AIM： To investigate integrin β3 mRNA and vascular endothelial growth factor （VEGF） protein expression in gastric carcinoma, and its correlation with microvascular density, growth-pattern, invasion, metastasis and ...AIM： To investigate integrin β3 mRNA and vascular endothelial growth factor （VEGF） protein expression in gastric carcinoma, and its correlation with microvascular density, growth-pattern, invasion, metastasis and prognosis. METHODS： In situ hybridization（ISH） of integrin β3 mRNA and immunohistochemistry of VEGF and CD34 protein were performed on samples from 118 patients with gastric cancer. RESULTS： The positive rate of integrin β3 mRNA in non-tumor gastric mucosa （20%） was significantly lower than that of the gastric cancer tissue （52.5%, X^2 = 10.20, P 〈 0.01）. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the positive expression rates of integrin β3 mRNA were significantly higher than those in patients of expanding type （P 〈 0.01）, stage T1-T2 （P 〈 0.01）, non-vessel invasion （P 〈 0.01）, without lymphatic metastasis （P 〈 0.01）, without hepatic and peritoneal metastasis （P 〈 0.01）, respectively. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the positive expression rates of VEGF protein were significantly higher than those in patients of expanding type （P 〈 0.01）, stage T1-T2 （P 〈 0.01）, non-vessel invasion （P 〈 0.01）, without lymphatic metastasis （P 〈 0.01）, without hepatic and peritoneal metastasis （P 〈 0.01）, respectively. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the mean MVD were significantly higher than those in patients of expanding type （P 〈 0.01）, stage T1-T2 （P 〈 0.01）, non-vessel invasion （P 〈 0.01）, without lymphatic metastasis （P 〈 0.01）, without hepatic and peritoneal metastasis （P 〈 0.01）, respectively. It was found that the positive expression rate of integrin β3 mRNA was positively related to that of VEGF protein （P 〈 0.01） and MVD （P 〈 0.05）, meanwhile the positive expression rate of VEGF protein was positively related to MVD （P 〈 0.05）. The mean survival period in patients with positive expression of integrin β3 mRNA and VEGF, and MVD ≥54.9/mm^2 was significantly shorter than that in patients with negative expression of integrin β3 mRNA （P 〈 0.05） and VEGF （P 〈 0.01）, and MVD 〈 54.9/mm^2 （P 〈 0.01）. Five-year survival rate in patients with positive expression of integrin β3 mRNA and VEGF, and MVD ≥54.9/mm^2 was significantly lower than those with negative expression of integrin β3 mRNA （P 〈 0.05）, VEGF （P 〈 0.05）, and MVD 〈 54.9/mm^2 （P 〈 0.01）. CONCLUSION： Integrin β3 and VEGF expression can synergistically enhance tumor angiogenesis, and may play a crucial role in invasion and metastasis of gastric carcinoma. Therefore, they may be prognostic biomarkers and novel molecular therapeutic targets.展开更多
To investigate the effect of α-zearalenol on angiotensin If-induced β3 integrin mRNA expression in human umbilical vein endothelial cells （HUVECs）. Methods The mRNA level in integrin β3 was determined by reverse ...To investigate the effect of α-zearalenol on angiotensin If-induced β3 integrin mRNA expression in human umbilical vein endothelial cells （HUVECs）. Methods The mRNA level in integrin β3 was determined by reverse transcription-polymerase chain reaction. Endothelial NF-κB activity was determined by the luciferase activity assay of plasmid NF-κB-LUC. Results The angiotensin Ⅱ- induced β3 integrin mRNA expression was inhibited by α-zearalenol and 17β-estradiol （10nmol/L ^-1 μmol/L）, but not influenced by ICI 182, 780, a pure competitive antagonist for estrogen receptor or a nitric oxide inhibitor N^ω-Nitro-L-arginine methyl ester hydrochloride. Alpha-zearalenol and 17β-estradiol suppressed the angiotensin Ⅱ-induced activation of NF-κB in endothelial cells. Condusion Alpha-zearalenol inhibits angiotensin Ⅱ-induced integrin β3 mRNA expression by suppressing NF-κB activation in endothelial cells.展开更多
BACKGROUND Non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH),an inflammatory subtype of non-alcoholic fatty liver disease(NAFLD),are currently unavailable.AIM To develop an integrin αvβ3-targeted ...BACKGROUND Non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH),an inflammatory subtype of non-alcoholic fatty liver disease(NAFLD),are currently unavailable.AIM To develop an integrin αvβ3-targeted molecular imaging modality to differentiate NASH.METHODS Integrinαvβ3 expression was assessed in Human LO2 hepatocytes Scultured with palmitic and oleic acids(FFA).Hepatic integrinαvβ3 expression was analyzed in rabbits fed a high-fat diet(HFD)and in rats fed a high-fat,high-carbohydrate diet(HFCD).After synthesis,cyclic arginine-glycine-aspartic acid peptide(cRGD)was labeled with gadolinium(Gd)and used as a contrast agent in magnetic resonance imaging(MRI)performed on mice fed with HFCD.RESULTS Integrin αvβ3 was markedly expressed on FFA-cultured hepatocytes,unlike the control hepatocytes.Hepatic integrin αvβ3 expression significantly increased in both HFD-fed rabbits and HFCD-fed rats as simple fatty liver(FL)progressed to steatohepatitis.The distribution of integrinαvβ3 in the liver of NASH cases largely overlapped with albumin-positive staining areas.In comparison to mice with simple FL,the relative liver MRI-T1 signal value at 60 minutes post-injection of Gd-labeled cRGD was significantly increased in mice with steatohepatitis(P<0.05),showing a positive correlation with the NAFLD activity score(r=0.945;P<0.01).Hepatic integrin αvβ3 expression was significantly upregulated during NASH development,with hepatocytes being the primary cells expressing integrin αvβ3.CONCLUSION After using Gd-labeled cRGD as a tracer,NASH was successfully distinguished by visualizing hepatic integrin αvβ3 expression with MRI.展开更多
Accurate preoperative prediction of lymph node metastasis(LNM)in esophageal cancer(EC)patients is of crucial clinical significance for treatment planning and prognosis.AIM To develop a clinical radiomics nomogram that...Accurate preoperative prediction of lymph node metastasis(LNM)in esophageal cancer(EC)patients is of crucial clinical significance for treatment planning and prognosis.AIM To develop a clinical radiomics nomogram that can predict the preoperative lymph node(LN)status in EC patients.METHODS A total of 32 EC patients confirmed by clinical pathology(who underwent surgical treatment)were included.Real-time fluorescent quantitative reverse transcription-polymerase chain reaction was used to detect the expression of B7-H3 mRNA in EC tissue obtained during preoperative gastroscopy,and its correlation with LNM was analyzed.Radiomics features were extracted from multi-modal magnetic resonance imaging of EC using Pyradiomics in Python.Feature extraction,data dimensionality reduction,and feature selection were performed using XGBoost model and leave-one-out cross-validation.Multivariable logistic regression analysis was used to establish the prediction model,which included radiomics features,LN status from computed tomography(CT)reports,and B7-H3 mRNA expression,represented by a radiomics nomogram.Receiver operating characteristic area under the curve(AUC)and decision curve analysis(DCA)were used to evaluate the predictive performance and clinical application value of the model.RESULTS The relative expression of B7-H3 mRNA in EC patients with LNM was higher than in those without metastasis,and the difference was statistically significant(P<0.05).The AUC value in the receiver operating characteristic(ROC)curve was 0.718(95%CI:0.528-0.907),with a sensitivity of 0.733 and specificity of 0.706,indicating good diagnostic performance.The individualized clinical prediction nomogram included radiomics features,LN status from CT reports,and B7-H3 mRNA expression.The ROC curve demonstrated good diagnostic value,with an AUC value of 0.765(95%CI:0.598-0.931),sensitivity of 0.800,and specificity of 0.706.DCA indicated the practical value of the radiomics nomogram in clinical practice.CONCLUSION This study developed a radiomics nomogram that includes radiomics features,LN status from CT reports,and B7-H3 mRNA expression,enabling convenient preoperative individualized prediction of LNM in EC patients.展开更多
Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although c...Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer(MIBC),it has a poor survival rate.Therefore,this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B(APOBEC3B)expressing MIBC.Methods:Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC.The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis.Western blot analysis was performed to confirm differences in phosphorylated Chk1(pChk1)expression according to the APOBEC3B expression.Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin.Results:There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC.Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels.Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression.Compared to cisplatin single treatment,combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression.Conclusion:Our study shows that APOBEC3B’s higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition.This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.展开更多
Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic ...Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.展开更多
The purpose of this study was to investigate changes of β 3 integrins and extra cellular matrix proteins including fibronectin (FN), laminin (LN) and collagen type Ⅳ (CL typeⅣ) on the endometrium of secret...The purpose of this study was to investigate changes of β 3 integrins and extra cellular matrix proteins including fibronectin (FN), laminin (LN) and collagen type Ⅳ (CL typeⅣ) on the endometrium of secretory phase from 31 fertile women (fertility group)and 34 women with unexplained infertility (infertility group) by a histochemical method.The results were as follows:In glandular epithelium, β 3 integrin appeared in the mid secretory phase and continued to late secretory phase in the fertility group, but was not expressed during the secretory phase in the infertility group. Extracellular matrix proteins from the fertility group were expressed more strongly in mid secretory phase than that in the early secretory phase, and were weakest in the late secretory phase. Compared with the fertility group, the levels of extracellular matrix proteins in the infertility group were elevated in the secretory phase. In conclusion: our current study demonstrate that β 3 integrin and extracellular matrix proteins are expressed at different levels in the endometrium during the menstrual cycle. They are involved in endometrial changes during the menstrual cycle and during the implantation of the blastocyst. Their unusual expression result in the failure of implantation.展开更多
Previous studies of integrin αvβ3 have focused on ischemic brain damage, although the role of integrin αvβ3 in ischemic preconditioning （IP） has rarely been reported. The present study analyzed the effects of IP...Previous studies of integrin αvβ3 have focused on ischemic brain damage, although the role of integrin αvβ3 in ischemic preconditioning （IP） has rarely been reported. The present study analyzed the effects of IP on integrin αvβ3 mRNA expression following cerebral ischemia through the use of hematoxylin-eosin staining and real-time quantitative polymerase chain reaction techniques. Integrin avid3 mRNA expression in the ischemia group peaked at 24 hours after ischemia-reperfusion. In the IP ＋ ischemia group, integrin αvβ3 mRNA expression increased after 24 hours, but remained significantly less than the ischemia group, and expression continued to increase until 7 days after ischemiaJreperfusion. These results demonstrate that IP effectively attenuated upregulation of integrin αvβ3 mRNA expression at 24 hours after ischemia.展开更多
The effects of mifepristone with misoprostol on the expression of the integrin β 3 and intercellular adhesion molecule 1 (ICAM 1) in decidua and chorionic villi tissues in early pregnancy in 10 cases were investigate...The effects of mifepristone with misoprostol on the expression of the integrin β 3 and intercellular adhesion molecule 1 (ICAM 1) in decidua and chorionic villi tissues in early pregnancy in 10 cases were investigated by immuno flow cytometry (the experiment group). At the same time, the other 10 cases induced by mechanical vacuum aspiration were collected as the control. The results showed that, the positive rate of integrin β 3 and ICAM 1 in decidua of the experiment group were 19.1±5.01% and 20.61 ±6.51%; while those in chorionic villi were 21.32±4.38% and 20.29± 6.49%, which were significantly lower than those in the control group. These results suggested that integrin β 3 and ICAM 1 may take part in the maintenance of early pregnancy. The mechanism of mifepristone induced abortion may be mediated by the down regulation of the integrin β 3 and ICAM 1 expression in decidua and chorionic villi.展开更多
Objective To investigate the effect of sirolimus ( SRL) on the expression of integrin αυβ3 mRNA in vascular smooth muscle cells of cardiac allografts in rats, and the possible mechanism of SRL in the prevention of ...Objective To investigate the effect of sirolimus ( SRL) on the expression of integrin αυβ3 mRNA in vascular smooth muscle cells of cardiac allografts in rats, and the possible mechanism of SRL in the prevention of cardiac allograft vasculopathy. Methods Heterotopic heart transplantation models were established Hearts展开更多
基金a grant from Zhejiang Province Natural Science Foundation, No. M303843
文摘AIM： To investigate integrin β3 mRNA and vascular endothelial growth factor （VEGF） protein expression in gastric carcinoma, and its correlation with microvascular density, growth-pattern, invasion, metastasis and prognosis. METHODS： In situ hybridization（ISH） of integrin β3 mRNA and immunohistochemistry of VEGF and CD34 protein were performed on samples from 118 patients with gastric cancer. RESULTS： The positive rate of integrin β3 mRNA in non-tumor gastric mucosa （20%） was significantly lower than that of the gastric cancer tissue （52.5%, X^2 = 10.20, P 〈 0.01）. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the positive expression rates of integrin β3 mRNA were significantly higher than those in patients of expanding type （P 〈 0.01）, stage T1-T2 （P 〈 0.01）, non-vessel invasion （P 〈 0.01）, without lymphatic metastasis （P 〈 0.01）, without hepatic and peritoneal metastasis （P 〈 0.01）, respectively. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the positive expression rates of VEGF protein were significantly higher than those in patients of expanding type （P 〈 0.01）, stage T1-T2 （P 〈 0.01）, non-vessel invasion （P 〈 0.01）, without lymphatic metastasis （P 〈 0.01）, without hepatic and peritoneal metastasis （P 〈 0.01）, respectively. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the mean MVD were significantly higher than those in patients of expanding type （P 〈 0.01）, stage T1-T2 （P 〈 0.01）, non-vessel invasion （P 〈 0.01）, without lymphatic metastasis （P 〈 0.01）, without hepatic and peritoneal metastasis （P 〈 0.01）, respectively. It was found that the positive expression rate of integrin β3 mRNA was positively related to that of VEGF protein （P 〈 0.01） and MVD （P 〈 0.05）, meanwhile the positive expression rate of VEGF protein was positively related to MVD （P 〈 0.05）. The mean survival period in patients with positive expression of integrin β3 mRNA and VEGF, and MVD ≥54.9/mm^2 was significantly shorter than that in patients with negative expression of integrin β3 mRNA （P 〈 0.05） and VEGF （P 〈 0.01）, and MVD 〈 54.9/mm^2 （P 〈 0.01）. Five-year survival rate in patients with positive expression of integrin β3 mRNA and VEGF, and MVD ≥54.9/mm^2 was significantly lower than those with negative expression of integrin β3 mRNA （P 〈 0.05）, VEGF （P 〈 0.05）, and MVD 〈 54.9/mm^2 （P 〈 0.01）. CONCLUSION： Integrin β3 and VEGF expression can synergistically enhance tumor angiogenesis, and may play a crucial role in invasion and metastasis of gastric carcinoma. Therefore, they may be prognostic biomarkers and novel molecular therapeutic targets.
基金This work was supported by the National Natural Science Foundation of China (No. 39730020, No. 39730220)
文摘To investigate the effect of α-zearalenol on angiotensin If-induced β3 integrin mRNA expression in human umbilical vein endothelial cells （HUVECs）. Methods The mRNA level in integrin β3 was determined by reverse transcription-polymerase chain reaction. Endothelial NF-κB activity was determined by the luciferase activity assay of plasmid NF-κB-LUC. Results The angiotensin Ⅱ- induced β3 integrin mRNA expression was inhibited by α-zearalenol and 17β-estradiol （10nmol/L ^-1 μmol/L）, but not influenced by ICI 182, 780, a pure competitive antagonist for estrogen receptor or a nitric oxide inhibitor N^ω-Nitro-L-arginine methyl ester hydrochloride. Alpha-zearalenol and 17β-estradiol suppressed the angiotensin Ⅱ-induced activation of NF-κB in endothelial cells. Condusion Alpha-zearalenol inhibits angiotensin Ⅱ-induced integrin β3 mRNA expression by suppressing NF-κB activation in endothelial cells.
基金Supported by the National Natural Science Foundation of China,No.81670513and Young Scientists Fund of the National Natural Science Foundation of China,No.81900511。
文摘BACKGROUND Non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH),an inflammatory subtype of non-alcoholic fatty liver disease(NAFLD),are currently unavailable.AIM To develop an integrin αvβ3-targeted molecular imaging modality to differentiate NASH.METHODS Integrinαvβ3 expression was assessed in Human LO2 hepatocytes Scultured with palmitic and oleic acids(FFA).Hepatic integrinαvβ3 expression was analyzed in rabbits fed a high-fat diet(HFD)and in rats fed a high-fat,high-carbohydrate diet(HFCD).After synthesis,cyclic arginine-glycine-aspartic acid peptide(cRGD)was labeled with gadolinium(Gd)and used as a contrast agent in magnetic resonance imaging(MRI)performed on mice fed with HFCD.RESULTS Integrin αvβ3 was markedly expressed on FFA-cultured hepatocytes,unlike the control hepatocytes.Hepatic integrin αvβ3 expression significantly increased in both HFD-fed rabbits and HFCD-fed rats as simple fatty liver(FL)progressed to steatohepatitis.The distribution of integrinαvβ3 in the liver of NASH cases largely overlapped with albumin-positive staining areas.In comparison to mice with simple FL,the relative liver MRI-T1 signal value at 60 minutes post-injection of Gd-labeled cRGD was significantly increased in mice with steatohepatitis(P<0.05),showing a positive correlation with the NAFLD activity score(r=0.945;P<0.01).Hepatic integrin αvβ3 expression was significantly upregulated during NASH development,with hepatocytes being the primary cells expressing integrin αvβ3.CONCLUSION After using Gd-labeled cRGD as a tracer,NASH was successfully distinguished by visualizing hepatic integrin αvβ3 expression with MRI.
基金The Yancheng Key Research and Development Program(Social Development),No.YCBE202324。
文摘Accurate preoperative prediction of lymph node metastasis(LNM)in esophageal cancer(EC)patients is of crucial clinical significance for treatment planning and prognosis.AIM To develop a clinical radiomics nomogram that can predict the preoperative lymph node(LN)status in EC patients.METHODS A total of 32 EC patients confirmed by clinical pathology(who underwent surgical treatment)were included.Real-time fluorescent quantitative reverse transcription-polymerase chain reaction was used to detect the expression of B7-H3 mRNA in EC tissue obtained during preoperative gastroscopy,and its correlation with LNM was analyzed.Radiomics features were extracted from multi-modal magnetic resonance imaging of EC using Pyradiomics in Python.Feature extraction,data dimensionality reduction,and feature selection were performed using XGBoost model and leave-one-out cross-validation.Multivariable logistic regression analysis was used to establish the prediction model,which included radiomics features,LN status from computed tomography(CT)reports,and B7-H3 mRNA expression,represented by a radiomics nomogram.Receiver operating characteristic area under the curve(AUC)and decision curve analysis(DCA)were used to evaluate the predictive performance and clinical application value of the model.RESULTS The relative expression of B7-H3 mRNA in EC patients with LNM was higher than in those without metastasis,and the difference was statistically significant(P<0.05).The AUC value in the receiver operating characteristic(ROC)curve was 0.718(95%CI:0.528-0.907),with a sensitivity of 0.733 and specificity of 0.706,indicating good diagnostic performance.The individualized clinical prediction nomogram included radiomics features,LN status from CT reports,and B7-H3 mRNA expression.The ROC curve demonstrated good diagnostic value,with an AUC value of 0.765(95%CI:0.598-0.931),sensitivity of 0.800,and specificity of 0.706.DCA indicated the practical value of the radiomics nomogram in clinical practice.CONCLUSION This study developed a radiomics nomogram that includes radiomics features,LN status from CT reports,and B7-H3 mRNA expression,enabling convenient preoperative individualized prediction of LNM in EC patients.
基金supported by St.Vincent’s Hospital,the Research Institute of Medical Science(Grant Number:SVHR-2021-03).
文摘Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer(MIBC),it has a poor survival rate.Therefore,this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B(APOBEC3B)expressing MIBC.Methods:Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC.The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis.Western blot analysis was performed to confirm differences in phosphorylated Chk1(pChk1)expression according to the APOBEC3B expression.Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin.Results:There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC.Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels.Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression.Compared to cisplatin single treatment,combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression.Conclusion:Our study shows that APOBEC3B’s higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition.This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.
基金supported by Fondo Nacional de Desarrollo Científico y Tecnológico(FONDECYT)#1200836,#1210644,and#1240888,and Agencia Nacional de Investigación y Desarrollo(ANID)-FONDAP#15130011(to LL)FONDECYT#3230227(to MFG).
文摘Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.
文摘The purpose of this study was to investigate changes of β 3 integrins and extra cellular matrix proteins including fibronectin (FN), laminin (LN) and collagen type Ⅳ (CL typeⅣ) on the endometrium of secretory phase from 31 fertile women (fertility group)and 34 women with unexplained infertility (infertility group) by a histochemical method.The results were as follows:In glandular epithelium, β 3 integrin appeared in the mid secretory phase and continued to late secretory phase in the fertility group, but was not expressed during the secretory phase in the infertility group. Extracellular matrix proteins from the fertility group were expressed more strongly in mid secretory phase than that in the early secretory phase, and were weakest in the late secretory phase. Compared with the fertility group, the levels of extracellular matrix proteins in the infertility group were elevated in the secretory phase. In conclusion: our current study demonstrate that β 3 integrin and extracellular matrix proteins are expressed at different levels in the endometrium during the menstrual cycle. They are involved in endometrial changes during the menstrual cycle and during the implantation of the blastocyst. Their unusual expression result in the failure of implantation.
基金the National Natural Science Foundation of China,No. 30870849,81071068the Science and Technology Planning Project of Guangdong Province,No. 2009B030801101
文摘Previous studies of integrin αvβ3 have focused on ischemic brain damage, although the role of integrin αvβ3 in ischemic preconditioning （IP） has rarely been reported. The present study analyzed the effects of IP on integrin αvβ3 mRNA expression following cerebral ischemia through the use of hematoxylin-eosin staining and real-time quantitative polymerase chain reaction techniques. Integrin avid3 mRNA expression in the ischemia group peaked at 24 hours after ischemia-reperfusion. In the IP ＋ ischemia group, integrin αvβ3 mRNA expression increased after 24 hours, but remained significantly less than the ischemia group, and expression continued to increase until 7 days after ischemiaJreperfusion. These results demonstrate that IP effectively attenuated upregulation of integrin αvβ3 mRNA expression at 24 hours after ischemia.
文摘The effects of mifepristone with misoprostol on the expression of the integrin β 3 and intercellular adhesion molecule 1 (ICAM 1) in decidua and chorionic villi tissues in early pregnancy in 10 cases were investigated by immuno flow cytometry (the experiment group). At the same time, the other 10 cases induced by mechanical vacuum aspiration were collected as the control. The results showed that, the positive rate of integrin β 3 and ICAM 1 in decidua of the experiment group were 19.1±5.01% and 20.61 ±6.51%; while those in chorionic villi were 21.32±4.38% and 20.29± 6.49%, which were significantly lower than those in the control group. These results suggested that integrin β 3 and ICAM 1 may take part in the maintenance of early pregnancy. The mechanism of mifepristone induced abortion may be mediated by the down regulation of the integrin β 3 and ICAM 1 expression in decidua and chorionic villi.
文摘Objective To investigate the effect of sirolimus ( SRL) on the expression of integrin αυβ3 mRNA in vascular smooth muscle cells of cardiac allografts in rats, and the possible mechanism of SRL in the prevention of cardiac allograft vasculopathy. Methods Heterotopic heart transplantation models were established Hearts
