The Mechanism of Astragaloside IV in NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome-mediated Pyroptosis after Intracerebral Hemorrhage.

Honggang Wu, Shu Chen, Guoliang You, Bo Lei, Li Chen, Jiachuan Wu, Niandong Zheng, Chao You
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Abstract

Background: Intracerebral hemorrhage (ICH) is one of the most common subtypes of stroke.

Objectives: This study aimed to investigate the mechanism of Astragaloside IV (AS-IV) on inflammatory injury after ICH.

Methods: The ICH model was established by the injection of collagenase and treated with ASIV (20 mg/kg or 40 mg/kg). The neurological function, water content of the bilateral cerebral hemisphere and cerebellum, and pathological changes in brain tissue were assessed. The levels of interleukin-1 beta (IL-1β), IL-18, tumor necrosis factor-alpha, interferon-gamma, and IL-10 were detected by enzyme-linked immunosorbent assay. The levels of Kruppel-like factor 2 (KLF2), NOD-like receptor family pyrin domain containing 3 (NLRP3), GSDMD-N, and cleaved-caspase-1 were detected by reverse transcription-quantitative polymerase chain reaction and Western blot assay. The binding relationship between KLF2 and NLRP3 was verified by chromatin-immunoprecipitation and dual-luciferase assays. KLF2 inhibition or NLRP3 overexpression was achieved in mice to observe pathological changes.

Results: The decreased neurological function, increased water content, severe pathological damage, and inflammatory response were observed in mice after ICH, with increased levels of NLRP3/GSDMD-N/cleaved-caspase-1/IL-1β/IL-18 and poorly-expressed KLF2 in brain tissue. After AS-IV treatment, the neurological dysfunction, high brain water content, inflammatory response, and pyroptosis were alleviated, while KLF2 expression was increased. KLF2 bonded to the NLRP3 promoter region and inhibited its transcription. Down-regulation of KLF2 or upregulation of NLRP3 reversed the effect of AS-IV on inhibiting pyroptosis and reducing inflammatory injury in mice after ICH.

Conclusion: AS-IV inhibited NLRP3-mediated pyroptosis by promoting KLF2 expression and alleviated inflammatory injury in mice after ICH.

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黄芪皂苷 IV 在脑出血后 NOD 样受体家族含吡啶域 3 炎症体介导的脓毒症中的作用机制
背景:脑出血(ICH)是中风最常见的亚型之一:脑出血(ICH)是中风最常见的亚型之一:本研究旨在探讨黄芪皂苷 IV(AS-IV)对 ICH 后炎性损伤的作用机制:方法:通过注射胶原酶建立 ICH 模型,并用 ASIV(20 mg/kg 或 40 mg/kg)治疗。评估神经功能、双侧大脑半球和小脑的含水量以及脑组织的病理变化。酶联免疫吸附试验检测了白细胞介素-1β(IL-1β)、IL-18、肿瘤坏死因子-α、γ干扰素和IL-10的水平。反转录-定量聚合酶链反应和 Western 印迹法检测了 Kruppel 样因子 2(KLF2)、NOD 样受体家族含 pyrin 结构域 3(NLRP3)、GSDMD-N 和裂解-caspase-1 的水平。染色质免疫沉淀和双荧光素酶试验验证了 KLF2 和 NLRP3 之间的结合关系。在小鼠体内抑制 KLF2 或过表达 NLRP3,观察病理变化:结果:小鼠 ICH 后出现神经功能下降、含水量增加、严重病理损伤和炎症反应,脑组织中 NLRP3/GSDMD-N/cleaved-caspase-1/IL-1β/IL-18 水平升高,KLF2 表达低下。经过AS-IV治疗后,神经功能障碍、脑含水量高、炎症反应和热蛋白沉积等症状得到缓解,而KLF2的表达却有所增加。KLF2 与 NLRP3 启动子区域结合并抑制其转录。KLF2的下调或NLRP3的上调逆转了AS-IV在抑制小鼠ICH后的脓毒症和减轻炎症损伤方面的作用:结论:AS-IV通过促进KLF2的表达抑制了NLRP3介导的脓毒症,减轻了ICH后小鼠的炎症损伤。
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