Resveratrol and pinostilbene confer neuroprotection against aging-related deficits through an ERK1/2-dependent mechanism

Age-related declines in motor function may be due, in part, to an increase in oxidative stress in the aging brain leading to dopamine (DA) neuronal cell death. In this study, we examined the neuroprotective effects of natural antioxidants resveratrol and pinostilbene against age-related DAergic cell death and motor dysfunction using SH-SY5Y neuroblastoma cells and young, middle-aged, and old male C57BL/6 mice. Resveratrol and pinostilbene protected SH-SY5Y cells from a DA-induced decrease in cell viability. Dietary supplementation with resveratrol and pinostilbene inhibited the decline of motor function observed with age. While DA and its metabolites (DOPAC and HVA), dopamine transporter, and tyrosine hydroxylase levels remain unchanged during aging or treatment, resveratrol and pinostilbene increased ERK1/2 activation in vitro and in vivo in an age-dependent manner. Inhibition of ERK1/2 in SH-SY5Y cells decreased the protective effects of both compounds. These data suggest that resveratrol and pinostilbene alleviate age-related motor decline via the promotion of DA neuronal survival and activation of the ERK1/2 pathways

Pterostilbene Acts through Metastasis-Associated Protein 1 to Inhibit Tumor Growth, Progression and Metastasis in Prostate Cancer

<div><p>The development of natural product agents with targeted strategies holds promise for enhanced anticancer therapy with reduced drug-associated side effects. Resveratrol found in red wine, has anticancer activity in various tumor types. We reported earlier on a new molecular target of resveratrol, the metastasis-associated protein 1 (MTA1), which is a part of nucleosome remodeling and deacetylation (NuRD) co-repressor complex that mediates gene silencing. We identified resveratrol as a regulator of MTA1/NuRD complex and re-activator of p53 acetylation in prostate cancer (PCa). In the current study, we addressed whether resveratrol analogues also possess the ability to inhibit MTA1 and to reverse p53 deacetylation. We demonstrated that pterostilbene (PTER), found in blueberries, had greater increase in MTA1-mediated p53 acetylation, confirming superior potency over resveratrol as dietary epigenetic agent. In orthotopic PCa xenografts, resveratrol and PTER significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis. Furthermore, MTA1-knockdown sensitized cells to these agents resulting in additional reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling showing increased p53 acetylation, higher apoptotic index and less angiogenesis <i>in vivo</i> in all xenografts treated with the compounds, and particularly with PTER. Altogether, our results indicate MTA1 as a major contributor in prostate tumor malignant progression, and support the use of strategies targeting MTA1. Our strong pre-clinical data indicate PTER as a potent, selective and pharmacologically safe natural product that may be tested in advanced PCa.</p> </div

Design, synthesis, and docking studies of novel benzimidazoles for the treatment of metabolic syndrome

In addition to lowering blood pressure, telmisartan, an angiotensin (AT(1)) receptor blocker, has recently been shown to exert pleiotropic effects as a partial agonist of nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma). On the basis of these findings and docking pose similarity between telmisartan and rosiglitazone in PPAR gamma active site, two classes of benzimidazole derivatives were designed and synthesized as dual PPAR gamma agonist/angiotensin II antagonists for the possible treatment of metabolic syndrome. Compound 4, a bisbenzimidazole derivative showed the best affinity for the AT(1) receptor with a K(i) = 13.4 nM, but it was devoid of PPAR gamma activity. On the other hand 9, a monobenzimidazole derivative, showed the highest activity in PPAR gamma transactivation assay (69% activation) with no affinity for the AT(1) receptor. Docking studies lead to the designing of a molecule with dual activity, 10, with moderate PPARgamma activity (29%) and affinity for the AT(1) receptor (K(i) = 2.5 microM)

Effects of resveratrol and pterostilbene on spontaneous metastasis: involvement of MTA1.

<p>A. BL images of metastasis are shown. Signals detected after prostate removal consisted of metastatic and non-specific signals. Removal of skin and muscles eliminated non-specificity. B. <i>Top, ex vivo</i> images of metastatic organs. <i>Bottom,</i> Validation of metastatic lesions (T) in kidneys (K), liver (Li) and lung/heart (L/H) by H&E staining. C, quantitative analysis of total metastatic Luc signals in Total Flux (photons/sec/cm2/sr). Open circles represent outliers. *p<0.05; **p<0.01; ***p<0.001 are pairwise comparisons vs. EV-Ctrl. D, quantitative analysis of organ-specific metastasis calculated by luciferase signals as Total Flux (photons/sec/cm²/sr). Color-coded histograms of signals for each group are shown. PTER was more effective in inhibiting metastasis in all organs compared to Res in EV-group. In MTA1-knockdown group, Res exhibited more effects by eliminating kidney metastasis.</p

Chemical structures of stilbenes.

<p>Resveratrol (Res), <i>trans</i>-3,5,4′-trihydroxystilbene; Pterostilbene (PTER), <i>trans</i>-3,5-dimethoxystilbene; Trimethoxy-Resveratrol (3M-Res), <i>trans</i>-3,5,4′-trimethoxystilbene; Piceatannol (PIC), <i>trans</i>-3,5,3′4′-tetrahydroxystilbene; Dimethoxystyrylaniline (DMSA), <i>trans</i>-4-(3,5-dimethoxystyryl)aniline; Diacetyl-Resveratrol (2Ac-Res), <i>trans</i>-3,5-diacetylstilbene; Triacetyl-Resveratrol (3Ac-Res), <i>trans</i>-3,5,4′-triacetylstilbene.</p

MTA1-mediated therapeutic activity of resveratrol and pterostilbene in orthotopic PCa xenografts.

<p>Male nude mice were injected orthotopically with Du145-EV-Luc (EV) or Du145-MTA1shRNA-Luc (MTA1shRNA) cells and treated with vehicle (Ctrl), Res or PTER, 50 mg/kg/day, every day, i.p. A. Normalized representative BL images of mice from each group are shown. B, <i>left</i>, Quantitative analysis of tumor light emission in Total Flux (photons/sec/cm2/sr) is plotted against time. The means ± SE are shown (n = 6 at the start), *p = 0.05. <i>Right</i>, log trends for each group are shown. Significant growth inhibition was detected in EV- vs. MTA1shRNA-tumors as groups, **p<0.01 and between EV-Ctrl vs. MTA1shRNA-Res and MTA1shRNA-PTER, ***p<0.001.</p

Pterostilbene increases MTA1-mediated p53 acetylation in Du145 cells.

<p>Du145-EV and Du145-MTA1shRNA cells (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057542#pone.0057542.s001" target="_blank">Fig. S1</a>) were treated with 50 µM of Res or PTER for 24 hr and analyzed for MTA1, p53, Ac-p53 by Western blot as described in “<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057542#s2" target="_blank">Materials and methods</a>”. A representative blot is shown. Quantitation of Ac-p53/p53 ratio was conducted by Image J software and data shown as mean±SEM from three independent experiments.</p