GLP-1RA及SGLT-2i是ADA和中华医学会糖尿病学分会推荐的新型降糖药物,具有低血糖风险小、兼具心血管保护及降低体重等代谢获益的特点。高尿酸血症是2型糖尿病的独立危险因素,在临床实践中,人们一直在关注预防SUA的升高。据估计,患者SUA...GLP-1RA及SGLT-2i是ADA和中华医学会糖尿病学分会推荐的新型降糖药物,具有低血糖风险小、兼具心血管保护及降低体重等代谢获益的特点。高尿酸血症是2型糖尿病的独立危险因素,在临床实践中,人们一直在关注预防SUA的升高。据估计,患者SUA每升高1 mg/dl,发生T2DM的风险就会增加17%。国内外学者研究结果提示SGLT-2i能兼顾降糖的同时降低SUA水平;最近国外研究显示GLP-1RA还可以降低SUA水平,但仍存在矛盾。国内学者对此研究报告甚少。还需要更多的研究填补此领域的空白,为更好地预防2型糖尿的发生及发展作出贡献。GLP-1RA and SGLT-2i are new hypoglycemic drugs recommended by ADA and Diabetes Branch of Chinese Medical Association, which have the characteristics of low risk of hypoglycemia, metabolic benefits such as cardiovascular protection and weight reduction. Hyperuricemia is an independent risk factor for type 2 diabetes, and much attention has been paid to the prevention of elevated SUA in clinical practice. It is estimated that every 1 mg/dl elevation of patient SUA causes a 17% increase in the risk of developing T2DM. The results of domestic and foreign scholars suggest that SGLT-2i can reduce SUA level while lowering glucose;recent foreign studies show that GLP-1RA can also reduce SUA level, but there are still contradictions. Domestic scholars have few reports on this. More studies are needed to fill the gap in this field to contribute to better prevention of the occurrence and development of type 2 diabetes mellitus.展开更多
慢性心力衰竭(CHF)作为心血管疾病的终末阶段,其治疗策略面临多重挑战。钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂通过多维度机制改善心功能。大型临床试验已证实其在射血分数保留型(HFpEF)、合并糖尿病及肾功能不全等特殊心衰人群中的显...慢性心力衰竭(CHF)作为心血管疾病的终末阶段,其治疗策略面临多重挑战。钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂通过多维度机制改善心功能。大型临床试验已证实其在射血分数保留型(HFpEF)、合并糖尿病及肾功能不全等特殊心衰人群中的显著疗效。而益气活血疗法则通过调节气血循环、抑制TGF-β_(1)/FN通路、改善微循环及线粒体自噬等多靶点机制,在改善心功能指标和降低炎症因子方面展现独特优势。基于PubMed、Web of Science和Scopus等数据库的文献分析,本文综述了益气活血疗法与SGLT-2抑制剂联合应用在改善CHF预后中的协同效应。现有证据显示,联合方案可能通过机制互补进一步降低心血管死亡和住院风险,为CHF治疗提供新方向,但其在不同亚型患者中的疗效差异仍需深入研究。展开更多
SGLT-2抑制剂中芳基取代基是影响药物活性强弱的关键,本研究以恩格列净为先导化合物,对其芳基取代基进行修饰改造,设计合成4种新的SGLT-2抑制剂关键中间体,采用分子对接技术验证其设计合理性,经过酰氯化、亲电取代、亲核取代、还原四步...SGLT-2抑制剂中芳基取代基是影响药物活性强弱的关键,本研究以恩格列净为先导化合物,对其芳基取代基进行修饰改造,设计合成4种新的SGLT-2抑制剂关键中间体,采用分子对接技术验证其设计合理性,经过酰氯化、亲电取代、亲核取代、还原四步反应合成出产率最高可达90.2%的SGLT-2抑制剂关键中间体。最终结构均经1H-NMR、13C-NMR、HRMS联合验证。该路线具有操作简便、绿色高效、产率高的特点。为筛选出高活性SGLT-2抑制剂提供新思路。The aryl substituents in SGLT-2 inhibitors are the key factors affecting the strength of drug activity. In this study, empagliflozin was taken as the lead compound, and its aryl substituents were modified and transformed to design and synthesize four new key intermediates of SGLT-2 inhibitors. The rationality of the design was verified by molecular docking technology. The key intermediates of SGLT-2 inhibitors with a maximum yield of 90.2% were synthesized through four-step reactions including acyl chlorination, electrophilic substitution, nucleophilic substitution and reduction. The final structures were all jointly verified by 1H-NMR, 13C-NMR and HRMS. This synthetic route has the characteristics of simple operation, being environmentally friendly, highly efficient and having a high yield. It provides new ideas for screening out highly active SGLT-2 inhibitors.展开更多
目的 探讨ADAMTSL3(Adisintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3)在大鼠糖尿病肾病心肌纤维化中的作用机制和SGLT-2抑制剂(Sodium-glucose co-transporter 2)的应用效果。方法 SPF级雄性Wi...目的 探讨ADAMTSL3(Adisintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3)在大鼠糖尿病肾病心肌纤维化中的作用机制和SGLT-2抑制剂(Sodium-glucose co-transporter 2)的应用效果。方法 SPF级雄性Wistar大鼠28只经高脂高糖饲料喂养联合腹腔注射链脲佐菌素(SMZ)50 mg/kg进行糖尿病肾病造模,造模成功后分为模型组和治疗组,另设正常对照组大鼠,治疗组给予SGLT-2抑制剂(卡格列净10 mg/kg)灌胃。3组大鼠进行心脏B超动态分析心脏结构改变。对大鼠心肌组织进行病理染色、qRT-PCR、Western Blot检测ADAMTSL3基因表达水平,同时观察使用SGLT-2抑制剂后大鼠心肌的病理改变。结果 与正常对照组相比,模型组在左心室重量(LVM)、左心室收缩末壁厚度(LVPWs)、左心室短轴缩短率(LVFS%)、左射血分数(LVEF%)上的差异均有统计学意义(P<0.05)。与模型组相比,治疗组大鼠糖尿病肾病诱导心肌组织纤维化相对面积降低,以及在大鼠心肌纤维化中的Ⅰ型胶原蛋白(CollagenⅠ)、纤维连接蛋白(Fibronectin)表达降低(P<0.05)。与正常对照组相比,模型组大鼠心肌组织的ADAMTSL3蛋白表达显著增加;与模型组相比,治疗组大鼠心肌组织的ADAMTSL3蛋白表达显著降低(P<0.05)。与正常对照组相比,模型组中衰老标志物p-p53、p21、p16表达水平升高;与模型组相比,治疗组p-p53、p16表达水平均降低,差异有统计学意义(P<0.05)。结论 ADAMTSL3表达与纤维化相关,因此ADAMTSL3参与促进糖尿病肾病大鼠心肌纤维化,SGLT-2抑制剂治疗可逆转其心肌纤维化病变。展开更多
文摘GLP-1RA及SGLT-2i是ADA和中华医学会糖尿病学分会推荐的新型降糖药物,具有低血糖风险小、兼具心血管保护及降低体重等代谢获益的特点。高尿酸血症是2型糖尿病的独立危险因素,在临床实践中,人们一直在关注预防SUA的升高。据估计,患者SUA每升高1 mg/dl,发生T2DM的风险就会增加17%。国内外学者研究结果提示SGLT-2i能兼顾降糖的同时降低SUA水平;最近国外研究显示GLP-1RA还可以降低SUA水平,但仍存在矛盾。国内学者对此研究报告甚少。还需要更多的研究填补此领域的空白,为更好地预防2型糖尿的发生及发展作出贡献。GLP-1RA and SGLT-2i are new hypoglycemic drugs recommended by ADA and Diabetes Branch of Chinese Medical Association, which have the characteristics of low risk of hypoglycemia, metabolic benefits such as cardiovascular protection and weight reduction. Hyperuricemia is an independent risk factor for type 2 diabetes, and much attention has been paid to the prevention of elevated SUA in clinical practice. It is estimated that every 1 mg/dl elevation of patient SUA causes a 17% increase in the risk of developing T2DM. The results of domestic and foreign scholars suggest that SGLT-2i can reduce SUA level while lowering glucose;recent foreign studies show that GLP-1RA can also reduce SUA level, but there are still contradictions. Domestic scholars have few reports on this. More studies are needed to fill the gap in this field to contribute to better prevention of the occurrence and development of type 2 diabetes mellitus.
文摘慢性心力衰竭(CHF)作为心血管疾病的终末阶段,其治疗策略面临多重挑战。钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂通过多维度机制改善心功能。大型临床试验已证实其在射血分数保留型(HFpEF)、合并糖尿病及肾功能不全等特殊心衰人群中的显著疗效。而益气活血疗法则通过调节气血循环、抑制TGF-β_(1)/FN通路、改善微循环及线粒体自噬等多靶点机制,在改善心功能指标和降低炎症因子方面展现独特优势。基于PubMed、Web of Science和Scopus等数据库的文献分析,本文综述了益气活血疗法与SGLT-2抑制剂联合应用在改善CHF预后中的协同效应。现有证据显示,联合方案可能通过机制互补进一步降低心血管死亡和住院风险,为CHF治疗提供新方向,但其在不同亚型患者中的疗效差异仍需深入研究。
文摘SGLT-2抑制剂中芳基取代基是影响药物活性强弱的关键,本研究以恩格列净为先导化合物,对其芳基取代基进行修饰改造,设计合成4种新的SGLT-2抑制剂关键中间体,采用分子对接技术验证其设计合理性,经过酰氯化、亲电取代、亲核取代、还原四步反应合成出产率最高可达90.2%的SGLT-2抑制剂关键中间体。最终结构均经1H-NMR、13C-NMR、HRMS联合验证。该路线具有操作简便、绿色高效、产率高的特点。为筛选出高活性SGLT-2抑制剂提供新思路。The aryl substituents in SGLT-2 inhibitors are the key factors affecting the strength of drug activity. In this study, empagliflozin was taken as the lead compound, and its aryl substituents were modified and transformed to design and synthesize four new key intermediates of SGLT-2 inhibitors. The rationality of the design was verified by molecular docking technology. The key intermediates of SGLT-2 inhibitors with a maximum yield of 90.2% were synthesized through four-step reactions including acyl chlorination, electrophilic substitution, nucleophilic substitution and reduction. The final structures were all jointly verified by 1H-NMR, 13C-NMR and HRMS. This synthetic route has the characteristics of simple operation, being environmentally friendly, highly efficient and having a high yield. It provides new ideas for screening out highly active SGLT-2 inhibitors.
文摘目的 探讨ADAMTSL3(Adisintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3)在大鼠糖尿病肾病心肌纤维化中的作用机制和SGLT-2抑制剂(Sodium-glucose co-transporter 2)的应用效果。方法 SPF级雄性Wistar大鼠28只经高脂高糖饲料喂养联合腹腔注射链脲佐菌素(SMZ)50 mg/kg进行糖尿病肾病造模,造模成功后分为模型组和治疗组,另设正常对照组大鼠,治疗组给予SGLT-2抑制剂(卡格列净10 mg/kg)灌胃。3组大鼠进行心脏B超动态分析心脏结构改变。对大鼠心肌组织进行病理染色、qRT-PCR、Western Blot检测ADAMTSL3基因表达水平,同时观察使用SGLT-2抑制剂后大鼠心肌的病理改变。结果 与正常对照组相比,模型组在左心室重量(LVM)、左心室收缩末壁厚度(LVPWs)、左心室短轴缩短率(LVFS%)、左射血分数(LVEF%)上的差异均有统计学意义(P<0.05)。与模型组相比,治疗组大鼠糖尿病肾病诱导心肌组织纤维化相对面积降低,以及在大鼠心肌纤维化中的Ⅰ型胶原蛋白(CollagenⅠ)、纤维连接蛋白(Fibronectin)表达降低(P<0.05)。与正常对照组相比,模型组大鼠心肌组织的ADAMTSL3蛋白表达显著增加;与模型组相比,治疗组大鼠心肌组织的ADAMTSL3蛋白表达显著降低(P<0.05)。与正常对照组相比,模型组中衰老标志物p-p53、p21、p16表达水平升高;与模型组相比,治疗组p-p53、p16表达水平均降低,差异有统计学意义(P<0.05)。结论 ADAMTSL3表达与纤维化相关,因此ADAMTSL3参与促进糖尿病肾病大鼠心肌纤维化,SGLT-2抑制剂治疗可逆转其心肌纤维化病变。
