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关键词： Non-small cell lung cancer   Ferroptosis   FEZF1-AS1   TNF-alpha   NF-kappa B  

摘要： ObjectiveThe purpose of this research was to examine the impact of FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) on ferroptosis regulation in non-small cell lung cancer (NSCLC) cells and to understand its molecular *** effects of FEZF1-AS1 silencing on NSCLC cell proliferation, invasion, migration, and apoptosis were evaluated through functional assays, utilizing the Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, flow cytometry, and Transwell assays. The levels of cellular reactive oxygen species, malondialdehyde, glutathione, and Fe2+ were measured using commercial assay kits. Proteins related to ferroptosis and the tumor necrosis factor-alpha (TNF-alpha)/nuclear factor-kappa B (NF-kappa B) axis were analyzed using Western blot. Finally, rescue experiments were carried out by treating the cells with ***1-AS1 expression was significantly upregulated in NSCLC cells. Moreover, FEZF1-AS1 silencing suppressed proliferation, migration, and invasion, while enhancing ferroptosis sensitivity in NSCLC cell lines. This knockdown also inhibited the TNF-alpha/NF-kappa B pathway. TNF-alpha attenuated both pro-ferroptotic and anti-tumor effects of FEZF1-AS1 silencing in NSCLC cells. Mechanistically, knockdown of FEZF1-AS1 modulates ferroptosis and malignant behaviors in NSCLC cells through suppression of the TNF-alpha/NF-kappa B *** study uncovers a previously unrecognized mechanistic axis in which FEZF1-AS1 promotes NSCLC progression through suppressing ferroptosis by activating the TNF-alpha/NF-kappa B axis.

关键词： SpyCatcher-SpyTag system   PEGylation   Outer membrane vesicles, Pyroptosis   IL-1Ra   IL-1Ra  

摘要： Mortality resulting from sepsis is highly associated with secondary acute lung injury, and although the gut-lung axis is of significant importance, treatment strategies leveraging this understanding remains limited. Here, we developed an Escherichia coli strain named Delta PESI that highly expresses IL-1Ra via outer membrane vesicles (OMVs) and PEGylated this strain through the SpyCatcher-SpyTag system for enhanced activity and colonization. Oral administration of Delta PESI reinforces epithelial barrier integrity in the gut, inhibits inflammatory cascade in the peripheral circulation, modulates macrophage polarization and pyroptosis in the lung, thereby significantly mitigating the dysregulated systemic inflammatory response. Furthermore, Delta PESI exhibits favorable biosafety characteristics, thus demonstrating strong potential for clinical translation. Hence, this study proposes a promising strategy for the oral administration of engineered probiotics to effectively alleviate intestinal and pulmonary inflammatory responses through modulation of the gut-lung crosstalk.

摘要： PURPOSE:Immune checkpoint inhibitors (ICI) have increasing application in endometrial cancer, underscoring the need for robust biomarkers for patient selection. JAK1 pathogenic variants (PV) have previously been implicated in immune evasion. Here, we identify biomarkers predictive of ICI response in endometrial cancer and the implications of JAK1 PV in this context. EXPERIMENTAL DESIGN:This is a translational study of tumors from 84 endometrial cancer patients treated with ICI. High-throughput proteomic-based profiling was used to quantify 193 phospho-/protein expression levels, including key JAK/STAT signaling pathway components. Associations with clinical outcomes were assessed using multivariate regression analysis. The functional consequences of JAK1 PV were explored through in vitro signaling assays and analyses of TCGA database. RESULTS:MHC-I expression correlated with improved progression-free survival (p = 0.035), validated in orthogonal approaches. Notably, a subset of patients harboring JAK1 PVs demonstrated exceptional survival on ICI. In TCGA cohort of microsatellite instability-high (MSI-H) and DNA polymerase epsilon (POLE)-mutated tumors, homozygous loss of JAK1 (JAK1Hom) trended toward decreased survival, whereas heterozygous loss of JAK1 (JAK1Het) was associated with significantly improved survival (p = 0.026), suggesting partial retention of antigen presentation pathways. Among our ICI-treated MSI-H tumor samples, NK cell marker NCAM1 was associated with improved survival (p=0.02). CONCLUSIONS:These data support MHC-I as a potential predictive biomarker for ICI response in endometrial cancer. Additionally, we show that partial retention of JAK1 signaling in JAK1Het tumors is associated with improved survival, potentially attributable to enhanced NK cell activity in tumors with low MHC-I expression.

关键词： Tanshinone IIA   Type 2 diabetes mellitus   Beta-cell dysfunction   Bioinformatics   Inflammation   Endoplasmic reticulum stress  

摘要： Type 2 diabetes mellitus (T2DM) is a severe metabolic disorder in which pancreatic injury plays a pivotal role in disease progression. Tanshinone IIA (TanIIA), a bioactive compound extracted from Salvia miltiorrhiza, has shown therapeutic potential in diabetes management. However, its protective effects on pancreatic injury and underlying pharmacological mechanisms remain unclear. In this study, TanIIA significantly reduced fasting blood glucose, improved insulin resistance, and alleviated islet structural damage and beta-cell apoptosis. Potential TanIIA targets were initially predicted through integrated network pharmacology, weighted gene co-expression network analysis (WGCNA), and differential gene expression analysis. Based on these integrated data, five machine learning algorithms were applied to identify candidate targets. PTGS2, NR4A2, MGLL, GABRA2, and IL-6 were determined to be core targets and were validated by qRT-PCR, with functional enrichment indicating that the JAK-STAT pathway is a key regulatory axis. Molecular docking revealed strong binding affinities between TanIIA and these core targets, with calculated binding energies of -8.7 (PTGS2), -7.6 (NR4A2), -9.8 (MGLL), -8.3 (GABRA2), and - 7.5 (IL-6) kcal/mol. Furthermore, molecular dynamics simulations confirmed the stable interaction between TanIIA and IL-6. In vivo experiments further demonstrated that TanIIA modulated the IL-6/JAK2/STAT3 pathway In vivo experiments further demonstrated that TanIIA modulated the IL-6/JAK2/STAT3 pathway, suppressed proinflammatory cytokines, promoted anti-inflammatory IL-10 expression, and regulated macrophage polarization, thereby improving the inflammatory microenvironment in islets. Additionally, TanIIA activated the PI3K-AKT pathway, alleviated glucolipotoxicity-induced endoplasmic reticulum (ER) stress, and downregulated ER stress-related proteins including p-IRE1 alpha, GRP78, XBP1s, and CHOP, ultimately inhibiting beta-cell apoptosis. Collectively, these find

摘要： Herpes simplex encephalitis (HSE) is a devastating disease with high mortality and serious sequelae. Genetic defects in the IFN-I pathway predispose individuals to HSE, but underlying mechanisms remain unclear. Using transgenic mice with the IRF3 R278Q mutation, ortholog to HSE-associated IRF3 R285Q, and iPSC-derived CNS cells from a pediatric patient carrying the variant, we investigated mechanisms in HSE. IRF3 R278Q transgenic mice exhibited aggravated HSV-1 brain disease and elevated CNS viral loads. Accordingly, microglia from the IRF3 R278Q mice showed reduced HSV-1-induced IFN-I expression. Surprisingly, unaltered Ifnb levels along with elevated levels of inflammatory cytokines were detected in infected transgenic mouse brains, correlating with higher viral load. This was successfully modeled in patient microglia. Multiomics-based immune profiling revealed an inflammatory monocyte population in the infected IRF3 R278Q mouse brain, which was enriched for NF-kappa B activation. NF-kappa B inhibition improved disease outcomes, surpassing the effect of acyclovir. These findings suggest that IFN-I defects lead to elevated levels of HSV-1 replication in the brain, which subsequently enables NF-kappa B-driven immunopathology, offering insights with therapeutic potential.

关键词： Thyroid eye disease   Satralizumab   Interleukin-6   Interleukin-6 receptor   Anti-interleukin-6 receptor  

摘要： IntroductionThyroid eye disease (TED) is a rare, autoimmune, orbital inflammatory disorder that is disfiguring, debilitating, and potentially sight-threatening. There is an unmet need for a fast-acting, durable, systemic disease-modifying therapy in active TED, for which current options are associated with relapses and side effects, and for chronic inactive TED, which is largely managed with surgery. Satralizumab is a recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody that prevents IL-6 from binding to its receptor, thereby reducing proinflammatory and profibrotic signaling. The SatraGO-1 and SatraGO-2 trials evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab in participants with active, moderate-to-severe, and chronic inactive ***-1 and SatraGO-2 were two identically designed, 72-week, double-masked, placebo-controlled, multicenter, two-stage randomization, phase 3 trials in adults with active, moderate-to-severe TED or chronic inactive TED. Participants were randomized 1:1 to receive satralizumab or matching placebo. Based on the proptosis response assessed at week 24, nonresponders received satralizumab every 4 weeks (Q4W), while responders were rerandomized in a 1:1 ratio to receive satralizumab or placebo Q4W through week 44. The primary end point was the proportion of participants with active, moderate-to-severe TED who achieved >= 2-mm reduction in proptosis in the study eye from baseline at week ***-1 and SatraGO-2 enrolled 131 and 127 participants, *** SatraGO-1 and SatraGO-2 trials investigated IL-6R inhibition via satralizumab in TED. Satralizumab offers a potential disease-modifying treatment option for TED while minimizing safety risks associated with current *** registration: SatraGO-1 (NCT05987423) and SatraGO-2 (NCT06106828).ConclusionsThe SatraGO-1 and SatraGO-2 trials investigated IL-6R inhibition via satralizumab in TED.

摘要： Aging-related neuroinflammation drives cognitive decline;however, the mechanisms by which gut microbiota-modulating bioactive compounds, such as rice bran peptide KF-8, mitigate this process remain unclear. Here, KF-8 was shown to ameliorate age-related traits in aged mice by reshaping gut microbiota, notably by stabilizing Akkermansia muciniphila (AKK), to suppress systemic inflammation and cognitive deficits. Specifically, antibiotic-treated mice receiving KF-8 exhibited neuroinflammation and declined cognition. KF-8 and AKK synergistically attenuated pro-inflammatory pathways, particularly TNF-alpha, in the blood and in the hippocampus. While TNF-alpha antibodies mirrored KF-8's benefits, TNF-alpha recombinant protein negated KF-8's protective effects. Combined KF-8 and AKK interventions aligned with TNF-alpha antibody outcomes, underscoring TNF-alpha's pivotal role. Our findings reveal that KF-8 enhances healthy aging by modulating gut microbiota, sustaining AKK, and suppressing TNF-alpha-driven neuroinflammation, thereby rescuing cognitive function in aged mice.

关键词： Adipose Tissue   Meal   Protein Turnover   Skeletal Muscle   Stable Isotopes   Tocilizumab  

摘要： CONTEXT:Sarcopenic obesity, the loss of muscle mass and function in people with obesity, may result from altered muscle protein synthesis and degradation. Chronic low-grade inflammation, particularly interleukin-6 (IL-6) has been implicated. OBJECTIVE:To assess the role of IL-6 in protein and amino acid metabolism during fasting and postprandial states in humans with healthy weight or obesity at whole-body, skeletal muscle and subcutaneous adipose tissue levels. METHODS:In this placebo-controlled, non-randomized, participant-blinded study, 12 men with healthy weight and 12 men with obesity received placebo (0.9% saline) or three weeks of IL-6 receptor (IL-6R) blockade with tocilizumab. Isotope dilution/incorporation techniques and arteriovenous balance measurements were applied in fasted and postprandial states. The trial was originally designed to examine IL-6 effects on fat storage (reported previously). Here, we present pre-specified exploratory outcomes on amino acid and protein turnover. RESULTS:Obesity was associated with reduced meal-induced muscle-protein gain driven by impaired suppression of muscle protein degradation, and with reduced appearance of amino acids from meals. In both groups, IL-6R blockade increased fasting and postprandial plasma amino acids, and reduced postprandial plasma protein synthesis without affecting skeletal muscle protein turnover. In the healthy weight group, it also increased amino acid appearance from the meal and postprandial phenylalanine oxidation. CONCLUSION:Obesity impairs meal-induced muscle-protein gain, through insufficient suppression of protein degradation. Basal IL-6 activity does not regulate muscle protein turnover but influences amino acid metabolism and protein synthesis in extra-muscular tissues.