How much successful are the medicinal chemists in modulation of SIRT1: A critical review

Kumar, Ashwani; Chauhan, Shilpi

doi:10.1016/j.ejmech.2016.04.063

Cited by 52 publications

(35 citation statements)

References 190 publications

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“…Although activation of SIRT1 or SIRT3 may appear attractive as a pharmacologic protective strategy, it should be cautioned that the specificity of many SIRT‐activating drugs is uncertain, with stilbenes such as resveratrol plus several commercial SIRT1‐activating drugs called into question 15 . In addition, inactivation of the NAD + ‐recycling enzyme NAMPT phenocopies SIRT1 inhibition in preventing cardioprotection, 93,106 suggesting that NAD + availability is a critical determinant for the cardioprotective efficacy of SIRT1.…”

Section: Targeting Metabolic Pathways To Combat Cardiac Irimentioning

confidence: 99%

Cardiac metabolism as a driver and therapeutic target of myocardial infarction

Zuurbier

Bertrand

Beauloye

et al. 2020

J Cellular Molecular Medi

125

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Reducing infarct size during a cardiac ischaemic‐reperfusion episode is still of paramount importance, because the extension of myocardial necrosis is an important risk factor for developing heart failure. Cardiac ischaemia‐reperfusion injury (IRI) is in principle a metabolic pathology as it is caused by abruptly halted metabolism during the ischaemic episode and exacerbated by sudden restart of specific metabolic pathways at reperfusion. It should therefore not come as a surprise that therapy directed at metabolic pathways can modulate IRI. Here, we summarize the current knowledge of important metabolic pathways as therapeutic targets to combat cardiac IRI. Activating metabolic pathways such as glycolysis (eg AMPK activators), glucose oxidation (activating pyruvate dehydrogenase complex), ketone oxidation (increasing ketone plasma levels), hexosamine biosynthesis pathway (O‐GlcNAcylation; administration of glucosamine/glutamine) and deacetylation (activating sirtuins 1 or 3; administration of NAD+‐boosting compounds) all seem to hold promise to reduce acute IRI. In contrast, some metabolic pathways may offer protection through diminished activity. These pathways comprise the malate‐aspartate shuttle (in need of novel specific reversible inhibitors), mitochondrial oxygen consumption, fatty acid oxidation (CD36 inhibitors, malonyl‐CoA decarboxylase inhibitors) and mitochondrial succinate metabolism (malonate). Additionally, protecting the cristae structure of the mitochondria during IR, by maintaining the association of hexokinase II or creatine kinase with mitochondria, or inhibiting destabilization of FOF1‐ATPase dimers, prevents mitochondrial damage and thereby reduces cardiac IRI. Currently, the most promising and druggable metabolic therapy against cardiac IRI seems to be the singular or combined targeting of glycolysis, O‐GlcNAcylation and metabolism of ketones, fatty acids and succinate.

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Section: Targeting Metabolic Pathways To Combat Cardiac Irimentioning

confidence: 99%

Cardiac metabolism as a driver and therapeutic target of myocardial infarction

Zuurbier

Bertrand

Beauloye

et al. 2020

J Cellular Molecular Medi

125

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“…SIRT1 is the most well-studied member of the mammalian Sirtuins and its deacetylase activity plays a crucial role in metabolic responses to nutritional availability in different tissues and in physiological processes known to be affected during aging. Consequently, the modulation of SIRT1 activity can represent a potential therapeutic approach for treating age-related or metabolic diseases in order to improve the quality of life and extend health span [12], [17], [19], [20], [21].…”

Section: Introductionmentioning

confidence: 99%

During yeast chronological aging resveratrol supplementation results in a short-lived phenotype Sir2-dependent

et al. 2017

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Resveratrol (RSV) is a naturally occurring polyphenolic compound endowed with interesting biological properties/functions amongst which are its activity as an antioxidant and as Sirtuin activating compound towards SIRT1 in mammals. Sirtuins comprise a family of NAD+-dependent protein deacetylases that are involved in many physiological and pathological processes including aging and age-related diseases. These enzymes are conserved across species and SIRT1 is the closest mammalian orthologue of Sir2 of Saccharomyces cerevisiae. In the field of aging researches, it is well known that Sir2 is a positive regulator of replicative lifespan and, in this context, the RSV effects have been already examined. Here, we analyzed RSV effects during chronological aging, in which Sir2 acts as a negative regulator of chronological lifespan (CLS). Chronological aging refers to quiescent cells in stationary phase; these cells display a survival-based metabolism characterized by an increase in oxidative stress. We found that RSV supplementation at the onset of chronological aging, namely at the diauxic shift, increases oxidative stress and significantly reduces CLS. CLS reduction is dependent on Sir2 presence both in expired medium and in extreme Calorie Restriction. In addition, all data point to an enhancement of Sir2 activity, in particular Sir2-mediated deacetylation of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (Pck1). This leads to a reduction in the amount of the acetylated active form of Pck1, whose enzymatic activity is essential for gluconeogenesis and CLS extension.

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“…Many studies have shown that SIRT1 can regulate multiple physiological processes, including gene transcription, glucose homeostasis, cellular stress response, and immune response through its capability of deacetylating various factors. The target proteins of deacetylation by SIRT1 include histones, transcriptional regulators (p53; forkhead box O transcription factors, FoxOs; Nuclear factor κB, NF-κB; hypoxia-inducible factors 2α, hypoxia-inducible factors 2α, HIF 2α), enzymes (acetyl-CoA synthase1, AceCS1), and other signaling molecules such as peroxisome proliferator activated receptor γ co-activator 1α (PGC1-α), thus affecting crucial cellular pathways in physiological and pathological processes [8]. The renal protected effects of SIRT1 have been demonstrated in various kidney diseases [9].…”

Section: Introductionmentioning

confidence: 99%

Genistein Ameliorates Ischemia/Reperfusion-Induced Renal Injury in a SIRT1-Dependent Manner

Yang

Zhu

et al. 2017

Nutrients

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Renal ischemia/reperfusion (I/R) injury continues to be a complicated situation in clinical practice. Genistein, the main isoflavone found in soy products, is known to possess a wide spectrum of biochemical and pharmacological activities. However, the protective effect of genistein on renal I/R injury has not been well investigated. In the current study, we explore whether genistein exhibits its renal-protective effects through SIRT1 (Sirtuin 1) in I/R-induced mice model. We found the treatment of genistein significantly reduced renal I/R-induced cell death, simultaneously stimulating renal cell proliferation. Meanwhile, SIRT1 expression was up-regulated following the administration of genistein in renal region. Furthermore, pharmacological inhibition or shRNA-mediated depletion of SIRT1 significantly reversed the protective effect of genistein on renal dysfunction, cellular damage, apoptosis, and proliferation following I/R injury, suggesting an indispensible role of the increased SIRT1 expression and activity in this process. Meanwhile, the reduced p53 and p21 expression and increased PCNA (Proliferating Cell Nuclear Antigen) expression were blocked after the depletion of SIRT1 compared with the genistein treatment group in the renal I/R process. Hence, our results provided further experimental basis for the potential use of genistein for the treatment of kidney disease with deficiency of SIRT1 activity.

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How much successful are the medicinal chemists in modulation of SIRT1: A critical review

Cited by 52 publications

References 190 publications

Cardiac metabolism as a driver and therapeutic target of myocardial infarction

Cardiac metabolism as a driver and therapeutic target of myocardial infarction

During yeast chronological aging resveratrol supplementation results in a short-lived phenotype Sir2-dependent

Genistein Ameliorates Ischemia/Reperfusion-Induced Renal Injury in a SIRT1-Dependent Manner

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