06 May 2014 In Phenolic compounds

Misfolded proteins associated with diverse aggregation disorders assemble not only into a single toxic conformer, but rather a suite of aggregated conformers with unique biochemical properties and toxicities. To what extent small molecules can target and neutralize specific aggregated conformers is poorly understood. Therefore, we have investigated the capacity of resveratrol to recognize and remodel five conformers (monomers, soluble oligomers, non-toxic oligomers, fibrillar intermediates and amyloid fibrils) of the Abeta1-42 peptide associated with Alzheimer's disease. We find that resveratrol selectively remodels three of these conformers - soluble oligomers, fibrillar intermediates and amyloid fibrils - into an alternative aggregated species that is non-toxic, high molecular weight and unstructured. Surprisingly, resveratrol does not remodel non-toxic oligomers or accelerate Abeta monomer aggregation, despite that both conformers possess random coil secondary structures indistinguishable from soluble oligomers and significantly different from their beta-sheet rich, fibrillar counterparts. We expect that resveratrol and other small molecules with similar conformational specificity will aid in illuminating the conformational epitopes responsible for Abeta-mediated toxicity.

06 May 2014 In Phenolic compounds

Resveratrol, which may occur in wine, was suggested to act as a chemopreventive agent against the carcinogenic effects of ethanol. The assumption was based on data from experimental animals, which have shown that resveratrol above certain thresholds may reduce the incidence of tumours in several of the alcohol-related cancer sites (colon, liver and female breast). Using a probabilistic Monte Carlo type methodology, we estimated daily intake based on chemical analysis of resveratrol (n = 672) and ethanol (n = 867). Benchmark dose (BMD)-response modelling was conducted for resveratrol based on eight animal experiments, whereas BMD data for ethanol were taken from the literature. The margin of exposure (MOE) was calculated for both substances as an indicator if the intake may reach effective dosages. For intake of one 100-mL glass of wine, the average MOE was found to be 4.1 for ethanol and 459,937 for resveratrol. In the best-case scenario for resveratrol (e.g., very high contents and assuming a low effective dosage), the minimum MOE would be 111, which means that 111 glasses of wine need to be consumed daily to reach the BMD. The MOE ratio between resveratrol and ethanol is 166,128 on average, meaning that per glass of wine, ethanol is more than 100,000 times more potent than resveratrol. As resveratrol intake may not optimally reach the effective dosage, our study excludes a preventive effect of this substance on alcohol-related cancer. Commercial information about cancer-preventive or -protective effects of resveratrol in wine is misleading and must be prohibited.

06 May 2014 In Phenolic compounds

Abnormal angiogenesis is central to the pathophysiology of diverse disease processes including cancers, ischemic and atherosclerotic heart disease, and visually debilitating eye disease. Resveratrol is a naturally occurring phytoalexin that has been demonstrated to ameliorate and decelerate the aging process as well as blunt end organ damage from obesity. These effects of resveratrol are largely mediated by members of the sirtuin family of proteins. We demonstrate that resveratrol can inhibit pathological angiogenesis in vivo and in vitro by a sirtuin-independent pathway. Resveratrol inhibits the proliferation and migration of vascular endothelial cells by activating eukaryotic elongation factor-2 kinase. The active kinase in turn phosphorylates and inactivates elongation factor-2, a key mediator of ribosomal transfer and protein translation. Functional inhibition of the kinase by gene deletion in vivo or RNA as well as pharmacological inhibition in vitro is able to completely reverse the effects of resveratrol on blood vessel growth. These studies have identified a novel and critical pathway that promotes aberrant vascular proliferation and one that is amenable to modulation by pharmacological means. In addition, these results have uncovered a sirtuin-independent pathway by which resveratrol regulates angiogenesis.

06 May 2014 In Phenolic compounds

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.

Page 7 of 18

Contact us

We love your feedback. Get in touch with us.

  • Tel: +32 (0)2 230 99 70
  • Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Disclaimer

The authors have taken reasonable care in ensuring the accuracy of the information herein at the time of publication and are not responsible for any errors or omissions. Read more on our disclaimer and Privacy Policy.