Antihyperglycemic Potential of Quercetin-3-glucoside Isolated from Leucaena leucocephala Seedpods via the SIRT1/AMPK/GLUT4 Signaling Cascade.

Leucaena leucocephala. (Lam.) de Wit, a traditional medicinal plant, has been reported among the ethnic communities of Mexico, Indonesia, China, and India for the treatment of diabetes, obesity, and related complications. This study investigates the antihyperglycemic activity of the plant and its isolated active compound quercetin-3-glucoside. Further, bioactivity guided marker assisted development of an enriched bioactive fraction toward enhancing insulin sensitization was carried out. The enriched fraction was also found to contain 397.96 mg/g of quercetin-3-glucoside along with three other marker compounds, which were also isolated and identified. Quercetin-3-glucoside, out of the four isolated marker compounds from the plant, showed the most significant bioactivity when tested in palmitate-induced insulin-resistant C2C12 myotubes. The compound also showed significant upregulation of sirtuin1 (SIRT1) followed by enhancement of insulin-dependent signaling molecules SIRT1/AMPK/PGC1-α and GLUT4 translocation. Molecular dynamics studies showed the compound having stable interactions with the SIRT1 protein. SIRT1 upregulation has been associated with enhanced insulin sensitivity in skeletal muscle, increasing the glucose uptake by muscle cells. The prepared enriched fraction also modulated the SIRT1/AMPK/GLUT4 pathway. The findings of the present study may find future application toward the development of botanical or phytopharmaceutical drugs from the traditionally important plant L. leucocephala against type II diabetes.

Free radical scavenging polyphenols isolated from Phyllanthus niruri L. ameliorates hyperglycemia via SIRT1 induction and GLUT4 translocation in in vitro and in vivo models.

Type 2 diabetes milletus (T2DM) is a complex multifaceted disorder characterized by insulin resistance in skeletal muscle. Phyllanthus niruri L. is well reported sub-tropical therapeutically beneficial ayurvedic medicinal plant from Euphorbiaceae family used in various body ailments such as metabolic disorder including diabetes. The present study emphasizes on the therapeutic potential of Phyllanthus niruri L. and its phytochemical(s) against insulin resistance conditions and impaired antioxidant activity thereby aiding as an anti-hyperglycemic agent in targeting T2DM. Three compounds were isolated from the most active ethyl acetate fraction namely compound 1 as 1-O-galloyl-6-O-luteoyl-ß-D-glucoside, compound 2 as brevifolincarboxylic acid and compound 3 as ricinoleic acid. Compounds 1 and 2, the two polyphenols enhanced the uptake of glucose and inhibited ROS levels in palmitate induced C2C12 myotubes. PNEAF showed the potent enhancement of glucose uptake in palmitate-induced insulin resistance condition in C2C12 myotubes and significant ROS inhibition was observed in skeletal muscle cell line. PNEAF treated IR C2C12 myotubes and STZ induced Wistar rats elevated SIRT1, PGC1-α signaling cascade through phosphorylation of AMPK and GLUT4 translocation resulting in insulin sensitization. Our study revealed an insight into the efficacy of marker compounds isolated from P. niruri and its enriched ethyl acetate fraction as ROS scavenging agent and helps in attenuating insulin resistance condition in C2C12 myotubes as well as in STZ induced Wistar rat by restoring glucose metabolism. Overall, this study can provide prospects for the marker-assisted development of P. niruri as a phytopharmaceutical drug for the insulin resistance related diabetic complications.

Halogen bonding assisted site-selective C-3 triaryl methylation of indoles and N-triaryl methylation of imidazoles.

Halogen bonding triggered by the Lewis basic nature of acetonitrile catalyzes the site-selective C-3 triaryl methylation of indoles and N-triaryl methylation of imidazoles with trityl chlorides under catalyst-, metal-, and additive-free conditions at room temperature. This method generates a quaternary carbon centre appended to a heterocyclic moiety. UV-Vis and FT-IR analyses indicate the existence of halogen bonding which is the driving force of the reaction. This approach is suitable for a wide range of substrates, furnishing moderate to excellent yields (up to 100%) of triaryl methylated products under ambient reaction conditions. Equimolar amounts of reactants are sufficient to obtain the optimum yield and in some cases pure products can be obtained without column chromatography.

Xanthosine, a purine glycoside mediates hepatic glucose homeostasis through inhibition of gluconeogenesis and activation of glycogenesis via regulating the AMPK/ FoxO1/AKT/GSK3ß signaling cascade.

Type 2 Diabetes Mellitus (T2DM) is characterized by hepatic insulin resistance, which results in increased glucose production and reduced glycogen storage in the liver. There is no previous study in the literature that has explored the role of Xanthosine in hepatic insulin resistance. Moreover, mechanistic explanation for the beneficial effects of Xanthosine in lowering glucose production in diabetes is yet to be determined. This study for the first time investigated the beneficial effects of Tribulus terrestris (TT) and its active constituent, Xanthosine on gluconeogenesis and glycogenesis in Free Fatty Acid (FFA)-induced CC1 hepatocytes and streptozotocin (STZ)-induced Wistar rats. Xanthosine enhanced glucose uptake and decreased glucose production through phosphorylation of AMP-activated protein kinase (AMPK) and forkhead box transcription factor O1 (FoxO1), and downregulation of two rate limiting enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression in FFA-induced CC1 cells. Xanthosine also prevented FFA-induced decreases in the phosphorylation of AKT/Protein kinase B, glycogen synthase kinase-3ß (GSK3ß), and increased glycogen synthase (GS) phosphorylation to increase the glycogen content in the hepatocytes. Moreover, in STZ-induced diabetic rats, oral administration of TT n-butanol fraction (TTBF) enriched with compound Xanthosine (10, 50 & 100 mg/kg body weight) improved insulin sensitivity, reduced fasting blood glucose levels, improved glucose homeostasis by reducing gluconeogenesis via AMPK/FoxO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via AKT/GSK3ß-mediated GS activation. Overall, Xanthosine may be developed further for treating insulin resistance and hyperglycemia in T2DM.