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关键词： Allergic asthma   Th2   BCG   IL-12   Recombinant BCG   Therapeutic strategy  

摘要： Allergic asthma is a chronic respiratory disorder driven by a T helper type 2 (Th2)-mediated immune response that involves eosinophils and mast cell recruitment to affected tissues, eliciting inflammatory cytokines and IgE production. Typical symptoms in more severe cases include wheezing, shortness of breath, chest tightness, persistent coughing, excessive mucus production, and airway hyperresponsiveness. Current therapies, which focus on suppressing the immune system, mitigate the symptoms but are generally insufficient to address the disease. Mycobacterium bovis bacillus Calmette-Gu & eacute;rin (BCG) platform, initially developed as an attenuated vaccine for tuberculosis (TB), induces a potent T helper type 1 (Th1) polarized immune response, making it a promising candidate for treating Th2-dominant conditions, such as allergic asthma, ultimately alleviating the symptoms. BCG can be genetically modified to express antigens of other pathogens or immunogenic proteins, such as IL-12p70. In this review, we examine the potential of BCG as a novel therapeutic platform for allergic asthma, focusing on its ability to modulate the immune response via IL-12.

摘要： Background:Inflammasome activation promotes atherosclerosis in clonal hematopoiesis (CH). Active inflammasomes secrete both IL-1β and IL-18. Plasma IL-18 levels are elevated in CH. Genetic deficiency of IL-18 has been shown to reduce atherosclerosis in non-CH murine models. However, whether IL-18 inhibition promotes atherosclerosis in control or CH is unknown. Methods and results:mice were transplanted with bone marrow (BM) from (20%) and wild-type (80%) mice or with control BM, fed a Western-type diet (WTD) for 8, 10 or 16 weeks and administered control or IL-18 IgG from 4 weeks onwards. IL-18 antibody treatment increased plaque collagen content and cap thickness. Unexpectedly, IL-18 antibody treatment increased the size of early lesions and promoted formation of advanced lesions with large necrotic cores in CH mice. IL-18 antibody treatment was associated with diminished interferon (IFN)-γ and AIM2 levels and reduced macrophage pyroptosis especially in CH mice. However, IL-18 antibodies increased cleaved Caspase-3 and TUNEL macrophages (indicating increased apoptosis) and reduced efferocytosis. Sc-RNA-seq analysis showed that IL-18 antibody treatment reduced expression of genes, a marker of IFN-γ signaling, and of genes mediating efferocytosis ( , in resident-like macrophage subpopulations in CH mice. Consistently, IFN-γ injection increased and expression in resident peritoneal macrophages. Conclusions:Despite improvements in collagen and fibrous cap thickness in CH mice, IL-18 antibody treatment increased advanced necrotic lesions, reflecting a shift from pyroptotic to apoptotic cell death coupled with defective efferocytosis, events which were coordinated by reduced IFN-γ signaling. These findings indicate a mixed atherosclerosis phenotype resulting from IL-18 inhibition, advocating for alternative therapeutic strategies. Inhibition of IL-18 has been considered as a novel therapeutic approach to reduce atherosclerosis and stabilize atherosclerotic pl

关键词： Legionella pneumophila   Legionnaires' Disease   neutrophils   neutrophil extracellular traps   NETs   IL-1beta  

摘要： Introduction Legionella pneumophila is the causative agent of Legionnaires' Disease (LD), an atypical pneumonia with potentially fatal outcome. Neutrophils, the first line of defense, infiltrate the lungs during L. pneumophila infection, although the precise immune mechanisms involved remain *** This study aims to examine in vitro the interaction of neutrophils with L. pneumophila. Neutrophils from healthy individuals were infected with opsonized and non-opsonized bacteria. Phagocytosis was assessed by immunolabeling, and reactive oxygen species (ROS) generation by flow cytometry. The ability of neutrophils to form Neutrophil Extracellular Traps (NETs) in response to L. pneumophila and the impact of these NETs on bacterial proliferation were examined. Immunolabeling and Western blotting were used for specific NET-associated epitope *** It was demonstrated that neutrophils phagocytose opsonized L. pneumophila, while non-opsonized bacteria were not phagocytosed. Opsonized bacteria triggered ROS production, unlike non-opsonized bacteria. Neutrophils released NETs upon L. pneumophila interaction in a ROS-independent manner, but these NETs failed to inhibit bacterial proliferation. Notably, IL-1b was detected on *** This study provides evidence that neutrophils react to L. pneumophila through phagocytosis, the production of ROS, and NET release. IL-1b on NETs could play a role in complicated LD cases. These findings contribute to the understanding of neutrophil-mediated immune responses in LD.

关键词： 炎癌转化   中药   癌性疼痛   炎症因子   临床研究  

摘要： 目的:基于炎癌转化探讨癌瘤外敷方联合定向透药治疗癌痛的疗效及对血清IL-6、TNF-α的影响。方法：将符合纳入标准的60例患者随机分成对照组及观察组，各30例。对照组予盐酸羟考酮缓释片口服，观察组在对照组基础上加用癌瘤外敷方联合中医定向透药，比较2组患者总有效率、止痛起效及持续时间、NRS评分、QLQ-C30生活质量评分和血清IL-6、TNF-α变化。结果：治疗结束后对照组总有效率86.67%，观察组总有效率93.33%，差异有统计学意义（P＜0.05）；观察组的止痛起效时间与持续时间均优于对照组（P＜0.05）；2组患者治疗后NRS评分、QLQ-C30生活质量评分及血清IL-6、TNF-α水平均较治疗前改善（P＜0.05），且改善程度观察组优于对照组（P＜0.05）。结论：癌瘤外敷方联合中医定向透药能有效缩短药物起效时间、延长持续时间，并能缓解患者腹痛症状、改善生活质量、降低血清IL-6、TNF-α水平。

关键词： sepsis   immune response   inflammation   NF kappa B signaling   biomarkers   therapeutic targets  

摘要： Sepsis is a life-threatening condition characterized by systemic inflammation and organ dysfunction, with a complex and not yet fully elucidated molecular basis. Central to its pathogenesis is a dysregulated immune response. In this study, we performed a comprehensive multi-omics analysis on transcriptomic datasets retrieved from the GEO database, including samples from sepsis patients (n = 23) and healthy controls (n = 27). and identified a pivotal role of Interleukin-1 receptor 2 (IL-1R2) in modulating inflammatory responses in sepsis. Transcriptomic integration revealed activation of critical signaling pathways, including NF kappa B/NLRP3, associated with sepsis-induced immune dysregulation. We identified a pivotal role of Interleukin-1 receptor 2 (IL-1R2) in modulating inflammatory responses in sepsis, with IL-1R2 showing a 2.1-fold upregulation in septic patients. Transcriptomic integration revealed the activation of 42 significantly enriched signaling pathways, with 26 upregulated and 26 downregulated pathways. Notably, the NF kappa B/NLRP3 signaling axis emerged as a central hub of immune dysregulation. Gene Ontology (GO) enrichment analysis highlighted "neutrophil activation involved in immune response" as the top biological process. Our findings suggest that IL-1R2 functions as a key immunoregulatory molecule and represents a promising therapeutic target. Moreover, we observed distinct patterns of oxidative stress regulation and immune cell activation, with potential biomarkers correlating with disease severity. These insights not only enhance the molecular understanding of sepsis but also point toward novel precision therapeutic strategies focused on modulating inflammation to improve patient outcomes.

关键词： Metabolic dysfunction-associated steatohepatitis   Hepatic stellate cells   Hepatocellular carcinoma   Protein kinase R-like endoplasmic reticulum kinase   Interleukin-1 beta  

摘要： Palmitic acid (PA) absorption from the intestine is increased in metabolic dysfunction-associated steatohepatitis (MASH). It induces endoplasmic reticulum (ER) stress and interleukin-1 beta (IL-1 beta) production in hepatic stellate cells (HSCs). Protein kinase R-like endoplasmic reticulum kinase (PERK) is an ER stress sensor protein involved in HSC activation and liver fibrosis. However, its role in HSCs during hepatocellular carcinoma (HCC) progression remains unclear. This study clarified the process of IL-1 beta production via PERK in HSCs and explored the mechanism underlying MASH-related HCC progression. HSCs were treated with PA or transfected with PERK small-interfering RNA (siRNA) or PERK plasmid. Proliferation, scratch, and Transwell assays were performed on HCC cells cultured in the conditioned medium (CM) from HSCs. PA treatment increased PERK and IL-1 beta expression in HSCs. PERK knockdown decreased IL-1 beta expression, while its overexpression increased it in HSCs. The CM from PA-treated HSCs showed elevated IL-1 beta levels and enhanced HCC cells' proliferation, migration, and invasion;however, these effects were suppressed by PERK knockdown in HSCs. RNA-sequencing analysis revealed that p38 delta mitogen-activated protein kinase (MAPK) is the intermediate molecule between PERK and IL-1 beta in HSCs. In the tumor microenvironment of MASH-related HCC, PERK in HSCs promotes HCC progression via the p38 delta MAPK/IL-1 beta axis.

摘要： Accurate prediction of symptomatic radiation therapy-induced pneumonitis (RT-IP) remains an important clinical challenge. Currently, mean lung dose and volume of the lungs receiving a 20 Gy threshold of ≤20 Gy and ≤35%, respectively, are utilized to reduce the incidence of pneumonitis to 20%. However, its occurrence is not entirely predictable even at the recommended threshold levels. Hence, in this study, we aimed to evaluate several biological markers, specifically chromosome aberrations by peptide nucleic acid fluorescence in situ hybridization (PNA-FISH), γH2AX, serum IL-6, and IL-17, as potential predictors of symptomatic (grade ≥2) radiation therapy-induced pneumonitis. We prospectively enrolled patients with locally advanced lung cancer. Peripheral blood samples were collected from eleven patients before, during (2 Gy, 20 Gy, 60/66 Gy), and one month after chemoradiotherapy. We then compared these biomarkers between overreactors (grade ≥2 RT-IP) and non-overreactors (grade 0 to 1 RT-IP). Our findings show that chromosome aberration frequency, serum IL-6, and IL-17 after 20 Gy are higher in overreactors than in non-overreactors. Moreover, overreactors accumulated more complex aberrations, such as tricentrics, quadricentrics, and quintacentrics. While chromosome aberration frequency correlated with mean lung dose and IL-17, a pneumonitis marker, IL-6 correlated with the irradiated volume after 20 Gy. Receiver operating characteristic curve analysis further showed that chromosome aberration frequency and IL-6 have the highest specificity for predicting grade ≥2 RT-IP among the assays. In conclusion, we demonstrated the superior predictive capability of PNA-FISH-based chromosome aberration frequency and serum IL-6 for radiation therapy-induced pneumonitis in lung cancer patients. This supports the usefulness of these biomarkers for predicting radiation therapy-induced pneumonitis.

关键词： Immune Checkpoint Inhibitor   Head and Neck Cancer   Macrophage   JAK-STAT   Immunotherapy  

摘要： Background Immune checkpoint blockade therapy has shown limited efficacy in head and neck squamous cell carcinoma (HNSCC). Sialic acid binding immunoglobulin-like lectin (Siglec)-15 has been identified as a novel immune evasion biomarker, while the role of Siglec-10 in the specific immune suppressive tumor microenvironment remains largely *** Immunohistochemical assays were employed to investigate the correlation of the expressions of Siglec-10 and Siglec-15 with the clinicopathological features as well as the prognosis of immunotherapy in patients with HNSCC. The Gene Expression Omnibus datasets were used to identify the upstream transcriptional regulators of SIGLEC10 in tumor-associated macrophages (TAMs) and the downstream biological functions it mediates. These findings were then validated through in vitro and in vivo experiments. The impact of Siglecg deficiency on the efficacy of immunotherapy and the activation of CD8+T cells was analyzed in mouse HNSCC tumor-bearing *** The expression of Siglec-G/10, rather than that of Siglec-15, was positively correlated with immune suppressive marker programmed death-ligand 1 (PD-L1) expression and was associated with cervical lymph node metastasis, poorer pathologic stage, and lower sensitivity to immunotherapy. Siglecg deficiency rescued the immune suppressive tumor microenvironment, as evidenced by decreased TAM-associated phenotype and increased CD8+T cell infiltration and activation, which inhibited tumor growth significantly. Single-cell sequence and transcription factor prediction revealed that signal transducer and activator of transcription 6 (STAT6) could induce Siglec-G/10 transcription. Interleukin (IL)-4 could upregulate Siglec-G/10 expression significantly via STAT6 activation, as proved by overexpression and inhibition of STAT6. Signal transduction mechanism revealed that Siglec-G/10 could promote TAM differentiation and activation via increasing HIF1 alpha (hypoxia-inducible factor 1

关键词： N6-methyladenosine (m(6)A)   epitranscriptome   RNA methylation   STEMI   inflammation   tocilizumab  

摘要： Background Epitranscriptomics, with m6A as the most prevalent in mammals, is a novel treatment target for inflammatory diseases, including cardiovascular diseases. However, little is known about m6A RNA-regulation during myocardial infarction (MI). Methods In this explorative sub-study of the ASSAIL-MI trial, we used whole blood samples from patients with acute ST-elevation MI (STEMI) (n=6) at admission and after 3-7 days, and from healthy control subjects (n=3). RNA was isolated, and m6A sites were analyzed using human m6A single nucleotide resolution microarray analysis. mRNA levels were analyzed using RNA sequencing analysis. Results Compared with controls, patients with STEMI had a strikingly different pattern of m6A deposition. In total, 845 m6A methylation sites in whole blood RNA were hypomethylated and 36 were hypermethylated compared with controls. Of the hypomethylated transcripts, 194 transcripts were lower expressed, while 197 transcripts were higher expressed. The m6A pattern changed from an overall hypomethylation at admission to an overall hypermethylation 3-7 day after admission. Anti-inflammatory treatment with tocilizumab further altered the m6A deposition. Conclusions In this hypothesis generating study, m6A deposition differs STEMI patients and healthy controls. The m6A pattern changes over the course of 3-7 days. This response is, at least to some degree, is modulated by blocking the IL-6 receptor. Our data may suggest that this post-transcriptional regulation of RNA is involved in the immune response during STEMI, highlighting its potential as a target for therapy in MI.

关键词： terpinen-4-ol   HepG2   network pharmacology   HIF-1 alpha   TGF-beta 1   IL-6  

摘要： Background and Objective: Alcoholic liver disease (ALD) is a major health burden caused by chronic alcohol consumption, leading to oxidative stress, inflammation, and fibrosis. Current treatments are limited, highlighting the need for novel therapeutic agents. This study investigated the hepatoprotective effects of 'Terpinen-4-ol (T4OL)', a natural monoterpene from tea tree oil, against ethanol-induced liver injury, focusing on its molecular and cellular mechanisms. Materials and Methods: Network pharmacology and molecular docking were employed to predict T4OL's interaction with ALD-associated targets. Human HepG2 cells were used to validate the in silico findings. Cells were exposed to ethanol (8%) prior to treatment with T4OL or silymarin (SIL), and cytotoxicity was assessed through MTT, crystal violet, and trypan blue assays. Moreover, ELISA and qPCR were conducted to evaluate antioxidant, inflammatory, and fibrotic markers. Results: Network pharmacology analysis suggested that T4OL exerts its hepatoprotective effects by suppressing inflammatory and fibrotic mediators (HIF-1 alpha, TGF-beta 1, and TNF-alpha). Docking studies also exhibited a strong binding affinity of T4OL to key ALD targets, with docking scores comparable to SIL. In addition, T4OL (13-1300 mu M) dose-dependently protected HepG2 cells from ethanol-induced damage, restoring viability by up to 80% at 650 mu M. It significantly elevated antioxidant levels (GSH by 2.5-fold, SOD by 1.8-fold) and suppressed pro-inflammatory and fibrotic markers (IL-6, COL1A1, TIMP-1) by 40-60%. At higher concentrations (650-1300 mu M), T4OL outperformed SIL in cytoprotection and anti-fibrotic effects. Conclusions: T4OL mitigates ethanol-induced liver injury by targeting oxidative stress, inflammation, and fibrosis pathways, demonstrating superior efficacy to SIL at optimal doses. Its multi-target action supports its potential as a therapeutic candidate for ALD.