Sirtuin Modulators: Past, Present, and Future Perspectives

Fiorentino, Francesco; Mautone, Nicola; Menna, Martina; D’Acunzo, Francesca; Mai, Antonello; Rotili, Dante

doi:10.4155/fmc-2022-0031

Cited by 37 publications

(31 citation statements)

References 147 publications

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“…1050 Only 23.9% (n = 17) of published RCTs explored the effects of SIRT activators on physiological function. As a well-known SIRT activator, 1051 resveratrol (n = 10, 14.1%) received more attention compared with SRT2104 (n = 7, 9.9%) in these studies. Several RCTs showed that resveratrol supplementation could effectively increase the expression or concentration of SIRT1.…”

Section: Rcts Of Sirt Proteinsmentioning

confidence: 99%

The sirtuin family in health and disease

Zhang

Chen

et al. 2022

Sig Transduct Target Ther

288

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Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.

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Section: Rcts Of Sirt Proteinsmentioning

confidence: 99%

The sirtuin family in health and disease

Zhang

Chen

et al. 2022

Sig Transduct Target Ther

288

View full text Add to dashboard Cite

show abstract

“…During the past 50 years, the involvement of SIRTs in cancer biology has been studied, and the accumulated evidence reveals their regulatory role in several important steps during the development and progression of different tumor types [ 103 , 169 , 170 , 171 , 172 ]. SIRTs are involved in various biological pathways in which they could act as either tumor suppressors or activators, depending on the stage of the disease, the histological type, and the tumor microenvironment [ 173 ].…”

Section: Discussionmentioning

confidence: 99%

“…The discovery of small molecule regulators that target SIRTs has become a topic of intense interest the past 30 years with several hundred articles investigating new molecular targets as possible regulators of sirtuins’ enzymatic activity in normal cells and disease. Unfortunately, translating SIRT regulators from the bench to the clinics, faces absences of selective compounds with favorable pharmacokinetic and pharmacodynamic profiles [ 102 , 103 , 104 , 105 ]. Therefore, only 70 studies and respective agents have passed through the preclinical phase and were finely tested in clinical trials as potential treatment options in coronary disease, COVID-19, neurodegenerative disease, diabetes, kidney disease, and cancer [ 106 ].…”

Section: Sirt Proteins: An Overview Of Structure and Functionmentioning

confidence: 99%

Exploring the Multi-Faceted Role of Sirtuins in Glioblastoma Pathogenesis and Targeting Options

Kunadis

Piperi

2022

IJMS

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Recent advances in glioblastoma (GB) research have shed light on the molecular characteristics, the defected intracellular signaling pathways, and the genetic and epigenetic alterations involved in their pathogenesis. Despite constant efforts, GB remains an aggressive malignant tumor with limited therapeutic approaches, poor prognosis, and a low survival rate. Emerging evidence points towards the crucial impact of epigenetic post-translational modifications in cancer development with emphasis on the regulatory role of histone deacetylation in several key cellular processes, including metabolic pathways, regulation of stress response, senescence, proliferation, DNA repair, and apoptosis. The silent information regulator proteins (Sirtuins) are deacetylases of histone and non-histone proteins that have been recently implicated in the initiation as well as in the progression of GB. Herein, we provide a critical overview of the emerging functional role and mechanism of action of the seven Sirtuins (SIRT1-7) in GB and discuss their potential targeting options in clinical practice.

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“…Some SIRT family members also possess broad-spectrum protein lysine deacylase, mono-ADP-ribosylase, and lipoamidase activities . Given their ability to catalyze the removal of many PTMs, sirtuins are involved in several biological processes, including DNA damage repair, aging, cell cycle regulation, gene expression, metabolism, longevity, and stress response. − It is worth noting that epigenetic and metabolic pathways are tightly interconnected. Indeed, most enzymes that catalyze epigenetic modifications use crucial metabolites as cosubstrates (for example, S -adenosyl methionine, α-ketoglutarate, acetyl- and acyl-CoA, FAD/FADH 2 , and NAD + /NADH) .…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5

et al. 2022

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Sirtiun 5 (SIRT5) is a NAD + -dependent protein lysine deacylase primarily located in mitochondria. SIRT5 displays an affinity for negatively charged acyl groups and mainly catalyzes lysine deglutarylation, desuccinylation, and demalonylation while possessing weak deacetylase activity. SIRT5 substrates play crucial roles in metabolism and reactive oxygen species (ROS) detoxification, and SIRT5 activity is protective in neuronal and cardiac physiology. Moreover, SIRT5 exhibits a dichotomous role in cancer, acting as context-dependent tumor promoter or suppressor. Given its multifaceted activity, SIRT5 is a promising target in the design of activators or inhibitors that might act as therapeutics in many pathologies, including cancer, cardiovascular disorders, and neurodegeneration. To date, few cellular-active peptide-based SIRT5 inhibitors (SIRT5i) have been described, and potent and selective small-molecule SIRT5i have yet to be discovered. In this perspective, we provide an outline of SIRT5’s roles in different biological settings and describe SIRT5 modulators in terms of their mode of action, pharmacological activity, and structure–activity relationships.

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Sirtuin Modulators: Past, Present, and Future Perspectives

Cited by 37 publications

References 147 publications

The sirtuin family in health and disease

The sirtuin family in health and disease

Exploring the Multi-Faceted Role of Sirtuins in Glioblastoma Pathogenesis and Targeting Options

Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5

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