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关键词： Decitabine   PDGC   Differentiation therapy   Immunity   NK cells  

摘要： Poorly differentiated gastric cancer (PDGC) is characterized by high invasiveness, rapid progression, and poor prognosis for patients. Differentiation therapy has long been a promising approach by manipulating the differentiation state of tumor cells to inhibit tumor growth, offering fewer side effects. Decitabine (DAC), is known as an inhibitor of DNA methylation, thus reactivating the transcription of previously methylated silenced genes associated with differentiation to induce a more differentiated state. This study used the differentiation-inducing agents DAC to treat two PDGC cell lines, MKN45 and NUGC4, and explored the impact of DAC on cell proliferation and influence of their sensitivity to Natural Killer cells (NK cells) mediated cytotoxicity. The results demonstrated a significant reduction in cell proliferation, migration, and invasion without affecting cell viability after DAC treatment. Additionally, transcriptomic analysis revealed that DAC-treated PDGC cells upregulated multiple immune-related genes, including the gene encoding for tumor necrosis factor alpha (TNF-alpha). Co-culture study of NK cells and PDGC cells showed that DAC treatment enhanced the sensitivity of these cancer cells to NK cell-mediated cytotoxicity, and TNF-alpha played a crucial role in promoting NK cell cytotoxicity. Following the subcutaneous implantation of tumors in nude mice, DAC administration significantly inhibited the growth of PDGC tumors and induced the upregulation of differentiation related genes. In summary, DAC effectively reduces the malignant characteristics of the PDGC cells by promoting their transition towards a higher state of differentiation and enhancing their sensitivity to NK cell-mediated killing, providing new insights for the mechanisms of the antitumor effects of DAC.

关键词： AP1-S1   AP1-B1   AP1-G1   AP1-M1   Prognosis   HLA-loss   Immunological regulation  

摘要： The clathrin adaptor protein 1 (AP1) plays a pivotal role in the endocytosis of cell surface proteins and transportation between the golgi apparatus and lysosomes. Despite its critical functions, the implications of AP1 dysregulation in human cancers have yet to be elucidated. The structural analysis of AP1 subunits was conducted utilizing data from the Protein Data Bank (PDB), which is composed of four subunits: AP1-S1, AP1-B1, AP1-G1, and AP1-M1. Notably, the expression levels of AP1 subunits exhibit significant variability between tumor and normal tissues across different cancer types using data from the CPTAC, GEO, and TCGA databases. Kaplan-Meier (K-M) curve analysis has revealed that certain AP1 subunits are correlated with patient prognosis in various cancers. For instance, the AP1-S1 subunit is related to poor survival outcomes in head and neck squamous carcinoma, clear cell renal cell carcinoma, and lung adenocarcinoma. Furthermore, the aberrant expression of AP1-S1 demonstrated a negative correlation with immune cells infiltration, particularly in lung adenocarcinoma. Concurrently, a significant negative relationship between AP1-S1 and HLA molecules was observed, indicating a potential mechanism for AP1-induced HLA degradation. In vitro experiments demonstrated that the knockdown of AP1-S1 led to an upregulation of HLA-B protein expression and inhibited the viability, migration, and invasion capabilities of tumor cells in lung adenocarcinoma cell lines, specifically A549 and H1299. Immunohistochemical staining further revealed the abnormal expression of AP1-S1 in lung adenocarcinoma specimens. Through a comprehensive pan-cancer multi-omics analysis and experimental validation, this study explored the prognostic significance of four AP1 subunits. Additionally, it examined the regulatory relationship between AP1S1 and HLA-B, which may play a role in immune escape. Additionally, the research identified AP1-S1 as a valuable biomarker and a potential target for

摘要： Diffuse large B-cell lymphoma (DLBCL) remains a major clinical challenge and requires the development of new therapeutic approaches. The identification of cuproptosis, a newly defined form of copper-induced cell death, has provided innovative insights for cancer therapy. Here, we report that loss of the mitochondrial matrix reductase FDX1 in DLBCL cells impairs the antitumor effect of elesclomol (ES), which performs its function by transporting excess copper into cells. Overexpressing (OE) FDX1 significantly sensitized DLBCL cells to ES-induced cell death in vitro and enhanced the anticancer activity of ES in vivo. Furthermore, treatment with ES in FDX1-high expression patient-derived xenograft (PDX) showed a significantly greater inhibitory effect than in FDX1-low expression PDX. Mechanistically, FDX1 promotes the induction of IFN-beta-dependent PANoptosis by increasing IRF3 phosphorylation in DLBCL cells upon ES treatment. Consistent with this finding, patient cohort analysis revealed that FDX1 expression correlated positively with enhanced IRF3 phosphorylation. Together, our findings are the first to identify the central role of FDX1 in synergizing with ES to activate IFN-beta signaling and induce PANoptosis. This study enables us to re-explore the clinical anticancer potential of ES as a novel therapeutic strategy for DLBCL.

关键词： Succinate   Type 2 immunity   IL-4   Hif-1 alpha   Colitis  

摘要： Inflammatory bowel disease (IBD) remains a pressing global health challenge, necessitating novel therapeutic strategies. Succinate, a metabolite known for its role in type 2 immunity and tuft cell activation in the small intestine, presents its potential in IBD management. However, its impact on colonic inflammation has not been explored. Here, we demonstrate that succinate administration induces a type 2 immune response, significantly alleviating dextran sulfate sodium (DSS)-induced colonic inflammation. Succinate enhances antibacterial capacity, reduces intestinal permeability, and reshapes the colonic cytokine milieu. Mechanistically, succinate promotes myeloid cell expansion in peripheral blood, mesenteric lymph nodes, and the colonic lamina propria. The protective effects of succinate were abolished in Ccr2-/- mice, confirming the role of monocyte recruitment, but persisted in Rag1- /- mice, indicating independence from adaptive immunity. Adoptive transfer of monocytes from succinate-treated donors mitigated intestinal inflammation in recipient mice. Transcriptomic analysis revealed heightened expression of Il1b and Il6, and higher lactate production in monocytes upon lipopolysaccharide (LPS) stimulation, highlighting a reprogrammed pro-inflammatory trained immunity phenotype. Finally, we identify the IL-4R alpha/Hif-1 alpha axis is critical for succinate-mediated protection. These findings reveal the ability of succinate to reprogram monocytes into protective intestinal macrophages via induction of type 2 response, restoring homeostasis through enhanced barrier function and immune modulation. Our study positions thus uncover succinate as a promising therapeutic candidate for IBD.

关键词： Cell signaling  

摘要： Persisting programmed cell death-1 (PD-1) signaling impairs T cell effector function, which is highly associated with T cell exhaustion and immunotherapy failure. However, the mechanism responsible for PD-1 deubiquitination and T cell dysfunction remains unclear. Here, we show that ubiquitin-specific peptidase 24 (USP24) promotes PD-1 protein stability by removing K48-linked polyubiquitin. Increased interleukin-6 level transcriptionally activates the USP24 expression, which leads to PD-1 stabilization. Furthermore, USP24 deficiency reduces PD-1 levels in CD8+ T cells and attenuates EgfrL858R-driven lung tumorigenesis in Usp24C1695A catalytic deficient mice. Targeting PD-1 stability with the USP24-specific inhibitor USP24-i-101 boosts cytotoxic T cell activity, restrains lung tumor growth, and achieves superior therapeutic effects when combined with anti-CTLA4 immunotherapy. Clinically, patients with lung cancer exhibiting high USP24 expression in tumor-infiltrating CD8+ T cells display exhausted features and show unfavorable responses to immunotherapy. Our findings dissect the mechanism for regulating enhanced PD-1 stability in tumor-infiltrating CD8+ T cells and reveal USP24 as a potential target of antitumor immunotherapy.

关键词： Inflammatory bowel disease   Phellodendrine   IL-17 signaling pathway   Intestinal mucosal barrier   Inflammation  

摘要： Background: Phellodendrine (PHE) has anti-inflammatory and antioxidant effects. However, the function of PHE in treating inflammatory bowel disease (IBD) has not been fully elucidated. The aim of this study was to investigate the effects and mechanisms of PHE on IBD with in vivo and in vitro assays. Materials and Methods: Bioinformatics was used to identify hub genes associated with IBD pathogenesis. Virtual screening was applied to predicting the natrual compounds targeting hub genes. A mouse model with colitis was established by oral administration of 3 % dextran sulfate (DSS), and the mice were treated with normal saline or PHE (30 mg/kg/day or 80 mg/kg/day). On day 14, the mice were sacrificed and their colons were collected for measurement and histological analysis. The pathological change and inflammation of the tissues in different groups also were evaluated. In addition, the intestinal epithelial Caco-2 cell line was treated with lipopolysaccharide (LPS) to establish an in vitro intestinal inflammation model. CCK-8 assay and flow cytometry were used to detect the effects of PHE (10 mu M or 40 mu M) on cell viability and apoptosis. Western blot was used to the investigate the regulatory effects of PHE on the expression levels of zonula occludens 1 (ZO-1), occludin, claudin1, collagen type I alpha 1 (COL1A1), vascular cell adhesion molecule 1 (VCAM1), interleukin-17 A (IL-17 A), phosphorylated AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). Results: COL1A1 and VCAM1 were identified as therapeutic targets in IBD. PHE was identified as a natural drug simultaneously targeting COL1A1 and VCAM1. PHE treatment alleviates the weight loss and symptoms of mice induced by acute colitis. PHE treatment reduced myeloperoxidase (MPO) activity and pro-inflammatory cytokine levels in colonic tissues, and inhibited expression levels of COL1A1, VCAM1 and IL-17 A, and promoted expression levels of ZO-1, occludin and claudin-1. In vitro, PHE treatmen

关键词： Allergic rhinitis   The aryl hydrocarbon receptor   M2 macrophage  

摘要： Background: Epidemiological evidence suggests that environmental pollutants precipitate the occurrence of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR), a receptor or sensor for various contaminants, is closely related to immunomodulation and the polarization of M2 macrophages. However, the mechanisms involving AhR and M2 macrophages in AR remain unclear. Methods: Bioinformatics analysis of GEO datasets (GSE180697 and GSE180697) assessed AhR and IL4I1 expression levels, which were then verified in the nasal mucosa, monocytes and serum of patients with AR using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Primary human mononuclear cells were isolated from peripheral blood using a magnetic separation technique, and THP-1 cell lines with IL4I1 overexpression or downexpression were established through lentiviral constructs. M2 macrophages were induced with the cytokines CSF, IL4 and IL13 and then treated with the AhR agonist FICZ or inhibitor CH223191. The polarization of M2 macrophages was measured by flow cytometry and western blotting. Furthermore, primary nasal epithelial cells and macrophages were co-cultured to assess the epithelial-mesenchymal transition (EMT) in epithelial cells. The AR murine model was established using ovalbumin (OVA). Inflammation within the nasal mucosa and lung tissue was examined after CH223191 or IL4I1 treatment. Results: Nuclear translocation of AhR and upregulation of IL4I1 was observed in peripheral mononuclear cells and nasal mucosal tissue of patients with AR. Through the activation of AhR, IL4I1 promoted M2 macrophage polarization. Furthermore, modulation of the IL4I1/AhR axis regulated the migratory impact of OVA on T-M2 cells. The IL4I1/AhR axis was involved in the regulation of M2 macrophage-associated EMT and contributed to the expression of IL-33 and STAT6 phosphorylation in epithelial cells. In AR mice, increased A

关键词： Abdominal aortic aneurysm   Macrophages   M1 macrophage polarization   IL-7/IL-7R   NF-kappa B pathway  

摘要： BackgroundAbdominal aortic aneurysm (AAA) is a common degenerative disease of the abdominal aorta, which can result in extremely high mortality owing to the rupture of the abdominal aorta. The activation of IL-7R has been shown to modulate the inflammatory responses, which play an important role in the progression of AAAs. However, the mechanism of IL-7/IL-7R axis in AAAs is still *** study aims to investigate the effects of IL-7R on AAAs and the underlying mechanisms ***-type C57BL/6 and IL-7R knockout mice were used as experimental subjects. ELISA analysis, histological staining, western blotting and qPCR were performed to explore effects of IL-7R deficiency in the formation and development of elastase-induced AAAs. Transwell, CCK8, and immunofluorescence assays detected the migration and polarization of RAW264.7 macrophages in *** demonstrated that IL-7R was elevated in mice with AAAs. Blocking IL-7R can inhibit the formation of AAAs and reduce aortic dilatation, elastic layer degradation, and inflammatory cell infiltration. Knockout of IL-7R suppressed the migration, infiltration and M1 polarization of macrophages. Moreover, inhibition of the NF-kappa B signaling pathway by BAY 11-7082 attenuated the macrophage-mediated inflammatory responses caused by IL-7R *** short, this study showed that IL-7R promotes the infiltration and migration of macrophages by regulating M1 macrophage polarization, possibly in part via activation of the NF-kappa B pathway, which may be associated with the development of AAAs.

关键词： amino acid residues   Aves   beta-2-microglobulin   birds   Carduelis   codons   diseases   HLA   hydrogen bound   intron   malaria   Marek's disease   MHC (Major Histocompatibility Complex)   molecules   Passeriformes   Serinus   Spinus   vertebrates   wild birds  

摘要： There are about 5000 species of Passeriformes birds, which are half of the extant ones. Their class I MHC molecules are found to be different from all other studied vertebrates, including other bird species;i.e., amino acid residues 10 and 96 are not the seven canonic residues extant in all other vertebrate molecules. Thus, the canonic residues in MHC class I vertebrate molecules are reduced to five. These differences have physical effects in MHC (Major Histocompatibility Complex) class I alpha chain interaction with beta-2-microglobulin but have yet unknown functional effects. Also, introns show specific Passeriformes distinction both in size and invariance. The studies reviewed in this paper on MHC structure have been done in wild birds that cover most of the world's passerine habitats. In this context, we are going to expose the most commonly occurring bird diseases with the caveat that MHC and disease linkage pathogenesis is not resolved. In addition, this field is poorly studied in birds;however, common bird diseases like malaria and Marek's disease are linked to MHC. On the other hand, the main established function of MHC molecules is presenting microbial and other antigens to T cells in order to start immune responses, and they also may modulate the immune system through NK receptors and other receptors (non-classical class I MHC molecules). Also, structural and polymorphic differences between classical class I molecules and non-classical class I molecules are at present not clear, and their definition is blurred. These passerine exceptional MHC class I molecules may influence linkage to diseases, transplantation, and other MHC presentation and self-protection functions. Further studies in more Passeriformes species are ongoing and needed.