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研究生:陳詩詩
研究生(外文):Shih-Shih Chen
論文名稱:以免疫調節及細胞再生觀點探討山藥生物活性之研究
指導教授:吳榮燦
指導教授(外文):Rong-Tsun Wu
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物藥學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:105
中文關鍵詞:山藥腸道免疫細胞再生
外文關鍵詞:Dioscorea spp.mucosal immunitycell regeneration
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摘要
山藥為中國及亞洲國家廣泛使用的藥用植物,具有補中益氣、不飢延年功效。目前仍無研究證實口服山藥能促進免疫調節功能。本實驗首先便觀察口服山藥塊莖去除澱粉後所得多糖成份對免疫反應的影響。我們證實,在系統免疫方面,口服山藥多糖能明顯促進脾臟自然殺手細胞毒殺作用、脾臟細胞對裂殖原Con A反應的能力,及骨髓細胞對顆粒球/單核球幹細胞生長因子刺激增生的反應。
在黏膜免疫方面,我們利用兩種不同抗原:白蛋白及肺炎雙球莢膜多糖疫苗,以口服方式引發小鼠的抗體免疫反應,同時將山藥多糖加入小鼠日常飲水中作為免疫調節劑。結果證實,山藥多糖可以引起肺炎雙球莢膜多糖疫苗專一性的血清IgG及黏膜IgA抗體反應。並且能夠突破口服耐受性限制,引起口服水溶性白蛋白的小鼠,血清IgG及黏膜IgA的抗體免疫反應。
為了解山藥多糖在黏膜免疫調節機制,我們進一步觀察腸道細胞激素反應,包括腸道上皮淋巴細胞、固有層及Peyer’s patch等組織。在固有層及Peyer’s patch中,輔助性T細胞第一型細胞激素,IFN-;第二型細胞激素IL-4、IL-6;以及第三型細胞激素TGF-,均因口服山藥多糖而被大量刺激表現。這或許可以解釋山藥多糖對腸道免疫調節的作用。另外,山藥多糖能促進腸道上皮細胞中,具有抵抗微生物能力的小分子蛋白質cryptdin (defensin family)基因大量表現。因此,由細胞激素表現的結果顯示,山藥可能透過細胞激素活性的調控,促進黏膜免疫反應,達到免疫調節的作用。
山藥所含的類固醇已被應用於合成人體所需的多種類固醇產品。實驗初步證實口服山藥甲醇粗萃物對於系統免疫反應沒有顯著的生物活性。但是在體外實驗(in vitro)中,山藥甲醇粗萃物對於腦神經及骨髓中的祖原細胞則具有促進細胞增生及形態改變的活性。
骨質疏鬆症造成的原因包括骨形成與再吸收的速率失去平衡。成骨細胞負責骨形成,鹼性磷酸為成骨細胞活性的標記。山藥甲醇粗萃物能刺激骨細胞增生及分化,以補充骨中的造骨祖原細胞及促進造骨細胞的成熟。
幹細胞在發育過程中主要參與在組織更新,以確保器官長久生存。源自成體特定組織的幹細胞,目前發現具有替代多種身體組織的潛力。山藥甲醇粗萃物或許因此能藉由促進細胞再生的活性,預防或治療一些與老化相關的疾病,如神經退化性疾病及骨質疏鬆症。
在本研究中,我們了解山藥多糖在系統及黏膜免疫上確實具有免疫調節作用。且山藥低分子的甲醇粗萃物具有促進腦神經及骨髓祖原細胞生長及分化的細胞再生能力。
Abstract
Dioscorea spp., a medical herb, has been widely used as a remedy for promotion of health and longevity in China and other Asian countries, but no scientific evidences of their immune-potentiation effects by oral administration have been documented. In our study, immune responses of non-starch polysaccharide components of tubers from Dioscorea spp. by oral administration were examined. In systemic immunity, the cytotoxic activity of natural killers, and the proliferative activity of ConA-induced splenocytes, the proliferative activity of GM-CSF-stimulated bone marrow cells on Dioscorea polysaccharides diet were significantly enhanced.
In mucosal immunity, we used two different antigens: ovalbumin and Pneumovax 23 vaccine to induce humoral immune responses in mice by gastric intubation. Additionally, Dioscorea polysaccharides were supplemented in daily drink for mice as an immunomodulator. For an immunomodulator, a feed of Dioscorea polysaccharides not only abrogated the induction of oral tolerance stimulated by ovalumin feeding in mice but also induced the ovalbumin and Pneumovax-specific serum IgG and mucosal IgA antibody responses.
We attempted to clarify the mechanism of the mucosal immunomodulation of Dioscorea polysaccharides on cytokine responses. Cytokine production by intestinal epithilium lymphocytes, lamina propria and Peyer’s patch of mice orally administrated with Dioscorea polysaccharides was examined. Weak Th1 cytokine IFN-gamma, strong Th2 cytokine IL-4, IL-6 and TGF mRNA expressions were induced. Innate anti-microbial peptide cryptdin (defensin family) mRNA production by intestinal epithilium lymphocytes was also induced. Taken together, our study demonstrated that Dioscorea polysaccharides have differential effects on the expression of various cytokines, which likely contribute to its immunomodulatory activity.
Dioscorea steroid extract is used in commercial steroid synthesis and consumed by people. In our study, methanol extracts of Dioscorea had no obvious effects in systemic immune responses. But when we investigated the effect of methanol extracts of Dioscorea on the progenitor cells, we found that methanol extract of Dioscorea added to neuron progenitor cells and bone marrow cell cultures induced stem cell proliferation and morphological changes.
Bone loss in postmenopausal osteoporosis is mainly due to decreased bone formation or increased bone resorption. Bone formation is mediated by osteoblasts and alkaline phosphatase is a biological marker of osteoblast activity. We proved that methanol extract of Dioscorea stimulation of bone cell proliferation and differentiation, possibly to promote the recruitment and maturation of primitive osteogenic precursors present of bone and marrow.
Stem cells may arise late in development, to act principally in tissue renewal, thus ensuring an organism''''''''s long-term survival. Tissue-specific adult stem cells have the potential to contribute to replenishment of multiple adult tissues. Methanol extracts of Dioscorea may improve cell regeneration to prevent or cure several age-related diseases such as neuron degeneration diseases and osteoporosis.
In this study, we demonstrated that polysaccharides of Dioscorea spp. did have their effects on immunomodulation in both systemic and mucoal immunity. And methanol crude extract of Dioscorea spp. contains bioacitive compounds capable of stimulating the proliferation and differentiation of progenitor cells in brain and bone marrow, in related with their cell regeneration function.
目錄
目錄……………………………………………………………………… I
圖次…………………………………………………………………… II
表次…………………………………………………………………… IV
縮寫表………………………………………………………………… VI
中文摘要……………………………………………………………… 1
英文摘要……………………………………………………………… 3
緒論…………………………………………………………………… 6
試藥及器材…………………………………………………………… 14
方法…………………………………………………………………… 21
結果…………………………………………………………………… 36
討論…………………………………………………………………… 43
參考文獻……………………………………………………………… 56
圖表說明……………………………………………………………… 67
附圖…………………………………………………………………… 104
圖次
圖1:Purification of mGM-CSF ……………………………………………… 67
圖2:Effect of Dioscorea polysaccharides on mitogenic responses of Con A- stimulated
splenocytes in C3H mice………………………………………………………… 68
圖3:Effect of Dioscorea polysaccharides on natural killer cell mediated cytotoxicity
in C3H mice……………………………………………………………………… 69
圖4:Effect of Dioscorea polysaccharides on the proliferation activity of bone marrow
cells in C3H mice………………………………………………………………… 70
圖5:Effects of Pneumovax 23 vaccine specific mucosal IgA induced by oral
immunization and long term feeding with Dioscorea polysaccharides as an
immunomodulator on 20 wk C57BL/6 mice. …………..................……..… 71
圖6:Effects of Pneumovax 23 vaccine specific mucosal IgA induced by oral
immunization and long term feeding with Dioscorea polysaccharides as an
immunomodulator on 10 wk C57BL/6 mice.…………………………….. 72
圖7:Effects of ovalbumin specific mucosal IgA antibody induced by oral
immunization and long term feeding with Dioscorea polysaccharides as an
immunomodulator on 20wk C57BL/6 mice……………………………… 73
圖8:Effects of ovalbumin specific mucsoal IgA antibody induced by oral
immunization and long term feeding with Dioscorea polysaccharides as an
immunomodulator on 20wks C3H mice .……………………….……… 74
圖9:Effects of Pneumovax 23 vaccine specific serum antibodies induced by oral
immunization and long term feeding with Dioscorea polysaccharides as an
immunomodulator on 10 wk C57BL/6 mice…………………………………….. 75
圖10:Effects of ovalbumin specific serum IgG and IgM antibody induced by oral
immunization and long term feeding with Dioscorea polysaccharides as an
immunomodulator on 20 wk C57BL/6 mice……………………….……. 76
圖11:Effects of ovalbumin specific serum IgG and IgM antibody induced by oral
immunization and long term feeding with Dioscorea polysaccharides as an
immunomodulator on 20wk C3H mice…………….……………………... 77
圖12:Polymerase chain reaction analysis of cytokine-specific mRNA in Peyer’s patch
isolated from mice fed with Dioscorea polysaccharides………………………… 78
圖13:Polymerase chain reaction analysis of cytokine-specific mRNA in lamina propria
isolated from mice fed with Dioscorea polysaccharides………………………… 79
圖14:Polymerase chain reaction analysis of cryptdin mRNA in enterocyte isolated from
mice fed with Dioscorea polysaccharides……………………………...………… 80
圖15:Effects of methanol extracts of Dioscorea on GM-SCF-stimulated bone marrow
cells in C3H mice……………………………………………...………………… 81
圖16:Effects of methanol extracts of Dioscorea on mitogenic responses of Con A-
stimulated splenocytes in C3H mice……………………………………...………. 82
圖17:Effects of methanol extracts of Dioscorea on natural killer cell- mediated
cytotoxicity in C3H mice.……………………………............………...……….… 83
圖18:Polymerase chain reaction analysis of cytokine-specific mRNA in lamina propria
isolated from mice fed with MeOH extracts of Dioscorea.……………………..... 84
圖19:Effects of different partition fractions of methanol extracts of Dioscorea
and DHEA on mitogenic responses of osteogenic cell in vitro........... 85
圖20:Orally administration effects of methanol extracts of Dioscorea on mitogenic
responses of osteogenic cell in C57BL/6 mice...................................................... 86
圖21:Effects of different partition fractions of methanol extracts of Dioscorea
on alkaline phosphatase activity in osteoblasts cultures in vitro……………… 87
圖22:Orally administration effects of methanol extracts of Dioscorea on on
alkaline phosphatase activity in osteoblasts cultures in C57BL/6 mice..………… 88
圖23:Effects of methanol extracts of Dioscorea on morphological changes of murine
osteoblast cells.…...………….….….….….……..…….……………………… 89
圖24:Effects of methanol extracts of Dioscorea on morphological changes of
the primary cultured bone marrow cells from P5 mice…………………… 90
圖25:Effects of DHEA on morphological changes of the primary cultured
bone marrow cells from P5 mice............................................................................. 91
圖26:Effects of different partition fractions of methanol extracts of Dioscorea
and DHEA on proliferation responses of bone marrow cells in C3H mice. 92
圖27:Effects of methanol extracts of Dioscorea on morphological changes of
the primary cultured bone marrow cells from 8wk mice….………..…… 93
圖28:Effect of DHEA on morphological changes of the primary cultured bone
marrow cells from 8wk mice...........................................….………...................… 94
圖29:Effects of methanol extracts of Dioscorea on morphological changes of
secondary passaged P1 brain progenitor cells…………..…..……..…… 95
表次
表1:List of the weights and yields of partition fractions of Dioscorea spp…………… 96
表2:List of weights and recoveries of rmGM-CSF purification……………………… 97
表3:Effects of different partition fractions of methanol extracts of Dioscorea spp. on
the EGF-stimulated proliferation and morphological change of primary cultured
bone marrow cells from 20wk mice……………………………..………………… 98
表4:Effects of DHEA on the EGF-stimulated proliferation and morphological change
of primary cultured bone marrow cells from 8wk mice…………………………… 99
表5:Effects of methanol extracts of Dioscorea spp. on the GM-CSF-stimulated
proliferation and morphological change of primary cultured bone marrow cells
from 20wk mice……………………….…………………………….……..……… 100
表6:Effects of DHEA and different partition fractions of methanol extracts of
Dioscorea spp. on the GM-CSF-stimulated proliferation and morphological
change of primary cultured bone marrow cells from 8wk mice…………………... 101
表7:Effects of methanol extracts of Dioscorea spp. on the proliferation and
morphological change of secondary passage P1 progenitor cells from mice brain.. 102
表8:Effects of different partition fractions of methanol extracts of Dioscorea spp. on
the proliferation and morphological change of secondary passage P1 progenitor
cells from mice brain.......….........….........….........………………………………. 103
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