博碩士論文 982204021 詳細資訊




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姓名 陳怡君(Yi-Jyun Chen)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 植化物紫草素在小鼠皮膚上增加血管通透性之研究
(Use of Shikonin for Enhancing Vascular Permeability in Skin Tissues)
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摘要(中) 在過去的一系列實驗研究中,紫草素(shikonin),是由紫草(Lithospermum erythrorhizon)所萃取出來的主要成分,已被證實具有許多不同之細胞學及分生學之生物活性及藥理活性,例如傷口癒合、抗發炎及抗腫瘤等之活性等。此篇研究之主要目的為研判紫草素是否及如何涉及血管通透性之調節。在本文中,我們利用純化之紫草素塗抹於不同部位的小鼠皮膚上,包括耳朵、腹部及腿部之皮膚,而後分別於不同時間點手術取下處理過之皮膚標本,測試並探討在其調節血管通透性扮演重要角色之matrix metalloproteinases-2和-9(MMP-2和-9)以及E-cadherin之表現量。並且藉由Evans blue dye自血管滲入組織間的現象觀察血管通透性之情況。實驗結果顯示紫草素能夠提升小鼠皮膚中Evans blue dye的滲出量,以及經由紫草素塗抹之皮膚組織的MMP-9 and MMP-2酵素表現量也比控制組的量高出許多。此外,紫草素還能夠局部控制皮膚之血管通透性。在組織切片中,我觀察到小鼠皮膚的皮下層(subcutaneous layer)之厚度明顯增加。為了進一步探討紫草素在小鼠皮膚之組織是否會促進發炎反應,我們評估了與發炎反應相關之細胞激素interleukin-1β (IL-1β)及interleukin-6 (IL-6)之表現量,令人驚訝的是,經由紫草素塗抹之皮膚組織也可偵測到高量的IL-1β及IL-6。綜合以上所述,紫草素能夠有效增加皮膚之血管通透性及同時促進類似輕度發炎之反應,因此在改善藥物輸送效率及專一性的臨床應用上,我們認為紫草素具有作為不同皮膚敷劑藥物佐劑之潛力。
摘要(英) Various previous studies have shown that shikonin, which is derived from medicinal plant Lithospermum erythrorhizon, can display diverse pharmacological beneficial effects or strong and specific bioactivities, e.g., in wound healing-, anti-inflammatory- and anti-tumor bioactivities. The aim of my present experimental study is to address whether and how shikonin may be involved in the regulation of vascular permeability in mouse skin tissues. Shikonin-treated skin samples originating from different organs, including ear, abdominal and leg skin of test mice, were collected at different time points tested, and protein expression levels of matrix metalloproteinases (MMP) and E-cadherin determined. Activity of vascular permeability was investigated by measuring the level of extravasation of Evans blue dye from blood vessels by Miles assay; also determined by the expression levels of MMP-2, MMP-9 and E-cadherin. MMP-2 and MMP-9 are two representative members of the MMPs family that play a critical role in regulation of vascular permeability. As revealed by Miles assay, shikonin exhibited high activity in extravasation of Evans blue dye from blood vessels to the adjacent dermal tissues, clearly indicating its leakage. Shikonin-treated skins samples showed higher protein expression levels for MMP-9 and MMP-2 when compared with vehicle control samples. To further evaluate whether shikonin can confer pro-inflammatory effect on skin tissue, the expression level of IL-1β and IL-6 were determined. High levels of IL-1β and IL-6 were found in shikonin-treated skins. Together, our data indicate that topical application of shikonin can effectively enhance vascular permeability in test skin, suggesting that shikonin may be clinically applicable as a potential adjuvant for use on improving the efficiency and specificity of drug delivery into adjacent tissues.
關鍵字(中) ★ 紫草素
★ 血管通透性
★ 皮下層
★ 發炎反應
關鍵字(英) ★ inflammation
★ MMP-9
★ MMP-2
★ subcutaneous layer
★ vascular permeability
★ shikonin
論文目次 目錄
頁次
中文提要 i
英文提要 ii
誌謝 iii
目錄 iv
縮寫說明 vi
1. Introduction 1
1-1 Enhanced Vascular Permeability in Pharmacological Use 1
1-2 Regulatory Mechanisms for Vascular Permeability 2
1-3 Roles of Matrix Metalloproteinases and E-cadherin 3
1-4 Interkeukin-1β and Interkeukin-6 for Inflammation in Skin 5
1-5 Shikonin 7
2. Materials and Methods 9
2-1 Chemicals 9
2-2 Animals 9
2-3 Treatment for Induction of Vascular Permeability 9
2-4 Measurement of Vascular Permeability by Miles Assay 10
2-5 Histological Evaluation of Abdominal Skin in Test Mice: Hematoxylin-Eosin Staining 11
2-6 Extraction of Proteins from Skin Tissues 12
2-7 Western Blot Analysis 12
2-8 ELISA 13
3. Results 14
3-1 Vascular Permeability in Skin Tissue Enhanced by Topical Application of Shikonin 14
3-2 Exudation of Evans Blue Dye from Skin Tissues is Enhanced by Shikonin Treatment 16
3-3 Induction of Matrix Metalloproteinases Activity in Skin Tissues by Shikonin Treatment 17
3-4 Shikonin Suppresses the Expression of E-cadherin in Skin Tissues 18
3-5 Morphological Changes in Dermal and Subcutaneous Layers of Test Abdominal Skin Tissues 19
3-6 Evaluation of the Shikonin Dosage Effect on Vascular Permeability in Ear, Abdominal and Leg Skin Tissues 20
3-7 Shikonin Treatment Induces Expression of IL-1β and IL-6 in Mouse Skin Tissues 21
4. Discussion 23
4-1 Shikonin-induced Vascular Permeability and Inflammatory Response 23
4-2 Shikonin may Confer Differential Effects on Thin versus Thick Skin Tissues 24
4-3 Comparison on Stimulation on IL-1β and IL-6 Expression between Shikonin and TPA-treated Skin Tissues 25
4-4 Anti- and Pro-inflammatory Effects of Shikonin 26
4-5 Accumulation of Pharmaceuticals or Drugs at Targeted Skin Sites for Drug Delivery 27
4-6 Relationship between Tissue Chemotaxis and Enhanced Vascular Permeability 28
4-7 Perspective of Shikonin-induced Vascular Permeability for Drug Delivery……….. 29
5. Conclusion 30
6. Figures 31
7. Reference 50
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指導教授 葉靖輝、楊寧蓀
(Ching-Hui Yeh、Ning-Sun Yang)
審核日期 2012-1-18
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