An overview of Sirtuins as potential therapeutic target: Structure, function and modulators

Wang, Yijie; He, Jiang; Liao, Mengya; Hu, Mingxing; Li, Wenzhen; Ouyang, Hongling; Wang, Xin; Ye, Tinghong; Zhang, Yiwen; Ouyang, Liang

doi:10.1016/j.ejmech.2018.10.028

Cited by 165 publications

(109 citation statements)

References 196 publications

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“…The role of SIRT1, an NAD + -dependent histone deacetylase, in the progress and protection of retinal degeneration has been reported in great details in several disease models [45,46]. Jaliffa, C et al found that the pathologic expression pattern of SIRT1 was correlated with initial retinal degeneration in rd10 mice [47].…”

Section: Discussionmentioning

confidence: 99%

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Yan

Long²,

Wei

et al. 2020

BMC Ophthalmol

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Background: Retinitis pigmentosa (RP) is a kind of inherited retinal degenerative diseases characterized by the progressive loss of photoreceptors. RP has been a conundrum without satisfactory countermeasures in clinic until now. Acetaldehyde dehydrogenase 2 (ALDH2), a major enzyme involved in aldehyde detoxification, has been demonstrated to be beneficial for a growing number of human diseases, such as cardiovascular dysfunction, diabetes mellitus and neurodegeneration. However, its protective effect against RP remains unknown. Our study explored the impact of ALDH2 on retinal function and structure in N-methyl-N-nitrosourea (MNU)-induced RP rats. Methods: Rats were gavaged with 5 mg/kg Alda-1, an ALDH2 agonist, 5 days before and 3 days after MNU administration. Assessments of retinal function and morphology as well as measurement of specific proteins expression level were conducted. Results: Electroretinogram recordings showed that Alda-1 administration alleviated the decrease in amplitude caused by MNU, rendering protection of retinal function. Mitigation of photoreceptor degeneration in MNU-treated retinas was observed by optical coherence tomography and retinal histological examination. In addition, Western blotting results revealed that ALDH2 protein expression level was upregulatedwith increased expression of SIRT1 protein after the Alda-1 intervention. Besides, endoplasmic reticulum stress (ERS) was reduced according to the significant downregulation of GRP78 protein, while apoptosis was ameliorated as shown by the decreased expression of PARP1 protein.Conclusions: Together, our data demonstrated that ALDH2 could provide preservation of retinal function and morphology against MNU-induced RP, with the underlying mechanism at least partly related to the modulation of SIRT1, ERS and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Yan

Long²,

Wei

et al. 2020

BMC Ophthalmol

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“…Besides histones, a multitude of non-histone proteins such as transcription factors (p53, NF-kB, PGC1α) and DNA repair proteins (Ku70, PARP1) [12] are recognized as SIRT targets. Through their numerous substrates, SIRTs control different molecular pathways including energy metabolism, cell survival, DNA repair, tissue regeneration, inflammation, neuronal signalling, and even circadian rhythms [13,14]. SIRT1, the most well-studied member of the SIRT family [15], has a role in all these processes.…”

Section: Introductionmentioning

confidence: 99%

“…In light of its involvement in a number of human diseases as well as its health benefits, SIRT1 has emerged as an attractive drug target for the treatment of various disorders [13]. In recent years, several studies adopting different approaches including high-throughput screening (HTS), computer-or fragment-based screenings, focused library screening in combination with extensive structure-activity relationship studies, and in vitro and in vivo tests have identified and characterized small molecules able to modulate SIRT1 activity [18].…”

Section: Introductionmentioning

confidence: 99%

Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence

et al. 2020

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Nebbioso (2020) Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence, Epigenetics, 15:6-7, 664-683, ABSTRACT SIRT1, a NAD + -dependent deacetylase, is the most well-studied member of class III histone deacetylases. Due to its wide range of activities and substrate targets, this enzyme has emerged as a major regulator of different physiological processes. However, SIRT1-mediated alterations are also implicated in the pathogenesis of several conditions, including metabolic and neurodegenerative disorders, and cancer. Current evidence highlights the potential role of SIRT1 as an attractive therapeutic target for disease prevention and treatment strategies, thus propelling the development of new pharmacological agents. By high-throughput screening of a large library of compounds, we identified SCIC2 as an effective SIRT1 activator. This small molecule showed enzymatic activity of 135.8% at 10 μM, an AC 50 value of 50 ± 1.8 µM, and bound SIRT1 with a K D of 26.4 ± 0.6 μM. In order to potentiate its SIRT1-activating ability, SCIC2 was subjected to modelling studies, leading to the identification of a more potent derivative, SCIC2.1. SCIC2.1 displayed higher SIRT1 activity (175%; AC 50 = 36.83 ± 2.23 µM), stronger binding to SIRT1, and greater cell permeability than SCIC2. At cellular level, both molecules did not alter the cell cycle progression of cancer cells and normal cells, and were able to strengthen SIRT1-mediated effects in stress response. Finally, SCIC2 and SCIC2.1 attenuated induction of senescence by reducing senescenceassociated β-galactosidase activity. Our findings warrant further investigation of these two novel SIRT1 activators in in vivo and human studies. ARTICLE HISTORY

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“…Based on our results, we suggest that the pharmacological activation of Sirt1 is involved in oxidative stress response promoted by the EA-Aa, probably through the activation of the ERK/Nrf2 pathway which increases catalase-mediated antioxidant defense. Plants that have phenolic compounds as part of its constitution have already been represented as potent sirtuin activators [77][78][79][80] and consequently the pathways associated with it.…”

mentioning

confidence: 99%

Acrocomia aculeata(Jacq.) Lodd. ex Mart. Leaves Increase SIRT1 Levels and Improve Stress Resistance

Alfredo

Matafome

Iacia

et al. 2020

Oxidative Medicine and Cellular Longevity

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Oxidative stress is a metabolic disorder linked with several chronic diseases, and this condition can be improved by natural antioxidants. The fruit pulp of the palm Acrocomia aculeata (Jacq.) Lodd. ex Mart. is widely used in the treatment of various illnesses, but as far as we know, there are no reports regarding the properties of its leaves. Thus, we aimed to evaluate the antioxidant activity of A. aculeata leaf extracts obtained with water (EA-Aa), ethanol (EE-Aa), and methanol (EM-Aa) solvents. The extracts were chemically characterized, and their antioxidant activity was assessed through the scavenging of the free radicals DPPH and ABTS. EE-Aa and EM-Aa showed the highest amounts of phenolic compounds and free radical scavenging activity. However, EA-Aa was more efficient to protect human erythrocytes against AAPH-induced hemolysis and lipid peroxidation. Thus, we further show the antioxidant effect of EA-Aa in preventing AAPH-induced protein oxidation, H2O2-induced DNA fragmentation, and ROS generation in Cos-7 cells. Increased levels of Sirt1, catalase, and activation of ERK and Nrf2 were observed in Cos-7 treated with EA-Aa. We also verify increased survival in nematodes C. elegans, when induced to the oxidative condition by Juglone. Therefore, our results showed a typical chemical composition of plants for all extracts, but the diversity of compounds presented in EA-Aa is involved in the lower toxicity and antioxidant properties provided to the macromolecules tested, proteins, DNA, and lipids. This protective effect also proven in Cos-7 and in C. elegans was probably due to the activation of the Sirt1/Nrf2 pathway. Altogether, the low toxicity and the antioxidant properties of EA-Aa showed in all the experimental models support its further use in the treatment of oxidative stress-related diseases.

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An overview of Sirtuins as potential therapeutic target: Structure, function and modulators

Cited by 165 publications

References 196 publications

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence

Acrocomia aculeata(Jacq.) Lodd. ex Mart. Leaves Increase SIRT1 Levels and Improve Stress Resistance

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