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摘要： BackgroundIndoleamine 2,3-dioxygenase (IDO) impairs anti-pathogen and anti-tumour immunity. Mesenchymal stem cells (MSCs) modulate immunity via IDO but also suppress IFN-gamma. While MSC IDO induction by IFN-gamma is established, other drivers in this immunosuppressive setting remain *** bone marrow mesenchymal stem cells (MSCs) with IDO or IL-10RA knockdown were co-cultured with healthy donor T cells to assess immunosuppression. PDAC organoid anticancer activity was also tested in these ***-culturing MSCs with T cells in an IL-10RA-enriched environment enhances IDO expression, resulting in T cell suppression. Moreover, IL-10RA-positive MSCs collected from co-cultures with IL-10 supplementation show increased IDO expression. Conversely, MSCs with IL-10RA knockdown exhibit a significant reduction in IDO RNA and protein expression, as well as STAT3 phosphorylation status, which is a known upstream signalling pathway in IDO gene regulation, in T cell co-cultures. Down-regulation of IL-10RA also inhibits IDO activity in MSCs, resulting in reduced T cell suppression, and enabling the co-cultured T cells to kill PDAC *** research reveals IL-10RA as a pharmacological target in stromal cells for enhancing T cell-mediated PDAC eradication by downregulating IDO via blocked IL-10/IL-10RA signalling in MSCs. This advances IL-10RA interference in the tumour microenvironment (TME) to restore T cell cytotoxicity against cancers.

关键词： CD30   dermatitis   inflammation   OX40   skin   therapy   TNF  

摘要： BackgroundBlocking IL-13 is highly efficacious in patients with Th2-biased atopic dermatitis (AD), and recent clinical data have highlighted that targeting the T cell costimulatory molecules OX40 and OX40L (TNFSF4) holds promise for future treatment of *** asked whether targeting another T cell costimulatory molecule, CD30L (TNFSF8), might also be a possible treatment option in ***-cell RNA-seq data from human AD skin lesions was analyzed to identify pathogenic IL-13- or IL-22-producing T cells and assess expression of CD30 and its ligand in comparison to OX40 and its ligand. Additionally, a murine model of AD with repetitive exposure to house dust mite allergen was used to compare neutralizing antibodies against CD30L with those against IL-13 or *** of several scRNA-seq datasets from skin lesions of AD patients showed that transcripts for CD30 or CD30L were found expressed with OX40 or OX40L in the primary T cell populations that also expressed mRNA for IL13 and/or IL22. Suggesting that this could be therapeutically relevant, mice treated prophylactically with a blocking CD30L antibody were protected from developing maximal allergen-induced AD features, including epidermal and dermal thickening, immune cell infiltration, and expression of AD-related genes, similar to mice treated with a blocking IL-13 antibody. Moreover, therapeutic neutralization of CD30L in mice with experimental AD also reduced all of the pathological skin lesion features to a comparable extent as blocking *** data suggest that targeting the CD30-CD30L axis might hold promise as a future therapeutic intervention in human AD, similar to targeting the OX40-OX40L axis.

关键词： cancer immunity   gastric cancer   interferon-gamma signaling   N-6-methyladenosine   YTHDF proteins  

摘要： Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon-gamma (IFN-gamma) signaling, in which IFN-gamma is linked to improved responsiveness to ICIs. Herein, the roles of RNA N-6-methyladenosine (m6A) modifications in regulation of IFN-gamma signaling and the responsiveness to ICIs are unveiled. The m6A-binding protein YTH N-6-methyladenosine RNA-binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN-gamma in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN-gamma responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN-gamma signaling, leading to reduced RNA stability and consequent downregulation of IFN-gamma signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor-infiltrating lymphocytes, which are attributed to the augmentation of IFN-gamma signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN-gamma signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy.

关键词： bioinformatics analysis   CD8A   emergency   GZMA   IL7R   sepsis  

摘要： Purpose Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. However, the relationship between biomarkers and sepsis remains unclear. This study aimed to find potential molecular biomarkers, which could do some help to patients with *** The sepsis dataset GSE28750, GSE57065 was downloaded from the GEO database, and ten patients with or without sepsis from our hospital were admitted for RNA-seq and the differentially expressed genes (DEGs) were screened. The Metascape database was used for functional enrichment analysis and was used to found the differential gene list. Protein-protein interaction network was used and further analyzed by using Cytoscape and STRING. Logistic regression and Correlation analysis were used to find the potential molecular *** Taking the intersection of the three datasets yielded 287 differential genes. The enrichment results included Neutrophil degranulation, leukocyte activation, immune effectors process, positive regulation of immune response, regulation of leukocyte activation. The top 10 key genes of PPI connectivity were screened using cytoHubba plugin, which were KLRK1, KLRB1, IL7R, GZMA, CD27, PRF1, CD8A, CD2, IL2RB, and GZMB. All of the hub genes are higher expressed in health group of different databases. Logistic regression showed that IL7R, GZMA and CD8A proteins were analyzed and all of them were statistically significant. Correlation analysis showed that there was a statistically significant correlation between IL7R, GZMA and *** KLRK1, KLRB1, IL7R, GZMA, CD27, PRF1, CD8A, CD2, IL2RB, GZMB are key genes in sepsis, which associated with the development of sepsis. However, IL7R, GZMA and CD8A may serve as the attractively potential molecular biomarkers for sepsis.

关键词： Dry eye   IL-37   lacrimal gland   NF kappa B   PTEN  

摘要： PurposeThis study aims to investigate the role of Interleukin-37 (IL-37) in mouse models of dry *** murine models of dry eye were employed in this investigation. The evaluation of the anti-inflammatory impact of IL-37 (200 mu l, 10 mu g/ml) on dry eye mice involved intraperitoneal injections administered once daily for 7 days. Additionally, intraperitoneal injection of VO-Ohpic trihydrate (VO, 0.25 mg/kg) in dry eye mice was performed to investigate the role of PTEN in the IL-37 anti-inflammatory signaling pathway. Tear production was assessed using phenol red cotton thread, while corneal damage was examined through sodium fluorescein staining using a slit lamp. Histological alterations in the lacrimal gland were observed through H&E staining. PAS staining was used to assess conjunctival goblet cells. The levels of NF kappa B-P65, p-NF kappa B-P65, IL-1 beta, IL-6, TNF-alpha, CD3, AQP5, alpha-SMA and PTEN proteins were determined via Western blotting or *** IL-37 treatment, both dry eye models exhibited reduced corneal fluorescence staining scores and enhanced tear production. In lacrimal gland, the expression of p-NF kappa B-P65, IL-1 beta, IL-6, CD3 and TNF-alpha was diminished, while PTEN, AQP5, alpha-SMA expression increased after IL-37 treatment in both dry eye mice. However, the intraperitoneal injection of VO significantly attenuated the anti-inflammatory effect of IL-37 on dry eye ***-37 emerges as an anti-inflammatory mediator within the lacrimal gland of dry eye mice, exerting its effects through the IL-37-PTEN-NF kappa B signaling pathway.

关键词： transglutaminase 2   calcification   autophagy   interleukin-6   autocrine   endothelial cells  

摘要： Introduction Endothelial cell (EC) calcification is an important marker of atherosclerotic calcification. ECs play a critical role not only in atherogenesis but also in intimal calcification, as they have been postulated to serve as a source of osteoprogenitor cells that initiate this process. While the role of transglutaminase 2 (TG2) in cellular differentiation, survival, apoptosis, autophagy, and cell adhesion is well established, the mechanism underlying the TG2-mediated regulation of EC calcification is yet to be fully *** The TG2 gene was overexpressed or silenced by using siRNA and recombinant adenovirus. RT-PCR and WB were used to analyze the relative expression of target genes and proteins. 5-BP method analyzed TG2 activity. mCherry-eGFP-LC3 adenovirus and transmission electron microscopy analyzed EC autophagy level. Calcium concentrations were measured by using a calcium colorimetric assay kit. Alizarin red S staining assay analyzed EC calcification level. Elisa analyzed IL-6 level. Establishing EC calcification model by using a calcification medium (CM).Results Our findings demonstrated that CM increased TG2 activity and expression, which activated the NF-kappa B signaling pathway, and induced IL-6 autocrine signaling in ECs. Furthermore, IL-6 activated the JAK2/STAT3 signaling pathway to suppress cell autophagy and promoted ECs *** ECs are not only critical for atherogenesis but also believed to be a source of osteoprogenitor cells that initiate intimal calcification. Previous research has shown that TG2 plays an important role in the development of VC, but the mechanism by which it exerts this effect is not yet fully understood. Our results demonstrated that TG2 forms complexes with NF-kappa B components inhibition of autophagy promoted endothelial cell calcification through EndMT. Therefore, our research investigated the molecular mechanism of EC calcification, which can provide new insights into the pathogenesis of

关键词： Hepatocellular carcinoma   Lenvatinib   Neutrophil   Neutrophil extracellular trap   Cuproptosis  

摘要： BackgroundLenvatinib is a potent first-line therapy for patients with hepatocellular carcinoma (HCC), but it also increased the number of neutrophils in HCC tumor ***3, MPO-DNA, elastase and MPO activity were measured for assessing neutrophil extracellular traps (NETs) in vivo and in vitro. Cell cuproptosis was assessed by measurement of copper content, FDX1, and pyruvate. The functions of lenvatinib, DNase I, interleukin 33 (IL33) neutralizing antibody and GPX4 in tumor growth were explored in *** induced NETs in the HCC tumor microenvironment via HCC cells, but not through the direct stimulation of neutrophils. In addition, NET clearance by DNase I improves the efficacy of lenvatinib therapy in HCC mouse models. Mechanistically, lenvatinib promoted the expression and secretion of IL33 by HCC cells that triggered NET formation. Moreover, IL33 knockdown in Hepa1-6 cells improved lenvatinib efficacy in Hepa1-6-bearing HCC model mice and reduced NET formation in the tumor microenvironment. Subsequently, lenvatinib increased IL33 production by increasing the NDUFA4L2 expression in HCC cells. Furthermore, we found that IL33 triggered NET formation in neutrophils by increasing the protein expression of PADI4 via the Akt/mTOR signaling pathway. Rapamycin inhibition of mTOR reduced PADI4 expression and NET formation. Consistently, PADI4 inhibition by the selective PAD4 inhibitor GSK484 hydrochloride (GSK484) improved lenvatinib response to HCC therapy. Importantly, NETs contribute to lenvatinib resistance by inhibiting cuproptosis, but not apoptosis, pyroptosis, or ferroptosis in HCC cells. Treatment with GSK484 reversed the inhibitory effects of NETs on cuproptosis and sensitized the HCC cells to *** study revealed that lenvatinib-induced NETs inhibited the cuproptosis of HCC cells, suggesting that targeting the IL33/PADI4/NET axis represents a promising therapeutic strategy for ameliorating lenvatinib resi

关键词： MHCⅡ抗原肽-T细胞受体结合预测   大模型   ProtT5模型   免疫治疗  

摘要： T细胞受体（TCR）与抗原肽的特异性结合在调节和介导免疫的过程中发挥着关键作用，为肿瘤疫苗设计提供了必要的基础。近年来的研究主要集中在主要组织相容性复合体（MHC）Ⅰ类抗原的TCR预测，针对MHCⅡ类抗原的TCR预测研究尚不充分，仍存在较大的提升空间。本研究利用ProtT5大模型进行MHCⅡ类抗原肽和TCR结合预测研究，探究其特征提取能力。此外，对模型进行微调，并构建前馈神经网络结构进行融合从而实现预测模型。实验结果显示，本研究提出的方法较传统方法表现更佳，预测准确度达到0.96,AUC达到了0.93，验证了本文提出模型的有效性。

关键词： Retinal Pigment Epithelium   DNA Repair   Serine and Arginine Rich Splicing Factor 1   Interleukin-6  

摘要： Chronic inflammation has been associated with the progression of age-related macular degeneration (AMD) and diabetic retinopathy (DR), and the levels of various inflammatory factors are significantly increased in intraocular fluids of patients with AMD and DR. Therefore, elucidating the roles of inflammatory factors in the oxidative damage of RPE cells will help uncover the pathogenesis of AMD and DR. We have previously demonstrated that E2F1 plays an important role in the antioxidant capacity of RPE cells. Here, our transcriptome analysis shows that E2F1 affected the expressions of DNA repair genes in RPE cells. In addition, we found that E2F1 transactivated the splicing factor SRSF1. SRSF1 knockdown promoted DNA oxidative damage and apoptosis and decreased the mRNA stability of DNA repair genes XRCC2, POLK and LIG4 in RPE cells. Moreover, we found that SRSF1 could bind to the RNA stabilizing factor MATR3, and knockdown of the latter affected the mRNA stability of these DNA repair genes. Notably, interleukin-6 (IL-6), an inflammatory factor upregulated in intraocular fluids of patients with AMD and DR, decreased SRSF1 expression by inducing acetylation of E2F1 at the K125 position. Consistently, SRSF1 overexpression relieved IL-6-induced DNA oxidative damage and apoptosis in RPE cells. In vivo experiment results also confirmed that IL-6 could aggravate retinal oxidative damage. In conclusion, high levels of IL-6 in the eyes of patients with AMD and DR destabilize the mRNAs of DNA repair genes by disrupting the expression of SRSF1, leading to abnormal repair of DNA oxidative damage in RPE cells.

摘要： Trisomy 21 (TS21), also known as Down syndrome (DS), increases pediatric mortality risk from respiratory syncytial virus (RSV) by nine-fold, yet its underlying immunological basis remains unclear. Here, we investigated RSV-induced immunological responses in TS21 airway epithelial cells (AECs), the primary site of respiratory virus entry and host defense. TS21 AECs exhibit hyperactive interferon (IFN) signaling and reduced RSV infectivity, but they also show impaired type-III IFN responses during viral infection. Furthermore, TS21 AECs demonstrate heightened production of proinflammatory mediators CXCL5 and CXCL10 both before and after RSV exposure. Infants with DS suffering from severe viral bronchiolitis demonstrate dysregulated airway immune responses in vivo, characterized by diminished type-III IFN levels and increased CXCL5/CXCL10 secretion. Our results indicate that RSV severity in DS is not due to impaired viral control but to dysregulated airway proinflammatory responses, offering new therapeutic opportunities to mitigate the severity of RSV infection in children with DS.