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关键词： Cerebellar motor disorders   Lead toxicity   Cucumis sativus   Caspase-3   TNF-alpha  

摘要： Cerebellar Motor Disorders (CMDs) are characterized by unsteady gait and uncoordinated movements. Reports indicate that CMDs are caused by congenital malformations, hereditary ataxia, and heavy metal exposure, such as Lead. The antioxidant-rich nature of plants, such as Cucumis sativus (Cucumber), has been well-documented. Accordingly, this study investigated the protective activity of aqueous Cucumis sativus fruit extract (CS) in a lead acetate (Pb) rat model of CMD. Forty Wistar rats (n = 8) were randomly assigned into five groups and treated for twenty-eight days as follows: Group A served as control;Group B received 100 mg/kg body weight (bw) of Pb;Group C received 500 mg/kg bw of CS and Pb;Group D received 1000 mg/kg bw of CS and Pb;Group E received 200 mg/kg bw of Vitamin-E and Pb. Thereafter, neurobehavioral activities, antioxidant enzymes, lipid peroxidation, nitric oxide, Pb concentration, Caspase-3, TNF-alpha, and cerebella histology were evaluated. Findings revealed that Pb-exposed rats demonstrated significant (p < 0.05) weight loss, impaired motor functions, dysregulated antioxidant enzymes activity, increased lipid peroxidation, elevated cerebellar nitric oxide and Pb concentration, as well as degenerating Purkinje cells and vacuolations in the cerebellum. Also, a significant upregulation (p < 0.05) of Caspase-3 and TNF-alpha was observed in the cerebella of Pb-exposed rats. However, pretreatment with CS mitigated (p < 0.05) these adverse effects induced by Pb. Taken together, this study offers novel insights into the role of CS as a promising neuroprotective agent and provides translational research evidence demonstrating that CS can be further developed into drugs useful against CMDs.

关键词： Systemic lupus erythematosus (SLE)   Lupus nephritis (LN)   Granzyme B   Cytotoxicity   PI3K  

摘要： Objective: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease which is affected by the environmental, genetic factors as well as the immune system. Previous reports have implicated IFN-alpha in the pathogenesis of SLE. Up to date, however, no research has ever investigated the effect of IFN-alpha on CD8+T cells, which might be implicated in the pathogenesis of SLE. In the present study, we aimed to explore the pathologic role of IFN-alpha in regard to dysfunction of CD8+T cells in SLE. Methods: Serum level of IFN-alpha was detected in SLE and healthy controls (HC). Surface expression of lysosomeassociated membrane protein 1 (LAMP-1;CD107a) and secretion of granzyme B of CD8+T cells was measured in SLE and HC with or without IFN-alpha co-stimulation/PI3K inhibitor. Results: Our results demonstrated that there was increased surface expression of CD107a of CD8+T cells in SLE patients compared with healthy controls (HC), indicating enhanced cytotoxicity of CD8+T cells in SLE patients. Meanwhile, increased secretion of granzyme B was also detected in CD8+T cells of SLE compared with HC, which correlated with the disease activity (SLEDAI). Furthermore, elevated serum level of IFN-alpha in SLE was confirmed in our study. In vitro study, granzyme B secretion by CD8+T cells was upregulated upon IFN-alpha costimulation, which was consistent with enhanced cytotoxicity of CD8+T cells upon IFN-alpha costimulation, as reflected by elevated surface expression of CD107a. PI3K inhibitor reversed increased granzyme B synthesis upon IFN-alpha costimulation in a dose-dependent manner. Conclusion: In summary, elevated serum level of IFN-alpha was responsible for increased secretion of granzyme B and enhanced cytotoxicity of CD8+T cells in SLE and this process may be related to PI3K pathway. Relevant molecules and mechanism remains to be explored in the future.

关键词： GRAVIT-D   IL-1 beta   Inflammation   Obesity   Pregnancy   Vitamin D3  

摘要： Background: Maternal and placental inflammatory activity is carefully regulated during pregnancy and changes in inflammatory status are associated with pregnancy complications and health deficits in the offspring including adverse effects on ***/obesity is associated with chronic inflammation, thereby contributing to adverse effects. Disturbingly, overweight and obesity are highly prevalent among pregnant women worldwide. Vitamin D (vitD) possess immunomodulatory effects and is believed to support healthy pregnancy. Endocrinological societies recommend empiric vitD supplementation in pregnancy but there is no consensus on the minimal supplementation dose Methods: An adjacent study to GRAVIT-D (no. NCT04291313, ***), a double-blinded randomized trial investigating the clinical benefits of increasing vitD supplementation in pregnancy from 400IU to 3600IU/ day from gestational week 11-16 onwards. In a subgroup, (n = 156), multiplex ELISA targeting third-semester serum levels of IL-1 beta, IL-6, IL-10, TNF alpha, MCP-1, and IL-17A was performed. Inflammation signals were correlated with the vitD dose given, subsequently analysing the effect of vitD in relation to the pre-pregnancy body mass index (BMI) within each treatment arm comparing the inflammatory response in WHO-defined BMI groups, < 25, 25-30 and > 30 kg/m(2). Main Results: High pre-pregnancy BMI was associated with increased IL6 and MCP1 in both the 400IU and the 3600 IU exposed group. IL1 beta levels increased with BMI if using a 400IU/day supplement. High dose vitD supplementation ameliorated BMI effects on IL1 beta. Conclusion and Perspectives: Increased vitD supplementation during pregnancy may ameliorate some overweight/ obesity-induced inflammatory activity. Further studies are needed to determine the vitD need in pregnancies complicated by obesity and overweight.

关键词： clinical relevance   IL4   inflammation   prognostic model   pulmonary hypertension  

摘要： Background: The anti-inflammatory cytokine interleukin-4 (IL4) has been recognised as a protective factor in various cardiovascular events, yet its prognostic value in patients with pulmonary hypertension (PH) remains unclear. The study aimed to measure the levels of plasma IL4 in patients with PH and to explore their potential association with disease risk and outcomes. Methods: In this observational study, we analysed the levels of plasma IL4 in 766 PH patients and 191 healthy controls in Shanghai Pulmonary Hospital from October 2009 to January 2024. To establish the correlations between plasma IL4 levels and the risk and outcomes of PH, all patients were followed up from June 2013 to June 2024. The Spearman correlation test was employed to evaluate the relationships between IL4 and right heart catheterisation parameters among patients with PH. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic performance of IL4 for PH. The Cox proportional hazards models and Kaplan-Meier survival curves were used to assess the prognostic value of IL4 levels. Logistic regression analysis was performed to predict PH incidence. A nomogram was constructed to predict mortality, and its clinical utility was validated using decision curve analysis (DCA). Results: Plasma IL4 levels were significantly decreased in patients with PH compared with controls (p < 0.001), as well as in different PH groups (p < 0.05 for all). The logistic regression analyses indicated that the lower IL4 levels were associated with the high risk of PH (OR = 0.79, 95% CI: 0.716-0.872;p < 0.001). IL4 levels correlated inversely with NT-proBNP (r = -0.10, p < 0.05) and mPAP (r = -0.01, p < 0.05), and positively with CI (r = 0.12, p < 0.05) and PaSaO2 (r = 0.11, p < 0.05), indicating an association with disease severity. Kaplan-Meier analysis revealed that patients with IL4 >= 2.8774 pg/mL had a 3-year cumulative survival rate of 91.28%, compared with 82.83% for those with IL4 <

关键词： HLA typing   HLA-DQA1*06 NEW   next generation sequencing  

摘要： HLA-DQA1*06:09 differs from HLA-DQA1*06:01:01:02 by one nucleotide substitution in Exon 2, codon 23 GGC > AGC.

关键词： COCs   IL-11/PI3K/AKT   POI   apoptosis   ovarian granulosa cells  

摘要： BACKGROUND:Premature ovarian insufficiency (POI) is characterized by a reduction in primary follicle count along with abnormal follicle development. This study aims to explore the impact of combined oral contraceptives (COCs) on the apoptosis of ovarian granulosa cells, which are instrumental for follicular development, in POI and the underlying mechanisms, to provide theoretical guidance for the treatment of POI. METHODS:A rat model of POI was established using tripterygium glycoside tablets. After treatment with COCs, the therapeutic effect of the animals was verified by means of hematoxylin-eosin staining, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). Flow cytometry, cell counting kit-8 (CCK-8), quantitative polymerase chain reaction, and Western blotting were utilized to investigate the impact of COCs on granulosa cell apoptosis, as well as the function of the interleukin (IL)-11/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Further experiments were also conducted to verify whether COCs could inhibit granulosa cell apoptosis through this pathway. RESULTS:COCs treatment was effective in improving ovarian granulosa cell status, reducing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and increasing estradiol levels in the POI rats ( < 0.01). IL-11 silencing promoted apoptosis in POI granulosa cells by inhibiting the PI3K/AKT pathway. COCs treatment partially reversed these effects by upregulating IL-11 expression and restoring PI3K/AKT pathway activity. This resulted in increased levels of B-cell lymphoma 2 () ( < 0.05) and cytochrome P450 family 19 subfamily A member 1 () ( < 0.01), while suppressing the expression of Bax and cleaved-cysteine-aspartic acid protease 3 (cleaved-caspase 3) ( < 0.001). CONCLUSION:Our findings demonstrated that COCs protect ovarian granulosa cells from apoptosis in rats with POI, an effect mediated through the IL-11/PI3K/AKT signaling cascade.

关键词： Adaptive immunity   Cytokines and Chemokines  

关键词： Ovarian Cancer   Transcriptomics   Single-Cell Sequencing   Prognostic Model   Gene Expression  

摘要： Ovarian cancer represents a malignancy characterized by high incidence and mortality rates, necessitating further elucidation of its underlying mechanisms. We conducted an analysis using bulk transcriptomic data of ovarian cancer and normal ovarian tissues, as well as single-cell sequencing data according to publicly available databases. Through calculation of Gene Set Variation Analysis (GSVA) scores for TNF family genes, weighted gene co-expression network analysis (WGCNA) for hub genes identification, and subsequent Gene Ontology (GO) enrichment analysis, we delineated pathways crucial in ovarian cancer pathogenesis. Furthermore, differential expression gene analysis facilitated the identification of genes with pronounced expression levels in tumor tissues and their intersection with hub genes, followed by GO analyses across molecular functions (MF), cellular components (CC), and biological processes (BP). Utilizing multivariable Cox regression and LASSO analyses, we constructed a prognostic model comprising 14 genes (GFPT2, PDE4B, PODNL1, TGFBI, CSF1R, PTGIS, SFRP2, COL5A2, TRAC, SLAMF7, VCAN, GBP1P1, C2, TRBV28). Both training and validation sets demonstrated robust diagnostic and prognostic capabilities. Clinical information and immune cell infiltration analyses were further conducted based on the model. In the single-cell sequencing analysis, reducing dimensional complexity and classifying cell types were performed, followed by exploration of gene expression patterns within each subtype and investigation of temporal expression variations across cell subtypes. Biological functional exploration and drug sensitivity analyses were also conducted. Our study contributes novel insights and theoretical foundations for prognosis, treatment, and development of drugs in patients.