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关键词： disitamab vedotin   RC48   bladder cancer   TNF signaling pathway   NF-kappa B signaling pathway  

摘要： Disitamab Vedotin has shown good therapeutic efficacy against bladder cancer. Although its mechanism is clear, the regulation of gene expression in bladder cancer cells by Disitamab Vedotin is not fully understood. We searched the GEO database and identified the GSE237789 dataset, in which researchers treated the bladder cancer cell line SW780 with Disitamab Vedotin and performed high-throughput transcriptome sequencing. Compared with the control SW780 cells, the expression levels of the vast majority of genes (16,223/16,390, 98.98%) in Disitamab Vedotin-treated SW780 cells remained unchanged. Only one hundred fifty-nine genes (0.97%) were upregulated, and eight genes (0.05%) were downregulated. Enrichment analysis results showed that the related differentially expressed genes (DEGs) were mainly enriched in the TNF signaling pathway, NF-kappa B signaling pathway, and other pathways. Protein-protein interaction analysis revealed that 10 genes, TNF, IL1B, IL1A, CXCL8, CXCL1, CCL2, MMP9, ICAM1, CXCL10, and CCL20, had the highest connectivity, and all of these genes belong to the TNF signaling pathway. These results suggest that the TNF signaling pathway is the key pathway regulated by Disitamab Vedotin in bladder cancer cells, which may represent a stress response of bladder cancer cells to Disitamab Vedotin.

关键词： IL-1 superfamily   evolution   therapeutic targets   disease implications   cross-species analysis  

摘要： An important area of interest for therapeutic development is the IL-1 superfamily, a critical group of immune regulators with profound implications in a variety of disorders. This study clarifies the evolutionary patterns of IL-1 family members by thoroughly analyzing more than 400 animal species, demonstrating their ancient roots that extend back to the earliest vertebrates. Important results show that, although IL-1 ligands expanded significantly over the evolution of mammals, their corresponding receptors remained remarkably structurally conserved. Identifying both lineage-specific adaptations and evolutionarily conserved residues provides vital information for treatment design. These findings point to the possibility of two different therapeutic strategies: addressing species-specific variants may allow for more targeted interventions, whereas focusing on conserved motifs may result in broad-acting treatments. The study also identified less well-known species as useful models for comprehending early immune systems. In addition to advancing our knowledge of the function of the IL-1 family in autoimmune, inflammatory, and carcinogenic illnesses, this research lays the groundwork for the development of more potent targeted therapeutics by creating an evolutionary framework for the IL-1 family.

关键词： 4-dimensional computed tomography   heterogeneity   interleukin-6   mechanical ventilation   X-ray velocimetry  

摘要： This study aimed to characterize how peak inspiratory pressure (PIP) and positive end-expiratory pressure (PEEP) influence regional lung volume heterogeneity as a result of mechanical ventilation and the influence of this heterogeneity on markers of inflammation within the lungs. Four groups of BALB/C mice (n = 7 or 8 per group) were mechanically ventilated for 2 h using low or high (12 cmH(2)O or 20 cmH(2)O) peak inspiratory pressure (PIP) with or without 2 cmH(2)O positive end-expiratory pressure (PEEP). Four-dimensional computed tomography (4-DCT) images were acquired using synchrotron-based radiation source at baseline and after 2 h. Regional tidal volumes were obtained by 4-D cross-correlational X-ray velocimetry, whereas end-expiratory volume was quantified by Hounsfield units. Tissue was harvested from 10 lung regions, and expression of IL-6 and monocyte chemo-attractant protein 1 (MCP-1) was quantified using qPCR. We found a significant reduction in specific end-expiratory volume (sEEV) in mice ventilated with low PIP and no PEEP and a reduction in tidal volume in groups without PEEP. End-expiratory volume heterogeneity decreased in the low PIP and no PEEP group, whereas tidal volume heterogeneity decreased in the equivalent high PIP group, potentially due to regional redistribution of lung volumes. We found associations between IL-6 expression and tidal volume heterogeneity. In this study, we have demonstrated that changes in PIP and PEEP impact atelectasis, overdistension, and heterogeneity, and that increases in tidal volume heterogeneity may be driving IL-6-mediated biotrauma. These findings highlight the importance of considering the spatial distribution of tidal volumes as a driver of lung injury during mechanical ventilation. NEW & NOTEWORTHY The combination of low inspiratory and expiratory pressure promotes atelectasis but is not associated with markers of injury in the healthy lung during short-term ventilation. High inspiratory pressures promote t

关键词： Fluoxetine   Treatment-resistance   IL-17   JAK1-STAT6 signaling pathway  

摘要： Aims: This study aims to investigate the role of IL-17 in fluoxetine resistance in depression. Methods: The Weighted Gene Coexpression Network Analysis (WGCNA) was utilized to analyze differentially expressed genes between response to antidepressant (GRA) group and the resistance to antidepressant (AR) group. Furthermore, a treatment resistance model of depression was established in Chronic unpredictable mild stress (CUMS) mice administrated with fluoxetine (widely used clinical medication for the treatment of depression) according to sucrose preference rate. Depression-like behaviors in mice were detected in Control group, CUMS group, GRA group, AR group, and SR1001 (Th17 differentiation inhibitor) group. Subsequently, HT22 cells were exposed to IL-17 secreted by Th17 differentiation. Transcriptome sequencing from the Control and IL-17 group was used to screen differential genes. HT22 cells were then transfected with si-JAK1 or si-STAT6. Th17 differentiation, the integrity of the blood-brain barrier (BBB), JAK1-STAT6 signaling pathway related proteins were detected by western blot, immunocytochemistry, flow cytometric analysis, ELISA experiments, immunofluorescence, and PCR. Result: The WGCNA showed that Th17 differentiation played an important role in the treatment resistance of depression. The results of the following animal experiments showed that fluoxetine resistance resulted in a reduction in total distance and average speed in the Open Field Test (OFT), an increase in immobility time during the Forced Swim Test (FST) and Tail Suspension Test (TST). It also regulated the expression of the SERT protein, Th17 differentiation, IL-17 secretion, and compromised the integrity of BBB, yielding similar outcomes in CUMS mice. However, these results could be reversed by SR1001. Moreover, IL-17 effectively elevated the SERT protein level and activated the JAK1-STAT6 signaling pathway in vivo and in vitro.

关键词： IL-22   Predictive biomarker   Radiation   Intestinal injury   Radiosensitivity  

摘要： Considering the beneficial role played by IL-22 in alleviating radiation-induced intestinal injury through its promotion of epithelial regeneration, it was hypothesized that individuals with elevated IL-22 levels might display either minimal intestinal injury or increased resistance following ionizing irradiation exposure. To assess the impact of IL-22 on intestinal radiosensitivity, IL-22 expression levels was detected in serum of normal mice. Mice naturally with high or low levels of IL-22 or pretreated with IL-22 or anti-IL-22 were subjected to 10 Gy of total abdominal radiation (TAI). Daily observation, morphometric analysis, quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry and western blot were employed to measure weight loss, survival rate, cell proliferation and death, and DNA damage. Furthermore, influence of IL-22 pretreatment on survival of intestinal organoid exposed to 6 Gy X-rays was evaluated. The results showed that IL-22 expression levels were varied between individuals. Surprisingly, mice with high IL-22 levels displayed exacerbated intestinal injury manifesting as increased weight loss, reduced regeneration capacity and more cell apoptosis. Notably, a strong positive correlation between weight loss and IL-22 expression level was observed. Additionally, pretreatment with IL-22 resulted in increased mortality accompanied by enhanced cell apoptosis and DNA damage in crypt of early exposure, as well as diminished survival of intestinal organoid, while pretreatment with anti-IL22 antibody alleviated the intestinal injury. In this study, we established a direct link between IL-22 and radiosensitivity, suggesting IL-22 could be used as a potential biomarker for predicting individual intestinal radiosensitivity prior to radiation exposure.

关键词： IL-27   Diabetic wound healing   Macrophage   M1-to-M2 polarization   STAT3  

摘要： Diabetic foot ulcer (DFU), a serious complication of diabetes, is a life-threatening disease that often leads to lower limb amputation and a shortened lifespan. Interleukin-27 (IL-27) is a member of the IL-12 family and has the potential to exert dual effects on the immune response. The role of IL-27 in diabetic skin wound healing is unknown. The aim of this study was to investigate whether there is abnormal expression of IL-27 in diabetic skin and whether supplementation with IL-27 can promote diabetic wound healing by modulating macrophage polarization. We established a streptozotocin (STZ)-induced diabetic mouse model and constructed diabetic wounds. We assessed protein expression by western blotting (WB) and immunohistochemical (IHC) staining. We also performed hematoxylin-eosin (H&E) staining and Masson's trichrome staining. In the presence of lipopolysaccharide (LPS) and high glucose (HG), we treated the mononuclear macrophage line RAW264.7 and bone marrow-derived macrophages (BMDMs) with IL-27. To assess macrophage polarization, we examined the expression of inducible nitric oxide synthase (iNOS), IL-1 beta and arginase-1 (Arg-1). To understand the underlying mechanisms, we used macrophage IL-27ra knockout mice to knockout macrophage IL-27 receptors. Our in vivo experiments revealed that the expression of IL-27 in the skin of diabetic mice was significantly decreased and that supplementation with IL-27 promoted diabetic wound healing. In vitro, compared with the LPS group, supplementation with IL-27 alleviated the suppression of multiple cellular functions, such as iNOS and IL-1 beta expression, cell migration, and phagocytosis, in macrophages after HG exposure. Mechanistically, we found that IL-27 expression was decreased and that the activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation was inhibited in diabetic skin, leading to an inability of wound macrophages to polarize to an M1 phenotype effectively, which in turn

关键词： Biological sciences   Immunology   Components of the immune system   Specialized functions of cells  

摘要： Chimeric antigen receptors-natural killer (CAR-NK) cells are a promising new cancer treatment approach. They possess distinct benefits over CAR-T cells, including an intrinsic ability to differentiate between malignant and non-malignant cells, and a lower risk of graft-versus-host disease. Here, we evaluated two CAR-NK-92 cell lines, targeting either CD276 or HER2, and their potential on-target/off-tumor effects in vitro. CD276-directed CAR-NK-92 cells showed little dependence on target antigen density, while HER2-directed CAR-NK-92 displayed a pronounced dependence on target antigen density, mostly sparing target cells with low amounts of HER2. The activity of both cell lines was modulated by the expression of HLA-I on target cells, ultimately reducing their activity against non-malignant cells. Lower modulation of activity of HER2-directed CAR-NK-92 can be explained by the lower surface expression of inhibitory NK receptors, such as NKG2A and ILT-2. These results underscore the importance of thoroughly testing new cell products to fine-tune anti-cancer activity, while limiting potential on-target/off-tumor toxicity.

关键词： Components of the immune system   Immunology   Transcriptomics  

摘要： Janus kinases (JAK) mediate signaling pathways of multiple cytokines, including interferon-gamma (IFN-gamma), which plays a pivotal role in rheumatoid arthritis (RA) pathogenesis. Although JAK inhibitors (JAKi) have demonstrated efficacy for RA, their molecular effects on macrophages remain incompletely understood. We investigate the impact of JAKi on IFN-gamma-induced gene expression in human macrophages, uncovering that JAKi selectively modulates only a subset of IFN-gamma-induced genes. Integrated transcriptomic and epigenomic analyses demonstrate that JAKi effectively inhibits IFN-gamma signature genes associated with IRF1-STAT1-depen-dent accessible chromatin regions. However, genes regulated by AP-1 and C/EBP remain insensitive to JAKi and overlap significantly with TNF-induced genes. Single-cell analysis of RA patient samples identifies macrophage subpopulations with variable JAKi sensitivity. Certain JAKi-insensitive genes in IFN-gamma-primed macrophages are suppressed by JNK inhibitors. Our findings elucidate JAKi responsiveness mechanisms through IFN-gamma-induced epigenomic remodeling, providing insights into inflammatory regulation in RA and suggesting strategies to overcome JAKi resistance.

关键词： immunotherapy   T cell immunity   pMHC-I   gene level regulation   epigenetic level regulation   protein level regulation  

摘要： T cell immune responses are triggered by antigenic peptides presented through major histocompatibility complex class Is (pMHC-Is), which play an important role in the genesis, development, and therapy of tumors. The capacity of a specific pMHC-I to elicit T cell responses is deeply influenced by its expression level (quantity) and its immunogenicity (quality). Tumor cells can evade T cell immunity by down-regulating the quantity of pMHC-Is or selectively eliminating highly immunogenic antigenic peptides. Augmenting the quantity or quality of pMHC-Is is essential for tumor immunotherapy. However, the complexity of pMHC-I regulation and tumor heterogeneity pose challenges to clinical strategies. Consequently, developing approaches grounded in comprehensive analyses of pMHC-I regulatory mechanisms remains a focal point in the research of T cell immunity. In this review, we discuss how tumors modulate their surface pMHC-Is through genetic, epigenetic, and proteomic mechanisms and summarize potential therapeutic strategies targeting these mechanisms, which may provide a valuable reference for the development of novel tumor immunotherapies based on pMHC-I *** cells can achieve immune escape by interfering with the quantity and quality of pMHC-Is, and corresponding immunotherapy can also be achieved by the regulation of pMHC-Is.

关键词： Evolutionary biology   Genomics   Ornithology  

摘要： The major histocompatibility complex (MHC) genes are vital for the adaptive immune response in vertebrates and are widely used in conservation genetics to represent adaptive variation. Accurate genotyping of MHC alleles is essential for effective conservation, particularly for endangered species like the yellow cardinal (Gubernatrix cristata). However, the absence of locus-specific primers and the highly repetitive nature of these genes present a technical limitation when using short-read sequencing technologies. We produced the first high-quality long-read reference genome for the yellow cardinal. This genome reveals sustained high genome-wide heterozygosity despite inbreeding, with homozygosity patterns and effective population size estimates indicating a long-term decline. We identified seven genomic MHC-I loci, while amplicon sequencing with non-locus specific primers had not confirmed more than two MHC-I loci. Our study also revealed mismatches in primer binding sites across multiple loci, emphasizing the need for high-quality, long-read genomic data to understand the genomic architecture of MCH and to accurately assess locus specific MHC variation.