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研究生:吳若維
研究生(外文):Joe-Wei Wu
論文名稱:探討天然物LHZ-7在活化的膠質細胞中抗發炎之作用機轉
論文名稱(外文):Investigate the Anti-inflammatory Mechanisms of the Natural Compound LHZ-7 in Activated BV2 Microglial Cells
指導教授:蕭哲志蕭哲志引用關係
口試委員:黃聰龍陳彥州
口試日期:2015-01-09
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學科學研究所
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:2015
畢業學年度:103
語文別:英文
論文頁數:77
中文關鍵詞:膠質細胞抗發炎
外文關鍵詞:BV2 Microglial CellsAnti-inflammatory
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  • 被引用被引用:0
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  • 收藏至我的研究室書目清單書目收藏:0
在神經發炎性疾病或神經退化性疾病中,都和發炎反應與氧化壓力有著密切的關係,而其中神經膠細胞的過度活化在疾病發展中扮演重要的角色。過度活化的神經膠細胞所分泌的各種前發炎細胞激素(例如一氧化氮) 會導致神經細胞的死亡,因此藉由抑制神經膠細胞的過度活化所產生的一氧化氮可達到減緩神經性疾病的發展。
本篇研究顯示,在小膠質細胞中,Nectria balsamea真菌萃取出的天然物LHZ-7可依濃度效應抑制脂多醣 (LPS) 所引發的發炎介質一氧化氮合成酶 (iNOS) 和一氧化氮的表現。此外,LHZ-7 對於小膠質細胞並沒有明顯細胞毒性。LPS刺激下訊息傳遞結果顯示LHZ-7會抑制inhibitor-?羠-?? (I?羠-??) 的降解,但對於AKT 和MAPK 路徑 (如 ERK,JNK,p38) 並沒有影響。有趣的是我們發現,單獨給予LHZ-7 即會促進小膠質細胞heme oxygenase-1 (HO-1) 大量表現。進一步研究指出,ERK抑制劑、Nrf2 siRNA 以及抗氧化劑NAC 可以阻斷LHZ-7所誘導的HO-1表現。此外,前處理HO-1活性抑制劑SnPP可反轉LPS刺激下,LHZ-7抑制小膠質細胞釋放一氧化氮的效果。綜合以上結果,我們認為LHZ-7可能是透過誘導HO-1表現並且抑制NFκB的活化而降低LPS所引發的一氧化氮生成。
Oxidative stress and inflammation have been implicated in many neuro-inflammatory and neuro-degenerative diseases. The glial activation plays an important role in the progression of these diseases. Over-activated glial cells can secrete various proinflammatory mediators, such as Nitric oxide (NO) and Interleukin-1 (IL-1???w, which may contribute to neuron death. Inhibition of glial activation may alleviate neurodegeneration under these conditions.
In this study, we found that the natural compound LHZ-7 (1–20 ?嵱), ioslated from Nectria balsamea, significantly inhibited LPS-induced iNOS expression and NO production in LPS-activated BV2 cells. In addition, cell viability was slightly affected by LHZ-7. In signaling pathways, LHZ-7 decreased the degradation of inhibitor-?羠-?? (I?羠??) but had no effects on the activation of AKT and MAPK (such as ERK, JNK, p38) in LPS-activated BV2 cells. Notably, we found that LHZ-7 alone strongly up-regulated the expression of heme oxygenase-1 (HO-1) in BV2 cells. ERK inhibitor (PD98059), knockdown of Nrf2, or antioxidant (NAC) could block the LHZ-7-induced HO-1 expression. Furthermore, blocking HO-1 activity by treatment of SnPP abrogated the inhibitory effect of LHZ-7 on the NO production in LPS-activated BV2 cells. Taken together, LHZ-7 up-regulated the expression of HO-1 protein and inhibited the LPS-induced NO production through NF?羠 inhibition.
中文摘要 4
ABSTRACT 5
ABBREVIATION 6
1. INTRODUCTION 8
1.1. INFLAMMATION AND CNS DISEASES 8
1.2. THE RESIDENT MACROPHAGES IN THE BRAIN: MICROGLIA 9
1.3. NITRIC OXIDE (NO) AND INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) 10
1.4. ROS 12
1.5. SIGNALINGS INVOLVE IN THE NEURODEGENERATIVE DISEASE 12
1.5.1. NF?羠 SIGNALING 12
1.5.2. MAPK SIGNALING 13
1.5.3. AKT SIGNALING 14
1.6. HEME OXYGENASE-1 (HO-1) 15
1.7. AIM 16
2. MATERIAL AND METHODS 17
2.1. MATERIALS 17
2.2. CELL CULTURE 18
2.2.1. BV2 MICROGLIAL CELL CULTURE 18
2.2.2. PRIMARY MICROGLIAL CELLS 19
2.3. BIOLOGICAL AND BIOCHEMICAL METHODS 20
2.3.1. CELL VIABILITY 20
2.3.2. MEASUREMENT OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS) 20
2.3.3. MEASUREMENT OF NITRIC OXIDE PRODUCTION 21
2.3.4. TOTAL PROTEIN PREPARATION 22
2.3.5. SDS-POLYACRYLAMIDE GEL ELECTROPHORESIS (PAGE) AND WESTERN BLOT ANALYSIS 22
2.4. MOLECULAR BIOLOGICAL METHODS 23
2.4.1. ISOLATION OF TOTAL RNA AND REVERSE-TRANSCRIPTION POLYMERASE CHAIN REACTION (RT-PCR) 23
2.4.2. TRANSIENT TRANSFECTION OF CELLS 24
2.5. ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) 25
2.6. DATA ANALYSIS 25
3. RESULTS 26
3.1. EFFECTS OF LHZ-7 ON HO-1 EXPRESSION IN BV2 MICROGLIAL CELLS 26
3.2. EFFECT OF LHZ-7 ON ROS FORMATION AND HO-1 EXPRESSION IN BV2 MICROGLIAL CELLS. 26
3.3. EFFECT OF CELL SIGNALING ON LHZ-7- MEDIATED HO-1 EXPRESSION IN BV2 MICROGLIAL CELLS. 27
3.4. EFFECT OF ERK SIGNALING ON LHZ-7- MEDIATED HO-1 EXPRESSION IN BV2 MICROGLIAL CELLS. 28
3.5. EFFECT OF NAC ON LHZ-7- MEDIATED HO-1 EXPRESSION IN BV2 MICROGLIAL CELLS. 29
3.6. EFFECT OF NRF2 SIGNALING ON LHZ-7- MEDIATED HO-1 EXPRESSION IN BV2 MICROGLIAL CELLS. 29
NRF2 IS WELL KNOWN AS A TRANSCRIPTION FACTOR THAT REGULATE ANTIOXIDANT ENZYME, INCLUDING HO-1, WHICH IS INVOLVE IN THE CELLULAR ANTIOXIDANT RESPONSES AS WELL AS ACUTE INFLAMMATION[87,88] THEREFORE, WE EXAMINED WHETHER NRF2 SIGNALING INVOLVE IN LHZ-7 INDUCED HO-1 PROTEIN EXPRESSION IN BV2 MICROGLIAL CELLS. KNOCKDOWN OF NRF2 BY SIRNA BLOCKED LHZ-7-MEDIATED HO-1 EXPRESSION AS WELL AS KNOCKDOWN OF HO-1 (LHZ-7: 1.59 ± 0.19 FOLDS, SICONTROL: 1.78 ± 0.31 FOLDS, SINRF2: 1.28 ± 0.16 FOLDS, N=5) (FIG. 9), SUGGESTING THAT LHZ-7 INDUCES HO-1 EXPRESSION THROUGH THE NRF2 SIGNALING. 29
3.7. EFFECTS OF LHZ-7- MEDIATED HO-1 EXPRESSION ON LPS-INDUCED NO PRODUCTION IN BV2 MICROGLIAL CELLS. 30
3.8. EFFECTS OF LHZ-7 ON LPS-INDUCED NO PRODUCTION AND INOS EXPRESSION IN BV2 MICROGLIAL CELLS 30
3.9. EFFECTS OF LHZ-7 ON LPS-INDUCED INOS EXPRESSION IN PRIMARY MICROGLIAL CELLS 31
3.10. EFFECTS OF LHZ-7 ON BV2 MICROGLIAL CELLS VIABILITY 32
3.11. EFFECTS OF LHZ-7 ON LPS-INDUCED NF?羠 ACTIVATION IN BV2 MICROGLIAL CELLS 33
3.12. EFFECTS OF LHZ-7 ON LPS-INDUCED AKT IN BV2 MICROGLIAL CELLS 33
3.13. EFFECTS OF LHZ-7 ON LPS-INDUCED ERK IN BV2 MICROGLIAL CELLS 34
3.14. EFFECTS OF LHZ-7 ON LPS-INDUCED JNK IN BV2 MICROGLIAL CELLS 34
3.15. EFFECTS OF LHZ-7 ON LPS-INDUCED P38 IN BV2 MICROGLIAL CELLS 35
3.16. EFFECTS OF LHZ-7 ON LPS-INDUCED 36
3.17. EFFECTS OF LHZ-7 ON LPS-INDUCED IL-1?? IN BV2 MICROGLIAL CELLS 36
4. DISCUSSION 38
4.1. ACTIVATED MICROGLIA AND INFLAMMATION 38
4.2. LPS AND ACTIVATED MICROGLIA 39
4.3. NO AND INFLAMMATION 39
4.4. SIGNALING INVOLVE IN LPS-INDUCED INFLAMMATION PATHWAY 40
4.5. HO-1 AND INFLAMMATION 41
4.6. PATHWAY INVOLVE IN LHZ-7-INDUCED HO-1 42
4.7. HO-1 AND MORPHOLOGY 43
5. CONCLUSION 45
6. FIGURES 46
7. REFERENCES 68
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