Recurrent pregnancy loss （RPL） is a condition with complex etiologies, to which both genetic and envi- ronmental factors may contribute. During the last decade, studies indicated that the expression patterns of the ...Recurrent pregnancy loss （RPL） is a condition with complex etiologies, to which both genetic and envi- ronmental factors may contribute. During the last decade, studies indicated that the expression patterns of the pro- kineticin receptor （PKR1 and PKR2） are closely related to early pregnancy. However, there are few studies on the role of PKR1 and PKR2 in RPL. In this study, we purpose to investigate the association between polymorphisms of the prokineticin receptor （PKR1 rs4627609 and PKR2 rs6053283） and RPL on a group of 93 RPL cases and 169 healthy controls. Genotyping of the single nucleotide polymorphisms （SNPs） was performed using a Sequenom MassARRAY iPLEX system. The results revealed a significant association between PKR2 rs6053283 polymorphism and RPL （P=0.003）, whereas no association was observed between PKR1 rs4627609 polymorphism and RPL （P=-0.929） in the Chinese Han population.展开更多
Objective To evaluate whether mono（2‐ethylhexyl） phthalate（MEHP） affects genomic DNA methylation and the methylation status of some specific genes such as patched gene（PTCH） and smoothened gene（SMO） in LNCaP ...Objective To evaluate whether mono（2‐ethylhexyl） phthalate（MEHP） affects genomic DNA methylation and the methylation status of some specific genes such as patched gene（PTCH） and smoothened gene（SMO） in LNCaP cells. Methods LNCaP cells were treated with MEHP（0, 1, 5, 10, and 25 μmol/L） for 3 days. An ELISA assay was preformed to detect genomic methylation, including 5‐methylcytosine（5‐mC） and 5‐hydroxymethylcytosine（5‐hmC） content. A pyrosequencing assay was applied to assess DNA methylation in PTCH and SMO gene promoters. The correlation between DNA methylation and gene expression was assessed. Results The proportion of cytosines with 5‐mC methylation in LNCaP cells was significantly decreased by MEHP（1, 5, 10, and 25 μmol/L） in a dose‐dependent manner（P 〈 0.01）. For genes in the Hedgehog pathway, there was no significant MEHP concentration‐dependent difference in the DNA methylation of PTCH and SMO. Conclusion MEHP might affect the progression of prostate cancer through its effect on global DNA methylation.展开更多
Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent...Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent that human diseases can also be caused by copy number variations （CNVs）, especially patient- specific novel CNVs （lafrate et al., 2004; Sebat et al., 2004; Redon et al., 2006; LuDski, 2007; Zhan~ et al.. 2009： Wu et al.. 2015）.展开更多
In pregnancy,the maternal immune system(including innate and adaptive immunity)makes elaborate adjustments to endure the embryo’s expression of paternal antigens and to protect the embryo from attacks by invading pat...In pregnancy,the maternal immune system(including innate and adaptive immunity)makes elaborate adjustments to endure the embryo’s expression of paternal antigens and to protect the embryo from attacks by invading pathogens such as bacteria or viruses.1 As the predominant innate immune cells during gestation,natural killer(NK)cells have been proven to mediate the establishment of maternal-fetal immune tolerance and to initiate appropriate defenses against infections.2 Tim-3,a member of the T-cell immunoglobulin and mucin domain proteins,has emerged as a key molecule in both innate and adaptive responses and represents a promising novel therapeutic target.展开更多
Objective:To investigate whether kynurenine/aryl hydrocarbon receptor(AHR)affects the maternal-fetal tolerance by involving the differentiation of T helper 17(Th17)/regulatory T(Treg)cells,and to provide theoretical b...Objective:To investigate whether kynurenine/aryl hydrocarbon receptor(AHR)affects the maternal-fetal tolerance by involving the differentiation of T helper 17(Th17)/regulatory T(Treg)cells,and to provide theoretical basic for new treatment of unexplained abortion.Methods:Flow cytometry(FCM)was used to detect the expression of AHR in peripheral/decidual CD4+T,Treg,and Th17 cells.The effect of Kyn on the differentiation of peripheral/decidual naïve T-cells under Treg-/Th17-polarizing condition was detected by FCM;enzyme-linked immunosorbent assay was performed to examine the level of Kyn in villus and decidual tissues from normal pregnancy(NP)and unexplained abortion(UA).Student’s t-test in the case of two groups or one-way ANOVA in multiple groups was used.Results:AHR expression in CD4+T-cells was decreased in decidua versus blood in early pregnancy(P<0.0001).Kyn could promote the differentiation of peripheral and decidual naïve T-cells to Th17 cells under Treg-polarizing conditions(P<0.01).There was no statistical significance about the concentration of Kyn in decidual or villi tissues between NP and UA,and compared with NP,the expression of AHR in decidual CD4+T-cells from UA was increased(P<0.001).Conclusions:Kyn/AHR promotes Th17 and restricts Treg cells’differentiation,which is involved in maintaining the balance of Treg/Th17 cells at the maternal-fetal interface.展开更多
Background:To investigate the regulatory effect of interleukin-24(IL-24)on cell viability of human chorionic trophoblast cell line(HTR-8/SVneo cells).Methods:Immunohistochemical staining was used to detect the express...Background:To investigate the regulatory effect of interleukin-24(IL-24)on cell viability of human chorionic trophoblast cell line(HTR-8/SVneo cells).Methods:Immunohistochemical staining was used to detect the expression of IL-24 and its receptors IL-20R1,IL-20R2,and IL-22R1 in villus tissue at early normal pregnancy.The effect of thymic stromal lymphopoietin(TSLP)and chemokine CCL2 on the expression of IL-24 in human chorionic trophoblast cell line HTR-8/SVneo cells was analyzed by In-cell Western.In addition,the effect of recombinant human IL-24(rhIL-24)and CCL2 on the viability of HTR-8/SVneo cells was analyzed by MTT assay.Results:IL-24 and its receptors showed a strong positive staining in trophoblasts at early normal pregnancy.Compared with control group,expression of IL-24 in HTR-8/SVneo cells was significantly inhibited after in vitro stimulation of recombinant human CCL2 protein(rhCCL2)(P<0.001).The viability of HTR-8/SVneo cells was significantly decreased after treatment with rhIL-24(P<0.001).In contrast,anti-IL-24 neutralizing antibody significantly enhanced the viability of HTR-8/SVneo cells(P<0.01).In addition,rhCCL2(100μg/L);enhanced the viability of HTR-8/SVneo cells(P<0.01)in vitro,but this effect was inhibited by treatment with rhIL-24.Conclusions:CCL2 enhances the viability of human trophoblast cell line HTR-8/SVneo cells in vitro by inhibiting the secretion of IL-24,which may be beneficial to blastocyst implantation and placental development.展开更多
Circular RNAs(circRNAs)represent a mysterious class of noncoding RNAs that are generated by the circularization of exons or introns and characterized as being highly stable and abundant.Although circRNAs have been stu...Circular RNAs(circRNAs)represent a mysterious class of noncoding RNAs that are generated by the circularization of exons or introns and characterized as being highly stable and abundant.Although circRNAs have been studied for several decades,our knowledge of these molecules remains limited.With the development of innovative bioinformatic tools and sequencing methods,comprehensive studies of circRNAs are now available in the literature.There is emerging evidence to show that circRNAs play roles in the regulation of gene expression.In this review,several primary potential functions of circRNAs are summarized;these include binding to microRNA/RNA-binding proteins,inhibiting/promoting messenger RNA translation,and their own translation.展开更多
Numerous studies have shown aberrant immune cell function in endometriosis,including T cells,B cells,natural killer cells,and macrophages(MΦ).These alterations are thought to be induced by various mechanisms that pro...Numerous studies have shown aberrant immune cell function in endometriosis,including T cells,B cells,natural killer cells,and macrophages(MΦ).These alterations are thought to be induced by various mechanisms that promote the disease.Regulatory T cells(Tregs)may account for a decreased ability of newly recruited leukocytes to initiate effective immune responses against viable endometrial fragments,permitting their survival.Tregs differentiate during the development of endometriosis,which confer immunosuppression or play other roles in disease progression.In this review,we provide an overview of the regulation and roles of Tregs in endometriosis.These data provide further scientific evidence for the altered immune response in endometriosis,which could be a potential target in the treatment of endometriosis.This review could create new diagnostic strategies and effective immune-targeted therapies for this highly prevalent disease.Recent progress in the field indicates that these goals may be achieved in the future.展开更多
Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effec...Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effective method. Methods: A total of 153 Han Chinese women with sporadic POI were systematically analyzed for trinucleotide repeats within the FMR1 gene. We employed an improved strategy to screen for cytosine-guanine-guanine repeats in the 5’ untranslated region of the FMR1 gene. Before using the previously reported Fragil Ease polymerase chain reaction(PCR) method for premutation identification, we developed a new cost-effective PCR-based method to exclude most of the normal allele carriers during the initial screening stage. Results: In our initial screening, 62.1% of women with POI were found to carry heterozygous normal alleles of FMR1, which were recognized by our sensitive and cost-effective method. The remaining women were further screened for the presence of the FMR1 premutation. We identified a Han Chinese woman with a premutation allele of FMR1 out of 153 sporadic POI women(0.7%). Conclusions: The frequent FMR1 premutation in Caucasian individuals with POI may not be a common genetic cause of sporadic POI in the Han Chinese population.展开更多
T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal development.Although it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs...T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal development.Although it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs)involving T are not well established.Here,we report a family with 15 CVM patients distributed across 4 generations.All affected individuals carry a heterozygous mutation,T c.596A>G(p.Q199R),which is not found in unaffected family members,indicating co-segregation of the genotype and phenotype.In vitro assays show that T p.Q199R increases the nucleocytoplasmic ratio and enhances its DNA-binding affinity,but reduces its transcriptional activity compared to the wild-type.To determine the pathogenicity of this mutation in vivo,we generated a Q199R knock-in mouse model that recapitulates the human CVM phenotype.Most heterozygous Q199R mice show subtle kinked or shortened tails,while homozygous mice exhibit tail filaments and severe vertebral deformities.Overall,we show that the Q199R mutation in T causes CVM in humans and mice,providing previously unreported evidence supporting the function of T in the genetic etiology of human CVM.展开更多
Objective:To explore the association between interpersonal relationship and erectile dysfunction(ED)of middle-aged and elderly men.Methods:A population-based cross-sectional research was conducted in the rural area of...Objective:To explore the association between interpersonal relationship and erectile dysfunction(ED)of middle-aged and elderly men.Methods:A population-based cross-sectional research was conducted in the rural area of Jiashan County,Zhejiang Province,in 2016.Middle-aged and elderly men(aged 40-80)were selected as study participants.The face-to-face questionnaire was collected,including basic information,lifestyles,interpersonal relationship,and sexual function.The interpersonal relationship was evaluated based on marital relationship,neighborhood relationship,and relatives/friends relationship.According to the International index of erectile function,the study participants were divided into ED group(mild ED,moderate-to-severe ED),and non-ED group.Correlations were evaluated between interpersonal relationship indices and the prevalence or the severity of ED.Potential confounders were adjusted by the logistical regression model.Results:There were 674 study participants with average age of 60.4±8.5 years,and 489 ED patients with prevalence of 72.6%.With age increasing,the prevalence and the severity of ED increased significantly.The men who could get help from spouse when an emergency occurred or who were more cared about by their neighbors had lower ED risk,and odds ratios(ORs)(95%confidence intervals[CIs])were 0.23(0.13-0.42)and 0.58(0.46-0.75),respectively.After the adjustment of the covariates(age,education degree,household income,smoking,and drinking),the ORs(95%CIs)were 0.29(0.14-0.60)and 0.54(0.39-0.74),respectively.Good marital relationship and good neighborhood relationship were associated with a less severity of ED.展开更多
Decidual immune cells(DICs),including T-cells,regulatory T-cells,macrophages/dendritic cells,natural killer cells,and neutrophils,are resident at the maternal-fetal interface,and play vital roles in regulating trophob...Decidual immune cells(DICs),including T-cells,regulatory T-cells,macrophages/dendritic cells,natural killer cells,and neutrophils,are resident at the maternal-fetal interface,and play vital roles in regulating trophoblast migration,decidual angiogenesis,immune tolerance,placentation,and decidualization during the early pregnancy.Extensive researches have revealed that these maternal DICs cooperated with each other,or with maternal decidual stromal cells,or with fetal-derived trophoblasts,and further formed a special maternal-fetal cross talk at the maternal-fetal interface,which was essential for the construction and maintenance of physiological pregnancy.Once aberrant cross talk and immune regulation arise,many pregnancy complications will inevitably occur,such as spontaneous abortion,intrauterine growth restriction(IUGR),preeclampsia(PE),and preterm birth.Here,we reviewed how critical immune cells are either enriched or excluded from the decidua,how their function is regulated within the decidua,and how they variously contribute to pregnancy success or failure.展开更多
Despite impressive progress being made in investigating the mechanisms underlying endometriosis,the pathophysiology of this disease remains unclear.Although typical methods used for diagnosing endometriosis such as ul...Despite impressive progress being made in investigating the mechanisms underlying endometriosis,the pathophysiology of this disease remains unclear.Although typical methods used for diagnosing endometriosis such as ultrasound,magnetic resonance imaging,and blood tests are available,these are also inefficient,and effective noninvasive diagnostic methods are lacking.The advances in high-throughput omics techniques have enabled metabolomics to become an effective approach for discovering promising biomarkers.The aberrant metabolism associated with serious symptoms of endometriosis in women has been revealed in recent years.Analyzing the global metabolic patterns in patients with endometriosis may help deepen the understanding of the disease mechanism and have a significant impact on future diagnostic and treatment methods for endometriosis.Herein,we reviewed relevant studies on metabolic changes in patients with endometriosis and discussed the changes in metabolites both in biological fluids and endometriosis tissues.The findings discussed in this review have potential diagnostic implications and will enhance the understanding of the pathophysiological processes underlying the disease.展开更多
Decidual macrophages (dMΦ) are distinct from the conventional macrophages present in other tissues and express M2macrophage markers, but the molecular mechanisms of formation and the roles of M2 MΦ during pregnancy ...Decidual macrophages (dMΦ) are distinct from the conventional macrophages present in other tissues and express M2macrophage markers, but the molecular mechanisms of formation and the roles of M2 MΦ during pregnancy have not beencompletely elucidated. The crosstalk between decidual natural killer cells (dNK) and dMΦ plays an important role in themaintenance of maternal–fetal immune tolerance. Here, CXCL16 derived from first-trimester trophoblast cells induces thepolarization of human M2 macrophages. The M2 MΦ polarized by CXCL16 exhibit decreased interleukin-15 production, whichfacilitates the inactivation of NK cells. The cytotoxicity of NK cells is attenuated by the CXCL16-polarized M2 MΦ. The data shown inthe present study provide evidence to support the hypothesis that CXCL16 secreted by trophoblast cells is a key molecule involvedin decidual M2 MΦ polarization, which in turn regulates the killing ability of NK cells, thereby contributing to the homeostatic andimmune-tolerant milieu required for successful fetal development.展开更多
While several organs in mammals retain partial regen- erative capability following tissue damage, the underly- ing mechanisms remain unclear. Recently, the Hippo signaling pathway, better known for its function in org...While several organs in mammals retain partial regen- erative capability following tissue damage, the underly- ing mechanisms remain unclear. Recently, the Hippo signaling pathway, better known for its function in organ size control, has been shown to play a pivotal role in regulating tissue homeostasis and regeneration. Upon tissue injury, the activity of YAP, the major effector of the Hippo pathway, is transiently induced, which in turn promotes expansion of tissue-resident progenitors and facilitates tissue regeneration. In this review, with a general focus on the Hippo pathway, we will discuss its major components, functions in stem cell biology, involvement in tissue regeneration in different organs, and potential strategies for developing Hippo pathway- targeted regenerative medicines.展开更多
In addition to their use in relieving the symptoms of various diseases,ketogenic diets(KDs)have also been adopted by healthy individuals to prevent being overweight.Herein,we reported that prolonged KD exposure induce...In addition to their use in relieving the symptoms of various diseases,ketogenic diets(KDs)have also been adopted by healthy individuals to prevent being overweight.Herein,we reported that prolonged KD exposure induced cardiac fibrosis.In rats,KD or frequent deep fasting decreased mitochondrial biogenesis,reduced cell respiration,and increased cardiomyocyte apoptosis and cardiac fibrosis.Mechanistically,increased levels of the ketone body β-hydroxybutyrate(β-OHB),an HDAC2 inhibitor,promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription.This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis,leading to cardiomyocyte apoptosis and cardiac fibrosis.展开更多
Background:To determine the efficacy of the Caulis Sargentodoxae prescription,which is an empirical formula of Chinese herbs and has definite curative effects on endometriosis.Methods:The Caulis Sargentodoxae prescrip...Background:To determine the efficacy of the Caulis Sargentodoxae prescription,which is an empirical formula of Chinese herbs and has definite curative effects on endometriosis.Methods:The Caulis Sargentodoxae prescription on the growth of ectopic endometria was studied with a rat endometriosis(EMS)model.The EMS model was established by autoplastic transplantation.To study the curative effects of Chinese medicine on EMS in comparison with western medicine,gestrinone and an angiogenesis inhibitor were introduced.The rats were randomly divided into seven groups:normal group,model group,ovariectomized group,gestrinone(western medicine)group,Caulis Sargentodoxae prescription(Chinese medicine)group,apatinib(inhibitor)group,and combination(Chinese medicine+inhibitor)group.After administration for 21 days,the growth inhibitory rates of ectopic endometria in the treatment groups were evaluated,and the levels of vascular endothelial growth factor(VEGF)and VEGF receptor-2(VEGFR2)were detected by ELISA in the serum and peritoneal fluid,as well as in the ectopic endometrial tissues by real-time polymerase chain reaction and Western blotting.Results:The growth inhibitory rates of ectopic endometria in the treatment groups were significantly higher(P<0.05).In the Caulis Sargentodoxae prescription group,the levels of angiogenesis-related factors,including VEGF and VEGFR2,were reduced in the serum and peritoneal fluid compared with the model group(P<0.05).In addition,the positive expression of VEGF and VEGFR2 in ectopic endometria significantly decreased in the Caulis Sargentodoxae prescription group both at mRNA and protein levels.Conclusions:VEGF and VEGFR2 levels in the serum and peritoneal fluid can be used as a clinical reference for endometriotic pathogenesis and treatment,and the Caulis Sargentodoxae prescription has reliable therapeutic effects on EMS for its target-action ability to decrease angiogenesis.展开更多
In this article,published online 27 March 2018,in the“ACKNOWLEDGEMENTS”,it should be supplemented as follows:“This study was funded by a grant from the National Natural Science Foundation of China,number 81490744,a...In this article,published online 27 March 2018,in the“ACKNOWLEDGEMENTS”,it should be supplemented as follows:“This study was funded by a grant from the National Natural Science Foundation of China,number 81490744,awarded to Da-Jin Li.”The authors regret the omission.展开更多
A successful pregnancy requires the maternal immune system to recognize and tolerate the allogeneic fetus while maintaining defense against infection both systemically and in placental tissues.At the maternal–fetal i...A successful pregnancy requires the maternal immune system to recognize and tolerate the allogeneic fetus while maintaining defense against infection both systemically and in placental tissues.At the maternal–fetal interface,the trophoblasts in the placenta play an essential role in the suppression of maternal immune rejection of the fetus.To ensure maternal–fetal tolerance and successful placentation,delicate crosstalk is established among fetus-derived trophoblasts,maternal immune cells,and decidual stromal cells(DSCs)during normal pregnancy.Decidual immune cells not only participate in the maintenance of immune tolerance but also regulate the function of trophoblasts to promote fetal growth.An imbalance in this crosstalk may lead to adverse pregnancy outcomes,such as recurrent spontaneous abortion,preeclampsia,preterm birth,intrauterine growth restriction,and infection.Here we outline some of the important discoveries in recent years related to the mechanisms by which trophoblast-derived molecules induce maternal–fetal immune tolerance.展开更多
Long noncoding RNAs(lncRNAs)are known to be involved in transcriptional regulation and their deregulation is associated with the development of human diseases such as cancer.1,2 LncRNA can directly bind to purine-rich...Long noncoding RNAs(lncRNAs)are known to be involved in transcriptional regulation and their deregulation is associated with the development of human diseases such as cancer.1,2 LncRNA can directly bind to purine-rich double-stranded DNA sequences through Hoogsteen base pairing to form an RNA-DNA triplex motifs and regulate gene expression.3,4,5 However,its regulatory mechanisms and functions in tumors remain unclear.Here,we report that the LMNTD2 antisense RNA 1(LMNTD2-AS1,also known as AP006284.1)is highly expressed in prostate cancer(PCa)and positively correlated with the expression of its adjacent coding gene N-terminal Ras-association domain family 7(RASSF7).Mechanistically,AP006284.1 tethers to the RASSF7 promoter via RNA-DNA triplexes in cis-acting manner,which enhances chromatin accessibility and recruits the transcription factor complex GNL3/SFPQ to activate the expression of RASSF7,a repressor of the Hippo signaling pathway.Consistently,overexpression of either AP006284.1 or RASSF7 inactivated the Hippo signaling and malignant proliferation of PCa cells.展开更多
基金Project supported by the National Natural Science Foundation of China(No.81571503)
文摘Recurrent pregnancy loss （RPL） is a condition with complex etiologies, to which both genetic and envi- ronmental factors may contribute. During the last decade, studies indicated that the expression patterns of the pro- kineticin receptor （PKR1 and PKR2） are closely related to early pregnancy. However, there are few studies on the role of PKR1 and PKR2 in RPL. In this study, we purpose to investigate the association between polymorphisms of the prokineticin receptor （PKR1 rs4627609 and PKR2 rs6053283） and RPL on a group of 93 RPL cases and 169 healthy controls. Genotyping of the single nucleotide polymorphisms （SNPs） was performed using a Sequenom MassARRAY iPLEX system. The results revealed a significant association between PKR2 rs6053283 polymorphism and RPL （P=0.003）, whereas no association was observed between PKR1 rs4627609 polymorphism and RPL （P=-0.929） in the Chinese Han population.
基金supported by the National Science and Technology Major Projects for‘Major New Drugs Innovation and Development’(No.2011ZX09301‐003)partly supported by The Fourth Round of Three‐year Public Health Action Plan of Shanghai(No.15GWZK0202)
文摘Objective To evaluate whether mono（2‐ethylhexyl） phthalate（MEHP） affects genomic DNA methylation and the methylation status of some specific genes such as patched gene（PTCH） and smoothened gene（SMO） in LNCaP cells. Methods LNCaP cells were treated with MEHP（0, 1, 5, 10, and 25 μmol/L） for 3 days. An ELISA assay was preformed to detect genomic methylation, including 5‐methylcytosine（5‐mC） and 5‐hydroxymethylcytosine（5‐hmC） content. A pyrosequencing assay was applied to assess DNA methylation in PTCH and SMO gene promoters. The correlation between DNA methylation and gene expression was assessed. Results The proportion of cytosines with 5‐mC methylation in LNCaP cells was significantly decreased by MEHP（1, 5, 10, and 25 μmol/L） in a dose‐dependent manner（P 〈 0.01）. For genes in the Hedgehog pathway, there was no significant MEHP concentration‐dependent difference in the DNA methylation of PTCH and SMO. Conclusion MEHP might affect the progression of prostate cancer through its effect on global DNA methylation.
基金supported by the National Basic Research Program of China(No.2012CB944600)the National Key Research and Development Program of China(No.2016YFC0905100)+1 种基金the National Natural Science Foundation of China(Nos.31521003,31625015,31571297,31601046,31525014 and 91331204)the Science and Technology Commission of Shanghai Municipality(No.16YF1413900)
文摘Human genetic variants have long been known to play an important role in both Mendelian disorders and common diseases. Notably, pathogenic variants are not limited to single-nucleotide variants. It has become apparent that human diseases can also be caused by copy number variations （CNVs）, especially patient- specific novel CNVs （lafrate et al., 2004; Sebat et al., 2004; Redon et al., 2006; LuDski, 2007; Zhan~ et al.. 2009： Wu et al.. 2015）.
文摘In pregnancy,the maternal immune system(including innate and adaptive immunity)makes elaborate adjustments to endure the embryo’s expression of paternal antigens and to protect the embryo from attacks by invading pathogens such as bacteria or viruses.1 As the predominant innate immune cells during gestation,natural killer(NK)cells have been proven to mediate the establishment of maternal-fetal immune tolerance and to initiate appropriate defenses against infections.2 Tim-3,a member of the T-cell immunoglobulin and mucin domain proteins,has emerged as a key molecule in both innate and adaptive responses and represents a promising novel therapeutic target.
基金supported by grants from the Natural Science Foundation of China(No.81373868).
文摘Objective:To investigate whether kynurenine/aryl hydrocarbon receptor(AHR)affects the maternal-fetal tolerance by involving the differentiation of T helper 17(Th17)/regulatory T(Treg)cells,and to provide theoretical basic for new treatment of unexplained abortion.Methods:Flow cytometry(FCM)was used to detect the expression of AHR in peripheral/decidual CD4+T,Treg,and Th17 cells.The effect of Kyn on the differentiation of peripheral/decidual naïve T-cells under Treg-/Th17-polarizing condition was detected by FCM;enzyme-linked immunosorbent assay was performed to examine the level of Kyn in villus and decidual tissues from normal pregnancy(NP)and unexplained abortion(UA).Student’s t-test in the case of two groups or one-way ANOVA in multiple groups was used.Results:AHR expression in CD4+T-cells was decreased in decidua versus blood in early pregnancy(P<0.0001).Kyn could promote the differentiation of peripheral and decidual naïve T-cells to Th17 cells under Treg-polarizing conditions(P<0.01).There was no statistical significance about the concentration of Kyn in decidual or villi tissues between NP and UA,and compared with NP,the expression of AHR in decidual CD4+T-cells from UA was increased(P<0.001).Conclusions:Kyn/AHR promotes Th17 and restricts Treg cells’differentiation,which is involved in maintaining the balance of Treg/Th17 cells at the maternal-fetal interface.
基金This study was supported by the National Natural Science Foundation of China(NSFC)(81571509,31671200)the Program for Zhuoxue of Fudan University.
文摘Background:To investigate the regulatory effect of interleukin-24(IL-24)on cell viability of human chorionic trophoblast cell line(HTR-8/SVneo cells).Methods:Immunohistochemical staining was used to detect the expression of IL-24 and its receptors IL-20R1,IL-20R2,and IL-22R1 in villus tissue at early normal pregnancy.The effect of thymic stromal lymphopoietin(TSLP)and chemokine CCL2 on the expression of IL-24 in human chorionic trophoblast cell line HTR-8/SVneo cells was analyzed by In-cell Western.In addition,the effect of recombinant human IL-24(rhIL-24)and CCL2 on the viability of HTR-8/SVneo cells was analyzed by MTT assay.Results:IL-24 and its receptors showed a strong positive staining in trophoblasts at early normal pregnancy.Compared with control group,expression of IL-24 in HTR-8/SVneo cells was significantly inhibited after in vitro stimulation of recombinant human CCL2 protein(rhCCL2)(P<0.001).The viability of HTR-8/SVneo cells was significantly decreased after treatment with rhIL-24(P<0.001).In contrast,anti-IL-24 neutralizing antibody significantly enhanced the viability of HTR-8/SVneo cells(P<0.01).In addition,rhCCL2(100μg/L);enhanced the viability of HTR-8/SVneo cells(P<0.01)in vitro,but this effect was inhibited by treatment with rhIL-24.Conclusions:CCL2 enhances the viability of human trophoblast cell line HTR-8/SVneo cells in vitro by inhibiting the secretion of IL-24,which may be beneficial to blastocyst implantation and placental development.
基金This study was funded by the National Natural Science Foundation of China(No.81771655)the Innovation-oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation(No.CX2017-03).
文摘Circular RNAs(circRNAs)represent a mysterious class of noncoding RNAs that are generated by the circularization of exons or introns and characterized as being highly stable and abundant.Although circRNAs have been studied for several decades,our knowledge of these molecules remains limited.With the development of innovative bioinformatic tools and sequencing methods,comprehensive studies of circRNAs are now available in the literature.There is emerging evidence to show that circRNAs play roles in the regulation of gene expression.In this review,several primary potential functions of circRNAs are summarized;these include binding to microRNA/RNA-binding proteins,inhibiting/promoting messenger RNA translation,and their own translation.
文摘Numerous studies have shown aberrant immune cell function in endometriosis,including T cells,B cells,natural killer cells,and macrophages(MΦ).These alterations are thought to be induced by various mechanisms that promote the disease.Regulatory T cells(Tregs)may account for a decreased ability of newly recruited leukocytes to initiate effective immune responses against viable endometrial fragments,permitting their survival.Tregs differentiate during the development of endometriosis,which confer immunosuppression or play other roles in disease progression.In this review,we provide an overview of the regulation and roles of Tregs in endometriosis.These data provide further scientific evidence for the altered immune response in endometriosis,which could be a potential target in the treatment of endometriosis.This review could create new diagnostic strategies and effective immune-targeted therapies for this highly prevalent disease.Recent progress in the field indicates that these goals may be achieved in the future.
基金supported by the National Key Research and Development Program of China(2016YFC0905100)the National Natural Science Foundation of China(31625015,31521003,and 31571297).
文摘Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effective method. Methods: A total of 153 Han Chinese women with sporadic POI were systematically analyzed for trinucleotide repeats within the FMR1 gene. We employed an improved strategy to screen for cytosine-guanine-guanine repeats in the 5’ untranslated region of the FMR1 gene. Before using the previously reported Fragil Ease polymerase chain reaction(PCR) method for premutation identification, we developed a new cost-effective PCR-based method to exclude most of the normal allele carriers during the initial screening stage. Results: In our initial screening, 62.1% of women with POI were found to carry heterozygous normal alleles of FMR1, which were recognized by our sensitive and cost-effective method. The remaining women were further screened for the presence of the FMR1 premutation. We identified a Han Chinese woman with a premutation allele of FMR1 out of 153 sporadic POI women(0.7%). Conclusions: The frequent FMR1 premutation in Caucasian individuals with POI may not be a common genetic cause of sporadic POI in the Han Chinese population.
基金supported by the National Key R&D Program of China(2021YFC2701101 to H.W.and X.Y.)the National Natural Science Foundation of China(81930036 and 82150008 to H.W.,and 31000542 to X.Y.)the Commission of Science and Technology of Shanghai Municipality(20JC1418500 to H.W.).
文摘T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal development.Although it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs)involving T are not well established.Here,we report a family with 15 CVM patients distributed across 4 generations.All affected individuals carry a heterozygous mutation,T c.596A>G(p.Q199R),which is not found in unaffected family members,indicating co-segregation of the genotype and phenotype.In vitro assays show that T p.Q199R increases the nucleocytoplasmic ratio and enhances its DNA-binding affinity,but reduces its transcriptional activity compared to the wild-type.To determine the pathogenicity of this mutation in vivo,we generated a Q199R knock-in mouse model that recapitulates the human CVM phenotype.Most heterozygous Q199R mice show subtle kinked or shortened tails,while homozygous mice exhibit tail filaments and severe vertebral deformities.Overall,we show that the Q199R mutation in T causes CVM in humans and mice,providing previously unreported evidence supporting the function of T in the genetic etiology of human CVM.
基金National Science and Technology Basic Work Program(2013FY110500)the open project from Key Laboratory of Reproduction Regulation of NPFPC in 2017(2017KF03).
文摘Objective:To explore the association between interpersonal relationship and erectile dysfunction(ED)of middle-aged and elderly men.Methods:A population-based cross-sectional research was conducted in the rural area of Jiashan County,Zhejiang Province,in 2016.Middle-aged and elderly men(aged 40-80)were selected as study participants.The face-to-face questionnaire was collected,including basic information,lifestyles,interpersonal relationship,and sexual function.The interpersonal relationship was evaluated based on marital relationship,neighborhood relationship,and relatives/friends relationship.According to the International index of erectile function,the study participants were divided into ED group(mild ED,moderate-to-severe ED),and non-ED group.Correlations were evaluated between interpersonal relationship indices and the prevalence or the severity of ED.Potential confounders were adjusted by the logistical regression model.Results:There were 674 study participants with average age of 60.4±8.5 years,and 489 ED patients with prevalence of 72.6%.With age increasing,the prevalence and the severity of ED increased significantly.The men who could get help from spouse when an emergency occurred or who were more cared about by their neighbors had lower ED risk,and odds ratios(ORs)(95%confidence intervals[CIs])were 0.23(0.13-0.42)and 0.58(0.46-0.75),respectively.After the adjustment of the covariates(age,education degree,household income,smoking,and drinking),the ORs(95%CIs)were 0.29(0.14-0.60)and 0.54(0.39-0.74),respectively.Good marital relationship and good neighborhood relationship were associated with a less severity of ED.
基金supported by the National Basic Research Program of China(2015CB943300)the Major Research Program of the National Natural Science Foundation of China(NSFC)(8149044,81471548,and 31671200)+1 种基金the Oriented Project of Science and Technology Innovation from the Key Laboratory of Reproduction Regulation of NPFPCthe Program for Zhuoxue of Fudan University,China.
文摘Decidual immune cells(DICs),including T-cells,regulatory T-cells,macrophages/dendritic cells,natural killer cells,and neutrophils,are resident at the maternal-fetal interface,and play vital roles in regulating trophoblast migration,decidual angiogenesis,immune tolerance,placentation,and decidualization during the early pregnancy.Extensive researches have revealed that these maternal DICs cooperated with each other,or with maternal decidual stromal cells,or with fetal-derived trophoblasts,and further formed a special maternal-fetal cross talk at the maternal-fetal interface,which was essential for the construction and maintenance of physiological pregnancy.Once aberrant cross talk and immune regulation arise,many pregnancy complications will inevitably occur,such as spontaneous abortion,intrauterine growth restriction(IUGR),preeclampsia(PE),and preterm birth.Here,we reviewed how critical immune cells are either enriched or excluded from the decidua,how their function is regulated within the decidua,and how they variously contribute to pregnancy success or failure.
基金supported by the National Natural Science Foundation of China(81971456)to X.Q.W.National Natural Science Foundation of China(32070915)to D.J.L.National Key Basic Research Project(2015CB943300)to D.J.L.
文摘Despite impressive progress being made in investigating the mechanisms underlying endometriosis,the pathophysiology of this disease remains unclear.Although typical methods used for diagnosing endometriosis such as ultrasound,magnetic resonance imaging,and blood tests are available,these are also inefficient,and effective noninvasive diagnostic methods are lacking.The advances in high-throughput omics techniques have enabled metabolomics to become an effective approach for discovering promising biomarkers.The aberrant metabolism associated with serious symptoms of endometriosis in women has been revealed in recent years.Analyzing the global metabolic patterns in patients with endometriosis may help deepen the understanding of the disease mechanism and have a significant impact on future diagnostic and treatment methods for endometriosis.Herein,we reviewed relevant studies on metabolic changes in patients with endometriosis and discussed the changes in metabolites both in biological fluids and endometriosis tissues.The findings discussed in this review have potential diagnostic implications and will enhance the understanding of the pathophysiological processes underlying the disease.
基金This study was funded by grant number MOST 2015CB943300 awarded to Da-Jin Lia grant from the National Natural Science Foundation of China,number 81200425,awarded to Xiao-Qiu Wang+2 种基金a grant from the National Natural Science Foundation of China,number 81471548,awarded to D.-J.L.a grant from the National Natural Science Foundation of China,number 81571512,awarded to Q.F.a grant from The Department of Science and Technology in Shandong Province,number ZR2015JL027,awarded to Q.F.
文摘Decidual macrophages (dMΦ) are distinct from the conventional macrophages present in other tissues and express M2macrophage markers, but the molecular mechanisms of formation and the roles of M2 MΦ during pregnancy have not beencompletely elucidated. The crosstalk between decidual natural killer cells (dNK) and dMΦ plays an important role in themaintenance of maternal–fetal immune tolerance. Here, CXCL16 derived from first-trimester trophoblast cells induces thepolarization of human M2 macrophages. The M2 MΦ polarized by CXCL16 exhibit decreased interleukin-15 production, whichfacilitates the inactivation of NK cells. The cytotoxicity of NK cells is attenuated by the CXCL16-polarized M2 MΦ. The data shown inthe present study provide evidence to support the hypothesis that CXCL16 secreted by trophoblast cells is a key molecule involvedin decidual M2 MΦ polarization, which in turn regulates the killing ability of NK cells, thereby contributing to the homeostatic andimmune-tolerant milieu required for successful fetal development.
文摘While several organs in mammals retain partial regen- erative capability following tissue damage, the underly- ing mechanisms remain unclear. Recently, the Hippo signaling pathway, better known for its function in organ size control, has been shown to play a pivotal role in regulating tissue homeostasis and regeneration. Upon tissue injury, the activity of YAP, the major effector of the Hippo pathway, is transiently induced, which in turn promotes expansion of tissue-resident progenitors and facilitates tissue regeneration. In this review, with a general focus on the Hippo pathway, we will discuss its major components, functions in stem cell biology, involvement in tissue regeneration in different organs, and potential strategies for developing Hippo pathway- targeted regenerative medicines.
基金supported by the Grants from the State Key Development Programs of Basic Research of China(Nos.2019YFA0801900,2018YFC100242,2018YFA080030,2018YFA0801300,and 2018YFC1004700)the National Natural Science Foundation of China(Nos.31871432,81771627,31521003,31821002,91753207,81722021,81471454,31671483,31671453,and 31425008)。
文摘In addition to their use in relieving the symptoms of various diseases,ketogenic diets(KDs)have also been adopted by healthy individuals to prevent being overweight.Herein,we reported that prolonged KD exposure induced cardiac fibrosis.In rats,KD or frequent deep fasting decreased mitochondrial biogenesis,reduced cell respiration,and increased cardiomyocyte apoptosis and cardiac fibrosis.Mechanistically,increased levels of the ketone body β-hydroxybutyrate(β-OHB),an HDAC2 inhibitor,promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription.This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis,leading to cardiomyocyte apoptosis and cardiac fibrosis.
基金This work was supported by The Natural Science Foundation of China(grant no.81373684).
文摘Background:To determine the efficacy of the Caulis Sargentodoxae prescription,which is an empirical formula of Chinese herbs and has definite curative effects on endometriosis.Methods:The Caulis Sargentodoxae prescription on the growth of ectopic endometria was studied with a rat endometriosis(EMS)model.The EMS model was established by autoplastic transplantation.To study the curative effects of Chinese medicine on EMS in comparison with western medicine,gestrinone and an angiogenesis inhibitor were introduced.The rats were randomly divided into seven groups:normal group,model group,ovariectomized group,gestrinone(western medicine)group,Caulis Sargentodoxae prescription(Chinese medicine)group,apatinib(inhibitor)group,and combination(Chinese medicine+inhibitor)group.After administration for 21 days,the growth inhibitory rates of ectopic endometria in the treatment groups were evaluated,and the levels of vascular endothelial growth factor(VEGF)and VEGF receptor-2(VEGFR2)were detected by ELISA in the serum and peritoneal fluid,as well as in the ectopic endometrial tissues by real-time polymerase chain reaction and Western blotting.Results:The growth inhibitory rates of ectopic endometria in the treatment groups were significantly higher(P<0.05).In the Caulis Sargentodoxae prescription group,the levels of angiogenesis-related factors,including VEGF and VEGFR2,were reduced in the serum and peritoneal fluid compared with the model group(P<0.05).In addition,the positive expression of VEGF and VEGFR2 in ectopic endometria significantly decreased in the Caulis Sargentodoxae prescription group both at mRNA and protein levels.Conclusions:VEGF and VEGFR2 levels in the serum and peritoneal fluid can be used as a clinical reference for endometriotic pathogenesis and treatment,and the Caulis Sargentodoxae prescription has reliable therapeutic effects on EMS for its target-action ability to decrease angiogenesis.
文摘In this article,published online 27 March 2018,in the“ACKNOWLEDGEMENTS”,it should be supplemented as follows:“This study was funded by a grant from the National Natural Science Foundation of China,number 81490744,awarded to Da-Jin Li.”The authors regret the omission.
基金supported by grant number MOST 2017YFC1001400 awarded to D.-J.L.grants from the National Natural Science Foundation of China,numbers 81971456 and 81200425 awarded to X.-Q.W.grants from the National Natural Science Foundation of China,numbers 81471548 and 81490744 awarded to D.-J.L.
文摘A successful pregnancy requires the maternal immune system to recognize and tolerate the allogeneic fetus while maintaining defense against infection both systemically and in placental tissues.At the maternal–fetal interface,the trophoblasts in the placenta play an essential role in the suppression of maternal immune rejection of the fetus.To ensure maternal–fetal tolerance and successful placentation,delicate crosstalk is established among fetus-derived trophoblasts,maternal immune cells,and decidual stromal cells(DSCs)during normal pregnancy.Decidual immune cells not only participate in the maintenance of immune tolerance but also regulate the function of trophoblasts to promote fetal growth.An imbalance in this crosstalk may lead to adverse pregnancy outcomes,such as recurrent spontaneous abortion,preeclampsia,preterm birth,intrauterine growth restriction,and infection.Here we outline some of the important discoveries in recent years related to the mechanisms by which trophoblast-derived molecules induce maternal–fetal immune tolerance.
基金supported by grants from the State Key Development Programs of China(No.2018YFA0800300 to S-MZ)the National Natural Science Foundation of China(No.31821002,31930062 to S-MZ,81872373 to JY)+1 种基金the Shanghai Science and Technology Development Foundation(No.20ZR1404500 to YL)the Science and Technology Research Program of Shanghai(No.19DZ2282100 to HL).
文摘Long noncoding RNAs(lncRNAs)are known to be involved in transcriptional regulation and their deregulation is associated with the development of human diseases such as cancer.1,2 LncRNA can directly bind to purine-rich double-stranded DNA sequences through Hoogsteen base pairing to form an RNA-DNA triplex motifs and regulate gene expression.3,4,5 However,its regulatory mechanisms and functions in tumors remain unclear.Here,we report that the LMNTD2 antisense RNA 1(LMNTD2-AS1,also known as AP006284.1)is highly expressed in prostate cancer(PCa)and positively correlated with the expression of its adjacent coding gene N-terminal Ras-association domain family 7(RASSF7).Mechanistically,AP006284.1 tethers to the RASSF7 promoter via RNA-DNA triplexes in cis-acting manner,which enhances chromatin accessibility and recruits the transcription factor complex GNL3/SFPQ to activate the expression of RASSF7,a repressor of the Hippo signaling pathway.Consistently,overexpression of either AP006284.1 or RASSF7 inactivated the Hippo signaling and malignant proliferation of PCa cells.
