// Anna V. Kudryavtseva 1,2 , George S. Krasnov 1 , Alexey A. Dmitriev 1 , Boris Y. Alekseev 2 , Olga L. Kardymon 1 , Asiya F. Sadritdinova 1,2 , Maria S. Fedorova 1 , Anatoly V. Pokrovsky 3 , Nataliya V. Melnikova 1 , Andrey D. Kaprin 2 , Alexey A. Moskalev 1,4 and Anastasiya V. Snezhkina 1 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia 2 National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia 3 A.V. Vishnevsky Institute of Surgery, Moscow, Russia 4 Moscow Institute of Physics and Technology, Dolgoprudny, Russia Correspondence to: Anna V. Kudryavtseva, email: // Keywords : oxidative stress, mitochondrial dysfunction, ROS, aging, cancer, Gerotarget Received : November 23, 2015 Accepted : May 28, 2016 Published : June 05, 2016 Abstract Aging and cancer are the most important issues to research. The population in the world is growing older, and the incidence of cancer increases with age. There is no doubt about the linkage between aging and cancer. However, the molecular mechanisms underlying this association are still unknown. Several lines of evidence suggest that the oxidative stress as a cause and/or consequence of the mitochondrial dysfunction is one of the main drivers of these processes. Increasing ROS levels and products of the oxidative stress, which occur in aging and age-related disorders, were also found in cancer. This review focuses on the similarities between ageing-associated and cancer-associated oxidative stress and mitochondrial dysfunction as their common phenotype.

/pdf/mitochondrial-dysfunction-and-oxidative-stress-in-aging-and-3xigwgfqet.pdf

Mitochondrial dysfunction and oxidative stress in aging and cancer

Over the past three decades, selenium has been intensively investigated as an antioxidant trace element. It is widely distributed throughout the body, but is particularly well maintained in the brain, even upon prolonged dietary selenium deficiency. Changes in selenium concentration in blood and brain have been reported in Alzheimer's disease and brain tumors. The functions of selenium are believed to be carried out by selenoproteins, in which selenium is specifically incorporated as the amino acid, selenocysteine. Several selenoproteins are expressed in brain, but many questions remain about their roles in neuronal function. Glutathione peroxidase has been localized in glial cells, and its expression is increased surrounding the damaged area in Parkinson's disease and occlusive cerebrovascular disease, consistent with its protective role against oxidative damage. Selenoprotein P has been reported to possess antioxidant activities and the ability to promote neuronal cell survival. Recent studies in cell culture and gene knockout models support a function for selenoprotein P in delivery of selenium to the brain. mRNAs for other selenoproteins, including selenoprotein W, thioredoxin reductases, 15-kDa selenoprotein and type 2 iodothyronine deiodinase, are also detected in the brain. Future research directions will surely unravel the important functions of this class of proteins in the brain.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.2003.01854.x

Selenium and selenoproteins in the brain and brain diseases

Small molecules that alter protein function provide a means to modulate biological networks with temporal resolution. Here we demonstrate a potentially general and scalable method of identifying such molecules by application to a particular protein, Ure2p, which represses the transcription factors Gln3p and Nil1p1,2,3. By probing a high-density microarray of small molecules generated by diversity-oriented synthesis with fluorescently labelled Ure2p, we performed 3,780 protein-binding assays in parallel and identified several compounds that bind Ure2p. One compound, which we call uretupamine, specifically activates a glucose-sensitive transcriptional pathway downstream of Ure2p. Whole-genome transcription profiling and chemical epistasis demonstrate the remarkable Ure2p specificity of uretupamine and its ability to modulate the glucose-sensitive subset of genes downstream of Ure2p. These results demonstrate that diversity-oriented synthesis and small-molecule microarrays can be used to identify small molecules that bind to a protein of interest, and that these small molecules can regulate specific functions of the protein.

/pdf/dissecting-glucose-signalling-with-diversity-oriented-4h2bk4qd7q.pdf

Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays

Free radical pathology and antioxidant defense in schizophrenia: a review

In metabolism research, thermodynamics is usually used to determine the directionality of a reaction or the feasibility of a pathway. However, the relationship between thermodynamic potentials and fluxes is not limited to questions of directionality: thermodynamics also affects the kinetics of reactions through the flux-force relationship, which states that the logarithm of the ratio between the forward and reverse fluxes is directly proportional to the change in Gibbs energy due to a reaction (ΔrG′). Accordingly, if an enzyme catalyzes a reaction with a ΔrG′ of -5.7 kJ/mol then the forward flux will be roughly ten times the reverse flux. As ΔrG′ approaches equilibrium (ΔrG′ = 0 kJ/mol), exponentially more enzyme counterproductively catalyzes the reverse reaction, reducing the net rate at which the reaction proceeds. Thus, the enzyme level required to achieve a given flux increases dramatically near equilibrium. Here, we develop a framework for quantifying the degree to which pathways suffer these thermodynamic limitations on flux. For each pathway, we calculate a single thermodynamically-derived metric (the Max-min Driving Force, MDF), which enables objective ranking of pathways by the degree to which their flux is constrained by low thermodynamic driving force. Our framework accounts for the effect of pH, ionic strength and metabolite concentration ranges and allows us to quantify how alterations to the pathway structure affect the pathway's thermodynamics. Applying this methodology to pathways of central metabolism sheds light on some of their features, including metabolic bypasses (e.g., fermentation pathways bypassing substrate-level phosphorylation), substrate channeling (e.g., of oxaloacetate from malate dehydrogenase to citrate synthase), and use of alternative cofactors (e.g., quinone as an electron acceptor instead of NAD). The methods presented here place another arrow in metabolic engineers' quiver, providing a simple means of evaluating the thermodynamic and kinetic quality of different pathway chemistries that produce the same molecules.

/pdf/pathway-thermodynamics-highlights-kinetic-obstacles-in-52kiqcm1c3.pdf

Pathway thermodynamics highlights kinetic obstacles in central metabolism

The location of peroxide-utilizing enzymes has been studied in rat brain. Glutathione peroxidase and glutathione reductase distributions indicate that both enzymes are located in the cytoplasm and in the matrix space of “synaptosomal” and “free” mitochondria. On the other hand, catalase distribution parallels that of NADH-cytochrome c reductase (rotenone-insensitive), and appears to be associated with the outer membrane of brain mitochondria. Whereas no gross age-dependent changes in various marker enzymes were found, a gradual but significant increase in glutathione peroxidase from the soluble fraction of free mitochondria was detected. The consequences of such increase are discussed with regard to the reducing potential of the cell.

Age‐Dependent Variations in Peroxide‐Utilizing Enzymes from Rat Brain Mitochondria and Cytoplasm

The patterns of brain enzymes linked to energy metabolism have been determined in rats aged between 3 and 21 months and compared to those of the developing brain as an estimate of the senescent energy capacity of this organ. During aging, pyruvate kinase increases, pointing towards an enhancement of the glucose-dependence of this organ. However, NAD-isocitrate dehydrogenase declines, suggesting a reduction of Krebs cycle activity in the aged rat brain. An increase in cytoplasmic NAD-malate dehydrogenase found during aging could provide an alternative mechanism of NAD recovery.

Age-related quantitative changes in enzyme activities of rat brain.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2879%2980642-0

Evidence suggesting that the NADPH/NADP ratio modulates the splitting of the isocitrate flux between the glyoxylic and tricarboxylic acid cycles, in Escherichia coli

The activity of glutamate dehydrogenase (NADP+) (EC 1.4.1.4; NADP-GDH) of Saccharomyces cerevisiae is decreased under conditions in which intracellular ammonia concentration increases. A high internal ammonia concentration can be obtained (a) by increasing the ammonium sulphate concentration in the culture medium, and (b) by growing the yeast either in acetate + ammonia media, where the pH of the medium rises during growth, or in heavily buffered glucose + ammonia media at pH 7.5. Under these conditions cellular oxoglutarate concentrations do not vary and changes in NADP-GDH activity appear to provide a constant rate of oxoglutarate utilization. The following results suggest that the decrease in NADP-GDH activity in ammonia-accumulating yeast cells is brought about by repression of synthesis: (i) after a shift to high ammonium sulphate concentrations, the number of units of activity per cell decreased as the inverse of cell doubling; and (ii) the rate of degradation of labelled NADP-GDH was essentially the same in ammonia-accumulating yeast cells and in controls, whereas the synthesis constant was much lower in the ammonia-accumulating cells than in the controls.

/pdf/regulation-by-ammonium-of-glutamate-dehydrogenase-nadp-from-3wba7zf4um.pdf

Regulation by ammonium of glutamate dehydrogenase (NADP+) from Saccharomyces cerevisiae.

Ammonia accumulation in acetate-growing yeast.

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