Objective: To understand the relationship between C-erbB-2 and multidrug resistance (MDR) as well as its clini- cal significance. Methods: P-gp level was detected by flow cytometry and simultaneously to examine the C-...Objective: To understand the relationship between C-erbB-2 and multidrug resistance (MDR) as well as its clini- cal significance. Methods: P-gp level was detected by flow cytometry and simultaneously to examine the C-erbB-2 expression level by immunohistochemistry assay in the operating samples. Their relationship was analyzed from 59 cases with gastric carcinoma. Results: The P-gp positive expression was 38/59 (64.4%) cases with gastric carcinoma. The C-erbB-2 positive expression was 21/59 (35.6%) cases with gastric carcinoma. From the analysis of the P-gp and C-erbB-2 relationship, which was involving, range in the gastric carcinoma, that involving two or three sites were more than the site one, in the cases with C-erbB-2 negative. Compared this two groups, there was a significant difference (P = 0.026). When the C-erbB-2 was positive, the P-gp expression had a significant difference (P = 0.04) in comparing the III–IV stage (lymph node metastasis) with I–II stage (without lymph node metastasis). The tumor’s size, differentiation degree, ages and sex were not related to the C-erbB- 2 and P-gp expression. Conclusion: High level of P-gp expression was related to the C-erbB-2 positive expression in clinical III–IV stage patient with gastric carcinoma (lymph node metastasis). It suggested that the double positive patient might be a poor prognosis. However, when the C-erbB-2 was negative expression, the clinical staging (with lymph node metastasis) was not related to the P-gp expression in gastric carcinoma patients.展开更多
In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation...In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.展开更多
Background: Increased brain P-glycoprotein (P-gp) expression may play important role in resistance to antiseizure drugs. The present work aimed to overcome the drug resistance that develop due to overexpression of P-g...Background: Increased brain P-glycoprotein (P-gp) expression may play important role in resistance to antiseizure drugs. The present work aimed to overcome the drug resistance that develop due to overexpression of P-gp with subsequent increase in brain phenytoin level in epileptic rats, using either non-selective (indomethacin) or selective (celecoxib) cyclooxygenase inhibitors. Methods: Fifty-six adult male albino rats were randomly divided into seven groups. Epilepsy was induced using the lithium pilocarpine model. Rats received indomethacin (2.5 mg/kg) or celecoxib (20 mg/kg), either alone or combined with phenytoin (50 mg/kg). Seizures were evaluated using Racine score. Motor coordination was assessed using open field and rotarod tests. Phenytoin brain level was measured using High Performance Liquid Chromatography (HPLC), glutamate expression was measured using Enzyme Linked Immunosorbent Assay (ELISA), ATP Binding Cassette Subfamily B Member 1 (ABCB1) gene expression was assessed using Real Time-Polymerase Chain Reaction (RT-PCR), and immunohistochemical analysis was done for P-gp expression. Results: Phenytoin combination with either indomethacin or celecoxib had improved the Racine score, motor coordination on rotarod apparatus, and open field test results. Also, phenytoin combination with either indomethacin or celecoxib decreased brain glutamate level, ABCB1 gene and P-gp expression, and increased brain phenytoin level compared to treatment with phenytoin alone. This indicated that both P-gp inhibitors indomethacin and celecoxib, increased the level of phenytoin that reached the brain of rats. However, brain uptake of phenytoin was significantly enhanced using celecoxib rather than indomethacin (CI 95%, 17.092: 32.808, P-value Conclusion: Cyclooxygenase inhibition using either celecoxib or indomethacin resulted in downregulation of P-gp expression, with subsequent increase in brain phenytoin level in epileptic rats.展开更多
应用随机森林方法、开放源代码软件-CDK(Chemistry Development Kit)描述符与170个化合物的训练数据集[其中96个为磷糖蛋白(P-gp)底物],建立了P-gp底物的识别模型.研究了CDK描述符与P-gp底物识别的关系,结果表明,原子极化性和电荷偏面...应用随机森林方法、开放源代码软件-CDK(Chemistry Development Kit)描述符与170个化合物的训练数据集[其中96个为磷糖蛋白(P-gp)底物],建立了P-gp底物的识别模型.研究了CDK描述符与P-gp底物识别的关系,结果表明,原子极化性和电荷偏面积等分子属性对P-gp底物识别起到重要作用.该模型对训练集的预测正确率为99.42%;对外部测试集(42个化合物,其中24个为P-gp底物)的预测结果为P-gp底物、非底物及总测试集的识别正确率分别为87.50%,83.33%和85.71%.212个化合物数据集上的Leave-One-Out交叉验证识别正确率为77.4%.展开更多
基金the Zhejiang Medical and Health Science Foundation (No. 2005A09)
文摘Objective: To understand the relationship between C-erbB-2 and multidrug resistance (MDR) as well as its clini- cal significance. Methods: P-gp level was detected by flow cytometry and simultaneously to examine the C-erbB-2 expression level by immunohistochemistry assay in the operating samples. Their relationship was analyzed from 59 cases with gastric carcinoma. Results: The P-gp positive expression was 38/59 (64.4%) cases with gastric carcinoma. The C-erbB-2 positive expression was 21/59 (35.6%) cases with gastric carcinoma. From the analysis of the P-gp and C-erbB-2 relationship, which was involving, range in the gastric carcinoma, that involving two or three sites were more than the site one, in the cases with C-erbB-2 negative. Compared this two groups, there was a significant difference (P = 0.026). When the C-erbB-2 was positive, the P-gp expression had a significant difference (P = 0.04) in comparing the III–IV stage (lymph node metastasis) with I–II stage (without lymph node metastasis). The tumor’s size, differentiation degree, ages and sex were not related to the C-erbB- 2 and P-gp expression. Conclusion: High level of P-gp expression was related to the C-erbB-2 positive expression in clinical III–IV stage patient with gastric carcinoma (lymph node metastasis). It suggested that the double positive patient might be a poor prognosis. However, when the C-erbB-2 was negative expression, the clinical staging (with lymph node metastasis) was not related to the P-gp expression in gastric carcinoma patients.
基金supported by the National Key Research and Development Program of ChinaNos.2021YFC2 701800 and 2021YFC2 701805 (to QY)+2 种基金Open Research Fund of State Key Laboratory of Genetic EngineeringFudan UniversityNo.SKLGE-21 19 (to TXH and QY)
文摘In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.
文摘Background: Increased brain P-glycoprotein (P-gp) expression may play important role in resistance to antiseizure drugs. The present work aimed to overcome the drug resistance that develop due to overexpression of P-gp with subsequent increase in brain phenytoin level in epileptic rats, using either non-selective (indomethacin) or selective (celecoxib) cyclooxygenase inhibitors. Methods: Fifty-six adult male albino rats were randomly divided into seven groups. Epilepsy was induced using the lithium pilocarpine model. Rats received indomethacin (2.5 mg/kg) or celecoxib (20 mg/kg), either alone or combined with phenytoin (50 mg/kg). Seizures were evaluated using Racine score. Motor coordination was assessed using open field and rotarod tests. Phenytoin brain level was measured using High Performance Liquid Chromatography (HPLC), glutamate expression was measured using Enzyme Linked Immunosorbent Assay (ELISA), ATP Binding Cassette Subfamily B Member 1 (ABCB1) gene expression was assessed using Real Time-Polymerase Chain Reaction (RT-PCR), and immunohistochemical analysis was done for P-gp expression. Results: Phenytoin combination with either indomethacin or celecoxib had improved the Racine score, motor coordination on rotarod apparatus, and open field test results. Also, phenytoin combination with either indomethacin or celecoxib decreased brain glutamate level, ABCB1 gene and P-gp expression, and increased brain phenytoin level compared to treatment with phenytoin alone. This indicated that both P-gp inhibitors indomethacin and celecoxib, increased the level of phenytoin that reached the brain of rats. However, brain uptake of phenytoin was significantly enhanced using celecoxib rather than indomethacin (CI 95%, 17.092: 32.808, P-value Conclusion: Cyclooxygenase inhibition using either celecoxib or indomethacin resulted in downregulation of P-gp expression, with subsequent increase in brain phenytoin level in epileptic rats.
文摘应用随机森林方法、开放源代码软件-CDK(Chemistry Development Kit)描述符与170个化合物的训练数据集[其中96个为磷糖蛋白(P-gp)底物],建立了P-gp底物的识别模型.研究了CDK描述符与P-gp底物识别的关系,结果表明,原子极化性和电荷偏面积等分子属性对P-gp底物识别起到重要作用.该模型对训练集的预测正确率为99.42%;对外部测试集(42个化合物,其中24个为P-gp底物)的预测结果为P-gp底物、非底物及总测试集的识别正确率分别为87.50%,83.33%和85.71%.212个化合物数据集上的Leave-One-Out交叉验证识别正确率为77.4%.
