新型西格玛-1受体激动剂通过向亡和炎症通路来减轻脏缺血损伤
Akos R Toth1,2, Tamas Lakat1,2, Andras Budai3
1MTA-SE Lendület "Momentum" Diabetes Research Group, Budapest, Hungary.
Scientific reports
|November 14, 2025
概括
一种新的化合物VCC904125激活西格玛-1受体 (S1R) 来保护脏免受缺血-再输液损伤 (IRI). 这种新的治疗方法减少了损伤和炎症,为移植和急性损伤提供了希望.
科学领域:
- 腎臟病學 (nephrology) 是一種醫學.
- 药理学 药理学是指药理学的学科.
- 移植免疫学 移植免疫学
背景情况:
- 缺血-再输损伤 (IRI) 是急性损伤 (AKI) 的首要原因,其机制尚不清楚,治疗方法有限.
- 像fluvoxamine这样的西格玛-1受体 (S1R) 激动剂已经显示出对IRI和移植相关的移植损伤的保护作用.
- 开发具有减少副作用的向S1R调节器对于管理脏IRI至关重要.
研究的目的:
- 开发和评估一种新的S1R激动剂,VCC904125,用于减轻脏IRI,没有中枢神经系统的副作用.
- 在临床前模型中研究VCC904125对热和冷IRI的保护机制.
- 评估VCC904125在移植后改善结局的潜力.
主要方法:
- 一种具有有限血脑屏障透的新型S1R激动剂VCC904125被合成并测试在小鼠脏IRI模型中.
- 小鼠接受了VCC904125治疗,然后再进行脚和逆侧切除术,并在再输血后24小时和48小时进行评估.
- 一个ex vivo perfusion模型被用来评估VCC904125在移植冷藏期间的疗效.
主要成果:
- VCC904125显著降低了血液尿素 (BUN) 和血清肌水平,这是功能标志物.
- 基因组学分析和损伤分子-1 (KIM-1) 和中性纤维凝酶相关性脂卡林 (NGAL) 的表达得到了显著的改善VCC904125.
- 该化合物通过p53-Bax途径和调节的CaMKII-NF-κB信号传导抑制了亡,减少了促炎性细胞因子的产生.
- 在ex vivo模型中,VCC904125在患有冷性缺血的脏中显示出结构损伤的深刻改善.
结论:
- 通过VCC904125激活S1R,通过向关键的亡和炎症通路,有效地减轻脏IRI.
- VCC904125显示了热和冷IRI的治疗潜力,这表明它在损伤和移植中具有广泛的适用性.
- 这种新型化合物代表了一种有前途的治疗策略,用于改善移植结果和管理AKI.
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