Background and objective:In northern China's cold regions,the prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)exceeds 50%,significantly higher than the national and global rates.MASLD ...Background and objective:In northern China's cold regions,the prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)exceeds 50%,significantly higher than the national and global rates.MASLD is an important risk factor for cardiovascular and cerebrovascular diseases,including coronary heart disease,stroke,and tumors,with no specific therapeutic drugs currently available.The ethanol extract of cassia seed(CSEE)has shown promise in lowering blood lipids and improving hepatic steatosis,but its mechanism in treating MASLD remains underexplored.This study aims to investigate the therapeutic effects and mechanisms of CSEE.Methods:MASLD models were established in male Wistar rats and golden hamsters using a high fat diet(HFD).CSEE(10,50,250 mg/kg)was administered via gavage for six weeks.Serum levels of total cholesterol(TC),triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C),aspartate aminotransferase(AST),and alanine aminotransferase(ALT),as well as liver TC and TG,were measured using biochemical kits.Histopathological changes in the liver were evaluated using Oil Red O staining,Hematoxylin-eosin(H&E)staining,and transmission electron microscopy(TEM).HepG2 cell viability was assessed using the cell counting kit-8(CCK8)and Calcein-AM/PI staining.Network pharmacology was used to analyze drug-disease targets,and western blotting was used to confirm these predictions.Results:CSEE treatment significantly reduced serum levels of TC,TG,LDL-C,ALT,and AST,and improved liver weight,liver index,and hepatic lipid deposition in rats and golden hamsters.In addition,CSEE alleviated free fatty acid(FFA)-induced lipid deposition in HepG2 cells.Molecular biology experiments demonstrated that CSEE increased the protein levels of p-AMPK,p-ACC,PPARα,CPT1A,PI3K P110 and p-AKT,while decreasing the protein levels of SREBP1,FASN,C/EBPα,and PPARγ,thus improving hepatic lipid metabolism and reducing lipid deposition.The beneficial effects of CSEE were reversed by small molecule inhibitors of the signaling pathways in vitro.Conclusion:CSEE improves liver lipid metabolism and reduces lipid droplet deposition in Wistar rats and golden hamsters with MASLD by activating hepatic AMPK,PPARα,and PI3K/AKT signaling pathways.展开更多
Background:Cold exposure is linked to numerous diseases,yet the changes in key genes and pathways in mice under cold exposure remain unexplored.Understanding these alterations could offer insights into the mechanisms ...Background:Cold exposure is linked to numerous diseases,yet the changes in key genes and pathways in mice under cold exposure remain unexplored.Understanding these alterations could offer insights into the mechanisms of cold resistance and contribute valuable ideas for treating cold-related diseases.Methods:The dataset GSE148361 was obtained from the Gene Expression Omnibus(GEO)database.Differentially expressed genes(DEGs)were identified using the"limma"package in R software.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were performed on DEGs.The STRING(Search Tool for the Retrieval of Interacting Genes)database was used to construct a protein-protein interaction(PPI)network.Additionally,gene set enrichment analysis(GSEA)was conducted to identify pathways associated with key genes.miRNAs and upstream transcription factors(TFs)were predicted using the miRNet database.Results:A total of 208 DEGs were identified,with 137 upregulated and 71 downregulated.In biological processes,DEGs were enriched in nucleotide and purine-containing compound metabolism.For cellular components,DEGs were involved in condensed chromosomes and mitochondrial protein complexes.In molecular functions,proton transmembrane transporter activity was enriched.KEGG pathway analysis showed significant enrichment in biosynthesis of unsaturated fatty acids,fatty acids,and pyruvate metabolism.From the PPI network,12 hub genes were identified using MCODE.Four hub genes(Col3a1,Ifi203,Rtp4,Vcan)demonstrated similar trends in a validation set(GSE110420)and were significantly differentially expressed.GSEA analysis indicated that these four genes were enriched in pathways such as ECM-receptor interaction and cytokine-cytokine receptor interaction.The hub gene network included 93 miRNAs and one TF.Conclusion:This study identified four hub genes as potential diagnostic biomarkers for cold exposure,providing insights for further research on the effects of cold on gene expression and disease.展开更多
Background:Small ubiquitin-like modifiers(SUMO)ylation is a dynamic and reversible post-translational modification playing pivotal roles in the regulation of cancer,diabetes,heart failure,and neurological diseases.How...Background:Small ubiquitin-like modifiers(SUMO)ylation is a dynamic and reversible post-translational modification playing pivotal roles in the regulation of cancer,diabetes,heart failure,and neurological diseases.However,whether SUMO inhibitors also have anti-hypertension effect remains yet to be explored.Methods:Blood pressure was monitored in spontaneously hypertensive rats(SHR)after Tannic acid(TA)administration for 4 weeks.The contents of nitric oxide(NO)and endothelin-1(ET-1)in the serum of SHR were measured.Isolated endothelium-intact mesenteric artery rings were used to study relaxation effect of SUMO inhibitors.ERK5 SUMOylation was determined using co-immunoprecipitation(co-IP)and immunofluorescence(IF).NO levels were analyzed by IF.The expression levels of KLF2 and p-eNOS were semi-quantified by Western blot analysis.The transcriptional activity of eNOS promotor was assayed using ChIP-PCR.Results:Three SUMO inhibitors all reduced the phenylephrine(PE)-induced contraction of mesenteric artery rings in a concentration-dependent manner.Co-IP revealed that ponatinib promoted ERK5 SUMOylation,which was nulled following pre-treatment with the SUMO inhibitors.IF displayed that TA increased ERK5 accumulation and its co-localization with SUMO-1 in the nucleus.ChIP-PCR unveiled TA-induced enhancement of KLF2-dependent eNOS promoter activity and upregulation of eNOS/NO expression in HUVECs.In vivo,TA significantly lowered the blood pressure and improved the vascular reactivity by activating the KLF2/eNOS/NO pathway.Additionally,the level of NO was elevated along with decreased ET-1 levels in the serum of SHR.Conclusions:SUMO inhibitors inhibit ERK5 SUMOylation to promote KLF2-eNOS/NO signaling,indicating their therapeutic potential for the treatment of hypertension.展开更多
1.Double-sided role of vibration and shaking Removing vibration and shaking is a pivotal engineering task,which is showcased,for instance,in spacecraft attitude control systems that ensure a precise three-dimensional ...1.Double-sided role of vibration and shaking Removing vibration and shaking is a pivotal engineering task,which is showcased,for instance,in spacecraft attitude control systems that ensure a precise three-dimensional orientation.Vibration or shaking,such as precession caused by external torque,nutation stemming from off-axis angular momentum,and wobbling due to geometric misalignment,necessitate active and passive damping mechanisms.This principle extends beyond spacecraft to centrifugation techniques,pivotal not only in washing machines but also in a spectrum of biomedical apparatuses used for isolating cells and organelles and separating DNA and proteins.展开更多
Objective:Myocardial ischemia-reperfusion injury(MIRI)is one of the leading causes of death from cardiovascular disease in humans,especially in individuals exposed to cold environments.Long non-coding RNAs(lncRNAs)reg...Objective:Myocardial ischemia-reperfusion injury(MIRI)is one of the leading causes of death from cardiovascular disease in humans,especially in individuals exposed to cold environments.Long non-coding RNAs(lncRNAs)regulate MIRI through multiple mechanisms.This study explored the regulatory effect of lncRNA-AK138945 on myocardial ischemia-reperfusion injury and its mechanism.Methods:In vivo,8-to 12-weeks-old C57BL/6 male mice underwent ligation of the left anterior descending coronary artery for 50 minutes followed by reperfusion for 48 hours.In vitro,the primary cultured neonatal mouse ventricular cardiomyocytes(NMVCs)were treated with 100μmol/L hydrogen peroxide(H_(2)O_(2)).The knockdown of lncRNA-AK138945 was evaluated to detect cardiomyocyte apoptosis,and a glucose-regulated,endoplasmic reticulum stress-related protein 94(GRP94)inhibitor was used to detect myocardial injury.Results:We found that the expression level of lncRNA-AK138945 was reduced in MIRI mouse heart tissue and H2O2-treated cardiomyocytes.Moreover,the proportion of apoptosis in cardiomyocytes increased after lncRNA-AK138945 was silenced.The expression level of Bcl2 protein was decreased,and the expression level of Bad,Caspase 9 and Caspase 3 protein was increased.Our further study found that miR-1a-3p is a direct target of lncRNA-AK138945,after lncRNA-AK138945 was silenced in cardiomyocytes,the expression level of miR-1a-3p was increased while the expression level of its downstream protein GRP94 was decreased.Interestingly,treatment with a GRP94 inhibitor(PU-WS13)intensified H2O2-induced cardiomyocyte apoptosis.After overexpression of FOXO3,the expression levels of lncRNA-AK138945 and GRP94 were increased,while the expression levels of miR-1a-3p were decreased.Conclusion:LncRNA-AK138945 inhibits GRP94 expression by regulating miR-1a-3p,leading to cardiomyocyte apoptosis.The transcription factor Forkhead Box Protein O3(FOXO3)participates in cardiomyocyte apoptosis induced by endoplasmic reticulum stress through up-regulation of lncRNA-AK138945.展开更多
Background:Nonalcoholic fatty liver disease(NAFLD)is a chronic condition characterized by a progressive decline in liver function,leading to disruptions in liver integrity and metabolic function,resulting in lipid dep...Background:Nonalcoholic fatty liver disease(NAFLD)is a chronic condition characterized by a progressive decline in liver function,leading to disruptions in liver integrity and metabolic function,resulting in lipid deposition and excessive accumulation of extracellular matrix(ECM).The pathogenesis of NAFLD is complex and not yet fully understood,contributing to the absence of specific therapeutic strategies.Peroxisome proliferator-activated receptor gamma(PPARγ)is a ligand-activated transcription factor pivotal in regulating lipid and glucose metabolism.However,the impacts of PPARγon NAFLD remains insufficiently explored.Thus,this study aimed to investigate the role of PPARγin NAFLD and its underlying molecular mechanisms.Methods:Chemical detection kits were utilized to quantify collagen content,alanine aminotransferase(ALT),and aspartate aminotransferase(AST)level variations.Quantitative real-time polymerase chain reaction(qRT-PCR)was employed to assess alterations in extracellular matrix-related genes and inflammatory response genes in liver tissue and HepG2 cells,while western blotting was conducted to analyze the levels of both PPARγand the TGF-β/Smad signaling pathway.Results:Our findings unveiled significantly reduced PPARγexpression in a rat model of NAFLD,leading to subsequent activation of the TGF-β/Smad signaling pathway.Furthermore,PPARγactivation effectively mitigated NAFLD progression by inhibiting inflammation and fibrosis-related gene expression and collagen production.On a cellular level,PPARγactivation was found to inhibit the expression of extracellular matrix-related genes such as matrix metalloproteinase 2(MMP2)and matrix metalloproteinase 9(MMP9),along with inflammatory response genes interleukin(IL)-1βand IL-6.Additionally,PPARγactivation led to a significant decrease in the levels of ALT and AST.At the molecular level,PPARγnotably down-regulated the TGF-β/Smad signaling pathway,which is known to promote liver fibrosis.Conclusion:These groundbreaking findings underscore PPARγactivation as a promising therapeutic approach to delay NAFLD progression by targeting the TGF-β/Smad signaling pathway in hepatic cells.This highlights the potential of PPARγas a promising therapeutic target for NAFLD management in clinical settings.展开更多
Despite quitting smoking,patients with acute coronary syndrome(ACS)still have an increased risk of cardiovascular events.Clonal hematopoiesis of indeterminate potential(CHIP),which may be induced by smoking,has been i...Despite quitting smoking,patients with acute coronary syndrome(ACS)still have an increased risk of cardiovascular events.Clonal hematopoiesis of indeterminate potential(CHIP),which may be induced by smoking,has been identified to be associated with the development of coronary artery disease.However,it is unclear whether CHIP has a detrimental effect on the poor prognosis of ACS patients even after smoking cessation.This single-center,prospective cohort study will recruit 1,029 ACS patients undergoing complete percutaneous coronary intervention.The enrolled patients will be categorized into 3 groups based on their smoking status at admission:current smoker,non-smoker,and previous smoker.Previous smokers are defined as patients who have quit smoking for at least 1 year before experiencing the index ACS event.Whole-exome sequencing will be performed to identify the occurrence of CHIP in each patient.The primary endpoint is major adverse cardiovascular and cerebrovascular events,defined as a composite of cardiac death,non-fatal myocardial infarction,ischemia-driven revascularization,hospitalization for heart failure,and ischemic stroke.The association between CHIP and the primary endpoint will be determined by using Cox proportional hazard regression.This study aims to investigate the association among smoking cessation,CHIP,and the prognosis of ACS patients to provide new insights into the impact of CHIP on ACS patients,particularly among those who have quit smoking.The results will be published following the STROBE in a peer-reviewed scientific journal(Trial registration number:NCT04987268).展开更多
Despite recent advances in understanding the biology of aging,the field remains fragmented due to the lack of a central organizing hypothesis.Although there are ongoing debates on whether the aging process is programm...Despite recent advances in understanding the biology of aging,the field remains fragmented due to the lack of a central organizing hypothesis.Although there are ongoing debates on whether the aging process is programmed or stochastic,it is now evident that neither perspective alone can fully explain the complexity of aging.Here,we propose the pro-aging metabolic reprogramming(PAMRP)theory,which integrates and unifies the genetic-program and stochastic hypotheses.This theory posits that aging is driven by degenerative metabolic reprogramming(MRP)over time,requiring the emergence of pro-aging substrates and triggers(PASs and PATs)to predispose cells to cellular and genetic reprogramming(CRP and GRP).展开更多
1 Introduction Infants are born with a substantial amount of brown adipose tissue(BAT),primarily clustered around their upper back,shoulders,and upper chest[1].As age progresses,the primary BAT gradually diminishes,an...1 Introduction Infants are born with a substantial amount of brown adipose tissue(BAT),primarily clustered around their upper back,shoulders,and upper chest[1].As age progresses,the primary BAT gradually diminishes,and concomitantly,de novo lipogenesis(DNL)continues to occur in subcutaneous adipose tissue throughout the body.The abundance of BAT in young children enhances their thermogenic capacity,making weight gain challenging and increasing resistance to cold temperatures.In adults.展开更多
Brown adipose tissue(BAT),crucial for mammalian thermoregulation and energy metabolism,boasts a dense concentration of mitochondria.As a vital cellular organelle,mitochondria undergo substantial remodeling in cold env...Brown adipose tissue(BAT),crucial for mammalian thermoregulation and energy metabolism,boasts a dense concentration of mitochondria.As a vital cellular organelle,mitochondria undergo substantial remodeling in cold environments,playing a pivotal role in maintaining body temperature and energy balance[1].Mitochondrial dynamics.展开更多
Controlling energy expenditure during acute cold exposure is a fundamental aspect of metabolic dynamics in organisms.However,prior studies on cold-induced thermogenesis faced limitations,primarily focusing on brown ad...Controlling energy expenditure during acute cold exposure is a fundamental aspect of metabolic dynamics in organisms.However,prior studies on cold-induced thermogenesis faced limitations,primarily focusing on brown adipose tissue(BAT)and lacking precise in vivo flux measurements.This editorial aims to highlight the recent research by Bornstein et al.providing a comprehensive and quantitative insight into the intricate alterations in metabolic flux that drive this phenomenon[1].展开更多
Objective:Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study(THEMIS)filled an important data gap by showing a significant reduction of ischemic cardiovascular events in a ticagrelor plus as...Objective:Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study(THEMIS)filled an important data gap by showing a significant reduction of ischemic cardiovascular events in a ticagrelor plus aspirin cohort compared with placebo plus aspirin cohort among patients with coronary artery disease(CAD)and type 2 diabetes mellitus(T2DM)but without a history of myocardial infarction.This study aims to evaluate the applicability of the THEMIS results in a real-world clinical setting in China.Methods:This retrospective,observational cohort study used data from the Optimal antiPlatelet Therapy for Chinese patients with Coronary Artery Disease(OPT-CAD)study which enrolled participants who were hospitalized between November 2012 and December 2013.The 24-month cumulative incidence of major adverse cardiovascular event(MACE),major bleeding,and all-cause death in patients with T2DM and CAD(T2DM-CAD),T2DM and stable CAD(SCAD)(T2DM-SCAD),and T2DM and SCAD without prior myocardial infarction or stroke(THEMIS-like)were analyzed.Results:Data from 13,296 patients with CAD were included;the T2DM-CAD,T2DM-SCAD,and THEMIS-like cohorts comprised 3,344(25.2%),949(7.1%),and 509(3.8%)patients,respectively.The corresponding 24-month cumulative incidence of major bleeding was 38(1.1%),16(1.7%),and 8(1.6%),and that of MACEs was 250(7.5%),87(9.2%),and 29(5.7%),and all-cause death was 181(5.4%),84(8.9%),29(5.7%),respectively.The risk of MACE in the THEMIS-like cohort was approximate to that in the THEMIS trial(7.7%vs.8.5%in ticagrelor and placebo group,respectively).Conclusion:The incidence of MACE was substantial in the THEMIS-like cohort,suggesting that cardiovascular risk for future events correlates with the presence of cardiovascular disease across the CAD risk continuum.展开更多
Objective:Cold regions exhibit a high prevalence of cardiovascular disease,particularly acute myocardial infarction(AMI),which is one of the leading causes of death associated with cardiovascular conditions.Cardiovasc...Objective:Cold regions exhibit a high prevalence of cardiovascular disease,particularly acute myocardial infarction(AMI),which is one of the leading causes of death associated with cardiovascular conditions.Cardiovascular disease is closely linked to the abnormal expression of long non-coding RNA(lncRNA).This study investigates whether circulating levels of lncRNA cardiac conduction regulatory RNA(CCRR)could serve as a biomarker for AMI.Materials and methods:We measured circulating CCRR from whole blood samples collected from 68 AMI patients and 69 non-AMI subjects.An AMI model was established using C57BL/6 mice.Quantitative reverse transcription PCR(qRT-PCR)was used to assess CCRR expression.Exosomes were isolated from cardiomyocytes,and their characteristics were evaluated using electron microscope and nanoparticle tracking analysis.The exosome inhibitor GW4869 was employed to examine the effect of exosomal CCRR on cardiac function using echocardiography.Protein expression was detected using Western blot and immunofluorescence staining.Results:The circulating level of CCRR was significantly higher in AMI patients(1.93±0.13)than in non-AMI subjects(1.00±0.05,P<0.001).The area under the ROC curve(AUC)of circulating CCRR was 0.821.Similar changes in circulating CCRR levels were consistently observed in an AMI mouse model.Exosomal CCRR derived from hypoxia-induced cardiomyocytes and cardiac tissue after AMI were increased,a change that was reversed by GW4869.Additionally,CCRR-overexpressing exosomes improved cardiac function in AMI.Conclusion:Circulating lncRNA CCRR is a potential predictor of AMI.Exosomal CCRR plays a role in the communication between the heart and other organs through circulation.展开更多
The prevalence of cardiovascular diseases(CVDs)has increased markedly as the world population has aged.Long non-coding RNAs(lncRNAs)have been reported as novel regulators in diverse pathophysiological conditions.Here,...The prevalence of cardiovascular diseases(CVDs)has increased markedly as the world population has aged.Long non-coding RNAs(lncRNAs)have been reported as novel regulators in diverse pathophysiological conditions.Here,we performed RNA sequencing(RNA-seq)and observed that the lncRNA Zeb1os1(zinc finger E-box binding homeobox 1,opposite strand 1),which is known as ZEB1-AS1(zinc finger E-box binding homeobox 1 antisense 1)in humans,was upregulated in the aged mice hearts,senescent cardiomyocytes,and human blood from elderly individuals.The human blood ZEB1-AS1 level was positively relevant to human age but negatively relevant to peak E to peak A(E/A).Silencing Zeb1os1 ameliorated diastolic dysfunction and cardiac senescence in aged mice.On the other hand,Zeb1os1 overexpression triggered cardiac dysfunction resembling that observed in aged mice.Mechanistically,we provide compelling evidence that Zeb1os1 interacts with the transient receptor potential mucolipin 1(TRPML1)for ubiquitination(UB)-mediated degradation.This process inhibits lysosomal Ca^(2+)efflux,impairing lysosome function.In addition,the functional domain of Zeb1os1,which contains the key nucleotides responsible for the pro-senescence property of full-length Zeb1os1 in cardiomyocytes.Together,these data suggest that Zeb1os1 is a potential target for ameliorating lysosomal dysfunction and aging-related cardiac impairment.展开更多
Pathological cardiac hypertrophy,a major contributor to heart failure,is closely linked to mitochondrial function.The roles of long noncoding RNAs(lncRNAs),which regulate mitochondrial function,remain largely unexplor...Pathological cardiac hypertrophy,a major contributor to heart failure,is closely linked to mitochondrial function.The roles of long noncoding RNAs(lncRNAs),which regulate mitochondrial function,remain largely unexplored in this context.Herein,a previously unknown lncRNA,Gm20257,was identified.It markedly increased under hypertrophic stress in vivo and in vitro.The suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte hypertrophy.Conversely,the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensinⅡ-induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively,thus restoring cardiac function.Importantly,Gm20257 restored mitochondrial complexⅣlevel and enhanced mitochondrial function.Bioinformatics prediction showed that Gm20257 had a high binding score with peroxisome proliferator–activated receptor coactivator-1(PGC-1α),which could increase mitochondrial complex IV.Subsequently,Western blot analysis results revealed that Gm20257 substantially affected the expression of PGC-1α.Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that PGC-1αwas a direct downstream target of Gm20257.This interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial ATP.These findings suggest that Gm20257 improves mitochondrial function through the PGC-1α-mitochondrial complexⅣaxis,offering a novel approach for attenuating pathological cardiac hypertrophy.展开更多
Heart failure(HF)is one of the leading causes of mortality and morbidity worldwide.Despite current treatments can improve cardiac dysfunction in HF patients,the overall mortality rate remains high,indicating more effe...Heart failure(HF)is one of the leading causes of mortality and morbidity worldwide.Despite current treatments can improve cardiac dysfunction in HF patients,the overall mortality rate remains high,indicating more effective therapeutic strategies for HF are needed.展开更多
Cardiac conduction regulatory RNA(CCRR)has been documented as an antiarrhythmic lncRNA in our earlier investigation.This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca^(2+)homeostasis in ...Cardiac conduction regulatory RNA(CCRR)has been documented as an antiarrhythmic lncRNA in our earlier investigation.This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca^(2+)homeostasis in myocardial infarction(MI).Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca^(2+)homeostasis and reduced the heightened methylation level of SERCA2a following MI.These effects were also observed in CCRR overexpressing transgenic mice.A conserved sequence domain of CCRR mimicked the protective function observed with the full length.Furthermore,silencing CCRR in healthy mice led to intracellular Ca^(2+)overloading of cardiomyocytes.CCRR increased SERCA2a protein stability by upregulating FTO expression.The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation(RIP)analysis and RNA pulldown experiments.Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI.This study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO,thereby reducing the m^(6)A RNA methylation level of SERCA2a,ultimately preserving calcium homeostasis for myocardial contractile function in MI.Therefore,CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.展开更多
基金The animal protocols were approved by the Ethics Committee of the Second Affiliated Hospital of Harbin Medical University(SYDW2019-258).
文摘Background and objective:In northern China's cold regions,the prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)exceeds 50%,significantly higher than the national and global rates.MASLD is an important risk factor for cardiovascular and cerebrovascular diseases,including coronary heart disease,stroke,and tumors,with no specific therapeutic drugs currently available.The ethanol extract of cassia seed(CSEE)has shown promise in lowering blood lipids and improving hepatic steatosis,but its mechanism in treating MASLD remains underexplored.This study aims to investigate the therapeutic effects and mechanisms of CSEE.Methods:MASLD models were established in male Wistar rats and golden hamsters using a high fat diet(HFD).CSEE(10,50,250 mg/kg)was administered via gavage for six weeks.Serum levels of total cholesterol(TC),triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C),aspartate aminotransferase(AST),and alanine aminotransferase(ALT),as well as liver TC and TG,were measured using biochemical kits.Histopathological changes in the liver were evaluated using Oil Red O staining,Hematoxylin-eosin(H&E)staining,and transmission electron microscopy(TEM).HepG2 cell viability was assessed using the cell counting kit-8(CCK8)and Calcein-AM/PI staining.Network pharmacology was used to analyze drug-disease targets,and western blotting was used to confirm these predictions.Results:CSEE treatment significantly reduced serum levels of TC,TG,LDL-C,ALT,and AST,and improved liver weight,liver index,and hepatic lipid deposition in rats and golden hamsters.In addition,CSEE alleviated free fatty acid(FFA)-induced lipid deposition in HepG2 cells.Molecular biology experiments demonstrated that CSEE increased the protein levels of p-AMPK,p-ACC,PPARα,CPT1A,PI3K P110 and p-AKT,while decreasing the protein levels of SREBP1,FASN,C/EBPα,and PPARγ,thus improving hepatic lipid metabolism and reducing lipid deposition.The beneficial effects of CSEE were reversed by small molecule inhibitors of the signaling pathways in vitro.Conclusion:CSEE improves liver lipid metabolism and reduces lipid droplet deposition in Wistar rats and golden hamsters with MASLD by activating hepatic AMPK,PPARα,and PI3K/AKT signaling pathways.
文摘Background:Cold exposure is linked to numerous diseases,yet the changes in key genes and pathways in mice under cold exposure remain unexplored.Understanding these alterations could offer insights into the mechanisms of cold resistance and contribute valuable ideas for treating cold-related diseases.Methods:The dataset GSE148361 was obtained from the Gene Expression Omnibus(GEO)database.Differentially expressed genes(DEGs)were identified using the"limma"package in R software.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were performed on DEGs.The STRING(Search Tool for the Retrieval of Interacting Genes)database was used to construct a protein-protein interaction(PPI)network.Additionally,gene set enrichment analysis(GSEA)was conducted to identify pathways associated with key genes.miRNAs and upstream transcription factors(TFs)were predicted using the miRNet database.Results:A total of 208 DEGs were identified,with 137 upregulated and 71 downregulated.In biological processes,DEGs were enriched in nucleotide and purine-containing compound metabolism.For cellular components,DEGs were involved in condensed chromosomes and mitochondrial protein complexes.In molecular functions,proton transmembrane transporter activity was enriched.KEGG pathway analysis showed significant enrichment in biosynthesis of unsaturated fatty acids,fatty acids,and pyruvate metabolism.From the PPI network,12 hub genes were identified using MCODE.Four hub genes(Col3a1,Ifi203,Rtp4,Vcan)demonstrated similar trends in a validation set(GSE110420)and were significantly differentially expressed.GSEA analysis indicated that these four genes were enriched in pathways such as ECM-receptor interaction and cytokine-cytokine receptor interaction.The hub gene network included 93 miRNAs and one TF.Conclusion:This study identified four hub genes as potential diagnostic biomarkers for cold exposure,providing insights for further research on the effects of cold on gene expression and disease.
基金supported by the National Natural Science Foundation of China(82330011,U21A20339)the CAMS Innovation Fund for Medical Sciences(CIFMS,2020-I2M-5-003)+2 种基金the National Natural Science Foundation of China(No.82370302,31871175)Natural Science Foundation of Heilongjiang Province of China(No.YQ2019H003)College of Pharmacy,Harbin Medical University Excellent Young Talents Funding(No.2020-YQ-01).
文摘Background:Small ubiquitin-like modifiers(SUMO)ylation is a dynamic and reversible post-translational modification playing pivotal roles in the regulation of cancer,diabetes,heart failure,and neurological diseases.However,whether SUMO inhibitors also have anti-hypertension effect remains yet to be explored.Methods:Blood pressure was monitored in spontaneously hypertensive rats(SHR)after Tannic acid(TA)administration for 4 weeks.The contents of nitric oxide(NO)and endothelin-1(ET-1)in the serum of SHR were measured.Isolated endothelium-intact mesenteric artery rings were used to study relaxation effect of SUMO inhibitors.ERK5 SUMOylation was determined using co-immunoprecipitation(co-IP)and immunofluorescence(IF).NO levels were analyzed by IF.The expression levels of KLF2 and p-eNOS were semi-quantified by Western blot analysis.The transcriptional activity of eNOS promotor was assayed using ChIP-PCR.Results:Three SUMO inhibitors all reduced the phenylephrine(PE)-induced contraction of mesenteric artery rings in a concentration-dependent manner.Co-IP revealed that ponatinib promoted ERK5 SUMOylation,which was nulled following pre-treatment with the SUMO inhibitors.IF displayed that TA increased ERK5 accumulation and its co-localization with SUMO-1 in the nucleus.ChIP-PCR unveiled TA-induced enhancement of KLF2-dependent eNOS promoter activity and upregulation of eNOS/NO expression in HUVECs.In vivo,TA significantly lowered the blood pressure and improved the vascular reactivity by activating the KLF2/eNOS/NO pathway.Additionally,the level of NO was elevated along with decreased ET-1 levels in the serum of SHR.Conclusions:SUMO inhibitors inhibit ERK5 SUMOylation to promote KLF2-eNOS/NO signaling,indicating their therapeutic potential for the treatment of hypertension.
文摘1.Double-sided role of vibration and shaking Removing vibration and shaking is a pivotal engineering task,which is showcased,for instance,in spacecraft attitude control systems that ensure a precise three-dimensional orientation.Vibration or shaking,such as precession caused by external torque,nutation stemming from off-axis angular momentum,and wobbling due to geometric misalignment,necessitate active and passive damping mechanisms.This principle extends beyond spacecraft to centrifugation techniques,pivotal not only in washing machines but also in a spectrum of biomedical apparatuses used for isolating cells and organelles and separating DNA and proteins.
基金This work was supported in part by the National Natural Science Foundation of China(82370417,81970320,82270273)the Certificate of China Postdoctoral Science Foundation Grant(2021M693826)+1 种基金the postdoctoral funding from Heilongjiang Province(21042230046)the Hai Yan Youth Fund from Harbin Medical University Cancer Hospital(JJQN2021-09).
文摘Objective:Myocardial ischemia-reperfusion injury(MIRI)is one of the leading causes of death from cardiovascular disease in humans,especially in individuals exposed to cold environments.Long non-coding RNAs(lncRNAs)regulate MIRI through multiple mechanisms.This study explored the regulatory effect of lncRNA-AK138945 on myocardial ischemia-reperfusion injury and its mechanism.Methods:In vivo,8-to 12-weeks-old C57BL/6 male mice underwent ligation of the left anterior descending coronary artery for 50 minutes followed by reperfusion for 48 hours.In vitro,the primary cultured neonatal mouse ventricular cardiomyocytes(NMVCs)were treated with 100μmol/L hydrogen peroxide(H_(2)O_(2)).The knockdown of lncRNA-AK138945 was evaluated to detect cardiomyocyte apoptosis,and a glucose-regulated,endoplasmic reticulum stress-related protein 94(GRP94)inhibitor was used to detect myocardial injury.Results:We found that the expression level of lncRNA-AK138945 was reduced in MIRI mouse heart tissue and H2O2-treated cardiomyocytes.Moreover,the proportion of apoptosis in cardiomyocytes increased after lncRNA-AK138945 was silenced.The expression level of Bcl2 protein was decreased,and the expression level of Bad,Caspase 9 and Caspase 3 protein was increased.Our further study found that miR-1a-3p is a direct target of lncRNA-AK138945,after lncRNA-AK138945 was silenced in cardiomyocytes,the expression level of miR-1a-3p was increased while the expression level of its downstream protein GRP94 was decreased.Interestingly,treatment with a GRP94 inhibitor(PU-WS13)intensified H2O2-induced cardiomyocyte apoptosis.After overexpression of FOXO3,the expression levels of lncRNA-AK138945 and GRP94 were increased,while the expression levels of miR-1a-3p were decreased.Conclusion:LncRNA-AK138945 inhibits GRP94 expression by regulating miR-1a-3p,leading to cardiomyocyte apoptosis.The transcription factor Forkhead Box Protein O3(FOXO3)participates in cardiomyocyte apoptosis induced by endoplasmic reticulum stress through up-regulation of lncRNA-AK138945.
基金This research was funded by the National Natural Science Foundation of China(82273919 to Zhang Y)the HMU Marshal Initiative Funding(HMUMIF-21022 to Zhang Y).
文摘Background:Nonalcoholic fatty liver disease(NAFLD)is a chronic condition characterized by a progressive decline in liver function,leading to disruptions in liver integrity and metabolic function,resulting in lipid deposition and excessive accumulation of extracellular matrix(ECM).The pathogenesis of NAFLD is complex and not yet fully understood,contributing to the absence of specific therapeutic strategies.Peroxisome proliferator-activated receptor gamma(PPARγ)is a ligand-activated transcription factor pivotal in regulating lipid and glucose metabolism.However,the impacts of PPARγon NAFLD remains insufficiently explored.Thus,this study aimed to investigate the role of PPARγin NAFLD and its underlying molecular mechanisms.Methods:Chemical detection kits were utilized to quantify collagen content,alanine aminotransferase(ALT),and aspartate aminotransferase(AST)level variations.Quantitative real-time polymerase chain reaction(qRT-PCR)was employed to assess alterations in extracellular matrix-related genes and inflammatory response genes in liver tissue and HepG2 cells,while western blotting was conducted to analyze the levels of both PPARγand the TGF-β/Smad signaling pathway.Results:Our findings unveiled significantly reduced PPARγexpression in a rat model of NAFLD,leading to subsequent activation of the TGF-β/Smad signaling pathway.Furthermore,PPARγactivation effectively mitigated NAFLD progression by inhibiting inflammation and fibrosis-related gene expression and collagen production.On a cellular level,PPARγactivation was found to inhibit the expression of extracellular matrix-related genes such as matrix metalloproteinase 2(MMP2)and matrix metalloproteinase 9(MMP9),along with inflammatory response genes interleukin(IL)-1βand IL-6.Additionally,PPARγactivation led to a significant decrease in the levels of ALT and AST.At the molecular level,PPARγnotably down-regulated the TGF-β/Smad signaling pathway,which is known to promote liver fibrosis.Conclusion:These groundbreaking findings underscore PPARγactivation as a promising therapeutic approach to delay NAFLD progression by targeting the TGF-β/Smad signaling pathway in hepatic cells.This highlights the potential of PPARγas a promising therapeutic target for NAFLD management in clinical settings.
基金funded by Liaoning Provincial Science and Technology Project(2022-MS-045).
文摘Despite quitting smoking,patients with acute coronary syndrome(ACS)still have an increased risk of cardiovascular events.Clonal hematopoiesis of indeterminate potential(CHIP),which may be induced by smoking,has been identified to be associated with the development of coronary artery disease.However,it is unclear whether CHIP has a detrimental effect on the poor prognosis of ACS patients even after smoking cessation.This single-center,prospective cohort study will recruit 1,029 ACS patients undergoing complete percutaneous coronary intervention.The enrolled patients will be categorized into 3 groups based on their smoking status at admission:current smoker,non-smoker,and previous smoker.Previous smokers are defined as patients who have quit smoking for at least 1 year before experiencing the index ACS event.Whole-exome sequencing will be performed to identify the occurrence of CHIP in each patient.The primary endpoint is major adverse cardiovascular and cerebrovascular events,defined as a composite of cardiac death,non-fatal myocardial infarction,ischemia-driven revascularization,hospitalization for heart failure,and ischemic stroke.The association between CHIP and the primary endpoint will be determined by using Cox proportional hazard regression.This study aims to investigate the association among smoking cessation,CHIP,and the prognosis of ACS patients to provide new insights into the impact of CHIP on ACS patients,particularly among those who have quit smoking.The results will be published following the STROBE in a peer-reviewed scientific journal(Trial registration number:NCT04987268).
文摘Despite recent advances in understanding the biology of aging,the field remains fragmented due to the lack of a central organizing hypothesis.Although there are ongoing debates on whether the aging process is programmed or stochastic,it is now evident that neither perspective alone can fully explain the complexity of aging.Here,we propose the pro-aging metabolic reprogramming(PAMRP)theory,which integrates and unifies the genetic-program and stochastic hypotheses.This theory posits that aging is driven by degenerative metabolic reprogramming(MRP)over time,requiring the emergence of pro-aging substrates and triggers(PASs and PATs)to predispose cells to cellular and genetic reprogramming(CRP and GRP).
基金This study was funded by the National Natural Science Foundation of China(82270396).
文摘1 Introduction Infants are born with a substantial amount of brown adipose tissue(BAT),primarily clustered around their upper back,shoulders,and upper chest[1].As age progresses,the primary BAT gradually diminishes,and concomitantly,de novo lipogenesis(DNL)continues to occur in subcutaneous adipose tissue throughout the body.The abundance of BAT in young children enhances their thermogenic capacity,making weight gain challenging and increasing resistance to cold temperatures.In adults.
基金This study was financially supported by the National Natural Science Foundation of China(No.82270396).
文摘Brown adipose tissue(BAT),crucial for mammalian thermoregulation and energy metabolism,boasts a dense concentration of mitochondria.As a vital cellular organelle,mitochondria undergo substantial remodeling in cold environments,playing a pivotal role in maintaining body temperature and energy balance[1].Mitochondrial dynamics.
基金This study was funded by the National Natural Science Foundation of China(No.82270396).
文摘Controlling energy expenditure during acute cold exposure is a fundamental aspect of metabolic dynamics in organisms.However,prior studies on cold-induced thermogenesis faced limitations,primarily focusing on brown adipose tissue(BAT)and lacking precise in vivo flux measurements.This editorial aims to highlight the recent research by Bornstein et al.providing a comprehensive and quantitative insight into the intricate alterations in metabolic flux that drive this phenomenon[1].
基金supported by grants from the National Key Research and Development Program of China(2022YFC2503500 and 2022YFC2503504)and a research grant AstraZeneca。
文摘Objective:Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study(THEMIS)filled an important data gap by showing a significant reduction of ischemic cardiovascular events in a ticagrelor plus aspirin cohort compared with placebo plus aspirin cohort among patients with coronary artery disease(CAD)and type 2 diabetes mellitus(T2DM)but without a history of myocardial infarction.This study aims to evaluate the applicability of the THEMIS results in a real-world clinical setting in China.Methods:This retrospective,observational cohort study used data from the Optimal antiPlatelet Therapy for Chinese patients with Coronary Artery Disease(OPT-CAD)study which enrolled participants who were hospitalized between November 2012 and December 2013.The 24-month cumulative incidence of major adverse cardiovascular event(MACE),major bleeding,and all-cause death in patients with T2DM and CAD(T2DM-CAD),T2DM and stable CAD(SCAD)(T2DM-SCAD),and T2DM and SCAD without prior myocardial infarction or stroke(THEMIS-like)were analyzed.Results:Data from 13,296 patients with CAD were included;the T2DM-CAD,T2DM-SCAD,and THEMIS-like cohorts comprised 3,344(25.2%),949(7.1%),and 509(3.8%)patients,respectively.The corresponding 24-month cumulative incidence of major bleeding was 38(1.1%),16(1.7%),and 8(1.6%),and that of MACEs was 250(7.5%),87(9.2%),and 29(5.7%),and all-cause death was 181(5.4%),84(8.9%),29(5.7%),respectively.The risk of MACE in the THEMIS-like cohort was approximate to that in the THEMIS trial(7.7%vs.8.5%in ticagrelor and placebo group,respectively).Conclusion:The incidence of MACE was substantial in the THEMIS-like cohort,suggesting that cardiovascular risk for future events correlates with the presence of cardiovascular disease across the CAD risk continuum.
基金supported by grants from the Natural Science Foundation of China(81970202,81903609)by Natural Science Foundation of Heilongjiang Province,China(LH2022H002)+1 种基金by the Outstanding Young Talent Research Fund of College of Pharmacy,Harbin Medical University(2019-JQ-02)2021(the second batch)Research Funds for affiliated research institutes in Heilongjiang Province(CZKYF2021-2-C013).
文摘Objective:Cold regions exhibit a high prevalence of cardiovascular disease,particularly acute myocardial infarction(AMI),which is one of the leading causes of death associated with cardiovascular conditions.Cardiovascular disease is closely linked to the abnormal expression of long non-coding RNA(lncRNA).This study investigates whether circulating levels of lncRNA cardiac conduction regulatory RNA(CCRR)could serve as a biomarker for AMI.Materials and methods:We measured circulating CCRR from whole blood samples collected from 68 AMI patients and 69 non-AMI subjects.An AMI model was established using C57BL/6 mice.Quantitative reverse transcription PCR(qRT-PCR)was used to assess CCRR expression.Exosomes were isolated from cardiomyocytes,and their characteristics were evaluated using electron microscope and nanoparticle tracking analysis.The exosome inhibitor GW4869 was employed to examine the effect of exosomal CCRR on cardiac function using echocardiography.Protein expression was detected using Western blot and immunofluorescence staining.Results:The circulating level of CCRR was significantly higher in AMI patients(1.93±0.13)than in non-AMI subjects(1.00±0.05,P<0.001).The area under the ROC curve(AUC)of circulating CCRR was 0.821.Similar changes in circulating CCRR levels were consistently observed in an AMI mouse model.Exosomal CCRR derived from hypoxia-induced cardiomyocytes and cardiac tissue after AMI were increased,a change that was reversed by GW4869.Additionally,CCRR-overexpressing exosomes improved cardiac function in AMI.Conclusion:Circulating lncRNA CCRR is a potential predictor of AMI.Exosomal CCRR plays a role in the communication between the heart and other organs through circulation.
基金funded by the National Natural Science Foundation of China(82273919,82270396,and U21A20339)the China Postdoctoral Science Foundation(2023T160176)。
文摘The prevalence of cardiovascular diseases(CVDs)has increased markedly as the world population has aged.Long non-coding RNAs(lncRNAs)have been reported as novel regulators in diverse pathophysiological conditions.Here,we performed RNA sequencing(RNA-seq)and observed that the lncRNA Zeb1os1(zinc finger E-box binding homeobox 1,opposite strand 1),which is known as ZEB1-AS1(zinc finger E-box binding homeobox 1 antisense 1)in humans,was upregulated in the aged mice hearts,senescent cardiomyocytes,and human blood from elderly individuals.The human blood ZEB1-AS1 level was positively relevant to human age but negatively relevant to peak E to peak A(E/A).Silencing Zeb1os1 ameliorated diastolic dysfunction and cardiac senescence in aged mice.On the other hand,Zeb1os1 overexpression triggered cardiac dysfunction resembling that observed in aged mice.Mechanistically,we provide compelling evidence that Zeb1os1 interacts with the transient receptor potential mucolipin 1(TRPML1)for ubiquitination(UB)-mediated degradation.This process inhibits lysosomal Ca^(2+)efflux,impairing lysosome function.In addition,the functional domain of Zeb1os1,which contains the key nucleotides responsible for the pro-senescence property of full-length Zeb1os1 in cardiomyocytes.Together,these data suggest that Zeb1os1 is a potential target for ameliorating lysosomal dysfunction and aging-related cardiac impairment.
基金supported by the National Natural Science Foundation of China(Nos.82170299 and 82003757)Major Projects of the National Natural Science Foundation of China(No.82330011)+1 种基金the National Natural Science Foundation of China(No.82370279)the Postdoctoral Starting Fund of Heilongjiang Province(No.LBH-Q21121).
文摘Pathological cardiac hypertrophy,a major contributor to heart failure,is closely linked to mitochondrial function.The roles of long noncoding RNAs(lncRNAs),which regulate mitochondrial function,remain largely unexplored in this context.Herein,a previously unknown lncRNA,Gm20257,was identified.It markedly increased under hypertrophic stress in vivo and in vitro.The suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte hypertrophy.Conversely,the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensinⅡ-induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively,thus restoring cardiac function.Importantly,Gm20257 restored mitochondrial complexⅣlevel and enhanced mitochondrial function.Bioinformatics prediction showed that Gm20257 had a high binding score with peroxisome proliferator–activated receptor coactivator-1(PGC-1α),which could increase mitochondrial complex IV.Subsequently,Western blot analysis results revealed that Gm20257 substantially affected the expression of PGC-1α.Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that PGC-1αwas a direct downstream target of Gm20257.This interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial ATP.These findings suggest that Gm20257 improves mitochondrial function through the PGC-1α-mitochondrial complexⅣaxis,offering a novel approach for attenuating pathological cardiac hypertrophy.
基金This work was supported by the National Natural Science Foundation of China(82261160656,82241016,82030015,82270284)the National Key R&D Program of China(2021YFC2701104)+1 种基金Haihe Laboratory of Cell Ecosystem Innovation Fund(22HHXBSS00048)Tianjin Municipal Education Commission Scientific Research Project(Natural Science,No.2020ZD12).
文摘Heart failure(HF)is one of the leading causes of mortality and morbidity worldwide.Despite current treatments can improve cardiac dysfunction in HF patients,the overall mortality rate remains high,indicating more effective therapeutic strategies for HF are needed.
基金supported by the National Natural Science Foundation of China(81970202,81903609,U21A20339)the Natural Science Foundation of Heilongjiang Province,China(LH2022H002)+1 种基金the Outstanding Young Talent Research Fund of College of Pharmacy,Harbin Medical University(2019-JQ-02)2021(the second batch)Research Funds for affiliated research institutes in Heilongjiang Province(CZKYF2021-2-C013).
文摘Cardiac conduction regulatory RNA(CCRR)has been documented as an antiarrhythmic lncRNA in our earlier investigation.This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca^(2+)homeostasis in myocardial infarction(MI).Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca^(2+)homeostasis and reduced the heightened methylation level of SERCA2a following MI.These effects were also observed in CCRR overexpressing transgenic mice.A conserved sequence domain of CCRR mimicked the protective function observed with the full length.Furthermore,silencing CCRR in healthy mice led to intracellular Ca^(2+)overloading of cardiomyocytes.CCRR increased SERCA2a protein stability by upregulating FTO expression.The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation(RIP)analysis and RNA pulldown experiments.Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI.This study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO,thereby reducing the m^(6)A RNA methylation level of SERCA2a,ultimately preserving calcium homeostasis for myocardial contractile function in MI.Therefore,CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.
