Background Ciliopathies are a group of diseases associated with abnormal structure or function of primary cilia. Ciliopathies include polycystic kidney disease （PKD）, a pathology associated with vascular hypertensio...Background Ciliopathies are a group of diseases associated with abnormal structure or function of primary cilia. Ciliopathies include polycystic kidney disease （PKD）, a pathology associated with vascular hypertension. We previously showed that cilia length regulates cilia function, and cilia function is required for nitric oxide （NO） biosynthesis in endothelial cells. Because patients with PKD show abnormal sensory cilia function, the aim of our current study was to search for a targeted therapy focused on primary cilia, which we refer to as ＇cilio- therapy＇. Methods and Results In the present studies, our in vitro analyses refined fenoldopam as an equipotent and more specific dopa- minergic agonist to regulate cilia length and function. Our in vivo studies indicated that fenoldopam increased cilia length and serum NO thereby reducing blood pressure in a PKD mouse model. Our crossover, multicenter, double-blind and placebo-controlled clinical study further indicated that cilia-targeting therapy showed an overall reduction in mean arterial pressure in PKD patients. Conclusions Overall, our studies provide the first evidence of ciliotherapy as an innovative intervention in patients with abnormal primary cilia.展开更多
OBJECTIVE To investigate the putative role of the Notch1 receptor in cervical cancer carcinogenesis and progression. METHODS The expression of the Notch1 protein was analyzed by a Western-blotting approach in 40 cervi...OBJECTIVE To investigate the putative role of the Notch1 receptor in cervical cancer carcinogenesis and progression. METHODS The expression of the Notch1 protein was analyzed by a Western-blotting approach in 40 cervical cancer and 30 normal cervical tissues. Some tissues were examined using RT-PCR to determine mRNA levels. Celluar localization of the Notch1 protein in the paraffin-embedded cervical tissues was also analyzed by immunohistochemistry. RESULTS The Notch1 protein was detected in all 30 normal cervical tissues. In contrast, only 6 samples of 40 cervical cancer tissues showed Notch1 expression. The level of the Notch1 protein expression was significantly lower in cervical cancer tissues than that in normal tissue samples. In agreement with these observations, levels of Notch1 mRNA were found to be substantially down-regulated in cervical cancer tissues. In the immunohistochemistry staining assay, the Notch1 protein was shown to localize predominantly in the cytoplasm and nucleoli of the normal cervical squamous epithelium of the cervix, but no staining was observed in the cervical cancer cells. Notch1 expression was observed to correlate with the clinical disease stage, but there were no correlations with age, tumor size, grade or lymph node metastasis （P〉0.05）. The levels of Notch1 protein expression were significantly higher in early stages （Ⅰ-Ⅱa, 66.7%） compared to those in the advanced stages （Ⅱb～Ⅳ,12.6%）（P=0.001）. CONCLUSION Notch1 may play a role as a tumor suppressor in cervical tumorigenesis. Determination of Notch1 expression may be helpful for preoperative diagnosis and accuracy of staging. But its clinical use for cervical cancer requires further investigation.展开更多
Intracellular Ca2+homeostasis is essential for vascular function and blood pressure regulation.Because of their unique roles in regulating intracellular Ca2+concentration and vascular function,a novel class of non-sel...Intracellular Ca2+homeostasis is essential for vascular function and blood pressure regulation.Because of their unique roles in regulating intracellular Ca2+concentration and vascular function,a novel class of non-selective cation channels,called transient receptor potential(TRP)channels,have emerged at the frontier of hypertension research.Based on their role in vasculature function regulation,TRP channels can be divided into two functional subtypes:one that participates in vasoconstriction and one that participates in vasodilatation.A functional imbalance of these two subtypes of TRP channels may disturb intracellular calcium([Ca2+]i)homeostasis,and the consequent vascular dysfunction may contribute to the development of hypertension.The potential of these TRP channels as novel pharmacological targets for the treatment of human hypertension is of great interest.展开更多
文摘Background Ciliopathies are a group of diseases associated with abnormal structure or function of primary cilia. Ciliopathies include polycystic kidney disease （PKD）, a pathology associated with vascular hypertension. We previously showed that cilia length regulates cilia function, and cilia function is required for nitric oxide （NO） biosynthesis in endothelial cells. Because patients with PKD show abnormal sensory cilia function, the aim of our current study was to search for a targeted therapy focused on primary cilia, which we refer to as ＇cilio- therapy＇. Methods and Results In the present studies, our in vitro analyses refined fenoldopam as an equipotent and more specific dopa- minergic agonist to regulate cilia length and function. Our in vivo studies indicated that fenoldopam increased cilia length and serum NO thereby reducing blood pressure in a PKD mouse model. Our crossover, multicenter, double-blind and placebo-controlled clinical study further indicated that cilia-targeting therapy showed an overall reduction in mean arterial pressure in PKD patients. Conclusions Overall, our studies provide the first evidence of ciliotherapy as an innovative intervention in patients with abnormal primary cilia.
文摘OBJECTIVE To investigate the putative role of the Notch1 receptor in cervical cancer carcinogenesis and progression. METHODS The expression of the Notch1 protein was analyzed by a Western-blotting approach in 40 cervical cancer and 30 normal cervical tissues. Some tissues were examined using RT-PCR to determine mRNA levels. Celluar localization of the Notch1 protein in the paraffin-embedded cervical tissues was also analyzed by immunohistochemistry. RESULTS The Notch1 protein was detected in all 30 normal cervical tissues. In contrast, only 6 samples of 40 cervical cancer tissues showed Notch1 expression. The level of the Notch1 protein expression was significantly lower in cervical cancer tissues than that in normal tissue samples. In agreement with these observations, levels of Notch1 mRNA were found to be substantially down-regulated in cervical cancer tissues. In the immunohistochemistry staining assay, the Notch1 protein was shown to localize predominantly in the cytoplasm and nucleoli of the normal cervical squamous epithelium of the cervix, but no staining was observed in the cervical cancer cells. Notch1 expression was observed to correlate with the clinical disease stage, but there were no correlations with age, tumor size, grade or lymph node metastasis （P〉0.05）. The levels of Notch1 protein expression were significantly higher in early stages （Ⅰ-Ⅱa, 66.7%） compared to those in the advanced stages （Ⅱb～Ⅳ,12.6%）（P=0.001）. CONCLUSION Notch1 may play a role as a tumor suppressor in cervical tumorigenesis. Determination of Notch1 expression may be helpful for preoperative diagnosis and accuracy of staging. But its clinical use for cervical cancer requires further investigation.
文摘Intracellular Ca2+homeostasis is essential for vascular function and blood pressure regulation.Because of their unique roles in regulating intracellular Ca2+concentration and vascular function,a novel class of non-selective cation channels,called transient receptor potential(TRP)channels,have emerged at the frontier of hypertension research.Based on their role in vasculature function regulation,TRP channels can be divided into two functional subtypes:one that participates in vasoconstriction and one that participates in vasodilatation.A functional imbalance of these two subtypes of TRP channels may disturb intracellular calcium([Ca2+]i)homeostasis,and the consequent vascular dysfunction may contribute to the development of hypertension.The potential of these TRP channels as novel pharmacological targets for the treatment of human hypertension is of great interest.
