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Abstract Background superparamagnetic ferroferric oxide (Fe3O4) nanoparticles can be extensively functionalized for applications in drug enrichment and separation. Their high magnetic responsiveness and controllable surface modification enable rapid drug enrichment and separation under external magnetic fields. This study aimed to enhance the application potential of superparamagnetic Fe3O4 nanoparticles in the field of drug enrichment and separation by functionalizing these nanoparticles to improve their biocompatibility and targeting capabilities. Methods superparamagnetic Fe3O4 nanoparticles functionalized with dopamine were synthesized using benzyl alcohol as the solvent and iron acetylacetonate as the precursor. The dopamine-functionalized superparamagnetic iron oxide nanoparticles were used to analyze protein enrichment and separation. Characterization of the nanoparticles was conducted, including analysis of particle size distribution, Zeta potential, and fluorescence spectra using a fluorescence spectrophotometer. Results the Fe3O4 nanoparticles maintained high magnetism from the original material and exhibited uniform particle size distribution and stable Zeta potential. The saturation magnetization of dopamine-functionalized superparamagnetic Fe3O4 nanoparticles showed no significant difference compared to before coating, indicating minimal influence of dopamine on the internal magnetic core of the nanoparticles. The Fe3O4 nanoparticles demonstrated good biocompatibility and stability. Conclusion functionalization of superparamagnetic Fe3O4 nanoparticles significantly enhances their efficiency in drug enrichment and separation processes, suggesting broad applications in the pharmaceutical industry.

Abstract Objective It is well known that glucose and lipid metabolism disorders and insulin resistance are common in sepsis, which affect the occurrence and prognosis of multiple organ dysfunction in septic patients. Previous study reported the predictive value of triglyceride-glucose index (TyG), a clinical indicator for insulin resistance, in postoperative delirium patients. However, it remains unclear whether the TyG index is a novel predictive biomarker for sepsis-associated delirium. The aim of this study is to explore the relationship between TyG index and the risk of delirium in patients with sepsis. Methods Adult septic patients were identified from the MIMIC-IV database and divided into four groups based on the mean value of TyG. The primary outcome was the incidence of delirium. The association between TyG and the risk of developing delirium was evaluated by restricted cubic spline (RCS), multivariate logistic regression and subgroup analysis. Propensity Score Matching (PSM) method was used to balance the baseline data. Results A total of 3,331 septic patients were included in the analysis, and further divided into four groups: Q1 (TyG ≤ 8.67), Q2 (8.67 9.61). The RCS curves demonstrated a non-linear positive relationship between TyG index and the risk of developing delirium, and an optimal cut-of value 9.09 was recommended. After balancing the baseline information by PSM, patients in the TyG > 9.09 group had a significant higher incidence of delirium compared with those in the TyG ≤ 9.09 group. In logistic regression analysis, TyG > 9.09 was significantly associated with lower risk of developing delirium in both original cohort (OR 1.54–1.78, all P 0.05). In subgroup analysis, our findings were consistent (all OR > 1 in all subgroups). Conclusion Our study demonstrated an independent association between TyG index and increased risk of delirium in septic patients, indicating that TyG index can serve as a biomarker for delirium in sepsis.

Abstract Background Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H2) is widely considered as a useful neuroprotective and antioxidative therapeutic method for hypoxic-ischemic disease without toxic effects. However, whether H2 provides physiological angiogenesis promotion, neovascularization suppression and glial protection in the progression of ROP is largely unknown.This study aims to investigate the effects of H2 on retinal angiogenesis, neovascularization and neuroglial dysfunction in the retinas of oxygen-induced retinopathy (OIR) mice. Methods In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2−/−) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H2) inhalation were administered. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. To count the number of neovascularization endothelial nuclei, routine HE staining of retinal sections was conducted. Immunohistochemistry was performed using DyLight 594 labeled GSL I-isolectin B4 (IB4), as well as primary antibodies against proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), and Iba-1. Western blots were used to measure the expression of NF-E2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), Notch1, Dll4, and HIF-1α. Additionally, the expression of target genes such as NQO1, HO-1, Notch1, Hey1, Hey2, and Dll4 was measured. Human umbilical vein endothelial cells (HUVECs) treated with H2 under hypoxia were used as an in vitro model. RT-PCR was used to evaluate the mRNA expression of Nrf2, Notch/Dll4, and the target genes. The expression of reactive oxygen species (ROS) was observed using immunofluorescence staining. Results Our results indicate that 3–4% H2 does not disturb retinal physiological angiogenesis, but ameliorates vaso-obliteration and neovascularization in OIR mice. Moreover, H2 prevents the decreased density and reverses the morphologic and functional changes in retinal astrocytes caused by oxygen-induced injury. In addition, H2 inhalation reduces microglial activation, especially in the area of neovascularization in OIR mice. H2 plays a protective role in vascular regeneration by promoting Nrf2 activation and suppressing the Dll4-induced Notch signaling pathway in vivo. Also, H2 promotes the proliferation of HUVECs under hypoxia by negatively regulating the Dll4/Notch pathway and reducing ROS levels through Nrf2 pathway aligning with our findings in vivo.Moreover, the retinal oxygen-sensing mechanisms (HIF-1α/VEGF) are also involved in hydrogen-mediated retinal revascularization and neovascularization suppression. Conclusions Collectively, our results indicate that H2 could be a promising therapeutic agent for POR treatment and that its beneficial effect in human ROP might involve the activation of the Nrf2-Notch axis as well as HIF-1α/VEGF pathways. Graphical Abstract

ObjectivesPatients with sepsis are often comorbid with acute respiratory distress syndrome (ARDS), and the phenotypic characteristics of pulmonary and non-pulmonary infections leading to ARDS are still unclear. This study aimed to compare the phenotypic characteristics of ARDS resulting from pulmonary infections and other non-site infections and provide better guidance for clinical treatment.MethodsWe conducted a multicenter cohort analysis using data from the Tianjin Medical University General Hospital, Medical Information Mart for Intensive Care-IV (MIMIC-IV), and the electronic intensive care unit (eICU) databases. The study population consisted of adult patients diagnosed with sepsis and ARDS. The primary objectives were to compare the characteristics and outcomes of patients with pulmonary infection-induced ARDS and those with non-pulmonary infection-induced ARDS using Wilcoxon analysis, Kaplan–Meier curves, correlation analysis, propensity matching scores, and other statistical methods.ResultsPatients with ARDS by pulmonary infection may be more likely to have a history of chronic obstructive pulmonary disease, and abdominal infection was more likely to induce ARDS in sepsis patients with non-pulmonary infection. Pulmonary infections caused by Klebsiella pneumoniae and Acinetobacter baumannii were more likely to induce ARDS. The oxygenation index and prognosis of ARDS patients induced by pulmonary infection were worse than those caused by other infections, with lower PaO2, PaO2/FiO2, and ROX index and longer hospital stay. More ARDS patients with pulmonary infection were given mechanical ventilation therapy, with higher mortality, APACHE II, SOFA, and SAPS II. The further correlation analysis showed that the prognostic scores of ARDS patients were negatively correlated with PaO2/FiO2 and ROX index. The above results were confirmed to varying degrees by propensity matching scores, external cohort validation, and other methods.ConclusionPulmonary infection induces a worse prognosis of ARDS than other site infections in patients with sepsis and ARDS. These patients require heightened vigilance, early intervention, and possibly more aggressive management strategies.

Abstract Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.

Abstract 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

Abstract 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

Circulating nucleosome levels are commonly elevated in physiological and pathological conditions. Their potential as biomarkers for diagnosing and prognosticating sepsis remains uncertain due, in part, to technical limitations in existing detection methods. This scoping review explores the possible role of nucleosome concentrations in the diagnosis, prognosis, and therapeutic management of sepsis. A comprehensive literature search of the Cochrane and Medline libraries from 1996 to 1 February 2024 identified 110 potentially eligible studies, of which 19 met the inclusion criteria, encompassing a total of 39 SIRS patients, 893 sepsis patients, 280 septic shock patients, 117 other ICU control patients, and 345 healthy volunteers. The enzyme-linked immunosorbent assay [ELISA] was the primary method of nucleosome measurement. Studies consistently reported significant correlations between nucleosome levels and other NET biomarkers. Nucleosome levels were higher in patients with sepsis than in healthy volunteers and associated with disease severity, as indicated by SOFA and APACHE II scores. Non-survivors had higher nucleosome levels than survivors. Circulating nucleosome levels, therefore, show promise as early markers of NETosis in sepsis, with moderate diagnostic accuracy and strong correlations with disease severity and prognosis. However, the available evidence is drawn mainly from single-center, observational studies with small sample sizes and varied detection methods, warranting further investigation.

ObjectiveThis 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 methodsIn 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.ResultsThe 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

Abstract Background No consensus has been reached on an optimal blood lactate evaluation system although several approaches have been reported in the literature in recent years. A group-based trajectory modeling (GBTM) method could better stratify patients with acute respiratory distress syndrome (ARDS) complicated with sepsis in the intensive care unit (ICU). Patients and methods 760 patients from the comprehensive ICU of Tianjin Medical University General Hospital with ARDS complicated with sepsis were eligible for analysis. Serial serum lactate levels were measured within 48 h of admission. In addition to the GBTM lactate groups, the initial lactate, peak lactate level, the area under the curve of serial lactate (lactate AUC), and lactate clearance were also considered for comparison. The short- and long-term outcomes were the 30- and 90-day mortality, respectively. Results Three lactate groups were identified based on GBTM, with group 3 exhibiting the worse short- [hazard ratio (HR) for 30-day mortality: 2.96, 95% confidence interval (CI) 1.79–4.87, P

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

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.

METTL3 promotes LPS-induced cardiomyocytes inflammatory damage via IGF2BP1/m6A/HDAC4 axis.

Abstract Background Postoperative atelectasis occurs in 90% of patients receiving general anesthesia. Recruitment maneuvers (RMs) are not always effective and frequently associated with barotrauma and hemodynamic instability. It is reported that many natural physiological behaviors interrupted under general anesthesia could prevent atelectasis and restore lung aeration. This study aimed to find out whether a combined physiological recruitment maneuver (CPRM), sigh in lateral position, could reduce postoperative atelectasis using lung ultrasound (LUS). Methods We conducted a prospective, randomized, controlled trial in adults with open abdominal surgery under general anesthesia lasting for 2 h or longer. Subjects were randomly allocated to either control group (C-group) or CPRM-group and received volume-controlled ventilation with the same ventilator settings. Patients in CPRM group was ventilated in sequential lateral position, with the addition of periodic sighs to recruit the lung. LUS scores, dynamic compliance (Cdyn), the partial pressure of arterial oxygen (PaO2) and fraction of inspired oxygen (FiO2) ratio (PaO2/FiO2), and other explanatory variables were acquired from each patient before and after recruitment. Results Seventy patients were included in the analysis. Before recruitment, there was no significant difference in LUS scores, Cdyn and PaO2/FiO2 between CPRM-group and C-group. After recruitment, LUS scores in CPRM-group decreased significantly compared with C-group (6.00 [5.00, 7.00] vs. 8.00 [7.00, 9.00], p = 4.463e-11

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

ObjectivesOur previous study shows that serum ammonia in sepsis patients without hepatic failure is associated with a poor prognosis. The relationship between serum ammonia level and the prognosis of sepsis-associated encephalopathy (SAE) patients without hepatic failure remains unclear. We aimed to explore the relationship between serum ammonia levels and the prognosis of patients with SAE.Materials and methodsThis study is a retrospective cohort study. We collected 465 patients with SAE admitted to the intensive care unit (ICU) from Medical Information Mart for Intensive Care IV (MIMIC IV) from 2008 to 2019. Patients with SAE were divided into a survival group (369 patients) and a non-survival group (96 patients). We used the Wilcoxon signed-rank test and the multivariate logistic regression analysis to analyze the relationship between serum ammonia levels and the prognosis of patients with SAE. R software was used to analyze the dataset.ResultsThe primary outcome was the relationship between serum ammonia level and hospital mortality of SAE. The secondary outcomes were the relationship between serum ammonia level and hospital stays, simplified acute physiology score (SAPS II), Charlson, Glasgow coma scale (GCS), sequential organ failure assessment (SOFA), and lactate level of SAE. The mortality of patients with SAE was 20.6%. The serum ammonia level was not significantly associated with hospital mortality, longer hospital stays, higher SAPS II and Charlson scores, and lower GCS of patients with SAE. The serum ammonia level was associated with higher SOFA scores and lactate levels in patients with SAE. The SAPS II and Charlson scores were independent risk factors for death in patients with SAE.ConclusionSerum ammonia level was associated with higher SOFA scores and lactate levels in patients with SAE. In addition, the SAPS II and Charlson scores can be used to assess the prognosis of patients with SAE. Therefore, we should closely monitor serum ammonia, SAPS II, and Charlson levels in patients with SAE.

BackgroundThe maintenance of blood pressure is pivotal in preventing sepsis with acute kidney injury (AKI). Especially in sepsis patients treated with vasopressors. The optimal the blood pressure has been controversial to maintain renal perfusion. This study aims to explore the blood pressure target in sepsis with AKI.MethodsWe retrieved patient data from the MIMIC IV and eICU databases. The Lasso regression model was used to identify the relationship between blood pressure and sepsis in patients with AKI and remove collinearity among variables. Generalized additive models were used to estimate the blood pressure range in patients with sepsis with AKI. Statistical methods such as multivariable logistic regression, propensity score analysis, inversion probability-weighting, and doubly robust model estimation were used to verify the target blood pressure for patients with sepsis and AKI.ResultsIn total, 17874 patients with sepsis were included in this study. the incidence of AKI may be related to the level of mean article pressure (MAP) and diastolic blood pressure (DBP) in sepsis patients. The range of MAPs and DBPs may be 65-73 mmHg and 50-60 mmHg in AKI patients without hypertension. The range of MAPs and DBPs may be 70-80 mmHg and 54-62 mmHg in AKI patients with hypertension. The prognosis of sepsis with AKI was unaffected by MAP or DBP. Systolic blood pressure is not associated with sepsis in patients with AKI.ConclusionsTo ensure renal perfusion, AKI patients with hypertension may require a higher MAP [70-80] versus (65-73), mmHg] and DBP [(54-62) vs (50-60), mmHg] than patients without hypertension.

ObjectiveSepsis Associated Encephalopathy (SAE) is a common complication in critically ill patients and perioperative period, but its pathogenesis is still unclear. This study aimed to explore the effect of the HIF-1α (hypoxia-inducible factor-1α)/BNIP3L (Bcl-2/adenovirus E1B 19-kDa interaction protein) signaling pathway on SAE.MethodsC57BL/6J male mice were divided into four groups, using a random number table method: control group, sham group, sepsis group, sepsis+HIF-1α activity inhibitor (echinomycin) group. Sepsis was induced by cecal ligation and puncture (CLP). At 24 h after surgery, brain tissue was sampled. HE was staining to observe changes in the hippocampus structure. Fluoroscopy observes changes in mitochondrial structure. Western blot, QT-PCR, and immunofluorescence were used to assess the amount of expression of HIF-1α and BNIP3L in the hippocampus and mitochondrion of hippocampus neurons. Observation of neuronal apoptosis by TUNEL staining. Seven days after surgery, mice were tested in a Morris water maze test to assess cognitive function after CLP.ResultsOur results show that CLP-induced hippocampus-dependent cognitive deficits were accompanied with increased HIF 1a and decreased BNIP3L, increased protein levels of TNF-α, IL-6, and IL-β, and damage to mitochondrial structures and neuronal apoptosis in the hippocampus. In addition, administration of echinomycin rescues cognitive deficits, ameliorates HIF-1α and BNIP3L-mediated neuronal pyroptosis and damaged mitochondrial structures, and decreases the expression of TNF-α and IL-6 in the hippocampus.ConclusionsHIF-1α and the BNIP3L promote mitochondrial damage, and neuronal apoptosis and the expression of inflammatory factors may be the mechanism of SAE in critically ill patients and perioperative period

ObjectiveAcinetobacter baumannii is one of the most important pathogenic bacteria causing nosocomial infections and has a high mortality rate. Assessment of the microbiological characteristics and risk factors on prognosis associated with A.baumannii is essential. In this study, we aimed to investigate the clinical characteristics and prognostic risk factors of patients with A.baumannii bacteremia.Patients and MethodsThis study retrospectively analyzed the antibiotic resistance of pathogens based on the clinical data of A.baumannii bacteremia patients presented in a tertiary teaching hospital from 2017 to 2022. Logistic regression and decision tree identified the prognostic risk factors for patients with baumannemia. Kaplan-Meier method was used for survival analysis between MDR and Non-MDR groups. The area under receiver-operating characteristic curve (ROC curve) was used to compare the predictive value of the APACHE II score and Sequential Organ Failure Assessment (SOFA) score.ResultsA total of 110 patients with positive A. Baumannii blood cultures were included. Most of the patients were from intensive care unit (ICU) wards. The drug sensitivity results showed that the resistance rate of A. baumannii to colistin was the lowest (1.1%), followed by tigecycline (3.6%).The survival time of MDR group was significantly shorter than that of Non-MDR group. Multivariate analysis showed that, APACHE II score and SOFA score were independent risk factors affecting the prognosis of 28 days of A.baumannii bacteremia. And both scores displayed excellent AUROCs (SOFA: 0.909, APACHE II: 0.895 in predicting 28-day mortality). The two scoring systems were highly correlated and predicted no significant difference (r2 = 0.4410, P < 0.001). We found that SOFA > 7 and APACHE II > 21 are associated with significantly higher mortality rates.ConclusionA.baumannii bacteremia have the highest incidence in the ICU, with high drug resistance and mortality rates. The survival time of patients with MDR A. Baumannii bacteremia was significantly shortened. The SOFA score and APACHE II score can reflect the severity of A.baumannii bacteremia patients and evaluate the 28-day prognosis. In addition, for the convenience of calculation, the SOFA score may be more clinically useful than the APACHE II score in predicting the mortality rate of A.baumannii bacteremia.

ObjectivesSepsis-associated encephalopathy (SAE) patients in the intensive care unit (ICU) and perioperative period are administrated supplemental oxygen. However, the correlation between oxygenation status with SAE and the target for oxygen therapy remains unclear. This study aimed to examine the relationship between oxygen therapy and SAE patients.MethodsPatients diagnosed with sepsis 3.0 in the intensive care unit (ICU) were enrolled. The data were collected from the Medical Information Mart for Intensive Care IV (MIMIC IV) database and the eICU Collaborative Research Database (eICU-CRD) database. The generalized additive models were adopted to estimate the oxygen therapy targets in SAE patients. The results were confirmed by multivariate Logistic, propensity score analysis, inversion probability-weighting, doubly robust model, and multivariate COX analyses. Survival was analyzed by the Kaplan-Meier method.ResultsA total of 10055 patients from eICU-CRD and 1685 from MIMIC IV were included. The incidence of SAE patients was 58.43%. The range of PaO2 (97-339) mmHg, PaO2/FiO2 (189-619), and SPO2≥93% may reduce the incidence of SAE, which were verified by multivariable Logistic regression, propensity score analysis, inversion probability-weighting, and doubly robust model estimation in MIMIC IV database and eICU database. The range of PaO2/FiO2 (189-619) and SPO2≥93% may reduce the hospital mortality of SAE were verified by multivariable COX regression.ConclusionsSAE patients in ICU, including perioperative period, require conservative oxygen therapy. We should maintain SPO2≥93%, PaO2 (97-339) mmHg and PaO2/FiO2 (189-619) in SAE patients.

Ischemic stroke (IS) is one of the major causes of death and disability worldwide, and effective diagnosis and treatment methods are lacking. RNA methylation, a common epigenetic modification, plays an important role in disease progression. However, little is known about the role of RNA methylation modification in the regulation of IS. The aim of this study was to investigate RNA methylation modification patterns and immune infiltration characteristics in IS through bioinformatics analysis. We downloaded gene expression profiles of control and IS model rat brain tissues from the Gene Expression Omnibus database. IS profiles were divided into two subtypes based on RNA methylation regulators, and functional enrichment analyses were conducted to determine the differentially expressed genes (DEGs) between the subtypes. Weighted gene co-expression network analysis was used to explore co-expression modules and genes based on DEGs. The IS clinical diagnosis model was successfully constructed and four IS characteristic genes (GFAP, GPNMB, FKBP9, and CHMP5) were identified, which were significantly upregulated in IS samples. Characteristic genes were verified by receiver operating characteristic curve and real-time quantitative PCR analyses. The correlation between characteristic genes and infiltrating immune cells was determined by correlation analysis. Furthermore, GPNMB was screened using the protein-protein interaction network, and its regulatory network and the potential therapeutic drug chloroquine were predicted. Our finding describes the expression pattern and clinical value of key RNA methylation modification regulators in IS and novel diagnostic and therapeutic targets of IS from a new perspective.

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.

Abstract Background Myocardial ischemia-reperfusion injury (MIRI) is the most common cause of death worldwide. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the inflammatory response to MIRI. Dexmedetomidine (DEX), a specific agonist of α2-adrenergic receptor, is commonly used for sedation and analgesia in anesthesia and critically ill patients. Several studies have shown that dexmedetomidine has a strong anti-inflammatory effect in many diseases. Here, we investigated whether dexmedetomidine protects against MIRI by inhibiting the activation of the NLRP3 inflammasome in vitro. Methods We established an MIRI model in cardiomyocytes (CMs) alone and in coculture with cardiac fibroblasts (CFs) by hypoxia/reoxygenation (H/R) in vitro. The cells were treated with dexmedetomidine with or without MCC950 (a potent selective NLRP3 inhibitor). The beating rate and cell viability of cardiomyocytes, NLRP3 localization, the expression of inflammatory cytokines and NLRP3 inflammasome-related proteins, and the expression of apoptosis-related proteins, including Bcl2 and BAX, were determined. Results Dexmedetomidine treatment increased the beating rates and viability of cardiomyocytes cocultured with cardiac fibroblasts. The expression of the NLRP3 protein was significantly upregulated in cardiac fibroblasts but not in cardiomyocytes after H/R and was significantly attenuated by dexmedetomidine treatment. Expression of the inflammatory cytokines IL-1β, IL-18 and TNF-α was significantly increased in cardiac fibroblasts after H/R and was attenuated by dexmedetomidine treatment. NLRP3 inflammasome activation induced the increased expression of cleaved caspase1, mature IL-1β and IL-18, while dexmedetomidine suppressed H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. In addition, dexmedetomidine reduced the expression of Bcl2 and BAX in cocultured cardiomyocytes by suppressing H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. Conclusion Dexmedetomidine treatment can suppress H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts, thereby alleviating MIRI by inhibiting the inflammatory response.

Coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has no specific and effective treatment. The pathophysiological process of the COVID-19 is an excessive inflammatory response after an organism infects with a virus. Inflammatory storms play an important role in the development of the COVID-19. A large number of studies have confirmed that hydrogen has a therapeutic effect on many diseases via inhibiting excessive inflammatory cells and factors. Recently, a study led by the Academician Zhong Nanshan in China on the treatment of the patients with the COVID-19 by inhalation of a mixed gas composed of hydrogen and oxygen has attracted widespread international attention and hydrogen therapy has also been included in a new treatment plan for the COVID-19 in China. This study mainly describes the mechanism of occurrence of the COVID-19, summarizes the therapeutic effects and underlying mechanisms of hydrogen on the critical disease, and analyzes the feasibility and potential therapeutic targets of hydrogen for the treatment of the COVID-19.

Abstract Background We aimed to study the role of amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) glutamate receptor 2 (GluR2) subunit trafficking, and activity changes in short-term neuroprotection provided by propofol post-conditioning. We also aimed to determine the role of phosphoinositide-3-kinase (PI3K) in the regulation of these processes. Methods Rats underwent 1 h of focal cerebral ischemia followed by 23 h of reperfusion were randomly divided into 6 groups (n = 36 per group): sham- operation (S), ischemia–reperfusion (IR), propofol (P group, propofol 20 mg/kg/h at the onset of reperfusion for 2 h after 60 min of occlusion), and LY294002 (PI3K non-selective antagonist) + sham (L + S, LY294002 of 1.5 mg/kg was infused 30 min before sham operation), LY294002+ ischemia–reperfusion (L + IR, LY294002 of 1.5 mg/kg was infused 30 min before middle cerebral artery occlusion), LY294002 + IR + propofol (L + P, LY294002 of 1.5 mg/kg was infused 30 min before middle cerebral artery occlusion and propofol 20 mg/kg/h at the onset of reperfusion for 2 h after 60 min of occlusion). Results Compared with group IR, rats in group P had significant lower neurologic defect scores and infarct volume. Additionally, consistent with enhanced expression of PI3K-AMPAR GluR2 subunit complex substances in ipsilateral hippocampus, GluR2 subunits showed increased levels in both the plasma and postsynaptic membranes of neurons, while pGluR2 expression was reduced in group P. Furthermore, LY294002, the PI3K non-selective antagonist, blocked those effects. Conclusion These observations demonstrated that propofol post-conditioning revealed acute neuroprotective role against transient MCAO in rats. The short-term neuroprotective effect was contributed by enhanced GluR2 subunits trafficking to membrane and postsynaptic membranes of neurons, as well as down-regulated the expression of pGluR2 in damaged hippocampus. Finally, the above-mentioned protective mechanism might be contributed by increased combination of PI3K to AMPAR GluR2 subunit, thus maintained the expression and activation of AMPAR GluR2 in the ipsilateral hippocampus.

Abstract Background Ischemia-reperfusion (I/R) is a critical pathophysiological basis of cognitive dysfunction caused by ischemia stroke. Heme-oxygenase-1 (HO-1) is the rate-limiting enzyme for the elimination of excessive free heme by combining with hemopexin (HPX), a plasma protein that contributes to eliminating excessive free heme during ischemia stroke. This study aimed to elucidate whether HPX could alleviate cognitive dysfunction in rats subjected to cerebral I/R. Methods Rats were randomly divided into five groups: sham, MCAO, Vehicle, HPX and HPX + protoporphyrin IX (ZnPPIX). Cerebral I/R was induced by MCAO. Saline, vehicle, HPX and HPX + ZnPPIX were injected intracerebroventricularly at the moment after reperfusion. Morris water maze (MWM) test was used to detect the learning and cognitive function. Western blot was used to detect the expression of HO-1 in ischemic penumbra. CD31/vWF double labeling immunofluorescence was used to detect the neovascularization in the penumbra hippocampus. The structure and function of blood-brain barrier (BBB) was detected by the permeability of Evans Blue (EB), water content of the brain tissue, the Ang1/Ang2 and VE-cadherin expression. Results Our study verified that HPX improved the learning and memory capacity. Hemopexin up-regulated HO-1 protein expression, the average vessel density in the penumbra hippocampus and the VE- cadherin expression but decreased the permeability of EB, the water content of brain tissue and the ratio of Ang1/Ang2. The effects were reversed by ZnPPIX, an inhibitor of HO-1. Conclusion HPX can maintain the integrity of the blood-brain barrier and alleviate cognitive dysfunction after cerebral I/R through the HO-1 pathway.

Perioperative neurocognitive disorders (PND) is a common postoperative neurological complication. Neuroinflammation is a major cause that leads to PND. Autophagy, an intracellular process of lysosomal degradation, plays an important role in the development and maintenance of nervous system. PK11195 is a classic translocator protein (TSPO) ligand, which can improve the cognitive function of rats. In this study, we evaluate the protective effect of PK11195 on the learning and memory of rats. A rat model of lipopolysaccharide (LPS)-induced cognitive dysfunction was established by intraperitoneal injection of LPS. Morris Water Maze (MWM), Western blot, qRT-PCR, confocal microscopy and transmission electron microscopy (TEM) were used to study the role of TSPO-specific ligand PK11195 in LPS-activated mitochondrial autophagy in rat hippocampus. We found that PK11195 ameliorated LPS-induced learning and memory impairment, as indicated by decreased escape latencies, swimming distances and increased target quadrant platform crossing times and swimming times during MWM tests. TSPO, ATG7, ATG5, LC3B and p62 protein and mRNA expression increased in the hippocampus of PND model rats. The hippocampal microglia of PND model rats also have severe mitochondrial damage, and a large number of autophagosomes and phagocytic vesicles can be seen. PK11195 pretreatment significantly decreased the expression of TSPO, ATG7, ATG5, LC3B and p62 protein and mRNA, as well as mitochondrial damage. These findings suggested that PK11195 may alleviate the damage of LPS-induced cognitive dysfunction of rats by inhibiting microglia activation and autophagy.

Neurological dysfunction provoked by traumatic brain injury (TBI) makes a huge impact on individual learning ability, memory level, social participation, and quality of life. Pyroptosis, the caspase-1-dependent cell death, which is associated with the release of numerous pro-inflammatory factors, plays a major role in the pathological process after TBI. Inhibition of pyroptosis has been shown to be an attractive strategy for the treatment of various neurological disorders. Here, we found that Rhein, an anthraquinone derived from the medicinal plant rhubarb, attenuated TBI-induced upregulation of pro-inflammatory cytokines, blood lactate dehydrogenase (LDH), and pyroptosis-related proteins, as well as reduced neurological dysfunction in a mouse TBI model. Consistently, Rhein inhibitd equiaxial stretch-induced neuron pyroptosis, LDH release, and upregulation of pro-inflammatory factors in vitro. Thus, our study suggested that Rhein protected against neurological deficits after TBI via inhibiting neuronal pyroptosis.

Abstract Background Ischemia-reperfusion (I/R) is a critical pathophysiological change of ischemic stroke. Heme-oxygenase-1 (HO-1) is a rate-limiting enzyme of eliminating excessive free heme by combining with hemopexin (HPX), a plasma protein contributing to alleviating infarct size due to ischemia stroke. This study was to investigate whether HPX could improve angiogenesis after cerebral ischemia-reperfusion via up-regulating HO-1. Methods Rats were randomly divided into five groups: sham, MCAO, MCAO + Vehicle, MCAO + HPX and MCAO + HPX + protoporphyrin IX (ZnPPIX, an HO-1 inhibitor). Cerebral I/R was induced by MCAO. Saline, vehicle, HPX and HPX + ZnPPIX were respectively given to MCAO group, MCAO + Vehicle group, MCAO + HPX group and MCAO + HPX + ZnPPIX group at the moment after reperfusion by intracerebroventricular injection. Neurological behavioral scores(NBS) was assessed at 24 h and 7d after I/R. Real-time polymerase chain reaction (RT-PCR) was used to analyze the mRNA level of HO-1. Angiogenesis in penumbra area was assessed by immunofluorescence detection at 7d after I/R. Serum endothelial nitric oxide synthase (eNOS) was assessed by enzyme linked immunosorbent assay (ELISA) at 24 h and 7d after I/R. Results Compared with sham group, the NBS and the mRNA levels of HO-1 at 24 h and 7d after I/R in MCAO group decreased notably (P 0.05). In the MCAO + HPX group, compared with MCAO + Vehicle group, the NBS and the mRNA levels of HO-1 increased drastically at 24 h and 7d after I/R (P

In this study, we demonstrated the effects of a high-fiber diet on intestinal lesions, oxidative stress and systemic inflammation in a murine model of endotoxemia. C57BL/6 mice were randomly assigned to four groups: the control group (CONTROL), which received a commercial normal-fiber rodent diet comprising normal fiber; a CLP group, which received a commercial normal-fiber rodent diet and underwent caecal ligation puncture (CLP); a high-fiber group (HFG), which received a commercial high-fiber rodent diet; and a high fiber + CLP group (HFCLP) which received a commercial high-fiber rodent diet and underwent CLP (30%). The sepsis model was created via CLP after 2 weeks of dietary intervention. Notably, dietary high-fiber supplementation in HFCLP group improved survival rates and reduced bacterial loads, compared with CLP alone. In the HFCLP group, dietary fiber supplementation decreased the serum concentrations of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) and high-mobility group protein 1 (HMG-1) but raised the concentration of interleukin 10 (IL-10), compared with the levels in CLP mice. Meanwhile, high-fiber supplementation increased the relative proportions of Akkermansia and Lachnospiraceae. These data show that dietary high-fiber supplementation may be therapeutic for sepsis-induced lesions.

A large number of experimental and clinical studies have confirmed that brief remifentanil exposure can enhance pain sensitivity presenting as opioid-induced hyperalgesia (OIH). N-methyl-D-aspartate (NMDA) receptor antagonists have been reported to inhibit morphine analgesic tolerance in many studies. Recently, we found that glycogen synthase kinase-3β (GSK-3β) modulated NMDA receptor trafficking in a rat model of remifentanil-induced postoperative hyperalgesia. In the current study, it was demonstrated that GSK-3β inhibition prevented remifentanil-induced hyperalgesia via regulating the expression and function of spinal NMDA receptors in vivo and in vitro. We firstly investigated the effects of TDZD-8, a selective GSK-3β inhibitor, on thermal and mechanical hyperalgesia using a rat model of remifentanil-induced hyperalgesia. GSK-3β activity as well as NMDA receptor subunits (NR1, NR2A and NR2B) expression and trafficking in spinal cord L4-L5 segments were measured by Western blot analysis. Furthermore, the effects of GSK-3β inhibition on NMDA-induced current amplitude and frequency were studied in spinal cord slices by whole-cell patch-clamp recording. We found that remifentanil infusion at 1 μg·kg(-1)·min(-1) and 2 μg·kg(-1)·min(-1) caused mechanical and thermal hyperalgesia, up-regulated NMDA receptor subunits NR1 and NR2B expression in both membrane fraction and total lysate of the spinal cord dorsal horn and increased GSK-3β activity in spinal cord dorsal horn. GSK-3β inhibitor TDZD-8 significantly attenuated remifentanil-induced mechanical and thermal hyperalgesia from 2 h to 48 h after infusion, and this was associated with reversal of up-regulated NR1 and NR2B subunits in both membrane fraction and total lysate. Furthermore, remifentanil incubation increased amplitude and frequency of NMDA receptor-induced current in dorsal horn neurons, which was prevented with the application of TDZD-8. These results suggest that inhibition of GSK-3β can significantly ameliorate remifentanil-induced hyperalgesia via modulating the expression and function of NMDA receptors, which present useful insights into the mechanistic action of GSK-3β inhibitor as potential anti-hyperalgesic agents for treating OIH.