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The cardioprotective mechanisms of bradykinin-(1-9) in myocardial infarction were unclear. We investigated the effect of bradykinin-(1-9) on cardiac function, fibrosis, and autophagy induced by myocardial infarction and identified the mechanisms involved. To investigate the cardioprotective effect of bradykinin-(1-9), various doses of bradykinin-(1-9), its B2 receptor blocker HOE140, or their combination were administered to rats via subcutaneous osmotic minipump implantation before myocardial infarction. After 2 days, myocardial infarction was induced by ligation of the left anterior descending coronary artery. After 2 weeks, echocardiographic measurements and euthanasia were performed. Bradykinin-(1-9) treatment attenuated left ventricular dysfunction, fibrosis, and autophagy in rats with myocardial infarction, which was partially reversed by HOE140 administration. Moreover, the downregulatory effect of bradykinin-(1-9) on autophagy was partially reversed by combination with the PI3K inhibitor LY294002. Thus, bradykinin-(1-9) inhibits myocardial infarction-induced cardiomyocyte autophagy by upregulating the PI3K/Akt pathway.
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Infarto del Miocardio , Proteínas Proto-Oncogénicas c-akt , Ratas , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Bradiquinina/farmacología , Bradiquinina/metabolismo , Fosfatidilinositol 3-Quinasas , Infarto del Miocardio/metabolismo , Autofagia , FibrosisRESUMEN
No study has evaluated the impact of different iodinated contrast media on coronary contrast enhancement, using an injection protocol according to body surface area (BSA). Thus, the present study aimed to examine the usefulness and safety of personalized application of different iodine concentrations of contrast media in coronary computed tomographic (CT) angiography with a 2nd dual-source CT scanner in eliminating differences in coronary contrast enhancement based on a BSA-adapted injection protocol of contrast media. A total of 270 enrolled participants were randomly assigned to three groups: ioversol 320, ioversol 350 and iopromide 370 (n = 90 per group). The three groups were administered contrast media at a BSA-adjusted volume and flow rate with a fixed injection time of 15 seconds, and they subsequently received a 30-mL saline flush. All patients were scanned with a prospective electrocardiogram-gated protocol in a craniocaudal direction using a second-generation 128-slice dual-source CT system. The three iodinated contrast media used in coronary CT angiography exhibited similar diagnostic quality and safety. No significant differences were found in the contrast enhancement degrees, image quality scores, radiation doses and incidences of adverse effects among the three groups. The three contrast media used in coronary CT angiography with 320, 350 and 370 mg/mL iodine, respectively, have comparable diagnostic quality and safety. However, more large-scale, multinational, multi-centre and prospective trials are warranted.
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Angiografía por Tomografía Computarizada , Medios de Contraste , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Yodo , Oligoelementos , Adulto , Anciano , Angiografía por Tomografía Computarizada/métodos , Angiografía por Tomografía Computarizada/normas , Medios de Contraste/administración & dosificación , Medios de Contraste/efectos adversos , Medios de Contraste/química , Enfermedad de la Arteria Coronaria/patología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Procesamiento de Imagen Asistido por Computador/normas , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Patients with diabetes mellitus were often accompanied with hyperlipidemia. ATP-binding cassette sub-family A member1 (ABCA1) promotes the efflux of lipids and thereby mediates the metabolism of cholesterol. The aim of our study was to determine the associations of ABCA1 gene polymorphisms with the risks of diabetes mellitus and dyslipidemia in diabetic patients. METHODS: We retrieved literature about the relationship between ABCA1 gene polymorphisms (C69T and R230C) and the risk of diabetes through PubMed, Web of Science, EMBASE, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Cochrane database. Weighted mean difference (WMD) and odds ratio (OR) were used to compare continuous and dichotomous variables, respectively, accompanied by their 95% confidence interval (CI). RESULTS: A total of 1746 diabetic patients and 1292 non-diabetic controls were enrolled. All subjects were Caucasians. ABCA1 R230C T allele was significantly associated with reduced the risk of diabetes (OR = 0.75, 95% CI = 0.57-0.98, P = 0.04). There was no association of ABCA1 C69T gene polymorphisms with the risk of diabetes. However, subgroup analyses showed that the ABCA1 C69T gene mutation significantly reduced the risk of hypertriglyceridemia in diabetic patients as compared with that in non-diabetic subjects (dominant model: WMD =0.66, 95% CI = 0.52-0.8, P < 0.0001; recessive model: WMD = 0.47, 95%CI = 0.11-0.83, P = 0.01). CONCLUSIONS: ABCA1 R230C T allele gene mutation is a protective in decreasing the risk of diabetes in Caucasians and ABCA1 C69T gene mutation markedly influences the level of lipid metabolism in diabetic patients.
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Transportador 1 de Casete de Unión a ATP/genética , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Metabolismo de los Lípidos/genética , Mutación/genética , Genes Dominantes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Sesgo de Publicación , Factores de RiesgoRESUMEN
To explore the potential therapeutic effects of angiotensin(1-7) (Ang(1-7)), an endogenous ligand of the Mas receptor, on streptozotocin-induced diabetic nephropathy, male Wistar rats were randomly divided into two groups: a control group and a diabetic model group. After 12 weeks, the diabetic rats were divided into subgroups for 4-week treatments consisting of no-treatment group, small-, moderate-, and large-dose Ang(1-7) groups, a valsartan group, a large-dose Ang(1-7) plus valsartan group, and an A779 (antagonist of the Mas receptor) group, each with 15 rats. Ang(1-7) improved renal function, attenuated glomeruli sclerosis, oxidative stress, and cell proliferation, decreased the expression of collagen IV, TGF-ß1, VEGF, NOX4, p47phox, PKCα, and PKCß1, and the phosphorylation of Smad3. In the rat mesangial HBZY-1 cell line, Ang(1-7) decreased high-glucose-induced oxidative stress, the proliferation and expression of NOX4, p47phox, and TGF-ß1, the phosphorylation of Smad3, collagen IV, and VEGF, and the membrane translocation of PKCα and PKCß1. A779 blocked the effects of Ang(1-7) both in vivo and in vitro. The effects of large-dose Ang(1-7) alone and in combination with valsartan were superior to valsartan alone, but the combination had no significant synergistic effect compared with Ang(1-7) alone. Thus, Ang(1-7) ameliorated streptozotocin-induced diabetic renal injury. Large-dose treatment was superior to valsartan in reducing oxidative stress and inhibiting TGFß1/Smad3- and VEGF-mediated pathways.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Angiotensina I/uso terapéutico , Nefropatías Diabéticas/tratamiento farmacológico , Fragmentos de Péptidos/uso terapéutico , Angiotensina II/análogos & derivados , Angiotensina II/uso terapéutico , Animales , Proliferación Celular/efectos de los fármacos , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Masculino , Células Mesangiales/efectos de los fármacos , Células Mesangiales/metabolismo , Células Mesangiales/patología , Estrés Oxidativo/efectos de los fármacos , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Transducción de Señal , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Valsartán/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
We recently confirmed that angiotensin II (Ang II) type 1 receptor (AT1R) was overexpressed in hepatocellular carcinoma tissue using a murine hepatoma model. Angiotensin(Ang)-(1-7) has been found beneficial in ameliorating lung cancer and prostate cancer. Which receptor of Ang-(1-7) is activated to mediate its effects is much speculated. This study was designed to investigate the effects of Ang-(1-7) on hepatocellular carcinoma, as well as the probable mechanisms. H22 hepatoma-bearing mice were randomly divided into five groups for treatment: mock group, low-dose Ang-(1-7), high-dose Ang-(1-7), high-dose Ang-(1-7) + A779 and high-dose Ang-(1-7) + PD123319. Ang-(1-7) treatment inhibited tumor growth time- and dose-dependently by arresting tumor proliferation and promoting tumor apoptosis as well as inhibiting tumor angiogenesis. The effects of Ang-(1-7) on tumor proliferation and apoptosis were reversed by coadministration with A779 or PD123319, whereas the effects on tumor angiogenesis were completely reversed by A779 but not by PD123319. Moreover, Ang-(1-7) downregulated AT1R mRNA, upregulated mRNA levels of Ang II type 2 receptor (AT2R) and Mas receptor (MasR) and p38-MAPK phosphorylation and suppressed H22 cell-endothelial cell communication. Thus, Ang-(1-7) administration suppresses hepatocellular carcinoma via complex interactions of AT1R, AT2R and MasR and may provide a novel and promising approach for the treatment of hepatocellular carcinoma.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neovascularización Patológica/genética , Receptor de Angiotensina Tipo 1/biosíntesis , Receptor de Angiotensina Tipo 2/biosíntesis , Angiotensina I/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Ratones , Proteína Quinasa 11 Activada por Mitógenos/genética , Proteína Quinasa 11 Activada por Mitógenos/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Fragmentos de Péptidos/administración & dosificación , Fosforilación , Proto-Oncogenes Mas , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 2/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In diabetic patients, left ventricular (LV) remodeling is highly prevalent; however, little is known about the impact of diabetes on right ventricular (RV) structure and function. We recently found that overexpression of angiotensin (ANG)-converting enzyme 2 (ACE2), which metabolizes ANG-II to ANG-(1-7) and ANG-I to ANG-(1-9), may improve LV remodeling in diabetic cardiomyopathy (DCM). Here, we aimed to assess whether LV remodeling and dysfunction are paralleled by RV alterations and the effects of ANG-(1-7) on RV remodeling in DCM. After 12 wk of diabetes induced by a single intraperitoneal injection of streptozotocin, rats were treated with saline, ANG-(1-7), perindopril, ANG-(1-7) plus perindopril, ANG-(1-7) plus Mas receptor antagonist A779, or ANG-(1-7) plus ANG-II type 2 receptor antagonist PD123319 for 4 wk. RV remodeling in diabetic rats was indicated by fibrosis of the RV free wall in the absence of hypertrophy and apoptosis. Treatment with ANG-(1-7) prevented diabetes-induced RV fibrosis and dysfunction. ANG-(1-7) (800 ng·kg(-1)·min(-1)) was superior to perindopril in improving RV fibrosis. The major mechanisms involved a complex interaction of ANG-II type 2 and Mas receptors for subsequent downregulation of ACE expression and activity and ANG-II type 1 receptor expression, as well as upregulation of ACE2 expression and activity and the expression of ANG-II type 2 receptor and sarco(endo)plasmic reticulum Ca(2+)-ATPase. Thus RV fibrosis and dysfunction plays a central role in DCM, and ANG-(1-7) mitigates diabetes-induced RV alterations.
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Angiotensina I/farmacología , Cardiomiopatías Diabéticas/tratamiento farmacológico , Ventrículos Cardíacos/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Glucemia/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Colágeno/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Cardiomiopatías Diabéticas/sangre , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/fisiopatología , Fibrosis , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Lípidos/sangre , Masculino , Estrés Oxidativo/efectos de los fármacos , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/efectos de los fármacos , Proteínas Proto-Oncogénicas/metabolismo , Ratas Wistar , Receptor de Angiotensina Tipo 2/efectos de los fármacos , Receptor de Angiotensina Tipo 2/metabolismo , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Factor de Crecimiento Transformador beta1/metabolismo , Disfunción Ventricular Derecha/sangre , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
The evidence for sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the treatment of type 2 diabetes or chronic heart failure was sufficient but lacking in acute coronary syndrome (ACS). Our aim was to investigate the effects of SGLT2i on cardiovascular outcomes in ACS patients. Studies of SGLT2i selection in ACS patients were searched and pooled. Outcomes included all-cause death, adverse cardiovascular events, cardiac remodeling as measured by the left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD), cardiac function as assessed by the left ventricular ejection fraction (LVEF) and NT-proBNP, and glycemic control. Twenty-four studies with 12,413 patients were identified. Compared to the group without SGLT2i, SGLT2i showed benefits in reducing all-cause death (OR 0.72, 95% CI [0.61, 0.85]), major adverse cardiovascular events (MACE) (OR 0.44, 95% CI [0.30, 0.64]), cardiovascular death (OR 0.66, 95% CI [0.54, 0.81]), heart failure (OR 0.52, 95% CI [0.44, 0.62]), myocardial infarction (OR 0.68, 95% CI [0.56, 0.83]), angina pectoris (OR 0.37, 95% CI [0.17, 0.78]), and stroke (OR 0.48, 95% CI [0.24, 0.96]). Results favored SGLT2i for LVEDD (MD -2.03, 95% CI [-3.29, -0.77]), LVEF (MD 3.22, 95% CI [1.71, 4.72]), and NT-proBNP (MD -171.53, 95% CI [-260.98, -82.08]). Thus, SGLT2i treatment reduces the risk of all-cause death and MACE and improves cardiac remodeling and function in ACS patients.
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Pregnancy is normally contraindicated in pulmonary arterial hypertension (PAH). Thanks to medical advances, the prognosis for pregnancy in patients with PAH has improved. The aim of our study was to investigate pregnancy conditions and outcomes in patients with mild, moderate and severe PAH. We searched PubMed, Embase, CNKI, Wanfang and Weipu databases for studies published before May 2024. Data from 29 included studies from 1898 references were pooled and analyzed. We calculated the rates for each group as well as the risk ratio (RR) and 95% confidence interval (CI) between pairwise. There was no statistical difference in maternal and neonatal survival between the mild and moderate groups. Maternal survival in the mild, moderate and severe groups was 100.0%, 99.7% and 88.8%, respectively, and neonatal survival was 100.0%, 99.7% and 96.0%, respectively. The incidence of NYHA class III-IV, pregnancy loss, intensive care unit (ICU) admission, fetal growth restriction, and neonatal asphyxia was lowest in patients with mild PAH and highest in patients with severe PAH (P < 0.001). The incidence of vaginal deliveries and term pregnancies was highest in the mild group and lowest in the severe group (P < 0.001). In conclusion, pregnant women with mild PAH can safely deliver a newborn. Given similar survival rates but greater economic and medical burdens, caution is advised in the moderate group. Pregnancy in the severe group is considered contraindicated.
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Purpose: The systemic inflammation response index (SIRI) and the systemic immune inflammation index (SII) are indicators that reflect the body's overall systemic inflammatory response. Inflammation plays an important role in the pathogenesis of in-stent restenosis (ISR). The aim of this study was to investigate the predictive value of preoperative SIRI and SII for the occurrence of ISR in patients undergoing coronary stent implantation. Materials and Methods: We retrospectively analyzed the clinical, hematological, and angiographic data of 387 patients who underwent coronary angiography for recurrent angina after coronary stent implantation at Qilu Hospital of Shandong University. Receiver operating characteristic curve (ROC) analysis was used to determine the optimal cutoff values for SIRI and SII to predict ISR. Based on the optimal cutoff values for SIRI and SII, patients were categorized into high-SIRI, low-SIRI, high-SII, and low-SII groups. Multivariate logistic regression models were constructed to assess the predictive value of SIRI and SII for ISR >50% and ISR >70%. Results: This study included a total of 387 patients who underwent coronary angiography and follow-up at Qilu Hospital of Shandong University. Patients in the high-SIRI group had a higher incidence of ISR than those in the low-SIRI group (ISR >50%: 44.8% vs 30.7%, p = 0.018; ISR >70%: 41.5% vs 4.5%, p < 0.001). In addition, ISR occurred more frequently in patients with a higher SII than in patients with a lower SII (ISR >50%: 52.6% vs 35.7%, p = 0.001; ISR >70%: 51.9% vs 23%, p < 0.001). In multivariate logistic regression analysis, SIRI and SII were found to be independent predictive factors for ISR, both as continuous and categorical variables. In the ROC analysis, the optimal cutoff value for SIRI was set at 0.54 (sensitivity: 84.5%, specificity: 27%), and the optimal cutoff value for SII was set at 545.29 (sensitivity: 44.1%, specificity: 71.7%). Conclusion: Elevated preoperative SIRI and SII values help predict ISR and may serve as a useful screening tool to perform interventional procedures based on the patient's risk of ISR after stent implantation.
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OBJECTIVES: The question of whether dipeptidyl peptidase-4 inhibitors (DPP-4i) should be preferred as new glucose-lowering agents in heart failure is controversial. This studyaimed to evaluate the effects of DPP-4i treatment on all-cause mortality and cardiovascular outcomes in patients with heart failure. METHODS: We searched for available studies of DPP-4i therapy in heart failure and performed a pooled analysis. Outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), acute coronary syndrome, and acute myocardial infarction. RESULTS: Treatment with DPP-4i did not reduce the risk of all-cause death, cardiovascular death, or hospitalization for heart failure. Subgroup analyses showed that DPP-4i significantly reduced all-cause mortality in trials with > 40% female patients (OR 0.30, 95% CI [0.16, 0.58], P = 0.0003) and in trials with > 20% patients with heart failure with preserved ejection fraction (HFpEF) (OR 0.34, 95% CI [0.19, 0.60], P = 0.0003). Changes in LVEF and LVEDV showed no statistical differences between the 2 groups. Accordingly, DPP-4i did not alter the risk of acute coronary syndrome and acute myocardial infarction. CONCLUSIONS: DPP-4i may reduce all-cause mortality in heart failure patients in subgroups of women and HFpEF and has a high coronary safety profile.
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Síndrome Coronario Agudo , Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Insuficiencia Cardíaca , Infarto del Miocardio , Humanos , Femenino , Masculino , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/inducido químicamente , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inducido químicamente , Volumen Sistólico , Síndrome Coronario Agudo/tratamiento farmacológico , Función Ventricular Izquierda , Infarto del Miocardio/tratamiento farmacológico , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas , Hipoglucemiantes/efectos adversosRESUMEN
In this study, we evaluated the effectiveness and safety of bisoprolol, metoprolol, carvedilol, and nebivolol in the treatment of chronic heart failure. The results demonstrated that bisoprolol improved the prognosis of chronic heart failure in comparison with carvedilol, and carvedilol exerted similar effects as metoprolol succinate and nebivolol and better effect than metoprolol tartrate (evidence levels: bisoprolol > carvedilol = metoprolol succinate = nebivolol > metoprolol tartrate; " > " means "prior to").
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Background and aims: The predictive value of growth differentiation factor-15 (GDF-15) for individual cardiovascular outcomes remained controversial in patients with coronary artery disease (CAD). We aimed to investigate the effects of GDF-15 on all-cause death, cardiovascular death, MI and stroke in CAD patients. Methods: We searched PubMed, EMBASE, Cochrane library and Web of Science till 30 December, 2020. Hazard ratios (HRs) were combined with fixed or random effect meta-analyses. Subgroup analyses were performed in different disease types. Sensitivity analyses were used to evaluate the stability of the results. Publication bias was tested using funnel plots. Results: A total of 10 studies with 49,443 patients were included in this meta-analysis. Patients with the highest GDF-15 concentrations had significantly increased risk of all-cause death (HR 2.24; 95% CI: 1.95-2.57), cardiovascular death (HR 2.00; 95% CI: 1.66-2.42), MI (HR 1.42; 95% CI: 1.21-1.66) after adjusting clinical characteristics and prognostic biomarkers (hs-TnT, cystatin C, hs-CRP, and NT-proBNP) but except for stroke (HR 1.43; 95% CI: 1.01-2.03, p = 0.05). For the outcome of all-cause death and cardiovascular death, subgroup analyses revealed consistent results. Sensitivity analyses showed that the results were stable. Funnel plots showed that there was no publication bias. Conclusion: In CAD patients with elevated GDF-15 levels on admission, there were independently significant risks for all-cause death and cardiovascular death. The highest concentrations of GDF-15 had a lower predictive effect on MI than all-cause death and cardiovascular death. The association of GDF-15 with the outcome of stroke needs to be further studied.
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Novel enhancement-mode organic electrochemical transistors (OECTs) have been prepared by poly(3, 4-ethylenedioxythiophene)-poly(styrenesulfonate) de-doped polyethylenimine on the multi-walled carbon nanotube-modified viscose yarn. The fabricated devices exhibit low power consumption with a high transconductance of 6.7 mS, rapid response time < 2 s, and excellent cyclic stability. In addition, the device has washing durability and bending and long-term stability suitable for wearable applications. Biosensors based on enhancement-mode OECTs for the selective detection of adrenaline and uric acid (UA) are developed by using molecularly imprinted polymer (MIP)-functionalized gate electrodes. The detection limits of adrenaline and UA analysis are as low as 1 pM, with the linear ranges of 0.5 pM to 10 µM and 1 pM to 1 mM, respectively. Moreover, the sensor based on enhancement-mode transistors can efficiently amplify the current signals according to the modulation of the gate voltage. The MIP-modified biosensor has high selectivity in the presence of interferents and desirable reproducibility. Additionally, due to the wearable nature of the developed biosensor, this sensing tool has the capability of being integrated with fabrics. Therefore, it has successfully been applied in textiles for the determination of adrenaline and UA in artificial urine samples. The excellent recoveries and rsds are 90.22-109.05% and 3.97-6.94%, respectively. Ultimately, these sensitive, low-power, wearable, and dual-analyte sensors help to develop non-laboratory tools for early disease diagnosis and clinical research.
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Técnicas Biosensibles , Impresión Molecular , Polímeros Impresos Molecularmente , Técnicas Electroquímicas , Reproducibilidad de los Resultados , Electrodos , Límite de DetecciónRESUMEN
Cardiac fibrosis plays an indispensable role in cardiac tissue homeostasis and repair after myocardial infarction (MI). The cardiac fibroblast-to-myofibroblast differentiation and extracellular matrix collagen deposition are the hallmarks of cardiac fibrosis, which are modulated by multiple signaling pathways and various types of cells in time-dependent manners. Our understanding of the development of cardiac fibrosis after MI has evolved in basic and clinical researches, and the regulation of fibrotic remodeling may facilitate novel diagnostic and therapeutic strategies, and finally improve outcomes. Here, we aim to elaborate pathophysiology, examination and intervention of cardiac fibrosis after MI.
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Apolipoprotein E-knockout (ApoE(-/-)) mice, atherosclerosis-prone mice, show an autoimmune response, but the pathogenesis is not fully understood. We investigated the pathogenesis in female and male ApoE(-/-) mice. The spleens of all ApoE(-/-) and C57BL/6 (B6) mice were weighed. The serum IgG level and titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody were assayed by ELISA. Apoptosis of spleen tissue was evaluated by TUNEL. TLR4 level in spleen tissue was tested by immunohistochemistry and Western blot analysis. Levels of MyD88, p38, phosphorylated p38 (pp38), interferon regulatory factor 3 (IRF3) and Bcl-2-associated X protein (Bax) in spleen tissue were detected by Western blot analysis. We also survey the changes of serum autoantibodies, spleen weight, splenocyte apoptosis and the expressions of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue in male ApoE(-/-) mice after 4weeks of lipopolysaccharide (LPS), Toll-like receptor 4 ligand, administration. ApoE(-/-) mice showed splenomegaly and significantly increased serum level of IgG and titers of ANA and anti-dsDNA antibody as compared with B6 mice. Splenocyte apoptosis and the expression of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue were significantly lower in ApoE(-/-) than B6 mice. The expression of TLR4, MyD88, IRF3, pp38, and Bax differed by sex in ApoE(-/-) spleen tissue. The down-regulation of TLR4 signal molecules induced by LPS led to decreased expression of Bax and increased serum titers of ANA and anti-dsDNA antibody. Therefore, the TLR4 signal pathway may participate in maintaining the balance of splenocyte apoptosis and autoantibody production in ApoE(-/-) mice.
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Anticuerpos Antinucleares/sangre , Autoinmunidad/inmunología , ADN/inmunología , Bazo/inmunología , Receptor Toll-Like 4/inmunología , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/inmunología , Apoptosis/inmunología , Aterosclerosis/inmunología , Autoinmunidad/genética , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina G/sangre , Lipopolisacáridos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tamaño de los Órganos , Transducción de Señal , Bazo/anatomía & histología , Bazo/citología , Proteína X Asociada a bcl-2/biosíntesisRESUMEN
Patients having experienced the ischemia-reperfusion process are particularly vulnerable to subsequent heart attacks because this process can induce myocardial fibrosis, hallmarked by the release of reactive oxygen species and some proteases, such as cathepsin G, into the circulating blood. If these risk indicators can be monitored from the peripheral serum, early diagnosis and intervention may become a reality. For this purpose, we have designed an assay of free copper ions and cathepsin G in serum using only synthetic small molecules as the biosensing elements. No antibodies are needed to recognize the target protein, and no enzymes are needed to generate and amplify the biosensing signal. In this design, a short peptide can target-specifically recognize protease, while the copper ion in the serum can stimulate the photoelectrochemical activity of the probe, resulting in cross-linking of the serum proteins in a target protein-specific manner. Using this method, serum cathepsin G and free copper ion are found to be significantly elevated in the blood samples collected from patients with acute myocardial infarction and successful percutaneous coronary intervention in comparison with healthy controls, indicating a higher risk of subsequent myocardial injury and cardiovascular events. These results may point to the possible application of the proposed assay to evaluate the severity and prognosis of cardiac ischemia/reperfusion in the near future.
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Cobre , Infarto del Miocardio , Catepsina G , Humanos , Iones , Infarto del Miocardio/diagnóstico , Péptidos , ReperfusiónRESUMEN
Angiotensin-converting enzyme 2 (ACE2) has proven beneficial in attenuating diabetic cardiomyopathy (DCM) but has been found to be a substrate of a disintegrin and metalloprotease protein-17 (ADAM17). However, whether ADAM17 plays a role in the pathogenesis and intervention of DCM is obscure. In this study, we created cardiomyocyte-specific knockout of ADAM17 (A17α-MHCKO) mice, and left ventricular dimension, function, pathology and molecular biology were assessed in ADAM17fl/fl control, A17α-MHCKO control, ADAM17fl/fl diabetic and A17α-MHCKO diabetic mice. Both differentiated H9c2 cells and neonatal rat cardiomyocytes (NRCMs) were used to explore the molecular mechanisms underlying the effect of ADAM17 on DCM. The results showed that protein expression and activity of ADAM17 were upregulated whereas the protein expression of ACE2 was downregulated in the myocardium of diabetic mice. Cardiomyocyte-specific knockout of ADAM17 mitigated cardiac fibrosis and cardiomyocyte apoptosis and ameliorated cardiac dysfunction in mice with DCM. Bioinformatic analyses detected a number of genes enriched in metabolic pathways, in particular the AMPK signaling pathway, expressed differentially between the hearts of A17α-MHCKO and ADAM17fl/fl diabetic mice. The mechanism may involve activated AMPK pathway, increased autophagosome formation and improved autophagic flux, which reduced the apoptotic response in cardiomyocytes. In addition, hypoxia-inducible factor-1α (HIF-1α) might act as an upstream mediator of upregulated ADAM17 and ADAM17 might affect AMPK signaling via α1 A-adrenergic receptor (ADRA1A). These results indicated that ADAM17 activity and ACE2 shedding were enhanced in DCM, which was reversed by cardiomyocyte-specific ADAM17 knockout. Thus, inhibition of ADAM17 may provide a promising approach to the treatment of DCM.
Asunto(s)
Proteína ADAM17 , Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Remodelación Ventricular , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Enzima Convertidora de Angiotensina 2 , Animales , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/metabolismo , Ratones , Miocitos Cardíacos/metabolismo , Ratas , Remodelación Ventricular/genéticaRESUMEN
Background: Anticoagulants are promising regimens for treating coronavirus disease 2019 (COVID-19). However, whether prophylactic or intermediate-to-therapeutic dosage is optimal remains under active discussion. Methods: We comprehensively searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, ClinicalTrials, and MedRxiv databases on April 26, 2022. Two independent researchers conducted literature selection and data extraction separately according to predetermined criteria. Notably, this is the first meta-analysis on COVID-19, taking serious consideration regarding the dosage overlap between the 2 comparison groups of prophylactic anticoagulation (PA) and intermediate-to-therapeutic anticoagulation (I-TA). Results: We included 11 randomized controlled trials (RCTs) and 36 cohort studies with 27,051 COVID-19 patients. By analyzing all the RCTs, there was no significant difference in mortality between the PA and I-TA groups, which was further confirmed by trial sequential analysis (TSA) (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.71-1.22; P = 0.61; TSA adjusted CI: 0.71-1.26). The rate of major bleeding was remarkably higher in the I-TA group than in the PA group, despite adjusting for TSA (OR: 1.73; 95% CI: 1.15-2.60; P = 0.009; TSA adjusted CI: 1.09-2.58). RCTs have supported the beneficial effect of I-TA in reducing thrombotic events. After including all studies, mortality in the I-TA group was significantly higher than in the PA group (OR: 1.38; 95% CI: 1.15-1.66; P = 0.0005). The rate of major bleeding was similar to the analysis from RCTs (OR: 2.24; 95% CI: 1.86-2.69; P < 0.00001). There was no distinct difference in the rate of thrombotic events between the 2 regimen groups. In addition, in both critical and noncritical subgroups, I-TA failed to reduce mortality but increased major bleeding rate compared with PA, as shown in meta-analysis of all studies, as well as RCTs only. Meta-regression of all studies suggested that there was no relationship between the treatment effect and the overall risk of mortality or major bleeding (P = 0.14, P = 0.09, respectively). Conclusion: I-TA is not superior to PA for treating COVID-19 because it fails to lower the mortality rate but increases the major bleeding rate in both critical and noncritical patients.
RESUMEN
A disintegrin and metalloprotease domain family protein 17 (ADAM17) is a new member of renin-angiotensin system (RAS) but its role in the pathogenesis of diabetic cardiomyopathy (DCM) is obscure. To test the hypothesis that ADAM17 knockdown mitigates while ADAM17 overexpression aggravates cardiac fibrosis via regulating ACE2 shedding and myofibroblast transformation in diabetic mice, ADAM17 gene was knocked down and overexpressed by means of adenovirus-mediated short-hairpin RNA (shRNA) and adenovirus vector carrying ADAM17 cDNA, respectively, in a mouse model of DCM. Two-dimensional and Doppler echocardiography, histopathology and immunohistochemistry were performed in all mice and in vitro experiments conducted in primary cardiofibroblasts. The results showed that ADAM17 knockdown ameliorated while ADAM17 overexpression worsened cardiac dysfunction and cardiac fibrosis in diabetic mice. In addition, ADAM17 knockdown increased ACE2 while reduced AT1R expression in diabetic hearts. Mechanistically, ADAM17 knockdown decreased while ADAM17 overexpression increased cardiac fibroblast-to-myofibroblast transformation through regulation of TGF-ß1/Smad3 signaling pathway. In conclusion, ADAM17 knockdown attenuates while ADAM17 overexpression aggravates cardiac fibrosis via regulating ACE2 shedding and myofibroblast transformation through TGF-ß1/Smad3 signaling pathway in diabetic mice. Targeting ADAM17 may provide a promising approach to the prevention and treatment of cardiac fibrosis in DCM.
RESUMEN
Left ventricular (LV) dysfunction is a common comorbidity in diabetic patients, although the molecular mechanisms underlying this cardiomyopathic feature are not completely understood. Aldehyde dehydrogenase 2 (ALDH2) has been considered a key cardioprotective enzyme susceptible to oxidative inactivation. We hypothesized that hyperglycemia-induced oxidative stress would influence ALDH2 activity, and ALDH2 inhibition would lead to cardiac functional alterations in diabetic rats. Diabetes was induced by intraperitoneal (i.p.) injection of 60 mg/kg streptozotocin. Rats were divided randomly into four groups: control, untreated diabetic, diabetic treated with N-acetylcysteine (NAC) and diabetic treated with α-lipoic acid (α-LA). Cardiac contractile function, oxidative stress markers and reactive oxygen species (ROS) levels were assessed. ALDH2 activity and expression also were determined. The role of ALDH2 activity in change in hyperglycemia-induced mitochondrial membrane potential (Δψ) was tested in cultured neonatal cardiomyocytes. Myocardial MDA content and ROS were significantly higher in diabetic rats than in controls, whereas GSH content and Mn-SOD activity were decreased in diabetic rats. Compared with controls, diabetic rats exhibited significant reduction in LV ejection fraction and fractional shortening, accompanied by decreases in ALDH2 activity and expression. NAC and α-LA attenuated these changes. Mitochondrial Δψ was decreased greatly with hyperglycemia treatment, and high glucose combined with ALDH2 inhibition with daidzin further decreased Δψ. The ALDH2 activity can be regulated by oxidative stress in the diabetic rat heart. ALDH2 inhibition may be associated with LV reduced contractility, and mitochondrial impairment aggravated by ALDH2 inhibition might reflect an underlying mechanism which causes cardiac dysfunction in diabetic rats.