Neuronal protection by sirtuins in Alzheimer's disease

Anekonda, Thimmappa S.; Reddy, P. Hemachandra

doi:10.1111/j.1471-4159.2005.03492.x

Cited by 143 publications

(105 citation statements)

References 96 publications

(208 reference statements)

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“…Finally, the class III HDACs, or sirtuins, have been implicated in diverse biological processes including physiology, metabolism and longevity (Haigis and Guarente, 2006). Consistent with this regulation, sirtuin activators related to the polyphenol resveratrol have been shown to suppress age-associated diseases such as type II diabetes, obesity and cancer (Wood et al, 2004a, b;Kobayashi et al, 2005;Parker et al, 2005;Anekonda and Reddy, 2006;Baur et al, 2006).…”

Section: Introductionmentioning

confidence: 91%

“…Various small-molecule HDAC inhibitors that have shown antitumor activity in model systems have advanced into clinical trials (Lin et al, 2006;Gallinari et al, 2007), and SAHA (suberoylanilide hydroxamic acid, vorinostat) was recently shown to inhibit the growth of pancreatic cancer cells (Kumagai et al, 2007) and was recently approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma. There is also a therapeutic interest in the sirtuins as they have been linked to the correlation between caloric restriction and life span extension in model organisms such as yeast, worms, flies, fish and rodents; in mammals, sirtuin activity has been linked to counteracting age-associated diseases such as type II diabetes, obesity and neurodegenerative disorders (Wood et al, 2004a, b;Kobayashi et al, 2005;Parker et al, 2005;Anekonda and Reddy, 2006;Baur et al, 2006). The association of sirtuins with aging and diseases is discussed in greater detail in this issue of Oncogene (Saunders and Verdin, 2007).…”

Section: Overview Of Hdacsmentioning

confidence: 99%

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Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

2007

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The post-translational modification of histones plays an important role in chromatin regulation, a process that insures the fidelity of gene expression and other DNA transactions. Of the enzymes that mediate post-translation modification, the histone acetyltransferase (HAT) and histone deacetylase (HDAC) proteins that add and remove acetyl groups to and from target lysine residues within histones, respectively, have been the most extensively studied at both the functional and structural levels. Not surprisingly, the aberrant activity of several of these enzymes have been implicated in human diseases such as cancer and metabolic disorders, thus making them important drug targets. Significant mechanistic insights into the function of HATs and HDACs have come from the X-ray crystal structures of these enzymes both alone and in liganded complexes, along with associated enzymatic and biochemical studies. In this review, we will discuss what we have learned from the structures and related biochemistry of HATs and HDACs and the implications of these findings for the design of protein effectors to regulate gene expression and treat disease.

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Section: Introductionmentioning

confidence: 91%

Section: Overview Of Hdacsmentioning

confidence: 99%

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

2007

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“…An important posttranslational modification by Sirt1 is deacetylation of functionally critical proteins such as Pgc-1α, MyoD, Ucp2, Ku70, NFkb, p53 and c-Myc (46)(47)(48)(49). Multiple feedback loops have been identified in the transcription of Sirt1 (47).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1

Jian

Yang

Chaudry

et al. 2011

Mol Med

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Mitochondria play a critical role in metabolic homeostasis of a cell. Our recent studies, based on the reported interrelationship between c-Myc and Sirt1 (mammalian orthologue of yeast sir2 [silent information regulator 2]) expression and their role in mitochondrial biogenesis and function, demonstrated a significant downregulation of Sirt1 protein expression and an upregulation of c-Myc following trauma-hemorrhage (T-H). Activators of Sirt1 are known to improve mitochondrial function and the naturally occurring polyphenol resveratrol (RSV) has been shown to significantly increase Sirt1 activity by increasing its affinity to both NAD+ and the acetylated substrate. In this study we tested the salutary effect of RSV following T-H and its influence on Sirt1 expression. Rats were subjected to T-H or sham operation. RSV (8 mg/kg body weight, intravenously) or vehicle was administered 10 min after the onset of resuscitation, and the rats were killed 2 h following resuscitation. Sirtinol, a Sirt1 inhibitor, was administered 5 min prior to RSV administration. Cardiac contractility (±dP/dt) was measured and heart tissue was tested for Sirt1, Pgc-1α, c-Myc, cytosolic cytochrome C expression and ATP level. Left ventricular function, after T-H, was improved (P < 0.05) following RSV treatment, with significantly elevated expression of Sirt1 (P < 0.05) and Pgc-1α (P < 0.05), and decreased c-Myc (P < 0.05). We also observed significantly higher cardiac ATP content, declined cytosolic cytochrome C and decreased plasma tumor necrosis factor-α in the T-H-RSV group. The salutary effect due to RSV was abolished by sirtinol, indicating a Sirt1-mediated effect. We conclude that RSV may be a useful adjunct to resuscitation fluid following T-H.

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“…By itself, resveratrol is a potent anti-oxidant which is thought to be responsible for the French Paradox [65]; relating to the low incidence of cardiovascular disease in a French population with high intake of saturated fats. In addition to its demonstrated capacity to inhibit (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) fibril formation in vitro [16], resveratrol is also capable of promoting intracellular uptake and degradation of through a proteosome-dependent mechanism [66] and protecting against -induced neurotoxicity [67,68], possibly through activation of the NAD-dependent histone deacetylase, SIRT1 [69]. In the present study using the ELISA-based assay, catechin showed no inhibitory activity during the early stages of oligomerization, whereas rosmarinic acid demonstrated some activity at the highest concentration tested.…”

Section: Discussionmentioning

confidence: 99%

A Sensitive Aβ Oligomerization Assay for Identification of Small Molecule Inhibitors

Gonzales¹,

Orlando²

2009

TOBIOTJ

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Amyloid deposits found in Alzheimer's disease result from aggregation of peptide which leads to loss of synaptic function, chronic microglial activation and cognitive impairment. Because of this, identification of small molecule inhibitors of aggregation as potential therapeutics is a topic of current interest. The majority of inhibitor screening approaches rely on in vitro assays that lack the necessary sensitivity to distinguish low-molecular weight oligomers from larger, more advanced-stage fibrillar structures. Differentiating between these two structures is of vital concern since recent studies indicate that small, early-stage oligomers are the most neurotoxic form of peptide aggregate. To address this limitation, we have explored the adaptability of a recently described ELISA-based assay for discovery of small molecule inhibitors of oligomerization. Results show that this assay is highly sensitive as it is able to quantify oligomers with as little as 80 nM input peptide. In addition, data were obtained re-confirming the function of curcumin as a potent inhibitor of aggregation (IC 50 = 2 μM) and defining its inhibitor:peptide functional stoichiometry. Further examination of other known anti-aggregation compounds showed that this assay is able to discriminate between inhibitors of early-stage, low-molecular weight oligomers and later-stage, high-molecular weight fibrillar structures. These findings indicate that this new ELISA-based assay is capable of identifying novel small molecule inhibitors that function during the initial stages of peptide assembly.

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Neuronal protection by sirtuins in Alzheimer's disease

Cited by 143 publications

References 96 publications

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1

A Sensitive Aβ Oligomerization Assay for Identification of Small Molecule Inhibitors

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