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关键词： span>SCIDClinGenACMG/AMP guidelines  

关键词： IL-15/IL-15R alpha   intestinal stromal cell   5-FU   regeneration   organoid  

摘要： Interleukin (IL)-15 is critical for intestinal homeostasis, but the precise origin and functions of IL-15 involved in inflamed mucosal healing are not fully understood. This study demonstrated that IL-15/IL-15R alpha signaling was up-regulated during wound healing in 5-fluorouracil (5-FU)-induced intestinal mucositis. Moreover, a subset of podoplanin+ stromal cells located adjacent to crypts were the primary cellular source of IL-15 following gut damage. Stroma-specific IL-15 proved to be crucial for the regeneration of damaged intestine. The deletion of IL-15R alpha in intestinal epithelial cells compromised the recovery from intestinal injury. Moreover, compared with IL-15, IL-15/IL-15R alpha complex can more efficiently promote intestinal epithelial repair. When stimulating human-derived ileal organoids, IL-15/IL-15 complex induced epithelial proliferation through an STAT3-HIF-1 alpha signaling axis and afforded protection against 5-FU-induced epithelial damage. These findings innovatively demonstrated that stroma-specific IL-15 coordinates epithelial IL-15R alpha to accelerate wound healing in response to gut damage.

摘要： INTRODUCTION:This study is to analyze the value of serum amyloid A (SAA), interleukin-17 (IL-17), and the T helper cell 17/Regulatory T cell (Th17/Treg) ratio in the clinical diagnosis and prognostic evaluation of lower respiratory tract infection (LRTI) in elderly patients with chronic obstructive pulmonary disease (COPD). METHODS:A retrospective analysis was performed on 214 elderly COPD patients hospitalized between January 2022 and December 2023. Patients were divided into infection (n = 101) and non-infection groups (n = 113) based on microbiological findings. Serum SAA, IL-17 levels, and peripheral Th17/Treg ratios at admission were measured and correlated with pulmonary function indices (FEV1, FVC, FEV1/FVC). RESULTS:In the infection group, SAA, IL-17 levels and Th17/Treg ratio were higher (P < 0.05), while pulmonary function indices were lower (P < 0.05) than in the non-infection group. ROC analysis showed combined detection of SAA, IL-17, and Th17/Treg had higher diagnostic value (AUC = 0.970) than single indicators. Within the infection group, patients were further stratified by 60-day outcomes into favorable and poor prognosis subgroups. Multivariate logistic regression identified prolonged glucocorticoid therapy, elevated SAA, and increased Th17/Treg ratio as independent risk factors for poor prognosis, whereas IL-17 and mechanical ventilation were not statistically associated (P > 0.05). Combined biomarker analysis also yielded strong prognostic performance (AUC = 0.874). CONCLUSION:The combined assessment of SAA, IL-17, and Th17/Treg holds considerable value in the diagnosis and prognostic evaluation of LRTI in elderly COPD patients, providing new diagnostic and prognostic assessment tools for clinical practice.

关键词： Atopy   Ethanol extract   Perilla seed oil   Tumor necrosis factor-alpha   Interferon-gamma   Inflammatory response   Human keratinocyte HaCaT cells  

摘要： Chronic inflammatory atopic dermatitis (AD) is a skin disorder characterized by cutaneous inflammation and a dysfunctional skin barrier. Although perilla seed oil (PO) is known to exhibit various biological activities, including anti-cancer, anti-inflammatory, and anti-oxidant effects, its inhibitory effects together with the ethanol extract of PO (PE) on atopic and inflammatory responses in the dermal skin has not yet been investigated. In the present study, PE significantly reduced mRNA expressions of inflammation-associated cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta, IL-6, IL-8, and IL-33. Furthermore, PE decreased the levels of the chemokine, thymus- and activation-regulated chemokine (TARC/CCL17) in TNF-alpha and interferon (IFN)-gamma-stimulated human HaCaT keratinocytes. In addition, PE effectively suppressed activation of MAPK/NF-kappa B and JAK/STAT signaling pathways in HaCaT keratinocytes co-stimulated with TNF-alpha and IFN-gamma. These findings indicate that PE possesses anti-inflammatory and anti-atopic properties, suggesting its potential benefits in treating inflammatory skin diseases including AD.

关键词： ferroptosis   IFN-gamma   ischemia/reperfusion   JAK/STAT1 signaling pathway  

摘要： Interferon-gamma (IFN-gamma) is a soluble cytokine that binds to the IFN-gamma receptor and activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, modulating various cell functions. The present study investigated the potential role of IFN-gamma in ferroptosis after ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in mice using the middle cerebral artery occlusion (MCAO) model. This study evaluated neurological function, cerebral infarct volume, cerebral blood flow, neuronal apoptosis, oxidative stress, and ferroptosis. We first identified an increased protein level of IFN-gamma after cerebral ischemia. Treatment with the IFN-gamma inhibitor, Emapalumab, could significantly ameliorate neurological deficits, reduce infarct volume, and improve cerebral blood flow. In contrast, recombinant IFN-gamma (r-IFN-gamma) exacerbated these effects. In vivo experiments indicated that IFN-gamma inhibition attenuated neuronal apoptosis by regulating apoptotic proteins, including Bax, Bcl-2, and Caspase 3. Moreover, IFN-gamma inhibition reduced oxidative stress and ferroptosis by inhibiting the phosphorylation of STAT1 and the level of IRF1. Conversely, r-IFN-gamma increased I/R-induced neuronal apoptosis, oxidative stress, and ferroptosis. JAK or STAT1 inhibition could counteract the detrimental effects of r-IFN-gamma on cerebral ischemic injury. Our results indicate that r-IFN-gamma aggravates cerebral ischemic injury via activation of the JAK/STAT1/IRF1 signaling pathway. The IFN-gamma/JAK/STAT1/IRF1 signaling axis plays a crucial role in ferroptosis, suggesting that targeting this pathway may be a potential therapeutic strategy for ischemic stroke.

关键词： Drug delivery   Hepatocellular carcinoma   RNA vaccine   Tumour immunotherapy  

摘要： BACKGROUND:Motivating the immune system to target tumour cells plays an increasingly prominent role in the treatment of hepatocellular carcinoma (HCC), but challenges such as low overall response rates persist in current clinical practice. Tumour cell MHC-Class-I (MHC-I) downregulation and antigen loss are typical mechanisms of immune evasion. To this end, a dual-functional RNA-based strategy was conceived for HCC immunotherapy. METHODS:MHC-I expression on HCC and paratumour tissues from patients was assessed, and the correlations between MHC-I regulators and HCC prognosis were analyzed. Small interfering RNA (siRNA) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and mRNA encoding tumour antigens were encapsulated in a fluorinated lipid nanoparticle (LNP), which direct nucleic acids primarily to the liver, making it ideal for HCC treatment. Anti-tumour efficacy was investigated in an orthotopic HCC model, with single-cell RNA sequencing used for in-depth analysis of the tumour microenvironment (TME). RESULTS:A marked downregulation of MHC-I expression was observed in HCC tumour cells from a cohort of patients, with this MHC-I suppression correlating with poor prognosis and diminished responsiveness to immunotherapy. Among the various MHC-I regulators, PCSK9 is the only one that shows a significant correlation with the prognosis of HCC patients. Knockdown of PCSK9 inhibited MHC-I degradation and thus increased the efficiency of antigen presentation by up to sixfold compared to untreated tumour cells. The hybrid RNA LNPs (h-LNP) enhanced Th1-mediated immune responses, reinvigorating and expanding anti-tumour immunity within the TME. Following treatment with h-LNPs, the TME showed a pronounced infiltration of CD8 T cells and NK cells, coupled with a significant reduction in immune-suppressive populations, such as M2-like macrophages, in contrast to the controls. These changes in the immune landscape were accompanied by a marked inhibition of tumour gro

关键词： lncRNA   innate defense   italic>Cryptosporidium   intestinal epithelium   U90926   IFN-gamma  

摘要： Cryptosporidium infects the intestine in a wide variety of vertebrates, and intestinal epithelial cells provide the first line of defense against Cryptosporidium infection. Interferon gamma (IFN-gamma) from immune cells infiltrated at the site of infection plays a key role in the epithelial cell-intrinsic defense. Nevertheless, the success of the parasite is the result of its ability to evade the host immune responses. Increasing evidence suggests that long noncoding RNAs (lncRNA) participate in host-pathogen interactions, but the underlying mechanisms are not fully understood. We previously demonstrated that lncRNA U90926 is upregulated in response to infection but appears to be playing a pro-parasitic role given its ability to repress transcription of defense genes and aid the parasite during infection. We show here that inhibition of U90926 during Cryptosporidium infection increased expressions of Irgm2, Igtp, and Iigp1, which are known IFN-gamma-stimulated genes, in a gene-specific manner. Depletion of U90926 results in an increase in histone modifications associated with gene transactivation in the promoter regions of Irgm2, Igtp, and Ilgp1, suggesting U90926 is regulating defense gene expression via epigenetic modifications. U90926 can interact with Ehmt2, a potent euchromatic methyltransferase, in the promoter region of these defense genes to alter histone modifications. Knockout of U90926 enhances IFN-gamma-mediated inhibition of Cryptosporidium infection, suggesting that U90926 may modulate IFN-gamma-induced gene expression to suppress cell-intrinsic antimicrobial defenses. The data highlight a strategy Cryptosporidium has evolved to hijack host cell lncRNA machinery to suppress the immune response and allow for a robust infection.

关键词： Macrophage   Neuromediators   atopic dermatitis   human skin   inflammation  

关键词： Abnormal keratinization   Rumen   Transcriptome   pH  

摘要： High-grain diets can reduce rumen pH, which may damage the process of keratinization of the ruminal stratified squamous epithelium, leading to areas of abnormal keratinization (AK). However, the comprehension of molecular biological processes leading to the development of an AK area in the rumen is limited. A total of 48 wethers (2-month-old) were fed a diet containing 48% barley and 24% starch (DM basis) to induce AK development. Rumen fluid samples were collected via an oral stomach tube at 0, 2.5, and 6 h post-morning feeding on three consecutive days (d 58, 59, and 60) to measure pH. Following a 63-day feeding period, all lambs were slaughtered, and based on macroscopic pathological observation of the rumen, they were retrospectively classified into two categories of individuals: individuals with normal rumen (INR; n = 38) and individuals with abnormal keratinization rumen (IAKR; n = 10). Tissue samples from the AK and adjacent morphologically normal (MN) areas of IAKR were analyzed histologically and via RNA sequencing and quantitative real-time PCR (qRT-PCR). Statistical analysis used Shapiro-Wilk tests for histological and qRT-PCR data and linear mixed models for pH comparisons. Key genes and pathways were identified through Differential Expression Analysis (DEA), Weighted Gene Co-expression Network Analysis (WGCNA), and Gene Set Enrichment Analysis (GSEA). Compared to the INR, the IAKR had a lower rumen pH at 2.5 h post-morning feeding (5.352 vs 6.035, P < 0.01). Histological examination showed significant reductions in papillae length, width, and stratum corneum thickness in the AK area compared to the MN area (P < 0.01). Transcriptomic analysis revealed the gene expression downregulation of ACTR2, which play a role in tight junctions; Downregulation of SLC38A2, a gene involved in the protein digestion and absorption pathway, was also observed; The upregulation of MMP9 was observed in the IL-17 signaling pathway, contributing to tissue damage; The expressio

关键词： 系统性红斑狼疮   抗双链脱氧核糖核酸抗体   人附睾分泌蛋白4   疾病活动度  

摘要： 目的分析血清抗双链脱氧核糖核酸（dsDNA）抗体、人附睾分泌蛋白4（HE4），以及补体C3、C4与系统性红斑狼疮（SLE）患者疾病活动度的相关性。方法将2023年4月至2025年4月该院收治的178例SLE患者纳入观察组，同期于该院健康体检的181例健康者纳入健康组，检测并对比2组患者抗dsDNA抗体、HE4，以及补体C3、C4的差异；描绘受试者工作特征曲线分析抗dsDNA抗体、HE4，以及补体C3、C4联合或单一诊断SLE的效能；按SLE疾病活动度评分将观察组分为轻度活动（＜10分）组（75例）、中度活动（10～15分）组（66例）及重度活动（＞15分）组（37例），对比不同疾病活动度SLE患者抗dsDNA抗体、HE4，以及补体C3、C4的差异；并采用Pearson相关系数分析抗dsDNA抗体、HE4，以及补体C3、C4与SLE患者疾病活动度的相关性。结果观察组患者抗dsDNA抗体、HE4均明显高于健康组，补体C3、C4均明显低于健康组，抗dsDNA抗体、HE4，以及补体C3、C4联合诊断SLE的曲线下面积高于单一诊断，差异均有统计学意义（P＜0.05）。重度活动组患者抗dsDNA抗体、HE4均明显高于中、轻度活动组，补体C3、C4均明显低于中、轻度活动组，中度活动组患者抗dsDNA抗体、HE4均明显高于轻度活动组，补体C3、C4均明显低于轻度活动组，抗dsDNA抗体、HE4与SLE患者疾病活动度均呈正相关，补体C3、C4与患者疾病活动度均呈负相关，差异均有统计学意义（P＜0.05）。结论抗dsDNA抗体、HE4在SLE患者体内均呈异常高表达，补体C3、C4均呈异常低表达，四者与患者疾病活动度存在紧密的相关性，临床医生需对此予以高度重视。