Resveratrol is a natural organic compound, polyphenol, produced naturally by some plants in response to several harmful factors such as attack by pathogens, UV radiation, or increased oxidative stress. Many experiments suggest that it triggers mechanisms that counteract aging-related effects and plays a role in insulin resistance as well. It also possesses beneficial properties such as anti-cancer, anti-inflammatory, blood-sugar-lowering and cardiovascular effects. It is supposed to exhibit an interesting activity in neuroprotection -mainly through activation of sirtuins and counteraction in forming peptide aggregates. Still research is needed to evaluate exactly how resveratrol protects neurons, and to develop new, potential, therapeutic drugs.List of abbreviations: Aβ -beta amyloid, ADAM 10 -protein belonging to the family of alpha-secretases, AKT -serine/threonine kinase Akt, AMPK -AMP-dependent kinase, ARE -the antioxidant response element, BDNF -brain derived neurotrophic factor, CaMKKβ -calmodulin-dependent protein kinase kinase β, cAMP -adenosine 3',5'-cyclic monophosphate, COX1 -cyclooxygenase 1, DRP1 -dynamin-related protein, Epac1 -guanine nucleotide exchange factor, F 2α (8-iso-PGF 2α ) -8-iso-prostaglandin F 2α , GSK-3β-β -glycogen synthase kinase 3, HD -Huntington's disease, HSF1 -heat shock factor, HSP-70 -heat shock protein, LDL -low density lipoproteins, MeCP2 -transcriptional protein, MFN1 -mitofusin 1, MFN2 -mitofusin 2, mPGES-1 -microsomal prostaglandin E synthase 1, MPTP-1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MsrA -methionine sulfoxide reductase, NEP -neprilysin, MyoD -myoblast determination protein 1, NF -kB -nuclear transcription factor, Nrf2 -nuclear factor 2, OH -1 -heme oxygenase 1, OPA1 -optic atrophy 1, PD -Parkinson's disease, PDE -phosphodiesterase cyclic nucleotides, PI3K -phosphatidylinositol 3-kinase, PGC-1α -proliferator peroxisome-activated receptor gamma coactivator 1-alpha , PGE 2 -prostaglandin E 2 , RAR -retinoic acid receptor β, RNS -reactive nitrogen species, ROCK -Rho-dependent kinase, ROS -reactive oxygen species, RSV -resveratrol, SIRT1 -sirtuin 1, SIRT3 -sirtuin 3, SOD -superoxide dismutase, TMS -2,3',4,5' tetramethylstilbene, TORC1 -target-of-rapamycin complex 1, YY1 -transcription factor Yin Yang 1 Brought to you by | CAPES Authenticated Download Date | 10/5/15 2:17 PM98 J. GERSZON, A. RODACKA, M. PUCHAŁA

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Protein damage mediated by oxidation has been associated with aging and age-related diseases, in particular neurodegenerative diseases. The protein that is known to be one of the major targets of oxidative stress is glyceraldehyde- 3-phosphate dehydrogenase. GAPDH is believed to play a key role in certain neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Several recent studies have suggested that a wide range of variety of polyphenols including resveratrol may have neuroprotective effects. Here, we present data that clearly indicate the prooxidative properties of resveratrol and tiron in the inactivation of GAPDH induced by the superoxide anion generated via xanthine oxidase mediated oxidation of xanthine. Generated in the studied system tiron and resveratrol radicals are much more efficient in the inactivation of GAPDH than the superoxide anion alone. The analysis of CD spectra of protein exposed to the tiron and resveratrol radicals revealed little effect on the secondary structure of GAPDH. In both cases reduction of α-helical structure was followed by the increase in β-sheet conformation. Thus, the most probable mechanism of inactivation of GAPDH in the studied system is oxidation of cysteine residues in the catalytic center of the enzyme. Finally, molecular modeling of the resveratrol - GAPDH and tiron - GAPDH complexes showed potential binding sites for those antioxidants with binding affinity -45 kcal/mol and -48 kcal/mol respectively.

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is one of the key redox-sensitive proteins whose activity is largely affected by oxidative modifications at its highly reactive cysteine residue in the enzyme’s active site (Cys149). Prolonged exposure to oxidative stress may cause, inter alia, the formation of intermolecular disulfide bonds leading to accumulation of GAPDH aggregates and ultimately to cell death. Recently these anomalies have been linked with the pathogenesis of Alzheimer’s disease. Novel evidences indicate that low molecular compounds may be effective inhibitors potentially preventing the GAPDH translocation to the nucleus, and inhibiting or slowing down its aggregation and oligomerization. Therefore, we decided to establish the ability of naturally occurring compound, piceatannol, to interact with GAPDH and to reveal its effect on functional properties and selected parameters of the dehydrogenase structure. The obtained data revealed that piceatannol binds to GAPDH. The ITC analysis indicated that one molecule of the tetrameric enzyme may bind up to 8 molecules of polyphenol (7.3 ± 0.9). Potential binding sites of piceatannol to the GAPDH molecule were analyzed using the Ligand Fit algorithm. Conducted analysis detected 11 ligand binding positions. We indicated that piceatannol decreases GAPDH activity. Detailed analysis allowed us to presume that this effect is due to piceatannol ability to assemble a covalent binding with nucleophilic cysteine residue (Cys149) which is directly involved in the catalytic reaction. Consequently, our studies strongly indicate that piceatannol would be an exceptional inhibitor thanks to its ability to break the aforementioned pathologic disulfide linkage, and therefore to inhibit GAPDH aggregation. We demonstrated that by binding with GAPDH piceatannol blocks cysteine residue and counteracts its oxidative modifications, that induce oligomerization and GAPDH aggregation.