Mediators of Inflammation最新文献

Background: Sepsis leads to multiorgan damage, with the liver being the main target. Sirtuin 4 (Sirt4) plays a regulatory role in mitochondrial function and metabolism, but its mechanism in liver injury caused by sepsis remains unclear.

Methods: The mouse model of liver injury caused by sepsis was established by cecal ligation and puncture (CLP) surgery. The degree of liver injury in wild-type (WT) and Sirt4 gene total knockout (Sirt4-KO) mice was compared by serum AST, alanine aminotransferase (ALT), and histological analysis. The expression of mitophagy and mitochondrial dynamic indicators was detected by biochemical experiments.

Results: Liver injury in Sirt4-KO mice was more severe than that in WT mice after CLP, manifested as significant upregulation of mitophagy and mitochondrial dynamics imbalance. Mechanistically, Sirt4 deficiency increases mitochondrial fission and mitophagy, thereby leading to cellular damage.

Conclusions: Sirt4 knockout (KO) aggravates liver injury in sepsis through increasing mitochondrial fission and mitophagy, which indicates a promising direction for future clinical treatment.

Neonatal necrotizing enterocolitis (NEC) is an intestinal disease that occurs in the neonatal period. The purpose of this study was to investigate the role of 5'-aminolevulinate synthase 2 (ALAS2) in NEC-induced intestinal injury. In a neonatal mouse, NEC model was induced by high-osmolarity formula and hypoxia-cold stress, and ALAS2 expression was significantly downregulated in ileal tissues (p  < 0.01), coinciding with elevated oxidative stress (increased Fe²⁺/malondialdehyde [MDA] and decreased superoxide dismutase [SOD]), inflammation (increased TNF-α/interferon-gamma [IFN-γ]), and ferroptosis activation (increased acyl-CoA synthetase long-chain family member 4 [ACSL4] and decreased ferritin heavy chain 1 [FTH1] with mitochondrial shrinkage). In vitro, tumor necrosis factor-alpha (TNF-α)/IFN-γ-treated intestinal epithelial cell (IEC) exhibited progressive ALAS2 suppression and increased necrosis. Crucially, lentivirus-mediated ALAS2 overexpression reversed these effects, reducing cell necrosis by 22% while suppressing ferroptosis markers (Fe²⁺ accumulation, lipid reactive oxygen species [ROS], and mitochondrial depolarization) and oxidative damage (decreased MDA and restored glutathione [GSH]/catalase [CAT]/SOD). Untargeted metabolomics further revealed ALAS2-mediated modulation of nutrient metabolism and redox pathways. Collectively, ALAS2 ameliorates NEC by blocking oxidative stress-driven ferroptosis in IECs, proposing a novel therapeutic target.

Purpose: To investigate the therapeutic potential of recombinant thrombomodulin domain 1 (rTMD1) in diabetic corneal wound healing and to elucidate its underlying mechanisms using in vitro and in vivo models.

Methods: rTMD1 was produced using the Pichia pastoris expression system and purified. Human corneal epithelial cells (HCECs) were cultured under normal glucose (NG) and high glucose (HG) conditions, with or without rTMD1 treatment. Wound healing rates were evaluated using a scratch assay. Diabetes was induced in C57BL/6 mice via streptozotocin (STZ) injections. Corneal wounds were created and treated with rTMD1 or PBS, and wound healing was assessed via fluorescein staining. Inflammatory markers, including HMGB1, TLR4, NLRP3, and IL-1β, were analyzed via quantitative PCR (qPCR), Western blot, and immunofluorescence staining.

Results: In vitro, HCECs treated with rTMD1 under HG conditions demonstrated a higher wound healing rate compared to untreated cells (p = 0.0049). In vivo, rTMD1 significantly enhanced corneal wound healing in diabetic mice, with faster wound closure compared to PBS-treated controls at 24 h (p = 0.005) and 48 h (p < 0.0001). rTMD1 treatment reduced the expression of HMGB1, TLR4, NLRP3, and IL-1β at both mRNA and protein levels, indicating suppression of inflammation.

Conclusions: Topical application of rTMD1 promotes corneal epithelial wound healing in diabetic conditions by inhibiting HMGB1/TLR4/NLRP3-mediated inflammation. rTMD1 holds promise as a potential therapeutic agent for diabetic keratopathy, although further studies are needed to validate its clinical efficacy and safety.

Background: Peri-implantitis, a major contributor to dental implant failure, lacks comprehensive insights into tissue-specific heterogeneity as current researches predominantly focus on the whole peri-implant tissue rather than distinct molecular and cellular dynamics in gingiva and alveolar bone microenvironments. Furthermore, ethical challenges hinder the acquisition of healthy peri-implant tissues, limiting our understanding of peri-implantitis progression and the development of targeted therapies.

Methods: We established a controlled peri-implantitis model in beagle dogs, enabling ethical collection of healthy control tissues. Single-cell RNA sequencing (scRNA-seq) transcriptomics profiling was conducted on gingiva and alveolar bone tissues from diseased and healthy controls. Additionally, flow cytometry was utilized to further verify the identified subclusters and their involvement in peri-implantitis.

Results: Single-cell transcriptomic profiling unveiled a pronounced expansion of inflammation-associated cellular subsets in both gingival and alveolar bone microenvironments during peri-implantitis. Gingival tissues exhibited marked expansions in IL6⁺/IL18BP⁺ endothelial cell and CXCL8⁺ fibroblast, whereas APOD⁺ fibroblast dominated in peri-implantitis bone tissues. Gene-level profiling further identified upregulated pro-inflammatory chemokines (CXCL8, CXCL17, CCL24) within gingiva IL18BP⁺ endothelial cells. Notably, we discovered a unique ligand-receptor interaction C3 (APOD⁺ fibroblast)-C3AR1 (monocyte/macrophage) in alveolar bone tissue, implicating complement-dependent signaling in immune crosstalk.

Conclusions: Our study provides the first comparative atlas of soft/hard tissue remodeling in peri-implantitis at single-cell resolution. The expansion of IL6⁺/IL18BP⁺ endothelial cell and CXCL8⁺ fibroblast in gingiva, alongside APOD⁺ fibroblast-driven C3-C3AR1 signaling in alveolar bone, highlights distinct microenvironmental reprogramming between soft and hard tissues. These findings not only identify potential therapeutic targets but also validate the translational relevance of the canine model for peri-implantitis research.

Background: Acute respiratory distress syndrome (ARDS) is a critical illness with significant impacts on human respiratory health. Neutrophil extracellular traps (NETs), secreted by neutrophils, play dual roles in immune defense and tissue inflammation. Recent studies have highlighted the association between NETs and ARDS, yet no comprehensive bibliometric analysis has been conducted in this field. This study aims to analyze the research progress and evolving hot spots related to NETs in ARDS through bibliometric methods.

Methods: Articles published between 2011 and 2024 were retrieved from the Web of Science Core Collection (WoSCC), PubMed, and Embase. Data analysis was performed using visualization tools such as VOSviewer, CiteSpace, and Microsoft Office Excel 2021.

Results: A total of 328 articles were analyzed. The annual publication trend in this field has shown a steady increase, with China and the United States leading in research output. Frontiers in Immunology stands out for its high publication volume and citation count, indicating strong reference value. The most prolific author is Zhang, Hao from Zhongshan Hospital, Fudan University, while Egeblad, Mikala from Cold Spring Harbor Laboratory holds the highest citation count. Inflammatory response is a research focus in this field, and the association between NETs and thrombus formation represents an emerging research hotspot within the domain. Research and development of NETs-targeted therapies for acute lung injury (ALI) and ARDS is an important direction for future research.

Conclusion: This bibliometric analysis comprehensively summarizes research progress and hotspot evolution in NETs-related ARDS studies, providing valuable insights for researchers and inspiring future research directions.

Background: The relationship between immune-inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) and intestinal necrosis in different types of acute intestinal ischemia remains unclear.

Methods: A total of 138 patients with acute intestinal ischemia were divided into a nonnecrosis group (n = 65) and a necrosis group (n = 73). Least absolute shrinkage and selection operator (Lasso)-logistic regression model was used to identify independent risk factors for intestinal necrosis. Multivariate logistic regression was conducted to assess the associations between NLR and SII levels and intestinal necrosis. Sensitivity analyses were performed using smooth curve fitting, threshold effect analysis, subgroup analysis, and propensity score matching (PSM). .

Results: The optimal thresholds of NLR and SII for differentiating intestinal necrosis were 8.85 and 1492.11, respectively, while PLR showed no significant association. In Lasso-logistic regression analysis, vascular intestinal ischemia, NLR ≥ 8.85, SII≥ 1492.11, C-reactive protein (CRP), and D-dimer > 0.5 mg/L were independent risk factors for intestinal necrosis. After adjusting for potential confounding variables, the multivariate logistic regression analysis showed a positive correlation between natural logarithm (Ln)-NLR (OR = 20.187, 95% CI = 3.788-107.578, p  < 0.001) and Ln-SII (OR = 5.375, 95% CI = 1.141-25.313, p  < 0.033) and intestinal necrosis. Subgroup analysis showed a significant interaction between NLR, intestinal necrosis, and coronary heart disease (p interaction = 0.016). Smooth curve fitting indicated the relationship between Ln-NLR and Ln-SII and intestinal necrosis was nonlinear, with inflection points at 1.78 (NLR = 5.93) and 7.32 (SII = 1510.20), respectively. When NLR > 5.93 or SII < 1510.20, the risk of intestinal necrosis significantly increased. The associations remained robust after PSM.

Conclusion: This study demonstrates that elevated levels of NLR and SII are significantly associated with intestinal necrosis, suggesting that these biomarkers may help identify patients at higher risk of intestinal necrosis in acute intestinal ischemia. However, prospective studies are needed to validate their predictive value.

Background: Cancer-associated fibroblasts (CAFs), as a key component of the tumor microenvironment, have not been systematically elucidated in glioblastoma (GBM). Our study aims to develop a prognostic model integrating CAFs-related features, with the goal of providing new insights for precise stratification and optimized treatment strategies for GBM patients.

Methods: Utilizing GBM-related data from reputable public databases, we utilized the Seurat package in R to analyze single-cell RNA sequencing (scRNA-seq) data for the characterization of CAFs in GBM. We identified CAFs phenotypes and screened for key CAFs-related genes significantly associated with patient prognosis. Using regression analysis, we constructed a CAFs-based risk score, which was subsequently validated in multiple independent cohorts. A nomogram integrating the risk score and clinicopathological features was also developed. Furthermore, we systematically evaluated the prognostic and therapeutic relevance of the model in GBM patients through multi-dimensional analyses, including gene mutation profiling, pathway enrichment analysis, immune infiltration, immunotherapy response, and drug sensitivity analysis.

Results: A total of six CAFs-related genes (FAM241B, LSM2, IGFBP2, LOXL1, OSMR, and STOX1) were identified as significantly associated with GBM prognosis. We used it to construct the CAFs-based risk score model, which demonstrated robust prognostic performance across multiple cohorts and served as an independent predictor of overall survival in GBM patients, efficiently categorizing groups into high and low risk. By integrating clinical features, the nomogram model significantly increased predictive accuracy and reliability. Analytical results indicated a statistically significant association between the computed risk score and the level of immune cell infiltration. Furthermore, the established prognostic model exhibited robust efficacy in predicting patient outcomes following conventional targeted treatments as well as immunotherapeutic interventions.

Conclusions: This study introduces a GBM risk profiling framework and accompanying nomogram, offering exceptional accuracy in prognostic prediction for GBM. The framework and nomogram provide valuable insights into the roles of CAFs and key genes in GBM progression and immunity, and extend beyond classification by offering promising avenues for deciphering tumor mutations, mapping immune landscapes, refining drug predictions, and forecasting the efficacy of immunotherapeutic interventions. These findings have the potential to significantly improve personalized treatment strategies and patient outcomes.

Background/objective: Venous thromboembolism (VTE) remains a significant challenge in neurocritical care, with limited tailored risk assessment tools available for clinical practice. This study aimed to develop and validate a practical prediction model to support VTE prevention strategies in neurocritical patients.

Methods: A total of 605 neurocritical patients were retrospectively enrolled in the neurologic intensive care unit (NICU) from May 2022 to April 2024. The eligible patients were randomly divided into a training dataset and a testing dataset in a ratio of 7:3. Variables with significant univariate effects in the training dataset were selected for multivariable stepwise regression analysis. The model fitting goodness was tested using the Hosmer-Lemeshow test, the area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the model discrimination, and decision curve analysis (DCA) was used to test the clinical value of the model.

Results: The final model identified age, length of stay in the NICU, activated partial thromboplastin time (APTT), D-dimer, tracheotomy duration, pulmonary infection, antibiotic use, and dehydrating agents as key predictors. The nomogram demonstrated excellent discrimination (AUC 0.763, 95% CI: 0.714-0.811 in the training dataset; AUC 0.809, 95% CI: 0.732-0.885 in the testing cohort), strong calibration (Hosmer-Lemeshow test: p = 0.126 [training]; p = 0.823 [testing]) and consistent clinical net benefit across prevention thresholds (10%-40% risk probability).

Conclusions: The risk prediction model developed in this study can effectively predict VTE occurrence in neurocritical patients with good discrimination and clinical utility, providing a valuable tool for identifying high-risk individuals and performing early prevention and treatment measures.

Background: Diabetic kidney disease (DKD) is a multifactorial complication of diabetes involving mitochondrial dysfunction and immune cell infiltration. However, the causal relationships remain unclear.

Methods: We applied Mendelian randomization (MR) and single-cell RNA sequencing (scRNA-seq) to investigate the roles of mitochondrial gene expression and immune cells in DKD. Additionally, peripheral blood mononuclear cells (PBMCs) from DKD patients were analyzed for differential gene expression.

Results: Higher expression of mitochondrial genes PCCB, ACADM, ADHFE1, OCIAD1, and FIS1 increased DKD risk, while genes like NT5DC2, ATP5MC3, and GLYCTK decreased risk. Immune traits, including human leukocyte antigen (HLA)-DR + plasmacytoid dendritic cells (pDCs), mediated the effects of mitochondrial dysfunction on DKD. scRNA-seq revealed significant downregulation of ATP5MC3, GLYCTK, and NT5DC2 in podocytes (PODOs) and tubular cells in DKD kidneys, alongside increased infiltration of helper T cells, B cells, dendritic cells (DCs), and plasma cells. PBMC analysis highlighted the upregulation of proinflammatory genes (CXCL2, CXCL3, and others) in DKD patients.

Conclusion: This study highlights the complex interplay between mitochondrial dysfunction and immune cell infiltration in DKD pathogenesis. Key mitochondrial genes and immune traits identified here offer novel therapeutic targets such as ATP5MC3, GLYCTK, and DC pathways.

Irradiation (IRT) has been used extensively for the diagnosis and treatment of primary as well as metastatic brain tumors. Although the susceptibility of the radiation-induced brain injury or damage (RIBI) is partially associated with the sensitivity of particular cell types, pathways of injury in other types of brain disease or damage implicate the significance of the interaction between cell compartments. IRT-induced double-strand breaks (DSBs) are the utmost detrimental kind of DNA damage, which result in cell death as well as sustainable chromosomal reconfigurations following IRT exposure to the brain. It is worth noting that IRT-induced DSBs, and stimulation of interplay of key signaling pathways such as mitogen-activated protein kinases (MAPK), JAK/STAT, phosphoinositide-3-kinase/protein kinase B/AKT (PI3K-PKB/AKT), protein 53 (p53), mammalian target of rapamycin (mTOR), NF-kB, transforming growth factor beta (TGF-β), tumor necrosis factor (TNF), as well as reactive oxygen species (ROS) to either trigger radiosensitization or radioresistance as well as RIBI mechanisms. Also, IRT is capable of influencing fundamental immune players like cluster of differentiation markers, the complement cascade, T cells, B cells, interleukins, as well as chemotactic cytokines. Thus, the aim of this review is to explicate the key molecular signaling and immune mechanisms associated with IRT-induced neurological deficits following brain IRT.