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关键词： Bioactivity  

摘要： With the aim of isolating immunomodulatory compounds from the n-butanol extract of Boehmeria nivea leaves, nine megastigmane compounds were identified. Among these, the structure of the new compound 1, namely, "boehmegaside A", was established using NMR and HR-ESI-MS, and its absolute configurations were established through ECD calculations and DP4+ analysis using DFT-NMR chemical shift calculations. Furthermore, eight of these compounds were discovered for the first time in the Boehmeria genus, marking this the first report on megastigmane compounds isolated from this genus. Regarding their immunomodulatory activity, the isolated megastigmane compounds 3, 2, and 6 exhibited pro-inflammatory cytokine IL-1 beta secretion inhibitory activity. Compounds 3 and 6 significantly increased anti-inflammatory cytokine IL-10 secretion in LPS-activated RAW264.7 cells. Furthermore, the study on the mechanism of the immunomodulatory and other biological activities of megastigmane compounds through molecular docking simulations revealed that the planar structures of 3, 2, and 6 were critical in their ability to directly suppress TLR4 signalling. Instead, they attached to a nearby smooth area in TLR4. This interference likely disrupted the ability of TLR4 and MD-2 to form their primary contact interface and recognize LPS. These findings highlight the significant role of TLR4 in inflammation and immunity, indicating that these megastigmane compounds may be beneficial in treating various inflammatory disorders associated with immunological issues.

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

摘要： Background Severe sarcoidosis has been associated with peripheral blood (PB) total lymphopenia and high tumour necrosis factor alpha (TNF-alpha) levels, and the lymphopenia phenotype seems to respond poorly to conventional treatment. However, the mechanisms behind PB lymphopenia and its correlation with TNF-alpha levels remain unclear. Understanding the connections among PB lymphocyte subsets, TNF-alpha 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-alpha 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-alpha 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). 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-alpha 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 lymphopeni

关键词： Hemophilia A   therapeutic FVIII proteins   FVIII inhibitors   linkage disequilibrium and HLAII haplotype DRB1*15:01/DQB1*06:02   dendritic cell protein processing and presentation assays   therapeutic FVIII derived peptides   MHC-associated peptide proteomics   immunogenic potential  

摘要： Introduction: Hemophilia A (HA) patients (HAPs) with the human leukocyte antigen (HLA)-class-II (HLAII) haplotype DRB1*15:01/DQB1*06:02, and thus antigen presenting cells which express HLAII beta-polypeptide chains that form heterodimers of DR15- and DQ6-serotypes, respectively, have an increased risk of developing factor (F)VIII inhibitors (FEIs)-neutralizing antibodies against the therapeutic-FVIII-proteins (tFVIIIs) infused to prevent/arrest bleeding. As DRB1*15:01 and DQB1*06:02 exist in strong linkage disequilibrium, association analysis cannot determine which is the actual risk allele. Methods: To establish the true risk allele of this haplotype, we analyzed the tFVIII-derived peptides (tFVIII-dPs) bound to either the DR or DQ molecules that comprise the individual HLAII repertoires expressed by monocyte-derived dendritic cells obtained from 25 normal blood donors and six HAPs, four without and two with FEIs. We performed log-linear mixed model analyses, where the dependent variable is the log of the measured peptide count. Under Model 1, we analyzed an HLAII allele predictor consisting of ten levels (four DRB1 and six DQB1 alleles) in the fixed effects and variables in the random effects to account for non-independence. Model 2-where the HLAII allele variable consisted of only DRB1*15:01 and DQB1*06:02-compares the HLAII alleles. Results: Relative to the Model 1 reference, DRB1*15:01 and DQB1*06:02 significantly increased tFVIII-derived peptide counts, and DRB1*15:01 contributed significantly more than DQB1*06:02. Reported as risk ratios (RRs) and their 95% confidence interval (CI) lower- (LB) and upper-bound (UB), we found a RR (95% CI-LB, -UB) of 14.16 (10.38, 19.33) and 1.76 (1.24, 2.50) for DRB1*15:01 and DQB1*06:02, respectively. Under Model 2, we found an RR for DRB1*15:01 against DQB1*06:02 of 7.00 (5.80, 8.44). Discussion/conclusion: Our results suggest that DRB1*15:01 is the offending HLAII allele and that DR15 allotypes underlie the increased FEI ri

关键词： lung adenocarcinoma   HLA-A2   lactate dehydrogenase C   recombinant protein   peptides  

摘要： Background Lactate dehydrogenase C (LDHC) is a kind of cancer-testis antigen (CTA) that has been reported to be a biomarker for diagnosis, efficacy evaluation, and recurrence monitoring of lung adenocarcinoma (LUAD). This study aims to assess the value of LDHC in peptide-based vaccines for LUAD *** The LDHC recombinant protein was purified and its effect on PC9 cells was evaluated by wound healing assay, Transwell invasion, and migration assay. Ten HLA-A2-restricted LDHC-derived peptides were predicted and synthesized, and the affinity for the HLA-A2 molecule was analyzed by T2 binding assay and molecule docking. Enzyme-linked immunospot (ELISpot) and LDH cytotoxicity assay were performed to determine the interferon-gamma (IFN-gamma) release level and tumor cell lysis ability of peptide-induced specific cytotoxic T lymphocytes (CTLs).Results The LDHC recombinant protein promoted invasion and migration of PC9 cells. Three HLA-A2-restricted LDHC-derived peptides P2 (LDHC170-180, FRYLIGEKLGV), P5 (LDHC116-124, IMKSIIPAI), and P6 (LDHC172-180, YLIGEKLGV) had high affinity for the HLA-A2 molecule at 50 mu g/mL. P6 (LDHC172-180, YLIGEKLGV) elicited the strongest IFN-gamma-secreting cytotoxic T lymphocyte (CTL) response and exhibited potent cytotoxicity against HLA-A2-positive cells with high LDHC *** LDHC may serve as a targetable biomarker for peptide-based immunotherapy of LUAD.

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： 宫颈癌   高危人乳头瘤病毒   辅助T细胞1   辅助T细胞2   复发  

摘要： 本研究为探讨宫颈癌患者高危人乳头瘤病毒HR-HPV感染程度、辅助T细胞1(Th1)/辅助T细胞2(Th2)相关细胞因子与LEEP术后复发的关系，选取我院2017年1月至2019年1月收治的宫颈癌患者148例，随访5年根据其复发情况分为复发组和未复发组，其中复发组39例，未复发组109例。术前检测两组HR-HPV DNA载量、Th1细胞因子白细胞介素-2(IL-2)及干扰素γ(IFN-γ)、Th2细胞因子白细胞介素-4(IL-4)和白细胞介素-6(IL-6)水平，收集记录患者年龄、肿瘤大小、临床分期、肿瘤分化程度、浸润程度、淋巴结转移情况等临床资料。结果显示，复发组与未复发组相比，临床分期Ⅲ～Ⅳ期、低分化、深肌层浸润、淋巴结转移比例均更高（P<0.05）,HR-HPV-DNA、IL-4及IL-6水平更高，IL-2及IFN-γ水平更低（P<0.05）。HR-HPV-DNA、IL-4及IL-6水平与宫颈癌患者肿瘤低分化、临床分期Ⅲ～Ⅳ期、深肌层浸润、淋巴结转移呈正相关，IL-2、IFN-γ水平与这几类临床资料呈负相关（P<0.05）。HR-HPV-DNA、IL-4及IL-6水平为宫颈癌患者LEEP术后复发的危险因素，IL-2及IFN-γ水平为宫颈癌患者LEEP术后复发的保护因素（P<0.05）。HR-HPV-DNA、IL-2、IFN-γ、IL-4、IL-6、五种指标联合预测宫颈癌患者LEEP术后复发的曲线下面积（AUC）分别为0.681、0.741、0.838、0.835、0.807、0.945。随访5年，高HR-HPV-DNA载量患者复发率高于低HR-HPV-DNA载量患者（P<0.05）。以上结果表明，宫颈癌患者HR-HPV DNA载量、Th1/Th2细胞因子与术后复发相关，对宫颈癌术后复发有一定预测价值。

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

摘要： BackgroundChronic 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 *** 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- 1 alpha, IL- 1 beta), 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 ***-inflammatory markers, such as IL- 1 beta, 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- 1 beta/IL- 1RA and CXCL8/CXCL10 - as potential predictors of wound healing status. The IL- 1 beta/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).ConclusionsImmunomarker profiling via wound swabbing offers valuable insights into the wound healing process. Elevated levels of pro-inflammatory cytokines and MMPs are as

关键词： IFN gamma   PD-L1   CXCL10   immunotherapy   cancer   autoimmunity   inflammation   drug discovery  

摘要： Introduction IFN gamma plays both positive and negative roles in the regulation of innate and adaptive immune responses against tumors and virally infected tissues by upregulating CXCL10 and PD-L1 *** To identify novel pathways and drugs that regulate the IFN gamma-dependent PD-L1, we expressed GFP under the control of mouse PD-L1 promoter in mouse cancer cells that up regulate PD-L1 and CXCL10 in response to IFN gamma stimulation. Using these cells, we screened an FDA approved library of 1496 small molecules known for their ability to inhibit IFN gamma-dependent increase in *** We identified 46 drugs that up regulated and 4 that down regulated IFN gamma-dependent PD-L1 expression. We discovered that in addition to the known JAK inhibitors Ruxolitinib and Baricitinib, Dinaciclib, a CDK1/2/5/9 inhibitor, and Ganetespib, a Hsp90 inhibitor, significantly inhibit both PD-L1 and CXCL10 expression in the model cells. Furthermore, both drugs suppressed IFN gamma-dependent CXCL10 and PD-L1 expression in-vitro in primary human lung cells and human cancer cells. These drugs also significantly inhibited delayed-type hypersensitivity (DTH) in-vivo in an inflammation mouse *** Our novel screening platform can therefore be used in the future to identify novel immunomodulators and pathways in cancer and inflammation, expanding therapeutic horizons.

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

摘要： BackgroundRapid 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. ResultsFrom 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. ConclusionOur algorithm had a > 96% concordance for non-HLA-DRB genes at 3rd field on the first batch and > 88% concordance for non-HLA-