The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed...The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.展开更多
AIM:To investigate the utility of Beclin-1 and LC3,two autophagy-related proteins,in predicting the cetuximab efficacy in advanced colorectal cancer(ACRC) . METHODS:The data of 85 patients with ACRC treated at the Sun...AIM:To investigate the utility of Beclin-1 and LC3,two autophagy-related proteins,in predicting the cetuximab efficacy in advanced colorectal cancer(ACRC) . METHODS:The data of 85 patients with ACRC treated at the Sun Yat-sen University Cancer Center from March 1,2005 to December 31,2008 were studied,including 45 cases treated with cetuximab-containing chemotherapy and 40 cases treated with non-cetuximab-containing chemotherapy.Beclin-1 and LC3 expression was evaluated by immunohistochemistry,and KRAS status was evaluated by polymerase chain reaction. RESULTS:Beclin-1 and LC3 expression in ACRC wassignificantly correlated(r=0.44,P<0.01);however,LC3 was more highly expressed in cancerous tissues than in normal tissues(Z=-2.63,P<0.01) .In the cetuximab-containing chemotherapy group,patients with low LC3 expression had higher objective response rates(ORRs) than those with high LC3 expression(52.9%vs 17.9%,P=0.01) ,and patients with low Beclin-1 expression had a longer median progressionfree survival(PFS) than their counterparts with higher Beclin-1 expression(9.0 mo vs 3.0 mo,P=0.01) . However,neither of these predictive relationships was detected in the group treated with non-cetuximabcontaining chemotherapy.Patients with wild-type KRAS had higher ORRs(42.3%vs 9.1%,P=0.049) and disease control rates(DCRs)(73.1%vs 36.4%,P= 0.035) ,and longer median PFS(5.5 mo vs 2.5 mo,P= 0.02) than those with mutant KRAS in the cetuximabcontaining chemotherapy group.Neither Beclin-1(P= 0.52) nor LC3(P=0.32) expression was significantly correlated with KRAS status. CONCLUSION:Patients with low Beclin-1 expression had a longer PFS than those with high Beclin-1 expression,and patients with low LC3 expression had a higher ORR in ACRC patients treated with cetuximab-containing chemotherapy.展开更多
Fusarium graminearum,the primary pathogenic fungus responsible for Fusarium head blight(FHB)in wheat,secretes abundant chemical compounds that interact with host plants.In this study,a secreted protein FgHrip1,isolate...Fusarium graminearum,the primary pathogenic fungus responsible for Fusarium head blight(FHB)in wheat,secretes abundant chemical compounds that interact with host plants.In this study,a secreted protein FgHrip1,isolated from the culture filtrate of F.graminearum,was found to induce typical cell death in tobacco.The FgHrip1 gene was then cloned and expressed in Escherichia coli.Further bioassay analysis showed that the recombinant FgHrip1 induced early defense induction events,such as reactive oxygen species(ROS)production,callose deposition,and up-regulation of defense-related genes in tobacco.Furthermore,FgHrip1 significantly enhanced immunity in tobacco seedlings against Pseudomonas syringae pv.tabaci 6605(Pst.6605)and tobacco mosaic virus(TMV).FgHrip1-treated wheat spikes also exhibited defense-related transcript accumulation and developed immunity against FHB infection.Whereas the expression of FgHrip1 was induced during the infection process,the deletion of the gene impaired the virulence of F.graminearum.Our results suggest that FgHrip1triggers immunity and induces disease resistance in tobacco and wheat,thereby providing new insight into strategy for biocontrol of FHB.展开更多
Objective This study aimed to investigate the lipid-lowering activity of LFBEP-C1 in high glucose-fed Caenorhabditis elegans(C.elegans).Methods In this study,the fermented barley protein LFBEP-C1 was prepared and test...Objective This study aimed to investigate the lipid-lowering activity of LFBEP-C1 in high glucose-fed Caenorhabditis elegans(C.elegans).Methods In this study,the fermented barley protein LFBEP-C1 was prepared and tested for its potential anti-obesity effects on C.elegans.The worms were fed Escherichia coli OP50(E.coli OP50),glucose,and different concentrations of LFBEP-C1.Body size,lifespan,movement,triglyceride content,and gene expression were analyzed.The results were analyzed using ANOVA and Tukey's multiple comparison test.Results Compared with the model group,the head-swing frequency of C.elegans in the group of LFBEP-C1 at 20μg/mL increased by 33.88%,and the body-bending frequency increased by 27.09%.This indicated that LFBEP-C1 improved the locomotive ability of C.elegans.The average lifespan of C.elegans reached 13.55 days,and the body length and width of the C.elegans decreased after LFBEP-C1 intake.Additionally,LFBEP-C1 reduced the content of lipid accumulation and triglyceride levels.The expression levels of sbp-1,daf-2,and mdt-15 significantly decreased,while those of daf-16,tph-1,mod-1,and ser-4 significantly increased after LFBEP-C1 intake.Changes in these genes explain the signaling pathways that regulate lipid metabolism.Conclusion LFBEP-C1 significantly reduced lipid deposition in C.elegans fed a high-glucose diet and alleviated the adverse effects of a high-glucose diet on the development,lifespan,and exercise behavior of C.elegans.In addition,LFBEP-C1 regulated lipid metabolism mainly by mediating the expression of genes in the sterol regulatory element-binding protein,insulin,and 5-hydroxytryptamine signaling pathways.展开更多
The effects of mepiquat chloride(DPC)on the Cry1Ac protein content in Bacillus thuringiensis(Bt)cotton boll shells under high temperature and drought stress were investigated to provide a theoretical reference for Bt ...The effects of mepiquat chloride(DPC)on the Cry1Ac protein content in Bacillus thuringiensis(Bt)cotton boll shells under high temperature and drought stress were investigated to provide a theoretical reference for Bt cotton breeding and high-yield and-efficiency cotton cultivation.This study was conducted using Bt cotton cultivar‘Sikang 3'during the 2020 and 2021 growing seasons at Yangzhou University Farm,Yangzhou,Jiangsu Province,China.Potted cotton plants were exposed to high temperature and drought stress,and sprayed with either 20 mg L^(-1)DPC or water(CK).Seven days after treatment,the Cry1Ac protein content,α-ketoglutarate content,pyruvic acid content,glutamate synthase activity,glutamic oxaloacetic transaminase activity,soluble protein content,and amino acid content were measured,and transcriptome sequencing was performed.DESeq was used for differential gene analysis.Under the DPC treatment,the Cry1Ac protein content increased by 4.7-11.9% compared to CK.Theα-ketoglutarate content,pyruvic acid content,glutamate synthase activity,glutamic oxaloacetic transaminase activity,soluble protein content,and amino acid content all increased.Transcriptome analysis revealed 7,542 upregulated genes and 10,449 downregulated genes for DPC vs.CK.Gene ontology(GO)and Kyoto Encyclopedia of Gene and Genomes(KEGG)analyses showed that the differentially expressed genes were mainly involved in biological processes,such as carbon and amino acid metabolism.For example,genes encoding 6-phosphofructokinase,pyruvate kinase,glutamic pyruvate transaminase,pyruvate dehydrogenase,citrate synthase,isocitrate dehydrogenase,2-oxoglutarate dehydrogenase,glutamate synthase,1-pyrroline-5-carboxylate dehydrogenase,glutamic oxaloacetic transaminase,amino-acid N-acetyltransferase,and acetylornithine deacetylase were all significantly upregulated.The DPC treatment increased pyruvate,α-ketoglutarate,and oxaloacetate by increasing the operational rate of the glycolytic pathway of the citric acid cycle.It also significantly upregulated the genes encoding glutamate synthase,pyrrolidine-5-carboxylic acid dehydrogenase,glutamate oxaloacetate transaminase,and N-acetylglutamate synthetase,while it downregulated the genes encoding glutamine synthetase.Therefore,the synthesis of aspartic acid,glutamic acid,pyruvate,and arginine increased after treatment with DPC,and the Cry1Ac protein content was increased by regulating carbon and amino acid metabolism.展开更多
Despite the continuous developments and advancements in the treatment of gastric cancer(GC),which is one of the most prevalent types of cancer in China,the overall survival is still poor for most patients with advance...Despite the continuous developments and advancements in the treatment of gastric cancer(GC),which is one of the most prevalent types of cancer in China,the overall survival is still poor for most patients with advanced GC.In recent years,with the progress in tumor immunology research,attention has shifted toward immunotherapy as a therapeutic approach for GC.Programmed cell death protein 1(PD-1)inhibitors,as novel immunosuppressive medications,have been widely utilized in the treatment of GC.However,many patients are still resistant to PD-1 inhibitors and experience recurrence in the advanced stages of PD-1 immunotherapy.To reduce the occurrence of drug resistance and recurrence in GC patients receiving PD-1 immunotherapy,to maximize the clinical activity of immunosuppressive drugs,and to elicit a lasting immune response,it is essential to research the tumor microenvironment mechanisms leading to PD-1 inhibitor resistance in GC patients.This article reviews the progress in studying the factors influencing the resistance to PD-1 inhibitors in the GC tumor microenvironment,aiming to provide insights and a basis for reducing resistance to PD-1 inhibitors for GC patients in the future.展开更多
In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1(PTB) knockdown has been sho...In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1(PTB) knockdown has been shown to reprogram astrocytes to functional neurons in situ. In this study, we used AAV-PHP.e B-GFAP-sh PTB to knockdown PTB in a mouse model of ischemic stroke induced by endothelin-1, and investigated the effects of GFAP-sh PTB-mediated direct reprogramming to neurons. Our results showed that in the mouse model of ischemic stroke, PTB knockdown effectively reprogrammed GFAP-positive cells to neurons in ischemic foci, restored neural tissue structure, reduced inflammatory response, and improved behavioral function. These findings validate the effectiveness of in situ transdifferentiation of astrocytes, and suggest that the approach may be a promising strategy for stroke treatment.展开更多
基金supported by the National Natural Science Foundation of China,Nos.91849115 and U1904207(to YX),81974211 and 82171247(to CS)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No.2020-PT310-01(to YX).
文摘The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.
基金Supported by Grants from Science and Technology Planning Project of Guangdong Province,China,No.2010B031600317Administration of Traditional Chinese Medicine of Guangdong Province,China,No.20111169National Natural Science Foun-dation of China,No.81071872
文摘AIM:To investigate the utility of Beclin-1 and LC3,two autophagy-related proteins,in predicting the cetuximab efficacy in advanced colorectal cancer(ACRC) . METHODS:The data of 85 patients with ACRC treated at the Sun Yat-sen University Cancer Center from March 1,2005 to December 31,2008 were studied,including 45 cases treated with cetuximab-containing chemotherapy and 40 cases treated with non-cetuximab-containing chemotherapy.Beclin-1 and LC3 expression was evaluated by immunohistochemistry,and KRAS status was evaluated by polymerase chain reaction. RESULTS:Beclin-1 and LC3 expression in ACRC wassignificantly correlated(r=0.44,P<0.01);however,LC3 was more highly expressed in cancerous tissues than in normal tissues(Z=-2.63,P<0.01) .In the cetuximab-containing chemotherapy group,patients with low LC3 expression had higher objective response rates(ORRs) than those with high LC3 expression(52.9%vs 17.9%,P=0.01) ,and patients with low Beclin-1 expression had a longer median progressionfree survival(PFS) than their counterparts with higher Beclin-1 expression(9.0 mo vs 3.0 mo,P=0.01) . However,neither of these predictive relationships was detected in the group treated with non-cetuximabcontaining chemotherapy.Patients with wild-type KRAS had higher ORRs(42.3%vs 9.1%,P=0.049) and disease control rates(DCRs)(73.1%vs 36.4%,P= 0.035) ,and longer median PFS(5.5 mo vs 2.5 mo,P= 0.02) than those with mutant KRAS in the cetuximabcontaining chemotherapy group.Neither Beclin-1(P= 0.52) nor LC3(P=0.32) expression was significantly correlated with KRAS status. CONCLUSION:Patients with low Beclin-1 expression had a longer PFS than those with high Beclin-1 expression,and patients with low LC3 expression had a higher ORR in ACRC patients treated with cetuximab-containing chemotherapy.
基金financed by the National Key Research and Development Program of China(2017YFD0200900)。
文摘Fusarium graminearum,the primary pathogenic fungus responsible for Fusarium head blight(FHB)in wheat,secretes abundant chemical compounds that interact with host plants.In this study,a secreted protein FgHrip1,isolated from the culture filtrate of F.graminearum,was found to induce typical cell death in tobacco.The FgHrip1 gene was then cloned and expressed in Escherichia coli.Further bioassay analysis showed that the recombinant FgHrip1 induced early defense induction events,such as reactive oxygen species(ROS)production,callose deposition,and up-regulation of defense-related genes in tobacco.Furthermore,FgHrip1 significantly enhanced immunity in tobacco seedlings against Pseudomonas syringae pv.tabaci 6605(Pst.6605)and tobacco mosaic virus(TMV).FgHrip1-treated wheat spikes also exhibited defense-related transcript accumulation and developed immunity against FHB infection.Whereas the expression of FgHrip1 was induced during the infection process,the deletion of the gene impaired the virulence of F.graminearum.Our results suggest that FgHrip1triggers immunity and induces disease resistance in tobacco and wheat,thereby providing new insight into strategy for biocontrol of FHB.
基金supported by the priority academic program development of Jiangsu Higher education institutionsthe National Natural Science Foundation of China [31801538, 32072200]China Postdoctoral Science Foundation[2019M651747].
文摘Objective This study aimed to investigate the lipid-lowering activity of LFBEP-C1 in high glucose-fed Caenorhabditis elegans(C.elegans).Methods In this study,the fermented barley protein LFBEP-C1 was prepared and tested for its potential anti-obesity effects on C.elegans.The worms were fed Escherichia coli OP50(E.coli OP50),glucose,and different concentrations of LFBEP-C1.Body size,lifespan,movement,triglyceride content,and gene expression were analyzed.The results were analyzed using ANOVA and Tukey's multiple comparison test.Results Compared with the model group,the head-swing frequency of C.elegans in the group of LFBEP-C1 at 20μg/mL increased by 33.88%,and the body-bending frequency increased by 27.09%.This indicated that LFBEP-C1 improved the locomotive ability of C.elegans.The average lifespan of C.elegans reached 13.55 days,and the body length and width of the C.elegans decreased after LFBEP-C1 intake.Additionally,LFBEP-C1 reduced the content of lipid accumulation and triglyceride levels.The expression levels of sbp-1,daf-2,and mdt-15 significantly decreased,while those of daf-16,tph-1,mod-1,and ser-4 significantly increased after LFBEP-C1 intake.Changes in these genes explain the signaling pathways that regulate lipid metabolism.Conclusion LFBEP-C1 significantly reduced lipid deposition in C.elegans fed a high-glucose diet and alleviated the adverse effects of a high-glucose diet on the development,lifespan,and exercise behavior of C.elegans.In addition,LFBEP-C1 regulated lipid metabolism mainly by mediating the expression of genes in the sterol regulatory element-binding protein,insulin,and 5-hydroxytryptamine signaling pathways.
基金supported by the National Natural Science Foundation of China(31901462)the Natural Science Foundation of the Jiangsu Higher Education Institutions,China(22KJA210005)+1 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutions,China(PAPD)the Brand Professional Construction Program of Jiangsu Higher Education Institutions,China。
文摘The effects of mepiquat chloride(DPC)on the Cry1Ac protein content in Bacillus thuringiensis(Bt)cotton boll shells under high temperature and drought stress were investigated to provide a theoretical reference for Bt cotton breeding and high-yield and-efficiency cotton cultivation.This study was conducted using Bt cotton cultivar‘Sikang 3'during the 2020 and 2021 growing seasons at Yangzhou University Farm,Yangzhou,Jiangsu Province,China.Potted cotton plants were exposed to high temperature and drought stress,and sprayed with either 20 mg L^(-1)DPC or water(CK).Seven days after treatment,the Cry1Ac protein content,α-ketoglutarate content,pyruvic acid content,glutamate synthase activity,glutamic oxaloacetic transaminase activity,soluble protein content,and amino acid content were measured,and transcriptome sequencing was performed.DESeq was used for differential gene analysis.Under the DPC treatment,the Cry1Ac protein content increased by 4.7-11.9% compared to CK.Theα-ketoglutarate content,pyruvic acid content,glutamate synthase activity,glutamic oxaloacetic transaminase activity,soluble protein content,and amino acid content all increased.Transcriptome analysis revealed 7,542 upregulated genes and 10,449 downregulated genes for DPC vs.CK.Gene ontology(GO)and Kyoto Encyclopedia of Gene and Genomes(KEGG)analyses showed that the differentially expressed genes were mainly involved in biological processes,such as carbon and amino acid metabolism.For example,genes encoding 6-phosphofructokinase,pyruvate kinase,glutamic pyruvate transaminase,pyruvate dehydrogenase,citrate synthase,isocitrate dehydrogenase,2-oxoglutarate dehydrogenase,glutamate synthase,1-pyrroline-5-carboxylate dehydrogenase,glutamic oxaloacetic transaminase,amino-acid N-acetyltransferase,and acetylornithine deacetylase were all significantly upregulated.The DPC treatment increased pyruvate,α-ketoglutarate,and oxaloacetate by increasing the operational rate of the glycolytic pathway of the citric acid cycle.It also significantly upregulated the genes encoding glutamate synthase,pyrrolidine-5-carboxylic acid dehydrogenase,glutamate oxaloacetate transaminase,and N-acetylglutamate synthetase,while it downregulated the genes encoding glutamine synthetase.Therefore,the synthesis of aspartic acid,glutamic acid,pyruvate,and arginine increased after treatment with DPC,and the Cry1Ac protein content was increased by regulating carbon and amino acid metabolism.
基金Natural Science Foundation of Gansu Province,No.21JR1RA186and the Health Industry Research Program of Gansu Province,No.GSWSKY2021-043.
文摘Despite the continuous developments and advancements in the treatment of gastric cancer(GC),which is one of the most prevalent types of cancer in China,the overall survival is still poor for most patients with advanced GC.In recent years,with the progress in tumor immunology research,attention has shifted toward immunotherapy as a therapeutic approach for GC.Programmed cell death protein 1(PD-1)inhibitors,as novel immunosuppressive medications,have been widely utilized in the treatment of GC.However,many patients are still resistant to PD-1 inhibitors and experience recurrence in the advanced stages of PD-1 immunotherapy.To reduce the occurrence of drug resistance and recurrence in GC patients receiving PD-1 immunotherapy,to maximize the clinical activity of immunosuppressive drugs,and to elicit a lasting immune response,it is essential to research the tumor microenvironment mechanisms leading to PD-1 inhibitor resistance in GC patients.This article reviews the progress in studying the factors influencing the resistance to PD-1 inhibitors in the GC tumor microenvironment,aiming to provide insights and a basis for reducing resistance to PD-1 inhibitors for GC patients in the future.
基金supported by the National Natural Science Foundation of China,No.82071418the Natural Science Foundation of Fujian Province,No.2020J01612 (both to EH)。
文摘In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1(PTB) knockdown has been shown to reprogram astrocytes to functional neurons in situ. In this study, we used AAV-PHP.e B-GFAP-sh PTB to knockdown PTB in a mouse model of ischemic stroke induced by endothelin-1, and investigated the effects of GFAP-sh PTB-mediated direct reprogramming to neurons. Our results showed that in the mouse model of ischemic stroke, PTB knockdown effectively reprogrammed GFAP-positive cells to neurons in ischemic foci, restored neural tissue structure, reduced inflammatory response, and improved behavioral function. These findings validate the effectiveness of in situ transdifferentiation of astrocytes, and suggest that the approach may be a promising strategy for stroke treatment.
