RESUMEN
Remdesivir is one nucleotide analogue prodrug capable to terminate RNA synthesis in SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) by two distinct mechanisms. Although the "delayed chain termination" mechanism has been extensively investigated, the "template-dependent" inhibitory mechanism remains elusive. In this study, we have demonstrated that remdesivir embedded in the template strand seldom directly disrupted the complementary NTP incorporation at the active site. Instead, the translocation of remdesivir from the +2 to the +1 site was hindered due to the steric clash with V557. Moreover, we have elucidated the molecular mechanism characterizing the drug resistance upon V557L mutation. Overall, our studies have provided valuable insight into the "template-dependent" inhibitory mechanism exerted by remdesivir on SARS-CoV-2 RdRp and paved venues for an alternative antiviral strategy for the COVID-19 pandemic. As the "template-dependent" inhibition occurs across diverse viral RdRps, our findings may also shed light on a common acting mechanism of inhibitors.
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Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Antivirales/química , Humanos , Pandemias , ARN Viral/química , ARN Polimerasa Dependiente del ARN , Transcripción ViralRESUMEN
Atherosclerosis is a chronic inflammatory disease. Pathophysiological similarities between chronic infections and atherosclerosis triggered interests between these conditions. The seroepidemiological study showed that Helicobacter pylori strains that express cytotoxin-associated gene A (CagA), an oncoprotein and a major virulence factor, was positively correlated with atherosclerosis and related clinical events. Nevertheless, the underlying mechanism is poorly understood. In this study, the seroprevalence of infection by H. pylori and by strains express CagA assessed by enzyme-linked immunosorbent assay (ELISA) showed that the prevalence of CagA strains rather than H. pylori in patients was positively correlated with atherogenesis. Correspondingly, we found that CagA augmented the growth of plaque of ApoE-/- mice in the early stage of atherosclerosis and promoted the expression of adhesion molecules and inflammatory cytokines in mouse aortic endothelial cells (MAECs). Mechanistically, both si-NLRP3 and si-IL-1ß mitigated the promoting effect of CagA on the inflammatory activation of HAECs. In vivo, the inhibition of NLRP3 by MCC950 significantly attenuated the promoting effect of CagA on plaque growth of ApoE-/- mice. We also propose NLRP3 as a potential therapeutic target for CagA-positive H. pylori infection-related atherosclerosis and emphasize the importance of inflammation in atherosclerosis pathology.
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Antígenos Bacterianos/metabolismo , Aorta/patología , Aterosclerosis/sangre , Proteínas Bacterianas/metabolismo , Caspasa 1/metabolismo , Células Endoteliales/metabolismo , Infecciones por Helicobacter/sangre , Helicobacter pylori/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Placa Aterosclerótica/sangre , Anciano , Animales , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/inmunología , Aorta/metabolismo , Aterosclerosis/microbiología , Proteínas Bacterianas/inmunología , Modelos Animales de Enfermedad , Femenino , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/inmunología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Persona de Mediana Edad , Placa Aterosclerótica/microbiología , Estudios Seroepidemiológicos , Células THP-1RESUMEN
BACKGROUND: There is limited evidence to clarify the specific relationship between preoperative estimated glomerular filtration rate (preop-eGFR) and postoperative 30-day mortality in Asian patients undergoing non-cardiac and non-neuron surgery. We aimed to investigate details of this relationship. METHODS: We reanalyzed a retrospective analysis of the clinical records of 90,785 surgical patients at the Singapore General Hospital from January 1, 2012 to October 31, 2016. The main outcome was postoperative 30-day mortality. RESULTS: The average age of these recruited patients was 53.96 ± 16.88 years, of which approximately 51.64% were female. The mean of preop-eGFR distribution was 84.45 ± 38.56 mL/min/1.73 m2. Multivariate logistic regression analysis indicated that preop-eGFR was independently associated with 30-day mortality (adjusted odds ratio: 0.992; 95% confidence interval [CI] 0.990-0.995; P < 0.001). A U-shaped relationship was detected between preop-eGFR and 30-day mortality with an inflection point of 98.688 (P for log likelihood ratio test < 0.001). The effect sizes and confidence intervals on the right and left sides of the inflection point were 1.013 (1.007 to 1.019) [P < 0.0001] and 0.984 (0.981 to 0.987) [P < 0.0001], respectively. Preoperative comorbidities such as congestive heart failure (CHF), type 1 diabetes, ischemic heart disease (IHD), and anemia were associated with the odds ratio of preop-eGFR to 30-day mortality (interaction P < 0.05). DISCUSSION: The relationship between preop-eGFR and 30-day mortality is U-shaped. The recommended preop-eGFR at which the rate of the 30-day mortality was lowest was 98.688 mL/min/1.73 m2.
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Tasa de Filtración Glomerular , Procedimientos Quirúrgicos Operativos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Singapur/epidemiología , Procedimientos Quirúrgicos Operativos/mortalidadRESUMEN
BACKGROUND AND PURPOSE: Satellite sign is a novel neuroimaging marker for predicting hematoma expansion (HE), which is closely related to unfavorable prognosis in patients with spontaneous intracerebral hemorrhage (ICH). However, the predictive value of satellite sign varied according to previous studies. Thus, we conduct this meta-analysis to systematically review the application value of satellite sign in related studies. METHODS: We searched the literature in PubMed, Embase, and Web of Science from inception to April 10, 2020. Effect values, including sensitivity, specificity, and positive and negative likelihood ratio were pooled to assess the diagnostic value of satellite sign for HE in patients with ICH. RESULTS: The meta-analysis included five studies with a total of 1493 patients. Results showed that the pooled diagnostic sensitivity and specificity were 0.50 (95 % CI, 0.31-0.70) and 0.71 (95 % CI, 0.56-0.83), respectively. In addition, the pooled positive and negative likelihood ratios were 1.7 (95 % CI, 1.5-2.1) and 0.70 (95 % CI, 0.54-0.89), respectively. No significant publication bias was found. CONCLUSION: Satellite sign exhibited moderate sensitivity and specificity for predicting HE in patients with ICH. Further studies are needed to explore its value in clinical application.
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Hemorragia Cerebral/diagnóstico por imagen , Hematoma/diagnóstico por imagen , Humanos , Neuroimagen , Valor Predictivo de las Pruebas , Pronóstico , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos XRESUMEN
Recent advances suggest that abnormal fatty acid metabolism highly correlates with breast cancer, which provide clues to discover potential biomarkers of breast cancer. This study aims to identify serum free fatty acid (FFA) metabolic profiles and screen potential biomarkers for breast cancer diagnosis. Gas chromatography-mass spectrometry and our in-house fatty acid methyl ester standard substances library were combined to accurately identify FFA profiles in serum samples of breast cancer patients and breast adenosis patients (as controls). Potential biomarkers were screened by applying statistical analysis. A total of 18 FFAs were accurately identified in serum sample. Two groups of patients were correctly discriminated by the orthogonal partial least squares-discriminant analysis model based on FFA profiles. Seven FFA levels were significantly higher in serum from breast cancer patients than that in controls, and exhibited positive correlation with malignant degrees of disease. Furthermore, five candidates (palmitic acid, oleic acid, cis-8,11,14-eicosatrienoic acid, docosanoic acid and the ratio of oleic acid to stearic acid) were selected as potential serum biomarkers for differential diagnosis of breast cancer. Our study will help to reveal the metabolic signature of FFAs in breast cancer patients, and provides valuable information for facilitating clinical noninvasive diagnosis.
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Biomarcadores de Tumor/sangre , Neoplasias de la Mama , Ácidos Grasos no Esterificados/sangre , Cromatografía de Gases y Espectrometría de Masas/métodos , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Análisis Discriminante , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Persona de Mediana EdadRESUMEN
BACKGROUND: Evidence regarding the relationship between anemia and perioperative prognosis is controversial. The study was conducted to highlight the specific relationship between anemia and perioperative mortality in non-cardiac surgery patients over 18 years of age. METHODS: This study was a retrospective analysis of the electronic medical records of 90,784 patients at the Singapore General Hospital from January 1, 2012 to October 31, 2016. Multivariate regression, propensity score analysis, doubly robust estimation, and an inverse probability-weighting model was used to ensure the robustness of our findings. RESULTS: We identified 85,989 patients, of whom75, 163 had none or mild anemia (Hemoglobin>90g/L) and 10,826 had moderate or severe anemia (Hemoglobin≤90g/L). 8,857 patients in each study exposure group had similar propensity scores and were included in the analyses. In the doubly robust model, postoperative 30-day mortality rate was increased by 0.51% (n = 219) in moderate or severe anemia group (Odds Ratio, 1.510; 95% Confidence Interval (CI), 1.049 to 2.174) compared with none or mild anemia group (2.47% vs.1.22%, P<0.001). Moderate or severe anemia was also associated with increased postoperative blood transfusion rates (OR, 5.608; 95% CI, 4.026 to 7.811, P < 0.001). There was no statistical difference in Intensive Care Unit (ICU) admission rate among different anemia groups within 30 days after surgery (P=0.104). DISCUSSION: In patients undergoing non-cardiac surgery over 18 years old, moderate or severe preoperative anemia would increase the occurrence of postoperative blood transfusion and the risk of death, rather than ICU admission within 30 days after surgery.
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Anemia/complicaciones , Transfusión Sanguínea/estadística & datos numéricos , Mortalidad Hospitalaria , Complicaciones Posoperatorias/epidemiología , Adulto , Anciano , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Currently, 310 million patients undergo surgery every year worldwide, and there is still controversy over which anesthetic technique to choose for a considerable of surgeries.This study evaluates the association of the anesthetic technique with thirty-day mortality after noncardiac- and nonneurosurgery. METHODS: Electronic medical records of 90,785 patients who underwent non-cardiac- and nonneurosurgery at the *** General Hospital from January 1, 2012 to October 31, 2016, were subject to secondary retrospective analysis. The principal exposure was regional versus general anesthesia. Outcome measures were death, intensive care unit (ICU) admission and blood transfusion requirement within 30 days after surgery. Propensity-score matching was used to assemble a cohort of patients with similar baseline characteristics. RESULTS: We identified 90,785 patients, of whom 76,442 received regional anesthesia and 14,343 received general anesthesia. A total of 11,351 patients in the general anesthesia group had propensity scores similar to those of patients who received regional anesthesia and were included in the analyses. In the propensity-score matched cohort, the postoperative 30-day mortality rate was 0.75% (n = 85) in the regional anesthesia group (Odds Ratio, 0.567; 95% CI, 0.434 to 0.741; P = 0.00003) compared with 1.31% (n = 149) in the general anesthesia group. Regional anesthesia was also associated with a reduced rate of ICU admission compared with that of patients who received general anesthesia (0.44% vs. 2.68%; OR, 0.161; 95% CI, 0.119 to 0.217, P < 0.00001). There was a nonsignificant relationship between the anesthetic technique and postoperative blood transfusion (P = 0.082). CONCLUSIONS: The results of this observational, propensity score-matched cohort study suggest a significant association between regional anesthesia and low thirty-day mortality and a worse postoperative prognosis in patients who underwent noncardiac- and nonneurosurgery, which provides information for anesthetic technique decision making in the clinical setting.
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Anestesia de Conducción/métodos , Anestesia General/métodos , Puntaje de Propensión , Procedimientos Quirúrgicos Operativos/mortalidad , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Previous studies have revealed that triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) is one of major risk factors of insulin resistance and diabetes. However, study on the association between TG/HDL-C and diabetes mellitus (DM) risk is limited, especially in Chinese people. This study was undertaken to investigate the relationship between TG/HDL-C and incident of diabetes in a large cohort in Chinese population. METHODS: The present study was a retrospective cohort study. A total of 114,787 adults from Rich Healthcare Group in China, which includes all medical records for participants who received a health check from 2010 to 2016. The target independent variable and the dependent variable were triglyceride to high-density lipoprotein cholesterol ratio measured at baseline and incident of diabetes mellitus appeared during follow-up respectively. Covariates involved in this study included age, gender, body mass index, diastolic blood pressure, systolic blood pressure, fasting plasma glucose, total cholesterol, low density lipoprotein cholesterol, serum creatinine, smoking and drinking status and family history of diabetes. Cox proportional-hazards regression was used to investigate the association of TG/HDL-C and diabetes. Generalized additive models was used to identify non-linear relationships. Additionally, we also performed a subgroup analysis. It was stated that the data had been uploaded to the DATADRYAD website. RESULT: After adjusting age, gender, body mass index, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, low density lipoprotein cholesterol, serum creatinine, smoking and drinking status and family history of diabetes, result showed TG/HDL-C was positively associated with incident of diabetes mellitus (HR = 1.159, 95%CI (1.104, 1.215)). A non-linear relationship was detected between TG/HDL-C and incident of diabetes, which had an inflection point of TG/HDL-C was 1.186. The effect sizes and the confidence intervals on the left and right sides of the inflection point were 1.718(1.433,2.060) and 1.049(0.981,1.120), respectively. Subgroup analysis showed, the stronger association can be found in the population with fasting plasma glucose (FPG) < 6.1 mmol/L (P for interaction< 0.0001; HR = 1.296 with FPG < 6.1 mmol/L vs HR = 1.051 with FPG ≥ 6.1 mmol/L).The same trend was also seen in the population with body mass index (BMI)(≥18.5, < 24 kg/m2) (P for interaction = 0.010,HR = 1.324) and family history without diabetes(P for interaction = 0.025, HR = 1.170). CONCLUSION: TG/HDL-C is positively associated with diabetes risk. The relationship between TG/HDL-C and incident of diabetes is also non-linear. TG/HDL-C was strong positively related to incident of diabetes when TG/HDL-C is less than 1.186.
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HDL-Colesterol/sangre , Diabetes Mellitus/sangre , Diabetes Mellitus/epidemiología , Triglicéridos/sangre , Adulto , Glucemia/metabolismo , China , Colesterol/sangre , LDL-Colesterol/sangre , Creatinina/sangre , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
Osteosarcoma (OS) is the most common malignant bone tumor. The prognosis of metastatic and recurrent OS patients still remains unsatisfactory. Cisplatin reveals undeniable anti-tumor effect while induces severe side effects that threatening patients' health. Dynasore, a cell-permeable small molecule that inhibits dynamin activity, has been widely studied in endocytosis and phagocytosis. However, the anti-tumor effect of dynasore on OS has not yet been ascertained. In the present study, we suggested that dynasore inhibited cell proliferation, migration, invasion, and induced G0/G1 arrest of OS cells. Besides, dynasore repressed tumorigenesis of OS in xenograft mouse model. In addition, we demonstrated that dynasore improved the anti-tumor effect of cisplatin in vitro and in vivo without inducing nephrotoxicity and hepatotoxicity. Mechanistically, dynasore repressed the expression of CCND1, CDK4, p-Rb, and MMP-2. Furthermore, we found that dynasore exerts anti-tumor effects in OS partially via inhibiting STAT3 signaling pathway but not ERK-MAPK, PI3K-Akt or SAPK/JNK pathways. P38 MAPK pathway served as a negative regulatory mechanism in dynasore induced anti-OS effects. Taken together, our study indicated that dynasore does suppress cell proliferation, migration, and invasion via STAT3 signaling pathway, and enhances the antitumor capacity of cisplatin in OS. Our results suggest that dynasore is a novel candidate drug to inhibit the tumor growth of OS and enhance the anti-tumor effects of cisplatin.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/farmacología , Dinaminas/uso terapéutico , Hidrazonas/farmacología , Osteosarcoma/tratamiento farmacológico , Factor de Transcripción STAT3/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Separación Celular/métodos , Cisplatino/administración & dosificación , Sinergismo Farmacológico , Dinaminas/farmacología , Humanos , Hidrazonas/administración & dosificación , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Osteosarcoma/metabolismo , Osteosarcoma/patología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The biological functions of lipocalin-1 (LCN1) are involved in innate immune responses and act as a physiological scavenger of potentially harmful lipophilic molecules. However, the relevance of LCN1 with cancer is rarely concerned currently. The aim of this study is to address the relevance of LCN1 with BRCA by bioinformatics. In this study, we found that the expressions of LCN1 increased significantly in various cancerous tissues, including BRCA, compared with their adjacent normal tissues through the TIMER database. Furthermore, UALCAN database analysis showed that the expression of LCN1 increased gradually from stage 1 to stage 4 and was upregulated in BRCA patients with different races and subtypes compared with that in the normal. In addition, those patients with perimenopause and postmenopause status displayed higher LCN1 expression. Importantly, LCN1 genetic alterations, including copy number amplification, deep deletion, and missense mutation, could be found, and the alteration frequency showed difference in various invasive BRCA through cBioPortal database. Moreover, a positive correlation between LCN1 somatic copy number alterations and immune cell enrichments was revealed in basal like BRCA by GISTIC 2.0. Finally, analysis on prognostic value of LCN1 by Kaplan-Meier plotter showed that low LCN1 expression correlated with poor prognosis for relapse-free survival in all types of BRCA, overall survival in luminal B BRCA, distant metastasis free survival in human epithelial growth factor receptor-2 (HER2) positive BRCA, and postprogression survival (PPS) in luminal A BRCA. But high LCN1 expression also displayed poor prognosis for PPS in HER2 positive BRCA. The results together verified the significance of LCN1 in BRCA, suggesting that it may be a potential biomarker for BRCA diagnosis.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , Lipocalina 1/genética , Recurrencia Local de Neoplasia/genética , Receptor ErbB-2/genética , Biomarcadores de Tumor/inmunología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Variaciones en el Número de Copia de ADN , Bases de Datos Genéticas , Femenino , Humanos , Lipocalina 1/inmunología , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Perimenopausia/genética , Posmenopausia/genética , Posmenopausia/inmunología , Receptor ErbB-2/inmunología , Análisis de SupervivenciaRESUMEN
BACKGROUND: Seroepidemiological studies have highlighted a positive relation between CagA-positive Helicobacter pylori (H. pylori), atherosclerosis and related clinic events. However, this link has not been well validated. The present study was designed to explore the role of H. pylori PMSS1 (a CagA-positive strain that can translocate CagA into host cells) and exosomal CagA in the progression of atherosclerosis. METHODS: To evaluate whether H. pylori accelerates or even induces atherosclerosis, H. pylori-infected C57/BL6 mice and ApoE-/- mice were maintained under different dietary conditions. To identify the role of H. pylori-infected gastric epithelial cells-derived exosomes (Hp-GES-EVs) and exosomal CagA in atherosclerosis, ApoE-/- mice were given intravenous or intraperitoneal injections of saline, GES-EVs, Hp-GES-EVs, and recombinant CagA protein (rCagA). FINDINGS: CagA-positive H. pylori PMSS1 infection does not induce but promotes macrophage-derived foam cell formation and augments atherosclerotic plaque growth and instability in two animal models. Meanwhile, circulating Hp-GES-EVs are taken up in aortic plaque, and CagA is secreted in Hp-GES-EVs. Furthermore, the CagA-containing EVs and rCagA exacerbates macrophage-derived foam cell formation and lesion development in vitro and in vivo, recapitulating the pro-atherogenic effects of CagA-positive H. pylori. Mechanistically, CagA suppresses the transcription of cholesterol efflux transporters by downregulating the expression of transcriptional factors PPARγ and LXRα and thus enhances foam cell formation. INTERPRETATION: These results may provide new insights into the role of exosomal CagA in the pathogenesis of CagA-positive H. pylori infection-related atherosclerosis. It is suggested that preventing and eradicating CagA-positive H. pylori infection could reduce the incidence of atherosclerosis and related events.
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Antígenos Bacterianos/metabolismo , Aterosclerosis/metabolismo , Proteínas Bacterianas/metabolismo , Células Epiteliales/metabolismo , Células Espumosas/metabolismo , Mucosa Gástrica/metabolismo , Infecciones por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Animales , Aterosclerosis/microbiología , Aterosclerosis/patología , Células Epiteliales/microbiología , Células Epiteliales/patología , Células Espumosas/microbiología , Células Espumosas/patología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Infecciones por Helicobacter/patología , RatonesRESUMEN
Atherosclerotic cardio-cerebrovascular disease and death remain the leading cause of morbidity and mortality worldwide. Defective efferocytosis, the clearance of apoptotic cells by macrophages, is thought to lead to increased inflammation and necrotic core formation in atherosclerotic lesions. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here we show that lncRNA myocardial infarction associated transcript (MIAT) was markedly elevated in the serum of patients with symptoms of vulnerable atherosclerotic plaque and the macrophages of necrotic cores in an advanced atherosclerosis mouse model. MIAT knockdown attenuated atherosclerosis progression, reduced necrotic core size, and increased plaque stability in vivo. Furthermore, MIAT knockdown promoted clearance of apoptotic cells by macrophages in vivo and in vitro. Mechanistic studies revealed that MIAT acted as a micro RNA (miRNA) sponge to positively modulate the expression of anti-phagocytic molecule CD47 through sponging miR-149-5p. Together, these findings identified a macrophage MIAT/miR-149-5p /CD47 pathway as a key factor in the development of necrotic atherosclerotic plaques.
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Antígeno CD47/metabolismo , Enfermedades de las Arterias Carótidas/sangre , MicroARNs/metabolismo , Fagocitosis/genética , ARN Largo no Codificante/sangre , Regulación hacia Arriba , Anciano , Animales , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Noqueados para ApoE , MicroARNs/genética , Persona de Mediana Edad , Células RAW 264.7 , ARN Largo no Codificante/genética , TransfecciónRESUMEN
MicroRNAs (miRNAs/miRs) show great promise as novel cancer biomarkers. Several studies have revealed an association between abnormal miRNA expression and the risk of various cancer types. However, the diagnostic accuracy and reliability of miRNAs remains unclear. The present meta-analysis was performed to summarize the overall diagnostic performance of miR-195 for cancer. The PubMed, Cochrane Library, Wanfang and China National Knowledge Infrastructure databases were searched for associated literature published until December 10, 2017. Eligible studies were selected using multiple search strategies based on study selection criteria. Measures, including sensitivity and specificity, of the performance of miR-195 as a cancer diagnostic tool were pooled using bivariate meta-analysis models. All analyses were performed using Stata 14.0. The pooled analysis included 8 studies comprising 735 cases and 547 controls. The pooled diagnostic results calculated from all studies were as follows: Sensitivity, 0.79 [95% confidence interval (CI), 0.69-0.87]; specificity, 0.84 (95% CI, 0.68-0.93); positive likelihood ratio, 4.9 (95% CI, 2.50-9.50); negative likelihood ratio, 0.25 (95% CI, 0.18-0.35); diagnostic odds ratio, 20 (95% CI, 10.00-38.00); and area under the curve, 0.87 (95% CI, 0.84-0.90). Deeks' funnel plot asymmetry test suggested no potential publication bias (P=0.53). The present meta-analysis indicated that miR-195 could be a reliable non-invasive biomarker for the diagnosis of cancer. Further large-scale prospective studies are necessary to confirm the present findings and the clinical value of miR-195 for future diagnostics.
RESUMEN
Disruption of carotid vulnerable atherosclerotic plaque is responsible for acute ischemic stroke (AIS) and the early detection and intervention approach are greatly limited. Undertaking a microarray of microRNAs (miRNAs) in the plasma of AIS patients with carotid vulnerable plaques, miR-23a-5p was markedly elevated and was positively correlated with the plaque progression and vulnerability. Correspondingly, we found that miR-23a-5p expression was significantly increased in both plasma and macrophages from atherosclerosis mice. Bioinformatics analysis and in vitro knockdown experiments identified that ATP-binding cassette transporter A1/G1 as a novel target of miR-23a-5p. Luciferase reporter assays showed that miR-23a-5p repressed the 3' untranslated regions (UTR) activity of ABCA1/G1. Moreover, functional analyses demonstrated that transfection of miR-23a-5p inhibitor enhanced cholesterol efflux and decreased foam cell formation through upregulating ABCA1/G1 expression levels. Furthermore, long term in vivo systemically delivered miR-23a-5p antagomir significantly increased ABCA1/G1 expression in the aorta of ApoE-/- mice. Importantly, the miR-23a-5p antagomir therapy significantly reduced atherosclerosis progression and promoted plaque stability. Our observations indicate that miR-23a-5p promotes macrophage-derived foam cell formation and might be a key regulator contributing to atherosclerotic plaque progression and vulnerability.
Asunto(s)
Transportador 1 de Casete de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Macrófagos/metabolismo , MicroARNs/genética , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Regiones no Traducidas 3' , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Noqueados , Modelos Biológicos , Placa Aterosclerótica/patología , Células RAW 264.7 , Interferencia de ARNRESUMEN
Breast cancer-specific gene 1 (BCSG1), also referred to as γ-synuclein (SNCG), is highly expressed in human infiltrating breast carcinomas, but not in normal or benign breast tissue. The present study aimed to evaluate the effects of BCSG1 siRNA delivered by lentiviral vector on breast cancer cells and investigate the underlying mechanisms. BCSG1 RNAi lentiviral vector was constructed and transfected into MDA-MB-231 cells. BCSG1 mRNA levels were determined by quantitative polymerase chain reaction analysis. Cell proliferation, migration and apoptosis were evaluated by using the cell counting kit8, Transwell assay and flow cytometry, respectively, followed by western blotting to determine the relative levels of AKT, extracellular signalregulated kinase (ERK), p-AKT and p-ERK expression. BCSG1 mRNA levels were significantly reduced in MDA-MB231 cells following transfection of BCSG1 siRNA delivered by lentiviral vector. Cell migration and proliferation were significantly decreased and the cell cycle was arrested. Western blot analysis indicated that the protein levels of p-AKT and p-ERK were significantly lower in the BCSG1 siRNA-treated groups compared with the control and negative control groups. Therefore, BCSG1 siRNA delivered by lentiviral vector was able to significantly reduce BCSG1 expression, suppress cell migration and proliferation, possibly through the reduction of the protein levels of p-AKT and p-ERK.
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Movimiento Celular , Vectores Genéticos/metabolismo , Lentivirus/genética , Proteínas de Neoplasias/metabolismo , ARN Interferente Pequeño/metabolismo , gamma-Sinucleína/metabolismo , Apoptosis , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Proteínas de Neoplasias/genética , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , gamma-Sinucleína/genéticaRESUMEN
Emerging studies have illustrated that LncRNAs TUG1 play critical roles in multiple biologic processes. However, the LncRNA TUG1 expression and function in ischemic stroke have not been reported yet. In this study, we found that LncRNA TUG1 expression was significantly up-regulated in brain ischemic penumbra from rat middle carotid artery occlusion (MCAO) model, while similar results were also observed in cultured neurons under oxygen-glucose deprivation (OGD) insult. Knockdown of TUG1 decreased the ratio of apoptotic cells and promoted cells survival in vitro, which may be regulated by the elevated miRNA-9 expression and decreased Bcl2l11 protein. Furthermore, TUG1 could directly interact with miR-9 and down-regulating miR-9 could efficiently reverse the function of TUG1 on the Bcl2l11 expression. In summary, our result sheds light on the role of LncRNA TUG1 as a miRNA sponge for ischemic stroke, possibly providing a new therapeutic target in stroke.
Asunto(s)
Apoptosis , Proteína 11 Similar a Bcl2/genética , Isquemia Encefálica/genética , Encéfalo/patología , Regulación de la Expresión Génica , MicroARNs/genética , ARN Largo no Codificante/genética , Animales , Encéfalo/metabolismo , Isquemia Encefálica/patología , Células Cultivadas , Técnicas de Silenciamiento del Gen , Masculino , Neuronas/metabolismo , Neuronas/patología , Ratas Sprague-Dawley , Regulación hacia ArribaRESUMEN
OBJECTIVE: Puerarin, which shows beneficial and protective effects on cardiovascular diseases, is the main isoflavone extracted from Pueraria lobata (kudzu) root. The aim of this study was to investigate the effects of puerarin on in vitro myocardial proliferation and its underlying mechanism. METHODS: Myocardial differentiation of transgenic embryonic stem (ES) cells was performed by embryoid body-based differentiation method. The proliferation assay of cardiomyocytes (CMs) derived from ES cells (ES-CMs) was performed by EdU (5-Ethynyl-2'-deoxyuridine) staining. Flow cytometry was employed to determine the cell cycle distribution and apoptosis of purified ES-CMs. Quantitative real-time PCR was utilized to study the transcription of genes related to cell cycle progression. Signaling pathways relating to proliferation were studied by western blot analysis and application of specific inhibitors. RESULTS: Puerarin exerted a delayed inhibitory effect on the proliferation of ES-CMs at the early-stage differentiation. Meanwhile, puerarin slowed progression through G2/M phase without inducing apoptosis of ES-CMs. Further assays showed that puerarin up-regulated the transcription of Cyclin A2, Cyclin B1 and Cdk1 in ES-CMs. The ERK1/2 specific inhibitor PD0325901 and the PI3K specific inhibitor Wortmannin successfully reversed puerarin-induced up-regulation of Cdk1 but not Cyclin A2 and B1. CONCLUSION: These findings suggest that puerarin inhibits CM proliferation via slowing progression through G2/M phase during early-stage differentiation.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Isoflavonas/farmacología , Vasodilatadores/farmacología , Androstadienos/farmacología , Animales , Benzamidas/farmacología , Proteína Quinasa CDC2/genética , Proteína Quinasa CDC2/metabolismo , Diferenciación Celular/efectos de los fármacos , Ciclina A2/genética , Ciclina A2/metabolismo , Ciclina B1/genética , Ciclina B1/metabolismo , Difenilamina/análogos & derivados , Difenilamina/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Ratones , Células Madre Embrionarias de Ratones/citología , Células Madre Embrionarias de Ratones/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Raíces de Plantas/química , Raíces de Plantas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pueraria/química , Pueraria/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , WortmaninaRESUMEN
In this study, we examined whether sociolinguistic awareness and false belief were uniquely related in 3- and 4-year-old Cantonese-speaking children learning English as a second language. The English-use background of these children varied so that they possessed sociolinguistic awareness to different degrees. Results indicated that sociolinguistic awareness predicted false belief uniquely after controlling for age, nonverbal intelligence, English vocabulary, and family income for both the second language learners and the more balanced bilinguals. The group difference in false belief was adequately explained by the corresponding difference in sociolinguistic awareness over and above the other variables. Such findings provide evidence for the claim that false belief understanding is critically related to sociolinguistic awareness, which in turn is influenced by how a second language is learned.