Beneficial action of resveratrol: How and why (BNDF, etc.)– Feb 2016

Nutrition. 2016 Feb;32(2):174-8. doi: 10.1016/j.nut.2015.08.017
Diaz-Gerevini GT1, Repossi G2, Dain A1, Tarres MC3, Das UN4, Eynard AR5.

 Download the PDF from Sci-Hub via VitaminDWiki

Flavonoid resveratrol modulates the transcription factor NF-κB; inhibits the cytochrome P450 isoenzyme CYP1 A1; suppresses the expression and activity of cyclooxygenase enzymes; and modulates Fas/Fas-ligand-mediated apoptosis, p53, mammalian target of rapamycin, and cyclins and various phosphodiesterases. This increases the cytosolic cAMP that activates Epac1/CaMKKβ/AMPK/SIRT1/PGC-1α pathway, which in turn facilitates increased oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-α, interluekin-17 (IL-17), and other proinflammatory molecules, and thus is of benefit in autoimmune diseases.

In addition, resveratrol inhibits expression of hypoxia-inducible factor-1α and vascular endothelial growth factor, explaining its effective action against cancer.

Brain-derived neurotrophic factor (BDNF) that is involved in the pathogenesis of

• obesity,
• type 2 diabetes mellitus, and
• metabolic syndrome is also altered in
• depression,
• schizophrenia,
• bipolar disorder, and
• autism.

We noted that BDNF protects against cytotoxic actions of alloxan, streptozotocin, and benzo(a)pyrene. Resveratrol prevents bisphenol A-induced autism, type 2 diabetes mellitus, and metabolic syndrome, suggesting that it may augment BDNF synthesis and action. We also observed that BDNF levels are low in type 2 diabetes mellitus and that BDNF enhances production of antiinflammatory lipid, lipoxin A4, whose levels are low in diabetes mellitus. Thus, resveratrol may augment production of lipoxin A4. Resveratrol alters gut microbiota and influences stem cell proliferation and differentiation. These pleiotropic actions of resveratrol may explain the multitude of its actions and benefits.

Highlights

• We review the action of resveratrol on multiple enzymes, transcription factors and metabolic pathways.
• Resveratrol effects include facilitation of increased oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis.
• Resveratrol inhibits expressions of HIF-1α and VEGF explaining its effective action against cancer.
• Resveratrol triggers apoptosis of activated T cells and suppresses pro-inflammatory molecules and thus, is of benefit in autoimmune diseases.
• Resveratrol alters gut microbiota and influences stem cell proliferation and differentiation.

Conclusions – from PDF

Despite many beneficial actions of resveratrol, one major concern is its poor solubility and absorption when given orally. Poor bioavailability of resveratrol is attributed to its extensive hepatic gluconuridation and sulfation. A recent study (56) revealed that in ApcMin mice (a model of colorectal carcinogenesis) that received a high-fat diet, the low resveratrol dose suppressed intestinal adenoma development more potently than did the higher dose. It was noted that the efficacy of resveratrol correlated with activation of AMPK and increased expression of the senescence marker p21. The nonlinear dose responses observed for AMPK and mechanistic target of rapamycin (mTOR) signaling in mouse adenoma cells correlated with the autophagy and senescence observed.

Surprisingly, the effectiveness of low dose of resveratrol in protecting against colon cancer both in the mouse colon cancer cells and human colorectal tissues was found to be due to enhanced AMPK phosphorylation and autophagy and expression of the cytoprotective NAD(P)H dehydrogenase.

These observations suggest that sometimes lower dose of diet-derived agents are more effective than higher doses to prevent cancer. These results emphasize the need to perform a dose response studies and develop better methods to deliver diet-derived chemopreventive molecules such as resveratrol reach the target tissues by using modern technologies such as microencapsulation or nanoparticles (57, 58) to derive their beneficial actions.