Anti-angiogenic effect of chebulagic acid involves inhibition of the VEGFR2- and GSK-3β-dependent signaling pathways

2017 ◽  
Vol 95 (5) ◽  
pp. 563-570 ◽  
Author(s):  
A.P. Athira ◽  
C.S. Abhinand ◽  
K. Saja ◽  
A. Helen ◽  
P. Reddanna ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathways ◽  
Umbilical Vein ◽  
Docking Studies ◽  
Cell Contact ◽  
Downstream Signaling ◽  
Chebulagic Acid ◽  
Inhibition Of Angiogenesis ◽  
Gsk 3Β ◽  
Umbilical Vein Endothelial Cells

Inhibition of angiogenesis is a useful strategy to prevent cancer growth by targeting new vessels that grow to nourish actively proliferating tumor cells. Endothelial cells can use a number of different pathways to cause angiogenesis, and each step in these pathways can be targeted. The use of multi-targeted drugs is gaining much importance in this scenario. Our previous results have shown that chebulagic acid (a benzopyran tannin present in the fruits of Terminalia chebula) has anti-angiogenic properties. Thus, this study was designed to examine the molecular mechanism for the anti-angiogenic effects of chebulagic acid. Results from our investigations using molecular docking studies and human umbilical vein endothelial cells in culture suggested that chebulagic acid inhibits both GSK-3β-dependent β-catenin phosphorylation (an important mediator of VE-cadherin–β-catenin signaling) and VEGFR2 phosphorylation, which is an important step in VEGF signaling. Chebulagic acid inhibits angiogenesis by blocking both the VEGF–VEGFR2 complex and cell–cell contact dependent downstream signaling pathways.

scholarly journals Inhibition of AngiogenesisIn Vitroby Chebulagic Acid: A COX-LOX Dual Inhibitor

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
A. P. Athira ◽  
A. Helen ◽  
K. Saja ◽  
P. Reddanna ◽  
P. R. Sudhakaran
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Model Systems ◽  
Antiangiogenic Effect ◽  
Dual Inhibitor ◽  
Endogenous Factors ◽  
Human Umbilical Vein ◽  
Chebulagic Acid ◽  
Vessel Growth ◽  
Umbilical Vein Endothelial Cells

Angiogenesis is a crucial step in the growth of cancer and its metastasis. It is regulated by several endogenous factors which may stimulate or inhibit the new blood vessel growth. Besides these endogenous factors, several exogenous factors including some natural compounds are known to modulate angiogenesis. Angiogenesis being a potential target for drugs against a number of pathological conditions, search for compounds from natural sources that can affect angiogenesis is of great interest. The objective of our present study was to understand the effect of chebulagic acid, a COX-LOX dual inhibitor isolated from the fruits ofTerminalia chebulaRetz., on angiogenesis. The model systems used were rat aortic rings and human umbilical vein endothelial cells. The results showed that chebulagic acid exerts an antiangiogenic effect. This was evidenced from decreased sprouting in rat aortic rings and decrease in biochemical markers in endothelial cells treated with chebulagic acid. It downregulated the production of CD31, E-selectin, and vascular endothelial growth factor in human umbilical vein endothelial cells in culture (HUVEC). Further studies to understand the molecular mechanism of action of chebulagic acid revealed that CA exerts its anti angiogenic effect by modulating VE cadherin-βcatenin signalling in human umbilical vein endothelial cells.

scholarly journals Identification of Key Candidate Genes and Pathways of Candida albicans-Infected Human Umbilical Vein Endothelial Cells and Drug Screening

2019 ◽  
Vol 60 (1) ◽  
pp. 62-69
Author(s):  
Wei Jiang ◽  
Ping Liu ◽  
Jianlei Zhang ◽  
Wenjie Yang
Keyword(s):  
Endothelial Cells ◽  
Candida Albicans ◽  
Signaling Pathways ◽  
Umbilical Vein ◽  
Enrichment Analysis ◽  
Cell Receptor ◽  
Gene Set Enrichment Analysis ◽  
Purine Nucleotide ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells

AbstractCandida albicans is a common opportunistic pathogen that can cause serious infection by blood transmission. C. albicans enters the blood circulation and adheres to the endothelial cells of the vascular wall. However, the detailed mechanism of the effect of C. albicans on the endothelial cells remains unclear. In this study, the microarray expression profile of human umbilical vein endothelial cells exposed to C. albicans was analyzed. The 191 up-regulated genes were enriched in TNF, T cell receptor, and NF-kappa B signaling pathways. The 71 down-regulated genes were enriched in pyruvate metabolic, purine nucleotide metabolic, purine nucleotide biosynthetic, and humoral immune response processes. Gene set enrichment analysis showed that apoptosis, oxidative phosphorylation, IL6/JAK/STAT3 signaling pathways were enriched. Moreover, two hub genes with a high degree of connectivity, namely, MYC and IL6, were selected. Molecular screening of traditional Chinese medicine libraries was performed on the basis of the structure of MYC protein. The okanin had the highest docking score. MYC might be used as molecular targets for treatment. In addition, okanin may inhibit the infection of C. albicans. Thus, MYC can be subjected to further research.

scholarly journals Intracellular ascorbate tightens the endothelial permeability barrier through Epac1 and the tubulin cytoskeleton

2016 ◽  
Vol 311 (4) ◽  
pp. C652-C662 ◽  
Author(s):  
William H. Parker ◽  
Elizabeth Meredith Rhea ◽  
Zhi-Chao Qu ◽  
Morgan R. Hecker ◽  
James M. May
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Cyclic Amp ◽  
Umbilical Vein ◽  
Endothelial Permeability ◽  
Cell Contact ◽  
Permeability Barrier ◽  
Basal Cells ◽  
Microtubule Stabilization ◽  
Umbilical Vein Endothelial Cells

Vitamin C, or ascorbic acid, both tightens the endothelial permeability barrier in basal cells and also prevents barrier leak induced by inflammatory agents. Barrier tightening by ascorbate in basal endothelial cells requires nitric oxide derived from activation of nitric oxide synthase. Although ascorbate did not affect cyclic AMP levels in our previous study, there remains a question of whether it might activate downstream cyclic AMP-dependent pathways. In this work, we found in both primary and immortalized cultured endothelial cells that ascorbate tightened the endothelial permeability barrier by ∼30%. In human umbilical vein endothelial cells, this occurred at what are likely physiologic intracellular ascorbate concentrations. In so doing, ascorbate decreased measures of oxidative stress and also flattened the cells to increase cell-to-cell contact. Inhibition of downstream cyclic AMP-dependent proteins via protein kinase A did not prevent ascorbate from tightening the endothelial permeability barrier, whereas inhibition of Epac1 did block the ascorbate effect. Although Epac1 was required, its mediator Rap1 was not activated. Furthermore, ascorbate acutely stabilized microtubules during depolymerization induced by colchicine and nocodazole. Over several days in culture, ascorbate also increased the amount of stable acetylated α-tubulin. Microtubule stabilization was further suggested by the finding that ascorbate increased the amount of Epac1 bound to α-tubulin. These results suggest that physiologic ascorbate concentrations tighten the endothelial permeability barrier in unstimulated cells by stabilizing microtubules in a manner downstream of cyclic AMP that might be due both to increasing nitric oxide availability and to scavenging of reactive oxygen or nitrogen species.

scholarly journals Ninjurin 1 dodecamer peptide containing the N-terminal adhesion motif (N-NAM) exerts proangiogenic effects in HUVECs and in the postischemic brain

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Seung-Woo Kim ◽  
Hye-Kyung Lee ◽  
Song-I. Seol ◽  
Dashdulam Davaanyam ◽  
Hahnbie Lee ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathways ◽  
Umbilical Vein ◽  
Artery Occlusion ◽  
Tube Formation ◽  
Neuroprotective Effects ◽  
Angiogenic Effect ◽  
A Cell ◽  
Direct Binding ◽  
Umbilical Vein Endothelial Cells

Abstract Nerve injury-induced protein 1 (Ninjurin 1, Ninj1) is a cell adhesion molecule responsible for cell-to-cell interactions between immune cells and endothelial cells. In our previous paper, we have shown that Ninj1 plays an important role in the infiltration of neutrophils in the postischemic brain and that the dodecamer peptide harboring the Ninj1 N-terminal adhesion motif (N-NAM, Pro26-Asn37) inhibits infiltration of neutrophils in the postischemic brain and confers robust neuroprotective and anti-inflammatory effects. In the present study, we examinedt the pro-angiogenic effect of N-NAM using human umbilical vein endothelial cells (HUVECs) and rat MCAO (middle cerebral artery occlusion) model of stroke. We found that N-NAM promotes proliferation, migration, and tube formation of HUVECs and demonstrate that the suppression of endogenous Ninj1 is responsible for the N-NAM-mediated pro-angiogenic effects. Importantly, a pull-down assay revealed a direct binding between exogenously delivered N-NAM and endogenous Ninj1 and it is N-terminal adhesion motif dependent. In addition, N-NAM activated the Ang1-Tie2 and AKT signaling pathways in HUVECs, and blocking those signaling pathways with specific inhibitors suppressed N-NAM-induced tube formation, indicating critical roles of those signaling pathways in N-NAM-induced angiogenesis. Moreover, in a rat MCAO model, intranasal administration of N-NAM beginning 4 days post-MCAO (1.5 µg daily for 3 days) augmented angiogenesis in the penumbra of the ipsilateral hemisphere of the brain and significantly enhanced total vessel lengths, vessel densities, and pro-angiogenic marker expression. These results demonstrate that the 12-amino acid Ninj1 peptide, which contains the N-terminal adhesion motif of Ninj1, confers pro-angiogenic effects and suggest that those effects might contribute to its neuroprotective effects in the postischemic brain.

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