Papers by Z. Niatsetskaya
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 29, 2012
Oxidative stress and Ca(2+) toxicity are mechanisms of hypoxic-ischemic (HI) brain injury. This w... more Oxidative stress and Ca(2+) toxicity are mechanisms of hypoxic-ischemic (HI) brain injury. This work investigates if partial inhibition of mitochondrial respiratory chain protects HI brain by limiting a generation of oxidative radicals during reperfusion. HI insult was produced in p10 mice treated with complex I (C-I) inhibitor, pyridaben, or vehicle. Administration of P significantly decreased the extent of HI injury. Mitochondria isolated from the ischemic hemisphere in pyridaben-treated animals showed reduced H(2)O(2) emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to the Ca(2+)-triggered opening of the permeability transition pore. A protective effect of pyridaben administration was also observed when the reperfusion-driven oxidative stress was augmented by the exposure to 100% O(2) which exacerbated brain injury only in vehicle-treated mice. In vitro, intact brain mitochondria dramatically increased H(2)O(2) emission in response to hyperoxia...
Drug Metabolism and Disposition, 2008
The present work documents the first example of an enzyme-catalyzed β-elimination of a thioether ... more The present work documents the first example of an enzyme-catalyzed β-elimination of a thioether from a sulfonium cysteine S-conjugate. β-(S-Tetrahydrothiophenium)-L-alanine (THT-A) is the cysteine S-conjugate of busulfan. THT-A slowly undergoes a non-enzymatic β-elimination reaction at pH 7.4 and 37°C to yield tetrahydrothiophene, pyruvate and ammonia. This reaction is accelerated by a) rat liver, kidney and brain homogenates, b) isolated rat liver mitochondria, and c) pyridoxal 5′phosphate (PLP). A PLP-dependent enzyme in rat liver cytosol that catalyzes a β-lyase reaction with THT-A was identified as cystathionine γ-lyase. This unusual drug metabolism pathway represents an alternate route for intermediates in the mercapturate pathway.
Antioxidants & Redox Signaling, 2010
Mitochondrial dysfunction is a central feature of a number of acute and chronic neurodegenerative... more Mitochondrial dysfunction is a central feature of a number of acute and chronic neurodegenerative conditions, but clinically approved therapeutic interventions are only just emerging. Here we demonstrate the potential clinical utility of low molecular weight inhibitors of the hypoxia inducible factor prolyl-4-hydroxylases (HIF PHDs) in preventing mitochondrial toxin-induced cell death in mouse striatal neurons that express a ''knock-in'' mutant Huntingtin allele. Protection from 3-nitropropionic acid (3-NP, a complex II inhibitor)-induced toxicity by HIF PHD inhibition occurs without rescue of succinate dehydrogenase activity. Although HIF-1a mRNA is dramatically induced by mutant huntingtin, HIF-1a depletion by short interfering RNAs (siRNA) does not affect steady-state viability or protection from 3-NP-induced death by HIF PHD inhibitors in these cells. Moreover, 3-NP-induced complex II inhibition in control or mutant striatal neurons does not lead to activation of HIFdependent transcription. HIF PHD inhibition also protects cortical neurons from 3-NP-induced cytotoxicity. Protection of cortical neurons by HIF PHD inhibition correlates with enhanced VEGF but not PGC-1a gene expression. Together, these findings suggest that HIF PHD inhibitors are promising candidates for preventing cell death in conditions such as Huntington's disease and Alzheimer's disease that are associated with metabolic stress in the central nervous system. Antioxid. Redox Signal. 12, 435-443.
Cell Biochemistry and Function, 2008
Thyroid cells fall into the type of cells functioning during continuous production of high H 2 O ... more Thyroid cells fall into the type of cells functioning during continuous production of high H 2 O 2 concentrations. We studied the effect of H 2 O 2 -induced oxidative stress (0.1, 1.0 and 10.0 mM) on the activities of the key steps of iodide metabolism (uptake, oxidation and organification) in thyrocytes cultivated in an organ culture. After 60 min cultivation of cells in a medium containing H 2 O 2 at concentrations of 1.0 and 10.0 mM iodide (I À ) uptake, thyroperoxidase (TPO) activity and I À organification were completely inhibited. No restoration of the parameters studied was observed within the subsequent 24 h of cultivation. The inhibitory effect of 0.1 mM H 2 O 2 was reversible. Activation of I À uptake in the cultivated tissue and a 520-880% increase of the total I À content were observed after 8 and 24 h. The concentration of I À protein-bound fraction was raised by 220% after 24 h. A biphasic effect of 0.1 mM H 2 O 2 on TPO was observed: 76.2% and 72.2% inhibitions were seen after 2 and 8 h, respectively, whereas 40.0% enzyme activation was after 5 h. TPO activity was partially restored after 24 h and amounted to 65% of the initial value. The significant increase in the concentration of iodide protein-bound fraction, which was observed simultaneously with TPO inhibition, could be due to thyroglobulin non-enzymic iodination under H 2 O 2 -generated oxidative stress. The data obtained indicate that iodide oxidation, as a step in the biosynthesis of thyroid hormones, was most sensitive to oxidative stress activation. The impaired iodide uptake and its organification during oxidative stress can play a pathogenetic role in disturbed functions of thyroid cells.
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Papers by Z. Niatsetskaya