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关键词： NF-kappa B   nuclear factor kappa B   machine learning   chemical descriptors   high-throughput screening   inhibitor prediction tool  

摘要： Introduction Nuclear Factor kappa B (NF-kappa B) is a transcription factor whose upregulation is associated in chronic inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and asthma. In order to develop therapeutic strategies targeting NF-kappa B-related diseases, we developed a computational approach to predict drugs capable of inhibiting TNF-alpha induced NF-kappa B signaling *** We utilized a dataset comprising 1,149 inhibitors and 1,332 non-inhibitors retrieved from PubChem. Chemical descriptors were computed using the PaDEL software, and relevant features were selected using advanced feature selection *** Initially, machine learning models were constructed using 2D descriptors, 3D descriptors, and molecular fingerprints, achieving maximum AUC values of 0.66, 0.56, and 0.66, respectively. To improve feature selection, we applied univariate analysis and SVC-L1 regularization to identify features that can effectively differentiate inhibitors from non-inhibitors. Using these selected features, we developed machine learning models, our support vector classifier achieved a highest AUC of 0.75 on the validation *** Finally, this best-performing model was employed to screen FDA-approved drugs for potential NF-kappa B inhibitors. Notably, most of the predicted inhibitors corresponded to drugs previously identified as inhibitors in experimental studies, underscoring the model's predictive reliability. Our best-performing models have been integrated into a standalone software and web server, Nf kappa Bin. (https://***/raghava/nfkbin/).

关键词： 变应性鼻炎   最轻持续性炎症状态   鼻敏康合剂   白细胞介素-33（IL-33   IL-1 受体样2(ST2)  

摘要： 目的：探讨鼻敏康合剂对变应性鼻炎最轻持续性炎症状态(MPI）小鼠白介素-33（IL-33）/IL-1受体样2（ST2）信号通路的影响。方法：50只SPF级BALB/c雌性小鼠随机分为空白对照组（Control组）、变应性鼻炎模型组（AR组）、变应性鼻炎MPI模型组（MPI组）、鼻敏康合剂组（BMK组）和氯雷他定组（Loratadine组），每组10只。除Control组外，其余各组小鼠腹腔注射混悬液（卵清白蛋白+氢氧化铝粉剂+酸盐缓冲液）造成基础致敏，激发阶段给予4%卵清白蛋白（OVA）溶液滴鼻1周激成AR模型，而后2周变应性鼻炎模型组仍给予4%OVA维持，变应性鼻炎MPI模型组、鼻敏康合剂组和氯雷他定组予低浓度0.04%OVA滴鼻建立MPI模型。每日滴鼻前给药1次，对灌胃剂量（0.2mL/20g）进行换算，鼻敏康合剂组予鼻敏康合剂，氯雷他定组予氯雷他定溶解剂，其余各组则予同等剂量的PBS灌胃，连续干预14天。HE染色显示小鼠鼻黏膜组织病理结构情况，检测鼻腔灌洗液(NLF)白介素4（IL-4）、白介素5（IL-5）、白介素13（IL-13）和IL-33含量，RT-PCR观察鼻黏膜组织IL-33和ST2mRNA变化，Westernblot检测鼻黏膜组织ST2蛋白变化。结果：与Control组比较，AR组及MPI组打喷嚏、抓鼻次数显著升高（P<0.01），出现杯状细胞增生和嗜酸性粒细胞浸润，鼻腔灌洗液IL-4、IL-5、IL-13和IL-33水平显著升高（P<0.01），鼻黏膜组织IL-33和ST2mRNA表达均上调，ST2蛋白表达升高。给药后，与MPI组比较，BMK组和Loratadine组小鼠打喷嚏、抓鼻次数降低（P<0.01），鼻黏膜病理情况改善，鼻腔灌洗液IL-4、IL-5、IL-13和IL-33水平降低（P<0.01），鼻黏膜组织IL-33和ST2mRNA表达水平降低（P<0.01），ST2蛋白表达下降（P<0.01）。结论：鼻敏康合剂可能通过抑制IL-33 /ST2信号通路，改善变应性鼻炎MPI小鼠鼻腔炎症反应，控制AR发作。

关键词： Leonurus japonicus   lipid metabolism   thrombosis   TLR4/STAT3/TNF-alpha/IL-17A pathways  

摘要： Leonurus japonicus Houtt. (LJ) is a pivotal traditional Chinese medicine remedy for thrombosis;however, its potential mechanisms and active constituents remain unclear. In this study, LJ exhibits a significant antithrombotic effect on an arteriovenous bypass thrombosis rat, characterized by reductions in thrombus wet and dry weights, decreased maximum aggregation rate, increased thrombus formation inhibition rate, aggregation inhibition rate, alterations in fibrinogen and antithrombin III levels, and shortened coagulation indicators. Moreover, LJ significantly enhanced the erythrocyte staining area and intensity in an arachidonic acid-induced zebrafish heart. Network pharmacology indicated that LJ alleviates thrombosis by regulating TNF and IL-17 pathways. Metabolomics revealed that LJ significantly modulated 29 endogenous differential metabolites, linking it to the regulation of primary bile acid biosynthesis, IL-17, and TNF pathways. Zebrafish experiments and molecular docking suggested that kaempferol and apigenin exhibit antithrombotic effects by modulating TNF and IL-17 proteins. Finally, molecular dynamics simulation validated that kaempferol and apigenin have strong binding capabilities with TLR4, STAT3, TNF-alpha, and IL-17A, and their binding free energies are -20 to -27 and -13 to -15 kcal/mol, respectively. In conclusion, LJ exerts its antithrombotic effect by regulating lipid metabolism and inhibiting TLR4/STAT3/TNF-alpha/IL-17A pathways, with kaempferol and apigenin identified as bio-constituents. This plant holds significant potential for development and utilization in antithrombotic therapies.

摘要： BackgroundElevating major histocompatibility complex class I (MHC-I) levels in tumour cells can boost antitumour immunity and enhance immunotherapy for colorectal cancer (CRC). Screening an FDA-approved drug library showed that MEK inhibitors (MEKis) significantly increase MHC-I expression in CRC cells, though the mechanisms and antitumour effects of MEKis, as well as their impact on gut microbiota, remain ***-luciferase reporter system was employed to screen MHC-I inducers. MHC-I expression was analysed using qRT-PCR, flow cytometry, and western blot. OT-I TCR transgenic mice, subcutaneous mouse tumour models, RNA-seq, and ChIP-qPCR were used to identify the underlying mechanism. Gut microbiota was depleted using antibiotics cocktail and analysed via Shotgun sequencing, 16S rRNA sequencing and nontargeted metabolomic ***, particularly cobimetinib, increased MHC-I expression by inhibiting PRMT5-mediated repression of NLRC5, boosting CD8+ T cell-mediated immunity and enhancing PD-L1 blockade efficacy. Cobimetinib also altered gut microbiota, reducing L-arginine via arginase production, which compromised antitumour immunity. Arginase inhibition or L-arginine supplementation restored immune *** study uncovers a novel mechanism of MEKi-induced MHC-I expression and highlights the interplay between gut microbiota and antitumour immunity, providing insights for MEKi-based CRC immunotherapy.

关键词： Autoimmune Liver Disease   Cellular crosstalk   Biliary injury   Granzyme A   Gasdermin B   AIH   autoimmune hepatitis   HC   healthy control   AMA   anti-mitochondrial antibody   CHB   chronic hepatitis B   PBC   primary biliary cholangitis   NASH   nonalcoholic steatohepatitis   PDC-E2   E2 component of pyruvate dehydrogenase   ALP   alkaline phosphatase   ALT   alanine aminotransferase   AST   aspartate aminotransferase   GGT   gamma-glutamyl transferase   IgA   immunoglobulin A   IgG   immunoglobulin G   IgM   immunoglobulin M   TBIL   total bilirubin   HAI   hepatic activity index   H&E   hematoxylin and eosin   WT   wild type   DEGs   differentially expressed genes   GO   gene ontology   sCD40L   soluble CD40 ligand   GZMA   granzyme A   KEGG   kyoto encyclopedia of genes and genomes   T   RM   tissue-resident memory T cells   BECs   biliary epithelial cells   GSDMB   gasdermin B   GSDMD   gasdermin D   GSDME   gasdermin E   LDH   lactate dehydrogenase  

摘要： Background & Aims IL-15Rα mediates immune responses by binding and trans-presenting IL-15 to tissue-resident memory T (T RM ) cells, enabling sustained activation. Given the pivotal role of IL-15Rα/IL-15 signaling in autoimmune diseases, elucidating its organ-specific expression and pathogenic functions in primary biliary cholangitis (PBC) remains crucial. Methods Immunohistochemical staining was performed on liver tissues from patients with PBC (n=94), AIH (n=32), CHB (n=10), NASH (n=7) and HCs (n=10) to assess IL-15Rα expression. Flow cytometric analysis characterized intrahepatic IL-15Rα + B cells and CD4 + T RM cells .RNA-Seq was employed to delineate the transcriptomic signatures of in vitro-induced B cells and intrahepatic leukocytes. To investigate the cytotoxicity of T RM cells against cholangiocytes, we performed organoid co-culture system. Moreover, dnTGFβRII mice treated with anti-IL-15/IL-15Rα mAb were used for in-vivo validation. Results IL-15Rα + cells were significantly increased in PBC patients, primarily concentrated within the plasmablast B cell population, and positively correlated with hepatic inflammation severity. IL-15Rα + B cells enriched around bile ducts in PBC livers secrete CCL3 to recruit CCR5 + CD4 + T RM cells, enhancing their effector functions via IL-15Rα/IL-15 signaling. Notably, CCR5 + CD4 + T RM cells drive cholangiocyte pyroptosis through granzyme A-mediated GSDMB cleavage. Furthermore, blockade of IL-15Rα/IL-15 signaling ameliorates liver injury in PBC mouse models. Conclusions Our findings reveal an important pathogenic mechanism in PBC wherein IL-15Rα + B cells contribute to biliary injury by activating CCR5 + CD4 + T RM cells. This mechanism likely works in concert with other immune effector pathways in driving disease progression. Impact and implications This study reveals that IL-15Rα-expressing B cells manifest a pro-inflammatory phenotype and promote biliary injury by impairing immune homeostasis through aberrant activati

关键词： hepatitis B virus   antiviral agents   small interfering RNA   vaccine immunology   immunomodulation   functional cure  

摘要： Introduction Prevalence of chronic hepatitis B virus (HBV) infection remains a major global health issue. Research into a cure has focused on finite combinatorial interventions that aim to reduce HBV surface antigen (HBsAg), suppress virus specific immune tolerance, and induce an adaptive response that functionally controls the *** In C57BL/6 mice transduced with adeno-associated virus encoding the HBV genome, which replicate HBV and persistently express HBsAg at 104 IU/mL or higher, a combination of small interfering RNA (siRNA) knockdown of HBsAg expression followed by immunization with a self amplifying RNA therapeutic HBV vaccine failed to establish HBV control. Using this in vivo murine model, we screened for immunomodulatory agents added after HBV siRNA knockdown, and in combination with therapeutic vaccination, that may enhance the HBV adaptive immune response to control ***/Discussion In mice with very high levels of HBsAg (104-105 IU/mL), levels that are observed clinically during standard HBV therapy and that were brought low (102 IU/mL) by HBV siRNA pre-treatment prior to therapeutic vaccination, PDL1 blockade in combination with stabilized cytokines IL-2 or IL-15 led to immune control of HBsAg in vaccinated animals.

关键词： psoriasis   obesity   adipokines   anti-IL-17 biologics   anti-IL-23 biologics   gender  

摘要： Introduction Psoriasis is a chronic immune-mediated inflammatory skin disorder, frequently associated with comorbidities such as obesity, which can exacerbate its severity and hinder treatment efficacy. Psoriasis pathogenesis involves complex interactions among genetic, environmental, hormonal factors, and is characterized by dysregulated immune responses. In this study, we investigated the relationship between obesity and psoriasis, exploring the impact of circulating levels of adipokines on disease severity, comorbidities, and treatment response to anti-IL-17 and anti-IL-23 *** We conducted an observational study that included 91 patients with psoriasis eligible for biological therapy, as well as 26 healthy controls. Disease severity was assessed using PASI, along with the measurement of body composition. Serum samples were analyzed for the measurement of adipokine levels and lipid profiles. Clinical parameters, bioelectrical impedance analysis (BIA), serum adipokine levels (leptin, visfatin, adiponectin) and lipid profile were assessed at baseline and after 16 weeks of biologic *** Clinical parameters and adiposity-related indices were analyzed in 76 patients at both T0 and 16 weeks of anti-IL-17 and anti-IL-23 biological treatments, while serum adipokine levels were assessed in 66 patients. Psoriatic patients exhibited higher body mass index (BMI), waist circumference, fat mass (FM), and levels of visfatin (a pro-inflammatory adipokine), whereas adiponectin levels (an anti-inflammatory adipokine) were lower compared to controls. Circulating leptin (a pro-inflammatory adipokine) was significantly higher in female psoriatic patients and showed a positive correlation with the PASI score. Leptin also positively correlated with adiposity indices, while adiponectin showed negative correlations. Furthermore, in women, leptin levels were also associated with psoriatic arthritis, hypertension and, at lower extent, with type II diabetes. Final

关键词： repetitive overuse injury   repetitive strain injury   musculoskeletal injury   work-related musculoskeletal disorders   pain   ependyma   cingulate cortex  

摘要： Background Pain and sickness behaviors can be elicited by systemic inflammation. We sought to determine if mature rats displayed these behaviors following overuse injury and whether they correlated with inflammatory cytokines in musculoskeletal tissues, circulation, and the *** Mature female Sprague-Dawley rats were used: 26 controls and 41 rats trained across 6 weeks to pull at high force levels. Following training, 28 rats performed a high-repetition low-force task for 6 more weeks (task);the remaining rested (trained + rest). Behavioral data were collected at baseline, following training, and at study end. Tissues and serum were then collected and examined for the presence of inflammatory *** Following training, task and trained + rest rats exhibited grip strength declines and forepaw sensitivity, compared to baseline and controls. Following task or rest, these behavioral changes persisted in addition to a reduction in social interactions (with juvenile female rats) in task rats, whereas trained + rest rats exhibited only low grip strength. Pro-inflammatory cytokines were elevated in serum and forelimb musculoskeletal and nerve tissues in task relative to control rats;IL-6 was elevated in serum and tissues in task relative to trained + rest rats. IL-6 immunostaining was observed in brain ependymal cells and cingulate cortex of task and trained + rest rats relative to control rats, and one circumferential blood brain region of task rats relative to the other groups. Higher cytokine levels in tissues often correlated with poorer behavioral *** These data indicate that overuse injury induces inflammatory responses within the local/damaged tissues, circulation, and brain, which drives pain-related and sickness behaviors.

关键词： 过继细胞输注   嵌合抗原受体T细胞治疗   生物材料   药物递送   免疫细胞   肿瘤微环境   综述  

摘要： 过继细胞输注（ACT）疗法在血液系统肿瘤的治疗中疗效显著，但在实体瘤的治疗中存在浸润不足、免疫抑制微环境及潜在毒副作用等问题。近年来，不同尺寸的生物材料（如纳米粒、微球/微贴片和水凝胶）在细胞体外工程化、在体递送及肿瘤微环境调控等方面展现出独特优势。纳米粒可用于基因递送、人工抗原递呈系统构建和免疫微环境重塑；微球和微贴片增强了免疫细胞的扩增、靶向激活及局部滞留；水凝胶则通过在体基因工程化、三维培养支持和细胞因子共递送等方式提升ACT疗效。本文综述了ACT中多种生物材料在提升递送效率、增强抗肿瘤效应及降低毒副作用方面的重要潜力，为实体瘤免疫治疗的临床转化提供参考。

关键词： Anti-TNF   Intestinal Beh & ccedil   et's disease   Predictive factors   Treatment failure  

摘要： Objective Treatment options for intestinal Beh & ccedil;et's disease (BD) are limited. Despite the proven efficacy of infliximab and adalimumab, there is an urgent need to identify predictive factors for inadequate response or non-response to anti-TNF agents. Methods We conducted a retrospective cohort study involving 71 patients diagnosed with intestinal BD and treated with anti-TNF across four hospitals from August 2018 to December 2024. Demographic data, clinical symptoms, endoscopic findings, and laboratory parameters were collected at baseline and every 3 months after anti-TNF therapy until the latest follow-up appointment. The primary outcome was non-response or inadequate response to anti-TNF therapy, or presence of intestinal complications. Results During the study period, 35.2% (25/71) of patients met the primary outcome at a median follow-up time of 8.5 months. Pre-treatment endoscopic score greater than 2.5, presence of opportunistic infections, DAIBD score > 12.5, ESR > 14.50 mm/h, and CRP > 12.83 mg/L three months post-treatment were identified to be associated with anti-TNF treatment failure. ROC curve established by incorporating these variables demonstrated a strong predictive capacity for treatment failure (AUC = 0.930). An internal validation of ROC curve was performed by the bootstrap method, which demonstrated good accuracy and stability. We subsequently developed a nomogram model to calculate the risk of treatment failure based on the above variables. Conclusions Predictors of anti-TNF treatment failure in patients with intestinal BD included baseline endoscopic score, the occurrence of opportunistic infections, and DAIBD score, CRP and ESR at 3 months post-treatment. Our model can identify high-risk patients early, allowing for the timely optimization of treatment regimens.