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The search for novel tumor biomarkers and targets is of significant importance for the early clinical diagnosis and treatment of Hepatocellular Carcinoma (HCC). The mechanisms by which ATP citrate lyase (ACLY) promotes HCC progression remain unclear, and the connection between ACLY and REGγ has not been reported in the literature. In vitro, we will perform overexpression/knockdown of ACLY or overexpression/knockdown of REGγ to investigate the impact of ACLY on HCC cells and its underlying mechanisms. In vivo, we will establish mouse tumor models with overexpression/knockdown of ACLY or overexpression/knockdown of REGγ to study the effect of ACLY on mouse tumors and its mechanisms. Firstly, ACLY overexpression upregulated REGγ expression and activated the REGγ-proteasome pathway, leading to changes in the expression of downstream signaling pathway proteins. This promoted HCC cell proliferation, invasion, and migration in vitro, as well as tumor growth and metastasis in vivo. Secondly, ACLY overexpression increased acetyl-CoA production, upregulated the acetylation level of the REGγ promoter region histone H3K27ac, and subsequently induced REGγ expression. Lastly, enhanced acetylation of the REGγ promoter region histone H3K27ac resulted in upregulated REGγ expression, activation of the REGγ-proteasome pathway, changes in downstream signaling pathway protein expression, and promotion of HCC cell proliferation, invasion, and migration in vitro, as well as tumor growth and metastasis in vivo. Conversely, REGγ knockdown reversed these effects. ACLY and REGγ may serve as potential biomarkers and clinical therapeutic targets for HCC.
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BACKGROUND: Disruption to the blood brain barrier (BBB) is a leading factor associated with the development of postoperative cognitive dysfunction (POCD). Despite this, the underlying mechanism by which BBB disruption promotes POCD in the elderly population has not yet been not fully elucidated. RESULTS: In this study, we established a POCD mice model using isoflurane, and observed the highly expressed occludin and claudin 5 in brain tissues concomitant with the increased enrichment of CD4 positive cells and NK cells in the hippocampus of POCD mice compared to normal and non-POCD control. CONCLUSIONS: Our data suggests that peripheral immune cells may participate in the inflammatory reaction within the hippocampus, following the administration of anesthesia via inhalation with the destruction of the blood-brain barrier.
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Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/lesões , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/fisiopatologia , Inflamação/imunologia , Isoflurano/efeitos adversos , Linfócitos/imunologia , Complicações Pós-Operatórias/etiologia , Animais , Barreira Hematoencefálica/patologia , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Hipocampo/patologia , Células Matadoras Naturais/imunologia , Masculino , Camundongos Endogâmicos C57BL , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/fisiopatologiaRESUMO
Objective: Allergic asthma is driven by an antigen-specific immune response. This study aimed to identify immune-related differentially expressed genes in childhood asthma and establish a classification diagnostic model based on these genes. Methods: GSE65204 and GSE19187 were downloaded and served as training set and validation set. The immune cell composition was evaluated with ssGSEA algorithm based on the immune-related gene set. Modules that significantly related to the asthma were selected by WGCNA algorithm. The immune-related differentially expressed genes (DE-IRGs) were screened, the protein-protein interaction network and diagnostic model of DE-IRGs was constructed. The pathway and immune correlation analysis of hub DE-IRGs was analyzed. Results: Eight immune cell types exhibited varying levels of abundance between the asthma and control groups. A total of 112 differentially expressed immune-related genes (DE-IRGs) was identified. Through the application of four ranking methods (MCC, MNC, DEGREE, and EPC), 17 hub DE-IRGs with overlapping significance were further selected. Subsequently, 8 optimized were identified using univariate logistic regression analysis and the LASSO regression algorithm, based on which a robust diagnostic model was constructed. Notably, TNF and CD40LG emerged as direct participants in asthma-related signaling pathways, displaying a positive correlation with the immune cell types of immature B cells, activated B cells, activated CD8 T cells, activated CD4 T cells, and myeloid-derived suppressor cells. Conclusion: The diagnostic model constructed using the DE-IRGs (CCL5, CCR5, CD40LG, CD8A, IL2RB, PDCD1, TNF, and ZAP70) exhibited high and specific diagnostic value for childhood asthma. The diagnostic model may contribute to the diagnosis of childhood asthma.
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BACKGROUND: Childhood asthma is a chronic inflammatory disease of the respiratory tract characterized by bronchial inflammation, airway hyperresponsiveness, airflow disorder, and obstruction. Secreted frizzled-related protein 5 (SFRP5) may be associated with respiratory inflammatory diseases. This study investigated the effect of SFRP5 on human airway smooth muscle cells (HASMCs) to provide new ideas for treating asthma. METHODS: A total of 30 children with asthma and 30 children who had a physical examination at the same time were selected and divided into asthma and healthy groups. Serum SFRP5 levels were determined by enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (RT-qPCR). Lipofectamine 2000™ regent was used to transfect the SFRP5 overexpression plasmid (pc-SFRP5) or corresponding negative control (pc-NC) into HASMCs. HASMCs were treated with 10 µg/L platelet-derived growth factor-BB (PDGF-BB), which is an inducer to mimic the asthma-like condition at the cellular level of childhood asthma. HASMCs were divided into control, PDGF-BB (PDGF-BB treatment), PDGF-BB+pc-NC (pc-NC transfection and PDGF-BB treatment), and PDGF-BB+pc-SFRP5 (pc-SFRP5 transfection and PDGF-BB treatment) groups. Cell proliferation was measured by 5-ethynyl-2'-deoxyuridine (EdU) and cell counting kit-8 (CCK-8) assay. Cell migration was detected by Transwell assay. The protein expression was detected by western blot. RESULTS: Serum SFRP5 expression in the asthmatic group was decreased versus the healthy group (p < 0.0001). Induction of PDGF-BB decreased SFRP5 expression in HASMCs (p < 0.01). SFRP5 expression in the pc-SFRP5 group was increased (p < 0.01). The proliferation and migration of HASMCs increased after PDGF-BB treatment (p < 0.001, p < 0.0001), indicating that the asthma model was successfully inducted in vitro. Moreover, the expression of ß-catenin, cellular-myelocytomatosis viral oncogene (c-Myc), and cyclinD1 proteins in HASMCs increased after PDGF-BB treatment (p < 0.0001). SFRP5 overexpression partly inhibited PDGF-BB-induced proliferation, migration, and expressions of ß-catenin, c-Myc, and cyclinD proteins in HASMCs (p < 0.01, p < 0.001, p < 0.0001). CONCLUSIONS: Serum SFRP5 expression decreases in children with asthma. SFRP5 overexpression partially inhibits PDGF-BB-induced HASMC proliferation and migration by regulating the wingless-type mouse mammary tumor virus (MMTV) integration site family (Wnt)/ß-catenin pathway.
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Asma , beta Catenina , Animais , Criança , Camundongos , Humanos , Becaplermina/metabolismo , Becaplermina/farmacologia , beta Catenina/metabolismo , beta Catenina/farmacologia , Via de Sinalização Wnt/genética , Asma/genética , Asma/metabolismo , Asma/patologia , Proliferação de Células/genética , Pulmão/metabolismo , Movimento Celular , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Células Cultivadas , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
Expression and correlation of Chemerin and fatty acid-binding protein 4 (FABP4) in peripheral blood of gestational diabetes mellitus (GDM) patients were investigated. Sixty patients with GDM from March 2018 to March 2019 in the People's Hospital of Zhangqiu Area were selected as the study group (SG) and another 50 healthy pregnant women corresponding to their age and pregnancy were selected as the control group (CG). Enzyme linked immunosorbent assay (ELISA) was used to detect the expression of Chemerin and FABP4 in serum. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of Chemerin and FABP4 in peripheral blood for GDM patients. Pearson's correlation coefficient was used to analyze the correlation between Chemerin and FABP4 and the correlation between Chemerin and inflammatory factors such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Expression of Chemerin and FABP4 in peripheral blood of GDM patients were significantly higher than those in CG. The AUC of GDM patients diagnosed with Chemerin and FABP4 in peripheral blood was 0.820 and 0.814, while the AUC of GDM patients diagnosed with Chemerin combined with FABP4 in peripheral blood was 0.904. Expression of inflammatory factors IL-6 and TNF-α in the SG were significantly higher than those in the CG. Chemerin in the SG was positively correlated with FABP4 and positively correlated with inflammatory factors IL-6 and TNF-α. Patients with advanced age (≥35 years), family history of diabetes, hyperlipidemia, high pre-pregnancy BMI, high fasting blood glucose, high Chemerin and high FABP4 expression have high risk of GDM. In conclusion, Chemerin and FABP4 were upregulated in the peripheral blood of GDM patients. There was a positive correlation between the two and a positive correlation with the inflammatory factors IL-6 and TNF-α.
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BACKGROUND: Toll-like receptor 4 (TLR4)-induced initiation of mitogen-activated protein kinases and the nuclear factor-kappa B signaling cascade is reportedly involved in inflammatory responses during lung injury. Studies have found that volatile anesthetics, such as isoflurane and sevoflurane, inhibit inflammation. This investigation explored the protective effects of propofol and whether propofol potentiates the protective effects of sevoflurane against lipopolysaccharide (LPS)-induced acute lung injury. MATERIALS AND METHODS: Male BALB/c mice were treated with LPS (10µg/mouse; intranasal instillation) to induce acute lung injury. Mice were exposed to sevoflurane (3%; 6 hours) alone or combined with propofol (10 or 20mg/kg body weight; subcutaneously) followed by sevoflurane for 1 hour before the LPS challenge. RESULTS: Sevoflurane with or without propofol attenuated pulmonary edema, restored altered lung architecture and reduced influx of inflammatory cells into bronchoalveolar lavage fluid after the LPS challenge. LPS-mediated overproduction of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1ß, and interleukin-6 as well as nitric oxide, were reduced. Sevoflurane either alone or with propofol downregulated TLR4 and TLR4-mediated mitogen-activated protein kinase and nuclear factor-kappa B signaling. CONCLUSIONS: Combined exposure to propofol and sevoflurane was more effective than sevoflurane administered alone, suggesting the positive effects of propofol on sevoflurane-mediated anti-inflammatory effects.
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Lesão Pulmonar Aguda/induzido quimicamente , Lipopolissacarídeos , Éteres Metílicos/farmacologia , Propofol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Animais , Sinergismo Farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Sevoflurano , Receptor 4 Toll-Like/metabolismoRESUMO
Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is a potential remedial therapy for drug craving and relapse, but the mechanism is poorly understood. We investigated changes in neurotransmitter levels during high frequency stimulation (HFS) of the unilateral NAc on morphine-induced rats. Sixty adult Wistar rats were randomized into five groups: the control group (administration of saline), the morphine-only group (systematic administration of morphine without electrode implantation), the morphine-sham-stimulation group (systematic administration of morphine with electrode implantation but not given stimulation), the morphine-stimulation group (systematic administration of morphine with electrode implantation and stimulation) and the saline-stimulation group (administration of saline with electrode implantation and stimulation). The stimulation electrode was stereotaxically implanted into the core of unilateral NAc and microdialysis probes were unilaterally lowered into the ipsilateral ventral tegmental area (VTA), NAc, and ventral pallidum (VP). Samples from microdialysis probes in the ipsilateral VTA, NAc, and VP were analyzed for glutamate (Glu) and γ-aminobutyric acid (GABA) by high-performance liquid chromatography (HPLC). The levels of Glu were increased in the ipsilateral NAc and VP of morphine-only group versus control group, whereas Glu levels were not significantly changed in the ipsilateral VTA. Furthermore, the levels of GABA decreased significantly in the ipsilateral NAc, VP, and VTA of morphine-only group when compared with control group. The profiles of increased Glu and reduced GABA in morphine-induced rats suggest that the presence of increased excitatory neurotransmission in these brain regions. The concentrations of the Glu significantly decreased while the levels of GABA increased in ipsilateral VTA, NAc, and VP in the morphine-stimulation group compared with the morphine-only group. No significant changes were seen in the morphine-sham stimulation group compared with the morphine-only group. These findings indicated that unilateral NAc stimulation inhibits the morphine-induced rats associated hyperactivation of excitatory neurotransmission in the mesocorticolimbic reward circuit.