title: Thymoquinone, a bioactive component of Nigella sativa, normalizes insulin secretion from pancreatic β-cells under glucose overload via regulation of malonyl-CoA.
abstract: Thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) is a major bioactive component of Nigella sativa, a plant used in traditional medicine to treat a variety of symptoms, including elevated blood glucose levels in type 2 diabetic patients. Normalization of elevated blood glucose depends on both glucose disposal by peripheral tissues and glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. We employed clonal β-cells and rodent islets to investigate the effects of thymoquinone (TQ) and Nigella sativa extracts (NSEs) on GSIS and cataplerotic metabolic pathways implicated in the regulation of GSIS. TQ and NSE regulated NAD(P)H/NAD(P)(+) ratios via a quinone-dependent redox cycling mechanism. TQ content was positively correlated with the degree of redox cycling activity of NSE extracts, suggesting that TQ is a major component engaged in mediating NSE-dependent redox cycling. Both acute and chronic exposure to TQ and NSE enhanced GSIS and were associated with the ability of TQ and NSE to increase the ATP/ADP ratio. Furthermore, TQ ameliorated the impairment of GSIS following chronic exposure of β-cells to glucose overload. This protective action was associated with the TQ-dependent normalization of chronic accumulation of malonyl-CoA, elevation of acetyl-CoA carboxylase (ACC), fatty acid synthase, and fatty acid-binding proteins following chronic glucose overload. Together, these data suggest that TQ modulates the β-cell redox circuitry and enhances the sensitivity of β-cell metabolic pathways to glucose and GSIS under normal conditions as well as under hyperglycemia. This action is associated with the ability of TQ to regulate carbohydrate-to-lipid flux via downregulation of ACC and malonyl-CoA.
authors.affiliation: Department of Science, United States Coast Guard Academy, New London, Connecticut;
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Gray
authors.affiliation: University of Puerto Rico at Cayey, Cayey, Puerto Rico;
authors.forename: Delaine Zayasbazan
authors.initials: DZ
authors.lastname: Burgos
authors.affiliation: Department of Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island;
authors.forename: Tao
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island;
authors.forename: Navindra
authors.initials: N
authors.lastname: Seeram
authors.affiliation: Department of Science, United States Coast Guard Academy, New London, Connecticut;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rebar
authors.affiliation: Department of Science, United States Coast Guard Academy, New London, Connecticut;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Follmer
authors.affiliation: Department of Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island; Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida; and Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, Massachusetts eheart@health.usf.edu.
authors.forename: Emma A
authors.initials: EA
authors.lastname: Heart
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D002460:Cell Line; D015536:Down-Regulation; D054890:Fatty Acid Synthase, Type I / Q000187:drug effects / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D051379:Mice; D031881:Nigella sativa / Q000737:chemistry*; D010084:Oxidation-Reduction / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats
chemical_list: D016227:Benzoquinones; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; D010936:Plant Extracts; D008316:Malonyl Coenzyme A; D006861:Hydrogen Peroxide; D054890:Fatty Acid Synthase, Type I; D000103:Acetyl-CoA Carboxylase; D005947:Glucose; C003466:thymoquinone
keywords: acetyl-CoA carboxylase; insulin secretion; malonyl-CoA; thymoquinone; β-cells