Mediators of Inflammation最新文献

A series of intestine-related alterations have been considered a key factor in triggering sepsis, with increased apoptosis of intestinal epithelial cells (IECs) notably contributing to this process. Compromised gut barrier due to IEC apoptosis promotes bacterial translocation and inflammatory responses, which in turn escalates to further IEC death and barrier defects. Nevertheless, the precise mechanisms that safeguard IECs from apoptosis and interrupt this vicious cycle are yet to be elucidated. Here, we report that Grb2-associated binder 1 (Gab1) expression is diminished in the intestines of both septic patients and established sepsis models. Epithelial Gab1 deficiency rendered mice susceptible to lipopolysaccharide (LPS)-induced sepsis by sensitizing IECs to apoptosis, thereby contributing to systemic inflammation and markedly exacerbating septic lethality. Mechanistically, Gab1 mitigated apoptotic signaling via IKKβ-dependent NF-κB activation and subsequent transcriptional regulation of apoptotic genes in response to TNF-α. Collectively, our findings define a protective role for Gab1 in sepsis-induced intestinal injury by sustaining apoptotic balance and intestinal homeostasis, which provides new insights into therapeutic strategies for sepsis management, particularly those aiming at restoring immune homeostasis and improving barrier function.

Purpose: Allergic conjunctivitis (AC) is a condition with a rising prevalence that occasionally leads to irreversible visual impairment. However, few novel therapeutic targets have been identified for AC. The investigation aims to utilize the Mendelian randomization (MR) technique to explore the causal impacts exerted by the plasma proteome on AC.

Methods: An evaluation was conducted on a two-sample MR study utilizing 2,940 plasma proteins from the UK Biobank Pharma Proteomics Project (UKB-PPP) to investigate their causal links with AC. Confirmation of these MR results was achieved using Summary-data-based MR (SMR) and Bayesian colocalization techniques. Moreover, evaluations concerning the druggability of proteins, interactions among proteins, and phenome-wide MR (Phe-MR) studies were conducted to ascertain the functionalities of the identified proteins implicated in causality.

Results: MR analysis identified five circulating proteins (TLR1, ING1, RALY, CSF2, and ITGAM) whose genetically predicted plasma levels were significantly associated with AC risk (P _FDR < 0.05). Functional enrichment analysis of the identified proteins revealed statistically significant biologically relevant pathways, including macrophage activation and pathways of plasma membrane signaling receptor complex, suggesting underlying immune and receptor-mediated mechanisms in AC. SMR and HEIDI validation supports four (TLR1, ING1, ITGAM, and CSF2) of five MR-identified proteins as causal candidates for AC. Subsequent colocalization analysis provided further support for two credible proteins (ING1 and CSF2). Protein druggability suggests CSF2 and ING1 as novel and potentially druggable candidates for AC.

Conclusions: Our research identified proteins that appear to have causal effects and could serve as potential therapeutic targets for AC.

Objective: To analyze the direct and indirect associations between structural, functional, and systemic variables in patients with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and controls using structural equation modeling (SEM).

Methods: A cross-sectional observational study was conducted including 156 participants: 55 with POAG, 49 with NTG, and 52 age- and sex-matched controls. Clinical variables included intraocular pressure (IOP), central corneal thickness (CCT), vertical cup-to-disc ratio (VCDR), and visual-field mean deviation (MD). Systemic variables comprised age and cardiovascular risk factors (hypertension, diabetes, and dyslipidemia). SEM was applied to assess direct and indirect effects on the diagnosis of glaucoma.

Results: The model showed a good overall fit (χ ²(9) = 15.968; p = 0.068; χ ²/df = 1.774; CFI = 0.972; RMSEA = 0.071) and explained 46.0% of the variance in glaucoma diagnosis (R ² = 0.460). The most influential predictors were VCDR (β = 0.40), age (β = 0.14), and cardiovascular risk factors (β = 0.19). A significant negative correlation was observed between CCT and MD (r = -0.29), indicating greater functional damage in eyes with thinner corneas. An inverse association between cardiovascular risk burden and IOP was also identified (r = -0.18).

Conclusions: Our findings support the hypothesis of distinct glaucomatous phenotypes, including a vascular subtype with lower IOP and altered perfusion, potentially influenced by systemic comorbidities and chronic treatments. Reduced CCT was also confirmed as an independent marker of advanced functional loss. SEM helps disentangle complex mechanisms and may inform personalized therapeutic strategies, particularly in NTG.

Characterized by its capacity to induce organ failure, sepsis constitutes a life-threatening pathological state with high incidence and mortality rates. Current treatments primarily focus on antimicrobial therapy and organ support, lacking direct interventions targeting the restoration of cellular or organelle function. Among these mechanisms, mitochondrial dysfunction and overactivation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome stand out as key pathological hallmarks. As a classic inflammasome, the NLRP3 inflammasome, upon activation, drives cellular pyroptosis and massive release of inflammatory mediators. Beyond their role as cellular energy generators, mitochondria participate in the modulation of inflammatory responses and oxidative stress control. Mitochondrial quality control (MQC) serves as a prerequisite for the orderly performance of mitochondrial physiological functions. Disruption of MQC invariably results in mitochondrial dysfunction, triggering liberation of mitochondrial reactive oxygen species (mtROS) along with mitochondrial damage-associated molecular patterns (mtDAMPs), which serve as direct triggers for NLRP3 inflammasome formation and stimulation. This process disrupts MQC, exacerbates mitochondrial dysfunction, and forms a mutually reinforcing "MQC imbalance-NLRP3 overactivation" vicious cycle that drives disease progression. This review aims to: (1) systematically elucidate the complex bidirectional regulatory mechanisms between the NLRP3 inflammasome and MQC in the context of sepsis, (2) summarize the latest research progress on targeted intervention strategies based on this vicious cycle, and (3) discuss the challenges in clinical translation and future directions of these strategies.

Objective: Previous studies suggest a complex interaction between 3,3',5-triiodo-L-thyronine (T3) and inflammation, but this relationship remains unclear. This study investigates the association between free triiodothyronine (FT3) levels and inflammatory markers in the US population using National Health and Nutrition Examination Survey (NHANES) data.

Methods: This study analyzed NHANES data from three cycles between 2007 and 2012, using Spearman correlation tests and multivariate linear regression. Subgroup analyses and interaction tests were conducted based on age, gender, race, body mass index (BMI), thyroid-stimulating hormone, and free thyroxine (T4) to determine the correlations between FT3 and seven systemic inflammatory markers: C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-white blood cell ratio (PWR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI).

Results: A total of 2306 participants were included in this study. Univariate correlation analysis showed that CRP, NLR, MLR, and PLR were significantly negatively correlated with FT3 levels (all p  < 0.05). After adjusting for confounders, FT3 levels were significantly negatively associated with CRP, NLR, and PLR (all p  < 0.05). Subgroup analysis showed that age significantly modified the associations between FT3 and systemic inflammatory markers, such as CRP, NLR, MLR, SII, and SIRI (p-interaction < 0.05). The inverse associations were more consistent among individuals aged ≥ 65 years.

Conclusion: In the general population, FT3 levels exhibit inverse associations with systemic inflammatory markers.

Severe acute pancreatitis (SAP) is associated with high morbidity and mortality. Microcirculatory dysfunction is a critical pathological event in this process and a primary contributor to organ failure (OF). Despite the pivotal role of P-selectin in mediating the adhesion of activated platelets and leukocytes to the vascular endothelium, a process central to microcirculatory dysfunction, effective therapeutic interventions for SAP remain limited. Salvia miltiorrhiza, a traditional Chinese medicinal (TCM) herb, possesses well-documented pharmacological properties, including anti-inflammatory, anticoagulant, and microcirculation-improving effects. This review synthesizes recent advances in understanding the bioactive components of Salvia miltiorrhiza, which ameliorate microcirculation by modulating P-selectin expression and activity through mechanisms targeting its transcription, translation, or post-translational activation. Given the current lack of direct evidence in the context of SAP, we synthesized extensive findings from studies on cardiovascular, gastrointestinal, and inflammatory diseases, as well as from relevant acute pancreatitis (AP)/SAP models. These collective data demonstrate that Salvia miltiorrhiza effectively inhibits platelet aggregation, attenuates leukocyte adhesion, mitigates endothelial injury, and improves perfusion. Substantial evidence suggests that the bioactive compounds derived from Salvia miltiorrhiza function as effective agents against microcirculatory dysfunction by targeting P-selectin. Leveraging this well-defined mechanistic pathway and the promising therapeutic efficacy observed in AP/SAP models, targeting P-selectin with Salvia miltiorrhiza's bioactive compounds emerges as a compelling novel strategy for SAP-associated microcirculatory dysfunction, laying a groundwork for subsequent validation studies.

Background: Intestinal barrier dysfunction is a key driver of ulcerative colitis (UC) recurrence and chronic persistence. Modulating group 3 innate lymphoid cells (ILC3) activity and tryptophan-derived metabolites is crucial for enhancing mucosal repair in UC. Robinia pseudoacacia L. flower exosome-like nanoparticles (RFELNs) could ameliorate intestinal mucosal injury in mice. This study aimed to investigate the impact of RFELNs on intestinal barrier repair in UC mice and explore the underlying mechanisms.

Methods: Changes in body weight, food intake, DAI score, colon length, pathological score, and inflammatory factor level were performed to assess the therapeutic effect of RFELNs on DSS-stimulated UC mouse models. The effects of RFELNs on intestinal barrier integrity were assessed by intestinal barrier permeability analysis, Alcian Blue staining, immunohistochemistry (IHC), and western blot assays. IL-22 level was measured by immunofluorescent staining and ELISA assay. Besides, flow cytometry was performed to detect the proportions of ILC3 and NCR⁺ILC3 in the colon. Subsequently, an in vitro culture system consisting of NCM460 cells and MNK3 cells was established to determine potential mechanism of RFELNs' influence on UC.

Results: RFELNs prominently relieved pathological symptoms in UC mice, including weight loss, enhanced DAI score, shortened colon, and pathological colon damage. Moreover, RFELNs decreased the concentration of FITC-dextran and DAO level and enhanced D-lactate levels. Additionally, RFELNs significantly enhanced the number of colonic goblet cells, restored epithelial tight junctions (TJs), and upregulated TJ protein levels. Moreover, RFELNs enhanced IL-22 expression and the proportion of ILC3 cells and NCR⁺ILC3 cells. The protective effect of RFELNs on UC depends on AhR. Further, RFELNs activated AhR pathway by increasing the content of indole derivatives produced by tryptophan metabolism, thus promoting the repair of intestinal barrier damage.

Conclusion: RFELNs restored intestinal barrier function in UC mice by activating AhR/IL-22 signaling through regulation of gut microbiota-dependent tryptophan metabolism.

Background: Traumatic brain injury (TBI) is an important cause of disability and death worldwide. The development of neuroinflammation after TBI is related to the brain parenchyma. M1-type microglia play important roles in this process, but the specific mechanism through which regulating microglia M1 polarization is still not fully understood. This study aimed to investigate the role of ephrin receptor A4 (EPHA4) in the M1 polarization of microglia after TBI.

Methods: A TBI rat model was established by the controlled cortical impact (CCI) method, and M1 polarization of GMI-R1 cells was induced by lipopolysaccharide (LPS) treatment. Target genes associated with the progression of TBI were screened by transcriptome sequencing; the expression of key genes and proteins was detected by real-time quantitative PCR (RT‒qPCR), Western blot, ELISA, and immunofluorescence, and the damage of the rat brain tissue and the blood-brain barrier (BBB) was evaluated by hematoxylin‒eosin (HE) staining and Evans blue staining.

Results: This study revealed that EPHA4 expression is upregulated in the brain tissue of TBI rats and that treatment with its inhibitor, KYL peptide, can improve the progression of TBI. KYL peptide intervention downregulated the levels of the proinflammatory cytokines and upregulated the levels of the anti-inflammatory cytokines and inhibited the M1 polarization of microglia. The levels of the endoplasmic reticulum stress (ERS)-related proteins and Ca²⁺ were upregulated in TBI rats and downregulated after KYL peptide treatment but subsequently increased after 123C4 treatment. Our results showed that EPHA4 promoted the M1 polarization of microglia by enhancing ERS. Notably, mitogen-activated protein kinase (MAPK) signaling was significantly enriched in TBI. In vitro studies revealed that LPS treatment promoted the activation of MAPK signaling in GMI-R1 cells. A mechanistic study revealed that EPHA4 may activate ERS by activating the MAPK signaling pathway and promote M1 polarization of microglia after TBI.

Conclusion: Our study revealed that the EPHA4/MAPK axis may be a key regulatory factor in controlling microglial M1 polarization during brain injury. Blocking this signaling axis may represent a potential therapeutic approach for improving TBI.

Background: Clinical studies have demonstrated that the systemic immune-inflammation index (SII) is widely used to assess immunity and inflammation in patients. However, the association between SII and atopic dermatitis (AD) remains unclear. This study, based on the National Health and Nutrition Examination Survey (NHANES) database, aims to explore the relationship between SII and AD.

Methods: This study utilized NHANES data from 1999 to 2006, with a total of 8194 subjects included in the final analysis. We examined the associations between AD, SII, and other covariates by analyzing baseline characteristics and performing correlation analyses. Multivariate generalized linear models (GLMs) were used to analyze the correlation between AD and SII risk. A weighted multivariate logistic regression model was applied to examine the association between SII and AD. Additionally, a nomogram was constructed to predict the risk of developing AD. The eXtreme Gradient Boosting (XGBoost) algorithm was employed to evaluate feature importance. Finally, subgroup analysis was performed to further explore the relationship between SII and AD across different subpopulations.

Results: Significant differences were observed between the AD and control groups in terms of race, SII, SII group, and other variables. Furthermore, the p-values for SII (Q2 and Q3 groups) in all three models were less than 0.05, indicating that the influence of SII on the outcome was not significantly affected by other covariates. The weighted multivariate logistic analysis revealed that SII was strongly associated with AD as a risk factor. The nomogram demonstrated good predictive value for AD, and the XGBoost algorithm further confirmed the high predictive value of SII in AD diagnosis. Finally, subgroup analysis highlighted the significance of the association between SII and specific forms of dermatitis in various subpopulations.

Conclusion: Elevated SII is independently associated with increased AD risk. Although the cross-sectional design precludes causal inference, SII represents a cost-effective biomarker for AD risk stratification. Critically, emerging evidence positions SII as a predictor of therapeutic response-particularly to JAK inhibitors and biologics-highlighting its dual utility in risk assessment and precision management of AD.

Microglia-mediated neuroimmune responses have been implicated in central nervous system injury and disease pathogenesis. The α7 nicotinic acetylcholine receptor (α7 nAChR), which is expressed on microglia and participates in microenvironment interactions, is a key mediator of the cholinergic anti-inflammatory pathway. Nicotine activates the α7 nAChR, which may mediate the inflammation of microglia. This study aims to explore the modulatory effects of nicotine on neuroinflammation and its potential indirect neuroprotective effects using an in vitro microglial cell inflammation model. In our study, inflammatory phenotype indicators and molecular mechanisms of HMC3 cells were analyzed. Furthermore, an HMC3 microglia-SH-SY5Y neuronal coculture system was constructed to investigate the indirect neuroprotective effects of nicotine. The results demonstrated that nicotine exerted an inhibitory effect on the lipopolysaccharide-induced HMC3 microglia inflammation, promoted the release of neurotrophic factors, and neuronal survival by altering the immune environment. These effects appear to be mediated through the activation of α7 nAChR, leading to an increase in phosphorylation of PI3K. This study provides important insights into the immunomodulatory functions of low-concentration nicotine in the nervous system and contributes to a deeper understanding of its potential therapeutic applications.