Pristimerin,which is one of the compounds present in Celastraceae and Hippocrateaceae,has antitumor effects.However,its mechanism of action in esophageal squamous cell carcinoma(ESCC)remains unclear.This study aims to...Pristimerin,which is one of the compounds present in Celastraceae and Hippocrateaceae,has antitumor effects.However,its mechanism of action in esophageal squamous cell carcinoma(ESCC)remains unclear.This study aims to investigate the efficacy and mechanism of pristimerin on ESCC in vitro and in vivo.The inhibitory effect of pristimerin on cell growth was assessed using trypan blue exclusion and colony formation assays.Cell apoptosis was evaluated by flow cytometry.Gene and protein expressions were analyzed through quantitative reverse transcription-polymerase chain reaction(qRT-PCR),Western blotting,and immunohistochemistry.RNA sequencing(RNA-Seq)was employed to identify significantly differentially expressed genes(DEGs).Cell transfection and RNA interference assays were utilized to examine the role of key proteins in pristimerin's effect.Xenograft models were established to evaluate the antitumor efficiency of pristimerin in vivo.Pristimerin inhibited cell growth and induced apoptosis in ESCC cells.Upregulation of Noxa was crucial for pristimerin-induced apoptosis.Pristimerin activated the Forkhead box O3a(FoxO3a)signaling pathway and triggered FoxO3a recruitment to the Noxa promoter,leading to Noxa transcription.Blocking FoxO3a reversed pristimerin-induced Noxa upregulation and cell apoptosis.Pristimerin treatment suppressed xenograft tumors in nude mice,but these effects were largely negated in Noxa-KO tumors.Furthermore,the chemosensitization effects of pristimerin in vitro and in vivo were mediated by Noxa.This study demonstrates that pristimerin exerts an antitumor effect on ESCC by inducing AKT/FoxO3a-mediated Noxa upregulation.These findings suggest that pristimerin may serve as a potent anticancer agent for ESCC treatment.展开更多
The human endogenous retrovirus type W envelope glycoprotein(ERVWE1),located at chromosome 7q21–22,has been implicated in the pathophysiology of schizophrenia.Our previous studies have shown elevated ERVWE1 expressio...The human endogenous retrovirus type W envelope glycoprotein(ERVWE1),located at chromosome 7q21–22,has been implicated in the pathophysiology of schizophrenia.Our previous studies have shown elevated ERVWE1 expression in schizophrenia patients.Growing evidence suggests that autophagy dysfunction contributes to schizophrenia,yet the relationship between ERVWE1 and autophagy remains unclear.In this study,bioinformatics analysis of the human prefrontal cortex RNA microarray dataset(GSE53987)revealed that differentially expressed genes were predominantly enriched in autophagy-related pathways.Clinical data further demonstrated that serum levels of microtubuleassociated protein 1 light chain 3β(LC3B),a key marker of macroautophagy,were significantly elevated in schizophrenia patients compared to controls,and positively correlated with ERVWE1 expression.Cellular and molecular experiments suggested that ERVWE1 promoted macroautophagy by increasing the LC3B II/I ratio,enhancing autophagosome formation,and reducing sequestosome 1(SQSTM1)expression via upregulation of NADPH oxidase activator 1(NOXA1).Concurrently,NOXA1 downregulated the expression of key micromitophagy-related genes,including PTEN-induced kinase 1(PINK1),Parkin RBR E3 ubiquitin-protein ligase(Parkin),and the pyruvate dehydrogenase E1 subunitα1(PDHA1).As a result,ERVWE1,via NOXA1,inhibited micromitophagy by suppressing the expression of PINK1,Parkin,and PDHA1,thereby leading to impaired production of mitochondrialderived vesicles(MDVs).Mechanistically,ERVWE1 enhanced NOXA1 transcription by upregulating upstream transcription factor 2(USF2).In conclusion,ERVWE1 promotes macroautophagy and inhibits micromitophagy through USF2-NOXA1 axis,providing novel mechanistic insight into the role autophagy dysregulation in schizophrenia.These findings suggest that targeting autophagy pathways may offer novel therapeutic strategies for schizophrenia treatment.展开更多
Gambogenic acid(GNA),a bioactive compound derived from the resin of Garcinia hanburyi,has demonstrated significant antitumor properties.However,its mechanisms of action in oral squamous cell carcinoma(OSCC)remain larg...Gambogenic acid(GNA),a bioactive compound derived from the resin of Garcinia hanburyi,has demonstrated significant antitumor properties.However,its mechanisms of action in oral squamous cell carcinoma(OSCC)remain largely unclear.This study aimed to elucidate the apoptotic effects of GNA on OSCC cell lines CAL-27 and SCC-15.Our results indicated that GNA induced apoptosis by upregulating the pro-apoptotic protein Noxa.Mechanistic investigations revealed that GNA treatment led to the generation of reactive oxygen species(ROS),which activated endoplasmic reticulum(ER)stress,culminating in cell apoptosis.Inhibition of ROS production and ER stress pathways significantly mitigated GNA-induced Noxa upregulation and subsequent apoptosis.Furthermore,in vivo studies using a murine xenograft model demonstrated that GNA administration effectively inhibited the growth of CAL-27 tumors.Collectively,these findings underscore GNA’s potential as a therapeutic agent for the treatment of OSCC.展开更多
基金supported by the Projects of International Cooperation and Exchanges(Nos.G2022027004L,G2022027012L)the Hubei Province Natural Science Foundation of China(No.2022CFB481)+3 种基金the Natural Science Foundation of Hubei Provincial Department of Education(No.T2022021)the Advantages Discipline Group(Biology and Medicine)Project in Higher Education of Hubei Province(2021-2025)(Nos.2025BMXKQY2,2024XKQY26)the Innovative Research Program for Graduates of Hubei University of Medicine(No.YC2024003,YC2022033)the Student's Platform for Innovation and Entrepreneurship Training Program(Nos.202410929010,202210929005)。
文摘Pristimerin,which is one of the compounds present in Celastraceae and Hippocrateaceae,has antitumor effects.However,its mechanism of action in esophageal squamous cell carcinoma(ESCC)remains unclear.This study aims to investigate the efficacy and mechanism of pristimerin on ESCC in vitro and in vivo.The inhibitory effect of pristimerin on cell growth was assessed using trypan blue exclusion and colony formation assays.Cell apoptosis was evaluated by flow cytometry.Gene and protein expressions were analyzed through quantitative reverse transcription-polymerase chain reaction(qRT-PCR),Western blotting,and immunohistochemistry.RNA sequencing(RNA-Seq)was employed to identify significantly differentially expressed genes(DEGs).Cell transfection and RNA interference assays were utilized to examine the role of key proteins in pristimerin's effect.Xenograft models were established to evaluate the antitumor efficiency of pristimerin in vivo.Pristimerin inhibited cell growth and induced apoptosis in ESCC cells.Upregulation of Noxa was crucial for pristimerin-induced apoptosis.Pristimerin activated the Forkhead box O3a(FoxO3a)signaling pathway and triggered FoxO3a recruitment to the Noxa promoter,leading to Noxa transcription.Blocking FoxO3a reversed pristimerin-induced Noxa upregulation and cell apoptosis.Pristimerin treatment suppressed xenograft tumors in nude mice,but these effects were largely negated in Noxa-KO tumors.Furthermore,the chemosensitization effects of pristimerin in vitro and in vivo were mediated by Noxa.This study demonstrates that pristimerin exerts an antitumor effect on ESCC by inducing AKT/FoxO3a-mediated Noxa upregulation.These findings suggest that pristimerin may serve as a potent anticancer agent for ESCC treatment.
基金supported by the National Natural Science Foundation of China(No.82272321)the Stanley Foundation from the Stanley Medical Research Institute(SMRI),United States(No.06R-1366)。
文摘The human endogenous retrovirus type W envelope glycoprotein(ERVWE1),located at chromosome 7q21–22,has been implicated in the pathophysiology of schizophrenia.Our previous studies have shown elevated ERVWE1 expression in schizophrenia patients.Growing evidence suggests that autophagy dysfunction contributes to schizophrenia,yet the relationship between ERVWE1 and autophagy remains unclear.In this study,bioinformatics analysis of the human prefrontal cortex RNA microarray dataset(GSE53987)revealed that differentially expressed genes were predominantly enriched in autophagy-related pathways.Clinical data further demonstrated that serum levels of microtubuleassociated protein 1 light chain 3β(LC3B),a key marker of macroautophagy,were significantly elevated in schizophrenia patients compared to controls,and positively correlated with ERVWE1 expression.Cellular and molecular experiments suggested that ERVWE1 promoted macroautophagy by increasing the LC3B II/I ratio,enhancing autophagosome formation,and reducing sequestosome 1(SQSTM1)expression via upregulation of NADPH oxidase activator 1(NOXA1).Concurrently,NOXA1 downregulated the expression of key micromitophagy-related genes,including PTEN-induced kinase 1(PINK1),Parkin RBR E3 ubiquitin-protein ligase(Parkin),and the pyruvate dehydrogenase E1 subunitα1(PDHA1).As a result,ERVWE1,via NOXA1,inhibited micromitophagy by suppressing the expression of PINK1,Parkin,and PDHA1,thereby leading to impaired production of mitochondrialderived vesicles(MDVs).Mechanistically,ERVWE1 enhanced NOXA1 transcription by upregulating upstream transcription factor 2(USF2).In conclusion,ERVWE1 promotes macroautophagy and inhibits micromitophagy through USF2-NOXA1 axis,providing novel mechanistic insight into the role autophagy dysregulation in schizophrenia.These findings suggest that targeting autophagy pathways may offer novel therapeutic strategies for schizophrenia treatment.
基金supported by the Projects of International Cooperation and Exchanges(No.G2022027012L)the Natural Science Foundation of Hubei Provincial Department of Education(No.T2022021)+2 种基金the Advantages Discipline Group(Medicine)Project in Higher Education of Hubei Province(2021-2025)(Nos.2024XKQY26 and 2023BMXKQY2)the Open Project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research of Hubei University of Medicine(No.WDCM2023007)the Innovative Research Program for Graduates of Hubei University of Medicine(No.YC2022033,YC2024003).
文摘Gambogenic acid(GNA),a bioactive compound derived from the resin of Garcinia hanburyi,has demonstrated significant antitumor properties.However,its mechanisms of action in oral squamous cell carcinoma(OSCC)remain largely unclear.This study aimed to elucidate the apoptotic effects of GNA on OSCC cell lines CAL-27 and SCC-15.Our results indicated that GNA induced apoptosis by upregulating the pro-apoptotic protein Noxa.Mechanistic investigations revealed that GNA treatment led to the generation of reactive oxygen species(ROS),which activated endoplasmic reticulum(ER)stress,culminating in cell apoptosis.Inhibition of ROS production and ER stress pathways significantly mitigated GNA-induced Noxa upregulation and subsequent apoptosis.Furthermore,in vivo studies using a murine xenograft model demonstrated that GNA administration effectively inhibited the growth of CAL-27 tumors.Collectively,these findings underscore GNA’s potential as a therapeutic agent for the treatment of OSCC.
