Fuminori Hyodo

Kyushu University, Hukuoka, Fukuoka, Japan

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Publications (55)209.16 Total impact

  • Hinako Eto · Fuminori Hyodo · Kenji Nakano · Hideo Utsumi
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    ABSTRACT: The presence of malignant ascites in advanced cancer patients is associated with both a poor prognosis and quality of life, with a risk of abdominal infection and sepsis. Contemporary non-invasive visualization methods such as ultrasound, computed tomography and magnetic resonance imaging often struggle to differentiate malignant ascites from surrounding tissues. This study aimed to determine the utility of selective H2O imaging in the abdominal cavity with a free radical probe and deuterium oxide (D2O) contrast agent using in vivo dynamic nuclear polarization-MRI (DNP-MRI). Phantom imaging experiments established a linear relationship between H2O volume and image intensity using in vivo DNP-MRI. Similar results were obtained when the radical-D2O probe was used to determine selective and spatial information of H2O in vivo, modeled by the injection of saline into the abdominal cavity of mice. To demonstrate the utility of this method for disease, malignant ascites in peritoneal metastasis animal model was selected as one of the typical examples. In vivo DNP-MRI of peritoneal metastasis animal model was performed 7–21 days after intraperitoneal injection of luciferase-stably expressing the human pancreatic carcinoma (SUIT-2). The image intensity with increasing malignant ascites was significantly increased at days 7, 16, and 21. This increase corresponded to in vivo tumor progression, as measured by bioluminescent imaging. These results suggest that H2O signal enhancement in DNP-MRI using radical-D2O contrast is positively associated with the progression of dissemination and could be a useful biomarker for malignant ascites with cancer metastasis.
    No preview · Article · Jan 2016 · Analytical Chemistry
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    ABSTRACT: Disorders of skeletal muscle are often associated with inflammation and alterations in redox status. A non-invasive technique that could localize and evaluate the severity of skeletal muscle inflammation based on its redox environment would be useful for disease identification and monitoring, and for the development of treatments; however, no such technique currently exists. We describe a method for redox imaging of skeletal muscle using dynamic nuclear polarization magnetic resonance imaging (DNP-MRI), and apply this method to an animal model of local inflammation. Female C57/BL6 mice received injections of 0.5% bupivacaine into their gastrocnemius muscles. Plasma biomarkers, myeloperoxidase activity, and histological sections were assessed at 4 and 24h after bupivacaine injection to measure the inflammatory response. In vivo DNP-MRI was performed with the nitroxyl radicals carbamoyl-PROXYL (cell permeable) and carboxy-PROXYL (cell impermeable) as molecular imaging probes at 4 and 24h after bupivacaine administration. The images obtained after carbamoyl-PROXYL administration were confirmed with the results of l-band EPR spectroscopy. The plasma biomarkers, myeloperoxidase activity, and histological findings indicated that bupivacaine injection caused acute muscle damage and inflammation. DNP-MRI images of mice treated with carbamoyl-PROXYL or carboxy-PROXYL at 4 and 24h after bupivacaine injection showed similar increases in image intensity and decay rate was significantly increased at 24h. In addition, reduction rates in individual mice at 4h and 24h showed faster trends with bupivacaine injection than in their contralateral sides by image-based analysis. These findings indicate that in vivo DNP-MRI with nitroxyl radicals can non-invasively detect changes in the focal redox status of muscle resulting from locally-induced inflammation.
    No preview · Article · Oct 2015 · Free Radical Biology and Medicine

  • No preview · Article · Oct 2015

  • No preview · Article · Oct 2015
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    ABSTRACT: Altered antioxidant status has been implicated in schizophrenia. Microglia are major sources of free radicals such as superoxide in the brain, and play crucial roles in various brain diseases. Recent postmortem and imaging studies have in-dicated microglial activation in the brain of schizophrenia patients. Animal models that express some phenotypes of schizophrenia have revealed the underlying microglial pathology. In addition, minocycline, an antibiotic and the best known inhibitor of microglial activation, has therapeutic e‹cacy in schizophrenia. We have recently revealed that vari- ous antipsychotics directly affect microglia via proin‰ammatory reactions such as oxidative stress, by in vitro studies using rodent microglial cells. Based on these ˆndings, we have suggested that microglia are crucial players in the brain in schizophrenia, and modulating microglia may be a novel therapeutic target. In this review paper, we introduce our hypothesis based on the above evidence. The technique of in vivo molecular redox imaging is expected to be a powerful tool to clarify this hypothesis.
    Preview · Article · May 2015 · YAKUGAKU ZASSHI
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    Kazunori Anzai · Fuminori Hyodo

    Preview · Article · May 2015 · YAKUGAKU ZASSHI
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    Fuminori Hyodo · Shinji Ito · Hideo Utsumi
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    ABSTRACT: Tissue redox status is one of the most important parameters to maintain homeostasis in the living body. Numerous redox reactions are involved in metabolic processes, such as energy production in the mitochondrial electron transfer system. A variety of intracellular molecules such as reactive oxygen species, glutathione, thioredoxins, NADPH, flavins, and ascorbic acid may contribute to the overall redox status in tissues. Breakdown of redox balance may lead to oxidative stress and can induce many pathological conditions such as cancer, neurological disorders, and aging. Therefore imaging of tissue redox status and monitoring antioxidant levels in living organisms can be useful in the diagnosis of disease states and assessment of treatment response. In vivo redox molecular imaging technology such as electron spin resonance imaging (ESRI), magnetic resonance imaging (MRI), and dynamic nuclear polarization (DNP)-MRI (redox molecular imaging; ReMI) is emerging as a viable redox status imaging modality. This review focuses on the application of magnetic resonance technologies using MRI or DNP-MRI and redox-sensitive contrast agents.
    Preview · Article · May 2015 · YAKUGAKU ZASSHI

  • No preview · Article · Nov 2014 · Free Radical Biology and Medicine
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    ABSTRACT: Redox reactions that generate free radical intermediates are essential to metabolic processes. However, their intermediates can produce reactive oxygen species, which may promote diseases related to oxidative stress. We report here the use of dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) to conduct redox molecular imaging. Using DNP-MRI, we obtained simultaneous images of free radical intermediates generated from the CoQ10, FMN, and FAD involved in the mitochondrial electron transport chain, as well as the radicals derived from vitamins E and K1. Each of these free radicals was imaged in real time in a phantom comprising a mixture of free radicals localized in either lipophilic or aqueous environments. Changing the frequency of electron spin resonance (ESR) irradiation also allowed each of the radical species to be distinguished in the spectroscopic images. This study is the first to report the spectroscopic DNP-MRI imaging of free radical intermediates that are derived from endogenous species involved in metabolic processes.
    No preview · Article · Jul 2014 · Analytical Chemistry
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    ABSTRACT: Electron spin resonance (ESR) studies were carried out for 2mM 14N labeled deutrated permeable 3- methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MC-PROXYL) in pure water, 1 mM, 2 mM, 3 mM and 4 mM concentration of MC-PROXYL in 300 mM concentration of liposomal solution by using a L-band ESR spectrometer. The ESR parameters such as linewidth, hyperfine coupling constant, g-factor, partition parameter and permeability were reported. The partition parameter and permeability values indicate the maximum spin distribution in the lipid phase at 2 mM concentration. This study illustrates that ESR can be used to differentiate between the intra and extra-membrane water by loading the liposome vesicles with a lipid-permeable nitroxyl spin probe. From the ESR results, the radical concentration was optimized as 2 mM in liposomal solution for ESR phantom studies and experiments.
    Full-text · Article · Mar 2014
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    ABSTRACT: Electron spin resonance (ESR) studies were carried out for 14N-labeled deuterated 3-methoxy-carbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MC-PROXYL) and 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidin-1-oxyl (carboxy-PROXYL) in pure water and various concentrations of liposomal solutions by using 300 MHz ESR spectrometer. The ESR parameters such as the line width, hyperfine coupling constant, rotational correlation time, g-factor, partition parameter and permeability were reported for the samples. The line width broadening was observed for MC-PROXYL and carboxy-PROXYL in liposomal solution. The hyperfine coupling constant was observed for both nitroxyl spin probes. The permeable and impermeable nature of nitroxyl spin probes was demonstrated. The rotational correlation time increases with increasing concentration of liposome. The partition parameter increases with increasing concentration of liposome for MC-PROXYL, which indicates that the nitroxyl spin probes diffuse into lipid membrane. The permeability value decreases with increasing concentration of liposome, which reveals an increase in membrane permeability. The peaks corresponding to the lipid phase were observed for MC-PROXYL in liposomal solution, but not resolved for carboxy-PROXYL. These results confirm the permeable and impermeable nature of nitroxyl spin probes.
    Full-text · Article · Jan 2014
  • Fuminori Hyodo · Shinji Ito · Hideo Utsumi
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    ABSTRACT: There are many redox reactions to maintain the normal physiological conditions in the living body. A breakdown of the redox balance such as an overproduction of reactive oxygen/ nitrogen species and a decrease antioxidant defense may lead to oxidative stress. It can also induce many pathological conditions such as neurological disorders, inflammation, cancer, and ageing. Imaging of the tissue redox status could have one of the markers for drug discovery and clinical applications for novel diagnosis. Nitroxyl radicals have been utilized as a redox sensitive contrast agent in magnetic resonance imaging (MRI) and dynamic nuclear polarization (DNP)-MRI. Recently, we developed home-made DNP-MRI using the circularly transporting system of a sample for high-sensitive and redox analysis based on the anatomical structure by MRI. In this report, we demonstrate the application of the nitroxyl radical to magnetic resonance technique for monitoring the tissue redox status non-invasively.
    No preview · Article · Jan 2014 · Bunseki kagaku

  • No preview · Article · Nov 2013 · Free Radical Biology and Medicine

  • No preview · Article · Nov 2013 · Free Radical Biology and Medicine
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    ABSTRACT: Cyclic nitroxides are a diverse group of stable free radicals that have unique antioxidant properties. Because of their ability to interact with free radicals, they have been used for many years as biophysical tools. During the past 15–20 years, however, many interesting biochemical interactions have been discovered and harnessed for therapeutic applications. Biologically relevant effects of nitroxides have been described, including their ability to degrade superoxide and peroxide, inhibit Fenton reactions, and undergo radical–radical recombination. Cellular studies defined the activity of nitroxides in vitro. By modifying oxidative stress and altering the redox status of tissues, nitroxides have been found to interact with and alter many metabolic processes. These interactions can be exploited for therapeutic and research use, including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. Although much remains to be done, many applications have been well studied and some are currently being tested in clinical trials. The therapeutic and research uses of nitroxide compounds are reviewed here with a focus on the progress from initial development to modern trials.
    Full-text · Dataset · Sep 2013
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    ABSTRACT: Electron spin resonance (ESR) studies were carried out for 2mM 14N-labeled deutrated 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MC-PROXYL) and 3-carboxy-2,2,5,5,-tetramethyl-1-pyrrolidinyloxy (carboxy-PROXYL) in pure water and various concentrations of liposomal solutions by using 300 MHz ESR spectrometer. The ESR parameters such as the line width, hyperfine coupling constant, g-factor, rotational correlation time, partition parameter and permeability were reported for the samples. The permeable and impermeable nature of nitroxyl spin probes was demonstrated. The increased rotational correlation time was observed for MC-PROXYL, which indicates the permeable and less mobile nature of the nitroxyl spin probe. The obtained partition parameter and permeability values are used to quantify the permeable nature of the nitroxyl spin probe. The peaks correspond to lipid phase were observed for MC-PROXYL in liposomal solution, but that peak was not observed for carboxy-PROXYL. These results indicate the permeable and the impermeable nature of nitroxyl spin probes.
    Full-text · Article · Feb 2013
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    ABSTRACT: The recent development of a bi-modality magnetic resonance imaging/electron paramagnetic resonance imaging (MRI/EPRI) platform has enabled longitudinal monitoring of both tumor oxygenation and redox status in murine cancer models. The current study used this imaging platform to test the hypothesis that a more reducing tumor microenvironment accompanies the development of tumor hypoxia. To test this, the redox status of the tumor was measured using Tempol as a redox‑sensitive MRI contrast agent, and tumor hypoxia was measured with Oxo63, which is an oxygen-sensitive EPRI spin probe. Images were acquired every 1-2 days in mice bearing SCCVII tumors. The median pO2 decreased from 14 mmHg at 7 days after tumor implantation to 7 mmHg at 15 days after implantation. Additionally, the hypoxic fraction, defined as the percentage of the tumor that exhibited a pO2<10 mmHg, increased with tumor size (from 10% at 500 mm3 to 60% at 3,500 mm3). The rate of Tempol reduction increased as a function of tumor volume (0.4 min-1 at 500 mm3 to 1.7 min-1 at 3,500 mm3), suggesting that the tumor microenvironment became more reduced as the tumor grew. The results show that rapid Tempol reduction correlates with decreased tumor oxygenation, and that the Tempol decay rate constant may be a surrogate marker for tumor hypoxia.
    Full-text · Article · Sep 2012 · International Journal of Oncology
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    ABSTRACT: Electron spin resonance studies were carried out for 2mM 14N labeled 2H enriched 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MC-PROXYL) in pure water and 100, 200, 300, 400 mM concentrations of liposomal solution and 3–carboxy-2,2,5,5,-tetramethyl-1-pyrrolidinyloxy (carboxy-PROXYL) in pure water and 400 mM concentration of liposomal solution by using L-band ESR spectrometer. This study reveals that the permeability of MC-PROXYL in liposomal solution and impermeability of carboxy-PROXYL in 400 mM concentration of liposomal solution. This study illustrates that the ESR can be used to differentiate between the intra-and extra-membrane water by loading the liposome vesicles with a lipid permeable nitroxyl spin probe. The lipid membrane permeability of two different nitroxyl spin probes was demonstrated.
    Full-text · Article · Jun 2012
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    ABSTRACT: Overhauser-enhanced MRI (OMRI) enables visualization of free radicals in animals based on dynamic nuclear polarization. Real-time data of tissue redox status gathered from kinetic images of redox-sensitive nitroxyl radical probes using OMRI provided both anatomic and physiological information. Phantom experiments demonstrated the linear correlation between the enhancement factor and the concentration of a membrane-impermeable probe, carboxy-PROXYL (3-carboxy-2,2,5,5-tetramethyl- pyrrolidine-1-oxyl). Whole-body OMRI images illustrated the in vivo kinetics of carboxy-PROXYL for 25 min. Initial distribution was observed in lung, heart, liver, and kidney, but not brain, corresponding to its minimal lipophilicity. Based on these images (pixel size, 1.33 × 1.33 mm; slice thickness, 50mm), a time-concentration curve with low coefficient of variance (<0.21) was created to assess pharmacokinetic behaviors. A biexponential curve showed a distribution phase from 1 to 10 min and an elimination phase from 15 to 25 min. The α rate constant was greater than the β rate constant in ROIs, confirming that its pharmacokinetics obeyed a two-compartment model. As a noninvasive technique, combining OMRI imaging with redox probes to monitor tissue redox status may be useful in acquiring valuable information regarding organ function for preclinical and clinical studies of oxidative diseases.
    No preview · Article · Apr 2012 · Free Radical Biology and Medicine
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    ABSTRACT: Electron paramagnetic resonance (EPR) oximetry at 700 MHz operating frequency employing a surface coil resonator is used to assess tissue partial pressure of oxygen (pO(2)) using paramagnetic media whose linewidth and decay constant are related to oxygen concentration. Differences in extracellular and intracellular pO(2) in squamous cell carcinoma (SCC) tumor tissue were tested using several types of water-soluble paramagnetic media, which localize extracellularly or permeate through the cell membrane. The nitroxide carboxy-PROXYL (CxP) can only be distributed in blood plasma and extracellular fluids whereas the nitroxides carbamoyl-PROXYL (CmP) and TEMPOL (TPL) can permeate cell membranes and localize intracellularly. EPR signal decay constant and the linewidth of the intravenously administered nitroxides in SCC tumor tissues implanted in mouse thigh and the contralateral normal muscle of healthy mice breathing gases with different pO(2) were compared. The pO(2) in the blood can depend on the oxygen content in the breathing gas while tissue pO(2) was not directly influenced by pO(2) in the breathing gas. The decay constants of CmP and TPL in tumor tissue were significantly larger than in the normal muscles, and lower linewidths of CmP and TPL in tumor tissue was observed. The SCC tumor showed intracellular hypoxia even though the extracellular pO(2) is similar to normal tissue in the peripheral region.
    Full-text · Article · Jan 2011 · Biological & Pharmaceutical Bulletin

Publication Stats

1k Citations
209.16 Total Impact Points

Institutions

  • 2004-2015
    • Kyushu University
      • • Innovation Center for Medical Redox Navigation
      • • Graduate School of Pharmaceutical Sciences
      • • Faculty of Pharmaceutical Sciences
      Hukuoka, Fukuoka, Japan
  • 2006-2013
    • National Cancer Institute (USA)
      • • Radiation Biology Branch
      • • Center for Cancer Research
      Maryland, United States
  • 2012
    • Northern Inyo Hospital
      BIH, California, United States
  • 2010
    • Doshisha University
      Kioto, Kyōto, Japan
  • 2007-2010
    • National Institutes of Health
      • Branch of Radiation Biology
      Bethesda, MD, United States