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Mitochondrial antiviral signaling protein (MAVS) is a key innate immune adaptor on the outer mitochondrial membrane that acts as a switch in the immune signal transduction response to viral infections. Some studies have reported that MAVS mediates NF-κB and type I interferon signaling during viral infection and is also required for optimal NLRP3 inflammasome activity. Recent studies have reported that MAVS is involved in various cancers, systemic lupus erythematosus, kidney diseases, and cardiovascular diseases. Herein, we summarize the structure, activation, pathophysiological roles, and MAVS-based therapies for renal diseases. This review provides novel insights into MAVS's role and therapeutic potential in the pathogenesis of renal diseases.
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Enfermedades Renales , Transducción de Señal , Humanos , Inmunidad Innata , Enfermedades Renales/tratamiento farmacológico , FN-kappa B/metabolismoRESUMEN
Although an association between single polycyclic aromatic hydrocarbons (PAHs) adult exposure and telomere length has been reported, the evidence of mixed PAHs (1-napthol, 2-napthol, 3-fluorene, 2-fluorene, 3-phenanthrene, 1-phenanthrene, 2-phenanthrene, and 1-pyrene) exposure and telomere length in the adult general population is still not clear. A total of 1460 adults over the age of 20 years provided urine information on 8 PAHs and selected covariates from the 2001-2002 National Health and Nutrition Examination Survey (NHANES). Bayesian nuclear machine regression (BKMR) was conducted to analyze these associations of telomere length in multiple PAH-exposed environments. Linear regression is mainly used for correlation analysis of PAHs with selected covariate adjustments. Restricted cubic spline (RCS) is used to estimate the correlation between selected PAHs and telomere length. After adjusting for potential covariates, PAHs mixed exposure was negatively associated with telomere length. The linear regression results showed that 2-napthol and 2-fluorene were negatively correlated with telomere length. Telomere length decreased by 1.0% in the fully adjusted model per increment of one unit in the base-10-logarithm-transformed 2-napthol and 2-fluorene concentrations (P = 0.030 and 0.049, respectively). However, the other 6 PAH metabolites were not significantly different. In addition, RCS results showed that 2-napthol has a marginal dose effect relationship with telomere length. Our present study suggested that PAHs are negatively associated with telomere length in the general population of the USA. Considering that the low level of PAHs exposure in the general population can also induce reduced telomere length and potential health risks, future research is needed to explore potential mechanisms.
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Fenantrenos , Hidrocarburos Policíclicos Aromáticos , Adulto , Humanos , Adulto Joven , Hidrocarburos Policíclicos Aromáticos/metabolismo , Encuestas Nutricionales , Teorema de Bayes , Fluorenos , Telómero , BiomarcadoresRESUMEN
Background: Pioglitazone is considered a potential therapy for non-alcoholic fatty liver disease (NAFLD). However, different effects of pioglitazone on NAFLD have been demonstrated in diabetic and non-diabetic patients. Herein, a meta-analysis of randomized, placebo-controlled trials was carried out to indirectly compare pioglitazone in NAFLD patients with vs. without type 2 diabetes. Methods: Randomized controlled trials (RCTs) of pioglitazone vs. placebo involving NAFLD patients with or without type 2 diabetes/prediabetes collected from databases were enrolled into this analysis. Methodological quality was employed to evaluate the domains recommended by the Cochrane Collaboration. The analysis covered the changes in histology (fibrosis, hepatocellular ballooning, inflammation, steatosis), liver enzymes, blood lipids, fasting blood glucose (FBS), homeostasis model assessment-IR (HOMA-IR), weight and body mass index (BMI) before and after treatment, and adverse events. Results: The review covered seven articles, with 614 patients in total, of which three were non-diabetic RCTs. No difference was found in patients with vs. without type 2 diabetes in histology, liver enzymes, blood lipids, HOMA-IR, weight, BMI, and FBS. Moreover, no significant difference was revealed in adverse effects between NAFLD patients with diabetes and without DM, except the incidence of edema that was found to be higher in the pioglitazone group than in the placebo group in NAFLD patients with diabetes. Conclusions: Pioglitazone could exert a certain effect on alleviating NAFLD, which was consistent between non-diabetic NAFLD patients and diabetic NAFLD patients in improving histopathology, liver enzymes, and HOMA-IR and reducing blood lipids. Furthermore, there were no adverse effects, except the incidence of edema which is higher in the pioglitazone group in NAFLD patients with diabetes. However, large sample sizes and well-designed RCTs are required to further confirm these conclusions.
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Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Humanos , Pioglitazona/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Hipoglucemiantes/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , LípidosRESUMEN
BACKGROUND: Exposure to metals has been associated with liver-related disease. Few studies have explored the effect of sex stratification on adolescent liver function. METHOD: From the National Health and Nutrition Examination Survey (2011-2016), 1143 subjects aged 12-19 years were selected for analysis. The outcome variables were the levels of alanine aminotransferase (ALT), aspartate aminotransferase, and gamma-glutamyl transpeptidase. RESULTS: The results showed a positive association between serum zinc and ALT in boys (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.11-5.06). Serum mercury was associated with an increase in ALT level in girls (OR, 2.73; 95% CI, 1.14-6.57). Mechanistically, the efficacy mediated by total cholesterol accounted for 24.38% and 6.19% of the association between serum zinc and ALT. CONCLUSIONS: The results imply that serum heavy metals were associated with the risk of liver injury, possibly mediated by serum cholesterol, in adolescents.
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Metales Pesados , Oligoelementos , Adolescente , Femenino , Humanos , Masculino , Colesterol , Mercurio , Metales Pesados/sangre , Encuestas Nutricionales , Oligoelementos/sangre , Zinc , Hígado/fisiologíaRESUMEN
Background: Studies have shown that young maternal age at childbirth can increase the risk of attention-deficit/hyperactivity disorder (ADHD) in offspring, but a study of the U.S. population has not been reported. Moreover, there is no reported research on young and advanced maternal age at childbirth and whether it can contribute to the risk of learning disability (LD) in offspring. Methods: This study evaluated the association between young and advanced maternal age at childbirth and offspring risk of ADHD and LD in the U.S. population. Using data from 8,098 participants included in the National Health and Nutrition Examination Survey (NHANES) conducted in 1999-2004, we analyzed the association between maternal age at childbirth and ADHD and LD risk in offspring. Odds ratios (ORs) and 95% confidence intervals (CIs) for maternal age at childbirth in association with ADHD and LD risk in offspring were estimated using multivariate logistic regression models after adjustment for age, sex, race, body mass index (BMI), poverty income ratio, smoking status during pregnancy, and NHANES cycle. Restricted cubic spline (RCS) models were used to evaluate potential non-linear relationships. Sensitivity analyses were performed to ensure the reliability of the results. Results: Among all participants, the offspring of subjects with a maternal age at childbirth of 18-24 years had an increased risk of ADHD (OR = 1.34, 95% CI: 1.01, 1.79) and LD (OR = 1.36, 95% CI: 1.06, 1.79) or either ADHD or LD (OR = 1.48, 95% CI: 1.20, 1.81). Additionally, compared with subjects with a maternal age at childbirth of 25-29 years, subjects with a maternal age at childbirth of 35-39 years had lower odds of having offspring with ADHD (OR = 0.60, 95% CI: 0.36, 1.00) and higher odds of having offspring with LD (OR = 1.34, 95% CI: 1.01, 1.78). The relationship between maternal age at childbirth and LD risk presented a U-shaped curve. Conclusions: These results provide epidemiological evidence showing that young and advanced maternal age at childbirth are associated with ADHD and LD risk.
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Trastorno por Déficit de Atención con Hiperactividad , Discapacidades para el Aprendizaje , Embarazo , Femenino , Humanos , Edad Materna , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/etiología , Encuestas Nutricionales , Reproducibilidad de los Resultados , Discapacidades para el Aprendizaje/complicaciones , Discapacidades para el Aprendizaje/epidemiologíaRESUMEN
OBJECTIVES: The aim of this study is to assess Heparin-binding protein (HBP) as a diagnostic and prognostic biomarker of severe sepsis in the pediatric intensive care unit (PICU). METHODS: A multicenter, prospective study was conducted among children with sepsis in nine PICUs in China from October 2019 to June 2021. Plasma levels of HBP, procalcitonin (PCT), C-reactive protein (CRP), lactate, and white blood cell (WBC) count were determined at enrollment and 72 h after enrollment. RESULTS: Of 355 included patients, 132 patients were diagnosed with non-severe sepsis (referred to as sepsis), 223 patients had severe sepsis. Patients with severe sepsis had significantly elevated levels of HBP compared with sepsis (median 170.5 vs. 74.1 ng/mL, P < 0.001). Adding HBP to a diagnostic model with PCT and lactate could significantly improve the diagnostic capability for severe sepsis. The plasma levels of HBP correlated positively with the number of dysfunctional organs. After adjusting for confounding factors, the declined levels of HBP at 72 h had a significant association with decreased in-hospital mortality (adjusted odds ratio (aOR) 0.242, P < 0.001). The levels of HBP showed weak positive correlations with PCT, CRP, WBC, and no correlation to lactate. CONCLUSIONS: HBP at enrollment can be an independent indicator for severe sepsis and the dynamic changes at 72 h can be a predictor for in-hospital mortality in PICU.
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Sepsis , Niño , Humanos , Estudios Prospectivos , Biomarcadores , Proteína C-Reactiva/análisis , Unidades de Cuidado Intensivo Pediátrico , Polipéptido alfa Relacionado con Calcitonina , Ácido Láctico , PronósticoRESUMEN
BACKGROUND: Septic shock is a serious clinical syndrome leading to high mortality. A new anti-anemia drug Roxadustat (FG-4592) protected against cardiac injury and hypertension. However, its effect and mechanism on shock and cardiac dysfunction induced by sepsis require to be investigated. METHODS: C57BL/6j mice received FG-4592 (10 mg/kg/day) by i.p injection, followed by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) treatment. Mortality and shock status were monitored during the experiment. Cardiac function was assessed using echocardiography and serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) assay. TEM, COX-SDH staining and ATP production were used to evaluate mitochondrial function. A non-targeted metabolomic analysis was performed to evaluate the metabolic disorders. RESULTS: Both pre- and post-treatment of FG-4592 could improve the survival rate in LPS- and CLP-induced sepsis mice with a better effect in pre-treated animals. Meanwhile, FG-4592 improved systolic blood pressure and body temperature drop in septic mice along with alleviated cardiac dysfunction (as shown by the restoration of decreased LVEF and LVFS and increased LDH and CK-MB) and inflammation. Interestingly, we observed that FG-4592 improved mitochondrial oxidative stress possibly by upregulating the anti-oxidative enzymes of SOD2 and HO-1. Furthermore, FG-4592 improved the energy supply and glycerophospholipid metabolism in cardiomyocytes, possibly through upregulating the HIF-1α-targeted genes of LDHA and PDK1 in glycolysis and CHK-α, respectively. CONCLUSIONS: FG-4592 protected against mortality and shock in septic animals possibly by antagonizing mitochondrial oxidative stress and metabolic disorders. GENERAL SIGNIFICANCE: This study provides a potential of FG-4592 as a novel drug for treating septic shock.
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Cardiopatías , Sepsis , Choque Séptico , Ratones , Animales , Choque Séptico/tratamiento farmacológico , Ratones Endogámicos C57BL , Lipopolisacáridos/farmacología , Sepsis/tratamiento farmacológico , Sepsis/genética , Metabolismo Energético , Estrés OxidativoRESUMEN
Acute myelocytic leukemia (AML) is a malignancy of the stem cell precursors of the myeloid lineage. CD4+ and CD8+ T cells play pivotal roles in influencing AML progression but are functionally suppressed in the bone marrow microenvironment. We aimed to find hub genes related to T cell exhaustion and suppression, thereby providing evidence for immunotherapy. In this study, gene transcriptome expression data from TCGA and TARGET databases were utilized to find key genes. Firstly, CIBERSORT immune cell infiltration algorithm and WGCNA method were used to identify CD4+ and CD8+ T cells-related genes. Univariate and multivariate cox regression analyses were then introduced to construct the overall survival prognosis model and included hub genes. The ESTIMATE and ssGSEA scoring methods were used to analyze the correlation between the hub genes and immune activity. Single-cell transcriptome analysis was applied to detect the immune cells expressing hub genes, hence, to detect exact mechanisms. Consequently, FLT3LG and IFITM3P6 were determined to be positively correlated with patients' overall survival and microenvironment immune activity. Further study suggested FLT3-FLT3LG and IFITM3P6-miR-6748-3p-CBX7 signaling axes were involved in CD4+ and CD8+ T cells activation. This may be one of the mechanisms of T cells suppression in AML.
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Médula Ósea , Linfocitos T CD8-positivos , Factores de Crecimiento de Célula Hematopoyética , Leucemia Mieloide Aguda , Proteínas de la Membrana , Proteínas de Unión al ARN , Médula Ósea/metabolismo , Células de la Médula Ósea/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Complejo Represivo Polycomb 1/metabolismo , Pronóstico , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Microambiente TumoralRESUMEN
Evidence showing the association of perfluoroalkylated substance (PFAS) exposure with CVD risk is scarce. The objective of this study was to explore the relationships of CVD risk with mixed or individual serum PFAS levels among general adults. We analyzed combined data of 7904 adults who participated in the National Health and Nutrition Examination Survey 2003-2012 with a Bayesian kernel machine regression (BKMR) to examine the relationships of individual or mixed PFAS exposure with total CVD risk. A logistic regression model and restricted cubic spline (RCS) regression with multivariate adjustment were conducted to assess the relationships between individual serum PFAS levels and the risk of total CVD or its subtypes. A mediation model was applied to investigate how C-reactive protein (CRP) levels mediate the strength of the association. The BKMR results indicated a positive relationship between mixed PFAS exposure and total CVD risk; among the PFASs, perfluorooctane sulfonic acid (PFOS) had the highest posterior inclusion probability. As determined by logistic regression, a log-unit change in PFOS levels was positively related to a higher risk of heart attack and stroke in males (both P < 0.05). A nonlinear relationship was found between PFOS levels and stroke risk (P for nonlinearity = 0.04), as illustrated in the RCS plot. The mediation analysis showed that CRP levels mediated 8% and 1.2% of the relationship between serum PFOS and PFNA levels, respectively, and the prevalence of stroke. A significant relationship between higher serum PFAS concentrations and an increased risk of CVD was observed, mainly in males.
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Ácidos Alcanesulfónicos , Enfermedades Cardiovasculares , Contaminantes Ambientales , Fluorocarburos , Accidente Cerebrovascular , Adulto , Humanos , Masculino , Encuestas Nutricionales , Enfermedades Cardiovasculares/epidemiología , Teorema de BayesRESUMEN
Acute kidney injury (AKI) is a clinical syndrome characterized by morbidity, mortality, and cost. Cis-diamminedichloroplatinum (cisplatin) is a chemotherapeutic agent used to treat solid tumors and hematological malignancies, but its side effects, especially nephrotoxicity, limit its clinical application. Isoliquiritin (ISL), one of the major flavonoid glycoside compounds in licorice, has been reported to have anti-apoptotic, antioxidant, and anti-inflammatory activities. However, the effect and mechanism of ISL on cisplatin-induced renal proximal tubular cell injury remain unknown. In this study, mouse proximal tubular cells (mPTCs) and human proximal tubule epithelial cells (HK2) were administered increasing concentrations of ISL from 7.8125 to 250 µM. Moreover, mPTC and HK2 cells were pretreated with ISL for 6-8 h, followed by stimulation with cisplatin for 24 h. CCK-8 assay was performed to evaluate the cell viability. Apoptosis and reactive oxygen species (ROS) of cells were measured by using flow cytometer and western blotting. Our results showed that ISL had no obvious effect on cell viability. ISL decreased cisplatin-induced cell injury in a dose-dependent manner. ISL also protected against cisplatin-induced cell apoptosis. Meanwhile, the enhanced protein levels of Bax, cleaved caspase-3/caspase-3 ratio, levels of Pp-65/p-65, levels of IL-6, and the production of ROS induced by cisplatin were significantly attenuated by ISL treatment. Moreover, ISL markedly increased the protein levels of Bcl-2 and SOD2, which were reduced by cisplatin stimulation. These results showed that ISL ameliorated cisplatin-induced renal proximal tubular cell injury by antagonizing apoptosis, oxidative stress and inflammation.
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Doxorubicin (DOX) is broadly used in treating various malignant tumors. However, its cardiotoxicity limits its clinical use. Roxadustat (FG-4592) is a new hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor and has been approved for treating anemia in chronic kidney diseases (CKD) patients. However, the role of FG-4592 in DOX-induced cardiotoxicity remains unknown. In this study, mouse cardiac function was evaluated by echocardiography, plasma LDH/CK-MB, and heart HE staining. Cell viability, apoptosis, oxidative stress, inflammation, and HIF-target genes were evaluated in mouse cardiac tissue and cardiac cells exposed to DOX with FG-4592 pretreatment. DOX-sensitive HepG2 and MCF-7 cell lines were used to evaluate FG-4592 effect on the anticancer activity of DOX. We found that FG-4592 alleviated DOX-induced cardiotoxicity shown by the protection against cardiac dysfunction, cardiac apoptosis, and oxidative stress without the effect on inflammatory response. FG-4592 alone did not change the cardiac function, cardiomyocyte morphology, oxidative stress, and inflammation in vivo. FG-4592 could protect cardiomyocytes against DOX-induced apoptosis and ROS production in line with the upregulation of HIF-1α and its target genes of Bcl-2 and SOD2. Importantly, FG-4592 displayed anticancer property in cancer cells treated with or without DOX. These findings highlighted the protective effect of FG-4592 on DOX-induced cardiotoxicity possibly through upregulating HIF-1α and its target genes antagonizing apoptosis and oxidative stress.
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BACKGROUND: Heparin-binding protein (HBP), a potent inducer of increased vascular permeability, is a potentially useful biomarker for predicting outcomes in patients with postoperative myocardial injury-related cardiogenic shock (MIRCS). We aimed to evaluate and validate HBP as a prognostic biomarker for postoperative MIRCS. METHODS: We performed a case-control study in 792 patients undergoing cardiac surgery from January 1, 2016, to August 1, 2019, including 172 patients with postoperative MIRCS and 620 age- and sex-matched controls. The association between HBP and MIRCS was determined by multivariate logistic regression analysis. Receiver operating characteristic curves (ROCs) with area under the curve (AUC) were performed to calculate the cut-off value, sensitivity and specificity. The association between HBP and cardiac troponin T (cTnT) was determined by multivariable linear regression analysis. Blood samples were drawn from the coronary sinus and arterial line of the cardiopulmonary bypass (CPB) before aortic cross-clamping (time point 1) and 5 min after aortic declamping (time point 2). RESULTS: Before aortic cross-clamping, coronary sinus HBP (HBPCS1) showed no differences between the two groups. However, after declamping, the MIRCS group had a significantly higher sinus HBP level (HBPCS2) than did the control group. HBPCS2 predicted MIRCS with an AUC of 0.85 (95% CI: 0.81-0.89, cut-off: 220 ng/ml, sensitivity: 92% and specificity: 70%). After adjusting for confounding factors, we found that HBP was an independent risk factor for MIRCS (OR: 7.65, 95% CI: 4.86-12.06, P < 0.01) and was positively associated with cTnT (ß > 0, P < 0.01). CONCLUSIONS: Elevated levels of coronary sinus HBP were useful biomarkers for predicting MIRCS after cardiac surgery.
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Péptidos Catiónicos Antimicrobianos/sangre , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Choque Cardiogénico/etiología , Anciano , Biomarcadores/sangre , Proteínas Sanguíneas , Procedimientos Quirúrgicos Cardíacos/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Choque Cardiogénico/sangre , Choque Cardiogénico/diagnóstico , Choque Cardiogénico/mortalidad , Factores de Tiempo , Troponina T/sangre , Regulación hacia ArribaRESUMEN
Diabetic nephropathy (DN) is one of the leading causes of mortality in diabetic patients, but its pathogenesis is unclear. We aimed to study the role of the pro-ANP convertase Corin in the pathogenesis of DN. Corin and ANP expression in DN rat kidneys and high-glucose-treated HK-2 cells was analyzed by real-time PCR, western blotting, and immunohistochemical staining. The effect of Corin-siRNA or ANP-siRNA HK-2 cells on EA.hy926 cell migration was determined by scratch-wound healing assay. The expression of mitogen-activated protein kinase (MAPK) and endothelial NO synthase (eNOS) in EA.hy926 cells treated with conditioned medium from Corin-siRNA- or ANP-siRNA-transfected HK-2 cells was determined by western blotting. We found a significant reduction in Corin and ANP expression in DN rat kidneys. These results were recapitulated in HK-2 cells treated with high glucose. EA.hy926 cells treated with conditioned medium from Corin-deficient HK-2 cells had inhibited migration, increased MAPK activity, and decreased eNOS activity. Similar effects were observed with ANP-siRNA transfection. Finally, adding ANP to the Corin-deficient HK-2 conditioned medium rescued the above defects, indicating that Corin mediates its effects through ANP. In conclusion, Corin plays a renoprotective role through pro-ANP processing, and defects in Corin cause endothelial dysfunction through MAPK and eNOS signaling in DN.
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Nefropatías Diabéticas/metabolismo , Endotelio/patología , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Serina Endopeptidasas/metabolismo , Animales , Línea Celular , Proliferación Celular , Supervivencia Celular , Diabetes Mellitus Experimental , Endotelio/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/toxicidad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Túbulos Renales Proximales/citología , Masculino , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Óxido Nítrico Sintasa de Tipo III/genética , Interferencia de ARN , ARN Interferente Pequeño , Ratas Sprague-Dawley , Serina Endopeptidasas/genética , Serina Endopeptidasas/orinaRESUMEN
Cisplatin is extensively used and is highly effective in clinical oncology; nevertheless, nephrotoxicity has severely limited its widespread utility. Isoquercitrin (IQC), a natural flavonoid widely found in herbage, is well known and recognized for its antioxidant, anti-inflammatory, and anti-apoptotic properties. However, the potential effects and mechanism of IQC in cisplatin-induced acute kidney diseases remain unknown. In this study, we postulated the potential effects and mechanism of IQC upon cisplatin exposure in vivo and in vitro. For the in vivo study, C57BL/6J mice were pretreated with IQC or saline (50 mg/kg/day) by gavage for 3 days before cisplatin single injection (25 mg/kg). Renal function, apoptosis, inflammation, oxidative stress and p-ERK were measured to evaluate kidney injury. In vitro, mouse proximal tubular cells (mPTCs) and human proximal tubule epithelial cell line (HK2) were pretreated with or without IQC (80 µM for mPTCs and 120 µM for HK2) for 2 h and then co-administrated with cisplatin for another 24 h. Apoptosis, inflammation, ROS and p-ERK of cells were also measured. In vivo, IQC administration strikingly reduced cisplatin-induced nephrotoxicity as evidenced by the improvement in renal function (serum creatinine and blood urea nitrogen), kidney histology (PAS staining), apoptotic molecules (cleaved caspase-3, caspase-8, Bax and Bcl-2), inï¬ammatory cytokines (IL-1ß, IL-6, TNF-α, and COX-2), oxidative stress (MDA and total glutathione) and p-ERK. In line with in vivo findings, IQC markedly protected against cisplatin-induced cell injury in mPTCs and HK2 cells. Collectively, these findings demonstrated that IQC administration could significantly protect against cisplatin nephrotoxicity possibly through ameliorating apoptosis, inflammation and oxidative stress accompanied by cross talk with p-ERK. Furthermore, IQC may have potential therapeutic uses in the treatment of cisplatin-induced acute kidney injury.
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Diabetic cardiomyopathy (DCM) is a leading contributor to the increased morbidity and mortality rates associated with diabetes. Persistent inflammation has previously been reported to be involved in the pathogenesis of DCM. However, the exact underlying molecular mechanisms remain to be fully elucidated. In the present study, the role of spleen tyrosine kinase (Syk) and cJun Nterminal kinase (JNK) in NLR family pyrin domaincontaining 3 (NLRP3 inflammasome) activation in DCM were investigated in vivo and in vitro. Streptozotocin (65 mg/kg) was injected intraperitoneally into SpragueDawley rats to induce a rat model of diabetes. Neonatal rat cardiomyocytes and H9c2 cells were cultured to detect the expression of JNK, NLRP3 and its associated downstream molecules, following treatment with Syk/JNK inhibitor or Syk/JNKsmall interfering (si)RNA in high glucose (HG) conditions. It was revealed that the protein and mRNA expression levels of phospho (p)Syk, pJNK, NLRP3 and its associated downstream molecules, including interleukin (IL)1ß, were upregulated in vivo and in vitro. The JNK inhibitor significantly decreased the expression of NLRP3 and its downstream molecules in neonatal rat cardiomyocytes and H9c2 cells treated with HG. Furthermore, SyksiRNA and the Syk inhibitor markedly inhibited the HGinduced activation of JNK, followed by the downregulation of NLRP3 and its downstream molecules at the mRNA and protein levels in cells. Therefore, it was demonstrated that the HGinduced activation of NLRP3 was mediated by the activation of Syk/JNK, which subsequently increased the protein expression levels of mature IL1ß, suggesting that the Syk/JNK/NLRP3 signaling pathway serves a critical role in the pathogenesis of DCM.
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Diabetes Mellitus Experimental/inmunología , Cardiomiopatías Diabéticas/inmunología , Inflamasomas/inmunología , Proteínas Quinasas JNK Activadas por Mitógenos/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Quinasa Syk/inmunología , Animales , Línea Celular , Células Cultivadas , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/patología , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/patología , Masculino , Ratas Sprague-DawleyRESUMEN
Diabetic nephropathy (DN) is a serious complication of diabetes and can cause an increased mortality risk. It was previously reported that NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in the pathogenesis of diabetes. However, the underlying mechanism is not clearly understood. In the present study, the effects of spleen tyrosine kinase (Syk) and cJun Nterminal kinase (JNK) on the NLRP3 inflammasome were examined in vivo and in vitro. SpragueDawley rats were injected intraperitoneally with streptozotocin (65 mg/kg) to induce diabetes. HK2 cells and rat glomerular mesangial cells (RGMCs) were examined to detect the expression of JNK and NLRP3 inflammasomeassociated proteins following treatment with a Syk inhibitor or Syksmall interfering (si)RNA in a high glucose condition. In the present study, it was revealed that the protein and mRNA expression levels of NLRP3 inflammasomeassociated molecules and the downstream mature interleukin (IL)1ß were upregulated in vivo and in vitro. The Syk inhibitor and SyksiRNA suppressed high glucoseinduced JNK activation, and subsequently downregulated the activation of the NLRP3 inflammasome and mature IL1ß in HK2 cells and RGMCs. Furthermore, high glucoseinduced apoptosis of HK2 cells was reduced by the Syk inhibitor BAY613606. Therefore, the present results determined that high glucoseinduced activation of the NLRP3 inflammasome is mediated by Syk/JNK activation, which subsequently increased the protein expression level of IL1ß and mature IL1ß. The present study identified that the Syk/JNK/NLRP3 signaling pathway may serve a vital role in the pathogenesis of DN.
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Apoptosis , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Quinasa Syk/metabolismo , Animales , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/patología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND Primary Sjögren's syndrome (pSS) is one of the most common chronic systemic autoimmune diseases, and thrombocytopenia is one of the hematological manifestations of pSS. When platelet and endothelial cells are activated, P-selectin is expressed on the cell surface. This study aimed to investigate the role of P-selectin autoantibodies in the pathogenesis of thrombocytopenia in pSS. MATERIAL AND METHODS P-selectin autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA) in 38 pSS patients without thrombocytopenia and 32 pSS patients with thrombocytopenia, 32 idiopathic thrombocytopenic purpura (ITP) patients, and 35 healthy controls. RESULTS The plasma P-selectin autoantibodies (A490) in ITP patients and pSS patients with/without thrombocytopenia were significantly higher than those in healthy controls, but there were no significant differences between ITP patients and pSS patients with thrombocytopenia. The positive rate of P-selectin autoantibodies in pSS patients with thrombocytopenia was significantly higher than that in ITP patients. The platelet count was lower in P-selectin autoantibodies-positive patients, while among pSS patients with thrombocytopenia, the platelet count was lower in P-selectin autoantibodies-positive patients than in P-selectin autoantibodies-negative patients. In ITP patients and pSS patients with thrombocytopenia, the platelet count was lower in P-selectin autoantibodies-positive patients. CONCLUSIONS Elevated plasma P-selectin autoantibodies may play a role in the pathogenesis of thrombocytopenia in pSS patients.
Asunto(s)
Autoanticuerpos/sangre , Selectina-P/inmunología , Síndrome de Sjögren/sangre , Trombocitopenia/sangre , Adolescente , Adulto , Autoanticuerpos/inmunología , Plaquetas/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Síndrome de Sjögren/inmunología , Trombocitopenia/inmunologíaRESUMEN
BACKGROUND: Diabetic cardiomyopathy (DCM), a fatal cardiovascular complication of diabetes mellitus, often leads to progressive heart failure, however its pathogenesis remains unclear. Corin, a cardiac serine protease, is responsible for converting pro-atrial natriuretic peptide (pro-ANP) to biologically active atrial natriuretic peptide (ANP). It has been well established that corin deficiency is associated with the progression of hypertension, cardiac hypertrophy and heart failure. However, because the involvement of corin-mediated pro-ANP processing in DCM has not been clarified, this study aims to investigate the role of corin in the pathogenesis of DCM. METHODS: Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ 65 mg/kg) to Sprague-Dawley rats (180-220 g). DCM was confirmed by monitoring continuously transthoracic echocardiography every 4 weeks and hemodynamic measurements at 20 weeks. Myocardial disorder and fibrosis were detected by HE staining and Masson's trichrome staining. The mRNA and protein levels of corin and ANP in rat hearts and cardiomyocytes were determined by quantitative real-time PCR, western blotting and immunohistochemical staining, respectively. H9c2 cardiomyoblasts proliferation was detected by MTT colorimetric assay and viable cell counting with trypan blue. The effect of Corin-siRNA H9c2 cardiomyoblasts on EA.hy926 cells migration was measured by the wound healing scratch assay. RESULTS: The corin and ANP expression in mRNA and protein levels was decreased in DCM rat hearts. Corin and ANP levels of neonatal rat cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose were significantly lower than that of normal glucose treated. Precisely, corin and ANP levels decreased in DCM rats at 12, 16, 20 and 33 weeks; neonatal cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose at 36, 48 and 60 h demonstrated significant reduction in corin and ANP levels. Corin-siRNA H9c2 cardiomyoblasts showed decreased proliferation. Culture supernatants of Corin-siRNA H9c2 cardiomyoblasts prevented endothelial cell line EA.hy926 migration in the wound healing scratch assay. Furthermore, iso-lectin expression in arteriole and capillary endothelium was down-regulated in DCM rats. CONCLUSIONS: Our results indicate that corin plays an important role in cardioprotection by activating pro-atrial natriuretic peptide pathway in DCM. Corin deficiency leads to endothelial dysfunction and vascular remodeling.