Piceatannol

Piceatannol is a selective inhibitor of protein tyrosine kinase Syk. It could inhibit ICa,L, Ito, IKr, Ca2+ transients and Na+-Ca2+ exchange except IK1. Shows multiple biological activities such as anti-inflammatory, antiproliferative and immunomodulatory effects. In vitro: The treatment of human myeloid cells with piceatannol suppressed TNF-induced DNA binding activity of NF-κB. The effect of piceatannol was not restricted to myeloid cells, as TNF-induced NF-κB activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-κB activated by H2O2, PMA, LPS, okadaic acid, and ceramide. [1]

References:
[1]. Kazuhiro Ashikawa et al. Piceatannol Inhibits TNF-Induced NF-κB Activation and NF-κB-Mediated Gene Expression Through Suppression of IκBα Kinase and p65 Phosphorylation. J Immunol, 2002 Dec 1, 169(11):6490-7. [2]. Wen-Pin Chen et al. Piceatannol, a derivative of resveratrol, moderately slows INa inactivation and exerts antiarrhythmic action in ischaemia-reperfused rat hearts. Br J Pharmacol.2009 Jun, 157(3), 381-391.

Toxic effects of aflatoxin B1 on embryonic development of zebrafish (Danio rerio): potential activity of piceatannol encapsulated chitosan/poly (lactic acid) nanoparticles.[Pubmed:25322988]

Anticancer Agents Med Chem. 2015;15(2):248-57.

The aim was to analyse the efficacy of Piceatannol (PIC) loaded chitosan (CS)/poly(lactic acid)(PLA) nanoparticles (CS/PLA-PIC NPs) in zebra fish embryos exposed to aflatoxin B1 (AFB1). FTIR confirmed the chemical interaction between the polymers and drug. SEM showed the size of CS/PLA-PIC NPs approximately 87 to 200nm, compared to CS-PLA NPs of 150nm size. The size was further affirmed as 127nm (CS-PLA NPs) and 147nm (CS/PLA-PIC NPs) by zetasizer depiction. CS/PLA-PIC NPs have not illustrated toxicity at high concentrations when tested in zebrafish embryos. AFB1 wielded their toxic effects on the survival, spontaneous movement, hatching and heart rate and development of embryos were observed in both time and dose-dependent manner at 4muM. Our results suggested that the addition of CS/PLA-PIC NPs increases the survival, heart rate and hatching in time dependent manner at the dosage of 20mug/ml. These hopeful results may prompt the advancement of drug encapsulated polymeric nanoparticles which may have the potential role in improving the AFB1 induced toxicity in humans as well.

A review of the pharmacological effects of piceatannol on cardiovascular diseases.[Pubmed:24919577]

Phytother Res. 2014 Nov;28(11):1581-8.

The incidence of cardiovascular diseases (CVDs) is high in both developed and developing countries. It has a high global rate of mortality and causes heavy social burden. Drugs are available for managing or treating CVDs and its complications. Consumption of dietary supplements or functional foods for reducing the risk of CVDs has also gained wide recognition by the general public. Piceatannol, an analog and metabolite of resveratrol, is a natural stilbene commonly found in the skin of grapes and wine. Piceatannol is believed to be a potent compound with certain cardiovascular therapeutic effects, such as the prevention of hypercholesterolemia, arrhythmia, atherosclerosis, and angiogenesis. It also has vasorelaxation and antioxidant activities. A comprehensive review of Piceatannol concludes that Piceatannol has the potential to be developed into health products for the cardiovascular system to help modern society reduce the high CVD incidence. However, further investigations are warranted in order to increase the bioavailability and understand the biological mechanisms and safety of using Piceatannol.

Piceatannol inhibits effector T cell functions by suppressing TcR signaling.[Pubmed:25676533]

Int Immunopharmacol. 2015 Apr;25(2):285-92.

Piceatannol, a metabolite of resveratrol found in red wine and grapes, displays a wide spectrum of biological activity. Although the anti-oxidant, anti-inflammatory, and anti-tumorigenesis activity of Piceatannol has been extensively studied, its role in the adaptive immune response has received less attention. Here we investigated the role of Piceatannol, a well-known Syk inhibitor, in T cell activation, proliferation, and differentiation using isolated murine splenic T cells from C57BL/6 mice. Piceatannol treatment inhibited surface expression of CD4 and CD8 T cell activation markers CD25 and CD69, reduced production of cytokines IFNgamma, IL-2, and IL-17, and suppressed proliferation of activated T cells. Moreover, Piceatannol treatment significantly inhibited differentiation of CD4(+)CD25(-)CD62L(+) naive CD4 T cells into Th1, Th2, and Th17 cells, presumably due to inhibition of TcR signaling through p-Erk, p-Akt, and p-p38. Piceatannol appears to be a useful nutritional or pharmacological biomolecule that regulates effector T cell functions such as cytokine production, differentiation, and proliferation.

Piceatannol inhibits TNF-induced NF-kappaB activation and NF-kappaB-mediated gene expression through suppression of IkappaBalpha kinase and p65 phosphorylation.[Pubmed:12444159]

J Immunol. 2002 Dec 1;169(11):6490-7.

Piceatannol is an anti-inflammatory, immunomodulatory, and anti-proliferative stilbene that has been shown to interfere with the cytokine signaling pathway. Previously, we have shown that resveratrol suppresses the activation of the nuclear transcription factor NF-kappaB. Piceatannol, previously reported as a selective inhibitor of protein tyrosine kinase Syk, is structurally homologous to resveratrol. Whether Piceatannol can also suppress NF-kappaB activation was investigated. The treatment of human myeloid cells with Piceatannol suppressed TNF-induced DNA binding activity of NF-kappaB. In contrast, stilbene or rhaponticin (another analog of Piceatannol) had no effect, suggesting the critical role of hydroxyl groups. The effect of Piceatannol was not restricted to myeloid cells, as TNF-induced NF-kappaB activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-kappaB activated by H(2)O(2), PMA, LPS, okadaic acid, and ceramide. Piceatannol abrogated the expression of TNF-induced NF-kappaB-dependent reporter gene and of matrix metalloprotease-9, cyclooxygenase-2, and cyclin D1. When examined for the mechanism, we found that Piceatannol inhibited TNF-induced IkappaBalpha phosphorylation, p65 phosphorylation, p65 nuclear translocation, and IkappaBalpha kinase activation, but had no significant effect on IkappaBalpha degradation. Piceatannol inhibited NF-kappaB in cells with deleted Syk, indicating the lack of involvement of this kinase. Overall, our results clearly demonstrate that hydroxyl groups of stilbenes are critical and that Piceatannol, a tetrahydroxystilbene, suppresses NF-kappaB activation induced by various inflammatory agents through inhibition of IkappaBalpha kinase and p65 phosphorylation.

The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1.[Pubmed:11875742]

Br J Cancer. 2002 Mar 4;86(5):774-8.

Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukaemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from resveratrol by having an additional aromatic hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumours and catalyses aromatic hydroxylation reactions. We report here that the cancer preventative agent resveratrol undergoes metabolism by the cytochrome P450 enzyme CYP1B1 to give a metabolite which has been identified as the known antileukaemic agent Piceatannol. The metabolite was identified by high performance liquid chromatography analysis using fluorescence detection and the identity of the metabolite was further confirmed by derivatisation followed by gas chromatography-mass spectrometry studies using authentic Piceatannol for comparison. This observation provides a novel explanation for the cancer preventative properties of resveratrol. It demonstrates that a natural dietary cancer preventative agent can be converted to a compound with known anticancer activity by an enzyme that is found in human tumours. Importantly this result gives insight into the functional role of CYP1B1 and provides evidence for the concept that CYP1B1 in tumours may be functioning as a growth suppressor enzyme.

Inhibition of mast cell Fc epsilon R1-mediated signaling and effector function by the Syk-selective inhibitor, piceatannol.[Pubmed:7961959]

J Biol Chem. 1994 Nov 25;269(47):29697-703.

In RBL-2H3 rat tumor mast cells, antigens that cross-link the high affinity cell surface IgE receptor, Fc epsilon R1, activate at least two receptor-associated protein-tyrosine kinases, Lyn and Syk, and cause the tyrosine phosphorylation of the receptor beta and gamma subunits, PLC gamma 1, Vav, and other proteins. Cross-linking antigens also induce increased phosphatidylinositol turnover, Ca2+ mobilization, secretion, actin polymerization, spreading, and membrane ruffling. We have used the protein-tyrosine kinase inhibitor, Piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene), to explore the coupling of specific kinases to cellular responses. Piceatannol preferentially inhibits the activity of Syk as compared with Lyn when added to in vitro assays with isolated enzymes. Treatment of RBL-2H3 cells with Piceatannol strongly inhibits the antigen-stimulated activation of Syk measured in anti-Syk and anti-phosphotyrosine immune complex kinase assays at concentrations that have no effect on receptor subunit phosphorylation and maintain or increase the activity of Lyn in anti-phosphotyrosine immune complex kinase assays. In cells metabolically labeled with [32P]orthophosphate, Piceatannol inhibits the antigen-stimulated tyrosine phosphorylation of Syk and most other proteins. However, receptor subunit phosphorylation is unchanged. Selective inhibition of Syk in this manner blocks receptor-mediated down-stream cellular responses (inositol 1,4,5-trisphosphate production, secretion, ruffling, and spreading) while having only minor effects when these responses are induced with drugs that bypass the receptor complex. These results reveal receptor-mediated Lyn activation as a relatively Piceatannol-insensitive event that may contribute to receptor subunit phosphorylation and Syk activation but does not per se elicit cellular responses. Receptor-mediated Syk activation on the other hand is highly sensitive to Piceatannol, is essential to Fc epsilon R1-mediated cellular responses, and, based on the increased phosphorylation of Lyn in Piceatannol-treated cells, may be involved in terminating Lyn activity.

Piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene) is a naturally occurring protein-tyrosine kinase inhibitor.[Pubmed:2590224]

Biochem Biophys Res Commun. 1989 Nov 30;165(1):241-5.

Piceatannol (3,4,3'5'-tetrahydroxy-trans-stilbene), a plant secondary natural product that had previously been identified as an antileukemic principle, has been shown to be an inhibitor of protein-tyrosine kinase activity. Piceatannol inhibits the purified thymocyte protein-tyrosine kinase, p40, by competing for the peptide or protein substrate binding site (Ki = 15 microM). Piceatannol also inhibits the activity of the p56lck protein-tyrosine kinase measured either in LSTRA cell membranes or in intact cells. In contrast, Piceatannol does not inhibit the activity of the cAMP-dependent protein kinase.