BACKGROUND Heart transplantation is a crucial intervention for severe heart failure,yet the challenge of organ rejection is significant.Bone marrow mesenchymal stem cells(BMSCs)and their exosomes have demonstrated pot...BACKGROUND Heart transplantation is a crucial intervention for severe heart failure,yet the challenge of organ rejection is significant.Bone marrow mesenchymal stem cells(BMSCs)and their exosomes have demonstrated potential in modulating T cells,dendtitic cells(DCs),and cytokines to achieve immunomodulatory effects.DCs,as key antigen-presenting cells,play a critical role in shaping immune responses by influencing T-cell activation and cytokine production.Through this modulation,BMSCs and their exosomes enhance graft tolerance and prolonging survival.AIM To explore the immunomodulatory effects of exosomes derived from BMSCs overexpressing microRNA-540-3p(miR-540-3p)on cardiac allograft tolerance,focusing on how these exosomes modulating DCs and T cells activity through the CD74/nuclear factor-kappaB(NF-κB)pathway.METHODS Rat models were used to assess the impact of miR-540-3p-enhanced exosomes on immune tolerance in cardiac allografts.MiR-540-3p expression was manipulated in BMSCs,and derived exosomes were collected and administered to the rat models post-heart transplantation.The study monitored expression levels of major histocompatibility complex II,CD80,CD86,and CD274 in DCs,and quantified CD4^(+)and CD8^(+)T cells,T regulatory cells,and cytokine profiles.RESULTS Exosomes from miR-540-3p-overexpressing BMSCs lead to reduced expression of immune activation markers CD74 and NF-κB p65 in DCs and T cells.Rats treated with these exosomes showed decreased inflammation and improved cardiac function,indicated by lower levels of pro-inflammatory cytokines(interleukin-1β,interferon-γ)and higher levels of anti-inflammatory cytokines(interleukin-10,transforming growth factorβ1).Additionally,miR-540-3p skewed the profiles of DCs and T cells towards immune tolerance,increasing the ratio of T regulatory cells and shifting cytokine secretion to favor graft acceptance.CONCLUSION Exosomes derived from BMSCs overexpressing miR-540-3p significantly enhance immune tolerance and prolong cardiac allograft survival by modulating the CD74/NF-κB pathway,which regulates activities of DCs and T cells.These findings highlight a promising therapeutic strategy to improve heart transplantation outcomes and potentially reduce the need for prolonged immunosuppression.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact mo...BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.展开更多
Objective To investigate the differential expression of microRNA-144-3p in endometrial cells exposed to copper ions in vitro.The specific mechanism by which microRNA-144-3p is involved in Cu^(2+)-induced damage to the...Objective To investigate the differential expression of microRNA-144-3p in endometrial cells exposed to copper ions in vitro.The specific mechanism by which microRNA-144-3p is involved in Cu^(2+)-induced damage to the human endometrial epithelial cells(HEECs)was explored.Methods HEECs were cultured in copper-containing culture medium to simulate changes in the endometrium after copper intrauterine device(Cu-IUD)implantation.Reverse transcription quantitative PCR(RT-qPCR)was used to detect the differential expression of miR-144-3p in HEECs after Cu^(2+)treatment.MiRNAs,siRNAs and related inhibitors were used to treat HEECs.The expression levels of related downstream genes were then analyzed by RT-qPCR,Western blotting and immunofluorescence to explore the specific mechanism involved.Results MiR-144-3p was significantly upregulated in the Cu^(2+)-treated HEECs.The expression of P-NF-κB,MMP9,TGF-β3 and P-SMAD3 was significantly decreased in HEECs treated with 10μg/mL Cu^(2+).MiR-144-3p regulated the expression of metallothionein 1A(MT1A)and thrombospondin-1(THBS-1)in Cu^(2+)-treated HEECs.The expression of P-NF-κB can be regulated by MT1A,and an inhibitor of P-NF-κB can significantly reduce the expression of MMP9 in Cu^(2+)-treated HEECs.The expression of TGF-β3 can be regulated by THBS-1,and a TGF-β3 inhibitor can significantly reduce the expression of SMAD3 in Cu^(2+)-treated HEECs.The proliferative capacity of HEECs treated with MMP9 or SMAD3 inhibitors was significantly reduced.Conclusions The increased Cu^(2+)concentration led to the upregulation of miR-144-3p,further reducing the expression levels of its target genes(MT1A and THBS-1),which in turn downregulated the expression of NF-κB,MMP9,TGF-β3 and SMAD3,ultimately leading to increased endometrial cell damage and decreased cell proliferation.展开更多
基金Supported by the National Natural Science Foundation of China,No.82060299Medical Discipline Leader Project of Yunnan Provincial Health Commission,No.D-2019020+5 种基金Yunnan Provincial Government Ten Thousand Person-Top Young Talents Project,No.KH-SWRQNBJ-2019-002Clinical Medical Center of the First People’s Hospital of Yunnan Province,No.2021LCZXXF-XZ04 and No.2022LCZXKF-HX05Kunming Medical Joint Special Project-Outstanding Youth Cultivation Project,No.202101AY070001-034Kunming Medical Joint Special Project,No.202101AY070001-272Famous Doctor Project of“Xingdian Talent Support Plan”of Yunnan Province,No.XDYC-MY-2022-0037Yunnan Province 2023 Undergraduate Education and Teaching Reform Research Project,No.2023BKXJJG-F04002.
文摘BACKGROUND Heart transplantation is a crucial intervention for severe heart failure,yet the challenge of organ rejection is significant.Bone marrow mesenchymal stem cells(BMSCs)and their exosomes have demonstrated potential in modulating T cells,dendtitic cells(DCs),and cytokines to achieve immunomodulatory effects.DCs,as key antigen-presenting cells,play a critical role in shaping immune responses by influencing T-cell activation and cytokine production.Through this modulation,BMSCs and their exosomes enhance graft tolerance and prolonging survival.AIM To explore the immunomodulatory effects of exosomes derived from BMSCs overexpressing microRNA-540-3p(miR-540-3p)on cardiac allograft tolerance,focusing on how these exosomes modulating DCs and T cells activity through the CD74/nuclear factor-kappaB(NF-κB)pathway.METHODS Rat models were used to assess the impact of miR-540-3p-enhanced exosomes on immune tolerance in cardiac allografts.MiR-540-3p expression was manipulated in BMSCs,and derived exosomes were collected and administered to the rat models post-heart transplantation.The study monitored expression levels of major histocompatibility complex II,CD80,CD86,and CD274 in DCs,and quantified CD4^(+)and CD8^(+)T cells,T regulatory cells,and cytokine profiles.RESULTS Exosomes from miR-540-3p-overexpressing BMSCs lead to reduced expression of immune activation markers CD74 and NF-κB p65 in DCs and T cells.Rats treated with these exosomes showed decreased inflammation and improved cardiac function,indicated by lower levels of pro-inflammatory cytokines(interleukin-1β,interferon-γ)and higher levels of anti-inflammatory cytokines(interleukin-10,transforming growth factorβ1).Additionally,miR-540-3p skewed the profiles of DCs and T cells towards immune tolerance,increasing the ratio of T regulatory cells and shifting cytokine secretion to favor graft acceptance.CONCLUSION Exosomes derived from BMSCs overexpressing miR-540-3p significantly enhance immune tolerance and prolong cardiac allograft survival by modulating the CD74/NF-κB pathway,which regulates activities of DCs and T cells.These findings highlight a promising therapeutic strategy to improve heart transplantation outcomes and potentially reduce the need for prolonged immunosuppression.
基金Supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBJC00001the Key Discipline Special Project of Tianjin Municipal Health Commission,No.TJWJ2022XK016.
文摘BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.
文摘Objective To investigate the differential expression of microRNA-144-3p in endometrial cells exposed to copper ions in vitro.The specific mechanism by which microRNA-144-3p is involved in Cu^(2+)-induced damage to the human endometrial epithelial cells(HEECs)was explored.Methods HEECs were cultured in copper-containing culture medium to simulate changes in the endometrium after copper intrauterine device(Cu-IUD)implantation.Reverse transcription quantitative PCR(RT-qPCR)was used to detect the differential expression of miR-144-3p in HEECs after Cu^(2+)treatment.MiRNAs,siRNAs and related inhibitors were used to treat HEECs.The expression levels of related downstream genes were then analyzed by RT-qPCR,Western blotting and immunofluorescence to explore the specific mechanism involved.Results MiR-144-3p was significantly upregulated in the Cu^(2+)-treated HEECs.The expression of P-NF-κB,MMP9,TGF-β3 and P-SMAD3 was significantly decreased in HEECs treated with 10μg/mL Cu^(2+).MiR-144-3p regulated the expression of metallothionein 1A(MT1A)and thrombospondin-1(THBS-1)in Cu^(2+)-treated HEECs.The expression of P-NF-κB can be regulated by MT1A,and an inhibitor of P-NF-κB can significantly reduce the expression of MMP9 in Cu^(2+)-treated HEECs.The expression of TGF-β3 can be regulated by THBS-1,and a TGF-β3 inhibitor can significantly reduce the expression of SMAD3 in Cu^(2+)-treated HEECs.The proliferative capacity of HEECs treated with MMP9 or SMAD3 inhibitors was significantly reduced.Conclusions The increased Cu^(2+)concentration led to the upregulation of miR-144-3p,further reducing the expression levels of its target genes(MT1A and THBS-1),which in turn downregulated the expression of NF-κB,MMP9,TGF-β3 and SMAD3,ultimately leading to increased endometrial cell damage and decreased cell proliferation.
