课程文献中心 更多>>

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： diabetic ketoacidosis   interleukin 6   CAR   NLR  

摘要： Background and Objectives: The use of additional biomarkers to predict clinical course in diabetic ketoacidosis (DKA) is becoming increasingly important. The aim of this study was to investigate the relationship between interleukin-6 (IL-6) levels and the length of stay in the intensive care unit (ICU) in patients with DKA without signs of infection and to investigate the relationship between the neutrophil-lymphocyte ratio (NLR) and C-reactive protein (CRP) albumin ratio (CAR). Materials and Methods: This retrospective, single-center study included 78 patients with DKA without infection who were treated in the Medical ICU between July 2022 and June 2024. The patients were divided into two groups: moderate DKA (Group 1) and severe DKA (Group 2). The patients' IL-6 levels, peripheral blood inflammatory markers (CAR, NLR), Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and the duration of ICU stay were recorded. Results: The median duration of stay in the ICU was 2.00 (1-6) days in group 1 and 3.00 (1-26) days in group 2 (p = 0.001). The mean pH, HCO3, and CO2 values in Group 1 were 7.20 +/- 0.07, 13.58 +/- 2.11 mEq/L, and 29.45 +/- 6.27 mmHg, while the mean pH, HCO3, and PCO2 values in Group 2 were 7.01 +/- 0.11, 7.11 +/- 1.91 mEq/L, and 20.35 +/- 4.91 mmHg (p < 0.001, p < 0.001, p < 0.001, respectively). There was a strong positive correlation between IL-6 levels and the length of stay in the ICU (r = 0.813, p < 0.001). Additionally, there was a moderate positive correlation between the length of stay in the ICU with the severity of DKA (r = 0.475, p < 0.001), CAR (r = 0.336, p < 0.001), and NLR (r = 0.562, p < 0.001). Conclusions: Inflammatory markers such as NLR and CAR, and more specifically IL-6, were found to be associated with the clinical course and duration of stay in the ICU in patients with DKA.

关键词： NF kappa B   IL-1 beta   Signalling   IKK alpha   TAK-1   HUVECs  

摘要： In this study we examined the activation of the non-canonical NF kappa B signalling pathway in endothelial cells. In HUVECs, LIGHT stimulated a delayed induction of serine 866/870 p100 phosphorylation linked to p52 NF kappa B formation. Surprisingly, the canonical ligand, IL-1 beta, stimulated a rapid phosphorylation or p100 which was not associated with p52 formation. Inhibition of IKK alpha activity, using DN-IKK alpha adenovirus, IKK alpha siRNA or a novel first-in-class selective IKK alpha inhibitor, SU1261, revealed IL-1 beta induced p100 phosphorylation to be dependent on IKK alpha. In contrast, IKK beta inhibition was found to be without effect. The NIK inhibitor, CW15337, did not affect IL1 beta induced p100 phosphorylation however, both p100 and pIKK alpha/ beta phosphorylation was substantially reduced by inhibition of the upstream kinase TAK-1, suggesting phosphorylation of p100 is mediated by IKK alpha from within the canonical NEMO/IKK beta /IKK alpha complex. IL-1 beta also stimulated a rapid increase in nuclear translocation of p52, which was not affected by NIK inhibition, suggesting a source of p52 independent of p100 processing. Inhibition of TAK-1 abolished p52 and p65 nuclear translocation in response to IL-1 beta. SiRNA deletion or inhibition with dominant-negative virus of IKK alpha activity partially reduced p52 translocation, however pharmacological inhibition of IKK alpha was without effect. Inhibition of IKK beta abolished both p52 and p65 translocation. Taken together these results show that IL-1 beta stimulates a novel IKK alpha -dependent axis within the non-canonical NF kappa B pathway in endothelial cells which is NIK-independent and regulated by TAK-1. However, this pathway is not primarily responsible for the early nuclear translocation of p52, which is dependent on IKK beta. Elucidation of both these new pathways may be significant for NF kappa B biology within the endothelium.

关键词： cancer-associated fibroblasts   IL-17A   invasion   migration   prostate cancer  

摘要： Cancer-associated fibroblasts (CAFs) are key stroma cells that play dominant roles in the migration and invasion of several types of cancer through the secretion of inflammatory cytokine IL-17A. This study aims to identify the potential role and regulatory mechanism of CAFs-secreted IL-17A in the migration and invasion of prostate cancer (PC). CAFs and normal fibroblasts (NFs) were obtained from fresh PC and its adjacent normal tissues, respectively. PC cells LNCaP and DU145 were co-cultured with the conditioned medium from the CAFs and NFs. IL-17A level was determined by ELISA in the cell supernatant. CCK-8, wound healing, Transwell assay, western blot analysis, staining, and primary PC lung metastasis assays were employed in vivo or in vitro to explore the effect of CAFs and IL-17A secreted by them on proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) and metastasis of PC. CAFs stimulated the migration and invasion of PC cells. Importantly, CAFs exerted their roles by directly secreting IL-17A, leading to a significant increase in migration and invasion in PC cells. Mechanically, IL-17A promoted Smad3/p38 MAPK pathway-mediated EMT process, contributing to cell migration and invasion. Furthermore, CAFs secreting IL-17A activated the Smad3/p38 MAPK pathway and thus facilitated tumor growth and metastasis in nude mice. This study identifies a novel signaling pathway by which CAFs mediate migration and invasion of PC via upregulation of Smad3/p38 MAPK-mediated EMT in an IL-17A-dependent manner.

关键词： Brazilian population   HLA-C   new alleles   NGS   REDOME  

摘要： Identification of four novel HLA alleles, HLA-C*03:09:02:01, -C*07:04:32, -C*07:1152, and -C*08:300, in Brazilian individuals.

关键词： HLA‐A*01:471   HLA   novel allele   sequencing‐based typing  

摘要： HLA-A*01:471 differs from HLA-A*01:01:01:01 by one nucleotide substitution in codon 250 in exon 4.

关键词： allergic airway inflammation   group 2 innate lymphoid cells   gut microbiota   IL-33   OM-85  

摘要： Background: Type 2 innate lymphoid cells (ILC2s) are essential for maintaining immune regulation and promoting tissue homeostasis in allergic asthma. How the development of gut microbiota on neonatal ILC2s influences allergic airway inflammation remains unclear. Here we focus on offspring ILC2 development in the context of alterations in maternal gut microbiota. Methods: C57BL/6 maternal mice were gavaged with OM-85 during pregnancy and/or lactation, ILC2-driven allergic airway inflammation in the OVA-sensitized adult offspring was observed. ILC2 development in offspring early life were investigated using recombinant (r)IL-33, rIL-25 and Bromodeoxyuridine in the vivo experiments. Further ILC2 promoting factors- IL-33 and IL-25 production in offspring early life were analysed. Finally, we examined the changes in gut microbiota and its metabolites in both dams and pups, and explored the effects of short-chain fatty acids (SCFAs) on IL-33 expression and secretion. Results: Maternal OM-85 administration restrained ILC2-driven allergic airway inflammation in the OVA-sensitized adult offspring. During ILC2 development in offspring early life, maternal OM-85 administration suppressed IL-33 and IL-25 production to inhibit ILC2 expansion and ILC2 responsiveness to alarmins, and infantile ILC2s could persist into adulthood. Maternal OM-85 administration increased SCFAs in breast milk and SCFA-producing gut probiotics (predominant Bacteroides and Blautia) in offspring, especially during pregnancy and lactation. SCFAs down-regulated IL-33 expression and reduced IL-33 secretion by inhibited gasdermin D (GSDMD) formation. Conclusion: Maternal OM-85 administration restrains ILC2-driven allergic airway inflammation in adult offspring by increasing offspring intestinal SCFAs to modulate ILC2 development at an early stage, demonstrating that the transgenerational effects of maternal OM-85 exposure on offspring innate immunity.

关键词： chronic IL-1   HMOX1   GCLC   p62-KEAP1   NRF2  

摘要： Chronic inflammation is a cancer hallmark and chronic exposure to interleukin-1 (IL-1) transforms castration-sensitive prostate cancer (PCa) cells into more fit castration-insensitive PCa cells. p62 is a scaffold protein that protects cells from nutrient deprivation via autophagy and from cytotoxic reactive oxygen via NF kappa B and NRF2 antioxidant signaling. Herein, we report that the LNCaP PCa cell line acquires high basal accumulation of the p62-KEAP1 complex when chronically exposed to IL-1. p62 promotes non-canonical NRF2 antioxidant signaling by binding and sequestering KEAP1 to the autophagosome for degradation. But despite high basal p62-KEAP1 accumulation, only two of several NRF2-induced genes analyzed, GCLC and HMOX1, showed high basal mRNA levels, suggesting that the high basal p62-KEAP1 accumulation does not result in overall high basal NRF2 activity. Nutrient starvation induces NRF2-dependent GCLC upregulation and HMOX1 repression, and we found that chronic IL-1-exposed LNCaP cells show hypersensitivity to serum starvation-induced GCLC and HMOX1 regulation. Thus, chronic IL-1 exposure affects cell response to nutrient stress. While HMOX1 expression remains NRF2/KEAP1-dependent in chronic IL-1-exposed LNCaP cells, GCLC expression is NRF2/KEAP1-independent. Furthermore, the high basal p62-KEAP1 complex accumulation is not required to regulate GCLC or HMOX1 expression, suggesting cells chronically exposed to IL-1 evolve a novel NRF2-independent role for the p62/KEAP1 axis.

关键词： HLA   HLA-DQA1*01:157   novel allele   sequencing-based typing  

摘要： HLA-DQA1*01:157 differs from HLA-DQA1*01:01:01:01 by one nucleotide substitution in codon 199 in exon 4.

关键词： Salmonella Typhimurium   IFN-gamma   CD154   cecum   inflammation  

摘要： The cytokines IFN-gamma and CD154 have been well established, and they play pivotal roles in immune protection against Salmonella in mice, but their effects and specific mechanisms in Salmonella-infected chickens are less understood. In this study, we conducted animal experiments to screen the highly immunoprotective chIFN-gamma-chCD154 fusion protein compared with single protein chIFN-gamma or chCD154 in white Leghorn chickens. The results showed that compared with separate pretreatments with chIFN-gamma and chCD154, the fusion protein, chIFN-gamma-chCD154, synergistically increased survival of infected chickens, reduced bacterial load in feces and organs, and attenuated pathological damage to the liver and cecum. Pretreatment with chIFN-gamma-chCD154 also increased humoral immune responses, expression of the tight junction proteins zo-1, occludin, and claudin-1, and the relative abundance of Enterococcus_cecorum, Lactobacillus_helveticus, and Lactobacillus_agilis, which protect against intestinal inflammation. Compared with single protein pretreatment, chIFN-gamma-chCD154 significantly upregulated STAT1, IRF1, and GBP1 in infected chickens while decreasing mRNA expression of TLR4, MyD88, NF-kappa B, TNF-alpha, IL-6, and IL-1 beta. In summary, damage to the cecal epithelial barrier and the inflammation induced by S. typhimurium infection was alleviated by chIFN-gamma-chCD154 pretreatment through a mechanism involving the TLR4/MyD88/NF-kappa B and IFN-gamma/STAT/IRF1/GBP1 pathways.