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关键词： Yinchen   Quercetin   Interleukin   STAT3 activation   Immune hemolysis   Network pharmacology   Bioinformatics  

摘要： Yinchen (YC), the dried aerial parts of the medicinal plant Artemisia capillaris Thunb. (family Asteraceae), is primarily distributed across the Asia-Pacific Region. Although YC exhibits clinically validated efficacy against immune hemolytic disorders, its mechanistic underpinnings remain insufficiently elucidated in pharmacological research. This study investigates the potential targets and mechanisms of YC in treating immune hemolysis based on network pharmacology and bioinformatic analysis. Additionally, it aims to verify quercetin's anticomplement activity and inhibition of IL-6-induced STAT3 activation, a key component of YC, through in vitro experiments, molecular docking and molecular dynamics simulations. 13 active components in YC with 143 putative targets were identified by Network pharmacology. Quercetin, beta-sitosterol, and isorhamnetin were top-ranked by target count. 1231 gene targets related to immune hemolysis, with 60 overlapping targets mapping to both YC and the disease were identified. Quercetin exhibited inhibitory activity against both classical and alternative complement pathways, with IC50 values of 528.3 mg/L and 212.5 mg/L, respectively. Quercetin (80 mu M) suppressed IL-6-induced IgG secretion and attenuated STAT3 signaling in murine splenic lymphocytes, as evidenced by decreased levels of STAT3 mRNA expression, STAT3 and phosphorylated STAT3 (p-STAT3) proteins. Molecular docking analysis revealed quercetin's putative binding affinity to key complement system components (C1, C2, C3, C4, C5, C8, C9, Factor B) and IL-6, suggesting a dual mechanism of complement pathway modulation and IL-6/IL-6R interaction blockade. Simulation studies confirmed the stable interaction between C1s, C3, C5 and IL-6 and quercetin. Quercetin, a key component of Yinchen used in treating immune hemolysis, demonstrates anti-complement activity and can inhibit IL-6-induced STAT3 activation in vitro.

关键词： osteoarthritis   chondrocytes   IL-1 beta   LITAF   miR-450a-5p   CHON-001  

摘要： Objective. Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, causing severe pain and disability. Recent studies suggest that miR-450a-5p may regulate inflammatory pathways in OA. This study aimed to elucidate the role of miR-450a-5p in OA, providing a potential therapeutic target for the clinical treatment. Methods. Cartilage tissues were collected from OA patients undergoing knee replacement surgery, and CHON-001 cells were treated with interleukin (IL)-1 beta to induce an OA model in vitro. Real-time quantitative polymerase chain reaction was used to detect the miR-450a-5p expression, and Western blot determined the lipopolysaccharide-induced tumor necrosis factor (TNF)-alpha factor (LITAF) expression. The targeting relationship between LITAF and miR-450a-5p was verified by dual-luciferase reporter assay. Cell proliferation and apoptosis were assessed using the Cell Counting Kit-8 assay and flow cytometry, respectively. Levels of IL-6, IL-10, and TNF-alpha were measured via enzyme-linked immunosorbent assay. In addition, Western blot was employed to detect the expressions of matrix metalloproteinase-3 (MMP-3), collagen III, and aggrecan in extracellular matrix (ECM). Results. MiR-450a-5p expression was significantly down-regulated in OA tissues and IL-1 beta-induced CHON-001 cells (similar to 60%), while LITAF expression was markedly increased (similar to 1.8-fold). There was a negative correlation between miR-450a-5p and LITAF in OA tissues (r = -0.596, P < 0.01). MiR-450a-5p directly targeted and inhibited LITAF expression. Its overexpression promoted chondrocyte proliferation, reduced apoptosis and inflammatory cytokines, and mitigated ECM degradation. Conclusions. MiR-450a-5p inhibited LITAF expression, thereby attenuating apoptosis, inflammation, and ECM degradation in chondrocytes. It may serve as a promising therapeutic target for OA.

关键词： Oncolytic virus   Melanoma   Sarcoma   Head and Neck Cancer  

摘要： Background SKV-012 is a novel engineered oncolytic virus (containing the viral neurovirulence ICP34.5 gene transcribed by the Survivin promoter with an upstream genetic component of interleukin-12 (IL-12) driven by the cytomegalovirus promoter) that preferentially replicates in tumors and helps stimulate antitumor immune *** We evaluated SKV-012's safety and efficacy in preclinical models. In a phase I trial, patients with advanced solid tumors received intratumoral injections of escalating doses of SKV-012. Primary endpoints were safety and tolerability, while secondary endpoints were antitumor response and changes in the tumor microenvironment (TME), assessed by RECIST v1.1 criteria and multiplex immunohistochemistry and single-cell transcriptome *** SKV-012-infected tumor cells secreted high levels of IL-12 and exhibited increased ICP34.5 expression. The combination of oncolytic herpesvirus and IL-12 was proven to reshape the TME by increasing the infiltration of immune cells, thereby significantly inducing immune cell-mediated cytolysis of tumor cells both in vitro and in animal models. Based on this, we then tested the safety, efficacy and immunogenicity of SKV-012 in patients with advanced solid cancers in a phase I clinical trial (NCT06080984). No dose-limiting toxicities were observed, and adverse events were mild. Three patients achieved partial responses;one had stable disease and two had progressive disease. SKV-012 altered the TME, increasing CD8+ T cells, conventional dendritic cells, and programmed death-ligand 1 *** Intratumoral SKV-012 injections demonstrated a favorable safety profile and promising efficacy in animal models and patients with advanced cancers, thereby implicating its potential for clinical application in treatment-resistant advanced solid tumors.

关键词： ankylosing spondylitis   tenascin C   BASDAI   disease activity  

摘要： Background/Objectives: Ankylosing spondylitis (AS) is a severe chronic inflammatory rheumatic disease involving the spine, sacroiliacs, and peripheral joints. A lack of therapeutic response leads to severe sequelae. Currently, new markers are being tested to identify patients with poor outcomes. Tenascin C (TNC) is involved in triggering some relevant mechanisms of inflammation. Today, it remains unclear whether TNC levels might be useful as a biomarker of persistent activity. The aim of this study was to evaluate in AS whether serum levels of tenascin C are associated with persistent disease activity despite treatment. Methods: We included AS patients who had been treated with conventional synthetic disease-modifying antirheumatic drugs (cs-DMARDS) or anti-TNF agents for at least three months in a cross-sectional study. Response was assessed with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI);scores >= 4 indicate persistent disease activity, while scores < 4 indicate inactive disease. Serum TNC levels, C-reactive protein (CRP) levels, and Erythrocyte Sedimentation Rate (ESR) were determined through the ELISA technique, nephelometry, and the Westergren method, respectively. Results: We evaluated 58 patients with AS (62.1% men);of them, 33 (56.9%) had persistent active disease (BASDAI >= 4) despite treatment and 25 (43.1%) had inactive disease (BASDAI < 4). The median TNC level was 18.6 ng/mL. BASDAI correlated with TNC levels (rho: 0.528, p < 0.001), CRP (0.352, p = 0.007), and ESR (0.342, p = 0.009). Patients with persistently active AS had higher serum TNC levels than those with inactive AS (35.2 vs. 6 ng/mL, p < 0.001). No differences in TNC level were found in patients treated with cs-DMARDS vs. anti-TNF agents. The ROC curve for serum tenascin C in active AS patients had an area under the curve = 0.78 (CI 95%: 0.65-0.91) with optimal serum tenascin C cutoff (>13.85 ng/mL). Sensitivity for detecting active AS was higher with TNC compared to ESR

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： italic>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.