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关键词： 加味散偏汤   偏头痛   网络药理学   白细胞介素-17/核转录因子-κB信号通路   作用机制  

摘要： 目的：基于网络药理学和动物实验探讨加味散偏汤干预白细胞介素-17 (IL-17) /核转录因子(NF)-κB（NF-κB）信号通路对大鼠偏头痛神经源性炎症反应的作用机制。方法：通过网络药理学获得加味散偏汤调控偏头痛的潜在靶点及信号通路，并将核心成分和核心靶点进行分子对接。动物实验通过腹腔注射硝酸甘油（NTG）构建大鼠偏头痛模型，随机分组后灌胃给药，连续观察大鼠造模后1 h内每30 min时间段挠头次数；酶联免疫吸附测定（ELISA）检测大鼠三叉神经脊束核尾核（TNC）组织IL-17、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、一氧化氮（NO）和降钙素基因相关肽（CGRP）等含量；实时荧光定量聚合酶链式反应（real-time PCR）检测大鼠TNC区IL-17和IL-6 mRNA表达；免疫组织化学（IHC）检测大鼠TNC组织CGRP表达；Western blot法检测大鼠TNC组织IL-17、NF-κB p65、pNF-κB p65蛋白表达。结果：网络药理学显示，共得到加味散偏汤治疗偏头痛的化合物47个，“成分-疾病”交集靶点147个，主要活性成分为槲皮素、山柰酚、β-谷甾醇、木犀草素、豆甾醇等，核心靶点主要有TNF、IL6、IL1B、IL17等，涉及生物过程主要包括对异生物刺激、凋亡、转录调节的反应；细胞组分主要涉及大分子复合物、细胞外区、膜筏等；分子功能主要涉及酶结合力、蛋白结合、细胞因子活性等。KEGG通路预测主要有糖尿病并发症晚期糖基化终末产物受体（AGE-RAGE）信号通路、IL-17信号通路、肿瘤坏死因子（TNF）信号通路等。以上靶点和化合物分子对接结合活性均小于-2.0 kJ/mol。动物实验显示，与正常对照组比较，模型对照组大鼠在0～30 min及30～60 min时间段挠头次数均显著升高( P<0. 01)，TNC区组织中IL-17、IL-6、TNF-α、NO和CGRP含量显著升高（P<0.01）；TNC区组织的IL-17和IL-6 mRNA表达显著上调（P<0.01），CGRP、IL-17、pNF-κB p65蛋白表达明显上调（P<0.05或P<0.01）；与模型对照组比较，受试药物组大鼠以上时间段挠头次数明显降低（P<0. 05），TNC区组织中CGRP、IL-6、TNF-α和NO含量明显降低（P<0.05或P<0.01），加味散偏汤12.96 g/kg组TNC区组织中IL-17含量明显降低（P<0.05）；除加味散偏汤3.24 g/kg组外，其余各给药组大鼠TNC区组织IL-17和IL-6 mRNA表达明显下调（P<0.05或P<0.01）；各给药组大鼠TNC区组织CGRP、pNF-κB p65蛋白表达均明显下调（P<0.05或P<0.01），加味散偏汤12.96 g/kg组TNC区组织中IL-17蛋白表达显著下调（P<0.01）。结论：加味散偏汤能通过多成分、多靶点及多途径发挥治疗偏头痛的作用。同时，加味散偏汤可能通过干预IL-17/NF-κB信号通路，减轻神经源性炎症反应，发挥治疗偏头痛的作用。

关键词： Oral lichen planus   Gut microbiome   Dysbiosis   regulatory T cell   16S rRNA sequencing   single cell RNA sequencing (6 words)   B. longum   Bifidobacterium longum   B. adolescentis   Bifidobacterium adolescentis   CTLA-4   cytotoxic T-lymphocyte associated protein 4   F. prausnitzii   Faecalibacterium prausnitzii   HC   healthy control   IL   interleukin   LEfSe   linear discriminant analysis effect size   NSU   non-specific ulcer of oral mucosa   HK   hyperkeratosis   OED   oral epithelial dysplasia   OLP   oral lichen planus   OSCC   oral squamous cell carcinoma   PBMCs   peripheral blood mononuclear cells   PCoA   principal coordinate analysis   PERMANOVA   permutational analysis of variance   SCFA   short-chain fatty acid   scRNA-seq   single-cell RNA sequencing   Treg   regulatory T cell   TGF-β   transforming growth factor β  

摘要： Oral lichen planus (OLP) is a chronic inflammatory disorder with autoimmune features and malignant transformation risk, lacking a definitive treatment, with CD4 + T cells being pivotal in its pathogenesis. Dysbiosis, an imbalance in the microbiome, is linked to various autoimmune and inflammatory diseases, where CD4 + T cells play a significant role. Given these insights, the development of OLP might be influenced by dysbiosis. This study investigates the association between dysbiosis and CD4 + T cells in OLP. We collected stool and saliva samples from OLP patients, conducting 16S rRNA gene analysis and mass spectrometry, and assessed CD4 + T cell characteristics in lesions through multiplex immunofluorescence and single-cell RNA sequencing. Peripheral blood samples were subjected to flow cytometry and cell culture assays. Results showed extensive gut dysbiosis in OLP patients, notably a reduction in short-chain fatty acid (SCFA)-producing bacteria essential for regulatory T cell (Treg) differentiation. While various CD4 + T cell subsets, including Tregs, were present in tissues, these Tregs as unresponsive to specific antigens, showing reduced immunosuppressive molecule expression. The decline in SCFA-producing bacteria correlated with fewer activated Tregs in tissues and blood. These findings suggest that gut dysbiosis may contribute to OLP by impairing Treg regulation, influencing disease pathogenesis.

关键词： canine mammary tumors   recombinant IL-15   immunomodulation   antitumor efficacy   safety assessment  

摘要： This study investigated the safety and therapeutic potential of recombinant canine interleukin-15 (rcIL-15) as an adjunct to surgical excision in dogs with mammary gland tumors (MGTs). Sixty-one client-owned dogs were initially enrolled, and 55 completed the 12-week study. Dogs were assigned to a test group receiving rcIL-15 with surgery or a control group undergoing surgery alone. RcIL-15 was administered intravenously at 20 mu g/kg/day for two 4-day cycles, separated by a 10-day rest period. Clinical monitoring included physiological assessments, blood tests, and owner-reported quality of life (QoL) questionnaires. No significant adverse changes were observed in hematological, biochemical, or physiological parameters. RcIL-15 was well tolerated, with only mild and self-limiting gastrointestinal signs and injection site reactions. Dogs in the rcIL-15 group showed significantly improved QoL, particularly in pain, appetite, and activity. Notably, serum C-reactive protein levels decreased over time in the rcIL-15 group, suggesting reduced systemic inflammation. VEGF levels remained stable in the test group but increased in controls, while IFN-gamma concentrations rose significantly following rcIL-15 treatment, indicating immune activation. These findings suggest that rcIL-15 may enhance antitumor immunity and alleviate tumor-related inflammation without compromising safety. The combination of surgery and rcIL-15 improved clinical outcomes compared to surgery alone, supporting its use as a novel immunotherapeutic adjunct for canine MGTs. However, limitations include the short follow-up period and lack of cellular immune profiling. Further studies with longer follow-up and immunological assessment are warranted to confirm these results and explore the broader application of rcIL-15 in veterinary oncology.

关键词： ribosome-inactivating protein   alpha-MMC   lung cancer   antitumor activity   apoptosis   signaling pathway  

摘要： Background: Ribosome-inactivating proteins (RIPs) are a class of toxic proteins with RNA N-glycosidase activity, primarily found in plants. Due to their antiviral, antibacterial and anti-tumor biological activities, RIPs have received extensive attention all over the world. Alpha-momorcharin (alpha-MMC) is a typical type I ribosomal inactivation protein, showing excellent anti-tumor activity. Lung cancer is a leading cause of global morbidity and mortality;however, current treatments remain limited, and patient prognosis is ***: In this study, alpha-MMC was extracted from momordica charantia seeds, and a series of in vitro studies were carried out on lung cancer A549 and 95-D cells, such as cell proliferation, cycle, apoptosis, migration to invasion, etc. Further, Western blot was used to explore the Cyclin-CDK-CKI signaling pathway, Caspase cascade and TNF signaling pathway ***: Studies have shown that alpha-MMC can significantly inhibit the proliferation of lung cancer A549 and 95-D cells. alpha- MMC can co-mediate the TNF signaling pathway to participate in cell regulation through NF-kappa B (down-regulated p65/p50) and MAPK (downregulated p38/JNK) signaling pathways, and activate downstream effector factors of Caspase to induce apoptosis. The expression of Cyclin D, CDK4, Cyclin A and CDK2 was downregulated by cyclin-CDK-CKI signaling pathway, thus blocking the cell cycle in G0/G1 phase or S ***: alpha-MMC exhibited significant antitumor activity against lung cancer A549 and 95-D cells, which laid the experimental foundation for clinical research and development of novel anti-tumor drugs.

摘要： The live-attenuated measles vaccine (LAMV) protects against measles in a safe, efficacious and durable manner. However, the mechanism by which LAMV is attenuated is not well understood, contributing to the increased vaccine hesitancy that has caused a worldwide resurgence of measles. Here, we provide a molecular model of attenuation that implicates increased host innate immune responses and increased LAMV susceptibility to those responses. Our study leverages both and models of infection to find that acute induction of innate immunity in immune cells is the critical determinant of LAMV attenuation. We show that LAMV, in contrast to pathogenic wild type measles virus (MeV), causes a strong IFNα response in primary human peripheral blood mononuclear cells, which restricts viral replication and spread in a post-entry manner. LAMV can enter, transcribe viral mRNA and translate viral proteins in immune cells, but is not able to form infectious particles and spread from cell to cell. Specifically, we find that mutations conserved across LAMV strains in the P/V/C and H genes are responsible for the induction of IFNα and the restriction of infectious virus production. In PBMC cultures and in rhesus macaques, LAMV infection also results in the acute induction of proinflammatory cytokines that likely play a role in the immunogenicity of the vaccine. Overall, our study provides a virological and immunological framework for LAMV attenuation which can be leveraged in repurposing the LAMV backbone and in future vaccine design.

关键词： psoriasis   immunology  

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