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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18026完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉興華(Shing-Hwa Liu) | |
| dc.contributor.author | Huang-Jen Chen | en |
| dc.contributor.author | 陳煌仁 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:48:53Z | - |
| dc.date.copyright | 2015-09-25 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-07-15 | |
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O'Toole TE, Abplanalp W, Li X, Cooper N, Conklin DJ, Haberzettl P, Bhatnagar A. Acrolein decreases endothelial cell migration and insulin sensitivity through induction of let-7a. 2014. Toxicol Sci. 140: 271-282. 58. Thompson PA, Seyedi F, Lang NP, MacLeod SL, Wogan GN, Anderson KE, Tang YM, Coles B, Kadlubar FF. Comparison of DNA adduct levels associated with exogenous and endogenous exposures in human pancreas in relation to metabolic genotype. 1999. Mutat Res.424: 263-274. 59. Schoenberg MH, Büchler M, Pietrzyk C, Uhl W, Birk D, Eisele S, Marzinzig M, Beger HG. Lipid peroxidation and glutathione metabolism in chronic pancreatitis. 1995. Pancreas. 10: 36-43. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18026 | - |
| dc.description.abstract | 環境汙染物丙烯醛(acrolein)為液狀小分子化合物，具有不飽和羰基鍵，易與親核性分子結合。而環境中丙烯醛暴露主要來自物質不完全燃燒、油炸食物與抽菸等，其中又以抽菸為大宗。除了經由環境接觸丙烯醛外，丙烯醛也會透過氧化壓力和脂肪過氧化於人體內生成。暴露過量丙烯醛可能與阿茲海默症、腎衰竭與糖尿病成因相關，過往研究發現糖尿病患者與重度吸菸者其尿液中丙烯醛共價鍵結物皆顯著增加，且腎臟疾病病患常併發骨骼肌功能下降，而骨骼肌為人體主要代謝醣類的組織。已有文獻指出丙烯醛會造成骨骼肌肌管細胞萎縮，但對丙烯醛於骨骼肌分化/再生及醣類代謝機制仍待釐清。因此，本研究利用細胞與動物模式探討丙烯醛在骨骼肌肌肉生成(myogenesis)和醣類代謝上之角色。首先經由hematoxylin and eosin (H E)染色發現丙烯醛(0.125-1 μM)具劑量關係阻滯肌纖維母細胞(C2C12 myoblast)分化，同時抑制調節肌細胞能量之肌酸激酶活性。以西方墨點法分析，發現丙烯醛(1 μM)顯著減少骨骼肌分化指標蛋白(myosin heavy chain, myogenin and phospho-Akt)表現和抑制骨骼肌醣類代謝相關蛋白表現。丙烯醛亦造成細胞內肝醣含量增加與葡萄糖攝入減低。過度表現持續性活化態Akt於肌細胞內能恢復丙烯醛抑制之肌酸激酶活性、骨骼肌分化指標蛋白表現及葡萄糖運輸蛋白(glucose transporter 4)表現。動物模式方面，經由管餵小鼠丙烯醛四週(2.5 and 5 mg/kg)後，造成小鼠明顯體重下降且血糖躍升、胰島素驟降，其口服葡萄糖耐受性試驗丙烯醛暴露組呈現高峰延滯分布。藉由滾輪跑步裝置偵測小鼠肌肉強度，丙烯醛(5 mg/kg)造成小鼠肌肉強度下降。當小鼠進行甘油注射致骨骼肌受損試驗(experimental glycerol myopathy model)並再生五天後，丙烯醛(2.5 and 5 mg/kg)導致小鼠肌肉強度下降且比目魚肌重量顯著減少、其骨骼肌復原情形明顯受丙烯醛(2.5 and 5 mg/kg)阻滯。綜合上述，本研究發現丙烯醛抑制肌纖維母細胞分化與骨骼肌再生，並影響骨骼肌醣類代謝，導致小鼠血液葡萄糖濃度增高，其詳細機制在未來仍待探討。 | zh_TW |
| dc.description.abstract | Acrolein is a small molecule and extremely electrophilic aldehyde from foods, environment and tobacco. The endogenous sources of acrolein are related to metabolism of the anticancer drug cyclophosphamide and lipid peroxidation. Acrolein provokes its harmful influences through oxidative stress or inflammation during degradation of threonine and spermidine. High level acrolein was an environmental risk in daily unsaturated aldehyde consumption that contributed to the pathogenesis of Alzheimer’s disease, renal failure and diabetes. Dysfunction of skeletal muscle occurs in renal failure and diabetes patients that is due to oxidative stress and chronic inflammation. Besides, the urinary levels of acrolein adduct were both increased in type 2 diabetes and smoking habit. However, the effects of acrolein on myogenesis and glucose homeostasis in skeletal muscle still remain unclear. A non-cytotoxic dose of acrolein (1μM) repressed myogenic differentiation on C2C12 myoblasts, and then inhibited myotube formation by hematoxylin and eosin (H E) staining and creatinine kinase activity. Myogenic protein expressions (myosin heavy chain, myogenin and phosphorylation of Akt) were also decreased with acrolein treatment. Furthermore, glucose utilization plays an essential role of myogenesis and GLUT4 expresses predominant in skeletal muscle which responded to glucose uptake. Acrolein (1 μM) impaired glucose homeostasis by inhibition of protein expressions of glucose metabolic signalling on skeletal myotubes in vitro. Over-expression of constitutive activation of Akt on differentiation of C2C12 myoblasts reversed the expression of inhibitory myogenic makers and GLUT4 induced by acrolein. Moreover, acrolein (2.5 and 5 mg/kg/day) significantly retarded skeletal muscle regeneration in murine soleus muscles and exercise performance (rotarod) after glycerol injured soleus muscle. Exposure of ICR mice to acrolein prominently increased blood glucose, impaired glucose tolerance and decreased plasma insulin. Taken together, these results suggest that acrolein exposure is capable of impairing the myogenesis and glucose metabolism in vitro and in vivo. The further mechanism(s) will be investigated in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:48:53Z (GMT). No. of bitstreams: 1 ntu-104-R02447001-1.pdf: 3118744 bytes, checksum: fbe6d6a98a6b2ca62539a26dc3c0b041 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 目錄 口試委員會審定書 i 誌謝 iv 中文摘要 vi Abstract viii Abbreviation Summary x Part 1: Introduction 1 1.1 Sources and exposure routes of acrolein 1 1.2 Metabolism and toxicity of acrolein 2 1.3 The major energy consumption in skeletal muscle 3 Part 2: Aims 6 Part 3: Materials and Methods 7 3.1 Cell culture 7 3.2 Myogenic differentiation and acrolein (ACR) treatment 7 3.3 Estimation of cell viability 7 3.4 Protein extraction and Western blot analysis 8 3.5 Measurement of creatine kinase activity 9 3.6 Determination of glycogen content 9 3.7 Rotarod 10 3.8 Oral glucose tolerance test (OGTT) 10 3.9 Transient transfection 11 3.10 Animals 11 3.11 Muscle injured model 12 3.12 Membrane protein isolation 12 3.13 Glucose transport assay 13 3.14 Measurement of plasma insulin level 13 3.15 Statistics 14 Part 4: Results 15 4.1 Acrolein retards myogenic differentiation in C2C12 myoblastic cells 15 4.2 Phosphorylation of Akt is down-regulated by acrolein during myogenesis. …………………………………………………………………………..15 4.3 Acrolein effects on glucose transporter and glucose metabolic signalling in C2C12 myotubes. 16 4.4 Constitutive expression of Akt rescues the inhibitory effect of acrolein on GLUT4 in C2C12 myotubes. 17 4.5 Acrolein interferes skeletal muscle regeneration and function in vivo. 17 4.6 The influences of acrolein on the levels of blood glucose, plasma insulin and OGTT in male mice. 18 4.7 Acrolein impairs glycogen synthesis and glucose uptake, and increases the protein expression of 4-HNE in C2C12 myotubes. 19 Part 5: Discussion 21 Part 6: Conclusion 26 Part 7: References 27 Part 8: Figures and figure legends 36 Figure 1. Inhibitory effect of acrolein on myogenic differentiation in C2C12 cells. …………………………………………………………………………..36 Figure 2. Effects of acrolein on creatine kinase activity and protein expressions of myogenesis markers in C2C12 myoblasts. 38 Figure 3. Transfection with a constitutively active form of Akt rescues the inhibitory effect of acrolein by enhanced myotube formation, the activity of creatine kinase and myogenesis. 40 Figure 4. Effects of acrolein on GLUT4 recruitment and biosynthesis in C2C12 myotubes. 42 Figure 5. Acrolein interferes with glucose metabolic signals in C2C12 myotubes. …………………………………………………………………………..43 Figure 6. Overexpression of c.a. Akt ameliorates the inhibitory effect of acrolein on glucose transporter in myotubes. 44 Figure 7. Effects of acrolein on the levels of body weight, plasma insulin and blood glucose in 5-week-old male mice. 45 Figure 8. Effects of acrolein on the weight of soleus muscle and the latency on the rotarod after glycerol injury were treated with acrolein (2.5 or 5 mg/kg) in mice for 4 weeks. 46 Figure 9. Inhibitory effects of muscle regeneration after glycerol injury were exposed to 2.5 or 5 mg/kg acrolein in 5-week-old mice for 4 weeks. 47 Figure 10. Effects of acrolein on OGTT in male ICR mice with or without acrolein for 4 weeks. 48 Figure 11. Effects of acrolein on glucose uptake, glycogen content and protein expression of 4-HNE in differentiated myotubes. 49 | |
| dc.language.iso | en | |
| dc.title | 探討丙烯醛影響骨骼肌分化/再生及醣類代謝之機制 | zh_TW |
| dc.title | Acrolein Impairs Skeletal Muscle Myogenesis and Glucose Metabolism | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 許美鈴(Meei-Ling Sheu),姜至剛(Chih-Kang Chiang),楊榮森(Rong-Sen Yang) | |
| dc.subject.keyword | 丙烯醛,骨骼肌,肌肉生成,醣類代謝,肌纖維母細胞, | zh_TW |
| dc.subject.keyword | acrolein,skeletal muscle,myogenesis,glucose metabolism,myoblast,Akt,glucose transporter, | en |
| dc.relation.page | 49 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2015-07-15 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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