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摘要： Acute and chronic inflammation are important pathologies of benign airway stenosis (BAS) fibrosis, which is a frequent complication of critically ill patients. cGAS-STING signalling has an important role in inflammation and fibrosis, yet the function of STING in BAS remains unclear. Here we demonstrate using scRNA sequencing that cGAS‒STING signalling is involved in BAS, which is accompanied by increased dsDNA, expression and activation of STING. STING inhibition or deficiency effectively alleviates tracheal fibrosis of BAS mice by decreasing both acute and chronic inflammation. Macrophage depletion also effectively ameliorates BAS. Mechanistically, dsDNA from damaged epithelial cells activates the cGAS-STING pathway of macrophages and induces IL-6 to activate STAT3 and promote fibrosis. In summary, the present results suggest that cGAS-STING signalling induces acute inflammation and amplifies the chronic inflammation and tracheal fibrosis associated with benign airway stenosis, highlighting the mechanism and potential drug target of BAS.

关键词： Epiberberine   Chronic atrophic gastritis   IL33   EGFR  

摘要： Chronic atrophic gastritis (CAG) is a prevalent form of chronic gastritis that presents with chronic inflammation of the gastric mucosa, localised gastric mucosal glandular atrophy and intestinal metaplasia. Despite the existence of diagnostic criteria, effective therapeutic strategies for this condition remain to be developed. The objective of this study was to examine the potential therapeutic benefits of epiberberine in mitigating MNNGinduced CAG and to elucidate the underlying mechanisms. MNNG was employed to establish a CAG mouse model and a GES-1 cell model, and EPI was observed to be efficacious in ameliorating the gastric mucosal injury and inflammatory infiltration induced by MNNG in the CAG model mice, a finding that was subsequently validated in the GES-1 model cells. Bioinformatics analysis indicated that EPI may exert a direct effect on EGFR, thereby regulating the expression of IL-33 and thereby achieving the therapeutic effect of CAG. This hypothesis was also validated by molecular docking prediction, CETSA, and overexpression of EGFR in GES-1 model cells, using EGFR agonists and inhibitors to further demonstrate that EPI may act as an antagonist supplement to EGFR for the treatment of CAG.

关键词： Cancer   Cancer therapy   IL-1β   IPMN   Intraductal Papillary Mucinous Neoplasm   PDAC   PGE2   Pancreatic cancer   immune therapy   tumor microenvironment  

关键词： Glioblastoma   Endurance training   MitoQ supplementation   Behaviors   TLR4   NF-kappa beta  

摘要： Objective: The present study investigated the preventive effect of MitoQ supplementation and endurance training (ET) on the TLR4/CREB/ NF-kappa beta signaling pathway, antioxidant indices, and behaviors in C6-induced glioblastoma (GBM) in rats. Methods: 60 male Wistar rats were randomly divided into five groups (n = 12);Sham, Tumor, MitoQ, ET, and MitoQ + ET. Rats in the training groups performed endurance training (5 days per week), and MitoQ at the dose of 250 mu M/L daily was administered in drinking water for 8 weeks. At the end of the protocol, all groups except the sham group received 1*106 tumor cells /10 mu l culture medium. Two weeks after tumor induction, behavioral tests were performed, and then brain tissue was collected for the histopathology, measurement of antioxidant and inflammatory factors, TLR4, NF-kappa B proteins, and TLR4, NF-kappa beta, CREB, IL-1 ss, TNF-a, IL-10, Bax, Bcl-2, and Caspase-3 gene expression. Results: The increased level of TLR4 and NF-kappa beta protein expression in GBM rats decreased in the treatment groups. Gene expression of TLR4, NF-kappa beta, CREB, TNF-a, IL-10, and Bcl-2 increased in the tumor groups, and treatment groups decreased TLR4, NF-kappa B, Bcl-2, and CREB. In addition, social behaviors, balance, and memory were impaired in the tumor group, which combination group could improve these behaviors. Conclusion: In sum, the preventive effects of MitoQ as a beneficial immune reactive agent and exercise training in rats with C6-induced glioblastoma may be mediated via modulating oxidative stress, inflammatory factors, and down-regulation of the expression of TLR4.

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： 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： 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.