scholarly journals Selective small-molecule EPAC activators

2019 ◽  
Vol 47 (5) ◽  
pp. 1415-1427 ◽  
Author(s):  
Urszula Luchowska-Stańska ◽  
David Morgan ◽  
Stephen J. Yarwood ◽  
Graeme Barker
Keyword(s):  
Small Molecule ◽  
Cyclic Nucleotides ◽  
State Of The Art ◽  
Vascular Endothelial Cells ◽  
Vascular Inflammation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Vascular Endothelial ◽  
Secondary Messenger ◽  
Current State

Abstract The cellular signalling enzymes, EPAC1 and EPAC2, have emerged as key intracellular sensors of the secondary messenger cyclic 3′,5′-adenosine monophosphate (cyclic adenosine monophosphate) alongside protein kinase A. Interest has been galvanised in recent years thanks to the emergence of these species as potential targets for new cardiovascular disease therapies, including vascular inflammation and insulin resistance in vascular endothelial cells. We herein summarise the current state-of-the-art in small-molecule EPAC activity modulators, including cyclic nucleotides, sulphonylureas, and N-acylsulphonamides.

scholarly journals 17β-Estradiol Increases APE1/Ref-1 Secretion in Vascular Endothelial Cells and Ovariectomized Mice: Involvement of Calcium-Dependent Exosome Pathway

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1040
Author(s):  
Yu-Ran Lee ◽  
Hee-Kyoung Joo ◽  
Eun-Ok Lee ◽  
Sungmin Kim ◽  
Hao Jin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Vascular Inflammation ◽  
Vascular Endothelial ◽  
Endogenous Hormones ◽  
Imaging Data ◽  
Acetoxymethyl Ester ◽  
Multifunctional Protein ◽  
Ovariectomized Mice ◽  
17Β Estradiol

Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that can be secreted, and recently suggested as new biomarker for vascular inflammation. However, the endogenous hormones for APE1/Ref-1 secretion and its underlying mechanisms are not defined. Here, the effect of twelve endogenous hormones on APE1/Ref-1 secretion was screened in cultured vascular endothelial cells. The endogenous hormones that significantly increased APE1/Ref-1 secretion was 17β-estradiol (E2), 5?-dihydrotestosterone, progesterone, insulin, and insulin-like growth factor. The most potent hormone inducing APE1/Ref-1 secretion was E2, which in cultured endothelial cells, E2 for 24 h increased APE1/Ref-1 secretion level of 4.56 ± 1.16 ng/mL, compared to a basal secretion level of 0.09 ± 0.02 ng/mL. Among the estrogens, only E2 increased APE1/Ref-1 secretion, not estrone and estriol. Blood APE1/Ref-1 concentrations decreased in ovariectomized (OVX) mice but were significantly increased by the replacement of E2 (0.39 ± 0.09 ng/mL for OVX vs. 4.67 ± 0.53 ng/mL for OVX + E2). E2-induced APE1/Ref-1secretion was remarkably suppressed by the estrogen receptor (ER) blocker fulvestrant and intracellular Ca2+ chelator 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), suggesting E2-induced APE1/Ref-1 secretion was dependent on ER and intracellular calcium. E2-induced APE1/Ref-1 secretion was significantly inhibited by exosome inhibitor GW4869. Furthermore, APE1/Ref-1 level in CD63-positive exosome were increased by E2. Finally, fluorescence imaging data showed that APE1/Ref-1 co-localized with CD63-labled exosome in the cytoplasm of cells upon E2 treatment. Taken together, E2 was the most potent hormone for APE1/Ref-1 secretion, which appeared to occur through exosomes that were dependent on ER and intracellular Ca2+. Furthermore, hormonal effects should be considered when analyzing biomarkers for vascular inflammation.

scholarly journals Cytochemical methods for the localization of adenylate cyclase. A review and evaluation of the efficacy of the procedures.

1983 ◽  
Vol 31 (1) ◽  
pp. 85-93 ◽  
Author(s):  
L S Cutler
Keyword(s):  
Adenylate Cyclase ◽  
Cyclic Nucleotides ◽  
Cell Biology ◽  
Enzyme System ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cellular Functions ◽  
Cytochemical Localization ◽  
Biochemical Evaluation

The cytochemical procedures for localizing adenylate cyclase have been a source of controversy since their introduction. The importance of cyclic adenosine monophosphate (AMP), the product of adenylate cyclase's action on adenosine triphosphate (ATP), in cell biology is clear. Thus, the ability to localize this enzyme system reliably is an important tool in the study of various cellular functions. This report reviews the literature and presents a biochemical evaluation of the methods for localizing adenylate cyclase. The review and data presented serve to clarify many of the controversies surrounding this important cytochemical procedure. It is evident that although there are problems associated with localizing the enzyme, several valid procedures are currently available for the cytochemical localization of adenylate cyclase. In using these procedures, the effects of fixation and the capture agent on adenylate cyclase activity in the particular tissue being studied should be considered. Only repurified adenylyl imidodiphosphate [App(NH)p] should be used in the incubation medium. If care is taken, the use of these techniques can be of great value in the continued study of the role of cyclic nucleotides in cell biology.

Noradrenergic Overactivity in Chronic Schizophrenia: Evidence Based on Cerebrospinal Fluid Noradrenaline and Cyclic Nucleotide Concentrations

1980 ◽  
Vol 137 (4) ◽  
pp. 346-351 ◽  
Author(s):  
U. C. R. Gomes ◽  
B. C. Shanley ◽  
L. Potgieter ◽  
J. T. Roux
Keyword(s):  
Cerebrospinal Fluid ◽  
Cyclic Nucleotides ◽  
Homovanillic Acid ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Chronic Schizophrenia ◽  
Evidence Based ◽  
Chronic Schizophrenics ◽  
Hydroxyindoleacetic Acid ◽  
Lumbar Cerebrospinal Fluid

SummaryConcentrations of noradrenaline (NA), homovanillic acid, 5-hydroxyindoleacetic acid and cyclic nucleotides were determined in lumbar cerebrospinal fluid (CSF) from acute and chronic schizophrenics and various groups of psychiatric and non-psychiatric control subjects. Statistically significant increases in NA and cyclic adenosine monophosphate were found in CSF from chronic schizophrenics compared to all other groups. These results were shown by statistical analyses to be unrelated to medication. They may be interpreted as evidence for noradrenergic overactivity as a possible primary abnormality in chronic schizophrenia.

Secondary Messenger Systems in PTSD

2016 ◽  
Author(s):  
Ulrike Schmidt
Keyword(s):  
Second Messengers ◽  
Cyclic Adenosine Monophosphate ◽  
Second Messenger ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Brain Regions ◽  
Guanosine Monophosphate ◽  
Intracellular Camp ◽  
Post Traumatic Stress ◽  
Secondary Messenger

Second messengers such as cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), inositoltriphosphate, and diacylglycerol (DAG) are a prerequisite for the signal transduction of extracellular receptors. The latter are central for cellular function and thus are implicated in the pathobiology of a variety of disorders, such as schizophrenia, bipolar disorder, major depression, and post-traumatic stress disorder (PTSD). This chapter focuses on the involvement of second messenger molecules and their regulators as direct targets in human and animal PTSD and aims to stimulate the underdeveloped research in this field. The synthesis of literature reveals that second messengers clearly play a central role in PTSD-associated brain regions and processes. In particular, pituitary adenylate cyclase-activating polypeptide (PACAP), an important regulator of intracellular cAMP levels, as well as protein kinase c, the major target of DAG, belong to the hitherto most promising PTSD candidate molecules directly involved in second messenger signaling.

scholarly journals Cilostazol Improves Hyperglycemia-Induced Impairment of Angiogenesis by Stimulating Adiponectin/Adiponectin Receptor1/Sirtuin1

2021 ◽  
Author(s):  
Shih-Ya Tseng ◽  
Hsien-Yuan Chang ◽  
Yi-Heng Li ◽  
Ting-Hsing Chao
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Antiplatelet Agent ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Sirtuin 1

Abstract Background: Cilostazol is an antiplatelet agent with vasodilating effects that functions by increasing the intracellular concentration of cyclic adenosine monophosphate. However, the effect of cilostazol on adiponectin is still unclear. Purpose: We investigated the effects of cilostazol on adiponectin/adiponectin receptors and the Sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) signaling pathway to prevent high glucose (HG)-induced impairment of angiogenesis in vitro and in vivo. Methods and Results: Human umbilical vein endothelial cells (HUVECs) and human aortic smooth muscle cells (HASMCs) were cocultured in HG conditions. Adiponectin concentrations in the supernatant were significantly increased when HASMCs were treated with cilostazol but not significantly changed when only HUVECs were treated with cilostazol. Cilostazol treatment restored the expression of the adipoR1 and SIRT1 proteins and upregulated the phosphorylation of AMPKa1 in the HUVECs treated with HG but not adipoR2. Cilostazol prevented apoptosis and stimulated proliferation, chemotactic motility and capillary-like tube formation in HG-treated HUVECs through the adipoR1/AMPK/SIRT1 signaling pathway. In cilostazol-treated mice, recovery of the blood flow ratio after hindlimb ischemia and circulating CD34+CD45dim cells were significantly attenuated by adipoR1 knockdown but not adipoR2 knockdown. The expression of SIRT1, phosphorylation of AMPKa1/acetyl-CoA carboxylase and Akt/endothelial nitric oxide synthase in ischemic muscles were significantly attenuated by gene knockdown of adipoR1. Conclusions: Cilostazol prevents HG-induced endothelial dysfunction in vascular endothelial cells and enhances angiogenesis in hyperglycemic mice by upregulating the expression of adiponectin/adipoR1 and its SIRT1/AMPK downstream signaling pathway.

Effects of Supraphysiologic Levels of Estradiol on Endometrial Decidualization, sFlt1, and HOXA10 Expression

2019 ◽  
Vol 26 (12) ◽  
pp. 1626-1632 ◽  
Author(s):  
Hanh N. Cottrell ◽  
Venkataraman Deepak ◽  
Jessica B. Spencer ◽  
Neil Sidell ◽  
Augustine Rajakumar
Keyword(s):  
Growth Factor ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Controlled Ovarian Hyperstimulation ◽  
Vascular Endothelial ◽  
Endometrial Stromal Cells ◽  
Vitro Fertilization ◽  
Endothelial Growth Factor

Objective: Supraphysiologic estradiol (E2) levels associated with controlled ovarian hyperstimulation in high in vitro fertilization (IVF) responders may alter implantation and placentation and increase the risk of preeclampsia. Our hypothesis is that elevated E2 levels in vitro significantly alter endometrial decidualization, sFlt1, and HOXA10 expression. Methods: Human endometrial stromal cells were treated with a decidualization cocktail of medroxyprogesterone, cyclic adenosine monophosphate, and 3 concentrations of E2 10 nM (standard), 100 nM (intermediate), or 1000 nM E2 (high). Effects on sFlt1, prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP-1), vascular endothelial growth factor (VEGF), and HOXA10 were studied. Results: Prolactin, IGFBP-1, and VEGF significantly increased at all 3 E2 concentrations. While IGFBP-1 and VEGF did not change with increasing E2, PRL was less with high E2 (6.0 ng/mL ± 1.4 standard error of the mean) compared to standard (21.4 ± 3.2) and intermediate (19.8 ± 3.8). sFlt1 decrease was similar at all E2 concentrations. HOXA10 was lower at standard (10%) and intermediate (30%) as expected, but did not change with high E2. Conclusions: Supraphysiologic E2 levels associated with high IVF responders that exceed in vivo levels may impair in vitro endometrial decidualization. Although PRL did increase with high E2, the levels were, however, attenuated and 3.4-fold lower than standard and intermediate E2. sFlt1 was decreased under all 3 conditions with no differences between concentrations. Reduced HOXA10 was not observed with high E2. These findings suggest that elevated E2 levels in vitro may alter endometrial decidualization and subsequently affect implantation and placentation.

scholarly journals A Cell-Based PDE4 Assay in 1536-Well Plate Format for High-Throughput Screening

2008 ◽  
Vol 13 (7) ◽  
pp. 609-618 ◽  
Author(s):  
Steven A. Titus ◽  
Xiao Li ◽  
Noel Southall ◽  
Jianming Lu ◽  
James Inglese ◽  
...  
Keyword(s):  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Compound Screening ◽  
A Cell

The cyclic nucleotide phosphodiesterases (PDEs) are intracellular enzymes that catalyze the hydrolysis of 3,′5′-cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), to their corresponding 5′nucleotide monophosphates. These enzymes play an important role in controlling cellular concentrations of cyclic nucleotides and thus regulate a variety of cellular signaling events. PDEs are emerging as drug targets for several diseases, including asthma, cardiovascular disease, attention-deficit hyperactivity disorder, Parkinson's disease, and Alzheimer's disease. Although biochemical assays with purified recombinant PDE enzymes and cAMP or cGMP substrate are commonly used for compound screening, cell-based assays would provide a better assessment of compound activity in a more physiological context. The authors report the development and validation of a new cell-based PDE4 assay using a constitutively active G-protein—coupled receptor as a driving force for cAMP production and a cyclic nucleotide—gated cation channel as a biosensor in 1536-well plates. ( Journal of Biomolecular Screening 2008:609-618)

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