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塞拉斯衍生物通过调节信号来改善AIA大鼠的关节炎
Baixiong Huang1, Jerome P L Ng1, Dingqi Zhang1
1Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China.
概括
新的醇 (CEL) 衍生物COM5和COM6通过调节信号和未折叠蛋白反应 (UPR) 来表现出强大的抗关节炎作用. 这些衍生品的毒性明显低于CEL,为风湿性关节炎 (RA) 治疗提供了潜力.
科学领域:
- 药理学 药理学是指药理学的学科.
- 免疫学 免疫学 免疫学
- 药物发现 药物发现 药物发现
背景情况:
- (Ca2+) 信号在类风湿性关节炎 (RA) 发病过程中起作用.
- 塞拉斯 (CEL) 通过抑制质体/内质网膜Ca2+ ATPase (SERCA) 来抑制关节炎症状,但其临床使用因毒性而受到限制.
- 开发更安全,更有效的CEL衍生品对于RA治疗至关重要.
研究的目的:
- 开发和评估具有改善抗关节炎特性的新型CEL衍生物.
- 为了确定CEL衍生物的增强疗效和降低毒性潜在的RA治疗.
主要方法:
- 通过修改C29-炭酸部分,合成了6种CEL衍生物.
- 在体外查包括细胞毒性,细胞内Ca2+动态,自诱导和抗炎作用.
- 在辅助剂诱导关节炎 (AIA) 鼠的体内研究评估了通过3'RNA测序的治疗疗效和机制. 还进行了药理动力学和急性毒性研究.
主要成果:
- COM5和COM6在体外显示出低细胞毒性,强烈的抗炎作用和调节的Ca2+动态.
- 这两种衍生物都有效地抑制了AIA大鼠的关节炎症状,骨质侵蚀和促炎细胞因子,类似于CEL.
- COM5和COM6显著降低了急性毒性 (≥10倍低于CEL) 和调节了Ca2+相关的未折叠蛋白响应 (UPR) 途径.
结论:
- 结构修饰的CEL衍生物COM5和COM6具有强大的抗关节炎作用.
- 这些衍生物调节与Ca2+相关的UPR通路,提供与CEL相似的疗效,毒性大大降低.
- COM5和COM6代表了开发新型类风湿性关节炎治疗药物的有前途的候选人.
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