Infection is the leading cause of complication after liver transplantation, causing morbidity and mortality in the first months after surgery. Allograft rejection is mediated through adaptive immunological responses, ...Infection is the leading cause of complication after liver transplantation, causing morbidity and mortality in the first months after surgery. Allograft rejection is mediated through adaptive immunological responses, and thus immunosuppressive therapy is necessary after transplantation. In this setting, the presence of genetic variants of innate immunity receptors may increase the risk of post-transplant infection, in comparison with patients carrying wild-type alleles. Numerous studies have investigated the role of genetic variants of innate immune receptors and the risk of complication after liver transplantation, but their results are discordant. Tolllike receptors and mannose-binding lectin are arguably the most important studied molecules; however, many other receptors could increase the risk of infection after transplantation. In this article, we review the published studies analyzing the impact of genetic variants in the innate immune system on the development of infectious complications after liver transplantation.展开更多
Attention deficit hyperactivity disorder （ADHD） is one of the most common mental disorders in childhood, with a high heritability about 60% to 90%. Serotonin is a monoamine neurotransmitter. Numerous studies have re...Attention deficit hyperactivity disorder （ADHD） is one of the most common mental disorders in childhood, with a high heritability about 60% to 90%. Serotonin is a monoamine neurotransmitter. Numerous studies have reported the association between the serotonin receptor family （5-HTR） gene polymorphisms and ADHD, but the results are still controversial. In this study, we conducted a meta-analysis of the association between 5-HTRIB, 5-HTR2A, and 5-HTR2C genetic variants and ADHD. The results showed that the 861G allele of 5-HTRIB SNP rs6296 could significantly increase the risk of ADHD （OR= 1.09, 95% CI： 1.01-1.18）; the 5-HTR2C gene rs518147 （OR=1.69, 95% CI： 1.38-2.07） and rs3813929 （OR = 1.57, 95% CI： 1.25-1.97） were all associated with the risk of ADHD. In addition, we also carried on a case- control study to explore the relevance between potential candidate genes 5-HTR1A, 5-HTRIE, 5-HTR3A and ADHD. The results indicated that 5-HTRIA rs6295 genotype （CC＋CG vs. GG OR=Z00, 95% CI： 1.23-3.27） and allele （OR=1.77, 95% CI： 1.16-2.72） models were statistically significantly different between case group and control group. This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD, and it also provides more evidence for the etiology of ADHD.展开更多
Chimeric antigen receptors （CARs） are fusion molecules that may be genetically delivered ex-vivo to T-cells and other immune cell populations, thereby conferring specifcity for native target antigens found on the s...Chimeric antigen receptors （CARs） are fusion molecules that may be genetically delivered ex-vivo to T-cells and other immune cell populations, thereby conferring specifcity for native target antigens found on the surface of tumour and other target cell types. Antigen recognition by CARs is neither restricted by nor dependent upon human leukocyte antigen antigen expression, favouring widespread use of this technology across transplantation barriers. Signalling is delivered by a designer endodomain that provides a tailored and target-dependent activation signal to polyclonal circulating T-cells. Recent clinical data emphasise the enormous promise of this emer-ging immunotherapeutic strategy for B-cell malignancy, notably acute lymphoblastic leukaemia. In that context, CARs are generally targeted against the ubiquitous B-cell antigen, CD19. However, CAR T-cell immunotherapy is limited by potential for severe ontarget toxicity, notably due to cytokine release syndrome. Furthermore, effcacy in the context of solid tumours remains unproven, owing in part to lack of availability of safe tumourspecific targets, inadequate CAR T-cell homing and hostility of the tumour microenvironment to immune effector deployment. Manufacture and commercial development encountered with more traditional drug products. Finally, there is increasing interest in the application of this technology to the treatment of non-malignant disease states, such as autoimmunity, chronic infection and in the suppression of allograft rejection. Here, we consider the background and direction of travel of this emerging and highly promising treatment for malignant and other disease types.展开更多
The host immune system plays an instrumental role in the surveillance and elimination of tumors by recognizing and destroying cancer cells. In recent decades, studies have mainly focused on adoptive immunotherapy usin...The host immune system plays an instrumental role in the surveillance and elimination of tumors by recognizing and destroying cancer cells. In recent decades, studies have mainly focused on adoptive immunotherapy using engineered T cells for the treatment of malignant diseases. Through gene engraftment of the patient's own T cells with chimeric antigen receptor(CAR),they can recognize tumor specific antigens effectively and eradicate selectively targeted cells in an MHC-independent fashion.To date, CAR-T cell therapy has shown great clinical utility in patients with B-cell leukemias. Owing to different CAR designs and tumor complex microenvironments, genetically redirected T cells may generate diverse biological properties and thereby impact their long-term clinical performance and outcome. Meanwhile some unexpected toxicities that result from CAR-T cell application have been examined and limited the curative effects. Diverse important parameters are closely related with adoptively transferred cell behaviors, including CAR-T cells homing, CAR constitutive signaling, T cell differentiation and exhaustion. Thus, understanding CARs molecular design to improve infused cell efficacy and safety is crucial to clinicians and patients who are considering this novel cancer therapeutics. In this review, the developments in CAR-T cell therapy and the limitations and perspectives in optimizing this technology towards clinical application are discussed.展开更多
Background:Bitter taste receptors(Tas2rs)are generally considered to sense various bitter compounds to escape the intake of toxic substances.Bitter taste receptors have been found to widely express in extraoral tissue...Background:Bitter taste receptors(Tas2rs)are generally considered to sense various bitter compounds to escape the intake of toxic substances.Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo.Methods:To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues,multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene-editing technique.A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes.Then,T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice.Quantitative real-time polymerase chain reaction(qRT-PCR)and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds.Perception to taste substance was also studied using twobottle preference tests.Results:We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique.Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice.But qRT-PCR results revealed the changed expression profile of m Tas2rs gene in taste buds of these mutant mice.With two-bottle preference tests,these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105.In addition,these mutant mice showed a loss of taste perception to quinine dihydrochloride,denatonium benzoate,and cucurbitacin B(CuB).Gnat3-mediated taste receptor and its signal pathway contribute to CuB perception.Conclusions:These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound-induced responses mediated by these TAS2Rs in many extraoral tissues.展开更多
We previously reported that Dai-saiko-to (Da-Chai-Hu-Tang), a traditional Japanese kampo medicine, increased LDL receptor mRNA expression in the liver of the hypercholesterolemic rabbits. In this study, we focused on ...We previously reported that Dai-saiko-to (Da-Chai-Hu-Tang), a traditional Japanese kampo medicine, increased LDL receptor mRNA expression in the liver of the hypercholesterolemic rabbits. In this study, we focused on LDL receptor gene expression in a human hepatoma cell line (HepG2) treated with Dai-saiko-to extract and the extracts of eight herbs presented in Dai-saiko-to. Dai-saiko-to extract significantly increased LDL receptor gene and SREBP2 gene expression compared with the control. The extracts of four herbs, Bupleurum root, Pinellia tuber, Scutellaria root and Peony root significantly increased the LDL receptor gene expression. Whereas, Jujube, Immature orange, Ginger and Rhubarb extracts did not change the gene expression. These results suggest that Dai-saiko-to increased the expression of the cholesterol transport gene (LDL receptor) regulated by SREBP2 gene in the human hepatoma cell line. The pharmacological activity of Dai-saiko-to against hypercholesterolemia and atheromatous lesions related for these four herbal components.展开更多
Motivation:Virus receptors are presented on the cell surfaces of a host and are key for viral infection of host cells.However,no unified resource for the study of viral receptors is currently available.Results:To addr...Motivation:Virus receptors are presented on the cell surfaces of a host and are key for viral infection of host cells.However,no unified resource for the study of viral receptors is currently available.Results:To address this problem,we built EVIHVR,a platform for analyzing the expression and variation,and for the identification of human virus receptors.EVIHVR provides three functions:(1)Receptor expression function for browsing and analyzing the expression of human virus receptors in various human tissues/cells;(2)Receptor gene polymorphism function for analyzing the genetic polymorphism of human virus receptors in different human populations and human tissues;and(3)Predict receptor function for identifying potential virus receptors based on differential expression analysis.EVIHVR can become a useful tool for the analysis and identification of human virus receptors.展开更多
Ongoing insulin therapy maintains LDL receptors at highly expressed state in Type-1 diabetic people;yet Type-1 diabetics are liable of having higher plasma LDL level. This disparity has raised doubt on the probability...Ongoing insulin therapy maintains LDL receptors at highly expressed state in Type-1 diabetic people;yet Type-1 diabetics are liable of having higher plasma LDL level. This disparity has raised doubt on the probability of existence of functionally active LDL receptor in such people. Confocal microscopy and immunoprecipitation have made it evident that a portion of insulin and LDL receptors remain together in a co-localized mode, which only gets freed in presence of insulin. The findings of this study have shown that insulin therapy protects Type-1 diabetic people from the pathogenesis of atherosclerosis by decimating the inactivity of the co-localized LDL receptors in addition to its regular effect of having increased glucose tolerance. The existence of co-localized state of these two receptors and their dependence on insulin for independent activity has, at least, presented a reason for developing hypercholesterolemia and advanced coronary atherosclerotic lesion in chronic Type-1 diabetic subjects.展开更多
Objective To examine the relationship of single-nucleotide polymorphisms(SNPs)in candidate genes with the lipid responses to simvastatin.Methods Chinese patients were treated with simvastatin 40 mg daily for at least ...Objective To examine the relationship of single-nucleotide polymorphisms(SNPs)in candidate genes with the lipid responses to simvastatin.Methods Chinese patients were treated with simvastatin 40 mg daily for at least 6 weeks.20 SNPs in 11 genes were genotyped.Results 95 patients age(mean±SD)57.5±10.6 years completed the treatment.The Adiponectin 45T>G polymorphism was significantly related to absolute reductions in total cholesterol(TC)and LDL-cholesterol with a trend(P=0.053)for percentage reductions in TC(TT∶TG∶GG=-38.4%∶-35.6%∶-32.6%).Similar findings were seen with LDL-Receptor(LDLR)SNPs(2052T>C and 1866C>T)with absolute reductions in TC and LDL-cholesterol significantly associated.The Breast Cancer Resistance Protein(ABCG2)421C>A polymorphism was related(P<0.05)to HDL-cholesterol response(CC∶CA∶AA=+0.50%∶-5.73%∶-11.41%).Conclusions Adiponectin,LDLR and ABCG2 SNPs had some influence on the lipid responses to simvastatin.展开更多
文摘Infection is the leading cause of complication after liver transplantation, causing morbidity and mortality in the first months after surgery. Allograft rejection is mediated through adaptive immunological responses, and thus immunosuppressive therapy is necessary after transplantation. In this setting, the presence of genetic variants of innate immunity receptors may increase the risk of post-transplant infection, in comparison with patients carrying wild-type alleles. Numerous studies have investigated the role of genetic variants of innate immune receptors and the risk of complication after liver transplantation, but their results are discordant. Tolllike receptors and mannose-binding lectin are arguably the most important studied molecules; however, many other receptors could increase the risk of infection after transplantation. In this article, we review the published studies analyzing the impact of genetic variants in the innate immune system on the development of infectious complications after liver transplantation.
文摘Attention deficit hyperactivity disorder （ADHD） is one of the most common mental disorders in childhood, with a high heritability about 60% to 90%. Serotonin is a monoamine neurotransmitter. Numerous studies have reported the association between the serotonin receptor family （5-HTR） gene polymorphisms and ADHD, but the results are still controversial. In this study, we conducted a meta-analysis of the association between 5-HTRIB, 5-HTR2A, and 5-HTR2C genetic variants and ADHD. The results showed that the 861G allele of 5-HTRIB SNP rs6296 could significantly increase the risk of ADHD （OR= 1.09, 95% CI： 1.01-1.18）; the 5-HTR2C gene rs518147 （OR=1.69, 95% CI： 1.38-2.07） and rs3813929 （OR = 1.57, 95% CI： 1.25-1.97） were all associated with the risk of ADHD. In addition, we also carried on a case- control study to explore the relevance between potential candidate genes 5-HTR1A, 5-HTRIE, 5-HTR3A and ADHD. The results indicated that 5-HTRIA rs6295 genotype （CC＋CG vs. GG OR=Z00, 95% CI： 1.23-3.27） and allele （OR=1.77, 95% CI： 1.16-2.72） models were statistically significantly different between case group and control group. This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD, and it also provides more evidence for the etiology of ADHD.
基金Supported by The Wellcome TrustCancer Research UK+9 种基金Bayerthe Medical Research CouncilBreast Cancer NowLeukaemia and Lymphoma ResearchWorldwide Cancer ResearchJune Hancock Mesothelioma FoundationJon Moulton Charitable FoundationPancreatic Cancer United Kingdomthe Experimental Cancer Medicine Centre at King’s College Londonthe National Institute for Health Research(NIHR) Biomedical Research Centre based at Guy’s and St Thomas’NHS Foundation Trust and King’s College London
文摘Chimeric antigen receptors （CARs） are fusion molecules that may be genetically delivered ex-vivo to T-cells and other immune cell populations, thereby conferring specifcity for native target antigens found on the surface of tumour and other target cell types. Antigen recognition by CARs is neither restricted by nor dependent upon human leukocyte antigen antigen expression, favouring widespread use of this technology across transplantation barriers. Signalling is delivered by a designer endodomain that provides a tailored and target-dependent activation signal to polyclonal circulating T-cells. Recent clinical data emphasise the enormous promise of this emer-ging immunotherapeutic strategy for B-cell malignancy, notably acute lymphoblastic leukaemia. In that context, CARs are generally targeted against the ubiquitous B-cell antigen, CD19. However, CAR T-cell immunotherapy is limited by potential for severe ontarget toxicity, notably due to cytokine release syndrome. Furthermore, effcacy in the context of solid tumours remains unproven, owing in part to lack of availability of safe tumourspecific targets, inadequate CAR T-cell homing and hostility of the tumour microenvironment to immune effector deployment. Manufacture and commercial development encountered with more traditional drug products. Finally, there is increasing interest in the application of this technology to the treatment of non-malignant disease states, such as autoimmunity, chronic infection and in the suppression of allograft rejection. Here, we consider the background and direction of travel of this emerging and highly promising treatment for malignant and other disease types.
基金supported by the grants from the National Key Research and Development Program of China (2016YFC1303501 and 2016YFC1303504)the Science and Technology Planning Project of Beijing City (Z151100003915076)the National Natural Science Foundation of China (81472612 and 81501682)
文摘The host immune system plays an instrumental role in the surveillance and elimination of tumors by recognizing and destroying cancer cells. In recent decades, studies have mainly focused on adoptive immunotherapy using engineered T cells for the treatment of malignant diseases. Through gene engraftment of the patient's own T cells with chimeric antigen receptor(CAR),they can recognize tumor specific antigens effectively and eradicate selectively targeted cells in an MHC-independent fashion.To date, CAR-T cell therapy has shown great clinical utility in patients with B-cell leukemias. Owing to different CAR designs and tumor complex microenvironments, genetically redirected T cells may generate diverse biological properties and thereby impact their long-term clinical performance and outcome. Meanwhile some unexpected toxicities that result from CAR-T cell application have been examined and limited the curative effects. Diverse important parameters are closely related with adoptively transferred cell behaviors, including CAR-T cells homing, CAR constitutive signaling, T cell differentiation and exhaustion. Thus, understanding CARs molecular design to improve infused cell efficacy and safety is crucial to clinicians and patients who are considering this novel cancer therapeutics. In this review, the developments in CAR-T cell therapy and the limitations and perspectives in optimizing this technology towards clinical application are discussed.
基金Shanghai Science and Technology Commission“R&D Public Service Platform and Institutional Capacity Improvement Project”,Grant/Award Number:21DZ2291300National Science and Technology Major Project,Grant/Award Number:2017ZX10304402-001-006 and 2017ZX10304402-001-012Start-on Funding from Shanghai Public Health Clinical Center,Grant/Award Number:KY-GW-2019-11,KYGW-2019-19 and KY-GW-2021-39。
文摘Background:Bitter taste receptors(Tas2rs)are generally considered to sense various bitter compounds to escape the intake of toxic substances.Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo.Methods:To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues,multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene-editing technique.A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes.Then,T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice.Quantitative real-time polymerase chain reaction(qRT-PCR)and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds.Perception to taste substance was also studied using twobottle preference tests.Results:We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique.Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice.But qRT-PCR results revealed the changed expression profile of m Tas2rs gene in taste buds of these mutant mice.With two-bottle preference tests,these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105.In addition,these mutant mice showed a loss of taste perception to quinine dihydrochloride,denatonium benzoate,and cucurbitacin B(CuB).Gnat3-mediated taste receptor and its signal pathway contribute to CuB perception.Conclusions:These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound-induced responses mediated by these TAS2Rs in many extraoral tissues.
文摘We previously reported that Dai-saiko-to (Da-Chai-Hu-Tang), a traditional Japanese kampo medicine, increased LDL receptor mRNA expression in the liver of the hypercholesterolemic rabbits. In this study, we focused on LDL receptor gene expression in a human hepatoma cell line (HepG2) treated with Dai-saiko-to extract and the extracts of eight herbs presented in Dai-saiko-to. Dai-saiko-to extract significantly increased LDL receptor gene and SREBP2 gene expression compared with the control. The extracts of four herbs, Bupleurum root, Pinellia tuber, Scutellaria root and Peony root significantly increased the LDL receptor gene expression. Whereas, Jujube, Immature orange, Ginger and Rhubarb extracts did not change the gene expression. These results suggest that Dai-saiko-to increased the expression of the cholesterol transport gene (LDL receptor) regulated by SREBP2 gene in the human hepatoma cell line. The pharmacological activity of Dai-saiko-to against hypercholesterolemia and atheromatous lesions related for these four herbal components.
基金This work was supported by the Hunan Provin-cial Natural Science Foundation of China(2020JJ3006,2019JJ20004)the National Natural Science Founda-tion of China(32170651)。
文摘Motivation:Virus receptors are presented on the cell surfaces of a host and are key for viral infection of host cells.However,no unified resource for the study of viral receptors is currently available.Results:To address this problem,we built EVIHVR,a platform for analyzing the expression and variation,and for the identification of human virus receptors.EVIHVR provides three functions:(1)Receptor expression function for browsing and analyzing the expression of human virus receptors in various human tissues/cells;(2)Receptor gene polymorphism function for analyzing the genetic polymorphism of human virus receptors in different human populations and human tissues;and(3)Predict receptor function for identifying potential virus receptors based on differential expression analysis.EVIHVR can become a useful tool for the analysis and identification of human virus receptors.
文摘Ongoing insulin therapy maintains LDL receptors at highly expressed state in Type-1 diabetic people;yet Type-1 diabetics are liable of having higher plasma LDL level. This disparity has raised doubt on the probability of existence of functionally active LDL receptor in such people. Confocal microscopy and immunoprecipitation have made it evident that a portion of insulin and LDL receptors remain together in a co-localized mode, which only gets freed in presence of insulin. The findings of this study have shown that insulin therapy protects Type-1 diabetic people from the pathogenesis of atherosclerosis by decimating the inactivity of the co-localized LDL receptors in addition to its regular effect of having increased glucose tolerance. The existence of co-localized state of these two receptors and their dependence on insulin for independent activity has, at least, presented a reason for developing hypercholesterolemia and advanced coronary atherosclerotic lesion in chronic Type-1 diabetic subjects.
文摘Objective To examine the relationship of single-nucleotide polymorphisms(SNPs)in candidate genes with the lipid responses to simvastatin.Methods Chinese patients were treated with simvastatin 40 mg daily for at least 6 weeks.20 SNPs in 11 genes were genotyped.Results 95 patients age(mean±SD)57.5±10.6 years completed the treatment.The Adiponectin 45T>G polymorphism was significantly related to absolute reductions in total cholesterol(TC)and LDL-cholesterol with a trend(P=0.053)for percentage reductions in TC(TT∶TG∶GG=-38.4%∶-35.6%∶-32.6%).Similar findings were seen with LDL-Receptor(LDLR)SNPs(2052T>C and 1866C>T)with absolute reductions in TC and LDL-cholesterol significantly associated.The Breast Cancer Resistance Protein(ABCG2)421C>A polymorphism was related(P<0.05)to HDL-cholesterol response(CC∶CA∶AA=+0.50%∶-5.73%∶-11.41%).Conclusions Adiponectin,LDLR and ABCG2 SNPs had some influence on the lipid responses to simvastatin.
