Vitamin C (ascorbic acid, AA) is a cofactor for many important enzymatic reactions and a powerful antioxidant. AA provides protection against oxidative stress by acting as a scavenger of reactive oxygen species, either directly or indirectly by recycling of the lipid-soluble antioxidant, α-tocopherol (vitamin E). Only a few species, including humans, guinea pigs, and zebrafish, cannot synthesize AA. Using an untargeted metabolomics approach, we examined the effects of α-tocopherol and AA deficiency on the metabolic profiles of adult zebrafish. We found that AA deficiency, compared with subsequent AA repletion, led to oxidative stress (using malondialdehyde production as an index) and to major increases in the metabolites of the purine nucleotide cycle (PNC): IMP, adenylosuccinate, and AMP. The PNC acts as a temporary purine nucleotide reservoir to keep AMP levels low during times of high ATP utilization or impaired oxidative phosphorylation. The PNC promotes ATP regeneration by converting excess AMP into IMP, thereby driving forward the myokinase reaction (2ADP → AMP + ATP). On the basis of this finding, we investigated the activity of AMP deaminase, the enzyme that irreversibly deaminates AMP to form IMP. We found a 47% increase in AMP deaminase activity in the AA-deficient zebrafish, complementary to the 44-fold increase in IMP concentration. These results suggest that vitamin C is crucial for the maintenance of cellular energy metabolism.
"Xanthosine, the corresponding nucleoside of xanthine, has been linked to stagger in sheep, thus associating purine to motor neuron disease . Further, recent studies have shown that ascorbate levels act on the purine metabolism pathway, which suggests that the effect of lithium on ascorbate and purine metabolites that was observed in this study could be linked . "
[Show abstract][Hide abstract] ABSTRACT: We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1(154Q/+) ). To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1(154Q/+) mice, with and without lithium treatment, were performed using gas chromatography time-of-flight mass spectrometry and BinBase mass spectral annotations. We detected 416 metabolites, of which 130 were identified. We observed specific metabolic perturbations in Sca1(154Q/+) mice and major effects of lithium on metabolism, centrally and peripherally. Compared to wild-type, Sca1(154Q/+) cerebella metabolic profile revealed changes in glucose, lipids, and metabolites of the tricarboxylic acid cycle and purines. Fewer metabolic differences were noted in Sca1(154Q/+) mouse plasma versus wild-type. In both genotypes, the major lithium responses in cerebellum involved energy metabolism, purines, unsaturated free fatty acids, and aromatic and sulphur-containing amino acids. The largest metabolic difference with lithium was a 10-fold increase in ascorbate levels in wild-type cerebella (p<0.002), with lower threonate levels, a major ascorbate catabolite. In contrast, Sca1(154Q/+) mice that received lithium showed no elevated cerebellar ascorbate levels. Our data emphasize that lithium regulates a variety of metabolic pathways, including purine, oxidative stress and energy production pathways. The purine metabolite level, reduced in the Sca1(154Q/+) mice and restored upon lithium treatment, might relate to lithium neuroprotective properties.
PLoS ONE 08/2013; 8(8):e70610. DOI:10.1371/journal.pone.0070610 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With the advent of genetic engineering, zebrafish (Danio rerio) were recognized as an attractive model organism to study many biological processes. Remarkably, the small size and optical transparency of zebrafish larvae enable high-resolution imaging of live animals. Zebrafish respond to various environmental and pathological factors with robust oxidative stress. In this article, we provide an overview of the molecular mechanisms involved in oxidative stress and antioxidant response in zebrafish. Existing applications of genetically encoded fluorescent sensors allow imaging, in real time, of the production of H(2)O(2) and studying its involvement in inflammatory responses, as well as activation of the oxidation-sensitive transcription factors HIF and NRF2. Oxidative stress, combined with hyperlipidemia, leads to oxidation of lipoproteins, the process that contributes significantly to the development of atherosclerosis in humans. Recent work found that feeding zebrafish a high-cholesterol diet results in hypercholesterolemia, vascular lipid accumulation, and extreme lipoprotein oxidation. Generation of a transgenic zebrafish expressing a green fluorescent protein-tagged human antibody to malondialdehyde (MDA)-modified LDL makes possible the in vivo visualization of MDA epitopes in the vascular wall and testing of the efficacy of antioxidants and dietary interventions. Thus, using zebrafish as a model organism provides important advantages in studying the roles of reactive oxygen species and lipid oxidation in basic biologic and pathologic processes.
Free Radical Biology and Medicine 08/2012; 53(7):1411-20. DOI:10.1016/j.freeradbiomed.2012.08.004 · 5.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: More needs to be done by the private sector to optimize the drug discovery and development pipeline. In addition, significant efforts should also be focused on the understanding of mechanism of diseases, on the characterization of unexplored biochemical pathways and on the validation of new protein targets. Chemical genomics, which uses chemical probes to help understand the complexity of biological systems at the gene and protein levels, has proven in recent years to be an important tool. Experimental and computational chemical genomic screenings have been used by the private sector and recently also by academia and non-profit institutions for drug repurposing or repositioning to find new indications for known drugs. A detailed overview of the current initiatives in drug repurposing, initiated by the major governmental funding agencies around the world is reported. The push towards greater efficiency is encouraging drug repurposing and other techniques in chemical genomics. Finding the best ways to improve translational research and accelerate the regulation of clinical phases means being able to launch safer drugs into the market faster.
Current topics in medicinal chemistry 10/2012; 12(17). DOI:10.2174/156802612804547344 · 3.40 Impact Factor
Xiao-Xin Dai, Xing Duan, Xiang-Shun Cui, Nam-Hyung Kim, Bo Xiong, Shao-Chen Sun
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