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

1. Koenders, M.I.; van den Berg, W.B. Novel therapeutic targets in rheumatoid arthritis. Trends in pharmacological sciences 2015.
2. Wolfe, A.M.; Kellgren, J.H.; Masi, A.T. The epidemiology of rheumatoid arthritis: a review. II. Incidence and diagnostic criteria. Bulletin on the rheumatic diseases 1968, 19, 524-529.
3. van Vollenhoven, R.F. Sex differences in rheumatoid arthritis: more than meets the eye... BMC medicine 2009, 7, 12.
4. Noguchi, M.; Kimoto, A.; Kobayashi, S.; Yoshino, T.; Miyata, K.; Sasamata, M. Effect of celecoxib, a cyclooxygenase-2 inhibitor, on the pathophysiology of adjuvant arthritis in rat. European journal of pharmacology 2005, 513, 229-235.
5. Firestein, G.S. Evolving concepts of rheumatoid arthritis. Nature 2003, 423, 356-361.
6. Silman, A.J.; Pearson, J.E. Epidemiology and genetics of rheumatoid arthritis. Arthritis research 2002, 4 Suppl 3, S265-272.
7. Yamashita, A.; Yonemitsu, Y.; Okano, S.; Nakagawa, K.; Nakashima, Y.; Irisa, T.; Iwamoto, Y.; Nagai, Y.; Hasegawa, M.; Sueishi, K. Fibroblast growth factor-2 determines severity of joint disease in adjuvant-induced arthritis in rats. Journal of immunology 2002, 168, 450-457.
8. Noss, E.H.; Brenner, M.B. The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis. Immunological reviews 2008, 223, 252-270.
9. Scott, D.L.; Smith, C.; Kingsley, G. Joint damage and disability in rheumatoid arthritis: an updated systematic review. Clinical and experimental rheumatology 2003, 21, S20-27.
10. Koenders, M.I.; van den Berg, W.B. Novel therapeutic targets in rheumatoid arthritis. Trends in pharmacological sciences 2015, 36, 189-195.
11. Emery, P. Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment. Rheumatology 2012, 51 Suppl 5, v22-30.
12. Joensuu, J.T.; Aaltonen, K.J.; Aronen, P.; Sokka, T.; Puolakka, K.; Tuompo, R.; Korpela, M.; Vasala, M.; Ilva, K.; Nordstrom, D., et al. Cost-Effectiveness of Biologics Compared to Conventional Disease-Modifying Antirheumatic Drugs for Treatment of Rheumatoid Arthritis in Finland. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research 2015, 18, A648.
13. Rubbert-Roth, A.; Finckh, A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis research & therapy 2009, 11 Suppl 1, S1.
14. Benucci, M.; Li Gobbi, F.; Meacci, F.; Manfredi, M.; Infantino, M.; Severino, M.; Testi, S.; Sarzi-Puttini, P.; Ricci, C.; Atzeni, F. Antidrug antibodies against TNF-blocking agents: correlations between disease activity, hypersensitivity reactions, and different classes of immunoglobulins. Biologics : targets & therapy 2015, 9, 7-12.
15. Agarwal, S.K. Core management principles in rheumatoid arthritis to help guide managed care professionals. Journal of managed care pharmacy : JMCP 2011, 17, S03-08.
16. Cuzzocrea, S.; Mazzon, E.; Paola, R.D.; Genovese, T.; Muia, C.; Caputi, A.P.; Salvemini, D. Effects of combination M40403 and dexamethasone therapy on joint disease in a rat model of collagen-induced arthritis. Arthritis and rheumatism 2005, 52, 1929-1940.
17. Shiozawa, S.; Tsumiyama, K.; Yoshida, K.; Hashiramoto, A. Pathogenesis of joint destruction in rheumatoid arthritis. Archivum immunologiae et therapiae experimentalis 2011, 59, 89-95.
18. Long, C.L.; Humphrey, M.B. Osteoimmunology: the expanding role of immunoreceptors in osteoclasts and bone remodeling. BoneKEy reports 2012, 1.
19. Zaiss, M.M.; Axmann, R.; Zwerina, J.; Polzer, K.; Guckel, E.; Skapenko, A.; Schulze-Koops, H.; Horwood, N.; Cope, A.; Schett, G. Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis and rheumatism 2007, 56, 4104-4112.
20. Boyle, W.J.; Simonet, W.S.; Lacey, D.L. Osteoclast differentiation and activation. Nature 2003, 423, 337-342.
21. Hayashi, H.; Nakahama, K.; Sato, T.; Tuchiya, T.; Asakawa, Y.; Maemura, T.; Tanaka, M.; Morita, M.; Morita, I. The role of Mac-1 (CD11B/CD18) in osteoclast differentiation induced by receptor activator of nuclear factor-kappaB ligand. FEBS letters 2008, 582, 3243-3248.
22. Yago, T.; Nanke, Y.; Ichikawa, N.; Kobashigawa, T.; Mogi, M.; Kamatani, N.; Kotake, S. IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-alpha antibody: a novel mechanism of osteoclastogenesis by IL-17. Journal of cellular biochemistry 2009, 108, 947-955.
23. McInnes, I.B.; Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nature reviews. Immunology 2007, 7, 429-442.
24. Jung, S.M.; Kim, K.W.; Yang, C.W.; Park, S.H.; Ju, J.H. Cytokine-mediated bone destruction in rheumatoid arthritis. Journal of immunology research 2014, 2014, 263625.
25. Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nature reviews. Immunology 2007, 7, 292-304.
26. Okamoto, K.; Takayanagi, H. Regulation of bone by the adaptive immune system in arthritis. Arthritis research & therapy 2011, 13, 219.
27. Sitara, D.; Aliprantis, A.O. Transcriptional regulation of bone and joint remodeling by NFAT. Immunological reviews 2010, 233, 286-300.
28. Manara, M.; Sinigaglia, L. Bone and TNF in rheumatoid arthritis: clinical implications. RMD open 2015, 1, e000065.
29. Brennan, F.M.; McInnes, I.B. Evidence that cytokines play a role in rheumatoid arthritis. The Journal of clinical investigation 2008, 118, 3537-3545.
30. Kay, J.; Calabrese, L. The role of interleukin-1 in the pathogenesis of rheumatoid arthritis. Rheumatology 2004, 43 Suppl 3, iii2-iii9.
31. Arend, W.P.; Dayer, J.M. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis and rheumatism 1990, 33, 305-315.
32. Yu, J.J.; Ruddy, M.J.; Wong, G.C.; Sfintescu, C.; Baker, P.J.; Smith, J.B.; Evans, R.T.; Gaffen, S.L. An essential role for IL-17 in preventing pathogen-initiated bone destruction: recruitment of neutrophils to inflamed bone requires IL-17 receptor-dependent signals. Blood 2007, 109, 3794-3802.
33. van den Berg, W.B.; Miossec, P. IL-17 as a future therapeutic target for rheumatoid arthritis. Nature reviews. Rheumatology 2009, 5, 549-553.
34. Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.; Prinsep, M.R. Marine natural products. Natural product reports 2015, 32, 116-211.
35. Aneiros, A.; Garateix, A. Bioactive peptides from marine sources: pharmacological properties and isolation procedures. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2004, 803, 41-53.
36. Mayer, A.M.; Rodriguez, A.D.; Taglialatela-Scafati, O.; Fusetani, N. Marine pharmacology in 2009-2011: marine compounds with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action. Marine drugs 2013, 11, 2510-2573.
37. Abad, M.J.; Bedoya, L.M.; Bermejo, P. Natural marine anti-inflammatory products. Mini reviews in medicinal chemistry 2008, 8, 740-754.
38. Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436-444.
39. Medzhitov, R. Origin and physiological roles of inflammation. Nature 2008, 454, 428-435.
40. Serhan, C.N.; Savill, J. Resolution of inflammation: the beginning programs the end. Nature immunology 2005, 6, 1191-1197.
41. Hamade, E.; Habib, A.; Hachem, A.; Hussein, A.H.; Abbas, M.; Hirz, T.; Al Masri, M.; Faour, W.H. Biological and anti-inflammatory evaluation of two thiazole compounds in RAW cell line: potential cyclooxygenase-2 specific inhibitors. Medicinal chemistry 2012, 8, 401-408.
42. Shin, H.S.; Kang, S.I.; Yoon, S.A.; Ko, H.C.; Kim, S.J. Sinensetin attenuates LPS-induced inflammation by regulating the protein level of IkB-a. Bioscience, biotechnology, and biochemistry 2012, 76, 847-849.
43. Yang, C.P.; Huang, G.J.; Huang, H.C.; Chen, Y.C.; Chang, C.I.; Wang, S.Y.; Chang, H.S.; Tseng, Y.H.; Chien, S.C.; Kuo, Y.H. The effect of the aerial part of lindera akoensis on lipopolysaccharides (LPS)-induced nitric oxide production in RAW264.7 cells. International journal of molecular sciences 2013, 14, 9168-9181.
44. Jin, Q.; Lee, C.; Lee, J.W.; Yeon, E.T.; Lee, D.; Han, S.B.; Hong, J.T.; Kim, Y.; Lee, M.K.; Hwang, B.Y. 2-Phenoxychromones and prenylflavonoids from Epimedium koreanum and their inhibitory effects on LPS-induced nitric oxide and interleukin-1b production. Journal of natural products 2014, 77, 1724-1728.
45. Li, Q.; Verma, I.M. NF-kappaB regulation in the immune system. Nature reviews. Immunology 2002, 2, 725-734.
46. Yamamoto, Y.; Gaynor, R.B. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. The Journal of clinical investigation 2001, 107, 135-142.
47. Lowik, C.W.; Nibbering, P.H.; van de Ruit, M.; Papapoulos, S.E. Inducible production of nitric oxide in osteoblast-like cells and in fetal mouse bone explants is associated with suppression of osteoclastic bone resorption. The Journal of clinical investigation 1994, 93, 1465-1472.
48. Ralston, S.H.; Ho, L.P.; Helfrich, M.H.; Grabowski, P.S.; Johnston, P.W.; Benjamin, N. Nitric oxide: a cytokine-induced regulator of bone resorption. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 1995, 10, 1040-1049.
49. Nagy, G.; Clark, J.M.; Buzas, E.I.; Gorman, C.L.; Cope, A.P. Nitric oxide, chronic inflammation and autoimmunity. Immunology letters 2007, 111, 1-5.
50. Korhonen, R.; Lahti, A.; Kankaanranta, H.; Moilanen, E. Nitric oxide production and signaling in inflammation. Current drug targets. Inflammation and allergy 2005, 4, 471-479.
51. Chun, K.S.; Cha, H.H.; Shin, J.W.; Na, H.K.; Park, K.K.; Chung, W.Y.; Surh, Y.J. Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-kappaB. Carcinogenesis 2004, 25, 445-454.
52. Toriyabe, M.; Omote, K.; Kawamata, T.; Namiki, A. Contribution of interaction between nitric oxide and cyclooxygenases to the production of prostaglandins in carrageenan-induced inflammation. Anesthesiology 2004, 101, 983-990.
53. Marchand, F.; Perretti, M.; McMahon, S.B. Role of the immune system in chronic pain. Nature reviews. Neuroscience 2005, 6, 521-532.
54. Cheon, H.; Rho, Y.H.; Choi, S.J.; Lee, Y.H.; Song, G.G.; Sohn, J.; Won, N.H.; Ji, J.D. Prostaglandin E2 augments IL-10 signaling and function. Journal of immunology 2006, 177, 1092-1100.
55. Rocha, J.; Peixe, L.; Gomes, N.C.; Calado, R. Cnidarians as a source of new marine bioactive compounds an overview of the last decade and future steps for bioprospecting. Marine drugs 2011, 9, 1860-1886.
56. Leal, M.C.; Calado, R.; Sheridan, C.; Alimonti, A.; Osinga, R. Coral aquaculture to support drug discovery. Trends in biotechnology 2013, 31, 555-561.
57. Cheng, S.Y.; Chuang, C.T.; Wang, S.K.; Wen, Z.H.; Chiou, S.F.; Hsu, C.H.; Dai, C.F.; Duh, C.Y. Antiviral and anti-inflammatory diterpenoids from the soft coral Sinularia gyrosa. Journal of natural products 2010, 73, 1184-1187.
58. Chen, W.F.; Chakraborty, C.; Sung, C.S.; Feng, C.W.; Jean, Y.H.; Lin, Y.Y.; Hung, H.C.; Huang, T.Y.; Huang, S.Y.; Su, T.M., et al. Neuroprotection by marine-derived compound, 11-dehydrosinulariolide, in an in vitro parkinson's model: a promising candidate for the treatment of parkinson's disease. Naunyn-Schmiedeberg's archives of pharmacology 2012, 385, 265-275.
59. Lin, Y.Y.; Jean, Y.H.; Lee, H.P.; Chen, W.F.; Sun, Y.M.; Su, J.H.; Lu, Y.; Huang, S.Y.; Hung, H.C.; Sung, P.J., et al. A soft coral-derived compound, 11-epi-sinulariolide acetate suppresses inflammatory response and bone destruction in adjuvant-induced arthritis. PloS one 2013, 8, e62926.
60. Lin, Y.F.; Kuo, C.Y.; Wen, Z.H.; Lin, Y.Y.; Wang, W.H.; Su, J.H.; Sheu, J.H.; Sung, P.J. Flexibilisquinone, a new anti-inflammatory quinone from the cultured soft coral Sinularia flexibilis. Molecules 2013, 18, 8160-8167.
61. Takaki, H.; Koganemaru, R.; Iwakawa, Y.; Higuchi, R.; Miyamoto, T. Inhibitory effect of norditerpenes on LPS-induced TNF-alpha production from the okinawan soft coral, Sinularia sp. Biological & pharmaceutical bulletin 2003, 26, 380-382.
62. Roman-Blas, J.A.; Jimenez, S.A. NF-kappaB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society 2006, 14, 839-848.
63. Tak, P.P.; Firestein, G.S. Nf-kappab: A key role in inflammatory diseases. The Journal of clinical investigation 2001, 107, 7-11.
64. Lin, Y.Y.; Lin, S.C.; Feng, C.W.; Chen, P.C.; Su, Y.D.; Li, C.M.; Yang, S.N.; Jean, Y.H.; Sung, P.J.; Duh, C.Y., et al. Anti-inflammatory and analgesic effects of the marine-derived compound excavatolide B isolated from the culture-type formosan gorgonian briareum excavatum. Marine drugs 2015, 13, 2559-2579.
65. Wei, W.C.; Lin, S.Y.; Chen, Y.J.; Wen, C.C.; Huang, C.Y.; Palanisamy, A.; Yang, N.S.; Sheu, J.H. Topical application of marine briarane-type diterpenes effectively inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and dermatitis in murine skin. Journal of biomedical science 2011, 18, 94.
66. Lee, H.P.; Huang, S.Y.; Lin, Y.Y.; Wang, H.M.; Jean, Y.H.; Wu, S.F.; Duh, C.Y.; Wen, Z.H. Soft coral-derived lemnalol alleviates monosodium urate-induced gouty arthritis in rats by inhibiting leukocyte infiltration and iNOS, COX-2 and c-Fos protein expression. Marine drugs 2013, 11, 99-113.
67. Lee, H.P.; Lin, Y.Y.; Duh, C.Y.; Huang, S.Y.; Wang, H.M.; Wu, S.F.; Lin, S.C.; Jean, Y.H.; Wen, Z.H. Lemnalol attenuates mast cell activation and osteoclast activity in a gouty arthritis model. The Journal of pharmacy and pharmacology 2015, 67, 274-285.
68. Sheu, J.H.; Sung, P.J.; Cheng, M.C.; Liu, H.Y.; Fang, L.S.; Duh, C.Y.; Chiang, M.Y. Novel cytotoxic diterpenes, excavatolides A-E, isolated from the formosan gorgonian Briareum excavatum. Journal of natural products 1998, 61, 602-608.
69. Wang, Y.C.; Hung, H.C.; Feng, C.W.; Huang, S.Y.; Chen, C.H.; Lin, Y.Y.; Chen, Y.C.; Yang, S.N.; Su, J.H.; Sheu, J.H., et al. Dihydroaustrasulfone alcohol (WA-25) impedes macrophage foam cell formation by regulating the transforming growth factor-beta1 pathway. International journal of molecular sciences 2015, 16, 10507-10525.
70. Chen, Y.C.; Wen, Z.H.; Lee, Y.H.; Chen, C.L.; Hung, H.C.; Chen, C.H.; Chen, W.F.; Tsai, M.C. Dihydroaustrasulfone alcohol inhibits PDGF-induced proliferation and migration of human aortic smooth muscle cells through inhibition of the cell cycle. Marine drugs 2015, 13, 2390-2406.
71. Li, P.C.; Sheu, M.J.; Ma, W.F.; Pan, C.H.; Sheu, J.H.; Wu, C.H. Anti-restenotic roles of dihydroaustrasulfone alcohol involved in inhibiting PDGF-BB-stimulated proliferation and migration of vascular smooth muscle cells. Marine drugs 2015, 13, 3046-3060.
72. Smith, I.R.S., M.D. Pigments of marine animals. Aust. J. Chem. 1971, 24, 13.
73. Bokesch, H.R.; Cartner, L.K.; Fuller, R.W.; Wilson, J.A.; Henrich, C.J.; Kelley, J.A.; Gustafson, K.R.; McMahon, J.B.; McKee, T.C. Inhibition of ABCG2-mediated drug efflux by naphthopyrones from marine crinoids. Bioorganic & medicinal chemistry letters 2010, 20, 3848-3850.
74. Francesconi, K.A. Pigments of some echinoderms collected from western australian waters. Australian Journal of Chemistry 1980, 33, 4.
75. Wright, A.D.; Nielson, J.L.; Tapiolas, D.M.; Motti, C.A.; Ovenden, S.P.; Kearns, P.S.; Liptrot, C.H. Detailed nmr, including 1,1-adequate, and anticancer studies of compounds from the echinoderm Colobometra perspinosa. Marine drugs 2009, 7, 565-575.
76. Bartolin, G.L.; Erdman, T.R.; Scheuer, P.J. Anthraquinone pigments from the crinoid Comanthus bennetti. Tetrahedron 1973, 29, 4.
77. Lin, Y.Y.; Tsai, S.J.; Chiang, M.Y.; Wen, Z.H.; Su, J.H. Anti-inflammatory anthraquinones from the crinoid Himerometra magnipinna. Natural product communications 2015, 10, 317-318.
78. Lai, Y.Y.; Chen, L.C.; Wu, C.F.; Lu, M.C.; Wen, Z.H.; Wu, T.Y.; Fang, L.S.; Wang, L.H.; Wu, Y.C.; Sung, P.J. New cytotoxic 24-homoscalarane sesterterpenoids from the sponge Ircinia felix. International journal of molecular sciences 2015, 16, 21950-21958.
79. Whuang, T.Y.; Tsai, W.C.; Chen, N.F.; Chen, Z.C.; Tsui, K.H.; Wen, Z.H.; Su, Y.D.; Chang, Y.C.; Chen, Y.H.; Lu, M.C., et al. Columnaristerol a, a novel 19-norsterol from the formosan octocoral Nephthea columnaris. Bioorganic & medicinal chemistry letters 2016, 26, 4966-4969.
80. Huang, S.Y.; Chen, N.F.; Chen, W.F.; Hung, H.C.; Lee, H.P.; Lin, Y.Y.; Wang, H.M.; Sung, P.J.; Sheu, J.H.; Wen, Z.H. Sinularin from indigenous soft coral attenuates nociceptive responses and spinal neuroinflammation in carrageenan-induced inflammatory rat model. Marine drugs 2012, 10, 1899-1919.
81. Islam, S.; Hassan, F.; Tumurkhuu, G.; Dagvadorj, J.; Koide, N.; Naiki, Y.; Mori, I.; Yoshida, T.; Yokochi, T. Bacterial lipopolysaccharide induces osteoclast formation in RAW 264.7 macrophage cells. Biochemical and biophysical research communications 2007, 360, 346-351.
82. Guo, C.; Hou, G.Q.; Li, X.D.; Xia, X.; Liu, D.X.; Huang, D.Y.; Du, S.X. Quercetin triggers apoptosis of lipopolysaccharide (LPS)-induced osteoclasts and inhibits bone resorption in RAW264.7 cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2012, 30, 123-136.
83. Wu, G.J.; Chen, W.F.; Hung, H.C.; Jean, Y.H.; Sung, C.S.; Chakraborty, C.; Lee, H.P.; Chen, N.F.; Wen, Z.H. Effects of propofol on proliferation and anti-apoptosis of neuroblastoma SH-SY5Y cell line: New insights into neuroprotection. Brain research 2011, 1384, 42-50.
84. Lowry, O.H.; Rosebrough, N.J.; Farr, A.L.; Randall, R.J. Protein measurement with the folin phenol reagent. The Journal of biological chemistry 1951, 193, 265-275.
85. Chen, L.C.; Lin, Y.Y.; Jean, Y.H.; Lu, Y.; Chen, W.F.; Yang, S.N.; Wang, H.M.; Jang, I.Y.; Chen, I.M.; Su, J.H., et al. Anti-inflammatory and analgesic effects of the marine-derived compound comaparvin isolated from the crinoid Comanthus bennetti. Molecules 2014, 19, 14667-14686.
86. Jean, Y.H.; Chen, W.F.; Duh, C.Y.; Huang, S.Y.; Hsu, C.H.; Lin, C.S.; Sung, C.S.; Chen, I.M.; Wen, Z.H. Inducible nitric oxide synthase and cyclooxygenase-2 participate in anti-inflammatory and analgesic effects of the natural marine compound lemnalol from formosan soft coral Lemnalia cervicorni. European journal of pharmacology 2008, 578, 323-331.
87. Sano, H.; Hla, T.; Maier, J.A.; Crofford, L.J.; Case, J.P.; Maciag, T.; Wilder, R.L. In vivo cyclooxygenase expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis and rats with adjuvant and streptococcal cell wall arthritis. The Journal of clinical investigation 1992, 89, 97-108.
88. Turull, N.; Queralt, J. Effect of the cox-2 selective inhibitor l-745,337 on inflammation and organ prostaglandin E2 (PGE2) levels in adjuvant arthritic rats. Inflammation 2000, 24, 533-545.
89. Salvemini, D.; Mazzon, E.; Dugo, L.; Serraino, I.; De Sarro, A.; Caputi, A.P.; Cuzzocrea, S. Amelioration of joint disease in a rat model of collagen-induced arthritis by M40403, a superoxide dismutase mimetic. Arthritis and rheumatism 2001, 44, 2909-2921.
90. Brand, D.D.; Latham, K.A.; Rosloniec, E.F. Collagen-induced arthritis. Nature protocols 2007, 2, 1269-1275.
91. Yocum, D.E.; Allen, J.B.; Wahl, S.M.; Calandra, G.B.; Wilder, R.L. Inhibition by cyclosporin a of streptococcal cell wall-induced arthritis and hepatic granulomas in rats. Arthritis and rheumatism 1986, 29, 262-273.
92. Baharav, E.; Mor, F.; Halpern, M.; Weinberger, A. Lactobacillus GG bacteria ameliorate arthritis in lewis rats. The Journal of nutrition 2004, 134, 1964-1969.
93. Lin, Y.Y.; Jean, Y.H.; Lee, H.P.; Lin, S.C.; Pan, C.Y.; Chen, W.F.; Wu, S.F.; Su, J.H.; Tsui, K.H.; Sheu, J.H., et al. Excavatolide B attenuates rheumatoid arthritis through the inhibition of osteoclastogenesis. Marine drugs 2017, 15.
94. Bas, D.B.; Su, J.; Sandor, K.; Agalave, N.M.; Lundberg, J.; Codeluppi, S.; Baharpoor, A.; Nandakumar, K.S.; Holmdahl, R.; Svensson, C.I. Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis and rheumatism 2012, 64, 3886-3896.
95. Tsuboi, H.; Matsui, Y.; Hayashida, K.; Yamane, S.; Maeda-Tanimura, M.; Nampei, A.; Hashimoto, J.; Suzuki, R.; Yoshikawa, H.; Ochi, T. Tartrate resistant acid phosphatase (TRAP) positive cells in rheumatoid synovium may induce the destruction of articular cartilage. Annals of the rheumatic diseases 2003, 62, 196-203.
96. Morko, J.; Kiviranta, R.; Joronen, K.; Saamanen, A.M.; Vuorio, E.; Salminen-Mankonen, H. Spontaneous development of synovitis and cartilage degeneration in transgenic mice overexpressing cathepsin k. Arthritis and rheumatism 2005, 52, 3713-3717.
97. Wei, Z.F.; Lv, Q.; Xia, Y.; Yue, M.F.; Shi, C.; Xia, Y.F.; Chou, G.X.; Wang, Z.T.; Dai, Y. Norisoboldine, an anti-arthritis alkaloid isolated from Radix linderae, attenuates osteoclast differentiation and inflammatory bone erosion in an aryl hydrocarbon receptor-dependent manner. International journal of biological sciences 2015, 11, 1113-1126.
98. Fong, C.C.; Wei, F.; Chen, Y.; Yu, W.K.; Koon, C.M.; Leung, P.C.; Fung, K.P.; Lau, C.B.; Yang, M. Danshen-gegen decoction exerts proliferative effect on rat cardiac myoblasts H9C2 via MAPK and insulin pathways. Journal of ethnopharmacology 2011, 138, 60-66.
99. Bingham, D.; John, C.M.; Levin, J.; Panter, S.S.; Jarvis, G.A. Post-injury conditioning with lipopolysaccharide or lipooligosaccharide reduces inflammation in the brain. Journal of neuroimmunology 2013, 256, 28-37.
100. Shalapour, S.; Karin, M. Immunity, inflammation, and cancer: An eternal fight between good and evil. The Journal of clinical investigation 2015, 125, 3347-3355.
101. Rakoff-Nahoum, S. Why cancer and inflammation? The Yale journal of biology and medicine 2006, 79, 123-130.
102. Folmer, F.; Harrison, W.T.; Tabudravu, J.N.; Jaspars, M.; Aalbersberg, W.; Feussner, K.; Wright, A.D.; Dicato, M.; Diederich, M. Nf-kappaB-inhibiting naphthopyrones from the Fijian echinoderm Comanthus parvicirrus. Journal of natural products 2008, 71, 106-111.
103. Chovolou, Y.; Ebada, S.S.; Watjen, W.; Proksch, P. Identification of angular naphthopyrones from the philippine echinoderm Comanthus species as inhibitors of the NF-kappaB signaling pathway. European journal of pharmacology 2011, 657, 26-34.
104. Sakurai, M.; Kohno, J.; Yamamoto, K.; Okuda, T.; Nishio, M.; Kawano, K.; Ohnuki, T. TMC-256A1 and C1, new inhibitors of IL-4 signal transduction produced by aspergillus niger var niger TC 1629. The Journal of antibiotics 2002, 55, 685-692.
105. Sakuma, Y.T., J.I. Higa, T. . New naphthopyrone pigments from the crinoid Comanthus parvicirrus. Australian Journal of Chemistry 1987, 40, 4.
106. Lee, N.K.K.Y.H. New cytotoxic anthraquinones from the crinoid ptilometra: 1'-deoxyrhodoptilometrin-6-o-sulfate and rhodoptilometrin-6-O-sulfate. Bull. Korean Chem. Soc. 1995, 16, 3.
107. Takahashi, D.; Maoka, T.; Tsushima, M.; Fujitani, K.; Kozuka, M.; Matsuno, T.; Shingu, T. New quinone sulfates from the crinoids Tropiometra afra macrodiscus and Oxycomanthus japonicus. Chemical & pharmaceutical bulletin 2002, 50, 1609-1612.
108. Crystallographic data for compound 5 have been deposited with the cambridgecrystallographic data centre (deposition number ccdc 939051). Copies of the data can be obtained, free of charge, on application to the director, ccdc, 12 union road, cambridge cb2 1ez, uk (fax: +44-1223-336033 or e-mail: Deposit@ccdc.Cam.Ac.Uk).
109. Liu, A.; Chen, H.; Wei, W.; Ye, S.; Liao, W.; Gong, J.; Jiang, Z.; Wang, L.; Lin, S. Antiproliferative and antimetastatic effects of emodin on human pancreatic cancer. Oncology reports 2011, 26, 81-89.
110. Han, J.W.; Shim, D.W.; Shin, W.Y.; Heo, K.H.; Kwak, S.B.; Sim, E.J.; Jeong, J.H.; Kang, T.B.; Lee, K.H. Anti-inflammatory effect of emodin via attenuation of NLRP3 inflammasome activation. International journal of molecular sciences 2015, 16, 8102-8109.
111. Paleolog, E.M. Angiogenesis in rheumatoid arthritis. Arthritis research 2002, 4 Suppl 3, S81-90.
112. Huber, L.C.; Distler, O.; Tarner, I.; Gay, R.E.; Gay, S.; Pap, T. Synovial fibroblasts: Key players in rheumatoid arthritis. Rheumatology 2006, 45, 669-675.
113. Pettit, A.R.; Walsh, N.C.; Manning, C.; Goldring, S.R.; Gravallese, E.M. RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology 2006, 45, 1068-1076.
114. McFarland, H.I.; Nahill, S.R.; Maciaszek, J.W.; Welsh, R.M. CD11b (Mac-1): a marker for CD8+ cytotoxic T cell activation and memory in virus infection. Journal of immunology 1992, 149, 1326-1333.
115. Takayanagi, H. The role of NFAT in osteoclast formation. Annals of the New York Academy of Sciences 2007, 1116, 227-237.
116. Chen, C.X.; Chen, J.Y.; Kou, J.Q.; Xu, Y.L.; Wang, S.Z.; Zhu, Q.; Yang, L.; Qin, Z.H. Suppression of inflammation and arthritis by orally administrated cardiotoxin from Naja naja atra. Evidence-based complementary and alternative medicine : eCAM 2015, 2015, 387094.
117. Khan, M.A.; Subramaneyaan, M.; Arora, V.K.; Banerjee, B.D.; Ahmed, R.S. Effect of Withania Somnifera (ashwagandha) root extract on amelioration of oxidative stress and autoantibodies production in collagen-induced arthritic rats. Journal of complementary & integrative medicine 2015, 12, 117-125.
118. Netsu, T.; Kondo, N.; Arai, K.; Ogose, A.; Endo, N. Osteoconductive action of alendronate after implantation of beta tricalcium phosphate in rat adjuvant-induced arthritis. Journal of bone and mineral metabolism 2012, 30, 609-618.
119. Marchesan, J.T.; Gerow, E.A.; Schaff, R.; Taut, A.D.; Shin, S.Y.; Sugai, J.; Brand, D.; Burberry, A.; Jorns, J.; Lundy, S.K., et al. Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis. Arthritis research & therapy 2013, 15, R186.
120. Mahajan, S.; Hogan, J.K.; Shlyakhter, D.; Oh, L.; Salituro, F.G.; Farmer, L.; Hoock, T.C. Vx-509 (decernotinib) is a potent and selective janus kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease. The Journal of pharmacology and experimental therapeutics 2015, 353, 405-414.
121. Wei, W.C.; Sung, P.J.; Duh, C.Y.; Chen, B.W.; Sheu, J.H.; Yang, N.S. Anti-inflammatory activities of natural products isolated from soft corals of taiwan between 2008 and 2012. Marine drugs 2013, 11, 4083-4126.
122. Liaw, C.C.; Shen, Y.C.; Lin, Y.S.; Hwang, T.L.; Kuo, Y.H.; Khalil, A.T. Frajunolides E-K, briarane diterpenes from Junceella fragilis. Journal of natural products 2008, 71, 1551-1556.
123. Liaw, C.C.; Lin, Y.C.; Lin, Y.S.; Chen, C.H.; Hwang, T.L.; Shen, Y.C. Four new briarane diterpenoids from taiwanese gorgonian Junceella fragilis. Marine drugs 2013, 11, 2042-2053.
124. Bendele, A. Animal models of rheumatoid arthritis. Journal of musculoskeletal & neuronal interactions 2001, 1, 377-385.
125. Cremer, M.A.; Townes, A.S.; Kang, A.H. Adjuvant-induced arthritis in rats. Evidence that autoimmunity to homologous collagens types I, II, IX and XI is not involved in the pathogenesis of arthritis. Clinical and experimental immunology 1990, 82, 307-312.
126. Trentham, D.E.; Townes, A.S.; Kang, A.H. Autoimmunity to type II collagen an experimental model of arthritis. The Journal of experimental medicine 1977, 146, 857-868.
127. Kaminska, B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy from molecular mechanisms to therapeutic benefits. Biochimica et biophysica acta 2005, 1754, 253-262.
128. Thalhamer, T.; McGrath, M.A.; Harnett, M.M. MAPKs and their relevance to arthritis and inflammation. Rheumatology 2008, 47, 409-414.
129. Sheu, J.H.; Chen, Y.H.; Chen, Y.H.; Su, Y.D.; Chang, Y.C.; Su, J.H.; Weng, C.F.; Lee, C.H.; Fang, L.S.; Wang, W.H., et al. Briarane diterpenoids isolated from gorgonian corals between 2011 and 2013. Marine drugs 2014, 12, 2164-2181.
130. Jo, Y.H.; Park, H.C.; Choi, S.; Kim, S.; Bao, C.; Kim, H.W.; Choi, H.K.; Lee, H.J.; Auh, J.H. Metabolomic analysis reveals cyanidins in black raspberry as candidates for suppression of lipopolysaccharide-induced inflammation in murine macrophages. Journal of agricultural and food chemistry 2015, 63, 5449-5458.
131. Su, Y.D.; Su, T.R.; Wen, Z.H.; Hwang, T.L.; Fang, L.S.; Chen, J.J.; Wu, Y.C.; Sheu, J.H.; Sung, P.J. Briarenolides K and L, new anti-inflammatory briarane diterpenoids from an octocoral Briareum sp. (Briareidae). Marine drugs 2015, 13, 1037-1050.
132. Shuto, T.; Jimi, E.; Kukita, T.; Hirata, M.; Koga, T. Granulocyte-macrophage colony stimulating factor suppresses lipopolysaccharide-induced osteoclast-like cell formation in mouse bone marrow cultures. Endocrinology 1994, 134, 831-837.
133. Abu-Amer, Y.; Ross, F.P.; Edwards, J.; Teitelbaum, S.L. Lipopolysaccharide-stimulated osteoclastogenesis is mediated by tumor necrosis factor via its p55 receptor. The Journal of clinical investigation 1997, 100, 1557-1565.
134. De Klerck, B.; Carpentier, I.; Lories, R.J.; Habraken, Y.; Piette, J.; Carmeliet, G.; Beyaert, R.; Billiau, A.; Matthys, P. Enhanced osteoclast development in collagen-induced arthritis in interferon-gamma receptor knock-out mice as related to increased splenic CD11b+ myelopoiesis. Arthritis research & therapy 2004, 6, R220-231.
135. Fernandes, J.C.; Wang, H.; Jreyssaty, C.; Benderdour, M.; Lavigne, P.; Qiu, X.; Winnik, F.M.; Zhang, X.; Dai, K.; Shi, Q. Bone-protective effects of nonviral gene therapy with folate-chitosan DNA nanoparticle containing interleukin-1 receptor antagonist gene in rats with adjuvant-induced arthritis. Molecular therapy : the journal of the American Society of Gene Therapy 2008, 16, 1243-1251.
136. Kubota, T.; Hoshino, M.; Aoki, K.; Ohya, K.; Komano, Y.; Nanki, T.; Miyasaka, N.; Umezawa, K. NF-kappaB inhibitor dehydroxymethylepoxyquinomicin suppresses osteoclastogenesis and expression of NFATc1 in mouse arthritis without affecting expression of RANKL, osteoprotegerin or macrophage colony-stimulating factor. Arthritis research & therapy 2007, 9, R97.
137. Yamaguchi, Y.; Sakai, E.; Sakamoto, H.; Fumimoto, R.; Fukuma, Y.; Nishishita, K.; Okamoto, K.; Tsukuba, T. Inhibitory effects of tert-Butylhydroquinone on osteoclast differentiation via up-regulation of heme oxygenase-1 and down-regulation of HMGB1 release and NFATc1 expression. Journal of applied toxicology : JAT 2014, 34, 49-56.
138. Udagawa, N.; Takahashi, N.; Katagiri, T.; Tamura, T.; Wada, S.; Findlay, D.M.; Martin, T.J.; Hirota, H.; Taga, T.; Kishimoto, T., et al. Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors. The Journal of experimental medicine 1995, 182, 1461-1468.
139. Redlich, K.; Hayer, S.; Ricci, R.; David, J.P.; Tohidast-Akrad, M.; Kollias, G.; Steiner, G.; Smolen, J.S.; Wagner, E.F.; Schett, G. Osteoclasts are essential for TNF-alpha-mediated joint destruction. The Journal of clinical investigation 2002, 110, 1419-1427.
140. Braun, T.; Zwerina, J. Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritis. Arthritis research & therapy 2011, 13, 235.
141. Takayanagi, H. New developments in osteoimmunology. Nature reviews. Rheumatology 2012, 8, 684-689.
142. Lubberts, E. The IL-23-IL-17 axis in inflammatory arthritis. Nature reviews. Rheumatology 2015, 11, 562.
143. Kaneko, M.; Tomita, T.; Nakase, T.; Ohsawa, Y.; Seki, H.; Takeuchi, E.; Takano, H.; Shi, K.; Takahi, K.; Kominami, E., et al. Expression of proteinases and inflammatory cytokines in subchondral bone regions in the destructive joint of rheumatoid arthritis. Rheumatology 2001, 40, 247-255.
144. Kim, K.C.; Lee, C.H. MAP kinase activation is required for the MMP-9 induction by TNF-stimulation. Archives of pharmacal research 2005, 28, 1257-1262.
145. Hou, W.S.; Li, Z.; Gordon, R.E.; Chan, K.; Klein, M.J.; Levy, R.; Keysser, M.; Keyszer, G.; Bromme, D. Cathepsin k is a critical protease in synovial fibroblast-mediated collagen degradation. The American journal of pathology 2001, 159, 2167-2177.
146. Chimenti, M.S.; Triggianese, P.; Conigliaro, P.; Candi, E.; Melino, G.; Perricone, R. The interplay between inflammation and metabolism in rheumatoid arthritis. Cell death & disease 2015, 6, e1887.
147. Talero, E.; Garcia-Maurino, S.; Avila-Roman, J.; Rodriguez-Luna, A.; Alcaide, A.; Motilva, V. Bioactive compounds isolated from microalgae in chronic inflammation and cancer. Marine drugs 2015, 13, 6152-6209.
148. Thao, N.P.; Luyen, B.T.; Ngan, N.T.; Song, S.B.; Cuong, N.X.; Nam, N.H.; Kiem, P.V.; Kim, Y.H.; Minh, C.V. New anti-inflammatory cembranoid diterpenoids from the vietnamese soft coral Lobophytum crassum. Bioorganic & medicinal chemistry letters 2014, 24, 228-232.
149. Thao, N.P.; Nam, N.H.; Cuong, N.X.; Luyen, B.T.; Tai, B.H.; Kim, J.E.; Song, S.B.; Kiem, P.V.; Minh, C.V.; Kim, Y.H. Inhibition of NF-kappab transcriptional activation in HEPG2 cells by diterpenoids from the soft coral Sinularia maxima. Archives of pharmacal research 2014, 37, 706-712.
150. Cuong, N.X.; Thao, N.P.; Luyen, B.T.; Ngan, N.T.; Thuy, D.T.; Song, S.B.; Nam, N.H.; Kiem, P.V.; Kim, Y.H.; Minh, C.V. Cembranoid diterpenes from the soft coral Lobophytum crassum and their anti-inflammatory activities. Chemical & pharmaceutical bulletin 2014, 62, 203-208.
151. Ahmed, A.F.; Wu, M.H.; Wang, G.H.; Wu, Y.C.; Sheu, J.H. Eunicellin-based diterpenoids, australins A-D, isolated from the soft coral Cladiella australis. Journal of natural products 2005, 68, 1051-1055.
152. Wen, Z.H.; Chao, C.H.; Wu, M.H.; Sheu, J.H. A neuroprotective sulfone of marine origin and the in vivo anti-inflammatory activity of an analogue. European journal of medicinal chemistry 2010, 45, 5998-6004.
153. Lin, S.W.; Huang, S.C.; Kuo, H.M.; Chen, C.H.; Ma, Y.L.; Chu, T.H.; Bee, Y.S.; Wang, E.M.; Wu, C.Y.; Sung, P.J., et al. Coral-derived compound WA-25 inhibits angiogenesis by attenuating the VEGF/VEGFR2 signaling pathway. Marine drugs 2015, 13, 861-878.
154. Han, Z.; Boyle, D.L.; Chang, L.; Bennett, B.; Karin, M.; Yang, L.; Manning, A.M.; Firestein, G.S. C-jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. The Journal of clinical investigation 2001, 108, 73-81.
155. Chen, S.C.; Chien, Y.C.; Pan, C.H.; Sheu, J.H.; Chen, C.Y.; Wu, C.H. Inhibitory effect of dihydroaustrasulfone alcohol on the migration of human non-small cell lung carcinoma A549 cells and the antitumor effect on a lewis lung carcinoma-bearing tumor model in C57bl/6J mice. Marine drugs 2014, 12, 196-213.
156. Kanner, J.; Kinsella, J.E. Lipid deterioration initiated by phagocytic cells in muscle foods: Beta-carotene destruction by a myeloperoxidase-hydrogen peroxide-halide system. Journal of agricultural and food chemistry 1983, 31, 370-376.
157. Matheson, N.R.; Wong, P.S.; Travis, J. Enzymatic inactivation of human alpha-1-proteinase inhibitor by neutrophil myeloperoxidase. Biochemical and biophysical research communications 1979, 88, 402-409.
158. Wang, J.Y.; Yuan, Y.; Chen, X.J.; Fu, S.G.; Zhang, L.; Hong, Y.L.; You, S.F.; Yang, Y.Q. Extract from Eucommia ulmoides oliv. Ameliorates arthritis via regulation of inflammation, synoviocyte proliferation and osteoclastogenesis in vitro and in vivo. Journal of ethnopharmacology 2016.
159. Dong, L.; Xia, S.; Gao, F.; Zhang, D.; Chen, J.; Zhang, J. 3,3'-diindolylmethane attenuates experimental arthritis and osteoclastogenesis. Biochemical pharmacology 2010, 79, 715-721.
160. Li, X.; Yuan, F.L.; Lu, W.G.; Zhao, Y.Q.; Li, C.W.; Li, J.P.; Xu, R.S. The role of interleukin-17 in mediating joint destruction in rheumatoid arthritis. Biochemical and biophysical research communications 2010, 397, 131-135.
161. Matsumoto, M.; Sudo, T.; Saito, T.; Osada, H.; Tsujimoto, M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappaB ligand (RANKL). The Journal of biological chemistry 2000, 275, 31155-31161.