Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo.

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (valproate) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with valproate improved the swimming of the MJD zebrafish, affected levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3. Proteomic analysis of protein lysates generated from the treated and untreated MJD zebrafish also predicted that valproate treatment had activated the sirtuin longevity signaling pathway and this was confirmed by findings of increased SIRT1 protein levels and sirtuin activity in valproate treated MJD zebrafish and HEK293 cells expressing ataxin-3 84Q, respectively. Treatment with resveratrol (another compound known to activate the sirtuin pathway), also improved swimming in the MJD zebrafish. Co-treatment with valproate alongside EX527, a SIRT1 activity inhibitor, prevented induction of autophagy by valproate and the beneficial effects of valproate on the movement in the MJD zebrafish, supporting that they were both dependent on sirtuin activity. These findings provide the first evidence of sodium valproate inducing activation of the sirtuin pathway. Further, they indicate that drugs that target the sirtuin pathway, including sodium valproate and resveratrol, warrant further investigation for the treatment of MJD and related neurodegenerative diseases.

Brief Communication: SIR-2.1-dependent lifespan extension of Caenorhabditis elegans by oxyresveratrol and resveratrol.

Resveratrol (RES) has been studied for its effects on the lifespan extension of Caenorhabditis elegans, but controversy still remains on its mechanism related with SIR-2. In this study, longevity assay was performed to confirm SIR-2-dependent lifespan extension of C. elgeans with RES and oxyresveratrol (OXY), an isomer of hydroxylated RES using loss-of-function mutants of C. elegans including sir-2.1 mutant. The results showed that OXY and RES significantly (P < 0.05) extended the lifespan of C. elegans compared with the control. OXY and RES also significantly (P < 0.05) increased the mRNA expression levels of sir-2.1 and aak-2 in a dose-dependent manner and increased the protein expression levels of SIR-2.1. OXY and RES treatment extended the lifespan in daf-16 loss-of-function mutants, which suggested that lifespan extension was not occurring via the activation of DAF-16. However, OXY and RES failed to extend the lifespan in loss-of-function mutants of sir-2.1 and aak-2 Therefore, OXY and RES extend the lifespan of C. elegans by overexpression of SIR-2.1, which is related to lifespan extension through calorie restriction and the AMP-activated protein kinase (AMPK) pathway, although this process is independent of the FOXO/DAF-16 pathway.

Alkaloids from psychotria target sirtuins: in silico and in vitro interaction studies.

Epigenetic enzymes such as histone deacetylases play a crucial role in the development of ageing-related diseases. Among the 18 histone deacetylase isoforms found in humans, class III histone deacetylases, also known as sirtuins, seem to be promising targets for treating neurodegenerative conditions. Recently, Psychotria alkaloids, mainly monoterpene indoles, have been reported for their inhibitory properties against central nervous system cholinesterase and monoamine oxidase proteins. Given the multifunctional profile of these alkaloids in the central nervous system, and the fact that the indole scaffold has been previously associated with sirtuin inhibition, we hypothesized that these indole derivatives could also interact with sirtuins. In the present study, alkaloids previously isolated from Psychotria spp. were evaluated for their potential interaction with human sirtuin 1 and sirtuin 2 by molecular docking and molecular dynamics simulation approaches. The in silico results allowed for the selection of five potentially active compounds, namely, prunifoleine, 14-oxoprunifoleine, E-vallesiachotamine, Z-vallesiachotamine, and vallesiachotamine lactone. The sirtuin inhibition of these compounds was confirmed in vitro in a dose-response manner, with preliminary information on their pharmacokinetics properties.

A review of the sirtuin system, its clinical implications, and the potential role of dietary activators like resveratrol: part 1.

The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that the sirtuins are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Responses of this system to environmental factors, as well as its role in health and disease, are currently incompletely characterized and at most partially understood. This article reviews the mammalian sirtuin system, discusses the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarizes research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. Polyphenols, especially resveratrol, influence sirtuins. Existing evidence on these nutritional compounds, as they relate to the sirtuin system, is reviewed. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer, are discussed.

A review of the sirtuin system, its clinical implications, and the potential role of dietary activators like resveratrol: part 2.

The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that they are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Part 1 of this article provided an overview of the mammalian sirtuin system, discussed the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarized research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer are discussed. Research on the ability of nutritional substances, especially resveratrol, to influence sirtuin expression and function, and hence alter the courses of some clinical situations, is also reviewed.

Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury.

Traumatic brain injury (TBI) produces a state of vulnerability that reduces the brain capacity to cope with secondary insults. The silent information regulator 2 (Sir2) has been implicated with maintaining genomic stability and cellular homeostasis under challenging situation. Here we explore the possibility that the action of Sir2alpha (mammalian Sir2) in the brain can extend to serve neuronal plasticity. We provide novel evidence showing that mild TBI reduces the expression of Sir2alpha in the hippocampus, in proportion to increased levels of protein oxidation. In addition, we show that dietary supplementation of omega-3 fatty acids that ameliorates protein oxidation was effective to reverse the reduction of Sir2alpha level in injured rats. Given that oxidative stress is a subproduct of dysfunctional energy homeostasis, we measured AMP-activated protein kinase (AMPK) and phosphorylated-AMPK (p-AMPK) to have an indication of the energy status of cells. Hippocampal levels of total and phosphorylated AMPK were reduced after TBI and levels were normalized by omega-3 fatty acts supplements. Further, we found that TBI reduced ubiquitous mitochondrial creatine kinase (uMtCK), an enzyme implicated in the energetic regulation of Ca2+-pumps and in the maintenance of Ca2+-homeostasis. Omega-3 fatty acids supplements normalized the levels of uMtCK after lesion. Furthermore, we found that the correlation between Sir2alpha and AMPK or p-AMPK was disrupted by TBI, but restored by omega-3 fatty acids supplements. Our results suggest that TBI may compromise neuronal protective mechanisms by involving the action of Sir2alpha. In addition, results show the capacity of omega-3 fatty acids to counteract some of the effects of TBI by normalizing levels of molecular systems associated with energy homeostasis.

Myristica fragrans Houtt. methanolic extract induces apoptosis in a human leukemia cell line through SIRT1 mRNA downregulation.

BACKGROUND: Myristica fragrans Houtt. (nutmeg) contains antibacterial, antiviral and anti-cancer activities. However the mechanisms underlying those activities have not been clearly explained. OBJECTIVE: To study the effect of Myristica fragrans Houtt. methanolic extract on Jurkat human leukemia T cell line. MATERIAL AND METHOD: Methanol extract of Myristica fragrans Houtt. (Myristicaceae) was used to study the effect on Jurkat cell metabolic activity using an MTT assay and on apoptosis using annexin V staining. Expression of SIRT1 gene was determined by RT-PCR. RESULTS: At the concentrations 50 and 100 ig/mL, the methanol extract of Myristica fragrans Houtt significantly inhibited Jurkat cell proliferation and induced apoptosis as detected by annexin V staining. Downregulation of SIRT1 mRNA expression in Jurkat cells was observed even when the amount of methanol extract was 10 microg/mL. CONCLUSION: Methanol extract of Myristica fragrans Houtt induced apoptosis of Jurkat leukemia T cell line in a mechanisms involving SIRTI mRNA downregulation.