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关键词： IL-33   ST2   and pain   glial cells   inflammation   superoxide anion  

摘要： Reactive oxygen species such as superoxide anion have varied roles in inflammation and pain, which can be mimicked by potassium superoxide (KO), the superoxide anion donor. Interleukin (IL)-33 has pleiotropic functions by activating its receptor suppression of tumorigenicity 2 (ST2). However, the role of IL-33/ST2 signaling in inflammatory pain initiated by reactive oxygen species (ROS) such as superoxide anion has not been investigated, which was the aim of the present study. IL-33 levels were assessed by enzyme-linked immunosorbent assay (ELISA). Mechanical and thermal hyperalgesia and overt pain were evaluated by electronic von Frey, hot plate, and abdominal writhing/paw flinching/licking, respectively. Edema and leukocyte recruitment (myeloperoxidase assay and total/differential cell count), antioxidant capacity, superoxide anion production and lipid peroxidation were assessed. Paw skin and spinal cord messenger ribonucleic acid (mRNA) expression of pro-inflammatory mediators and glial markers in the spinal cord were evaluated. Immunofluorescence was used to detect spinal glial and neuronal c-Fos activation. KO injection triggered IL-33 production in the paw skin and spinal cord of mice, induced hyperalgesia, edema, neutrophil recruitment to the paw tissue, overt pain-like behavior, and leukocyte recruitment to the peritoneum that were reduced in ST2 deficient mice. In the paw skin and spinal cord, KO triggered IL-33/ST2-dependent oxidative stress, and mRNA expression of inflammatory molecules, which were reduced by ST2 deficiency. KO induced spinal cord glial (at mRNA/protein levels) and neuronal activation in IL-33/ST2-dependent manner. IL-33/ST2 signaling mediates, at least in part, superoxide anion-induced inflammatory pain by modulating local and spinal inflammatory events.

关键词： Cytokines   Gene expression   IFN-γ   IL-12   Measles   Subacute sclerosing panencephalitis  

摘要： Background: Subacute sclerosing panencephalitis (SSPE) is a rare but fatal neurological syndrome resulting from persistent measles virus infection in the central nervous system. Despite the availability of a measles vaccine, SSPE continues to pose a significant health burden, and immunogenetic risk factors remain unclear. We aimed to study the role of the interleukin 12 (IL-12)/interferon-gamma (IFN-γ) axis, known for it's significance in antiviral defense, in the development of SSPE. Methods: This cross-sectional case-control study recruited consecutive age and sex-matched SSPE cases (n = 51) and controls (n = 51). Gene expressions were quantified for IL-12B, IFNG, IL-12RB1, STAT4, IFNGR1, IFNGR2, STAT1, IRF8, and ISG15 genes using quantitative realtime PCR. Additionally, plasma levels of IL-12p40, IL-12p70, and IFN-γ were measured using the multiplex suspension array platform. Furthermore, single nucleotide polymorphisms (SNPs) in IL-12B, IL-12RB1, IFNG, IFNGR1, IFNGR2, and ISG15 genes were examined using TaqMan SNP genotyping assays. Statistical analyses compared gene expressions, cytokine levels, and alleles and genotypes frequencies between SSPE patients and controls. Results: Significant alterations in the expression of key IL-12 pathway-related genes were observed in SSPE patients compared to controls, including lower STAT4 (p = 0.0445) and higher IFNGR1 (p = 0.0005) and IRF8 (p = 0.0229). Elevated plasma levels of IL-12p70 (p = 0.0015) and IFN-γ (p = 0.0381) were also observed in SSPE patients. Additionally, associations with SSPE were found for the rs3212227 SNP in IL-12B (p = 0.048), the rs1059293 SNP in IFNGR2 (p = 0.052), and the rs1921 SNP in ISG15 (p = 0.054) genes. Notably, gene-gene interactions among these genes exhibited associations with SSPE. Conclusion: This study provides novel insights into the dysregulation of the IL-12/IFN-γ immune axis in SSPE and underscores the complex interplay between host genetics and viral infection in disease pathoge

关键词： 外泌体   三阴性乳腺癌   放射疗法   T淋巴细胞   调节性  

摘要： 目的探讨放射线照射后三阴性乳腺癌（TNBC）细胞释放的外泌体对免疫细胞的影响。方法培养3种TNBC细胞（MDA-MB-231、MDA-MB-453、MDA-MB-468细胞）生长至70%愈合度时，一组给予8 Gy剂量照射，另一组无干预措施。照射后48 h收集细胞培养上清液。随后，将上清液与外周血单个核细胞中的淋巴细胞共同培养，并通过荧光显微镜拍照确认T细胞对外泌体的摄取情况。同时，使用流式细胞术检测细胞中调节性T细胞（Treg细胞）的表达情况。通过t检验比较两组间Treg细胞分化差异（用Treg细胞阳性率表示）。结果透射电子显微镜扫描及纳米粒子分析法分析显示，实验中提取的外囊泡为外泌体。淋巴细胞将外泌体吞噬，吞噬后外泌体主要集中在细胞质。3种三阴性乳腺癌细胞释放的外泌体与淋巴细胞共同培养后，与空白组比较，Treg细胞分化增加（1.07%、0.60%、0.63%比0.30%，P<0.01）。此外，照射后三阴性乳腺癌细胞释放的外泌体进一步增加了Treg细胞的分化（MDA-MB-231组1.07%比1.81%，P<0.01；MDA-MB-453组0.6%比0.93%，P<0.05）。结论TNBC细胞释放的外泌体可以促进Treg细胞的分化，而照射后的TNBC细胞释放的外泌体进一步促进了Treg细胞的分化。

关键词： Hepatitis B virus   LY6E   Peg-IFN-α   TRIM6  

摘要： BACKGROUND:Pegylated interferon alpha (Peg-IFN-α) has the potential to eradicate hepatitis B surface antigen (HBsAg). This study aimed to investigate whether the expression levels of lymphocyte antigen 6 family member E (LY6E) and tripartite motif-containing protein 6 (TRIM6) mRNAs in peripheral blood mononuclear cells (PBMCs) of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) patients is associated with the response to Peg-IFN-α treatment and HBsAg clearance. METHODS:In this prospective study, HBeAg-negative chronic HBV patients treated with Peg-IFN-α were followed for 48 weeks. The participants were classified into two groups, the virological response (VR) group and nonvirological response (NVR) group, according to the changes in HBV DNA and HBsAg levels observed at week 48 of treatment. Furthermore, these patients were divided into a serological response (SR) group and a nonserological response (NSR) group, depending on whether they exhibited a loss of serum HBsAg or evidence of seroconversion. The expression levels of LY6E and TRIM6 mRNAs in PBMCs were evaluated using real-time quantitative PCR with fluorescence detection. The diagnostic performance of LY6E and TRIM6 was assessed by analyzing the receiver operating characteristic (ROC) curve and calculating the area under the ROC curve (AUC). RESULTS:After the treatment period, the observed VR and SR rates were 44.64% and 28.57%, respectively. Dynamic changes in LY6E and TRIM6 mRNA levels were significantly different between the VR and NVR groups and between the SR and NSR groups. Multivariate analysis revealed that TRIM6 was independently associated with VR at weeks 12 and 24 of Peg-IFN-α therapy and with SR at week 12; in addition, LY6E was independently associated with VR at week 12 and SR at week 24. At week 24, the area under the curve (AUC) for LY6E in the prediction of VR was 0.6942, and the AUC for the prediction of SR was 0.7766; at week 12, TRIM6 had AUCs of 0.7600 for the predic

关键词： IL-4/STAT6 signaling pathway   LKB1   M2 macrophage polarization   Renal fibrosis   Sodium butyrate (NaB)  

摘要： BACKGROUND:Renal firosis is a critical pathological characteristic of chronic kidney disease, and current antifibrotic therapies has limited efficacy. Sodium butyrate (NaB) has been shown to be highly effective in mitigating bleomycin-induced pulmonary fibrosis; however, its specific impact on renal fibrosis and the underlying mechanisms remain unclear. This study aims to elucidate the role and mechanism of NaB in renal fibrosis by using a mouse model of renal fibrosis induced through Unilateral Ureteral Obstruction (UUO) and folic acid (FA) administration. RESULTS:NaB significantly decreased the distribution of collagen fibers in renal tissues and mitigated fibrosis in a dose-dependent manner. Further analysis indicated that NaB inhibited M2 macrophage polarization in the renal tissues of UUO model mice by blocking the phosphorylation of STAT6, hence reducing renal fibrosis. Additionally, in vitro experiments demonstrated that NaB inhibited fibroblast activation induced by M2 macrophages. Mechanistic studies revealed that NaB attenuates fibroblast activation and M2 macrophage polarization by upregulating LKB1 and inhibiting the activation of the STAT6 signaling pathway. CONCLUSION:NaB may exert its effects by inhibiting the activation of the IL-4/STAT6 signaling pathway through the upregulation of LKB1, which suppress the polarization of M2 macrophages and consequently reduce renal fibrosis. These findings establish a theoretical foundation for NaB as a novel drug candidate for renal fibrosis and indicate its potential applicability in clinical treatments for this condition.

关键词： Anticonvulsant   Ketamine-Xylazine   NMRI mice   Neuroinflammation   Pentylenetetrazol (PTZ)  

摘要： INTRODUCTION AND OBJECTIVE:Epilepsy is one of the most common chronic brain disorders worldwide. This study aimed to determine the effect of Galbanic acid on seizures. MATERIALS AND METHODS:In this study, 40 NMRI mice were used and divided into 4 groups. The control group received 10 mg/kg normal saline. Three groups received Galbanic acid at doses of 10, 20, and 40 mg/kg. The positive control group received diazepam with a dose of 10 mg/kg. All injections were made intraperitoneally for one week. Seizures were induced in all mice by injection of 90 mg/kg Pentylenetetrazole (PTZ). Then the latency of seizure onset in each of the experimental groups was recorded. After anesthesia with Ketamine 100 mg/kg and Xylazine 10 mg/kg, blood samples were taken and after decapitation, the hippocampus was isolated and the expression of αTNF-, IL1β, and TLR4 genes in this region was measured. RESULTS:Galbanic acid increased the delay in seizure onset, decreased brain and serum nitrite levels, and decreased the expression of αTNF-, IL1β, and TLR4 genes in brain tissue compared to the control group (P < 0.01, p < 0.001). CONCLUSION:Galbanic acid reduced nitrite and the expression of αTNF-, IL1β, and TLR4, leading to a decrease in neuroinflammation and, as a result, a delay in seizure onset in mice.

关键词： Cumulus cells   Developmental potential   Oocyte aging   Ovine   Tumor necrosis factor-alpha  

摘要： Post-maturation oocyte aging (PMOA) is known to significantly impair the developmental potential of oocytes;however, comprehensive studies on ovine PMOA remain limited. In mice, cumulus cells (CCs) accelerate oocyte aging by releasing cytokines, but the roles of CCs and cytokines in PMOA of domestic animals are poorly understood. This study aimed to elucidate the involvement of CCs and tumor necrosis factor (TNF)-alpha in the PMOA of ovine oocytes. Our findings reveal that PMOA significantly reduced blastocyst rates and the expression of development-promoting genes, while increasing oocyte degeneration and activation rates, along with expression of development-inhibiting genes, compared to newly matured oocytes. These detrimental effects were more pronounced in oocytes aged as cumulus-oocyte complexes than as cumulus-denuded oocytes. Additionally, PMOA led to increased apoptotic rates, TNF-alpha production, and TNF receptor 1 (TNFR1) expression in CCs, coupled with a significant reduction in the expression of anti-apoptotic genes. Mature oocytes expressed TNFR1, with levels decreasing significantly during PMOA. Importantly, the addition of the TNF-alpha antagonist Etanercept to the aging medium markedly improved parthenogenetic embryo development and the expression of competence-related genes, while mitigating CC apoptosis during PMOA of COCs. In conclusion, PMOA compromises developmental potential while heightening oocyte degeneration and activation sensitivity in ovine oocytes. Cumulus cells exacerbate PMOA through increased TNF-alpha signaling activity, highlighting the potential of TNF-alpha antagonists as therapeutic agents to counteract the deleterious effects of PMOA.

摘要： This study aimed to determine the prevalence of oral and maxillofacial anomalies among newborns in the Ha’il Region, Saudi Arabia, and to explore associations with parental health, socioeconomic status, and environmental factors. Given the scarcity of regional data on congenital anomalies, this research furthers the understanding of localised health risks and could inform targeted interventions. A cross-sectional hospital-based study was conducted involving 40,000 newborns born between December 2019 and June 2024. Data were collected from medical records and parental interviews at one of the main hospitals in the Ha’il Region. Anomalies were categorised and analysed using the Statistical Package for Social Sciences software, with statistical significance set atp< 0.05. Forty-seven cases (0.146%) of oral and maxillofacial anomalies were identified, with a higher prevalence seen in female newborns. Relationship were found between these anomalies and parental smoking, socioeconomic status, and parental health history. Anomalies, such as cleft lips and palates, were more frequent in females, while other conditions, like the eruption of chlorodontia, were exclusive to males. This study underscores the importance of addressing environmental and socioeconomic factors to prevent congenital anomalies. These findings provide crucial data for healthcare planning in the Ha’il Region, aligning with Saudi’s Vision 2030 objectives related to improving neonatal and maternal care.

关键词： ASD   Choroid plexus   Ependyma   IFN-γ   MIA   Ventriculomegaly  

摘要： Maternal immune activation (MIA) is a principal environmental risk factor contributing to autism spectrum disorder (ASD) and can be causally linked to ASD symptoms. In our study, we found that MIA triggered by poly (I: C) injection caused ventriculomegaly in offspring due to the dysfunction of the choroid plexus (Chp) and ependyma. We subsequently identified a sustained enhancement of interferon-γ (IFN-γ) signaling in the brain and serum of MIA offspring. Further study revealed that increased IFN-γ signaling could disrupt the barrier function of Chp epithelial cells by activating macrophages, and suppress the differentiation of primary ependymal cells via the signal transducer and activator of transcription 1/3 signaling. The effects of MIA on the offspring were mitigated by administration of IFNGR-blocking antibody in pregnant dams, while systemic maternal administration of IFN-γ was sufficient to mimic the effect of MIA. Overall, our findings revealed that ventriculomegaly caused by IFN-γ signaling could be a critical factor in compromising fetal brain development in MIA-induced ASD and provide a mechanistic framework for the association between maternal inflammation and abnormal development of ventricles in the offspring.

关键词： Alzheimer's disease   BDNF   Neuroprotection   Oxidative stress   Paeoniflorin   PDK3   TNF-α  

摘要： Metabolic dysregulation causes diseases like diabetes and cancer, making PDKs attractive targets. However, a thorough investigation into the unique roles played by the different members of the PDK family, especially PDK3, about memory loss and related diseases like Alzheimer's disease (AD) is still lacking. The current study investigates PF's potential to reduce PDK3-associated toxicity in neurodegenerative illnesses, including AD. The association between PF and PDK3 presents a significant opportunity for medication development and AD therapy approaches. PF efficiently suppresses PDK3 activity, as demonstrated by molecular docking and biophysical characterization, providing an in-depth understanding of their molecular interactions. PF significantly inhibited PDK3 in a concentration-dependent manner with an IC50 value of 4.88 µM. Considering this, the current investigation also explores the biological component of PF, which exhibits potential in treating AD and is primarily associated with neuroprotection. In the present study, a 3-hour pre-treatment of PF was administered at varying concentrations (4, 6, and 8 µM) in response to the 24-hour SCP (2 mM)-mediated toxicity. Based on the results of in silico and biophysical characterization, it is concluded that PF inhibits the PDK3 activity. Additionally, it can enhance cell viability, suppress ROS expression, impede apoptosis, and downregulate TNF-α expression. When combined, these actions help to prevent neuronal death in an in vitro model of SCP. PF strengthens the memory marker, which is confirmed through BDNF expression. This study found that all results were more effective at lower and moderate doses of PF. Our research indicates that PF boosts memory, decelerates the progression of oxidative stress, and could potentially serve as a dose-dependent treatment for AD. © 2025