Mediators of Inflammation最新文献

Aims: This study aimed to investigate the effects of low intensity pulsed ultrasound (LIPUS) combined with imipenem (IMI) on inflammatory responses and organ protection in septic rats.

Results: The study involved 230 Sprague-Dawley (SD) rats, with 80 used for survival analysis and 150 for sampling over 72 h. Histological examination (hematoxylin and eosin [H&E] staining) and transmission electron microscopy (TEM) revealed that LIPUS combined with IMI significantly alleviated spleen tissue damage and reduced mitochondrial edema. Key inflammatory cytokines, such as interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and IL-6 were significantly decreased, while IL-10 levels increased in the LIPUS + IMI group (p < 0.05). The combined treatment also reduced the expression of cytokines, such as IL-1 receptor (IL-1R), nuclear factor kappa B p65 (NF-κB p65), transforming growth factor-beta (TGF-β), and high mobility group protein box 1 (HMGB1), indicating a reduction in inflammation (p < 0.05).

Conclusion and innovation: This study presents a novel approach by integrating LIPUS with IMI, providing a noninvasive and effective strategy to mitigate cytokine storms, optimize antibiotic use, and reduce organ damage in sepsis. The protective effects observed are primarily attributed to the inhibition of the IL-1R/NF-κB signaling pathway, which significantly improves survival outcomes in septic rats. This combined therapy has potential for enhancing sepsis treatment protocols.

Background: Acute lung injury (ALI) is characterized by significant neutrophil infiltration in the lungs, representing a life-threatening condition with diverse etiologies. However, the mechanisms regulating neutrophil-alveolar epithelial interactions and the pathophysiological roles of neutrophil infiltration in ALI remain incompletely understood.

Methods: A dose of 20 mg/kg lipopolysaccharide (LPS) was intratracheally instilled to induce ALI models in 10-week-old male microRNA-223 knockout mice (miR-223^-/-) and wild-type (WT) mice, with control group mice receiving an equal volume of phosphate-buffered saline (PBS). After 24 h of instillation, lung tissues and peripheral blood were collected from the mice. In vivo, quantitative PCR (qPCR) measured miR-223 and neutrophil elastase (NE) mRNA levels, while Western blot (WB), enzyme-linked immunosorbent assay (ELISA), and hematoxylin-eosin (H&E) staining assessed neutrophil extracellular traps (NETs) markers (H3Cit, myeloperoxidase [MPO]), inflammatory cytokines (TNF-α, IL-1β, and IL-6), and lung injury severity. In vitro, HL-60-derived neutrophil-like cells were cocultured with alveolar epithelial cells under LPS stimulation. The roles of the miR-223/NE/NETs axis were further investigated using the NETs inhibitor GSK484 and the NE inhibitor Sivelestat.

Results: WB experiments showed an increase in NETs-related proteins MPO and H3Cit in the lungs of WT ALI mice, with significantly enhanced expression in miR-223^-/- mice. The lung injury scores and mortality rates in miR-223^-/- mice were significantly exacerbated, accompanied by increased neutrophil infiltration in the lungs. Levels of inflammatory factors (TNF-α, IL-1β, and IL-6) in the serum of miR-223^-/- mice were significantly elevated. In vitro coculture experiments demonstrated that miR-223 deficiency in neutrophil-like cells augmented NETs formation and inflammatory responses, leading to increased damage to alveolar epithelial cells. However, in vivo inhibition of NETs with GSK484 or NE with Sivelestat in miR-223^-/- mice significantly attenuated neutrophil infiltration, inflammation, and lung injury, and improved survival. Similarly, Sivelestat pretreatment reduced NET formation and conferred protection against ALI. Consistent with the in vivo findings, inhibition of NETs with GSK484 or NE with Sivelestat in the coculture system similarly attenuated epithelial damage and inflammatory response.

Conclusion: This study reveals that the miR-223/NE axis critically regulates NETs formation, modulating neutrophil inflammatory infiltration and neutrophil-epithelial interactions to exacerbate ALI. These findings provide potential therapeutic targets for ALI.

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.