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Lipids. 2019 Dec 22. doi: 10.1002/lipd.12208. [Epub ahead of print]

Inhibition of Calcineurin and Glycogen Synthase Kinase-3β by Ricinoleic Acid Derived from Castor Oil.

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Center for Liberal Arts and Sciences, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, 028-3694, Japan.
Graduate School of Agriculture, Iwate University, Morioka, 020-8550, Japan.
Faculty of Agriculture, Iwate University, Morioka, 020-8550, Japan.
The United Graduate School of Agricultural Sciences, Iwate University, Morioka, 020-8550, Japan.
Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Nara, 630-0192, Japan.


Ricinoleic acid (RA) is the main fatty acid component of castor oil and was found to inhibit Ca2+ -signal transduction pathway-mediated cell cycle regulation in a yeast-based drug screening assay. RA is expected to have antidiabetic, antiallergy, and/or anticancer properties but its target molecule is unknown. To identify a novel pharmacological effect of RA, we investigated its target molecule in the Ca2+ -signal transduction pathway. RA inhibition of calcineurin (CN) was examined in a yeast-based CN inhibitor screening assay using the rsp5A401E mutant and in a phosphatase assay using recombinant human CN. RA showed growth-restoration activity at 5 μg/spot in the CN inhibitor screening assay with the rsp5A401E yeast strain. Furthermore, it directly inhibited CN without immunophilins at Ki = 33.7 μM in a substrate-competitive manner. The effects of RA on CN in mammalian cells were further evaluated by measuring β-hexosaminidase (β-HEX) release in RBL-2H3 cells. RA at 50 μM suppressed the release of β-HEX from RBL-2H3 cells. Moreover, this compound was found to inhibit glycogen synthase kinase-3β (GSK-3β), as determined by a kinase assay using recombinant human GSK-3β. RA inhibited GSK-3β at Ki = 1.43 μM in a peptide substrate-competitive manner. The inhibition of GSK-3β by this molecule was further assessed in mammalian cells by measuring the inhibition of glucose production in H4IIE rat hepatoma cells. RA at 25 μM suppressed glucose production in these cells. These findings indicate that RA and/or castor oil could be a useful functional fatty acid to treat allergy or type 2 diabetes.


Ca2+-signal transduction; Calcineurin; GSK-3β; H4IIE cells; Ricinoleic acid; Saccharomyces cerevisiae


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