Mediators of Inflammation最新文献

Autoimmune disorders encompass a varied range of diseases in which the immune system mistakenly targets and attacks the body's own tissues. The causes of the conditions are unknown. It is presumed that various genetic, environmental, and immune factors all play a part. Nowadays, therapies concentrate mainly on anti-inflammatory agents with immunosuppressant medications. New research highlights the central role of decoy receptors (DcRs) in regulating the immune system. DcRs are molecular traps for cytokines and other signaling molecules, preventing them from binding to functional receptors and influencing inflammatory processes. Their activity is context-dependent, shifting the balance between protective and pathogenic responses, and DcR dysregulation has been implicated in the development of autoimmune diseases. Understanding DcR function is critical for the design of potential therapeutic interventions. DcR mechanisms are reviewed here with emphasis on structural and disease-specific functions. Targeting DcRs is a promising strategy to reconstitute immune homeostasis. Understanding the dual regulatory functions and context-dependent mechanisms is critical for designing new therapies that reduce autoimmune pathogenesis without compromising host defense mechanisms.

Background: Standard modifiable risk factors (SMuRFs) are important causative factors leading to coronary atherosclerosis. However, a significant number of individuals develop coronary atherosclerosis despite the absence of SMuRFs. Inflammation is another major cause of atherosclerosis, and this study aims to investigate the association of the novel inflammatory markers systemic immune inflammatory index (SII) and systemic inflammatory response index (SIRI) with mortality in patients with coronary heart disease (CHD) with and without SMuRFs.

Methods: In this study, we included 1708 CHD participants from the 1999-2018 National Health and Nutrition Examination Survey (NHANES). Patients were categorized into ≥ 1SMuRF and SMuRF-less groups by questionnaire and serologic testing. SII and SIRI were categorized into four groups according to quartiles. Multivariate weighted Cox regression was used to explore the risk factors associated with mortality in patients with or without SMuRFs. Restricted cubic spline (RCS) curve was used to assess their nonlinear correlation.

Results: In patients with ≥1 SMuRF, all-cause mortality (SII:hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.18-1.84, p  < 0.001; SIRI:HR 1.66, 95%CI 1.31-2.10, p  < 0.001) and cardiovascular mortality (SII:HR 1.52, 95%CI 1.07-2.17, p = 0.020; SIRI:HR 1.63, 95%CI 1.11-2.38, p = 0.011) were significantly higher in the SII Q4 and SIRI Q4 group compared to the SII Q1 and SIRI Q1 group, respectively. In patients with SMuRF-less, the incidence of all-cause mortality was also significantly higher in the group with higher levels of SII, SIRI (SII:HR 3.32, 95%CI 1.45-7.59, p = 0.004; SIRI:HR 4.25, 95%CI 1.67-10.80, p = 0.002), but no significant difference was observed in cardiovascular mortality for SII (SII:HR 2.21, 95%CI 0.54-8.97, p = 0.272), while a significant association was found for SIRI (SIRI:HR 11.69, 95%CI 1.43-95.21, p = 0.028). The RCS analysis showed a linear trend between high levels of SII, SIRI, and elevated all-cause mortality, and cardiovascular mortality in patients with ≥1 SMurRF. In contrast, a positive linear trend between SII, SIRI, and all-cause mortality, but no significant association with cardiovascular mortality was observed in the group with SMuRF-less.

Conclusions: The findings showed that SII and SIRI were positively associated with all-cause mortality in a population with CHD irrespective of the presence or absence of SMuRFs. The present study suggests that inflammation may be an important factor in the poor prognosis of patients with no specific cardiovascular risk factors, which needs to be further argued by more prospective studies.

[This retracts the article DOI: 10.1155/2017/5958429.].

Background: Wilson's disease (WD), caused by mutations in the ATP7B gene, leads to copper accumulation and multi-organ damage. Exosomal microRNAs (miRNAs) play a crucial role in cell-to-cell communication and the pathogenesis of diseases, yet their study in WD remains unreported. This study aims to characterize the serum exosomal miRNA signature in WD patients and investigate its potential as a source of biomarkers and therapeutic targets.

Methods: Serum exosomes from WD patients and healthy controls were isolated for RNA sequencing to identify differentially expressed miRNAs (DE-miRNAs). An integrated bioinformatics approach was employed, encompassing Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Disease Ontology (DO) analyses to systematically decipher the functional roles, pathway involvements, and disease associations of the DE-miRNAs. Selected DE-miRNAs were validated by RT-qPCR.

Results: We identified 59 DE-miRNAs (23 upregulated, 34 downregulated) in WD patient serum exosomes. GO analysis revealed their significant involvement in signal transduction, metal ion binding, and metabolic pathways. KEGG analysis highlighted alterations in key signaling cascades, including Ras, PI3K-Akt, and Hippo pathways. Reactome analysis further uncovered disruptions in specific biological modules, notably ubiquitin-mediated proteolysis, GPCR signaling, and spliceosome assembly. DO enrichment demonstrated significant associations with hepatocellular carcinoma, neuropsychiatric disorders, and metabolic diseases. RT-qPCR validation confirmed the reliability of DE-miRNA expression patterns (p  < 0.05).

Conclusions: This study establishes the first comprehensive landscape of serum exosomal miRNAs in WD, revealing their involvement in an interconnected network of pathological processes. Our findings provide a novel conceptual framework for understanding WD pathophysiology and pinpoint promising candidates for biomarker development.

[This corrects the article DOI: 10.1155/2023/3236911.].

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.