Life sciences · 2026
Chikusetsu saponin IVa mitigates septic cardiac injury by targeting DRP1 to suppress mitochondrial damage and NLRP3 inflammasome activation.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Tian Wen, Yu Zhi-Yong, Li Zhuo, Zheng Xu-Yang, Ding Yi-Di, Yu Deng-Hui, Hu Fei, Li Meng-Yuan, Yang Xiao-Fei, Shen Huan-Jun, Lian Jian-Qi
Аннотация
AIMS: Sepsis-induced myocardial injury represents a serious complication with limited treatment options. Chikusetsu saponin IVa (CHS), a triterpenoid saponin derived from Rhizoma Panacis japonica, exhibits potent anti-inflammatory and cardioprotective properties, positioning it as a promising candidate.
MATERIALS AND METHODS: To elucidate the therapeutic potential and mechanism of CHS in septic cardiac dysfunction, the effects of CHS administration on lipopolysaccharide (LPS, 40 mg/kg, i.p.) and cecal ligation and puncture (CLP)-induced septic murine models were evaluated through echocardiography and histological analyses. Network pharmacology and limited proteolysis-mass spectrometry (LiP-MS) were exploited to dissect the specific mechanisms and targets of CHS. Immunofluorescence, co-immunoprecipitation, and electron microscopy were performed to validate the effects of CHS on mitochondrial integrity, inflammasome assembly, and pyroptotic injury in LPS-ATP-stimulated cardiomyocytes.
KEY FINDINGS: CHS administration significantly mitigated LPS-induced cardiac injury and dysfunction of mice. CHS effectively inhibited NLRP3 upregulation, Caspase-1 activation, GSDMD cleavage, and subsequent pyroptosis both in vivo and in vitro. LiP-MS and microscale thermophoresis identified DRP1 as the direct binding protein of CHS. Cellular thermal shift assay and drug affinity responsive target stability assays further indicated that CHS improved the proteolytic and thermal stability of DRP1. CHS or DRP1 inhibitor (Mdivi1) blocked LPS-ATP-stimulated DRP1 phosphorylation, reduced mitochondrial fragmentation, and ROS overproduction. Consistently, CHS diminished LPS-ATP-induced NLRP3-TXNIP interaction and inflammasome assembly, thereby reducing cellular membrane rupture and pyroptotic cell death, whereas DRP1 overexpression exerted the opposite effect.
SIGNIFICANCE: CHS represents a promising therapeutic candidate for septic cardiomyopathy by targeting DRP1-mediated mitochondrial dynamics and the NLRP3 inflammasome.
MATERIALS AND METHODS: To elucidate the therapeutic potential and mechanism of CHS in septic cardiac dysfunction, the effects of CHS administration on lipopolysaccharide (LPS, 40 mg/kg, i.p.) and cecal ligation and puncture (CLP)-induced septic murine models were evaluated through echocardiography and histological analyses. Network pharmacology and limited proteolysis-mass spectrometry (LiP-MS) were exploited to dissect the specific mechanisms and targets of CHS. Immunofluorescence, co-immunoprecipitation, and electron microscopy were performed to validate the effects of CHS on mitochondrial integrity, inflammasome assembly, and pyroptotic injury in LPS-ATP-stimulated cardiomyocytes.
KEY FINDINGS: CHS administration significantly mitigated LPS-induced cardiac injury and dysfunction of mice. CHS effectively inhibited NLRP3 upregulation, Caspase-1 activation, GSDMD cleavage, and subsequent pyroptosis both in vivo and in vitro. LiP-MS and microscale thermophoresis identified DRP1 as the direct binding protein of CHS. Cellular thermal shift assay and drug affinity responsive target stability assays further indicated that CHS improved the proteolytic and thermal stability of DRP1. CHS or DRP1 inhibitor (Mdivi1) blocked LPS-ATP-stimulated DRP1 phosphorylation, reduced mitochondrial fragmentation, and ROS overproduction. Consistently, CHS diminished LPS-ATP-induced NLRP3-TXNIP interaction and inflammasome assembly, thereby reducing cellular membrane rupture and pyroptotic cell death, whereas DRP1 overexpression exerted the opposite effect.
SIGNIFICANCE: CHS represents a promising therapeutic candidate for septic cardiomyopathy by targeting DRP1-mediated mitochondrial dynamics and the NLRP3 inflammasome.