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  • Out With Aspirin, Ibuprofen & Acetaminophen; Exosomal Resveratrol Exerts Anti-Inflammatory Action Via Its Influence Over microRNAs

    July 29, 2017: by Bill Sardi

    Since inflammation is a component of virtually all diseases the molecular mechanisms leading to the anti-inflammatory effects of resveratrol deserve more attention, say researchers.

    Among the myriad biological actions of resveratrol, a chief property is its anti-inflammatory action. [Journal Medicinal Food April 2017]  While many of the mechanisms behind its anti-inflammatory action have been described, this does not mean that present explanations are totally inclusive.  In fact, it appears resveratrol works independently of the Sirtuin1 survival gene, which is not involved in its anti-inflammatory action.

    The Sirtuin1 gene is strongly activated by resveratrol and this gene is also identified as the chief gene that mimics many of the effects of a lifespan-doubling calorie restricted diet.  But while Sirtuin1 is widely heralded as a longevity gene, it was surprising to learn that a recently published study shows it plays no role in resveratrol’s anti-inflammatory action.

    While resveratrol is sometimes mistakenly claimed to exert strong antioxidant activity it is only a modest antioxidant.  So just how does resveratrol inhibit such strong anti-inflammatory properties independent of blocking oxygen and nitrogen free radicals?

    Researchers find that a protein known as KSRP binds with resveratrol to regulate inflammation.

    Resveratrol/KSRP markedly reduces the pro-inflammatory proteins known as interleukin-8 (IL-8), tumor necrosis factor (TNFa), and nitric oxide (iNOS).  This triple anti-inflammatory action is evidence of why resveratrol is widely heralded as a molecular cure-all.

    Resveratrol/KSRP douses the flames of inflammation by degrading microRNA that instigates inflammation.

    MicroRNA was once believed to play only a minor role in the genetic activity in the human body.  Now microRNAs are called “The Guiding Hand Of The Human Genome” (library of genes).  [Nature Dec 19, 2002]

    The anti-inflammatory effect of resveratrol-KSRP was demonstrated in both animal and human cells.

    A novel finding is that resveratrol provokes exosomes, tiny vesicles (sacs) emitted from cells that transport small molecules like microRNAs into connective tissue in between cells.

    Exosomes were once thought to be nothing more than cellular debris but now are appreciated for their ability to transmit signals between living cells.

    It is not surprising to learn that measurement of five microRNAs in blood samples is more predictive of mortal risk than the well-known Framingham Risk Score. [Scientific Reports July 3, 2017]  MicroRNA may, in this author’s opinion, replace the current cholesterol paradigm that reigns in the practice of medicine today.

    Resveratrol exerts control over all three mechanisms that control genes: (1) histone body wrapping around bundles of DNA with a process called methylation; (2) synthesis of gene proteins, called gene expression; and influence over microRNA.

    If drug maker Bayer had introduced resveratrol in 1899 instead of willow-bark inspired aspirin, the world would be in a far better place today.

    ©2017 Bill Sardi, ResveratrolNews.com

    Chart: Resveratrol Inhibits Inflammation


    Resveratrol post-transcriptionally regulates pro-inflammatory gene expression via regulation of KSRP RNA binding activity.

    Bollmann F1, Art J1, Henke J1, Schrick K1, Besche V2, Bros M2, Li H1, Siuda D1, Handler N3, Bauer F3, Erker T3, Behnke F4, Mönch B5, Härdle L6, Hoffmann M7, Chen CY8, Förstermann U1, Dirsch VM9, Werz O5, Kleinert H10, Pautz A11.

    Abstract

    Resveratrol shows beneficial effects in inflammation-based diseases like cancer, cardiovascular and chronic inflammatory diseases. Therefore, the molecular mechanisms of the anti-inflammatory resveratrol effects deserve more attention. In human epithelial DLD-1 and monocytic Mono Mac 6 cells resveratrol decreased the expression of iNOS, IL-8 and TNF-α by reducing mRNA stability without inhibition of the promoter activity. Shown by pharmacological and siRNA-mediated inhibition, the observed effects are SIRT1-independent. Target-fishing and drug responsive target stability experiments showed selective binding of resveratrol to the RNA-binding protein KSRP, a central post-transcriptional regulator of pro-inflammatory gene expression. Knockdown of KSRP expression prevented resveratrol-induced mRNA destabilization in human and murine cells. Resveratrol did not change KSRP expression, but immunoprecipitation experiments indicated that resveratrol reduces the p38 MAPK-related inhibitory KSRP threonine phosphorylation, without blocking p38 MAPK activation or activity. Mutation of the p38 MAPK target site in KSRP blocked the resveratrol effect on pro-inflammatory gene expression. In addition, resveratrol incubation enhanced KSRP-exosome interaction, which is important for mRNA degradation. Finally, resveratrol incubation enhanced its intra-cellular binding to the IL-8, iNOS and TNF-α mRNA. Therefore, modulation of KSRP mRNA binding activity and, thereby, enhancement of mRNA degradation seems to be the common denominator of many anti-inflammatory effects of resveratrol.

    © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

    PMID: 25352548 PMCID: PMC4227754 DOI: 10.1093/nar/gku1033

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