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BACKGROUND: Radioactive iodine-125 (125I) microparticle therapy is a new type of internal radiation therapy that has shown unique advantages in the treatment of malignant tumors, especially hepatocellular carcinoma. Patients with hepatocellular carcinoma frequently experience portal vein embolism, which exacerbates the difficulty and complexity of treatment. 125I particles, used in local radiotherapy, can directly act on tumor tissue and reduce damage to surrounding healthy tissue. Through retrospective analysis, this study discussed the efficacy and safety of radioactive 125I particles in portal vein embolization patients with hepatocellular carcinoma in order to provide more powerful evidence supporting clinical treatment. AIM: To investigate the effect of transcatheter arterial chemoembolization combined with portal vein 125I particle implantation in the treatment of primary liver cancer patients with portal vein tumor thrombus and its influence on liver function. METHODS: The clinical data of 96 patients with primary liver cancer combined with portal vein tumor thrombus admitted to our hospital between January 2020 and December 2023 were retrospectively analyzed. Fifty-two patients received treatment with transcatheter arterial chemoembolization and implantation of 125I particles in the portal vein (combination group), while 44 patients received treatment with transcatheter arterial chemoembolization alone (control group). The therapeutic effects on tumor lesions, primary liver cancer, and portal vein tumor embolisms were compared between the two groups. Changes in relevant laboratory indexes before and after treatment were evaluated. The t test was used to compare the measurement data between the two groups, and the χ 2 test was used to compare the counting data between groups. RESULTS: The tumor lesion response rate in the combination group (59.62% vs 38.64%) and the response rate of patients with primary liver cancer complicated with portal vein tumor thrombus (80.77% vs 59.09%) were significantly greater than those in the control group (χ 2 = 4.196, 5.421; P = 0.041, 0.020). At 8 wk after surgery, the serum alpha-fetoprotein, portal vein main diameter, and platelet of the combined group were significantly lower than those of the control group, and the serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin were significantly greater than those of the control group (t = 3.891, 3.291, 2.330, 3.729, 3.582, 4.126; P < 0.05). The serum aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels of the two groups were significantly greater than those of the same group 8 wk after surgery (P < 0.05), and the peripheral blood platelet, alpha-fetoprotein, and main portal vein diameter were significantly less than those of the same group before surgery (P < 0.05). CONCLUSION: In patients with primary liver cancer and a thrombus in the portal vein, transcatheter arterial chemoembolization plus portal vein 125I implantation is more effective than transcatheter arterial chemoembolization alone. However, during treatment it is crucial to pay attention to liver function injury caused by transcatheter arterial chemoembolization.
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Background: Warfarin has become the first choice for anticoagulation in patients who need lifelong anticoagulation due to its clinical efficacy and low price. However, the anticoagulant effect of warfarin is affected by many drugs, foods, etc. accompanied by a high risk of bleeding and embolism. The Vitamin K epoxide reductase complex 1 (VKORC1) and Cytochrome P450 2C9 (CYP2C9) genotypic variation can influence the therapeutic dose of warfarin. However, it is not clear whether there is a correlation between warfarin dose and liver function, kidney function and metabolic markers such as uric acid (UA) in patients with different genotypes. We performed a single-center retrospective cohort study to evaluate the factors affecting warfarin dose and to establish a dose conversion model for warfarin patients undergoing heart valve replacement. Methods: We studied 343 patients with a mechanical heart valve replacement, compared the doses of warfarin in patients with different warfarin-related genotypes (CYP2C9 and VKORC1), and analyzed the correlation between liver function, kidney function, UA and other metabolic markers and warfarin dose in patients with different genotypes following heart valve replacement. Results: Genotype analysis showed that 72.01% of patients had CYP2C9*1/*1 and VKORC1 mutant AA genotypes. Univariate regression analysis revealed that the warfarin maintenance dose was significantly correlated with gender, age, body surface area (BSA), UA and genotype. There was no correlation with liver or kidney function. Multiple linear regression analysis showed that BSA, genotype and UA were the independent factors influencing warfarin dose. Conclusions: There is a significant correlation between UA content and warfarin dose in patients with heart valve replacement genotypes CYP2C9*1/*1/VKORC1(GA+GG), CYP2C9*1/*1/VKORC1AA and CYP2C9*1/*1/VKORC1AA.
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BACKGROUND: This study determines the role and mechanism of APS in cyclophosphamide-induced myelosuppression in mice and bone mesenchymal stem cells (BMSCs) cell model. METHODS: Cy-induced myelosuppression mice and BMSCs cell model were established. Fifty C57BL/6 mice (weighing 20 ± 2â¯g) were randomly divided into five groups. Femur and tibia samples, bone marrow samples, and blood samples were collected 3 days after the last injection of Cy. Histopathology changes and cell apoptosis were detected. Cell viability, apoptosis, cycle distribution, reactive oxygen species activity, osteogenesis ability, and protein levels were detected. γ-H2AX and senescence-associated ß-galactosidase activity expression was detected by immunofluorescence. Cy-induced senescence and Wnt/ß-catenin related protein levels were detected using western blotting. RESULTS: The results showed that APS effectively induced Cy-induced histological injury and cell apoptosis rate. After treated with APS, ROS and ALP levels were significantly increased. In BMSCs, cell viability, apoptosis, and cell cycle distribution were also influenced by APS treatment. Compared with the control group, cell viability was significantly increased, the cell apoptosis rate was decreased while the number of cells remained in the G0-G1 phase was increased. Meanwhile, ROS levels were significantly increased in APS group. Cell senescence and Wnt/ß-catenin related protein (γ-H2AX, SA-ß-gal, p21, p16, p-ß-catenin/ ß-catenin, c-Myc, and AXIN2) levels were also altered both in vivo and in vitro. Interestingly, the effects of APS were reversed by BML-284. CONCLUSION: Our results indicate that APS protected Cy-induced myelosuppression through the Wnt/ß-catenin pathway and APS is a potential therapeutic drug for Cy-induced myelosuppression.
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Apoptose , Astrágalo , Ciclofosfamida , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Polissacarídeos , Animais , Ciclofosfamida/toxicidade , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Apoptose/efeitos dos fármacos , Camundongos , Polissacarídeos/farmacologia , Astrágalo/química , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Masculino , beta Catenina/metabolismo , Senescência Celular/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Osteogênese/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacosRESUMO
A one-step solvent-mediated transfer printing technology (sTPT) is proposed to fabricate printable silver (Ag) electrodes. This simple approach can realize the residuals in the active layer serving as the mediator due to the capillary action without the use of any additional solvent. The as-cast polydimethylsiloxane (PDMS) was used as the stamp in the fabrication process. The residual solvent and the as-cast PDMS stamps simplified the fabrication process, while the transfer-printed Ag electrodes presented favorable conductivity and improved hydrophobicity due to the presence of residual PDMS on the surface of Ag, indicating the superiority as the top electrode for organic photodetectors (OPDs). Compared to the devices with the top Ag electrodes fabricated by the conventional evaporation method, we demonstrated that the OPDs with transfer-printed Ag electrodes presented better performance than that of the reference devices, including suppressed dark current, enlarged linear dynamic range, shortened response time, and optimized durability. These improved performances can be attributed to the fewer traps at the interface between the active layer and Ag electrodes. The sTPT may be a promising method for the fabrication of OPDs owing to the simplified fabrication process and enhanced device performance.
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Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus (DM). However, the mechanisms underlying DCM-induced cardiac injury remain unclear. Recently, the role of cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) signaling and pyroptosis in DCM has been investigated. Based on our previous results, this study was designed to examine the impact of irisin, mitochondrial ubiquitin ligase (MITOL/MARCH5), and cGAS/STING signaling in DCM-induced cardiac dysfunction and the effect of gasdermin D (GSDMD)-dependent pyroptosis. High-fat diet-induced mice and H9c2 cells were used for cardiac geometry and function or pyroptosis-related biomarker assessment at the end of the experiments. Here, we show that DCM impairs cardiac function by increasing cardiac fibrosis and GSDMD-dependent pyroptosis, including the activation of MITOL and cGAS/STING signaling. Our results confirmed that the protective role of irisin and MITOL was partially offset by the activation of cGAS/STING signaling. We also demonstrated that GSDMD-dependent pyroptosis plays a pivotal role in the pathological process of DCM pathogenesis. Our results indicate that irisin treatment protects against DCM injury, mitochondrial homeostasis, and pyroptosis through MITOL upregulation.
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Diabetes Mellitus , Cardiomiopatias Diabéticas , Animais , Camundongos , Cardiomiopatias Diabéticas/patologia , Fibronectinas , Nucleotidiltransferases , Piroptose , Remodelação Ventricular , RatosRESUMO
OBJECTIVE: Estrogen is indispensable in health and disease and mainly functions through its receptors. The protection of the cardiovascular system by estrogen and its receptors has been recognized for decades. Numerous studies with a focus on estrogen and its receptor system have been conducted to elucidate the underlying mechanism. Although nuclear estrogen receptors, including estrogen receptor-α and estrogen receptor-ß, have been shown to be classical receptors that mediate genomic effects, studies now show that GPER mainly mediates rapid signaling events as well as transcriptional regulation via binding to estrogen as a membrane receptor. With the discovery of selective synthetic ligands for GPER and the utilization of GPER knockout mice, significant progress has been made in understanding the function of GPER. In this review, the tissue and cellular localizations, endogenous and exogenous ligands, and signaling pathways of GPER are systematically summarized in diverse physiological and diseased conditions. This article further emphasizes the role of GPER in vascular pathology and physiology, focusing on the latest research progress and evidence of GPER as a promising therapeutic target in hypertension, pulmonary hypertension, and atherosclerosis. Thus, selective regulation of GPER by its agonists and antagonists have the potential to be used in clinical practice for treating such diseases.
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Estrogênios , Receptores de Estrogênio , Animais , Camundongos , Proteínas de Ligação ao GTP , Camundongos Knockout , Receptores de Estrogênio/genética , Receptores Acoplados a Proteínas G/genética , Transdução de SinaisRESUMO
Doxorubicin (DOX) chemotherapy in cancer patients increases the risk of the occurrence of cardiac dysfunction and even results in congestive heart failure. Despite the great progress of pathology in DOX-induced cardiomyopathy, the underlying molecular mechanisms remain elusive. Here, we investigate the protective effects and the underlying mechanisms of melatonin in DOX-induced cardiomyopathy. Our results clearly show that oral administration of melatonin prevented the deterioration of cardiac function caused by DOX treatment, which was evaluated by left ventricular ejection fraction and fractional shortening as well as cardiac fibrosis. The ejection fraction and fractional shortening in the DOX group were 49.48% and 25.5%, respectively, while melatonin treatment increased the ejection fraction and fractional shortening to 60.33 and 31.39 in wild-type mice. Cardiac fibrosis in the DOX group was 3.97%, while melatonin reduced cardiac fibrosis to 1.95% in wild-type mice. Sirt3 is a mitochondrial deacetylase and shows protective effects in diverse cardiovascular diseases. Therefore, to test whether Sirt3 is a key factor in protection, Sirt3 knockout mice were used, and it was found that the protective effects of melatonin in DOX-induced cardiomyopathy were partly abolished. Further analysis revealed that Sirt3 and its downstream molecule TFEB were downregulated in response to DOX treatment, while melatonin administration was able to significantly enhance the expressions of Sirt3 and TFEB. Our in vitro study demonstrated that melatonin enhanced lysosomal function by increasing the Sirt3-mediated increase at the TFEB level, and the accumulation of autolysosomes induced by DOX treatment was attenuated. Thus, autophagic flux disrupted by DOX treatment was restored by melatonin supplementation. In summary, our results demonstrate that melatonin protects the heart against DOX injury by the restoration of autophagic flux via the activation of the Sirt3/TFEB signaling pathway.
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Objectives: Although lymphocyte-monocyte ratio (LMR) is a potential prognostic biomarker in many tumor indications, a doubt occurs around its association with head and neck squamous cell carcinoma (HNSCC). We aimed to evaluate the predictive value of LMR in patients with HNSCC. Methods: We searched PubMed, Web of Science, EMBASE, and the Cochrane database from inception to May 8, 2023 for systematic review and meta-analysis on LMR and outcomes related to HNSCC development. STATA software was used to estimate the correlation between LMR and prognosis. The risk ratio (hazard ratio, HR) and 95% confidence interval l (CI) for overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and progression-free survival (PFS) were calculated, and the association between LMR and OS was further validated by subgroup analysis. The source of heterogeneity with the results of subgroup analysis was analyzed by meta-regression analysis. This meta-analysis was registered at PROSPERO (CRD42023418766). Results: After a comprehensive exploration, the results of 16 selected articles containing 5,234 subjects were evaluated. A raised LMR was connected to improved OS (HR = 1.36% CI [1.14-1.62] P = 0.018), DFS (HR = 0.942, 95% CI [0.631-1.382], P = 0.02), and PFS (HR = 0.932, 95% CI [0.527-1.589], P < 0.022). Subgroup analysis indicated that patients with a low LMR level had a poor prognosis with a critical value of ≥4. The LMR was found to be prognostic for cases with an LMR of <4. The meta-regression analysis showed that the cut-off values and treatment methods were the primary sources of high heterogeneity in patients with HNSCC. Conclusions: Our study suggested that an elevated LMR is a potential prognostic biomarker in patients with HNSCC and could be used to predict patient outcomes.
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Neoplasias de Cabeça e Pescoço , Monócitos , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Prognóstico , Linfócitos , Neoplasias de Cabeça e Pescoço/diagnóstico , BiomarcadoresRESUMO
Mitochondrial aldehyde dehydrogenase (ALDH2) offers proven cardiovascular benefit although its impact in diabetes remains elusive. This study examined the effect of ALDH2 overexpression (OE) and knockout (KO) on diabetic cardiomyopathy and mechanism involved with a focus on mitochondrial integrity. ALDH2 OE and KO mice were challenged with streptozotocin (STZ, 200 mg/kg. i.p.) to establish diabetes. Diabetic patients displayed reduced plasma ALDH2 activity, cardiac remodeling and diastolic dysfunction. STZ challenge prompted reduced respiratory exchange ratio (RER), dampened fractional shortening, ejection fraction, increased LV end systolic and diastolic diameters, cardiac remodeling, cardiomyocyte contractile and intracellular Ca2+ defects (depressed peak shortening and maximal velocity of shortening/relengthening, prolonged relengthening, dampened intracellular Ca2+ rise and clearance), myocardial ultrastructural injury, oxidative stress, apoptosis and mitochondrial damage, the effects of which were overtly attenuated and accentuated by ALDH2 OE and KO, respectively. Immunoblotting revealed downregulated mitochondrial proteins PPARγ coactivator 1α (PGC-1α) and UCP-2, Ca2+ regulatory proteins including SERCA and Na+-Ca2+ exchanger, elevated phospholamban, dampened autophagy and mitophagy (LC3B ratio, TOM20, Parkin, FUNDC1 and BNIP3), disrupted phosphorylation of Akt, GSK3ß and Foxo3a, and elevated PTEN phosphorylation, the effect of which was reversed and worsened by ALDH2 OE and KO, respectively (except FUNDC1 and BNIP3). In vivo and in vitro data revealed that novel ALDH2 activator torezolid/Alda-1 protected against STZ or high glucose-induced cardiac anomalies, the effect was nullified by inhibition of Akt, GSK3ß, Parkin and mitochondrial coupling. Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt, GSK3ß activation, parkin mitophagy and mitochondrial function.
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The incidence of heart failure mainly resulting from cardiac hypertrophy and fibrosis increases sharply in post-menopausal women compared with men at the same age, which indicates a cardioprotective role of estrogen. Previous studies in our group have shown that the novel estrogen receptor G Protein Coupled Receptor 30 (GPR30) could attenuate myocardial fibrosis caused by ischemic heart disease. However, the role of GPR30 in myocardial hypertrophy in ovariectomized mice has not been investigated yet. In this study, female mice with bilateral ovariectomy or sham surgery underwent transverse aortic constriction (TAC) surgery. After 8 weeks, mice in the OVX + TAC group exhibited more severe myocardial hypertrophy and fibrosis than mice in the TAC group. G1, the specific agonist of GPR30, could attenuate myocardial hypertrophy and fibrosis of mice in the OVX + TAC group. Furthermore, the expression of LC3II was significantly higher in the OVX + TAC group than in the OVX + TAC + G1 group, which indicates that autophagy might play an important role in this process. An in vitro study showed that G1 alleviated AngiotensionII (AngII)-induced hypertrophy and reduced the autophagy level of H9c2 cells, as revealed by LC3II expression and tandem mRFP-GFP-LC3 fluorescence analysis. Additionally, Western blot results showed that the AKT/mTOR pathway was inhibited in the AngII group, whereas it was restored in the AngII + G1 group. To further verify the mechanism, PI3K inhibitor LY294002 or autophagy activator rapamycin was added in the AngII + G1 group, and the antihypertrophy effect of G1 on H9c2 cells was blocked by LY294002 or rapamycin. In summary, our results demonstrate that G1 can attenuate cardiac hypertrophy and fibrosis and improve the cardiac function of mice in the OVX + TAC group through AKT/mTOR mediated inhibition of autophagy. Thus, this study demonstrates a potential option for the drug treatment of pressure overload-induced cardiac hypertrophy in postmenopausal women.
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Estenose da Valva Aórtica , Proteínas Proto-Oncogênicas c-akt , Camundongos , Feminino , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Estrogênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Estenose da Valva Aórtica/patologia , Autofagia , Fibrose , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miocárdio/metabolismoRESUMO
Ample evidence suggests that estrogen replacement therapy is associated with beneficial effects with regard to cardiovascular diseases when the therapy is initiated temporally close to menopause but not when it is initiated later. Little is known about the complex interactions between hormone receptors after menopause. Coronary artery function and cardiac function were measured in rats that had either received no treatment or had been pretreated with an androgen receptor (AR) antagonist and/or a GPER agonist G-1. ICI 182,780 was used to block the classical estrogen receptors (ERs) to investigate their complex interactions with GPER. The beneficial effects of GPER were only observed by blocking ARs and classical ERs in aged female rats. The results demonstrate that GPER activation is a potential therapeutic target for the inhibition of age-dependent coronary artery dysfunction and cardiac dysfunction under the condition of blocking ARs and classical ERs after menopause. CLINICAL RELEVANCE: The risk of cardiovascular disease in postmenopausal women significantly increased. The role of sex hormones and their receptors during this process is still complicated. Our present study demonstrated that the imbalance of androgen and estrogen may contribute to the impairment of vascular reactivity and subsequent cardiac function. Treatment with GPER agonist G1 combined with the inhibition of ERα and ERß could improve vascular function and reduce the myocardial ischemia reperfusion injury. These findings may provide the novel and effective strategy for the treatment of cardiovascular diseases in postmenopausal women.
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Doenças Cardiovasculares , Receptores de Estrogênio , Feminino , Ratos , Animais , Receptores de Estrogênio/metabolismo , Estrogênios , Receptores Acoplados a Proteínas G/metabolismo , Artérias/metabolismo , Envelhecimento , Proteínas de Ligação ao GTPRESUMO
Sepsis-induced cardiac dysfunction is a leading cause of mortality in intensive care units. However, the molecular mechanisms underlying septic cardiomyopathy remain elusive. Irisin is a cleaved product of fibronectin type III domain-containing protein 5 (FNDC5) that protects the heart from ischemia/reperfusion injury through upregulation of mitochondrial ubiquitin ligase (MITOL). Gasdermin D (GSDMD)-dependent pyroptosis plays a pivotal role in septic cardiomyopathy by regulating mitochondrial homeostasis. However, whether irisin can regulate MITOL to inhibit GSDMD-dependent pyroptosis in septic cardiomyopathy is yet to be investigated. Thus, this study was designed to explore the role of irisin in septic cardiomyopathy and its underlying molecular mechanisms. Our results demonstrate that irisin improves cardiac function against sepsis-induced cardiac dysfunction by reducing cardiac inflammation and myocardial pyroptosis. Using MITOL siRNA in vitro, the results revealed that the protective role of irisin against lipopolysaccharide (LPS)-induced cell injury was mediated by MITOL activation and the resulting inhibition of GSDMD-dependent pyroptosis. Moreover, irisin alleviated LPS-induced H9c2 cell injury by suppressing IL-1ß expression and reducing serum LDH and CK-MB concentrations in a MITOL/GSDMD-dependent manner. Collectively, our data suggest that irisin treatment ameliorates cardiac dysfunction in septic cardiomyopathy by activating MITOL and inhibiting GSDMD-dependent pyroptosis. These findings highlight the clinical relevance and therapeutic potential of irisin and MITOL for the management of sepsis-induced cardiac dysfunction.
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Cardiomiopatias , Cardiopatias , Sepse , Cardiomiopatias/etiologia , Fibronectinas , Humanos , Inflamação , Ligases , Lipopolissacarídeos/metabolismo , Piroptose/fisiologia , Sepse/complicações , Sepse/metabolismo , UbiquitinasRESUMO
Advanced aging exhibits altered cardiac geometry and function involving mitochondrial anomaly. Natural compounds display promises in the regulation of cardiac homeostasis via governance of mitochondrial integrity in aging. This study examined the effect of oleanolic acid (OA), a natural pentacyclic triterpenoid with free radical scavenging and P450 cyclooxygenase-regulating properties, on cardiac aging and mechanisms involved with a focus on mitophagy. Young (4-5 month-old) and old (22-24 month-old) mice were treated with OA for 6 weeks prior to assessment of cardiac function, morphology, ultrastructure, mitochondrial integrity, cell death and autophagy. Our data revealed that OA treatment alleviated aging-induced changes in myocardial remodeling (increased heart weight, chamber size, cardiomyocyte area and interstitial fibrosis), contractile function and intracellular Ca2+ handling, apoptosis, necroptosis, inflammation, autophagy and mitophagy (LC3B, p62, TOM20 and FUNDC1 but not BNIP3 and Parkin). OA treatment rescued aging-induced anomalies in mitochondrial ultrastructure (loss of myofilament alignment, swollen mitochondria, increased circularity), mitochondrial biogenesis and O2- production without any notable effect at young age. Interestingly, OA-offered benefit against cardiomyocyte aging was nullified by deletion of the mitophagy receptor FUNDC1 using FUNDC1 knockout mice, denoting an obligatory role for FUNDC1 in OA-elicited preservation of mitophagy. OA reconciled aging-induced changes in E3 ligase MARCH5 but not FBXL2, and failed to affect aging-induced rises in IP3R3. Taken together, our data indicated a beneficial role for OA in attenuating cardiac remodeling and contractile dysfunction in aging through a FUNDC1-mediated mechanism.
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Ácido Oleanólico , Triterpenos , Envelhecimento , Animais , Proteínas de Membrana/metabolismo , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Mitofagia/fisiologia , Miócitos Cardíacos/metabolismo , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , Triterpenos/farmacologiaRESUMO
Warfarin is clinically used as the first choice for long-term anticoagulant therapy, and for the prevention of thromboembolic events. However, when used at low doses in the long term or high doses in the short term, warfarin treatment may result in tissue calcifications-such as calcifications in the coronary arteries, peripheral vascular system, blood vessels of patients with atrial fibrillation and chronic kidney disease, and vascular valves-and atherosclerotic plaque calcification. These warfarin-induced calcifications may affect cardiovascular function and exacerbate diseases such as diabetes and hypertension. Studies have shown that quercetin, osteoprotegerin, sclerosin, and sodium thiosulfate may alleviate these effects by interfering in the Wnt/ ß -catenin, TG2/ ß -catenin, Bone Morphogenetic Protein 2 (BMP2), and Eicosapentaenoic Acid/Matrix Metallopeptidase-9 (EPA/MMP-9) pathways, respectively. Nevertheless, the mechanism underlying warfarin-induced calcification remains unknown. Therefore, the question as to how to effectively attenuate the calcification induced by warfarin and ensure its anticoagulant effect remains an urgent clinical problem that needs to be resolved. To utilize warfarin rationally and to effectively attenuate the calcifications, we focused on the clinical phenomena, molecular mechanisms, and potential strategies to prevent calcification. Highlighting these aspects could provide new insights into the effective utilization of warfarin and the reduction of its associated calcification effects.
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The incidence of type 2 diabetes mellitus (T2DM) has been increasing globally, and T2DM patients are at an increased risk of major cardiac events such as myocardial infarction (MI). Nevertheless, the molecular mechanisms underlying MI injury in T2DM remain elusive. Ubiquitin-specific protease 10 (USP10) functions as a NICD1 (Notch1 receptor) deubiquitinase that fine-tunes the essential myocardial fibrosis regulator Notch signaling. Follistatin-like protein 1 (FSTL1) is a cardiokine with proven benefits in multiple pathological processes including cardiac fibrosis and insulin resistance. This study was designed to examine the roles of FSTL1/USP10/Notch1 signaling in MI-induced cardiac dysfunction in T2DM. High-fat-diet-treated, 8-week-old C57BL/6J mice and db/db T2DM mice were used. Intracardiac delivery of AAV9-FSTL1 was performed in T2DM mice following MI surgery with or without intraperitoneal injection of crenigacestat (LY3039478) and spautin-1. Our results demonstrated that FSTL1 improved cardiac function following MI under T2DM by reducing serum lactate dehydrogenase (LDH) and myocardial apoptosis as well as cardiac fibrosis. Further in vivo studies revealed that the protective role of FSTL1 against MI injury in T2DM was mediated by the activation of USP10/Notch1. FSTL1 protected cardiac fibroblasts (CFs) against DM-MI-induced cardiofibroblasts injury by suppressing the levels of fibrosis markers, and reducing LDH and MDA concentrations in a USP10/Notch1-dependent manner. In conclusion, FSTL1 treatment ameliorated cardiac dysfunction in MI with co-existent T2DM, possibly through inhibition of myocardial fibrosis and apoptosis by upregulating USP10/Notch1 signaling. This finding suggests the clinical relevance and therapeutic potential of FSTL1 in T2DM-associated MI and other cardiovascular diseases.
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The incidence of cardiovascular diseases was significantly increased in postmenopausal women. The protection of estrogen in the cardiovascular system has been further reported for decades. Although menopausal hormone therapy has been used in many clinical trials, the debatable results indicate that the studies for elucidating the precise molecular mechanism are urgently required. G protein-coupled estrogen receptor 30 (GPR30) is a membrane receptor of estrogen and displays protective roles in diverse cardiovascular diseases. Previous studies have revealed that ERK1/2-mediated MMP-9 signaling was involved in ischemic heart diseases. However, the role of ERK1/2-mediated MMP-9 signaling in the protection of GPR30 against cardiac hypertrophy in aged female mice has not been investigated. Our present study demonstrated that GPR30 overexpression and its agonist G1 co-administration reduced transverse aortic constriction-induced myocardial fibrosis and preserved cardiac function in aged female mice. MMP-9 expression was markedly increased via ERK1/2 phosphorylation in transverse aortic constriction-injured myocardium of aged female mice. Further results showed that GPR30/G1 activation decreased MMP-9 expression via ERK1/2 inhibition, which further reduced TGF-ß1 expression. Inhibition of the ERK1/2 signaling pathway by its inhibitor PD98059 suppressed the induction of the cardiomyocyte MMP-9 level caused by the GRP30 antagonist G15 and inhibited TGF-ß1 expression in cardiac fibroblast in vitro. In summary, our results from in vivo and in vitro studies indicated that GPR30 activation inhibited myocardial fibrosis and preserved cardiac function via inhibiting ERK-mediated MMP-9 expression. Thus, the present study may provide the novel drug targets for prevention and treatment of cardiac pathological hypertrophy in postmenopausal women.
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Myocardial ischemia/reperfusion injury is a common clinical problem and can result in severe cardiac dysfunction. Previous studies have demonstrated the protection of electroacupuncture against myocardial ischemia/reperfusion injury. However, the role of X-box binding protein I (XBP1) signaling pathway in the protection of electroacupuncture was still elusive. Thus, we designed this study and demonstrated that electroacupuncture significantly improved cardiac function during myocardial ischemia/reperfusion injury and reduced cardiac infarct size. Electroacupuncture treatment further inhibited cardiac injury manifested by the decrease of the activities of serum lactate dehydrogenase and creatine kinase-MB. The results also revealed that electroacupuncture elevated the expressions of XBP1, glucose-regulated protein 78 (GRP78), Akt, and Bcl-2 and decreased the Bax and cleaved Caspase 3 expressions. By using the inhibitor of XBP1 in vitro, the results revealed that suppression of XBP1 expression could markedly increase the activities of lactate dehydrogenase and creatine kinase-MB and cell apoptosis, thus exacerbating stimulated ischemia/reperfusion-induced H9c2 cell injury. Compared with stimulated ischemia/reperfusion group, inhibition of XBP1 inhibited the downstream GRP78 and Akt expressions during stimulated ischemia/reperfusion injury. Collectively, our data demonstrated that electroacupuncture treatment activated XBP1/GRP78/Akt signaling to protect hearts from myocardial ischemia/reperfusion injury. These findings revealed the underlying mechanisms of electroacupuncture protection against myocardial ischemia/reperfusion injury and may provide novel therapeutic targets for the clinical treatment of myocardial ischemia/reperfusion injury.
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BACKGROUND: Myocardial ischemia/reperfusion (MI/R) injury imposes devastating cardiovascular sequelae in particular cardiac dysfunction as a result of restored blood flow. However, the mechanism behind MI/R injury remains elusive. Mitochondrial ubiquitin ligase (MITOL/MARCH5) is localized at the mitochondria-ER contact site and may be activated in response to a variety of pathophysiological processes, such as apoptosis, mitochondrial injury, ER stress, hypoxia, and reactive oxygen species (ROS) generation. Irisin as a cleaved product of fibronectin type III domain-containing protein 5 (FNDC5) displays cardioprotection in diverse cardiac diseases. METHODS: This study was designed to examine the role of irisin and MITOL in MI/R injury. Male C57BL/6J mice (8-10-week-old) were administered adenovirus MITOL shRNA through intracardiac injection followed by MI/R surgery through ligation and release the slipknot of cardiac left anterior descending coronary artery. RESULTS: Our results showed that irisin improved myocardial function in the face of MI/R injury as evidenced by reduced myocardial infarct size, apoptotic rate, serum lactate dehydrogenase (LDH), ROS generation, and malondialdehyde (MDA) levels as well as lessened ER stress injury. Moreover, our results indicated that protective role of irisin was mediated by upregulation of MITOL. Irisin also protected H9c2 cells against simulated I/R through negating ER stress, apoptosis, ROS and MDA levels, as well as facilitating superoxide dismutase (SOD) by way of elevated MITOL expression. CONCLUSIONS: To this end, our data favored that irisin pretreatment protects against MI/R injury, ER stress, ROS production, and mitochondrial homeostasis through upregulation of MITOL. These findings depicted the therapeutic potential of irisin and MITOL in the management of MI/R injury in patients with ST-segment elevation.
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OBJECTIVE: Mesenchymal stem cells (MSCs) show unique advantages in cardiomyocyte repairment. Exosomes derived from MSCs can enhance the viability of myocardial cells after ischemia/reperfusion (I/R) injury and regulate inflammation response. The study was designed to ascertain whether MSCs-exo protect the myocardium against I/R injury through inhibiting pyroptosis, and the underlying mechanisms. METHODS AND RESULTS: Experiments were carried out in H/R and I/R model. Cell viability was inhibited and NLRP3 and caspase1 protein levels were upregulated in H/R model. However, MSCs could inhibit cell apoptosis and pyroptosis in H/R model. Moreover, we used MSCs-exo to treated H/R model, and flow cytometric analysis results showed the inhibition function of MSCs-exo on cell apoptosis, and Western blot data suggested that NLRP3 and Caspase-1 expressions were downregulated in H/R model. Furthermore, exosomal miR-320b targeted NLRP3 protein, and MSCs-exo OE could inhibit NLRP3 expression and pyroptosis in H/R. In addition, the inhibition function of MSCs-exo on pyroptosis also was found in I/R model, and HE and Tunel staining also got similar results. CONCLUSION: Exosomes derived from mesenchymal stem cells could protect the myocardium against ischemia/reperfusion injury through inhibiting pyroptosis.
Assuntos
Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Piroptose , Animais , Células Cultivadas , Humanos , Masculino , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Second-hand smoking evokes inflammation and cardiovascular diseases. Recent evidence has revealed a pivotal role for deranged autophagy in smoke exposure-induced cardiac anomalies. This study evaluated the impact of haploinsufficiency of the mTOR-independent autophagy protein Beclin1 on side-stream smoke exposure-induced cardiac anomalies and mechanism(s) involved. Adult WT and Beclin1 haploinsufficiency (Becn+/-) mice were exposed to cigarette smoke for 1 h daily for 90 days. Echocardiographic, cardiomyocyte function, intracellular Ca2+, autophagy, mitophagy, apoptosis and inflammation were examined. DHE staining was employed to evaluate O2- level. Our data revealed that Beclin1 deficiency exacerbated smoke exposure-induced myocardial anomalies in geometry, fractional shortening, cardiomyocyte function, intracellular Ca2+ handling, TEM ultrastructure, and inflammation along with pronounced apoptosis and O2- production. Side-stream smoke provoked excessive autophagy/mitophagy, mtDNA release, and activation of innate immune response signals cyclic GMP-AMP synthase (cGAS) and its effector - stimulator of interferon genes (STING), the effect was abolished or unaffected by Becn haploinsufficiency. STING phosphorylation was overtly promoted by smoke exposure in Becn+/- mice. Smoke exposure also suppressed phosphorylation of mTOR although it facilitated that of ULK1 in both groups. In vitro data revealed that inhibition of cGAS or STING failed to affect smoke extract-induced mitophagy although they abrogated smoke extract-induced cardiomyocyte dysfunction except cGAS inhibition in Becn+/- mice. These data suggest that Beclin1 is integral in the maintenance of cardiac homeostasis under side-stream smoke exposure via a STING-mediated mechanism.