Sirtuin activators and inhibitors: Promises, achievements, and challenges

Han, Dongmei; Sinclair, David A.; Ellis, James L.; Steegborn, Clemens

doi:10.1016/j.pharmthera.2018.03.004

Cited by 371 publications

(303 citation statements)

References 169 publications

(307 reference statements)

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“…Inspired by this study, we planned to carry out docking simulations by GOLD program (Jones et al, 1997). It has been reported that the indole EX-527 (6chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) proved to be a nanomolar SIRT1 inhibitor (Dai, Sinclair, Ellis, & Steegborn, 2018), whose hypothesized mechanism of inhibition has been reported (Zhao et al, 2013). To compare experimental and predicted binding modes, thus validating the docking procedure, in the first step of our in silico study, docking calculations were carried out by using EX-527 analogue by hydrophobic residues and maintains a fixed orientation through the π/π stacking between Phe273 and indole ring as reported by Zhao and coworkers (Zhao et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The link between the AMPK/SIRT1 axis and a flavonoid‐rich extract of Citrus bergamia juice: A cell‐free, in silico, and in vitro study

Maugeri

Ferlazzo

Luca

et al. 2019

Phytotherapy Research

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A previous report indicated that the flavonoid‐rich extract of bergamot juice (BJe) exerts an anti‐inflammatory effect through the activation of SIRT1 in leukemic monocytes THP‐1 exposed to lipopolysaccharide (LPS). In this study, we deeply investigate the mode of action of BJe, along with its major flavonoids on SIRT1 through cell‐free, in silico, and in vitro experimental models. In the cell‐free assay, all the tested compounds as well as the whole BJe inhibited the deacetylase activity of SIRT1. This finding was reinforced by the results of the in silico study. In THP‐1 cells exposed to LPS, a reduction of SIRT1 activity was observed, effect that was reverted by the pre‐incubation with either BJe or its major flavonoids. This effect was also observed at gene level. Employing an activator and an inhibitor of AMP‐activated protein kinase (AMPK; AICAR and dorsomorphin, respectively), we discovered its involvement in the activation of SIRT1 elicited by BJe or its major flavonoids in whole cell. Our study indicates the dual role of BJe and its components, depending on the employed experimental model as well as reveals their mode of action on the AMPK/SIRT1 axis, suggesting their role as promising candidates in pathologies in which this axis is implied.

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Section: Discussionmentioning

confidence: 99%

The link between the AMPK/SIRT1 axis and a flavonoid‐rich extract of Citrus bergamia juice: A cell‐free, in silico, and in vitro study

Maugeri

Ferlazzo

Luca

et al. 2019

Phytotherapy Research

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“…NAMPT is the ratelimiting enzyme in this pathway, and regulates sirtuin activity by modulating NAD + levels (Revollo et al, 2004). This entire pathway is related to aging processes (Dai et al, 2018), which were acquired by bilaterian animals along with tissue differentiation and cell cycle control mechanisms to evade cancer (Petralia et al, 2014). Indeed, these are the very types of biology with which PGRMC1 function is here implicated: suggesting that PGRMC1 phosphorylation could be involved in the mechanism(s) of animal aging.…”

Section: Discussionmentioning

confidence: 99%

PGRMC1 phosphorylation and cell plasticity 2: genomic integrity and CpG methylation

et al. 2019

Preprint

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SUMMARYProgesterone receptor membrane component 1 (PGRMC1) is often elevated in cancers, and exists in alternative states of phosphorylation. A motif centered on PGRMC1 Y180 was evolutionarily acquired concurrently with the embryological gastrulation organizer that orchestrates vertebrate tissue differentiation. Here, we show that mutagenic manipulation of PGRMC1 phosphorylation alters cell metabolism, genomic stability, and CpG methylation. Each of several mutants elicited distinct patterns of genomic CpG methylation. Mutation of S57A/Y180/S181A led to increased net hypermethylation, reminiscent of embryonic stem cells. Pathways enrichment analysis suggested modulation of processes related to animal cell differentiation status and tissue identity, as well as cell cycle control and ATM/ATR DNA damage repair regulation. We detected different genomic mutation rates in culture. A companion manuscript shows that these cell states dramatically affect protein abundances, cell and mitochondrial morphology, and glycolytic metabolism. We propose that PGRMC1 phosphorylation status modulates cellular plasticity mechanisms relevant to early embryological tissue differentiation.

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“…A small trial conducted on the sirtuin‐1 activator SRT2104 suggested that the compound may improve measures of arterial stiffness in healthy smokers and diabetic patients . Clinical trials are being performed to assess the effects of drugs targeting sirtuin activities in humans …”

Section: Effects Of Plant and Fungal Compounds On Healthspanmentioning

confidence: 99%

“…327 Clinical trials are being performed to assess the effects of drugs targeting sirtuin activities in humans. 328 The NAD + precursor nicotinamide mononucleotide (NMN; 36) reduced diabetes in aging mice. 329 Another study show that NMN increases physical endurance in old mice by activating SIRT1 in endothelial cells.…”

Section: Effects Of Plant and Fungal Compounds On Healthspanmentioning

confidence: 99%

Antiaging effects of bioactive molecules isolated from plants and fungi

Martel

Ojcius

et al. 2019

Medicinal Research Reviews

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Aging is influenced by many lifestyle choices that are under human control, including nutrition and exercise. The most effective known antiaging intervention consists of calorie restriction (CR), which increases lifespan in yeasts, worms, fruit flies, mice, and nonhuman primates. CR also improves healthspan by preventing the development of various aging‐related diseases such as cancer, cardiovascular disease, diabetes, and neurodegeneration. Many compounds isolated from plants and fungi prolong lifespan and prevent age‐related diseases in model organisms. These plant and fungal compounds modulate the same cellular and physiological pathways as CR, including those involving insulin and insulin‐like growth factor‐1, mammalian target of rapamycin, and sirtuins. Modulation of these aging‐related pathways results in the activation of various cellular processes such as autophagy, DNA repair, and neutralization of reactive oxygen species. Together, these cellular processes are believed to delay aging and prevent chronic diseases by improving bodily functions and stress resistance. We review here the mechanisms of action of plant and fungal molecules possessing antiaging properties and discuss the possibilities and challenges associated with the development of antiaging compounds isolated from natural products.

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Sirtuin activators and inhibitors: Promises, achievements, and challenges

Cited by 371 publications

References 169 publications

The link between the AMPK/SIRT1 axis and a flavonoid‐rich extract of Citrus bergamia juice: A cell‐free, in silico, and in vitro study

The link between the AMPK/SIRT1 axis and a flavonoid‐rich extract of Citrus bergamia juice: A cell‐free, in silico, and in vitro study

PGRMC1 phosphorylation and cell plasticity 2: genomic integrity and CpG methylation

Antiaging effects of bioactive molecules isolated from plants and fungi

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