Anti-inflammatory effects of paeoniflorin caused by regulation of the hif1a/miR-210/caspase1/GSDMD signaling pathway in astrocytes: a novel strategy for hypoxia-induced brain injury in rats
Anti-inflammatory effects of paeoniflorin caused by regulation of the hif1a/miR-210/caspase1/GSDMD signaling pathway in astrocytes: a novel strategy for hypoxia-induced brain injury in rats
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DOI：
10.1080/08923973.2021.1924194
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发表时间：
2021-06-11
影响因子：
3.3
通讯作者：
Yu, Qin
中科院分区：
文献类型：
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作者：
Jiang, Zhenxiu;Chen, Jun;Yu, Qin
背景：缺氧引起的损伤是阻塞性睡眠呼吸暂停低通气综合征（OSAHS）的典型症状，是高血压、心力衰竭和中风等多种疾病的危险因素。然而，由于所涉及的机制难以捉摸，目前还没有针对缺氧引起的损伤或 OSAHS 的有效治疗方法。目的：本研究旨在评估芍药苷对缺氧损伤的影响并探讨其潜在机制。材料与方法：采用SD大鼠和CTX-TNA2细胞缺氧模型评估芍药苷的作用，并采用Western blots和RT-PCR检测hif1a、miR-210、caspase1和GSDMD的表达。进行质粒转染以探讨miR-210在芍药苷作用中的作用。结果：首先，我们证实缺氧会导致大鼠脑部严重神经元损伤和炎症加剧，导致 caspase1、IL1b 和 IL18 表达升高。此外，结果显示，在缺氧条件下，星形胶质细胞被激活，焦亡水平增加，这表明焦亡在缺氧引起的脑损伤中发挥着关键作用。此外，我们发现与对照组相比，芍药苷治疗改善了缺氧诱导的星形胶质细胞焦亡。此外，我们检测到芍药苷对星形胶质细胞的影响中 hif1a/miR-210 信号传导的激活。正如预期的那样，当暴露于缺氧时，星形胶质细胞中 hif1a 和 miR-210 的表达显着上调，而芍药苷治疗逆转了这些增强。转染miR-210模拟物后，芍药苷诱导的焦亡减弱被抑制，同时ROS水平增加，LDH释放增加，表明miR-210在星形胶质细胞焦亡中发挥关键作用。结论：我们的研究结果表明，芍药苷通过抑制 hif1a/miR-210/caspase1/GSDMD 信号传导改善缺氧诱导的星形胶质细胞焦亡，为缺氧损伤和 OSAHS 的治疗提供有力的证据。
Context: Hypoxia-induced injury is a classic symptom of obstructive sleep apnea hypopnea syndrome (OSAHS), which is a risk factor of various diseases, such as hypertension, heart failure and stroke. However, there is no effective therapy for hypoxia-induced injury or OSAHS due to the elusive mechanism involved. Objective: This study aimed to assess the effects of paeoniflorin on hypoxia-induced injury and explore the underlying mechanism. Materials and methods: Hypoxic models of SD rats and CTX-TNA2 cells were used to assess the effect of paeoniflorin, and the expressions of hif1a, miR-210, caspase1 and GSDMD were detected using western blots and RT-PCR. Plasmid transfection was performed to explore the role of miR-210 in the effect of paeoniflorin. Results: Firstly, we confirmed that hypoxia induced severe neuronal injury and an enhancement of inflammation in the rat brain, with elevated expression of caspase1, IL1b and IL18. In addition, the results showed an activation of astrocytes and an increased level of pyroptosis under hypoxic conditions, which suggested a critical role of pyroptosis in hypoxiainduced injury of the brain. Furthermore, we found that compared with the controls, paeoniflorin treatment improved hypoxia-induced pyroptosis in astrocytes. Moreover, we detected the activation of hif1a/miR-210 signaling in the effects of paeoniflorin on astrocytes. As expected, the expression of hif1a and miR-210 was significantly upregulated in astrocytes when exposed to hypoxia, while paeoniflorin treatment reversed these enhancements. After transfection of miR-210 mimics, the attenuation of pyroptosis induced by paeoniflorin was suppressed, which was accompanied by an increase of ROS levels, as well as LDH release, indicating a critical role of miR-210 in pyroptosis in astrocytes. Conclusions: Our findings demonstrated that paeoniflorin improved hypoxia-induced pyroptosis in astrocytes via depressing hif1a/miR-210/caspase1/GSDMD signaling, providing robust evidence for the treatment of hypoxic injury and OSAHS.