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关键词： TLRs   DAMPs   M2 macrophage   IL-6   HSP72  

摘要： BackgroundM2-polarized macrophages aggressively modulate the tumor microenvironment and enhance tumor cell malignancy. As intracellular molecules are released by damaged or stressed cells, damage-associated molecular patterns (DAMPs) bind to toll-like receptors (TLRs) on cells in the tumor microenvironment, inducing inflammation and epithelial-mesenchymal transition. However, recent studies on the crosstalk between DAMPs and M2-polarized macrophages (M2 macrophages) during tumor progression have not provided conclusive *** investigated the role of toll-like receptors (TLRs) in IL-6 production by M2 macrophages and searched for cancer cell-derived DAMPs that can activate the TLRs responsible for IL-6 ***2 activation was required for IL-6 production by M2 macrophages. The malignancy of cancer cells was increased by the activation of this pathway. Cancer-derived HSP 72 acted as a ligand that stimulates the TLR2 signaling pathway in M2 macrophages, triggering IL-6 *** 2 stimulation in M2 macrophages enhances tumor malignancy by upregulating IL-6. Heat shock protein 72 (HSP72) is a potent TLR2 stimulator. Our findings reveal a connection between TLR2 and M2-polarized macrophages in tumor malignancy and may be useful for developing effective treatments for tumor relapse.

关键词： HLA‐B*40:542   next‐generation sequencing   novel allele  

摘要： HLA-B*40:542 differs from the HLA-B*40:23 allele by two nucleotide substitutions in exon 3.

关键词： NOD-like receptor   VHSV   Knockout   Zebrafish   Nlrc5  

摘要： Nucleotide-binding domain and leucine-rich repeat-containing receptors (NLRs) have complex and diverse functions. Studies in mammalian models have indicated a clear role of NLRC5 in the regulation of MHC-I gene expression. The nlrc5 KO zebrafish model was generated using CRISPR/Cas9 technology to understand its function with respect to VHSV. The VHSV infection experiment demonstrated higher mortality in nlrc5 KO fish with higher VHSV copy numbers. Virus-infected pathology, such as tissue swelling, hemorrhage, and eye bulging, was significantly higher in the nlrc5 KO fish. Expressional analysis of ifn system genes indicated the significant upregulation of ifn phi 1. Gene expression analysis during VHSV infection indicated a significant downregulation of MHC-I genes in the nlrc5 KO model compared to the wild-type (WT). Owing to the impact of MHC-I, the viral copy number may increase with higher mortality under VHSV infections. For neutrophil migration analysis, a nlrc5 KO and a neutrophil-labeled model were developed (nlrc5-/- Tg(mpx:mcherry)). Injury was generated in the caudal fin, and the injury site was stimulated with poly I: C. The number of neutrophils were reduced in the nlrc5 KO fish. Levels of critical cytokines responsible for neutrophil migration were significantly reduced in nlrc5 KO fish during VHSV infection. The data from the current study in zebrafish reconfirm the observations in mammalian models, and neutrophil migration analysis suggests that Nlrc5 may be associated with inflammatory activation in the presence of VHSV.

关键词： Lycium barbarum glycopeptide   Alkali burn   Inflammation   miR-21a-5p   Fibrosis  

摘要： Lycium barbarum glycopeptide (LbGp), derived from the Chinese medicinal plant Lycium barbarum, has demonstrated anti-inflammatory properties;however, its precise role and mechanism in corneal repair following injury remain elusive. The present research investigated the mechanisms and effects of LbGp on corneal repair following alkali burn injury using in vivo mouse models of corneal alkali burn and in vitro human keratocyte fibrosis models. Corneal inflammation, opacity, and epithelial defects were assessed via a slit lamp microscope. Results showed that LbGp-treated mice exhibited reduced edema, accelerated re-epithelialization, and decreased corneal opacity compared to the phosphate-buffered saline (PBS)-treated controls. Proteomic analysis revealed altered proteins enriched in the extracellular matrix among the control, injury, and LbGp treatment groups. Moreover, LbGp significantly attenuated TGF(3-1-induced myofibroblasts transdifferentiation from keratocytes. Consistently, LbGp treatment inhibited the upregulation of fibrosis markers (aSMA, fibronectin, and collagen III) at both the protein and mRNA levels after corneal alkali burns. LbGp also effectively suppressed the activation of the NF-xB/NLRP3/IL-1(3 signaling pathway and neutrophil infiltration following corneal alkali burn injury. Additionally, miR-21 was upregulated in TGF(3-1-stimulated keratocytes and in the alkali-burned mouse cornea. LbGp decreased miR-21 expression, while increasing expression of its target, Smad7, thereby dampening the TGF(3/Smad2/3 signaling pathway. This research demonstrates that LbGp promotes corneal healing by inhibiting inflammation and fibrosis after alkali burns, suggesting its potential as a supplementary therapy for corneal injury repair.

关键词： chimeric antigen receptor   T-cell therapy  

摘要： Background and Aims:Glypican-3 (GPC3) is a promising target for T-cell therapy in HCC. While chimeric antigen receptor (CAR) T cells targeting GPC3 have demonstrated therapeutic efficacy, their effectiveness is limited by challenges such as low persistence and shedding of surface GPC3. Natural T-cell receptors (TCRs) may serve as an alternative, though identifying GPC3-specific TCRs within the endogenous repertoire is *** and Results:We immunized human leucocyte antigen-A2 (HLA-A2) transgenic mice with an adenovirus expressing human GPC3, identifying a panel of TCRs that recognize the GPC3(522-530) epitope. We cloned 3 murine GPC3-TCRs (TCR-A, TCR-B, and TCR-C) and engineered primary human T cells (TCR-T). TCR-T cells effectively recognized GPC3+HLA-A2+ human HCC cells, with recognition diminished by GPC3 silencing and HLA-A2 blockade. TCR-B-T and TCR-C-T cells showed the highest reactivity, with TCR-B-T cells exhibiting superior effector functions, proliferative capacity, and therapeutic efficacy in xenograft HCC models. Notable, TCR-B-T cells outperformed second-generation 41BB GPC3-specific CAR-T cells, attributed to lower exhaustion, enhanced proliferation, greater effector function, and improved resilience. Furthermore, mixed dosing of CAR-T and TCR-B-T cells was significantly more effective than staggered dosing of the same cell type, suggesting potential synergistic ***:Transgenic TCRs join forces with CARs, expanding the arsenal of GPC3-targeting receptors for HCC T-cell therapy.

关键词： HLA‐DQA1   next‐generation sequencing   novel allele  

摘要： HLA-DQA1*05:06:02 shows one single nucleotide substitution at position 6 C > T in exon 1 compared with HLA-DQA1*05:06:01:01.

关键词： IL-17A   Alveolar epithelial cells   p53   Proteomics   scRNA-seq   Acute lung injury   Pulmonary fibrosis   Curcumin  

摘要： Acute lung injury (ALI) is primarily driven by an intense inflammation in the alveolar epithelium. Key to this is the pro-inflammatory cytokine, Interleukin 17 (IL-17), which influences pulmonary immunity and modifies p53 function. The direct role of IL-17A in p53-fibrinolytic system is still unclear, it is important to evaluate this mechanism to regulate the ALI progression to idiopathic pulmonary fibrosis (IPF). C57BL/6 mice, exposed to recombinant IL-17A protein and treated with curcumin, provided insight into IL-17A mechanisms and curcumin's potential for modulating early pulmonary fibrosis stages. A diverse methodology, including proteomics, single-cell RNA sequencing (scRNA-seq) integration, molecular, and Schroedinger approach were utilized. In silico approaches facilitated the potential interactions between curcumin, IL-17A, and apoptosis-related proteins. A notable surge in the expression levels of IL-17A, p53, and fibrinolytic components such as Plasminogen Activator Inhibitor-1 (PAI-I) was discerned upon the IL17A exposure in mouse lungs. Furthermore, the enrichment of pathways and differential expression of proteins underscored the significance of IL-17A in governing downstream regulatory pathways such as inflammation, NF-kappaB signaling, Mitogen-Activated Protein Kinases (MAPK), p53, oxidative phosphorylation, JAK-STAT, and apoptosis. The integration of scRNA-seq data from 20 IPF and 10 control lung specimens emphasized the importance of IL-17A mediated downstream regulation in PF patients. A potent immuno-pharmacotherapeutic agent, curcumin, demonstrated a substantial capacity to modulate the lung pathology and molecular changes induced by IL-17A in mouse lungs. Human IPF single cell data integration confirmed the effects of IL-17A mediated fibrinolytic components in ALI to IPF progression.

关键词： central nervous system inflammation   depression   electroacupuncture   inflammatory bowel disease   interleukin‐4   microglia  

摘要： AIMS:Depression is prevalent in inflammatory bowel disease (IBD) and linked to neuroinflammation. However, the underlying mechanisms remain unclear. Therefore, we investigated the efficacy of electroacupuncture in mice with IBD and depression. METHODS:An IBD mouse model of depression was established using 2.0% dextran sodium sulfate (DSS). After electroacupuncture, general condition and behavior were evaluated. Colon morphology was observed using hematoxylin and eosin staining. Serum inflammatory factors were detected using enzyme-linked immunosorbent assay. Microglial activation was measured using immunofluorescence. Hippocampal protein expression was assessed using Western blotting and real-time fluorescence quantitative polymerase chain reaction. RESULTS:DSS-induced model mice exhibited significant depression-like behaviors and colon pathology. Serum and colon IL-1β expression was elevated (p < 0.01), while IL-4, IL-10, and TGF-β1 expression was decreased (p < 0.01 or p < 0.05). Hippocampal microglial activation was evident, with increased IL-1β expression (p < 0.01) and reduced IL-4, IL-10, TGF-β1, JAK1, STAT6, and p-STAT6 expression (p < 0.01 or p < 0.05). Electroacupuncture resolved these changes; though its effects were significantly weakened after IL-4 and p-STAT6 inhibitor administration (p < 0.01 or p < 0.05). Transcriptomic sequencing of hippocampal tissue indicates that pro-inflammatory pathways such as TNF/NF-κB/mTOR are activated in the model group. Electroacupuncture can activate the IL-4-mediated JAK-STAT signaling pathway, inhibit the activation of pro-inflammatory signaling pathways, upregulate neuroprotective genes such as Slc2a3, Mef2d, and Jak1, and exert anti-inflammatory effects. CONCLUSION:IL-4-JAK1-STAT6 signaling may be an important pathway in mediating the efficacy of electroacupuncture in IBD with comorbid depression, particularly promoting microglial M2 polarization and improving neuroinflammation.

关键词： Acute myeloid leukemia   Cellular immunotherapy   HLA‐DR   αβ T cells   γδ T cells  

摘要： In addition to exhibiting significant cytotoxic capabilities, γδ T cells play a crucial role as a bridge between innate and adaptive immunity. Although γδ T cells have been demonstrated to orchestrate interactions with other immune cells, their impact on αβ T cells in the setting of acute myeloid leukemia (AML) remains unexplored. In this study, we found that functional deficiencies of αβ T cells were significantly associated with the downregulation of HLA-DR γδ T cells in patients newly diagnosed with AML. Vδ2 T cells, which constitute a predominant subset of γδ T cells in human peripheral blood, exhibited elevated levels of HLA-DR following ex vivo expansion. Notably, a lower dose of the expanded Vδ2 T cells did not induce direct cytotoxicity against AML cells; instead, they significantly enhanced the cytotoxic capacity of primary αβ T cells toward AML cells. Furthermore, blockade of HLA-DR on Vδ2 T cells markedly diminished this facilitating effect. Taken together, our findings demonstrate an important indirect role for Vδ2 T cells beyond their direct killing ability in the context of anti-AML immunity and provide novel insights into the therapeutic potential of adoptive Vδ2 T cell therapy.