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
BACKGROUND Colorectal cancer(CRC)is a common malignant tumor of the digestive tract worldwide,characterized by high incidence and mortality rates.AIM To investigate the expression of serum apurinic/apyrimidinic endonu...BACKGROUND Colorectal cancer(CRC)is a common malignant tumor of the digestive tract worldwide,characterized by high incidence and mortality rates.AIM To investigate the expression of serum apurinic/apyrimidinic endonuclease 1 autoantibodies(APE1-AAbs),peripheral pentraxin-3(PTX-3),and miR-486-3p in patients with CRC undergoing radical surgery and their relationship with postoperative recurrence and metastasis.METHODS A retrospective analysis was conducted on the clinical data of 154 CRC patients who underwent laparoscopic radical surgery in our hospital from January 2022 to January 2024.Patients were followed for one year postoperatively and divided into an occurrence group(n=28)and a non-occurrence group(n=126)based on whether they experienced recurrence or metastasis.The clinical data and the expression levels of APE1-AAbs,PTX-3,and miR-486-3p were compared between the two groups.Multivariate logistic regression analysis was performed to identify risk factors for postoperative recurrence and metastasis in CRC patients.The relationship of APE1-AAbs,PTX-3,and miR-486-3p with postoperative recurrence and metastasis was analyzed using Spearman correlation analysis.Receiver operating characteristic curves were drawn to evaluate the predictive value of serum APE1-AAbs,PTX-3,and miR-486-3p levels alone and their combination for postoperative recurrence and metastasis in CRC.RESULTS The occurrence group had significantly higher proportions of patients with an age≥60 years,lymph node metastasis,stage III disease,poor differentiation,tumor diameter>5 cm,and higher platelet count,carcinoembryonic antigen,and carbohydrate antigen 19-9 levels than the non-occurrence group(P<0.05).The expression levels of APE1-AAbs,PTX-3,and miR-486-3p in the occurrence group were significantly higher than those in the non-occurrence group(P<0.05).Multivariate logistic regression analysis showed that lymph node metastasis,stage III disease,poor differentiation,and elevated levels of APE1-AAbs,PTX-3,and miR-486-3p were risk factors for postoperative recurrence and metastasis in CRC patients(odds ratio>1,P<0.05).Spearman correlation analysis revealed that the levels of APE1-AAbs,PTX-3,and miR-486-3p were positively correlated with postoperative recurrence and metastasis in CRC patients(r=0.642,0.653,and 0.631,respectively,P<0.05).Receiver operating characteristic curve analysis showed that the area under the curve values for APE1-AAbs,PTX-3,and miR-486-3p levels alone and their combination in predicting postoperative recurrence and metastasis in CRC were 0.764,0.783,0.806,and 0.875,respectively,with the combination significantly outperforming individual markers(P<0.05).CONCLUSION Serum APE1-AAbs,PTX-3,and miR-486-3p levels are higher in CRC patients with postoperative recurrence and metastasis.These three markers are risk factors for postoperative recurrence and metastasis in CRC and can be used as predictive biomarkers.The combined detection of these markers has higher predictive value compared to individual tests.展开更多
Objective:Gastric cancer(GC)is a globally common cancer characterized by high incidence and mortality worldwide.Advances in the molecular understanding of GC provide promising targets for GC diagnosis and therapy.Long...Objective:Gastric cancer(GC)is a globally common cancer characterized by high incidence and mortality worldwide.Advances in the molecular understanding of GC provide promising targets for GC diagnosis and therapy.Long non-coding RNAs(lncRNAs)and their downstream regulators are regarded to be implicated in the progression of multiple types of malignancies.Studies have shown that the lncRNA small nucleolar RNA host gene 4(SNHG4)serves as a tumor promoter in various malignancies,while its function in GC has yet to be characterized.Therefore,our study aimed to explore the role and underlying mechanism of SNHG4 in GC.Methods:We used qRT-PCR to analyze SNHG4 expression in GC tissues and cells.Kaplan-Meier analysis was used to assess the correlation between SNHG4 expression and the survival rate of GC patients.Cellular function experiments such as CCK-8,BrdU,colony formation,flow cytometry analysis,and transwell were performed to explore the effects of SNHG4 on GC cell proliferation,apoptosis,cell cycle,migration,and invasion.We also established xenograft mouse models to explore the effect of SNHG4 on GC tumor growth.Mechanically,dual luciferase reporter assay was used to verify the interaction between SNHG4 and miR-409-3p and between miR-409-3p and cAMP responsive element binding protein 1(CREB1).Results:The results indicated that SNHG4 was overexpressed in GC tissues and cell lines,and was linked with poor survival rate of GC patients.SNHG4 promoted GC cell proliferation,migration,and invasion while inhibiting cell apoptosis and cell cycle arrest in vitro.The in vivo experiment indicated that SNHG4 facilitated GC tumor growth.Furthermore,SNHG4 was demonstrated to bind to miR-409-3p.Moreover,CREB1 was directly targeted by miR-409-3p.Rescue assays demonstrated that miR-409-3p deficiency reversed the suppressive impact of SNHG4 knockdown on GC cell malignancy.Additionally,miR-409-3p was also revealed to inhibit GC cell proliferation,migration,and invasion by targeting CREB1.Conclusion:In conclusion,we verified that the SNHG4 promoted GC growth and metastasis by binding to miR-409-3p to upregulate CREB1,which may deepen the understanding of the underlying mechanism in GC development.展开更多
Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's dis...Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's disease-related dementia.Our previous study identified the upregulation of microRNA-502-3p(miR-502-3p)and downregulation of GABA type A receptor subunitα-1 in Alzheimer's disease synapses.This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function.In vitro studies were perfo rmed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs.In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunitα-1 mRNA.Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunitα-1 gene and suppresses the luciferase activity.Furthermore,quantitative reve rse transcription-polymerase chain reaction,miRNA in situ hybridization,immunoblotting,and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunitα-1 level,while suppression of miR-502-3p increased the level of GABA type A receptor subunitα-1 protein.Notably,as a result of the overexpression of miR-502-3p,cell viability was found to be reduced,and the population of necrotic cells was found to be increased.The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney(HEK)recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function,suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function.Additionally,the levels of proteins associated with Alzheimer s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression.The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p.We propose that micro-RNA,in particular miR-502-3p,could be a potential therapeutic to rget to modulate GABAergic synapse function in neurological disorders,including Alzheimer's disease and Alzheimer's diseaserelated dementia.展开更多
BACKGROUND Diabetic kidney disease(DKD),characterized by increased urinary microalbumin levels and decreased renal function,is the primary cause of end-stage renal di-sease.Its pathological mechanisms are complicated ...BACKGROUND Diabetic kidney disease(DKD),characterized by increased urinary microalbumin levels and decreased renal function,is the primary cause of end-stage renal di-sease.Its pathological mechanisms are complicated and multifactorial;Therefore,sensitive and specific biomarkers are needed.Urinary exosome originate from diverse renal cells in nephron segments and partially mirror the pathological changes in the kidney.The microRNAs(miRNAs)in urinary exosome are remark-ably stable and highly tissue-specific for the kidney.METHODS Type 2 diabetic mellitus(T2DM)patients were recruited from the Second Hospital of Hebei Medical University and were divided into two groups:DM,diabetic pa-tients without albuminuria[urinary albumin to creatinine ratio(UACR)<30 mg/g]and DKD,diabetic patients with albuminuria(UACR≥30 mg/g).Healthy subjects were the normal control(NC)group.Urinary exosomal miR-145-5p,miR-27a-3p,and miR-29c-3p,were detected using real-time quantitative polymerase chain reaction.The correlation between exosomal miRNAs and the clinical in-dexes was evaluated.The diagnostic values of exosomal miR-145-5p and miR-27a-3p in DKD were determined using receiver operating characteristic(ROC)analysis.Biological functions of miR-145-5p were investigated by performing RESULTS Urinary exosomal expression of miR-145-5p and miR-27a-3p was more upregulated in the DKD group than in the DM group(miR-145-5p:4.54±1.45 vs 1.95±0.93,P<0.001;miR-27a-3p:2.33±0.79 vs 1.71±0.76,P<0.05)and the NC group(miR-145-5p:4.54±1.45 vs 1.55±0.83,P<0.001;miR-27a-3p:2.33±0.79 vs 1.10±0.51,P<0.001).The exosomal miR-145-5p and miR-27a-3p positively correlated with albuminuria and serum creatinine and negatively correlated with the estimated glomerular filtration rate.miR-27a-3p was also closely related to blood glucose,gly-cosylated hemoglobin A1c,and low-density lipoprotein cholesterol.ROC analysis revealed that miR-145-5p had a better area under the curve of 0.88[95%confidence interval(CI):0.784-0.985,P<0.0001]in diagnosing DKD than miR-27a-3p with 0.71(95%CI:0.547-0.871,P=0.0239).Bioinformatics analysis revealed that the target genes of miR-145-5p were located in the actin filament,cytoskeleton,and extracellular exosome and were involved in the pathological processes of DKD,including apoptosis,inflammation,and fibrosis.CONCLUSION Urinary exosomal miR-145-5p and miR-27a-3p may serve as novel noninvasive diagnostic biomarkers or promising therapeutic targets for DKD.展开更多
[目的]探讨circ_0001361靶向miR-486-3p对乳腺癌细胞增殖和凋亡的影响。[方法]通过集落形成实验、流式细胞术、CCK-8法评估circ_0001361和miR-486-3p对乳腺癌MDA-MB-231细胞克隆、凋亡以及细胞活力的影响。双荧光素酶检测circ_0001361与...[目的]探讨circ_0001361靶向miR-486-3p对乳腺癌细胞增殖和凋亡的影响。[方法]通过集落形成实验、流式细胞术、CCK-8法评估circ_0001361和miR-486-3p对乳腺癌MDA-MB-231细胞克隆、凋亡以及细胞活力的影响。双荧光素酶检测circ_0001361与miR-486-3p的相互作用。[结果]干扰circ_0001361表达显著性促进细胞凋亡(7.16%±0.65%vs 25.27%±2.32%,P<0.001)、上调miR-486-3p表达(0.96±0.06 vs 3.08±0.29,P<0.001)、降低细胞光密度值(0.82±0.07 vs 0.44±0.04,P<0.001)和克隆形成数(84.47±7.23 vs 39.69±3.76,P<0.001)。过表达circ_0001361显著性下调miR-486-3p表达(1.00±0.00 vs 0.45±0.05,P<0.001)、促进细胞凋亡(7.36%±0.66%vs 20.44%±2.17%,P<0.001)、降低细胞细胞光密度值(0.86±0.06 vs 0.51±0.05,P<0.001)和克隆形成数(89.62±7.35 vs 45.81±4.48,P<0.001)。circ_0001361与miR-486-3p直接结合。下调miR-486-3p表达显著性减弱干扰circ_0001361对MDA-MB-231细胞克隆形成数、凋亡率和细胞光密度值的影响(P<0.001)。[结论]干扰circ_0001361通过促进miR-486-3p表达来诱导乳腺癌细胞凋亡,并抑制其增殖。展开更多
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
Aim: To reveal the exonic and 3’UTR sequences of KRAS, TP53, APC, BRAF, PIK3CA genes in sporadic colorectal tumors and to investigate the clinical relevance of 3’UTR variations in miRNA profiles. Methods: In the stu...Aim: To reveal the exonic and 3’UTR sequences of KRAS, TP53, APC, BRAF, PIK3CA genes in sporadic colorectal tumors and to investigate the clinical relevance of 3’UTR variations in miRNA profiles. Methods: In the study, the exonic and 3’UTR sequences of five genes in 12 sporadic colorectal tumors were extracted by next generation sequencing. In tumors with variation in the 3’UTR region, the changes caused by the variation in the miRNA binding profile were detected. The expression profile of these miRNAs in colorectal and other solid tumors compared to normal tissue was determined. Pathway analysis was performed to determine which signaling pathways miRNAs affect. Results: Case-10 in our study was wild type KRAS and received cetuximab treatment and developed drug resistance. In this case, it was concluded that the expression of KRAS increased and tumorigenesis progressed due to miRNAs that do not bind to this region due to variations in the 3’UTR region. Among these miRNAs, hsa-miR-124-3p was found to have decreased expression in colorectal tumors and to be associated with the ECM-receptor interaction pathway. Conclusion: Variations in the 3’UTR regions of genes critical in the process of carsinogenesis are associated with drug resistance and the process of tumorigenesis.展开更多
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BACKGROUND Colorectal cancer(CRC)is a common malignant tumor of the digestive tract worldwide,characterized by high incidence and mortality rates.AIM To investigate the expression of serum apurinic/apyrimidinic endonuclease 1 autoantibodies(APE1-AAbs),peripheral pentraxin-3(PTX-3),and miR-486-3p in patients with CRC undergoing radical surgery and their relationship with postoperative recurrence and metastasis.METHODS A retrospective analysis was conducted on the clinical data of 154 CRC patients who underwent laparoscopic radical surgery in our hospital from January 2022 to January 2024.Patients were followed for one year postoperatively and divided into an occurrence group(n=28)and a non-occurrence group(n=126)based on whether they experienced recurrence or metastasis.The clinical data and the expression levels of APE1-AAbs,PTX-3,and miR-486-3p were compared between the two groups.Multivariate logistic regression analysis was performed to identify risk factors for postoperative recurrence and metastasis in CRC patients.The relationship of APE1-AAbs,PTX-3,and miR-486-3p with postoperative recurrence and metastasis was analyzed using Spearman correlation analysis.Receiver operating characteristic curves were drawn to evaluate the predictive value of serum APE1-AAbs,PTX-3,and miR-486-3p levels alone and their combination for postoperative recurrence and metastasis in CRC.RESULTS The occurrence group had significantly higher proportions of patients with an age≥60 years,lymph node metastasis,stage III disease,poor differentiation,tumor diameter>5 cm,and higher platelet count,carcinoembryonic antigen,and carbohydrate antigen 19-9 levels than the non-occurrence group(P<0.05).The expression levels of APE1-AAbs,PTX-3,and miR-486-3p in the occurrence group were significantly higher than those in the non-occurrence group(P<0.05).Multivariate logistic regression analysis showed that lymph node metastasis,stage III disease,poor differentiation,and elevated levels of APE1-AAbs,PTX-3,and miR-486-3p were risk factors for postoperative recurrence and metastasis in CRC patients(odds ratio>1,P<0.05).Spearman correlation analysis revealed that the levels of APE1-AAbs,PTX-3,and miR-486-3p were positively correlated with postoperative recurrence and metastasis in CRC patients(r=0.642,0.653,and 0.631,respectively,P<0.05).Receiver operating characteristic curve analysis showed that the area under the curve values for APE1-AAbs,PTX-3,and miR-486-3p levels alone and their combination in predicting postoperative recurrence and metastasis in CRC were 0.764,0.783,0.806,and 0.875,respectively,with the combination significantly outperforming individual markers(P<0.05).CONCLUSION Serum APE1-AAbs,PTX-3,and miR-486-3p levels are higher in CRC patients with postoperative recurrence and metastasis.These three markers are risk factors for postoperative recurrence and metastasis in CRC and can be used as predictive biomarkers.The combined detection of these markers has higher predictive value compared to individual tests.
文摘Objective:Gastric cancer(GC)is a globally common cancer characterized by high incidence and mortality worldwide.Advances in the molecular understanding of GC provide promising targets for GC diagnosis and therapy.Long non-coding RNAs(lncRNAs)and their downstream regulators are regarded to be implicated in the progression of multiple types of malignancies.Studies have shown that the lncRNA small nucleolar RNA host gene 4(SNHG4)serves as a tumor promoter in various malignancies,while its function in GC has yet to be characterized.Therefore,our study aimed to explore the role and underlying mechanism of SNHG4 in GC.Methods:We used qRT-PCR to analyze SNHG4 expression in GC tissues and cells.Kaplan-Meier analysis was used to assess the correlation between SNHG4 expression and the survival rate of GC patients.Cellular function experiments such as CCK-8,BrdU,colony formation,flow cytometry analysis,and transwell were performed to explore the effects of SNHG4 on GC cell proliferation,apoptosis,cell cycle,migration,and invasion.We also established xenograft mouse models to explore the effect of SNHG4 on GC tumor growth.Mechanically,dual luciferase reporter assay was used to verify the interaction between SNHG4 and miR-409-3p and between miR-409-3p and cAMP responsive element binding protein 1(CREB1).Results:The results indicated that SNHG4 was overexpressed in GC tissues and cell lines,and was linked with poor survival rate of GC patients.SNHG4 promoted GC cell proliferation,migration,and invasion while inhibiting cell apoptosis and cell cycle arrest in vitro.The in vivo experiment indicated that SNHG4 facilitated GC tumor growth.Furthermore,SNHG4 was demonstrated to bind to miR-409-3p.Moreover,CREB1 was directly targeted by miR-409-3p.Rescue assays demonstrated that miR-409-3p deficiency reversed the suppressive impact of SNHG4 knockdown on GC cell malignancy.Additionally,miR-409-3p was also revealed to inhibit GC cell proliferation,migration,and invasion by targeting CREB1.Conclusion:In conclusion,we verified that the SNHG4 promoted GC growth and metastasis by binding to miR-409-3p to upregulate CREB1,which may deepen the understanding of the underlying mechanism in GC development.
基金supported by the National Institute on Aging (NIA)National Institutes of Health (NIH)+3 种基金Nos.K99AG065645,R00AG065645R00AG065645-04S1 (to SK)NIH research grants,NINDS,No.R01 NS115834NINDS/NIA,No.R01 NS115834-02S1 (to LG)。
文摘Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's disease-related dementia.Our previous study identified the upregulation of microRNA-502-3p(miR-502-3p)and downregulation of GABA type A receptor subunitα-1 in Alzheimer's disease synapses.This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function.In vitro studies were perfo rmed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs.In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunitα-1 mRNA.Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunitα-1 gene and suppresses the luciferase activity.Furthermore,quantitative reve rse transcription-polymerase chain reaction,miRNA in situ hybridization,immunoblotting,and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunitα-1 level,while suppression of miR-502-3p increased the level of GABA type A receptor subunitα-1 protein.Notably,as a result of the overexpression of miR-502-3p,cell viability was found to be reduced,and the population of necrotic cells was found to be increased.The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney(HEK)recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function,suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function.Additionally,the levels of proteins associated with Alzheimer s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression.The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p.We propose that micro-RNA,in particular miR-502-3p,could be a potential therapeutic to rget to modulate GABAergic synapse function in neurological disorders,including Alzheimer's disease and Alzheimer's diseaserelated dementia.
基金Supported by the Nature Science Foundation of Hebei Province,No.H2023104011.
文摘BACKGROUND Diabetic kidney disease(DKD),characterized by increased urinary microalbumin levels and decreased renal function,is the primary cause of end-stage renal di-sease.Its pathological mechanisms are complicated and multifactorial;Therefore,sensitive and specific biomarkers are needed.Urinary exosome originate from diverse renal cells in nephron segments and partially mirror the pathological changes in the kidney.The microRNAs(miRNAs)in urinary exosome are remark-ably stable and highly tissue-specific for the kidney.METHODS Type 2 diabetic mellitus(T2DM)patients were recruited from the Second Hospital of Hebei Medical University and were divided into two groups:DM,diabetic pa-tients without albuminuria[urinary albumin to creatinine ratio(UACR)<30 mg/g]and DKD,diabetic patients with albuminuria(UACR≥30 mg/g).Healthy subjects were the normal control(NC)group.Urinary exosomal miR-145-5p,miR-27a-3p,and miR-29c-3p,were detected using real-time quantitative polymerase chain reaction.The correlation between exosomal miRNAs and the clinical in-dexes was evaluated.The diagnostic values of exosomal miR-145-5p and miR-27a-3p in DKD were determined using receiver operating characteristic(ROC)analysis.Biological functions of miR-145-5p were investigated by performing RESULTS Urinary exosomal expression of miR-145-5p and miR-27a-3p was more upregulated in the DKD group than in the DM group(miR-145-5p:4.54±1.45 vs 1.95±0.93,P<0.001;miR-27a-3p:2.33±0.79 vs 1.71±0.76,P<0.05)and the NC group(miR-145-5p:4.54±1.45 vs 1.55±0.83,P<0.001;miR-27a-3p:2.33±0.79 vs 1.10±0.51,P<0.001).The exosomal miR-145-5p and miR-27a-3p positively correlated with albuminuria and serum creatinine and negatively correlated with the estimated glomerular filtration rate.miR-27a-3p was also closely related to blood glucose,gly-cosylated hemoglobin A1c,and low-density lipoprotein cholesterol.ROC analysis revealed that miR-145-5p had a better area under the curve of 0.88[95%confidence interval(CI):0.784-0.985,P<0.0001]in diagnosing DKD than miR-27a-3p with 0.71(95%CI:0.547-0.871,P=0.0239).Bioinformatics analysis revealed that the target genes of miR-145-5p were located in the actin filament,cytoskeleton,and extracellular exosome and were involved in the pathological processes of DKD,including apoptosis,inflammation,and fibrosis.CONCLUSION Urinary exosomal miR-145-5p and miR-27a-3p may serve as novel noninvasive diagnostic biomarkers or promising therapeutic targets for DKD.
文摘[目的]探讨circ_0001361靶向miR-486-3p对乳腺癌细胞增殖和凋亡的影响。[方法]通过集落形成实验、流式细胞术、CCK-8法评估circ_0001361和miR-486-3p对乳腺癌MDA-MB-231细胞克隆、凋亡以及细胞活力的影响。双荧光素酶检测circ_0001361与miR-486-3p的相互作用。[结果]干扰circ_0001361表达显著性促进细胞凋亡(7.16%±0.65%vs 25.27%±2.32%,P<0.001)、上调miR-486-3p表达(0.96±0.06 vs 3.08±0.29,P<0.001)、降低细胞光密度值(0.82±0.07 vs 0.44±0.04,P<0.001)和克隆形成数(84.47±7.23 vs 39.69±3.76,P<0.001)。过表达circ_0001361显著性下调miR-486-3p表达(1.00±0.00 vs 0.45±0.05,P<0.001)、促进细胞凋亡(7.36%±0.66%vs 20.44%±2.17%,P<0.001)、降低细胞细胞光密度值(0.86±0.06 vs 0.51±0.05,P<0.001)和克隆形成数(89.62±7.35 vs 45.81±4.48,P<0.001)。circ_0001361与miR-486-3p直接结合。下调miR-486-3p表达显著性减弱干扰circ_0001361对MDA-MB-231细胞克隆形成数、凋亡率和细胞光密度值的影响(P<0.001)。[结论]干扰circ_0001361通过促进miR-486-3p表达来诱导乳腺癌细胞凋亡,并抑制其增殖。
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.
文摘Aim: To reveal the exonic and 3’UTR sequences of KRAS, TP53, APC, BRAF, PIK3CA genes in sporadic colorectal tumors and to investigate the clinical relevance of 3’UTR variations in miRNA profiles. Methods: In the study, the exonic and 3’UTR sequences of five genes in 12 sporadic colorectal tumors were extracted by next generation sequencing. In tumors with variation in the 3’UTR region, the changes caused by the variation in the miRNA binding profile were detected. The expression profile of these miRNAs in colorectal and other solid tumors compared to normal tissue was determined. Pathway analysis was performed to determine which signaling pathways miRNAs affect. Results: Case-10 in our study was wild type KRAS and received cetuximab treatment and developed drug resistance. In this case, it was concluded that the expression of KRAS increased and tumorigenesis progressed due to miRNAs that do not bind to this region due to variations in the 3’UTR region. Among these miRNAs, hsa-miR-124-3p was found to have decreased expression in colorectal tumors and to be associated with the ECM-receptor interaction pathway. Conclusion: Variations in the 3’UTR regions of genes critical in the process of carsinogenesis are associated with drug resistance and the process of tumorigenesis.
