臺灣博碩士論文加值系統

發炎反應 (inflammation) 為生物體受到外傷或外來物質入侵時的抵禦機制，通常發炎反應是為移除有害刺激或病源體及促進修復的保護措施，而對生物體具有益處；但長期發炎則與許多疾病具有相關性，故許多研究皆以抗發炎作為出發點，以探討樣品對於相關疾病的預防潛力。四氫薑黃素 (tetrahydrocurcumin, THC) 為薑黃素 (curcumin, CUR) 進入人體後之主要代謝物，因其具有較佳的溶解度與生物可利用率而被認為比起 CUR 具有更高的應用潛力；近期有學者發現，茶葉中之活性化物 (-)-epigallocatechin-3-gallate (EGCG) 可在小鼠體內作用，使其結構中 B 環上 4’ 位置之羥基 (-OH) 被胺基 (-NH2) 取代，形成 4’-NH2-EGCG，且與 EGCG 具有相似之生理活性；本實驗室則發現 THC 可經小鼠代謝形成 3-Amino-3-deoxy tetrahydrocurcumin (THC-NH2)，且利用 RAW 264.7 小鼠巨噬細胞證實 THC-NH2 比起 THC 更能有效抑制脂多醣 (lipopolysaccharide, LPS) 誘導之 iNOS (inducible nitric oxide synthase) 蛋白質表現量及其產物一氧化氮 (nitric oxide, NO) 之生成量，推測其可能具有的抗發炎潛力。
本研究利用 RAW 264.7 細胞深入探討 THC-NH2 對於發炎相關路徑的影響；結果顯示，THC-NH2 可抑制經 LPS 誘導之 RAW 264.7 細胞中 iNOS 以及 COX-2 的 mRNA 表現量；然而，THC-NH2 雖可抑制對於細胞中 iNOS 蛋白質水平，但對於COX-2 蛋白質水平卻隨劑量有上升之趨勢。經深入探討轉錄因子與上游蛋白發現，THC-NH2 可藉由抑制 PI3K/Akt 路徑進一步抑制 NF-κB subunit p65 之磷酸化，藉此減少 iNOS 與 COX-2 之 mRNA 表現量。而由蛋白質穩定性試驗發現，THC-NH2 具有延遲 COX-2 蛋白質降解之效果，由此推測其為造成COX-2 蛋白質水平隨樣品劑量上升之主因。動物實驗部分則利用雄性 ICR 小鼠進行短期之體內 (in vivo) 抗發炎試驗，利用促發炎劑 DSS (dextran sulfate sodium) 誘導小鼠腸道發炎，探討於飲食中添加 THC-NH2 是否具抑制發炎之效果；實驗結果顯示，攝取 THC-NH2 能抑制 DSS 造成的脾臟腫大以及腸道長度縮短 (shortening of colon length) 現象。綜合上述，THC-NH2 於細胞實驗中雖能抑制 LPS 誘導之 RAW264.7 的 iNOS 蛋白及其產物一氧化氮的產生，卻增加 COX-2 之蛋白表現；而在動物實驗中初步判斷 THC-NH2 具抑制 DSS 造成的小鼠腸道發炎之效果，但若要將 THC-NH2 應用於抗發炎相關之應用，可能仍需要未來更多研究佐證。

Inflammation is a defense mechanism, which is beneficial to organism, usually occurs during tissue damage or pathogenic invasion, in order to promote repair and regeneration, and lead to neutralization and removal of harmful stimuli or pathogens. Nonetheless, chronic inflammation has also been pointed out to be highly related to several diseases. Therefore, evaluation of anti-inflammatory capability has become a basic starting point or indicator in early research of inflammation-related diseases before further investigating the preventive potential of a sample to the particular disease. Tetrahydrocurcumin (THC) is one of the major metabolites of curcumin (CUR) after human intake. It has been recommended to be more applicable because of its higher solubility and bioavailability compared to CUR. On the other hand, recent study showed that (-)-epigallocatechin-3-gallate (EGCG), one of the bioactive compounds in tea could form 4’- NH2-EGCG when the hydroxyl group at 4’ position of B ring being substituted by amine group after mice intake, and surprisingly, 4’- NH2-EGCG exhibited similar physiological activity as EGCG in the study. The conversion of 3-Amino-3-deoxy tetrahydrocurcumin (THC-NH2) from THC is recently found as mice metabolite after digestion. In this study, THC-NH2 was postulated to be a promising anti-inflammation compound as it was found to be effective in restraining protein expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production of murine macrophage RAW 264.7 after induced by lipopolysaccharide (LPS).
The anti-inflammatory capability and related pathway of THC-NH2 were discussed by using RAW264.7 murine macrophage cell line. Although THC-NH2 had rendered efficacious effect on inhibiting mRNA level of iNOS and COX2 in RAW264.7 after being treated by LPS, it showed a contrastive result in protein expression, with repressive effect on iNOS but also adversely induced COX-2 expression in dose dependent trend. Investigating the transcription factors and upper stream protein expression of iNOS and COX-2, it had been demonstrated that THC-NH2 could inhibit the phosphorylation of NF-κB subunit p65 via PI3K/Akt pathway, resultant in decreased level in mRNA level. It was speculated that retarding effect of THC-NH2 on post-translated protein stability could be the leading reason of increasing protein level of COX-2 in dose-dependent manner. A short-term in vivo experiment using male ICR mice was designed to investigate anti-inflammation effect of THC-NH2 supplemented diet on colon inflammation induced with a pro-inflammation agent DSS (dextran sulfate sodium). Current result showed that THC-NH2 possessed effectual action on inhibiting colon shortening phenomenon and splenomegaly.
In summary, we highlighted that THC-NH2 could contribute in inhibiting iNOS expression and NO production in RAW 264.7 induced by LPS, but increment of COX-2 protein level might be a concomitant negative effect. Furthermore, preliminary data showed that THC-NH2 exhibited inhibitory capability in DSS-induced colonic inflammation in animal model. Nevertheless, further study and more research are imperative before finalizing its anti-inflammatory or preventive effect before being applied in anti-inflammatory medication.

謝誌 i
中文摘要 ii
Abstract iv
目錄 vi
附圖索引 ix
圖目錄 xi
縮寫表 ii
第壹章、文獻回顧 1
第一節 發炎反應 (inflammation) 之簡介 1
(一) 發炎反應之生理意義 1
(二) 發炎反應與 iNOS 以及 COX-2 之關係 2
(三) NF-κB 之調控 5
(四) PI3K/Akt 路徑之調控 6
第二節 樣品之簡介 7
(一) 薑黃素 7
(二) 四氫薑黃素 8
(三) 薑黃素與四氫薑黃素對於發炎反應之比較 9
(四) 化合物於體內之氨化現象 11
第三節 誘導發炎之細胞模式 12
(一) 巨噬細胞 (macrophage) 12
(二) LPS誘導 13
第四節 小鼠腸潰瘍模式 15
(一) 大腸之構造與功能簡介 15
(二) 大腸直腸癌的進程 17
(三) DSS (Dextran Sulfate Sodium) 之簡介 18
第貳章、實驗目的與架構 19
第一節 實驗目的 19
第二節 實驗架構 20
(一) 探討四氫薑黃素經小鼠代謝之產物 20
(二) 細胞實驗之架構 20
(三) 動物實驗之流程 21
(三) 動物實驗之架構 21
第參章、材料與方法 22
第一節 實驗材料 22
(一) 儀器與耗材 22
(二) 試劑與藥品 23
第二節 細胞實驗方法 25
(一) 細胞培養 25
(二) 細胞存活率試驗 26
(三) 細胞培養液中一氧化氮之測定 27
(四) 蛋白質穩定性之測定 29
(五) RT-q-PCR 30
(六) 蛋白質電泳與西方墨點法 34
第三節 動物實驗方法 40
(一) 實驗動物來源與飼養方式 40
(二) 小鼠糞便中 3-amino-3-deoxy tetrahydrocurcumin 之測定 40
(三) DSS 誘導腸潰瘍模式 43
第四節、統計分析 43
第肆章、結果 44
四氫薑黃素於生物體中之轉換 44
細胞實驗結果 44
第一節、THC-NH2 對於 RAW 264.7 小鼠巨噬細胞存活率之影響 44
第二節、THC-NH2 對於經 LPS 誘導 RAW 264.7 細胞一氧化氮生成量之影響 45
第三節、THC-NH2 對於經 LPS 誘導 RAW 264.7 細胞 iNOS 及 COX-2 蛋白質表現量之影響 45
第四節、THC-NH2 對於經 LPS 誘導 RAW 264.7 細胞 iNOS 及 COX-2 之 mRNA 表現量之影響 46
第五節、THC-NH2 對於經 LPS 誘導 RAW 264.7 細胞之轉錄因子 NF-κB 之影響 46
第六節、THC-NH2 對於經 LPS 誘導 RAW 264.7 細胞之 MAP kinase 以及 PI3K/Akt 路徑之影響 47
第七節、THC-NH2 對於轉譯後 COX-2 蛋白質穩定性之影響 47
動物實驗結果 48
第一節、THC-NH2 對於 DSS 誘導 ICR 小鼠產生之體重以及 DAI 變化 48
第二節、THC-NH2 對於 DSS 誘導 ICR 小鼠對於各臟器之影響 48
第三節、THC-NH2 對於 DSS 誘導 ICR 小鼠腸道組織之影響 48
第伍章、討論 49
第陸章、結論 52
第柒章、圖表 53
第捌章、參考文獻 66
附錄 75

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