目的:观察两类以前蛋白转化酶枯草溶菌素/kexin9型(PCSK9)为靶点的降脂治疗药物——小干扰RNA(small interfering RNA;siRNA)英克司兰与PCSK9单抗在我国急性冠状动脉综合征(acute coronary syndrome,ACS)患者中的疗效差异。方法:选取202...目的:观察两类以前蛋白转化酶枯草溶菌素/kexin9型(PCSK9)为靶点的降脂治疗药物——小干扰RNA(small interfering RNA;siRNA)英克司兰与PCSK9单抗在我国急性冠状动脉综合征(acute coronary syndrome,ACS)患者中的疗效差异。方法:选取2023年1月-2024年12月在天津市胸科医院心内科就诊且应用英克司兰或PCSK9单抗治疗的ACS患者87例,依据其用药种类不同,将其分为英克司兰组(n=34)和PCSK9单抗组(n=34)。收集分析真实世界中ACS患者治疗前及治疗后d 30,d 90,d 180时的低密度脂蛋白(low density lipoprotein,LDL)降幅、达标率及血脂谱,以评估治疗获益。通过标准差(standard deviation,SD)、平均连续变异度(average successive variability,ASV)、变异系数(coefficient of variation,CV)和校正独立于均值的变异性(variation independent of mean,VIM)评估两组的血脂变异性差异。结果:治疗后30 d时,英克司兰组和PCSK9单抗组患者LDL-C降幅(P=0.126)和达标率(P=0.300)无显著性差异;治疗后90 d及180 d时,英克司兰组LDL-C降幅(P=0.048;P=0.038)及达标率(P=0.006;P=0.010)均显著优于PCSK9单抗组。此外,与PCSK9单抗组相比,英克司兰组的血脂变异性更小(SD:0.16 vs 0.37,P=0.01;CV:19.15 vs 33.24,P=0.02;ASV:0.19 vs 0.48,P=0.01;VIM:18.57 vs 33.98,P=0.05)。结论:对ACS患者予以英克司兰治疗可同时实现短期和长期持续的LDL-C降低效果,提高达标率,且安全性良好。展开更多
PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑...PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑制剂可恢复LDLR再循环,降低LDL-C达60%~70%;2) 药物研发:单克隆抗体(Alirocumab、Evolocumab)显著降低MACE风险15%~20%,RNA干扰疗法(Inclisiran)实现半年一次给药,口服小分子(MK-0616)突破生物制剂限制;3) 多途径保护:除降脂外,PCSK9抑制剂通过抑制炎症(hs-CRP降低37%)、调节免疫(Treg/Th17平衡)及改善内皮功能(FMD提升12%)发挥协同效应。未来需聚焦长期安全性验证、成本效益优化及联合疗法开发,以全面提升ASCVD的防治水平。PCSK9 inhibitors have become a revolutionary strategy for the treatment of atherosclerotic cardiovascular disease (ASCVD) by targeting and regulating low-density lipoprotein receptor (LDLR) degradation. Based on the research progress at home and abroad, this paper systematically describes the following three aspects: 1) Molecular mechanism: PCSK9 binds to LDLR through catalytic domain, mediates lysosomal degradation, while inhibitors can restore LDLR recycling and reduce LDL-C by 60%~70%;2) Drug development: Monoclonal antibodies (Alirocumab, Evolocumab) significantly reduced the risk of MACE by 15%~20%, RNA interference therapy (Inclisiran) achieved semi-annual administration, and oral small molecules (MK0616) broke the limit of biologics;3) Multipathway protection: In addition to lipid-lowering, PCSK9 inhibitors play a synergistic role by inhibiting inflammation (37% reduction in hs-CRP), modulating immunity (Treg/Th17 balance), and improving endothelial function (12% increase in FMD). The future needs to focus on long-term safety validation, cost-effectiveness optimization, and combination therapy development to comprehensively improve the level of ASCVD prevention and treatment.展开更多
【目的】分析保山猪蛋白转化酶枯草素/酮蛋白4型(proprotein convertase subtilisin/kexin type 4,PCSK4)的分子特征、转录表达调控和蛋白功能。【方法】基于保山猪睾丸全转录组数据,通过生物信息学方法对PCSK4进行功能注释,并构建PCSK...【目的】分析保山猪蛋白转化酶枯草素/酮蛋白4型(proprotein convertase subtilisin/kexin type 4,PCSK4)的分子特征、转录表达调控和蛋白功能。【方法】基于保山猪睾丸全转录组数据,通过生物信息学方法对PCSK4进行功能注释,并构建PCSK4的长链非编码RNA和小RNA(miRNA)调控网络。【结果】PCSK4编码序列长2505 bp,编码834个氨基酸。蛋白质功能分析表明:PCSK4具有较多无规则卷曲和磷酸化位点。进化及邻近基因分析表明:PCSK4在进化过程中保守性较高。功能富集分析表明PCSK4与多个参与精子获能、受精、精卵识别的蛋白(如ACRBP、ACR、ADAM2等)存在互作关系,这些蛋白对应基因的表达量表明:PCSK4与MBTPS1、ACRBP、CDKN2A、DPY19L2显著相关。竞争性内源RNA调控网络分析表明5个miRNA可靶向调控PCSK4,功能注释显示其在生殖过程、蛋白质加工、受精等功能中发挥重要作用。【结论】本研究为进一步探讨PCSK4在保山猪精子发生过程,特别是受精与精子成熟阶段等重要生物学过程提供了基础资料。展开更多
文摘目的:观察两类以前蛋白转化酶枯草溶菌素/kexin9型(PCSK9)为靶点的降脂治疗药物——小干扰RNA(small interfering RNA;siRNA)英克司兰与PCSK9单抗在我国急性冠状动脉综合征(acute coronary syndrome,ACS)患者中的疗效差异。方法:选取2023年1月-2024年12月在天津市胸科医院心内科就诊且应用英克司兰或PCSK9单抗治疗的ACS患者87例,依据其用药种类不同,将其分为英克司兰组(n=34)和PCSK9单抗组(n=34)。收集分析真实世界中ACS患者治疗前及治疗后d 30,d 90,d 180时的低密度脂蛋白(low density lipoprotein,LDL)降幅、达标率及血脂谱,以评估治疗获益。通过标准差(standard deviation,SD)、平均连续变异度(average successive variability,ASV)、变异系数(coefficient of variation,CV)和校正独立于均值的变异性(variation independent of mean,VIM)评估两组的血脂变异性差异。结果:治疗后30 d时,英克司兰组和PCSK9单抗组患者LDL-C降幅(P=0.126)和达标率(P=0.300)无显著性差异;治疗后90 d及180 d时,英克司兰组LDL-C降幅(P=0.048;P=0.038)及达标率(P=0.006;P=0.010)均显著优于PCSK9单抗组。此外,与PCSK9单抗组相比,英克司兰组的血脂变异性更小(SD:0.16 vs 0.37,P=0.01;CV:19.15 vs 33.24,P=0.02;ASV:0.19 vs 0.48,P=0.01;VIM:18.57 vs 33.98,P=0.05)。结论:对ACS患者予以英克司兰治疗可同时实现短期和长期持续的LDL-C降低效果,提高达标率,且安全性良好。
文摘PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑制剂可恢复LDLR再循环,降低LDL-C达60%~70%;2) 药物研发:单克隆抗体(Alirocumab、Evolocumab)显著降低MACE风险15%~20%,RNA干扰疗法(Inclisiran)实现半年一次给药,口服小分子(MK-0616)突破生物制剂限制;3) 多途径保护:除降脂外,PCSK9抑制剂通过抑制炎症(hs-CRP降低37%)、调节免疫(Treg/Th17平衡)及改善内皮功能(FMD提升12%)发挥协同效应。未来需聚焦长期安全性验证、成本效益优化及联合疗法开发,以全面提升ASCVD的防治水平。PCSK9 inhibitors have become a revolutionary strategy for the treatment of atherosclerotic cardiovascular disease (ASCVD) by targeting and regulating low-density lipoprotein receptor (LDLR) degradation. Based on the research progress at home and abroad, this paper systematically describes the following three aspects: 1) Molecular mechanism: PCSK9 binds to LDLR through catalytic domain, mediates lysosomal degradation, while inhibitors can restore LDLR recycling and reduce LDL-C by 60%~70%;2) Drug development: Monoclonal antibodies (Alirocumab, Evolocumab) significantly reduced the risk of MACE by 15%~20%, RNA interference therapy (Inclisiran) achieved semi-annual administration, and oral small molecules (MK0616) broke the limit of biologics;3) Multipathway protection: In addition to lipid-lowering, PCSK9 inhibitors play a synergistic role by inhibiting inflammation (37% reduction in hs-CRP), modulating immunity (Treg/Th17 balance), and improving endothelial function (12% increase in FMD). The future needs to focus on long-term safety validation, cost-effectiveness optimization, and combination therapy development to comprehensively improve the level of ASCVD prevention and treatment.
