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研究生:林胤谷
研究生(外文):Yin Ku Lin
論文名稱:探討青黛對乾癬的療效及其在皮膚角質細胞中的藥理機轉
論文名稱(外文):Investigations on the therapeutic effect of indigo naturalis for psoriasis and its pharmacological mechanism in epidermal keratinocytes
指導教授:蘇中慧
指導教授(外文):J. H. S. Pang
學位類別:博士
校院名稱:長庚大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:206
中文關鍵詞:乾癬青黛角質細胞增殖分化緊密接合蛋白
外文關鍵詞:PsoriasisIndigo naturalisKeratinocytesProliferationDifferentiationTight junction proteins
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  • 被引用被引用:2
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乾癬是一種令人困擾且反覆發作的疾病,會嚴重影響病人的生活品質但確無法根治,青黛在傳統中國的文獻中曾經被報導具有口服治療乾癬的療效,然而缺乏實證醫學的研究基礎,且藥理作用機轉並不清楚,此外青黛對胃腸道的副作用也使其臨床的使用受到限制。
本研究採用隨機、觀察者單盲、基質對照的臨床實驗,來評估青黛單一外用治療在頑強難治之乾癬病患的療效和安全性。另外也探討青黛治療乾癬的藥理機轉和找出其活性成份。首先,對經過青黛治療的乾癬病人皮膚檢體,進行和細胞增殖、分化和緊密接合蛋白有關基因表現的篩選,並以上皮角質細胞的活體外模型來探討青黛提取物和其活性成份對這些基因表現的影響。
共有42位來自門診的慢性乾癬病人參加為期12週的臨床實驗,研究結果顯示,百分之74的患者經青黛藥膏治療後逹到痊癒或接近痊癒狀態。由活體外研究顯示,青黛提取物在對上皮角質細胞在無毒性的濃度下,能抑制PCNA和促進Involucrin的基因表現,此結果和經過青黛油膏治癒的乾癬病灶之免疫組織化學染色的結果一致,而靛玉紅可能是調控PCNA和Involucrin表現的主要活性成分。此外,我們的研究也證實青黛可透過上調角質細胞的Claudin-1、ZO-1和Occludin的基因表現以及增加經皮電阻和減少細胞間滲透能力來改善表皮屏障功能,而靛藍、靛玉紅和色胺酮等三種青黛主要成分都能增加角質細胞的表皮屏障功能,雖然這三種成分可能在乾癬的治療上扮演不同角色,但其中任何一種成分無法涵蓋青黛的所有的藥理功能,青黛的治療乾癬療效可能是來自這些不同的成分的協同作用。
總結我們的研究發現,青黛油膏劑型外用治療乾癬是安全和有效的,且可避免口服產生的副作用。青黛治療乾癬的可能機轉,包括抑制上皮角質細胞的過度增殖作用、使乾癬皮膚的上皮細胞分化功能和緊密接合蛋白表現回復正常,這些藥理學上的發現提供了青黛在臨床上療效的藥理基礎。我們相信青黛是具有潛力的乾癬替代療法,是一種非常有前景的天然藥物。
Psoriasis is a distressing, recurrent disease that significantly impairs the quality of life and has no permanent cure. Indigo naturalis has been reported in Chinese literature to exhibit anti-psoriatic effects with systemic therapy. However, its lacks evidence-based research results, and its pharmacology is unclear. Also, its gastrointestinal side effects have limited its use in clinical practice.
In this study, we constructed a randomized, observer-blinded, vehicle-controlled trial of indigo naturalis monotherapy on patients with recalcitrant psoriasis to evaluate the efficacy and safety of its topical application. Another important goal is to investigate the anti-psoriatic mechanism of indigo naturalis and to identify the active components. First, the expressions of genes associated with proliferation, differentiation, and tight junctions (TJ) in skin samples from patients with psoriasis topically treated with indigo naturalis were screened. We also constructed in vitro models using cultured epidermal keratinocytes to investigate the effects of indigo naturalis extract and its active components on these genes expressions.
A total of 42 outpatients with chronic plaque psoriasis were enrolled in the clinical study for 12 weeks. Study results showed 74 percent of patients experienced clearance of near-clearance of psoriasis lesions with indigo naturalis ointment. The results of in vitro studies showed that indigo naturalis inhibited proliferating cell nuclear antigen (PCNA) expression and increases involucrin expression at both the messenger (m)RNA and protein levels in cultured human keratinocytes with no cytotoxicity. These findings correlated well with the immunohistological results obtained from psoriatic lesions after indigo naturalis ointment treatment. Indirubin was found to be the major active component of indigo naturalis that modulated the expressions of PCNA and involucrin. We also demonstrated that indigo naturalis could increase skin barrier function by up-regulating claudin-1, ZO-1 and occludin expression of epidermal keratinocytes, increasing transepithelial electrical resistance (TER) and decreasing paracellular permeability. Indigo, indirubin and tryptanthrin, three major active components of indigo naturalis, all could increase epidermal barrier function in cultured keratinocytes. Each of them may provide individual different therapeutic effect on psoriasis, however, the effect of any one of them cannot fully represent all pharmacologic function found in indigo naturalis. It suggests that the synergistic effect of these different components were may contribute to the entire anti-psoriatic efficacy of indigo naturalis.
Together, we demonstrated that indigo naturalis formulated in an ointment is safe and efficacious for treating psoriasis and can avoid systemic adverse effects. The possible mechanism of indigo naturalis action in treating psoriasis may include inhibiting hyperproliferation of epidermal keratinocytes, and restoring epidermal differentiation and tight junctions in psoriatic skin. These pharmacological findings provide a rationale for the clinical efficacy of indigo naturalis in relieving psoriasis. We believe that indigo naturalis is a promising natural product that has great therapeutic potential as an alternative therapy for psoriasis.
長庚大學授權書……………………………………………………………… iii
致謝…………………………………………………………………………… iv
中文摘要……………………………………………………………………… v
Abstract…………………………………………………………………… vii
Table of Contents……………………………………………………… x
Chart Catalogue………………………………………………………… xv
Abbreviation……………………………………………………………… xix

Chapter 1. General Introduction
1.1. Background………………………………………………………… 1
1.2. Review of Psoriasis
1.2.1. Genetic and environmental triggers……………… 2
1.2.2. Epidemiology of psoriasis…………………………… 3
1.2.3. Clinical manifestations of psoriasis…………… 4
1.2.4. Pathogenesis of psoriasis…………………………… 5
1.2.5. Therapeutics in psoriasis…………………………… 7
1.2.6. Clinical measures of disease severity and outcome in psoriasis…………………………………………………… 9
1.3. Review of Related Studies
1.3.1. Traditional Chinese medicine for the treatment in psoriasis…………………………………………………………………10
1.3.2. Indigo naturalis’ profile and therapeutic potential………………………………………………………………………11
1.3.3. Our experience using indigo naturalis topically in treating psoriasis……………………………………………………13
1.4. Research Niche……………………………………………………16
1.5. Goals and Specific Aims………………………………………17
1.6. Tables (1-1~1-3)……………………………………………… 20
1.7. Figures (1-1~1-15)…………………………………………… 23
Chapter 2. The Evaluation of Efficacy and Safety in Patients with Recalcitrant Plaque-type Psoriasis Treated with Indigo Naturalis
2.1. Rationale, Experimental Models and Approaches……42
2.2. Materials and Methods
2.2.1 Clinical study design……………………………………42
2.2.2 Patients……………………………………………………… 43
2.2.3 Study medication……………………………………………43
2.2.4 Main outcome measurement……………………………… 44
2.2.5 Statistical analysis………………………………………45
2.3. Results
2.3.1 Demographics and compliance……………………………45
2.3.2 Main outcomes…………………………………………………47
2.3.3 Safety……………………………………………………………49
2.4. Discussion…………………………………………………………49
2.5. Tables (2-1~2-3…………………………………………………53
2.6. Figures (2-1~2-7……………………………………………… 56
Chapter 3. Anti-Psoriatic Effects of Indigo Naturalis on the Proliferation and Differentiation of Keratinocytes with Indirubin as the Active Component
3.1. Rationale, Experimental Models and Approaches…… 64
3.2. Materials and Methods
3.2.1. Immunohistochemical staining…………………………68
3.2.2. Reagents……………………………………………………… 68
3.2.3. Cell culture…………………………………………………69
3.2.4. 3-[4,5-Dimethylthiazol-2-yl]-2,5-dihenyltetrazolium bromide (MTT) colorimetric assay………70
3.2.5 Flow cytometry……………………………………………… 70
3.2.6 Immunofluorescent staining…………………………… 71
3.2.7 Quantitative RT/real-time PCR analysis……………71
3.2.8 Western blotting analysis………………………………72
3.2.9 High-performance liquid chromatography……………73
3.2.10. Statistical analysis……………………………………73
3.3. Results
3.3.1 Expressions of PCNA and involucrin in indigo naturalis-treated and vehicle-treated lesions of psoriatic patients…………………………………………………………………………74
3.3.2 Indigo naturalis decreased the number of keratinocytes…………………………………………………………………74
3.3.3. Effect of indigo naturalis on the cell cycle progression of keratinocytes…………………………………………75
3.3.4. Indigo naturalis down-regulated PCNA gene expression in keratinocytes……………………………………………75
3.3.5. Indigo naturalis up-regulated involucrin gene expression in keratinocytes……………………………………………76
3.3.6. Chromatographic fingerprint analysis of indigo naturalis………………………………………………………………………77
3.3.7. Indirubin, the major active component of indigo naturalis, exerted similar effects on keratinocytes………77
3.4. Discussion………………………………………………………… 78
3.5. Figures (3-1~3-7…………………………………………………81
Chapter 4. Indigo Naturalis Up-Regulates Epidermal Tight Junction Proteins in Psoriasis and Cultured Keratinocytes.
4.1. Rationale, Experimental Models and Approaches………90
4.2. Materials and Methods
4.2.1. Skin specimens used in the study……………………94
4.2.2. Reagents…………………………………………………………94
4.2.3. Cell culture and treatment…………………………… 95
4.2.4. Cytotoxicity test………………………………………… 95
4.2.5. Immunofluorescent microscopy…………………………95
4.2.6. Quantitative RT/real-time PCR analysis………… 95
4.2.7. Western blotting analysis………………………………96
4.2.8. Measurement of transepithelial electrical resistance (TER) and paracellular tracer flux……………… 96
4.2.9. Statistical analysis…………………………………… 98
4.3. Results
4.3.1. Indigo naturalis-treated lesions regained the expression of claudin-1, occludin and ZO-1……………………98
4.3.2. Cell viability of cultured keratinocyte in the presence of indigo naturalis extract…………………………… 99
4.3.3. Indigo naturalis extract induced expression of claudin-1, occludin and ZO-1 in cultured keratinocytes by immunofluorescent detection………………………………………… 99
4.3.4. Indigo naturalis extract up-regulated the gene expression of claudin-1, occludin, and ZO-1 in keratinocytes……………………………………………………………… 100
4.3.5. Indigo naturalis extract increased TER and decreased paracellular permeability of cultured keratinocytes……………………………………………………………… 101
4.3.6. Indigo, indirubin and tryptanthrin, three major active components of indigo naturalis, exerted similar effects on the induction of TJs in keratinocytes………… 101
4.4. Discussion…………………………………………………………… 102
4.5. Figures (4-1~4-9……………………………………………… 107
Chapter 5. Conclusions and Future Works
5.1. Conclusions……………………………………………………… 124
5.2. Future Works………………………………………………………128
5.3. Figures (5-1~5-5……………………………………………… 132
References…………………………………………………………………… 139
Appendix: List of Publications…………………………………… 152

Tables
Table 1-1. Limitations of traditional therapies for psoriasis………………………………………………………………………20
Table 1-2. Currently available psoriasis treatments………21
Table 1-3. Demographic characteristics of patients……… 22
Table 2-1. Inclusion and exclusion criteria………………… 53
Table 2-2. Intra-patient comparison trial baseline data…54
Table 2-3. Response based on baseline severity………………55

Figures
Figure 1-1. Chronic plaque psoriasis………………………………23
Figure 1-2. The march of psoriasis…………………………………24
Figure 1-3. Clinical features of psoriasis…………………… 26
Figure 1-4. (A) Scalp psoriasis. (B) Nail psoriasis. (C) Severely affected psoriatic nails. (D) “Sausage digit” in psoriatic arthritis…………………………………………………………27
Figure 1-5. Histological appearance of chronic psoriatic plaques……………………………………………………………………………28
Figure 1-6. Histological components of a mature psoriatic plaque compared with normal skin…………………………………… 29
Figure 1-7. Translational arcs of discovery in psoriasis…31
Figure 1-8. Strobilanthes formosanus Moore (Acanthaceae)…33
Figure 1-9. Indirubin is the active component of the Chinese anti-leukemia Traditional Medicine recipe Danggui Longhui Wan…………………………………………………………………… 34
Figure 1-10. A 41-year-old man with a 20-year history of plaque-type psoriasis………………………………………………………35
Figure 1-11. An 8-year-old male child with a 2-year history of psoriasis……………………………………………………………………36
Figure 1-12. A 45-year-old man with an 8-year history of plaque-type psoriasis………………………………………………………37
Figure 1-13. Clinical improvement on the appearance of skin lesions after indigo naturalis ointment treatment……………38
Figure 1-14. Changes in mean clinical score and reduced percentage on indigo naturalis ointment- and vehicle-treated plaques during the 8-week treatment period…………39
Figure 1-15. Effect of topically applied indigo naturalis ointment on the expression of Ki-67, filaggrin and CD3 in target lesions…………………………………………………………………40
Figure 2-1. Indigo naturalis ointment………………………………56
Figure 2-2. Clinical photographic examples of rating of percentage of clearing…………………………………………………… 57
Figure 2-3. Clinical photographic examples of rating scaling (A-E), erythema (F-J) and induration (K-O)………… 59
Figure 2-4. Trial profile……………………………………………… 60
Figure 2-5. Changes in mean clinical score and area coverage in indigo naturalis ointment- and vehicle-treated plaques……………………………………………………………………………61
Figure 2-6. Patients were categorized into six groups based on the different extent of individual improvement at week 12……………………………………………………………………………………62
Figure 2-7. Clinical improvement on the appearance of skin lesions after the indigo naturalis ointment treatment…… 63
Figure 3-1. Expressions of PCNA and involucrin in indigo naturalis-treated and vehicle-treated psoriatic skin………81
Figure 3-2. Effect of indigo naturalis on the cell viability of cultured keratinocytes…………………………………82
Figure 3-3. Effect of indigo naturalis on modulating the cell cycle progression of keratinocytes………………………… 83
Figure 3-4. Indigo naturalis down-regulated PCNA gene expression in human keratinocytes……………………………………84
Figure 3-5. Indigo naturalis up-regulated involucrin gene expression in human keratinocytes……………………………………86
Figure 3-6. Chromatographic fingerprint of indigo naturalis…………………………………………………………………………88
Figure 3-7. Effects of indigo and indirubin on keratinocytes………………………………………………………………… 89
Figure 4-1. Regenerated expressions of the claudin-1, occludin and ZO-1 in psoriatic skin section treated with indigo naturalis……………………………………………………………107
Figure 4-2. Indigo naturalis extract up-regulated claudin-1, occludin and ZO-1 gene expression in cultured keratinocytes in a dose-dependent manner as analyzed by fluorescent immunocytochemical staining…………………………109
Figure 4-3. Indigo naturalis extract up-regulated claudin-1, occludin and ZO-1 gene expression in cultured keratinocytes in time-dependent manner analysis by fluorescent immunocytochemical staining…………………………111
Figure 4-4. RT/real-time PCR analysis of mRNA expression for claudin-1, occludin and ZO-1 in cultured keratinocytes treated with indigo naturalis extract……………………………113
Figure 4-5. Protein expressions of claudin-1, occludin and ZO-1 after indigo naturalis extract treatment………………115
Figure 4-6. Effects of indigo naturalis on epidermal barrier function……………………………………………………………117
Figure 4-7. Indigo, indirubin and tryptanthrin up-regulated claudin-1, occludin and ZO-1 gene expressions in cultured keratinocytes…………………………………………………………………119
Figure 4-8. Indigo, indirubin and tryptanthrin effect on epidermal barrier function…………………………………………… 121
Figure 4-9. Indigo naturalis possess a synergistic effect with indirubin, indigo and tryptanthrin demonstrated by TER measurement……………………………………………………………………123
Figure 5-1. Refined formula ointment made from the indigo naturalis extract………………………………………………………… 132
Figure 5-2. RT/real-time PCR analysis of mRNA expressions for VCAM-1, RANTES and IL-8 in cultured vascular endothelial cells treated with indigo naturalis extract…133
Figure 5-3. Indigo naturalis extract inhibited the in vivo angiogenesis in CAM assay………………………………………………134
Figure 5-4. Regenerated expression of the plakophilin 1 in psoriatic skin section treated with indigo naturalis…… 136
Figure 5-5. Indigo naturalis up-regulated plakophilin 1 gene expression in human keratinocytes………………………… 137
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