Phosphorylation closely correlating with adenylate cyclase Role of VASP in signal transduction pathways in platelets, its VASP-knockout mice exhibit enhanced thrombin-induced plateletĪctivation and impaired cyclic AMP-dependent inhibition ( 19). Response to cyclic AMP/cyclic GMP in platelets correlates withįibrinogen receptor inhibition ( 18). VASP, but that protein kinase C (PKC) may also have this ability That PKA and PKG are not the only kinases able to phosphorylate (PKG also known as protein kinase G) in some vascular tissues It is also noteworthy that cyclicĪMP may cross-activate the cyclic GMP-dependent protein kinase Involved in the phosphorylation of VASP ( 15). In platelets, PKA activation has been shown to be
Mediator of the numerous effects associated with increased cyclicĪMP levels. (PKA also known as protein kinase A) is considered the main As VASP is a commonĭownstream target of various signaling pathways, an increasingĪttention to this molecule has been paid in platelet studies Regulator of actin reorganization in platelets. Vasodilator-stimulated phosphoprotein (VASP) is a Another study revealed that theĪdministration of nobiletin protected rat brains from ischemicĭamage by activating the Akt/cyclic AMP response element-binding Neuroinflammation among 8 common tangerine flavonoids ( 10). Synthase (iNOS), tumor necrosis factor-α (TNF-α) and interleukinĭemonstrated that nobiletin was the most potent inhibitor of Pathways, as well as the translocation of nuclear factor-κB (NF-κB)Īnd the subsequent gene expression of inducible nitric oxide Kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) The extracellular signal-regulated kinase (ERK), c-Jun N-terminal This compound possesses potentĪnti-neuroinflammatory abilities by suppressing the activation of Nobiletin has been reported to protect PC12 cells from hydrogenĮthanol-induced liver injury by augmenting the phosphorylation ofĪMP-activated protein kinase (AMPK) ( 8). Nobiletin has been reported to be an encouraging antioxidant andĪnti-inflammatory agent in the treatment of asthma, colitis and
(mandarin orange), Citrus unshiu Markovich, Citrusĭepressa (shiikuwasa) and Citrus limon (lemon) ( 2– 4). Has been found in very high concentrations in immature citrus peelsĭifferent citrus species, such as Citrus reticulata Blanco Nobiletin, a major flavonoid polymethexylatedįlavone (5,6,7,8,3′,4′-hexamethoxyflavone PMF) found in citrus, Nevertheless, the exact mechanisms responsible for these effects need to be further confirmed in future studies. Taken together, our findings suggest that nobiletin induces VASP phosphorylation in human platelets through non-cyclic nucleotide-related mechanisms. 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. 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. 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). ), intracellular reactive oxygen species (ROS) and on protein carbonylation, respectively.
Moreover, electron spin resonance, dichlorofluorescein fluorescence and western blotting techniques revealed that nobiletin did not affect hydroxyl radicals (OH 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. 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. This was confirmed by the use of inhibitors of adenylate cyclase (SQ22536) and guanylate cyclase oxadiazoloquinoxalin-1-one (ODQ)], since they prevented VASP phosphorylation induced by nobiletin. In the present study, we demonstrate that VASP is phosphorylated by nobiletin in human platelets via a non-cyclic nucleotide-related mechanism. Vasodilator-stimulated phosphoprotein (VASP) is a common substrate for cyclic AMP and cyclic GMP-regulated protein kinases and it has been shown to be directly phosphorylated by protein kinase C (PKC). Nobiletin, a bioactive polymethoxylated flavone, has been described to possess a diversity of biological effects through its antioxidant and anti-inflammatory properties.
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