Objective:Inhibition of HIV-1 integrase is an important strategy for the treatment of HIV and AIDS.There-fore, HIV-1 integrase inhibitory activity of 3-aroyl-1,1-dioxo-1,4,2-benzodithiazines has been analyzed with dif...Objective:Inhibition of HIV-1 integrase is an important strategy for the treatment of HIV and AIDS.There-fore, HIV-1 integrase inhibitory activity of 3-aroyl-1,1-dioxo-1,4,2-benzodithiazines has been analyzed with different physicochemical parameters.Methods:In the present work,quantitative structure activity relationship studies were performed on a series of benzodithiazines as HIV-1 integrase inhibitors using the modeling software Win CAChe version 6.1.Multiple linear regression analysis was performed to derive quantitative structure activity relationship models which were further evaluated for statistical significance and predictive power by internal and external validation.Results:The best QSAR models were having good correlation coefficient (r) with low standard error of estimation(SEE) and cross validated square of correlation coefficient (q^2 ).The robustness of the models was checked by Y-randomization test and they were identified as good predictive models.The model for HIV integrase(wt) inhibitory activity of benzodithiazines suggest that the increase of dipole moment(Z) of molecules leads to reduce 3’processing and strand transfer inhibitory activity, substitution with high electro positive groups is conducive for the 3’processing inhibitory activity,and the increase in heat of formation is favorable for 3 -processing and strand transfer inhibitory activity.Conclusion: The model for HIV integrase(C65s) inhibitory activity of benzodithiazines suggest that the increase of dipole moment(X) of molecules leads to reduce 3’processing and strand transfer inhibitory activity,and the substitution with high hydrophobic groups is conducive for the 3’processing and strand transfer inhibitory.展开更多
周围神经病变是2型糖尿病最常见的并发症之一,常表现为感觉功能减退,部分病人还可出现神经病理性疼痛。虽然血脂异常和高血糖被认为是糖尿病周围神经病变的重要诱因,但炎症在其发病机制中的具体作用尚不清楚。该研究采用高脂高果糖饮食(...周围神经病变是2型糖尿病最常见的并发症之一,常表现为感觉功能减退,部分病人还可出现神经病理性疼痛。虽然血脂异常和高血糖被认为是糖尿病周围神经病变的重要诱因,但炎症在其发病机制中的具体作用尚不清楚。该研究采用高脂高果糖饮食(high-fat and high-fructose diet,HFHFD)诱导小鼠出现肥胖及糖尿病前期代谢改变,探索其对周围神经系统的影响。结果发现,HFHFD喂养3个月后小鼠出现持续性的热痛觉减退,而表皮神经纤维密度的显著下降则出现在第6个月。通过单细胞测序分析观察到,在轴突变性发生之前,CCR2^(+)巨噬细胞已大量浸润至HFHFD小鼠的坐骨神经中。这些巨噬细胞与神经压迫损伤模型中浸润的巨噬细胞在转录水平上具有高度相似性,表现出小胶质细胞样的基因表达特征,且此时尚未出现明显的轴突缺失或脱髓鞘现象。当通过遗传或药物方式阻断CCR2信号通路、抑制巨噬细胞的募集后,小鼠表现出更严重的热痛觉减退,且皮肤感觉神经纤维的丢失明显加速。条件性敲除巨噬细胞中表达的Lgals3(编码Galectin-3)基因,也加速了感觉神经轴突终末的变性。该研究表明,在2型糖尿病前期阶段,外周神经中的巨噬细胞通过分泌Galectin-3,发挥延缓感觉神经退变的保护作用。这提示增强并维持这种早期的神经保护性免疫反应,有望成为延缓甚至预防糖尿病周围神经病变发生的新策略。展开更多
文摘Objective:Inhibition of HIV-1 integrase is an important strategy for the treatment of HIV and AIDS.There-fore, HIV-1 integrase inhibitory activity of 3-aroyl-1,1-dioxo-1,4,2-benzodithiazines has been analyzed with different physicochemical parameters.Methods:In the present work,quantitative structure activity relationship studies were performed on a series of benzodithiazines as HIV-1 integrase inhibitors using the modeling software Win CAChe version 6.1.Multiple linear regression analysis was performed to derive quantitative structure activity relationship models which were further evaluated for statistical significance and predictive power by internal and external validation.Results:The best QSAR models were having good correlation coefficient (r) with low standard error of estimation(SEE) and cross validated square of correlation coefficient (q^2 ).The robustness of the models was checked by Y-randomization test and they were identified as good predictive models.The model for HIV integrase(wt) inhibitory activity of benzodithiazines suggest that the increase of dipole moment(Z) of molecules leads to reduce 3’processing and strand transfer inhibitory activity, substitution with high electro positive groups is conducive for the 3’processing inhibitory activity,and the increase in heat of formation is favorable for 3 -processing and strand transfer inhibitory activity.Conclusion: The model for HIV integrase(C65s) inhibitory activity of benzodithiazines suggest that the increase of dipole moment(X) of molecules leads to reduce 3’processing and strand transfer inhibitory activity,and the substitution with high hydrophobic groups is conducive for the 3’processing and strand transfer inhibitory.
文摘周围神经病变是2型糖尿病最常见的并发症之一,常表现为感觉功能减退,部分病人还可出现神经病理性疼痛。虽然血脂异常和高血糖被认为是糖尿病周围神经病变的重要诱因,但炎症在其发病机制中的具体作用尚不清楚。该研究采用高脂高果糖饮食(high-fat and high-fructose diet,HFHFD)诱导小鼠出现肥胖及糖尿病前期代谢改变,探索其对周围神经系统的影响。结果发现,HFHFD喂养3个月后小鼠出现持续性的热痛觉减退,而表皮神经纤维密度的显著下降则出现在第6个月。通过单细胞测序分析观察到,在轴突变性发生之前,CCR2^(+)巨噬细胞已大量浸润至HFHFD小鼠的坐骨神经中。这些巨噬细胞与神经压迫损伤模型中浸润的巨噬细胞在转录水平上具有高度相似性,表现出小胶质细胞样的基因表达特征,且此时尚未出现明显的轴突缺失或脱髓鞘现象。当通过遗传或药物方式阻断CCR2信号通路、抑制巨噬细胞的募集后,小鼠表现出更严重的热痛觉减退,且皮肤感觉神经纤维的丢失明显加速。条件性敲除巨噬细胞中表达的Lgals3(编码Galectin-3)基因,也加速了感觉神经轴突终末的变性。该研究表明,在2型糖尿病前期阶段,外周神经中的巨噬细胞通过分泌Galectin-3,发挥延缓感觉神经退变的保护作用。这提示增强并维持这种早期的神经保护性免疫反应,有望成为延缓甚至预防糖尿病周围神经病变发生的新策略。
