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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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.

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key redox-sensitive protein, the activity of which is largely affected by oxidative modifications at its highly reactive cysteine residue in the active site of the enzyme (Cys-152). These modifications occur as a result of S-thiolation, S-nitrosylation or disulfide bonds that lead to aggregate formation. The oxidative changes not only affect the glycolytic function but also stimulate the participation of GAPDH in numerous cellular processes. In this review we describe how thiol modification of Cys-152 in GAPDH re-routes metabolic pathways in the cell and converts a metabolic enzyme into a pro-apoptotic factor. Especially interesting issue is the participation of GAPDH in the regulation of expression of endothelin 1 and nitrosylation of nuclear proteins. In the last section we describe involvement of GAPDH in the processes associated with neurodegenerative diseases.

Gerszon J., Rodacka A. (2016): Determination of trans-resveratrol action on two different types of neuronal cells, neuroblastoma and hippocampal cells. Czech J. Food Sci., 34: 118-126.The effects of resveratrol on a cancer cell line derived from the nervous system, neuroblastoma and a cell line derived from hippocampal neurons under hydrogen peroxide-induced oxidative stress were evaluated and compared. Our studies indicate that resveratrol exerts different effects on tumour and normal cells. Interestingly, in the presence of an oxidising factor resveratrol can sensitise cancer cells and decrease their viability substantially. Under conditions of oxidative stress similar to those found in the tumour environment, resveratrol also intensified apoptosis in Neuro-2a cells. Our data indicate that resveratrol does not protect neuronal, hippocampal cells from oxidative damage.