Browsing by Subject "Superoxide Dismutase"
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Item Open Access A new SOD mimic, Mn(III) ortho N-butoxyethylpyridylporphyrin, combines superb potency and lipophilicity with low toxicity.(Free radical biology & medicine, 2012-05) Rajic, Zrinka; Tovmasyan, Artak; Spasojevic, Ivan; Sheng, Huaxin; Lu, Miaomiao; Li, Alice M; Gralla, Edith B; Warner, David S; Benov, Ludmil; Batinic-Haberle, InesThe Mn porphyrins of k(cat)(O(2)(.-)) as high as that of a superoxide dismutase enzyme and of optimized lipophilicity have already been synthesized. Their exceptional in vivo potency is at least in part due to their ability to mimic the site and location of mitochondrial superoxide dismutase, MnSOD. MnTnHex-2-PyP(5+) is the most studied among lipophilic Mn porphyrins. It is of remarkable efficacy in animal models of oxidative stress injuries and particularly in central nervous system diseases. However, when used at high single and multiple doses it becomes toxic. The toxicity of MnTnHex-2-PyP(5+) has been in part attributed to its micellar properties, i.e., the presence of polar cationic nitrogens and hydrophobic alkyl chains. The replacement of a CH(2) group by an oxygen atom in each of the four alkyl chains was meant to disrupt the porphyrin micellar character. When such modification occurs at the end of long alkyl chains, the oxygens become heavily solvated, which leads to a significant drop in the lipophilicity of porphyrin. However, when the oxygen atoms are buried deeper within the long heptyl chains, their excessive solvation is precluded and the lipophilicity preserved. The presence of oxygens and the high lipophilicity bestow the exceptional chemical and physical properties to Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP(5+). The high SOD-like activity is preserved and even enhanced: log k(cat)(O(2)(.-))=7.83 vs 7.48 and 7.65 for MnTnHex-2-PyP(5+) and MnTnHep-2-PyP(5+), respectively. MnTnBuOE-2-PyP(5+) was tested in an O(2)(.-) -specific in vivo assay, aerobic growth of SOD-deficient yeast, Saccharomyces cerevisiae, where it was fully protective in the range of 5-30 μM. MnTnHep-2-PyP(5+) was already toxic at 5 μM, and MnTnHex-2-PyP(5+) became toxic at 30 μM. In a mouse toxicity study, MnTnBuOE-2-PyP(5+) was several-fold less toxic than either MnTnHex-2-PyP(5+) or MnTnHep-2-PyP(5+).Item Open Access Associations between superoxide dismutase, malondialdehyde and all-cause mortality in older adults: a community-based cohort study.(BMC geriatrics, 2019-04-15) Mao, Chen; Yuan, Jin-Qiu; Lv, Yue-Bin; Gao, Xiang; Yin, Zhao-Xue; Kraus, Virginia Byers; Luo, Jie-Si; Chei, Choy-Lye; Matchar, David Bruce; Zeng, Yi; Shi, Xiao-MingBackground
Oxidative stress is an important theory of aging but population-based evidence has been lacking. This study aimed to evaluate the associations between biomarkers of oxidative stress, including plasma superoxide dismutase (SOD) activity and malondialdehyde (MDA), with all-cause mortality in older adults.Methods
This is a community-based cohort study of 2224 participants (women:1227, median age: 86 years). We included individuals aged 65 or above and with plasma SOD activity and/or MDA tests at baseline. We evaluated the hazard ratios (HRs) and 95% confidence intervals (CIs) by multivariable Cox models.Results
We documented 858 deaths during six years of follow-up. There was a significant interaction effect of sex with the association between SOD activity and mortality (P < 0.001). Compared with the lowest quintile, the risk of all-cause mortality was inversely associated with increasing quintiles of plasma SOD activity in women(P-trend< 0.001), with adjusted HRs for the second through fifth quintiles of 0.73 (95% CI 0.53-1.02), 0.52(95% CI 0.38-0.72), 0.53(95% CI 0.39-0.73), and 0.48(95% CI 0.35-0.66). There were no significant associations between SOD activity and mortality in men (P-trend = 0.64), and between MDA and mortality in all participants (P-trend = 0.79).Conclusions
Increased activity of SOD was independently associated with lower all-cause mortality in older women but not in men. This epidemiological study lent support for the free radical/oxidative stress theory of aging.Item Open Access Comprehensive pharmacokinetic studies and oral bioavailability of two Mn porphyrin-based SOD mimics, MnTE-2-PyP5+ and MnTnHex-2-PyP5+.(Free radical biology & medicine, 2013-05) Weitner, Tin; Kos, Ivan; Sheng, Huaxin; Tovmasyan, Artak; Reboucas, Julio S; Fan, Ping; Warner, David S; Vujaskovic, Zeljko; Batinic-Haberle, Ines; Spasojevic, IvanThe cationic, ortho Mn(III) N-alkylpyridylporphyrins (alkyl=ethyl, E, and n-hexyl, nHex) MnTE-2-PyP(5+) (AEOL10113, FBC-007) and MnTnHex-2-PyP(5+) have proven efficacious in numerous in vivo animal models of diseases having oxidative stress in common. The remarkable therapeutic efficacy observed is due to their: (1) ability to catalytically remove O2(•-) and ONOO(-) and other reactive species; (2) ability to modulate redox-based signaling pathways; (3) accumulation within critical cellular compartments, i.e., mitochondria; and (4) ability to cross the blood-brain barrier. The similar redox activities of both compounds are related to the similar electronic and electrostatic environments around the metal active sites, whereas their different bioavailabilities are presumably influenced by the differences in lipophilicity, bulkiness, and shape. Both porphyrins are water soluble, but MnTnHex-2-PyP(5+) is approximately 4 orders of magnitude more lipophilic than MnTE-2-PyP(5+), which should positively affect its ability to pass through biological membranes, making it more efficacious in vivo at lower doses. To gain insight into the in vivo tissue distribution of Mn porphyrins and its impact upon their therapeutic efficacy and mechanistic aspects of action, as well as to provide data that would ensure proper dosing regimens, we conducted comprehensive pharmacokinetic (PK) studies for 24h after single-dose drug administration. The porphyrins were administered intravenously (iv), intraperitoneally (ip), and via oral gavage at the following doses: 10mg/kg MnTE-2-PyP(5+) and 0.5 or 2mg/kg MnTnHex-2-PyP(5+). Drug levels in plasma and various organs (liver, kidney, spleen, heart, lung, brain) were determined and PK parameters calculated (Cmax, C24h, tmax, and AUC). Regardless of high water solubility and pentacationic charge of these Mn porphyrins, they are orally available. The oral availability (based on plasma AUCoral/AUCiv) is 23% for MnTE-2-PyP(5+) and 21% for MnTnHex-2-PyP(5+). Despite the fivefold lower dose administered, the AUC values for liver, heart, and spleen are higher for MnTnHex-2-PyP(5+) than for MnTE-2-PyP(5+) (and comparable for other organs), clearly demonstrating the better tissue penetration and tissue retention of the more lipophilic MnTnHex-2-PyP(5+).Item 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, IBased 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.Item Open Access Dual-Enzyme-Loaded Multifunctional Hybrid Nanogel System for Pathological Responsive Ultrasound Imaging and T2-Weighted Magnetic Resonance Imaging.(ACS nano, 2015-06) Wang, Xia; Niu, Dechao; Li, Pei; Wu, Qing; Bo, Xiaowan; Liu, Boji; Bao, Song; Su, Teng; Xu, Huixiong; Wang, QigangA dual-enzyme-loaded multifunctional hybrid nanogel probe (SPIO@GCS/acryl/biotin-CAT/SOD-gel, or SGC) has been developed for dual-modality pathological responsive ultrasound (US) imaging and enhanced T2-weighted magnetic resonance (MR) imaging. This probe is composed of functionalized superparamagnetic iron oxide particles, a dual enzyme species (catalase and superoxide dismutase), and a polysaccharide cationic polymer glycol chitosan gel. The dual-modality US/MR imaging capabilities of the hybrid nanogel for responsive US imaging and enhanced T2-weighted MR imaging have been evaluated both in vitro and in vivo. These results show that the hybrid nanogel SGC can exhibit efficient dual-enzyme biocatalysis with pathological species for responsive US imaging. SGC also demonstrates increased accumulation in acidic environments for enhanced T2-weighted MR imaging. Further research on these nanogel systems may lead to the development of more efficient US/MR contrast agents.Item Open Access Methoxy-derivatization of alkyl chains increases the in vivo efficacy of cationic Mn porphyrins. Synthesis, characterization, SOD-like activity, and SOD-deficient E. coli study of meta Mn(III) N-methoxyalkylpyridylporphyrins.(Dalton transactions (Cambridge, England : 2003), 2011-04) Tovmasyan, Artak G; Rajic, Zrinka; Spasojevic, Ivan; Reboucas, Julio S; Chen, Xin; Salvemini, Daniela; Sheng, Huaxin; Warner, David S; Benov, Ludmil; Batinic-Haberle, InesCationic Mn(III) N-alkylpyridylporphyrins (MnPs) are potent SOD mimics and peroxynitrite scavengers and diminish oxidative stress in a variety of animal models of central nervous system (CNS) injuries, cancer, radiation, diabetes, etc. Recently, properties other than antioxidant potency, such as lipophilicity, size, shape, and bulkiness, which influence the bioavailability and the toxicity of MnPs, have been addressed as they affect their in vivo efficacy and therapeutic utility. Porphyrin bearing longer alkyl substituents at pyridyl ring, MnTnHex-2-PyP(5+), is more lipophilic, thus more efficacious in vivo, particularly in CNS injuries, than the shorter alkyl-chained analog, MnTE-2-PyP(5+). Its enhanced lipophilicity allows it to accumulate in mitochondria (relative to cytosol) and to cross the blood-brain barrier to a much higher extent than MnTE-2-PyP(5+). Mn(III) N-alkylpyridylporphyrins of longer alkyl chains, however, bear micellar character, and when used at higher levels, become toxic. Recently we showed that meta isomers are ∼10-fold more lipophilic than ortho species, which enhances their cellular accumulation, and thus reportedly compensates for their somewhat inferior SOD-like activity. Herein, we modified the alkyl chains of the lipophilic meta compound, MnTnHex-3-PyP(5+) via introduction of a methoxy group, to diminish its toxicity (and/or enhance its efficacy), while maintaining high SOD-like activity and lipophilicity. We compared the lipophilic Mn(III) meso-tetrakis(N-(6'-methoxyhexyl)pyridinium-3-yl)porphyrin, MnTMOHex-3-PyP(5+), to a hydrophilic Mn(III) meso-tetrakis(N-(2'-methoxyethyl)pyridinium-3-yl)porphyrin, MnTMOE-3-PyP(5+). The compounds were characterized by uv-vis spectroscopy, mass spectrometry, elemental analysis, electrochemistry, and ability to dismute O(2)˙(-). Also, the lipophilicity was characterized by thin-layer chromatographic retention factor, R(f). The SOD-like activities and metal-centered reduction potentials for the Mn(III)P/Mn(II)P redox couple were similar-to-identical to those of N-alkylpyridyl analogs: log k(cat) = 6.78, and E(1/2) = +68 mV vs. NHE (MnTMOHex-3-PyP(5+)), and log k(cat) = 6.72, and E(1/2) = +64 mV vs. NHE (MnTMOE-3-PyP(5+)). The compounds were tested in a superoxide-specific in vivo model: aerobic growth of SOD-deficient E. coli, JI132. Both MnTMOHex-3-PyP(5+) and MnTMOE-3-PyP(5+) were more efficacious than their alkyl analogs. MnTMOE-3-PyP(5+) is further significantly more efficacious than the most explored compound in vivo, MnTE-2-PyP(5+). Such a beneficial effect of MnTMOE-3-PyP(5+) on diminished toxicity, improved efficacy and transport across the cell wall may originate from the favorable interplay of the size, length of pyridyl substituents, rotational flexibility (the ortho isomer, MnTE-2-PyP(5+), is more rigid, while MnTMOE-3-PyP(5+) is a more flexible meta isomer), bulkiness and presence of oxygen.Item Open Access MnSOD is implicated in accelerated wound healing upon Negative Pressure Wound Therapy (NPWT): A case in point for MnSOD mimetics as adjuvants for wound management.(Redox biology, 2019-01) Bellot, Gregory Lucien; Dong, Xiaoke; Lahiri, Amitabha; Sebastin, Sandeep Jacob; Batinic-Haberle, Ines; Pervaiz, Shazib; Puhaindran, Mark EdwardNegative Pressure Wound Therapy (NPWT), a widely used modality in the management of surgical and trauma wounds, offers clear benefits over conventional wound healing strategies. Despite the wide-ranging effects ascribed to NPWT, the precise molecular mechanisms underlying the accelerated healing supported by NPWT remains poorly understood. Notably, cellular redox status-a product of the balance between cellular reactive oxygen species (ROS) production and anti-oxidant defense systems-plays an important role in wound healing and dysregulation of redox homeostasis has a profound effect on wound healing. Here we investigated potential links between the use of NPWT and the regulation of antioxidant mechanisms. Using patient samples and a rodent model of acute injury, we observed a significant accumulation of MnSOD protein as well as higher enzymatic activity in tissues upon NPWT. As a proof of concept and to outline the important role of SOD activity in wound healing, we replaced NPWT by the topical application of a MnSOD mimetic, Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP5+, MnE, BMX-010, AEOl10113) in the rodent model. We observed that MnE is a potent wound healing enhancer as it appears to facilitate the formation of new tissue within the wound bed and consequently advances wound closure by two days, compared to the non-treated animals. Taken together, these results show for the first time a link between NPWT and regulation of antioxidant mechanism through the maintenance of MnSOD activity. Additionally this discovery outlined the potential role of MnSOD mimetics as topical agents enhancing wound healing.Item Open Access Phosphatase and tensin homologue/protein kinase B pathway linked to motor neuron survival in human superoxide dismutase 1-related amyotrophic lateral sclerosis.(Brain : a journal of neurology, 2011-02) Kirby, Janine; Ning, Ke; Ferraiuolo, Laura; Heath, Paul R; Ismail, Azza; Kuo, Su-Wei; Valori, Chiara F; Cox, Laura; Sharrack, Basil; Wharton, Stephen B; Ince, Paul G; Shaw, Pamela J; Azzouz, MimounGene expression profiling has been used previously with spinal cord homogenates and laser capture microdissected motor neurons to determine the mechanisms involved in neurodegeneration in amyotrophic lateral sclerosis. However, while cellular and animal model work has focused on superoxide dismutase 1-related amyotrophic lateral sclerosis, the transcriptional profile of human mutant superoxide dismutase 1 motor neurons has remained undiscovered. The aim of this study was to apply gene expression profiling to laser captured motor neurons from human superoxide dismutase 1-related amyotrophic lateral sclerosis and neurologically normal control cases, in order to determine those pathways dysregulated in human superoxide dismutase 1-related neurodegeneration and to establish potential pathways suitable for therapeutic intervention. Identified targets were then validated in cultured cell models using lentiviral vectors to manipulate the expression of key genes. Microarray analysis identified 1170 differentially expressed genes in spinal cord motor neurons from superoxide dismutase 1-related amyotrophic lateral sclerosis, compared with controls. These genes encoded for proteins in multiple functional categories, including those involved in cell survival and cell death. Further analysis determined that multiple genes involved in the phosphatidylinositol-3 kinase signalling cascade were differentially expressed in motor neurons that survived the disease process. Functional experiments in cultured cells and primary motor neurons demonstrate that manipulating this pathway by reducing the expression of a single upstream target, the negative phosphatidylinositol-3 kinase regulator phosphatase and tensin homology, promotes a marked pro-survival effect. Therefore, these data indicate that proteins in the phosphatidylinositol-3 kinase pathway could represent a target for therapeutic manipulation in motor neuron degeneration.Item Open Access Potential involvement of intracellular pH in a mouse model of amyotrophic lateral sclerosis.(Amyotrophic lateral sclerosis & frontotemporal degeneration, 2014-03) Kuo, Su-Wei; Jiang, Mingchen; Heckman, CjItem Open Access Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential.(Antioxid Redox Signal, 2010-09-15) Batinić-Haberle, Ines; Rebouças, Júlio S; Spasojević, IvanOxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO(3)(*-), peroxyl radical, and less efficiently H(2)O(2). By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and/or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds.