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BACKGROUND: Hypercoagulability emerges as a central pathological feature and clinical complication in nephrotic syndrome. Increased platelet activation and aggregability are closely related to hypercoagulability in nephrotic syndrome. Monocyte-platelet aggregates (MPAs) have been proposed to represent a robust biomarker of platelet activation. The aim of this study was to investigate levels of the circulating MPAs and MPAs with the different monocyte subsets to evaluate the association of MPAs with hypercoagulability in nephrotic syndrome. METHODS: Thirty-two patients with nephrotic syndrome were enrolled. In addition, thirty-two healthy age and sex matched adult volunteers served as healthy controls. MPAs were identified by CD14 monocytes positive for CD41a platelets. The classical (CD14 + + CD16-, CM), the intermediate (CD14 + + CD16+, IM) and the non-classical (CD14 + CD16++, NCM) monocytes, as well as subset specific MPAs, were measured by flow cytometry. RESULTS: Patients with nephrotic syndrome showed a higher percentage of circulating MPAs as compared with healthy controls (p < 0.001). The percentages of MPAs with CM, IM, and NCM were higher than those of healthy controls (p = 0.012, p < 0.001 and p < 0.001, respectively). Circulating MPAs showed correlations with hypoalbuminemia (r=-0.85; p < 0.001), hypercholesterolemia (r = 0.54; p < 0.001), fibrinogen (r = 0.70; p < 0.001) and D-dimer (r = 0.37; p = 0.003), but not with hypertriglyceridemia in nephrotic syndrome. The AUC for the prediction of hypercoagulability in nephrotic syndrome using MPAs was 0.79 (95% CI 0.68-0.90, p < 0.001). The sensitivity of MPAs in predicting hypercoagulability was 0.71, and the specificity was 0.78. CONCLUSION: Increased MPAs were correlated with hypercoagulability in nephrotic syndrome. MPAs may serve as a potential biomarker for thrombophilic or hypercoagulable state and provide novel insight into the mechanisms of anticoagulation in nephrotic syndrome.
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OBJECTIVE: To evaluate whether the effect of radiofrequency ablation can be improved by using sacubitril/valsartan (S/V) to control blood pressure in hypertensive patients with persistent atrial fibrillation. METHODS: A total of 63 and 67 hypertension patients with persistent atrial fibrillation were enrolled in an S/V group and ACEI/ARB group, respectively. All patients underwent radiofrequency catheter ablation (RFCA). The blood pressure of the two groups was controlled within the range of 100-140 mmHg (high pressure) and 60-90 mmHg (low pressure). The clinical outcomes of the two groups were observed after 12 months of follow-up. RESULTS: No significant differences in blood pressure were observed between the S/V and ACEI/ARB groups. In addition, the recurrence rate of atrial fibrillation between the two groups was not different. The left atrial diameter was an independent predictor of recurrence (HR = 1.063, P = 0.008). However, in the heart failure subgroup, the recurrence rate of S/V was significantly lower than that of the ACEI/ARB group (P = 0.005), and Cox regression analysis showed that the recurrence risk of atrial fibrillation of the S/V group was 0.302 lower than that of the ACEI/ARB group. NT-proBNP, LVEF, and LAD were significantly improved in hypertension patients with heart failure when comparing cases before and at the end of follow-up. CONCLUSIONS: S/V is better than ACEI/ARB in reducing the recurrence of persistent atrial fibrillation in patients with hypertension and heart failure after RFCA.
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BACKGROUND: Inflammation has been implicated in the progressive exacerbation of valvular atrial fibrillation (VAF) and thrombogenesis. This study aimed to analyze the association of systemic inflammation as measured by six indices with left atrial thrombus (LAT) in patients with VAF. METHODS: This comparative cross-sectional analytical study included 434 patients with VAF. Logistic regression analysis was used to assess the predictive value of LAT using six inflammation indices: neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio (MLR), white blood cell-to-mean platelet volume ratio, neutrophil-to-mean platelet volume ratio, systemic immune inflammation index, and systemic inflammation response index. Receiver operating characteristic curves were plotted, and the area under these curves (AUC) were calculated to evaluate the discriminative ability of the indices. RESULTS: Transesophageal echocardiography revealed LAT in 143 (32.9%) patients. All six indices reflected a positive correlation with C-reactive protein levels. Multivariate logistic analysis revealed that these indices were independent predictors of LAT, and MLR appeared to perform best (odds ratio 12.006 [95% confidence interval (CI) 3.404-42.347]; P < 0.001; AUC 0.639 [95% CI 0.583-0.694]; P < 0.001). CONCLUSIONS: Selected inflammatory indices were significantly and independently associated with LAT among patients with VAF.
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Fibrilação Atrial , Cardiopatias , Trombose , Humanos , Estudos Transversais , Fatores de Risco , Cardiopatias/complicações , Trombose/diagnóstico por imagem , Trombose/etiologia , Ecocardiografia Transesofagiana , Inflamação/diagnóstico , Inflamação/complicaçõesRESUMO
BACKGROUND: The prognostic nutritional index (PNI) and geriatric nutritional risk index (GNRI) are well known indicators for adverse outcomes in various diseases, but there is no evidence on their association with the risk of left atrial thrombus (LAT) in patients with valvular atrial fibrillation (VAF). METHODS: A comparative cross-sectional analytical study was conducted on 433 VAF patients. Demographics, clinical characteristics and echocardiographic data were collected and analyzed. Patients were grouped by the presence of LAT detected by transesophageal echocardiography. RESULTS: LAT were identified in 142 patients (32.79%). The restricted cubic splines showed an L-shaped relationship between PNI and LAT. The dose-response curve flattened out near the horizontal line with OR = 1 at the level of 49.63, indicating the risk of LAT did not decrease if PNI was greater than 49.63. GNRI was negative with the risk of LAT and tended to be protective when greater than 106.78. The best cut-off values of PNI and GNRI calculated by receiver operating characteristics curve to predict LAT were 46.4 (area under these curve [AUC]: 0.600, 95% confidence interval [CI]:0.541-0.658, P = 0.001) and 105.7 (AUC: 0.629, 95% CI:0.574-0.684, P<0.001), respectively. Multivariable logistic regression analysis showed that PNI ≤ 46.4 (odds ratio: 2.457, 95% CI:1.333-4.526, P = 0.004) and GNRI ≤ 105.7 (odds ratio: 2.113, 95% CI:1.076-4.149, P = 0.030) were independent predictors of LAT, respectively. CONCLUSIONS: Lower nutritional indices (GNRI and PNI) were associated with increased risk for LAT in patients with VAF.
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Fibrilação Atrial , Cardiopatias , Trombose , Humanos , Idoso , Avaliação Nutricional , Estudos Transversais , Fatores de Risco , Cardiopatias/etiologia , Trombose/etiologia , Trombose/complicações , Ecocardiografia Transesofagiana/efeitos adversos , Estudos RetrospectivosRESUMO
KEY MESSAGE: The bHLH transcription factor, PPLS1, interacts with SiMYB85 to control the color of pulvinus and leaf sheath by regulating anthocyanin biosynthesis in foxtail millet (Setaria italica). Foxtail millet (Setaria italica), a self-pollinated crop with numerous small florets, is difficult for cross-pollination. The color of pulvinus and leaf sheath with purple being dominant to green is an indicative character and often used for screening authentic hybrids in foxtail millet crossing. Deciphering molecular mechanism controlling this trait would greatly facilitate genetic improvement of cultivars in foxtail millet. Here, using the F2 bulk specific-locus amplified fragment sequencing approach, we mapped the putative causal gene for the purple color of pulvinus and leaf sheath (PPLS) trait to a 100 Kb region on chromosome 7. Expression analyses of the 15 genes in this region revealed that Seita.7G195400 (renamed here as PPLS1) was differentially expressed between purple and green cultivars. PPLS1 encodes a bHLH transcription factor and is localized in the nucleus with a transactivation activity. Furthermore, we observed that expression of a MYB transcription factor gene, SiMYB85 (Seita.4G086300) involved in anthocyanin biosynthesis, shows a totally positive association with that of PPLS1. Heterologous co-expression of both PPLS1 and SiMYB85 in tobacco leaves led to elevated anthocyanin accumulation and expression of some anthocyanin-related genes. Furthermore, PPLS1 physically interacts with SiMYB85. Taken together, our results suggest that PPLS1 interacts with SiMYB85 to control the color of pulvinus and leaf sheath by regulating anthocyanin biosynthesis in foxtail millet.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Plantas/genética , Pulvínulo/genética , Setaria (Planta)/genética , Fatores de Transcrição/genética , Antocianinas/química , Clorofila/química , Cor , Biologia Computacional , Regulação da Expressão Gênica de Plantas , Fenótipo , Filogenia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Contemporary studies have identified rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene as a new genetic marker in modulating the QT interval and sudden cardiac death (SCD) in general populations. However, the conclusions were not coincident. Therefore, we conducted for the first time a system evaluation of the relativity of rs10494366, the QT interval, and sudden death by meta-analysis. In our study, the meta-analysis displayed the GG genotype of rs10494366 correlated with the QT interval in women with no heterogeneity, and in diabetes mellitus (DM) patients with minor heterogeneity. In the Caucasian population, the correlation of rs10494366 and sudden death was significant. The heterogeneity referred to the relevance between rs10494366 and sudden death in the Asian population. In conclusion, the minor allele of rs10494366 may have an impact on the QT interval in women or DM patients and may have a potential role in sudden death in the Caucasian population.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Morte Súbita Cardíaca/epidemiologia , Predisposição Genética para Doença/epidemiologia , Síndrome do QT Longo/genética , Síndrome do QT Longo/mortalidade , Polimorfismo de Nucleotídeo Único/genética , Alelos , Povo Asiático/genética , China , Morte Súbita Cardíaca/etnologia , Eletrocardiografia , Feminino , Genótipo , Humanos , Masculino , Análise de SobrevidaRESUMO
TGF-ß1-induced excessive deposition of ECM and EMT process of tubular epithelial cells play critical roles in the development and progression of fibrosis in diabetic nephropathy (DN). Orai1 has been demonstrated to be involved in TGF-ß1-induced EMT via TGF-ß/Smad3 pathway. We are aimed to explore the effects of miR-93 on TGF-ß1-induced EMT process in HK2 cells. In this study, our data showed that miR-93 was dramatically decreased in renal tissues of patients with DN and TGF-ß1-stimulated HK2 cells. Moreover, the decreased level of miR-93 was closely associated with the increased expression of Orai1. Overexpression of miR-93 decreased Orai1 expression, and then suppressed TGF-ß1-mediated EMT and fibrogenesis. Next, we predicted that the Orai1 was a potential target gene of miR-93, and demonstrated that miR-93 could directly target Orai1. SiRNA targeting Orai1 was sufficient to suppress TGF-ß1-induced EMT and fibrogenesis in HK2 cells. Furthermore, Overexpression of Orai1 partially reversed the protective effect of miR-93 overexpression on TGF-ß1-mediated EMT and fibrogenesis in HK2 cells. Taken together, Orai1 and miR-93 significantly impact on the progression of TGF-ß1-mediated EMT and fibrogenesis in HK2 cells, and they may represent novel targets for the prevention strategies of fibrosis in the context of DN.
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Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Expressão Gênica/genética , Rim/patologia , MicroRNAs/genética , MicroRNAs/fisiologia , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , Fator de Crescimento Transformador beta1 , Regulação para Cima/genética , Células Cultivadas , Fibrose , HumanosRESUMO
Myocardial infarction (MI) is an extremely severe cardiovascular disease, which ranks as the leading cause of sudden death worldwide. Studies have proved that cardiac injury following MI can cause cardiomyocyte apoptosis and myocardial fibrosis. Bilobalide (Bilo) from Ginkgo biloba leaves have been widely reported to possess excellent cardioprotective effects. However, concrete roles of Bilo in MI have not been investigated yet. We here designed both in vitro and in vivo experiments to explore the effects of Bilo on MI-induced cardiac injury and the underlying mechanisms of its action. We conducted in vitro experiments using oxygen-glucose deprivation (OGD)-treated H9c2 cells. Cell apoptosis in H9c2 cells was assessed by conducting flow cytometry assay and evaluating apoptosis-related proteins with western blotting. MI mouse model was established by performing left anterior descending artery (LAD) ligation. Cardiac function of MI mice was determined by assessing ejection fraction (EF), fractional shortening (FS), left ventricular end-systolic diameter (LVESD), and left ventricular end-diastolic diameter (LVEDD). Histological changes were analyzed, infarct size and myocardial fibrosis were measured by hematoxylin and eosin (H&E) and Masson staining in cardiac tissues from the mice. The apoptosis of cardiomyocytes in MI mice was assessed by TUNEL staining. Western blotting was applied to detect the effect of Bilo on c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinases (p38 MAPK) signaling both in vitro and in vivo. Bilo inhibited OGD-induced cell apoptosis and lactate dehydrogenase (LDH) release in H9c2 cells. The protein levels of p-JNK and p-p38 were significantly downregulated by Bilo treatment. SB20358 (inhibitor of p38) and SP600125 (inhibitor of JNK) suppressed OGD-induced cell apoptosis as Bilo did. In MI mouse model, Bilo improved the cardiac function and significantly reduced the infarct size and myocardial fibrosis. Bilo inhibited MI-induced cardiomyocytes apoptosis in mice. Bilo suppressed the protein levels of p-JNK and p-p38 in cardiac tissues from MI mice. Bilo alleviated OGD-induced cell apoptosis in H9c2 cells and suppressed MI-induced cardiomyocyte apoptosis and myocardial fibrosis in mice via the inactivation of JNK/p38 MAPK signaling pathways. Thus, Bilo may be an effective anti-MI agent.
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Bilobalídeos , Infarto do Miocárdio , Camundongos , Animais , Bilobalídeos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/farmacologia , Apoptose , FibroseRESUMO
Athetis lepigone (Möschler) (Lepidoptera: Noctuidae) is an important insect pest of corn crops in China. To determine the effect of temperature on A. lepigone growth, and to provide a forecasting model for this pest, the development and fecundity of A. lepigone under five different temperatures (18, 21, 24, 27, 30 °C) was investigated, and an experimental population life table was constructed based on the obtained results. The results showed that the duration of development of A. lepigone decreased as the temperature increased from 18 to 30 °C. Approximately 95% of mature larvae stopped pupating at 18 °C, and about 70% of mature larvae stopped pupating at 21 °C. When the growth chamber temperature was above 24 °C, no growth arrest was observed. The results indicated that the optimum growth temperature of A. lepigone was about 26.47 °C. In this study, the highest survival rate, fecundity per female, and population index trend were observed when the temperature was set at 27 °C. The percentages of larvae that could spin cocoons after the 5th or 6th instar differed at the different temperatures. The developmental threshold temperatures for A. lepigone eggs, larvae, pre-pupae, pupae, preoviposition females, and the whole generation (i.e., egg to oviposition) were 11.03, 9.04, 15.08, 11.79, 11.63, and 10.84 °C, respectively, and their effective accumulative temperatures were 63.51, 339.42, 30.04, 118.41, 35.06 and 574.08 degree-days, respectively. Based on the effective accumulative temperature law, this pest insect can have four generations in most of the Huang-Huai region of China, and two to three generations annually in some cold regions. Athetis lepigone may have four generations in the mid-southern part of Hebei Province. This prediction matches the field survey results.
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Controle de Insetos , Mariposas/fisiologia , Animais , China , Feminino , Fertilidade , Larva/crescimento & desenvolvimento , Larva/fisiologia , Tábuas de Vida , Masculino , Mariposas/crescimento & desenvolvimento , Óvulo/crescimento & desenvolvimento , Óvulo/fisiologia , Pupa/crescimento & desenvolvimento , Pupa/fisiologia , TemperaturaRESUMO
BACKGROUND: Recent studies suggest that mutation of the slow delayed rectifier potassium channel (IKs) contributes to familial atrial fibrillation (FAF). In the current study, we identified common genetic variants of KCNQ1 and explored the potential association between KCNQ1 polymorphism with lone AF (LAF). METHODS: Clinical data and blood samples were collected from 190 Han Chinese patients with sporadic AF and matched healthy controls. Variants of the KCNQ1 gene were identified using single-strand conformational polymorphism (SSCP) analysis. A case-control association study in KCNQ1 identified six known single-nucleotide polymorphisms (SNPs) during SSCP screening of the 190 LAF patients and 190 healthy controls. RESULTS: One of the SNPs in KCNQ1 was strongly associated with LAF; significant allelic association was detected rs59233444 (P = 0.013, OR = 1.469, 95% confidence interval (CI): 1.083-1.993). A multiple regression analysis indicated that rs59233444 is an independent risk factor for LAF. Twelve new variants were identified in KCNQ1, including one in the 5'-UTR, two in the 3'-UTR, six in introns, two synonymous substitutions, and one missense substitution. Variants c.1009C>T, c.1860C>T, and c.+2285C>T were not present in the 190 controls, and the others were identified in controls at various frequencies. CONCLUSIONS: rs59233444, a common SNP but not mutation in the coding regions of the KCNQ1 gene, is a risk factor for LAF in Chinese Han population.
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Fibrilação Atrial/etnologia , Fibrilação Atrial/genética , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Canal de Potássio KCNQ1/genética , Polimorfismo de Nucleotídeo Único/genética , China/epidemiologia , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prevalência , Fatores de RiscoRESUMO
Ventricular fibrillation (VF) is a life-threatening arrhythmia that usually happens in patients with structural heart diseases. However, fever-induced ventricular fibrillation in structurally normal hearts was reported, and the four main diseases associated with these cases were Brugada syndrome, long QT syndrome, idiopathic ventricular fibrillation, and non-cardiovascular diseases. In this review, we analyzed this phenomenon and its clinical characteristics.
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Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) has a well-established role in myocardial infarction, yet its involvement in atrial fibrosis and atrial fibrillation (AF) has not been elucidated. As cardiac arrhythmias caused by AF are a major global health concern, we investigated whether SHP-1 modulates AF development. The degree of atrial fibrosis was examined using Masson's trichrome staining, and SHP-1 expression in the human atrium was assessed using quantitative polymerase chain reaction (qPCR), immunohistochemistry (IHC), and western blotting (WB). We also examined SHP-1 expression in cardiac tissue from an AF mouse model, as well as in angiotensin II (Ang II)-treated mouse atrial myocytes and fibroblasts. We found that SHP-1 expression was reduced with the aggravation of atrial fibrosis in clinical samples of patients with AF. SHP-1 was also downregulated in the heart tissue of AF mice and Ang II-treated myocytes and fibroblasts, compared with that in the control groups. Next, we demonstrated that SHP-1 overexpression alleviated AF severity in mice by injecting a lentiviral vector into the pericardial space. In Ang II-treated myocytes and fibroblasts, we observed excessive extracellular matrix (ECM) deposition, reactive oxygen species (ROS) generation, and transforming growth factor beta 1 (TGF-ß1)/mothers against decapentaplegic homolog 2 (SMAD2) pathway activation, all of which were counteracted by the overexpression of SHP-1. Our WB data showed that STAT3 activation was inversely correlated with SHP-1 expression in samples from patients with AF, AF mice, and Ang II-treated cells. Furthermore, administration of colivelin, a STAT3 agonist, in SHP-1-overexpressing, Ang II-treated myocytes and fibroblasts resulted in higher levels of ECM deposition, ROS generation, and TGF-ß1/SMAD2 activation. These findings indicate that SHP-1 regulates AF fibrosis progression by modulating STAT3 activation and is thus a potential treatment target for atrial fibrosis and AF.
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Fibrilação Atrial , Humanos , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Fibrose , Angiotensina II , Fator de Transcrição STAT3/metabolismoRESUMO
Bacterial biofilms encased in extracellular polymeric substances to create protected microenvironments are typically challenging to disperse by common antibiotics and cannot be in situ visualized under current modalities. Herein, a pH-responsive branched polymer [poly(MBA-AEPZ)-AEPZ-NA] capable of overcoming antibiotic resistance and real-time visualizing biofilms for fluorescence imaging-guided infection control is reported. The positively charged polymer can effectively penetrate bacterial biofilms, neutralize the anionic character, and then disrupt the structural integrity, thus significantly promoting the transport of antibiotics into biofilms. The polymer shows a weak fluorescence emission intensity under physiological conditions (pH 7.4) but emits intense green-light emission within the localized biofilm microenvironment (pH 5.5) to real-time visualize bacterial biofilms. A therapeutic system made of the polymer and a model antibiotic can significantly reduce the dosages of the drug, thereby minimizing biofilm-induced drug resistance. Notably, a green fluorescent polymer responding to localized pH conditions is demonstrated in living zebrafish. This work confirmed that combinations of the pH-responsive branched polymer and antibiotics could be administered to overcome drug resistance and realize fluorescence imaging-guided treatment of bacterial biofilm infections.
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Polímeros , Peixe-Zebra , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Biofilmes , Concentração de Íons de Hidrogênio , Polímeros/farmacologiaRESUMO
BACKGROUND: Recent research has found that single nucleotide polymorphisms (SNPs) in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with altered QT intervals and sudden cardiac death (SCD). However, the clinical utility and implications of NOS1AP SNPs remain unclear. Thus, this study aimed to explore the influence of NOS1AP SNPs in patients with implantable cardioverter defibrillator (ICD) for secondary prevention. METHODS: We conducted a case-control study to evaluate the most studied SNPs in NOS1AP (rs12143842, rs10494366, rs12567209, and rs16847548) in patients with ICD for secondary prevention. Patients were followed for up to 36 months from the time of ICD implantation. ICD interrogation data at 3 and 12 months, including rapid ventricular arrhythmia episodes and appropriate therapies, were then analyzed. RESULTS: A significant association was observed between rs10494366 and ICD recipients who experienced appropriate therapies. After a mean follow-up time of 31.70 ± 9.15 months, we detected significant differences among the three rs10494366 genotype groups in the distribution of ICD shocks and appropriate therapies, as well as in the correlation of rs10494366 and ICD shocks. According to Kaplan-Meier and Cox regression analyses, patients with the TT genotype had a higher risk of SCD than those with the GG genotype. CONCLUSIONS: The present study revealed that NOS1AP SNP rs10494366 was associated with appropriate therapies. Specifically, the TT genotype increased ICD shocks and SCD risk in patients with ICD for secondary prevention for the first time.
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Proteínas Adaptadoras de Transdução de Sinal , Morte Súbita Cardíaca , Desfibriladores Implantáveis , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal/genética , Estudos de Casos e Controles , Morte Súbita Cardíaca/prevenção & controle , Humanos , Fatores de Risco , Prevenção SecundáriaRESUMO
Background: Degradation of pro-inflammatory macrophage-mediated connexin 43 (Cx43) plays an important role in post-myocardial infarction (MI) arrhythmogenesis, microRNA (miR)-155 produced by macrophages has been shown to mediate post-MI effects. We hypothesized that miR-155 inhibition attenuated MI-induced Cx43 degradation by reducing pro-inflammatory macrophage activation. Methods: MI was induced by permanent ligation of the left anterior descending coronary artery in male C57BL/6 mice. Lipopolysaccharide (LPS)-stimulated mice bone marrow-derived macrophages (BMDMs) and hypoxia-induced neonatal rat cardiomyocytes (NRCMs) were used in vitro models. qRT-PCR, Western-blot and immunofluorescence were used to analyze relevant indicators. Results: The expression levels of miR-155, interleukin-1 beta (IL-1ß), and matrix metalloproteinase (MMP)7 were higher in MI mice and LPS-treated BMDMs than in the sham/control groups, treatment with a miR-155 antagomir reversed these effects. Moreover, miR-155 inhibition reduced ventricular arrhythmias incidence and improved cardiac function in MI mice. Cx43 expression was decreased in MI mice and hypoxia-exposed NRCMs, and hypoxia-induced Cx43 degradation in NRCMs was reduced by application of conditioned medium from LPS-induced BMDMs treated with the miR-155 antagomir, but increased by conditioned medium from BMDMs treated with a miR-155 agomir. Importantly, NRCMs cultured in conditioned medium from LPS-induced BMDMs transfected with small interfering RNA against IL-1ß and MMP7 showed decreased hypoxia-mediated Cx43 degradation, and this effect also was diminished by BMDM treatment with the miR-155 agomir. Additionally, siRNA-mediated suppressor of cytokine signaling 1 (SOCS1) knockdown in LPS-induced BMDMs promoted Cx43 degradation in hypoxia-exposed NRCMs, and the effect was reduced by the miR-155 inhibition. Conclusions: MiR-155 inhibition attenuated post-MI Cx43 degradation by reducing macrophage-mediated IL-1ß and MMP7 expression through the SOCS1/nuclear factor-κB pathway.
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Biofilm infections present an enormous challenge in today's healthcare settings. Currently, pH-switchable antibacterial agents are being developed to eradicate biofilms. However, most pH-switchable antibacterial agents are less lethal to planktonic bacteria under neutral conditions, and cannot prevent the dispersed bacteria from seeding acute infection again. Herein, this work reports the applications of semiconducting polymer dots (Pdots) with a double adhesion mechanism in imaging and inhibiting bacteria inside (weak acidic conditions) and outside (neutral conditions) biofilms. Clew-like Pdots were prepared by covalently linking phenylboronic acid (PBA) and pH-responsive naphthalimide (NA) ramification in semiconducting polymers. Under neutral conditions, the Pdots combined with bacteria through the formation of boronate esters between PBA and diols. Under weakly acidic conditions, the partial borate bond fractured, and the Pdots adhered onto the bacterial surface through the positively charged NA in Pdots. Furthermore, the Pdots display negligible toxicity to mammalian cells and tissues. More importantly, the Pdots can selectively damage the bacterial membrane and inhibit bacteria in vivo. This work highlights the feasibility of using semiconducting Pdots to image and inhibit bacteria inside and outside biofilms, which represents a highly effective strategy to cope with biofilm infections.
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Antibacterianos/farmacologia , Materiais Biocompatíveis/farmacologia , Biofilmes/efeitos dos fármacos , Polímeros/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Masculino , Teste de Materiais , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Estrutura Molecular , Naftalimidas/química , Naftalimidas/farmacologia , Tamanho da Partícula , Polímeros/síntese química , Polímeros/química , Pontos Quânticos/química , Semicondutores , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/patologia , Staphylococcus aureus/crescimento & desenvolvimento , Propriedades de Superfície , Células Tumorais CultivadasRESUMO
Bacterial infection is one of the most significant public health challenges due to the limited choices of antibiotics which can overcome antibiotic-resistant bacteria. The promising nonantibiotic therapeutic alternatives for antibiotic-resistant bacterial infection are urgently needed to reduce the disease burden. Herein, the water-soluble branched poly(amino ester) with inherently antibacterial (chemotherapy) and enhanced inflammatory response activity (immunotherapy) was prepared via Michael addition polymerization to combat bacterial infection. These polymers can not only damage bacteria walls, leading to the death of bacteria but also activate macrophages to low-output nitric oxide (NO), TNF-α and interleukin (IL)-1ß to kill and clean bacteria. Importantly, these polymers can efficiently inhibit aminoglycoside-resistant P. aeruginosa even at a low dose of 500 nmol L-1. Furthermore, these polymers can treat subcutaneous bacterial infections in vivo. In this study, we first report a water-soluble branched polymer to combat bacteria through the combination of chemotherapy and immunotherapy, which will open a new path to design promising potential therapeutic alternatives for bacterial infection.
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Infecções Bacterianas , Polímeros , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Humanos , Imunoterapia , ÁguaRESUMO
Bacterial infections caused by biofilms are severe clinical problems, resulting in high drug resistance by limiting the penetration of antibiotics. Herein, a near-infrared (NIR)-activated chem/photodynamic/photothermal combined therapeutic agent is proposed by loading fluorescein isothiocyanate (FITC), ultrasmall copper sulfide nanoparticles (Cu2-xSNPs), and ε-polylysine (PLL) onto mesoporous silica nanoparticles (MSNs) through a layer-by-layer self-assembly approach. FITC-doped MSNs are prepared to monitor the permeability and accumulation of nanocomposites into biofilms. MSNs can also act as hosts for the synthesis of ultrasmall Cu2-xSNPs, which has effective photodynamic and photothermal ablation against bacteria under NIR light irradiation. Moreover, biodegradable PLL introduced can not only enhance adhesion toward the bacterial surface to increase the effectiveness of phototherapy but also damage bacteria through electrostatic interaction. As a result, the prepared nanocomposites could not only penetrate biofilms but also ablate biofilms through combined chem/photodynamic/photothermal effects under NIR light irradiation. Furthermore, the nanocomposites could treat bacterial infections in vivo with negligible tissue toxicity. Overall, the finely designed nanocomposites are anticipated to display promising applications in imaging-guided chem/photodynamic/photothermal combined therapy for bacterial infections.
Assuntos
Antibacterianos/farmacologia , Materiais Biocompatíveis/farmacologia , Fotoquimioterapia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/química , Materiais Biocompatíveis/química , Biofilmes/efeitos dos fármacos , Cobre/química , Cobre/farmacologia , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/farmacologia , Raios Infravermelhos , Masculino , Teste de Materiais , Testes de Sensibilidade Microbiana , Nanocompostos/química , Tamanho da Partícula , Porosidade , Ratos , Ratos Sprague-Dawley , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Sulfetos/química , Sulfetos/farmacologia , Propriedades de SuperfícieRESUMO
Nuclear receptor-binding SET domain 3 (NSD3) is a lysine methyltransferase that plays important roles in multiple biological activities; however; its potential roles in the cardiovascular system remain unknown. In this study, we found that NSD3 expression is reduced by isoproterenol (ISO) stimuli both in vitro and in vivo. Overexpression of NSD3 attenuates ISO-induced cardiomyocyte hypertrophy. Mechanistically, ISO treatment decreases H3K27me2/3 modifications on the atrial natriuretic factor (ANF) promoter by suppressing NSD3 and inhibits the association between NSD3 and bromodomain-containing protein 4 (BRD4), thus suppressing the BRD4-mediated H3K27ac modifications, which ultimately promote ANF transcription and cardiomyocyte hypertrophy. In conclusion, NSD3 decreases ANF expression and, thereby, attenuates ISO-induced cardiomyocyte hypertrophy.
Assuntos
Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Isoproterenol/farmacologia , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Linhagem Celular , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/genética , Histonas/química , Histonas/metabolismo , Lisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismoRESUMO
The olfaction system of insects plays an important role in mediating various physiological behaviors, including locating hosts, avoiding predators, and recognizing mates and oviposition sites. Therefore, some key genes in the system present valuable opportunities as targets for developing novel green pesticides. Athetis lepigone, a noctuid moth can feed on more than 30 different host plants making it a serious polyphagous pest worldwide, and it has become one of the major maize pests in northern China since 2011. However, there are no reports on effective and environmentally friendly pesticides for the control of this pest. In this study, we identified 28 genes encoding putative odorant binding proteins (OBPs) and 20 chemosensory protein (CSPs) genes based on our previous A. lepigone transcriptomic data. A tissue expression investigation and phylogenetic analysis were conducted in an effort to postulate the functions of these genes. Our results show that nearly half (46.4%) of the AlOBPs exhibited antennae-biased expression while many of the AlCSPs were highly abundant in non-antennal tissues. These results will aid in exploring the chemosensory mechanisms of A. lepigone and developing environmentally friendly pesticides against this pest in the future.