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
T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue ...T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin.Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0,10,and 100 nanograms per gram body weight per day(ng/(g·day)),respectively.Morphological,pathological,and ultrastructural alterations in cardiac tissue were meticulously examined.Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites.The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected.The results showed that exposure to T-2 toxin elicited myocardial tissue disorders,interstitial hemorrhage,capillary dilation,and fibrotic damage.Mitochondria were markedly impaired,including swelling,fusion,matrix degradation,and membrane damage.Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiacmetabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway.T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress.In conclusion,the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway.This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.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.
基金supported by the National Natural Science Foundation of China(No.81872567).
文摘T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin.Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0,10,and 100 nanograms per gram body weight per day(ng/(g·day)),respectively.Morphological,pathological,and ultrastructural alterations in cardiac tissue were meticulously examined.Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites.The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected.The results showed that exposure to T-2 toxin elicited myocardial tissue disorders,interstitial hemorrhage,capillary dilation,and fibrotic damage.Mitochondria were markedly impaired,including swelling,fusion,matrix degradation,and membrane damage.Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiacmetabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway.T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress.In conclusion,the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway.This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.
