Polycystic kidney diseases: From molecular discoveries to targeted therapeutic strategies

Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways. Received 8 August 2007; received after revision 19 September 2007; accepted 2 October 2007     

丹参酮IIA调控孕烷X受体的转录因子活性诱导肝细胞癌细胞对索拉非尼耐受

本文旨在探索丹参酮IIA对孕烷X受体(pregnane X receptor),PXR转录因子活性的影响,确定丹参酮IIA诱导肝细胞癌(Hepatocellular carcinoma,HCC)细胞对分子靶向药物索拉非尼等耐受的分子机制。使用系列浓度梯度的丹参酮IIA处理HCC细胞系MHCC97-H细胞,检测丹参酮IIA对PXR转录因子活性以及PXR下游耐药基因表达的影响。同时在裸鼠中利用MHCC97-H细胞建立HCC肿瘤模型,对动物给予丹参酮IIA后,再使用分子靶向药物索拉非尼对动物进行抗肿瘤治疗,确定丹参酮IIA对索拉非尼抗肿瘤作用的影响。利用液相色谱-质谱联用技术(LC-MS/MS)检测丹参酮IIA对MHCC97-H细胞及肿瘤组织中索拉非尼代谢与清除速率(半衰期)的影响。结果显示,丹参酮IIA能够在HCC细胞中诱导PXR的转录因子活性、上调PXR下游耐药相关基因CYP3A4以及MDR-1的表达、加速分子靶向药物索拉非尼在HCC细胞中的代谢与清除作用,最终诱导HCC细胞对分子靶向药物索拉非尼的耐受。这表明, 丹参酮IIA调控孕烷X受体的转录因子活性诱导肝细胞癌细胞对索拉非尼耐受。     

老年性痴呆的病因及其治疗药物的研究进展

老年性痴呆(Alzheimer’s Disease，AD)是一种渐次性的中枢神经退行性疾病，AD患在认知功能方面明显下降且伴有严重的行为异常现象，因此AD被认为是危害人类健康的一大综合症，由于AD具有多重分子病理，故对其病因和生化机理很难达到一致，本主要阐述一些人们普遍接受的病变机理，并介绍一些有效或潜在的治疗方案与药物作用机理。