Quercetin and ethanol attenuate the progression of atherosclerotic plaques with concomitant up regulation of paraoxonase1 (PON1) gene expression and PON1 activity in LDLR-/- mice.

BACKGROUND: As moderate wine drinking is atheroprotective, it is clinically relevant to elucidate its possible mechanism/s of action/s. Our objective is to demonstrate the potential benefits of the wine components, quercetin and ethanol, on the development of aortic plaques with parallel changes in antiatherogenic factors. METHODS AND RESULTS: The effects of quercetin and ethanol on the development of aortic atherosclerotic lesions, liver PON1 gene expression, and serum PON1 activity were measured in LDLR(-/-) mice on an atherogenic diet for 4 and 8 weeks. Depending on the duration and dosage of these modulators, 12.5 to 25 mg/dl quercetin (12.5Q to 25Q) and 18 to 25% ethanol, the magnitude of decreases in aortic lesions caused by moderate ethanol and quercetin ranged from 20 to 70% (p < 0.05 to p < 0.001) based on ultrasound biomicroscopy (UBM) analyses, and from 18 to 61% (p < 0.05 to p < 0.001) based on morphometric analyses. The composite plot of all the UBM and morphometric data showed significant correlation between these 2 methods (p = 0.0001, Pearson r = 0.79 for 4-week treatment; p = 0.000004, Pearson r = 0.84 for 8-week treatment). Concomitantly, 4-week treatments with 12.5Q and 18% ethanol up regulated liver PON1 mRNA by 41% (p < 0.05) and 37% (p < 0.05), respectively, accompanied by 92% (p < 0.001) and 61% (p < 0.001) increases in serum PON1 activity, respectively. The corresponding values after 8-week treatment with 12.5Q and 18% ethanol were 23% (p < 0.05) and 40% (p < 0.02) with respect to the up regulation of liver PON1 mRNA expression, while the stimulations of serum PON1 activity were 75% (p < 0.001) and 90% (p < 0.001), respectively. CONCLUSIONS: Based on these findings, we conclude that quercetin and moderate ethanol significantly inhibit the progression of atherosclerosis by up regulating the hepatic expression of the antiatherogenic gene, PON1, with concomitant increased serum PON1 activity.

Quercetin up-regulates paraoxonase 1 gene expression with concomitant protection against LDL oxidation.

Paraoxonase 1 (PON1) protects the oxidative modification of low-density lipoprotein (LDL) and is a major anti-atherosclerotic protein component of high-density lipoprotein (HDL). Quercetin, a ubiquitous plant flavonoid, has been shown to have a number of bioactivities and may offer a variety of potential therapeutic uses. We explored the roles of quercetin in the regulation of PON1 expression, serum and liver activity and protective capacity of HDL against LDL oxidation in rats. Compared to the pair-fed control group, feeding quercetin (10 mg/L) in the liquid diet for 4 weeks increased (a) hepatic expression of PON1 by 35% (p<0.01), (b) serum and liver PON1 activities by 29% (p<0.05) and 57% (p<0.01), respectively, and (c) serum homocysteine thiolactonase (HCTL) activity by 23% (p<0.05). Correspondingly, the lag time of low-density lipoprotein (LDL) oxidation was increased by >3-fold (p<0.001) with plasma HDL from quercetin-fed group compared to the HDL from control group. Our data suggest that quercetin has antiatherogenic effect by up regulating PON1 gene expression and its protective capacity against LDL oxidation.

Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications.

Two members of the family of low-density lipoprotein receptors (i.e., very low-density lipoprotein [VLDL] receptor and apolipoprotein E [apoE] type 2 receptor) are expressed in brain, where they bind and transduce reelin, a secreted glycoprotein that shares structural analogies with extracellular matrix proteins. In the developing fetal brain, reelin-signal transduction is critical for the correct positioning of neurons and the formation of appropriate synaptic connections, whereas in the mature brain, reelin participates in the mediation of experience-dependent synaptic plasticity. An important "downstream" consequence of the reelin-signal transduction cascade is inhibition of the phosphorylation of tau, a protein that regulates microtubule assembly and stability. Importantly, hyperphosphorylated tau comprises the paired helical filament, whose pathological deposition as neurofibrillary tangles is implicated in Alzheimer's disease; hyperphosphorylated tau is also implicated in the pathogenesis of other neurodegenerative disorders. Isoforms of apoE may affect the binding of reelin to its cell surface receptors and, thereby, influence tau phosphorylation, whereas insulin, insulin-like growth factor-1, and the lithium ion have actions within the cell at the level of the specific tyrosine kinases involved in the phosphorylation of tau. These data support the exploration of pharmacotherapeutic interventions designed to prevent or reduce the burden of hyperphosphorylated tau. Impaired reelin-signal transduction due to an actual deficiency of reelin expression may occur in at least some patients with psychotic disorders, especially schizophrenia; conceivably, hyperphosphorylation of tau would result from deficient transduction of reelin in schizophrenia. Schizophrenia has been conceptualized as a neurodevelopmental disorder of impaired synaptic "connectivity", whose consequence does not become fully apparent until late adolescence or early adulthood. In summary, hyperphosphorylation of tau may be an underlying point of pathological convergence for several neuropsychiatric disorders, and prevention of tau hyperphosphorylation may be an important therapeutic target.