BACKGROUND The progression of non-alcoholic fatty liver disease(NAFLD)to non-alcoholic steatohepatitis(NASH)and liver fibrosis remains poorly understood,though liver sinusoidal endothelial cells(LSECs)are thought to p...BACKGROUND The progression of non-alcoholic fatty liver disease(NAFLD)to non-alcoholic steatohepatitis(NASH)and liver fibrosis remains poorly understood,though liver sinusoidal endothelial cells(LSECs)are thought to play a central role in disease pathogenesis.AIM To investigate the role of TSC22D1 in NAFLD fibrosis through its regulation of LSEC dysfunction and macrophage polarization.METHODS We analysed single-cell transcriptomic data(GSE129516)from NASH and normal INTRODUCTION Non-alcoholic fatty liver disease(NAFLD)is a global health issue associated with increasing rates of obesity and metabolic syndrome.NAFLD encompasses a spectrum of conditions,ranging from simple steatosis to more severe manifestations such as non-alcoholic steatohepatitis(NASH),fibrosis,cirrhosis,and hepatocellular carcinoma.Liver fibrosis represents a critical stage in NAFLD progression because of its strong association with impaired liver function,progression to end-stage liver disease,and increased disease-related mortality[1].The pathogenesis of NAFLD is multifactorial and involves complex interactions between genetic predispositions,insulin resistance,dietary factors,and chronic inflammation[2].Liver sinusoidal endothelial cells(LSECs),which are highly specialized endothelial cells lining the hepatic sinusoids,critically contribute to both the pathogenesis and progression of NAFLD[3,4].In NAFLD,LSECs undergo structural alterations such as reduced fenestrations,which impair hepatic microcirculation and hinder the exchange of lipids and other substances,thereby promoting lipid accumulation in hepatocytes[5].Furthermore,dysfunctional LSECs exacerbate hepatic inflammation and fibrogenesis by releasing pro-inflammatory cytokines and fibrogenic mediators,such as transforming growth factor-β(TGF-β).These factors activate hepatic stellate cells(HSCs),resulting in the pathological accumulation of extracellular matrix components[6].LSECs are also highly susceptible to oxidative stress,further aggravating hepatic injury[7,8].Importantly,LSECs influence macrophage polarization by producing chemotactic and immunomodulatory factors,thereby promoting the recruitment and activation of M1-type pro-inflammatory CONCLUSION In conclusion,this study provides a comprehensive understanding of the role of TSC22D1 in the pathogenesis of NAFLD fibrosis.We elucidated the mechanisms through which TSC22D1 drives LSEC microvascularization and EndMT,as well as its role in promoting the secretion of TWEAK,which induces macrophage polarization towards the M1 phenotype.These findings offer novel insights into the pathophysiology of NAFLD,particularly the interplay between endothelial dysfunction,inflammation,and fibrosis.Importantly,our results highlight the potential of TSC22D1 as a therapeutic target for NAFLD.Future research should focus on validating these mechanisms in human clinical cohorts and deve-loping targeted interventions,such as TSC22D1 inhibitors or modulators of the TWEAK/FN14 signalling pathway,to translate these findings into effective treatments for NAFLD progression to fibrosis.展开更多
BACKGROUND Gastric cancer(GC)is a prevalent malignant tumor of the gastrointestinal system.ZNF710 is a transcription factor(TF),and zinc finger protein 710(ZNF710)-AS1-201 is an immune-related long noncoding RNA(lncRN...BACKGROUND Gastric cancer(GC)is a prevalent malignant tumor of the gastrointestinal system.ZNF710 is a transcription factor(TF),and zinc finger protein 710(ZNF710)-AS1-201 is an immune-related long noncoding RNA(lncRNA)that is upregulated in GC cells.AIM To assess the correlation between ZNF710-AS1-201 and immune microenvir-onment features and to investigate the roles of ZNF710-AS1-201 in the invasion and metastasis processes of GC cells.METHODS We obtained data from The Cancer Genome Atlas and Wujin Hospital.We assessed cell growth,migration,invasion,and programmed cell death using cell counting kit-8,EdU,scratch,Transwell,and flow cytometry assays.Quantitative real-time polymerase chain reaction(qRT-PCR)was used to identify the potential downstream targets of ZNF710-AS1-201.RESULTS In GC tissues with low ZNF710-AS1-201 expression,immunoassays detected significant infiltration of various antitumor immune cells,such as memory CD8 T cells and activated CD4 T cells.In the low-expression group,the half-maximal inhibitory concentrations(IC_(50)s)of 5-fluorouracil,cisplatin,gemcitabine,and trametinib were lower,whereas the IC_(50)s of dasatinib and vorinostat were higher.The malignant degree of GC was higher and the stage was later in the high-expression group.Additionally,patients with high expression of ZNF710-AS1-201 had lower overall survival and disease-free survival rates.In vitro,the overexpression of ZNF710-AS1-201 greatly enhanced growth,metastasis,and infiltration while suppressing cell death in HGC-27 cells.In contrast,the reduced expression of ZNF710-AS1-201 greatly hindered cell growth,enhanced apoptosis,and suppressed the metastasis and invasion of MKN-45 cells.The expression changes in ZNF710 were significant,but the corresponding changes in isocitrate dehydrogenase-2,Semaphorin 4B,ARHGAP10,RGMB,hsa-miR-93-5p,and ZNF710-AS1-202 were not consistent or statistically significant after overexpression or knockdown of ZNF710-AS1-201,as determined by qRT-PCR.CONCLUSION Immune-related lncRNA ZNF710-AS1-201 facilitates the metastasis and invasion of GC cells.It appears that ZNF710-AS1-201 and ZNF710 have potential as effective targets for therapeutic intervention in GC.Nevertheless,it is still necessary to determine the specific targets of the ZNF710 TF.展开更多
基金Supported by the Changzhou Science and Techology Program,No.CJ20241048Changzhou High-Level Medical Talents Training Project,No.2022CZBJ105+1 种基金Development Foundation of the Affiliated Hospital of Xuzhou Medical University,No.XYFC202304 and No.XYFM202307The Open Project of Jiangsu Provincial Key Laboratory of Laboratory Medicine,No.JSKLM-Z-2024-002.
文摘BACKGROUND The progression of non-alcoholic fatty liver disease(NAFLD)to non-alcoholic steatohepatitis(NASH)and liver fibrosis remains poorly understood,though liver sinusoidal endothelial cells(LSECs)are thought to play a central role in disease pathogenesis.AIM To investigate the role of TSC22D1 in NAFLD fibrosis through its regulation of LSEC dysfunction and macrophage polarization.METHODS We analysed single-cell transcriptomic data(GSE129516)from NASH and normal INTRODUCTION Non-alcoholic fatty liver disease(NAFLD)is a global health issue associated with increasing rates of obesity and metabolic syndrome.NAFLD encompasses a spectrum of conditions,ranging from simple steatosis to more severe manifestations such as non-alcoholic steatohepatitis(NASH),fibrosis,cirrhosis,and hepatocellular carcinoma.Liver fibrosis represents a critical stage in NAFLD progression because of its strong association with impaired liver function,progression to end-stage liver disease,and increased disease-related mortality[1].The pathogenesis of NAFLD is multifactorial and involves complex interactions between genetic predispositions,insulin resistance,dietary factors,and chronic inflammation[2].Liver sinusoidal endothelial cells(LSECs),which are highly specialized endothelial cells lining the hepatic sinusoids,critically contribute to both the pathogenesis and progression of NAFLD[3,4].In NAFLD,LSECs undergo structural alterations such as reduced fenestrations,which impair hepatic microcirculation and hinder the exchange of lipids and other substances,thereby promoting lipid accumulation in hepatocytes[5].Furthermore,dysfunctional LSECs exacerbate hepatic inflammation and fibrogenesis by releasing pro-inflammatory cytokines and fibrogenic mediators,such as transforming growth factor-β(TGF-β).These factors activate hepatic stellate cells(HSCs),resulting in the pathological accumulation of extracellular matrix components[6].LSECs are also highly susceptible to oxidative stress,further aggravating hepatic injury[7,8].Importantly,LSECs influence macrophage polarization by producing chemotactic and immunomodulatory factors,thereby promoting the recruitment and activation of M1-type pro-inflammatory CONCLUSION In conclusion,this study provides a comprehensive understanding of the role of TSC22D1 in the pathogenesis of NAFLD fibrosis.We elucidated the mechanisms through which TSC22D1 drives LSEC microvascularization and EndMT,as well as its role in promoting the secretion of TWEAK,which induces macrophage polarization towards the M1 phenotype.These findings offer novel insights into the pathophysiology of NAFLD,particularly the interplay between endothelial dysfunction,inflammation,and fibrosis.Importantly,our results highlight the potential of TSC22D1 as a therapeutic target for NAFLD.Future research should focus on validating these mechanisms in human clinical cohorts and deve-loping targeted interventions,such as TSC22D1 inhibitors or modulators of the TWEAK/FN14 signalling pathway,to translate these findings into effective treatments for NAFLD progression to fibrosis.
基金Changzhou Sci and Tech Program,No.CJ20220008Young Talent Development Plan of Changzhou Health Commission,No.CZQM2020118+2 种基金Changzhou High-Level Medical Talents Training Project,No.2022CZBJ105Cultivation Project of Changzhou Medical Center,Nanjing Medical University,No.CMCB202211Development Foundation of Affiliated Hospital of Xuzhou Medical University,No.XYFC202304,and No.XYFM202307。
文摘BACKGROUND Gastric cancer(GC)is a prevalent malignant tumor of the gastrointestinal system.ZNF710 is a transcription factor(TF),and zinc finger protein 710(ZNF710)-AS1-201 is an immune-related long noncoding RNA(lncRNA)that is upregulated in GC cells.AIM To assess the correlation between ZNF710-AS1-201 and immune microenvir-onment features and to investigate the roles of ZNF710-AS1-201 in the invasion and metastasis processes of GC cells.METHODS We obtained data from The Cancer Genome Atlas and Wujin Hospital.We assessed cell growth,migration,invasion,and programmed cell death using cell counting kit-8,EdU,scratch,Transwell,and flow cytometry assays.Quantitative real-time polymerase chain reaction(qRT-PCR)was used to identify the potential downstream targets of ZNF710-AS1-201.RESULTS In GC tissues with low ZNF710-AS1-201 expression,immunoassays detected significant infiltration of various antitumor immune cells,such as memory CD8 T cells and activated CD4 T cells.In the low-expression group,the half-maximal inhibitory concentrations(IC_(50)s)of 5-fluorouracil,cisplatin,gemcitabine,and trametinib were lower,whereas the IC_(50)s of dasatinib and vorinostat were higher.The malignant degree of GC was higher and the stage was later in the high-expression group.Additionally,patients with high expression of ZNF710-AS1-201 had lower overall survival and disease-free survival rates.In vitro,the overexpression of ZNF710-AS1-201 greatly enhanced growth,metastasis,and infiltration while suppressing cell death in HGC-27 cells.In contrast,the reduced expression of ZNF710-AS1-201 greatly hindered cell growth,enhanced apoptosis,and suppressed the metastasis and invasion of MKN-45 cells.The expression changes in ZNF710 were significant,but the corresponding changes in isocitrate dehydrogenase-2,Semaphorin 4B,ARHGAP10,RGMB,hsa-miR-93-5p,and ZNF710-AS1-202 were not consistent or statistically significant after overexpression or knockdown of ZNF710-AS1-201,as determined by qRT-PCR.CONCLUSION Immune-related lncRNA ZNF710-AS1-201 facilitates the metastasis and invasion of GC cells.It appears that ZNF710-AS1-201 and ZNF710 have potential as effective targets for therapeutic intervention in GC.Nevertheless,it is still necessary to determine the specific targets of the ZNF710 TF.
