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关键词： Multiple myeloma   IL-17   Immunotherapy   MM progression   Adjuvant therapy   Bone marrow microenvironment  

摘要： Multiple myeloma (MM), a plasma cell malignancy, despite the progress in treatment, is still a challenge for both clinicians and affected patients. Modern treatment regimens including monoclonal antibodies, bispecific antibodies, CAR-T cell therapy as well as new generations of immunomodulatory drugs and proteasome inhibitors significantly improved clinical outcomes. Nonetheless, there is still a room for improvement and novel therapeutic strategies. IL-17-related signaling is a relatively undiscovered area in MM research. It was established that IL-17 is the growth factor for plasma cells including their malignant counterparts, is associated with myelomagenesis and disease progression. Furthermore, IL-17 axis can be pharmacologically targeted by monoclonal antibodies currently being used in different indications. In this narrative review we summarized the role of IL-17 axis in MM. Specifically, we focused on the role of IL-17 in MM development and progression with a particular emphasis upon clinical implications. Moreover, we have briefly summarized the potential role of therapeutic interference with IL-17-related singling and have outlined future research directions.

关键词： Crohn's disease   Omvoh   Skyrizi   Stelara   Tremfya   adverse effects   dosage   drug interactions   efficacy   guselkumab   lactation   mirikizumab   pregnancy   risankizumab   safety   ustekinumab  

关键词： computational protein design   human leukocyte antigen   peptide antigen   cell receptor   HLA  

摘要： Recognition of epitopic peptide antigens presented on class I major histocompatibility complex (MHC- I) proteins by T cell receptors (TCRs) forms the cornerstone of immune surveillance, leading to a plethora of adaptive immune responses. Characterization of TCR:peptide/MHC- I interactions is critical for understanding immune recognition, and developing immunotherapies, but the large variation in docking orientations of TCRs on their peptide/MHC- I targets challenges structural modeling. NMR spectroscopy could potentially resolve this ambiguity, but the large size of the TCR:peptide/MHC- I complex limits data quality. Here, we demonstrate that a designed MHC- I protein, SMART A*02:01, enables facile solution mapping of MHC- I:TCR interactions at scale. Our approach can be combined with computational modeling and structure- guided engineering to aid the development of TCR- based therapeutics.

关键词： IL-5   IL-9   allergic asthma   polymorphism   sensitivity  

摘要： BackgroundThe purpose of this research is to examine whether or not there is a connection between polymorphisms in the IL-5 and IL-9 genes and the prevalence of allergic asthma in Iraqi *** investigate the variants in the genes rs2069812T/C (IL-5) and rs1859430 C/T (IL-9) and their association with the likelihood of developing allergic *** hundred forty, one hundred twenty without asthma and one hundred twentywith the condition, made up the healthy subjects. We determined the levels of IL-5 and IL-9 using the enzyme-linked immunosorbent assay (ELISA) after separating sera from peripheral blood. Additionally, the allele-specific PCR method was used to identify the polymorphism distribution of rs2069812 (IL-5) and rs1859430 (IL-9).ResultsStudy participants with allergic asthma had significantly higher levels of interleukin (IL)-9 and interleukin (IL)-5 than those in the healthy subjects: 2 and 2.39 ± 0.18 pg/ml, compared to 1.004 ± 0.04 pg/ml and 2.21 ± 0.16 pg/ml, respectively, with a significance level of P < 0.05. In terms of age, gender, and place of residence, there was no statistically significant difference between the ill group and the healthy control group. The patients' group had 66 cases of the heterozygous genotype TG compared to 58 cases in the control group. Thus, the TG genotype was associated with an increased risk of allergic asthma illness (etiologic fraction: 0.2963) and an odds ratio of 2.4074 (95% CI: 1.2462-4.6505). The patients' group also had a higher frequency of the homozygous genotype GG (65 cases vs. 54 cases in the control group). The odds ratio for allergic asthma illness was 1.0578 (95% CI: 0.6386-1.7522), and the etiologic fraction was 0.0299, indicating that genotype GG was a risk *** findings provide more evidence that interleukin-5 and interleukin-9 play critical roles in allergic asthma, particularly in eosinophilic inflammation. Consequently, it is important to target them in order

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： 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