Di(2-ethylhexyl)phthalate(DEHP),an environ-mental endocrine disruptor,has hormone-like activity and endocrine-disrupting effects.However,the types of reproductive hormones associated with DEHP vary across the studies....Di(2-ethylhexyl)phthalate(DEHP),an environ-mental endocrine disruptor,has hormone-like activity and endocrine-disrupting effects.However,the types of reproductive hormones associated with DEHP vary across the studies.Thus,we conducted a systematic review and meta-analysis to pool existing epidemiological evidence.We searched three databases up to January 31,2024,for eligible original studies to ultimately include 37 studies from eight countries with a total of 28911 participants.DEHP exposure was evaluated with urinary metabolites.Since the main types,production sites,blood concentrations,and functions of reproductive hormones differ between men and women,we reported the combined effect values by gender.Subgroup analyses were conducted by age,subfertility status,and the national sociodemographic index(SDI)level.Furthermore,the effect of maternal exposure during pregnancy on children’s reproductive hormone levels was analyzed separately.Overall,in general,in men,DEHP was positively correlated with sex hormone binding-globulin(SHBG)and adversely correlated with total testosterone(TT),free androgen index(FAI),and follicle-stimulating hormone(FSH).Results indicated that among men of reproductive age,DEHP exposure was associated with more significant hormonal suppression in infertile men compared with fertile men.Notably,age subgroup analysis among women revealed that postmenopausal women were more vulnerable to DEHP,which was related to lower TT and estradiol(E2).However,this study did not observe a significant association between prenatal DEHP metabolites and reproductive hormone levels in children.Our research identifies the most susceptible hormones(androgen suppression)after DEHP exposure and suggests that infertile men and postmenopausal women are in great need of more attention as sensitive populations.展开更多
Aberrant expression of Myc is one of the most common oncogenic events in human cancers.Scores of Myc inhibitors are currently under development for treating Myc-driven cancers.In addition to directly targeting tumor c...Aberrant expression of Myc is one of the most common oncogenic events in human cancers.Scores of Myc inhibitors are currently under development for treating Myc-driven cancers.In addition to directly targeting tumor cells,Myc inhibition has been shown to modulate the tumor microenvironment to promote tumor regression.However,the effect of Myc inhibition on immune cells in the tumor microenvironment remains poorly understood.Here,we show that the adaptive immune system plays a vital role in the antitumor effect of pharmacologic inhibition of Myc.Combining genetic and pharmacologic approaches,we found that Myc inhibition enhanced CD8 T cell function by suppressing the homeostasis of regulatory T(Treg)cells and the differentiation of resting Treg(rTreg)cells to activated Treg(aTreg)cells in tumors.Importantly,we demonstrated that different Myc expression levels confer differential sensitivity of T cell subsets to pharmacologic inhibition of Myc.Although ablation of the Myc gene has been shown to suppress CD8 T cell function,Treg cells,which express much less Myc protein than CD8 T cells,are more sensitive to Myc inhibitors.The differential sensitivity of CD8 T and Treg cells to Myc inhibitors resulted in enhanced CD8 T cell function upon Myc inhibition.Our findings revealed that Myc inhibitors can induce an antitumor immune response during tumor progression.展开更多
Upon recognition of foreign antigens,naïve B cells undergo rapid activation,growth,and proliferation.How B-cell growth and proliferation are coupled with activation remains poorly understood.Combining CRISPR/Cas9...Upon recognition of foreign antigens,naïve B cells undergo rapid activation,growth,and proliferation.How B-cell growth and proliferation are coupled with activation remains poorly understood.Combining CRISPR/Cas9-mediated functional analysis and mouse genetics approaches,we found that Dhx33,an activation-induced RNA helicase,plays a critical role in coupling B-cell activation with growth and proliferation.Mutant mice with B-cell-specific deletion of Dhx33 exhibited impaired B-cell development,germinal center reactions,plasma cell differentiation,and antibody production.Dhx33-deficient B cells appeared normal in the steady state and early stage of activation but were retarded in growth and proliferation.Mechanistically,Dhx33 played an indispensable role in activation-induced upregulation of ribosomal DNA(rDNA)transcription.In the absence of Dhx33,activated B cells were compromised in their ability to ramp up 47S ribosomal RNA(rRNA)production and ribosome biogenesis,resulting in nucleolar stress,p53 accumulation,and cellular death.Our findings demonstrate an essential role for Dhx33 in coupling B-cell activation with growth and proliferation and suggest that Dhx33 inhibition is a potential therapy for lymphoma and antibody-mediated autoimmune diseases.展开更多
Cellular immunity mediated by CD8+T cells plays an indispensable role in bacterial and viral clearance and cancers.However,persistent antigen stimulation of CD8+T cells leads to an exhausted or dysfunctional cellular ...Cellular immunity mediated by CD8+T cells plays an indispensable role in bacterial and viral clearance and cancers.However,persistent antigen stimulation of CD8+T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors.Numerous studies have shown that glycogen synthase kinase 3(GSK3)controls the function and development of immune cells,but whether GSK3 affects CD8+T cells is not clearly elucidated.Here,we demonstrate that mice with deletion of Gsk3αand Gsk3βin activated CD8+T cells(DKO)exhibited decreased CTL differentiation and effector function during acute and chronic viral infection.In addition,DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+T cells.Strikingly,anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice.Mechanistically,GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT,thereby in turn dampening NFAT-mediated exhaustion-related gene expression,including TOX/TOX2 and PD-1.Thus,we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.42375184 and 42105165)Research Funds of Center for Big Data and Population Health of IHM(Grant No.JKS2022011)Natural Science Research Key Project of University of Anhui Province(Grant No.2023AH050652).
文摘Di(2-ethylhexyl)phthalate(DEHP),an environ-mental endocrine disruptor,has hormone-like activity and endocrine-disrupting effects.However,the types of reproductive hormones associated with DEHP vary across the studies.Thus,we conducted a systematic review and meta-analysis to pool existing epidemiological evidence.We searched three databases up to January 31,2024,for eligible original studies to ultimately include 37 studies from eight countries with a total of 28911 participants.DEHP exposure was evaluated with urinary metabolites.Since the main types,production sites,blood concentrations,and functions of reproductive hormones differ between men and women,we reported the combined effect values by gender.Subgroup analyses were conducted by age,subfertility status,and the national sociodemographic index(SDI)level.Furthermore,the effect of maternal exposure during pregnancy on children’s reproductive hormone levels was analyzed separately.Overall,in general,in men,DEHP was positively correlated with sex hormone binding-globulin(SHBG)and adversely correlated with total testosterone(TT),free androgen index(FAI),and follicle-stimulating hormone(FSH).Results indicated that among men of reproductive age,DEHP exposure was associated with more significant hormonal suppression in infertile men compared with fertile men.Notably,age subgroup analysis among women revealed that postmenopausal women were more vulnerable to DEHP,which was related to lower TT and estradiol(E2).However,this study did not observe a significant association between prenatal DEHP metabolites and reproductive hormone levels in children.Our research identifies the most susceptible hormones(androgen suppression)after DEHP exposure and suggests that infertile men and postmenopausal women are in great need of more attention as sensitive populations.
基金This study was supported by the National Natural Science Foundation of China(31770953,81830047,81961138008 to CX,32070877 to W-HL,and 31570883 to NX)1000 Young Talents Program of China(NX)the Fundamental Research Funds for the Central Universities of China-Xiamen University(20720170064 to CX).
文摘Aberrant expression of Myc is one of the most common oncogenic events in human cancers.Scores of Myc inhibitors are currently under development for treating Myc-driven cancers.In addition to directly targeting tumor cells,Myc inhibition has been shown to modulate the tumor microenvironment to promote tumor regression.However,the effect of Myc inhibition on immune cells in the tumor microenvironment remains poorly understood.Here,we show that the adaptive immune system plays a vital role in the antitumor effect of pharmacologic inhibition of Myc.Combining genetic and pharmacologic approaches,we found that Myc inhibition enhanced CD8 T cell function by suppressing the homeostasis of regulatory T(Treg)cells and the differentiation of resting Treg(rTreg)cells to activated Treg(aTreg)cells in tumors.Importantly,we demonstrated that different Myc expression levels confer differential sensitivity of T cell subsets to pharmacologic inhibition of Myc.Although ablation of the Myc gene has been shown to suppress CD8 T cell function,Treg cells,which express much less Myc protein than CD8 T cells,are more sensitive to Myc inhibitors.The differential sensitivity of CD8 T and Treg cells to Myc inhibitors resulted in enhanced CD8 T cell function upon Myc inhibition.Our findings revealed that Myc inhibitors can induce an antitumor immune response during tumor progression.
基金the National Natural Science Foundation of China(31570882,31770950 and 32070877 to W-H.L,and 81961138008 to CX)the Fundamental Research Funds for the Central Universities of China-Xiamen University(20720170064 to CX)the Sanofi Institute for Biomedical Research(SIBR).
文摘Upon recognition of foreign antigens,naïve B cells undergo rapid activation,growth,and proliferation.How B-cell growth and proliferation are coupled with activation remains poorly understood.Combining CRISPR/Cas9-mediated functional analysis and mouse genetics approaches,we found that Dhx33,an activation-induced RNA helicase,plays a critical role in coupling B-cell activation with growth and proliferation.Mutant mice with B-cell-specific deletion of Dhx33 exhibited impaired B-cell development,germinal center reactions,plasma cell differentiation,and antibody production.Dhx33-deficient B cells appeared normal in the steady state and early stage of activation but were retarded in growth and proliferation.Mechanistically,Dhx33 played an indispensable role in activation-induced upregulation of ribosomal DNA(rDNA)transcription.In the absence of Dhx33,activated B cells were compromised in their ability to ramp up 47S ribosomal RNA(rRNA)production and ribosome biogenesis,resulting in nucleolar stress,p53 accumulation,and cellular death.Our findings demonstrate an essential role for Dhx33 in coupling B-cell activation with growth and proliferation and suggest that Dhx33 inhibition is a potential therapy for lymphoma and antibody-mediated autoimmune diseases.
基金supported by the National Natural Science Foundation of China(31770953,81830047,and 81961138008 to CX and 32070877 to W-HL),1000 Young Talents Program of China(NX)the Fundamental Research Funds for the Central Universities of China-Xiamen University(20720170064 to CX).
文摘Cellular immunity mediated by CD8+T cells plays an indispensable role in bacterial and viral clearance and cancers.However,persistent antigen stimulation of CD8+T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors.Numerous studies have shown that glycogen synthase kinase 3(GSK3)controls the function and development of immune cells,but whether GSK3 affects CD8+T cells is not clearly elucidated.Here,we demonstrate that mice with deletion of Gsk3αand Gsk3βin activated CD8+T cells(DKO)exhibited decreased CTL differentiation and effector function during acute and chronic viral infection.In addition,DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+T cells.Strikingly,anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice.Mechanistically,GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT,thereby in turn dampening NFAT-mediated exhaustion-related gene expression,including TOX/TOX2 and PD-1.Thus,we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.
