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https://www.readbyqxmd.com/read/28533546/prostaglandin-e2-inhibits-matrix-mineralization-by-human-bone-marrow-stromal-cell-derived-osteoblasts-via-epac-dependent-camp-signaling
#1
Ali Mirsaidi, André N Tiaden, Peter J Richards
The osteoinductive properties of prostaglandin E2 (PGE2) and its signaling pathways have led to suggestions that it may serve as a potential therapeutic strategy for bone loss. However, the prominence of PGE2 as an inducer of bone formation is attributed primarily to findings from studies using rodent models. In the current study, we investigated the effects of PGE2 on human bone marrow stromal cell (hBMSC) lineage commitment and determined its mode of action. We demonstrated that PGE2 treatment of hBMSCs significantly altered the expression profile of several genes associated with osteoblast differentiation (RUNX2 and ALP) and maturation (BGLAP and MGP)...
May 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28512254/catecholamines-facilitate-vegf-dependent-angiogenesis-via-%C3%AE-2-adrenoceptor-induced-epac1-and-pka-activation
#2
Jaspal Garg, Yu-Xi Feng, Sepp R Jansen, Julian Friedrich, Frank Lezoualc'h, Martina Schmidt, Thomas Wieland
Chronic stress has been associated with the progression of cancer and antagonists for β-adrenoceptors (βAR) are regarded as therapeutic option. As they are also used to treat hemangiomas as well as retinopathy of prematurity, a role of endothelial β2AR in angiogenesis can be envisioned. We therefore investigated the role of β2AR-induced cAMP formation by analyzing the role of the cAMP effector molecules exchange factor directly activated by cAMP 1 (Epac1) and protein kinase A (PKA) in endothelial cells (EC)...
April 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28489680/cyclic-amp-epac-signaling-pathway-contributes-to-repression-of-puma-transcription-in-melanoma-cells
#3
Alexander J Lakhter, Samisubbu R Naidu
The universal second messenger cAMP regulates numerous cellular processes. Although the cAMP-signaling pathway leads to induction of gene transcription, it remains unknown whether this pathway contributes toward suppression of transcription. Here, we show that blockade of cAMP signaling using MDL12330A led to an increase in PUMA transcript levels, but not p21 in melanoma cells. cAMP downstream component Epac activation was essential for suppression of PUMA transcription as an Epac agonist reversed the effects of MDL12330A...
May 4, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28476918/endothelial-camp-deactivates-ischemia-reperfusion-induced-microvascular-hyperpermeability-via-rap1-mediated-mechanisms
#4
Adam H Korayem, Patricio E Mujica, Haruo Aramoto, Ricardo G Durán, Prerna R Nepali, David D Kim, Andrew L Harris, Fabiola A Sánchez, Walter N Duran
Approaches to reduce excessive edema due to the microvascular hyperpermeability that occurs during ischemia-reperfusion (I/R) are needed to prevent muscle compartment syndrome. We tested the hypothesis that cAMP-activated mechanisms actively restore barrier integrity in postischemic striated muscle. We found, using I/R in intact muscles and hypoxia-reoxygenation (H/R, an I/R mimic) in human microvascular endothelial cells (HMVEC), that hyperpermeability can be deactivated by increasing cAMP levels through application of forskolin...
May 5, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28476660/%C3%AE-adrenergic-induced-sr-ca-2-leak-is-mediated-by-an-epac-nos-pathway
#5
Laëtitia Pereira, Dan J Bare, Samuel Galice, Thomas R Shannon, Donald M Bers
Cardiac β-adrenergic receptors (β-AR) and Ca(2+)-Calmodulin dependent protein kinase (CaMKII) regulate both physiological and pathophysiological Ca(2+) signaling. Elevated diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) contributes to contractile dysfunction in heart failure and to arrhythmogenesis. β-AR activation is known to increase SR Ca(2+) leak via CaMKII-dependent phosphorylation of the ryanodine receptor. Two independent and reportedly parallel pathways have been implicated in this β-AR-CaMKII cascade, one involving exchange protein directly activated by cAMP (Epac2) and another involving nitric oxide synthase 1 (NOS1)...
May 2, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28475672/lithium-and-an-epac-specific-inhibitor-esi-09-synergistically-suppress-pancreatic-cancer-cell-proliferation-and-survival
#6
Xinshuo Wang, Cheng Luo, Xiaodong Cheng, Meiling Lu
Our previous studies showed that while lithium suppresses proliferation and induces apoptosis in pancreatic cancer cells, the inhibition of exchange proteins directly activated by cyclic adenosine monophosphate (cAMP) (EPAC)1 blocks pancreatic cancer cell migration and invasion. In this study, we further investigated the combinatory effects of lithium and EPAC-specific inhibitor (ESI)-09, an EPAC-specific inhibitor, on pancreatic cancer cell proliferation and viability, and explored whether lithium synergistically cooperates with EPAC inhibition in suppressing pancreatic cancer cell tumorigenicity...
May 5, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28474133/erratum-to-dynamic-monitoring-of-gi-o-protein-mediated-decreases-of-intracellular-camp-by-fret-based-epac-sensors
#7
Ursula Storch, Julie Straub, Serap Erdogmus, Thomas Gudermann, Michael Mederos Y Schnitzler
No abstract text is available yet for this article.
May 4, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28466587/camp-signalling-in-insulin-and-glucagon-secretion
#8
REVIEW
A Tengholm, E Gylfe
The "second messenger" archetype cAMP is one of the most important cellular signalling molecules with central functions including the regulation of insulin and glucagon secretion from the pancreatic β- and α-cells, respectively. cAMP is generally considered as an amplifier of insulin secretion triggered by Ca(2+) elevation in the β-cells. Both messengers are also positive modulators of glucagon release from α-cells, but in this case cAMP may be the important regulator and Ca(2+) have a more permissive role...
May 3, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28451724/chronic-loss-of-inhibitor-1-diminishes-cardiac-ryr2-phosphorylation-despite-exaggerated-camkii-activity
#9
Stefan Neef, Jordi Heijman, Kristian Otte, Matthias Dewenter, Ali R Saadatmand, Stefanie Meyer-Roxlau, Christopher L Antos, Johannes Backs, Dobromir Dobrev, Michael Wagner, Lars S Maier, Ali El-Armouche
Inhibitor-1 (I-1) modulates protein phosphatase 1 (PP1) activity and thereby counteracts the phosphorylation by kinases. I-1 is downregulated and deactivated in failing hearts, but whether its role is beneficial or detrimental remains controversial, and opposing therapeutic strategies have been proposed. Overactivity of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) with hyperphosphorylation of ryanodine receptors (RyR2) at the CaMKII-site is recognized to be central for heart failure and arrhythmias...
April 27, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28445587/cb1-receptors-downregulate-a-camp-epac2-plc-pathway-to-silence-the-nerve-terminals-of-cerebellar-granule-cells
#10
Beatris Alonso, David Bartolomé-Martín, José Javier Ferrero, Jorge Ramírez-Franco, Magdalena Torres, José Sánchez-Prieto
Cannabinoid receptors mediate short-term retrograde inhibition of neurotransmitter release, as well as long-term depression of synaptic transmission at excitatory synapses. The responses of individual nerve terminals in VGLUT1-pHluorin transfected cerebellar granule cells to cannabinoids have shown that prolonged activation of cannabinoid type 1 receptors (CB1Rs) silences a subpopulation of previously active synaptic boutons. Adopting a combined pharmacological and genetic approach to study the molecular mechanisms of CB1R-induced silencing, we found that adenylyl cyclase inhibition decreases cAMP levels while it increases the number of silent synaptic boutons and occludes the induction of further silencing by the cannabinoid agonist HU-210...
April 26, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28440284/cyp2j2-and-its-metabolites-eets-attenuate-insulin-resistance-via-regulating-macrophage-polarization-in-adipose-tissue
#11
Meiyan Dai, Lujin Wu, Peihua Wang, Zheng Wen, Xizhen Xu, Dao Wen Wang
Macrophages in adipose tissue are associated with obesity-induced low-grade inflammation, which contributed to insulin resistance and the related metabolic diseases. Previous studies demonstrated the beneficial effects of epoxyeicosatrienoic acids (EETs) on metabolic disorders and inflammation. Here we investigated the effects of CYP2J2-EETs-sEH metabolic pathway on insulin resistance in mice and the potential mechanisms. High fat diet (HFD)-induced obesity caused metabolic dysfunction with more weight gain, elevated glucose and lipids levels, impaired glucose tolerance and insulin sensitivity, while increase in EETs level by rAAV-mediated CYP2J2 overexpression, administration of sEH inhibit TUPS or EETs infusion significantly attenuated these metabolic disorders...
April 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28433631/detection-of-camp-and-of-pka-activity-in-saccharomyces-cerevisiae-single-cells-using-fluorescence-resonance-energy-transfer-fret-probes
#12
Sonia Colombo, Serena Broggi, Maddalena Collini, Laura D'Alfonso, Giuseppe Chirico, Enzo Martegani
In Saccharomyces cerevisiae the second messenger cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) play a central role in metabolism regulation, stress resistance and cell cycle progression. To monitor cAMP levels and PKA activity in vivo in single S. cerevisiae cells, we expressed an Epac-based FRET probe and a FRET-based A-kinase activity reporter, which were proven to be useful live-cell biosensors for cAMP levels and PKA activity in mammalian cells. Regarding detection of cAMP in single yeast cells, we show that in wild type strains the CFP/YFP fluorescence ratio increased immediately after glucose addition to derepressed cells, while no changes were observed when glucose was added to a strain that is not able to produce cAMP...
April 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28416632/null-epac-mutants-reveal-a-sequential-order-of-versatile-camp-effects-during-drosophila-aversive-odor-learning
#13
Antje Richlitzki, Philipp Latour, Martin Schwärzel
Here, we define a role of the cAMP intermediate EPAC in Drosophila aversive odor learning by means of null epac mutants. Complementation analysis revealed that EPAC acts downstream from the rutabaga adenylyl cyclase and in parallel to protein kinase A. By means of targeted knockdown and genetic rescue we identified mushroom body Kenyon cells (KCs) as a necessary and sufficient site of EPAC action. We provide mechanistic insights by analyzing acquisition dynamics and using the "performance increment" as a means to access the trial-based sequential organization of odor learning...
May 2017: Learning & Memory
https://www.readbyqxmd.com/read/28399451/identification-of-novel-2-benzo-d-isoxazol-3-yl-2-oxo-n-phenylacetohydrazonoyl-cyanide-analoguesas-potent-epac-antagonists
#14
Na Ye, Yingmin Zhu, Zhiqing Liu, Fang C Mei, Haiying Chen, Pingyuan Wang, Xiaodong Cheng, Jia Zhou
Two series of novel EPAC antagonists are designed, synthesized and evaluated in an effort to develop diversified analogues based on the scaffold of the previously identified high-throughput (HTS) hit 1 (ESI-09). Further SAR studies reveal that the isoxazole ring A of 1 can tolerate chemical modifications with either introduction of flexible electron-donating substitutions or structurally restrictedly fusing with a phenyl ring, leading to identification of several more potent and diversified EPAC antagonists (e...
April 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28396013/specific-sirt1-activator-mediated-improvement-in-glucose-homeostasis-requires-sirt1-independent-activation-of-ampk
#15
Sung-Jun Park, Faiyaz Ahmad, Jee-Hyun Um, Alexandra L Brown, Xihui Xu, Hyeog Kang, Hengming Ke, Xuesong Feng, James Ryall, Andrew Philp, Simon Schenk, Myung K Kim, Vittorio Sartorelli, Jay H Chung
The specific Sirt1 activator SRT1720 increases mitochondrial function in skeletal muscle, presumably by activating Sirt1. However, Sirt1 gain of function does not increase mitochondrial function, which raises a question about the central role of Sirt1 in SRT1720 action. Moreover, it is believed that the metabolic effects of SRT1720 occur independently of AMP-activated protein kinase (AMPK), an important metabolic regulator that increases mitochondrial function. Here, we show that SRT1720 activates AMPK in a Sirt1-independent manner and SRT1720 activates AMPK by inhibiting a cAMP degrading phosphodiesterase (PDE) in a competitive manner...
April 2017: EBioMedicine
https://www.readbyqxmd.com/read/28386636/dynamic-monitoring-of-gi-o-protein-mediated-decreases-of-intracellular-camp-by-fret-based-epac-sensors
#16
Ursula Storch, Julie Straub, Serap Erdogmus, Thomas Gudermann, Michael Mederos Y Schnitzler
Analysis of G-protein-coupled receptor (GPCR) signaling, in particular of the second messenger cAMP that is tightly controlled by Gs- and Gi/o-proteins, is a central issue in biomedical research. The classical biochemical method to monitor increases in intracellular cAMP concentrations consists of a radioactive multicellular assay, which is well established, highly sensitive, and reproducible, but precludes continuous spatial and temporal assessment of cAMP levels in single living cells. For this purpose, Förster resonance energy transfer (FRET)-based Epac cAMP sensors are well suitable...
April 6, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28383060/phosphodiesterase-4b-negatively-regulates-endotoxin-activated-interleukin-1-receptor-antagonist-responses-in-macrophages
#17
Jing-Xing Yang, Kou-Chou Hsieh, Yi-Ling Chen, Chien-Kuo Lee, Marco Conti, Tsung-Hsien Chuang, Chin-Pyng Wu, S-L Catherine Jin
Activation of TLR4 by lipopolysaccharide (LPS) induces both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Type 4 phosphodiesterases (PDE4) are key cAMP-hydrolyzing enzymes, and PDE4 inhibitors are considered as immunosuppressors to various inflammatory responses. We demonstrate here that PDE4 inhibitors enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-activated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28356349/camp-a-multifaceted-modulator-of-immune-synapse-assembly-and-t-cell-activation
#18
REVIEW
Vijay Bharathi Arumugham, Cosima T Baldari
T Lymphocyte activation involves a substantial reorganization of the membranous and intracellular compartments. Signaling complexes assemble and dismantle in a highly ordered fashion in both compartments and orchestrate the activation of T cells with high sensitivity and specificity. TCR ligation leads to a short burst of cAMP production, which is centrally required for T cell activation; however, sustained elevations in intracellular cAMP concentrations are immunosuppressive. Emerging evidence of the existence of local cAMP pools gleaned from studies on other cell types suggests that cAMP compartmentalization may account, in part, for these opposing effects...
March 29, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28353063/the-microrna-7-mediated-reduction-in-epac-1-contributes-to-vascular-endothelial-permeability-and-enos-uncoupling-in-murine-experimental-retinopathy
#19
Veronica Garcia-Morales, Julian Friedrich, Lysanne M Jorna, Manuel Campos-Toimil, Hans-Peter Hammes, Martina Schmidt, Guido Krenning
AIMS: To investigate the consequences of oxidative stress and hypoxia on EPAC-1 expression during retinopathy. METHODS: Oxygen-induced retinopathy was induced in mice and EPAC-1 expression investigated by immunofluorescence. In silico analyses were used to identify a link between EPAC-1 expression and microRNA-7-5p in endothelial cells and confirmed by western blot analyses on cells expressing microRNA-7-5p. In vitro, endothelial cells were either incubated at 2% oxygen or transfected with microRNA-7-5p, and the effects of these treatments on EPAC-1 expression, endothelial hyperpermeability and NO production were assessed...
March 28, 2017: Acta Diabetologica
https://www.readbyqxmd.com/read/28341741/endogenous-prostaglandin-e2-amplifies-il-33-production-by-macrophages-through-an-e-prostanoid-ep-2-ep4-camp-epac-dependent-pathway
#20
Sachin K Samuchiwal, Barbara Balestrieri, Hannah Raff, Joshua A Boyce
When activated through toll-like receptors (TLRs), macrophages generate IL-33, an IL-1 family member that induces innate immune responses through ST2 signaling. LPS, a TLR4 ligand, induces macrophages to generate prostaglandin E2 (PGE2) through inducible COX-2 and microsomal PGE2 synthase 1 (mPGES-1) (1). We demonstrate that IL-33 production by bone marrow-derived murine macrophages (bmMFs) requires the generation of endogenous PGE2 and the intrinsic expression of EP2 receptors to amplify NF-κB-dependent, LPS-induced IL-33 expression via exchange protein activated by cAMP (EPAC)...
May 19, 2017: Journal of Biological Chemistry
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