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Nicotinamide Augments the Anti-Inflammatory Properties of Resveratrol through PARP1 Activation.

ABSTRACT: Resveratrol (RSV) and nicotinamide (NAM) have garnered considerable attention due to their anti-inflammatory and anti-aging properties. NAM is a transient inhibitor of class III histone deacetylase SIRTs (silent mating type information regulation 2 homologs) and SIRT1 is an inhibitor of poly-ADP-ribose polymerase-1 (PARP1). The debate on the relationship between RSV and SIRT1 has precluded the use of RSV as a therapeutic drug. Recent work demonstrated that RSV facilitates tyrosyl-tRNA synthetase (TyrRS)-dependent activation of PARP1. Moreover, treatment with NAM is sufficient to facilitate the nuclear localization of TyrRS that activates PARP1. RSV and NAM have emerged as potent agonists of PARP1 through inhibition of SIRT1. In this study, we evaluated the effects of RSV and NAM on pro-inflammatory macrophages. Our results demonstrate that treatment with either RSV or NAM attenuates the expression of pro-inflammatory markers. Strikingly, the combination of RSV with NAM, exerts additive effects on PARP1 activation. Consistently, treatment with PARP1 inhibitor antagonized the anti-inflammatory effect of both RSV and NAM. For the first time, we report the ability of NAM to augment PARP1 activation, induced by RSV, and its associated anti-inflammatory effects mediated through the induction of BCL6 with the concomitant down regulation of COX-2.

SUBMITTER: Yanez M

PROVIDER: S-EPMC6629694 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Nicotinamide Augments the Anti-Inflammatory Properties of Resveratrol through PARP1 Activation.

Yanez Maria M Jhanji Megha M Murphy Kendall K Gower R Michael RM Sajish Mathew M Jabbarzadeh Ehsan E

Scientific reports 20190715 1

Resveratrol (RSV) and nicotinamide (NAM) have garnered considerable attention due to their anti-inflammatory and anti-aging properties. NAM is a transient inhibitor of class III histone deacetylase SIRTs (silent mating type information regulation 2 homologs) and SIRT1 is an inhibitor of poly-ADP-ribose polymerase-1 (PARP1). The debate on the relationship between RSV and SIRT1 has precluded the use of RSV as a therapeutic drug. Recent work demonstrated that RSV facilitates tyrosyl-tRNA synthetase ...[more]

PMID: 31308445

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Project description:Background:Resveratrol is a natural polyphenol found in berries, roots and wine that is well known to have anti-inflammatory and anti-oxidative properties. The anti-inflammatory effect has been reported for both immune cells and connective tissues, but only few studies have investigated effects on immune mediated inflammatory arthritis. None of which have studied this effect when combining resveratrol with methotrexate or adalimumab, two major drugs in the treatment of immune mediated inflammatory arthritis.We therefore aimed to investigate the anti-inflammatory effect of resveratrol alone and in combination with methotrexate or adalimumab in ex vivo models of immune mediated inflammatory arthritis. We furthermore aimed to describe any variations in this effect based on disease activity and cellular composition of the synovial fluid infiltrate. Methods:Synovial fluid mononuclear cells from patients with rheumatoid arthritis (n?=?7) and spondyloarthritis (n?=?7) were cultured for either 48 h or 21 days. In both models, synovial fluid mononuclear cells were treated with resveratrol alone or in combination with methotrexate or adalimumab. Monocyte chemoattractant protein 1, matrix metalloproteinase 3 and tartrate resistant acidic phosphatase were measured to quantify inflammation, enzymatic degradation and osteoclast differentiation, respectively. Results:Resveratrol reduced monocyte chemoattractant protein 1 production by synovial fluid mononuclear cells significantly (p?=?0.005) compared to untreated controls. The effect of resveratrol was greatest in cultures from patients with low disease activity, i.e. DAS28CRP???3.2 (p?=?0.022), and in cultures dominated by lymphocytes (p?=?0.03). Further, the combination of methotrexate and resveratrol significantly reduced monocyte chemoattractant protein 1 levels compared with methotrexate alone in cultures from patients with low disease activity (p?=?0.016), and in cultures with high lymphocyte count (p?=?0.011). Resveratrol did not significantly affect matrix metalloproteinase 3 and tartrate resistant acidic phosphatase production. Conclusion:Resveratrol has anti-inflammatory properties in our ex vivo model of immune mediated inflammatory arthritis. Results show an additive effect of resveratrol, when combined with methotrexate in samples dominated by lymphocytes and samples from patients with low disease activity. This suggests further investigations in vitro and whether this effect may also be present in a clinical setting.

Project description:Aging-induced structural and functional alterations of the neurovascular unit lead to impairment of neurovascular coupling responses, dysregulation of cerebral blood flow, and increased neuroinflammation, all of which contribute importantly to the pathogenesis of age-related vascular cognitive impairment (VCI). There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in age-related neurovascular and cerebromicrovascular dysfunction. Our recent studies demonstrate that restoring cellular NAD+ levels in aged mice rescues neurovascular function, increases cerebral blood flow, and improves performance on cognitive tasks. To determine the effects of restoring cellular NAD+ levels on neurovascular gene expression profiles, 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. Transcriptome analysis of preparations enriched for cells of the neurovascular unit was performed by RNA-seq. Neurovascular gene expression signatures in NMN-treated aged mice were compared with those in untreated young and aged control mice. We identified 590 genes differentially expressed in the aged neurovascular unit, 204 of which are restored toward youthful expression levels by NMN treatment. The transcriptional footprint of NMN treatment indicates that increased NAD+ levels promote SIRT1 activation in the neurovascular unit, as demonstrated by analysis of upstream regulators of differentially expressed genes as well as analysis of the expression of known SIRT1-dependent genes. Pathway analysis predicts that neurovascular protective effects of NMN are mediated by the induction of genes involved in mitochondrial rejuvenation, anti-inflammatory, and anti-apoptotic pathways. In conclusion, the recently demonstrated protective effects of NMN treatment on neurovascular function can be attributed to multifaceted sirtuin-mediated anti-aging changes in the neurovascular transcriptome. Our present findings taken together with the results of recent studies using mitochondria-targeted interventions suggest that mitochondrial rejuvenation is a critical mechanism to restore neurovascular health and improve cerebral blood flow in aging.

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Nicotinamide Augments the Anti-Inflammatory Properties of Resveratrol through PARP1 Activation.

Publications

Nicotinamide Augments the Anti-Inflammatory Properties of Resveratrol through PARP1 Activation.

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