Identified 15 years ago, the
mouse carries a spontaneous mutation that encodes a fusion protein with neuroprotective properties. In a Perspective,
discusses new work (
et al.) that identifies the Nmnat1 fragment of the fusion protein as mediating neuroprotection by boosting NAD biosynthesis and
increasing the activity of the NAD-dependent deacetylase, SIRT1, a regulator of transcription.
"However, excessive activation of PARP depletes NAD + for glyceraldehyde-3-phosphate dehydrogenase in glycolytic pathway, resulting in cell death due to ATP depletion (Sheline et al., 2003). Accordingly, it was suggested that NAD + enhancers could be a promising candidate for neuroprotection in neurodegenerative diseases including stroke and Alzheimer's disease (Bedalov and Simon, 2004; Ying, 2008). "
[Show abstract][Hide abstract] ABSTRACT: The present study was aimed to investigate the effects of MB12662, a synthetic dunnione compound, on cisplatin-induced vomiting reflexes and intestinal, renal, immune system, and hematopoietic toxicities in ferrets and mice, respectively. Male ICR mice were orally administered MB12662 (5, 10, 25 or 50 mg/kg) for 10 days, during which intraperitoneally challenged with cisplatin (3.5 mg/kg) from day 4 to 7, and sacrificed on day 10 for the pathological examination. Male ferrets were orally administered MB12662 (25, 50 or 100 mg/kg) for 7 days, subcutaneously challenged with cisplatin (5 mg/kg), and monitored for vomiting reflexes and survival of the animals. Four-day injection of cisplatin (3.5 mg/kg) to mice caused body weight loss and degeneration and atrophy of intestinal villi, reducing villi/crypt ratio to a half level of control animals. Cisplatin also induced renal and hepatic toxicities, and depletion of splenocytes and bone marrow progenitor cells. The systemic toxicities including decreased villi/crypt ratio, immune system atrophy, splenocyte depletion, and decreased cellularity in bone marrow were improved by MB12662. Cisplatin (5 mg/kg) induced retching and emetic responses of ferrets, which were remarkably attenuated by MB12662 in a dose-dependent manner. All the ferrets pretreated with MB12662 survived the challenge of cisplatin, in comparison with 40% mortality in vehicle-treated animals, and blood parameters of nephrotoxicity and hepatotoxicity were markedly recovered. It is expected that MB12662 could be a candidate for the body protection against burden, including emesis, of chemotherapeutic agents.
Biomolecules and Therapeutics 09/2015; 23(5):449-57. DOI:10.4062/biomolther.2015.034 · 1.73 Impact Factor
"Both SIRT1 and mTOR have been linked to age-associated diseases with SIRT1 activation having a protective effect, whereas inhibition of mTOR conferring a beneficial effect. For example, SIRT1 activation confers a therapeutic effect in type 2 diabetes, obesity and neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis, whereas inhibition of mTOR is protective against cardiovascular and neurological diseases, diet-induced obesity and cancer , , , , , , , . Autophagy, a mechanism important in regulating stress response and aging is negatively regulated by mTOR , , whereas SIRT1 has been reported to activate autophagy by deacetylating several essential components of the autophagy machinery . "
[Show abstract][Hide abstract] ABSTRACT: The IGF/mTOR pathway, which is modulated by nutrients, growth factors, energy status and cellular stress regulates aging in various organisms. SIRT1 is a NAD+ dependent deacetylase that is known to regulate caloric restriction mediated longevity in model organisms, and has also been linked to the insulin/IGF signaling pathway. Here we investigated the potential regulation of mTOR signaling by SIRT1 in response to nutrients and cellular stress. We demonstrate that SIRT1 deficiency results in elevated mTOR signaling, which is not abolished by stress conditions. The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner. Furthermore, we demonstrate that SIRT1 interacts with TSC2, a component of the mTOR inhibitory-complex upstream to mTORC1, and regulates mTOR signaling in a TSC2 dependent manner. These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex.
PLoS ONE 02/2010; 5(2):e9199. DOI:10.1371/journal.pone.0009199 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxidative imbalance is a prominent feature in Alzheimer's disease and ageing. Increased levels of reactive oxygen species (ROS) can result in disordered cellular metabolism due to lipid peroxdation, protein-cross linking, DNA damage and the depletion of nicotinamide adenine dinucleotide (NAD(+)). NAD(+) is a ubiquitous pyridine nucleotide that plays an essential role in important biological reactions., from ATP production and secondary messenger signaling, to transcriptional regulation and DNA repair. Chronic oxidative stress may be associated with NAD(+) depletion and a subsequent decrease in metabolic regulation and cell viability. Hence, therapies targeted toward maintaining intracellular NAD(+) pools may prove efficacious in the protection of age-dependent cellular damage, in general, and neurodegeneration in chronic central nervous system inflammatory diseases such as Alzheimer's disease, in particular.
Neurotoxicity Research 09/2008; 13(3-4):173-84. DOI:10.1007/BF03033501 · 3.54 Impact Factor
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