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Maitra D.,Cs Mott Center For Human Growth And Development | Shaeib F.,Cs Mott Center For Human Growth And Development | Abdulhamid I.,Childrens Hospital of Michigan | Abdulridha R.M.,Cs Mott Center For Human Growth And Development | And 5 more authors.
Free Radical Biology and Medicine | Year: 2013

Myeloperoxidase (MPO) is a heme-containing enzyme that generates hypochlorous acid (HOCl) from chloride (Cl-) and hydrogen peroxide (H 2O2). It is implicated in the pathology of several chronic inflammatory conditions such as cardiovascular and pulmonary diseases and cancer. Recently we have shown that HOCl can destroy the heme prosthetic group of hemoproteins. Here, we investigated whether the HOCl formed during steady-state catalysis is able to destroy the MPO heme moiety and thereby function as a major source of free iron. UV-visible spectra and H 2O2-specific electrode measurements recorded during steady-state HOCl synthesis by MPO showed that the degree of MPO heme destruction increased after multiple additions of H2O2 (10 mM), precluding the enzyme from functioning at maximum activity (80-90% inhibition). MPO heme destruction occurred only in the presence of Cl-. Stopped-flow measurements revealed that the HOCl-mediated MPO heme destruction was complex and occurred through transient ferric species whose formation and decay kinetics indicated it participates in heme destruction along with subsequent free iron release. MPO heme depletion was confirmed by the buildup of free iron utilizing the ferrozine assay. Hypochlorous acid, once generated, first equilibrates in the solution as a whole before binding to the heme iron and initiating heme destruction. Eliminating HOCl from the MPO milieu by scavenging HOCl, destabilizing the MPO-Compound I-Cl complex that could be formed during catalysis, and/or inhibiting MPO catalytic activity partially or completely protects MPO from HOCl insults. Collectively, this study elucidates the bidirectional relationship between MPO and HOCl, which highlights the potential role of MPO as a source of free iron. © 2013 Published by Elsevier Inc. Source


Rappolee D.A.,Cs Mott Center For Human Growth And Development | Rappolee D.A.,Wayne State University | Rappolee D.A.,Barbara Ann Karmanos Cancer Institute | Rappolee D.A.,University of Windsor | And 5 more authors.
Systems Biology in Reproductive Medicine | Year: 2012

This hypothesis and review introduces rules of stem cell stress responses that provide biomarkers and alternative testing that replaces or reduces gestational tests using whole animals. These rules for the stress responses of cultured stem cells validate the organismal strategy of the stress response and show that it emulates what must happen if the conceptus implants during a response to stress in vivo. Specifically there is a profound threshold during a stress dose response where stem cell accumulation is significantly reduced. Below this threshold stress enzymes manage the stress response by converting anabolic to catabolic processes and by suppressing apoptosis, without affecting differentiation. However above this threshold the stem cell survival response converts to an organismal survival response where stress enzymes switch to new substrates and mediate loss of potency factors, gain of early essential differentiated lineages, and suppression of later essential lineages. Stressed stem cells 'compensate' for lower accumulation rates by differentiating a higher fraction of cells, and the organismal survival response further enhances adaptation by prioritizing the differentiation of early essential lineages. Thus compensatory and prioritized differentiation and the sets of markers produced are part of a response of cultured embryos and stem cells that emulate what must happen during implantation of a stressed gestation. Knowledge of these markers and use of stressed stem cell assays in culture should replace or reduce the number of animals needed for developmental toxicity and should produce biomarkers for stressed development in vitro and in vivo. © 2012 Informa Healthcare USA, Inc. Source

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