Growth factors, including nerve growth factor (NGF), have been hypothesized to play a role in resistance to chemotherapeutic agent-induced apoptosis. Induction by NGF of resistance to apoptosis is primarily thought to be the result of its binding to its high-affinity receptor, TrkA. The low-affinity NGF receptor, p75, has long been thought merely to facilitate NGF binding to TrkA. However, we have previously shown that the binding of NGF to its low-affinity receptor, p75, protects neuroblastoma cells that do not express TrkA against apoptosis induced by enediyne chemotherapeutic agents. In cells that express both receptors, it is not clear what determines which receptor is responsible for the protective effect of NGF. We now show that, in enediyne-treated SH-SY5Y neuroblastoma transfectants with native levels of p75 and a low TrkA/p75 ratio (1/100), the anti-apoptotic effect of NGF requires binding to p75. In contrast, in transfectants with native levels of p75 and a high TrkA/p75 ratio (100/100), NGF treatment prevents enediyne-induced apoptosis by a mechanism independent of p75 binding. Treatment of low TrkA/p75 ratio cells with NGF results in activation and nuclear translocation of NF-κB and tyrosine phosphorylation of TrkA. Analogous treatment of high TrkA/p75 ratio cells results only in phosphorylation of TrkA even though nuclear factor (NF)-κB signaling is not inactive and can be initiated by other ligands. The ratio of TrkA/p75 in cells that express both receptors probably contributes to the determination of which of the two known roles of p75 (i.e., TrkA independent or TrkA facilitatory) are responsible for NGF-mediated protection from enediyne-induced apoptosis.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that belongs to the nuclear receptor family that plays a critical role in adipocyte differentiation and lipid metabolism. Here we report for the first time that PPARgamma is expressed in human renal cortical collecting ducts (CCD), segments of the nephor involved in regulation of sodium and water homeostasis via action of the epithelial sodium channel (ENaC). ENaC activity is regulated by the hormones aldosterone and insulin, primarily through co-ordinate actions on serum and glucocorticoid regulated kinase 1 (SGK1). We show that SGK1 activity is stimulated by treatment of a human CCD cell line with PPARgamma agonists, paralleled by an increase in SGK1 mRNA that is abolished by pretreatment with a specific PPARgamma antagonist, and that this leads to increased levels of cell surface ENaCalpha. Electrophoretic mobility shift assays suggest that these effects are caused by binding of PPARgamma to a specific response element in the SGK1 promoter. Our results identify SGK1 as a target for PPARgamma and suggest a novel role for PPARgamma in regulation of sodium re-absorption in the CCD via stimulation of ENaC activity. This pathway may play a role in sodium retention caused by activation of PPARgamma in man.
Natural and synthetic progestins may pose a threat to wild fish populations living in receiving waters. In this study, the effects of norethindrone (NET) on the sex differentiation of zebrafish (Dario renio) and the mechanisms underlying these effects were investigated. Juvenile zebrafish (20 days post fertilization, pdf) were exposed to environmentally relevant concentrations (5, 50, 500, and 1000 ng L−1) for 45 d. Sex ratio of the NET-exposed populations, the histology of the gonads and the transcriptional profile of the regulatory genes involved in sex differentiation and steroidogenesis were examined. The results showed that a significantly higher ratio of male/female was induced in the zebrafish populations exposed to NET at concentrations higher than 32.3 ng L−1. Exposure to NET caused acceleration of sexual mature in males and a delay in ovary maturation in female zebrafish. Among the genes regulating sexual differentiation, transcripts of Dmrt1 showed a dose-dependent increase while transcripts of Figa and Fox12 showed a dose-dependent decrease in response to exposure to NET. For genes regulating the steroidogenesis, the expressions of Cyp11a1, Cyp17, Cyp19a1a, and Cyp11b were significantly down-regulated by exposure to NET, while Hsd17b3 expression was significantly up-regulated by exposure to NET at 421.3 and 892.9 ng L−1. For the receptor genes in the gonads, the transcriptional expression of Pgr, Ar, and Mr was significantly up-regulated at 421.3 and 892.9 ng L−1 of NET. For genes involved in the hypothalamic–pituitary axis, the transcriptional expression of Gnrh3 and Pomc was significantly up-regulated by exposure to NET with the exception for Gnrh3 at 4.2 ng L−1. The results demonstrated that exposure to NET at the juvenile stage could affect gonad differentiation and sex ratio, which might be accounted for by the alterations of the transcriptional expressions of genes along the hypothalamic–pituitary–gonadal (HPG) and hypothalamic–pituitary–adrenal (HPA) axes.
The rat fed with the compound drug Zhi Mu and Shi Gao was made into an animal model of deficiency cold syndrome. The deficiency cold state was kept for more than 7 days after stopping the drug. So the animal model is good for studing the therapeutic effect of products of heat nature. After 3 therapeutic days with Fu Jiang and Shen Qi compounds, the D beta H activity in serum, cortisone in adrenal gland and NE, DA amount in brain were increased, but serotonin was decreased, and after 7 days the effect was increased significantly. Both compounds could excite the sympathetic nerve and endocrine system in the peripheral and central nervous systems. Shen Qi compound acts quickly, but does not last as long as Fu Jiang. The effect will be better if the two compounds are used together.
Sodium formononetin-3'-sulphonate (Sul-F) is a derivative of the isoflavone formononetin. In this study, we investigated whether Sul-F can regulate angiogenesis and the potential mechanism in vitro.We examined the effects of Sul-F on cell proliferation, cell invasion, and tube formation in the human umbilical vein endothelial cell line (HUVEC). To better understand the mechanism involved, we investigated effects of the following compounds: cAMP response element-binding protein (CREB) inhibitor 2-naphthol-AS-E-phosphate (KG-501), early growth response 3 (Egr-3) siRNA, vascular endothelial growth factor (VEGF) antagonist soluble VEGF receptor 1 (sFlt-1), VEGF receptor 2 blocker SU-1498, Wnt5a antagonist WIF-1 recombinant protein (WIF-1), and inhibitor of Wnt/β-catenin recombinant Dickkopf-1 protein (DKK-1). HUVEC proliferation was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). A scratch adhesion test was used to assess cell invasion ability. Matrigel tube formation assay was performed to test capillary tube formation ability. Activation of the VEGF/CREB/Egr-3/Vascular cell adhesion molecule 1 (VCAM-1) pathway in HUVEC was tested by Western blot analysis.Our results suggest that Sul-F induced angiogenesis in vitro by enhancing cell proliferation, invasion, and tube formation. The increase in proliferation and tube formation by Sul-F was counteracted by DKK-1, WIF-1, SU1498, KG-501, sFlt-1, and Egr-3 siRNA.These results may suggest that Sul-F induces angiogenesis in vitro via a programed Wnt/β-catenin pathway and VEGF/CREB/Egr-3/VCAM-1 signaling axis.
Type 1 diabetes (T1D) is a metabolic disease commonly affecting adolescents and causing various health complications. Corn silk (CS), a traditional Chinese medicine with medicinal and edible properties, has been extensively researched for its anti-diabetes and anti-inflammatory effects. This study aimed to investigate the hypoglycemic effect of CS extract on T1D mice by modulating the composition of gut microbiota. The results demonstrated that CS extract had a significant therapeutic effect on STZ-induced T1D by reducing the fasting blood glucose (FBG) levels and pancreas injury. Moreover, CS extract was found to modify the gut microbiota by altering the abundance of Firmicutes, Actinobacteria, Desulfobacterota, and Proteobacteria, which subsequently influenced the production of short-chain fatty acids (SCFAs). These SCFAs then mediated the expression of G protein-coupled receptor 41 (GPR41), interleukin-10 (IL-10), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), ultimately resulting in a reduction in the inflammatory response.
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