Quercetin 3,5,7,3′,4′-pentamethyl ether from Kaempferia parviflora directly and effectively activates human SIRT1

Zhang, Mimin; Lü, Peng; Terada, Tohru; Sui, Miaomiao; Furuta, Haruka; Iida, Kilico; Katayama, Yukie; Lü, Yi; Suzuki, Michio; Asakura, Tomiko; Shimizu, Kentaro; Hakuno, Fumihiko; Takahashi, Shinichiro; Shimada, Naoyuki; Yang, Jinwei; Ishikawa, Tsutomu; Tatsuzaki, Jin; Nagata, Koji

doi:10.1038/s42003-021-01705-1

Cited by 16 publications

(11 citation statements)

References 50 publications

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“…The K D values between resveratrol and SIRT1•NAD + and SIRT1•ADPr were comparable, suggesting ADPr likely had the same effect on SIRT1 conformation as NAD + and was a serviceable substitution. Our K D values were comparable to those obtained by isothermal calorimetry (ITC) in previous studies ( Zhang et al, 2021 ). Our K D for resveratrol and apo SIRT1 was 28 μM, slightly lower than a literature K D of 50 μM.…”

Section: Resultssupporting

confidence: 90%

The differing effects of a dual acting regulator on SIRT1

Hur,

Huynh,

Leong

et al. 2023

Front. Mol. Biosci.

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SIRT1 is an NAD+-dependent protein deacetylase that has been shown to play a significant role in many biological pathways, such as insulin secretion, tumor formation, lipid metabolism, and neurodegeneration. There is great interest in understanding the regulation of SIRT1 to better understand SIRT1-related diseases and to better design therapeutic approaches that target SIRT1. There are many known protein and small molecule activators and inhibitors of SIRT1. One well-studied SIRT1 regulator, resveratrol, has historically been regarded as a SIRT1 activator, however, recent studies have shown that it can also act as an inhibitor depending on the identity of the peptide substrate. The inhibitory nature of resveratrol has yet to be studied in detail. Understanding the mechanism behind this dual behavior is crucial for assessing the potential side effects of STAC-based therapeutics. Here, we investigate the detailed mechanism of substrate-dependent SIRT1 regulation by resveratrol. We demonstrate that resveratrol alters the substrate recognition of SIRT1 by affecting the KM values without significantly impacting the catalytic rate (kcat). Furthermore, resveratrol destabilizes SIRT1 and extends its conformation, but the conformational changes differ between the activation and inhibition scenarios. We propose that resveratrol renders SIRT1 more flexible in the activation scenario, leading to increased activity, while in the inhibition scenario, it unravels the SIRT1 structure, compromising substrate recognition. Our findings highlight the importance of substrate identity in resveratrol-mediated SIRT1 regulation and provide insights into the allosteric control of SIRT1. This knowledge can guide the development of targeted therapeutics for diseases associated with dysregulated SIRT1 activity.

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Section: Resultssupporting

confidence: 90%

The differing effects of a dual acting regulator on SIRT1

Hur,

Huynh,

Leong

et al. 2023

Front. Mol. Biosci.

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“…In particular, binding of Sirt1 within the p53 promoter inhibits transcription of the TP53 gene and thus confers protection against rotenone-induced injury by suppressing p53 expression [223]. Recently, it has been shown that quercetin 3,5,7,3 ,4 -pentamethyl ether, a natural sirtuin-activating compound, directly interacts with Sirt1 and strongly stimulates its deacetylase activity by enhancing its binding affinity for p53-derived peptides [224]. Hence, these findings suggest that the effects of quercetin against rotenone-induced toxicity could be mediated via the Sirt1/p53 pathway.…”

Section: Quercetinmentioning

confidence: 99%

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

et al. 2021

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Neurodegenerative diseases are one of the leading causes of disability and death worldwide. Intracellular transduction pathways that end in the activation of specific transcription factors are highly implicated in the onset and progression of pathological changes related to neurodegeneration, of which those related to oxidative stress (OS) and neuroinflammation are particularly important. Here, we provide a brief overview of the key concepts related to OS- and neuroinflammation-mediated neuropathological changes in neurodegeneration, together with the role of transcription factors nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB). This review is focused on the transcription factor p53 that coordinates the cellular response to diverse genotoxic stimuli, determining neuronal death or survival. As current pharmacological options in the treatment of neurodegenerative disease are only symptomatic, many research efforts are aimed at uncovering efficient disease-modifying agents. Natural polyphenolic compounds demonstrate powerful anti-oxidative, anti-inflammatory and anti-apoptotic effects, partially acting as modulators of signaling pathways. Herein, we review the current understanding of the therapeutic potential and limitations of flavonols in neuroprotection, with emphasis on their anti-oxidative, anti-inflammatory and anti-apoptotic effects along the Nrf2, NF-κB and p53 pathways. A better understanding of cellular and molecular mechanisms of their action may pave the way toward new treatments.

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“…An alternative hypothesis for the findings associated with quercetin treatment in our study may be related to its known regulatory function of members of the sirtuin family of proteins, consistent with a metabolic role in tissue regeneration. Quercetin and related polyphenols are potent activators of Sirtuin 1, a nicotinamide-dependent histone deacetylase that regulates cell survival via the p53-mediated pathway [ 23 ]. Given their regenerative effects, activation of the sirtuin proteins have been proposed for the treatment of age-related diseases, including type 2 diabetes mellitus [ 24 ], cancer [ 25 , 26 ], and neurodegeneration [ 27 ], as well as for extending organismal lifespans [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Quercetin Decreases Corneal Haze In Vivo and Influences Gene Expression of TGF-Beta Mediators In Vitro

et al. 2022

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We have previously reported the flavonoid, quercetin, as a metabolic regulator and inhibitor of myofibroblast differentiation in vitro. Our current study evaluated the effects of topical application of quercetin on corneal scar development using two different animal models followed by RNA analysis in vitro. Wild-type C57BL/6J mice were anesthetized and the corneal epithelium and stroma were manually debrided, followed by quercetin (0.5, 1, 5, or 50 mM) or vehicle application. Corneal scarring was assessed for 3 weeks by slit lamp imaging and clinically scored. In a separate animal study, six New Zealand White rabbits underwent lamellar keratectomy surgery, followed by treatment with 5 mM quercetin or vehicle twice daily for three days. Stromal backscattering was assessed at week 3 by in vivo confocal microscopy. In mice, a single dose of 5 mM quercetin reduced corneal scar formation. In rabbits, stromal backscattering was substantially lower in two out of three animals in the quercetin-treated group. In vitro studies of human corneal fibroblasts showed that quercetin modulated select factors of the transforming growth factor-β (TGF-β) signaling pathway. These results provide evidence that quercetin may inhibit corneal scarring. Further studies in a larger cohort are required to validate the efficacy and safety of quercetin for clinical applications.

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Quercetin 3,5,7,3′,4′-pentamethyl ether from Kaempferia parviflora directly and effectively activates human SIRT1

Cited by 16 publications

References 50 publications

The differing effects of a dual acting regulator on SIRT1

The differing effects of a dual acting regulator on SIRT1

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

Quercetin Decreases Corneal Haze In Vivo and Influences Gene Expression of TGF-Beta Mediators In Vitro

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