Preeclampsia is associated with over-activation of the innate immune system in the placenta,in which toll-like receptor 4(TLR4) plays an essential part.With their potent anti-inflammatory effects,statins have been s...Preeclampsia is associated with over-activation of the innate immune system in the placenta,in which toll-like receptor 4(TLR4) plays an essential part.With their potent anti-inflammatory effects,statins have been suggested as potential prevention or treatment of preeclampsia,although evidence remains inadequate.Herewith,we investigated whether pravastatin could ameliorate preeclampsia-like phenotypes in a previously established lipopolysaccharide(LPS)-induced rat preeclampsia model,through targeting the TLR4/NF-κB pathway.The results showed that pravastatin reduced the blood pressure [maximum decline on gestational day(GD) 12,(101.33±2.49) mmHg vs.(118.3±1.37) mmHg,P〈0.05] and urine protein level [maximum decline on GD9,(3,726.23± 1,572.86) μg vs.(1,991.03 ±609.37)μg,P〈 0.05],which were elevated following LPS administration.Pravastatin also significantly reduced the rate of fetal growth restriction in LPS-treated rats(34.10% vs.8.99%,P〈0.05).Further pathological analyses suggested a restoration of normal spiral artery remodeling in preeclampsia rats by pravastatin treatment.These effects of pravastatin were associated with decreased TLR4/NF-κB protein levels in the placenta and IL-6/MCP-1 levels in serum.Additionally,no obvious abnormalities in fetal liver,brain,and kidney were found after administration of pravastatin.These results provide supportive evidence for use of pravastatin in preventing preeclampsia.展开更多
OBJECTIVE Midkine (MK),a new member of the heparin-binding growth factor family,was found recently to have a highexpression level in many carcinoma specimens,including thoseof the esophagus,gall bladder,pancreas,color...OBJECTIVE Midkine (MK),a new member of the heparin-binding growth factor family,was found recently to have a highexpression level in many carcinoma specimens,including thoseof the esophagus,gall bladder,pancreas,colorectum,breast andlung.Estrogen receptor beta (ER-β),a recently cloned estrogenreceptor subtype,was also found to be highly expressed in lungtumor tissue,in contrast to a lower level of expression in normallung tissue.However,few relevant studies on these proteins havebeen published.The aims of our study were to investigate theexpression of midkine and ER-β proteins in non-small cell lungcancer (NSCLC) and to examine the relationship between theirexpression and the clinicopathologic data as well as to analyse thecorrelation of their expression in NSCLC.METHODS By immunohistochemistry,MK and ER-β were ex-amined in 24 surgically resected cases of NSCLC with their corre-sponding paraneoplastic and normal lung tissues.RESULTS MK and ER-β were overexpressed in NSCLC.Thelevels of MK and ER-β expression in NSCLC were found to be sig-nificantly negatively correlated with the pathological classification(P=0.042 and 0.021,respectively),and their expression decreasedwith a raise in the classification.Spearman's correlation analysisshowed that the correlation of their expression in NSCLC wasstrong (correlation coefficient[r_s]= 0.535,P=0.007<0.01).CONCLUSION The expression levels of MK and ER-β to someextent reflect the malignant degree of NSCLC,and their combineddetection may be of great value in early diagnosis,treatments ofpatients with NSCLC and can predict the prognoses.展开更多
Asherman's syndrome(AS) is a common disease that presents endometrial regeneration disorder. However, little is known about its molecular features of this aregenerative endometrium in AS and how to reconstruct the...Asherman's syndrome(AS) is a common disease that presents endometrial regeneration disorder. However, little is known about its molecular features of this aregenerative endometrium in AS and how to reconstruct the functioning endometrium for the patients with AS. Here, we report that ΔNp63 is significantly upregulated in residual epithelial cells of the impaired endometrium in AS; the upregulated-ΔNp63 induces endometrial quiescence and alteration of stemness. Importantly, we demonstrate that engrafting high density of autologous bone marrow mononuclear cells(BMNCs) loaded in collagen scaffold onto the uterine lining of patients with AS downregulates ΔNp63 expression, reverses ΔNp63-induced pathological changes, normalizes the stemness alterations and restores endometrial regeneration. Finally, five patients achieved successful pregnancies and live births. Therefore, we conclude that ΔNp63 is a crucial therapeutic target for AS. This novel treatment significantly improves the outcome for the patients with severe AS.展开更多
The disturbance of maternal immune tolerance to a semiallogeneic fetus is recognized as one of the key pathologies of preeclampsia(PE),in which an imbalance between the inflammation-limiting regulatory T cells(Tregs)a...The disturbance of maternal immune tolerance to a semiallogeneic fetus is recognized as one of the key pathologies of preeclampsia(PE),in which an imbalance between the inflammation-limiting regulatory T cells(Tregs)and the inflammationmediating Th17 cells plays an essential role.Previously,we reported that the abnormal upregulation of tetraspannin CD81 in trophoblast cells(fetal component)participated in the pathogenesis of PE.However,as one of the potential immune regulatory molecules,whether CD81 induces PE by interfering with the balance of the maternal immune system has not yet been clarified.Thus,we investigated the relationship between the upregulation of CD81 in trophoblast cells and the imbalance of Treg and Th17 cells in mothers.Here,we demonstrated that upregulation of CD81 in trophoblast cells was accompanied by a decrease in Treg cells and an increase in Th17 cells in both the basal plate(placental maternal side)and peripheral blood of patients with PE.In vitro culture of naïve T cells with medium from the CD81-overexpressing trophoblast cell line HTR-8 resulted in enhanced differentiation of T cells into Th17 cells and decreased the formation of Tregs,which was dependent on the paracrine signaling of IL-6 in trophocytes,induced by CD81.In a CD81-induced PE rat model,we found a significant shift of T cell differentiation towards Th17 cells,and administration of IL-6 antibody mitigated the PE phenotype and the imbalance of the Treg/Th17 cells.These results define a vital regulatory cascade involving trophocyte-derived CD81,IL-6,and maternal Treg/Th17 cells in the pathogenesis of PE and suggests new therapeutic approaches based on CD81 and IL-6 downregulation to prevent human PE.展开更多
Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly due to their immunosuppressive properties. Although interleukin-1β (IL-1β) is one of the most important inf...Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly due to their immunosuppressive properties. Although interleukin-1β (IL-1β) is one of the most important inflammatory mediators, growing evidence indicates that IL-1β signaling elicits the immunosuppressive properties of MSCs. However, it remains unclear how IL-1β signaling accomplishes this activity. Here, we focus on the therapeutic efficacy of IL-1β-primed MSCs in the dextran sulfate sodium (DSS)-induced colitis model, in addition to the underlining mechanisms. We first found that IL-1β-primed MSCs, without any observable phenotype change in vitro, significantly attenuated the development of DSS-induced murine colitis. Moreover, IL-1β-primed MSCs modulated the balance of immune cells in the spleen and the mesenteric lymph nodes (MLNs) through elevating cyclooxygenase-2 (COX-2), IL-6 and IL-8 expression and influencing the polarization of peritoneal macrophages. Importantly, I L- 1β-pri med MSCs possessed an enhanced ability to migrate to the inflammatory site of the gut via upregu lation of chemoki ne receptor type 4 (CXCR4) expression. In summary, IL-1β-primed MSCs have improved efficacy in treating DSS-induced colitis, which at least partly depends on their increased immunosuppressive capacities and enhanced migration ability.展开更多
Immune activation at the maternal-fetal interface is a main pathogenic factor of preeclampsia(PE).Neutrophils(PMNs)are activated in PE patients,but the mechanism and consequences of PMN activation need to be further e...Immune activation at the maternal-fetal interface is a main pathogenic factor of preeclampsia(PE).Neutrophils(PMNs)are activated in PE patients,but the mechanism and consequences of PMN activation need to be further explored.Here,we demonstrated that interleukin-32(IL-32)expression was significantly upregulated in syncytiotrophoblasts(STBs)and that IL-32β was the major isoform with increased expression in the placenta of severe PE(sPE)patients.Furthermore,the level of IL-32 expression in the placenta was correlated with its level in the serum of sPE patients,indicating that IL-32 in the serum is derived mainly from the placenta.Then,in vitro experiments showed that IL-32β could highly activate PMNs and that these IL-32β-activated PMNs were better able to adhere to endothelial cells(HUVECs)and enhance the expression of vascular cell adhesion molecule-1(VCAM-1)and intercellular cell adhesion molecule-1(ICAM-1)in HUVECs,which could be reversed by preincubation with the NADPH oxidase inhibitor VAS 2870.In addition,we showed that IL-32β mainly activated PMNs by binding to proteinase 3.Finally,IL-32β administration induced a PE-like phenotype in a pregnant mouse model.This study provides evidence of the involvement of IL-32β in the pathogenesis of PE.展开更多
Toll-like receptor 9 (TLR9) is expressed intracellularly by dendritic cells (DCs) and specifically recognizes unmethylated CpG motif. Recognition of TLR9 to CpG DNA can induce DC maturation followed by the subsequ...Toll-like receptor 9 (TLR9) is expressed intracellularly by dendritic cells (DCs) and specifically recognizes unmethylated CpG motif. Recognition of TLR9 to CpG DNA can induce DC maturation followed by the subsequent immune responses. Here, RNA interference (RNAi) was used to identify the effect of CpG DNA signaling on DC function. The results showed that transfection of DCs with siRNA specific for TLR9 gene significantly down-regulated TLR9 expression. Immature DCs transfected with TLR9 siRNA did not differentiate into mature DCs with exposure to CpG. TLR9 siRNA-treated DCs expressed low levels of MHC II and CD40 without reducing endocytosis. Furthermore, TLR9 siRNA-transfected DCs exhibited a decreased allostimulatory capacity in a lymphocyte proliferation assay and attenuated Thl responses by decreasing IL-12p70 production. Our findings indicate that siRNA in silencing TLR9 gene in DCs may offer a potential tool to study the TLR9-CpG pathway.展开更多
Color stability of dental resin modified glass ionomer (RMGI) has been a challenge to dentistry; therefore, systematic changes in 2-hydroxyethyl methacrylate (HEMA) content were performed experimentally to find an...Color stability of dental resin modified glass ionomer (RMGI) has been a challenge to dentistry; therefore, systematic changes in 2-hydroxyethyl methacrylate (HEMA) content were performed experimentally to find an idea to enhance the color stability. Changes in color (△E*ab) and color coordinates (△L*, △a* and △b*) of experimental 10-50 wt pct HEMA-added dental glass ionomers (HAGIs) and corresponding RMGIs were determined after 5000 cycles of thermocycling. Color changes of HAGIs were not influenced by the HEMA content while △L*, △a* and △b* values were influenced by the HEMA content. Color stability of 30% or 40% HEMA-added HAGIs was not different from those of the commercial RMGIs. Since the influence of HEMA itself on the color stability of HAGIs was limited, compositional modification to increase the color stability of these materials should be developed.展开更多
The human endometrium is a dynamic tissue that undergoes approximately 400 cycles of proliferation,decidualization,shedding,and regeneration.With the observation that superficial stratum functionalis loss and swift re...The human endometrium is a dynamic tissue that undergoes approximately 400 cycles of proliferation,decidualization,shedding,and regeneration.With the observation that superficial stratum functionalis loss and swift reepithelization occur every month,an original hypothesis is that stem cells,especially endometrial epithelial stem cells harbored in the deeper basalis,take on the responsibility of repairing and regenerating the endometrial functionalis.展开更多
基金funded by the following Grants:National Natural Science Foundation of China,Grant/Award Number:81370724,81571463 and 81401225Innovative Research Program for Postgraduate in Higher Education Institutions of Jiangsu Province for the year 2016,Grant/Award Number:KYLX16_1111
文摘Preeclampsia is associated with over-activation of the innate immune system in the placenta,in which toll-like receptor 4(TLR4) plays an essential part.With their potent anti-inflammatory effects,statins have been suggested as potential prevention or treatment of preeclampsia,although evidence remains inadequate.Herewith,we investigated whether pravastatin could ameliorate preeclampsia-like phenotypes in a previously established lipopolysaccharide(LPS)-induced rat preeclampsia model,through targeting the TLR4/NF-κB pathway.The results showed that pravastatin reduced the blood pressure [maximum decline on gestational day(GD) 12,(101.33±2.49) mmHg vs.(118.3±1.37) mmHg,P〈0.05] and urine protein level [maximum decline on GD9,(3,726.23± 1,572.86) μg vs.(1,991.03 ±609.37)μg,P〈 0.05],which were elevated following LPS administration.Pravastatin also significantly reduced the rate of fetal growth restriction in LPS-treated rats(34.10% vs.8.99%,P〈0.05).Further pathological analyses suggested a restoration of normal spiral artery remodeling in preeclampsia rats by pravastatin treatment.These effects of pravastatin were associated with decreased TLR4/NF-κB protein levels in the placenta and IL-6/MCP-1 levels in serum.Additionally,no obvious abnormalities in fetal liver,brain,and kidney were found after administration of pravastatin.These results provide supportive evidence for use of pravastatin in preventing preeclampsia.
基金This work was supported by a grant from General Program of Jiangsu Province Hygiene Department(No.K200601)
文摘OBJECTIVE Midkine (MK),a new member of the heparin-binding growth factor family,was found recently to have a highexpression level in many carcinoma specimens,including thoseof the esophagus,gall bladder,pancreas,colorectum,breast andlung.Estrogen receptor beta (ER-β),a recently cloned estrogenreceptor subtype,was also found to be highly expressed in lungtumor tissue,in contrast to a lower level of expression in normallung tissue.However,few relevant studies on these proteins havebeen published.The aims of our study were to investigate theexpression of midkine and ER-β proteins in non-small cell lungcancer (NSCLC) and to examine the relationship between theirexpression and the clinicopathologic data as well as to analyse thecorrelation of their expression in NSCLC.METHODS By immunohistochemistry,MK and ER-β were ex-amined in 24 surgically resected cases of NSCLC with their corre-sponding paraneoplastic and normal lung tissues.RESULTS MK and ER-β were overexpressed in NSCLC.Thelevels of MK and ER-β expression in NSCLC were found to be sig-nificantly negatively correlated with the pathological classification(P=0.042 and 0.021,respectively),and their expression decreasedwith a raise in the classification.Spearman's correlation analysisshowed that the correlation of their expression in NSCLC wasstrong (correlation coefficient[r_s]= 0.535,P=0.007<0.01).CONCLUSION The expression levels of MK and ER-β to someextent reflect the malignant degree of NSCLC,and their combineddetection may be of great value in early diagnosis,treatments ofpatients with NSCLC and can predict the prognoses.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01030505)Key research and development program of Jiangsu province (BE2016612), Jiangsu Biobank of Clinical Resources (BM2015004)+1 种基金the Key Laboratory for Maternal-Fetal Medicine from the Health Department of Jiangsu Province, China (XK201102)Project of Nanjing clinical medicine center and the National Natural Science Foundation of China (81401223)
文摘Asherman's syndrome(AS) is a common disease that presents endometrial regeneration disorder. However, little is known about its molecular features of this aregenerative endometrium in AS and how to reconstruct the functioning endometrium for the patients with AS. Here, we report that ΔNp63 is significantly upregulated in residual epithelial cells of the impaired endometrium in AS; the upregulated-ΔNp63 induces endometrial quiescence and alteration of stemness. Importantly, we demonstrate that engrafting high density of autologous bone marrow mononuclear cells(BMNCs) loaded in collagen scaffold onto the uterine lining of patients with AS downregulates ΔNp63 expression, reverses ΔNp63-induced pathological changes, normalizes the stemness alterations and restores endometrial regeneration. Finally, five patients achieved successful pregnancies and live births. Therefore, we conclude that ΔNp63 is a crucial therapeutic target for AS. This novel treatment significantly improves the outcome for the patients with severe AS.
基金by the National Natural Science Foundation of China(81571462,81600353,and 81701472)Jiangsu Provincial Key Medical Center(YXZXB2016004)+1 种基金Jiangsu Biobank of Clinical Resources(BM2015004)Jiangsu Province Grant for Science and Technology(BK20161106).
文摘The disturbance of maternal immune tolerance to a semiallogeneic fetus is recognized as one of the key pathologies of preeclampsia(PE),in which an imbalance between the inflammation-limiting regulatory T cells(Tregs)and the inflammationmediating Th17 cells plays an essential role.Previously,we reported that the abnormal upregulation of tetraspannin CD81 in trophoblast cells(fetal component)participated in the pathogenesis of PE.However,as one of the potential immune regulatory molecules,whether CD81 induces PE by interfering with the balance of the maternal immune system has not yet been clarified.Thus,we investigated the relationship between the upregulation of CD81 in trophoblast cells and the imbalance of Treg and Th17 cells in mothers.Here,we demonstrated that upregulation of CD81 in trophoblast cells was accompanied by a decrease in Treg cells and an increase in Th17 cells in both the basal plate(placental maternal side)and peripheral blood of patients with PE.In vitro culture of naïve T cells with medium from the CD81-overexpressing trophoblast cell line HTR-8 resulted in enhanced differentiation of T cells into Th17 cells and decreased the formation of Tregs,which was dependent on the paracrine signaling of IL-6 in trophocytes,induced by CD81.In a CD81-induced PE rat model,we found a significant shift of T cell differentiation towards Th17 cells,and administration of IL-6 antibody mitigated the PE phenotype and the imbalance of the Treg/Th17 cells.These results define a vital regulatory cascade involving trophocyte-derived CD81,IL-6,and maternal Treg/Th17 cells in the pathogenesis of PE and suggests new therapeutic approaches based on CD81 and IL-6 downregulation to prevent human PE.
文摘Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly due to their immunosuppressive properties. Although interleukin-1β (IL-1β) is one of the most important inflammatory mediators, growing evidence indicates that IL-1β signaling elicits the immunosuppressive properties of MSCs. However, it remains unclear how IL-1β signaling accomplishes this activity. Here, we focus on the therapeutic efficacy of IL-1β-primed MSCs in the dextran sulfate sodium (DSS)-induced colitis model, in addition to the underlining mechanisms. We first found that IL-1β-primed MSCs, without any observable phenotype change in vitro, significantly attenuated the development of DSS-induced murine colitis. Moreover, IL-1β-primed MSCs modulated the balance of immune cells in the spleen and the mesenteric lymph nodes (MLNs) through elevating cyclooxygenase-2 (COX-2), IL-6 and IL-8 expression and influencing the polarization of peritoneal macrophages. Importantly, I L- 1β-pri med MSCs possessed an enhanced ability to migrate to the inflammatory site of the gut via upregu lation of chemoki ne receptor type 4 (CXCR4) expression. In summary, IL-1β-primed MSCs have improved efficacy in treating DSS-induced colitis, which at least partly depends on their increased immunosuppressive capacities and enhanced migration ability.
基金funded by grants from the National Key R&D Program of China(2018YFC1004404)National Natural Science Foundation of China(81701474 and 82071600)+5 种基金Jiangsu Provincial Key Medical Center(YXZXB2016004)China Postdoctoral Science Foundation(2019M651807)Key Research and Development Program of Jiangsu Province(BE2019706)Jiangsu Biobank of Clinical Resources(BM2015004)The Open Project of Jiangsu Biobank of Clinical Resources(SBK202006001)Maternal and Child Health Project in Jiangsu Province(F201742).
文摘Immune activation at the maternal-fetal interface is a main pathogenic factor of preeclampsia(PE).Neutrophils(PMNs)are activated in PE patients,but the mechanism and consequences of PMN activation need to be further explored.Here,we demonstrated that interleukin-32(IL-32)expression was significantly upregulated in syncytiotrophoblasts(STBs)and that IL-32β was the major isoform with increased expression in the placenta of severe PE(sPE)patients.Furthermore,the level of IL-32 expression in the placenta was correlated with its level in the serum of sPE patients,indicating that IL-32 in the serum is derived mainly from the placenta.Then,in vitro experiments showed that IL-32β could highly activate PMNs and that these IL-32β-activated PMNs were better able to adhere to endothelial cells(HUVECs)and enhance the expression of vascular cell adhesion molecule-1(VCAM-1)and intercellular cell adhesion molecule-1(ICAM-1)in HUVECs,which could be reversed by preincubation with the NADPH oxidase inhibitor VAS 2870.In addition,we showed that IL-32β mainly activated PMNs by binding to proteinase 3.Finally,IL-32β administration induced a PE-like phenotype in a pregnant mouse model.This study provides evidence of the involvement of IL-32β in the pathogenesis of PE.
基金This work supported by grants from the National Natural Science Foundation (No. 30771959), Natural Science Research Foundation of Jiangsu Province (No. BK2006119) and Technology Research for Advanced Medicine of Jiangsu province (No. BG2007604).
文摘Toll-like receptor 9 (TLR9) is expressed intracellularly by dendritic cells (DCs) and specifically recognizes unmethylated CpG motif. Recognition of TLR9 to CpG DNA can induce DC maturation followed by the subsequent immune responses. Here, RNA interference (RNAi) was used to identify the effect of CpG DNA signaling on DC function. The results showed that transfection of DCs with siRNA specific for TLR9 gene significantly down-regulated TLR9 expression. Immature DCs transfected with TLR9 siRNA did not differentiate into mature DCs with exposure to CpG. TLR9 siRNA-treated DCs expressed low levels of MHC II and CD40 without reducing endocytosis. Furthermore, TLR9 siRNA-transfected DCs exhibited a decreased allostimulatory capacity in a lymphocyte proliferation assay and attenuated Thl responses by decreasing IL-12p70 production. Our findings indicate that siRNA in silencing TLR9 gene in DCs may offer a potential tool to study the TLR9-CpG pathway.
基金supported by the Korea Science and Engineering Foundation (KOSEF) Science Research Center grant funded by the Korean Ministry of Education,Science and Technology (MEST) through Bone Metabolism Research Center (No.0617-20080007)
文摘Color stability of dental resin modified glass ionomer (RMGI) has been a challenge to dentistry; therefore, systematic changes in 2-hydroxyethyl methacrylate (HEMA) content were performed experimentally to find an idea to enhance the color stability. Changes in color (△E*ab) and color coordinates (△L*, △a* and △b*) of experimental 10-50 wt pct HEMA-added dental glass ionomers (HAGIs) and corresponding RMGIs were determined after 5000 cycles of thermocycling. Color changes of HAGIs were not influenced by the HEMA content while △L*, △a* and △b* values were influenced by the HEMA content. Color stability of 30% or 40% HEMA-added HAGIs was not different from those of the commercial RMGIs. Since the influence of HEMA itself on the color stability of HAGIs was limited, compositional modification to increase the color stability of these materials should be developed.
基金funded by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16040302)the National Natural Science Foundation of China(81971336)。
文摘The human endometrium is a dynamic tissue that undergoes approximately 400 cycles of proliferation,decidualization,shedding,and regeneration.With the observation that superficial stratum functionalis loss and swift reepithelization occur every month,an original hypothesis is that stem cells,especially endometrial epithelial stem cells harbored in the deeper basalis,take on the responsibility of repairing and regenerating the endometrial functionalis.