TAZ激活剂衍生物对C2C12细胞肌分化的作用
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摘要
目的目的应用C2C12肌肉分化模型,探讨9种TAZ激活剂IBS008738衍生物对肌分化的作用。方法设计合成IBS008738衍生物,C2C12细胞按分化培养液中相应终浓度处理细胞,荧光显微镜下观察分化后肌管并行免疫染色,用Image J软件测量并计算融合指数。结果设计合成的9种衍生物经1H NMR确认结构及纯度,作用于分化C2C12细胞3d后,IBS008738衍生物中KI-1表现出了强于IBS008738的促肌分化的作用,显示肌管粗,数量增多,融合指数增高,且呈现剂量-效应关系。结论衍生物KI-1与IBS008738共同结构可能是IBS008738的促进肌肉分化的功能成分,对其强化可开发出更具效能的抗肌萎缩药物。
Objective To investigate the effect of 9 kinds of TAZ activator IBS008738 derivatives on muscle differentiation using C2 C12 cell model. Methods The IBS008738 derivatives were designed and synthesized, C2 C12 cells were treated by control or the compounds respectively at various final concentration, the myotubes were stained and observed under the fluorescence microscopy. The diameter of the myotubes was measured by Image J software and the fusion index was calculated. Results The structure and purity of 9 derivatives were confirmed by 1 H NMR. After acting on the differentiation of C2 C12 cells for three days, derivative KI-1 of IBS008738 showed stronger myodifferentiation than IBS008738, the diameter and the number of myotubes were increased, the fusion index was higher, and the effects are dosedependent. Conclusion Derivative KI-1 may be a functional component of IBS008738, could be used to develop more potent drugs against muscle atrophy.
Objective To investigate the effect of 9 kinds of TAZ activator IBS008738 derivatives on muscle differentiation using C2 C12 cell model. Methods The IBS008738 derivatives were designed and synthesized, C2 C12 cells were treated by control or the compounds respectively at various final concentration, the myotubes were stained and observed under the fluorescence microscopy. The diameter of the myotubes was measured by Image J software and the fusion index was calculated. Results The structure and purity of 9 derivatives were confirmed by 1 H NMR. After acting on the differentiation of C2 C12 cells for three days, derivative KI-1 of IBS008738 showed stronger myodifferentiation than IBS008738, the diameter and the number of myotubes were increased, the fusion index was higher, and the effects are dosedependent. Conclusion Derivative KI-1 may be a functional component of IBS008738, could be used to develop more potent drugs against muscle atrophy.
引文
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[2]Jeong H,Bae S,An SY,et al.TAZ as a novel enhancer of MyoD-mediated myogenic differentiation[J].FASEB J,2010,24(9):3310-3320.
[3]Jang EJ,Jeong H,Kang JO,et al.TM-25659 en-hances osteogenic differentiation and suppresses adipo-genic differentiation by modulating the transcriptional co-activator TAZ[J].Br J Pharmacol,2012,165(5):1584-1594.
[4]Kawano S,Maruyama J,Nagashima S,et al.A cell-based screening for TAZ activators identifies ethacridine,a widely used antiseptic and abortifacient,as a compound that promotes dephosphorylation of TAZ and inhibits adipogenesis in C3H10T1/2 cells[J].J Biochem,2015,158(5):413-423.
[5]Yang Z,Nakagawa K,Sarkar A,et al.Screening with a novel cellbased assay for TAZ activators identifies a compound that enhances myogenesis in C2C12 cells and facilitates muscle repair in the muscle injury model[J].Mol Cell Biol,2014,34(9):1607-1621.
[6]Kodaka M,Yang Z,Nakagawa K,et al.A new cell-based assay to evaluate myogenesis in mouse myoblast C2C12 cells.[J].Exp Cell Res,2015,336(2):171-181.
[7]Zou R,Li D,Wang G,et al.TAZ Activator Is Involved in IL-10-Mediated Muscle Responses in an Animal Model of Traumatic Brain Injury[J].Inflammation,2017,40(1):100-105.
[8]Menconi M,Gonnella P,Petkova V,et al.Dexamethasone and corticosterone induce similar,but not identical,muscle wasting responses in cultured L6 and C2C12 myotubes[J].J Cell Biochem,2008,105(2):353-564.
[9]Johnson R,Halder G.The two faces of Hippo:targeting the Hippo pathway for regenerative medicine and cancer treatment[J].Nat Rev Drug Discov,2014,13(1):63-79.
[10]Yin H,Que R,Liu C,et al.Survivin-targeted drug screening platform identifies a matrine derivative WM-127 as a potential therapeutics against hepatocellular carcinoma[J].Cancer Lett,2018,425:54-64.
[11]Inoue Y,Hibino M,Murata I,et al.A Nanocarrier Skin-Targeted Drug Delivery System using an Ascorbic Acid Derivative[J].Pharm Res,2017,35(1):1-8.