RESUMO
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.
Assuntos
Armadilhas Extracelulares , Hiperuricemia , Insuficiência Renal Crônica , Humanos , Hiperuricemia/complicações , Actinas , Ácido Úrico , Caspases , Inflamação , Fibrose , Gasderminas , Proteínas de Ligação a FosfatoRESUMO
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.
Assuntos
Aterosclerose , Piroptose , Animais , Camundongos , Gasderminas , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células Endoteliais/metabolismo , Aterosclerose/genética , Inflamassomos/metabolismoRESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Técnicas Eletroquímicas , Receptores ErbB , Exodesoxirribonucleases , Neoplasias Pulmonares , Mutação , Receptores ErbB/genética , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Exodesoxirribonucleases/química , Exodesoxirribonucleases/metabolismo , Exodesoxirribonucleases/genética , Técnicas Biossensoriais , Reação em Cadeia da Ligase , Limite de Detecção , Proteínas ViraisRESUMO
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.
Assuntos
Injúria Renal Aguda , Insuficiência Renal Crônica , Animais , Masculino , Camundongos , Injúria Renal Aguda/patologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Ácido Fólico , Gasderminas , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , Piroptose , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismoRESUMO
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.
Assuntos
Injúria Renal Aguda , Sepse , Humanos , Curva ROC , Unidades de Terapia Intensiva , Modelos Logísticos , Pró-Calcitonina , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/epidemiologia , Sepse/complicações , Sepse/epidemiologia , Estudos RetrospectivosRESUMO
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.
Assuntos
Pinos Ortopédicos , Fixação Intramedular de Fraturas , Fraturas do Quadril , Titânio , Humanos , Feminino , Estudos Retrospectivos , Masculino , Fixação Intramedular de Fraturas/métodos , Idoso , Fraturas do Quadril/cirurgia , Resultado do Tratamento , Pessoa de Meia-Idade , Fraturas do Fêmur/cirurgia , Idoso de 80 Anos ou mais , Suporte de CargaRESUMO
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.
Assuntos
Magnésio , Insuficiência Renal Crônica , Adulto , Humanos , Estudos Transversais , Insuficiência Renal Crônica/epidemiologia , Taxa de Filtração Glomerular , Inquéritos Epidemiológicos , Fatores de RiscoRESUMO
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.
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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.
Assuntos
Doença Celíaca , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Análise da Randomização Mendeliana , Insuficiência Renal Crônica , Humanos , Doença Celíaca/genética , Doença Celíaca/complicações , Insuficiência Renal Crônica/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Feminino , Masculino , Fatores de RiscoRESUMO
As an enzyme-free exponential nucleic acid amplification method, the click chemistry-mediated ligation chain reaction (ccLCR) has shown great prospects in the molecular diagnosis. However, the current optics-based ccLCR is challenged by remarkable nonspecific amplification, severely hindering its future application. This study demonstrated that the severe nonspecific amplification was generated probably due to high random collision in the high DNA probe concentration (µM level). To solve this hurdle, a nucleic acid template-dominated ccLCR was constructed using nM-level DNA probes and read on an electrochemical platform (cc-eLCR). Under the optimal conditions, the proposed cc-eLCR detected a low-level nucleic acid target (1 fM) with a single-base resolution. Furthermore, this assay was applied to detect the target of interest in cell extracts with a satisfactory result. The proposed cc-eLCR offers huge possibility for click chemistry-mediated enzyme-free exponential nucleic acid amplification in the application of medical diagnosis and biomedical research.
Assuntos
Técnicas Biossensoriais , RNA , Química Click/métodos , Técnicas Biossensoriais/métodos , DNA/química , Sondas de DNA/genética , Sondas de DNA/química , Técnicas de Amplificação de Ácido Nucleico/métodos , Técnicas Eletroquímicas/métodos , Limite de Detecção , Hibridização de Ácido NucleicoRESUMO
Due to the comparable stability between the perfect-base pair and the wobble-base pair, a precise differentiation of the wobble-type allele has remained a challenge, often leading to false results. Herein, we proposed a ligase chain reaction (LCR)-based ratiometric electrochemical DNA sensor, namely, R-eLCR, for a precise typing of the wobble-type allele, in which the traditionally recognized "negative" signal of wobble-base pair-mediated amplification was fully utilized as a "positive" one and a ratiometric readout mode was employed to ameliorated the underlying potential external influence and improved its detection accuracy in the typing of the wobble-type allele. The results showed that the ratio between current of methylene blue (IMB) and current of ferrocene (IFc) was partitioned in three regions and three types of wobble-type allele were thus precisely differentiated (AA homozygote: IMB/IFc > 2; GG homozygote: IMB/IFc < 1; GA heterozygote: 1 < IMB/IFc < 2); the proposed R-eLCR successfully discriminated the three types of CYP2C19*2 allele in nine cases of human whole blood samples, which was consistent with those of the sequencing method. These results evidence that the proposed R-eLCR can serve as an accurate and robust alternative for the identification of wobble-type allele, which lays a solid foundation and holds great potential for precision medicine.
Assuntos
Técnicas Biossensoriais , Reação em Cadeia da Ligase , Humanos , Alelos , Genótipo , Citocromo P-450 CYP2C19 , Técnicas Eletroquímicas , Ouro , Limite de DetecçãoRESUMO
AIM: Idiopathic membranous nephropathy (IMN) is a common type of nephrotic syndrome, and is associated with acute kidney injury (AKI). We investigated the association of multiple variables with AKI in patients with IMN. METHODS: The data of 187 patients with biopsy-proven IMN were examined. Renal outcome was defined as progression to end-stage renal disease (ESRD). Binary logistic regression and Kaplan-Meier's analysis were used for statistical analysis. RESULTS: During follow-up, 46 (24.6%) patients developed AKI. The incidence of AKI was greater in males than females (p < .01). The AKI group had higher uric acid, lower serum PLA2R antibody positive, and worse baseline kidney function (all p < .01). Most patients in the AKI group had stage I (71.74%) or stage II (21.74%). The AKI group had higher renal tubular injury score and chronicity index (both p < .05). Binary logistic regression indicated that uric acid and baseline estimated glomerular filtration rate (eGFR) were independent risk factors for AKI in patients with IMN (p < .05). The optimal cutoff value of serum uric acid for predicting AKI was 402.50 µmol/L and the baseline eGFR was 96.83 mL/min/1.73 m2. Kaplan-Meier's analysis showed that the cumulative renal survival rate was lower in the AKI group (p = .047). CONCLUSIONS: AKI increases the risk of poor prognosis in IMN patients and the high uric acid and low baseline eGFR were considered independent predictors for developing AKI in patients with IMN.
Assuntos
Injúria Renal Aguda , Glomerulonefrite Membranosa , Masculino , Feminino , Humanos , Glomerulonefrite Membranosa/complicações , Ácido Úrico , Rim , Prognóstico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/complicações , Estudos RetrospectivosRESUMO
OBJECTIVE: To evaluate the chronic health risk of heavy metals and metalloid in drinking water through oral ingestion in a typical area. METHODS: Monitoring data of seven heavy metals and metalloid elements(Hg, As, Pb, Ni, Mn, Cr~(6+) and Cd) in drinking water in a typical area of Huaihe River Basin were collected from 2015 to 2019. The health risks of heavy metals and metalloid in drinking water in the area were assessed using the classic four-step health risk assessment model. RESULTS: The average concentrations of Hg, As, Pb, Ni, Mn, Cr~(6+) and Cd in drinking water in the typical area of Huaihe River Basin were(0.13±0.45), (0.49±0.49), (0.34±0.99), (1.10±2.49), (32.29±126.64), (2.13±0.50) and(0.03±0.04) µg/L, respectively. In which, Hg, Mn and Ni exceeded the limit of the Standard for Drinking Water(GB 5749-2006), the exceedance rates were 2.14%, 6.79% and 0.3%, respectively, and the maximum exceedance times were 2.61, 8.90 and 0.34, respectively. The chronic non-carcinogenic risks of Hg, As, Pb, Ni, Mn, Cr~(6+) and Cd were 1.32×10~(-2), 4.99×10~(-2), 2.97×10~(-3), 1.68×10~(-3), 7.04×10~(-3), 2.17×10~(-2) and 1.83×10~(-3), respectively. The carcinogenic risks of As, Pb, Cr~(6+) and Cd were 2.24×10~(-5), 8.82×10~(-8), 3.25×10~(-5) and 5.86×10~(-7), respectively. CONCLUSION: Hg, Mn and Ni in drinking water exceeded the standard in a typical area of Huaihe River Basin from 2015 to 2019. The chronic non-carcinogenic risks of Hg, As and other 7 heavy metals and metalloid are at an acceptable level(HQ≤1), while As and Cr~(6+) have certain carcinogenic risks(10~(-6)≤CR≤10~(-4)).
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Água Potável , Metaloides , Metais Pesados , Poluentes Químicos da Água , Cádmio , China , Água Potável/análise , Água Potável/química , Monitoramento Ambiental , Chumbo , Mercúrio , Metaloides/análise , Metais Pesados/análise , Medição de Risco , Rios , Poluentes Químicos da Água/análise , HumanosRESUMO
PURPOSE: Acute kidney injury (AKI) is a common complication and associated with a poor clinical outcome. In this study, we developed and validated a model for predicting the risk of AKI through machine learning methods in critical care patients with acute cerebrovascular disease. METHODS: This study was a retrospective study based on two different cohorts. Five machine learning methods were used to develop AKI risk prediction models. We used six popular metrics (AUROC, F2-Score, accuracy, sensitivity, specificity and precision) to evaluate the performance of these models. RESULTS: We identified 2935 patients in the MIMIC-III database and 499 patients in our local database to develop and validate the AKI risk prediction model. The incidence of AKI in these two different cohorts was 18.3% and 61.7%, respectively. Analysis showed that several laboratory parameters (serum creatinine, hemoglobin, white blood cell count, bicarbonate, blood urea nitrogen, sodium, albumin, and platelet count), age, and length of hospital stay, were the top ten important factors associated with AKI. The analysis demonstrated that the XGBoost had higher AUROC (0.880, 95%CI: 0.831-0.929), indicating that the XGBoost model was better at predicting AKI risk in patients with acute cerebrovascular disease than other models. CONCLUSIONS: This study developed machine learning methods to identify critically ill patients with acute cerebrovascular disease who are at a high risk of developing AKI. This result suggested that machine learning techniques had the potential to improve the prediction of AKI risk models in critical care.
Assuntos
Injúria Renal Aguda/patologia , Transtornos Cerebrovasculares/patologia , Aprendizado de Máquina , Injúria Renal Aguda/etiologia , Idoso , Transtornos Cerebrovasculares/complicações , China , Cuidados Críticos , Bases de Dados Factuais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Curva ROC , Estudos RetrospectivosRESUMO
Kv4 pore-forming subunits co-assemble with ß-subunits including KChIP2 and DPP6 and the resultant complexes conduct cardiac transient outward K+ current (Ito). Compound NS5806 has been shown to potentate Ito in canine cardiomyocytes; however, its effects on Ito in other species yet to be determined. We found that NS5806 inhibited native Ito in a concentration-dependent manner (0.1~30 µM) in both mouse ventricular cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but potentiated Ito in the canine cardiomyocytes. In HEK293 cells co-transfected with cloned Kv4.3 (or Kv4.2) and ß-subunit KChIP2, NS5806 significantly increased the peak current amplitude and slowed the inactivation. In contrast, NS5806 suppressed the current and accelerated inactivation of the channels when cells were co-transfected with Kv4.3 (or Kv4.2), KChIP2 and another ß-subunit, DPP6-L (long isoform). Western blot analysis showed that DPP6-L was dominantly expressed in both mouse ventricular myocardium and hiPSC-CMs, while it was almost undetectable in canine ventricular myocardium. In addition, low level of DPP6-S expression was found in canine heart, whereas levels of KChIP2 expression were comparable among all three species. siRNA knockdown of DPP6 antagonized the Ito inhibition by NS5806 in hiPSC-CMs. Molecular docking simulation suggested that DPP6-L may associate with KChIP2 subunits. Mutations of putative KChIP2-interacting residues of DPP6-L reversed the inhibitory effect of NS5806 into potentiation of the current. We conclude that a pharmacological modulator can elicit opposite regulatory effects on Kv4 channel complex among different species, depending on the presence of distinct ß-subunits. These findings provide novel insight into the molecular design and regulation of cardiac Ito. Since Ito is a potential therapeutic target for treatment of multiple cardiovascular diseases, our data will facilitate the development of new therapeutic Ito modulators.
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Potenciais de Ação/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Canais de Potássio Shal/efeitos dos fármacos , Tetrazóis/farmacologia , Potenciais de Ação/fisiologia , Animais , Cricetulus/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular/métodos , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismoRESUMO
The human ether-á-go-go related gene (hERG, KCNH2) encodes the pore-forming subunit of the potassium channel responsible for a fast component of the cardiac delayed rectifier potassium current (IKr). Outward IKr is an important determinant of cardiac action potential (AP) repolarization and effectively controls the duration of the QT interval in humans. Dysfunction of hERG channel can cause severe ventricular arrhythmias and thus modulators of the channel, including hERG inhibitors and activators, continue to attract intense pharmacological interest. Certain inhibitors of hERG channel prolong the action potential duration (APD) and effective refractory period (ERP) to suppress premature ventricular contraction and are used as class III antiarrhythmic agents. However, a reduction of the hERG/IKr current has been recognized as a predominant mechanism responsible for the drug-induced delayed repolarization known as acquired long QT syndromes (LQTS), which is linked to an increased risk for "torsades de pointes" (TdP) ventricular arrhythmias and sudden cardiac death. Many drugs of different classes and structures have been identified to carry TdP risk. Hence, assessing hERG/IKr blockade of new drug candidates is mandatory in the drug development process according to the regulatory agencies. In contrast, several hERG channel activators have been shown to enhance IKr and shorten the APD and thus might have potential antiarrhythmic effects against pathological LQTS. However, these activators may also be proarrhythmic due to excessive shortening of APD and the ERP.
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Canais de Potássio Éter-A-Go-Go , Síndrome do QT Longo , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Canais de Potássio Éter-A-Go-Go/genética , Coração , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/tratamento farmacológicoRESUMO
Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by severe neuronal loss. Necroptosis, or programmed cell necrosis, is mediated by the receptor interacting protein kinase-1 and -3/mixed lineage kinase domain-like protein (RIP1/RIP3/MLKL) pathway, and is involved in several neurodegenerative diseases. Here we aimed to explore the involvement of necroptosis in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP)-induced PD and determine the potential mechanisms. We found that the protein levels of RIP1, RIP3, and MLKL increased significantly in a MPTP-induced mouse PD model. High expression of RIP1/RIP3/MLKL was associated with severe loss of dopaminergic neurons. Pretreatment with necrostatin-1 or the knockout of the RIP3/MLKL gene to block necroptosis pathway dramatically ameliorated PD by increasing dopamine levels and rescuing the loss of dopaminergic neurons, independent of the apoptotic pathway. Moreover, upregulation of inflammatory cytokines in MPTP-treated mice was partially inhibited by deletion of RIP3 or MLKL gene, indicating that a positive feedback loop exists between these genes and inflammatory cytokines. Our data indicate that RIP1/RIP3/MLKL-mediated necroptosis is involved in the pathogenesis of MPTP-induced PD. Downregulating the expression of RIP1, RIP3, or MLKL can significantly attenuate MPTP-induced PD. Future therapy targeting necroptosis may be a promising new option.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Necroptose/fisiologia , Doença de Parkinson/metabolismo , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Although acute kidney injury (AKI) is a known risk factor for adverse clinical outcomes in patients with spontaneous intracerebral haemorrhage (SICH), little is known about the predisposing factors that contribute to renal failure and short-term prognosis in the setting of SICH already complicated by AKI. In this study, we aimed to identify the renal failure factors in SICH patents with AKI. METHODS: Five hundred forty-three patients with SICH complicated by differential severities of AKI who were admitted to the First Affiliated Hospital of Fujian Medical University from January 2016 to December 2018 were retrospectively studied. Logistic regression and receiver operator characteristic (ROC) curve analysis were performed to determine the best predictive and discriminative variables. Multivariate Cox regression analysis was performed to identify prognostic factors for renal recovery. RESULTS: In the multivariable adjusted model, we found that hypernatremia, metabolic acidosis, elevated serum creatine kinase, hyperuricaemia, proteinuria, and the use of colloids and diuretics were all independent risk factors for the occurrence of stage 3 AKI in SICH patients. The area under the curve analysis indicated that hypernatremia and hyperuricaemia were predictive factors for stage 3 AKI, and the combination of these two parameters increased their predictability for stage 3 AKI. Kaplan-Meier survival curves revealed that the renal recovery rate in SICH patients with stages 1 and 2 AKI was significantly higher than that in SICH patients with stage 3 AKI. Multivariate Cox regression analysis suggested that hypernatremia and the occurrence of stage 3 AKI are predictors for poor short-term renal recovery. CONCLUSIONS: These findings illustrate that hypernatremia and hyperuricaemia represent potential risk factors for the occurrence of stage 3 AKI in SICH patients. Those patients with hypernatremia and stage 3 AKI were associated with a poor short-term prognosis in renal recovery.
Assuntos
Injúria Renal Aguda/epidemiologia , Hemorragia Cerebral/terapia , Diuréticos/uso terapêutico , Hipernatremia/epidemiologia , Hiperuricemia/epidemiologia , Respiração Artificial/estatística & dados numéricos , Injúria Renal Aguda/metabolismo , Adulto , Idoso , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/metabolismo , Creatina Quinase/metabolismo , Creatinina/metabolismo , Progressão da Doença , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prognóstico , Modelos de Riscos Proporcionais , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Vitiligo is a common depigment of skin disorder due to loss of functional melanocytes. Recently, the phototherapy with a 308-nm xenon-chloride excimer laser (UVB laser) is wildly used in vitiligo treatment. However, excessive UVB will induce photo-damage and photo-carcinogenesis in melanocytes. Previous studies revealed a protective effect of heat on UVB-induced melanocyte damage. In this study, we combined heat stress pretreatment with UVB to evaluate whether heat stress pretreatment has an ameliorative effect on UVB-induced damage. Human primary melanocytes (HMCs) were cultured and irradiated with a 308-nm laser with/without heat treatment. MTT assay, apoptosis analysis, and comet assay were conducted to monitor the damage of HMCs. Western blot and immunofluorescence staining were performed to assess the expression and subcellular localization of HSP70. HMCs heated at 42 °C for 1 h exhibit no cytotoxicity. Furthermore, preheat treatment attenuated the UVB laser-induced injury, reduced the DNA damage, and attenuated the cell apoptosis. The level and the localization of HSP70 determined the protective effects against UVB-induced DNA damage. Combining preheat treatment with a 308-nm xenon-chloride excimer laser would be a potential therapeutic method not only promotes the repigment of vitiligo but also reduces the UVB-induced photo-damage.
Assuntos
Dano ao DNA , Resposta ao Choque Térmico/genética , Resposta ao Choque Térmico/efeitos da radiação , Lasers/efeitos adversos , Melanócitos/metabolismo , Melanócitos/efeitos da radiação , Apoptose/genética , Apoptose/efeitos da radiação , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Raios Ultravioleta/efeitos adversosRESUMO
Chemotherapy-induced nephrotoxicity limits the success of cancer therapy. Landau et al. now describe a mechanism by which a first dose of cisplatin renders the kidney sensitive to necroptosis mediated by a second dose. Unresolved injury and sustained necrosis, therefore, may represent a pathophysiological means of transition from acute kidney injury to chronic kidney disease.