Renal cell carcinoma(RCC)is a challenging urologic malignancy characterized by its aggressive nature,including invasion,metastasis,and treatment resistance.To explore multi-targeted therapies,we established an advance...Renal cell carcinoma(RCC)is a challenging urologic malignancy characterized by its aggressive nature,including invasion,metastasis,and treatment resistance.To explore multi-targeted therapies,we established an advanced clear cell renal cell carcinoma(cc RCC)model via orthotopic tumor transplantation in mice,and established another model simulating post-surgical recurrence by performing radical nephrectomy.We engineered a genetic circuit to reprogram the host liver as a bioreactor,enabling the production and delivery of in vivo self-assembled si RNAs(IVSA-si RNAs)for co-targeting VEGFR2 and m TOR.The efficacy and toxicity of this IVSA-si RNA system were evaluated and compared with the combination therapy of sunitinib and everolimus.In the established models,the combination therapy of sunitinib and everolimus showed efficacy but induced severe adverse effects.In contrast,IVSA-si RNAs potently silenced VEGFR2 and m TOR expression,achieving therapeutic effects in both advanced and radical nephrectomy cc RCC models without discernible toxicity.展开更多
目的:研究有氧运动对2型糖尿病大鼠肾脏VEGF-A、VEGFR2蛋白表达的影响,并对其可能机制进行探讨。方法:通过高糖高脂饲喂5周加低剂量腹腔注射STZ复制2型糖尿病大鼠模型,7周后成模SD大鼠被随机分为糖尿病安静组和糖尿病运动组,另设正常对...目的:研究有氧运动对2型糖尿病大鼠肾脏VEGF-A、VEGFR2蛋白表达的影响,并对其可能机制进行探讨。方法:通过高糖高脂饲喂5周加低剂量腹腔注射STZ复制2型糖尿病大鼠模型,7周后成模SD大鼠被随机分为糖尿病安静组和糖尿病运动组,另设正常对照组。采用7周有氧游泳运动只对糖尿病运动组进行干预,实验末测定血糖、24 h UA、肾皮质VEGF-A及VEGFR2和p-VEGFR2蛋白的表达及光镜、电镜观察肾小球形态结构的变化。结果:光镜下糖尿病运动组大鼠肾小球增大不明显,毛细血管袢大多数开放,球囊壁渗出、粘连等现象较糖尿病安静组明显改善;基底膜无明显增厚,足突融合等现象较糖尿病安静组均有所减轻;血糖浓度和24 h UA排泄量降低显著(P<0.05或P<0.01);肾皮质VEGF-A、VEGFR2和p-VEGFR2蛋白的表达均较糖尿病安静组显著降低(P<0.05或P<0.01)。结论:运动对2型糖尿病大鼠肾脏有保护作用,其作用机制可能是通过其降低血糖及下调2型糖尿病状态下表达增加的VEGF-A和VEGFR2蛋白水平,而减轻大鼠肾脏损伤。展开更多
基金supported by grants from the National Natural Science Foundation of China(No.32022015,31871295 and 82373158)the Training Program of the Major Research Plan of the National Natural Science Foundation of China(No.92268120)+1 种基金the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study(No.SN-ZJU-SIAS-008)CAMS Innovation Fund for Medical Sciences(No.CIFMS-2021-I2M-5–015)。
文摘Renal cell carcinoma(RCC)is a challenging urologic malignancy characterized by its aggressive nature,including invasion,metastasis,and treatment resistance.To explore multi-targeted therapies,we established an advanced clear cell renal cell carcinoma(cc RCC)model via orthotopic tumor transplantation in mice,and established another model simulating post-surgical recurrence by performing radical nephrectomy.We engineered a genetic circuit to reprogram the host liver as a bioreactor,enabling the production and delivery of in vivo self-assembled si RNAs(IVSA-si RNAs)for co-targeting VEGFR2 and m TOR.The efficacy and toxicity of this IVSA-si RNA system were evaluated and compared with the combination therapy of sunitinib and everolimus.In the established models,the combination therapy of sunitinib and everolimus showed efficacy but induced severe adverse effects.In contrast,IVSA-si RNAs potently silenced VEGFR2 and m TOR expression,achieving therapeutic effects in both advanced and radical nephrectomy cc RCC models without discernible toxicity.
文摘目的:研究有氧运动对2型糖尿病大鼠肾脏VEGF-A、VEGFR2蛋白表达的影响,并对其可能机制进行探讨。方法:通过高糖高脂饲喂5周加低剂量腹腔注射STZ复制2型糖尿病大鼠模型,7周后成模SD大鼠被随机分为糖尿病安静组和糖尿病运动组,另设正常对照组。采用7周有氧游泳运动只对糖尿病运动组进行干预,实验末测定血糖、24 h UA、肾皮质VEGF-A及VEGFR2和p-VEGFR2蛋白的表达及光镜、电镜观察肾小球形态结构的变化。结果:光镜下糖尿病运动组大鼠肾小球增大不明显,毛细血管袢大多数开放,球囊壁渗出、粘连等现象较糖尿病安静组明显改善;基底膜无明显增厚,足突融合等现象较糖尿病安静组均有所减轻;血糖浓度和24 h UA排泄量降低显著(P<0.05或P<0.01);肾皮质VEGF-A、VEGFR2和p-VEGFR2蛋白的表达均较糖尿病安静组显著降低(P<0.05或P<0.01)。结论:运动对2型糖尿病大鼠肾脏有保护作用,其作用机制可能是通过其降低血糖及下调2型糖尿病状态下表达增加的VEGF-A和VEGFR2蛋白水平,而减轻大鼠肾脏损伤。
