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
Background:Statins are the cornerstone of low-density lipoprotein cholesterol(LDL-C)-lowering therapy;however,the therapeutic efficacy of statins in countering atherosclerotic cardiovascular disease(ASCVD)is compromis...Background:Statins are the cornerstone of low-density lipoprotein cholesterol(LDL-C)-lowering therapy;however,the therapeutic efficacy of statins in countering atherosclerotic cardiovascular disease(ASCVD)is compromised by the concurrent elevation of proprotein convertase subtilisin/kexin type 9(PCSK9),a pivotal molecule that increases LDL-C levels.Aerobic exercise lowers PCSK9 levels,but the underlying mechanism remains unclear.Therefore,we investigated how aerobic exercise can ameliorate statin-induced increases in PCSK9 levels.Methods:Three-week-old male American Institute of Cancer Research(ICR)mice were fed a high-fat-cholesterol diet(HFD)for 12 weeks and then administered atorvastatin alone or atorvastatin combined with aerobic exercise(Statin+Ex).Moreover,a total of 165 participants with stable coronary heart disease(CHD)enrolled at the Inpatient and Outpatient Departments of the Second Xiangya Hospital of Central South University,China,from January 2018 to July 2020 were randomized into the Statin group(male/female=51/33)and Statin+Ex group(male/female=52/29).Patients in the Statin+Ex group underwent treadmill exercise of 45-60 min/day for 7 days.Results:Aerobic exercise effectively alleviated statin-induced PCSK9 upregulation in human patients with CHD and hypercholesterolemic ICR mice(all p<0.05).Mechanistically,our findings revealed that aerobic exercise induced elevated epoxyeicosatrienoic acids(EETs)plasma levels while concurrently reducing the activity of soluble epoxide hydrolase(sEH)(all p<0.05),an enzyme responsible for EETs degradation.Further,EETs significantly suppressed PCSK9 expression,subsequently reducing the LDL-C levels(all p<0.05);this effect was mediated via the activation of the forkhead box O3a-silent mating type information regulation 2 homolog 6(FoxO3a-Sirt6)axis,with no impact on the sterol regulatory element binding protein 2 and 3-hydroxy-3-methylglutaryl-CoA reductase(SREBP2-HMGCR)pathway.Conclusion:Our study sheds light on the paradigm of"Exercise is Medicine",providing evidence to support the use of statins combined with exercise in reducing LDL-C levels,and unveils potential avenues for clinical applications of sEH inhibitors,presenting novel prospects for therapeutic interventions in ASCVD.展开更多
叉头框蛋白O3a(fork head box O3a,FoxO3a)是叉头框蛋白FOX转录因子O亚型家族中成员,作为一种转录调节因子在多种疾病的发生与发展中发挥重要调节作用。线粒体是细胞能量代谢的主要场所,也是维持细胞生长和功能的一类关键细胞器。线粒...叉头框蛋白O3a(fork head box O3a,FoxO3a)是叉头框蛋白FOX转录因子O亚型家族中成员,作为一种转录调节因子在多种疾病的发生与发展中发挥重要调节作用。线粒体是细胞能量代谢的主要场所,也是维持细胞生长和功能的一类关键细胞器。线粒体功能受到多种转录因子调控。FoxO3a可定位于线粒体,通过调节细胞核与线粒体之间的相互作用,对线粒体功能产生重要影响,其机制与调节线粒体能量代谢、生物合成、自噬、分裂/融合,以及线粒体钙稳态密切相关。该文重点综述了FoxO3a的生物学功能、及其对线粒体的调控作用与机制。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.81871858 and No.82172550).
文摘Background:Statins are the cornerstone of low-density lipoprotein cholesterol(LDL-C)-lowering therapy;however,the therapeutic efficacy of statins in countering atherosclerotic cardiovascular disease(ASCVD)is compromised by the concurrent elevation of proprotein convertase subtilisin/kexin type 9(PCSK9),a pivotal molecule that increases LDL-C levels.Aerobic exercise lowers PCSK9 levels,but the underlying mechanism remains unclear.Therefore,we investigated how aerobic exercise can ameliorate statin-induced increases in PCSK9 levels.Methods:Three-week-old male American Institute of Cancer Research(ICR)mice were fed a high-fat-cholesterol diet(HFD)for 12 weeks and then administered atorvastatin alone or atorvastatin combined with aerobic exercise(Statin+Ex).Moreover,a total of 165 participants with stable coronary heart disease(CHD)enrolled at the Inpatient and Outpatient Departments of the Second Xiangya Hospital of Central South University,China,from January 2018 to July 2020 were randomized into the Statin group(male/female=51/33)and Statin+Ex group(male/female=52/29).Patients in the Statin+Ex group underwent treadmill exercise of 45-60 min/day for 7 days.Results:Aerobic exercise effectively alleviated statin-induced PCSK9 upregulation in human patients with CHD and hypercholesterolemic ICR mice(all p<0.05).Mechanistically,our findings revealed that aerobic exercise induced elevated epoxyeicosatrienoic acids(EETs)plasma levels while concurrently reducing the activity of soluble epoxide hydrolase(sEH)(all p<0.05),an enzyme responsible for EETs degradation.Further,EETs significantly suppressed PCSK9 expression,subsequently reducing the LDL-C levels(all p<0.05);this effect was mediated via the activation of the forkhead box O3a-silent mating type information regulation 2 homolog 6(FoxO3a-Sirt6)axis,with no impact on the sterol regulatory element binding protein 2 and 3-hydroxy-3-methylglutaryl-CoA reductase(SREBP2-HMGCR)pathway.Conclusion:Our study sheds light on the paradigm of"Exercise is Medicine",providing evidence to support the use of statins combined with exercise in reducing LDL-C levels,and unveils potential avenues for clinical applications of sEH inhibitors,presenting novel prospects for therapeutic interventions in ASCVD.
文摘目的研究血管内皮细胞在冠状动脉疾病中的作用,着重阐明转录因子叉头框蛋白O3a(forkhead box O3a,FOXO3a)调控靶标基因表达和可变剪接在血管内皮细胞损伤中的作用。方法通过在人血管内皮细胞系中过表达FOXO3a,利用转录组技术获得转录组数据。分析FOXO3a调控的潜在靶标基因的表达水平和可变剪接模式,以及这些基因的功能。结果FOXO3a过表达的HUVEC细胞中,与对照组比较,419个基因差异表达。基因本体论(gene ontology,GO)和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)分析结果显示,上调基因富集在炎性信号通路,下调基因富集在代谢通路。基于转录组数据进行可变剪切分析,发现1784个可变剪切事件的模式在FOXO3a过表达组和对照组间发生显著差异。GO和KEGG分析结果显示,差异可变剪切基因富集在细胞凋亡相关通路。结论FOXO3a通过调控免疫炎症、脂类代谢和细胞凋亡相关基因的表达和可变剪接,影响血管内皮细胞凋亡,可能影响冠心病的发生。
文摘叉头框蛋白O3a(fork head box O3a,FoxO3a)是叉头框蛋白FOX转录因子O亚型家族中成员,作为一种转录调节因子在多种疾病的发生与发展中发挥重要调节作用。线粒体是细胞能量代谢的主要场所,也是维持细胞生长和功能的一类关键细胞器。线粒体功能受到多种转录因子调控。FoxO3a可定位于线粒体,通过调节细胞核与线粒体之间的相互作用,对线粒体功能产生重要影响,其机制与调节线粒体能量代谢、生物合成、自噬、分裂/融合,以及线粒体钙稳态密切相关。该文重点综述了FoxO3a的生物学功能、及其对线粒体的调控作用与机制。
