痛風性關節炎是否具有治療作用。
實驗結果發現cardamonin經由調控轉錄因子NF-κB和AP-1路徑，抑制IL-1β誘發的下游發炎因子COX-2、PGE2、MMPs和iNOS蛋白表現，在活體外培養的關節軟骨中使用番紅-固綠染色也看到cardamonin能緩解IL-1β所引起的細胞外基質成分流失。cardamonin在軟骨細胞中通過磷酸化p38和ERK路徑來活化Nrf2訊號促進抗氧化蛋白表現，減少IL-1β刺激軟骨細胞生成的NO和ROS。痛風性關節炎細胞實驗中，在MSU刺激下J744.1巨噬細胞株會活化NLRP3發炎小體，進而生成IL-1β，而cardamonin能抑制此路徑及COX-2的表現量。使用在大鼠的動物實驗中發現，誘發給予腹腔注射cardamonin的預防組及誘發後關節內注射的治療組，都可以明顯抑制於關節內注射尿酸結晶後引起的滑膜發炎反應。
上述結果顯示，cardamonin具有良好的抗氧化和抗發炎反應，應用在退化性關節炎中能保護軟骨細胞及具有治療痛風性關節炎的功效。

Cardamonin, a chalcone isolated mostly from Zingiberaceae plants has been reported to exert anti-inflammatory and anti-oxidant properties. Osteoarthritis (OA) is a common degenerative joint disorder with progressive cartilage destruction and joint dysfunction. Interleukin (IL)-1β is one of the potent cytokine identified in osteoarthritic synovial fluid and triggers a succession of cartilage catabolic effects. Gouty arthritis (GA) arises an acute inflammatory response results from the precipitation of monosodium urate (MSU) crystals in the joint. The uptake of MSU by macrophages activates NLRP3 inflammasome, thus triggering IL-1β production. Osteoarthritis and gouty arthritis both ended up in joint destruction and pain. The aim of this study was to investigate the protective effects of cardamonin on chondrocytes and macrophages in OA and GA models respectively.
Cardamonin inhibits the overexpression of COX-2, MMPs and iNOS in IL-1β induced chondrocytes by western blots, as well as the secretion of PGE2, NO, and matrix metalloproteinases (MMPs). DNA binding activities of NF-κB, AP-1 and STAT-3 in IL-1β-induced chondrocyte were attenuated by cardamonin treatment. Cardamonin restored the IL-1β-induced glycosaminoglycan degradation in ex vivo articular cartilage. Meanwhile, cardamonin reduced the generation of ROS by the induction of Nrf2 pathway through p38 and ERK activation in OA chondrocytes. Cardamonin can also reduce COX-2 expression and IL-1β secretion by inhibiting inflammasome pathway of NLRP3 and mature caspase-1in MSU-stimulated J744.1 macrophages. Moreover, cardamonin attenuates the acute inflammation induced by intra-articular injection of MSU crystals in rat model.
In conclusion, this study demonstrates that cardamonin may be of value in treatment of osteoarthritis and gouty arthritis through its anti-nitrosative and anti-inflammatory activities.

目錄
考試審定書 II
授權書 IV
誌謝 V
中文摘要 VI
英文摘要 VIII
目錄 IX
圖目錄 XI
第一章 緒論 1
1.1 退化性關節炎 (osteoarthritis, OA) 1
1.1.1 退化性關節炎的危險因子 2
1.1.2 關節炎中的發炎介質 3
1.1.3 退化性關節炎與氧化壓力 4
1.1.4 退化性關節炎的治療 6
1.2 痛風性關節炎 (Gouty arthritis) 7
1.2.1 痛風性關節炎的危險因子 7
1.2.2 痛風與NLRP3發炎小體 9
1.2.3 痛風性關節炎的治療策略 10
1.3 小豆蔻明 (cardamonin) 11
1.3.1 Cardamonin的來源與特性 11
1.3.2 Cardamonin的抗發炎作用 13
1.3.3 Cardamonin的抗氧化特性 13
1.3.4 Cardamonin在腫瘤細胞的研究 14
1.3.5 Cardamonin的抗感染作用 15
1.4 研究動機 16
1.5 研究目的 16
第二章 材料與方法 17
2.1 實驗材料 17
2.1.1 化學藥品 17
2.1.2 抗體 18
2.2 實驗方法 19
2.2.1 實驗設計流程圖 19
2.2.2 細胞毒殺性試驗 (MTT assay) 19
2.2.3 初級軟骨細胞培養 (Primary culture) 20
2.2.4 酵素免疫分析法 (Enzyme-Linked ImmunoSorbent Assay, ELISA) 21
2.2.5 活性氧化物質測定 (Reactive oxygen species measurement) 22
2.2.6 活性氮化物測定 (Griess Reaction) 23
2.2.7 蛋白質萃取及定量 23
2.2.8 西方墨點法 (Western blotting) 25
2.2.9 明膠酵素活性分析 (Gelatin Zymography) 28
2.2.10 電泳移動偏移分析 (Electrophoretic mobility shift assay, EMSA) 29
2.2.11 組織處理 31
2.2.12 番紅-固綠染色 (Safranin O - fast green staining) 31
2.2.13 動物實驗 (Animal experiment) 33
2.2.14 統計分析 33
第三章 結果 34
3.1 cardamonin對於人類關節軟骨細胞的影響 34
3.1.1 cardamonin對於軟骨細胞生長情形的影響 34
3.1.2 cardamonin對IL-1β刺激下軟骨細胞發炎物質的影響 34
3.1.3 cardamonin對IL-1β刺激下軟骨細胞分泌MMPs的影響 35
3.1.4 cardamonin對IL-1β刺激下軟骨細胞表面TLRs的影響 36
3.1.5 cardamonin於活體外模式下對ECM的影響 36
3.1.6 cardamonin對轉譯因子的活化與抑制 37
3.1.7 cardamonin對IL-1β刺激下軟骨細胞ROS的影響 38
3.1.8 cardamonin藉由Nrf2活化軟骨細胞中的抗氧化蛋白 38
3.1.9 cardamonin對於IL-1β刺激下軟骨細胞Akt、MAPK路徑的影響 39
3.2 cardamonin對J774.1巨噬細胞株的影響 41
3.2.1 cardamonin對J774.1巨噬細胞株生長情形的影響 41
3.2.2 cardamonin對MSU刺激下J774.1蛋白質表現的影響 41
3.2.3 痛風性關節炎動物實驗 42
第四章 討論 44
4.1.1 cardamonin抑制IL-1β誘發軟骨細胞的發炎 44
4.1.2 cardamonin可能影響的機轉 45
4.1.3 cardamonin抑制MSU誘發的大鼠膝關節發炎反應 46
4.1.4 cardamonin的作用濃度 47
第五章 結論 48
第六章 參考文獻 49
附圖 57

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