Cell Life Versus Cell Longevity: The Mysteries Surrounding the NAD+ Precursor Nicotinamide

Li, Faqi; Chong, Zhao Zhong; Maiese, Kenneth

doi:10.2174/092986706776361058

Cited by 113 publications

(173 citation statements)

References 241 publications

(372 reference statements)

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“…Yet, Wnt1 also may rely upon the central pathways of Akt1 that have been shown to promote cellular integrity and survival during free radical injury [16,19], oxidative stress [17,18], tumor invasion [36], cell longevity [37], and amyloid toxicity [13][14][15]. Evidence for the dependence of Wnt1 on the Akt pathway can be drawn from a variety of cell populations.…”

Section: Discussionmentioning

confidence: 99%

Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

Chong

Maiese

2007

Cellular Signalling

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164

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Initially described as a modulator of embryogenesis for a number of organ systems, Wnt1 has recently been linked to the development of several neurodegenerative disorders, none being of greater significance than Alzheimer's disease. We therefore examined the ability of Wnt1 to oversee vital pathways responsible for cell survival during β-amyloid (Aβ 1-42 )exposure. Here we show that Wnt1 is critical for protection in the SH-SY5Y neuronal cell line against genomic DNA degradation, membrane phosphatidylserine (PS) exposure, and microglial activation, since these neuroprotective attributes of Wnt1 are lost during gene silencing of Wnt1 protein expression. Intimately tied to Wnt1 protection is the presence and activation of Akt1. Pharmacological inhibition of the PI 3-K pathway or gene silencing of Akt1 expression can abrogate the protective capacity of Wnt1. Closely aligned with Wnt1 and Akt1 are the integrated canonical pathways of synthase kinase-3β (GSK-3β) and β-catenin. Through Akt1 dependent pathways, Wnt1 phosphorylates GSK-3β and maintains β-catenin integrity to insure its translocation from the cytoplasm to the nucleus to block apoptosis. Our work outlines a highly novel role for Wnt1 and its integration with Akt1, GSK-3β, and β-catenin to foster neuronal cell survival and repress inflammatory microglial activation that can identify new avenues of therapy against neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

Chong

Maiese

2007

Cellular Signalling

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164

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“…Chronic PARP activation quickly depletes cellular NAD stores, administration of NAM has been shown to inhibit PARP, increase levels of NAD in cortical areas affected by ischemic events, and restore ATP levels (Chang et al, 2002, Sadanaga-Akiyoshi et al, 2003, Tam et al, 2005. NAM has also been shown to prevent cellular injury, due to inflammation, by maintaining membrane asymmetry and inhibiting several cytokines (Li et al, 2006). NAM activates protein kinase B and inhibits forkhead transcription factor's transcription of proapoptotic genes.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide treatment induces behavioral recovery when administered up to 4 hours following cortical contusion injury in the rat

Hoane¹,

Pierce²,

Holland³

et al. 2008

Neuroscience

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Recent studies have demonstrated nicotinamide (NAM), a soluble B-group vitamin, to be an effective treatment in experimental models of TBI. However, research on this compound has been limited to administration regimens starting shortly after injury. This study was conducted to establish the window of opportunity for NAM administration following controlled cortical impact (CCI) injury to the frontal cortex. Groups of rats were assigned to NAM (50 mg/kg), saline (1 ml/kg), or sham conditions and received contusion injuries or sham procedures. Injections of NAM or saline were administered at 15 min, 4 hrs, or 8 hrs post-injury, followed by five boosters at 24 hr intervals. Following the last injection, blood was taken for serum NAM analysis. Animals were tested on a variety of tasks to assess somatosensory performance (bilateral tactile adhesive removal and vibrissae-forelimb placement) and cognitive performance (reference and working memory) in the Morris water maze. The results of the serum NAM analysis showed that NAM levels were significantly elevated in treated animals. Behavioral analysis on the tactile removal test showed that all NAM-treated groups facilitated recovery of function compared to saline treatment. On the vibrissae-forelimb placing test all NAM-treated groups also were significantly different from the saline-treated group. However, the acquisition of reference memory was only significantly improved in the 15-min and 4-hr groups. In the working memory task both the 15-min and 4-hr groups also improved working memory compared to saline treatment. The window of opportunity for NAM treatment is task-dependent and extends to 8 hrs for the sensorimotor tests but only extends to 4 hrs post-injury in the cognitive tests. These results suggest that a 50 mg/kg treatment regimen starting at the clinically relevant time point of 4 hrs may result in attenuated injury severity in the human TBI population.

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“…The loss of membrane phospholipid asymmetry leads to the externalization of membrane PS residues and assists microglia to target cells for phagocytosis [33,[40][41][42][43]. This process occurs with the expression of the phosphatidylserine receptor (PSR) on microglia during oxidative stress [11,44], since blockade of PSR function in microglia prevents the activation of microglia [41,45]. As an example, externalization of membrane PS residues occur in neurons during anoxia [46][47][48], nitric oxide exposure [49,50], and during the administration of agents that induce the production of reactive oxygen species, such as 6-hydroxydopamine [51].…”

Section: The Role Of Oxidative Stress In Dmmentioning

confidence: 99%

“…In addition, mitochondria are a significant source of superoxide radicals that are associated with oxidative stress [10,17]. Blockade of the electron transfer chain at the flavin mononucleotide group of complex I or at the ubiquinone site of complex III results in the active generation of free radicals which can impair mitochondrial electron transport and enhance free radical production [11,57]. Furthermore, mutations in the mitochondrial genome have been associated with the potential development of a host of disorders, such as hypertension, hypercholesterolemia, and hypomagnesemia [64,65].…”

Section: The Role Of Oxidative Stress In Dmmentioning

confidence: 99%

“…For example, DM can impair vascular integrity and alter cardiac output [9] that eventually diminishes the capacity of sensitive cognitive regions of the brain leading to functional impairment and dementia [10][11][12]. Disease of the nervous system can become the most debilitating complications for DM and affect sensitive cognitive regions of the brain, such as the hippocampus that modulates memory function, resulting in significant functional impairment and dementia [13].…”

Section: Introductionmentioning

confidence: 99%

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Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

Maiese

2008

Biomedicine & Pharmacotherapy

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SummaryOxidative stress is a principal pathway for the dysfunction and ultimate destruction of cells in the neuronal and vascular systems for several disease entities, non promoting the ravages of oxidative stress to any less of a degree than diabetes mellitus. Diabetes mellitus is increasing in incidence as a result of changes in human behavior that relate to diet and daily exercise and is predicted to affect almost 400 million individuals worldwide in another two decades. Furthermore, both type 1 and type 2 diabetes mellitus can lead to significant disability in the nervous and cardiovascular systems, such as cognitive loss and cardiac insufficiency. As a result, innovative strategies that directly target oxidative stress to preserve neuronal and vascular longevity could offer viable therapeutic options to diabetic patients in addition to more conventional treatments that are designed to control serum glucose levels. Here we discuss the novel application of nicotinamide, Wnt signaling, and erythropoietin that modulate cellular oxidative stress and offer significant promise for the prevention of diabetic complications in the nervous and vascular systems. Essential to this process is the precise focus upon diverse as well as common cellular pathways governed by nicotinamide, Wnt signaling, and erythropoietin to outline not only the potential benefits, but also the challenges and possible detriments of these therapies. In this way, new avenues of investigation can hopefully bypass toxic complications, or at the very least, avoid contraindications that may limit care and offer both safe and robust clinical treatment for patients.

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Cell Life Versus Cell Longevity: The Mysteries Surrounding the NAD+ Precursor Nicotinamide

Cited by 113 publications

References 241 publications

Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

Nicotinamide treatment induces behavioral recovery when administered up to 4 hours following cortical contusion injury in the rat

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

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