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1.
Sci Rep ; 14(1): 19839, 2024 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-39191928

RESUMEN

The compound NS5806 is a Kv4 channel modulator. This study investigated the chronic effects of NS5806 on cardiac hypertrophy induced by transverse aortic constriction (TAC) in mice in vivo and on neonatal rat ventricular cardiomyocyte hypertrophy induced by endothelin-1 (ET-1) in vitro. Four weeks after TAC, NS5806 was administered by gavage for 4 weeks. Echocardiograms revealed pronounced left ventricular (LV) hypertrophy in TAC-treated mice compared with sham mice. NS5806 attenuated LV hypertrophy, as manifested by the restoration of LV wall thickness and weight and the reversal of contractile dysfunction in TAC-treated mice. NS5806 also blunted the TAC-induced increases in the expression of cardiac hypertrophic and fibrotic genes, including ANP, BNP and TGF-ß. Electrophysiological recordings revealed a significant prolongation of action potential duration and QT intervals, accompanied by an increase in susceptibility to ventricular arrhythmias in mice with cardiac hypertrophy. However, NS5806 restored these alterations in electrical parameters and thus reduced the incidence of mouse sudden death. Furthermore, NS5806 abrogated the downregulation of the Kv4 protein in the hypertrophic myocardium but did not influence the reduction in Kv4 mRNA expression. In addition, NS5806 suppressed in vitro cardiomyocyte hypertrophy. The results provide novel insight for further ion channel modulator development as a potential treatment option for cardiac hypertrophy.


Asunto(s)
Cardiomegalia , Miocitos Cardíacos , Canales de Potasio Shal , Animales , Ratones , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Canales de Potasio Shal/metabolismo , Canales de Potasio Shal/genética , Cardiomegalia/metabolismo , Cardiomegalia/patología , Cardiomegalia/tratamiento farmacológico , Masculino , Ratas , Ratones Endogámicos C57BL , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/patología , Modelos Animales de Enfermedad , Compuestos de Fenilurea , Tetrazoles
2.
Anal Chem ; 96(33): 13379-13388, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39105793

RESUMEN

Highly sensitive detection of low-frequency EGFR-L858R mutation is particularly important in guiding targeted therapy of nonsmall-cell lung carcinoma (NSCLC). To this end, a ligase chain reaction (LCR)-based electrochemical biosensor (e-LCR) with an inverted sandwich-type architecture was provided by combining a cooperation of lambda exonuclease-RecJf exonuclease (λ-RecJf exo). In this work, by designing a knife-like DNA substrate (an overhang ssDNA part referred to the "knife arm") and introducing the λ-RecJf exo, the unreacted DNA probes in the LCR were specially degraded while only the ligated products were preserved, after which the ligated knife-like DNA products were hybridized with capture probes on the gold electrode surface through the "knife arms", forming the inverted sandwich-type DNA structure and bringing the methylene blue-label close to the electrode surface to engender the electrical signal. Finally, the sensitivity of the e-LCR could be improved by 3 orders of magnitude with the help of the λ-RecJf exo, and due to the mutation recognizing in the ligation site of the employed ligase, this method could detect EGFR-L858R mutation down to 0.01%, along with a linear range of 1 fM-10 pM and a limit detection of 0.8 fM. Further, the developed method could distinguish between L858R positive and negative mutations in cultured cell samples, tumor tissue samples, and plasma samples, whose accuracy was verified by the droplet digital PCR, holding a huge potential in liquid biopsy for precisely guiding individualized-treatment of NSCLC patients with advantages of high sensitivity, low cost, and adaptability to point-of-care testing.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Técnicas Electroquímicas , Receptores ErbB , Exodesoxirribonucleasas , Neoplasias Pulmonares , Mutación , Receptores ErbB/genética , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Exodesoxirribonucleasas/química , Exodesoxirribonucleasas/metabolismo , Exodesoxirribonucleasas/genética , Técnicas Biosensibles , Reacción en Cadena de la Ligasa , Límite de Detección , Proteínas Virales
3.
Plant Physiol Biochem ; 215: 109036, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39128404

RESUMEN

In plants, microRNAs (miRNAs) are a class of important small RNAs involved in their growth and development, and play a very significant role in regulating their tissue coloring. In this paper, the mechanisms on miRNA regulation of plant coloring are mainly reviewed from three aspects: macroscopic physiological and molecular foundations related to tissue coloring, miRNA biosynthesis and function, and specific analysis of miRNA regulation studies on leaf color, flower color, fruit color, and other tissue color formation in plants. Furthermore, we also systematically summarize the miRNA regulatory mechanisms identified on pigments biosynthesis and color formation in plants, and the regulatory mechanisms of these miRNAs mentioned on the existing researches can be divided into four main categories: directly targeting the related transcription factors, directly targeting the related structural genes, directly targeting the related long noncoding RNAs (LncRNAs) and miRNA-mediated production of trans-acting small interfering RNAs (ta-siRNAs). Together, these research results aim to provide a theoretical reference for the in-depth study of plant coloring mechanism and molecular breeding study of related plants in the future.


Asunto(s)
Regulación de la Expresión Génica de las Plantas , MicroARNs , ARN de Planta , MicroARNs/genética , MicroARNs/metabolismo , ARN de Planta/genética , ARN de Planta/metabolismo , Plantas/genética , Plantas/metabolismo , Pigmentación/genética , Hojas de la Planta/genética , Hojas de la Planta/metabolismo , Flores/genética
4.
Med Sci Monit ; 30: e944383, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39039768

RESUMEN

BACKGROUND The evidence on use of supplementary titanium cable cerclage (TCC) in treating femoral subtrochanteric fractures (FSF) remains scarce. Therefore, this study aimed to investigate the potential therapeutic effects for FSF patients using TCC. MATERIAL AND METHODS A retrospective study of 68 FSF patients treated by a long intramedullary (IM) nailing with (Observation group, n=41) or without (Control group, n=27) TCC was conducted from January 2020 to December 2021. The primary outcome measure was time to postoperative full weight-bearing. Secondary outcome measures were operation time, intraoperative blood loss, number of blood transfusions needed, varus angle loss, excellent and good rate of fracture reduction, Harris score, and survival rate. RESULTS Patients were followed up for 13 to 36 months. The excellent and good rate of fracture reduction was 100% in the Observation group versus 92.6% in the Control group (P=0.013), and the varus angle loss and time to postoperative full weight-bearing in the Observation group were significantly less than in the Control group (P<0.05). The intraoperative blood loss in the Observation group was significantly higher than in the Control group (P<0.001). No differences were noted between groups for Harris scores and survival rates at last follow-up. CONCLUSIONS TCC fixation combined with IM nailing can improve the excellent and good rate of fracture reduction and reduce varus angle loss, as well as shorten the time to full weight-bearing and promote early functional exercise, which offers an effective treatment option for FSF patients who have failed closed reduction.


Asunto(s)
Clavos Ortopédicos , Fijación Intramedular de Fracturas , Fracturas de Cadera , Titanio , Humanos , Femenino , Estudios Retrospectivos , Masculino , Fijación Intramedular de Fracturas/métodos , Anciano , Fracturas de Cadera/cirugía , Resultado del Tratamiento , Persona de Mediana Edad , Fracturas del Fémur/cirugía , Anciano de 80 o más Años , Soporte de Peso
5.
Ren Fail ; 46(2): 2357246, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38832490

RESUMEN

OBJECTIVE: A two-sample Mendelian randomization (MR) analysis was performed to elucidate the causal impact of celiac disease on the risk of chronic kidney disease (CKD). METHODS: The study comprised data from three genome-wide association studies involving individuals of European ancestry. The study groups included participants with celiac disease (n = 24,269), CKD (n = 117,165), and estimated glomerular filtration rate levels based on serum creatinine (eGFRcrea, n = 133,413). We employed four widely recognized causal inference algorithms: MR-Egger, inverse variance weighted (IVW), weighted median, and weighted mode. To address potential issues related to pleiotropy and overall effects, MR-Egger regression and the MR-PRESSO global test were performed. Heterogeneity was assessed using Cochran's Q test. RESULTS: We identified 14 genetic variants with genome-wide significance. The MR analysis provided consistent evidence across the various methodologies, supporting a causal relationship between celiac disease and an elevated risk of CKD (odds ratio (OR)IVW = 1.027, p = 0.025; ORweighted median = 1.028, P = 0.049; ORweighted mode = 1.030, p = 0.044). Furthermore, we observed a causal link between celiac disease and a decreased eGFRcrea (ORIVW = 0.997, P = 2.94E-06; ORweighted median = 0.996, P = 1.68E-05; ORweighted mode = 0.996, P = 3.11E-04; ORMR Egger = 0.996, P = 5.00E-03). We found no significant evidence of horizontal pleiotropy, heterogeneity, or bias based on MR-Egger regression, MR-PRESSO, and Cochran's Q test. CONCLUSION: The results of this study indicate a causal relationship between celiac disease and an increased risk of CKD.


Asunto(s)
Enfermedad Celíaca , Estudio de Asociación del Genoma Completo , Tasa de Filtración Glomerular , Análisis de la Aleatorización Mendeliana , Insuficiencia Renal Crónica , Humanos , Enfermedad Celíaca/genética , Enfermedad Celíaca/complicaciones , Insuficiencia Renal Crónica/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Femenino , Masculino , Factores de Riesgo
6.
Adv Healthc Mater ; 13(22): e2401087, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38696899

RESUMEN

Hypoxia, a ubiquitous hallmark in cancer, underscores the significance of targeting HIF-1α, the principal transcriptional factor of hypoxic responses, for effective cancer therapy. Herein, DNA yokes, a novel class of DNA nanomaterials harboring specific HIF-1α binding sequences (hypoxia response elements, HREs), are introduced as nanopharmaceuticals for cancer treatment. Comprising a basal tetrahedral DNA nanostructure and four HRE-bearing overhanging chains, DNA yokes exhibit exceptional stability and prolonged intracellular retention. The investigation reveals their capacity to bind HIF-1α, thereby disrupting its interaction with the downstream genomic DNAs and impeding transcriptional activity. Moreover, DNA yokes facilitate HIF-1α degradation via the ubiquitination pathway, thereby sequestering it from downstream targets and ultimately promoting its degradation. In addition, DNA yokes attenuate cancer cell proliferation, migration, and invasion under hypoxic conditions, while also displaying preferential accumulation within tumors, thereby inhibiting tumor growth and metastasis in vivo. This study pioneers a novel approach to cancer therapy through the development of DNA-based drugs characterized by high stability and low toxicity to normal cells, positioning DNA yokes as promising candidates for cancer treatment.


Asunto(s)
ADN , Subunidad alfa del Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Humanos , ADN/química , ADN/metabolismo , Animales , Línea Celular Tumoral , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Nanoestructuras/química , Antineoplásicos/farmacología , Antineoplásicos/química , Ratones Endogámicos BALB C , Movimiento Celular/efectos de los fármacos , Elementos de Respuesta
7.
Toxicology ; 505: 153830, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38754619

RESUMEN

The use of tyrosine kinase inhibitors (TKIs) has resulted in significant occurrence of arrhythmias. However, the precise mechanism of the proarrhythmic effect is not fully understood. In this study, we found that nilotinib (NIL), vandetanib (VAN), and mobocertinib (MOB) induced the development of "cellrhythmia" (arrhythmia-like events) in a concentration-dependent manner in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Continuous administration of NIL, VAN, or MOB in animals significantly prolonged the action potential durations (APD) and increased susceptibility to arrhythmias. Using phosphoproteomic analysis, we identified proteins with altered phosphorylation levels after treatment with 3 µM NIL, VAN, and MOB for 1.5 h. Using these identified proteins as substrates, we performed kinase-substrate enrichment analysis to identify the kinases driving the changes in phosphorylation levels of these proteins. MAPK and WNK were both inhibited by NIL, VAN, and MOB. A selective inhibitor of WNK1, WNK-IN-11, induced concentration- and time-dependent cellrhythmias and prolonged field potential duration (FPD) in hiPSC-CMs in vitro; furthermore, administration in guinea pigs confirmed that WNK-IN-11 prolonged ventricular repolarization and increased susceptibility to arrhythmias. Fingding indicated that WNK1 inhibition had an in vivo and in vitro arrhythmogenic phenotype similar to TKIs. Additionally,three of TKIs reduced hERG and KCNQ1 expression at protein level, not at transcription level. Similarly, the knockdown of WNK1 decreased hERG and KCNQ1 protein expression in hiPSC-CMs. Collectively, our data suggest that the proarrhythmic effects of NIL, VAN, and MOB occur through a kinase inhibition mechanism. NIL, VAN, and MOB inhibit WNK1 kinase, leading to a decrease in hERG and KCNQ1 protein expression, thereby prolonging action potential repolarization and consequently cause arrhythmias.


Asunto(s)
Potenciales de Acción , Arritmias Cardíacas , Miocitos Cardíacos , Piperidinas , Proteómica , Pirimidinas , Quinazolinas , Humanos , Arritmias Cardíacas/inducido químicamente , Animales , Proteómica/métodos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Piperidinas/farmacología , Piperidinas/toxicidad , Pirimidinas/toxicidad , Pirimidinas/farmacología , Quinazolinas/toxicidad , Quinazolinas/farmacología , Potenciales de Acción/efectos de los fármacos , Inhibidores de Proteínas Quinasas/toxicidad , Inhibidores de Proteínas Quinasas/farmacología , Fosforilación , Canal de Potasio ERG1/metabolismo , Canal de Potasio ERG1/antagonistas & inhibidores , Canal de Potasio ERG1/genética , Cobayas , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Canal de Potasio KCNQ1/metabolismo , Canal de Potasio KCNQ1/genética , Canal de Potasio KCNQ1/efectos de los fármacos , Fosfoproteínas/metabolismo , Relación Dosis-Respuesta a Droga
8.
Toxicol Lett ; 397: 23-33, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38734218

RESUMEN

Osimertinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used for cancer treatment, can cause significant cardiac toxicity. However, the specific mechanism of osimertinib-induced cardiotoxicity is not fully understood. In this study, we administered osimertinib to mice and neonatal rat ventricular myocytes (NRVMs). We observed significant structural and functional damage to the hearts of these mice, along with a marked increase in cardiac injury biomarkers and accompanying ultrastructural damage to mitochondria. We integrated 4D label-free protein quantification and RNA-Seq methods to analyze the sequencing data of NRVMs under osimertinib treatment (0 and 2.5 µM). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis evidenced that differentially expressed genes (DEGs)and differentially expressed proteins (DEPs) were distinctly enriched for oxidative phosphorylation (OXPHOs). Simultaneously, osimertinib primarily affected the contents of adenosine triphosphate (ATP). Further investigations revealed that osimertinib disrupts the functions of the ATP synthase (complex V), leading to a reduction in ATP production. Taken together, our data demonstrated that osimertinib causes mitochondrial dysfunction, which in turn leads to the onset of cardiac toxicity.


Asunto(s)
Acrilamidas , Compuestos de Anilina , Cardiotoxicidad , Mitocondrias Cardíacas , Miocitos Cardíacos , Proteómica , Animales , Acrilamidas/toxicidad , Compuestos de Anilina/toxicidad , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/ultraestructura , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/ultraestructura , Proteómica/métodos , Ratones , Ratas , Masculino , Transcriptoma/efectos de los fármacos , Ratones Endogámicos C57BL , Inhibidores de Proteínas Quinasas/toxicidad , Inhibidores de Proteínas Quinasas/farmacología , Ratas Sprague-Dawley , Adenosina Trifosfato/metabolismo , Indoles , Pirimidinas
10.
PeerJ ; 12: e17266, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38650643

RESUMEN

Objective: Whether serum uric acid (SUA) at baseline could been identiûed as a risk factor for progression in IgA nephropathy (IgAN) patients remains unclear, therefore, long- term SUA control levels must be monitored. We aimed to investigate the relevant factors affecting time-averaged SUA (TA-SUA) and to assess the prognostic value of TA-SUA in IgAN. Methods: This retrospective study included 152 patients with IgAN. The relationships between TA-SUA and clinicopathological features and renal outcomes (defined as the doubling of the baseline serum creatinine level or end-stage renal disease) were analyzed in groups divided by quartiles of TA-SUA levels, the presence of hyperuricemia, and sex. Results: Patients with high TA-SUA levels had higher levels of baseline SUA, blood urea nitrogen (BUN), triglycerides, serum C3 and serum C4 and were more likely to be male and have hypertension, proteinuria, poor renal function, and pathological injuries including high grades of tubular atrophy/interstitial fibrosis (T1-T2). These patients had a poorer prognosis compared with patients with low TA-SUA levels. The TA-SUA level was positively correlated with baseline age and BUN, triglycerides, serum C3, and serum C4 levels, and negatively correlated with baseline eGFR. Survival curve analysis indicated that persistent hyperuricemia was associated with significantly poorer renal outcomes than normo-uricemia in both men and women. The TA-SUA level also was an independent predictor of renal outcome in patients with IgAN, with optimal cutoû values of 451.38 µmol/L (area under the curve (AUC) = 0.934) for men and 492.83 µmol/L (AUC = 0.768) for women. Conclusions: The TA-SUA level is associated with triglyceride level, complement component levels, renal function, and pathological severity of IgAN, and it may be a prognostic indicator in male and female patients with IgAN.


Asunto(s)
Glomerulonefritis por IGA , Ácido Úrico , Humanos , Glomerulonefritis por IGA/sangre , Glomerulonefritis por IGA/patología , Masculino , Femenino , Ácido Úrico/sangre , Estudios Retrospectivos , Adulto , Pronóstico , Hiperuricemia/sangre , Persona de Mediana Edad , Progresión de la Enfermedad , Factores de Riesgo , Fallo Renal Crónico/sangre
11.
Artículo en Inglés | MEDLINE | ID: mdl-38639613

RESUMEN

Background: Upper gastrointestinal bleeding encompasses bleeding arising from esophageal, gastric, duodenal, or pancreaticobiliary lesions above the Treitz ligament. Research indicates a close association between improper diet and upper gastrointestinal bleeding. Objective: This study aims to investigate the application effects of individualized diet nursing combined with the modified Glasgow-Blatchford scoring system in patients with upper gastrointestinal bleeding. Design: A randomized controlled study was conducted. Setting: The study took place at the First Hospital of Hebei Medical University. Participants: From January 2021 to October 2022, 80 patients with upper gastrointestinal bleeding were selected at our hospital. Using a random number table, they were divided into a control group and an observation group, each comprising 40 cases. Interventions: The control group received routine nursing, while the observation group received individualized diet nursing based on the Glasgow-Blatchford score in addition to routine nursing. Primary Outcome Measures: (1) bleeding frequency, hemostasis time, and hospital stay; (2) re-bleeding rate; (3) Glasgow-Blatchford scores; (4) quality of life; and (5) nursing satisfaction. Results: In the observation group, bleeding frequency, hemostasis time, and hospital stay significantly reduced compared to the control (P < .05). Post-nursing, the observation group had a lower re-bleeding rate (χ2=11.25, P < .05). Before nursing, no statistical differences existed in Glasgow-Blatchford and quality of life scores between groups (P > .05). Post-nursing, both groups saw reduced Glasgow-Blatchford scores, more so in the observation group (P < .05). Quality of life scores increased in both, more notably in the observation group (P < .05). Overall nursing satisfaction was higher in the observation group (P < .05). Conclusions: Individualized diet nursing, based on the Glasgow-Blatchford score, improves cure rates and quality of life and warrants promotion.

12.
Cell Death Differ ; 31(5): 635-650, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38493248

RESUMEN

Diquat (DQ) poisoning is a severe medical condition associated with life-threatening implications and multiorgan dysfunction. Despite its clinical significance, the precise underlying mechanism remains inadequately understood. This study elucidates that DQ induces instability in the mitochondrial genome of endothelial cells, resulting in the accumulation of Z-form DNA. This process activates Z-DNA binding protein 1 (ZBP1), which then interacts with receptor-interacting protein kinase 3 (RIPK3), ultimately leading to RIPK3-dependent necroptotic and ferroptotic signaling cascades. Specific deletion of either Zbp1 or Ripk3 in endothelial cells simultaneously inhibits both necroptosis and ferroptosis. This dual inhibition significantly reduces organ damage and lowers mortality rate. Notably, our investigation reveals that RIPK3 has a dual role. It not only phosphorylates MLKL to induce necroptosis but also phosphorylates FSP1 to inhibit its enzymatic activity, promoting ferroptosis. The study further shows that deletion of mixed lineage kinase domain-like (Mlkl) and the augmentation of ferroptosis suppressor protein 1 (FSP1)-dependent non-canonical vitamin K cycling can provide partial protection against DQ-induced organ damage. Combining Mlkl deletion with vitamin K treatment demonstrates a heightened efficacy in ameliorating multiorgan damage and lethality induced by DQ. Taken together, this study identifies ZBP1 as a crucial sensor for DQ-induced mitochondrial Z-form DNA, initiating RIPK3-dependent necroptosis and ferroptosis. These findings suggest that targeting the ZBP1/RIPK3-dependent necroptotic and ferroptotic pathways could be a promising approach for drug interventions aimed at mitigating the adverse consequences of DQ poisoning.


Asunto(s)
ADN Mitocondrial , Ferroptosis , Necroptosis , Proteínas de Unión al ARN , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Animales , Humanos , Masculino , Ratones , ADN Mitocondrial/metabolismo , ADN Mitocondrial/genética , Ferroptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Necroptosis/efectos de los fármacos , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Diquat/toxicidad
13.
Cell Mol Life Sci ; 81(1): 114, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38436813

RESUMEN

Hyperuricemia is an independent risk factor for chronic kidney disease (CKD) and promotes renal fibrosis, but the underlying mechanism remains largely unknown. Unresolved inflammation is strongly associated with renal fibrosis and is a well-known significant contributor to the progression of CKD, including hyperuricemia nephropathy. In the current study, we elucidated the impact of Caspase-11/Gasdermin D (GSDMD)-dependent neutrophil extracellular traps (NETs) on progressive hyperuricemic nephropathy. We found that the Caspase-11/GSDMD signaling were markedly activated in the kidneys of hyperuricemic nephropathy. Deletion of Gsdmd or Caspase-11 protects against the progression of hyperuricemic nephropathy by reducing kidney inflammation, proinflammatory and profibrogenic factors expression, NETs generation, α-smooth muscle actin expression, and fibrosis. Furthermore, specific deletion of Gsdmd or Caspase-11 in hematopoietic cells showed a protective effect on renal fibrosis in hyperuricemic nephropathy. Additionally, in vitro studies unveiled the capability of uric acid in inducing Caspase-11/GSDMD-dependent NETs formation, consequently enhancing α-smooth muscle actin production in macrophages. In summary, this study demonstrated the contributory role of Caspase-11/GSDMD in the progression of hyperuricemic nephropathy by promoting NETs formation, which may shed new light on the therapeutic approach to treating and reversing hyperuricemic nephropathy.


Asunto(s)
Trampas Extracelulares , Hiperuricemia , Insuficiencia Renal Crónica , Humanos , Hiperuricemia/complicaciones , Actinas , Ácido Úrico , Caspasas , Inflamación , Fibrosis , Gasderminas , Proteínas de Unión a Fosfato
14.
BMC Public Health ; 24(1): 187, 2024 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-38225595

RESUMEN

BACKGROUND: Magnesium (Mg) is both an essential macro-element and a known catalyst, and it plays a vital role in various physiological activities and mechanisms in relation to chronic kidney disease (CKD). However, epidemiological evidence involving this is limited and not entirely consistent. This study aims to explore the association of serum Mg concentrations with the risk of CKD among general Chinese adults. METHODS: A total of 8,277 Chinese adults were included in the wave of 2009 from the China Health and Nutrition Survey (CHNS). The primary outcome was the risk of CKD, which was defined as the estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Multivariable logistic regression model was used to examine the relationship of serum Mg concentrations with the risk of CKD. RESULTS: Included were 8,277 individuals, with an overall CKD prevalence of 11.8% (n = 977). Compared with the first quartile of serum Mg, the multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for participants in the second, third, and fourth quartiles of serum Mg were 0.74 (0.58, 0.93), 0.87 (0.69, 1.11) and 1.29 (1.03, 1.61), respectively. Similar results were observed in our several sensitivity analyses. Restricted cubic spline analysis demonstrated a nonlinear (similar "J"-shaped) association between serum Mg concentrations and the risk of CKD (Pnonlinearity <0.001), with a threshold at around a serum Mg value of 2.2 mg/dL. CONCLUSIONS: Our results suggested a similar "J"-shaped association between serum Mg concentration and the risk of CKD among Chinese adults. Further large prospective studies are needed to verify these findings.


Asunto(s)
Magnesio , Insuficiencia Renal Crónica , Adulto , Humanos , Estudios Transversales , Insuficiencia Renal Crónica/epidemiología , Tasa de Filtración Glomerular , Encuestas Epidemiológicas , Factores de Riesgo
15.
Acta Neurol Belg ; 124(3): 871-877, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38285160

RESUMEN

OBJECTIVE: To investigate the effects of electronic biofeedback combined with nursing intervention and conventional drug treatment on cognitive function in patients with vascular cognitive impairment-no dementia (VCIND). METHODS: A total of 102 patients with VCIND treated in the Department of Neurology from January 2021 to May 2022 were enrolled and divided into the routine treatment group and biofeedback group according to different treatment methods. The routine treatment group was given conventional drug therapy and nursing intervention; for the biofeedback group, electronic biofeedback therapy was added, based on the routine treatment group. The Montreal Cognitive Assessment, (MoCA), Alzheimer's Disease Assessment Scale-Cognitive Subscale, (ADAS-cog), and Hamilton Depression Scale (HAMD) were checked before treatment, 2 weeks after treatment, and 3 months after treatment. RESULTS: At 3 months of treatment, the scores of the MoCA and ADAS-cog scales in the biofeedback group were better than those in the routine treatment group, while no difference was detected in the HAMD scores before and after treatment and between the two groups. CONCLUSION: Electronic biofeedback therapy for VCIND can significantly improve the MoCA score, reduce the ADAS-cog score and improve the cognitive level of patients and can be used as a complementary treatment for VCIND.


Asunto(s)
Biorretroalimentación Psicológica , Disfunción Cognitiva , Humanos , Femenino , Masculino , Anciano , Disfunción Cognitiva/terapia , Disfunción Cognitiva/enfermería , Biorretroalimentación Psicológica/métodos , Persona de Mediana Edad , Resultado del Tratamiento
16.
Nephrol Dial Transplant ; 39(8): 1344-1359, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-38244230

RESUMEN

BACKGROUND AND HYPOTHESIS: Acute kidney injury (AKI) could progress to chronic kidney disease (CKD) and the AKI-CKD transition has major clinical significance. A growing body of evidence has unveiled the role of pyroptosis in kidney injury. We postulate that GSDMD and GSDME exert cumulative effects on the AKI-CKD transition by modulating different cellular responses. METHODS: We established an AKI-CKD transition model induced by folic acid in wildtype (WT), Gsdmd-/-, Gsdme-/-, and Gsdmd-/-Gsdme-/- mice. Tubular injury, renal fibrosis and inflammatory responses were evaluated. In vitro studies were conducted to investigate the interplay among tubular cells, neutrophils, and macrophages. RESULTS: Double deletion of Gsdmd and Gsdme conferred heightened protection against AKI, mitigating inflammatory responses, including the formation of neutrophil extracellular traps (NETs), macrophage polarization and differentiation, and ultimately renal fibrosis, compared with wildtype mice and mice with single deletion of either Gsdmd or Gsdme. Gsdme, but not Gsdmd deficiency, shielded tubular cells from pyroptosis. GSDME-dependent tubular cell death stimulated NETs formation and prompted macrophage polarization towards a pro-inflammatory phenotype. Gsdmd deficiency suppressed NETs formation and subsequently hindered NETs-induced macrophage-to-myofibroblast transition (MMT). CONCLUSION: GSDMD and GSDME collaborate to contribute to AKI and subsequent renal fibrosis induced by folic acid. Synchronous inhibition of GSDMD and GSDME could be an innovative therapeutic strategy for mitigating the AKI-CKD transition.


Asunto(s)
Lesión Renal Aguda , Insuficiencia Renal Crónica , Animales , Masculino , Ratones , Lesión Renal Aguda/patología , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ácido Fólico , Gasderminas , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Piroptosis , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/metabolismo
17.
Lab Invest ; 104(4): 100337, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38266921

RESUMEN

Atherosclerosis is a chronic inflammatory cardiovascular disease with a high-morbidity and mortality rate. An increasing number of studies have addressed the crucial contribution of gasdermin D (GSDMD)-mediated pyroptosis, which is triggered by the inflammasomes to the development of atherosclerosis. However, the underlying mechanism is still unclear. This study aimed to uncover the detailed role of GSDMD in the development of atherosclerosis. An atherosclerotic model was established in Gsdmd-/-/Ldlr-/- mice and Gsdmd+/+/Ldlr-/- mice fed with a high-fat diet. The atherosclerotic lesions, the activation of GSDMD, and the expression level of inflammatory cytokines and chemokines were evaluated. Gsdmd deletion ameliorated the atherosclerotic lesion sizes and the infiltration of immune cells and inflammatory cells in the aortas of mice. Additionally, Gsdmd deletion suppressed the pyroptosis of macrophages and endothelial cells induced by the serum of Ldlr-/- mice fed with a high-fat diet. Furthermore, the formation of neutrophil extracellular traps was also attenuated by knockout of Gsdmd. Bone marrow chimeras confirmed that the genetic deficiency of Gsdmd in both immune cells and intrinsic cells played a role in the promotion of arteriosclerosis. Collectively, our study demonstrated that Gsdmd deletion hindered the pathogenesis of atherosclerosis by inhibiting endothelial cell and macrophage cell death, and the formation of neutrophil extracellular traps.


Asunto(s)
Aterosclerosis , Piroptosis , Animales , Ratones , Gasderminas , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células Endoteliales/metabolismo , Aterosclerosis/genética , Inflamasomas/metabolismo
19.
J Intensive Care Med ; 39(5): 465-476, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-37964547

RESUMEN

BACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) is a critical condition with significant clinical implications, yet there is a need for a predictive model that can reliably assess the risk of its development. This study is undertaken to bridge a gap in healthcare by creating a predictive model for SA-AKI with the goal of empowering healthcare providers with a tool that can revolutionize patient care and ultimately lead to improved outcomes. METHODS: A cohort of 615 patients afflicted with sepsis, who were admitted to the intensive care unit, underwent random stratification into 2 groups: a training set (n = 435) and a validation set (n = 180). Subsequently, a multivariate logistic regression model, imbued with nonzero coefficients via LASSO regression, was meticulously devised for the prognostication of SA-AKI. This model was thoughtfully rendered in the form of a nomogram. The salience of individual risk factors was assessed and ranked employing Shapley Additive Interpretation (SHAP). Recursive partition analysis was performed to stratify the risk of patients with sepsis. RESULTS: Among the panoply of clinical variables examined, hypertension, diabetes mellitus, C-reactive protein, procalcitonin (PCT), activated partial thromboplastin time, and platelet count emerged as robust and independent determinants of SA-AKI. The receiver operating characteristic curve analysis for SA-AKI risk discrimination in both the training set and validation set yielded an area under the curve estimates of 0.843 (95% CI: 0.805 to 0.882) and 0.834 (95% CI: 0.775 to 0.893), respectively. Notably, PCT exhibited the most conspicuous influence on the model's predictive capacity. Furthermore, statistically significant disparities were observed in the incidence of SA-AKI and the 28-day survival rate across high-risk, medium-risk, and low-risk cohorts (P < .05). CONCLUSION: The composite predictive model, amalgamating the quintet of SA-AKI predictors, holds significant promise in facilitating the identification of high-risk patient subsets.


Asunto(s)
Lesión Renal Aguda , Sepsis , Humanos , Curva ROC , Unidades de Cuidados Intensivos , Modelos Logísticos , Polipéptido alfa Relacionado con Calcitonina , Lesión Renal Aguda/etiología , Lesión Renal Aguda/epidemiología , Sepsis/complicaciones , Sepsis/epidemiología , Estudios Retrospectivos
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