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关键词： miR-15b-5p   HMGB1   TLR4   IL-33   Asthma  

摘要： The pathophysiologic processes of asthma are characterized not only by significant changes in miRNA expression but also by the modulation of HMGB1 and its downstream effectors. However, the specific roles of miR-15b-5p and HMGB1 in asthma remain poorly understood. This study explores the regulatory role of miR-15b-5p in asthma by targeting HMGB1. We utilized HMGB1-conditioned knockout mice (Sftpc-cre;HMGB1flox/flox) in type II alveolar epithelial cells (AT2), induced with house dust mite (HDM), to establish a mouse model of asthma. Results demonstrated that AT2 cell-specific deletion of HMGB1 attenuated allergen-induced airway hyperresponsiveness and reduced airway inflammation. Concurrently, miR-15b-5p levels were significantly reduced in wild-type (WT) asthmatic mice, while HMGB1, TLR4, and IL-33 levels were elevated. Administration of miR-15b5p agomir mirrored the effects of HMGB1 knockdown, reducing peribronchiolar inflammatory cells and ameliorating airway inflammation and remodeling. A luciferase reporter gene assay system was employed to predict and verify HMGB1 as a direct target of miR-15b-5p. Overexpression of miR-15b-5p significantly inhibited apoptosis and activation of HMGB1, TLR4, and IL-33, and decreased NLRP3, Caspase-1, and IL-1 beta expression. In vitro, miR-15b-5p overexpression and HMGB1 knockdown attenuated HDM-induced cellular inflammation and production of Cleaved-caspase-9, Cleaved-caspase-3, and Bax, while enhancing mitochondrial membrane potential. This study suggests that miR-15b-5p acts as a protective mechanism against allergic airway inflammation by inhibiting the HMGB1/TLR4/IL-33 signaling pathway in AT2 cells. Targeting the HMGB1/TLR4/IL-33 signaling by miR-15b-5p may offer a potential therapeutic strategy for asthma.

关键词： CAR T cells   CCR5   IL-12   TumorMircoenvironment  

摘要： Chimeric antigen receptor (CAR) T cell therapy for solid tumors faces significant challenges, including inadequate infiltration, limited proliferation, diminished effector function of CAR T cells, and an immunosuppressive tumor microenvironment (TME). In this study, we utilized The Cancer Genome Atlas database to identify key chemokines (CCL4, CCL5, and CCR5) associated with T cell infiltration across various solid tumor types. The CCL4/CCL5-CCR5 axis emerged as significantly correlated with the presence of T cells within tumors, and enhancing the expression of CCR5 in CAR T cells bolstered their migratory capacity. Furthermore, single-cell immunoprofiling of tumor tissues revealed that macrophages within the TME primarily interact with CD8+ T cells, impeding their tumor response. However, CAR T cells engineered to secrete Interleukin (IL)-12 can counteract macrophage-mediated immunosuppression and augment T cell functionality. To address these obstacles, we employed esophageal carcinoma as a model to develop mesothelin-targeted CAR T cells co-expressing CCR5 and IL-12 (CARTmeso-5-12), subsequently assessing their antitumor capabilities in vitro and in vivo. The CARTmeso-5-12 cells demonstrated enhanced tumor infiltration due to overexpression of CCR5, and IL-12 secretion further amplified CAR T cell efficacy by attenuating the suppressive influence of tumor-infiltrating macrophages, thus improving tumor eradication.

关键词： 神经氨酸酶抑制剂   活性腔   抗体募集   蛋白质降解   单克隆抗体  

摘要： 神经氨酸酶是流感病毒表面重要的糖蛋白，在流感病毒生命周期的出芽释放阶段发挥着不可替代的作用，是药物设计的理想靶点。目前已有神经氨酸酶抑制剂应用于流感的临床治疗，但是由于用药选择的单一性及流感病毒潜在的变异性，神经氨酸酶耐药毒株逐渐成为公众的担忧，因此神经氨酸酶新型抑制剂的研发成为研究热点。本研究精选近10年代表性案例，对神经氨酸酶抑制剂的发展状况进行综述，以期为研发具有更强活性及抗耐药性的神经氨酸酶抑制剂提供参考。

关键词： circFAM64A   Bladder cancer   IL-6   JAK/STAT   Proliferation   Immune evasion  

摘要： Background: The significance of circular RNA in tumour biology is increasingly recognized. This study aims to explore the value of circFAM64A(3) in the proliferation and immune evasion of bladder cancer. Methods: Bioinformatics were used to identify the differentially expressed circular RNAs in bladder cancer. Proliferation assay, co-culture assay and flow cytometry assay confirmed the oncogenic and immune-evading characteristics of circFAM64A(3) in bladder cancer in vitro and in vivo. Further, mRNA sequencing, RNA pulldown, and RNA immunoprecipitation were used to confirm the downstream targets and pathways regulated by circFAM64A(3). CUT&TAG assay confirmed HIF-1 alpha promoted the expression of circFAM64A(3) under hypoxic. Results: CircFAM64A(3) was significantly high expression in bladder cancer tissues and related with poor prognosis of bladder cancer patients. CircFAM64A(3) promoted bladder cancer cells proliferation and immune evasion in vitro and in vivo. Mechanistically, circFAM64A(3) acted as a sponge to miR-149-5p and reduced the binding of miR-149-5p to IL-6 3 '-UTR. Then, IL-6 activated the JAK/STAT pathway and caused an increase of PDL1. Under hypoxic environment, HIF-1 alpha bound to the promoter of FAM64A and promoted circFAM64A(3) transcription. Conclusion: HIF-1 alpha/circFAM64A(3)/miR-149-5p/IL-6 axis was an important regulatory pathway in bladder cancer proliferation and immune evasion. CircFAM64A(3) may serve as a novel and potentially valuable biological target.

关键词： 草鱼出血病   大型海藻   GCRV   肠道微生物   补体  

摘要： 为研究饲料中添加大型海藻对感染呼肠孤病毒(GCRV)的草鱼(Ctenopharyngodon idella)肠道菌群和免疫的影响,在草鱼饲料中分别添加5%的马尾藻(Sargassum hemiphyllum)、紫杉状海门冬(Asparagopsis taxiformis)、龙须菜(Gracilaria lemaneiformis)藻粉,饲喂草鱼2个月。采用腹腔注射,构建草鱼GCRV感染模型,分析宿主肠道微生物群落和免疫响应。结果显示,饲料中添加大型海藻显著提高了健康草鱼肠道菌群的多样性,改变了特有微生物数量。有效减缓了GCRV感染1d后的草鱼肠道菌群多样性的降低,缩小了GCRV感染4—7d草鱼肠道菌群的组间差异,降低了感染后肠道菌群的紊乱。其中饲料中添加马尾藻和龙须菜组肠道中弧菌属(Vibrio)相对丰度显著降低;饲料中添加马尾藻组肠道中鲸杆菌属(Cetobacterium)相对丰度降低,而拟杆菌属(Bacteroides)相对丰度增加。共现网络分析显示,大型海藻提高了感染GCRV的草鱼肠道菌群现网络的复杂度,增强肠道菌群的稳定性。蛋白表达结果显示,感染后第1天,饲料中添加马尾藻组草鱼血清中促炎补体成分C5a含量增加,而饲料中添加龙须菜组补体成分C5a含量降低。相关性分析表明,补体蛋白C5、C5a成分及其受体(C5aR)的上调表达与肠道中致病菌群相对丰度显著正相关,而与碳水化合物和膳食纤维消化菌群负相关。综上,饲料中添加大型海藻缓解了GCRV感染对草鱼肠道菌群带来的不利影响,并调节感染草鱼的补体表达,可为从饲料开发方面防控草鱼出血病提供新思路。

关键词： Papillary thyroid cancer   DPP4   T cell exhaustion   IL13-IL13RA2 axis   Mesenchymal-to-epithelial transition  

摘要： Background: Papillary thyroid cancer (PTC) is among the most prevalent forms of endocrine malignancy with a rapid rise in incidence rates worldwide;however, the composition and characteristics of its immune microenvironment is poorly understand. Here, this work investigated the precise function of Dipeptidyl peptidase 4 (DPP4) in tumor-infiltrated T cells within PTC by investigating its role in cytokine-mediated signaling pathways. Methods: TCGA and GEO data as well as human PTC specimens confirmed the expression of DPP4 in PTC. The CIBERSORT and TIMER tool were used to analyze the distribution of tumor-infiltrating immune cells in PTC. CD8+ T cells from PTC patient's peripheral blood were cultured and used in a three-dimensional model for direct co-culture with PTC tumors to investigate DPP4 function. Results: Bioinformatic analyses has uncovered a significant upregulation of DPP4, which enhances the survival and migration of PTC cells in vitro. DPP4 upregulation significantly correlated with advanced grades, stages, and poor progression-free survival. DPP4 influences immune function and the exhaustion of CD8+ T cells through the IL13-IL13RA2 axis. The inhibition of DPP4 reduces CD8+ T cell exhaustion and IL13 secretion, while also blocking the IL13-IL13RA2 axis, thereby promoting the mesenchymal-to-epithelial transition of PTC cells. Conclusion: Blocking DPP4 leads to the conversion of exhausted CD8+ T cells with decreased IL13 level, resulting in downregulation of IL13RA2 to promote mesenchymal-to-epithelial transition of PTC cells. This highlights DPP4 as a potential therapeutic target, particularly between CD8+ T cells and PTC cells via IL13-IL13RA2 axis, and represents a novel avenue for combined immunotherapy in PTC.

摘要： Organ transplantation is the last-resort option to treat organ failure. However, less than 10% of patients benefit from this only option due to lack of major histocompatibility complex (MHC)-matched donor organs and 25%-80% of donated organs could not find MHC-matched recipients. T cell allorecognition is the principal mechanism for allogeneic graft rejection. We herein present a "donor MHC-specific thymus vaccination" (DMTV) strategy to induce T cell tolerance to both autologous and allogeneic donor MHC. Allogeneic MHC molecules were expressed in the recipient thymus through adeno-associated virus-mediated delivery, which led to stable expression of allogeneic MHC together with the autologous MHC in the engineered thymus. During local T cell education, those T cells recognizing either autologous MHC or allogeneic MHC were equally depleted. We constructed C57BL/6-MHC and BALB/c-MHC dual immunocompatible mice via thymus vaccination of C57BL/6-MHC into the BALB/c thymus and observed long-term graft tolerance after transplantation of C57BL/6 skin and C57BL/6 mouse embryonic stem cells into the vaccinated BALB/c mice. We also validated our DMTV strategy in a bone marrow, liver, thymus (BLT)-humanized mouse model for immunocompatible allotransplantation of human embryonic stem cells. Our study suggests that the DMTV strategy is a potent avenue to introduce a donor compatible immune system in recipients, which overcomes the clinical dilemma of the extreme shortage of MHC-matched donor organs for treating patients with end-stage organ failure.

关键词： 急性淋巴细胞白血病   黄曲霉菌   护理  

摘要： 该文结合临床资料并回顾相关文献分析了1例急性淋巴细胞白血病合并皮肤黄曲霉菌真菌病的临床特点及护理经验。该案患者化疗后出现多处皮肤软组织感染，伴高热、高钾血症，合并多种影响创口愈合的因素，病理结果诊断为皮肤黄曲霉菌真菌感染。多学科专家会诊后，给予外科清创，配合全身治疗，患者生命体征平稳，好转出院。出院后继续门诊换药，至出院后22 d，全部创口愈合。

关键词： 非洲猪瘟病毒(ASFV)   H108R蛋白   多克隆抗体   免疫原性  

摘要： 本研究旨在制备ASFV H108R蛋白，通过免疫小鼠评价该蛋白的免疫原性，为该蛋白作为疫苗候选抗原的研究提供理论依据。利用生物信息学工具分析H108R蛋白的结构及基本理化性质，选择编码蛋白33-108 AA的基因序列串联融合到原核表达载体，转化后经IPTG诱导表达，用镍亲和层析纯化目标蛋白质。免疫小鼠利用流式细胞术检测脾脏活化的CD4+和CD8+T淋巴细胞，分离小鼠血清测定特异性抗体滴度，利用WB和IFA鉴定多克隆抗体的特异性。并用试剂盒检测血清中细胞因子含量，将血清与ASFV-GFP病毒孵育评估抗体是否能抑制病毒的复制。生物信息学分析表明H108R蛋白为亲水性蛋白质，有跨膜区，无信号肽，蛋白二三级结构中存在较多α-螺旋。SDS-PAGE、Western blotting显示IPTG诱导后，成功表达纯化H108R蛋白。蛋白免疫小鼠后能够诱导小鼠脾脏T细胞的活化，刺激机体产生更高水平的细胞因子。免疫制备的多克隆抗体效价为1∶128 000，能与ASFV-GFP病毒特异性结合，与病毒孵育后能明显抑制病毒的复制。本研究成功表达制备了ASFV H108R蛋白，免疫能够诱导脾脏T淋巴细胞活化，引起细胞因子水平升高，制备的多克隆抗体能够明显抑制病毒的复制，具有较好的免疫原性，为深入研究H108R蛋白的生物学功能及疫苗研究奠定基础。