Resveratrol-like Compounds as SIRT1 Activators

Abstract

The sirtuin 1 (SIRT1) activator resveratrol has emerged as a promising candidate for the prevention of vascular oxidative stress, which is a trigger for endothelial dysfunction. However, its clinical use is limited by low oral bioavailability. In this work, we have applied a previously developed computational protocol to identify the most promising derivatives from our in-house chemical library of resveratrol derivatives. The most promising compounds in terms of SIRT1 activation and oral bioavailability, predicted in silico, were evaluated for their ability to activate the isolated SIRT1 enzyme. Then, we assessed the antioxidant effects of the most effective derivative, compound 3d, in human umbilical vein endothelial cells (HUVECs) injured with H2O2 100 µM. The SIRT1 activator 3d significantly preserved cell viability and prevented an intracellular reactive oxygen species increase in HUVECs exposed to the oxidative stimulus. Such effects were partially reduced in the presence of a sirtuin inhibitor, sirtinol, confirming the potential role of sirtuins in the activity of resveratrol and its derivatives. Although 3d appeared less effective than resveratrol in activating the isolated enzyme, the effects exhibited by both compounds in HUVECs were almost superimposable, suggesting a higher ability of 3d to cross cell membranes and activate the intracellular target SIRT1.

Oxidative Stress: A Suitable Therapeutic Target for Optic Nerve Diseases?

“…This molecule was reported to preserve from visual function deficiency, attenuating oxidative stress, inflammation and inhibiting axonal degeneration in TON models [502]. Finally, the before reported resveratrol, which can activate SIRT1 and subsequently Nrf2 [263,264], appears to possess curative effects also in TON models. In fact, this compound showed protective effects on RGC in optic nerve crush models, attenuating oxidative stress [503].…”

“…These effects contribute to its beneficial antioxidant effects in the TM [262]. Resveratrol is also an activator of suirtin1 (SIRT1), a nuclear NAD⁺-dependent deacetylase, highly relevant for regulation of several antioxidant genes, performed by triggering the Nrf2/ARE (antioxidant response elements) pathway [263,264]. In an experimental rat model of glaucoma, resveratrol has been shown to delay the loss of RGCs [265].…”

Influence of Polyphenols on Adipose Tissue: Sirtuins as Pivotal Players in the Browning Process

“…Many natural polyphenols are SIRT1 activators and have been widely investigated for their ability to modulate adipose cell metabolism [148] (Table 3 summarizes the studies supporting this hypothesis). Resveratrol activates SIRT1 by mediating a plethora of beneficial effects including antioxidant, anti-inflammatory, anti-carcinogenic, and anti-adipogenic effects, resulting in increased mitochondrial respiration and enhanced energy expenditure [58,149,150]. Indeed, resveratrol promoted aerobic capacity (which consists of higher oxygen consumption and longer running time) in mice fed with a HF diet and KKay mice treated with resveratrol added to food, supplying a dose of 200 or 400 mg/kg/day.…”

Recent Advances in Natural Polyphenol Research

“…The potential of antioxidative and repair pathways decreases with age, causing several adverse effects such as the risk of neurodegenerative diseases such as Parkinson's disease, memory loss, Alzheimer's disease, atherosclerosis, and cancers due to the accumulation of reactive oxygen Polyphenols, due to their oxidizing ability, can protect from the damaging effects of ROS. Therefore, they can be used as active compounds in several formulations preventing oxidative stress [197,198]. The loading of polyphenols into lipid nanocarriers (NCs) is an essential tool for increasing bioavailability, reducing degradation, and protecting antioxidant polyphenols' activity.…”