Trends in Pharmacological Sciences
ReviewDichotomous Sirtuins: Implications for Drug Discovery in Neurodegenerative and Cardiometabolic Diseases
Section snippets
Overview of Sirtuin Research
Sirtuins are highly conserved enzyme homologs of the Saccharomyces cerevisiae silent information regulator 2 (Sir2) gene, initially identified as genetic silencing factors in yeast and later found to extend longevity in several organisms 1, 2. Similar to yeast Sir2 [3], the mammalian sirtuins (SIRT1–7) (Box 1) are a family of conserved enzymes with NAD+-dependent deacylase (see Glossary) activity. Given that sirtuins exhibit ubiquitous tissue distribution and act on many protein substrates in
Sirtuins in Neurodegenerative Diseases
Sirtuins have been implicated in the modulation of age-related neurodegenerative disorders and the toxicity associated with different proteins, namely α-synuclein, huntingtin, tau, or amyloid β (Aβ) peptide [6]. Here, we discuss the most relevant studies that produced contradictory results on the biological and therapeutic roles of sirtuins in major neurodegenerative disorders and frequently associated comorbidities, such as depression, cognitive deficits, stroke, neuropathic pain, and seizures.
Sirtuins in Cardiometabolic Diseases
It is widely accepted that compromised sirtuin activity and/or expression contributes to the pathogenesis of cardiovascular and metabolic diseases [45]. While a significant proportion of these studies have demonstrated that increasing sirtuin activity and/or expression in mice can mitigate disease syndromes, some reports also show the opposite effects in certain diseases and settings. Here, we review these contrasting findings.
Potential Causes for the Observed Dichotomy of Sirtuins
Here, we discuss the putative causes of the observed dichotomy in the activity of sirtuins when modulated pharmacologically and genetically.
Concluding Remarks and Future Perspectives
Owing to their broad spectrum of health-promoting effects, sirtuins have emerged as attractive therapeutic targets for several age-related diseases. However, accumulating evidence demonstrates distinct functions and disease outcomes following genetic and/or pharmacological sirtuin modulation, suggesting that sirtuins are capable of functioning as either positive or negative regulators of disease-associated pathways (Figure 1). Although the mechanisms underlying these apparently contradictory
Acknowledgments
This work was supported by European Regional Development Fund (FEDER), through Programa Operacional Factores de Competitividade COMPETE2020 and National funds via Fundação para a Ciência e a Tecnologia (FCT) under the projects POCI-01-0145-FEDER-007440, UID/NEU/04539/2013, UID/NEU/04539/2019, POCI-01-0145-FEDER-030167, POCI-01-0145-FEDER-031712, PTDC/SAU-NUT/31712/2017, and CENTRO-01-0145-FEDER-000012-HealthyAging. H.L. is supported by a PhD scholarship from FCT (SFRH/BD/121923/2016). We are
Glossary
- α-synuclein
- aggregation-prone presynaptic neuronal protein that is linked to the pathogenesis of PD.
- Amyloid β (Aβ)
- peptide derived from the amyloid precursor protein (APP) that forms the amyloid plaques found in the brains of patients with AD.
- Demalonylation
- removal of a malonyl group from a specific lysine residue of a target protein.
- Demyristoylation
- removal of a myristoyl group attached covalently by an amide bond to the alpha-amino group of an N-terminal glycine residue.
- Desuccinylation
- removal of
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The role of microRNA-34 family in Alzheimer's disease: A potential molecular link between neurodegeneration and metabolic disorders
2021, Pharmacological ResearchCitation Excerpt :The important roles of PTP1B related to obesity and diabetes were confirmed by a deletion of PTP1B gene in mice [209,210]. Decreased levels of SIRT1 and its co-substrate (NAD+) can be seen in many age related diseases, including neurodegeneration, diabetes and cancer [211–214]. Interestingly, SIRT1 can be regulated directly by miR-34a and there is evidence showing the connection between low levels of hepatic SIRT1 and high levels of miR-34a in fatty liver disease and obesity [43,215].
Common risk factors and therapeutic targets in obstructive sleep apnea and osteoarthritis: An unexpectable link?
2021, Pharmacological ResearchCitation Excerpt :Although this antagonistic crosstalk between NF-κB and SIRT1 is far more complex, its outcome is either the persistence of inflammation associated with glycolytic energy flux, oxidative stress and cellular senescence, if NF-κB predominates, as occurs in OA, OSA and many other conditions associated with aging and metabolic disturbances; or the resolution of inflammation with increased energy production through oxidative phosphorylation and cell survival, when SIRT1 expression and activity are restored [9,10]. In line with this, pre-clinical and clinical studies suggest that resveratrol and other SIRT1 activators have beneficial effects on lipid and glucose metabolism, improving cognitive functions in models of neurodegenerative diseases and causing an overall anti-aging effect [11,226]. In vitro and in vivo studies of OA indicate that inducing SIRT1 expression and/or activity has protective effects, reducing inflammatory and catabolic responses, increasing the production of major cartilage matrix components and promoting chondrocyte survival [50,54,56,227–231].
Hit-to-lead optimization on aryloxybenzamide derivative virtual screening hit against SIRT
2021, Bioorganic and Medicinal ChemistryCitation Excerpt :Mammalian SIRTs consist of seven isoforms (SIRT1-7), which show different subcellular localizations and enzymatic functions.2 The SIRT enzymes have been engaged in various pathologies such as cancer, neurodegeneration, diabetes, inflammation, cardiovascular diseases and therefore, the modulation of SIRTs is of therapeutic importance.3–12 SIRT1 and SIRT2 are the best studied members of sirtuin family at present, and several SIRT1/2 inhibitors have been described, including nicotinamide, splitomicin and its analogues, sirtinol, tenovin, suramin and its analogues, cambinol, salermide, toxoflavin, thiobarbiturates, and other compounds.1,13–19