Heat shock protein beta-1 may be involved in regulating ferroptosis in cells.The expression of heat shock protein beta-1 is upregulated after stroke;however,the underlying mechanism of action of heat shock protein bet...Heat shock protein beta-1 may be involved in regulating ferroptosis in cells.The expression of heat shock protein beta-1 is upregulated after stroke;however,the underlying mechanism of action of heat shock protein beta-1 in cerebral ischemia/reperfusion injury remains unclear.Here,using both in vivo and in vitro models of ischemic injury-middle cerebral artery occlusion/reperfusion in C57BL/6J mice and oxygen-glucose deprivation/reoxygenation in BV-2 microglial cells-we observed that heat shock protein beta-1 overexpression significantly reduced infarct volume,mitigated neuronal loss,and improved neurological outcomes.Mechanistically,heat shock protein beta-1 attenuated lipid peroxidation,intracellular iron accumulation,and reactive oxygen species generation in microglia;this was accompanied by enhanced glutathione peroxidase 4 expression and suppressed nuclear factor-κB pathway activation.Notably,the pharmacological activation of nuclear factor-κB with phorbol 12-myristate 13-acetate reversed the protective effects of heat shock protein beta-1,confirming the functional relevance of this pathway.Together,our findings indicate that heat shock protein beta-1 exerts neuroprotective effects against cerebral ischemia/reperfusion injury by suppressing microglial ferroptosis and pro-inflammatory activation via modulation of the nuclear factor-κB/glutathione peroxidase 4 signaling axis.These findings establish heat shock protein beta-1 as a critical regulator of the nuclear factor-κB/glutathione peroxidase 4 axis in microglia,thereby offering a dual-targeted strategy to inhibit ferroptosis and inflammation in ischemic stroke.Importantly,our study highlights heat shock protein beta-1 as a promising therapeutic candidate for preserving neurological function following cerebral ischemic injury.展开更多
Objective To investigate the optimal dosage of pirfenidone for the treatment of pulmonary fibrosis induced by bleomycin in Wistar rats, and the alteration of expressions of transforming growth factor beta-1 （ TGF-β1...Objective To investigate the optimal dosage of pirfenidone for the treatment of pulmonary fibrosis induced by bleomycin in Wistar rats, and the alteration of expressions of transforming growth factor beta-1 （ TGF-β1 ）, tissue inhibitor of metalloproteinase-1 （ TIMP-1 ）, and matrix metalloproteinase-13 （ MMP-13 ） in lung tissue. Methods Male Wistar rats were endotracheally instilled with bleomycin or normal saline. Pirfenidone （25-800 mg · kg^-l · d^-1 ）, dexamethasone （3 mg/kg）, or 1% carboxymethylcellulose sodium were given daily by feed 2 days before instillation of bleomycin. Groups T7 and T14 were fed pirfenidone 50 mg · kg^-1 · d^-1 at 7 days or 14 daYs after bleomycin instillation. Lungs were harvested at 28 days after bleomycin instillation. Patholological changes in luffg tissues were evaluated with HE staining. Lung collagen was stained by sirius red and measured by content of hydroxypro- line. Expression of proteins of TGF-β1 TIMP-1, and MMP-13 were detected by Western blotting. Results At doses of 25, 50, and 100 mg· kg^- 1 · d ^- 1, pirfenidone had significant anti-fibrotic effects for bleomy- cin-induced rat pulmonary fibrosis, and these effects were most significantly attenuated at the dosage of 50 mg · kg^-1 ·d^ -1（ HE： P 〈 0. 01, P 〈 0.01, and P = 0.064; sirius red： P 〈0.05, P 〈 0.01, and P 〈 0.05 ; hydroxyproline： P = 0.595, P 〈 0.01, and P = 0.976）. Pirfenidone at a dosage of 50 mg · kg^- l · d^-1 inhibited protein expression of TGF-131 and TIMP-1 in lung tissue in the early phase （0.79 and 0.75 times of control group）, but had no effect on ex- nr^eelnn nf MMP-13. Conclusion Low dose pirfenidone, especially at dosage of 50 mg · kg^-1 · d^-1, has significant anti-fibrotic effects on bleomycin-induced rat pulmonary fibrosis. Pirfenidone partially inhibits the enhancement of the expression of TGF-131 and TIMP-β1 in lung tissue.展开更多
目的:分析选择性β_(1)受体阻滞剂治疗高血压的有效性和安全性,进一步更新选择性β_(1)受体阻滞剂的循证医学证据。方法:计算机检索中国知网(CNKI)、万方(Wanfang)、维普(VIP)、中国生物医学文献服务系统(SinoMed)、PubMed、Embase、Coc...目的:分析选择性β_(1)受体阻滞剂治疗高血压的有效性和安全性,进一步更新选择性β_(1)受体阻滞剂的循证医学证据。方法:计算机检索中国知网(CNKI)、万方(Wanfang)、维普(VIP)、中国生物医学文献服务系统(SinoMed)、PubMed、Embase、Cochrane Library,搜集关于选择性β_(1)受体阻滞剂治疗高血压患者的随机对照试验,检索时间均为建库至2024年5月。由两名研究者独立进行文献进行筛选、提取资料并评估纳入研究的偏倚风险,采用Cochrane偏倚风险工具对纳入研究进行质量评价,采用R4.4.0软件进行网状Meta分析,计算各结局指标的累积排序概率图下面积(the surface under the cumulative ranking,SUCRA)以比较不同干预措施的有效性与安全性。结果:SUCRA值排序结果显示,在降低收缩压方面:比索洛尔(79.33%)>阿替洛尔(57.46%)>美托洛尔缓释剂(51.12%)>美托洛尔速释剂(12.08%);降低舒张压方面:压比索洛尔(77.38%)>阿替洛尔(65.63%)>美托洛尔缓释剂(51.41%)>美托洛尔速释剂(5.57%);降低24 h动态收缩压方面:比索洛尔(92.44%)>美托洛尔速释剂(54.09%)>美托洛尔缓释剂(52.47%)>阿替洛尔(1.01%);降低24 h动态舒张压方面:比索洛尔(95.24%)>美托洛尔速释剂(52.52%)>美托洛尔缓释剂(46.82%)>阿替洛尔(5.4%);降低心率幅度方面:比索洛尔(97.88%)>阿替洛尔(66.98%)>美托洛尔缓释剂(22.72%)>美托洛尔速释剂(12.42%);降低24 h动态心率方面:美托洛尔缓释剂(69.49%)>比索洛尔(54.97%)>阿替洛尔(39.39%)>美托洛尔速释剂(36.17%);不良反应发生率方面:阿替洛尔(81.38%)>美托洛尔缓释剂(54.86%)>比索洛尔(48.97%)>美托洛尔速释剂(14.79%)。结论:比索洛尔、阿替洛尔、美托洛尔速释剂和美托洛尔缓释剂治疗高血压时均有明显的有效性,其中比索洛尔的有效性最为显著,而阿替洛尔的总不良反应发生率较高,临床使用时应给予关注。展开更多
基金“Dawn”Program of Shanghai Education Commission,No.22SG37(to PY)the National Natural Science Foundation of China,Nos.82371313(to PY),82401536(to YongxinZ).
文摘Heat shock protein beta-1 may be involved in regulating ferroptosis in cells.The expression of heat shock protein beta-1 is upregulated after stroke;however,the underlying mechanism of action of heat shock protein beta-1 in cerebral ischemia/reperfusion injury remains unclear.Here,using both in vivo and in vitro models of ischemic injury-middle cerebral artery occlusion/reperfusion in C57BL/6J mice and oxygen-glucose deprivation/reoxygenation in BV-2 microglial cells-we observed that heat shock protein beta-1 overexpression significantly reduced infarct volume,mitigated neuronal loss,and improved neurological outcomes.Mechanistically,heat shock protein beta-1 attenuated lipid peroxidation,intracellular iron accumulation,and reactive oxygen species generation in microglia;this was accompanied by enhanced glutathione peroxidase 4 expression and suppressed nuclear factor-κB pathway activation.Notably,the pharmacological activation of nuclear factor-κB with phorbol 12-myristate 13-acetate reversed the protective effects of heat shock protein beta-1,confirming the functional relevance of this pathway.Together,our findings indicate that heat shock protein beta-1 exerts neuroprotective effects against cerebral ischemia/reperfusion injury by suppressing microglial ferroptosis and pro-inflammatory activation via modulation of the nuclear factor-κB/glutathione peroxidase 4 signaling axis.These findings establish heat shock protein beta-1 as a critical regulator of the nuclear factor-κB/glutathione peroxidase 4 axis in microglia,thereby offering a dual-targeted strategy to inhibit ferroptosis and inflammation in ischemic stroke.Importantly,our study highlights heat shock protein beta-1 as a promising therapeutic candidate for preserving neurological function following cerebral ischemic injury.
基金Supported by National Ministry of Education Doctor Foundation of China(20020023045)
文摘Objective To investigate the optimal dosage of pirfenidone for the treatment of pulmonary fibrosis induced by bleomycin in Wistar rats, and the alteration of expressions of transforming growth factor beta-1 （ TGF-β1 ）, tissue inhibitor of metalloproteinase-1 （ TIMP-1 ）, and matrix metalloproteinase-13 （ MMP-13 ） in lung tissue. Methods Male Wistar rats were endotracheally instilled with bleomycin or normal saline. Pirfenidone （25-800 mg · kg^-l · d^-1 ）, dexamethasone （3 mg/kg）, or 1% carboxymethylcellulose sodium were given daily by feed 2 days before instillation of bleomycin. Groups T7 and T14 were fed pirfenidone 50 mg · kg^-1 · d^-1 at 7 days or 14 daYs after bleomycin instillation. Lungs were harvested at 28 days after bleomycin instillation. Patholological changes in luffg tissues were evaluated with HE staining. Lung collagen was stained by sirius red and measured by content of hydroxypro- line. Expression of proteins of TGF-β1 TIMP-1, and MMP-13 were detected by Western blotting. Results At doses of 25, 50, and 100 mg· kg^- 1 · d ^- 1, pirfenidone had significant anti-fibrotic effects for bleomy- cin-induced rat pulmonary fibrosis, and these effects were most significantly attenuated at the dosage of 50 mg · kg^-1 ·d^ -1（ HE： P 〈 0. 01, P 〈 0.01, and P = 0.064; sirius red： P 〈0.05, P 〈 0.01, and P 〈 0.05 ; hydroxyproline： P = 0.595, P 〈 0.01, and P = 0.976）. Pirfenidone at a dosage of 50 mg · kg^- l · d^-1 inhibited protein expression of TGF-131 and TIMP-1 in lung tissue in the early phase （0.79 and 0.75 times of control group）, but had no effect on ex- nr^eelnn nf MMP-13. Conclusion Low dose pirfenidone, especially at dosage of 50 mg · kg^-1 · d^-1, has significant anti-fibrotic effects on bleomycin-induced rat pulmonary fibrosis. Pirfenidone partially inhibits the enhancement of the expression of TGF-131 and TIMP-β1 in lung tissue.
文摘目的:分析选择性β_(1)受体阻滞剂治疗高血压的有效性和安全性,进一步更新选择性β_(1)受体阻滞剂的循证医学证据。方法:计算机检索中国知网(CNKI)、万方(Wanfang)、维普(VIP)、中国生物医学文献服务系统(SinoMed)、PubMed、Embase、Cochrane Library,搜集关于选择性β_(1)受体阻滞剂治疗高血压患者的随机对照试验,检索时间均为建库至2024年5月。由两名研究者独立进行文献进行筛选、提取资料并评估纳入研究的偏倚风险,采用Cochrane偏倚风险工具对纳入研究进行质量评价,采用R4.4.0软件进行网状Meta分析,计算各结局指标的累积排序概率图下面积(the surface under the cumulative ranking,SUCRA)以比较不同干预措施的有效性与安全性。结果:SUCRA值排序结果显示,在降低收缩压方面:比索洛尔(79.33%)>阿替洛尔(57.46%)>美托洛尔缓释剂(51.12%)>美托洛尔速释剂(12.08%);降低舒张压方面:压比索洛尔(77.38%)>阿替洛尔(65.63%)>美托洛尔缓释剂(51.41%)>美托洛尔速释剂(5.57%);降低24 h动态收缩压方面:比索洛尔(92.44%)>美托洛尔速释剂(54.09%)>美托洛尔缓释剂(52.47%)>阿替洛尔(1.01%);降低24 h动态舒张压方面:比索洛尔(95.24%)>美托洛尔速释剂(52.52%)>美托洛尔缓释剂(46.82%)>阿替洛尔(5.4%);降低心率幅度方面:比索洛尔(97.88%)>阿替洛尔(66.98%)>美托洛尔缓释剂(22.72%)>美托洛尔速释剂(12.42%);降低24 h动态心率方面:美托洛尔缓释剂(69.49%)>比索洛尔(54.97%)>阿替洛尔(39.39%)>美托洛尔速释剂(36.17%);不良反应发生率方面:阿替洛尔(81.38%)>美托洛尔缓释剂(54.86%)>比索洛尔(48.97%)>美托洛尔速释剂(14.79%)。结论:比索洛尔、阿替洛尔、美托洛尔速释剂和美托洛尔缓释剂治疗高血压时均有明显的有效性,其中比索洛尔的有效性最为显著,而阿替洛尔的总不良反应发生率较高,临床使用时应给予关注。
