Phytoestrogens are estrogen-like compounds of plant origin. The pharmacological activities of phytoestrogens are predominantly due to their antioxidant, anti-inflammatory and lipid-lowering properties, which are mediated via the estrogen receptors (ERs): estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) and possibly G protein-coupled estrogen receptor 1 (GPER). Gypenoside XVII (GP-17) is a phytoestrogen that is widely used to prevent cardiovascular disease, including atherosclerosis, but the mechanism underlying these therapeutic effects is largely unclear. This study aimed to assess the anti-atherogenic effects of GP-17 and its mechanisms in vivo and in vitro. In vivo experiments showed that GP-17 significantly decreased blood lipid levels, increased the expression of antioxidant enzymes and decreased atherosclerotic lesion size in ApoE−/− mice. In vitro experiments showed that GP-17 significantly prevented oxidized low-density lipoprotein (Ox-LDL)-induced endothelial injury. The underlying protective mechanisms of GP-17 were mediated by restoring the normal redox state, up-regulating of the ratio of Bcl-2 to Bax and inhibiting the expression of cleaved caspase-3 in Ox-LDL-induced human umbilical vein endothelial cell (HUVEC) injury. Notably, we found that GP-17 treatment predominantly up-regulated the expression of ERα but not ERβ. However, similar to estrogen, the protective effect of GP-17 could be blocked by the ER antagonist ICI182780 and the phosphatidylinositol 3-kinase (PI3K) antagonist LY294002. Taken together, these results suggest that, due to its antioxidant properties, GP-17 could alleviate atherosclerosis via the ERα-mediated PI3K/Akt pathway.
The corticotropin-releasing factor (CRF) peptides CRF and urocortins 1 to 3 are crucial regulators of mammalian stress and inflammatory responses, and they are also implicated in disorders such as anxiety, depression, and drug addiction. There is considerable interest in the physiological mechanisms by which CRF receptors mediate their widespread effects, and here we report that the native CRF receptor 1 (CRFR1) endogenous to the human embryonic kidney 293 cells can functionally couple to mammalian Ca V 3.2 T-type calcium channels. Activation of CRFR1 by either CRF or urocortin (UCN) 1 reversibly inhibits Ca V 3.2 currents (IC 50 of ϳ30 nM), but it does not affect Ca V 3.1 or Ca V 3.3 channels. Blockade of CRFR1 by the antagonist astressin abolished the inhibition of Ca V 3.2 channels. The CRFR1-dependent inhibition of Ca V 3.2 channels was independent of the activities of phospholipase C, tyrosine kinases, Ca 2ϩ /calmodulin-dependent protein kinase II, protein kinase C, and other kinase pathways, but it was dependent upon a cholera toxin-sensitive G protein-mediated mechanism relying upon G protein ␥ subunits (G␥). The inhibition of Ca V 3.2 channels via the activation of CRFR1 was due to a hyperpolarized shift in their steady-state inactivation, and it was reversible upon washout of the agonists. Given that UCN affect multiple aspects of cardiac and neuronal physiology and that Ca V 3.2 channels are widespread throughout the cardiovascular and nervous systems, the results point to a novel and functionally relevant CRFR1-Ca V 3.2 T-type calcium channel signaling pathway.The corticotropin-releasing factor (CRF) family, consisting of CRF, urocortin 1 (UCN), UCN2, and UCN3, are critical regulators of stress and inflammatory responses, and they have been variously associated with being cardioprotective and contributing toward alcohol and drug dependencies (Reul and Holsboer, 2002;Bale and Vale, 2004;Bruijnzeel and Gold, 2005;Gravanis and Margioris, 2005). The two major receptors for CRF and UCNs, CRF receptor (CRFR)1 and CRFR2, have been identified as G protein-coupled receptors (GPCRs) that can mediate responses via activation of the protein kinase signaling pathways (Bruijnzeel and Gold, 2005;Gravanis and Margioris, 2005). CRF has a higher affinity for CRFR1 than for CRFR2, UCN shows high affinity for both CRFR1 and CRFR2, whereas UCN2 and UCN3 are selective for CRFR2 (Bale and Vale, 2004). The CRFR1 is expressed primarily in the brain and pituitary, and activation of CRFR1 exerts numerous central and peripheral effects associated with pathological diseases (Dautzenberg and Hauger, 2002). Within the hypothalamus-pituitary axis, CRF and CRF-related peptides such as UCN activate CRFR1 receptors to regulate pituitary function in response to stress T.W
BackgroundGastric cancer (GC) is one of the most common types of malignancy and is associated with high morbidity and mortality rates around the world. With poor clinical outcomes, potential biomarkers for diagnosis and prognosis are important to investigate.ObjectiveThe aim of this study is to investigate the gene expression module of GC and to identify potential diagnostic and prognostic biomarkers.MethodMicroarray data (GSE13911, GSE29272, GSE54129, and GSE79973), including 293 stomach tumor tissues and 196 normal tissues, were analyzed to identify differentially expressed genes (DEGs). DEGs were identified in four profiles by intersecting four overlapping subsets, including 90 downregulated and 45 upregulated DEGs in common. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analyses have been showed that extracellular matrix was the most enriched signal pathway. Furthermore, hub genes were analyzed by protein–protein interaction network and clinical outcomes were assessed by Kaplan–Meier survival analysis. Two independent datasets were used to validate the differential expression of two hub genes: Serpin Family E Member 1 (SERPINE1) and Secreted Protein Acidic and Cysteine Rich (SPARC).ResultsValidation of independent datasets indicated that SERPINE1 and SPARC expression were drastically increased in gastric tumor tissues and associated with poor outcomes in GC patients. The expression of SERPINE1 was related to race (Asian and White) (P< 0.05).ConclusionSERPINE1 and SPARC were significantly upregulated in gastric tissues and associated with poor outcomes. The investigations of SERPINE1 and SPARC may promote their predictive and prognostic value in GC.
Propranolol suppresses tumor growth in a variety of preclinical solid tumor models, with a number of proposed cell signaling and immunological mechanisms. We want to confirm the potential mechanisms, including reduced phosphorylation of AKT/MAPK pathways, as well as enhanced CD8+ T‐cell–mediated antitumor immune response. To clarify the mechanism of propranolol activity in colorectal cancer, the therapeutic activity of propranolol was then assessed in CT26WT tumors engrafted in BALB/C mice. Then the effect of propranolol treatment was also examined by randomizing patients undergoing surgical resection of a previously untreated colorectal cancer to propranolol or placebo group and treated for 1 week prior to surgery. CT26WT tumor size was smaller after propranolol than vehicle control. Propranolol downregulated the expression of p‐AKT/p‐ERK/p‐MEK in tumor tissue. The frequency of tumor CD8+ T cells was significantly elevated in propranolol‐treated mice. The expression of GzmB/IFN‐γ/T‐bet in the CD8+ T‐cell population was significantly increased in propranolol treated mice tumor tissue. In propranolol‐treated surgical specimens, the expression of p‐ERK was decreased and the frequency of CD8+ was significantly elevated. The expression of GzmB in the CD8+ T‐cell population was significantly increased in propranolol‐treated subjects. Together, these data show propranolol simultaneously activating autologous CD8+ T cells and decreasing the expression of p‐AKT/p‐ERK/p‐MEK in mouse tumor models, while inhibiting the expression of p‐ERK in clinical colorectal cancer. Effort is now needed to further dissect whether both pathways are required for antitumor effect, as the activity of this old drug is moved forward.
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