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系統識別號 U0007-0908201108361400
論文名稱(中文) 石榴抗痤瘡之活性成分研究
論文名稱(英文) The Anti-acne Principle Constituents of Punica granatum Linne
校院名稱 臺北醫學大學
系所名稱(中) 藥學系(博士班)
系所名稱(英) Pharmacy (PhD)
學年度 99
學期 2
出版年 100
研究生(中文) 李佳蓉
研究生(英文) Chia-Jung Lee
學號 D301095007
學位類別 博士
語文別 中文
口試日期 2011-07-12
論文頁數 122頁
口試委員 指導教授-王靜瓊
委員-黃怡超
委員-蔡東湖
委員-呂彥禮
委員-陳彥州
委員-侯文琪
委員-李慶國
中文關鍵字 痤瘡  石榴  唇形科植物  痤瘡桿菌  金黃色葡萄球菌  脂質分解酵素  角質細胞增生  發炎反應 
英文關鍵字 anti-acne  pomegranate  Lamiaceae plants  Propionibacterium acnes  Staphylococcus aureus  lipase  keratinocytes  inflammrtion 
學科別分類
中文摘要 痤瘡(acne)俗稱青春痘,是一種常見的皮膚疾病,好發於青春期或荷爾蒙失調的病人,也常見於成年人。痤瘡產生包含許多複雜因素如:毛囊角化異常、皮脂分泌旺盛、荷爾蒙失調、毛囊內細菌增生(痤瘡桿菌、金黃色葡萄球菌),或由細菌所誘發之發炎反應。常見的治療方式是使用角質溶解劑與抗生素,但部份藥物皮膚刺激性過高,或痤瘡桿菌與金黃色葡萄球菌產生抗藥性,因此開發具有更安全有效的治療藥物,是一個很重要的議題。
根據古代典籍與健保資料庫進行痤瘡常用藥材之探勘,配合市售抗痘產品調查,以抑制金黃葡萄球菌 (Staphylococcus aureus) 與痤瘡桿菌(Propionibacterium acnes)生長之抗菌能力、抑制脂質分解酵素活性、抗發炎與抗氧化做為活性篩選標的,並分析植物化學成分,找尋中草藥之抗痤瘡活性與植物成分關聯性,做為日後開發抗痤瘡藥物開發之研究依歸。結果顯示,固澀藥中石榴、訶子,同時具有良好的抗菌與抗發炎活性,及抑制脂質分解酵素的活性。植物化學成分分析中也發現,石榴與訶子含有最高的總多酚類成分。再以唇形科植物所建立抗痤瘡活性與植物化學成分含量之關聯性探討,結果發現:植物具有抗發炎作用則抗菌活性也較強,利用SPSS軟體以無母數分析法進行回歸分析,其相關係數(R = 0.767,p<0.01)。而清除DPPH自由基之抗氧化活性與總多酚及總黃酮類含量之關係也明顯成正比(R = 0.542及0.613,p<0.01)。
34種常用於治療青春痘之中藥中,以石榴50%甲醇萃取物具有好的抗發炎及抗菌效果,比其他藥材明顯,且具有抗氧化與抑制脂質分解酵素活性,又富含多酚類成分,因此本論文將針對石榴,進行抗痤瘡活性成分分離鑑定,與抗痤瘡活性機制探討。首先,利用不同溶劑萃取石榴,其中以70%丙酮萃取物抗菌活性最強,且總多酚類成分含量最多,繼而利用抗痤瘡桿菌與金黃色葡萄球菌進行活性追蹤,配合Diaion、TSK與ODS等管柱分離,結果得到4個具有抗菌活性成分,punicalagin (1)、punicalin (2)、strictinin A (3)與granatin B (4)。將4個活性多酚成分進行抗痤瘡活性評估,結果顯示:
(1). 1與2對P. acnes之最小抑菌濃度(MIC)為6.25 μg/disc,S. aureus之MIC為12.5 μg/disc。
(2). 1、3及4於200 μg/ml時,抑制超過30%脂質分解酵素活性。
(3). 1-4與角質細胞(HaCaT cell) 作用24小時後,具有明顯的劑量依存性抑制角質細胞增生,在無細胞毒性之濃度下 (25 μg/ml) ,1與2可抑制由testosterone所誘導之角質細胞增生。
(4). 以不影響細胞存活率的濃度下與巨噬細胞(RAW264.7)共同培養,1-4皆具有抑制LPS或P. acnes誘導細胞產生nitric oxide (NO) 作用,及抑制iNOS蛋白質表現。4亦具有抑制COX-2蛋白質表現,而降低前列腺素(PGE2)產生。另外1-4也具有抑制P. acnes刺激單核球細胞(THP-1)細胞產生促發炎細胞激素 (TNF-α與IL-8)的分泌。
綜合而論,利用古代典籍考究與現代科學的驗證,我們發現清熱藥與固澀藥中,富含多酚類成分,具有抗菌與抗發炎活性,且70%丙酮萃取多酚類含量最高。根據抗痤瘡活性追蹤分離石榴得到4個多酚類成分,皆具有抗菌、抑制脂質分解酵素、抑制角質細胞增生與抗發炎作用,又以1與2抗菌與抑制角質細胞增生活性最強,而4對LPS或P. acnes誘導之RAW264.7與THP-1細胞,抑制發炎介質(NO、PGE2、TNF-α與IL-8)活性最明顯。所以不同的多酚成分,對不同的痤瘡病因有不同效果,因此推測石榴70% 丙酮萃取物具有抗痤瘡作用,故將其進行單一劑量皮膚毒性評估,結果顯示石榴萃取物於10 mg/site之大鼠皮膚上,無明顯毒性。綜合結果,石榴萃取物中的主成分同時抑制多種痤瘡發生的病因,且萃取物無皮膚刺激,若加以定量確保品質,推測石榴萃取物式轉譯成抗痤瘡醫藥品的好原料。
英文摘要 Acne is a common skin condition and usually appears in young adolescents with hormone imbalance. Major causes in acne formation include increased sebum production by overactive oil glands, retention hyperkeratosis to block the skin pores, activity of normal skin bacteria (Propionibacterium acnes and Staphylococcus aureus) and inflammation. Nowadays, therapeutic strategy for acne vulgaris is applying keratolytic agents and antibiotics. However, the increasing incidences of skin irritation and antibiotic resistance were found in recent acne remedies. Hence, it is urgent to explore an agent with abilities in inhibiting P. acnes and S. aureus growth, suppressing inflammatory responses and reducing skin irritation. The objective of this study was to discover an anti-acne traditional Chinese medicine (TCM) through system reviewing the ancient articles and National Health Insurance research database, surveying the commercial products, selecting the candidate TCM extracts and evaluating the anti-microbial and anti-inflammatory effects.
In this study, inhibitory abilities of herbal extracts on S. aureus and P. acnes growth and lipase activities, anti-inflammatory and anti-oxidative activities were used as evaluation platforms of the anti-acne effects. Punica granatum Linn. (pomegranate) and Terminalia chebula Retz. showed stronger anti-bacterial and anti-inflammatory activities than the others. P. granatum, T. chebula and S. baicalensis also significantly inhibited lipase activity. In the phytochemical analysis, P. granatum and T. chebula were rich in polyphenolics. Based on the commercial survey, Lamiaceae plants were the most popular source in anti-acne cosmetics. Moreover, we used 28 kinds of Lamiaceae plants with the similar genus combined with published experimental methods to establish the correlations between anti-acne abilities and phytochemical contents. Results showed that polyphenolic contents had the good correlations with anti-oxidative, anti-inflammatory and anti-bacterial activities (R = 0.767, p < 0.01). Good correlation was also found between anti-inflammatory and anti-bacterial activities (R = 0.542 and 0.613, p < 0.01).
Secondly, 50 % methanol pomegranate extracts showed more significant anti-oxidative, lipase inhibitory effects, anti-inflammatory and anti-bacterial activities than the others. Therefore, anti-acne principal constituents of pomegranate were explored for its active mechanisms. Firstly, pomegranate peel was extracted via different solvents and results showed that 70% acetone Pomegranate extracts was rich in the most polyphenolics and showed the strongest inhibitory activity against S. aureus and P. acnes. Column chromatography combined with in vitro bioassay-guided fractionation was used to isolate the anti-acne principal components from the pomegranate. Four hydrolysable tannins Punicalagin (1), Punicalin (2), Strictinin A (3) and Granatin B (4) were obtained with yields of 0.093%, 0.015%, 0.003%, and 0.013%, respectively. Among them, minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) of 1 and 2 were 6.25 and 12.5 μg, respectively. 1, 3 and 4 (200 μg/ml) displayed more than 30% of lipase inhibitory effects. All these four components significantly inhibited HaCaT cell proliferations in a concentration-dependent manner after 24 hr treatments. Besides, 1 and 2 significantly reduced the testosterone-induced HaCaT cell proliferations at a non-toxic concentration (25 μg/ml). These pomegranate-polyphenolic components also decreased LPS- and heat-killed P. acnes-induced NO productions through down-regulating iNOS expression in RAW 246.7 cells, while 4 could reduce COX-2 expressions, resulting in decreasing PGE2 productions. Moreover, these pomegranate-polyphenolic components also reduced heat-killed P. acnes-induced TNF-α and IL-8 secretions. According to above results, different pomegranate-polyphenolic components showed different anti-acne effects. We suggested that pomegranate extract was a good anti-acne material source. Therefore, the pomegranate extrct was evaluated for the skin irritation. The results showed that extracts did not display significant toxicity on Wistar rat.
Taken together, active principal constituents of pomegranate extracts could inhibit different pathogenic factors of acne without skin irritations. We suggested that pomegranate was suitable to develop the anti-acne agent.
論文目次 目錄
中文摘要 1
英文摘要 3
縮寫表 5
第一章、緒論 7
第二章、實驗材料與方法 38
第一節、實驗材料 38
ㄧ、常用於青春痘之中草藥樣品 38
1. 臨床常用痤瘡治療之中藥 38
2. 常添加於抗痤瘡產品之唇形科植物 39
二、細胞株與細菌株 41
三、實驗動物 41
四、化學試劑 41
五、溶媒、試藥、分離管柱及管柱添充劑 42
六、細胞培養皿 43
七、儀器設備 43
第二節、實驗方法 36
一、植物萃取物製備 36
二、待測樣品配製 36
三、石榴活性成分之萃取、分離及結構鑑定 45
1. 石榴成分之萃取 45
2. 石榴之單離與精製 45
四、植物化學成分分析 47
1. 總多酚類含量測定:Folin-Ciocalteu reaction 47
1-1. 分析原理 47
1-2. 分析步驟 47
1-3. 含量換算 47
2. 黃酮類 (Condense Tannin )含量測定:Vanillin Assay 47
2-1. 分析原理 47
2-2. 分析步驟 47
2-3. 含量換算 47
五、抗痤瘡活性分析 47
1. 體外抗菌試驗- Staphylococcus aureus與Propionibacterium acne 47
1-1. 分析原理 47
1-2. 試液配製 48
1-3. 紙錠瓊脂擴散試驗(Disc Agar Diffusion Test)分析步驟 48
2. 細菌形態學分析 49
2-1. 分析原理 49
2-2. 試液配製 49
2-3. 實驗步驟 49
3. 脂肪分解酵素(Lipase)活性的抑制 49
3-1. 分析原理 49
3-2. 分析步驟 49
4. 角質細胞增生抑制實驗 49
4-1. 分析原理 49
4-2. 試液配製 50
4-3. HaCaT 細胞 培養與分析步驟 50
5. 體外抗發炎試驗 50
5-1. 分析原理 50
5-2. 試液配製 50
5-3. RAW 264.7 吞噬細胞培養與分析步驟 51
6. 痤瘡桿菌誘導體外抗發炎試驗 52
6-1. 分析原理 52
6-2. 試液配製 52
6-3. THP-1 人類單核球細胞培養與分析步驟 52
7. 發炎相關蛋白質(iNOS與COX-2)表現量分析 53
7-1. 分析原理 53
7-2. 試劑製備 53
7-3. SDS-PAGE之製作 54
7-4. 分析步驟 55
8. PGE2 、IL-8、TNF-α含量分析 55
8-1. 分析原理 55
8-2. 分析步驟 55
9. 植物萃取物清除1,1-diphenyl-2-picrylhydrazyl (DPPH)之能力 56
9-1. 分析原理 56
9-2. 分析步驟 56
10. 統計學分析 56
六、相關性分析 56
七、皮膚毒性試驗 57
1. 體內動物實驗-單一劑量皮膚毒性試驗 57
1-1. 實驗目的 57
1-2. 實驗步驟 57
第三章、實驗結果 58
第一節、常用於治療青春痘之中草藥抗痤瘡作用 58
一、常用之抗痤瘡中草藥之抗菌活性分析 58
二、常用之抗痤瘡植物之脂質分解酵素活性分析 58
三、常用之抗痤瘡植物之抗發炎活性分析 59
四、常用之抗痤瘡植物之抗氧化活性分析 59
第二節、臨床與市售常用之抗痤瘡植物植物化學成分檢測 64
一、常用之抗痤瘡植物之總多酚類含量測定 64
二、常用之抗痤瘡植物之黃酮類總含量測定 64
第三節、抗痤瘡活性與植物化學成分含量之關聯性探討 50
第四章、討論 54
一、現代中醫常用於抗痤瘡藥材 54
二、抗痤瘡活性關聯性評估 56
三、具開發潛力之抗痘痤瘡中草藥 57
第四節、石榴抗菌活性成分分離與鑑定 71
一、不同溶劑萃取之石榴樣品抗菌活性評估 71
二、石榴抗菌活性成分分離與鑑定 73
1. 石榴各劃分部抗菌活性分析 73
2. 活性成分之結構鑑定 75
第五節、石榴多酚抗痤瘡活性評估 76
一、石榴多酚抗菌活性評估 76
二、石榴多酚脂質分解酵素抑制活性評估 79
三、石榴多酚角質細胞增生抑制評估 80
1. 不同誘導劑對角質細胞(HaCaT cell)之增生作用 81
2. 石榴多酚對於角質細胞(HaCaT cell)增生之抑制作用 82
四、石榴多酚抗發炎活性評估 84
1. 石榴多酚於LPS誘導RAW264.7細胞產生COX-2 蛋白質與PGE2抑制作用 84
2. 石榴多酚於熱處理痤瘡桿菌誘導RAW264.7細胞 與THP-1細胞產生NO及PGE2抑制作用 89
3. 熱處理痤瘡桿菌誘導THP-1細胞產生IL-8 92
4. 石榴多酚於熱處理痤瘡桿菌誘導人類單核球細胞(THP-1)產生IL-8與TNF-α抑制作用 92
第六節、石榴萃取物皮膚毒性評估 95
一、單一劑量皮膚毒性試驗 95
1. 正對照組Neomycin與Esculetin 評估量表之建立 95
2. 石榴萃取物之單一劑量皮膚急性毒性試驗 95
二、石榴萃取物單一劑量皮膚毒性之切片分析 102
第四章、討論 103
參考文獻 111

圖目錄
圖一、石榴生藥形態 29
圖二、石榴多酚分離流程圖 46
圖三、唇形科植物抗痤瘡活性分析 68
圖四、唇形科植物化學成分分析 68
圖五、不同溶劑萃取石榴樣品之抗菌活性分析 72
圖六、石榴分離所得之四個ellagitannin 化學結構, punicalagin (1)、punicalin (2)、strictinin A (3)及granatin B (4) 75
圖七、石榴多酚樣品之抗菌活性分析 77
圖八、痤瘡桿菌處理石榴多酚後之形態圖 78
圖九、石榴萃取物與石榴多酚抑制脂質分解酵素活性 79
圖十、誘導劑對角質細胞增生作用 81
圖十一、石榴多酚抑制角質細胞增生之作用 83
圖十二、石榴多酚於LPS誘導RAW264.7細胞產生PGE2之抑制作用 85
圖十三、石榴多酚punicalagin (A), punicalin (B), strictinin A (C) 與granatin B (D)於8 小時及 18 小時抑制由LPS (500 ng/ml)誘導 RAW 264.7 細胞產生iNOS 與 COX-2 蛋白質表現變化 86
圖十四、熱處理之痤瘡桿菌誘導RAW264.7細胞產生NO與石榴多酚之抑制作用 90
圖十五、熱處理之痤瘡桿菌誘導RAW264.7細胞產生PGE2與石榴多酚之抑制作用 91
圖十六、熱處理之痤瘡桿菌不同劑量(A)與不同時間(B)誘導人類單核球細胞產生IL-8 93
圖十七、石榴多酚於熱處理痤瘡桿菌誘導人類單核球細胞產生IL-8(A)與TNF-α(B)之抑制作用 94
圖十八、不同濃度的Neomycin所引發之大鼠急性皮膚毒性 97
圖十九、不同濃度的Esculetin所引發之大鼠急性皮膚毒性 99
圖二十、不同濃度石榴萃取物所引發之大鼠急性皮膚毒性 101
圖二十一、石榴萃取物於皮膚之單一劑量毒性組織切片 102
圖二十二、痤瘡誘導發炎反應機制圖 108


表目錄
表一、中醫治療痤瘡之常用內服方劑 16
表二、中醫治療痤瘡之常用外用方劑 18
表三、古代典籍中常用於治療痤瘡之外用方劑中藥材使用頻率 20
表四、中西醫痤瘡病名與概論對照 21
表五、現代中醫臨床常用於抗痤瘡之方劑 22
表六、現代中醫臨床常用於抗痤瘡之藥材 22
表七、多酚類成分分類表 24
表八、常用於開發抗痘活性的實驗方法 25
表九、石榴現代藥理活性整理 32
表十、石榴皮目前已知分離純化之成分 34
表十一、石榴汁目前已知分離純化之成分 35
表十二、石榴子目前已知分離純化之成分 36
表十三、34種臨床常用之抗痤瘡中藥 38
表十四、28種市售唇形科植物 39
表十五之一、34種常用抗痤瘡中藥萃取物之抗菌活性分析 60
表十五之二、34種常用抗痤瘡中藥萃取物之抑制NO產生、清除DPPH自由基與抑制Lipase酵素活性分析 61
表十六之一、28種唇形科萃取物之抗菌、抑制NO產生與清除DPPH自由基活性分析 62
表十六之二、28種唇形科萃取物之抗菌、抑制NO產生與清除DPPH自由基活性分析 63
表十七、34種常用之抗痤瘡中草藥之植物化學成分分析 65
表十八、唇形科植物萃取物植物化學成分分析 66
表十九、唇形科植物中植物成分與抗痤瘡活性之關聯性 69
表二十、薰衣草屬、鼠尾草屬、迷迭香屬與羅勒屬植物中植物成分與抗痤瘡活性之關聯性 70
表二十一、不同溶劑萃取之石榴樣品多酚類含量分析 71
表二十二、經Diaion管柱層析之不同極性沖提物抗菌活性 73
表二十三、經TSK管柱層析不同極性之沖提物抗菌活性 74
表二十四、石榴多酚最小抑菌濃度與最小殺菌濃度比較 76
表二十五、Neomycin單一劑量皮膚刺激試驗紅腫比較 96
表二十六、紅腫程度評分比較表 96
表二十七、Neomycin紅腫程度評分比較表 96
表二十八、Esculetin之單一劑量皮膚急性毒性試驗評分表 98
表二十九、Esculetin皮膚塗藥前後紅腫比較 98
表三十、石榴萃取物之單一劑量皮膚急性毒性試驗評分表 100
表三十一、石榴萃取物皮膚塗藥前後紅腫比較 100
表三十二、34種常用抗痤瘡之中藥材藥效分類 103
表三十三、清熱藥功效分類 104
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