Design, mechanism of action, bioavailability and therapeutic effects of mn porphyrin-based redox modulators.

dc.contributor.author

Tovmasyan, A

dc.contributor.author

Sheng, H

dc.contributor.author

Weitner, T

dc.contributor.author

Arulpragasam, A

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Lu, M

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Warner, DS

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Vujaskovic, Z

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Spasojevic, I

dc.contributor.author

Batinic Haberle, I

dc.date.accessioned

2021-06-01T14:09:58Z

dc.date.available

2021-06-01T14:09:58Z

dc.date.issued

2013-01

dc.date.updated

2021-06-01T14:09:56Z

dc.description.abstract

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.

dc.identifier

000341715

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1011-7571

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1423-0151

dc.identifier.uri

https://hdl.handle.net/10161/23280

dc.language

eng

dc.publisher

S. Karger AG

dc.relation.ispartof

Medical principles and practice : international journal of the Kuwait University, Health Science Centre

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10.1159/000341715

dc.subject

Animals

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Neoplasms

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Central Nervous System Diseases

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Diabetes Mellitus

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Disease Models, Animal

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Manganese

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Porphyrins

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Superoxide Dismutase

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Free Radical Scavengers

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Contrast Media

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Area Under Curve

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Oxidation-Reduction

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Oxidative Stress

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Biological Availability

dc.title

Design, mechanism of action, bioavailability and therapeutic effects of mn porphyrin-based redox modulators.

dc.type

Journal article

duke.contributor.orcid

Sheng, H|0000-0002-4325-2940

duke.contributor.orcid

Spasojevic, I|0000-0001-9890-6246

pubs.begin-page

103

pubs.end-page

130

pubs.issue

2

pubs.organisational-group

School of Medicine

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Neurobiology

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Duke Institute for Brain Sciences

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Surgery

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Anesthesiology, Neuroanesthesia

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Duke

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Basic Science Departments

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University Institutes and Centers

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Institutes and Provost's Academic Units

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Clinical Science Departments

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Anesthesiology

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Radiation Oncology

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Duke Cancer Institute

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Medicine, Medical Oncology

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Institutes and Centers

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Medicine

pubs.publication-status

Published

pubs.volume

22

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