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关键词： Metabolic-associated fatty liver disease   Hepatocellular carcinoma   Steatosis   Protein-protein interaction   Hepatic stellate cells   Cytokine signaling  

摘要： Dysregulation of hepatic metabolism is a crucial factor in the development of fatty liver disease and significantly increases the risk of hepatocellular carcinoma (HCC). This study aims to identify the genes implicated in the prognosis of HCC among individuals suffering from metabolic fatty liver disease. We analysed protein-protein interaction (PPI) networks and constructed a weighted gene co-expression network analysis (WGCNA) using high-throughput gene expression profiling datasets. Our meta-analysis uncovered 442 differentially expressed genes (DEGs), comprising 30 upregulated and 412 downregulated genes. We constructed a PPI network from the DEGs and identified significant hub genes based on their degree centrality scores. Additionally, WGCNA highlighted impactful genes and tightly correlated modules, leading to the creation of a gene interaction network specific to metabolism-associated fatty liver disease (MAFLD). Pathway analysis revealed the candidate regulatory gene interleukin-7 receptor (IL7R), which is involved in cytokine-mediated signalling across both interaction networks. Pro-inflammatory cytokines interact with IL7R, activating the JAK/STAT pathway that influences gene expression throughout progression to HCC. IL7R activates STAT3, affecting the behaviour of activated hepatic stellate cells following initial liver damage. Furthermore, the expression of the IL7R gene was validated as a predictor of HCC malignancy through a logistic regression model, resulting in an accuracy of 92%. Findings suggest that IL7R could be the target gene associated with metabolism-linked HCC. It could significantly impact the management of metabolic-associated fatty liver disease (MAFLD) and may help enhance HCC diagnostics to improve patient outcomes.

关键词： Sunitinib malate   Colorectal cancer cells   Autocrine IL-6/STAT3 pathway   c-MYC   TWIST   MMP2  

摘要： Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor with specificity for VEGFR, KIT, FLT3, and PDGFR, has demonstrated clinical efficacy as a first- to third-line treatment for refractory renal carcinoma. Our previous research indicated that sunitinib malate suppresses intestinal polyp proliferation by downregulating IL-6 mRNA expression, suggesting a potential analogous mechanism in colorectal carcinoma inhibition. This study aimed to elucidate the pharmacological effects and molecular mechanisms of sunitinib malate on colorectal carcinoma using HCT116, RKO, HT29, and SW480 cell lines in vitro and HCT116-derived xenografts in nude mice in vivo. We employed a comprehensive array of experimental techniques, including CCK-8/MTT assays for cell viability, Transwell and/or wound healing assays for migration, and Western blot and immunohistochemistry for protein expression analysis. Our findings demonstrate that sunitinib malate significantly inhibits colorectal cancer cell proliferation and migration in vitro. Moreover, in the xenograft model, sunitinib malate markedly suppressed colorectal tumor growth in vivo. Notably, we observed significant downregulation of c-MYC, TWIST, and MMP2 expression both in vitro and in vivo following sunitinib malate treatment. These results collectively suggest that sunitinib malate exerts its anti-colorectal carcinoma effects, at least in part, by disrupting the autocrine IL-6/STAT3/c-MYC/TWIST/MMP2 signaling axis.

关键词： 时间分辨荧光   米酵菌酸   单克隆抗体   快速检测   免疫层析法  

摘要： 米酵菌酸是一种非热敏性的强呼吸性毒素，目前缺乏快速、灵敏、准确的检测方法。该研究将时间分辨荧光微球标记米酵菌酸单克隆抗体，开发适合复杂食品基质的米酵菌酸时间分辨荧光免疫层析检测法。对探针制备、试纸条制作和样品前处理等关键步骤进行了优化。结果表明，在最适条件下，该方法的定性检测限为6.0 μg/kg，定量检测限为1.0 μg/kg，半抑制浓度为1.5 μg/kg。方法特异性较好，与毒黄素等的交叉反应率均小于2.0%；米粉、木耳和银耳等样品的回收率在94.0%～107.9%，变异系数为1.3%～6.5%。与LC-MS/MS检测结果的相关性较高(R2= 0.99)。该方法稳定性较好，准确性和灵敏度较高，可以用于食品中米酵菌酸的快速检测以及现场大规模的初步筛查。

关键词： Inula japonica   caffeoylglucaricacids   caffeoylquinic acids   skin aging   antioxidant   anti-inflammation  

摘要： This study investigated the secondary metabolites of Inula japonica leaves and determined their corresponding anti-skin aging properties. LC-MS-based molecular networking and compound isolation identified caffeoylglucaric and caffeoylquinic acids as the principal components of the 30% ethanolic extract of I. japonica leaves (IJE). The chemical structures of three previously unreported caffeoylglucaric acids, namely, inulajaponic acids A-C (1, 2, and 4), were determined. IJE and its compounds exhibited significant inhibitory effects against ROS and MMP-1 production in TNF-alpha-induced NHDF cells. In particular, compound 4 suppressed ROS, MMP-1, IL-6, and IL-8 production, while promoting the production of procollagen type I alpha 1. Mechanistic studies revealed that 4 attenuates the phosphorylation of ERK, JNK, NF-kappa B, and c-Jun, suggesting that it regulates inflammatory cytokines and prevents collagen degradation via MAPK-NF-kappa B/AP-1 signaling pathways. Furthermore, 4 downregulated iNOS and COX-2 expression and upregulated HO-1 expression, demonstrating its ability to reduce the inflammatory responses associated with skin aging.

关键词： combined diagnosis   IL-8   MMP-9   MPO   post-infectious bronchiolitis obliterans  

摘要： This study investigates the diagnostic potential of matrix metalloproteinase-9 (MMP-9), IL-8, and myeloperoxidase (MPO) in bronchoalveolar lavage fluid (BALF) as combined biomarkers for post-infectious bronchiolitis obliterans (PIBO) in children. BALF samples from children with PIBO were analyzed using ELISA to quantify MMP-9, IL-8, and MPO levels. Receiver operating characteristic (ROC) curves were used to assess their diagnostic values, while Pearson correlation analysis examined their associations with lung function and inflammation markers. A PIBO mouse model was established via nebulized nitric acid inhalation, and targeted inhibition of MMP-9, IL-8, and MPO using small interfering RNAs (siRNAs) was performed given via intratracheal administration. The effects on airway inflammation and pathological lung changes were evaluated. Bioinformatics analysis identified upstream microRNAs (miRNAs) regulating MMP-9, IL-8, and MPO, which were validated using dual-luciferase assay and Western blotting. Results revealed significant upregulation of MMP-9, IL-8, and MPO in the BALF of children with PIBO. Combined detection of these biomarkers demonstrated high diagnostic accuracy. MMP-9, IL-8, and MPO levels in BALF were negatively correlated with lung function indicators but positively correlated with inflammatory factors. Targeted inhibition of these molecules reduced airway hyperresponsiveness and inflammation in PIBO mice. miR-766-3p was downregulated in the lung tissues of PIBO mice and in the BALF of affected children, showing a negative correlation with MMP-9, IL-8, and MPO. Functional assays confirmed that miR-766-3p directly targeted MMP-9, IL-8, and MPO. In conclusion, MMP-9, IL-8, and MPO serve as reliable combined biomarkers for PIBO diagnosis and may aid in early clinical identification. miR-766-3p is an upstream miRNA for MMP-9, IL-8, and MPO.

摘要： The tumor environment of prostate cancer (PCa) tissues of high Gleason score has been proved to be more immune suppressive and has higher extracellular matrix (ECM) stiffness, but whether ECM mechanical stiffness is the cause of higher ability of invasiveness and immune escape of PCa with high Gleason score remains uncertain. In this study, we showed that higher polyacrylamide hydrogels (PAAG) stiffness resulted in the progression and immune escape of PCa via integrin beta 1/FAK/YAP axis. The translocation of YAP into cell nucleus to bind to TEAD2 promoted the transcriptional activation of USP8. NBR1 could be ubiquitinated, and then degraded, via interacting with P62/SQSTM1 and through autophagy-lysosome pathway. Increased expression of USP8 promoted the abundance of NBR1 via K63-linked de-ubiquitination and PD-L1 via K48-linked de-ubiquitination in response to high PAAG stiffness. NBR1-mediated selective autophagy accelerated the degradation of MHC-1 of PCa. The USP8 inhibitor presented a potential application value in sensitizing immunotherapy of PCa. Taken together, we identified a USP8-mediated de-ubiquitination mechanism that involves in the process of high PAAG stiffness-mediated high expression of PD-L1 and low expression of MHC-1 of PCa cells, which provided a rationale of immunotherapy sensitization of PCa via USP8 inhibition.

关键词： 加味黄连阿胶汤   中风   睡眠障碍   炎症因子   睡眠质量  

摘要： 目的 分析加味黄连阿胶汤对中风后睡眠障碍患者中医证候积分、血浆白细胞介素-10（Interleukin-10，IL-10）、肿瘤坏死因子-α（Tumor necrosis factor-α，TNF-α）、神经元特异性烯醇化酶（Neuron-specific enolase，NSE）水平及睡眠质量的影响。方法 纳入我院2021.3～2023.5收治的120例中风后睡眠障碍患者，随机分为联合组（n=60）、对照组（n=60），2组常规药物治疗及经颅磁刺激治疗，联合组加用加味黄连阿胶汤，2组治疗均持续6周。对比2组治疗前后中医证候积分，血浆IL-10、TNF-α、NSE等指标，以及睡眠质量变化，分析两种治疗方案的临床价值。结果 2组治疗6周后腰膝酸软、五心烦热、口干咽燥、潮热盗汗症候积分均较治疗前下降；联合组治疗6周后各项中医证候积分均低于对照组，差异有统计学意义（P<0.05）。2组治疗6周后血浆IL-10较治疗前升高，TNF-α、NSE均较治疗前下降；联合组治疗6周后血浆IL-10高于对照组，其，TNF-α、NSE均低于对照组，差异有统计学意义（P<0.05）。2组治疗6周后匹兹堡睡眠质量指数（Pittsburgh sleep quality index，PSQI）各因子评分及总分均较治疗前下降；联合组治疗6周PSQI量表各因子评分及总分均低于对照组，差异有统计学意义（P<0.05）。结论 在常规药物治疗的基础上，给予加味黄连阿胶汤能够改善中风后睡眠障碍患者中医证候积分、调节炎症反应并促进神经功能恢复，对于患者睡眠质量的改善有积极影响。

摘要： IgM antibodies are preformed pentameric or hexameric molecules that can be engineered to generate high affinity and high avidity fully human antibody therapeutics. In this study, we report an immunocytokine, IGM-7354, which was designed to bind multiple PD-L1 receptors while trans-presenting a single IL-15/IL-15Rα complex on the joining chain to IL-15Rβγ-expressing cytotoxic natural killer (NK) and CD8+ T-cells. We evaluated the pharmacological and anti-tumor properties of IGM-7354 in preclinical models. IGM-7354 induced potent proliferation of NK and CD8+ T-cells, both in vitro using healthy human PBMCs and in vivo in humanized mice, through the IL-15/IL-15Rα complex. In a mixed-lymphocyte reaction assay with exhausted human T-cells, IGM-7354 restored the secretion of IFNγ compared to the IL-15/IL-15Rα complex or anti-PD-L1 alone, suggesting a rescue of exhausted T-cells in vitro. Robust single agent activity was observed in the humanized PD-L1+ MDA-MB-231 breast cancer mouse model. Anti-tumor responses were enhanced by adding IGM-7354 to the anti-CD38 daratumumab in RPMI-8226 multiple myeloma or anti-CD19 CAR T-cell therapies in Raji lymphoma models. Finally, in cynomolgus monkeys, pharmacodynamic activity of increased NK and CD8+ T-cell proliferation was observed in multiple tissue compartments. Taken together, this study demonstrates the feasibility of developing a safe and effective IgM-based immunocytokine for the treatment of cancer, exploiting the multivalency of an IgM antibody to bind PD-L1 with high affinity and avidity and stimulate NK and CD8+ T-cell effectors.