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
The incidence rate of kidney diseases in China has always remained high.At present,the clinical treatment mainly focuses on symptomatic treatment to delay the progression of the disease,and there is a lack of economic...The incidence rate of kidney diseases in China has always remained high.At present,the clinical treatment mainly focuses on symptomatic treatment to delay the progression of the disease,and there is a lack of economical and effective treatment methods.MicroRNA plays an important regulatory role in the occurrence and development of diseases.This study aims to explore the role and regulatory mechanism of miR⁃142a⁃3p in adriamycin(ADR)⁃induced renal tubular epithelial cell(TCMK⁃1)injury,with a focus on its potential as a therapeutic target for ADR nephropathy.First,cell viability was assessed using the CCK⁃8 kit,and a mouse renal tubular epithelial cell model induced by ADR was established.Subsequently,alterations in miR⁃142a⁃3p and its target gene ATG16L1 mRNA levels were quantified using RT⁃qPCR.Western blotting was used to detect the protein levels of autophagy marker proteins and pyroptosis marker proteins.Monodansylcadaverin(MDC)staining was performed and the autophagy of cells was detected by flow cytometry.The results showed that the relative expression of miR⁃142a⁃3p in TCMK⁃1 cells induced by ADR was increased and the relative expression of its target gene ATG16L1 was decreased(P<0.0001).Western blotting results showed that the levels of p62(P<0.001)and pyroptosis⁃related proteins(P<0.001)were increased,while the protein levels of autophagy⁃related proteins were decreased(P<0.05).The flow cytometry results showed that there was no difference in the mean fluorescence intensity of autoph⁃agosomes between the ADR group and the autophagosome inhibitor group(3⁃MA group)(P>0.05),indicating that after ADR induction,cell autophagy was inhibited and pyroptosis was enhanced.When the expression of miR⁃142a⁃3p was inhibited by transfecting miR⁃142a⁃3p inhibitor,the relative expression level of the target gene ATG16L1 was restored(P<0.001).Western blotting showed that the protein level of p62(P<0.01)and pyroptosis⁃related proteins(P<0.01)were decreased,and the protein level of autophagy⁃related proteins was restored(P<0.001).Flow cytometry results further indicated that cell autophagy was restored(P<0.0001).In conclusion,ADR targets ATG16L1 through miR⁃142a⁃3p to reduce the autophagy level of TCMK⁃1,and simultaneously activates GSDMD⁃mediated pyroptosis.展开更多
BACKGROUND We aimed to identify the key proteins of miR-142-3p that regulate ferroptosis and ultimately control the downstream effectors of cardiomyocyte growth.AIM To investigate the role of miR-142-3p in regulating ...BACKGROUND We aimed to identify the key proteins of miR-142-3p that regulate ferroptosis and ultimately control the downstream effectors of cardiomyocyte growth.AIM To investigate the role of miR-142-3p in regulating ferroptosis and its impact on diabetes-induced myocardial infarction via the PI3K/AKT/GSK3βpathway.METHODS We constructed bones mesenchymal stem cells(BMCs)with low miR-142-3p expression and investigated its role using cell flow cytometry and western blotting(WB).A diabetes myocardial infarction model was established using streptozotocin and coronary artery ligation.The rats were divided into six groups(n=15 per group):Control,sham surgery model,liraglutide intervention,BMCs intervention,and low miR-142-3p BMCs intervention.Interventions lasted for 7 days and BMCs injected for once.Blood glucose levels were monitored,and myocardial infarction improvements were assessed via electrocardiogra,general heart observation,staining techniques,and WB analysis.RESULTS We observed that miR-142-3p increased BMC apoptosis and affected AKT and GSK3β.The myocardial infarction drug,liraglutide,BMCs,and miR-142-3p low expression BMCs intervention showed improvement in differing degrees.The liraglutide and BMCs showed significant blood glucose reduction(0.05).BMCs increased the expression of PI3K,AKT,and GSK3,leading to an increase in the myocardial infarction intervention group,liraglutide,and BMCs intervention groups.The low miR-142-3p expression intervention with BMCs group had the lowest PI3K and AKT protein expression.Liraglutide improved ferroptosis markers(increased COX-2,decreased GPX4 and CHCHD6).Low miR-142-3p BMCs increased COX-2,GPX4,and CHCHD6.CCM3 and VEGFR2 expression increased in BMCs and low miR-142-3p groups,promoting myocardial repair,but decreased in the low miR-142-3p groups.CONCLUSION The preliminary results showed that the therapeutic mechanism of BMCs in diabetes myocardial infarction may involve miR-142-3p via the PI3K/AKT/GSK-3βaxis,which jointly inhibits ferroptosis and programmed death.展开更多
The generation of defects,such as cracks and pores,presents significant challenges for high-strength met-als and alloys fabricated by the quick-emerging additive manufacturing technology,and subsequent post-processing...The generation of defects,such as cracks and pores,presents significant challenges for high-strength met-als and alloys fabricated by the quick-emerging additive manufacturing technology,and subsequent post-processing treatments are often necessary before their practical applications.In this work,a novel heat treatment approach,involving a pre-softening treatment before hot isostatic pressing(HIP),is developed to facilitate the crack-healing in René142 superalloy produced through laser powder bed fusion.Results demonstrate that René142 alloy exhibits a propensity for severe cracking across a wide range of printing parameters,primarily in the form of solidification cracks and liquation cracks.These cracks are formed mainly due to a wide solidification range,the presence of a liquid film,and the concentration of resid-ual stress.The pre-softening solution heat treatment significantly reduces dislocation density and resid-ual stress levels,and the subsequent HIP together leads to a defect-free,dense structure for René142 superalloy.Consequently,the René142 alloy processed by the pre-softening HIP treatment achieves an excellent combination of yield strength(850 MPa),ultimate tensile strength(1227 MPa),and elongation(13.7%),with pseudo-equiaxed grains(120-150μm)and squareγ'precipitates(approximately 540 nm).These findings provide valuable insights for exploring crack elimination methods in other nickel-based superalloys fabricated through additive manufacturing.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The incidence rate of kidney diseases in China has always remained high.At present,the clinical treatment mainly focuses on symptomatic treatment to delay the progression of the disease,and there is a lack of economical and effective treatment methods.MicroRNA plays an important regulatory role in the occurrence and development of diseases.This study aims to explore the role and regulatory mechanism of miR⁃142a⁃3p in adriamycin(ADR)⁃induced renal tubular epithelial cell(TCMK⁃1)injury,with a focus on its potential as a therapeutic target for ADR nephropathy.First,cell viability was assessed using the CCK⁃8 kit,and a mouse renal tubular epithelial cell model induced by ADR was established.Subsequently,alterations in miR⁃142a⁃3p and its target gene ATG16L1 mRNA levels were quantified using RT⁃qPCR.Western blotting was used to detect the protein levels of autophagy marker proteins and pyroptosis marker proteins.Monodansylcadaverin(MDC)staining was performed and the autophagy of cells was detected by flow cytometry.The results showed that the relative expression of miR⁃142a⁃3p in TCMK⁃1 cells induced by ADR was increased and the relative expression of its target gene ATG16L1 was decreased(P<0.0001).Western blotting results showed that the levels of p62(P<0.001)and pyroptosis⁃related proteins(P<0.001)were increased,while the protein levels of autophagy⁃related proteins were decreased(P<0.05).The flow cytometry results showed that there was no difference in the mean fluorescence intensity of autoph⁃agosomes between the ADR group and the autophagosome inhibitor group(3⁃MA group)(P>0.05),indicating that after ADR induction,cell autophagy was inhibited and pyroptosis was enhanced.When the expression of miR⁃142a⁃3p was inhibited by transfecting miR⁃142a⁃3p inhibitor,the relative expression level of the target gene ATG16L1 was restored(P<0.001).Western blotting showed that the protein level of p62(P<0.01)and pyroptosis⁃related proteins(P<0.01)were decreased,and the protein level of autophagy⁃related proteins was restored(P<0.001).Flow cytometry results further indicated that cell autophagy was restored(P<0.0001).In conclusion,ADR targets ATG16L1 through miR⁃142a⁃3p to reduce the autophagy level of TCMK⁃1,and simultaneously activates GSDMD⁃mediated pyroptosis.
基金Supported by Health Commission Project,No.Z2014334Natural Science Foundation of Guangxi Province,China,No.2020GXNSFAA238036.
文摘BACKGROUND We aimed to identify the key proteins of miR-142-3p that regulate ferroptosis and ultimately control the downstream effectors of cardiomyocyte growth.AIM To investigate the role of miR-142-3p in regulating ferroptosis and its impact on diabetes-induced myocardial infarction via the PI3K/AKT/GSK3βpathway.METHODS We constructed bones mesenchymal stem cells(BMCs)with low miR-142-3p expression and investigated its role using cell flow cytometry and western blotting(WB).A diabetes myocardial infarction model was established using streptozotocin and coronary artery ligation.The rats were divided into six groups(n=15 per group):Control,sham surgery model,liraglutide intervention,BMCs intervention,and low miR-142-3p BMCs intervention.Interventions lasted for 7 days and BMCs injected for once.Blood glucose levels were monitored,and myocardial infarction improvements were assessed via electrocardiogra,general heart observation,staining techniques,and WB analysis.RESULTS We observed that miR-142-3p increased BMC apoptosis and affected AKT and GSK3β.The myocardial infarction drug,liraglutide,BMCs,and miR-142-3p low expression BMCs intervention showed improvement in differing degrees.The liraglutide and BMCs showed significant blood glucose reduction(0.05).BMCs increased the expression of PI3K,AKT,and GSK3,leading to an increase in the myocardial infarction intervention group,liraglutide,and BMCs intervention groups.The low miR-142-3p expression intervention with BMCs group had the lowest PI3K and AKT protein expression.Liraglutide improved ferroptosis markers(increased COX-2,decreased GPX4 and CHCHD6).Low miR-142-3p BMCs increased COX-2,GPX4,and CHCHD6.CCM3 and VEGFR2 expression increased in BMCs and low miR-142-3p groups,promoting myocardial repair,but decreased in the low miR-142-3p groups.CONCLUSION The preliminary results showed that the therapeutic mechanism of BMCs in diabetes myocardial infarction may involve miR-142-3p via the PI3K/AKT/GSK-3βaxis,which jointly inhibits ferroptosis and programmed death.
基金support of the National Natural Science Foundation of China(Project Nos.52371012 and 52301060).
文摘The generation of defects,such as cracks and pores,presents significant challenges for high-strength met-als and alloys fabricated by the quick-emerging additive manufacturing technology,and subsequent post-processing treatments are often necessary before their practical applications.In this work,a novel heat treatment approach,involving a pre-softening treatment before hot isostatic pressing(HIP),is developed to facilitate the crack-healing in René142 superalloy produced through laser powder bed fusion.Results demonstrate that René142 alloy exhibits a propensity for severe cracking across a wide range of printing parameters,primarily in the form of solidification cracks and liquation cracks.These cracks are formed mainly due to a wide solidification range,the presence of a liquid film,and the concentration of resid-ual stress.The pre-softening solution heat treatment significantly reduces dislocation density and resid-ual stress levels,and the subsequent HIP together leads to a defect-free,dense structure for René142 superalloy.Consequently,the René142 alloy processed by the pre-softening HIP treatment achieves an excellent combination of yield strength(850 MPa),ultimate tensile strength(1227 MPa),and elongation(13.7%),with pseudo-equiaxed grains(120-150μm)and squareγ'precipitates(approximately 540 nm).These findings provide valuable insights for exploring crack elimination methods in other nickel-based superalloys fabricated through additive manufacturing.
