A study of ad-proline peptidomimetic inhibitor of melanoma and endothelial cell invasion through activity towards MMP-2 and MMP-9

MedChemComm ◽  
2015 ◽  
Vol 6 (2) ◽  
pp. 277-282 ◽  
Author(s):  
Francesca Bianchini ◽  
Chiara Calugi ◽  
Jessica Ruzzolini ◽  
Gloria Menchi ◽  
Lido Calorini ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Enzyme Inhibition ◽  
Cell Invasion ◽  
Network Formation ◽  
Capillary Network ◽  
Inhibition Kinetics ◽  
Enzyme Inhibition Kinetics

Ad-proline peptidomimetic targeting MMP-2 and MMP-9 was identified from a pool of compounds following enzyme inhibition kinetics and Matrigel sponge assays, showing the capacity of blocking capillary network formationin vivo.

scholarly journals Acute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells

2008 ◽  
Vol 295 (1) ◽  
pp. H174-H184 ◽  
Author(s):  
Katherine A. Radek ◽  
Elizabeth J. Kovacs ◽  
Richard L. Gallo ◽  
Luisa A. DiPietro
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Signaling ◽  
Network Formation ◽  
Ethanol Exposure ◽  
Capillary Network ◽  
Ethanol Metabolism ◽  
Vegf Receptor ◽  
Acute Ethanol

Physiological angiogenesis is regulated by various factors, including signaling through vascular endothelial growth factor (VEGF) receptors. We previously reported that a single dose of ethanol (1.4 g/kg), yielding a blood alcohol concentration of 100 mg/dl, significantly impairs angiogenesis in murine wounds, despite adequate levels of VEGF, suggesting direct effects of ethanol on endothelial cell signaling (40). To examine the mechanism by which ethanol influences angiogenesis in wounds, we employed two different in vitro angiogenesis assays to determine whether acute ethanol exposure (100 mg/dl) would have long-lasting effects on VEGF-induced capillary network formation. Ethanol exposure resulted in reduced VEGF-induced cord formation on collagen and reduced capillary network structure on Matrigel in vitro. In addition, ethanol exposure decreased expression of endothelial VEGF receptor-2, as well as VEGF receptor-2 phosphorylation in vitro. Inhibition of ethanol metabolism by 4-methylpyrazole partially abrogated the effect of ethanol on endothelial cell cord formation. However, mice treated with t-butanol, an alcohol not metabolized by alcohol dehydrogenase, exhibited no change in wound vascularity. These results suggest that products of ethanol metabolism are important factors in the development of ethanol-induced changes in endothelial cell responsiveness to VEGF. In vivo, ethanol exposure caused both decreased angiogenesis and increased hypoxia in wounds. Moreover, in vitro experiments demonstrated a direct effect of ethanol on the response to hypoxia in endothelial cells, as ethanol diminished nuclear hypoxia-inducible factor-1α protein levels. Together, the data establish that acute ethanol exposure significantly impairs angiogenesis and suggest that this effect is mediated by changes in endothelial cell responsiveness to both VEGF and hypoxia.

Longan seed polyphenols inhibit α-amylase activity and reduce postprandial glycemic response in mice

2021 ◽  
Author(s):  
Ting He ◽  
lei zhao ◽  
Yan Chen ◽  
Xin Zhang ◽  
Zhuoyan Hu ◽  
...  
Keyword(s):  
Enzyme Inhibition ◽  
Amylase Activity ◽  
Glycemic Response ◽  
Inhibition Assay ◽  
Inhibition Kinetics ◽  
Enzyme Inhibition Kinetics ◽  
Longan Seed ◽  
Kinetics Of

The effects of longan seed polyphenols (LSPs) on postprandial glycemic response in mice were investigated, enzyme inhibition kinetics of LSPs against α-amylase were studied using an inhibition assay in vitro,...

scholarly journals Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5358
Author(s):  
Narayan D. Chaurasiya ◽  
Jacob Midiwo ◽  
Pankaj Pandey ◽  
Regina N. Bwire ◽  
Robert J. Doerksen ◽  
...  
Keyword(s):  
Natural Products ◽  
Enzyme Inhibition ◽  
Selective Inhibition ◽  
Monoamine Oxidase A ◽  
Inhibition Kinetics ◽  
Free Energies ◽  
Mao B ◽  
Mao A ◽  
Enzyme Inhibition Kinetics ◽  
Binding Free Energies

A set of structurally related O-methylated flavonoid natural products isolated from Senecio roseiflorus (1), Polygonum senegalense (2 and 3), Bhaphia macrocalyx (4), Gardenia ternifolia (5), and Psiadia punctulata (6) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds 1, 2, and 5 showed selective inhibition of MAO-A, while 4 and 6 showed selective inhibition of MAO-B. Compound 3 showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds 1–3 and 5 with MAO-A, and compounds 3 and 6 with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by 1 and 3, while a partially-reversible mixed-type inhibition by 5. Similarly, enzyme inhibition-kinetics analysis with compounds 3, 4, and 6, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that 1 selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the O-methylated flavonoids (1 and 4–6) and chalcones (2 and 3) to MAO-A matched closely with the trend in the experimental IC50′s. Analysis of the binding free-energies suggested better interaction of 4 and 6 with MAO-B than with MAO-A. The natural O-methylated flavonoid (1) with highly potent inhibition (IC50 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.

Understanding the bioaccessibility, α-amylase and α-glucosidase enzyme inhibition kinetics of Allmania nodiflora (L.) R.Br. ex Wight polyphenols during in vitro simulated digestion

2022 ◽  
Vol 372 ◽  
pp. 131294
Author(s):  
Gayathri Jagadeesan ◽  
Kasipandi Muniyandi ◽  
Ashwini Lydia Manoharan ◽  
Gayathri Nataraj ◽  
Parimelazhagan Thangaraj
Keyword(s):  
Enzyme Inhibition ◽  
Inhibition Kinetics ◽  
Simulated Digestion ◽  
Enzyme Inhibition Kinetics ◽  
Kinetics Of

Inhibition of endothelial cell activation by bHLH protein E2-2 and its impairment of angiogenesis

Blood ◽  
2010 ◽  
Vol 115 (20) ◽  
pp. 4138-4147 ◽  
Author(s):  
Aya Tanaka ◽  
Fumiko Itoh ◽  
Koichi Nishiyama ◽  
Toshiaki Takezawa ◽  
Hiroki Kurihara ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Activation ◽  
Network Formation ◽  
Mutational Analysis ◽  
Luciferase Reporter ◽  
Bhlh Protein ◽  
Endothelial Cell Activation ◽  
Helix Loop Helix ◽  
Mediated Effects

E2-2 belongs to the basic helix-loop-helix (bHLH) family of transcription factors. E2-2 associates with inhibitor of DNA binding (Id) 1, which is involved in angiogenesis. In this paper, we demonstrate that E2-2 interacts with Id1 and provide evidence that this interaction potentiates angiogenesis. Mutational analysis revealed that the HLH domain of E2-2 is required for the interaction with Id1 and vice versa. In addition, Id1 interfered with E2-2–mediated effects on luciferase reporter activities. Interestingly, injection of E2-2–expressing adenoviruses into Matrigel plugs implanted under the skin blocked in vivo angiogenesis. In contrast, the injection of Id1-expressing adenoviruses rescued E2-2–mediated inhibition of in vivo angiogenic reaction. Consistent with the results of the Matrigel plug assay, E2-2 could inhibit endothelial cell (EC) migration, network formation, and proliferation. On the other hand, knockdown of E2-2 in ECs increased EC migration. The blockade of EC migration by E2-2 was relieved by exogenous expression of Id1. We also demonstrated that E2-2 can perturb VEGFR2 expression via inhibition of VEGFR2 promoter activity. This study suggests that E2-2 can maintain EC quiescence and that Id1 can counter this effect.

scholarly journals Type 5 phosphodiesterase expression is a critical determinant of the endothelial cell angiogenic phenotype

2009 ◽  
Vol 296 (2) ◽  
pp. L220-L228 ◽  
Author(s):  
Bing Zhu ◽  
Li Zhang ◽  
Mikhail Alexeyev ◽  
Diego F. Alvarez ◽  
Samuel J. Strada ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Network Formation ◽  
Microvascular Endothelial Cells ◽  
Critical Determinant ◽  
Angiogenic Potential ◽  
Matrigel Plug ◽  
Microvascular Endothelial

Type 5 phosphodiesterase (PDE5) inhibitors increase endothelial cell cGMP and promote angiogenesis. However, not all endothelial cell phenotypes express PDE5. Indeed, whereas conduit endothelial cells express PDE5, microvascular endothelial cells do not express this enzyme, and they are rapidly angiogenic. These findings bring into question whether PDE5 activity is a critical determinant of the endothelial cell angiogenic potential. To address this question, human full-length PDE5A1 was stably expressed in pulmonary microvascular endothelial cells. hPDE5A1 expression reduced the basal and atrial natriuretic peptide (ANP)-stimulated cGMP concentrations in these cells. hPDE5A1-expressing cells displayed attenuated network formation on Matrigel in vitro and also produced fewer blood vessels in Matrigel plug assays in vivo; the inhibitory actions of hPDE5A1 were reversed using sildenafil. To examine whether endogenous PDE5 activity suppresses endothelial cell angiogenic potential, small interfering RNA (siRNA) constructs were stably expressed in pulmonary artery endothelial cells. siRNA selectively decreased PDE5 expression and increased basal and ANP-stimulated cGMP concentrations in these conduit cells. PDE5 downregulation increased network formation on Matrigel in vitro and increased blood vessel formation in Matrigel plug assays in vivo. Collectively, our results indicate that PDE5 activity is an essential determinant of angiogenesis and suggest that PDE5 downregulation in microvascular endothelium imparts a stable, enhanced angiogenic potential to this cell type.

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