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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉興華 | |
| dc.contributor.author | Ying-Ju Chen | en |
| dc.contributor.author | 陳瀅如 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:17:48Z | - |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-07-26 | |
| dc.identifier.citation | 1. Campo GM, Avenoso A, Campo S, et al. (2010) Molecular size hyaluronan differently modulates toll-like receptor-4 in LPS-induced inflammation in mouse chondrocytes. Biochimie 92:204–215.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17514 | - |
| dc.description.abstract | 骨關節炎(osteoarthritis)又稱為退化性關節炎(degenerative joint disease)，常伴隨著關節軟骨的破壞退化及慢性炎症的表現。發炎前驅物質interleukin(IL)-1β會刺激許多使軟骨退化的媒介像是matrix metalloproteinases (MMPs)的產生，因此在退化性關節炎的致病過程中扮演著重要的角色。隨著年紀的增長，體內會有
經過糖化的蛋白稱為糖化終產物(Advanced glycation end products, AGEs)不斷堆積，尤其在關節中，並且和由老化所引起退化性關節炎中軟骨的損壞及受傷有非常密切的關係。EGb761 是一種銀杏葉片的萃取物；厚朴酚是一種從厚朴(Magnolia officinalis)中萃取出的天然小分子萃取物，這兩種天然物質在過去文獻中已經被證實具有抗發炎的作用。本論文研究主要利用in vitro 及in vivo 的模式，去模擬軟骨的發炎反應，並且探討EGb761 及honokiol 對於退化性關節炎的治療效果。另一方面，本論文也探討人類軟骨細胞由AGEs 所引起的發炎反應中，peroxisome proliferator-activated receptor γ (PPARγ)、 toll-like receptor 4 (TLR4)以及AGEs 受體(receptor for AGEs, RAGE)所扮演的角色。實驗共分為三個部分。 第一個部分主要在探討EGb761 是否能抑制人類軟骨細胞中，由脂多醣(lipopolysaccharide, LPS)及第一介白素-1β(interleukin-1β, IL-1β)所引起的發炎反應；並以一個退化性關節炎的大鼠模式，來探討EGb761 是否具有保護軟骨的作用。研究結果顯示，LPS 在人類軟骨細胞中會大量引發前列腺素(prostaglandin E2, PGE2)和一氧化氮(nitric oxide, NO)的產生以及環氧化酶(cyclooxygen 2, COX-2)和誘導型一氧化氮合成酶(inducible nitric oxide synthase, iNOS)蛋白的表現。另外，LPS 也能調控toll-like receptor-4 (TLR4)、其下游TNF-receptor-associated factor 6(TRAF6)以及nuclear factor (NF)-κB 的訊息傳遞路徑。在由IL-1β所模擬的發炎反應也有一樣的趨勢。而以上這些由LPS 或IL-1β所引起發炎相關的反應都能被EGb761 以及其主要成分quercetin 和kampferol 所抑制。在退化性關節炎的大鼠模式中，血液中PGE2 及NO、組織切片軟骨的改變以及COX-2 和nitrotyrosine 的表現也都有增加的趨勢；而在餵食EGb761 的組別中，這些現象也都有被抑制。 第二個部分主要想探討厚朴酚在退化性關節炎的模式下對於軟骨的發炎是否具有治療的作用。研究結果顯示，厚朴酚在人類軟骨細胞中能抑制由IL-1β所引起的PGE2、NO 及IL-6 的產生及COX-2 和iNOS 蛋白的表現。此外，也能透過抑制細胞核內IKK/IκBα/NF-κB 的活化來減少軟骨的發炎反應。另一方面，厚朴酚也能顯著的抑制由IL-1β 所引起MMP-13 的產生以及collagen II 的表現減少。 第三個部分主要在探討人類軟骨細胞由AGEs 所引起的發炎反應中， PPARγ、TLR4 以及 RAGE 所扮演的角色。研究結果顯示人類軟骨細胞在AGEs的刺激下，會大量產生IL-6 與MMP-13 以及使COX-2 和high-mobility group protein B1 的蛋白表現量增加，並使collgen II 的表現量減少。同時，AGEs 也能活化核內轉錄因子NF-κB 的表現。此外，AGEs 也會隨著時間及劑量，正向調控TLR4 及RAGE 的表現以及負向調控PPARγ 的表現。給予TLR4 及RAGE 的抗 體則能夠有效的抑制由AGEs 所引起和發炎反應相關的訊息傳遞及PPARγ 的負向調控；給予PPARγ 的致效劑pioglitazone 也能抑制由AGEs 所引起和發炎反應相關的訊息傳遞。另一方面，給予p38 mitogen-activated protein kinases、c-Jun N-terminal kinase 和NF-κB 的抑制劑能夠抑制由AGEs 所引起PPARγ 的負向調 控及collagen II 表現的減少。 綜合以上，結果證實EGb761 在人類軟骨細胞及退化性關節炎大鼠的模式中，具有抗發炎的作用；另外，結果也證實厚朴酚能夠透過IKK/IκBα/NF-κB 訊息傳遞路徑對於由IL-1β 所引起的軟骨退化具有保護的作用；未來EGb761 和厚朴酚也許可以做為退化性關節炎治療用藥的新選擇。除此之外，我們的結果也證實在人類軟骨細胞中，AGEs 會經由TLR4 和RAGE AGEs 在人類軟骨細胞中能夠透 過TLR4 及RAGE 來增加PPARγ 的負向調控和collagen II 表現減少所媒介的發炎反應，證明了TLR4、RAGE 和PPARγ 在由於AGEs 的堆積所引起退化性關節炎致病過程中扮演著重要的角色。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:17:48Z (GMT). No. of bitstreams: 1 ntu-102-F96447013-1.pdf: 4620627 bytes, checksum: f17f063967e4babe5a9a540e7717ede4 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii Abstract vi Abbreviation x 1. Introduction 1 [Figure 1.1] Osteoarthritis exhibits an imbalance in cartilage matrix turnover 8 [Figure 1.2] COX-2 and iNOS expression in the chondrocyte is induced by inflammatory mediators such as IL-1β and TNF-α 8 [Figure 1.3] Formation of AGEs 9 [Figure 1.4] Current osteoarthritis treatment options 9 [Figure 1.5] Chemical structure of EGb761 10 [Figure 1.6] Chemical structure of honokiol 10 [Table 1.1] Cytokines involved in the pathophysiology of OA 11 2. Materials and Methods 12 2.1. Ethics statement 12 2.2. Reagents 12 2.3. Isolation and culture of chondrocytes from human articular cartilage 13 2.4. Preparation of AGEs 14 2.5. Cell viability assay 14 2.6. Measurement of NO production 14 2.7. Measurement of PGE2 production 15 2.8. Measurements of IL-6 production 15 2.9. Measurements of MMP-13 production 15 2.10. Western blot analysis 16 2.11. Preparation of nuclear extracts and NF-κB activation measurement 16 2.12. Experimental animals and surgical procedures 17 2.13. Histological analysis and immunohistochemistry 18 2.14. Histological examination 19 2.15. Statistics 19 3. Results and discussion 20 3.1. EGb761 inhibits inflammatory responses in human chondrocytes and shows chondroprotection in osteoarthritic rat knee 20 3.1.1. Results 20 3.1.1.1. EGb761 and its active components inhibit inflammatory responses in human chondrocytes 20 3.1.1.2. EGb761 and its active components suppress the activation of TLR4/TRAF6 and NF-κB signaling pathway in human chondrocytes 20 3.1.1.3. EGb761 suppresses IL-1β-induced inflammatory responses in human chondrocytes 21 3.1.1.4. EGb761 shows an anti-Inflammatory effect in a rat OA model 21 3.1.2. Discussion 22 [Figure 3.1.1] 26 [Figure 3.1.2] 27 [Figure 3.1.3] 28 [Figure 3.1.4] 29 [Figure 3.1.5] 30 [Figure 3.1.6] 31 [Figure 3.1.7] 32 [Figure 3.1.8] 33 [Figure 3.1.9] 34 3.2. Honokiol, a low molecular weight natural product, prevents inflammatory response and cartilage matrix degradation in human osteoarthritis chondrocytes 35 3.2.1. Results 35 3.2.1.1. Inhibitory effects of honokiol on IL-1β-induced productions of NO and PGE2 and expressions of iNOS and COX-2 in human OA chondrocytes. 35 3.2.1.2. Honokiol suppressed IL-1β-stimulated inflammatory responses through inhibition of IKK/IκBα/NF-κB signaling. 36 3.2.1.3. Honokiol inhibited IL-1β-induced productions of IL-6 and MMP-13 and the reduction expression of collagen II. 36 3.2.2. Discussion 37 [Figure 3.2.1] 41 [Figure 3.2.2] 43 [Figure 3.2.3] 44 [Figure 3.2.4] 45 [Figure 3.2.5] 46 3.3. Advanced glycation end products induce peroxisome proliferator-activated receptor down-regulation-related inflammatory signals in human chondrocytes via toll-like receptor-4 and receptor for advanced glycation end products 47 3.3.1. Results 47 3.3.1.1. AGEs induce inflammatory responses in human OA chondrocytes. 47 3.3.1.2. Involvement of TLR4 and RAGE in AGEs-increased inflammatory responses in human OA chondrocytes. 48 3.3.1.3. AGEs down-regulate PPARγ expression via TLR4 and RAGE in human OA chondrocytes. 48 3.3.1.4. PPARγ agonist pioglitazone reverses the AGEs-increased inflammatory responses in human OA chondrocytes. 49 3.3.1.5. Involvement of MAPK signaling in AGEs-induced PPARγ down-regulation. 50 3.3.2. Discussion 51 [Figure 3.3.1] 56 [Figure 3.3.2] 57 [Figure 3.3.3] 58 [Figure 3.3.4] 60 [Figure 3.3.5] 62 [Figure 3.3.6] 64 [Figure 3.3.7] 65 [Figure 3.3.8] 67 [Figure 3.3.9] 69 [Figure 3.3.10] 71 4. Conclusion and future perspectives 72 [Figure] The proposed schematic representation of our study 74 5. References 75 List of publications 93 | |
| dc.language.iso | en | |
| dc.title | 發炎及糖化終產物對於軟骨細胞之病理作用機制及治療之探討 | zh_TW |
| dc.title | Studies on the pathological mechanisms and therapy of
inflammation and advanced glycation end products on chondrocytes | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 楊榮森,蕭水銀,符文美,湯智昕 | |
| dc.subject.keyword | 退化性關節炎,軟骨細胞,發炎,銀杏萃取物,厚朴酚,糖化終產物,過氧化?增生物基活受體, | zh_TW |
| dc.subject.keyword | osteoarthritis,chondrocyte,inflammation,EGb761,honokiol,advanced glycation end products,PPARγ, | en |
| dc.relation.page | 93 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-07-26 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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