课程文献中心 更多>>

关键词： Aortic dissection/aneurysms   Inflammation   Mitochondrial uncoupling proteins 1   Phenotype switching   TLR4/NLRP3/IL-1β signaling pathway  

摘要： Thoracic aortic aneurysms and dissection (TAAD) is a life-condition associated with high morbidity and mortality. Research has proven that inflammation contributes to the progression of TAAD. Mitochondrial uncoupling protein 1 (UCP1) can inhibit the release of inflammatory factors in perivascular adipose tissue (PVAT), regulate fat and inflammation, to confer vascular protection. However, whether UCP1 can ameliorate TAAD has not been clarified. In this study, aortas were harvested from organ donors and TAAD patients to explore the expression of UCP1 and Toll-like receptor 4 (TLR4)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/interleukin-1β (IL-1β) signaling pathway. Meanwhile, in vitro and in vivo models of TAAD were constructed to clarify the impact of UCP1 expression on VSMCs and TAAD. UCP1 expression was significantly downregulated and the TLR4/NLRP3/IL-1β signaling pathway was activated in TAAD in vivo. Moreover, UCP1 inhibited the migration, invasion, apoptosis, and phenotype switching of VSMCs in vitro. UCP1 significantly blocked the β-aminopropionitrile (BAPN)-induced TAAD formation and rupture in mice, suppressed aortic dilation, elastic fiber fragmentation, and apoptosis in the aorta. It also activated the TLR4/NLRP3/IL-1β signaling pathway to alleviate aortic inflammation and prevent the degradation of systolic phenotype proteins and phenotype switching of VSMCs. These effects suggest that UCP1 may inhibit TAAD formation by blocking the TLR4/NLRP3/IL-1β signaling pathway and VSMC phenotype switching.

关键词： IL-6   STAT3   colitis   Akkermansia muciniphila   Crohn's disease  

摘要： Background Inflammatory bowel disease is a long-standing inflammatory disorder that influences the intestinal tract. The intent of this research is to explore whether the relative abundance of Akkermansia muciniphila is related to the IL6/STAT3 pathway and the fundamental molecular mechanisms of A. muciniphila on a trinitrobenzene sulfonic acid (TNBS)-induced enteritis mouse model, including the expression of inflammatory cytokines and proteins in the IL6/STAT3 signaling *** The association between the A. muciniphila and IL6/STAT3 was investigated by using mucosal biopsies and fecal samples. TNBS-induced colitis mouse models were performed to elucidate the underlying mechanisms. The alteration of intestinal microbiota was organized by 16s rRNA *** In Crohn's disease patients, the level of STAT3 and IL-6 presented a negative relationship with A. muciniphila. The expression of IL-6, p-STAT3, and STAT3 was downregulated in A.m+TNBS group, indicating A. muciniphila may inhibit the IL6/STAT3 pathway in TNBS-induced enteritis in vivo. To investigate the potential defensive role of A. muciniphila supplementation in vivo with TNBS-induced enteritis, 16S rRNA sequencing was performed to analyze changes in the intestinal microbiota composition. The results revealed a marked increase in microbial diversity and abundance within the A. muciniphila-treated group, suggesting a beneficial modulation of the gut microbiome associated with the *** Our findings declared that A. muciniphila supplementation alleviates gastrointestinal inflammation through IL-6/STAT3 signaling pathway. This protective effect was mediated by the downregulation of the IL-6 and STAT3, highlighting a potential mechanism by which A. muciniphila modulates inflammatory responses. This work disclosed that A. muciniphila demonstrates a defensive influence against TNBS-induced enteritis in vivo, proposing it qualified as a unique therapeutic focusing on modulating

关键词： HSV-1   ocular   herpes   HLA transgenic rabbit   CD8(+) T cell   prime/pull/keep vaccine  

摘要： Herpes simplex virus type 1 (HSV-1) continues to be one of the most prevalent viral infections globally, with approximately 3.72 billion individuals affected worldwide. A clinical herpes vaccine is still lacking. In the present study, a novel prime/pull/keep vaccine was tested in a human leukocyte antigen transgenic rabbit model of ocular herpes (HLA-A*0201 Tg rabbit). Ten asymptomatic (ASYMP) CD8(+) T-cell peptide epitopes and 3 CD4(+) T-cell epitopes were selected from the HSV-1 glycoproteins D and B (gD and gB), viral tegument proteins (VP11/12 and VP13/14), and the DNA replication-binding helicase (UL9), all preferentially recognized by CD8(+) and CD4(+) T cells from "naturally protected" HSV-1-seropositive healthy ASYMP individuals (who never had recurrent corneal herpetic disease). HLA Tg rabbits were ocularly infected with HSV-1, then during latency at day 30 post-infection, the rabbits were ocularly vaccinated with a recombinant neurotropic AAV8 vector (10(7)GC/ eye) encoding for the 10 CD8(+) T-cell peptide and 4 CD4(+) T-cell peptide (prime), T-cell attracting CXCL-11 (pull), and T-cell keeping IL-2/IL-15 cytokines (keep). The rabbits were followed up for corneal disease and viral loads in tears for 28 days. The frequency, function, and protective efficacy of HSV-specific CD8(+) T cells induced by the prime/pull/keep vaccine were assessed in the trigeminal ganglia (TG), cornea, spleen, and peripheral blood. Compared to the mock group (unvaccinated), the peptides/CXCL11/IL-2/IL-15 vaccine generated frequent resident CD8(+) T cells that infiltrated the TG. In ocularly HSV-1-infected and prime/pull/keep vaccinated rabbits, CD8(+) T cell mobilization and retention into TG were associated with a significant reduction in corneal herpes infection and disease. These findings draw attention to the novel prime/pull/keep therapeutic vaccine strategy to mobilize and retain antiviral T cells to tissues protecting them against herpetic infection and disease.

关键词： IL-4Rα monoclonal antibody   Pharmacokinetics   Phase I   Population pharmacokinetic model   Safety   TQH2722  

摘要： The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of TQH2722, an Interleukin-4 receptor alpha (IL-4Rα) monoclonal antibody, in healthy subjects. In this randomized, double-blind and placebo-controlled trial, TQH2722 was subcutaneously injected as single-ascending dose (n = 46; 50, 150, 300, 600 and 1200 mg) or multiple-ascending dose (n = 20; 150 and 600 mg; four doses every 2 weeks). Subjects were monitored for adverse events and blood samples were collected for pharmacokinetics. A population pharmacokinetic model was developed and validated. TQH2722 was well tolerated with no serious or severe adverse events observed. After a single dose, the maximum concentration occurred at 3-7 days, with t ranged from 2.65 to 17.43 days. Four repeated dosing caused about 3-fold degree of accumulation for C and AUC. Regardless of single or multiple doses, the exposure showed a nonlinear and greater than dose proportional increase. A two-compartment model taking into account the mechanistic target-mediated drug disposition process with parallel linear and nonlinear Michaelis-Menten (MM) elimination and first-order absorption well described the pharmacokinetics of TQH2722. In conclusion, TQH2722 was safe and well tolerated, and its PK profiles were well characterized, supporting its further clinical development in patients.

摘要： The function of islet macrophages is poorly understood. They promote glucose-stimulated insulin secretion (GSIS) in lean mice, however, the underlying mechanism has remained unclear. We show that activation of the free fatty acid receptor FFAR4 on islet macrophages leads to interleukin-6 (IL-6) release and that IL-6 promotes β-cell function. This mechanism is required for GSIS in lean male mice, but does not function anymore in islets from people with obesity and obese type 2 diabetic male mice. In islets from obese mice, FFAR4 downstream signaling in macrophages is strongly reduced, resulting in impaired FFAR4-mediated IL-6 release. However, IL-6 treatment can still improve GSIS in islets from people with obesity and obese type 2 diabetic mice. These data show that a defect in FFAR4-mediated macrophage activation contributes to reduced GSIS in type 2 diabetes and suggest that reactivating islet macrophage FFAR4 and promoting or mimicking IL-6 release from islet macrophages improves GSIS in type 2 diabetes.

关键词： H3K4me3   RIPK1   Serotonin   TG2   TNF  

摘要： The receptor interacting protein kinase 3 (RIPK3) is the main player in the activation of necroptosis, a pro-inflammatory regulated cell death modality induced by many different stimuli. RIPK3 is epigenetically regulated by DNA methylation and can be expressed when its promoter is associated with H3K4me3 histone. In this study, we show that Transglutaminase 2 protein (TG2) is necessary to induce necroptosis pathway allowing the expression of Ripk3 gene. Indeed, cells lacking TG2 show a strong downregulation of Ripk3 gene and are resistant to necroptotic stimuli. TG2 is known to promote the serotonylation of H3K4me3 histone (H3K4me3Q5ser) regulating in this way the target gene expression. Interestingly, we find that TG2 interacts with both histones H3K4me3 and H3K4me3Q5ser and these post-translational modifications are associated with the Ripk3 promoter only in presence of TG2. In addition, the absence of the H3K4me3Q5ser, in cells lacking TG2, is correlated with Ripk3 gene methylation. Altogether, these results indicate that RIPK3 expression requires TG2 mediated serotonylation of H3K4me3 to prevent Ripk3 promoter methylation, thus favouring its expression and necroptosis induction.

摘要： Interleukin-1 (IL-1)/IL-1 receptor family consists of activators and inhibitors which play a key role in inflammation, emergency myelopoiesis, and myeloid cell activation. The latter includes the IL-1R2 decoy receptor. To investigate the expression and significance of IL-1R2 in sepsis, we conducted high-dimensional flow cytometry of circulating cells from patients stratified according to the Sequential Sepsis-Related Organ Failure Assessment (SOFA) score. Here we report that the IL-1 decoy receptor is selectively upregulated on the plasma membrane of leukocytes and, in particular, monocytes from septic patients, and downregulated in septic shock. Flow cytometry combined with transcriptomic analysis of publicly available datasets indicated that IL-1R2 is associated with the differentiation of monocytes to a population of circulating monocytic cells with macrophage features (Mono/M phi). In vitro stimulation of monocytes from healthy donors with Colony Stimulating Factors (CSFs), in particular GM-CSF and Lipopolysaccharides (LPS), induced IL-1R2+ Mono/M phi, which recapitulated the characteristics of sepsis-associated monocytic cells, including low expression of HLA-DR, high levels of macrophage markers such as MS4A4A and CD63, immune checkpoints, immunosuppressive molecules and selected scavenger receptors. Membrane-associated IL-1R2 and MS4A4A correlated with immunological markers, cytokine storm, and clinical parameters (e.g., SOFA score, creatinine, survival), reflecting the infection severity in hospitalized ***, in sepsis IL-1R2 is expressed in a subset of circulating monocytes co-expressing mature macrophage and immune dysfunction features with clinical significance.

关键词： anastomotic leakage   rectal cancer   IL-17   intraoperative hypothermia   risk factor  

摘要： Objective: In this prospective observational cohort study, we aim to investigate the risk factors for early postoperative anastomotic leakage (AL) in patients undergoing rectal cancer resection. Methods:This study included 459 patients with rectal cancer who underwent treatment at our hospital from January 2021 to October 2022. All patients were hospitalized for 1 week postoperatively and observed for the occurrence of AL. Fasting venous blood samples (5 mL) were collected from all cases 1 day before surgery and 1, 2, and 3 days after surgery, and serum levels of interleukins (IL)-17, IL-6, IL-1 beta, tumor necrosis factor-alpha, and C-reactive protein (CRP) were determined using enzyme-linked immunosorbent assay. Demographic, clinical data, intraoperative hypothermia, and nutritional indicators were collected for all patients. Statistical analysis was performed using SPSS 25.0 software. Results: AL patients had significantly lower hemoglobin, albumin (ALB) levels, and a higher proportion of intraoperative hypothermia compared to patients in the non-AL group (P < .05). On the first, second, and third days after surgery, patients in the AL group had significantly higher levels of serum CRP, IL-1 beta, and IL-17 compared to the non-AL group. Pearson's correlation analysis showed a positive correlation between serum IL-17 levels and CRP levels. Serum IL-17 had the highest predictive value for early AL, with an area under the curve (AUC) of 0.755 cutoff value of 94.77 pg/mL, a sensitivity of 70.1%, and a specificity of 66.0%. Moreover, logistic regression analysis indicated that intraoperative hypothermia, decreased ALB levels, and increased CRP, IL-1 beta, and IL-17 levels on the first day after surgery were identified as risk factors for early AL in rectal cancer patients. Conclusions:This study found a significant elevation of IL-17 levels in the serum of patients who experienced early postoperative AL. Furthermore, intraoperative hypothermia and elevated IL-17 level

关键词： Flash nanocomplexation   Flash nanoprecipitation   TNF-alpha antibody   Sustained release   Hyaluronic acid hydrogel   Long-acting injectable   Inflammatory bowel disease   Chronic colitis  

摘要： Inflammatory bowel diseases (IBD) are chronic, remitting, and relapsing conditions of the gastrointestinal tract with incompletely elucidated etiology. The anti-TNF-alpha mAbs represent one of aflash nanocomplexation and flash nanoprecipitation process, resulting in particles with a narrow size distribution and tunable release profile, with the longest in vitro release lasting over four months. These mAb-releasing NPs are then incorporated into hyaluronic acid hydrogel microparticles (MPs) to enhance tissue retention, thus extending the duration of mAb release in vivo. A single i.m. injection of the LAI can maintain the serum mAb level above the therapeutically effective concentration for over 100 days in healthy mice. In a 9-week study using a dextran sulfate-induced chronic colitis model, the anti-TNF-alpha LAI formulation demonstrates substantial therapeutic efficacy and a better safety profile than free mAb injections. This work demonstrates the effectiveness of this LAI system in maintaining a persistent serum mAb level and its potential as a versatile, safer, and effective delivery system for antibody therapeutics.

摘要： BACKGROUND:Hantavirus causes hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Strong inflammatory responses and vascular leakage are important hallmarks of these often fatal diseases. The mechanism behind pathogenesis is unknown and no specific treatment is available. IL-6 was recently highlighted as a biomarker for HPS/HFRS severity. IL-6 signaling is complex and context dependent: while classical signaling generally provide protective responses, trans-signaling can cause severe pathogenic responses. Here, we investigated a potential role for IL-6 trans-signaling in hantavirus pathogenesis. METHODS:Effects of IL-6 trans-signaling during in vitro hantavirus infection were assessed using primary human endothelial cells treated with recombinant soluble IL-6 receptor (sIL-6R). Plasma from Puumala orthohantavirus-infected HFRS patients (n=28) were analyzed for IL-6 trans-signaling potential and its associations to severity. FINDINGS:In vitro, sIL-6R treatment of infected cells enhanced IL-6 and CCL2 secretion, upregulated ICAM-1, and affected VE-cadherin leading to a disrupted cell barrier integrity. HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R/sgp130 ratio suggesting enhanced IL-6 trans-signaling potential. Plasma sgp130 levels negatively correlated with number of interventions and positively with albumin levels. Patients receiving oxygen treatment displayed a higher sIL-6R/sgp130 ratio compared to patients that did not. INTERPRETATION:IL-6 trans-signaling is linked to hantavirus pathogenesis. Targeting IL-6 trans-signaling might provide a therapeutic strategy for treatment of severe HFRS and perhaps also HPS.