目的:母亲围孕期服用叶酸是迄今为止减少子代先天性心脏病(congenital heart disease,CHD)最有效的一级预防措施,既往研究提示其相关机制涉及基因和环境因素,但仍未阐明。本研究旨在探讨母亲围孕期服用叶酸、叶酸受体1基因(FOLR1)和叶...目的:母亲围孕期服用叶酸是迄今为止减少子代先天性心脏病(congenital heart disease,CHD)最有效的一级预防措施,既往研究提示其相关机制涉及基因和环境因素,但仍未阐明。本研究旨在探讨母亲围孕期服用叶酸、叶酸受体1基因(FOLR1)和叶酸受体2基因(FOLR2)多态性及两者的交互作用与子代CHD的关系,以期为围孕期叶酸服用剂量的个体化指导提供流行病学证据。方法:采用医院为基础的病例对照研究,招募2017年12月至2020年3月在湖南省儿童医院确诊的569例单纯性CHD患儿的母亲为病例组,以同期、该院确诊的无先天性疾病的652例正常儿的母亲为对照组。通过以问卷为基础的面对面访谈,收集母亲人口学信息和围孕期相关暴露信息,同时采集母亲静脉血5 mL用于FOLR1和FOLR2基因多态性检测。采用多因素logistic回归分析探讨母亲围孕期服用叶酸、FOLR1和FOLR2基因多态性及两者交互作用与子代CHD的关联性。结果:多因素logistic回归分析显示:调整混杂因素后,围孕期服用叶酸能够显著降低子代CHD的风险[调整的相对危险比(adjusted odds ratio,aOR)=0.58,95%CI:0.35~0.95]。母亲FOLR1基因位点rs2071010(G/A vs G/G:aOR=0.67,95%CI:0.47~0.96)与子代CHD风险显著相关[P<0.05,错误发现率P值(false discovery rate P value,FDR;)<0.1];FOLR2基因位点rs514933(T/C vs T/T:aOR=0.60,95%CI:0.43~0.84;C/C vs T/T:aOR=0.55,95%CI:0.33~0.90)在显性模型[(T/C+C/C)vs T/T:aOR=0.59,95%CI:0.43~0.81]和加性模型(C/C vs T/C vs T/T:aOR=0.70,95%CI:0.56~0.88)下均与子代CHD风险显著相关(均P<0.05,FDR;<0.1)。rs2071010 G→A(aOR=0.59,95%CI:0.41~0.86)和rs514933 T→C(aOR=0.52,95%CI:0.37~0.74)与母亲围孕期服用叶酸在子代CHD发生中存在交互作用(P<0.05,FDR;<0.1)。结论:母亲携带FOLR1基因rs2071010G→A与FOLR2基因rs514933 T→C的突变型能够降低子代CHD的发生风险,且围孕期服用叶酸可以强化SNP rs2071010和SNP rs514933对子代发生CHD的保护作用。展开更多
Folate receptor alpha(FOLR1)is vital for cells ingesting folate(FA).FA plays an indispensable role in cell pro-liferation and survival.However,it is not clear whether the axis of FOLR1/FA has a similar function in vir...Folate receptor alpha(FOLR1)is vital for cells ingesting folate(FA).FA plays an indispensable role in cell pro-liferation and survival.However,it is not clear whether the axis of FOLR1/FA has a similar function in viral replication.In this study,we used vesicular stomatitis virus(VSV)to investigate the relationship between FOLR1-mediated FA deficiency and viral replication,as well as the underlying mechanisms.We discovered that FOLR1 upregulation led to the deficiency of FA in HeLa cells and mice.Meanwhile,VSV replication was notably sup-pressed by FOLR1 overexpression,and this antiviral activity was related to FA deficiency.Mechanistically,FA deficiency mainly upregulated apolipoprotein B mRNA editing enzyme catalytic subunit 3B(APOBEC3B)expression,which suppressed VSV replication in vitro and in vivo.In addition,methotrexate(MTX),an FA metabolism inhibitor,effectively inhibited VSV replication by enhancing the expression of APOBEC3B in vitro and in vivo.Overall,our present study provided a new perspective for the role of FA metabolism in viral infections and highlights the potential of MTX as a broad-spectrum antiviral agent against RNA viruses.展开更多
Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and‘cold’tumor immunosuppressive microenvironment.Here,we present a dual-targeting peptide-drug conjugate(PDC)f...Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and‘cold’tumor immunosuppressive microenvironment.Here,we present a dual-targeting peptide-drug conjugate(PDC)for tumor inhibition.Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E(MMAE)into tumor cells via C-X-C chemokine receptor type 4(CXCR4)and folate receptor 1(FOLR1)for synergistic inhibition of growth and metastasis.Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity.The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8^(+)T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells.Therefore,our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.展开更多
文摘目的:母亲围孕期服用叶酸是迄今为止减少子代先天性心脏病(congenital heart disease,CHD)最有效的一级预防措施,既往研究提示其相关机制涉及基因和环境因素,但仍未阐明。本研究旨在探讨母亲围孕期服用叶酸、叶酸受体1基因(FOLR1)和叶酸受体2基因(FOLR2)多态性及两者的交互作用与子代CHD的关系,以期为围孕期叶酸服用剂量的个体化指导提供流行病学证据。方法:采用医院为基础的病例对照研究,招募2017年12月至2020年3月在湖南省儿童医院确诊的569例单纯性CHD患儿的母亲为病例组,以同期、该院确诊的无先天性疾病的652例正常儿的母亲为对照组。通过以问卷为基础的面对面访谈,收集母亲人口学信息和围孕期相关暴露信息,同时采集母亲静脉血5 mL用于FOLR1和FOLR2基因多态性检测。采用多因素logistic回归分析探讨母亲围孕期服用叶酸、FOLR1和FOLR2基因多态性及两者交互作用与子代CHD的关联性。结果:多因素logistic回归分析显示:调整混杂因素后,围孕期服用叶酸能够显著降低子代CHD的风险[调整的相对危险比(adjusted odds ratio,aOR)=0.58,95%CI:0.35~0.95]。母亲FOLR1基因位点rs2071010(G/A vs G/G:aOR=0.67,95%CI:0.47~0.96)与子代CHD风险显著相关[P<0.05,错误发现率P值(false discovery rate P value,FDR;)<0.1];FOLR2基因位点rs514933(T/C vs T/T:aOR=0.60,95%CI:0.43~0.84;C/C vs T/T:aOR=0.55,95%CI:0.33~0.90)在显性模型[(T/C+C/C)vs T/T:aOR=0.59,95%CI:0.43~0.81]和加性模型(C/C vs T/C vs T/T:aOR=0.70,95%CI:0.56~0.88)下均与子代CHD风险显著相关(均P<0.05,FDR;<0.1)。rs2071010 G→A(aOR=0.59,95%CI:0.41~0.86)和rs514933 T→C(aOR=0.52,95%CI:0.37~0.74)与母亲围孕期服用叶酸在子代CHD发生中存在交互作用(P<0.05,FDR;<0.1)。结论:母亲携带FOLR1基因rs2071010G→A与FOLR2基因rs514933 T→C的突变型能够降低子代CHD的发生风险,且围孕期服用叶酸可以强化SNP rs2071010和SNP rs514933对子代发生CHD的保护作用。
基金National Natural Science Foundation of China(No.31970149,81900823)The Major Research and Development Project(2018ZX10301406)Nanjing University-Ningxia University Collaborative Project(Grant#2017BN04).
文摘Folate receptor alpha(FOLR1)is vital for cells ingesting folate(FA).FA plays an indispensable role in cell pro-liferation and survival.However,it is not clear whether the axis of FOLR1/FA has a similar function in viral replication.In this study,we used vesicular stomatitis virus(VSV)to investigate the relationship between FOLR1-mediated FA deficiency and viral replication,as well as the underlying mechanisms.We discovered that FOLR1 upregulation led to the deficiency of FA in HeLa cells and mice.Meanwhile,VSV replication was notably sup-pressed by FOLR1 overexpression,and this antiviral activity was related to FA deficiency.Mechanistically,FA deficiency mainly upregulated apolipoprotein B mRNA editing enzyme catalytic subunit 3B(APOBEC3B)expression,which suppressed VSV replication in vitro and in vivo.In addition,methotrexate(MTX),an FA metabolism inhibitor,effectively inhibited VSV replication by enhancing the expression of APOBEC3B in vitro and in vivo.Overall,our present study provided a new perspective for the role of FA metabolism in viral infections and highlights the potential of MTX as a broad-spectrum antiviral agent against RNA viruses.
基金supported by the Program for the Ministry of Education“Peptide Drugs”Innovation Team(No.IRT_15R27,China)the CAMS Innovation Fund for Medical Sciences(CIFMS,Nos.2019-I2M-5-074,2021-I2M-1-026,2021-I2M-3-001,2022-I2M-2-002,and 2023-I2M-QJ-010,China)+1 种基金the Fundamental Research Funds for the Central Universities(No.lzujbky-2023-11,China)the Key Research and Development Program of Gansu Province(23YFFA0047,China).
文摘Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and‘cold’tumor immunosuppressive microenvironment.Here,we present a dual-targeting peptide-drug conjugate(PDC)for tumor inhibition.Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E(MMAE)into tumor cells via C-X-C chemokine receptor type 4(CXCR4)and folate receptor 1(FOLR1)for synergistic inhibition of growth and metastasis.Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity.The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8^(+)T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells.Therefore,our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.
