Browsing by Subject "Free Radical Scavengers"

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Open Access
Design, mechanism of action, bioavailability and therapeutic effects of mn porphyrin-based redox modulators.
(Medical principles and practice : international journal of the Kuwait University, Health Science Centre, 2013-01) Tovmasyan, A; Sheng, H; Weitner, T; Arulpragasam, A; Lu, M; Warner, DS; Vujaskovic, Z; Spasojevic, I; Batinic Haberle, I
Based on aqueous redox chemistry and simple in vivo models of oxidative stress, Escherichia coli and Saccharomyces cerevisiae, the cationic Mn(III) N-substituted pyridylporphyrins (MnPs) have been identified as the most potent cellular redox modulators within the porphyrin class of drugs; their efficacy in animal models of diseases that have oxidative stress in common is based on their high ability to catalytically remove superoxide, peroxynitrite, carbonate anion radical, hypochlorite, nitric oxide, lipid peroxyl and alkoxyl radicals, thus suppressing the primary oxidative event. While doing so MnPs could couple with cellular reductants and redox-active proteins. Reactive species are widely accepted as regulators of cellular transcriptional activity: minute, nanomolar levels are essential for normal cell function, while submicromolar or micromolar levels impose oxidative stress, which is evidenced in increased inflammatory and immune responses. By removing reactive species, MnPs affect redox-based cellular transcriptional activity and consequently secondary oxidative stress, and in turn inflammatory processes. The equal ability to reduce and oxidize superoxide during the dismutation process and recently accumulated results suggest that pro-oxidative actions of MnPs may also contribute to their therapeutic effects. All our data identify the superoxide dismutase-like activity, estimated by log k(cat)O2-*), as a good measure for the therapeutic efficacy of MnPs. Their accumulation in mitochondria and their ability to cross the blood-brain barrier contribute to their remarkable efficacy. We summarize herein the therapeutic effects of MnPs in cancer, central nervous system injuries, diabetes, their radioprotective action and potential for imaging. Few of the most potent modulators of cellular redox-based pathways, MnTE2-PyP5+, MnTDE-2-ImP5+, MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+, are under preclinical and clinical development.
Open Access
Mitochondrial Quality Control as a Therapeutic Target.
(Pharmacol Rev, 2016-01) Suliman, Hagir B; Piantadosi, Claude A
In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control.