臺灣博碩士論文加值系統

海洋長久以來以被認為是治療人類疾病中興新藥物開發的重要來源。現今已從超過24000個海洋衍生化合物中成功開發出可供臨床醫藥上使用的8個海洋藥物。然而，在諸多的研究中指出人類的許多疾病中如腫瘤、神經退化性疾病和免疫疾病等，發炎反應在其中扮演重要的角色。因此抗發炎活性在海洋藥物的開發中為重要且必須的生物活性篩選目標。類風濕性關節炎(RA)為一種自體免疫且發炎性疾病，主要的特徵為關節處的滑膜發炎並伴隨噬骨細胞活化作用導致軟骨和硬骨的損壞。因此，在此次研究中我們針對海百合及軟珊瑚的衍生化合物進行抗發炎與抗關節炎的生物活性分析。由結果顯示在海百合的化合物中有4個具有抗發炎潛力，可顯著抑制酯多醣誘發小鼠巨噬細胞發炎模式。此外，我們針對過去已被定義具有抗發炎、抗腫瘤及鎮痛效果之軟珊瑚化合物excavatolide B (Exc-B)和W2AL5 進行抗關節炎活性之研究。在動物模式的結果顯示，Exc-B和W2AL5均可有效改善類風濕性關節炎的病理組織特徵和發炎性蛋白質的表現。同時我們抑評估Exc-B 和W2AL5對於抑制噬骨細胞新生之作用。結果顯示Exc-B 和W2AL5可經由透過抑制絲裂原活化蛋白激酶(MAPK)和噬骨細胞相關蛋白的表現達到抑制噬骨細胞新生之作用。因此由已上發現的成果證實海洋化合物治療人類發炎性疾病可視為具有潛力之策略，同時可作為有效治療關節炎之良好方略。

The sea has long been considered an important resource for the development of novel drugs aimed at treating human diseases, and there are eight marine drugs discovery from over 24,000 marine-derived compounds currently used in clinical medicine. Meanwhile, many types of research have indicated that inflammation plays important roles in human diseases such as cancer, neurodegenerative diseases, and immune diseases. Therefore, anti-inflammatory activity is an essential bioactivity to screen for when seeking to develop marine compounds. Rheumatoid arthritis (RA) is an autoimmune-mediated inflammatory disease which is characterized by synovial inflammation, as well as joint damage, cartilage destruction, and bone erosion with osteoclast activation. Thus, we screened for the anti-inflammatory or anti-arthritic activity of crinoid- and coral-derived compounds in this study. The results showed that there are 4 crinoid-derived compounds that exhibited anti-inflammatory activity in lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cells. Moreover, we also studied the anti-arthritic effects of excavatolide B (Exc-B) and W2AL5 in vivo studies, both of which have been identified as anti-inflammatory, anti-cancer agents and analgesics in past research studies. We found that both Exc-B and W2AL5 could significantly attenuate the characteristics of RA by improving histopathological features and reducing the expressions of pro-inflammatory and osteoclastic proteins in animal models. We also found that both Exc-B and W2AL5 exhibited anti-osteoclastogenesis activity via their respective reductions of the activity of the mitogen-activated protein kinases (MAPK) pathway and the expressions of osteoclastic-related proteins. Hence, these findings strongly suggest that marine compounds offer a potential strategy for treating inflammatory diseases and could also provide a useful therapeutic strategy for the treatment of arthritis.

項目 頁碼
論文審定書.………………………………………………………………… i
謝誌…….…………………………………………………………………… ii
中文摘要.…………………………………………………………………… iii
Abstract…………………………………………………………………… iv
General introduction…………………………………………………... 1
Rheumatoid arthritis (RA)…...…………………………………………. 1
Pathogenesis of RA ……………….…………………………………… 2
Osteoclastogenesis in RA ……………….…………………………….. 3
The anti-inflammatory strategy for RA………………………….…...... 4
Anti-inflammatory marine compounds potential for RA……………… 6
The anti-inflammatory of coral derived compounds for RA …….……. 7
Specific aim…………………………………………………….……… 8
General Material and Methods……………………………………... 11
Marine compounds preparation ………………………………………... 11
Compounds preparation from Comanthus bennetti……….…………..... 11
Compounds preparation from Himerometra magnipinna ……………… 12
Compounds preparation of excavatolide B……………………..……… 13
Preparation of W2AL5 ……………………..……………………..…… 13
Cytotoxicity testing ……………………………………….…………… 14
The inflammatory Assay………………………………………….……. 15
LPS induced RAW264.7 osteoclast like cell ……………………..….... 16
Real-Time PCR Analysis ……………………………..……….….…… 16
Immunocytochemistry ………………………………………..….……. 18
Western blotting analysis……………………………………….……… 19
Animals………………………………………………………….……... 20
Animal models of rheumatoid arthritis ………………………………... 21
Micro-CT imaging………………………………………………..……. 22
Histopathological examination and immunohistochemical stain……… 22
Preparation of synovial tissue for western blotting analysis…………… 25
Measurements of cytokine levels………………………………………. 27
Statistical analysis…………………………………………..…….……. 27

Part I: Isolation of anti-inflammatory marine compounds the Two Crinoids Comanthus bennetti and Himerometra magnipinna


Introduction…………………………………………………….. 29
Result……………………………………………………….…… 32
Marine compounds isolated from Comanthus bennetti………………… 32
Marine compounds isolated from Himerometra magnipinna…..……… 33
Cytotoxicity……………………………………………………………. 34
Anti-inflammatory……………………………………………………... 34
Discussion……………………………………………………….. 36
Anthraquinones for anti-inflammatory activity……………………..…. 36
Naphthopyrones for anti-inflammatory activity……………….…….…. 37

Part II: Excavatolide B: A soft coral-derived anti-inflammatory agent attenuates rheumatoid arthritis through the inhibition of osteoclastogenesis

Introduction…………………………………………….….…… 85
Results…………………………………………………….…….. 89
Exc-B inhibit LPS induced osteoclast like cell Formation………..…… 89
Effects of Exc-B on the clinical features of RA………………………… 90
Effects of Exc-B on histological features of RA…………………..…… 92
Effects of Exc-B on TRAP positive multinucleated cells formation in vivo…………………………………………………………….………..
93
Effects of Exc-B on NFATc1 of arthritic rats……………………….….. 94
Effects of Exc-B on cathepsin k, MMP2, MMP9, and CD11b in synovial tissue………………………………………………………………...….
95
Effects of Exc-B on cathepsin k, MMP2, and MMP9 in cartilage…….... 96
Effects of Exc-B on MAPK, HO-1, and HMGB 1 protein expression in synovial tissue………………………………………………….……….
98
Effects of Exc-B on M-CSF and IL-17A of blood serum………………. 99
Discussion……………………………………………………….. 100
Effect of Exc-B anti-inflammatory in vitro and in vivo……………….. 100
Effect of Exc-B anti-osteoclast activity……………..…………..…….. 102
The possible therapeutic mechanism of Exc-B on RA………………… 103
The immunomodulatory effects of Exc-B on RA……………………… 105
Coral Aquaculture for anti-inflammatory and anti-arthritis…………… 106

Part III: Anti-inflammatory properties of Dihydroaustrasulfone Alcohol (W2AL5) ameliorate rheumatoid arthritis through down-regulated osteoclastogenesis in CIA of rats

Introduction.……………………………………………………. 135
Results…………………………………………………………... 138
Clinical evaluation of W2AL5 on CIA-rats …………………….…..… 138
Micro-CT scan on ankle of CIA………………………………..….…... 139
Histopathological Effect of W2AL5 on CIA-rats………………...….… 140
Immunohistochemistry staining of multinucleated cells…………..….. 141
Immunohistochemistry staining of synovial tissue………….……….… 142
Effects of W2AL5 on M-CSF and IL-17A of blood serum……….….... 142
Western Blot Analysis for MAPK in synovial tissue……………...…... 143
Discussion……………………………………………….………. 144
Clinical evaluation of the effects of W2AL5 on inflammation in the CIA model…………………………………………………………………...
144
Effects of W2AL5 on osteoclastogenesis…………………...….……… 145
W2AL5 inhibition of osteoclastogenesis via regulation of pro-inflammatory mediators……………………………………………...…
146
Effects of W2AL5 on MAPK pathway……………………….………... 148
The immunomodulatory effects of W2AL5 on RA……………………. 149
General Conclusion…………………….………………..…...… 166
Reference……………………………………………………...… 167
Resume………………………………………………………….. 184
Published paper………………………………………………… 194

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