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关键词： breast cancer (BC)   CHDH   IL17RB/CREB   metastasis   migration  

摘要： The involvement of Choline Dehydrogenase (CHDH) in metabolic disorders and tumour progression has garnered significant scholarly interest. However, the specific role of CHDH in the metastasis and progression of breast cancer (BC) has been less thoroughly investigated. Our research indicates that CHDH protein expression is markedly elevated in breast cancer tissues compared to normal tissues, and this expression is positively correlated with the tumour node metastasis (TNM) stage of breast cancer. Furthermore, CHDH levels were found to be significantly higher in breast cancer cell lines relative to normal breast cells. The silencing of CHDH expression resulted in a reduction of breast cancer cell migration, while the overexpression of CHDH facilitated increased migration and tumour metastasis in vivo. Investigations into the underlying mechanisms revealed that CHDH influences the expression of IL17RB and activates Cyclic-AMP Response Element-Binding Protein (CREB), thereby mediating breast cancer metastasis. The application of an IL17RB antibody and the CREB inhibitor 666-15 effectively abolished CHDH-mediated migration of breast cancer cells in vitro. These findings suggest that CHDH plays a critical role in promoting breast cancer metastasis, potentially offering new targets and strategies for the treatment of metastatic breast cancer.

关键词： Diffuse systemic sclerosis   Disease susceptibility   HLA   Limited systemic sclerosis   Systemic sclerosis  

摘要： ObjectiveSystemic sclerosis (SSc) is a complex autoimmune connective tissue disease. Genetic factors may play a pivotal role in determining susceptibility to these disorders. HLA associations with SSc, especially HLA class II, were investigated in different populations but not in Tunisia. Our aim was to study HLA profile in South Tunisian patients with *** conducted a case-control study on 19 SSc patients and 123 healthy controls. HLA class I (HLA-A and -B) typing was performed using a microlymphocytotoxicity complement-dependent technique followed by polymerase chain reaction sequence specific primer (PCR-SSP). HLA class II DRB1/DQB1 of all patients and controls was genotyped using the PCR-SSP technique. Statistical analysis was performed using SPSS software and R *** SSc patients and 123 healthy controls were included. The HLA-DRB1*11 was associated with the genetic susceptibility to SSc (corrected p-value (pc) = 0.005;OR = 5.56;95% CI = [2-15.4]). The HLA-DQB1*03:01 had also increased the risk of SSc in our study (pc = 0.002;OR = 5.9;95% CI = [2-16.8]). Concerning HLA class I typing, we found a significant association between HLA-B53 and SSc (pc = 0.01;OR = 9;95% CI = [2.53-31.99]). The association of HLA-B53 was independent of HLA-DRB1*11 in binary logistic regression test (HLA-B53: p = 0.01;HLA-DRB1*11: p = 0.008). Concerning the haplotype study, a significant difference in the distribution of the haplotype B53-DRB1*11 was found between patients and controls (13.15% in SSc patients vs. 0.8% in controls;p = 1.33 10-5;HaploScore = 4.35).ConclusionOur results showed that in South Tunisia SSc is associated with HLA-DRB1*11 and DQB1*03:01 alleles. A susceptibility to SSc was found in positive HLA-B53 patients. This association of HLA alleles with SSc needs further *** Points center dot HLA-DR and DQ alleles represent the most common associations reported in Systemic Sclerosis (SSc).center dot In this study, in addition to the kno

关键词： molecular mimicry   autoreactivity   epitopes   autoimmunity   autoimmune disease   viral infection   SARS-CoV-2   COVID-19   autoantibodies   HLA   MHC   B cell   T cell   immunoinformatics  

摘要： This study investigated the role of molecular mimicry in the context of autoimmunity associated with viral infection, using SARS-CoV-2 as a model system. A bioinformatic analysis was performed to identify sequence homologies between the SARS-CoV-2 Spike (S) protein and the human proteome, with a specific focus on immunogenic regions to assess potential cross-reactivity. The analysis revealed homologous regions between the viral S protein and several human proteins, including DAAM2, CHL1, HAVR2/TIM3, FSTL1, FHOD3, MYO18A, EMILIN3, LAMP1, and alpha ENaC, which are predicted to be recognizable by B-cell receptors. Such recognition could potentially lead to the production of autoreactive antibodies, which can contribute to the development of autoimmune diseases. Furthermore, the study examined potential autoreactive CD4+ T-cell responses to human protein autoepitopes that could be presented by HLA class II molecules. Several HLA class II genetic variants were computationally associated with a higher likelihood of cross-reactive immune reactions following COVID-19, including HLA-DPA1*01:03/DPB1*02:01, HLA-DPA1*02:01/DPB1*01:01, HLA-DPA1*02:01/DPB1*05:01, HLA-DPA1*02:01/DPB1*14:01, HLA-DQA1*01:02/DQB1*06:02, HLA-DRB1*04:01, HLA-DRB1*04:05, HLA-DRB1*07:01, and HLA-DRB1*15:01. Additionally, seven T helper cell autoepitopes (YSEILDKYFKNFDNG, ERTRFQTLLNELDRS, AERTRFQTLLNELDR, RERKVEAEVQAIQEQ, NAINIGLTVLPPPRT, PQSAVYSTGSNGILL, TIRIGIYIGAGICAG) were identified that could be implicated in autoimmune T-cell responses through presentation by class II HLA molecules. These findings highlight the utility of viral B- and T-cell epitope prediction for investigating molecular mimicry as a possible mechanism in virus-associated autoimmunity.

关键词： IL-12 mRNA   Lipid nanoparticle   IFN gamma-IDO pathway   Cancer immunotherapy   Prodrug synthesis  

摘要： The administration of recombinant cytokines, particularly interleukin-12 (IL-12), holds promising clinical potential for treating various cancers. Sustained intratumoral delivery of IL-12 can restore tumor resident CD8+ effector T cells and induce the priming of antitumor CD8+ effector T cells. However, these CD8+ T cell-dependent anticancer efficacy is usually transient and accompanies the activation of immune suppressive CD4+Foxp3+ T regulatory cells. The underlying mechanism of T regulatory cell activation in IL-12 therapy is the upregulation of IFN gamma dependent indoleamine 2,3-dioxygenase (IDO) expression. Due to this negative feedback, the combinatorial use of drugs should be considered to enhance the efficacy of IL-12-mediated therapy. Herein, we designed a lipid nanoparticle (LNP) system which can successfully deliver an IDO inhibitor indoximod (IND) and IL-12 encoding mRNA. In order to increase the loading efficiency, the IND prodrug was synthesized by conjugating IND with cholesterol by ester linkage. Optimized IND prodrug encapsulating LNP successfully transfected tumor cells and macrophages, resulting in the secretion of IL-12 cytokine. With IL-12 transfection, macrophages upregulated T cell co-stimulation factor and released TNF alpha cytokine, indicating that the tumor microenvironment could be changed from cold tumor to hot tumor for immunotherapy. Also, by the elevated secretion of IL-12 cytokine, T cells release high levels of IFN gamma, which is a central role in IL-12-mediated immunotherapy. This co-delivery system presents a promising strategy to overcome the limitations of single IL-12-mediated therapy by simultaneously promoting antitumor immune responses and inhibiting immunosuppressive mechanisms, thereby enhancing the overall efficacy of cancer immunotherapy.

关键词： Ulcerative colitis   dual single-atom catalyst   engineered probiotic bacterium   IL-18 binding protein   oral delivery  

摘要： Ulcerative Colitis (UC) involves a complex pathological process characterized by excessive reactive oxygen species (ROS) production at lesion sites and gut microbiota dysregulation. Conventional therapies are often limited by their inability to concurrently address oxidative stress, immune dysregulation, and microbial imbalance. Herein, we developed an integrated bionanoplatform (DEI) by conjugating dual single-atom catalysts (DACs) with an engineered probiotic strain, Escherichia coli Nissle 1917 (EcN). This EcN was genetically modified to stably express interleukin-18 binding protein (IL-18BP). The DACs effectively scavenge ROS in intestinal tissues via multienzyme mimetic activities, while IL-18BP neutralizes pro-inflammatory cytokines to modulate the inflammatory milieu. Orally administered, the engineered EcN delivers and retains the DACs within the intestine, significantly enhancing ROS neutralization. Concomitantly, the DACs augment colonization of the engineered EcN, thereby amplifying its therapeutic efficacy. In a dextran sulfate sodium-induced mouse colitis model, DEI effectively mitigated colitis symptoms, attenuated inflammation, and restored the abundance and diversity of the intestinal microbiota, promoting intestinal homeostasis. This multifunctional bionanoplatform thus offers a promising synergistic strategy for UC treatment by integrating ROS scavenging, immune modulation, and microbiota restoration.

关键词： TRPV1   nose-to-brain infection   pneumococcus   host-pathogen interactions   invasive microorganisms  

摘要： The nasal cavity acts as a gateway through which pathogens can invade the human body. Streptococcus pneumoniae can infect the central nervous system directly through the nasal cavity. However, the regulatory mechanisms that govern the direct nose-to-brain invasion of S. pneumoniae remain unclear. The nasal cavity is innervated by both olfactory and trigeminal nerves, which will modulate the defense mechanism of the olfactory epithelium in different ways. Transient receptor potential vanilloid 1 (TRPV1), which is expressed in both nerves, maintains the regeneration ability of the olfactory epithelium. In this study, we investigated the role of TRPV1 against the nose-to-brain invasion of S. pneumoniae. Six-week-old mice were treated with methimazole and/or resiniferatoxin to ablate TRPV1 on the olfactory and trigeminal nerves, respectively. Bacterial density, cytokines/chemokine induction, and histologic changes were investigated after intranasal infection with S. pneumoniae. Olfactory epithelium ablation by methimazole increased intracranial invasion and mortality without bacteremia. Trigeminal TRPV1 ablation suppressed mortality. Intracranial invasion of S. pneumoniae induced IL-6 in the olfactory bulb. Olfactory epithelium ablation was associated with significantly higher TNF-alpha compared to trigeminal TRPV1 ablation. Intracranial invasion was suppressed by intranasal administration of a TRPV1 stimulant. TRPV1 on the olfactory nerve worked against intracranial invasion, whereas TRPV1 on the trigeminal nerve enhanced lethality via excessive cytokine/chemokine production. The effect of intranasal TRPV1 stimulation was dominant on the olfactory nerve and could suppress central nervous system infection via the nose-to-brain route. The current finding can bring new strategies against infection targeting *** study updates the current clinical concept of the pathogenesis of pneumococcal meningitis and bacteremia. The findings provide new insight into ho

关键词： AAV   articular bone erosion   autoinflammatory diseases   bone loss   DIRA   rheumatoid arthritis   sIL-1Ra  

摘要：

关键词： macrophage   T cell   immunophenotype   cell therapy  

摘要： Macrophages and T cells communicate under homeostatic and pathological conditions. Previous studies elucidated biochemical crosstalk between macrophages and T cells. However, recent technological advances in multiplex tissue imaging reveal that these cells are often located proximally. Notably, recent clinical studies link the proximity of macrophages and T cells to cancer outcomes. These observations suggest that physical contact between the two cell types might influence their phenotype and activity. However, systematic investigations of the potential role of physical contact between these cells are lacking. To address this gap, we developed three-dimensional (3D) coculture assays to study the potential role of physical contact between naive macrophages and activated CD8+ T cells cultured in 3D Matrigel matrix. Under contact conditions, macrophages and T cells were coencapsulated in the same matrix, whereas under no-contact conditions, they were cultured in matrix, separated by a Transwell membrane. Our findings indicated that T cells changed their migration behavior by stopping and moving over the surface of naive macrophages during coculture. We quantitatively determined T cells establish durable contact with macrophages, which informed our hypothesis that physical interactions between macrophage-T cells may induce phenotypic changes. Physical contact led to a 3-fold increase in IFN-gamma secretion, a key effector molecule of CD8+ T cells. The increase in IFN-gamma was mediated by JAK and led to a 2-fold upregulation of ICAM-1 and increased PD-L1 expression. Our findings point to a model whereby activated T cells migrate toward macrophages and are held in proximity by ICAM-1 adhesion molecules, leading to increased production of IFN-gamma and PD-L1 expression. These results establish that physical contact is an important determinant of macrophage and T cell states. Broadly, our study establishes a foundation to use biomaterials as a tool to provide mechanistic i

关键词： HLA   MICA/B   physiological expression   RNAseq   single-cell  

摘要： Abnormal expression of HLA class Ib, MICA and MICB molecules is associated with the evolution of pathological conditions and clinical settings. Here, we use RNA-sequencing data from two publicly-available projects, from different human organs and tissues and at single-cell level, to present their transcriptional expression throughout the human body, in comparison to that of HLA class Ia, HLA class II, their costimulatory molecules, and the main HLA transcription factors. Our analyses for 21 target genes reveal that median gene expression differs by orders of magnitude and that the classical/non-classical HLA distinction is not absolute for overall expression. Sixteen of the 21 target genes show correlated expressions, although careful analyses of individual expression patterns in tissues and organs highlight specificities. Tissue and organ expression patterns reveal that the lymphoid organs, lungs, and gastrointestinal tract organs display the highest expression of the HLA and HLA-related genes. At single-cell level, adipocytes, endothelial cells, and immune cells all have unexpectedly close expression patterns. The expression pattern of the 21 target genes in non-immune organs, such as the lung or colon, and in non-immune cells like adipocytes, questions the role of these organs and cell types in immune homeostasis and suggests additional, non-immune functions of these molecules. The lack of impact of the HLA transcription factors studied here on HLA regulation in non-immune tissues also supports a role for additional HLA transcription factors in these tissues. Finally, classical/non-classical HLA classification based on molecule structure and genetic polymorphism does not seem to extend to their expression.