课程文献中心 更多>>

关键词： Maternal high-fat diet   Kiss1 gene   Methylation   Ten-eleven translocation methylcytosine   dioxygenase 2   Interleukin-6  

摘要： Maternal high-fat diet (HFD) is known to impair the reproductive function of female offspring, but the underlying epigenetic mechanisms of this developmental programming remain unclear. In this study, female rats were fed either a control diet (CD;10 % kcal from fat) or an HFD (60 % kcal from fat) prior to and during gestation and lactation. After weaning, female offspring were randomly assigned to continue on either a CD or HFD, resulting in four groups: C/C, C/HF, HF/C, and HF/HF. Maternal HFD significantly reduced primordial follicle numbers, increased follicular atresia and granulosa cell apoptosis, and disrupted sex hormone levels in female offspring at 3 months of age. Female offspring from HFD-fed dams exhibited reduced Kiss1 gene expression and increased promoter methylation in both the ovaries and hypothalami. Additionally, the IL-6/STAT3 pathway was activated, and the expression of Ten-eleven translocation methylcytosine dioxygenase 2 (TET2), a key regulator of DNA demethylation, was downregulated. Post-weaning exposure to a normal diet partially attenuated these effects by 6 months of age. Furthermore, in vitro experiments demonstrated that IL-6/STAT3 signaling downregulated the expression of TET2 and Kisspeptin. Overall, our study demonstrates that maternal HFD consumption reduces TET2 expression in the ovaries and hypothalami of female offspring via the IL-6/STAT3 pathway, leading to Kiss1 promoter hypermethylation and a subsequent decrease in Kisspeptin levels. These findings highlight a potential epigenetic mechanism linking maternal diet to long-term reproductive toxicity in female offspring.

关键词： Obstructive nephropathy   TNF-alpha/RIPK/Caspase-8 axis   Necroptosis   Nrf2/HO-1 pathway   Renal fibrosis  

摘要： Obstructive nephropathy is a chronic condition that causes progressive kidney damage due to inflammation, oxidative stress, necroptosis, and fibrosis. The present study aimed to evaluate the potential chemopreventive effect of infliximab (TNF-alpha inhibitor) or umbelliferone (UMB, a natural antioxidant) individually and together to treat unilateral ureter ligation (UUL)-induced interstitial renal fibrosis in rats. The therapeutic effects were assessed through renal function biomarkers, histopathology, fibrosis, inflammation, oxidative stress, and necroptosis. UUL-induced renal injury led to increased serum biomarkers (urea, creatinine, uric acid), inflammation markers (TNF-alpha, NF-kappa B, IKK), oxidative stress (elevated NADPH oxidase and MDA, reduced Nrf2/HO-1, GSH, SOD), and necroptosis (upregulated RIPK1/RIPK3/p-RIPK3/MLKL/caspase-8), with substantial collagen deposition and fibrosis. Treatment with infliximab and UMB showed preventive effects by suppressing TNF-alpha signaling, reducing oxidative stress, and boosting antioxidant defense. Combined therapy provided superior results by downregulating TNF-alpha/RIPK/Caspase-8 pathways, enhancing Nrf2/HO-1 activity, reducing fibrosis, and restoring renal structure and function. Computational docking confirmed the ability of UMB to interact with TNF-alpha and RIPK3/MLKL binding sites. In conclusion, the combination of infliximab and UMB offers a promising multi-targeted approach to treat obstructive nephropathy and related chronic kidney diseases and highlights its potential to modulate key pathways involved in kidney fibrosis.

关键词： airway   epithelium   paediatrics   TSLP   viral bronchiolitis   virus  

摘要： Thymic stromal lymphopoietin (TSLP) is a primarily epithelial-derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. A total of 129 infants (<1-24 m, median age 10 m) with severe viral respiratory infections were enrolled for in vivo (n = 113), and in vitro studies (n = 16). Infants were classified as 'high TSLP' or 'low TSLP' for values above or below the 50th percentile. High versus low TSLP groups were compared in terms of type I-III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high versus low TSLP responses in vitro in the absence (baseline) or presence (stimulated) of a viral mimic (poly I:C). Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/mL vs. 63.4 pg/mL in low TSLP group, p = 0.007) and increased in vitro type I-III IFN AEC responses after stimulation with a viral mimic (poly I:C). At baseline, our RNAseq data showed that infants in the high TSLP group had significant upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro-inflammatory chemokine genes before stimulation. Infants in the high TSLP group also showed a baseline AEC pro-inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8). High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro-inflam

关键词： Visceral Leishmaniasis   L. donovani   Hypoalbuminemia   Albumin   CEBP-beta   IL-10  

摘要： Visceral leishmaniasis, caused by Leishmania donovani is characterized by clinicopathological features like hepatomegaly with loss of liver function, etc. Albumin is an essential parameter of liver function, performing various tasks like maintaining osmotic balance in blood vessels, preventing tissue fluid leakage, carrier properties, etc. Human VL patients and Leishmania donovani-infected hamsters (ExVL) were tested for their albumin levels. IL-10 derived from Leishmania donovani-infected monocytes and recombinant IL-10 were tested on HepG2 cells for CEBP-(3 and albumin expression with IL-10 blocking and JAK1/STAT3 inhibition. CEBP-(3 binding onto the albumin promoter and its silencing were performed to confirm its role in albumin expression. Low albumin, i. e., hypoalbuminemia, was found in visceral leishmaniasis and ExVL. Its levels were inversely associated with parasitic load and hepatic IL-10 in both models. When treated with Leishmania donovani-driven IL-10 from the infected monocytes and recombinant IL-10, there was a significant decrease in albumin expression from HepG2 cells in a JAK1/STAT3-dependent manner. To further explore the molecular mechanism behind hypoalbuminemia in Visceral leishmaniasis, CEBP-(3, a transcription factor having three isoforms (LAP1, LAP2, and LIP), was shown to increase upon recombinant IL-10 treatment and bind to the D site of the albumin promoter using Chromatin immunoprecipitation PCR. shRNA silencing results confirm CEBP-(3-mediated decrease in albumin levels. Our findings showed that increased hepatic IL-10 upon Leishmania donovani infection reduces albumin levels in a JAK1/STAT3 and CEBP-(3-dependent manner.

摘要： Background Results of the DRESS-PS trial showed that a tapering strategy with TNF inhibitors is non-inferior to continuation of the same TNF inhibitor dose for up to 12 months in patients with psoriatic arthritis and axial spondyloarthritis. This study aimed to describe the effectiveness of TNF inhibitor tapering for up to 24 months in patients who participated in the DRESS-PS trial. Methods This study was a 12-month observational extension of the original 12-month, open-label, non-inferiority DRESS-PS trial conducted at the Sint Maartenskliniek, Nijmegen and Woerden, the Netherlands. Patients aged 16 years and older with psoriatic arthritis or axial spondyloarthritis and stable low disease activity for at least 6 months participated in the original DRESS-PS trial. Patients were randomly assigned to either a treat-to-target tapering strategy (the intervention group), which involved extending the interval between TNF inhibitor doses, resulting in doses of 100%, 66%, 50%, or 0% of the defined daily dose, or to a treat-to-target strategy without tapering (the control group). All patients who participated in the DRESS-PS trial were eligible to participate in this extension study, in which treat-to-target tapering was allowed for all patients, and treatment decisions were made through shared decision making between physicians and patients. The primary outcome was the difference between the original intervention and control groups in the proportion of patients with low disease activity at 24 months;this difference (adjusted for stratification factors at randomisation) was compared, without and with imputation, with the prespecified non-inferiority margin of 20% from the original DRESS-PS trial, and non-inferiority was determined from the adjusted 95% CIs. There was no involvement of people with lived experience of psoriatic arthritis or axial spondyloarthritis in the design, recruitment, conduct, analysis, or reporting of this extension study. The DRESS-PS trial was regis

关键词： Interferon alpha-2b (IFN alpha 2b), Immunotherapy, JAK-STAT pathway, PEGylation   Probody technology   Dendritic cell vaccines  

摘要： Interferon alpha-2b (IFN alpha 2b) has been a pivotal drug in cancer immunotherapy since its FDA approval in the 1980s, demonstrating both direct and indirect anticancer benefits. It directly triggers cell cycle arrest and death via Bax/Bcl-2 regulation and inhibits angiogenesis, primarily mediated by the JAK-STAT system, which activates over 300 interferon-stimulated genes (ISGs). IFN alpha 2b indirectly increases immune surveillance by augmenting natural killer (NK) cell cytotoxicity, facilitating dendritic cell (DC) maturation, and bolstering T-cell activation, while concurrently inhibiting regulatory T cells (Tregs) and immunosuppressive cytokines such as TGF-(3. Clinically, IFN alpha 2b has shown effectiveness in melanoma, renal cell carcinoma (RCC), and hematologic malignancies. In stage III melanoma, high-dose IFN alpha 2b enhances relapse-free survival, decreasing recurrence by 28 %. RCC exhibits a response to IFN alpha 2b in conjunction with interleukin-2, attaining an 18 % objective response rate, but chronic myelogenous leukemia (CML) demonstrates a 76 % survival rate at 36 months. Combination therapy, particularly those incorporating immune checkpoint inhibitors such as pembrolizumab, have enhanced results in advanced melanoma, with objective response rates of 60 %. Innovations like pegylation (prolonging half-life to 48-72 h) and Probody technology (Pb-IFN alpha 2b) enhance safety and tumor specificity. Nonetheless, obstacles persist, including as dose-limiting toxicities, resistance associated with JAK-STAT dysregulation, and immunosuppressive tumor microenvironments. Innovative approaches like as dendritic cell-based vaccinations, biomarker-driven patient stratification, and sophisticated delivery methods seek to surmount these obstacles. As precision oncology advances, IFN alpha 2b continues to be an essential therapeutic agent, connecting its historical significance with future-oriented immunotherapy.

摘要： The cytogenetic risk category retains a pivotal role in the prediction of prognosis in acute myeloid leukemia (AML) patients undergoing hematopoietic stem cell transplantation (HSCT), however, its impact on secondary AML (sAML) is less established. We assessed whether the ELN 2022 cytogenetic risk score predicts outcomes in sAML patients in remission undergoing HSCT from HLA-matched donors performed between 2010 and 2022. Among 1119 patients, 829 had intermediate and 284 had adverse cytogenetics (6 with favorable risk were excluded). Engraftment rates was 72.4% vs. 99.5%. Acute graft-versus-host disease (GVHD) incidence did not differ, but 2-years all grades and extensive chronic GVHD were higher in the intermediate vs. adverse cytogenetics risk groups, hazard ratio (HR) = 0.72;p = 0.034 and HR = 0.58;p = 0.027, respectively. Two-year non-relapse mortality (NRM) was similar. All other HSCT outcomes were inferior in the adverse risk vs. intermediate-risk patients: The HR for 2-year relapse incidence (RI) was 2.48 (95% CI 1.95-3.15, p < 0.001). The HRs for 2-year leukemia-free survival (LFS), overall survival (OS), and GVHD-free/relapse-free survival (GRFS) were 1.62 (95% CI 1.34-1.95, p < 0.001), 1.59 (95% CI 1.3-1.93, p < 0.001) and 1.38 (95% CI 1.15-1.65, p < 0.001), respectively. We conclude that cytogenetic risk score predicts HSCT outcomes in sAML patients.

关键词： CLL   IL-9   STAT3   miR-155   miR-21  

摘要： Following the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 1A on p. 3067, the western blots shown for the STAT3 data in the upper right‑hand gels (for the N3, N4, and C5‑C8 experiments) were strikingly similar to the GAPDH data shown in the lower right‑hand gels (for the C14‑C16 and N6‑N8 experiments). Furthermore, in Fig. 2A on p. 3068, the phosphorylated (p‑)STAT western blots had apparently already appeared in a paper published by the same research group in the journal . After inspecting their original data, the authors realized that the data of interest in Figs. 1 and 2 had inadvertently been chosen incorrectly. The revised and corrected versions of Figs. 1 and 2, now showing replacement data for the upper and lower right‑hand gels in Fig. 1A and the upper three left‑hand panels in Fig. 2A, are shown on the next two pages. Note that the errors made with the assembly of the data in these figures did not affect the overall conclusions reported in the paper. The authors apologize to the Editor of and to the readership for any inconvenience caused. [Oncology Reports 39: 3064‑3072, 2018; DOI: 10.3892/or.2018.6367].