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Background: Advanced age significantly increases postoperative complication risk, including neurological dysfunction. While the liver plays a critical role in surgical recovery, age-related changes in hepatic function remain inadequately studied in perioperative risk assessment. Methylation-Controlled J protein (MCJ), an endogenous negative regulator of mitochondrial function, represents a promising therapeutic target due to its role in exacerbating oxidative stress and compromising metabolic resilience in aging.

Methods: Young (4-5 months) and aged (24 months), male and female C57BL/6J mice underwent 60-minute laparotomy surgery or sham procedure. Treatment groups received hepatocyte-targeted GalNAc-siMCJ (10 mg/kg, subcutaneous) 72 hours pre-surgery based on established knockdown kinetics. Subclinical liver injury (plasma/tissue cytokeratin-18 (CK18), microRNA-122 (miR-122)), metabolic dysfunction (kynurenine pathway metabolites), blood-brain barrier integrity (cerebrospinal fluid (CSF)/plasma albumin ratio, calcium-binding protein S100B), neuroinflammation (glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1)), and cognitive function (open field, novel object recognition) were assessed 48 hours post-surgery.

Results: Despite normal transaminases (alanine aminotransferase (ALT) <46 IU/L, aspartate aminotransferase (AST) <69 IU/L), livers from aged mice exhibited significant subclinical injury after surgery, with elevated CK18 and miR-122 (p < 0.05 vs. aged-sham). This resulted in increased hepatic kynurenine and quinolinic acid (p < 0.05), blood-brain barrier disruption (increased S100B plasma levels and CSF/plasma albumin ratio), neuroinflammation (elevated Iba1 immunoreactivity in hippocampus), and cognitive impairment. Hepatic MCJ silencing prevented these alterations in aged mice (p < 0.05 vs. aged vehicle), without affecting young mice beyond reducing inflammatory markers.

Conclusions: Targeted hepatic MCJ inhibition mitigates subclinical liver injury, dysregulated kynurenine metabolism, and subsequent neuroinflammation in aged mice after surgery. This liver-brain axis modulation represents a potential therapeutic strategy to prevent perioperative neurological complications in vulnerable older surgical patients.

Background: Burn injury produces a complex biological response across multiple organ and biological systems. Nonetheless current understanding regarding the neurologic response to burn injury is limited. Research suggests that disruption of the blood-brain barrier (BBB) may play a role in central nervous system (CNS) damage following burn trauma. As such, the purpose of this study was to investigate systemic circulating biomarkers, frequently associated with neuronal injury, to gain an understanding of their relationship to burn injury severity.

Methods: Blood from fifty-six patients admitted to the burn intensive care units was taken within 24 hours and analyzed for four CNS-related biomarkers in plasma (i.e., ubiquitin C-terminal hydrolase L1 [UCH-L1], tau protein, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]). Clinical information regarding demographics, burn severity, and health outcomes were also obtained.

Results: We observed increased burn severity, as measured by total burn surface area (TBSA), was significantly associated with increased UCH-L1, NfL, and tau. GFAP was not associated with burn severity. In a predictive model of days spent in the hospital after injury, accuracy of the four CNS-related biomarkers was only improved by 1% when TBSA was included (i.e., 38.3% accuracy with only biomarkers vs. 39.4% accuracy with biomarkers and TBSA).

Conclusion: Overall, findings from this novel study highlight an association between burn injury severity and CNS-related biomarkers, thereby providing a foundation for future studies to explore both potential mechanisms associated with burn-related neurologic damage and associated functional impairments.

Hemorrhagic shock induces immune dysfunction via mesenteric lymph return, leading to systemic inflammatory response and multiple organ dysfunction. Dendritic cells (DCs) play a pivotal role in immune response following hemorrhagic shock. Therefore, identifying regulatory targets within DCs is essential for understanding hemorrhagic shock-induced immune dysfunction. Endoplasmic reticulum autophagy (ER-phagy), a selective form of autophagy, is critical for DC function. Here, we investigated the role of tumor necrosis factor-α-induced protein-8-like 2 (TIPE2), a protein known to regulate autophagy, in modulating DC ER-phagy after hemorrhagic shock. We analyzed the function and ER-phagy in splenic DCs from wild-type (WT) mice following hemorrhagic shock in vivo and DCs stimulated with post-hemorrhagic shock mesenteric lymph (PHSML) in vitro. Our results showed an increased number of autophagosomes containing endoplasmic reticulum (ER) structures, with significantly enhanced colocalization between ER and autophagosomes in DCs during hemorrhagic shock. The proliferation of CD4+ T cells co-cultured with DCs was weakened, and the expression of surface molecules on the DCs was significantly increased after stimulation with PHSML. Subsequently, WT, TIPE2-/- and TIPE2+/+ mice were used to further analyze the correlation between TIPE2 and ER-phagy in the context of hemorrhagic shock. The results demonstrated that under hemorrhagic shock conditions, TIPE2-/- mice exhibited a significantly reduced LC3-II/I ratio and elevated SEC61B expression in the spleen tissue compared to WT mice, suggesting a diminished level of ER-phagy. Conversely, TIPE2+/+ mice showed the opposite changes. Following stimulation with PHSML, the findings revealed a marked increase in the colocalization between ER and autophagosomes and a significant inhibition of DC function compared to the control group. Additionally, the deletion of TIPE2 weakened ER-phagy and decreased the inhibitory effect on DC function. In contrast, the overexpression of TIPE2 further enhanced ER-phagy and intensified the inhibition of DC function. In addition, TIPE2 is involved in the regulation of the non-classical ER-phagy receptor tripartite motif 13 (TRIM13) expression. These results suggest that ER-phagy is enhanced in DCs after hemorrhagic shock and that TIPE2 may regulate ER-phagy and DC function via TRIM13. This research provides a theoretical basis for future clinical therapeutic strategies targeting the regulation of ER-phagy to improve the function of DCs.

Background: Sepsis is a severe systemic inflammatory response, typically triggered by infection. When the body's response to infection becomes dysregulated, it can result in organ dysfunction, tissue damage, and even death. Sepsis can affect people of all ages, but older adults, individuals with weakened immune systems, and those with chronic illnesses are at greater risk. Timely diagnosis and immediate intervention are essential to enhance the chances of survival.

Objective: This study aims to develop a mortality risk prediction model for sepsis patients utilizing tree-based ensemble classifiers, with post-hoc interpretation through Shapley Additive Explanations (SHAP), to support clinical decision-making.

Methods: Clinical data of sepsis patients admitted to the intensive care unit (ICU) of the First Affiliated Hospital of Xinjiang Medical University were collected. The mice package was used to handle missing data, and the Synthetic Minority Oversampling Technique(SMOTE) algorithm was applied to oversample the minority class to address data imbalance. We applied seven models, including Random Forest(RF), k-Nearest Neighbors(KNN), Support Vector Machine (SVM), logistic regression, eXtreme Gradient Boosting (XGBoost), Logistic_Lasso Regression (Logistic_Lasso), and Light Gradient Boosting Machine (LightGBM), and compared their prediction performance using the area under the receiver operating characteristic curve (AUC), Precision-Recall Curve (PR), and Decision Curve Analysis (DCA). Based on these models, we applied both global and local interpretation approaches to elucidate model predictions and explore prognostic risk factors in sepsis patients.

Results: The RF model showed the best performance among the seven Machine Learning (ML) models, achieving an AUC of 0.9816. Both global and local explainability techniques were applied to interpret the decision-making mechanisms of the ML models.

Conclusion: Local explanation methods can interpret how ML models make predictions for individual outcomes. Global interpretation techniques help reveal how ML models respond across the entire feature landscape.

Severe burn injury induces prolonged immune dysfunction, but the underlying molecular mechanisms remain poorly defined. We hypothesized that burn injury causes epigenetic and transcriptional training of innate immune cells. Splenic F4/80⁺ macrophages were isolated from mice at 2, 9, and 14 days after 20% total body surface area (TBSA) contact burn. Targeted transcriptomics and chromatin profiling revealed a biphasic response: early transcriptional silencing of inflammatory genes (e.g., Stat3, Traf6, Nfkb1), followed by increased accessibility and expression of anti-inflammatory loci (Il10, Socs3). Metabolic genes showed persistent suppression of mitochondrial and oxidative phosphorylation programs. Canonical pathway analysis indicated early IL-10 signaling activation and long-term repression of classical macrophage activation. Chromatin remodeling included nucleosome repositioning events, supporting dynamic, locus-specific regulation. These findings challenge the notion that burn-induced immune suppression is solely due to systemic inflammation and instead suggest durable, epigenetically programmed alterations in macrophage function.

Background: Acute lung injury (ALI) caused by sepsis is a serious complication of sepsis and a major cause of death, and there is a lack of effective drug treatment. Transforming growth factor beta receptor II (TGFBR2) expression is related to sepsis and acute lung injury. Therefore, this study is to clarify the mechanism of TGFBR2 in sepsis-induced ALI.

Methods: The study stimulated human pulmonary microvascular endothelial cells (HPMECs) using lipopolysaccharides (LPS) to establish an in vitro ALI model. The protein and mRNA levels were detected using western blot and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The cell viability and proliferation were assessed using cell counting kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays, respectively. Flow cytometry was conducted to analyze cell apoptosis. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) levels. The reactive oxygen species (ROS) and malondialdehyde (MDA) levels were examined using corresponding detection kits. Bioinformatic analysis was used to predict the N6-methyladenosine (m6A) methylation modifications and the interaction between TGFBR2 and methyltransferase 14 (METTL14)/ubiquitin-specific protease 7 (USP7). RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), and dual-luciferase reporter gene assay were used to identify the association of TGFBR2 with METTL14 and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2). Besides, the ubibrowser database, co-immunoprecipitation (Co-IP), and deubiquitination assays were performed on the relationship between USP7 and TGFBR2. Finally, a mouse model of polymicrobial sepsis was established to analyze the effects of TGFBR2 on lung injury in vivo.

Results: TGFBR2 levels were highly expressed in the serum of sepsis-ALI patients and LPS-induced HPMECs. TGFBR2 knockdown remitted LPS-induced inhibition of viability and proliferation, as well as LPS-induced promoting effects on HPMEC apoptosis, inflammation, and oxidative stress. METTL14 and IGF2BP2 stabilized TGFBR2 mRNA expression through m6A methylation modification. Furthermore, silencing METTL14 protected HPMECs from LPS-induced injury by decreasing TGFBR2 expression. USP7 could stabilize the expression of TGFBR2 via deubiquitination, and si-USP7 ameliorated LPS-induced HPMEC damage via inhibiting TGFBR2 expression. TGFBR2 knockdown alleviated sepsis-induced ALI in vivo.

Conclusion: TGFBR2 facilitates the inflammation and oxidative stress in sepsis-induced ALI via METTL14/IGF2BP2-mediated m6A modification or USP7-regulated deubiquitination. These findings provide a novel potential therapeutic target for the treatment of sepsis-induced ALI.

Background: Patients with sepsis often exhibit a decrease in lymphatic numbers, which can be facilitated by protein arginine methyltransferase (PRMT). However, it is unclear how PRMT contributes to lymphopenia in sepsis.

Methods: This study employed the sepsis-related datasets (GSE65682 and GSE134347) and 9 PRMT genes. Firstly, we intersected the differentially expressed genes (DEGs) with weighted gene co-expression network analysis (WGCNA) module genes to identify DE-PRMT-related genes (DE-PRMT-RGs). Thereafter, candidate key genes were obtained after Mendelian randomization (MR) analysis and machine learning screening. Eventually, we subjected key genes identified by expression analysis and receiver operating characteristic (ROC) curves to gene set enrichment analysis (GSEA), immune infiltration analysis, immune checkpoint analysis, molecular docking, regulatory networks construction, and nomogram development.

Results: We firstly intersected 4,246 DEGs with 1,884 PRMT scoring module genes to obtain 969 DE-PRMT-RGs. Further MR analysis and machine learning jointly identified 5 candidate genes (CRLF3, ELAC2, PBX2, MCTP2, and EMB). Among these, ELAC2, PBX2, MCTP2, and EMB demonstrated consistent expression trends, with the area under the curve (AUC) values of the ROC curve exceeding 0.7 in GSE65682 and GSE134347. Therefore, they were defined as key PRMT-related genes. The GSEA analysis showed enrichment in cytoplasmic translation (ELAC2, MCTP2), non-coding RNA metabolism (EMB), and metabolic processes (PBX2). The immune infiltration analysis revealed a significant correlation between PBX2 and neutrophils, as well as between ELAC2/MCTP2/EMB with activated NK cells, CD8+ T cells.

Conclusion: In this study, ELAC2, PBX2, MCTP2 and EMB were identified as key genes related to PRMT for sepsis, which provided a theoretical basis for the study of sepsis.

Summary: Impact of sepsis on human T-cell function and outcome was assessed. In sepsis survivors, IFNγ-production in response to T-cell stimulation remains intact, while sepsis non-survivors display exaggerated IFNγ responses to TCR-independent stimuli.

Sepsis-induced acute lung injury (SI-ALI) is strongly influenced by ferroptosis, a regulated cell death pathway. Carnitine palmitoyltransferase 1A (CPT1A), known for its lysine succinyltransferase activity, regulates succinylation but its function in ferroptosis and SI-ALI remains to be elucidated. This study aim to determine the influence of CPT1A on ferroptotic processes in SI-ALI and to reveal the key regulatory mechanisms involved. The SI-ALI model was generated in C57BL/6 mice via cecal ligation and puncture (CLP), while alveolar epithelial cells MLE-12 were treated with lipopolysaccharides (LPS) to mimic SI-ALI in vitro. Quantitative PCR and Western blotting were employed to evaluate CPT1A levels in peripheral venous blood samples from SI-ALI patients, as well as in both the mouse and cellular models of SI-ALI. Ferroptosis was evaluated by measuring malondialdehyde, glutathione, Fe 2+ levels, and reactive oxygen species fluorescence intensity. To elucidate the underlying mechanisms, co-immunoprecipitation (co-IP) and standard IP techniques were utilized. Our findings indicated that CPT1A was downregulated in SI-ALI. Overexpression of CPT1A inhibited ferroptosis in the in vitro SI-ALI model by enhancing ACSL4 succinylation, thereby reducing ACSL4 expression. Notably, overexpression of ACSL4 counteracted CPT1A-mediated ferroptosis suppression in vitro. Moreover, CPT1A overexpression ameliorated pulmonary pathology and suppressed ferroptosis activation in the lungs of SI-ALI mice. Collectively, the results indicate that CPT1A alleviated SI-ALI through the inhibition of ferroptosis by promoting ACSL4 succinylation, providing a novel theoretical foundation and potential therapeutic target for SI-ALI treatment.