Pharmacological actions of nobiletin in the modulation of platelet function

Vaiyapuri, Sakthivel; Roweth, Harvey G.; Ali, Marfoua S.; Unsworth, Amanda J.; Stainer, Alexander R.; Flora, Gagan D.; Crescente, Marilena; Jones, Chris I.; Moraes, Leonardo A.; Gibbins, Jonathan M.

doi:10.1111/bph.13191

Cited by 52 publications

(49 citation statements)

References 43 publications

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“…Moreover, at a maximum concentration of 30 µ M, nobiletin had no effects on the intracellular levels of cyclic AMP or cyclic GMP in human platelets, which is consistent with the recent observation by Vaiyapuri et al (21). Of note, our preliminary experiments revealed that nobiletin (30 µ M) markedly increased VASP phosphorylation in a similar manner to prostaglandin E 1 (PGE 1 ) (Fig.…”

Section: Introductionsupporting

confidence: 92%

Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms

Jayakumar

Lin

et al. 2016

International Journal of Molecular Medicine

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Nobiletin, a bioactive polymethoxylated flavone, has been described to possess a diversity of biological effects through its antioxidant and anti-inflammatory properties. Vasodilator-stimulated phosphoprotein (VASP) is a common substrate for cyclic AMP and cyclic GMP-regulated protein kinases [i.e., cyclic AMP-dependent protein kinase (PKA; also known as protein kinase A) and cyclic GMP-dependent protein kinase (PKG; also known as protein kinase G)] and it has been shown to be directly phosphorylated by protein kinase C (PKC). In the present study, we demonstrate that VASP is phosphorylated by nobiletin in human platelets via a non-cyclic nucleotide-related mechanism. This was confirmed by the use of inhibitors of adenylate cyclase (SQ22536) and guanylate cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)], since they prevented VASP phosphorylation induced by nobiletin. Furthormore, this event was also not affected by specific inhibitors of PKA (H-89), PKG (KT5823) and PKC (Ro318220), representing cyclic nucleotide-dependent pathways upon nobiletin-induced VASP phosphorylation. Similarly, inhibitors of p38 mitogen-activated protein kinase (MAPK; SB203580), extracellular signal-regulated kinase 2 (ERK2; PD98059), c-Jun N-terminal kinase 1 (JNK1; SP600125), Akt (LY294002) and nuclear factor-κB (NF-κB; Bay11-7082) did not affect nobiletin-induced VASP phosphorylation. Moreover, electron spin resonance, dichlorofluorescein fluorescence and western blotting techniques revealed that nobiletin did not affect hydroxyl radicals (OH•), intracellular reactive oxygen species (ROS) and on protein carbonylation, respectively. Furthermore, the nobiletin-induced VASP phosphorylation was surprisingly reversed by the intracellular antioxidant, N-acetylcysteine (NAC), but not by the inhibitor of NADPH oxidase, diphenyleneiodonium chloride (DPI). It was surprising to observe the differential effects of nobiletin and NAC on VASP phosphorylation in human platelets, since they both have been reported to have antioxidant properties. The likely explanation for this discrepancy is that NAC may bind to allosteric sites on the receptor different from those that nobiletin binds to in human platelets. Taken together, our findings suggest that nobiletin induces VASP phosphorylation in human platelets through non-cyclic nucleotide-related mechanisms. Nevertheless, the exact mechanisms responsible for these effects need to be further confirmed in future studies.

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Section: Introductionsupporting

confidence: 92%

Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms

Jayakumar

Lin

et al. 2016

International Journal of Molecular Medicine

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“…Moreover, quercetin (25–100 μM) inhibited collagen‐induced fibrinogen binding to its receptor, perhaps by causing conformational changes to the GPIIb IIIa receptor, thus reducing the affinity of fibrinogen for the receptor binding site (Oh et al , ). Similar findings have been reported for nobiletin (6.25–200 μM), a flavonoid found in citrus fruit (Vaiyapuri et al , ).…”

Section: Polyphenols As Pharmacological Agentssupporting

confidence: 89%

Bioactive polyphenols and cardiovascular disease: chemical antagonists, pharmacological agents or xenobiotics that drive an adaptive response?

Goszcz

Duthie

Stewart

et al. 2017

British J Pharmacology

127

117

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Polyphenols are widely regarded to have a wide range of health-promoting qualities, including beneficial effects on cardiovascular disease. Historically, the benefits have been linked to their well-recognized powerful antioxidant activity. However, the concept that the beneficial effects are attributable to direct antioxidant activity in vivo does not pay sufficient heed to the fact that polyphenols degrade rapidly, are poorly absorbed and rapidly metabolized, resulting in very low bioavailability. This review explores alternative mechanisms by which polyphenols, or their metabolites, exert biological activity via mechanisms that can be activated by physiologically relevant concentrations. Evidence is presented to support the action of phenolic derivatives on receptors and signalling pathways to induce adaptive responses that drive changes in endogenous antioxidant, antiplatelet, vasodilatory and anti-inflammatory effects. The implications are that in vitro antioxidant measures as predictors of polyphenol protective activity in vivo hold little relevance and that closer attention needs to be paid to bioavailable metabolites to understand the mode of action of these diet-derived components. LINKED ARTICLESThis article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc Abbreviations A549, adenocarcinomic human alveolar basal epithelial cells; CD62P, P-selectin; CSE, cigarette smoke extract; EGCG, epigallocatechin-3-gallate; eNOS, endothelial NOS; ER-α/β, oestrogen receptor-α/β; GR, glutathione reductase; GSL, glutamylcysteine ligase; GST, GSH-S-transferase; HO1, haem oxygenase 1; ICAM-1, intercellular adhesion molecule 1; IκB-α, inhibitor of κ-B α; Nrf2, nuclear factor E2-related factor 2;˙OH, hydroxyl radical; ONOO À , peroxynitrite; ox-LDL, oxidized LDL; VCAM-1, vascular cell adhesion molecule 1

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“…Numerous studies have investigated the possible BP-lowering effect of different flavonoids, such as Apocynum venetum and rutin [30,33,34,35]. Nobiletin has been shown to lower cholesterol and improve microcirculation properties [36]. However, the antihypertensive effect of nobiletin has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

Nobiletin Relaxes Isolated Mesenteric Arteries by Activating the Endothelial Ca<sup>2+</sup>-eNOS Pathway in Rats

Yang

Lin

et al. 2016

J Vasc Res

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Aims: Nobiletin, a natural polymethoxylated flavonoid compound, has various beneficial properties, such as anticancer, anti-inflammatory, and antioxidant effects, and it also improves memory. Therefore, we investigated the effects and mechanisms of nobiletin on rat isolated mesenteric arteries (MAs). Methods: We examined vasodilation induced by nobiletin on rat isolated MA rings with a tension study, the expression and activity of endothelial nitric oxide synthase (eNOS) with Western blotting, NO production with DAF- FMDA fluorescence, and intracellular Ca²⁺ concentration ([Ca²⁺]i) with Fluo-3AM. Results and Conclusion: Our study showed that nobiletin elicited a dose-dependent vasodilation in phenylephrine precontracted MA rings, but it did not elicit the same response in pulmonary artery rings. Vasodilation was related to endothelium and activated partly by eNOS. Vasodilation was inhibited by denudation of the endothelium or inhibition of eNOS activity. Nobiletin increased NO production by promoting the phosphorylation of eNOS at Ser-1177 without changing the level of eNOS expression in rat mesenteric artery endothelial cells (RMAECs). Nobiletin increased the concentration of endothelial [Ca²⁺]i, which enhances eNOS activity in RMAECs. In summary, vasodilation induced by nobiletin was dependent on the endothelium and partly on eNOS activation, which is mediated by high endothelial [Ca²⁺]i. Results suggest nobiletin may offer a therapeutic benefit and could potentially be used as a vasodilator for the treatment of hypertension.

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Pharmacological actions of nobiletin in the modulation of platelet function

Cited by 52 publications

References 43 publications

Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms

Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms

Bioactive polyphenols and cardiovascular disease: chemical antagonists, pharmacological agents or xenobiotics that drive an adaptive response?

Nobiletin Relaxes Isolated Mesenteric Arteries by Activating the Endothelial Ca<sup>2+</sup>-eNOS Pathway in Rats

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