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Abstract: Introduction: Intestinal injury is often caused by systemic ischemia-reperfusion injury early after cardiac arrest (CA) and resuscitation. Artesunate (Art) has been confirmed to protect vital organs against diverse of regional I/R injury. This study aimed to investigate the effect of Art on intestinal injury after CA and cardiopulmonary resuscitation (CPR) in swine. Methods: Twenty-two swine were randomly divided into three groups: sham (n = 6), CA/CPR (n = 8), and CA/CPR + Art (n = 8). The CA/CPR swine model was established by inducing 9 min of untreated ventricular fibrillation (VF) followed by 6 min of CPR. Five minutes after resuscitation, 4.8 mg/kg of Art was intravenously administered for 2 h in the CA/CPR + Art group. Intestinal fatty acid-binding protein and diamine oxidase concentrations were compared among the three groups before CA and at 1, 2, 4, and 24 h after resuscitation. At 24 h after resuscitation, intestinal zonula occluden-1 (ZO-1), occludin, apoptosis, caspase-3/gasdermin E (GSDME)-mediated pyroptosis proteins concentrations, and proinflammatory cytokine concentrations were examined to evaluate intestinal injury. Results: During CPR, spontaneous circulation was achieved in seven and six swine in the CA/CPR and CA/CPR + Art groups, respectively. Serum intestinal fatty acid-binding protein and diamine oxidase concentrations were significantly higher and intestinal tissue ZO-1 and occludin concentrations were significantly lower in the CA/CPR and CA/CPR + Art groups than in the sham group. However, Art treatment resulted in markedly improved levels of intestinal injury biomarkers compared with those in the CA/CPR group. Additionally, intestinal apoptosis and concentrations of caspase-3/GSDME-mediated pyroptosis proteins and proinflammatory cytokines were significantly higher in the CA/CPR and CA/CPR + Art groups than in the sham group. However, these variables were significantly lower in the CA/CPR + Art group than in the CA/CPR group. Conclusions: Art treatment effectively alleviates postresuscitation intestinal injury, possibly by inhibiting the caspase-3/GSDME-mediated pyroptosis pathway in a swine CA and CPR model.

Abstract: Background: Sepsis, a systemic inflammation syndrome initiated by infection, poses significant challenges due to its intricate pathophysiology. T cells play a crucial role in combating infections during sepsis. Despite previous observations indicating T-cell dysfunction in sepsis, reliable in vitro detection methods were lacking, and the factors influencing these impairments remained unclear. Methods: We developed a novel method using the D 4 -Chip to assess sepsis T-cell migration function. This microfluidic platform enabled precise analysis of migration function under controlled conditions. Additionally, We explored the impact of the plasma microenvironment on T-cell behavior, along with the redox environment in sepsis, and assessed the potential efficacy of Mitoquinone mesylate (MitoQ), a mitochondrial-targeted drug. Results: Our findings revealed impaired migration function in sepsis T cells compared to healthy controls. Interestingly, sepsis plasma enhanced the migration of healthy T cells, yet incubation with healthy plasma did not fully restore migration impairments in sepsis T cells. Subsequent investigations uncovered a significant increase in NADH/NAD+ levels in sepsis T cells, with healthy T cells exposed to various sepsis plasma conditions also showing elevated NADH/NAD+ levels. Importantly, MitoQ normalized abnormal intracellular NADH/NAD+ levels and enhanced the migration ability of T cells. Conclusions: Short-term incubation with sepsis plasma does not directly inhibit T-cell migration but instead affects T-cell function by disrupting the intracellular redox environment. Improving the intracellular redox environment of sepsis patients contributes to restoring impaired migration and proliferation, with MitoQ demonstrating therapeutic potential.

Abstract: Background: Neutrophil extracellular traps (NETs), and its formation and release, known as NETosis, may play a role in the initiation of thrombin generation (TG) in trauma. The objective of this study was to assess whether trauma patients, who develop symptomatic venous thromboembolism (VTE), have increased levels of plasma citrullinated histone H3 (CitH3) and accelerated TG kinetics. Methods: Patients presenting to a level I trauma center as trauma activations had samples collected within 12 h of time of injury, alongside healthy volunteers (HV). CitH3 was measured by enzyme-linked immunosorbent assay, and TG data were measured using a TG analyzer, comparing results between patients developing symptomatic VTE versus those who did not, within 90 days of injury. Data were expressed as median and quartiles (Q1, Q3), and tested using Wilcoxon rank-sum or Fisher's exact test, or 1-sample test of Spearman's correlation, P < 0.05 considered significant. Results: 39 trauma patient samples were analyzed (10 with and 29 without VTE), and compared to 15 HV samples. CitH3 levels in patients who developed VTE were significantly greater as compared to those who did not (12.8 ng/mL [7.1, 30.8]; 3.0 ng/mL [1.8,6.8], P = 0.024), with levels in both groups greater compared to HV (1.2 [0.3, 4.1], P = 0.003, P = 0.012), respectively. TG profiles were accelerated in patients developing VTE, with differences in peak height (337.6 nM [304.4, 356.0]; 231.8 nM [180.2, 281.8], P = 0.008), endogenous thrombin potential (1718.5 nM*min [1,500, 1794]; 1208.5 nM*min [1,072, 1,417], P = 0.003) and velocity index (213.2 nM/min [162.3, 260.5]; 124.3 nM/min [93.2, 223.1], P = 0.03), respectively. Conclusion: Trauma patients developing VTE exhibit increased NETosis, measured by increased CitH3 levels and accelerated TG early after injury, outlining an area for further understanding VTE after trauma.

Abstract: Background: Sepsis, a life-threatening response to infection leading to systemic inflammation and organ dysfunction, has been hypothesized to be influenced by metabolic alterations in cerebrospinal fluid (CSF). Despite extensive research, the specific metabolic pathways contributing to sepsis remain unclear. This study aims to elucidate the causal relationships between CSF metabolites and sepsis risk using Mendelian randomization (MR), offering insights that could lead to novel therapeutic strategies. Methods: We conducted a two-sample MR analysis using genetic variants as instrumental variables (IVs) to investigate 338 CSF metabolites identified through a genome-wide association study. Data on sepsis-related outcomes were extracted from the genome-wide association study catalog encompassing 486,484 individuals of European descent. IVs were rigorously selected based on stringent genetic association and linkage disequilibrium criteria. Statistical analyses, including inverse variance weighting (IVW) and weighted median methods, were performed using the "TwoSampleMR" package in R software, supplemented by comprehensive sensitivity analyses to ensure the robustness of our findings. Results: Our analysis identified 19 CSF metabolites causally associated with sepsis risk. Notably, metabolites such as 1-palmitoyl-2-stearoyl-gpc (16:0/18:0) and 2-hydroxyglutarate showed significant negative correlations with sepsis risk. The reverse MR analysis further revealed that sepsis could negatively impact certain CSF metabolite levels, particularly ribonate, suggesting a bidirectional relationship. These relationships were substantiated by rigorous statistical testing and sensitivity analyses confirming the absence of horizontal pleiotropy and the stability of our results across various MR methods. Conclusions: This study demonstrates significant causal associations between specific CSF metabolites and the risk of developing sepsis, highlighting the potential for these metabolites to serve as biomarkers or therapeutic targets. The bidirectional nature of these findings also suggests that sepsis itself may alter metabolic profiles, offering further avenues for intervention.

Abstract: Background: Severe injuries caused by accidents, such as traumatic brain injury (TBI) or thoracic trauma (TT), continue to be the leading cause of death in younger people with relevant socioeconomic impact. Fast and targeted diagnostics is essential for further therapy decisions and prognosis. The following study investigates neuron-specific enolase (NSE) as a potential biomarker for lung injury after blunt TT. Methods: This is a retrospective analysis of prospectively collected data in a level 1 trauma center from 2014 to 2020. Serum levels of NSE and ILs (IL-6, IL-10) in injured patients (n = 41) with isolated TT (Abbreviated Injury Scale score of the thorax ≥3) compared with isolated TBI (Abbreviated Injury Scale score of the head ≥3) were assessed from days 0 to 5 after trauma. The extent of lung injury was quantified by Hounsfield scale in computed tomography scans. Results : Thirty patients with TT (median Injury Severity Score = 20, age 50 ± 17 years, 83.3% were male) and 11 patients with TBI (median Injury Severity Score = 25, age 54 ± 17 years, 27.3% were male) were included. After TT, NSE concentration increased initially after trauma with a peak value on the day of admission (8.51 ± 3.68 ng/mL) compared with healthy controls (4.51 ± 1.504 ng/mL, P < 0.001). Isolated TT and TBI lead to equally strong NSE release ad the day of admission. There is a significant linear relationship ( r = 0.636, P = 0.035) between serum NSE levels and severity of pulmonary contusion at the time of admission and after 24 h. Conclusion : A significant NSE release after isolated TT peaks on the day of admission. The extent of lung contusion volume (defined as alveolar parenchymal density) correlates with NSE serum concentration. Thus, NSE has predictive value for the extent of pulmonary contusion. However, according to these data, NSE seems to have no diagnostic value as a TBI biomarker in concomitant TT.

Abstract: Aim: This study aimed to elucidate whether the application of the mitochondrial division inhibitor Mdivi-1 can protect organ function and prolong the treatment window for traumatic hemorrhagic shock. Methods: Before definitive hemostasis treatment, Mdivi-1 (0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg) was administered to uncontrolled hemorrhagic shock (UHS) model rats. Lactate Ringer's solution plus hydroxyethyl starch (130/0.4) was used as a control. The effects of Mdivi-1 on blood loss; fluid demand; survival time; vital organ function; myocardial mitochondrial structure; mitochondrial function of the heart, liver, kidney, and intestine; and oxidative stress at 1 h after hypotensive resuscitation (50-60 mm Hg) were investigated. In addition, we investigated the effect of varying doses of Mdivi-1 on the maintenance time of hypotensive resuscitation without definitive hemostasis and the beneficial effect of Mdivi-1 after prolonging the duration of hypotensive resuscitation to 2 h. Results: Compared to conventional resuscitative fluid, Mdivi-1 significantly reduced blood loss and fluid demand, improved important organ functions during hypotensive resuscitation, improved animal survival, and reduced the incidence of early death. Mdivi-1 significantly alleviated oxidative stress injury, reduced mitochondrial damage, and restored myocardial mitochondrial structure and mitochondrial function of the heart, liver, kidney, and intestine. In addition, Mdivi-1 increased the maintenance time of hypotensive resuscitation and improved rat survival after the duration of hypotensive resuscitation was prolonged to 2 h. Conclusion: Mdivi-1 significantly prolonged the treatment window for traumatic hemorrhagic shock to 2 h in UHS model rats. The underlying mechanism may be that Mdivi-1 inhibits excessive mitochondrial fission and oxidative stress and improves the structure and function of mitochondria.