Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of...Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.展开更多
Objective:To investigate the relationship between serum levels of C1q tumor necrosis factorrelated protein 4(CTRP4)and hypersensitive C reactive protein(hs-CRP)and coronary heart disease(CHD)and its clinical value.Met...Objective:To investigate the relationship between serum levels of C1q tumor necrosis factorrelated protein 4(CTRP4)and hypersensitive C reactive protein(hs-CRP)and coronary heart disease(CHD)and its clinical value.Methods:128 patients underwent coronary angiography in our hospital,63 males,65 women,Based on blood sugar levels and coronary angiography,Divided into pure coronary heart disease(CHD)group 62 cases,Coronary heart disease with diabetes(DM+CHD)group 66 cases,A total of 126 patients were selected as control group,65 men,61 women,CTRP4 and hs-CRP levels in serum,Using Pearson correlation analysis to assess the correlation between Gennisi score and CTRP4、hs-CRP,Analysis of three groups of biochemical indicators,CTRP4、hs-CRP level changes and clinical significance.Results:The CTRP4、hs-CRP level of DM+CHD group was significantly higher than that of control group and CHD group(P DM+CHD 0.05).The CTRP4、hs-CRP level of the three-vessel coronary artery lesion group in the experimental group was higher than that in the two-vessel lesion group(P﹤0.05),Double branch lesion group was higher than single branch lesion group(P﹤0.05);Correlation analysis shows,There was a significant positive correlation between the CTRP4、hs-CRP level of CHD group and DM+CHD group and the Gennisi score(P DM+CHD 0.05).ROC curves show,CTRP4 and hs-CRP levels had predictive value(CHD group,AUC=0.940,0.934,DM+CHD group,AUC=0.980,0.964),Two associations(CHD:AUC=0.961,P﹤0.001,DM+CHD group:AUCDM+CHD 0.982,P﹤0.001)the predictive value is high.Conclusion:Serum CTRP4 and hs-CRP are positively related to the severity of coronary heart disease,and the sensitivity and specificity of predicting coronary heart disease are high,which is helpful for the identification and early prevention of coronary heart disease,and has certain clinical reference value.展开更多
AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resis...AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resistance in hepatocellular carcinoma(HCC)and to study the efficacy of agonistic TRAIL antibodies,as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis. METHODS:Surface expression of TRAIL receptors (TRAIL-R1-4)and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting,respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs.HCC cellswere treated with kinase inhibitors and chemotherapeutic drugs.Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS:TRAIL-R1 and-R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However,treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates.Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002[inhibition of phosphoinositol- 3-kinase(PI3K)],AG1478(epidermal growth factor receptor kinase),PD98059(MEK1),rapamycin(mam- malian target of rapamycin)and the multi-kinase inhibitor Sorafenib.Furthermore,the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance:knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells.Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION:Our data identify the blockage of survival kinases,combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82102295(to WG),82071339(to LG),82001119(to JH),and 81901994(to BZ).
文摘Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.
基金Key research and development plan of the department of science and technology of Anhui province(No.1804h08020246)Key natural science research project of Anhui provincial colleges and universities(No.KJ2019A0401)Young talents project of Anhui provincial colleges and universities(No.gxyq2018039)。
文摘Objective:To investigate the relationship between serum levels of C1q tumor necrosis factorrelated protein 4(CTRP4)and hypersensitive C reactive protein(hs-CRP)and coronary heart disease(CHD)and its clinical value.Methods:128 patients underwent coronary angiography in our hospital,63 males,65 women,Based on blood sugar levels and coronary angiography,Divided into pure coronary heart disease(CHD)group 62 cases,Coronary heart disease with diabetes(DM+CHD)group 66 cases,A total of 126 patients were selected as control group,65 men,61 women,CTRP4 and hs-CRP levels in serum,Using Pearson correlation analysis to assess the correlation between Gennisi score and CTRP4、hs-CRP,Analysis of three groups of biochemical indicators,CTRP4、hs-CRP level changes and clinical significance.Results:The CTRP4、hs-CRP level of DM+CHD group was significantly higher than that of control group and CHD group(P DM+CHD 0.05).The CTRP4、hs-CRP level of the three-vessel coronary artery lesion group in the experimental group was higher than that in the two-vessel lesion group(P﹤0.05),Double branch lesion group was higher than single branch lesion group(P﹤0.05);Correlation analysis shows,There was a significant positive correlation between the CTRP4、hs-CRP level of CHD group and DM+CHD group and the Gennisi score(P DM+CHD 0.05).ROC curves show,CTRP4 and hs-CRP levels had predictive value(CHD group,AUC=0.940,0.934,DM+CHD group,AUC=0.980,0.964),Two associations(CHD:AUC=0.961,P﹤0.001,DM+CHD group:AUCDM+CHD 0.982,P﹤0.001)the predictive value is high.Conclusion:Serum CTRP4 and hs-CRP are positively related to the severity of coronary heart disease,and the sensitivity and specificity of predicting coronary heart disease are high,which is helpful for the identification and early prevention of coronary heart disease,and has certain clinical reference value.
基金Supported by Research grants from Merck KGaA,Darmstadt,Germany,to Schulze-Bergkamen H
文摘AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resistance in hepatocellular carcinoma(HCC)and to study the efficacy of agonistic TRAIL antibodies,as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis. METHODS:Surface expression of TRAIL receptors (TRAIL-R1-4)and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting,respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs.HCC cellswere treated with kinase inhibitors and chemotherapeutic drugs.Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS:TRAIL-R1 and-R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However,treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates.Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002[inhibition of phosphoinositol- 3-kinase(PI3K)],AG1478(epidermal growth factor receptor kinase),PD98059(MEK1),rapamycin(mam- malian target of rapamycin)and the multi-kinase inhibitor Sorafenib.Furthermore,the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance:knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells.Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION:Our data identify the blockage of survival kinases,combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC.
