臺灣博碩士論文加值系統

北冬蟲夏草與冬蟲夏草已長年應用於中國傳統文化，近代醫學研究指出北冬蟲夏草較冬蟲夏草在抑制體外癌細胞增生與免疫系統調節上，具有更優越之功效，但對其詳細的機轉則尚未有確切的報導，因此本篇研究旨在闡明北冬蟲夏草的抗腫瘤與免疫調節機轉，利用口腔癌動物模式與小鼠乾癬模式探討與證明北冬蟲夏草的功效。口腔癌模式中，小鼠透過飲用水連續攝取北冬蟲夏草的液態發酵液(500 mg/kg/day與1500 mg/kg/day) 20周後，明顯觀察到口腔腫瘤的大小與惡性程度被抑制。進一步地利用由小鼠口腔腫瘤所分離出的細胞株，證明北冬蟲夏草發酵液與其中的蟲草素皆可顯著抑制口腔腫瘤細胞之增生，此現象透過影響上皮細胞生長因子接受器(EGFR)與介白素17接受器(IL-17RA)的訊號傳導，更發現介白素17A (IL-17A)的產生量與分泌介白素17A的免疫細胞數量也顯著地被北冬蟲夏草發酵液與蟲草素所抑制。另外，北冬蟲夏草發酵液與蟲草素可顯著增加抗腫瘤免疫力與減少抑制免疫力提升的細胞表面蛋白分子PD-L1之表現。在乾癬動物模式中，小鼠接受北冬蟲夏草發酵液所製備的乳液連續塗抹六天後，背部皮膚的乾癬嚴重程度與表皮細胞之厚度均顯著地被改善。細部分析發現，此症狀之改善也與降低IL-17A的產生量與抑制分泌介白素17A的免疫細胞數量有關。體外細胞實驗與體內免疫染色結果均顯示，北冬蟲夏草發酵液與蟲草素皆可顯著抑制人類角質細胞與小鼠皮膚上皮細胞之增生。綜合以上結果，本研究證明北冬蟲夏草發酵液與蟲草素可顯著抑制小鼠口腔癌之產生與惡化程度、口腔癌之細胞增生、EGFR與IL-17RA的訊號傳導、IL-17A之表現量、分泌IL-17A的免疫細胞數量、小鼠乾癬嚴重程度、皮膚上皮細胞之厚度與角質細胞的增生，另可提升抗腫瘤免疫力。因此，北冬蟲夏草發酵液具極高之價值與潛力，可開發為一輔助性之藥材運用於人體上。

Cordyceps militaris was shown to have anti-tumor, anti-inflammatory, and anti-diabetic functions, but detailed mechanisms are still obscure. Interleukin-17A (IL-17A) is an important pro-inflammatory cytokine belonging to the family of IL-17. The cytokine can be produced by many types of cells, such as αβ T cells, γδ T cells, neutrophils, mast cells, and epithelial cells. Among these cells, αβ T cells and γδ T cells are the major sources. IL-17A has been considered as a molecular target for treatment of cancers and autoimmune diseases. This study used two mouse models: oral cancer and psoriasis to evaluate the anti-tumor and anti-inflammatory effects of a CM preparation (CMP) and cordycepin, a bioactive ingredient of CMP. Our results show that mice receiving CMP at 500 mg/kg/day or 1500 mg/kg/day through drinking water for 20 weeks had significant decrease in the incidence and multiplicity of squamous cell carcinoma in the tongue. We used the 4NAOC-1 cell line, a cell line established by our laboratory, to demonstrate that both CMP and cordycepin significantly inhibited cell proliferation via disrupting the epidermal growth factor receptor (EGFR) and interleukin-17 receptor A (IL-17RA) signaling. In addition, the production of IL-17A and the percentage of IL-17A-expressing CD4+ T cells were significantly suppressed by CMP and cordycepin. Importantly, CMP and cordycepin markedly enhanced tumoricidal activity of splenocytes and peritoneal macrophages, and decreased the expression of program death ligand 1 (PD-L1) in 4NAOC-1 cells. In the mouse model for psoriasis, topical application of CMP lotion significantly alleviated the severity of psoriasiform lesions and epidermal thickness in the skin. These effects were also mediated by decreasing in the production of IL-17A and the percentage of IL-17A-expressing CD4+ T cells in the skin and spleen. Furthermore, CMP and cordycepin inhibited the proliferation of keratinocytes. Combines all these results, CMP and cordycepin are potential candidates for the prevention and treatment of oral cancer and psoriasis in humans.

中文摘要 iii
ABSTRACT v
Related Publication vii
Contents viii
List of Figures xii
Abbreviation List xiv

1. Introduction 1
2. Objects of this Study 3
3. Literature Review 4
3.1 Cordyceps militaris (CM) 4
3.2 Bioactive functions of CM and its ingredients: focusing on anti-tumor and immunomodulatory effects 4
3.3 Interleukin-17 (IL-17) and its intracellular signaling 6
3.4 IL-17A and its tumor-promoting or tumor-suppressing functions 7
3.5 IL-17A and the development of psoriasis 9
4. Part I:
Cordycepin and a preparation from Cordyceps militaris inhibit malignant transformation and proliferation by decreasing EGFR and IL-17RA signaling in a murine oral cancer model 11
Abstract 11
4.1 Introduction 12
4.2 Materials and Methods 14
4.2.1 CM preparation (CMP) 14
4.2.2 Analysis of bioactive ingredients 14
4.2.3 Induction of oral cancer and intervention with CMP 15
4.2.4 Observation and histopathological examination 15
4.2.5 Immunohistochemical staining and quantification 16
4.2.6 Assays for tumoricidal activities 17
4.2.7 Establishment of 4NAOC-1 cell line and related assays 18
4.2.8 Western blotting 19
4.2.9 Flow cytometric assays for membrane proteins 20
4.2.10 Ex vivo mononuclear cell stimulation 20
4.2.11 ELISA for cytokines in the serum and culture supernatants 21
4.2.12 In vitro differentiation of IL-17A-expressing cells 21
4.2.13 Ex vivo TNFα stimulation 21
4.2.14 Measurement of mRNA transcripts 22
4.2.15 Assay for gelatinases activity with zymography 22
4.2.16 Complete blood count (CBC) and differential count (DC) 22
4.2.17 Statistical analysis 23
4. 3 Results 24
4.3.1 CMP inhibited tumor growth 24
4.3.2 CMP inhibited malignant transformation 24
4.3.3 Both CMP and cordycepin suppressed proliferation of 4NAOC-1 cells 25
4.3.4 Both CMP and cordycepin inhibited mitosis and EGFR signaling in 4NAOC-1 cells 25
4.3.5 Both CMP and cordycepin inhibited IL-17RA signaling 25
4.3.6 Both CMP and cordycepin reduced IL-17A production 26
4.3.7 CMP and its ingredients enhanced anti-tumor immune activities 26
4.3.8 CMP prevented leucopenia and lymphopenia, and decreased inflammatory markers expression in the blood 27
4.4 Discussion 28
4.5 Conclusion 31
5. Part II:
Cordycepin-containing Cordyceps militaris lotion alleviates imiquimod-induced psoriasiform lesions in mice by inhibiting IL-17A production, Th17 differentiation, and keratinocyte proliferation 32
Abstract 32
5.1 Introduction 33
5.2 Materials and Methods 35
5.2.1 Preparation of cordycepin-containing Cordyceps militaris lotion 35
5.2.2 Psoriasis murine model and intervention with CM lotion 36
5.2.3 Histological examination and dorsal skin thickness measurement 36
5.2.4 Immunohistochemistry and immunofluorescence staining 37
5.2.5 Ex vivo mononuclear cell stimulation and flow cytometric analysis 37
5.2.6 Measurement of cytokines in skin protein lysates and in the serum 38
5.2.7 In vitro differentiation of Th17 cells 38
5.2.8 Western blot of splenic tissues 39
5.2.9 Cultivation of human keratinocyte and related proliferation assays 40
5.2.10 Statistical analysis 41
5.3 Results 42
5.3.1 Cordycepin-containing CM lotion suppressed the severity of psoriasiform lesions and epidermal thickness in mice 42
5.3.2 Imiquimod-induced psoriasiform lesions were infiltrated with immune cells and cordycepin-containing CM lotion decreased skin levels of cytokines 42
5.3.3 Cordycepin-containing CM lotion inhibited systemic inflammation in mice 42
5.3.4 Cordycepin inhibited IL-17A production, Th17 differentiation, and AhR pathway 43
5.3.5 CMP and cordycepin suppressed keratinocyte proliferation in vivo and in vitro 43
5.4 Discussion 45
5.5 Conclusion 48
6. General Conclusions 49
7. List of Figures 50
References 84

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