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Background: Acute respiratory distress syndrome (ARDS) is a serious pathological process with high mortality. Ferroptosis is pivotal in sepsis, whose regulatory mechanisms in sepsis-induced ARDS remains unknown. We aimed to determine key ferroptosis-related genes in septic ARDS and investigate therapeutic traditional Chinese medicine (TCM).

Method: Sepsis-induced ARDS dataset obtained from Gene Expression Omnibus (GEO) was analyzed to identify ferroptosis-related differentially expressed genes (FRDEGs). Enrichment analysis and protein-protein interaction (PPI) network construction were performed to identify hub genes. Immune cells infiltration was analyzed and competitive endogenous RNA (ceRNA) network was constructed. The diagnostic value of hub genes in septic ARDS was analyzed and the occurrence of ferroptosis and the expression of hub genes were detected. TCM targeting hub genes was predicted via SymMap database and was verified.

Results: 16 FRDEGs were obtained, among which the top four genes (IL1B, TXN, MAPK3, HSPB1) were selected as hub genes, which may be potential diagnostic markers of septic ARDS. Immunoassay showed that sepsis-induced ARDS and hub genes were closely related to immune cells. The ceRNA network showed 26 microRNAs and 38 long noncoding RNA (lncRNAs). Ferroptosis occurred and the expressions of IL1B, MAPK3 and TXN were increased in septic ARDS mice and LPS-challenged human pulmonary alveolar epithelial cells (HPAEpiCs). Sea buckthorn alleviated septic lung injury and affected hub genes expression.

Conclusions: Ferroptosis-related genes of IL1B, MAPK3 and TXN serve as potential diagnostic genes for sepsis-induced ARDS. Sea buckthorn may be therapeutic medication for ARDS. This study provides a new direction for septic ARDS treatment.

Background: Severe respiratory syncytial virus (RSV) pneumonia is a leading cause of hospitalization and morbidity in infants and young children. Early identification of severe RSV pneumonia is crucial for timely and effective treatment by pediatricians. Currently, no prediction model exists for identifying severe RSV pneumonia in children.

Methods: This study aimed to construct a diagnostic prediction model for severe RSV pneumonia in children using a machine learning algorithm. We analyzed data from the Gene Expression Omnibus (GEO) Series, including training dataset GSE246622 and testing dataset GSE105450, to identify differential genes between severe and mild-to-moderate RSV pneumonia in children. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the differential genes, followed by the construction of a protein-protein interaction (PPI) network. An artificial neural network (ANN) algorithm was then used to develop and validate a diagnostic prediction model for severe RSV pneumonia in children.

Results: We identified 34 differentially expressed genes between the severe and mild-to-moderate RSV pneumonia groups. Enrichment analysis revealed that these genes were primarily related to pathogenic infection and immune response. From the PPI network, we identified 10 hub genes and, using the random forest algorithm, screened out 20 specific genes. The ANN-based diagnostic prediction model achieved an area under the curve (AUC) value of 0.970 in the training group and 0.833 in the testing group, demonstrating the model's accuracy.

Conclusions: This study identified specific biomarkers and developed a diagnostic model for severe RSV pneumonia in children. These findings provide a robust foundation for early identification and treatment of severe RSV pneumonia, offering new insights into its pathogenesis and improving pediatric care.

Background: Severe injuries caused by accidents, like traumatic brain injury (TBI) or thoracic trauma (TT) continue to be the leading cause of death in younger people with relevant socio-economic impact. Fast and targeted diagnostics is essential for further therapy decisions and prognosis. The following study investigates 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 Neuron-specific Enolase (NSE) and Interleukins (IL-6, IL-10) in injured patients (n = 41) with isolated TT (AISthorax ≥ 3) compared to isolated TBI (AIShead ≥ 3) were assessed from day 0 to 5 after trauma. The extend of lung injury was quantified by Hounsfield scale in CT scans.

Results: 30 patients with TT (ISSmed = 20, age 50y ± 17, 83,3% male) and 11 patients with TBI (ISSmed = 25, age 54y ± 17,27,3% 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 to healthy controls (4.51 ± 1.504 ng/ml, p < 0.001). Isolated thoracic trauma 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 hours.

Conclusion: A significant NSE release after isolated thoracic trauma 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: Background: Sepsis accounts for substantial morbidity and mortality motivating investigators to continue the search for pathways and molecules driving the pathogenesis of the disease. The current study examined if the novel C-type lectin receptor (CLR), Clec2d, plays a significant role in the pathogenesis of sepsis. Methods: Clec2d knockout (KO) mice were fully backcrossed onto the C57/BL6 background. Acute endotoxemia was induced with an intraperitoneal injection of lipopolysaccharide (LPS). Sepsis was induced in two different models, cecal ligation and puncture (CLP) and Pseudomonas aeruginosa pneumonia. Both models were treated with antibiotics and fluid resuscitation. In the sepsis models, physiologic and hematologic measurements were measured at 24 h by collecting a small sample of peripheral blood. Mortality was followed for 14 days. Results : A total of 197 mice were studied, 58 wild type (WT) and 54 knock-out (KO) in the LPS model; 27 wild type and 21 KO mice in the CLP model; and 22 WT and 15 KO mice in the pneumonia model. Clec2d KO mice had greater mortality in the LPS and CLP studies but not the pneumonia model. There were significant differences in multiple parameters determined 24 h post sepsis between mice who subsequently died and those lived. Consistent with previous reports in the CLP model, higher concentrations of IL-6, increased numbers of peripheral blood lymphocytes and greater renal injury were found in the dying mice. In contrast, in the pneumonia model, IL-6 was higher in the surviving mice; however, the IL-6 levels in the pneumonia model (0.6 ± 0.3 ng/mL mean ± SEM) were less than 2% of the IL-6 levels of mice that died in the CLP model (41 ± 9 ng/mL, mean ± SEM). There were no differences in the lymphocyte count or renal injury between living and dying mice in the pneumonia model. In both sepsis models, dying mice had lower heart rates, respiratory rates, and body temperatures. These values were also lower in the KO mice compared to the WT in CLP, but the breath rate and body temperature were increased in the KO pneumonia mice. Conclusion: The C-type lectin receptor Clec2d plays a complicated role in the pathogenesis of sepsis, which varies with source of infection as demonstrated in the models used to study the disease. These data highlight the heterogeneity of the responses to sepsis and provide further evidence that a single common pathway driving sepsis organ injury and death likely does not exist.

Abstract: Mitochondrial dysfunction is a recognized feature of sepsis, characterized by ultrastructural damage, diminished oxidative phosphorylation, and depletion of mitochondrial antioxidant capacity observed in deceased septic patients. LPS tolerance induces a controlled response to sepsis. This study aimed to evaluate the function of tolerant mitochondria after cecal ligation and puncture (CLP)-induced sepsis. Mytochondrial oxygen consumption was determined using polarography. Extraction and quantification of RNA for the expression of Tfam, Nrf-1, and Ppargc-1α, and respiratory complex activity were measured. CLP-tolerant animals presented preserved respiratory rates of S3 and S4 and a ratio of respiratory control (RCR) compared to CLP-nontolerant animals with reduced oxidative phosphorylation and increased uncoupled respiration. Complex I Vmax was reduced in septic animals; however, CLP animals sustained normal Vmax. Mitochondrial biogenesis was preserved in CLP-tolerant animals compared to the CLP-nontolerant group, likely due to increased TFAM expression. LPS tolerance protected septic animals from mitochondrial dysfunction, favoring mitochondrial biogenesis and preserving mitochondrial respiration and respiratory complex I activity.

Abstract: Introduction: A 2003 landmark study identified the prevalence of early trauma-induced coagulopathy (eTIC) at 28% with a strong association with mortality of 8.9%. Over the last 20 years, there have been significant advances in both the fundamental understanding of eTIC and therapeutic interventions. Methods: A retrospective cohort study was performed from 2018 to 2022 on patients ≥18 using prospectively collected data from two level 1 trauma centers and compared to data from 2003. Demographics, laboratory data, and clinical outcomes were obtained. Results: There were 20,107 patients meeting criteria: 65% male, 85% blunt, mean age 54 ± 21 years, median Injury Severity Score 10 (10, 18), 8% of patients were hypotensive on arrival, with an all-cause mortality 6.0%. The prevalence of eTIC remained high at 32% in patients with an abnormal prothrombin time and 10% with an abnormal partial thromboplastin time, for an overall combined prevalence of 33.4%. Coagulopathy had a major impact on mortality over all injury severity ranges, with the greatest impact with lower Injury Severity Score. In a hybrid logistic regression/Classification and Regression Trees analysis, coagulopathy was independently associated with a 2.1-fold increased risk of mortality (95% confidence interval 1.5-2.9); the predictive quality of the model was excellent [area under the receiver operating characteristic curve (AUROC) 0.932]. Conclusion: The presence of eTIC conferred a higher risk of death across all disease severities and was independently associated with a greater risk of death. Biomarkers of coagulopathy associated with eTIC remain strongly predictive of poor outcome despite advances in trauma care.

Abstract: Backgrounds: This study aimed to investigate the relationship between Cx43 expression and autophagy mediated by the AMPK-mTOR-Ulk1 signaling pathway in jaundice heart. Methods: In this study, a jaundice model was established in common bile duct ligation (CBDL) rats. Cardiac injury was assessed using various methods including myocardial injury indicators, echocardiography, transmission electron microscopy, hematoxylin and eosin staining, Masson staining, immunohistochemical analyses, and immunofluorescence staining. We investigated the regulatory relationship between Cx43, autophagy, and the AMPK-mTOR-ULK pathway in vivo by administering autophagy agonists (Rapa), autophagy inhibitors (3-MA), and Cx43 inhibitors (Gap 26). In vitro , we observed the relationship between autophagy and the AMPK-mTOR-ULK1 pathway in cells by exposing them to the AMPK inhibitor Compound C and the AMPK activator AICAR. Results: We found that CBDL induced autophagy through the AMPK-mTOR-ULK pathway, leading to the inhibition of myocardial dysfunction. Rapamycin pretreatment with CBDL3d exhibited a protective effect against myocardial injury and promoted autophagy. In contrast, 3-MA had no impact. Pretreatment with rapamycin at CBDL2w enhanced autophagy and aggravated cardiac injury; however, inhibition of autophagy using 3-MA attenuated cardiac injury. Cell viability was enhanced by AMPK inhibitors and inhibited by AMPK agonists. In addition, we observed that increased autophagy led to decreased Cx43 expression, which negatively affected cardiac function. Conclusions: CBDL induces myocardial injury in rats and activates autophagy through the AMPK-mTOR-ULK pathway, resulting in decreased Cx43 protein levels. A moderate increase in early autophagy in CBDL can improve cardiac injury, while late inhibition of autophagy can reduce myocardial injury.

Abstract: Diabetes and myocardial ischemia reperfusion (MIR) injury are characterized by oxidative stress, inflammation, autophagy disorders, and cardiac contractile dysfunction. Klotho and SIRT1 regulate the level of oxidative stress to participate in the regulation of many physiological functions such as cell survival, aging, apoptosis, autophagy, mitochondrial biogenesis, and inflammation. We hypothesized that the activation of Klotho/SIRT1 signaling pathway could attenuate MIR in diabetic rats. Type 1 diabetes and MIR injury model were established to examine this hypothesis in vivo . Primary rat cardiomyocytes and H9c2 cells were exposed to high glucose conditions and hypoxia/reoxygenation (H/R) insult in vitro . Hemodynamic parameters of heart function, myocardial infarct size, oxidative stress, markers of MIR injury or cell viability, and the mRNA and protein expression of Klotho and SIRT1 were measured. There was lower expression of Klotho and SIRT1 in diabetic MIR hearts than in nondiabetic rats, as well as significantly increased oxidative stress levels and decreased autophagy levels. Recombinant Klotho (rKlotho) protein and the SIRT1 agonist SRT1720 could significantly attenuate MIR injury in diabetes by activating Klotho/SIRT1 signaling pathway to reduce oxidative stress and restore autophagy levels. These findings suggest that the Klotho/SIRT1 pathway plays an important role in MIR injury in diabetic rats, and rKlotho protein and agonist SRT1720 have therapeutic potential for alleviating diabetic myocardial IR injury by activating Klotho/SIRT1 to reduce oxidative stress and restore autophagy levels.