课程文献中心 更多>>

关键词： B-cells   Lymphopenia   NK cells   Sarcoidosis   T-cells   TNF-α   Treatment  

摘要： BACKGROUND:Severe sarcoidosis has been associated with peripheral blood (PB) total lymphopenia and high tumour necrosis factor α (TNF-α) levels, and the lymphopenia phenotype seems to respond poorly to conventional treatment. However, the mechanisms behind PB lymphopenia and its correlation with TNF-α levels remain unclear. Understanding the connections among PB lymphocyte subsets, TNF-α and clinical phenotype including treatment status could offer insights into how to individualize therapy. METHODS:PB samples from 65 consecutive sarcoidosis patients were collected at the Department of Respiratory Medicine, Karolinska University Hospital. Total lymphocyte, T-, B- and natural killer cell and TNF-α serum concentrations were measured and correlated to clinical parameters. Penias were defined as values below the lower limit of normal. The medical charts were retrospectively searched for the first PB total lymphocyte count, mostly recorded at time around diagnosis. RESULTS:PB total lymphopenia was observed in 35% of patients, was present since time around diagnosis, and associated with a need for treatment later (p = 0.005). Lymphocyte counts did not change by therapy, except for an increase in patients receiving TNF-α inhibitors (TNFi) (p < 0.05). B-cell penia, observed in 37% of patients, was the most common abnormality, also in patients with normal total lymphocyte counts, while T-cell penia mainly occurred in patients with total lymphopenia (91 vs 5%, p < 0.001). CONCLUSIONS:B-cell penia is common in sarcoidosis patients while T-cell penia is mainly a feature of the sarcoidosis PB lymphopenia phenotype. Increased lymphocyte counts during TNFi treatment suggests that TNF-α signaling is of importance for sarcoidosis associated lymphopenia.

关键词： Colitis-associated colorectal cancer   Traditional Chinese medicine   Network pharmacology   Transcriptomics   Inflammation-to-cancer transformation   IL-17RA/ACT1/NF-kappa B signaling axis  

摘要： Ethnopharmacological relevance: Inflammation-to-cancer transformation is critical for the progression of ulcerative colitis to colitis-associated colorectal cancer (CAC). Aim of the study: To explore the role and potential mechanisms of Qingre Huayu Jianpi prescription (QHJ) treatment in the development of CAC. Materials and methods: Combined network pharmacology and transcriptome analyses were used to investigate QHJ-associated targets and pathways in the context of CAC. Using clinical data and a murine CAC model, we examined QHJ effects on pathological morphology, inflammatory factors, and key target pathways. Results: Network pharmacology analysis identified the interleukin 17 receptor A (IL-17RA)/ACT1/nuclear factor kappa B (NF-kappa B) axis as critical in the inflammation-to-CAC transformation and for QHJ effects in CAC. Western blot and multiplex immunofluorescence analyses revealed significant upregulation of the IL-17RA/ACT1/NF-kappa B axis along with matrix metalloproteinase (MMP)7, MMP9, and chemokine ligand 2 (CCL2) in human tumor tissues. QHJ significantly ameliorated CAC-related symptoms in mice in vivo by downregulating the IL-17RA/ ACT1/NF-kappa B axis. This reduced the number of colorectal adenomas, increased colorectal length, and improved the structure of colonic mucosal glands. Additionally, QHJ inhibited the expression of pro-inflammatory factors and decreased the levels of MMP7, MMP9, and CCL2, ultimately suppressing the inflammation-to-cancer transformation. Conclusion: QHJ exhibited significant therapeutic effects on CAC in mice, likely due to its inhibitory action on the IL-17RA/ACT1/NF-kappa B axis. This study lays the foundation for research into the pathogenesis of CAC and the clinical application of QHJ.

关键词： Adipose tissue   Cell biology   Glucose metabolism   Metabolism   Obesity  

摘要： Type 2 innate lymphoid cells (ILC2) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We employed cell systems and genetic models to examine the mechanism through which interleukin-13 (IL-13), an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drives beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPARγ-related pathways. The latter is mediated by increased expression and activity of PPARγ through IL-13 receptor α1 (IL-13Rα1) downstream effectors, STAT6 and p38 MAPK, respectively. Il13 knockout (Il13KO) or preadipocyte Il13ra1 knockout (Il13ra1KO) mice are refractory to cold- or β-3 adrenergic agonist-induced beiging in inguinal white adipose tissue, whereas Il4 knockout mice show no defects in beige adipogenesis. Il13KO and Il13ra1KO mouse models exhibit increased body weight/fat mass and dysregulated glucose metabolism but have a mild cold intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also find that genetic variants of human IL13RA1 are associated with body mass index and type 2 diabetes. These results suggest that IL-13 signaling-regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation.

关键词： Immunoassay   Immunomarker   Tissue regeneration   Wound healing   Wound infection   Wound micro-environment   Wound swabbing  

摘要： BACKGROUND:Chronic wounds, such as diabetic foot ulcers, venous leg ulcers, and post-surgical wound healing disorders pose a significant challenge due to prolonged healing, risk of infection, and impaired quality of life. Persistent inflammation and impaired tissue remodeling are common in these wounds. Traditional diagnostic methods, including visual inspection and microbiological cultures, offer limited insight into the wound micro-environment. Immunomarker profiling could provide a deeper understanding of the molecular mechanisms underpinning wound healing, offering potential biomarkers for infection status and healing progression. METHODS:This observational, multi-center cohort study, part of the 'Wound-BIOME' project, analyzed 110 swab samples from patients with acute and chronic wounds using multiplex immunoassays. Clinical parameters such as wound type, healing status, regeneration stage, and microbial burden were recorded. Total protein concentration was assessed, and 35 key immunomarkers, including cytokines (e.g. IL- 1α, IL- 1β), chemokines (CCL2, CXCL8, CXCL10), growth factors (FGF- 2, VEGF) and matrix metalloproteinases (MMP- 7, MMP- 9, MMP- 13), were quantified. Statistical analyses were performed to correlate immunomarker levels with clinical outcomes. RESULTS:Pro-inflammatory markers, such as IL- 1β, IL- 18 and chemokines like CCL2 and CXCL8, were significantly elevated in non-healing and infected wounds compared to healing wounds. The study identified two new immunomarker ratios - IL- 1β/IL- 1RA and CXCL8/CXCL10 - as potential predictors of wound healing status. The IL- 1β/IL- 1RA ratio showed the highest accuracy for distinguishing healing from non-healing wounds (AUC = 0.6837), while the CXCL8/CXCL10 ratio was most effective in identifying infection (AUC = 0.7669). CONCLUSIONS:Immunomarker profiling via wound swabbing offers valuable insights into the wound healing process. Elevated levels of pro-inflammatory cytokines and MMPs are associated with

关键词： Human leukocyte antigen typing   Long read sequencing   Organ transplantation   Oxford nanopore technology  

摘要： BACKGROUND:Rapid turnaround time for a third-field resolution deceased donor human leukocyte antigen (HLA) typing is critical to improve organ transplantation outcomes. Third generation DNA sequencing platforms such as Oxford Nanopore (ONT) offer the opportunity to deliver rapid results at single nucleotide level resolution, in particular sequencing data that could be denoised computationally. Here we present a computational pipeline for up-to third-field HLA allele typing following ONT sequencing. RESULTS:From a R10.3 flow cell batch of 31 samples of known HLA allele types, up to 10,000 ONT reads were aligned using BWA aligner to reference allele sequences from the IPD-IMGT/HLA database. For each gene, the top two hits to reference alleles at the third field were selected. Using our pipeline, we obtained the following percent concordance at the 1st, 2nd and 3rd field: HLA-A (98.4%, 98.4%, 98.4%), HLA-B (100%, 96.8%, 96.8%), HLA-C (100%, 98.4%, 98.4%), HLA-DPA1 (100%, 96.8%, 96.8%), HLA-DPB1 (100%, 100%, 98.4%), HLA-DQA1 (100%, 98.4%, 98.4%), HLA-DQB1 (100%, 98.4%, 98.4%), HLA-DRB1 (83.9%, 64.5%, 64.5%), HLA-DRB3 (82.6%, 73.9%, 73.9%), HLA-DRB4 (100%, 100%, 100%) and HLA-DRB5 (100%, 100%, 100%). By running our pipeline on an additional R10.3 flow cell batch of 63 samples, the following percent concordances were obtained:: HLA-A (100%, 96.8%, 88.1%), HLA-B (100%, 90.5.4%, 88.1%), HLA-C (100%, 99.2%, 99.2%), HLA-DPA1 (100%, 98.4%, 97.6%), HLA-DPB1 (98.4%, 97.6%, 92.9%), HLA-DQA1 (100%, 100%, 98.4%), HLA-DQB1 (100%, 97.6%, 96.0%), HLA-DRB1 (88.9%, 68.3%, 68.3%), HLA-DRB3 (81.0%, 61.9%, 61.9%), HLA-DRB4 (100%, 97.4%, 94.7%) and HLA-DRB5 (73.3%, 66.7%, 66.7%). In addition, our pipeline demonstrated significantly improved concordance compared to publicly available pipeline HLA-LA and concordances close to Athlon2 in commercial development. CONCLUSION:Our algorithm had a > 96% concordance for non-HLA-DRB genes at 3rd field on the first batch and > 88% concordance for non-H

关键词： acute soft tissue injury   contusion   pulse radiofrequency   TNF/mTOR signaling  

摘要： Objective: Acute traumatic muscle injuries are common and result in substantial loss of time and risk of recurrence. Pulsed radiofrequency (PR) is a strategy that has been gradually adopted for treating muscle injuries in clinical practice. However, the molecular mechanism underlying its therapeutic effects is currently *** and Methods: In this study, we screened the gene expression profiles of rats with muscle contusion obtained from the online dataset GSE162565. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the differentially expressed genes were conducted. Further, we established an acute soft tissue injury (ASTI) rat model and applied PR treatment. Muscle swelling rate analysis, malondialdehyde (MAD) and superoxide dismutase (SOD) content, inflammatory cytokine release, and hematoxylin and eosin staining of the gastrocnemius muscles of ASTI and ASTI + PR rats were performed, and the results were compared with those of control rats. Further, we evaluated the gene expression of Ccl1, interleukin-6 (IL-6), nuclear factor-kappa-B-inhibitor alpha (Nfkbia), Akt1, Jun, Fos, and Caps3 in the model and PR-treated groups, all of which are key genes in the tumor necrosis factor (TNF)/mechanistic target of rapamycin (mTOR) signaling pathway according to the KEGG ***: The results revealed that 52 genes involved in the TNF/mTOR signaling pathway were closely associated with ASTI progression in rats. PR treatment significantly reduced the malondialdehyde content but increased the SOD content in ASTI model rat muscles, efficiently alleviated muscle contusions and reduced TNF-alpha and IL-1 beta production. Moreover, PR treatment significantly decreased Ccl1, IL-6, and Nfkbia expression but increased Akt1, Jun, Fos, and Caps3 levels in ASTI models. These data indicate that PR alleviated ASTI in rats by mediating redox homeostasis and the inflammatory response, which might be modulated by the TNF/mTOR signaling

摘要： αβ T cell receptors (TCR) co-recognise peptide (p) antigens that are presented by major histocompatibility complex (MHC) molecules. While marked variations in TCR-p-MHC docking topologies have been observed from structural studies, the co-recognition paradigm has held fast. Using HLA-DQ2.5-peptide tetramers, here we identify a TRAV12-1-TRBV5-1 G9 TCR from human peripheral blood that binds HLA-DQ2.5 in a peptide-agnostic manner. The crystal structures of TCR-HLA-DQ2.5-peptide complexes show that the G9 TCR binds HLA-DQ2.5 in a reversed docking topology without contacting the peptide, with the TCR contacting the β1 region of HLA-DQ2.5 and distal from the peptide antigen binding cleft. High-throughput screening of HLA class I and II molecules finds the G9 TCR to be pan-HLA-DQ2 reactive, with leucine-55 of HLA-DQ2.5 being a key determinant underpinning G9 TCR specificity excluding other HLA-II allomorphs. Consistent with the functional assays, the interactions of the G9 TCR and HLA-DQ2.5 precludes CD4 binding, thereby impeding T cell activation. Collectively, we describe a naturally selected αβTCR from human peripheral blood that deviates from the TCR-p-MHC co-recognition paradigm.

关键词： Andrographolide   Inflammation   Nanostructured lipid carrier   Stress   TNF-alpha  

摘要： This study aimed to improve the delivery efficacy of andrographolide (Andro) by encapsulating it in nanostructured lipid carriers (NLCs) and to evaluate its effectiveness in reducing systemic inflammation. These AndroNLCs exhibited homogeneity with a particle size of 131.40 ± 1.30 nm and approximately 89% encapsulation efficiency. AndroNLCs potentially enhanced oral efficacy by improving gastrointestinal stability, with reduced toxicity and inflammation in SH-SY5Y neuroblastoma cells. Inflammation was induced in sexually active C57BL/6 male mice with five intraperitoneal doses of 63 µg/kg TNF-alpha every three days. This was accompanied by daily oral administration of 10 mg/kg AndroNLCs, venlafaxine, or 1 mg/kg dexamethasone for 14 days. Mice with TNF-alpha-induced inflammation showed sickness signs and abnormal behaviors, assessed via physical changes, anxiety and depression tests (i.e., open field, elevated-T maze, tail suspension, and forced swimming), and biochemical assays. These changes included weight loss and compensatory responses to inflammation, as indicated by increased immune- and stress-modulated organ weights, elevated serum corticosterone levels, altered liver function markers, and higher levels of hippocampal IL-6 and TNF-alpha. Furthermore, histological analysis showed pyknotic cells, reduced layer thickness, and decreased hippocampal cell survival. Conversely, AndroNLCs significantly improved stress- and inflammation-related markers, alleviated behavioral abnormalities, reduced liver toxicity, and restored hippocampal morphology, showing effects greater than Andro alone and comparable to traditional treatments. These findings suggest that AndroNLCs have therapeutic effects on neuroinflammation but may risk contributing to mood disorders.

关键词： Signaling pathways   elderly patients.   occlusion   stenosis   vertebral artery  

摘要： INTRODUCTION:Vertebral artery stenosis/occlusion leads to ischemic brain cell injury due to partial or complete disruptions of blood flow to the brain. OBJECTIVE:The objective of the present research was to investigate the TNF-α/TLR4/IL-6/NF-κB signaling pathway and ROS/NOX4/p38/MDA signaling pathway in elderly patients with vertebral artery stenosis/occlusion. METHODS:Levels of tumor necrosis factor-alpha (TNF-α), toll-like receptor 4 (TLR4), interleukin 6 (IL-6), nuclear factor kappa-B (NF-κB), reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), p38 mitogen-activated protein kinase (p38) and malondialdehyde (MDA) were evaluated in blood samples from elderly patients with vertebral artery stenosis/ occlusion. RESULTS:Expression levels of TNF-α, TLR4, IL-6, NF-κB, ROS, NOX4, p38, and MDA were significantly higher in the Vertebral Artery Stenosis (VAS) 61-70% group compared with the control group and VAS 50%-60% group, respectively (P<0.01). The expression levels of these markers were significantly higher in the VAS 81-99% group compared with VAS 61-70% group and VAS 71-80% group, respectively (P<0.01), and were further increased in VAS 100% (occlusion) group compared with VAS 71-80% group and VAS 81-99% group, respectively (P<0.01). CONCLUSION:Mutual interactions of TNF-α/TLR4/IL-6/NF-κB and ROS/NOX4/p38/MDA signaling pathways were associated with the pathogenesis of vertebral artery stenosis/occlusion in elderly patients.