Nitric Oxide-Donating Derivatives of Chrysin Stimulate Angiogenesis and Upregulating VEGF Production

Angiogenesis, the development of new capillaries from pre-existing vessels, requires the coordinate activation of endothelial cells, which migrate and proliferate to form functional vessels. Endothelial dysfunction and decreased nitric oxide bioavailability may underscore the impairment of angiogenesis. As such, the delivery of exogenous NO is an attractive therapeutic option that has been used to therapeutic angiogenesis. In this paper, a novel group of hybrid nitric oxide-releasing chrysin derivatives was synthesized. The results indicated that all these chrysin derivatives exhibited promotion of endothelial migration and tubulogenesis in vitro as well as stimulation angiogenesis in vivo.Furthermore, all compounds released NO upon incubation with phosphate buffer at pH 7.4 and enhanced VEGF secretion and VEGF mRNA expression of endothelial cells. These hybrid ester NO donor prodrugs offer a potential drug design concept for the development of therapeutic or preventive agents for angiogenesis deficiency due to ischemic diseases.

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Differential regulation of metabolism by nitric oxide andS-nitrosothiols in endothelial cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00210.2011 ◽

2011 ◽

Vol 301 (3) ◽

pp. H803-H812 ◽

Cited By ~ 21

Author(s):

Anne R. Diers ◽

Katarzyna A. Broniowska ◽

Victor M. Darley-Usmar ◽

Neil Hogg

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Oxidative Phosphorylation ◽

Metabolic Pathways ◽

Nitrosative Stress ◽

Surrogate Marker ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

No Donor

S-nitrosation of thiols in key proteins in cell signaling pathways is thought to be an important contributor to nitric oxide (NO)-dependent control of vascular (patho)physiology. Multiple metabolic enzymes are targets of both NO and S-nitrosation, including those involved in glycolysis and oxidative phosphorylation. Thus it is important to understand how these metabolic pathways are integrated by NO-dependent mechanisms. Here, we compared the effects of NO and S-nitrosation on both glycolysis and oxidative phosphorylation in bovine aortic endothelial cells using extracellular flux technology to determine common and unique points of regulation. The compound S-nitroso-l-cysteine (l-CysNO) was used to initiate intracellular S-nitrosation since it is transported into cells and results in stable S-nitrosation in vitro. Its effects were compared with the NO donor DetaNONOate (DetaNO). DetaNO treatment caused only a decrease in the reserve respiratory capacity; however, l-CysNO impaired both this parameter and basal respiration in a concentration-dependent manner. In addition, DetaNO stimulated extracellular acidification rate (ECAR), a surrogate marker of glycolysis, whereas l-CysNO stimulated ECAR at low concentrations and inhibited it at higher concentrations. Moreover, a temporal relationship between NO- and S-nitrosation-mediated effects on metabolism was identified, whereby NO caused a rapid impairment in mitochondrial function, which was eventually overwhelmed by S-nitrosation-dependent processes. Taken together, these results suggest that severe pharmacological nitrosative stress may differentially regulate metabolic pathways through both intracellular S-nitrosation and NO-dependent mechanisms. Moreover, these data provide insight into the role of NO and related compounds in vascular (patho)physiology.

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Development of Antimicrobial Nitric Oxide-Releasing Fibers

Pharmaceutics ◽

10.3390/pharmaceutics13091445 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1445

Author(s):

Daniel C. Wang ◽

Justin R. Clark ◽

Richard Lee ◽

Adam H. Nelson ◽

Anthony W. Maresso ◽

...

Keyword(s):

Nitric Oxide ◽

Release Kinetics ◽

Antimicrobial Properties ◽

No Donor ◽

Long Term Stability ◽

Effective Delivery ◽

Culture Models ◽

Delivery Platform ◽

Nitric Oxide Releasing

Nitric oxide (NO) is a highly reactive gas molecule, exhibiting antimicrobial properties. Because of its reactive nature, it is challenging to store and deliver NO efficiently as a therapeutic agent. The objective of this study was to develop NO-releasing polymeric fibers (NO-fibers), as an effective delivery platform for NO. NO-fibers were fabricated with biopolymer solutions of polyvinyl pyrrolidone (PVP) and ethylcellulose (EC), and derivatives of N-diazeniumdiolate (NONOate) as NO donor molecules, using an electrospinning system. We evaluated in vitro NO release kinetics, along with antimicrobial effects and cytotoxicity in microorganisms and human cell culture models. We also studied the long-term stability of NONOates in NO-fibers over 12 months. We demonstrated that the NO-fibers could release NO over 24 h, and showed inhibition of the growth of Pseudomonas aeruginosa (P. aeruginosa) and methicillin-resistant Staphylococcus aureus (MRSA), without causing cytotoxicity in human cells. NO-fibers were able to store NONOates for over 12 months at room temperature. This study presents the development of NO-fibers, and the feasibility of NO-fibers to efficiently store and deliver NO, which can be further developed as a bandage.

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Nitric oxide enhances hydrogen peroxide-mediated endothelial permeability in vitro

AJP Cell Physiology ◽

10.1152/ajpcell.1997.273.5.c1581 ◽

1997 ◽

Vol 273 (5) ◽

pp. C1581-C1587 ◽

Cited By ~ 30

Author(s):

Naotsuka Okayama ◽

Christopher G. Kevil ◽

Loisann Correia ◽

David Jourd’Heuil ◽

Makoto Itoh ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Endothelial Permeability ◽

Reactive Oxygen ◽

Iron Chelator ◽

Reactive Oxygen Metabolites ◽

No Donor ◽

Spermine Nonoate ◽

Oxygen Metabolites

The objective of this study was to evaluate the effects of nitric oxide (NO) on H2O2-mediated endothelial permeability. H2O2(0.1 mM) increased permeability at 90 min to 298% of baseline. Spermine NONOate (SNO), an NO donor, at 0.1 or 1 mM did not alter permeability. However, 0.1 mM H2O2+ 1 mM SNO increased permeability to 764%, twice that of 0.1 mM H2O2alone. These treatments were not directly toxic to endothelial cells. This NO effect was concentration dependent, inasmuch as 0.1 mM SNO did not significantly change H2O2-mediated permeability. The NO-enhanced, H2O2-dependent permeability required the simultaneous presence of NO and H2O2, inasmuch as preincubation with SNO for 30 min followed by 0.1 mM H2O2did not alter permeability. Staining of endothelial junctions showed widening of the intercellular space only in junctions of cells exposed to H2O2(0.1 mM) + SNO (1 mM). Furthermore, NO did not affect H2O2metabolism by endothelial cells but significantly depleted intracellular glutathione. This reduction of cell glutathione produced by NO exposure recovered 15–30 min after removal of the NO donor. NO-enhanced permeability was completely blocked by methionine (1 mM), a scavenger of reactive oxygen species, and by the iron chelator desferrioxamine (0.1 mM). These results suggest that NO may exacerbate the effects of H2O2-dependent increase in endothelial monolayer permeability via the iron-catalyzed formation of reactive oxygen metabolites.

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Identification of nitric oxide-releasing derivatives of oleanolic acid as potential anti-colon cancer agents

RSC Advances ◽

10.1039/c5ra00270b ◽

2015 ◽

Vol 5 (25) ◽

pp. 19445-19454 ◽

Cited By ~ 7

Author(s):

Junjie Fu ◽

Yu Zou ◽

Zhangjian Huang ◽

Chang Yan ◽

Qimeng Zhou ◽

...

Keyword(s):

Nitric Oxide ◽

Colon Cancer ◽

Signaling Pathways ◽

Oleanolic Acid ◽

Nitric Oxide Releasing ◽

Derivatives Of ◽

Cancer Activity

NO-releasing hybrid 6 regulates colon cancer-related signaling pathways, exhibiting potent anti-colon cancer activity in vitro and in vivo.

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Synthesis and in vitro biological evaluation of nitric oxide-releasing derivatives of hydroxylcinnamic acids as anti-tumor agents

Chinese Chemical Letters ◽

10.1016/j.cclet.2013.03.006 ◽

2013 ◽

Vol 24 (5) ◽

pp. 415-418 ◽

Cited By ~ 4

Author(s):

Ming-Dong Lu ◽

Xiao Zhou ◽

Yao-Jun Yu ◽

Pi-Hong Li ◽

Wei-Jian Sun ◽

...

Keyword(s):

Nitric Oxide ◽

Biological Evaluation ◽

Nitric Oxide Releasing ◽

Derivatives Of

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Cadmium attenuates bradykinin-driven nitric oxide production by interplaying with the localization pattern of endothelial nitric oxide synthase

Biochemistry and Cell Biology ◽

10.1139/o09-018 ◽

2009 ◽

Vol 87 (4) ◽

pp. 605-620 ◽

Cited By ~ 14

Author(s):

Syamantak Majumder ◽

Ravi Gupta ◽

Himabindu Reddy ◽

Swaraj Sinha ◽

Ajit Muley ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Egg Yolk ◽

Tube Formation ◽

Nitric Oxide Production ◽

Localization Pattern ◽

Oxide Production ◽

Endothelial Migration ◽

Endothelial Functions

Cadmium, a ubiquitous heavy metal, interferes with endothelial functions and angiogenesis. Bradykinin is a Ca-mobilizing soluble peptide that acts via nitric oxide to promote vasodilation and capillary permeability. The objective of the present study was to explore the Cd implications in bradykinin-dependent endothelial functions. An egg yolk angiogenesis model was employed to evaluate the effect of Cd on bradykinin-induced angiogenesis. The results demonstrate that 100 nmol/L Cd attenuated bradykinin-dependent angiogenesis. The results of the in vitro wound healing and tube formation assays by using EAhy 926, a transformed endothelial cell line, suggest that Cd blocked bradykinin-mediated endothelial migration and tube formation by 38% and 67%, respectively, while nitric oxide supplementation could reverse the effect of Cd on bradykinin-induced endothelial migration by 94%. The detection of nitric oxide by using a DAF-2DA fluorescent probe, Griess assay, and ultrasensitive electrode suggests that Cd blocked bradykinin-induced nitric oxide production. Fluorescence imaging of eNOS-GFP transfected endothelial cells, immunofluroscence, and Western blot studies of Cd and bradykinin-treated cells show that Cd interfered with the localization pattern of eNOS, which possibly attenuates nitric oxide production in part. Additionally, Ca imaging of Cd- and bradykinin-treated cells suggests that Cd blocked bradykinin-dependent Ca influx into the cells, thus partially blocking Ca-dependent nitric oxide production in endothelial cells. The results of this study conclude that Cd blunted the effect of bradykinin by interfering with the Ca-associated NOS activity specifically by impeding subcellular trafficking of eNOS.

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Resveratrol and grape juice: Effects on redox status and nitric oxide production of endothelial cells in in vitro preeclampsia model

Pregnancy Hypertension ◽

10.1016/j.preghy.2021.01.001 ◽

2021 ◽

Vol 23 ◽

pp. 205-210

Author(s):

Mayara Caldeira-Dias ◽

Sarah Viana-Mattioli ◽

Jackeline de Souza Rangel Machado ◽

Mattias Carlström ◽

Ricardo de Carvalho Cavalli ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Grape Juice ◽

Redox Status ◽

Nitric Oxide Production ◽

Oxide Production

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Nitric oxide preconditioning regulates endothelial monolayer integrity via the heat shock protein 90-soluble guanylate cyclase pathway

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00498.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. H893-H903 ◽

Cited By ~ 14

Author(s):

Galina N. Antonova ◽

Connie M. Snead ◽

Alexander S. Antonov ◽

Christiana Dimitropoulou ◽

Richard C. Venema ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Heat Shock ◽

Heat Shock Protein ◽

Cell Injury ◽

Soluble Guanylate Cyclase ◽

Heat Shock Protein 90 ◽

Protective Effects ◽

No Donor ◽

Spermine Nonoate

Large (pathological) amounts of nitric oxide (NO) induce cell injury, whereas low (physiological) NO concentrations often ameliorate cell injury. We tested the hypotheses that pretreatment of endothelial cells with low concentrations of NO (preconditioning) would prevent injury induced by high NO concentrations. Apoptosis, induced in bovine aortic endothelial cells (BAECs) by exposing them to either 4 mM sodium nitroprusside (SNP) or 0.5 mM N-(2-aminoethyl)- N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) for 8 h, was abolished by 24-h pretreatment with either 100 μM SNP, 10 μM spermine NONOate, or 100 μM 8-bromo-cGMP (8-Br-cGMP). Repair of BAECs following wounding, measured as the recovery rate of transendothelial electrical resistance, was delayed by 8-h exposure to 4 mM SNP, and this delay was significantly attenuated by 24-h pretreatment with 100 μM SNP. NO preconditioning produced increased association and expression of soluble guanyl cyclase (sGC) and heat shock protein 90 (HSP90). The protective effect of NO preconditioning, but not the injurious effect of 4 mM SNP, was abolished by either a sGC activity inhibitor 1H-[1,2,4]oxadiazolo-[4,3- a]quinoxalin-1-one (ODQ) or a HSP90 binding inhibitor (radicicol) and was mimicked by 8-Br-cGMP. We conclude that preconditioning with a low dose of NO donor accelerates repair and maintains endothelial integrity via a mechanism that includes the HSP90/sGC pathway. HSP90/sGC may thus play a role in the protective effects of NO-generating drugs from injurious stimuli.

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