Intracellular Hypoxia of Tumor Tissue Estimated by Noninvasive Electron Paramagnetic Resonance Oximetry Technique Using Paramagnetic Probes

Matsumoto, Atsuko; Matsumoto, Shingo; Matsumoto, Shingo; Hyodo, Fuminori; Sowers, Anastasia L.; Kościelniak, Janusz; Devasahayam, Nallathamby; Subramanian, S.; Mitchell, James B.; Krishna, Murali C.

doi:10.1248/bpb.34.142

Cited by 23 publications

(16 citation statements)

References 24 publications

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“…(8)(9)(10)(11)(12)(13)(14). Hydroxylamine and oxoammonium are superoxide dismutase (SOD) mimetics and can restore nitroxide radical (10,12,15,16). The interaction of oxoammonium with superoxide occurs very fast (rate constant ~10 9 M -1 s -1 ) (16).…”

mentioning

confidence: 99%

Detection of Redox Imbalance in Normal Lymphocytes with Induced Mitochondrial Dysfunction – EPR Study

Georgieva

Zhelev

Aoki

et al. 2016

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The present study describes a new approach for direct imaging of redox status in live cells using paramagnetic spin-probes, which allows evaluation of the level of oxidative stress due to overproduction of superoxide. The method is based on redox cycling of cell/mitochondria-penetrating nitroxide radicals (e.g. mito-TEMPO) and their electron-paramagnetic resonance (EPR) contrast, which makes them useful molecular sensors for analysis of redox status and oxidative stress in cells and tissues. Oxidative stress was induced in normal human lymphocytes by treatment with 2-methoxyestradiol and rotenone (ME/Rot) at different concentrations. This combination provokes mitochondrial dysfunction, which is accompanied by overproduction of superoxide. The EPR measurements were performed in dynamics on X-Band spectrometer after addition of mito-TEMPO to cell suspensions. The intensity of the EPR signal in untreated cells decreased significantly, which indicates a conversion of paramagnetic mito-TEMPO to its non-contrast diamagnetic form (hydroxylamine - mito-TEMPOH) due to reduction. In ME/Rot-treated cells, the signal decreased more slowly and to a lower level with increasing the concentration of ME/Rot. These data indicate an induction of oxidative stress in the cells in a concentration-dependent manner. A very good positive correlation between the intensity of EPR signal of mito-TEMPO and the intracellular level of superoxide was found, analyzed by conventional dihydroethidium test (R=0.9143, p<0.001). In conclusion, our study demonstrated that cell-penetrating paramagnetic spin-probes, such as mito-TEMPO, are valuable tools for EPR imaging of the superoxide level in live cells, as well as for EPR imaging of mitochondrial dysfunction and metabolic activity, accompanied by superoxide imbalance.

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confidence: 99%

Detection of Redox Imbalance in Normal Lymphocytes with Induced Mitochondrial Dysfunction – EPR Study

Georgieva

Zhelev

Aoki

et al. 2016

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“…The total concentration of each nitroxyl probe (reduced + oxidized) was calculated by analysing the oxidation of reduced probe by adding potassium ferricyanide. This showed that the accumulation of CxP 40 in the liver was significantly reduced compared with the membrane-permeable probe CmP 41 and EDA-PROXYL showed significantly higher accumulation in the liver compared with both CmP and CxP (by about 3-and fivefold, respectively). This suggests that the transport of EDA-PROXYL from blood into liver cells is more efficient than that of CmP and CxP.…”

Section: Resultsmentioning

confidence: 90%

Development of a novel molecular probe for the detection of liver mitochondrial redox metabolism

Hosain

Hyodo

Mori

et al. 2020

Sci Rep

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Redox status influences the course of the inflammatory, metabolic, and proliferative liver diseases. Oxidative stress is thought to play a crucial and sustained role in the pathological progression of early steatosis to severe hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Oxidative stress induced by reactive oxygen species which are generated in the mitochondria can lead to chronic organelle damage in hepatocytes. Currently, the diagnosis of liver disease requires liver biopsy, which is invasive and associated with complications. The present report describes the development of a novel molecular probe, EDA-PROXYL, with higher reactivity and mitochondrial selectivity than standard carboxyl-PROXYL and carbamoyl-PROXYL probes. The membrane permeability of our probe improved in aqueous environments which led to increased accumulation in the liver and interaction of EDA-PROXYL with the carnitine transporter via the amine (NH3+) group further increased accumulation. This increased mitochondrial sensitivity and enhanced accumulation highlight the potential of EDA-PROXYL as a molecular probe for determining metabolic reactions of the mitochondria. Thus, this novel probe could be a tool for the evaluation of redox status of the mitochondria to assess the degree of liver injury and, ultimately, the response to pharmacological therapy.

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“…It has also been reported that CmP exhibits in vivo reductions in muscle and/or tumor tissues . CmP, which has limited membrane permeability, can partly localize in cellular membranes , but cannot pass through the BBB.…”

Section: Resultsmentioning

confidence: 99%

Brain contrasting ability of blood‐brain‐barrier–permeable nitroxyl contrast agents for magnetic resonance redox imaging

Matsumoto¹,

Yamasaki

Nakamura

et al. 2015

Magnetic Resonance in Med

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Intracellular Hypoxia of Tumor Tissue Estimated by Noninvasive Electron Paramagnetic Resonance Oximetry Technique Using Paramagnetic Probes

Cited by 23 publications

References 24 publications

Detection of Redox Imbalance in Normal Lymphocytes with Induced Mitochondrial Dysfunction – EPR Study

Detection of Redox Imbalance in Normal Lymphocytes with Induced Mitochondrial Dysfunction – EPR Study

Development of a novel molecular probe for the detection of liver mitochondrial redox metabolism

Brain contrasting ability of blood‐brain‐barrier–permeable nitroxyl contrast agents for magnetic resonance redox imaging

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