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关键词： Epilepsy   Saikosaponin a   Ferroptosis   Akt/ERK   IL-1  

摘要： Saikosaponin A (SSa), a triterpenoid saponin isolated from Astragalus membranaceus, possesses multiple pharmacological properties, including anticonvulsant, antiepileptic, and anti-inflammatory activities. This study aimed to elucidate the molecular mechanisms by which SSa exerts therapeutic effects in temporal lobe epilepsy (TLE), with a particular focus on the involvement of ferroptosis pathways. In a kainic acid-induced TLE mouse model, electroencephalography (EEG) was used to monitor seizure frequency. Behavioral tests were employed to evaluate cognitive, learning, and memory functions. Additionally, molecular biology techniques were used to investigate the neuroprotective mechanisms of SSa. EEG recordings showed that SSa treatment significantly reduced seizure frequency and severity. Behavioral assessments indicated improvements in cognition, learning, and memory. Histological analysis revealed decreased neuronal death in the hippocampus. Transmission electron microscopy and Golgi-Cox staining demonstrated a marked increase in hippocampal neuron density following SSa treatment. At the cellular level, SSa significantly downregulated the expression of IL-17, phosphorylated Akt (p-Akt), and phosphorylated ERK (p-ERK) in Erastin-induced ferroptotic hippocampal neurons. Notably, the inhibitory effect of SSa on ferroptosis was reversed by IL-17 agonist treatment, suggesting that IL-17 plays a pivotal role in this pathway. In conclusion, SSa alleviates seizures and improves cognitive function in TLE by inhibiting IL-17/Akt/ERK-mediated ferroptosis in hippocampal neurons.

关键词： Biomarker   Diagnostic accuracy   Interleukin-6   IL-6   Late-onset neonatal sepsis  

摘要： Late-onset neonatal sepsis (LONS) remains a leading cause of morbidity and mortality in neonates, particularly among preterm and low birth weight infants. Interleukin-6 (IL-6) has emerged as a promising biomarker for early detection of LONS, yet the diagnostic performance of IL-6 remains inconsistent across studies. This meta-analysis aimed to evaluate the overall diagnostic accuracy of IL-6 in detecting LONS and to assess the certainty of evidence using the GRADE approach. A comprehensive search of five databases was conducted up to July 15, 2025. Twenty-two studies were eligible for inclusion, of which 20 (n = 3527 neonates) were included in the meta-analysis. A bivariate random-effects model was used to estimate pooled sensitivity and specificity, and the area under the SROC curve was used to assess overall diagnostic accuracy. Pooled sensitivity and specificity were 85.2% (95% CI: 80.0-89.3%) and 84.1% (95% CI: 77.5-89.0%), respectively. The positive and negative likelihood ratios were 5.43 and 0.18, with a diagnostic odds ratio of 31.4. The AUC was 0.91, indicating excellent diagnostic accuracy. Subgroup and sensitivity analyses confirmed the robustness of the findings, and no significant threshold effect was detected. However, suspected publication bias was noted. The GRADE assessment rated the certainty of evidence as moderate. Conclusion: IL-6 demonstrates high diagnostic accuracy for LONS and may serve as a valuable tool for early identification, though standardization of cutoff thresholds and further validation studies are warranted. What is Known:center dot IL-6 is an early-rising biomarker for late-onset neonatal sepsis (LONS), but its diagnostic accuracy varies across *** is New:center dot This meta-analysis used a bivariate model to estimate IL-6 performance, yielding high pooled sensitivity (85.2%) and specificity (84.1%).

关键词： EBV   tonsil   children   CD4+T cell   CD8+T cells  

摘要： Introduction Epstein-Barr virus (EBV) infects B lymphocytes and establishes lifelong persistence in the B cells. While systemic T-cell responses have been well characterized, the local immune response at the site of viral entry in children from undeveloped countries remains poorly *** Tonsillar CD4 and CD8 T cells in 32 pediatric patients undergoing tonsillectomy were classified as primary infected (PI), EBV carriers (EC), and non-infected children by serology. T-cell subsets were assessed by flow cytometry, whereas LMP1 and EBNA2 viral proteins were evaluated by *** A higher percentage of activated HLA-DR+ CD8 T cells in PI patients was demonstrated. Notably, PD-1 expression was increased in both PI and EC, in particular in activated HLA-DR+ CD8 T cells. Positive correlations of EBNA2 with follicular helper T cells and Th1 cells, as well as a negative correlation between EBNA2 and activated CD8 T cells, were *** These findings suggest that, during asymptomatic primary infection by EBV, activated CD8 T cells are observed, but they may be cells that may exhibit features of exhaustion, which probably explains the absence of symptoms. PD-1 expression in CD8 T cells remains in EC. Additionally, Tfh, Th1, and CD8 T cells may influence the expression of EBNA2 and LMP1 latent viral antigens in tonsils.

关键词： Kidney organoid   Kidney transplantation   Allograft rejection   HiPSC  

摘要： The aim of this study is to establish an in vitro co-culture system to model allograft rejection using kidney organoids system derived from human induced pluripotent stem cells (hiPSCs). We co-cultured kidney organoids derived from wild-type hiPSCs with HLA-mismatched peripheral blood mononuclear cells (PBMCs) from healthy controls (HC) for 24 h. To assess allogeneic rejection modeling, we measured the expression of HLA molecules, (HLA-ABC and HLA-DR), and evaluated cellular damage in the kidney organoids. Additionally, we analyzed the distribution of T cells and their subsets within the co-cultured PBMCs. The immunosuppressive effect of tacrolimus was also evaluated in this co-culture system. Transcriptomic analysis, conducted using RNA sequencing, identified molecules associated with allogeneic rejection. When kidney organoids were co-cultured with alloreactive PBMCs for 24 h, HLA-ABC and HLA-DR expression significantly increased in kidney organoid cells. Additionally, kidney organoids showed reduced cell viability and increased apoptosis compared to syngeneic controls, as assessed by flow cytometry and Annexin V/PI staining. However, treatment with tacrolimus reduced HLA expression in a dose-dependent manner, highlighting the diminished alloimmune responses. Further analysis of PBMC subsets revealed shifts in T helper (TH) and cytotoxic T cell (TC) populations under allogeneic conditions, including increased effector TH and TC cells. Transcriptomic analysis through RNA sequencing identified 256 differentially expressed genes (DEGs), with notable immune-related pathways such as NF-kappa B and TNF signaling involved in allograft rejection. These results provide evidence that a co-culture system with allogeneic kidney organoids and PBMCs can potentially model transplant rejection in vitro.

关键词： 牛结节性皮肤病病毒   山羊痘病毒   A33R蛋白   多克隆抗体   病毒复制  

摘要： 为获得牛结节性皮肤病病毒（LSDV）A33R蛋白的多克隆抗体，并进行免疫学鉴定，本研究利用293F表达系统表达A33R蛋白并验证蛋白的抗原性，将纯化后的重组A33R蛋白作为免疫原3次免疫BALB /c小鼠，获得多克隆抗体。包被不同来源的6种抗原检测多抗的特异性，包被A33R蛋白及灭活羊痘AV41病毒测定其效价，利用中和实验测定多抗的中和效价。此外，利用该抗体测定灭活LSDV及灭活羊痘AV41复制过程中A33R的表达情况。结果表明，本研究成功表达了A33R蛋白并制备了A33R多抗，A33R多抗与LSDV的其它蛋白L1R、A27L、P32不反应，也不与其它常见感染牛或羊的ORFV B2L蛋白、BCoV S蛋白、PPRV N蛋白反应；包被A33R蛋白，多抗效价为1:1 968 300，包被灭活AV41，多抗效价为1:800；进一步测定A33R多抗血清表明血清具有中和效应，且中和效价为 1:64。病毒感染6 h，没有检测到A33R的表达，但是24 h后在LSDV和AV41感染的细胞中均检测到A33R的大量表达。本研究成功的研究结果不仅为进一步研制A33R的单克隆抗体奠定了基础，也为LSDV等痘病毒的复制感染规律的研究和后续疫苗的研发奠定了基础。

关键词： Copyrights  

摘要： Ulcerative colitis is a chronic nonspecific intestinal inflammatory disease, which usually occurs in the rectal and colonic mucosa and submucosa. Ligustilide, a major component derived from Angelica sinensis (Oliv.) Diels, exerts anti-inflammation effect. However, its impact and molecular mechanism on colitis remain obscure. In this study, in vivo and in vitro experiments verified that ligustilide protected against colitis by suppressing macrophage-mediated inflammation and repairing intestinal barrier. Of note, we utilized a thermal proteome profiling strategy to preliminarily find early growth response factor 1 (EGR1) as a target of ligustilide. Cellular thermal shift assay, drug affinity responsive target stability, and surface plasmon resonance analysis revealed that ligustilide directly targeted His386 to bind to EGR1. Furthermore, RNA-sequencing, dual luciferase reporter gene assay, and rescue experiments illustrated that ligustilide disturbed the nuclear translocation of EGR1 and broke its combination with a disintegrin and metalloproteinase 17 (ADAM17) promoter, thereby inhibiting ADAM17 transcription and downstream tumor necrosis factor-alpha (TNF-alpha) production, as well as expression of inflammatory proteins cyclooxygenase 2 and inducible nitric oxide synthase. Finally, the in vivo experiment with EGR1 overexpression proved that EGR1 was essential for the protective effects of ligustilide on colitis mice. Taken together, our study demonstrates that ligustilide targets EGR1 to inhibit the EGR1-ADAM17-TNF alpha pathway, thus alleviating macrophage-mediated intestinal inflammation and restoring gut barrier.

摘要： We developed a cell type-specific proteogenomic approach to reveal novel or unannotated open reading frames (nuORFs) using transcriptomics, ribosomal profiling, and proteomic analysis of human pancreatic β-cells using stem cell-derived β-cells and/or cadaveric islets. Our analysis revealed translational regulation of β-cell-specific pathways during differentiation and identified 965 nuORFs, with a majority exhibiting protein support and substantial β-cell specificity. A primate-specific ORF located in the 5' untranslated region of the type 1 diabetes risk gene TYK2 may act as a translational activator. We provide HLA class I immunopeptidomic data from cytokine-stimulated human β-cells and demonstrate their utility in coculture assays with autoreactive T-cell transductants. Taken together, our results define the human β-cell translatome, an important resource to the research field.

关键词： 肥大细胞   MST1   I型超敏反应   综述  

摘要： 超敏反应，是指机体接触抗原并致敏后，再次受到相同抗原刺激时表现出的敏感性增高的免疫反应。其中，由免疫球蛋白E （IgE）和肥大细胞介导的超敏反应称为I型超敏反应。肥大细胞广泛分布于体内各种组织器官的结缔组织和黏膜层，是I型超敏反应中的重要效应细胞。在这一过程中，肥大细胞再次与特异性过敏原蛋白接触时，IgE会与之交联，诱发细胞的激活并脱颗粒，随后产生组胺、细胞因子、趋化因子，以及新合成的花生四烯酸和多种蛋白质来调节I型超敏反应。巨噬细胞刺激因子1（MST1）在细胞生物学过程中扮演着多种重要角色，涉及多种细胞的迁移凋亡、增殖、代谢和细胞骨架调控等领域。本综述将探讨MST1激酶的调控机制以及其对I型超敏反应的影响，以期为过敏性疾病的机制和防控研究提供新的思路。

关键词： psoriasis   psoriatic arthritis   guselkumab   therapy   transcriptome  

摘要： Objectives: The aim of this study was to evaluate the transcriptome of peripheral blood mononuclear cells (PBMCs) derived from patients affected by psoriasis (PSO) and psoriatic arthritis (PSA) following treatment with guselkumab, an interleukin (IL)-23 inhibitor. Methods: mRNA was extracted by PBMCs, before and after 24 weeks of treatment with guselkumab, and RNA sequencing was performed in paired-end mode by Illumina technology using the Novaseq6000 platform. log2FoldChange > 1 and p(adj) < 0.05 were the established cutoff to discriminate genes differentially expressed between pre- and post-therapy. For annotation and predictive enrichment analysis of deregulated genes in biological pathways, RStudio was used, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were queried. Cytoscape_v3.10.3 was used for the development of the network between deregulated genes. Results: Six na & iuml;ve active patients with PSO and PSA, diagnosed with a duration <2 years, were assessed before and after 24 weeks of treatment with guselkumab. Performing the quality check and filtering analyses, we found 506 transcripts deregulated between pre- and post-therapy, of which 129 were upregulated and 377 were downregulated. The most upregulated mRNAs included SYTL3, CPT1A, TMEM208, GINS4, and TNFRSF13C. The most downregulated mRNAs included CCR2, TPT1, MYCBP, CMPK1, and TMEM65. Enrichment with the GO database showed the following main deregulated processes: "protein targeting", "the establishment of protein localization to membrane", and "metabolism of fatty acids". The analysis of the main macro-process showed the several pathways deregulated after therapy, including signaling related to ethanol metabolism, thermogenesis, oxidative phosphorylation, and fatty acid metabolism (KEGG). Conclusions: Our findings may give further insights into manipulated mechanistic pathways by IL-23 inhibition in patients with PSO and PSA.