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Atherosclerosis (AS) is a pivotal pathological basis of cardiovascular and cerebrovascular diseases, and circular RNAs (circRNAs) has been disclosed to exert a vital part in the progression of AS. However, the functions of circ_0004872 in the progression of AS is indistinct. In this context, we aimed to elucidate the role of circ_0004872 and the potential mechanism in AS. The level of circ_0004872, miR-424-5p and fibroblast growth factor receptor substrate 2 (FRS2) was detected using quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was monitored by Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine (EDU) assays. The invasion and migration capabilities of VSMCs were tested by transwell assays and wound-healing assay, respectively. Western blot was adopted to check the protein levels of CyclinD1, Vimentin and FRS2. Dual-luciferase reporter and RNA immunoprecipitation assay were executed to manifest the interaction between miR-424-5p and circ_0004872 or FRS2. The level of circ_0004872 was increased in the serum samples of AS patients and ox-LDL-exposed VSMCs. Ox-LDL exposure triggered cell proliferation, invasion and migration ability of VSMCs. depletion of circ_0004872 partly weakened ox-LDL-mediated effects in VSMCs. Mechanistically, circ_0004872 functioned as a sponge of miR-424-5p, and miR-424-5p inhibition partly alleviated circ_0004872 deficiency-mediated influences in VSMCs. Additionally, miR-424-5p interacted with FRS2, and miR-424-5p constrained dysfunction in ox-LDL-stimulated VSMCs via reducing FRS2 level. Notably, circ_0004872 functioned as a sponge of miR-424-5p to elevate FRS2 expression. Circ_0004872 accelerated ox-LDL-induced damage via mediating miR-424-5p/FRS2 axis.
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BACKGROUND: The left bundle branch block (LBBB) is associated with ventricular septal mid-wall fibrosis (SMF) in patients with dilated cardiomyopathy (DCM). However, whether LBBB is also associated with SMF in patients with preserved left ventricular ejection fraction (LVEF) remains unclear. METHODS: We performed a retrospective study of 210 patients with preserved LVEF (male, n = 116; female, n = 94; mean age, 44 ± 17 years). LBBB was defined as QRS duration ≥140 ms for men or ≥ 130 ms for women, QS or rS in V1-V2, mid-QRS notching or slurring in at least two leads (V1, V2, V5, V6, I, and aVL). SMF determined by late gadolinium-enhancement cardiovascular magnetic resonance was defined as stripe-like or patchy mid-myocardial hyper-enhancement in the interventricular septal segments. RESULTS: SMF was detected in 24.8% (52/210) of these patients. The proportion of patients with SMF with LBBB was higher than the proportion of patients with SMF without LBBB (58.3% vs. 20.4%; P < 0.001). In the forward multivariate logistic analysis, LBBB (OR, 4.399; 95% CI, 1.774-10.904; P = 0.001) and age (OR, 1.028; 95% CI, 1.006-1.051; P = 0.011) were independently associated with SMF. The presence of LBBB showed a sensitivity of 27%%, specificity of 94%, positive predictive value of 58%%, and negative predictive value of 80% for the detection of SMF. CONCLUSION: LBBB was significantly associated with SMF in hospitalized patients with preserved LVEF. Screening with a resting 12lead ECG may help to identify patients who are at a high risk of the presence of SMF.
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Función Ventricular Izquierda , Tabique Interventricular , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Volumen Sistólico , Bloqueo de Rama/diagnóstico , Electrocardiografía , Estudios Retrospectivos , FibrosisRESUMEN
OBJECTIVES: The protective role of sodium glucose cotransporter 2 (SGLT2) inhibitors in renal outcomes has been revealed by large cardiovascular outcome trials among patients with type 2 diabetes. However, the effect of SGLT2 inhibitors on lupus nephritis (LN) and its underlying mechanisms remain unknown. METHODS: We applied empagliflozin treatment to lupus-prone MRL/lpr mice to explore the renal protective potential of SGLT2 inhibitors. An SGLT2 knockout monoclonal podocyte cell line was generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms. RESULTS: In MRL/lpr mice treated with empagliflozin, the levels of mouse anti-dsDNA IgG-specific antibodies, serum creatinine and proteinuria were markedly decreased. For renal pathology assessment, both the glomerular and tubulointerstitial damages were lessened by administration of empagliflozin. The levels of SGLT2 expression were increased and colocalised with decreased synaptopodin in the renal biopsy samples from patients with LN and MRL/lpr mice with nephritis. The SGLT2 inhibitor empagliflozin could alleviated podocyte injury by attenuating inflammation and enhanced autophagy by reducing mTORC1 activity. Nine patients with LN treated with SGLT2 inhibitors with more than 2 months of follow-up showed that the use of SGLT2 inhibitors was associated with a significant decrease in proteinuria from 29.6% to 96.3%. Moreover, the estimated glomerular filtration rate (eGFR) was relatively stable during the treatment with SGLT2 inhibitors. CONCLUSION: This study confirmed the renoprotective effect of SGLT2 inhibitors in lupus mice, providing more evidence for non-immunosuppressive therapies to improve renal function in classic autoimmune kidney diseases such as LN.
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Diabetes Mellitus Tipo 2 , Nefritis Lúpica , Podocitos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Ratones , Autofagia , Inmunoglobulina G/metabolismo , Inflamación/patología , Riñón/patología , Nefritis Lúpica/tratamiento farmacológico , Ratones Endogámicos MRL lpr , Podocitos/patología , Proteinuria , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , HumanosRESUMEN
The co-evolution of peptide formation and membrane self-assembly is considered an essential step in the origin of life. However, more research is required on both processes, particularly on the interaction between prebiotic simple fatty-acid membranes and peptide synthesis. In this study, the sodium trimetaphosphate (P3 m)-activated peptide formation reaction of phenylalanine (Phe) in an alkaline decanoic acid-decanol vesicle system was systematically investigated. The experimental results showed that peptide formation could competitively occur with N-acyl amino acid (NAA) formation. NAA formation did not follow the traditional P3 m-activated peptide formation reaction involving the intermediate cyclic acylphosphoramidate (CAPA). Decanoic acid was activated by P3 m to form a mixed anhydride, which then reacted with an amino acid to form the amide NAA. As a kind of membrane-forming amphiphile, NAA can form vesicles independently and reduce the critical vesicle concentration of the fatty-acid vesicles. Moreover, 11 other representative amino acids, namely alanine (Ala), aspartic acid (Asp), glutamic acid (Glu), glycine (Gly), isoleucine (Ile), leucine (Leu), proline (Pro), serine (Ser), threonine (Thr), valine (Val), and arginine (Arg), were selected for investigation. All of them reacted with decanoic acid to form NAA via the activation effect of P3 m. The abovementioned mechanism involving P3 m-activated carboxylic acid has not been reported in the literature. Our experimental results indicate that the participation of decanoic acid in the P3 m activation-based peptide formation reaction system plays a significant role in the emergence of functionalized protocells. The P3 m activation effect can provide diversified raw membrane materials to form and stabilize protocell membranes; moreover, the small peptides, such as Phe-Leu, formed in the same reaction system can induce the amplification of primitive cells. This implies that synergistic symbiosis between membrane and peptide can be realized via the P3 m activation effect.
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Células Artificiales , Secuencia de Aminoácidos , Aminoácidos , Fragmentos de Péptidos , Ácido Glutámico , Ácidos DecanoicosRESUMEN
3D hierarchical carbon nanocages (hCNC) are becoming new platforms for advanced energy storage and conversion due to their unique structural characteristics, especially the combination of multiscale pore structure with high conductivity of sp2 carbon frameworks, which can promote the mass/charge synergetic transfer in various electrochemical processes. Herein, the MgO@ZnO composite-template method is developed to construct hCNC and nitrogen-doped hCNC (hNCNC), which integrates the advantages of the in situ MgO template method and ZnO self-sacrificing template method. The hierarchical MgO template provides the scaffold for depositing carbon nanocages, while the self-sacrificing ZnO template helps create abundant micropores while promoting the graphitization degree, so that the microstructures of the products are effectively regulated. The optimized hCNC and hNCNC have an increased specific surface area and conductivity, which can further boost the mass/charge synergetic transfer. As the electrode materials of supercapacitors, the optimal hCNC(hNCNC) exhibits a high specific capacitance of 281(348) F g-1 in KOH and 276(297) F g-1 in EMIMBF4 electrolytes at 1 A g-1 . The ultrahigh energy and power densities are realized, accompanied by a high-rate capability and long cycling stability. The record-high energy densities of 141.8-71.4 Wh kg-1 are achieved in EMIMBF4 at power densities of 10.0-250.4 kW kg-1 .
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Although some nucleotide binding, leucine-rich repeat immune receptor (NLR) proteins conferring resistance to specific viruses have been identified in dicot plants, NLR proteins involved in viral resistance have not been described in monocots. We have used map-based cloning to isolate the CC-NB-LRR (CNL) Barley stripe mosaic virus (BSMV) resistance gene barley stripe resistance 1 (BSR1) from Brachypodium distachyon Bd3-1 inbred line. Stable BSR1 transgenic Brachypodium line Bd21-3, barley (Golden Promise) and wheat (Kenong 199) plants developed resistance against BSMV ND18 strain. Allelic variation analyses indicated that BSR1 is present in several Brachypodium accessions collected from countries in the Middle East. Protein domain swaps revealed that the intact LRR domain and the C-terminus of BSR1 are required for resistance. BSR1 interacts with the BSMV ND18 TGB1 protein in planta and shows temperature-sensitive antiviral resistance. The R390 and T392 residues of TGB1ND (ND18 strain) and the G196 and K197 residues within the BSR1 P-loop motif are key amino acids required for immune activation. BSR1 is the first cloned virus resistance gene encoding a typical CNL protein in monocots, highlighting the utility of the Brachypodium model for isolation and analysis of agronomically important genes for crop improvement.
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Brachypodium , Hordeum , Hordeum/genética , Brachypodium/genética , Proteínas Repetidas Ricas en Leucina , Dominios ProteicosRESUMEN
BACKGROUND: Complete right bundle branch block (CRBBB) is an important predictor of atrial fibrillation (AF) recurrence after pulmonary vein isolation. However, the association between CRBBB and AF development remains unclear. METHODS: We performed a retrospective study of 2639 patients (male, n = 1549; female, n = 1090; mean age, 58 ± 13 years). CRBBB was defined as a late R (R') wave in lead V1 or V2 with a slurred S wave in lead I and/or lead V6 with a prolonged QRS duration (≥120 ms). RESULTS: Among the 2639 patients, CRBBB was detected in 40 patients (1.5%), and the prevalence of AF was 7.4% (196/2639). The proportion of patients with AF and CRBBB was higher than the proportion of patients with AF without CRBBB (22.5% vs. 7.2%; p = 0.001). In the forward multivariate logistic analysis, CRBBB (odds ratio [OR], 3.329; 95% confidence interval [CI], 1.350-8.211; p = 0.009), complete left bundle branch block (OR, 2.209; 95% CI, 1.238-3.940; p = 0.007), age (OR, 1.020; 95% CI, 1.005-1.035; p = 0.009), valvular heart disease (OR, 2.332; 95% CI, 1.531-3.552; p < 0.001), left atrial diameter (OR, 1.133; 95% CI, 1.104-1.163; p < 0.001), left ventricular ejection fraction (OR, 1.023; 95% CI, 1.006-1.041; p = 0.007), and class I or III anti-arrhythmic drug use (OR, 10.534; 95% CI, 7.090-15.651; p < 0.001) were associated with AF. CONCLUSION: Complete right bundle branch block was significantly associated with AF development in hospitalized patients with cardiovascular diseases.
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Fibrilación Atrial , Bloqueo de Rama , Anciano , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Bloqueo de Rama/complicaciones , Bloqueo de Rama/diagnóstico , Bloqueo de Rama/epidemiología , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
Fibrosis serves a critical role in driving atrial remodelling-mediated atrial fibrillation (AF). Abnormal levels of the transcription factor PU.1, a key regulator of fibrosis, are associated with cardiac injury and dysfunction following acute viral myocarditis. However, the role of PU.1 in atrial fibrosis and vulnerability to AF remain unclear. Here, an in vivo atrial fibrosis model was developed by the continuous infusion of C57 mice with subcutaneous Ang-II, while the in vitro model comprised atrial fibroblasts that were isolated and cultured. The expression of PU.1 was significantly up-regulated in the Ang-II-induced group compared with the sham/control group in vivo and in vitro. Moreover, protein expression along the TGF-ß1/Smads pathway and the proliferation and differentiation of atrial fibroblasts induced by Ang-II were significantly higher in the Ang-II-induced group than in the sham/control group. These effects were attenuated by exposure to DB1976, a PU.1 inhibitor, both in vivo and in vitro. Importantly, in vitro treatment with small interfering RNA against Smad3 (key protein of TGF-ß1/Smads signalling pathway) diminished these Ang-II-mediated effects, and the si-Smad3-mediated effects were, in turn, antagonized by the addition of a PU.1-overexpression adenoviral vector. Finally, PU.1 inhibition reduced the atrial fibrosis induced by Ang-II and attenuated vulnerability to AF, at least in part through the TGF-ß1/Smads pathway. Overall, the study implicates PU.1 as a potential therapeutic target to inhibit Ang-II-induced atrial fibrosis and vulnerability to AF.
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Fibrilación Atrial/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteína smad3/metabolismo , Transactivadores/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/metabolismo , Angiotensina II/toxicidad , Animales , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/etiología , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Células Cultivadas , Fibrosis , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Miocardio/patología , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patología , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Transactivadores/metabolismoRESUMEN
BACKGROUND: In patients with atrial fibrillation (AF) and functional mitral regurgitation (MR), catheter ablation reduces the severity of MR and improves cardiac remodeling. However, its effects on prognosis are uncertain. METHODS: This retrospective study included 151 consecutive patients with AF and functional MR, 82 (54.3%) of whom were treated by catheter ablation (Ablation group) and 69 (45.7%) with drug therapy without ablation (Non-ablation group). Forty-three pairs of these patients were propensity matched on the basis of age, CHA2DS2-VASc scores, and left ventricular ejection fraction. The primary outcome evaluated was severity of MR, cardiac remodeling and the combined incidence of subsequent heart failure-related hospitalization and strokes/transient ischemic attacks. RESULTS: Patients in the Ablation group showed a significant decrease in the severity of MR (p < 0.001), a significant decrease in the left atrial diameter (p = 0.010), and significant improvement in the left ventricular ejection fraction (p = 0.015). However, patients in the Non-ablation group showed only a significant decrease in the severity of MR (p = 0.004). The annual incidence of the studied events was 4.9% in the Ablation group and 16.7% in the Non-ablation group, the incidence being significantly lower in the ablation than Non-ablation group (p = 0.026) according to Kaplan-Meier curve analyses. According to multivariate Cox regression analysis, catheter ablation therapy (hazard ratio [HR] 0.27, 95% confidence interval [CI] 0.09-0.84; p = 0.024) and heart failure at baseline (HR 3.84, 95% CI 1.07-13.74; p = 0.038) were independent predictors of the incidence of the studied events. CONCLUSIONS: Among patients with AF and functional MR, catheter ablation was associated with a significantly lower combined risk of heart failure-related hospitalization and stroke than in a matched cohort of patients receiving drug therapy alone.
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Antiarrítmicos/uso terapéutico , Fibrilación Atrial/terapia , Ablación por Catéter , Insuficiencia de la Válvula Mitral/fisiopatología , Válvula Mitral/fisiopatología , Potenciales de Acción , Anciano , Antiarrítmicos/efectos adversos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/fisiopatología , Ablación por Catéter/efectos adversos , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Frecuencia Cardíaca , Humanos , Ataque Isquémico Transitorio/etiología , Masculino , Persona de Mediana Edad , Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/complicaciones , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Recuperación de la Función , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/etiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
To investigate the protective effect and mechanism of curcumin on aorta in rats with metabolic syndrome,72 SD rats were randomly divided into blank control group,model control group,positive control group,curcumin low,middle and high dose groups.The rat model of metabolic syndrome was established in all groups except the blank control group. After the intervention by curcumin,the blood pressure,blood lipid,blood glucose,serum insulin and insulin sensitivity index were measured. The contents of serum leptin(LP),adiponectin(ADP) and tumor necrosis factor-α(TNF-α) in rat aorta were detected by enzyme-linked immunosorbent assay(ELISA),and the pathological changes of rat thoracic aorta were observed by HE staining and electron microscope scanning. Western blot assay was used to detect the expression of inducible nitric oxide synthase(i NOS) and endothelial nitric oxide synthase(e NOS) in rats. The results showed that the blood lipid level,fasting blood glucose,fasting insulin,insulin sensitivity index,systolic blood pressure,LP,TNF-α and intima/media thickness ratio in the model control group were significantly higher than those in the blank control group. As compared with the model control group,the levels of blood lipids,fasting blood glucose,fasting insulin,insulin sensitivity index,systolic blood pressure,LP,TNF-α and intima/media thickness ratio were significantly decreased in positive control group,low,middle and high dose curcumin groups. The difference was statistically significant. The results of HE staining showed that the intima of the thoracic aorta in the model group was significantly thickened; the endothelial cell membrane was wrinkled and the organelle was ruptured. The intima of the thoracic aorta in the positive control group was slightly thickened and the structure of endothelial cells was intact,with no foam cells and no abnormality in the adventitia. There was no significant thickening of the thoracic aorta in the low,middle and high dose curcumin groups,and the endothelial cells were still intact. The results of Western blot assay showed that the expression levels of i NOS and e NOS were decreased significantly in the model group,while the expression levels of i NOS and e NOS were increased significantly in the positive control group and curcumin groups. The results indicated that curcumin had a certain protective effect on the aorta of rats with metabolic syndrome and improves the aortic endothelial dysfunction,and its mechanism may be related to the fact that curcumin could reduce the production of oxygen free radicals and up-regulate the expression of i NOS and e NOS in aorta.
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Curcumina/farmacología , Síndrome Metabólico , Sustancias Protectoras/farmacología , Animales , Aorta , Aorta Torácica , Células Endoteliales , Ratas , Ratas Sprague-DawleyRESUMEN
Interatrial block (IAB) is associated with a multitude of medical conditions. The aim of this retrospective study was to investigate whether CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke) score is positively associated with the development of IAB. A total of 1072 patients (men, 555; women, 517; mean age, 61 ± 14 years) were included in the study. P-wave duration was measured manually using a caliper. IAB was defined as a P-wave duration of ≥ 120 ms on a 12-lead electrocardiogram. CHADS2 scores were calculated retrospectively. Among the 1072 patients, the prevalence of IAB was 36.1% (387/1072). In multivariate analysis, increased CHADS2 score (odds ratio [OR], 1.810; 95% confidence interval [CI], 1.577-2.077; P < 0.001), coronary artery disease (OR, 1.536; 95% CI, 1.065-2.216; P = 0.022), and increased left atrial diameter (OR, 1.039; 95% CI, 1.008-1.071; P = 0.013) were independently associated with IAB. The percentages of patients with IAB among those with a CHADS2 score of 0, 1, 2, 3, 4, 5, and 6 were 20.6%, 33.0%, 45.0%, 55.9%, 61.9%, 77.8%, and 100%, respectively (P < 0.001). There was a greater percentage of patients with a CHADS2 score of ≥ 2 with IAB compared with a CHADS2 score of < 2 (26.5% vsrsus 52.0%; P < 0.001). In receiver operating curve (ROC) analysis, CHADS2 score (area under the curve, 0.670; 95% CI, 0.636-0.704; P < 0.001) was predictive of IAB. In conclusion, CHADS2 score was significantly associated with the development of IAB in this study population.
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Técnicas de Apoyo para la Decisión , Bloqueo Interauricular/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Bloqueo Interauricular/etiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Curva ROC , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Mitochondrial autophagy is an important adaptive stress response and can be modulated by various key molecules. A previous study found that the regulator of calcineurin 1-1L (Rcan1-1L) may regulate mitochondrial autophagy and cause mitochondria degradation in neurocytes. However, the effect of Rcan1-1L on cardiomyocytes has not been determined. In the present study, we aimed to investigate the role of Rcan1-1L in angiotensin II (Ang II)-exposed human cardiomyocytes. Above all, Human adult cardiac myocytes (HACMs) were exposed to 200nmol/L Ang II for 4 days. Enhanced H2O2 production, cytochrome C release and mitochondrial permeability were observed in these cells, which were blocked by valsartan. Consistently, Ang II exposure significantly reduced cardiomyocyte viability. However, transfection of Rcan1-1L vector promoted cell viability and ameliorated the apoptosis caused by Ang II. Rcan1-1L clearly promoted mitochondrial autophagy in HACMs, with elevated autophagy protein (ATG) 5 and light chain 3 (LC3) expression. Transient mitochondrial biogenesis and reduced cytochrome C release was also induced by Rcan1-1L. Additionally, Rcan1-1L significantly inhibited calcineurin/nuclear factor of activated T cells (NFAT) signaling. We thus conclude that Rcan1-1L may play a protective role in Ang II-treated cardiomyocytes through the induction of mitochondrial autophagy, and may be an alternative method of cardiac protection.
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Autofagia , Peróxido de Hidrógeno/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mitocondrias Cardíacas/patología , Mitofagia/efectos de los fármacos , Proteínas Musculares/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Angiotensina II/farmacología , Proteína 5 Relacionada con la Autofagia , Supervivencia Celular , Células Cultivadas , Citocromos c/metabolismo , Proteínas de Unión al ADN , Humanos , Hipertensión/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Asociadas a Microtúbulos/biosíntesis , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Proteínas Musculares/genética , Miocitos Cardíacos/efectos de los fármacos , Factores de Transcripción NFATC/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Permeabilidad/efectos de los fármacosRESUMEN
Hyperhomocysteine has become a critical risk for atherosclerosis and can stimulate proliferation and migration of vascular smooth muscle cells (VSMCs). N-methyl-D-aspartic acid receptor (NMDAR) is a receptor of homocysteine and mediates the effects of homocysteine on VSMCs. Bioinformatics analysis has shown NMDAR is a potential target of microRNA-217 (miR-217), which exerts multiple functions in cancer tumorigenesis and carotid plaque progression. In this study, we sought to investigate the role of miR-217 in VSMCs phenotype transition under homocysteine exposure and elucidate its effect on atherosclerotic plaque formation. After treating with several doses of homocysteine (0-8 × 10(-4) mol/L) for 24 hours, the expression of miR-217 in HA-VSMCs and rat aortic VSMCs was not altered. Intriguingly, the expression of NMDAR mRNA and protein was reduced by homocysteine in a dose-dependent manner. Transfection of miR-217 mimic significantly inhibited the proliferation and migration of VSMCs with homocysteine treatment, while transfection of miR-217 inhibitor promoted VSMCs migration. Moreover, miR-217 mimic down-regulated while miR-217 inhibitor up-regulated NMDAR protein expression but not NMDAR mRNA expression. Through luciferase reporter assay, we showed that miR-217 could directly bind to the 3'-UTR of NMDAR. MiR-217 mimic transfection also released the inhibition of cAMP-response element-binding protein (CREB)-PGC-1α signalling induced by homocysteine. Additionally, restoration of PGC-1α expression via AdPGC-1α infection markedly suppressed VSMCs proliferation through the degradation of NADPH oxidase (NOX1) and reduction of reactive oxygen species (ROS). Collectively, our study identified the role of miR-217 in regulating VSMCs proliferation and migration, which might serve as a target for atherosclerosis therapy.
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Movimiento Celular/fisiología , Proliferación Celular/fisiología , Homocisteína/farmacología , MicroARNs/biosíntesis , Músculo Liso Vascular/metabolismo , Receptores de N-Metil-D-Aspartato/biosíntesis , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Línea Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Músculo Liso Vascular/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Interatrial block (IAB) is associated with an increased risk of atrial fibrillation (AF). The aim of this retrospective study was to investigate the association of a combination of IAB and the CHADS2 score, an AF-related risk score for ischemic stroke, with new onset AF in patients in sinus rhythm. A total of 1,571 patients (803 males, 768 females; mean age: 58 ± 16 years) were included in this study. IAB was defined as a P-wave duration > 120 ms in the 12-lead electrocardiogram, and a high CHADS2 score as ≥ 2 points. During the mean follow-up period of 4.8 ± 0.7 years, new onset AF occurred in 122 patients (16.1 per 1,000 patient-years). The incidence of new onset AF was 4.0 per 1,000 patient-years in patients with no IAB and a low CHADS2 score, and 44.0 per 1,000 patient-years in patients with IAB and a high CHADS2 score. In multivariate Cox regression analysis, the hazard ratio for IAB and a high CHADS2 score compared with no IAB and a low CHADS2 score was 12.18 (95% confidence interval: 6.22-23.87, P < 0.001), after adjustment for age, sex, coronary artery disease, valvular heart disease, smoking, medications, and echocardiographic parameters. In conclusion, IAB and a high CHADS2 score independently and synergistically predict new onset AF in patients in sinus rhythm, indicating an approximately 12-fold higher risk in patients with both IAB and a high CHADS2 score. Patients meeting these criteria should have more aggressive early intervention to prevent AF.
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Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Electrocardiografía , Adulto , Anciano , Anciano de 80 o más Años , Función Atrial/fisiología , Femenino , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/fisiopatologíaRESUMEN
Icariin is an important pharmacologically active flavonol diglycoside that can inhibit inflammation in lipopolysaccharide (LPS)-stimulated macrophages. However, little is known about the molecular mechanisms underlying the inhibitory effect of Icariin in the formation of foam cells. In this study, macrophages were cultured with LPS and oxidized low-density lipoprotein (oxLDL) in the presence or absence of Icariin. RT-PCR and western blot were used to detect the levels of mRNA and protein expression of CD36, scavenger receptor class B type I (SR-BI) and the phosphorylation of p38MAPK. It was demonstrated that 4 µM or 20 µM Icariin treatment significantly inhibited the cholesterol ester (CE)/total cholesterol (TC) and oxLDL-mediated foam cell formation (P < 0.05). The binding of oxLDL to LPS-activated macrophages was also significantly hindered by Icariin (P < 0.05). Furthermore, Icariin down-regulated the expression of CD36 in LPS-activated macrophages in a dose-dependent manner and CD36 over-expression restored the inhibitory effect of Icariin on foam cell formation. The phosphorylation of p38MAPK was reduced by Icariin, indicating that Icariin reduced the expression of CD36 through the p38MAPK pathway. In addition, Icariin up-regulated SR-BI protein expression in a dose-dependent manner, and SR-BI gene silencing restored the inhibitory effect of Icariin on foam cell formation. These data demonstrate that Icariin inhibited foam cell formation by down-regulating the expression of CD36 and up-regulating the expression of SR-BI. Therefore, our findings provide a new explanation as to why Icariin could inhibit atherosclerosis.
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Antiinflamatorios/farmacología , Antígenos CD36/metabolismo , Flavonoides/farmacología , Células Espumosas/efectos de los fármacos , Receptores Depuradores de Clase B/metabolismo , Aterosclerosis/tratamiento farmacológico , Antígenos CD36/genética , Técnicas de Cultivo de Célula , Línea Celular , Células Espumosas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Lipopolisacáridos/farmacología , Lipoproteínas LDL/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Receptores Depuradores de Clase B/genéticaRESUMEN
The barley stripe mosaic virus (BSMV) triple gene block 1 (TGB1) protein is required for virus cell-to-cell movement. However, little information is available about how these activities are regulated by post-translational modifications. In this study, we showed that the BSMV Xinjiang strain TGB1 (XJTGB1) is phosphorylated in vivo and in vitro by protein kinase CK2 from barley and Nicotiana benthamiana. Liquid chromatography tandem mass spectrometry analysis and in vitro phosphorylation assays demonstrated that Thr-401 is the major phosphorylation site of the XJTGB1 protein, and suggested that a Thr-395 kinase docking site supports Thr-401 phosphorylation. Substitution of Thr-395 with alanine (T395A) only moderately impaired virus cell-to-cell movement and systemic infection. In contrast, the Thr-401 alanine (T401A) virus mutant was unable to systemically infect N. benthamiana but had only minor effects in monocot hosts. Substitution of Thr-395 or Thr-401 with aspartic acid interfered with monocot and dicot cell-to-cell movement and the plants failed to develop systemic infections. However, virus derivatives with single glutamic acid substitutions at Thr-395 and Thr-401 developed nearly normal systemic infections in the monocot hosts but were unable to infect N. benthamiana systemically, and none of the double mutants was able to infect dicot and monocot hosts. The mutant XJTGB1T395A/T401A weakened in vitro interactions between XJTGB1 and XJTGB3 proteins but had little effect on XJTGB1 RNA-binding ability. Taken together, our results support a critical role of CK2 phosphorylation in the movement of BSMV in monocots and dicots, and provide new insights into the roles of phosphorylation in TGB protein functions.
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Quinasa de la Caseína II/metabolismo , Hordeum/metabolismo , Nicotiana/metabolismo , Proteínas de Plantas/metabolismo , Virus ARN/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas no Estructurales Virales/metabolismo , Hordeum/virología , Fosforilación , Procesamiento Proteico-Postraduccional , Nicotiana/virologíaRESUMEN
Mitochondrial dysfunction induced by myocardial ischemia is the primary cause of cardiac cell death. Specific removal of damaged mitochondria through mitophagy may be beneficial for cardiomyocyte protection against ischemia. Regulator of calcineurin 1-1L (Rcan1-1L) has been implicated in mitophagy induction in neurons. However, whether or not Rcan1-1L can evoke mitophagy in cardiomyocytes during hypoxia remains unknown. This study aims to investigate the effect of Rcan1-1L overexpression on cardiomyocytes during hypoxia and the possible underlying mechanism. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that Rcan1-1L overexpression inhibited cell growth under normoxic conditions, whereas Rcan1-1L overexpression significantly reversed the growth inhibition induced by hypoxia. The results of terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling assay showed that cell apoptosis induced by hypoxia was markedly reduced by Rcan1-1L overexpression. In addition, Rcan1-1L overexpression inhibited the expression of the proapoptotic protein Bcl-2-associated death promoter and increased that of the antiapoptotic protein Bcl-2. Rcan1-1L overexpression opened the mitochondrial permeability transition pore and decreased mitochondrial mass. Meanwhile, the release of reactive oxygen species from mitochondria was suppressed by Rcan1-1L. Autophagy flow activation represented by mammalian target of rapamycin inhibition and microtubule-associated protein light chain 3 (LC3) upregulation was also demonstrated. Compared with endoplasmic reticulum and Golgi apparatus protein markers, the mitochondrial protein marker translocase of outer mitochondrial membranes 20 (TOM20) was downregulated by Rcan1-1L overexpression. Moreover, Rcan1-1L increased mitophagy receptor Parkin translocation into mitochondria from cytosol. Additionally, the effect of Rcan1-1L on cell growth, cell apoptosis and mitochondria mass was blocked by Parkin expression silencing. Overall, these data suggest that Rcan1-1L protects cardiomyocytes from hypoxia-induced apoptosis by inducing mitophagy partly through Parkin. This study provided novel insights into the prevention and treatment of ischemic heart disease.
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Apoptosis/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/fisiología , Mitofagia/efectos de los fármacos , Proteínas Musculares/fisiología , Miocitos Cardíacos/efectos de los fármacos , Apoptosis/genética , Western Blotting , Inhibidores de la Calcineurina/farmacología , Técnicas de Cultivo de Célula , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/genética , Células Cultivadas , Proteínas de Unión al ADN , Regulación de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Mitofagia/genética , Proteínas Musculares/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Plásmidos , Isoformas de Proteínas , Especies Reactivas de Oxígeno/metabolismo , TransfecciónRESUMEN
Inherited factor XIII (FXIII) deficiency is an extremely rare and under-diagnosed autosomal recessive inherited coagulopathy, which is caused by genetic defects in the F13A1 or F13B gene. More than 200 genetic mutations have been identified since the first case of inherited FXIII deficiency was reported. This study aimed to identify underlying gene mutations in a patient with inherited FXIII deficiency who presented with recurrent intracerebral hemorrhage. Levels of plasma FXIII-A antigen were measured, F13A1 and F13B genes were sequenced, mutation information was analyzed, and the mutated protein structure was predicted using bioinformatics methods. Molecular genetic analysis identified four mutations of FXIII-related genes in the proband, including three previously reported mutations inherited from his parents (c.631G>A, p.Gly210Arg and c.1687G>A, p.Gly562Arg of F13A1 gene and c.344G>A, p.Arg115His of F13B gene) and a novel spontaneous mutation of F13A1 gene (c.2063C>G, p.Ser687Cys). Molecular structural modeling demonstrated that the novel Ser687Cys mutation may cause changes in the spatial structure of FXIII-A and increase its instability. In conclusion, we identified a novel and likely pathogenic mutation of the F13A1 gene, which enriched the gene mutation spectrum of inherited FXIII deficiency. The findings may provide promising targets for diagnosis and treatment of inherited FXIII deficiency.
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Deficiencia del Factor XIII , Factor XIIIa , Humanos , Factor XIIIa/química , Factor XIIIa/genética , Factor XIIIa/metabolismo , Deficiencia del Factor XIII/genética , Deficiencia del Factor XIII/diagnóstico , Factor XIII/genética , Mutación , HemorragiaRESUMEN
Background: Complications, including arrhythmia, following severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continue to be of concern. Omicron is the mainstream SARS-CoV-2 mutant circulating in mainland China. At present, there are few epidemiological studies concerning the relationship between arrhythmia and Omicron variant infection in mainland China. Objectives: To investigate the risk factors of arrhythmia in patients infected with the SARS-CoV-2 Omicron variant and the factors influencing prognosis. Methods: Data from 192 Omicron infected patients with symptoms of arrhythmia (AH group) and 100 Omicron infected patients without arrhythmia (Control group) were collected. Patients in the AH group were divided into the good and poor prognosis groups, according to the follow-up results 4-6 weeks after infection. The general and clinical data between the AH and Control groups, and between the good and poor prognosis groups were compared. The variables with differences between the groups were included in the multivariate logistic regression analysis, and the quantitative variables were analyzed by receiver operating characteristic curve to obtain their cut-off values. Results: Compared with the control group, the body mass index (BMI), proportion of patients with a history of arrhythmia, proportion of antibiotics taken, heart rate, moderate disease severity, white blood cell (WBC) count, and the aspartate aminotransferase, creatine kinase (CK), CK isoenzyme (CK-MB), myoglobin (Mb), high-sensitive troponin I (hs-cTnI), lymphocyte ratio and high sensitivity C-reactive protein (hs-CRP) levels in the AH group were significantly higher (p < 0.05). In addition, obesity (BMI ≥24 kg/m2), fast heart rate (≥100 times/min), moderate disease severity, and WBC, CK-MB and hs-cTnI levels were independent risk factors of arrhythmia for patients with Omicron infection (p < 0.05), and hs-CRP was a protective factor (p < 0.05). Compared with the good prognosis group, the age, proportion of patients with a history of arrhythmia, heart rate, proportion of moderate disease severity, and hs-CRP, CK, Mb and hs-cTnI levels were significantly higher in the poor prognosis group, while the proportion of vaccination was lower in the poor prognosis group (p < 0.05). Advanced age (≥65 years old), proportion of history of arrhythmia, moderate disease severity, vaccination, and hs-CRP, Mb and cTnI levels were independent factors for poor prognosis of patients with arrhythmia (p < 0.05). Conclusion: The factors that affect arrhythmia and the prognosis of patients infected with Omicron include obesity, high heart rate, severity of the disease, age. history of arrhythmia, WBC, hs-CRP, and myocardial injury indexes, which could be used to evaluate and prevent arrhythmia complications in patients in the future.
RESUMEN
Introduction: Kidney cancer is one of the most common and lethal urological malignancies. Discovering a biomarker that can predict prognosis and potential drug treatment sensitivity is necessary for managing patients with kidney cancer. SUMOylation is a type of posttranslational modification that could impact many tumor-related pathways through the mediation of SUMOylation substrates. In addition, enzymes that participate in the process of SUMOylation can also influence tumorigenesis and development. Methods: We analyzed the clinical and molecular data which were obtanied from three databases, The Cancer Genome Atlas (TCGA), the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC), and ArrayExpress. Results: Through analysis of differentially expressed RNA based on the total TCGA-KIRC cohort, it was found that 29 SUMOylation genes were abnormally expressed, of which 17 genes were upregulated and 12 genes were downregulated in kidney cancer tissues. A SUMOylation risk model was built based on the discovery TCGA cohort and then validated successfully in the validation TCGA cohort, total TCGA cohort, CPTAC cohort, and E-TMAB-1980 cohort. Furthermore, the SUMOylation risk score was analyzed as an independent risk factor in all five cohorts, and a nomogram was constructed. Tumor tissues in different SUMOylation risk groups showed different immune statuses and varying sensitivity to the targeted drug treatment. Discussion: In conclusion, we examined the RNA expression status of SUMOylation genes in kidney cancer tissues and developed and validated a prognostic model for predicting kidney cancer outcomes using three databases and five cohorts. Furthermore, the SUMOylation model can serve as a biomarker for selecting appropriate therapeutic drugs for kidney cancer patients based on their RNA expression.