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关键词： Carvedilol   Intestinal ischemia reperfusion   Interleukin 1(3   Vascular endothelial growth factor  

摘要： Intestinal ischemia reperfusion (IIR) is a life threating clinical disorder and a serious emergency case with high mortality rate. Finding ameliorative agents is a critical requisite to safeguard the tissue against its harmful effect not only on the intestine, but also on other organs especially the heart. Therefore, we tried in the current study to evaluate the role of carvedilol (CAR);an effective beta and alpha blocker with anti-oxidant, anti-apoptotic, antiinflammatory properties and a metabolic regulator, on both cardiac and intestinal tissue in a model of IIR. Rats were randomly allocated into 4 groups: Sham group, IIR group and CAR treated groups with IIR in 2 different doses;CAR treated group in low dose (CLD) (10 mg/kg), CAR treated group in high dose (CHD) (20 mg/kg). Interestingly, CAR significantly decreased the elevated levels of cardiac enzymes, tissue malondialdehyde (MDA), inflammasome, interleukin 1(3 (IL1(3), tumor necrosis factor alpha (TNF alpha) and caspase3. However, CAR co administration normalized the tissue level of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), antioxidant parameters;reduced glutathione (GSH), total antioxidant capacity (TAC) with obvious improvement of the histopathological changes. CAR could ameliorate IIR induced damage in a dose dependent manner via its anti-oxidant and anti-inflammatory properties with regulation of eNOS/VEGF-A and inflammasome/IL1(3/TNF alpha pathways and it can be considered as a potential therapeutic agent against such injury.

关键词： Autism spectrum disorders   Cytokines   Immune dysfunction   Low-dose IL-2   Regulatory t cell  

摘要： BACKGROUND:Autism spectrum disorder (ASD) is a complex neurodevelopmental condition for which there are no definitive medications targeting core symptoms. Growing evidence indicates that individuals with ASD exhibit immune dysfunction and evidence of peripheral and central inflammation. Immunotherapy interventions have shown promise in addressing this dysregulation. Notably, low-dose Interleukin-2 (Ld IL-2), an established treatment for certain autoimmune diseases, represents a potential therapeutic approach. Our study aims to investigate the association between Ld IL-2-induced immune modulation and behavioral improvements in children with ASD. This research may offer novel insights into potential treatment strategies for ASD. CASE PRESENTATION:In our previously completed single-arm, self-controlled clinical study (data unpublished), 24 ASD children with immune abnormalities received Ld IL-2 treatment, all of whom showed varying degrees of symptom improvement. This paper presents case reports of four ASD children who demonstrated marked clinical improvement and substantial correction of immune imbalance following treatment. The average age of 4 participants was approximately 6 years old, comprising two boys and two girls. Assessments using the Childhood Autism Rating Scale(CARS), Aberrant Behavior Checklist (ABC), Autism Treatment Evaluation Checklist (ATEC), Krug's Autism Behavior Scale (CABS), Hospital Anxiety and Depression Scale (HADS), and Caregiver Strain Questionnaire (CGSQ)revealed substantial behavioral improvements and no adverse events. Improvements persisted for three months post-treatment, with notable progress in Speech/Language/Communication and body/health/behavior domains. According to caregivers, there has been a observed improvement in the subjects' sleep quality, accompanied by a gradual restoration of overall physical health. Immune testing in the four pediatric patients revealed a marked decrease in both the proportion of Type 1 cytotoxic T cel

关键词： antibody mediated rejection   delayed graft function   donor specific antibodies   endothelial to mesenchymal transition   kidney transplantation  

摘要：

关键词： HLA   HLA-DRB3*02:238   novel allele   sequencing-based typing  

摘要： HLA-DRB3*02:238 differs from HLA-DRB3*02:24 by one nucleotide substitution in codon 60 in exon 2.

关键词： Arginase-1   Cytosolic release   TNF-alpha-siRNA   Silencing efficiency   Ulcerative colitis  

摘要： Efficient cytosolic delivery of small interfering RNA (siRNA) remains a challenge in RNA therapeutics, particularly for oral administration. Identifying new cytosolic stimulus-responsive targets is thus crucial for optimizing siRNA delivery. Given the elevated intracellular arginase-1 (Arg1) levels in inflamed colonic mucosa, we developed lipid nanoparticles (siRNA-LANPs) derived from L-arginine-modified chitosan (ACS) for the cytosolic release of TNF-alpha-siRNA to treat ulcerative colitis (UC). The siRNA-LANPs exhibited superior Arg1-binding affinity compared to its substrate, L-arginine, enabling rapid Arg1-responsive release. Moreover, we found that siRNA-LANPs maintained nanoparticle stability, and 84.5 % of the loaded siRNA remained intact in simulated digestive fluids over 12 h. Following oral administration, siRNA-LANPs efficiently penetrated the mucus layer and preferentially accumulated in inflamed colonic tissue compared to healthy colon tissue. In DSS-induced colitis mice, siRNA-LANPs significantly reduced disease severity through TNF-alpha silencing, achieving greater therapeutic efficacy than sulfasalazine (a first-line UC treatment). The siRNA-LANPs exhibited superior TNF-alpha silencing compared to transfection reagent Lipo3000 and TNF-alpha biologic agent infliximab. The enhanced performance was attributed to multiple endocytic pathways, improved lysosomal escape capability (29.7 %), and Arg1-mediated cytoplasmic siRNA release. In summary, Arg1 seems to be a promising intracellular target for stimulus-responsive, oral siRNA delivery in UC treatment.

关键词： Adoptive cell therapy - ACT   Chimeric antigen receptor - CAR   Macrophage   Tumor microenvironment - TME  

摘要： BACKGROUND:Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks hormone receptors and human epidermal growth factor receptor 2 (HER2) amplification, making it unresponsive to standard hormone or HER2-targeted therapies. Although immune checkpoint inhibitors (ICIs) have shown promise in tumors with high lymphocyte infiltration, their efficacy remains limited in tumors with minimal lymphocyte infiltration. Inflammatory macrophages are associated with better prognosis and response to ICIs. The tumor microenvironment (TME), however, is rich in interleukin (IL)-10 and transforming growth factor β (TGF β) inducing immunosuppressive, protumoral macrophages. Therefore, we engineer macrophages with a chimeric cytokine receptor (ChCR), designed to bind IL-10 or TGFβ and promote the generation of inflammatory and antitumoral active macrophages. Such genetically modified macrophages could be used as adoptive cell therapy (ACT). METHODS:The ChCRs consist of the extracellular domains of the IL-10 or TGFβ receptor fused to the intracellular domains of interferon (IFN)-γ receptor. Upon binding IL-10 or TGFβ, the ChCRs shall trigger STAT1 signaling, eventually rendering the macrophages pro-inflammatory. We transduced human primary macrophages with a lentiviral vector expressing the ChCR and analyzed their phenotype, secretome, and transcriptome following stimulation. Moreover, we assessed their antitumoral activity in a three-dimensional (3D) co-culture assay with TNBC spheroids. RESULTS:ChCR macrophages showed robust STAT1 activation in response to IL-10 or TGFβ stimulation, resulting in an inflammatory phenotype similar to IFN-γ-activated macrophages, as confirmed by phenotypic markers, and transcriptomic profiling. These stimulated ChCR macrophages demonstrated significant antitumoral effects in 3D TNBC spheroids. Moreover, ChCR stimulation led to the upregulation of and , chemokines essential for lymphocyte recruitment, and genes assoc

关键词： MHC-I Antigen Presentation   Immune Escape   GLDC   EGFR Activation   ICB Therapy  

摘要： Inadequate antigen presentation by MHC-I in tumor microenvironment (TME) is a common immune escape mechanism. Here, we show that glycine decarboxylase (GLDC), a key enzyme in glycine metabolism, functions as an inhibitor of MHC-I expression in EGFR-activated tumor cells to induce immune escape by a mechanism independent of its enzymatic activity. Upon EGFR activation, GLDC is phosphorylated by SRC and subsequently translocated to the nucleus in human NSCLC cells. Nuclear GLDC sequesters STAT1 co-activator SMARCE1, inhibiting STAT1-dependent transcription of the inflammatory genes IRF1 and NLRC5. Further, GLDC recruits DNMT1 to the IRF1/NLRC5 promoter inducing DNA hypermethylation, suppressing transcription of downstream MHC-I genes. Inhibition of GLDC restores MHC-I levels in tumor cells, improves tumor-specific CD8+ T cells functions in the TME, and rescues anti-tumor effects of PD-1 blockade therapy in mice. Our findings reveal a non-enzymatic nuclear function for GLDC in the suppression of MHC-I antigen presentation, suggesting new strategies for ICB-based combination immunotherapy.

摘要： Celiac disease, an enteropathy driven by a maladaptive immune response to dietary gluten, is marked by increased proliferation in intestinal crypts, or crypt hyperplasia. However, it is unknown whether this phenomenon is a compensatory response to loss of villus epithelial cells or if it is driven by independent mechanisms. In this issue of the JCI, Stamnaes et al. demonstrated that in untreated celiac disease, crypt cells had increased expression of proteins involved in the IFN response, with decreased expression of fatty acid metabolism pathways. These expression patterns were recapitulated in mice treated with IFN-γ, but not mice with intestinal epithelial cell-specific knockout of the IFN-γ receptor. The findings suggest that crypt cells were reprogrammed directly by IFN-γ signaling, independent of changes to epithelial villi.

关键词： Polydopamine   Silk fibroin   Niobium   Hydrogels   Osteogenesis and angiogenesis  

摘要： Bone defects, caused by various conditions present significant clinical challenges due to their complexity and the limitations of existing treatment options. In this study, a niobium-loaded polydopamine-silk fibroin hydrogel (PDA@SF@Nb Gel) was explored for its potential to repair bone defects, focusing on its ability to scavenge ROS, promote osteogenesis, and enhance angiogenesis. In vitro experiments confirmed the hydrogel's biocompatibility, non-toxicity, and ability to reduce ROS levels, while enhancing cell migration, osteogenic differentiation, and angiogenesis. In vivo, the rat bone defect model showed improved bone regeneration and structural integrity through X-ray, micro-CT imaging, and histological assessments, which confirmed the expression of key osteogenic and angiogenic markers. Transcriptomic analysis of treated chondrocytes showed restored cellular function and suppression of inflammatory pathways, with downregulation of IL-17A and IL-6 signaling. Western blot confirmed that PDA@SF@Nb Gel inhibited IL-6, IL-17, and the phosphorylation of JAK and STAT3, highlighting the role of the IL-17/IL-6-JAK/STAT3 axis in its anti-inflammatory effects. Inhibitor studies further validated this pathway. Biosafety evaluations confirmed the hydrogel's excellent biocompatibility and safety, reinforcing its potential for bone and vascular tissue regeneration in bone repair applications.

关键词： 非洲猪瘟病毒   B169L蛋白   原核表达   多克隆抗体  

摘要： B169L是非洲猪瘟病毒（ASFV）编码的一种膜蛋白，其具体生物学功能尚不明确。为探究其作用机制，本研究制备了B169L多克隆抗体。首先，通过在线生物信息学工具预测，B169L蛋白包含两段跨膜区和一个信号肽，提示其可能定位于内质网。随后，利用大肠杆菌原核表达系统表达并纯化去除跨膜区的B169L蛋白，以此免疫家兔获得多克隆抗体。免疫印迹结果表明，该抗体可特异性识别ASFV感染细胞中表达的B169L蛋白。上述结果表明，本研究成功制备了特异性的B169L多克隆抗体，为后续解析ASFV膜蛋白B169L的结构与功能奠定了实验基础。