YBX1 inhibits mitochondrial-mediated apoptosis in ischemic heart through the PI3K/AKT signaling pathway

Background:Myocardial infarction(MI)is associated with higher morbidity and mortality in the world,especially in cold weather.YBX1 is an RNA-binding protein that is required for pathological growth of cardiomyocyte by regulating cell growth and protein synthesis.But YBX1,as an individual RNA-binding protein,regulates cardiomyocytes through signaling cascades during myocardial infarction remain largely unexplored.Methods:In vivo,the mouse MI model was induced by ligating the left anterior descending coronary artery(LAD),and randomly divided into sham operation group,MI group,MI+YBX1 knockdown/overexpression group and MI+negative control(NC)group.The protective effect of YBX1 was verified by echocardiography and triphenyltetrazolium chloride staining.In vitro,mitochondrial-dependent apoptosis was investigated by using CCK8,TUNEL staining,reactive oxygen species(ROS)staining and JC-1 staining in hypoxic neonatal mouse cardiomyocytes(NMCMs).Results:YBX1 expression of cardiomyocytes was downregulated in a mouse model and a cellular model on the ischemic condition.Compared to mice induced by MI,YBX1 overexpression mediated by adeno-associated virus serotype 9(AAV9)vector reduced the infarcted size and improved cardiac function.Knockdown of endogenous YBX1 by shRNA partially aggravated ischemia-induced cardiac dysfunction.In hypoxic cardiomyocytes,YBX1 overexpression decreased lactic dehydrogenase(LDH)release,increased cell viability,and inhibited apoptosis by affecting the expression of apoptosis related proteins,while knockdown of endogenous YBX1 by siRNA had the opposite effect.Overexpression of YBX1 restored mitochondrial dysfunction in hypoxic NMCMs by increasing mitochondrial membrane potential and ATP content and decreasing ROS.In hypoxic NMCMs,YBX1 overexpression increased the expression of phosphorylated phosphatidylinositol 3 kinase(PI3K)/AKT,and the anti-apoptosis effect of YBX1 was eliminated t by LY294002,PI3K/AKT inhibitor.Conclusion:YBX1 protected the heart from ischemic damage by inhibiting the mitochondrial-dependent apoptosis through PI3K/AKT pathway.It is anticipated that YBX1 may serve as a novel therapeutic target for MI.

Notum protects against myocardial infarction-induced heart dysfunction by alleviating cardiac fibrosis

Background and Objective:Cardiac fibrosis is a pathological reparative process that follows myocardial infarctionand is associated with compromised cardiac systolic and reduced cardiac compliance.The Wnt signaling pathway is closely implicated in organ fibrosis,and Notum,a highly conserved secreted inhibitor,modulates Wnt signaling.The objective of this study was to explore the role and mechanism of Notum in cardiac fibrosis.Methods:A mouse model of cardiac remodeling was established through left coronary artery ligation surgery,with the addition of Notum injection following myocardial infarction surgery.The protective effect of Notum on myocardial infarction was assessed by evaluating cardiac function,including survival rate,echocardiographic assessment,and cardiac contraction analyses.Inflammatory cell necrosis and infiltration were confirmed through H&E and Masson staining.The expression of fibrosis-related genes andβ-catenin pathway markers was detected using Western blot quantificational RT-PCR(qRT-PCR).Additionally,EdU,wound healing,and immunofluorescence staining analyses were performed to detect the effect of Notum's in transforming growth factor beta-1(TGF-β1)induced myofibroblast transformation.Results:The administration of Notum treatment resulted in enhanced survival rates,improved cardiac function,and decreased necrosis and infiltration of inflammatory cells in mice subjected to left coronary artery ligation.Furthermore,Notum effectively impeded the senescence of cardiac fibroblasts and hindered their pathological transformation into cardiac fibroblasts.Additionally,it significantly reduced collagen production and attenuated the activation of the Wnt/β-catenin pathway.Our preliminary investigations successfully demonstrated the therapeutic potential of Notum in both fibroblasts in vitro and in a mouse model of myocardial infarction-induced cardiac fibrosis in vivo.Conclusion:Notum inhibition of the Wnt/β-catenin signaling pathway and cardiac fibroblast senescence ultimately hampers the onset of cardiac fibrosis.Our findings suggest that Notum could represent a new therapeutic strategy for the treatment of cardiac fibrosis.

Prevention and control measures of the major cold-region diseases (hypertension) in China

Hypertension is the most common cardiovascular condition in clinical practice and a major risk factor for stroke and cardiovascular events.There are more than 270 million hypertension patients in China,and the prevalence of hypertension in the high-latitude cold areas is significantly higher than in the low-latitude warm areas.The unique epidemiological characteristics and risk factors of hypertension in the cold regions of China urge for establishment of the prevention and control system for targeted and more effective management of the condition.

Antidiabetic agents:Do they hit the right targets?

Diabetes mellitus(DM)is a progressive metabolic disease characterized by chronic hyperglycemia and caused by different degree of pancreatic islet dysfunction and/or insulin resistance(IR).Long course DM can lead to a variety of macrovascular and microvascular complications which involve artery vessels,heart,kidney,retina,nervous system,etc.In recent years,DM has attracted more and more attention due to its high morbidity and mortality.In addition to achieve effective glycemic control,prevention of complications has also been considered a priority for type 2 diabetes mellitus(T2DM)management.Herein,we provide a comprehensive overview on the pharmacotherapeutics for T2DM and perspectives on the future directions of basic and translational research on anti-diabetic therapy and pharmatheutical development of new drugs.

Apelin aggravates the migration and invasion of non-small cell lung cancer cells via YAP1

Background:Apelin,an endogenous ligand of G-protein coupled receptor(GPCR),is a secreted peptide involved in the development of various tumors.However,the relationship between apelin and non-small cell lung cancer(NSCLC)is not quite clear.This study was designed to investigate the effect and mechanism of apelin on cell proliferation,migration and invasion of NSCLC cells.Methods:Twelve NSCLC specimens were collected for hematoxylin-eosin(HE)staining and immunohistochemistry analyses.Cell proliferation was examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and cell migration and invasion were assessed using wound-healing and transwell assays.The subcellular location of yes associated protein 1(YAP1)in A549 cells was determined by immunofluorescence.The mRNA and protein levels in NSCLC tissues and cell lines were measured by qRT-PCR and western blot,respectively.Results:Apelin was upregulated in tumor tissues compared with the adjacent tissues.Apelin promoted proliferation,migration,and invasion of A549 and H460 cells,which was reversed by competitive apelin receptor(APJ)antagonist ML221.Additionally,apelin upregulated YAP1 expression,whereas silence of YAP1 by small interfering RNA(siRNA)attenuated apelin-induced cell proliferation,migration and invasion and suppressed epithelial-mesenchymal transition progression.Conclusion:Apelin promotes NSCLC cells proliferation,migration,and invasion by modulating YAP1 and might be a potential therapeutic target for NSCLC treatment.

lncRNA Gm20257 alleviates pathological cardiac hypertrophy by modulating the PGC-1α–mitochondrial complexⅣaxis

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.

Preliminary evidence for the presence of multiple forms of cell death in diabetes cardiomyopathy

Diabetic mellitus(DM) is a common degenerative chronic metabolic disease often accompanied by severe cardiovascular complications(DCCs) as major causes of death in diabetic patients with diabetic cardiomyopathy(DCM) as the most common DCC. The metabolic disturbance in DCM generates the conditions/substrates and inducers/triggers and activates the signaling molecules and death executioners leading to cardiomyocyte death which accelerates the development of DCM and the degeneration of DCM to heart failure.Various forms of programmed active cell death including apoptosis, pyroptosis, autophagic cell death, autosis,necroptosis, ferroptosis and entosis have been identified and characterized in many types of cardiac disease.Evidence has also been obtained for the presence of multiple forms of cell death in DCM. Most importantly,published animal experiments have demonstrated that suppression of cardiomyocyte death of any forms yields tremendous protective effects on DCM. Herein, we provide the most updated data on the subject of cell death in DCM, critical analysis of published results focusing on the pathophysiological roles of cell death, and pertinent perspectives of future studies.

MicroRNAs in idiopathic pulmonary fibrosis: involvement in pathogenesis and potential use in diagnosis and therapeutics

MicroRNAs (miRNAs) are a class of phylogenetically conserved, non-coding short RNAs, 19-22 nt in length which suppress protein expression through base-pairing with the 3'-untranslated region of target mRNAs. miRNAs have been found to participate in cell proliferation, differentiation and apoptosis. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high lethality fibrotic lung disease for which currently there is no effective treatment. Some miRNAs have been reported to be involved in the pathogenesis of pulmonary fibrosis. In this review, we discuss the role of miRNAs in the pathogenesis, diagnosis and treatment of IPF. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND

Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling

Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid （aspirin） provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction （TAC） or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin （10 mg·kg^-1· d^-1）; the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II （10 nmol· L^-1） was treated with the human equivalent of low （10 or 100μmol·L^-1） and high （1000μmol·L^-1） aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, p-myosin heavy chain （IS-MHC）, atrial natriuretic peptide （ANP）, and b-type natriuretic peptide （BNP）. Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3~. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin.

LncRNA DACH1 protects against pulmonary fibrosis by binding to SRSF1 to suppress CTNNB1 accumulation

Idiopathic pulmonary fibrosis(IPF)is a progressive disease with unknown etiology and limited therapeutic options.Activation of fibroblasts is a prominent feature of pulmonary fibrosis.Here we report that lncRNA DACH1(dachshund homolog 1)is downregulated in the lungs of IPF patients and in an experimental mouse model of lung fibrosis.LncDACH1 knockout mice develop spontaneous pulmonary fibrosis,whereas overexpression of LncDACH1 attenuated TGF-β1-induced aberrant activation,collagen deposition and differentiation of mouse lung fibroblasts.Similarly,forced expression of LncDACH1 not only prevented bleomycin(BLM)-induced lung fibrosis,but also reversed established lung fibrosis in a BLM model.Mechanistically,LncDACH1 binding to the serine/arginine-rich splicing factor 1(SRSF1)protein decreases its activity and inhibits the accumulation of Ctnnb1.Enhanced expression of SRSF1 blocked the anti-fibrotic effect of LncDACH1 in lung fibroblasts.Furthermore,loss of LncDACH1 promoted proliferation,differentiation,and extracellular matrix(ECM)deposition in mouse lung fibroblasts,whereas such effects were abolished by silencing of Ctnnb1.In addition,a conserved fragment of LncDACH1 alleviated hyperproliferation,ECM deposition and differentiation of MRC-5 cells driven by TGF-β1.Collectively,LncDACH1 inhibits lung fibrosis by interacting with SRSF1 to suppress CTNNB1 accumulation,suggesting that LncDACH1 might be a potential therapeutic target for pulmonary fibrosis.