Mediators of Inflammation最新文献

Background: Atherosclerosis is an inflammatory cardiovascular disease. However, whether the association of immune cells in plaques promotes the progression of this disease has not yet been completely elucidated.

Materials and methods: Thus, this study aimed to investigate the relationship between C1q+ macrophages and CD8T cells through scRNA-seq data reanalysis, quantitative real-time PCR, and flow cytometry. Chromatin immunoprecipitation-quantitative polymerase chain reaction, western blot, and antibody-blocking experiments were performed to investigate the role of macrophage-CD8T interaction in atherosclerosis. An atherosclerotic mouse model was developed to confirm our findings.

Results: Mechanistically, Spi1 expression induced by granulocyte-macrophage colony-stimulating factor promoted C1q expression in the macrophages. Moreover, C1q+ macrophages suppressed CD8T cell apoptosis by upregulating Slc7a7 expression to enhance the L-arginine uptake of CD8T cells. CD8T-derived interferon-γ promoted macrophage activation to induce atherosclerosis. Blockade of the C1q-C1qbp axis attenuated atherosclerosis.

Conclusion: In conclusion, macrophages interacting with CD8T promote atherosclerosis development via the C1q-C1qbp axis.

Objective: To explore and validate the value of clinical parameters combined with plasma biomarkers for predicting acute respiratory distress syndrome (ARDS) in patients of high risks in the surgical intensive care unit (SICU).

Materials and methods: We conducted a prospective, observational study from January 2020 to December 2023, which enrolled 263 patients of high risks in the SICU of Peking University Third Hospital consecutively; they were classified as ARDS and non-ARDS according to whether ARDS occurred after enrollment. Collected clinical characteristics and blood samples within 24 hr of admission to SICU. Blood samples from the first day to the seventh day of SICU were collected from patients without ARDS, and patients with ARDS were collected until 1 day after ARDS onset, forming data based on time series. ELISA and CBA were used to measure plasma biomarkers. Endpoint of the study was the onset of ARDS. Cox proportional hazard regression analysis was used to find independent risk factors of the onset of ARDS, then constructed a nomogram and tested its goodness-of-fit.

Results: About 84 of 263 patients ended with ARDS. Univariate analysis found 15 risk factors showed differences between ARDS and non-ARDS, namely, interleukin 6, interleukin 8 (IL-8), angiopoietin Ⅱ, LIPS, APACHEⅡ, SOFA, PaO₂/FiO₂, age, sex, shock, sepsis, acute abdomen, pulmonary contusion, pneumonia, hepatic dysfunction. We included factors with p  < 0.2 in multivariate analysis and showed LIPS, PaO₂/FiO₂, IL-8, and receptor for advanced glycation end-products (RAGE) of the first day were independent risk factors for ARDS in SICU, a model combining them was good in predicting ARDS (C-index was 0.864 in total patients of high risks). The median of the C-index was 0.865, showed by fivefold cross-validation in the train cohort or validation cohort. The calibration curve shows an agreement between the probability of predicting ARDS and the actual probability of occurrence. Decision curve analysis indicated that the model had clinical use value. We constructed a nomogram that had the ability to predict ARDS in patients of high risks in SICU.

Conclusions: LIPS, PaO₂/FiO₂, plasma IL-8, and RAGE of the first day were independent risk factors of the onset of ARDS. The predictive ability for ARDS can be greatly improved when combining clinical parameters and plasma biomarkers.

The pathogenesis of acute lung injury is complex. Studies have demonstrated the role of neutrophil extracellular traps (NETs) in the process of lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, the underlying mechanism remains unclear. In this study, the regulation of Nrf2 in the formation of NETs, which was pathogenic in LPS-induced ALI, was identified by analyzing the levels of Cit-H3, lung function, lung tissue pathology, lung wet/dry ratio, the inflammatory cells, cytokines and proteins in the bronchoalveolar lavage fluid (BALF) and in addition, the activity of lung myeloperoxidase (MPO) was also measured. Results showed that the levels of Cit-H3 measured by western blot in Nrf2-knockout (KO) mice were higher compared with the WT mice after LPS stimulation. To further investigate the NETs formation was pathogenic during LPS-induced ALI, the Nrf2-KO mice were treated with DNase I. Results showed that DNase I improved lung function and lung tissue pathology and significantly reduced lung wet/dry ratio and proteins in the BALF. Besides, DNase I also attenuated the infiltration of inflammatory cells and the cytokines (TNF-α, IL-1β) production in the BALF and the activity of lung MPO. Therefore, these results together indicate that Nrf2 may intervene in the release of NETs during LPS-induced ALI in mice.

Extracellular vesicles play an important role in the progression of pancreatic adenocarcinoma (PAAD) through the transfer of proteins, mRNAs, and long noncoding RNAs (lncRNAs). However, the intricate interplay between extracellular vesicles-related lncRNAs and the tumor microenvironment (TME) remains poorly elucidated. Consequently, our investigation aimed to delineate the association between extracellular vesicles-related lncRNAs and the PAAD microenvironment. Initially, we identified differentially expressed lncRNAs (DELs) from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) project datasets. Subsequently, we validated the expression of these DELs within extracellular vesicles and assessed their prognostic implications in PAAD using the GSE133684 and TCGA datasets. Multiomics data were analyzed comprehensively, including genomic landscape, functional annotation, immune profiles, and therapeutic responses. Differential expression of selected lncRNAs in both cellular and exosomal fractions of PAAD was further confirmed through quantitative polymerase chain reaction (qPCR). Eight DELs were identified from TCGA and GTEx datasets, and two exosomal lncRNAs exhibited a significant correlation with overall survival, warranting further investigation. Specifically, elevated expression of LINC00996 correlated positively with immune infiltration and enhanced response to immunotherapy. Conversely, heightened expression of TRHED-AS1 was associated with compromised immune cell infiltration and diminished responsiveness to immunotherapy. Our study establishes a compelling link between two extracellular vesicles-related gene signatures, prognosis, and immune infiltration in PAAD. Notably, these signatures serve as robust prognostic indicators for PAAD patients, offering valuable insights for the strategic selection of immunotherapeutic interventions.

Background: The role of C-reactive protein (CRP), an inflammatory marker, in the development of sarcopenia remains uncertain.

Methods: This cross-sectional research involved the enrollment of 207 patients, classified into two groups: 74 patients with sarcopenia and 133 patients without sarcopenia. Clinical data of the participants, including hand grip strength, walking speed, appendicular lean mass (ALM), and calf circumference, were collected and recorded. We evaluated the extent to which CRP levels are associated with the risk of sarcopenia using both univariate and multivariate logistic regression models. Besides, the correlation between CRP levels, hand grip strength, ALM, and walking speed was examined using the Spearman rank correlation test. Moreover, we have employed the Mendelian randomization (MR) analysis technique to explore the causal relationship between CRP levels and the occurrence of sarcopenia.

Results: The sarcopenia group showed a higher proportion of older women, with significant differences in anemia prevalence, calf circumference, gait speed, ALM, hand grip strength, and elevated CRP levels compared to the control group. Logistic regression analyses identified CRP as an independent risk factor for sarcopenia (OR: 1.151, 95% CI:1.070-1.238, and P < 0.001). Correlation analysis results revealed a noteworthy inverse association with hand grip strength (R = -0.454 and P < 0.001), ALM (R = -0.426 and P < 0.001), and walking speed (R = -0.431 and P < 0.001). MR analysis provided further evidence of a significant detrimental link between genetically predicted CRP levels and essential sarcopenia characteristics, with consistent results across various statistical models.

Conclusions: Our study uncovered strong evidence supporting a noteworthy inverse association and causality between CRP concentrations and sarcopenia, indicating that CRP has the potential to serve as a biomarker for sarcopenia.

We investigated the role of toll-like receptors (TLRs) in inflammatory pathways in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph(-)MPNs). TLR2 expression was increased in ET, PV, and MPN (grouped as (PV + (ET) + MF)), whereas TLR4 was elevated only in MPN. TLR3, 7, and 9 were not elevated. Cultured monocyte-derived dendritic cells and plasma assays in TLR2-elevated patients were found to secrete more cytokines than those from TLR2-normal patients. These facts suggest that TLR2 is the major inflammatory pathways in MPN. We also measured S100A9 and reactive oxygen species (ROS), revealing increased S100A9 in PV, MF, and MPN, while ROS were only increased in MF. These data suggests that MPNs initially involve TLR2, with minor contributions from TLR4, and with S100A9, leading to ROS formation, JAK2 mutation, and progression to MF or leukemia. Furthermore, patients with JAK2 mutations or leukocytosis exhibited higher TLR2 expression. In leukocyte-platelet interactions, cells from MPN patients displayed a stronger response to a TLR2 agonist than TLR4 agonist. A TLR2 inhibitor (but not a TLR4 inhibitor) attenuated this response. Thrombosis incidence was higher in TLR2-elevated patients (29%) than in TLR2-normal patients (19%). These findings suggest that TLR2 likely contributes to thrombosis in MPN.

Inflammatory bowel disease (IBD), which encompasses Crohn's disease (CD) and ulcerative colitis (UC), is a complicated illness whose exact cause is yet unknown. Necroptosis is associated with IBD pathogenesis, leading to intestinal barrier abnormalities and uncontrolled inflammation. Molecules involved in necroptosis, however, exhibit different expression levels in IBD and its associated colorectal cancer. Multiple studies have shown that inhibiting these molecules alleviates necroptosis-induced IBD. Moreover, due to the severe scarcity of clinical medications for treating IBD caused by necroptosis, we review the various functions of crucial necroptosis molecules in IBD, the stimuli regulating necroptosis, and the current emerging therapeutic strategies for treating IBD-associated necroptosis. Eventually, understanding the pathogenesis of necroptosis in IBD will enable the development of additional therapeutic approaches for the illness.

Tendinopathy is one of the most frequent musculoskeletal disorders characterized by sustained tissue inflammation and oxidative stress, accompanied by extracellular matrix remodeling. Patients suffering from this pathology frequently experience pain, swelling, stiffness, and muscle weakness. Current pharmacological interventions are based on nonsteroidal anti-inflammatory drugs; however, the effectiveness of these strategies remains ambiguous. Accumulating evidence supports that oral supplementation of natural compounds can provide preventive, and possibly curative, effects. Vitamin C (Vit C), collagen peptides (Coll), resveratrol (Res), and astaxanthin (Asx) were reported to be endowed with potential beneficial effects based on their anti-inflammatory and antioxidant activities. Here, we analyzed the efficacy of a novel combination of these compounds (Mix) in counteracting proinflammatory (IL-1β) and prooxidant (H₂O₂) stimuli in human tenocytes. We demonstrated that Mix significantly impairs IL-6-induced IL-1β secretion, NF-κB nuclear translocation, and MMP-2 production; notably, a synergistic effect of Mix over the single compounds could be observed. Moreover, Mix was able to significantly counteract H₂O₂-triggered ROS production. Together, these results point out that Mix, a novel combination of Vit C, Coll, Resv, and Asx, significantly impairs proinflammatory and prooxidant stimuli in tenocytes, mechanisms that contribute to the onset of tendinopathies.

Sepsis has been the leading cause of death in ICU patients. CD4+ T cells are the mainstay of the body's immune system, and the depletion of CD4+ T cells in sepsis is of great concern. Cytotoxic T lymphocyte-associated protein 4 (CTLA4) is a negative immunomodulator for T cell activation and degradation through the autophagy-lysosome pathway. Mammalian target of rapamycin (mTOR) is the most classical upstream regulator of autophagy. With a mouse model of sepsis through cecal ligation and puncture (CLP), T cell specific-mTOR/tuberous sclerosis complex 1 (TSC1)-knockout mice, and bafilomycin A1, a specific autophagosome-lysosome (A-L) fusion inhibitor, we primarily proved that mTOR could modulate the expression and accumulation of CTLA4 by regulating the onset process of autophagy such as A-L fusion. Given such a regulatory relationship, targeting mTOR could provide new light to improve immune function in sepsis, and the prospect of using rapamycin in the clinic would be worth exploring further.

Background: The albumin-bilirubin (ALBI) grade has surfaced as a viable substitute for assessing liver functional reserve in individuals afflicted with hepatocellular carcinoma (HCC). ALBI grade also demonstrates the capacity to stratify distinct patient subcohorts bearing disparate prognostic implications in not only HCC but also other inflammatory diseases like acute pancreatitis. However, the association between ALBI grade and clinical outcomes of acute kidney injury (AKI) remains mysterious.

Methods: The dataset was sourced from the Multiparameter Intelligent Monitoring in Intensive Care Database IV (MIMIC-IV) version 2.0. ALBI grade was calculated in a nomogram utilizing albumin and bilirubin. In order to ascertain the connection between ALBI grades and clinical outcomes of patients with AKI, Cox proportional hazards regression analysis was employed with in-hospital, 30- and 90-day mortality as end points, respectively. The Kaplan-Meier (K-M) curve was employed to gauge the cumulative incidence of mortality based on various ALBI grades. To explore potential nonlinear relationships, the Restricted Cubic Spline (RCS) approach was adopted. Furthermore, a subgroup analysis was conducted to validate the durability of the correlation between ALBI grade and in-hospital mortality. Furthermore, equilibrium of confounding variables was also achieved through the application of propensity score matching (PSM).

Results: The study encompassed a total of 12,518 patients (ALBI grade 1 : 2878, grade 2 : 6708, and grade 3 : 2932). Patients with heightened ALBI grades displayed a significant correlation with increased mortality in both univariate and various multivariate Cox regression models. RCS depicted a predominantly linear relationship. The robustness of the correlation was also affirmed across multifarious subpopulations through subgroup analysis. The association still remains after PSM.

Conclusion: Elevated ALBI grade was associated with worse clinical outcomes of critically ill patients with AKI.