Inflammation最新文献

Objective: Patients with rheumatoid arthritis (RA) have increased mortality and morbidity rates owing to cardiovascular diseases (CVD). Timely detection of CVD in RA can greatly improve patient prognosis; however, this technique remains challenging. We aimed to investigate the risk factors for CVD incidence in patients with RA.

Methods: This retrospective study included RA patients without CVD risk factors (n = 402), RA with CVD risk factors (n = 394), and RA with CVD (n = 201). Their data on routine examination indicators, vascular endothelial growth factor (VEGF), and immune cells were obtained from medical records. The characteristic variables between each group were screened using univariate analysis, least absolute shrinkage and selection operator (LASSO), random forest (RF), and logistic regression (LR) models, and individualized nomograms were further established to more conveniently observe the likelihood of CVD in RA.

Results: Univariate analysis revealed significantly elevated levels of white blood cells (WBC), blood urea nitrogen (BUN), creatinine, creatine kinase (CK), lactate dehydrogenase (LDH), VEGF, serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), apolipoprotein B100 (ApoB100), and apolipoprotein E (ApoE) in RA patients with CVD, whereas apolipoprotein A1 (ApoA1) and high-density lipoprotein/cholesterol (HDL/TC) were decreased. Furthermore, the ratio of regulatory T (Treg) cells exhibiting excellent separation performance in RA patients with CVD was significantly lower than that in other groups, whereas the ratios of Th1/Th2/NK and Treg cells were significantly elevated. The LASSO, RF, and LR models were also used to identify the risk factors for CVD in patients with RA. Through the final selected indicators screened using the three machine learning models and univariate analysis, a convenient nomogram was established to observe the likelihood of CVD in patients with RA.

Conclusions: Serum lipids, lipoproteins, and reduction of Treg cells have been identified as risk factors for CVD in patients with RA. Three nomograms combining various risk factors were constructed to predict CVD occurring in patients with RA (RA with/without CVD risk factors).

Physiological processes in organisms exhibit circadian rhythms that optimize fitness and anticipate environmental changes. Luminal signals such as food or metabolites synchronize bowel activity, and disruptions in these rhythms are linked to metabolic disorders and gastrointestinal inflammation. To characterize the intrinsic intestinal rhythms and assess disruptions due to continuous darkness or light exposure, C57BL/6 mice were exposed to standard light-dark conditions or continuous light/darkness for 48 h, with evaluations at four timepoints. We assessed intestinal morphology, mucus production, nitric oxide levels and permeability. Under standard light: dark cycles, mice showed changes in intestinal morphology consistent with normal tract physiology. Continuous light exposure caused marked alterations in the small intestine´s epithelium and lamina propria, reduced nitric oxide production in the colon, and predominant neutral mucins. Enhanced permeability was indicated by higher FITC-dextran uptake and increased frequency of IgG-coated bacteria. Additionally, the 48 h-disruption influenced DSS-induced colitis with attenuation in L:L group, or exacerbation in D:D group, of clinical signs. These findings highlight the critical role of circadian rhythms in gut histoarchitecture and function, demonstrating that short-term disruptions in light-dark cycles can compromise intestinal barrier integrity and impact inflammatory outcomes.

Sepsis and septic shock are life-threatening systemic inflammatory conditions and among the most frequent causes of morbidity and mortality globally. Preclinical evidence has identified a number of diazepine-based compounds with therapeutic potential in inflammatory diseases. However, the potential anti-inflammatory properties of diazepines in the overwhelming immune response during sepsis have been rarely examined. Thus, the current study aimed to identify a new diazepine compound with therapeutic potential in sepsis. Assessing the inflammatory response of macrophages to Lipopolysaccharides (LPS) in vitro identified 2-[7-(trifluoromethyl)-2,3-dihydro-1H-1,4-diazepin-5-yl]phenol (2-TDDP) as a potential anti-inflammatory agent. It reduced secretion of Interleukin-1β (IL-1β), IL-6, IL-12p70, IL-18, Tumor necrosis factor-α (TNF-α), Interferon-γ (IFN-γ), IFN-β, and increased the secretion of IL-10. In a mouse model of LPS-induced endotoxin shock, 2-TDDP reduced mortality and attenuated inflammation-induced tissue injury in the spleen, liver, kidney, and lung. This was accompanied by reduced serum levels of IL-1β, IL-6, IL-12p70, TNF-α, IFN-γ, IFN-β, and increased levels of IL-10. Importantly, 2-TDDP suppressed the Toll-like receptor 4 (TLR4)/Nuclear factor-κB (NF-κB) and TLR4/Interferon regulatory factor 3 (IRF3) signaling pathways through a reduction in the expression of TLR4, Myeloid differentiation primary response 88 (MyD88), P65, and TNF receptor-associated factor 3 (Traf3). Moreover, 2-TDDP suppressed the expression of CD86, Programmed death-ligand 1 (PD-L1) and C5a receptor (C5aR), but not Major histocompatibility complex II (MHCII). Analysis of splenic lymphocyte populations revealed a decrease in the number of CD4⁺, CD8⁺, and B cells. Collectively, these findings introduced the dihydrodiazepine 2-TDDP as a new anti-inflammatory agent with potent therapeutic potential in endotoxin shock, paving an avenue for future clinical application.

This study investigates the role of S100A9 in sepsis-associated AKI (SA-AKI) through the lens of pyroptosis, a controlled form of cell death mediated by the gasdermin protein family. Using C57BL/6 mice and S100A9 knockout mice subjected to cecal ligation and puncture (CLP), RNA sequencing and bioinformatics analyses revealed differentially expressed genes (DEGs) related to inflammation and immune responses, with notable upregulation of S100A9. Functional enrichment analyses (GO and KEGG) indicated these DEGs are involved in interferon-beta response, immune processes, and cell adhesion. Protein-protein interaction (PPI) network analyses further emphasized S100A9's pivotal role in SA-AKI.Clinical validation measured S100A9 levels in serum and urine samples from SA-AKI patients and healthy volunteers, finding elevated S100A9 levels in the former. In vivo experiments showed that S100A9 knockout mice exhibited reduced kidney injury and inflammation, indicated by lower serum creatinine, urea nitrogen, and inflammatory markers (IL-1β and IL-18). Histopathological analyses and immunohistochemistry confirmed less renal damage and reduced expression of cleaved IL-1β and GSDMD-N in S100A9-deficient mice. Electron microscopy and Western blotting validated that S100A9 deficiency mitigates caspase-1-dependent pyroptosis.Cellular experiments with HK-2 cells demonstrated that S100A9 knockdown alleviated LPS-induced cell damage and reduced pyroptosis markers. These findings illuminate S100A9's involvement in NLRP3 inflammasome activation and pyroptosis, suggesting potential therapeutic targets for SA-AKI. Targeting S100A9 may offer new therapeutic avenues, improving outcomes for sepsis-related kidney injury patients. Future research should aim to validate these findings in larger clinical settings.

Oligomeric forms of α-synuclein (α-syn) are critical in the formation of α-synuclein fibrils, exhibiting neurotoxic properties that are pivotal in the pathogenesis of Parkinson's disease (PD). A salient feature of this pathology is the disruption of the protein folding capacity of the endoplasmic reticulum (ER), leading to a perturbation in the ER's protein quality control mechanisms. The accumulation of unfolded or misfolded proteins instigates ER stress. However, the onset of ER stress and the consequent activation of the Unfolded Protein Response (UPR) and Endoplasmic Reticulum-Associated Degradation (ERAD) pathways do not merely culminate in apoptosis when they fail to restore cellular homeostasis. More critically, this condition initiates a cascade of reactions involving ER-related structures and organelles, resulting in multifaceted cellular damage and, potentially, a feedback loop that precipitates neuroinflammation. In this review, we elucidate the interplay between UPR and ERAD, as well as the intricate crosstalk among the ER and other organelles such as mitochondria, lysosomes, and the Golgi apparatus, underscoring their roles in the neurodegenerative process.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease which manifests as joint destruction and bone erosion, could be caused by both genetic and environmental factors. Currently, the causes of RA are unknown, and targeted therapies are often associated with side effects and contraindications. The detection rate of RA in women is higher than men (3:1), however, there is still a lack of comprehensive understanding of the relationship between sex and RA. We hypothesized gender differences in RA prevalence and their associated mechanisms by performing genome-wide transcriptome analysis of synovial biopsy samples. The results indicated that myoglobin (MB) was differentially expressed between males and females, with higher expression in males than females in healthy populations, while the opposite was observed in RA patients. MB interacted with HLA class II histocompatibility antigen, DM beta (HLA-DMB) and the inflammatory factor interleukin 6 (IL-6) in the human synovial cell line MH7A.

This study aimed to investigate how aquaporin 1 (AQP1) modulates hypoxia-inducible factor-1α (HIF1α) to promote glycolysis and drive the M1 polarization of macrophages. Within 12 h post-treatment with LPS to induce acute kidney injury in rats, a significant upregulation of AQP1 and HIF1α protein levels was noted in serum and kidney tissues. This elevation corresponded with a decrease in blood glucose concentrations and an enhancement of glycolytic activity relative to the control group. Furthermore, there was a pronounced reduction in the circulating levels of the anti-inflammatory cytokine IL-10, accompanied by an upregulation in the levels of the pro-inflammatory cytokines IL-6 and TNF-α. The administration of an HIF1α inhibitor reversed these effects, which did not affect the production of AQP1 protein. In cellular assays, AQP1 knockdown mitigated the increase in HIF1α expression induced by LPS. Furthermore, the suppression of HIF1α with PX-478 led to decreased expression levels of Hexokinase 2 (HK2) and Lactate Dehydrogenase A (LDHA), indicating that AQP1 regulates glycolysis through HIF1α. M1 polarization of macrophages was reduced by AQP1 knockdown and was further diminished by the addition of an HIF1α inhibitor. Inhibition of the glycolytic process not only weakened M1 polarization but also promoted M2 polarization, thereby reducing the release of inflammatory cytokines. These findings provide a novel perspective for developing therapeutic strategies that target AQP1 and HIF1α, potentially improving the treatment of sepsis-associated AKI.

Sepsis is a severe and life-threatening disease caused by infection, characterized by a dysregulated immune response. Unfortunately, effective treatment strategies for sepsis are still lacking. The intricate interplay between metabolism and the immune system limits the treatment options for sepsis. During sepsis, there is a profound shift in cellular energy metabolism, which triggers a metabolic reprogramming of immune cells. This metabolic alteration impairs immune responses, giving rise to excessive inflammation and immune suppression. Recent research has demonstrated that UCP2 not only serves as a critical target in sepsis but also functions as a key metabolic switch involved in immune cell-mediated inflammatory responses. However, the regulatory mechanisms underlying this modulation are complex. This article focuses on UCP2 as a target and discusses metabolic reprogramming during sepsis and the complex regulatory mechanisms between different stages of inflammation. Our research indicates that overexpression of UCP2 reduces the Warburg effect, restores mitochondrial function, and improves the prognosis of sepsis. This discovery aims to provide a promising approach to address the significant challenges associated with metabolic dysfunction and immune paralysis.

Hepatic encephalopathy (HE) is a serious brain disorder which associated with neurological and psychiatric manifestations. Oxidative stress and neuroinflammation and apoptosis play main roles in the development of brain damage in HE. Levetiracetam is an antiseizure drug with established antioxidant and anti-inflammatory activities. In the present study we investigated the therapeutic effects of levetiracetam against brain injury in HE and its underlying mechanisms of action. Male C57BL/6 mice were subjected to the induction of HE by the injection of thioacetamide (200 mg/kg) for 2 days. Mice were treated with levetiracetam at two doses (50 or 100 mg/kg/day) for 3 days in the treatment groups. Animals were subjected to a behavioral test and the brain tissues were dissected for histopathological, biochemical, gene expression and immunofluorescence analysis. The results showed that levetiracetam alleviated body weight loss and improved locomotor activity of mice with HE. Levetiracetam treatment decreased the histopathological changes, lipid peroxidation and protein carbonylation while restored the antioxidants (GSH, SOD and CAT) in the brain. Levetiracetam decreased the expression and activity of NF-κB, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IFN-γ) in the brain tissue. Administration of levetiracetam inhibited iNOS/NO pathway and myeloperoxidase (MPO) activity in the brain. Moreover, caspase-3 was decreased and the ratio of Bcl2/Bax was increased in the brain of mice treated with levetiracetam. These findings suggest that levetiracetam may be a promising therapeutic agent for brain injury in HE through inhibiting the oxidative, inflammatory and apoptotic pathways.

Retinal inflammation is a pivotal characteristic observed in various retinal degenerative disorders, notably age-related macular degeneration (AMD), primarily orchestrated by the activation of microglia. Targeting the inhibition of microglial activation has emerged as a therapeutic focal point. Quercetin (Qu), ubiquitously present in dietary sources and tea, has garnered attention for its anti-neuroinflammatory properties. However, the impact of Qu on retinal inflammation and the associated mechanistic pathways remains incompletely elucidated. In this study, retinal inflammation was induced in adult male C57BL/6 J mice through intraperitoneal administration of LPS. The results revealed that Qu pre-treatment induces a phenotypic shift in microglia from M1 phenotype to M2 phenotype. Furthermore, Qu attenuated retinal inflammation and stabilized the integrity of the blood-retina barrier (BRB). In vitro experiments revealed that Qu impedes microglial activation, proliferation, and migration, primarily via modulation the ERK/STAT3 signaling pathway. Notably, these actions of Qu significantly contributed to the preservation of photoreceptors. Consequently, Qu pre-treatment holds promise as an effective strategy for controlling retinal inflammation and preserving visual function.