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.

Clinical Efficacy Analysis of Tiotropium Bromide Combined with Budesonide and Formoterol Inhalation in Treating COPD

Objective:To analyze the clinical efficacy of tiotropium bromide(TB)combined with budesonide formoterol(BUD/FM)inhalation in treating chronic obstructive pulmonary disease(COPD).Methods:62 COPD patients admitted to the hospital between June 2020 and December 2022 were selected as samples for this study.The patients were divided into a combination group and a conventional group using the random number table method,with 31 cases in each group.The patients in the combination group were treated with TB combined with BUD/FM inhalation,whereas the patients in the conventional group were treated with BUD/FM inhalation only.The treatment efficacy and changes in lung function indicators of both groups were compared.Results:The total efficacy of treatment in the combined group was higher than that in the conventional group,and the difference was statistically significant(P<0.05).Before treatment,there was no difference in pulmonary function indicators between the two groups(P>0.05).After three months of treatment,all lung function indicators of the combined group were higher than those of the conventional group,and the difference was statistically significant(P<0.05).Conclusion:Combining TB with BUD/FM inhalation therapy increases the efficacy of treatment for patients with COPD.Besides,it also improves lung function and leads to a better prognosis.

PEP06 polypeptide 30 is a novel clusterdissociating agent inhibiting αv integrin/FAK/Src signaling in oral squamous cell carcinoma cells

Collectively migrating tumor cells have been recently implicated in enhanced metastasis of epithelial malignancies.In oral squamous cell carcinoma(OSCC),av integrin is a crucial mediator of multicellular clustering and collective movement in vitro;however,its contribution to metastatic spread remains to be addressed.According to the emerging therapeutic concept,dissociation of tumor clusters into single cells could significantly suppress metastasis-seeding ability of carcinomas.This study aimed to investigate the anti-OSCC potential of novel endostatin-derived polypeptide PEP06 as a clusterdissociating therapeutic agent in vitro.Firstly,we found marked enrichment ofαv integrin in collectivelyinvading multicellular clusters in human OSCCs.Our study revealed that metastatic progression of OSCC was associated with augmented immunostaining of av integrin in cancerous lesions.Following PEP06treatment,cell clustering on fibronectin,migration,multicellular aggregation,anchorage-independent survival and colony formation of OSCC were significantly inhibited.Moreover,PEP06 suppressed av integrin/FAK/Sre signaling in OSCC cells.PEP06-induced loss of active Src and E-cadherin from cell-cell contacts contributed to diminished collective migration of OSCC in vitro.Overall,these results suggest that PEP06 polypeptide 30 inhibiting av integrin/FAK/Src signaling and disrupting E-cadherin-based intercellular junctions possesses anti-metastatic potential in OSCC by acting as a cluster-dissociating therapeutic agent.

LncDACH1 promotes mitochondrial oxidative stress of cardiomyocytes by interacting with sirtuin3 and aggravates diabetic cardiomyopathy

Diabetic cardiomyopathy(DCM)is a common complication in diabetic patients.The molecular mechanisms of DCM remain to be fully elucidated.The intronic long noncoding RNA of DACH1(lnc DACH1)has been demonstrated to be closely associated with heart failure and cardiac regeneration.In this study,we investigated the role of lnc DACH1 in DCM and the underlying molecular mechanisms.The expression of lnc DACH1 was increased in DCM hearts and in high glucose-treated cardiomyocytes.Knockout of lnc DACH1 reduced mitochondrial oxidative stress,cell apoptosis,cardiac fibrosis and hypertrophy,and improved cardiac function in DCM mice.Overexpression of lnc DACH1 exacerbated mitochondria-derived reactive oxygen species(ROS)level and apoptosis,decreased activity of manganese superoxide dismutase(Mn-SOD);while silencing of lnc DACH1 attenuated ROS production,mitochondrial dysfunction,cell apoptosis,and increased the activity of Mn-SOD in cardiomyocytes treated with high glucose.Lnc DACH1 directly bound to sirtuin3(SIRT3)and facilitated its degradation by ubiquitination,therefore promoting mitochondrial oxidative injury and cell apoptosis in mouse hearts.In addition,SIRT3 silencing abrogated the protective effects of lnc DACH1 deficiency in cardiomyocytes.In summary,lnc DACH1 aggravates DCM by promoting mitochondrial oxidative stress and cell apoptosis via increasing ubiquitination-mediated SIRT3 degradation in mouse hearts.Inhibition of lnc DACH1 represents a novel therapeutic strategy for the intervention of diabetic cardiomyopathy.

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.