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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82872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 | Yuan-Cheng Lin | en |
| dc.contributor.author | 林園宸 | zh_TW |
| dc.date.accessioned | 2022-11-25T08:01:26Z | - |
| dc.date.copyright | 2021-08-31 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-09 | |
| dc.identifier.citation | 1. R. Sartori, V. Romanello, and M. Sandri, 'Mechanisms of muscle atrophy and hypertrophy: implications in health and disease,' Nat Commun, vol. 12, no. 1, pp. 330, 2021. 2. W. J. Evans, and W. W. Campbell, 'Sarcopenia and age-related changes in body composition and functional capacity,' J Nutr, vol. 123, no. 2 Suppl, pp. 465-8, 1993. 3. J. E. Morley, A. M. Abbatecola, J. M. Argiles, V. Baracos, J. Bauer, S. Bhasin, T. Cederholm, A. J. S. Coats, S. R. Cummings, and W. J. Evans, 'Sarcopenia with limited mobility: an international consensus,' Journal of the American Medical Directors Association, vol. 12, no. 6, pp. 403-409, 2011. 4. R. H. Jacomo, T. R. Nascimento, M. Lucena da Siva, M. C. Salata, A. T. Alves, P. R. C. da Cruz, and J. Batista de Sousa, 'Exercise regimens other than pelvic floor muscle training cannot increase pelvic muscle strength-a systematic review,' J Bodyw Mov Ther, vol. 24, no. 4, pp. 568-574, 2020. 5. S. Cohen, J. A. Nathan, and A. L. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82872 | - |
| dc.description.abstract | "肌少症是由多種因素引起的過度肌肉蛋白質降解和肌肉細胞或組織死亡，使肌肉功能受損或質量喪失的現象。肌少症發生在許多疾病中，像是癌症、愛滋病、充血性心力衰竭及腎衰竭等。氯化三丁基錫(tributyltin chloride, TBTCL)是一種內分泌干擾物質，已知內分泌干擾物與肥胖、糖尿病等疾病有關，這些疾病也是肌少症的危險因子。另外，先前研究證實，某些內分泌干擾物與低出生體重有關，例如雙酚A、鎘等。我們過去的研究發現，TBTCL可經由抑制FoxO1訊號路徑來調控肌肉降解相關蛋白E3 ubiquitin ligases的表現，使肌肉萎縮與功能喪失。目前治療肌少症的方法主要以運動和飲食控制來延緩肌肉萎縮，但對於行動不便的患者（如：長期臥病在床的患者或老人）無法有效使用，且更棘手的是，目前臨床上仍然未具有FDA核可之藥物可治療肌少症，因此迫切需要可以改善肌肉萎縮的治療方法。近幾年來，許多醫學研究將已批准的藥物用於新的適應症，與新藥開發相比，老藥新用大幅減少藥物開發的成本和時間，提供了一個重要的優勢。目前有兩類GLP-1R agonists已經廣泛在臨床上治療第二型糖尿病，分別為exendin-4和liraglutide。先前的研究證實，給予exendin-4可以改善囓齒類動物由慢性腎臟病和dexamethasone引起的骨骼肌萎縮。因此本篇研究想得知，exendin-4和liraglutide這兩種GLP-1R agonists是否可以逆轉TBTCL所造成的肌肉萎縮的現象。在in vitro實驗中，首先，我們進行MTT及western blot assay檢測TBTCL誘導C2C12 myotube萎縮的最適濃度，找到以TBTCL 0.25及0.5 M給予myotube 24小時均造成凋亡及萎縮相關因子表達量顯著提升，我們使用對myotube毒性較低的TBTCL 0.25 M進行後續實驗。接著進行exendin-4及liraglutide不同劑量對C2C12 myotube存活率的影響，取各自不會造成myotube毒性的濃度exendin-4 50 nM及liraglutide 200 nM進行後續測試。接著，進行MTT assay及H E staining觀察在單獨給予TBTCL與加入exendin-4和liraglutide之後對C2C12 myotube的myotube存活率及cell morphology影響，顯示exendin-4和liraglutide可以改善TBTCL所造成C2C12 myotube存活率、數量及直徑減少的現象。此外，western blot的結果顯示，單獨給予TBTCL會造成C2C12 myotube中細胞凋亡相關蛋白、E3 ubiquitin ligases及myostatin表達量提升，顯示TBTCL會誘導骨骼肌細胞凋亡及萎縮，然而這些現象可以有效地藉由給予exendin-4和liraglutide改善。此外，TBTCL還會降低GLP-1R在myotube membrane中的含量，並且調節與凋亡和萎縮有關的GLP-1R下游分子，活化JNK、FoxO1並抑制ERK訊號路徑，並且這些反應皆被exendin-4顯著逆轉。在in vivo實驗中，我們發現TBTCL顯著增加小鼠血清中AST、ALT、BUN、creatinine以及P的濃度，這些指標表示腎臟、肝臟及骨骼肌受到損害，而給予exendin-4降低了這些指標的表現。也發現在骨骼肌中，TBTCL顯著降低了soleus的質量及後肢抓力，且exendin-4回復了小鼠的肌肉質量及力量。在soleus組織切片中也觀察到，exendin-4恢復了由TBTCL減少的CSA。接著我們使用western blot檢測soleus中的蛋白質表現，結果顯示TBTCL顯著升高凋亡及萎縮相關蛋白質表現，而這些表現被exendin-4降低。然而我們發現，在soleus中，給予TBTCL及exendin-4治療後AMPK反應皆活化，因此推測exendin-4的治療效果不是透過AMPK。此外，經由IHC發現了exendin-4會提升由TBTCL減弱在soleus中GLP-1R的表現量。最後，我們使用western blot檢測GLP-1R下游訊號因子在soleus中的表現，發現給予TBTCL會抑制ERK並活化JNK、FoxO1訊號路徑，而exendin-4逆轉了這些表現。因此，我們的結論得知，在in vitro及in vivo實驗中，exendin-4和liraglutide可能會透過活化GLP-1R及調節其下游訊號分子來改善由TBTCL誘導的骨骼肌萎縮。我們的研究提供了GLP-1R agonists在治療TBTCL誘導之肌肉萎縮中的潛在應用。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T08:01:26Z (GMT). No. of bitstreams: 1 U0001-0908202110150700.pdf: 3512415 bytes, checksum: bd118d591c46420de001c9f4c945b987 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "口試委員會審定書 i 誌謝 ii 中文摘要 iv Abstract vi List of abbreviation xi Part 1: Introduction 1 1.1 The severity of sarcopenia 1 1.2 Endocrine disruptor chemicals (EDCs) 2 1.3 The impact of tributyltin chloride (TBTCL) 2 1.4 Drug repurposing 4 1.5 Glucagon-like peptide-1 receptor (GLP-1R) agonists 4 1.6 Myogenesis 7 Part 2: Aims 10 Part 3: Materials and methods 11 3.1 Cell culture 11 3.2 Myogenic differentiation 11 3.3 Tributyltin chloride (TBTCL) and GLP-1 receptor agonists 11 3.4 Differentiated myotubes treatment with TBTCL, exendin-4 and liraglutide 12 3.5 Cell viability and the loss of myotube assay 12 3.6 The cell morphological analysis 13 3.7 Protein extraction and western blot analysis 14 3.8 Rodent animals 15 3.9 In vivo serum biochemical measurement 16 3.10 Muscle fatigue task and grip strength tests 16 3.11 Histological analysis of muscle sections 17 3.12 Immunohistochemistry (IHC) 17 3.13 Statistics 18 Part 4: Results 19 4.1 TBTCL induced myotube loss and atrophy in murine C2C12-derived myotubes. 19 4.2 Lower dose of GLP-1 receptor agonists exendin-4 or liraglutide alone would not change the protein expressions in C2C12 myotubes. 20 4.3 GLP-1 receptor agonists exendin-4 and liraglutide mitigated TBTCL-induced myotube viability decreasing and atrophic effect in C2C12 myotubes. 20 4.4 Exendin-4 and liraglutide ameliorated TBTCL-induced skeletal muscle C2C12 myotube apoptosis and atrophy may via GLP-1R activating. 21 4.5 Exendin-4 protected the abnormal index of serum biochemical profile from TBTCL-impaired male ICR mice. 22 4.6 Exendin-4 recovered protection of muscle mass and hind-limb grip strength in TBTCL-treated mice. 24 4.7 Exendin-4 restored the cross-sectional area in soleus muscle of TBTCL-induced skeletal muscle atrophy ICR mice. 24 4.8 Exendin-4 decreased TBTCL-induced skeletal muscle apoptosis-related protein expressions. 25 4.9 Exendin-4 downregulated the expression of E3 ubiquitin ligases induced by TBTCL in skeletal muscle of male ICR mice. 25 4.10 Exendin-4 increased the GLP-1R expression in soleus of atrophy mice reduced by TBTCL. 26 4.11 Effects of TBTCL and exendin-4-regulated signaling pathway in male ICR mice. 26 Part 5: Discussion 28 Part 6: Conclusion 35 Part 7: Figures and figure legends 36 Part 8: References 59" | |
| dc.language.iso | en | |
| dc.title | 類升糖素胜肽-1受體致效劑對內分泌干擾物三丁基錫引發的體外和體內肌肉萎縮模型的影響 | zh_TW |
| dc.title | Evaluation of the Effects of Glucagon-like Peptide-1 Receptor Agonists on Endocrine Disruptor Tributyltin-triggered Muscle Atrophy in vitro and in vivo | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 姜至剛(Hsin-Tsai Liu),洪冠予(Chih-Yang Tseng) | |
| dc.subject.keyword | 氯化三丁基錫,類升糖素胜肽-1受體致效劑,骨骼肌,肌肉萎縮,肌少症,凋亡, | zh_TW |
| dc.subject.keyword | tributyltin chloride,GLP-1R agonists,skeletal muscle,sarcopenia,muscle wasting,apoptosis, | en |
| dc.relation.page | 71 | |
| dc.identifier.doi | 10.6342/NTU202102196 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2021-08-09 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| dc.date.embargo-lift | 2023-09-01 | - |
| 顯示於系所單位： | 毒理學研究所 | |
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