Citrus Flavonoids Luteolin, Apigenin, and Quercetin Inhibit Glycogen Synthase Kinase-3β Enzymatic Activity by Lowering the Interaction Energy Within the Binding Cavity

Abstract

Pancreatic cancer studies have shown that inhibition of glycogen synthase kinase-3β (GSK-3β) leads to decreased cancer cell proliferation and survival by abrogating nuclear factor κB (NFκB) activity. In this investigation, various citrus compounds, including flavonoids, phenolic acids, and limonoids, were individually investigated for their inhibitory effects on GSK-3β by using a luminescence assay. Of the 22 citrus compounds tested, the flavonoids luteolin, apigenin, and quercetin had the highest inhibitory effects on GSK-3β, with 50% inhibitory values of 1.5, 1.9, and 2.0 μM, respectively. Molecular dockings were then performed to determine the potential interactions of each citrus flavonoid with GSK-3β. Luteolin, apigenin, and quercetin were predicted to fit within the binding pocket of GSK-3β with low interaction energies (-76.4, -76.1, and -84.6 kcal·mol(-1), respectively) and low complex energies (-718.1, -688.1, and -719.7 kcal·mol(-1), respectively). Our results indicate that several citrus flavonoids inhibit GSK-3β activity and suggest that these have potential to suppress the growth of pancreatic tumors.

Dose- and Time-Dependent Neuroprotective Effects of Pycnogenol® following Traumatic Brain Injury

“…[51][52][53][54][55][56] The interaction of the bioflavonoids with these cascades can inhibit apoptotic processes and improve cell survival. [57][58][59][60][61][62] In conclusion, this study demonstrates the substantial neuroprotective effects of PYC following moderate to severe TBI in rats by reducing oxidative stress and sparing synaptic proteins. The results show a relatively long therapeutic window (up to 4 h) for PYC treatment following neurotrauma, with the same protective effects in both the cortex and the hippocampus.…”

Molecular docking of citrus flavonoids with some targets related to diabetes

“…GSK-3β inactivates GS by phosphorylation resulting in glycogen synthesis inhibition (Khanfar et al, 2010;Wauwe, 2003). It has been reported that some flavonoids, such as luteolin, rutin, narirutin, etc., could bind with B-ring hydroxyls stabilized by hydrogen bonding with Arg 141 and Tyr 134 in the hinge; A-ring hydroxyls stabilized by hydrogen bonding with Asn 64, Gly 65, Lys 85, and Asp 200 residues in the glycine-rich loop (Johnson et al, 2011). Our results indicated that four citrus flavonoids could form H-bonds or via other interactions with the above amino acid residues.…”

“…It is one of the important targets in the treatment of T2D. Inhibitors of GSK-3β have antidiabetic properties because they improve insulin sensitivity, glycogen synthesis, and glucose metabolism in skeletal muscles of diabetic patients (Akhtar and Bharatam, 2012;Johnson et al, 2011;Khanfar et al, 2010;Wauwe, 2003).…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…It should be noted that memantine, an uncompetitive N-methyl-d-aspartate (NMDA) antagonist, protected against axon neurodegeneration and glutamate-induced excitotoxicity caused by Aβ peptide (213) and ameliorated symptoms in human AD (214). Another interesting feature of quercetin is its capacity to inhibit tau hyperphosphorylation, through SIRT1 (215,216) or alternate pathways (217,218), that occurs primarily in vulnerable brain regions in AD and other tauopathies (89,219,220). Quercetin also displays antiamyloidogenic properties, illustrated by its ability to reduce BACE1 and Aβ levels in mice (217), prevent Aβ aggregation (221,222), promote autophagy (221,223) and bind to BACE1 catalytic core as an inhibitor (224).…”