Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 165
Filtrar
1.
BMC Anesthesiol ; 24(1): 72, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38395800

RESUMO

BACKGROUND: Approximately 40 to 60% of patients with sepsis develop sepsis-induced cardiomyopathy (SIC), which is associated with a substantial increase in mortality. We have found that molecular hydrogen (H2) inhalation improved the survival rate and cardiac injury in septic mice. However, the mechanism remains unclear. This study aimed to explore the regulatory mechanism by which hydrogen modulates autophagy and its role in hydrogen protection of SIC. METHODS: Cecal ligation and puncture (CLP) was used to induce sepsis in adult C57BL/6J male mice. The mice were randomly divided into 4 groups: Sham, Sham + 2% hydrogen inhalation (H2), CLP, and CLP + H2 group. The 7-day survival rate was recorded. Myocardial pathological scores were calculated. Myocardial troponin I (cTnI) levels in serum were detected, and the levels of autophagy- and mitophagy-related proteins in myocardial tissue were measured. Another four groups of mice were also studied: CLP, CLP + Bafilomycin A1 (BafA1), CLP + H2, and CLP + H2 + BafA1 group. Mice in the BafA1 group received an intraperitoneal injection of the autophagy inhibitor BafA1 1 mg/kg 1 h after operation. The detection indicators remained the same as before. RESULTS: The survival rate of septic mice treated with H2 was significantly improved, myocardial tissue inflammation was improved, serum cTnI level was decreased, autophagy flux was increased, and mitophagy protein content was decreased (P < 0.05). Compared to the CLP + H2 group, the CLP + H2 + BafA1 group showed a decrease in autophagy level and 7-day survival rate, an increase in myocardial tissue injury and cTnI level, which reversed the protective effect of hydrogen (P < 0.05). CONCLUSION: Hydrogen exerts protective effect against SIC, which may be achieved through the promotion of autophagy and mitophagy.


Assuntos
Cardiomiopatias , Sepse , Humanos , Camundongos , Masculino , Animais , Camundongos Endogâmicos C57BL , Autofagia , Cardiomiopatias/etiologia , Cardiomiopatias/prevenção & controle , Sepse/complicações , Sepse/patologia , Hidrogênio/farmacologia , Hidrogênio/uso terapêutico
2.
Curr Med Res Opin ; 40(4): 575-582, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38385550

RESUMO

BACKGROUND: Accurate identification of delirium in sepsis patients is crucial for guiding clinical diagnosis and treatment. However, there are no accurate biomarkers and indicators at present. We aimed to identify which combinations of cognitive impairment-related biomarkers and other easily accessible assessments best predict delirium in sepsis patients. METHODS: One hundred and one sepsis patients were enrolled in a prospective study cohort. S100B, NSE, and BNIP3 L biomarkers were detected in plasma and cerebrospinal fluid and patients' optic nerve sheath diameter (ONSD). The optimal biomarkers identified by Logistic regression are combined with other factors such as ONSD to filter out the perfect model to predict delirium in sepsis patients through Logistic regression, Naïve Bayes, decision tree, and neural network models. MAIN RESULTS: Among all biomarkers, compared with BNIP3 L (AUC = .706, 95% CI = .597-.815) and NSE (AUC = .711, 95% CI = .609-.813) in cerebrospinal fluid, plasma S100B (AUC = .729, 95% CI = .626-.832) had the best discrimination performance for delirium in sepsis patients. Logistic regression analysis showed that the combination of cerebrospinal fluid BNIP3 L with plasma S100B, ONSD, neutrophils, and age provided the best discrimination to cognitive impairment in sepsis patients (accuracy = .901, specificity = .923, sensitivity = .911), which was better than Naïve Bayes, decision tree, and neural network models. Neutrophils, ONSD, and cerebrospinal fluid BNIP3 L were consistently the major contributors in a few models. CONCLUSIONS: The logistic regression showed that the combination model was strongly correlated with cognitive dysfunction in sepsis patients.


Assuntos
Delírio , Encefalopatia Associada a Sepse , Sepse , Humanos , Encefalopatia Associada a Sepse/diagnóstico , Estudos Prospectivos , Prognóstico , Teorema de Bayes , Biomarcadores , Sepse/complicações , Sepse/diagnóstico , Proteínas de Membrana , Proteínas Proto-Oncogênicas , Subunidade beta da Proteína Ligante de Cálcio S100
3.
J Immunol ; 212(8): 1345-1356, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38407485

RESUMO

The one-carbon metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is critical for cancer cell proliferation and immune cell phenotypes, but whether it can contribute to macrophage inflammatory responses remains unclear. In this study, we show that MTHFD2 was upregulated by LPS in murine macrophages upon activation of the TLR4-MyD88-IKKα/ß-NF-κB signaling pathway. MTHFD2 significantly attenuated LPS-induced macrophage proinflammatory cytokine production through its enzymatic activity. Notably, ablation of myeloid MTHFD2 rendered mice more sensitive to septic shock and CCl4-induced acute hepatitis. Mechanistically, MTHFD2 restrained IKKα/ß-NF-κB activation and macrophage inflammatory phenotype by scavenging reactive oxygen species through the generation of NADPH. Our study reveals MTHFD2 as a "self-control" mechanism in macrophage-mediated inflammatory responses.


Assuntos
Quinase I-kappa B , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio , Quinase I-kappa B/metabolismo , Lipopolissacarídeos , Transdução de Sinais , Macrófagos
4.
Shock ; 61(3): 424-432, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38320216

RESUMO

ABSTRACT: Background: Sepsis-induced liver injury leads to extensive necroptosis in hepatocytes, which is the main factor of liver dysfunction. This study aims to investigate the protective effect of dexmedetomidine (DEX) on septic liver and to explore whether its molecular mechanism is related to the modulation of necroptosis. Methods: The model of septic liver injury was induced by cecal ligation and puncture (CLP) in rats. DEX and necrostatin-1(Nec-1), a specific antagonist of necroptosis, were administered 1 h before CLP. The levels of arterial blood gas, serum aspartate aminotransferase, and alanine aminotransferase were measured at 6, 12 and 24 h after CLP. The survival rate was observed 24 h after CLP. Liver pathological changes and apoptosis, the contents of IL-6 and TNF-α in liver tissue homogenates, the ROS content in liver tissue, and the expression levels of RIP1, RIP3, MLKL, and HMGB1 were detected. Results: At 6, 12, and 24 h after CLP, the levels of aspartate aminotransferase, and alanine aminotransferase levels increased, and liver enzyme levels gradually increased with the progression of sepsis. In arterial blood gas analysis, P a O 2 gradually decreased and lactic acid concentration gradually increased during these three periods. The morphological impairment of liver tissues, increased apoptosis, elevated inflammatory factors (IL-6 and TNF-α), increased ROS level, and necroptosis components (RIP1, RIP3, MLKL, and HMGB1) were all observed in sepsis rats. However, these injuries can be ameliorated by pretreatment with DEX. Meanwhile, Nec-1 pretreatment also reduced the expression of RIP1, RIP3, MLKL, HMGB1, and ROS level. Conclusion: Our study suggests that DEX alleviates septic liver injury, and the mechanism is associated with the inhibition of necroptosis.


Assuntos
Dexmedetomidina , Proteína HMGB1 , Sepse , Ratos , Animais , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Interleucina-6 , Necroptose , Alanina Transaminase , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Aspartato Aminotransferases
5.
Front Microbiol ; 15: 1296059, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38322313

RESUMO

Objective: This study aimed to evaluate the clinical value of dynamic monitoring of neutrophil/lymphocyte ratio (NLR), APACHE II (Acute Physiology and Chronic Health Evaluation II) score, and Sequential Organ Failure Assessment (SOFA) score in predicting 28-day prognosis and drug resistance in patients with bloodstream infection with Acinetobacter baumannii-calcoaceticus complex (Abc complex). Patients and methods: In this research, individuals admitted to Tianjin Medical University General Hospital from January 2017 to March 2023 with bloodstream infections and a minimum of one Abc complex positive blood culture were chosen. The risk factors for the 28-day prognosis and drug resistance were analyzed using logistic regression. The NLR, APACHE II score, and SOFA score were evaluated for predicting 28-day prognosis and drug resistance using an ROC curve analysis. The data were analyzed using R Studio to find correlations and conduct survival analysis with the Kaplan-Meier method. Results: The final statistical analysis included a total of 129 patients with bloodstream infections caused by Abc complex. Independent risk factors predicting mortality within 28 days were identified as follows: the SOFA score and APACHE II scores at 24 h, and APACHE II scores at 72 h after the onset of blood infection (p < 0.05). NLR, SOFA score, and APACHE II score did not predict drug resistance. Patients with Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) had shorter survival times than those with carbapenem-sensitive strains (40.77 days vs. 47.65 days, respectively, p = 0.0032). Conclusion: The prognosis of Abc complex bloodstream infection is affected by both SOFA and APACHE II scores. Both scoring systems have similar prognostic values at different time points after infection, but for computational convenience, it is recommended to use the SOFA score. NLR exhibits limited effectiveness in predicting mortality within 28 days. Carbapenem-resistant individuals with Abc complex experience significantly reduced survival time. None of the three factors-SOFA score, APACHE II score, and NLR-can early predict the occurrence of CRAB infections effectively.

6.
BMC Med ; 21(1): 456, 2023 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-37996902

RESUMO

OBJECTIVE: The European Society of Intensive Care Medicine (ESICM) recently recommended changes to the criteria of acute respiratory distress syndrome (ARDS), patients with high-flow oxygen were included, however, the effect of these changes remains unclear. Our objectives were to evaluate the performance of these new criteria and to compare the outcomes of patients meeting the new ARDS criteria with those meeting the Berlin ARDS criteria. METHODS: This was a retrospective cohort. The patients admitted to the intensive care unit (ICU) were diagnosed with ARDS. Patients were classified as meeting Berlin criteria ARDS (n = 4279), high-flow nasal oxygen (HFNO) criteria ARDS (n = 559), or new criteria ARDS (n = 4838). RESULTS: In comparison with HFNO criteria ARDS and new criteria ARDS, patients with Berlin criteria ARDS demonstrated lower blood oxygen levels assessed by PaO2/FiO2, SpO2/FiO2, and ROX (SpO2/FiO2/respiratory rate) (p < 0.001); and higher severity of illness assessed by the Sequential Organ Failure Assessment (SOFA) score, Acute Physiology And Chronic Health Evaluations (APACHE II), Simplified Acute Physiology Score (SAPS II) (p < 0.001), (p < 0.001), and longer ICU and hospital stays (p < 0.001). In comparison with the HFNO criteria, patients meeting Berlin criteria ARDS had higher hospital mortality (10.6% vs. 16.9%; p = 0.0082), 28-day mortality (10.6% vs. 16.5%; p = 0.0079), and 90-day mortality (10.7% vs. 17.1%; p = 0.0083). ARDS patients with HFNO did not have severe ARDS; Berlin criteria ARDS patients with severe ARDS had the highest mortality rate (approximately 33%). PaO2/FiO2, SpO2/FiO2, and ROX negatively correlated with the SOFA and APACHE II scores. The SOFA and APACHE II scores had high specificity and sensitivity for prognosis in patients with new criteria ARDS. CONCLUSION: The new criteria of ARDS reduced the severity of illness, length of stay in the ICU, length of hospital stays, and overall mortality. SOFA and APACHE II scores remain important in assessing the prognosis of patients with new criteria ARDS. TRIAL REGISTRATION: Registration number: ChiCTR2200067084.


Assuntos
Síndrome do Desconforto Respiratório , Humanos , Estudos Retrospectivos , Síndrome do Desconforto Respiratório/diagnóstico , Oxigênio , APACHE , Prognóstico , Unidades de Terapia Intensiva
7.
Emerg Med Int ; 2023: 6676033, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37869361

RESUMO

Objectives: Nonhepatic hyperammonemia often occurs in patients with sepsis. Ammonia plays an essential role in the occurrence of hepatic encephalopathy. However, the relationship between nonhepatic serum ammonia levels and sepsis-associated encephalopathy (SAE) remains unclear. Thus, we aimed to evaluate the association between serum ammonia levels and patients with SAE. Methods: Data of critically ill adults with sepsis who were admitted to the intensive care unit were retrieved from the Medical Information Mart for Intensive Care IV (MIMIC IV) between 2008 and 2019 and retrospectively analyzed. Data of patients with sepsis patients and serum ammonia not related to acute or chronic liver disease were not included. Results: Data from 720 patients with sepsis were included. SAE was found to have a high incidence (64.6%). After adjusting for other risk factors, a serum ammonia level of ≥45 µmol/L (odds ratio (OR): 3.508, 95% confidence interval (CI): 2.336-5.269, p < 0.001) was found to be an independent risk factor for patients with SAE; moreover, as the serum ammonia level increased, the hospital mortality of SAE gradually increased in a certain range (serum ammonia <150 µmol/L). Serum ammonia levels of ≥45 µmol/L were associated with higher Simplified Acute Physiology Score II and Sequential Organ Failure Assessment (SOFA) scores in patients with SAE. Besides, our study found that patients with SAE used opioid analgesics (OR:3.433, 95% CI: 1.360-8.669, p = 0.009) and the SOFA scores of patients with SAE (OR: 1.126, 95% CI: 1.062-1.194, p < 0.001) were significantly higher than those without SAE. Conclusions: Nonhepatic serum ammonia levels of ≥45 µmol/L evidently increased the incidence of SAE. Serum ammonia levels should be closely monitored in patients with sepsis.

8.
Int Immunopharmacol ; 124(Pt B): 111063, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37857120

RESUMO

Sepsis-induced lung injury is an acute hypoxic respiratory insufficiency caused by systemic infectious factors that results in alveolar epithelial cell and capillary endothelial cell injury, diffuse pulmonary interstitial edema, and alveolar edema. Heme oxygenase (HO)-1 is usually associated with inflammation and has anti-inflammatory effects. Autophagy is a degradation pathway that eliminates cellular metabolic waste and plays an important protective role during stress. The phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt) signaling pathway plays a key role in mediating cellular responses to inflammatory reactions. Therefore, we hypothesized that HO-1 is associated with autophagy and regulated by the PI3K/Akt signaling pathway in mice with sepsis-induced lung injury. Sepsis-induced lung injury was induced in mice using cecal ligation and puncture (CLP). Hemin or Sn-protoporphyrin IX (SnPP) was administered via intraperitoneal injection before surgery. Survival rates were observed during days 1-7 after the surgery; lung histology was discerned 24 h after the surgery; pro-inflammatory and anti-inflammatory factors in plasma and lung tissue were measured using enzyme-linked immunosorbent assay (ELISA); HO-1, Beclin-1, microtubule-associated protein 1 light chain 3B (LC3B)-II, p62 and lysosome associated membrane protein (LAMP)2 protein expression levels were measured 24 h after the surgery; HO-1 and LC3B-II protein expression levels were observed using immunofluorescence 24 h after the surgery; and autophagosomes were detected using electron microscopy 24 h after the surgery. Furthermore, when PI3K inhibitors LY294002, PI3K activators Recilisib and hemin were administered before the surgery, Akt, p-Akt, HO-1, and LC3-II levels were measured 24 h post-surgery. We found that HO-1 overexpression increased the survival rate and inhibited sepsis-induced lung injury. HO-1 overexpression attenuated the levels of proinflammatory cytokines (TNF-α, IL-1ß) and increased the anti-inflammatory cytokine (IL-10, HO-1) overexpression. Moreover, HO-1 overexpression was also associated with increased expression of Beclin-1, LC3B-II and LAMP2 protein expression; decreased p62 protein expression; and significantly increased autophagosome formation. The results for HO-1-downregulated mice contrasted with those mentioned above. LY294002 inhibited p-Akt/Akt, HO-1, and LC3B-II protein expression; and hemin reversed the inhibitory effect of LY294002. The protective effect of HO-1 was involved in the mediation of autophagy, which may be regulated by the PI3K/Akt signaling pathway during sepsis-induced lung injury in mice.


Assuntos
Lesão Pulmonar Aguda , Sepse , Camundongos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Beclina-1/metabolismo , Hemina/farmacologia , Lesão Pulmonar Aguda/complicações , Citocinas/metabolismo , Autofagia , Sepse/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Edema , Heme Oxigenase-1/metabolismo
9.
Clin Nutr ; 42(12): 2328-2337, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37862819

RESUMO

BACKGROUND & AIMS: Polyunsaturated fatty acids (PUFAs) may play a vital role in maintaining skeletal muscle mass in the aged population. This study investigated the longitudinal relationship between the concentrations of erythrocyte membrane PUFAs and age-related changes in skeletal muscle mass over an average 6.5 years of follow-up in a Chinese middle-aged and older adult population. METHODS: A total of 1494 participants aged 57.4 ± 4.7 years were included in this study. Skeletal muscle mass was determined using dual-energy X-ray absorptiometry. Per year percent changes in the skeletal muscle index (Δ% SMI), appendicular skeletal muscle index (Δ% ASMI), and total body lean mass index (Δ% TBLMI) from baseline were calculated. Concentrations of total and individual cis-n-3 and cis-n-6 PUFAs of the erythrocyte membrane were determined using gas-liquid chromatography. RESULTS: Fully adjusted linear regression models showed that per unit increases in the concentrations of C18:2 n-6, C20:4 n-6, C22:4 n-6, and total n-6 PUFAs resulted in increases of 0.022%-0.155 % in the Δ% SMI (P for linearity: <0.001-0.006). Restricted cubic spline analysis revealed an inverted U-shaped relationship between the concentrations of C20:2 n-6, C22:5 n-3, C22:6 n-3, and total n-3 PUFAs and the Δ% SMI (P for non-linearity: <0.001-0.036). In addition, an inverted U-shaped curve was also detected for the relationships of the linoleic acid/α-linolenic acid ratio (P for non-linearity = 0.010) and n-6/n-3 PUFA ratio (P for non-linearity = 0.013) with the Δ% SMI, with the Δ% SMI peaking at respective ratios of 124.96 and 3.69. Similar associations were revealed by the Bayesian kernel machine regression model. No interaction effect was detected between the individual PUFAs for the Δ% SMI in the bivariate exposure-response analysis. Overall, similar results were observed for the Δ% ASMI and Δ% TBLMI. CONCLUSIONS: The associations between different individual PUFAs and age-related muscle loss in middle-aged and older adults may be different. Our results suggest that high concentrations of erythrocyte membrane n-6 PUFAs may be correlated with less skeletal muscle mass loss, whereas extremely high concentrations of n-3 PUFAs may be correlated with more muscle loss.


Assuntos
Membrana Eritrocítica , Ácidos Graxos Ômega-3 , Pessoa de Meia-Idade , Humanos , Idoso , Membrana Eritrocítica/química , Estudos Prospectivos , Teorema de Bayes , Ácidos Graxos Insaturados , Músculo Esquelético , Ácidos Graxos/análise
10.
Comput Med Imaging Graph ; 108: 102277, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37567045

RESUMO

The chest X-ray is commonly employed in the diagnosis of thoracic diseases. Over the years, numerous approaches have been proposed to address the issue of automatic diagnosis based on chest X-rays. However, the limited availability of labeled data for related diseases remains a significant challenge in achieving accurate diagnoses. This paper focuses on the diagnostic problem of thorax diseases and presents a novel deep reinforcement learning framework. This framework incorporates prior knowledge to guide the learning process of diagnostic agents, and the model parameters can be continually updated as more data becomes available, mimicking a person's learning process. Specifically, our approach offers two key contributions: (1) prior knowledge can be acquired from pre-trained models using old data or similar data from other domains, effectively reducing the dependence on target domain data; and (2) the reinforcement learning framework enables the diagnostic agent to be as exploratory as a human, leading to improved diagnostic accuracy through continuous exploration. Moreover, this method effectively addresses the challenge of learning models with limited data, enhancing the model's generalization capability. We evaluate the performance of our approach using the well-known NIH ChestX-ray 14 and CheXpert datasets, and achieve competitive results. More importantly, in clinical application, we make considerable progress. The source code for our approach can be accessed at the following URL: https://github.com/NeaseZ/MARL.


Assuntos
Aprendizagem , Doenças Torácicas , Humanos , Doenças Torácicas/diagnóstico por imagem , Tórax , Software
11.
BMJ Open ; 13(7): e074046, 2023 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-37518073

RESUMO

OBJECTIVE: To investigate the association between furosemide administration and clinical outcomes in patients with sepsis-associated acute kidney injury (SAKI) receiving renal replacement therapy (RRT). DESIGN: A retrospective observational cohort study. SETTING: The data were collected from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, which contains clinical data from more than 380 000 patients admitted to the intensive care units (ICUs) of the Beth Israel Deaconess Medical Center from 2008 to 2019. PARTICIPANTS: All adult patients with SAKI receiving RRT were enrolled. Data for each patient within the first 24 hours of ICU admission were extracted from the MIMIC-IV database. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was in-hospital mortality, and the secondary outcome was the length of hospital stay, length of ICU stay, RRT-free time and ventilator-free time. Logistic regression was used to investigate the association between furosemide administration and in-hospital mortality. Subgroup analysis was employed to explore the potential sources of heterogeneity. RESULTS: A total of 1663 patients with SAKI receiving RRT were enrolled in the study, of whom 991 patients (59.6%) were retrospectively allocated to the Furosemide group and 672 (40.4%) patients to the non-furosemide group. Univariate and multivariate logistic regression showed that furosemide administration was associated with reduced in-hospital mortality, respectively ((OR 0.77; 95% CI 0.63 to 0.93; p=0.008 < 0.05), (OR 0.59; 95% CI 0.46 to 0.75; p<0.001)). The association remained robust to different ways of adjusting for baseline confounding (all p<0.05). Subgroup analysis suggested that AKI-stage may be a source of heterogeneity. Patients in the furosemide group also had longer RRT-free time (p<0.001) and longer ventilator-free time (p<0.001) than those in the non-furosemide group. CONCLUSIONS: Furosemide is associated with decreased in-hospital mortality, longer RRT-free time and ventilator-free time in patients with SAKI receiving RRT.


Assuntos
Injúria Renal Aguda , Sepse , Adulto , Humanos , Estudos Retrospectivos , Furosemida/uso terapêutico , Terapia de Substituição Renal , Cuidados Críticos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Unidades de Terapia Intensiva , Sepse/complicações
12.
Int J Mol Sci ; 24(14)2023 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-37511084

RESUMO

Target biomarkers for H2 at both the protein and genome levels are still unclear. In this study, quantitative proteomics acquired from a mouse model were first analyzed. At the same time, functional pathway analysis helped identify functional pathways at the protein level. Then, bioinformatics on mRNA sequencing data were conducted between sepsis and normal mouse models. Differential expressional genes with the closest relationship to disease status and development were identified through module correlation analysis. Then, common biomarkers in proteomics and transcriptomics were extracted as target biomarkers. Through analyzing expression quantitative trait locus (eQTL) and genome-wide association studies (GWAS), colocalization analysis on Apoa2 and sepsis phenotype was conducted by summary-data-based Mendelian randomization (SMR). Then, two-sample and drug-target, syndrome Mendelian randomization (MR) analyses were all conducted using the Twosample R package. For protein level, protein quantitative trait loci (pQTLs) of the target biomarker were also included in MR. Animal experiments helped validate these results. As a result, Apoa2 protein or mRNA was identified as a target biomarker for H2 with a protective, causal relationship with sepsis. HDL and type 2 diabetes were proven to possess causal relationships with sepsis. The agitation and inhibition of Apoa2 were indicated to influence sepsis and related syndromes. In conclusion, we first proposed Apoa2 as a target for H2 treatment.


Assuntos
Apolipoproteína A-II , Diabetes Mellitus Tipo 2 , Lesão Pulmonar , Sepse , Animais , Camundongos , Biomarcadores , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Hidrogênio/farmacologia , Hidrogênio/uso terapêutico , Polimorfismo de Nucleotídeo Único , Proteômica , Sepse/tratamento farmacológico , Sepse/genética , Apolipoproteína A-II/genética , Apolipoproteína A-II/metabolismo
13.
Front Cell Neurosci ; 17: 1160761, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37333891

RESUMO

Post-operative sleep disturbance is a common feature of elderly surgical patients, and sleep fragmentation (SF) is closely related to post-operative cognitive dysfunction (POCD). SF is characterized by sleep interruption, increased number of awakenings and sleep structure destruction, similar to obstructive sleep apnea (OSA). Research shows that sleep interruption can change neurotransmitter metabolism and structural connectivity in sleep and cognitive brain regions, of which the medial septum and hippocampal CA1 are key brain regions connecting sleep and cognitive processes. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive method for the evaluation of neurometabolic abnormalities. Diffusion tensor imaging (DTI) realizes the observation of structural integrity and connectivity of brain regions of interest in vivo. However, it is unclear whether post-operative SF induces harmful changes in neurotransmitters and structures of the key brain regions and their contribution to POCD. In this study, we evaluated the effects of post-operative SF on neurotransmitter metabolism and structural integrity of medial septum and hippocampal CA1 in aged C57BL/6J male mice. The animals received a 24-h SF procedure after isoflurane anesthesia and right carotid artery exposure surgery. 1H-MRS results showed after post-operative SF, the glutamate (Glu)/creatine (Cr) and glutamate + glutamine (Glx)/Cr ratios increased in the medial septum and hippocampal CA1, while the NAA/Cr ratio decreased in the hippocampal CA1. DTI results showed post-operative SF decreased the fractional anisotropy (FA) of white matter fibers in the hippocampal CA1, while the medial septum was not affected. Moreover, post-operative SF aggravated subsequent Y-maze and novel object recognition performances accompanied by abnormal enhancement of glutamatergic metabolism signal. This study suggests that 24-h SF induces hyperglutamate metabolism level and microstructural connectivity damage in sleep and cognitive brain regions in aged mice, which may be involved in the pathophysiological process of POCD.

14.
Mol Pain ; 19: 17448069231178271, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37247385

RESUMO

Background: Fentanyl and its analogs are extensively used for pain relief. However, their paradoxically pronociceptive effects often lead to increased opioids consumption and risk of chronic pain. Compared to other synthetic opioids, remifentanil has been strongly linked to acute opioid hyperalgesia after exposure [remifentanil-induced hyperalgesia (RIH)]. The epigenetic regulation of microRNAs (miRNAs) on targeted mRNAs has emerged as an important pathogenesis in pain. The current research aimed at exploring the significance and contributions of miR-134-5p to the development of RIH. Methods: Both the antinociceptive and pronociceptive effects of two commonly used opioids were assessed, and miRNA expression profiles in the spinal dorsal horn (SDH) of mice acutely exposed to remifentanil and remifentanil equianalgesic dose (RED) sufentanil were screened. Next, the candidate miRNA level, cellular distribution, and function were examined by qPCR, fluorescent in situ hybridization (FISH) and Argonaute-2 immunoprecipitation. Furthermore, bioinformatics analysis, luciferase assays, miRNA overexpression, behavioral tests, golgi staining, electron microscopy, whole-cell patch-clamp recording, and immunoblotting were employed to investigate the potential targets and mechanisms underlying RIH. Results: Remifentanil induced significant pronociceptive effects and a distinct miRNA-profile from sufentanil when compared to saline controls. Among top 30 differentially expressed miRNAs spectrum, spinal miR-134-5p was dramatically downregulated in RIH mice but remained comparative in mice subjected to sufentanil. Moreover, Glutamate Receptor Ionotropic Kainate 3 (Grik3) was a target of miR-134-5p. The overexpression of miR-134-5p attenuated the hyperalgesic phenotype, excessive dendritic spine remodeling, excitatory synaptic structural plasticity, and Kainate receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in SDH resulting from remifentanil exposure. Besides, intrathecal injection of selective KA-R antagonist was able to reverse the GRIK3 membrane trafficking and relieved RIH. Conclusion: The miR-134-5p contributes to remifentanil-induced pronociceptive features via directly targeting Grik3 to modulate dendritic spine morphology and synaptic plasticity in spinal neurons.


Assuntos
Analgésicos Opioides , MicroRNAs , Animais , Camundongos , Analgésicos Opioides/efeitos adversos , Epigênese Genética , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Hibridização in Situ Fluorescente , Ácido Caínico/efeitos adversos , MicroRNAs/genética , Dor , Piperidinas/efeitos adversos , Receptores de Glutamato/metabolismo , Remifentanil/farmacologia , Sufentanil/efeitos adversos
16.
Clin Nutr ; 42(6): 887-898, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37086617

RESUMO

BACKGROUND & AIMS: Previous studies have suggested that circulating 25-hydroxyvitamin D (25 [OH]D, VD) and the gut microbiota-bile acid axis play crucial roles in metabolic health. Exploring the mediating role of the gut microbiota-bile acid axis would improve our understanding of the mechanisms underlying the effects of VD on human metabolic health. This study examined the association between plasma 25(OH)D and the prevalence/incidence of metabolic syndrome (MetS) and the mediating role of the gut microbiota-bile acid axis. METHODS: This prospective study included 3180 participants with plasma 25(OH)D data at baseline and 2966 participants with a 9-year follow-up. MetS was determined every three years. The gut microbiota was analyzed by 16S rRNA sequencing in 1752 participants, and targeted bile acid metabolites in feces were further determined in 974 participants using UPLC‒MS/MS at the middle of the study. Mediating roles of microbiota and bile acids in the VD-MetS associations were analyzed using mediation/path analyses adjusted for potential confounders. RESULTS: Among the 2966 participants who were followed-up, 1520, 193, 647, and 606 were MetS-free (normal), recovered, had incident MetS, and had persistent MetS, respectively. The multivariable-adjusted ORs (95% CIs) of MetS prevalence were 0.65 (0.50, 0.84) for baseline MetS and 0.46 (0.33, 0.65) for 9-year persistent MetS in quartile 4 (compared to quartile 1) of plasma 25(OH)D (median: 37.7 vs. 19.6, ng/ml). The corresponding HR (95% CI) of 9-year MetS incidence was 0.71 (0.56, 0.90) (all P-trend < 0.05). Higher VD concentrations were associated with greater α-diversity of the gut microbiota, which was inversely correlated with MetS risk. The groups classified by VD and MetS status had significantly different ß-diversity. Ruminiclostridium-6 and Christensenellaceae R-7 group were enriched in the high-VD group and were inversely associated with MetS. However, opposite associations were observed for Lachnoclostridium and Acidaminococcus. The overlapping differential microbial score (ODMS) developed from the four differential genera explained 12.2% of the VD-MetS associations (Pmediation = 0.015). Furthermore, the fecal bile acid score created from 11 differential bile acids related to ODMS and MetS mediated 34.2% of the association between ODMS and MetS (Pmediation = 0.029). Path analyses showed that the inverse association between plasma 25(OH)D and MetS could be mediated by the gut microbiota-bile acid axis. CONCLUSIONS: The findings suggest that the gut microbiota-bile acid axis partially mediates the beneficial association between plasma 25(OH)D and the risk of persistent MetS and incident MetS in the Chinese population.


Assuntos
Microbioma Gastrointestinal , Síndrome Metabólica , Adulto , Humanos , Estudos Prospectivos , Ácidos e Sais Biliares , RNA Ribossômico 16S , Cromatografia Líquida , População do Leste Asiático , Espectrometria de Massas em Tandem , Vitamina D , Vitaminas
17.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 35(2): 189-194, 2023 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-36916380

RESUMO

OBJECTIVE: To investigate whether propofol can cause injury to hippocampal mitochondria in neonatal rats and the regulation of excitatory amino acid receptor AMPA receptor. METHODS: Forty-eight Sprague-Dawley (SD) rats aged 7 days were randomly divided into control group, propofol group, propofol+AMPA receptor agonist AMPA group (propofol+AMPA group) and propofol+AMPA receptor inhibitor CNQX group (propofol+CNQX group), with 12 rats in each group. The rats in the propofol groups were intraperitoneally injected with 30 mg/kg propofol, while in control group with 3 mg/kg normal saline. Each group was given 1/2 of the first dose every 20 minutes after the first administration, three times a day, for three consecutive days. The rats in the propofol+AMPA group and the propofol+CNQX group were injected with 1 g/L AMPA or CNQX 5 µL through left ventricle after the first administration. Three days after administration, the rats were sacrificed to obtain brain tissue. Western blotting was used to determine the expression of AMPA receptor glutamate receptors (GluR1, GluR2) subunit totally (T) and on membrane (M) in hippocampus. The expression of dynamin-related protein-1 (DRP-1) and phosphorylated-DRP-1 (p-DRP-1) and mitofusin 2 (Mfn2) related to mitochondrial fission and fusion were determined. The adenosine triphosphate (ATP) content and ATPase activity were determined. RESULTS: Compared with the control group, GluR1 expression and its M/T ratio were significantly increased after treatment of propofol, GluR2 expression and its M/T ratio were significantly decreased, the ATP content and ATP-related enzyme activity were decreased significantly, while the expression of DRP-1 and its phosphorylation was significantly increased, and the expression of Mfn2 was significantly decreased. The changes indicated that repeated intraperitoneal injection of 30 mg/kg propofol leading to the injury of mitochondria in neural cells. Compared with the propofol group, the GluR1 expression and its M/T ratio further increased after AMPA agonist administration [T-GluR1 protein (T-GluR1/ß-actin): 2.41±0.29 vs. 1.72±0.11, M-GluR1 protein (M-GluR1/ß-actin): 1.18±0.15 vs. 0.79±0.09, M/T ratio: 0.78±0.12 vs. 0.46±0.08, all P < 0.01], GluR2 expression was significantly increased [T-GluR2 protein (T-GluR2/ß-actin): 0.65±0.13 vs. 0.30±0.14, P < 0.01; M-GluR2 protein (M-GluR2/ß-actin): 0.17±0.05 vs. 0.13±0.07, P > 0.05], but its M/T ratio was further decreased (0.27±0.10 vs. 0.41±0.08, P < 0.05). The ATP-related enzyme activity was further decreased, and the ATP content was further decreased (µmol/g: 0.32±0.07 vs. 0.70±0.10, P < 0.01). Mitochondria DRP-1 expression and its phosphorylation were further increased [DRP-1 protein (DRP-1/GAPDH): 2.75±0.36 vs. 1.70±0.19, p-DRP-1 protein (p-DRP-1/GAPDH): 0.99±0.14 vs. 0.76±0.15, both P < 0.05], and Mfn2 expression was further decreased (Mfn2/GAPDH: 0.23±0.12 vs. 0.54±0.12, P < 0.05). This indicated that the AMPA agonist increased the expression of the AMPA receptor GluR1 subunit on the cell membrane and shifted the GluR2 into the cell, thus increasing the mitochondrial injury caused by propofol. Compared with the propofol group, the GluR1 expression and its M/T ratio decreased significantly after AMPA inhibitor administration [T-GluR1 protein (T-GluR1/ß-actin): 0.99±0.14 vs. 1.72±0.11, M-GluR1 protein (M-GluR1/ß-actin): 0.21±0.07 vs. 0.79±0.09, M/T ratio: 0.21±0.07 vs. 0.46±0.08, all P < 0.01], the change of GluR2 expression was not significant, but its M/T ratio was significantly increased (0.59±0.09 vs. 0.41±0.08, P < 0.05). The ATP-related enzyme activity was increased significantly, and the ATP content was increased significantly (µmol/g: 0.87±0.12 vs. 0.70±0.10, P < 0.05). Mitochondria DRP-1 expression and its phosphorylation were significantly decreased [DRP-1 protein (DRP-1/GAPDH): 1.18±0.17 vs. 1.70±0.19, p-DRP-1 protein (p-DRP-1/GAPDH): 0.37±0.10 vs. 0.76±0.10, both P < 0.05], and Mfn2 expression was significantly increased (Mfn2/GAPDH: 0.78±0.10 vs. 0.54±0.12, P < 0.05). This indicated that AMPA inhibitor promoted the movement to the cell membrane of GluR2 subunits meanwhile inhibited the expression of GluR1 subunits, thus alleviating the injury of mitochondrial caused by propofol in the brain. CONCLUSIONS: Repeated intraperitoneal injection of 30 mg/kg propofol for 3 days can increase the expression of GluR1 subunits of AMPA receptor in 7-day neonatal rats hippocampus mainly distributing in the cell membrane, decrease the expression of GluR2 subunits moving into the cell, thus causing injury of mitochondrial function and dynamics, which can be aggravated by AMPA receptor agonist and alleviated by AMPA receptor inhibitors.


Assuntos
Propofol , Receptores de AMPA , Ratos , Animais , Receptores de AMPA/metabolismo , Ratos Sprague-Dawley , Propofol/farmacologia , Animais Recém-Nascidos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Actinas/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Hipocampo/metabolismo
18.
Int Immunopharmacol ; 118: 110009, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36963264

RESUMO

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a complication of the central nervous system in patients with sepsis. Currently, no effective treatment for sepsis is available. Hydrogen plays a protective role in different diseases; however, the detailed mechanism of hydrogen-treated disease remains unclear. The purpose of this study was to investigate the effect of hydrogen on SAE in vitro and in vivo and the mechanism of hydrogen in mitochondrial dynamics and its function in astrocytes and microglia stimulated by lipopolysaccharides (LPSs). METHODS: Animal models of SAE were generated by cecal ligation and puncture, and the SAE model was established by in vitro LPS stimulation. MTT, lactate dehydrogenase (LDH), reactive oxygen species (ROS), heme oxygenase-1 (HO-1) activity, mitochondrial membrane potential (MMP), and cell apoptosis assays were used to determine the effect of hydrogen on astrocytes and microglia stimulated by LPSs. The relationships between nuclear factor erythroid 2-related factor 2 (Nrf2), YY1, and HO-1 were examined by chromatin immunoprecipitation and co-immunoprecipitation. Mitochondrial homeostasis-related proteins in LPS-stimulated glial cells and brain tissues of SAE mice were detected by western blotting. The effects of hydrogen treatment in the SAE mouse model were investigated using Morris water maze and Y-maze analyses. RESULTS: After performing experiments with different concentrations of LPSs in vitro, we selected 1000 ng/ml for subsequent experiments. Hydrogen attenuated the increase in ROS, LDH, and apoptosis and promoted decreases in cell activity and MMP, further promoting an increase in HO-1 expression induced by LPSs in astrocytes and microglia. Moreover, hydrogen further promoted the expression of Nrf2, HO-1, PGC-1α, TFAM, PARKIN, and PINK1, inhibited LPS-induced OPA1 and MFN2 expression in astrocytes and microglia, and downregulated the expression of DRP1 after LPS induction. Intriguingly, hydrogen treatment enhanced the binding between Nrf2 and YY1. However, silencing Nrf2 or YY1 abolished the protective effects of hydrogen on cell activity, LDH, ROS, and MMP; apoptosis; and regulation of Nrf2, HO-1, PGC-1α, TFAM, OPA1, DRP1, MFN2, PARKIN, and PINK1 in microglia. Finally, hydrogen treatment improved the results of behavioral detection, apoptosis, Nrf2, HO-1, PGC-1α, TFAM, OPA1, DRP1, MFN2, PARKIN, PINK1, and cytokines in SAE in vivo. CONCLUSIONS: Hydrogen improved cell injury and mitochondrial quality, which were associated with HO-1 expression promoted by the Nrf2/YY1 complex in vitro. Thus, hydrogen treatment may represent a novel therapeutic method for treating SAE.


Assuntos
Encefalopatia Associada a Sepse , Sepse , Animais , Camundongos , Heme Oxigenase-1/metabolismo , Hidrogênio/farmacologia , Hidrogênio/uso terapêutico , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases/metabolismo , Espécies Reativas de Oxigênio , Sepse/complicações , Sepse/tratamento farmacológico , Encefalopatia Associada a Sepse/complicações , Transdução de Sinais
19.
J Inflamm Res ; 16: 809-826, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36876154

RESUMO

Purpose: Intra-abdominal infection is considered the second most common cause of sepsis and results in localized or diffused inflammation of the peritoneum. The main treatment for abdominal sepsis is an emergency laparotomy for source control. However, surgical trauma also causes inflammation, and patients become susceptible to postoperative complications. Therefore, it is necessary to identify biomarkers that can be used to distinguish sepsis from abdominal infection. This prospective study investigated whether cytokine levels in the peritoneum could predict complications and indicate severity of sepsis following emergency laparotomy. Methods: We prospectively observed 97 patients with abdominal infection admitted to the Intensive Care Unit (ICU). After emergency laparotomy,SEPSIS-3 criteria were used for the diagnosis of sepsis or septic shock. Blood and peritoneal fluid samples were drawn at postoperative admission to the ICU and cytokine concentrations were measured by flow cytometry. Results: Fifty-eight postoperative patients were enrolled. We found significant elevations in the peritoneal concentrations of IL-1ß, IL-6, TNF-α, IL-17, and IL-2 in patients with sepsis or septic shock compared to the patients without sepsis after surgery. Positive correlations between levels of these peritoneal cytokines with APACHE II scores were found: IL-6, in particular, had the highest correlation coefficient of 0.833. Meanwhile, IL-10 in blood, MCP-1 and IL-8 in both blood and peritoneum were simultaneously increased in patients with sepsis and septic shock, and also positively correlated with disease severity. Conclusion: The cytokine storm that occurs in the abdominal cavity after emergency laparotomy may be the main mechanism leading to sepsis. It may be valuable to measure IL-1ß, IL-6, TNF-α,IL-17, IL-2, MCP-1, and IL-8 in the peritoneal fluid, combined with serum IL-10, MCP-1 and IL-8, in a panel of cytokines, to assess the severity of sepsis and predict mortality from abdominal infection after emergency laparotomy.

20.
Shock ; 59(4): 569-575, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36802286

RESUMO

ABSTRACT: Background: It is unknown whether early renal replacement therapy (RRT) initiation strategy in intensive care unit (ICU) patients with both acute respiratory distress syndrome (ARDS) and sepsis with or without renal failure is clinically beneficial. Patients and methods: A total of 818 patients with both ARDS and sepsis admitted to the ICU of Tianjin Medical University General Hospital were included in the analysis. Early RRT was defined as initiating the RRT strategy within 24 h of admission. The relationship between early RRT and clinical outcomes, including primary (30-day mortality) and secondary (90-day mortality, serum creatinine, Pa o2 /Fi o2 , duration of invasive mechanical ventilation, cumulative fluid output, and cumulative fluid balance) outcomes, was compared using propensity score matching (PSM). Results: A total of 277 patients (33.9% of the total population) underwent an early RRT initiation strategy before PSM. After PSM, a cohort of 147 patients with early RRT and 147 patients without early RRT with matched baseline characteristics (including serum creatinine at admission) were constructed. Early RRT was not significantly associated with 30- (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.85-1.85; P = 0.258) or 90-day mortality (HR, 1.30; 95% CI, 0.91-1.87, P = 0.150). At each time point within 72 h after admission, there was no significant difference in serum creatinine, Pa o2 /Fi o2 and duration of mechanical ventilation between the early and the no early RRT groups. Early RRT significantly increased total output at all time points within 72 h of admission and reached a statistically significant negative fluid balance at 48 h. Conclusions: Early RRT initiation strategies had no statistically significant survival benefit in ICU patients with both ARDS and sepsis, with or without renal failure, nor did they significantly improve serum creatinine and oxygenation or shorten the duration of mechanical ventilation. The use and timing of RRT in such patients should be thoroughly investigated.


Assuntos
Injúria Renal Aguda , Síndrome do Desconforto Respiratório , Sepse , Humanos , Estudos Retrospectivos , Creatinina , Pontuação de Propensão , Injúria Renal Aguda/etiologia , Terapia de Substituição Renal/efeitos adversos , Sepse/terapia , Sepse/etiologia , Unidades de Terapia Intensiva , Síndrome do Desconforto Respiratório/terapia , Síndrome do Desconforto Respiratório/etiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...