Background:Long non-coding RNAs(lncRNAs)act as epigenetic regulators for tumor hallmarks.This investigation sought to probe the carcinogenic trait of PAN3-AS1 across pan-cancer comprehensively.Methods:We studied the d...Background:Long non-coding RNAs(lncRNAs)act as epigenetic regulators for tumor hallmarks.This investigation sought to probe the carcinogenic trait of PAN3-AS1 across pan-cancer comprehensively.Methods:We studied the diagnostic and prognostic features and the immune landscape of PAN3-AS1 across pan-cancer by bioinformatics approaches.The hierarchical regulatory networks governing PAN3-AS1 expression in colon cancer were explored via chromatin immunoprecipitation,luciferase activity assays,and RNA immunoprecipitation,etc.We screened drugs sensitive to WAP four-disulfide core domain 13(WFDC13)by virtual screening and molecular docking.Results:Single-cell transcriptomics demonstrated that a variety of immune populations abnormally expressed PAN3-AS1 beyond tumor cells.Integration of data from multiple databases revealed that PAN3-AS1 was highly expressed and associated with a bad prognosis in various malignancies.Notably,PAN3-AS1 expression was correlated with a suppressive immune microenvironment.Moreover,we observed poor immunotherapy efficacy when PAN3-AS1 was highly expressed in melanoma.In vitro assays and functional enrichment analysis revealed that PAN3-AS1 was associated with cell proliferation and the immune response in colon cancer.Our experiments confirmed that PAN3-AS1 facilitated WFDC13 expression through competitive binding to hsa-miR-423-5p in colon cancer.Moreover,the present paper illustrated that enhancer activity exerts an important modulatory ability for PAN3-AS1 expression.Conclusion:In short,PAN3-AS1 is a valuable biomarker for diagnosis and prognosis.PAN3-AS1 exhibits linkage to a cold tumor immune microenvironment(TME)and forecasts durable benefit from immunotherapy.Addressing the PAN3-AS1/miR-423-5p/WFDC13 axis might provide a novel option for improving immunotherapy efficacy in colon cancer.展开更多
α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively dete...α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.展开更多
Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration ...Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration and hydroxylation.So far,few crystal structures of plant P450s have been obtained.We determined the crystal structure of IFS from Medicago truncatula at 1.9 by MAD method using a selenomethionine substituted crystal and conducted molecular docking and mutagenesis study.The structure of IFS complexed with imidazole exhibits the helix Iα-loop-helix Iβmotif which corresponds to helix I of other P 450s.Compared with structures of common P450s,IFS/imidazole structure contains an extra domain,i.e.,theγ-domain.The structure reveals a homodimer in which theγ-domain of one molecule interacts with theβ-domain of another.The plane of heme group makes an angle of approximately 40°with the helix Iα-loop-helix Iβmotif.Molecular docking combined with mutagenesis study suggested that Trp-128 and Asp-300 might play important roles in substrate binding and recognition.Phe-301,Ser-303 and Gly-305 from the helix Iα-loop-helix Iβmotif may play important roles in the aryl-ring migration.These novel structural features reveal insights into the unique reaction mechanism of IFS and provide a basis for engineering IFS in leguminous crops for health purpose.展开更多
In addition to their well-established role in allergy mast cells have been described as contributing to functional regulation of both innate and adaptive immune responses in host defense. Mast cells are of hematopoiet...In addition to their well-established role in allergy mast cells have been described as contributing to functional regulation of both innate and adaptive immune responses in host defense. Mast cells are of hematopoietic origin but typically complete their differentiation in tissues where they express immune regulatory functions by releasing diverse mediators and cytokines. Mast cells are abundant at mucosal tissues which are portals of entry for common infectious agents in addition to allergens. Here, we review the current understanding of the participation of mast cells in defense against infection. We also discuss possibilities of exploiting mast cell activation to provide adequate adjuvant activity that is needed in high-quality vaccination against infectious diseases.展开更多
Objective To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha(PPP2R3A)and hexokinase 1(HK1)in glycolysis of hepatocellular carcinoma(HCC).Methods In HepG2 and Huh7 cells...Objective To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha(PPP2R3A)and hexokinase 1(HK1)in glycolysis of hepatocellular carcinoma(HCC).Methods In HepG2 and Huh7 cells,PPP2R3A expression was silenced by small interfering RNA(siRNA)and overexpression by plasmid transfection.The PPP2R3A-related genes were searched by RNA sequencing.Glycolysis levels were measured by glucose uptake and lactate production.QRT-PCR,ELISA,western blot and immunofluorescence assay were performed to detect the changes of PPP2R3A and HK1.Cell proliferation,migration and invasion assay were used to study the roles of HK1 regulation by PPP2R3A.Results RNA sequencing data revealed that PPP2R3A siRNA significantly downregulated the expression of HK1.PPP2R3A gene overexpression promotes,while gene silencing suppresses,the level of HK1 and glycolysis in HCC cells.In HCC tissue samples,PPP2R3A and HK1 were colocalized in the cytoplasm,and their expression showed a positive correlation.HK1 inhibition abrogated the promotion of glycolysis,proliferation,migration and invasion by PPP2R3A overexpression in liver cancer cells.Conclusion Our findings showed the correlation of PPP2R3A and HK1 in the glycolysis of HCC,which reveals a new mechanism for the oncogenic roles of PPP2R3A in cancer.展开更多
Objective:To evaluate the effects of a 48-week course of adefovir dipivoxil(ADV)plus Chinese medicine(CM)therapy,namely Tiaogan Jianpi Hexue(调肝健脾和血)and Tiaogan Jiedu Huashi(调肝解毒化湿)fomulae,in hepatitis B e ...Objective:To evaluate the effects of a 48-week course of adefovir dipivoxil(ADV)plus Chinese medicine(CM)therapy,namely Tiaogan Jianpi Hexue(调肝健脾和血)and Tiaogan Jiedu Huashi(调肝解毒化湿)fomulae,in hepatitis B e antigen(HBeAg)-positive Chinese patients.Methods:A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group(EG,received ADV plus CM)and control group(CG,received ADV plus CM-placebo)for 48 weeks.The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12,24,36,48,respectively.Secondary endpoints including liver functions(enzymes and bilirubin readings)were evaluated every 4 weeks at the beginning of week 24,36,and 48.Routine blood,urine,and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations.Adverse events(AEs)were documented.Results:The combination therapy demonstrated superior HBeAg loss at 48 weeks,without additional AEs.The full analysis population was 560 and 280 in each group.In the EG,population achieved HBeAg loss on week 12,24,36,and 48 were 25(8.90%),34(12.14%),52(18.57%),and 83(29.64%),respectively;the equivalent numbers in the CG were 20(7.14%),41(14.64%),54(19.29%),and 50(17.86%),respectively.There was a statistically significant difference between two groups on week 48(P<0.01).No additional AEs were found in EG.Subgroup analysis suggested different outcomes among treatment patterns.Conclusion:Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy.The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile(ChiCTR-TRC-11001263).展开更多
基金supported by the Shandong Province Medical and Health Technology Project(202303111442).
文摘Background:Long non-coding RNAs(lncRNAs)act as epigenetic regulators for tumor hallmarks.This investigation sought to probe the carcinogenic trait of PAN3-AS1 across pan-cancer comprehensively.Methods:We studied the diagnostic and prognostic features and the immune landscape of PAN3-AS1 across pan-cancer by bioinformatics approaches.The hierarchical regulatory networks governing PAN3-AS1 expression in colon cancer were explored via chromatin immunoprecipitation,luciferase activity assays,and RNA immunoprecipitation,etc.We screened drugs sensitive to WAP four-disulfide core domain 13(WFDC13)by virtual screening and molecular docking.Results:Single-cell transcriptomics demonstrated that a variety of immune populations abnormally expressed PAN3-AS1 beyond tumor cells.Integration of data from multiple databases revealed that PAN3-AS1 was highly expressed and associated with a bad prognosis in various malignancies.Notably,PAN3-AS1 expression was correlated with a suppressive immune microenvironment.Moreover,we observed poor immunotherapy efficacy when PAN3-AS1 was highly expressed in melanoma.In vitro assays and functional enrichment analysis revealed that PAN3-AS1 was associated with cell proliferation and the immune response in colon cancer.Our experiments confirmed that PAN3-AS1 facilitated WFDC13 expression through competitive binding to hsa-miR-423-5p in colon cancer.Moreover,the present paper illustrated that enhancer activity exerts an important modulatory ability for PAN3-AS1 expression.Conclusion:In short,PAN3-AS1 is a valuable biomarker for diagnosis and prognosis.PAN3-AS1 exhibits linkage to a cold tumor immune microenvironment(TME)and forecasts durable benefit from immunotherapy.Addressing the PAN3-AS1/miR-423-5p/WFDC13 axis might provide a novel option for improving immunotherapy efficacy in colon cancer.
基金supported by the Natural Science Foundation of Guangxi Zhuang Automomous Region,Nos.2019GXNSFDA245015(to MC),2022GXNSFBA035654(to HL)the National Natural Science Foundation of China,Nos.82360241(to MC),82304876(to HL)+1 种基金Scientific Research and Technology Development Project of Guilin City,Nos.20220139-3(to MC),20210218-5(to HL)Guangxi Medical and Health Key Discipline Construction Project(to QL)。
文摘α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.
文摘Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration and hydroxylation.So far,few crystal structures of plant P450s have been obtained.We determined the crystal structure of IFS from Medicago truncatula at 1.9 by MAD method using a selenomethionine substituted crystal and conducted molecular docking and mutagenesis study.The structure of IFS complexed with imidazole exhibits the helix Iα-loop-helix Iβmotif which corresponds to helix I of other P 450s.Compared with structures of common P450s,IFS/imidazole structure contains an extra domain,i.e.,theγ-domain.The structure reveals a homodimer in which theγ-domain of one molecule interacts with theβ-domain of another.The plane of heme group makes an angle of approximately 40°with the helix Iα-loop-helix Iβmotif.Molecular docking combined with mutagenesis study suggested that Trp-128 and Asp-300 might play important roles in substrate binding and recognition.Phe-301,Ser-303 and Gly-305 from the helix Iα-loop-helix Iβmotif may play important roles in the aryl-ring migration.These novel structural features reveal insights into the unique reaction mechanism of IFS and provide a basis for engineering IFS in leguminous crops for health purpose.
基金supported by Stiftelsen Clas Groschinskys MinnesfondKonsul Berghs Stiftelse, Swedensupported by a postdoctoral start-up grant from the Affiliated Hospital of Guizhou Medical University,Guiyang,China
文摘In addition to their well-established role in allergy mast cells have been described as contributing to functional regulation of both innate and adaptive immune responses in host defense. Mast cells are of hematopoietic origin but typically complete their differentiation in tissues where they express immune regulatory functions by releasing diverse mediators and cytokines. Mast cells are abundant at mucosal tissues which are portals of entry for common infectious agents in addition to allergens. Here, we review the current understanding of the participation of mast cells in defense against infection. We also discuss possibilities of exploiting mast cell activation to provide adequate adjuvant activity that is needed in high-quality vaccination against infectious diseases.
基金supported by National Natural Science Foundation of China [81372595]
文摘Objective To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha(PPP2R3A)and hexokinase 1(HK1)in glycolysis of hepatocellular carcinoma(HCC).Methods In HepG2 and Huh7 cells,PPP2R3A expression was silenced by small interfering RNA(siRNA)and overexpression by plasmid transfection.The PPP2R3A-related genes were searched by RNA sequencing.Glycolysis levels were measured by glucose uptake and lactate production.QRT-PCR,ELISA,western blot and immunofluorescence assay were performed to detect the changes of PPP2R3A and HK1.Cell proliferation,migration and invasion assay were used to study the roles of HK1 regulation by PPP2R3A.Results RNA sequencing data revealed that PPP2R3A siRNA significantly downregulated the expression of HK1.PPP2R3A gene overexpression promotes,while gene silencing suppresses,the level of HK1 and glycolysis in HCC cells.In HCC tissue samples,PPP2R3A and HK1 were colocalized in the cytoplasm,and their expression showed a positive correlation.HK1 inhibition abrogated the promotion of glycolysis,proliferation,migration and invasion by PPP2R3A overexpression in liver cancer cells.Conclusion Our findings showed the correlation of PPP2R3A and HK1 in the glycolysis of HCC,which reveals a new mechanism for the oncogenic roles of PPP2R3A in cancer.
基金Supported by the China National Science and Technology Major Projects,11th 5-year Project(No.2008ZX10005-006)。
文摘Objective:To evaluate the effects of a 48-week course of adefovir dipivoxil(ADV)plus Chinese medicine(CM)therapy,namely Tiaogan Jianpi Hexue(调肝健脾和血)and Tiaogan Jiedu Huashi(调肝解毒化湿)fomulae,in hepatitis B e antigen(HBeAg)-positive Chinese patients.Methods:A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group(EG,received ADV plus CM)and control group(CG,received ADV plus CM-placebo)for 48 weeks.The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12,24,36,48,respectively.Secondary endpoints including liver functions(enzymes and bilirubin readings)were evaluated every 4 weeks at the beginning of week 24,36,and 48.Routine blood,urine,and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations.Adverse events(AEs)were documented.Results:The combination therapy demonstrated superior HBeAg loss at 48 weeks,without additional AEs.The full analysis population was 560 and 280 in each group.In the EG,population achieved HBeAg loss on week 12,24,36,and 48 were 25(8.90%),34(12.14%),52(18.57%),and 83(29.64%),respectively;the equivalent numbers in the CG were 20(7.14%),41(14.64%),54(19.29%),and 50(17.86%),respectively.There was a statistically significant difference between two groups on week 48(P<0.01).No additional AEs were found in EG.Subgroup analysis suggested different outcomes among treatment patterns.Conclusion:Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy.The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile(ChiCTR-TRC-11001263).
