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The triglyceride glucose body mass index (TyG-BMI) is a potential indicator for insulin resistance, but its association with mortality in diabetic patients is unclear. This study investigates the relationship between TyG-BMI and all-cause and cardiovascular mortality in diabetics. The study included 3109 diabetic patients from the National Health and Nutrition Examination Survey (2001-2018). Mortality data were obtained from National Death Index records until 31 December 2019. Multivariate Cox models analyzed the association between TyG-BMI and mortality. Non-linear correlations were assessed using restricted cubic splines, and a two-piecewise Cox model evaluated the relationship on both sides of the inflection point. Over a median 7.25-year follow-up, 795 total and 238 cardiovascular deaths occurred. A U-shaped link was found between initial TyG-BMI and mortality in diabetic patients. Low TyG-BMI (< 279.67 for all-cause, < 270.19 for CVD) reduced death risks (all-cause: HR 0.77, 95% CI 0.69-0.86; CVD: HR 0.64, 95% CI 0.48-0.86). High TyG-BMI (> 279.67 for all-cause, > 270.19 for CVD) increased these risks (all-cause: HR 1.26, 95% CI 1.10-1.44; CVD: HR 1.33, 95% CI 1.06-1.68). In the NHANES study population, a U-shaped association was observed between the baseline TyG-BMI index and all-cause mortality or CVD in diabetic patients.
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Glucemia , Índice de Masa Corporal , Enfermedades Cardiovasculares , Diabetes Mellitus , Encuestas Nutricionales , Triglicéridos , Humanos , Masculino , Femenino , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/sangre , Persona de Mediana Edad , Triglicéridos/sangre , Estudios Retrospectivos , Glucemia/análisis , Glucemia/metabolismo , Diabetes Mellitus/mortalidad , Diabetes Mellitus/sangre , Anciano , Adulto , Factores de Riesgo , Modelos de Riesgos Proporcionales , Bases de Datos Factuales , Causas de MuerteRESUMEN
Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis (AS). Some reports have shown that homocysteine (Hcy) could accelerate the development of AS by promoting endothelial cell senescence. miRNAs were widely involved in the pathophysiology of HHcy. However, few studies have focused on the changes of miRNA-mRNA networks in the artery of HHcy patients. For this reason, RNA-sequencing was adopted to investigate the expression of miRNA and mRNA in HHcy model mouse arteries. We found that the expression of 216 mRNAs and 48 miRNAs were significantly changed. Using TargetScan and miRDB web tools, 29 miRNA-mRNA pairs were predicted. Notably, miR-20b-5p and FJX1 shared the highest predicted score in TargetScan, and further study indicated that the miR-20b-5p inhibitor significantly upregulated the FJX1 expression in HHcy human umbilical vein endothelial cells (HUVECs) model. PPI analysis revealed an important sub-network which was centered on CDK1. Gene ontology (GO) enrichment analysis showed that HHcy had a significant effect on cell cycle. Further experiments found that Hcy management increased reactive oxygen species (ROS) generation, the activity of senescence associated ß-galactosidase (SA-ß-gal) and the protein expression of p16 and p21 in HUVECs, which were rescued by miR-20b-5p inhibitor. In general, our research indicated the important role of miR-20b-5p in HHcy-related endothelial cell senescence.
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Aterosclerosis , Hiperhomocisteinemia , MicroARNs , Animales , Ratones , Aterosclerosis/genética , Senescencia Celular/genética , Células Endoteliales de la Vena Umbilical Humana , Hiperhomocisteinemia/genética , MicroARNs/genética , MicroARNs/metabolismo , ARN Mensajero/metabolismoRESUMEN
Objective: To investigate the protective effect of nicorandil on contrast-induced acute kidney injury (CIAKI) in patients with acute ST-segment elevation myocardial infarction (STEMI) after emergency percutaneous coronary intervention (PCI). Methods: This is a single-center, retrospective control study. A total of 156 patients with STEMI were divided into the nicorandil group (n = 55) and the control group (n = 101). The incidence of CIAKI, defined as an increase of >25% or absolute values > 44.2â µmol/L in serum creatinine (Scr) from baseline within 72â h of exposure to a contrast agent after exclusion of other causes, was the primary endpoint. The secondary endpoints were: (1) changes of Scr, estimated glomerular filtration rate (eGFR), uric acid, and ß2-microglobulin at 24/48/72â h and 5 to 7 days after PCI; (2) the peak value difference of creatine kinase isoenzymes (CK-MB) after PCI; (3) adverse events within 6 months after PCI. Results: The overall incidence of CIAKI was 21.8%; the incidence of CIAKI in the nicorandil group was significantly lower (12.7% [7/55]) than in the control group (26.7% [27/101]) (P = .043). Compared with the control group, Scr, uric acid, and ß2-microglobulin levels were lower, and the level of eGFR was higher in nicorandil group (P all < .05). The peak value of CK-MB in the nicorandil group was lower than that in the control group (105.30 [56.61, 232.04] vs 178.00 [77.08, 271.91]U/L, P = .042). There was no significant difference in adverse events between the 2 groups within 6 months after PCI. Moreover, multivariate logistic regression analysis showed that hypertension and diabetes were independent risk factors for CIAKI, while nicorandil treatment was a protective factor. Conclusion: Our data suggest that intravenous nicorandil after emergency PCI has a protective effect on the occurrence of CIAKI in STEMI patients.
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Lesión Renal Aguda , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Humanos , Nicorandil/efectos adversos , Intervención Coronaria Percutánea/efectos adversos , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/terapia , Ácido Úrico/efectos adversos , Estudios Retrospectivos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/epidemiología , Resultado del TratamientoRESUMEN
Background: Dual antiplatelet therapy (DAPT) with potent P2Y12 inhibitor is the cornerstone of acute coronary syndrome (ACS) management. Balancing the effects of different strategies of antiplatelet therapy including DAPT de-escalation, potent P2Y12 inhibitor monotherapy, and conventional DAPT is a hot topic. Methods: A systematic search was conducted from the MEDLINE, PubMed, and Embase through October 2021 to identify various DAPT strategies in randomized controlled trials (RCTs) for treatment of ACS patients after undergoing PCI with drug-eluting stent (DES). The network meta-analysis was performed to investigate the net clinic benefit of the DAPT de-escalation, potent P2Y12 inhibitor monotherapy, as well as conventional DAPT. The primary outcome was net adverse clinical events, defined as a composite of major bleeding and cardiac death, myocardial infarction, stroke, stent thrombosis, or target-vessel revascularization. The secondary outcomes include major adverse cardiac events and trial-defined major or minor bleeding. Results: A total of 14 RCTs with 63,982 patients were included. The DAPT de-escalation was associated with a lower risk of the primary outcome compared with potent P2Y12 inhibitor monotherapy (De-escalation vs monotherapy odds ratio (OR): 0.72 95% confidence interval (CI): 0.55-0.96), and other antiplatelet strategies (De-escalation vs clopidogrel + aspirin OR: 0.49 95% CI: 0.39-0.63; De-escalation vs prasugrel + aspirin OR: 0.76 95% CI: 0.59-0.98; De-escalation vs ticagrelor + aspirin OR: 0.76 95% CI: 0.55-0.90). There were no statistical differences in the incidence of bleeding (DAPT de-escalation vs P2Y12 inhibitor monotherapy OR: 0.73 95% CI: 0.47-1.12) and major adverse cardiac events (DAPT de-escalation vs P2Y12 inhibitor monotherapy OR: 0.79 95% CI: 0.59-1.08) between DAPT de-escalation and potent P2Y12 inhibitor monotherapy. Conclusions: This network meta-analysis showed that DAPT de-escalation would reduce the net adverse clinical events, compared with potent P2Y12 inhibitor monotherapy, for ACS patients undergone PCI treatment.
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Platelet mitophagy is a major pathway involved in the clearance of injured mitochondria during hemostasis and thrombosis. Prohibitin 2 (PHB2) has recently emerged as an inner mitochondrial membrane receptor involved in mitophagy. However, the mechanisms underlying PHB2mediated platelet mitophagy and activation are not completely understood. PHB2 is a highly conserved inner mitochondrial membrane protein that regulates mitochondrial assembly and function due to its unique localization on the mitochondrial membrane. The present study aimed to investigate the role and mechanism underlying PHB2 in platelet mitophagy and activation. Phorbol12myristate13acetate (PMA) was used to induce MEG01 cells maturation and differentiate into platelets following PHB2 knockdown. Cell Counting Kit8 assays were performed to examine platelet viability. Flow cytometry was performed to assess platelet mitochondrial membrane potential. RTqPCR and western blotting were conducted to measure mRNA and protein expression levels, respectively. Subsequently, platelets were exposed to CCCP and the role of PHB2 was assessed. The results of the present study identified a crucial role for PHB2 in platelet mitophagy and activation, suggesting that PHB2mediated regulation of mitophagy may serve as a novel strategy for downregulating the expression of platelet activation genes. Although further research into mitophagy is required, the present study suggested that PHB2 may serve as a novel therapeutic target for thrombosisrelated diseases due to its unique localization on the mitochondrial membrane.
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Plaquetas/efectos de los fármacos , Mitofagia/genética , Activación Plaquetaria/efectos de los fármacos , Proteínas Represoras/genética , Carbonil Cianuro m-Clorofenil Hidrazona/análogos & derivados , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Diferenciación Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Potencial de la Membrana Mitocondrial , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitofagia/efectos de los fármacos , Ésteres del Forbol/farmacología , Activación Plaquetaria/genética , Prohibitinas , Transducción de Señal/efectos de los fármacos , Trombosis/genética , Trombosis/patologíaRESUMEN
Previous studies have shown that nicorandil has a protective effect on cardiomyocytes. However, there is no study to investigate whether perioperative intravenous nicorandil can further reduce the myocardial infarct size in patients with ST-segment elevation myocardial infarction (STEMI) compared to the current standard of percutaneous coronary intervention (PCI) regimen. The CHANGE (China-Admini stration of Nicorandil Group) study is a multicenter, prospective, randomized, double-blind and parallel-controlled clinical study of STEMI patients undergoing primary PCI in China, aiming to evaluate the efficacy and safety of intravenous nicorandil in ameliorating the myocar dial infarct size in STEMI patients undergoing primary PCI and provide evidence-based support for myocardial protection strategies of STEMI patients.
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BACKGROUND: Cognitive impairment is one of common complications of acute respiratory distress syndrome (ARDS). Increasing evidence suggests that interleukin-1 beta (IL-1ß) plays a role in inducing neuronal apoptosis in cognitive dysfunction. The lung protective ventilatory strategies, which serve to reduce pulmonary morbidity for ARDS patients, almost always lead to hypercapnia. Some studies have reported that hypercapnia contributes to the risk of cognitive impairment and IL-1ß secretion outside the central nervous system (CNS). However, the underlying mechanism of hypercapnia aggravating cognitive impairment under hypoxia has remained uncertain. This study was aimed to explore whether hypercapnia would partake in increasing IL-1ß secretion via activating the NLRP3 (NLR family, pyrin domain-containing 3) inflammasome in the hypoxic CNS and in aggravating cognitive impairment. METHODS: The Sprague-Dawley (SD) rats that underwent hypercapnia/hypoxemia were used for assessment of NLRP3, caspase-1, IL-1ß, Bcl-2, Bax, and caspase-3 expression by Western blotting or double immunofluorescence, and the model was also used for Morris water maze test. In addition, Z-YVAD-FMK, a caspase-1 inhibitor, was used to treat BV-2 microglia to determine whether activation of NLRP3 inflammasome was required for the enhancing effect of hypercapnia on expressing IL-1ß by Western blotting or double immunofluorescence. The interaction effects were analyzed by factorial ANOVA. Simple effects analyses were performed when an interaction was observed. RESULTS: There were interaction effects on cognitive impairment, apoptosis of hippocampal neurons, activation of NLRP3 inflammasome, and upregulation of IL-1ß between hypercapnia treatment and hypoxia treatment. Hypercapnia + hypoxia treatment caused more serious damage to the learning and memory of rats than those subjected to hypoxia treatment alone. Expression levels of Bcl-2 were reduced, while that of Bax and caspase-3 were increased by hypercapnia in hypoxic hippocampus. Hypercapnia markedly increased the expression of NLRP3, caspase-1, and IL-1ß in hypoxia-activated microglia both in vivo and in vitro. Pharmacological inhibition of NLRP3 inflammasome activation and release of IL-1ß might ameliorate apoptosis of neurons. CONCLUSIONS: The present results suggest that hypercapnia-induced IL-1ß overproduction via activating the NLRP3 inflammasome by hypoxia-activated microglia may augment neuroinflammation, increase neuronal cell death, and contribute to the pathogenesis of cognitive impairments.
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Disfunción Cognitiva/metabolismo , Hipercapnia/metabolismo , Hipoxia/metabolismo , Interleucina-1beta/biosíntesis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factores de Edad , Animales , Disfunción Cognitiva/psicología , Hipercapnia/psicología , Hipoxia/psicología , Masculino , Aprendizaje por Laberinto/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: Angiotensin II (AngII), a vasoconstrictive peptide of the renin-angiotensin system (RAS), promotes hepatic fibrogenesis and induces microRNA-21(mir-21) expression. Angiotensin-(1-7) [Ang-(1-7)] is a peptide of the RAS, which attenuates liver fibrosis. Recently, it was reported that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome participated in liver fibrosis. However, it remains unclear how mir-21 mediates AngII-induced NLRP3 inflammasome activation. We investigate the role of AngII-induced mir-21 in the regulation of NLRP3 inflammasome/IL-1ß axis in liver fibrosis. RESULTS: In vivo, circulating mir-21 was upregulated in patients with liver fibrosis and was positively correlated with liver fibrosis and oxidation. Treatment with Ang-(1-7) inhibited mir-21, NLRP3 inflammasome, and liver fibrosis after bile duct ligation (BDL) or AngII infusion. Inhibition of mir-21 suppressed the Smad7/Smad2/3/NOX4, Spry1/ERK/NF-κB pathway, NLRP3 inflammasome, and liver fibrosis induced by AngII infusion. In vitro, AngII upregulated mir-21 expression via targeting Smad7 and Spry1 in primary hepatic stellate cells (HSCs). In contrast, Ang-(1-7) suppressed mir-21 expression and oxidation induced by AngII. Overexpression of mir-21 promoted oxidation, and collagen production enhanced the effect of AngII on NLRP3 inflammasome activation via the Spry1/ERK/NF-κB, Smad7/Smad2/3/NOX4 pathways. However, downregulation of mir-21 exerted the opposite effects. Innovation and Conclusions: Mir-21 mediates AngII-activated NLRP3 inflammasome and resultant HSC activation via targeting Spry1 and Smad7. Ang-(1-7) protected against BDL or AngII infusion-induced hepatic fibrosis and inhibited mir-21 expression. Antioxid. Redox Signal. 27, 1-20.
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Angiotensina II/farmacología , Inflamasomas/metabolismo , Cirrosis Hepática/genética , MicroARNs/genética , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Humanos , Interleucina-1beta/metabolismo , Cirrosis Hepática/metabolismo , Proteínas de la Membrana , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fosfoproteínas , Ratas , Proteína smad7/metabolismoRESUMEN
OBJECTIVE: To investigate the effect of angiotension II (AngII) on the activation of NLRP3 inflammasome and the expression of interleukin-1ß (IL-1ß) in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs cultured in vitro were treated with different concentrations of AngII for varying lengths of time to determine the optimal concentration and time for AngII exposure. To test the impact of different agents on the effect of AngII exposure, HUVECs were pretreated with AngII receptor blocker losartan, NAD(P)H inhibitor DPI and H(2)O(2) scavenger CAT, caspase 1 inhibitor YVAD, or NLRP3 siRNA for silencing NLRP3, and the protein levels of NOX4, NLRP3, caspase-1 and IL-1ß in HUVECs were analyzed by Western blotting. RESULTS: AngII treatment at the optimal concentration (10(-9) mol/L) for 12 h significantly increased the protein levels of NOX4, NLRP3, caspase1 and IL-1ß in HUVECs. Pretreatment with losartan, DPI, CAT, YVAD, or NLRP3 siRNA all attenuated the effects of AngII on the cells. CONCLUSION: AngII can induce vascular inflammation by promoting the production of reactive oxygen species and activating NLRP3 inflammasome to increase the protein expression of IL-1ß in HUVECs.
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Angiotensina II/farmacología , Proteínas Portadoras/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Proteínas Adaptadoras Transductoras de Señales/farmacología , Western Blotting , Caspasa 1/metabolismo , Humanos , Peróxido de Hidrógeno , NADPH Oxidasa 4 , NADPH Oxidasas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , ARN Interferente Pequeño , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Left ventricular non-compaction (LVNC) is a rare cardiomyopathy. Many genetic variants have been associated with LVNC. However, the number of the previous LVNC-associated variants that are common in the background population remains unknown. The aim of this study was to provide an updated list of previously reported LVNC-associated variants with biologic description and investigate the prevalence of LVNC variants in healthy general population to find false-positive LVNC-associated variants. METHODS AND RESULTS: The Human Gene Mutation Database and PubMed were systematically searched to identify all previously reported LVNC-associated variants. Thereafter, the Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC), that both represent the background population, was searched for all variants. Four in silico prediction tools were assessed to determine the functional effects of these variants. The prediction results of those identified in the ESP and ExAC and those not identified in the ESP and ExAC were compared. In 12 genes, 60 LVNC-associated missense/nonsense variants were identified. MYH7 was the predominant gene, encompassing 24 of the 60 LVNC-associated variants. The ESP only harbored nine and ExAC harbored 18 of the 60 LVNC-associated variants. In total, eight out of nine ESP-positive variants overlapped with the 18 variants identified in ExAC database. CONCLUSIONS: In this article, we identified 9 ESP-positive and 18 ExAC-positive variants of 60 previously reported LVNC-associated variants, suggesting that these variants are not necessarily the monogenic cause of LVNC.
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AIMS: Angiotensin II (Ang II) aggravates hepatic fibrosis by inducing NADPH oxidase (NOX)-dependent oxidative stress. Angiotensin-(1-7) [Ang-(1-7)], which counter-regulates Ang II, has been evidenced to protect against hepatic fibrosis. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, being activated by reactive oxygen species (ROS), is identified as a novel mechanism of liver fibrosis. However, whether the NLRP3 inflammasome involves in regulation of Ang II-induced hepatic fibrosis remains unclear. This study investigates the different effects of the Ang II and Ang-(1-7) on collagen synthesis by regulating the NLRP3 inflammasome/Smad pathway via redox balance modulation. RESULTS: In vivo, Ang-(1-7) improved bile duct ligation-induced hepatic fibrosis, reduced H2O2 content, protein levels of NOX4, and the NLRP3 inflammasome, whereas it increased glutathione (GSH) and nuclear erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE). In vitro, Ang II treatment elevated NOX4 protein expression and ROS production in hepatic stellate cells (HSCs), whereas it inhibited GSH and Nrf2-ARE, resulting in the activation of the NLRP3 inflammasome in the mitochondria of HSCs. NLRP3 depletion inhibited Ang II-induced collagen synthesis. Furthermore, Ang II increased NLRP3 and pro-IL-1ß levels by activating the Toll-like receptor 4 (TLR4)/MyD88/NF-κB pathway. Treatment with antioxidants, NOX4 small interference RNA (siRNA), or Nrf2 activator inhibited Ang II-induced NLRP3 inflammasome activation and collagen synthesis. In contrast, the action of Ang-(1-7) opposed the effects of Ang II. INNOVATION AND CONCLUSIONS: Ang-(1-7) improved liver fibrosis by regulating NLRP3 inflammasome activation induced by Ang II-mediated ROS via redox balance modulation. Antioxid. Redox Signal. 24, 795-812.
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Angiotensina I/fisiología , Inflamasomas/metabolismo , Cirrosis Hepática/metabolismo , Hígado/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fragmentos de Péptidos/fisiología , Angiotensina I/administración & dosificación , Animales , Elementos de Respuesta Antioxidante , Células Cultivadas , Colágeno Tipo I/biosíntesis , Cadena alfa 1 del Colágeno Tipo I , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Humanos , Hígado/patología , Masculino , Mitocondrias Hepáticas/fisiología , Factor 88 de Diferenciación Mieloide/metabolismo , NADPH Oxidasa 4 , NADPH Oxidasas/metabolismo , FN-kappa B/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Fragmentos de Péptidos/administración & dosificación , Multimerización de Proteína , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Sistema Renina-Angiotensina , Transducción de Señal , Proteínas Smad/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
OBJECTIVE: To observe epithelial-mesenchymal phenotypes and oxidative stress related protein expressions of the liver cells in a rat model of liver fibrosis induced by bile duct ligation and recanalization. METHODS: Twenty-four male Wistar rats were randomized into 4 groups, including a sham-operated group, two bile duct ligation groups with ligation for 2 and 4 weeks, and a bile duct ligation group with a 2-week ligation followed by a 2-week recanalization. HE staining and Masson staining were used to assess liver fibrosis in the rats, and immunohistochemistry and Western blotting were employed to detect expressions of the epithelial and mesenchymal marker proteins and oxidative stress-related proteins. RESULTS: Compared with the sham-operated group, the rats with bile duct ligation showed obvious liver fibrosis, which worsened as the ligation time extended, accompanied by significantly increased expression of α-SMA, collagen I, NOX(4) and vimetin and reduced E-cadherin expression. Compared with the rats with bile duct ligation for 4 weeks, the rats in bile duct ligation-recanalization group showed obviously lessened liver fibrosis, significantly lowered expressions of NOX(4) and mesenchymal cell maker proteins, and enhanced expressions of epithelial cell marker proteins. CONCLUSION: Bile duct ligation up-regulates mesenchymal phenotype-related proteins and NOX(4) protein expression and down-regulates the expression of epithelial phenotype-related proteins, and these changes can be reversed by subsequent bile duct recanalization.
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Células Epiteliales/citología , Hepatocitos/citología , Cirrosis Hepática/metabolismo , NADPH Oxidasas/metabolismo , Actinas/metabolismo , Animales , Conductos Biliares/cirugía , Cadherinas/metabolismo , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Hepatocitos/metabolismo , Ligadura , Masculino , NADPH Oxidasa 4 , Estrés Oxidativo , Fenotipo , Ratas , Ratas Wistar , Vimentina/metabolismoAsunto(s)
Aspirina/uso terapéutico , Stents Liberadores de Fármacos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Aspirina/administración & dosificación , Esquema de Medicación , Quimioterapia Combinada , Humanos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Factores de TiempoAsunto(s)
Aspirina/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéutico , Aspirina/efectos adversos , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Guías de Práctica Clínica como Asunto , Prevención Primaria/métodos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
BACKGROUND: Marfan syndrome (MFS) is a rare autosomal dominantly inherited connective tissue disorder with an estimated prevalence of 1:5,000. More than 1000 variants have been previously reported to be associated with MFS. However, the disease-causing effect of these variants may be questionable as many of the original studies used low number of controls. To study whether there are possible false-positive variants associated with MFS, four in silico prediction tools (SIFT, Polyphen-2, Grantham score, and conservation across species) were used to predict the pathogenicity of these variant. RESULTS: Twenty-three out of 891 previously MFS-associated variants were identified in the ESP. These variants were distributed on 100 heterozygote carriers in 6494 screened individuals. This corresponds to a genotype prevalence of 1:65 for MFS. Using a more conservative approach (cutoff value of >2 carriers in the EPS), 10 variants affected a total of 82 individuals. This gives a genotype prevalence of 1:79 (82:6494) in the ESP. A significantly higher frequency of MFS-associated variants not present in the ESP were predicted to be pathogenic with the agreement of ≥3 prediction tools, compared to the variants present in the ESP (p = 3.5 × 10-15). CONCLUSIONS: This study showed a higher genotype prevalence of MFS than expected from the phenotype prevalence in the general population. The high genotype prevalence suggests that these variants are not the monogenic cause of MFS. Therefore, caution should be taken with regard to disease stratification based on these previously reported MFS-associated variants.
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Exoma , Variación Genética , Síndrome de Marfan/genética , Biología Computacional , Reacciones Falso Positivas , Estudios de Asociación Genética , Genotipo , Humanos , Síndrome de Marfan/epidemiología , Fenotipo , PrevalenciaRESUMEN
Hypertension is known to be associated with platelet overactivity, but the direct effects of hydrostatic pressure on platelet function remain unclear. The present study sought to investigate whether elevated hydrostatic pressure is responsible for platelet activation and to address the potential role of peroxisome proliferator-activated receptor-γ (PPARγ). We observed that hypertensive patients had significantly higher platelet volume and rate of ADP-induced platelets aggregation compared to the controls. In vitro, Primary human platelets were cultured under standard (0 mmHg) or increased (120, 180, 240 mmHg) hydrostatic pressure for 18 h. Exposure to elevated pressure was associated with morphological changes in platelets. Platelet aggregation and PAC-1 (the active confirmation of GPIIb/IIIa) binding were increased, CD40L was translocated from cytoplasm to the surface of platelet and soluble CD40L (sCD40L) was released into the medium in response to elevated hydrostatic pressure (180 and 240 mmHg). The PPARγ activity was up-regulated as the pressure was increased from 120 mmHg to 180 mmHg. Pressure-induced platelet aggregation, PAC-1 binding, and translocation and release of CD40L were all attenuated by the PPARγ agonist Thiazolidinediones (TZDs). These results demonstrate that platelet activation and aggregation are increased by exposure to elevated pressure and that PPARγ may modulate platelet activation induced by high hydrostatic pressure.
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PPAR gamma/metabolismo , Agregación Plaquetaria/fisiología , Presión Sanguínea/fisiología , Ligando de CD40/metabolismo , Femenino , Humanos , Presión Hidrostática , Masculino , PPAR gamma/agonistas , Tiazolidinedionas/farmacologíaRESUMEN
As one of the most commonly used solvents, ethanol exhibits weak fluorescence when excited by ultraviolet (UV) light. Until now, the fluorescence of ethanol-doped nanoparticles has not been studied. In this paper, eleven different concentrations of SiO2 nanoparticles (diameter 100 nm) were doped in ethanol, and corresponding colloids were formed. The excitation and emission spectra of the colloids were measured. The experimental results indicated that the SiO2 nanoparticles obviously enhanced the fluorescence of ethanol. Under excitation at 306 nm, the enhancement effect is the best when the concentration of SiO2 nanoparticles is 4.452 x 10(12) ml(-1), and the enhancement factor is nearly 50 times at the peak position of 360 nm. At the excitation wavelength of 360 nm, the enhancement effect is the best when the concentration of SiO2 nanoparticles is 1.113 x 10(13) ml(-1), and the enhancement factor is nearly 40 times at the peak position of 397 nm. The result of this article will reduce the test limit of ethanol by two magnitudes.
Asunto(s)
Coloides/química , Etanol/química , Colorantes Fluorescentes/química , Nanopartículas/química , Dióxido de Silicio/química , Espectrometría de FluorescenciaRESUMEN
OBJECTIVE: To observe the protection of Heme oxygenase-1 (HO-1) from lipopolysaccharide (LPS)-induced cardiocyte injury and its mechanism. METHODS: Cardiocyte was isolated from SD neonate rat and cultured in vitro, and was divided into control group (normal culture), LPS group (with stimulation of 30 micromoL/L LPS for 1 hour), LPS + Hemin group (with same treatment to LPS group after stimulation of 5 micromoL/L Hemin for 1 hour), and LPS + ZnPP group (with same treatment to LPS group after stimulation of 3 micromoL/L ZnPP for 1 hour). The level of lactic-dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) were measured by thio-barbituric acid and xanthine oxidase techniques. The cell heart rhythm, survival rate and apoptosis rate were examined. The expressions of nuclear factor kappaB (NF-kappaB), HO-1 and tumor necrosis factor-alpha (TNF-alpha) were measured with Western blotting. The HO-1 mRNA was examined by RT-PCR. RESULTS: The level of LDH and MDA in LPS, LPS + Hemin, and LPS + ZnPP groups were (113 +/- 15), (79 +/- 13), (154 +/- 22) U/L, and (1.88 +/- 0.36), (1.16 +/- 0.32), (2.84 +/- 0.44) mmoL/L respectively, which were all obviously higher than those in control group [(69 +/- 10) U/L, (0.87 +/- 0.25) mmol/L, P < 0.05]. The level of SOD in LPS, PS + Hemin, and LPS + ZnPP groups (17.8 +/- 1.8, 22.5 +/- 2.4, 13.4 +/- 1.5 U/mL, respectively) was all obviously lower than that in control group (24.3 +/- 3.6 U/mL, P < 0.05). The apoptosis rate and heart rhythm were obviously higher and survival rate significantly lower in LPS, LPS + Hemin, and LPS + ZnPP groups than those in control group (P < 0.05). The level of HO-1mRNA in LPS, LPS + Hemin, and LPS + ZnPP groups was higher than that in control group (P < 0.01), among which LPS + Hemin group was the highest. The level of HO-1, TNF-alpha and NF-kappaB in LPS, LPS + Hemin, and LPS + ZnPP groups was higher than those in control group (P < 0.05), among which the level of HO-1 protein in LPS + Hemin group was the highest, the level of TNF-alpha and NF-kappaB in LPS + ZnPP group was highest. CONCLUSION: LPS can induce cardiocyte injury, which can be inhibited through the anti-inflammatory, anti-oxidant, and anti-apoptosis functions by HO-1.