Background: PAI-1 (plasminogen activator inhibitor-1) is a powerful regulator of fibrinolysis and plasma level is high in type 2 diabetes and cardio-vascular disease, which is determined by genetic polymorphisms in PA...Background: PAI-1 (plasminogen activator inhibitor-1) is a powerful regulator of fibrinolysis and plasma level is high in type 2 diabetes and cardio-vascular disease, which is determined by genetic polymorphisms in PAI-1 gene and environmental factors. The aim of the study was to examine the determinants of plasma PAI-1 Ag level among type 2 diabetes patients. Methods: 491 Tunisian type 2 diabetes patients had clinical evaluation (weight, high, BMI, Waist Circumference), laboratory investigations including FBG Hb1Ac, cholesterol, triglyceride;HDL-cholesterol was done;plasma PAI-1 antigen level was done with ELISA;−675 4G/5G and −844 G/A polymorphisms of PAI-1 gene was done by PCR-ASA and PCR-RFLP respectively. Results: The mean age for our patients was 58.3 ± 10.5 years;sex-ratio = 0.92;mean PAI-1 level was 34.6 ± 21.3 ng/ml. We didn’t find correlation between PAI-1 level and BMI, but we have found significant correlation between PAI-1 and waist circumference (p = 0.032), most enhanced in men (P = 0.002), T2D patients who have FBG > 11 mmol/l had PAI-1 Ag level higher than those who have FBG P = 0.034), but no difference found between T2D with high Hb1Ac > 8% and those with Hb1Ac < 8%, significant correlation was seen between PAI-1 level and LDL-cholesterol (P = 0.05), high correlation between PAI-1 Ag level and −675 4G/5G polymorphism genotype was seen, 4G/4G carriers had the highest PAI-1 level, 4G/5G had intermediary level and 5G/5G had the lowest level (P −844G/A polymorphism genotypes. Using multiple variable linear regression analysis, the independent factor associated with plasma PAI-1 level was −675 4G/5G polymorphism (regression coefficient β = 4.6, P Conclusion: the present study identifies −675 4G/5G not −844 G/A polymorphism of PAI gene as the principal determinant of plasma PAI-1 level in Tunisian T2D patients, the android fat distribution, dyslipidemia and hyperglycemia play a modest role in this variation.展开更多
Urokinase-type plasminogen activator （uPA） plays a crucial role in the regulation of plasminogen activation, tumor cell adhesion and migration. The inhibition of uPA activity is a promising mechanism for anti-cancer...Urokinase-type plasminogen activator （uPA） plays a crucial role in the regulation of plasminogen activation, tumor cell adhesion and migration. The inhibition of uPA activity is a promising mechanism for anti-cancer therapy. Most current uPA inhibitors employ a highly basic group （either amidine or guanidine group） to target the S1 pocket of uPA active site, which leads to poor oral bioavailability. Here we study the possibility of using less basic 2-aminobenzothiazole （ABT） as S1 pocket binding group. We report the crystal structures of uPA complexes with ABT or 2-amino-benzothiazole-6-carboxylic acid ethyl ester （ABTCE）. The inhibitory constants of these two inhibitors were measured by a chromogenic competitive assay, and it was found that ABTCE is a better inhibitor for uPA （Ki = 656 μM） than ABT （Ki = 5.03 mM）. This work shows that 2-amniobenzothiazole can be used as P1 group which may have better oral bioavailability than the commonly used amidine or guanidine group. We also found the ethyl ester group occupies the characteristic oxyanion hole and contacts to uPA 37- and 60-loops. Such work provides structural information for further improvements of potency and selectivity of this new class of uPA inhibitor.展开更多
Objective: To observe the effect of different dosages of ligustrazine (LG) on the level of plasminogen activator inhibitor-1 (PAI-1) activity in patients with type 2 diabetes mellitus. Methods: Ninety cases of type 2 ...Objective: To observe the effect of different dosages of ligustrazine (LG) on the level of plasminogen activator inhibitor-1 (PAI-1) activity in patients with type 2 diabetes mellitus. Methods: Ninety cases of type 2 diabetes mellitus inpatients were selected, and randomly divided into LG small dosage group (SDG), LG large dosage group (LDG) and control group. The 120 mg LG, 400 mg LG and normal saline 250 ml were given through intravenous dripping respectively, once daily, 20 days as one treatment course. Before and after treatment, all the patients had their fasting blood taken for PAI-1 and tissue plasminogen activator (t-PA) assessment test to perform the comparative study. Results:Seventy-three out of the 90 patients completed the observation course, the PAI-1 activity of three groups after treatment all lowered compared with that before treatment, and the difference between groups was also significant (all P<0. 01). After treatment the PAI-1 level of SDG and LDG of LG were all markedly lowered (all P<0. 01), the LDG's lowering was more evident than that of SDG, and comparison between these two groups of patients showed significant difference (P<0. 01). Although in the control group there was some difference between before and after treatment, it was not so significant like the above-mentioned two groups (P = 0. 0140). No adverse reaction occurred in the 3 groups during the observation period. Conclusion:LG could safely and effectively lower type 2 diabetes mellitus patient's plasma PAI-1 activity level, and LDG of LG proved to be particularly effective.展开更多
Objective:To explore the relationship between serum plasminogen activator inhibitor(PAI-1)level and Type 2 Diabetes Mellitus(T2DM)accompanied by overweight or obesity by observing not only the changes of PAI-1 level i...Objective:To explore the relationship between serum plasminogen activator inhibitor(PAI-1)level and Type 2 Diabetes Mellitus(T2DM)accompanied by overweight or obesity by observing not only the changes of PAI-1 level in T2DM patients with overweight or obesity,but also glucose and lipid metabolism related indicators,the changes of the inflammatory cytokines secreted by adipocytes,and then making an analysis on the correlation to PAI-1.Methods:36 cases of healthy examinees were selected as normal control group(NC group),and the experimental group can be divided into T2DM group(54 cases),Overweight/Obesity group(35 cases)and T2DM+Overweight/Obesity group(48 cases).Glucose and lipid metabolism related indicators such as fasting blood glucose(FBG),triglyceride(TG),total cholesterol(TC),low density lipoprotein cholesterol(LDL-C),glycated hemoglobin(HbA1c),fasting insulin(FINS),insulin resistance index(IR),body weight index(BMI)and inflammatory cytokines interleukin-6(IL-6),tumor necrosis factor(TNF-α)and PAI-1 were observed and compared between groups,and then made an analysis to explore the correlation of these factors to PAI-1.Results:(1)Compared with NC group,the levels of FBG,HbA1c,FINS and IR were increased in T2DM group,and the difference was of statistical significance.However,there was no statistically significant difference in TG,TC,LDL-C and BMI between NC group and T2DM group;the levels of FINS,IR,TG,LDL-C,TC and BMI were elevated in Overweight/Obesity group,and the difference was of statistical significance.However,there was no statistically significant difference in FBG and HbA1c;the levels of FBG,HbA1c,FINS,IR,TG,LDL-C,TC and BMI were up-regulated in T2DM+Overweight/Obesity group,and the difference was of statistical significance.Compared with T2DM group,the levels of TG,TC,LDL-C and BMI were increased in Overweight/Obesity group,and the difference was of statistical significance,however,the levels of FBG,HbA1c,FINS and IR were decreased,and the difference was statistically significant;The levels of FINS,IR,TG,TC,LDL-C and BMI were elevated in T2DM+Overweight/Obesity group,and the difference was of statistical significance,however,there was no statistically significant difference in FBG and HbA1c.Compared with Overweight/Obesity group,the levels of FBG,FINS,IR,HbA1c and LDL-C were increased in T2DM+Overweight/Obesity group,and the difference was of statistical significance.However,the difference in TG,TC and BMI was not statistically significant.(2)Compared with NC group,the levels of IL-6,TNF-αand PAI-1 were increased in T2DM group,Overweight/Obesity group and T2DM+Overweight/Obesity group,and the difference was statistically significant.Compared with T2DM group,the levels of IL-6 and TNF-αwere elevated in Overweight/Obesity group,and the difference was of statistical significance,but there was no statistically significant difference in PAI-1;the levels of IL-6,TNF-αand PAI-1 were up-regulated in T2DM+Overweight/Obesity group,and the difference was statistically significant.Compared with Overweight/Obesity group,there was no statistically significant difference in IL-6 and TNF-αbetween T2DM+Overweight/Obesity group and Overweight/Obesity group,but the level of PAI-1 was increased in T2DM+Overweight/Obesity group,and the difference was of statistical significance.(3)Multivariate Logistic Regression Analysis showed that HbA1c,IR,TG,BMI,IL-6 and TNF-αwere independently associated with the level of PAI-1(all p<.05).Conclusions:(1)The level of PAI-1 is higher in type 2 diabetes mellitus patients with overweight or obesity than that in patients only with type 2 diabetes mellitus,and it is one of causes that result in vascular complications.(2)The increase in the level of PAI-1 is considered to be associated with IL-6 and TNF-αsecreted by adipocytes.展开更多
AIM: To investigate the relationship between matrix metalloproteinase-2 (MMP-2) mRNA expression and clinicopathologic and urokinase-type plasminogen activator (uPA) system parameter and prognosis in human gastric canc...AIM: To investigate the relationship between matrix metalloproteinase-2 (MMP-2) mRNA expression and clinicopathologic and urokinase-type plasminogen activator (uPA) system parameter and prognosis in human gastric cancer.METHODS: Expression of MMP-2 mRNA, uPA, and uPA-R mRNA in tumor tissues and ≥5 cm adjacent normal tissues from 67 cases of gastric cancer was studied using RTPCR and Northern blot respectively. Survival analyses were done using the Kaplan-Meier method. RESULTS: The expression rates of MMP-2 mRNA, uPA and uPA-R mRNA in tumor tissues (31%, 41%, and 51%, respectively) were significantly higher than those in ≥5 cm adjacent tissues (19%, 11%, and 9%; χ2 = 4.59, 43.58, and 53.24 respectively, P＜0.05, 0.0001, and 0.0001, respectively). Expression of MMP-2 mRNA was significantly correlated with lymph node metastasis (metastasis:61.9%, no metastasis: 39.1%, χ2= 7.61, P＜0.05), Lauren's classification of diffuse/mixed types: 54.2%, intestinal type: 26.3%, χ2 = 4.25, P＜0.05, expression of uPA and uPA-R mRNA (uPA+: 55.1%, uPA-: 22.2% and uPA-R+: 54.9%, uPA-R-: 18.8%, x2= 5.72 and 6.40 respectively, P＜0.05). Kaplan-Meier survival analysis of MMP-2 mRNA expression did not show significant difference in all 67 cases, but revealed an association of the expression of MMP-2 mRNA, uPA, and uPA-R mRNA with worse prognosis (P = 0.0083, 0.0160, and 0.0094, respectively). CONCLUSION: MMP-2 may play an important role in the development of invasion and metastasis of gastric cancer.展开更多
Objective To investigate the association between plasminogen activator inhibitor(PAI)-2 expression and invasive potential in hepatocellular carcinoma(HCC) cells.Methods The HCC cell lines with high,low,and non-metasta...Objective To investigate the association between plasminogen activator inhibitor(PAI)-2 expression and invasive potential in hepatocellular carcinoma(HCC) cells.Methods The HCC cell lines with high,low,and non-metastatic potentials,namely MHCC97-H,MHCC97-L,and SMMC-7721 respectively,were cultured in vitro.Matrigel invasion assay and Western blot of PAI-2 protein expression were conducted.Results The number of invaded cells in MHCC97-L was significantly higher than that in SMMC-7721(P=0.005),whereas that in MHCC97-H was higher than in MHCC97-L(P=0.017) and SMMC-7721(P=0.001).Contrarily,PAI-2 protein expression was gradually reducing from SMMC-7721,MHCC97-L,to MHCC97-H(MHCC97-H vs.MHCC97-L,P<0.001;MHCC97-H vs.SMMC-7721,P=0.001;MHCC97-L vs.SMMC-7721,P=0.001).The Pearson's correlation analysis revealed a significant negative association between invaded cell number and PAI-2 expression(r= 0.892,P=0.001).Conclusion PAI-2 expression may be negatively associated with the invasive potential of HCC.展开更多
Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator（t PA） from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes t...Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator（t PA） from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles,and regulates the postsynaptic response to the presynaptic release of glutamate.Indeed,t PA has a bidirectional effect on the composition of the postsynaptic density（PSD） that does not require plasmin generation or the presynaptic release of glutamate,but varies according to the baseline level of neuronal activity.Hence,in inactive neurons t PA induces phosphorylation and accumulation in the PSD of the Ca^（2＋）/calmodulin-dependent protein kinase IIα（pCa MKIIα）,followed by pCa MKIIα-induced phosphorylation and synaptic recruitment of Glu R1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid（AMPA） receptors.In contrast,in active neurons with increased levels of pCa MKIIα in the PSD t PA induces pCa MKIIα and p Glu R1 dephosphorylation and their subsequent removal from the PSD.These effects require active synaptic N-methyl-D-aspartate（NMDA） receptors and cyclin-dependent kinase 5（Cdk5）-induced phosphorylation of the protein phosphatase 1（PP1） at T320.These data indicate that t PA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCa MKIIα/PP1 switch in the PSD.展开更多
文摘Background: PAI-1 (plasminogen activator inhibitor-1) is a powerful regulator of fibrinolysis and plasma level is high in type 2 diabetes and cardio-vascular disease, which is determined by genetic polymorphisms in PAI-1 gene and environmental factors. The aim of the study was to examine the determinants of plasma PAI-1 Ag level among type 2 diabetes patients. Methods: 491 Tunisian type 2 diabetes patients had clinical evaluation (weight, high, BMI, Waist Circumference), laboratory investigations including FBG Hb1Ac, cholesterol, triglyceride;HDL-cholesterol was done;plasma PAI-1 antigen level was done with ELISA;−675 4G/5G and −844 G/A polymorphisms of PAI-1 gene was done by PCR-ASA and PCR-RFLP respectively. Results: The mean age for our patients was 58.3 ± 10.5 years;sex-ratio = 0.92;mean PAI-1 level was 34.6 ± 21.3 ng/ml. We didn’t find correlation between PAI-1 level and BMI, but we have found significant correlation between PAI-1 and waist circumference (p = 0.032), most enhanced in men (P = 0.002), T2D patients who have FBG > 11 mmol/l had PAI-1 Ag level higher than those who have FBG P = 0.034), but no difference found between T2D with high Hb1Ac > 8% and those with Hb1Ac < 8%, significant correlation was seen between PAI-1 level and LDL-cholesterol (P = 0.05), high correlation between PAI-1 Ag level and −675 4G/5G polymorphism genotype was seen, 4G/4G carriers had the highest PAI-1 level, 4G/5G had intermediary level and 5G/5G had the lowest level (P −844G/A polymorphism genotypes. Using multiple variable linear regression analysis, the independent factor associated with plasma PAI-1 level was −675 4G/5G polymorphism (regression coefficient β = 4.6, P Conclusion: the present study identifies −675 4G/5G not −844 G/A polymorphism of PAI gene as the principal determinant of plasma PAI-1 level in Tunisian T2D patients, the android fat distribution, dyslipidemia and hyperglycemia play a modest role in this variation.
基金Supported by FJIRSM (SZD08003)National Natural Science Foundation of China (30811130467, 30625011)+1 种基金Ministry of Science of Technology (2006AA02A313, 2007CB914304)Chinese Academy of Sciences (KSCX2-YW-R-082)
文摘Urokinase-type plasminogen activator （uPA） plays a crucial role in the regulation of plasminogen activation, tumor cell adhesion and migration. The inhibition of uPA activity is a promising mechanism for anti-cancer therapy. Most current uPA inhibitors employ a highly basic group （either amidine or guanidine group） to target the S1 pocket of uPA active site, which leads to poor oral bioavailability. Here we study the possibility of using less basic 2-aminobenzothiazole （ABT） as S1 pocket binding group. We report the crystal structures of uPA complexes with ABT or 2-amino-benzothiazole-6-carboxylic acid ethyl ester （ABTCE）. The inhibitory constants of these two inhibitors were measured by a chromogenic competitive assay, and it was found that ABTCE is a better inhibitor for uPA （Ki = 656 μM） than ABT （Ki = 5.03 mM）. This work shows that 2-amniobenzothiazole can be used as P1 group which may have better oral bioavailability than the commonly used amidine or guanidine group. We also found the ethyl ester group occupies the characteristic oxyanion hole and contacts to uPA 37- and 60-loops. Such work provides structural information for further improvements of potency and selectivity of this new class of uPA inhibitor.
文摘Objective: To observe the effect of different dosages of ligustrazine (LG) on the level of plasminogen activator inhibitor-1 (PAI-1) activity in patients with type 2 diabetes mellitus. Methods: Ninety cases of type 2 diabetes mellitus inpatients were selected, and randomly divided into LG small dosage group (SDG), LG large dosage group (LDG) and control group. The 120 mg LG, 400 mg LG and normal saline 250 ml were given through intravenous dripping respectively, once daily, 20 days as one treatment course. Before and after treatment, all the patients had their fasting blood taken for PAI-1 and tissue plasminogen activator (t-PA) assessment test to perform the comparative study. Results:Seventy-three out of the 90 patients completed the observation course, the PAI-1 activity of three groups after treatment all lowered compared with that before treatment, and the difference between groups was also significant (all P<0. 01). After treatment the PAI-1 level of SDG and LDG of LG were all markedly lowered (all P<0. 01), the LDG's lowering was more evident than that of SDG, and comparison between these two groups of patients showed significant difference (P<0. 01). Although in the control group there was some difference between before and after treatment, it was not so significant like the above-mentioned two groups (P = 0. 0140). No adverse reaction occurred in the 3 groups during the observation period. Conclusion:LG could safely and effectively lower type 2 diabetes mellitus patient's plasma PAI-1 activity level, and LDG of LG proved to be particularly effective.
文摘Objective:To explore the relationship between serum plasminogen activator inhibitor(PAI-1)level and Type 2 Diabetes Mellitus(T2DM)accompanied by overweight or obesity by observing not only the changes of PAI-1 level in T2DM patients with overweight or obesity,but also glucose and lipid metabolism related indicators,the changes of the inflammatory cytokines secreted by adipocytes,and then making an analysis on the correlation to PAI-1.Methods:36 cases of healthy examinees were selected as normal control group(NC group),and the experimental group can be divided into T2DM group(54 cases),Overweight/Obesity group(35 cases)and T2DM+Overweight/Obesity group(48 cases).Glucose and lipid metabolism related indicators such as fasting blood glucose(FBG),triglyceride(TG),total cholesterol(TC),low density lipoprotein cholesterol(LDL-C),glycated hemoglobin(HbA1c),fasting insulin(FINS),insulin resistance index(IR),body weight index(BMI)and inflammatory cytokines interleukin-6(IL-6),tumor necrosis factor(TNF-α)and PAI-1 were observed and compared between groups,and then made an analysis to explore the correlation of these factors to PAI-1.Results:(1)Compared with NC group,the levels of FBG,HbA1c,FINS and IR were increased in T2DM group,and the difference was of statistical significance.However,there was no statistically significant difference in TG,TC,LDL-C and BMI between NC group and T2DM group;the levels of FINS,IR,TG,LDL-C,TC and BMI were elevated in Overweight/Obesity group,and the difference was of statistical significance.However,there was no statistically significant difference in FBG and HbA1c;the levels of FBG,HbA1c,FINS,IR,TG,LDL-C,TC and BMI were up-regulated in T2DM+Overweight/Obesity group,and the difference was of statistical significance.Compared with T2DM group,the levels of TG,TC,LDL-C and BMI were increased in Overweight/Obesity group,and the difference was of statistical significance,however,the levels of FBG,HbA1c,FINS and IR were decreased,and the difference was statistically significant;The levels of FINS,IR,TG,TC,LDL-C and BMI were elevated in T2DM+Overweight/Obesity group,and the difference was of statistical significance,however,there was no statistically significant difference in FBG and HbA1c.Compared with Overweight/Obesity group,the levels of FBG,FINS,IR,HbA1c and LDL-C were increased in T2DM+Overweight/Obesity group,and the difference was of statistical significance.However,the difference in TG,TC and BMI was not statistically significant.(2)Compared with NC group,the levels of IL-6,TNF-αand PAI-1 were increased in T2DM group,Overweight/Obesity group and T2DM+Overweight/Obesity group,and the difference was statistically significant.Compared with T2DM group,the levels of IL-6 and TNF-αwere elevated in Overweight/Obesity group,and the difference was of statistical significance,but there was no statistically significant difference in PAI-1;the levels of IL-6,TNF-αand PAI-1 were up-regulated in T2DM+Overweight/Obesity group,and the difference was statistically significant.Compared with Overweight/Obesity group,there was no statistically significant difference in IL-6 and TNF-αbetween T2DM+Overweight/Obesity group and Overweight/Obesity group,but the level of PAI-1 was increased in T2DM+Overweight/Obesity group,and the difference was of statistical significance.(3)Multivariate Logistic Regression Analysis showed that HbA1c,IR,TG,BMI,IL-6 and TNF-αwere independently associated with the level of PAI-1(all p<.05).Conclusions:(1)The level of PAI-1 is higher in type 2 diabetes mellitus patients with overweight or obesity than that in patients only with type 2 diabetes mellitus,and it is one of causes that result in vascular complications.(2)The increase in the level of PAI-1 is considered to be associated with IL-6 and TNF-αsecreted by adipocytes.
文摘AIM: To investigate the relationship between matrix metalloproteinase-2 (MMP-2) mRNA expression and clinicopathologic and urokinase-type plasminogen activator (uPA) system parameter and prognosis in human gastric cancer.METHODS: Expression of MMP-2 mRNA, uPA, and uPA-R mRNA in tumor tissues and ≥5 cm adjacent normal tissues from 67 cases of gastric cancer was studied using RTPCR and Northern blot respectively. Survival analyses were done using the Kaplan-Meier method. RESULTS: The expression rates of MMP-2 mRNA, uPA and uPA-R mRNA in tumor tissues (31%, 41%, and 51%, respectively) were significantly higher than those in ≥5 cm adjacent tissues (19%, 11%, and 9%; χ2 = 4.59, 43.58, and 53.24 respectively, P＜0.05, 0.0001, and 0.0001, respectively). Expression of MMP-2 mRNA was significantly correlated with lymph node metastasis (metastasis:61.9%, no metastasis: 39.1%, χ2= 7.61, P＜0.05), Lauren's classification of diffuse/mixed types: 54.2%, intestinal type: 26.3%, χ2 = 4.25, P＜0.05, expression of uPA and uPA-R mRNA (uPA+: 55.1%, uPA-: 22.2% and uPA-R+: 54.9%, uPA-R-: 18.8%, x2= 5.72 and 6.40 respectively, P＜0.05). Kaplan-Meier survival analysis of MMP-2 mRNA expression did not show significant difference in all 67 cases, but revealed an association of the expression of MMP-2 mRNA, uPA, and uPA-R mRNA with worse prognosis (P = 0.0083, 0.0160, and 0.0094, respectively). CONCLUSION: MMP-2 may play an important role in the development of invasion and metastasis of gastric cancer.
基金Supported by the National High Technology Research and Development Program of China (863 Program,2006AA02A308)the National Key Technologies Research and Development Program of China (2008ZX10002-016)the Beijing Municipal Key Project(H030230280410)
文摘Objective To investigate the association between plasminogen activator inhibitor(PAI)-2 expression and invasive potential in hepatocellular carcinoma(HCC) cells.Methods The HCC cell lines with high,low,and non-metastatic potentials,namely MHCC97-H,MHCC97-L,and SMMC-7721 respectively,were cultured in vitro.Matrigel invasion assay and Western blot of PAI-2 protein expression were conducted.Results The number of invaded cells in MHCC97-L was significantly higher than that in SMMC-7721(P=0.005),whereas that in MHCC97-H was higher than in MHCC97-L(P=0.017) and SMMC-7721(P=0.001).Contrarily,PAI-2 protein expression was gradually reducing from SMMC-7721,MHCC97-L,to MHCC97-H(MHCC97-H vs.MHCC97-L,P<0.001;MHCC97-H vs.SMMC-7721,P=0.001;MHCC97-L vs.SMMC-7721,P=0.001).The Pearson's correlation analysis revealed a significant negative association between invaded cell number and PAI-2 expression(r= 0.892,P=0.001).Conclusion PAI-2 expression may be negatively associated with the invasive potential of HCC.
基金supported in part by National Institutes of Health Grants NS-079331(to MY)and NS-091201(to MY)
文摘Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator（t PA） from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles,and regulates the postsynaptic response to the presynaptic release of glutamate.Indeed,t PA has a bidirectional effect on the composition of the postsynaptic density（PSD） that does not require plasmin generation or the presynaptic release of glutamate,but varies according to the baseline level of neuronal activity.Hence,in inactive neurons t PA induces phosphorylation and accumulation in the PSD of the Ca^（2＋）/calmodulin-dependent protein kinase IIα（pCa MKIIα）,followed by pCa MKIIα-induced phosphorylation and synaptic recruitment of Glu R1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid（AMPA） receptors.In contrast,in active neurons with increased levels of pCa MKIIα in the PSD t PA induces pCa MKIIα and p Glu R1 dephosphorylation and their subsequent removal from the PSD.These effects require active synaptic N-methyl-D-aspartate（NMDA） receptors and cyclin-dependent kinase 5（Cdk5）-induced phosphorylation of the protein phosphatase 1（PP1） at T320.These data indicate that t PA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCa MKIIα/PP1 switch in the PSD.
