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Ken-ichiro Matsumoto - One of the best experts on this subject based on the ideXlab platform.
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Presence of X-ray induced high concentrated hydrogen peroxide clusters
2019Co-Authors: Ueno Megumi, Nakanishi Ikuo, Ken-ichiro MatsumotoAbstract:Presence of high concetntrated hydrogen peroxide (H2O2) clusters in an aqueous solution during X-ray irradiation was demonstrated. A method to measure the distance between the clusters was attempted. X-ray induced H2O2 generation in the sample solution is related to the hydrogen-donor-independent reduction of Nitroxyl radical, however the reaction mechanisms are still in progress. In this study, the relation of H2O2 concentraion and hydrogen-donor-independent reduction of Nitroxyl radical was tested, and then the distance between localyzed H2O2 clusters was estimated.Reaction mixtures containing 0.1 mM of a Nitroxyl redox probe, TEMPOL or Carbamoyl-PROXYL, were prepared with containing several different concentrations (1.0 mM‒9.8 M) of H2O2. The reaction mixture was irradiated by 12000 μW/cm2 UVB for 2 min, and the reduction of the EPR signal of the nitorxyl radical was measured. An aliquot (2 µL) of 200 mM K3[Fe(CN)6] solution was added to 200 µL of the reaction mixture, and the time course of the EPR signal of the nitorxyl radical was measured. A series of Nitroxyl radical solutions with several different concentrations (0.06 μM‒2.28 mM) was irradiated with X-ray, and then the amount of reduction of Nitroxyl radical in each sample was measured by EPR. The UV induced EPR signal loss of the nitorxyl radical was increased with H2O2 higher than 10 mM. The EPR signal of nitorxyl radicals were decreased in the solution containing 1 M of H2O2, when K3[Fe(CN)6] was added to the reaction mixture. Oxidative stimulation by UVB irradiation or addition of K3[Fe(CN)6] could cause nitorxyl radical reduction in a high concentration H2O2 environment. This result suggests that ionizing radiations could prepare a high concentration H2O2 environment, which may be localized. Plotting reduction amount with density of Nitroxyl radical showed that the high concentration H2O2 clusters are with 43‒44 nm separation.The Society for Redox Biology and Medicine\u27s 26th Annual Conference (SfRBM 2019
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comparative studies with epr and mri on the in vivo tissue redox status estimation using redox sensitive Nitroxyl probes influence of the choice of the region of interest
Free Radical Research, 2018Co-Authors: Ken-ichiro Matsumoto, James B Mitchell, Murali C KrishnaAbstract:AbstractIn vivo decay rates of a Nitroxyl contrast agent were estimated by a MR redox imaging (MRRI) technique and compared with the decay rates obtained by the electron paramagnetic resonance spectroscopy (EPRS) and imaging (EPRI). MRRI is a dynamic imaging technique employing T1-weighted pulse sequence, which can visualise a Nitroxyl-induced enhancement of signal intensity by T1-weighted contrast. EPR techniques can directly measure the paramagnetic Nitroxyl radical. Both the squamous cell carcinoma (SCC) tumour-bearing and normal legs of a female C3H mouse were scanned by T1-weighted SPGR sequence at 4.7 T with the Nitroxyl radical, carbamoyl-proxyl (CmP), as the contrast agent. Similarly, the time course of CmP in normal muscle and tumour tissues was obtained using a 700-MHz EPR spectrometer with a surface coil. The time course imaging of CmP was also performed by 300 MHz CW EPR imager. EPRS and EPRI gave slower decay rates of CmP compared to the MRRI. Relatively slow decay rate at peripheral region o...
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Nitroxyl radicals for labeling of conventional therapeutics and noninvasive magnetic resonance imaging of their permeability for blood brain barrier relationship between structure blood clearance and mri signal dynamic in the brain
Molecular Pharmaceutics, 2009Co-Authors: Zhivko Zhelev, Ken-ichiro Matsumoto, Veselina Gadjeva, Rumiana Bakalova, Ichio Aoki, Kazunori Anzai, Iwao KannoAbstract:The present study describes a novel nonradioactive methodology for in vivo noninvasive, real-time imaging of blood−brain barrier (BBB) permeability for conventional drugs, using Nitroxyl radicals as spin-labels and magnetic resonance imaging (MRI). Two TEMPO-labeled analogues (SLENU and SLCNUgly) of the anticancer drug lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] were synthesized, using a substitution of the cyclohexyl part with Nitroxyl radical. Nonmodified Nitroxyl radical TEMPOL was used for comparison. The Nitroxyl derivatives were injected intravenously in healthy mice via the tail vein, and MR imaging of the brain was performed on a 7.0 T MRI. The MRI signal dynamic of SLENU and SLCNUgly followed the same kinetics as nonmodified TEMPO radical. SLENU and SLCNUgly were rapidly transported and randomly distributed in the brain tissue, which indicated that the exchange of cyclohexyl part of lomustine with TEMPO radical did not suppress the permeability of the anticancer drug for BBB. The sel...
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EPR signal reduction kinetic of several Nitroxyl derivatives in blood in vitro and in vivo
General Physiology and Biophysics, 2009Co-Authors: Zhivko Zhelev, Ken-ichiro Matsumoto, Veselina Gadjeva, Rumiana Bakalova, Ichio Aoki, Antoaneta Zheleva, Kazunori AnzaiAbstract:The present study is focused on the mechanism(s) of electron-paramagnetic resonance (EPR) signal reduction kinetic of several Nitroxyl radicals and Nitroxyl-labeled anticancer drugs in physiological solutions in the context of their application for evaluation of oxidation/reduction status of blood and tissues--an important step in biomedical diagnostics and planning of therapy of many diseases. The Nitroxyl derivatives were characterized with different size and water-solubility. Some of them are originally synthesized. In buffer, in the absence of reducing and oxidizing equivalents, the EPR signal intensity of all Nitroxyls was constant with the time. In serum and cell cultured medium, in an absence of cells and in a negligible amount of reducing and oxidizing equivalents, there was no significant EPR signal reduction, too. In vitro (in freshly isolated blood samples), the EPR signal intensity was characterized with slow decrease within 30 min, presumably as a result of interaction between the Nitroxyl derivative and blood cells. The EPR spectrum of hydrophobic Nitroxyls showed a slight anisotropy in cell-containing solutions and it did not changed in non-cell physiological solutions. This suggests for a limited motion of more hydrophobic Nitroxyls through their preferable location in cell membranes. In vivo (in the bloodstream of mice under anesthesia), the EPR signal reduction kinetic was characterized by two phases: i) a rapid enhancement within 30 s as a result of increasing of Nitroxyl concentration in the bloodstream after its intravenous injection, followed by ii) a rapid decrease (approximately 80-100%) within 2-5 min, presumably as a result of transportation of Nitroxyl in the tissues. The hydrophobic Nitroxyls were characterized with stronger and faster decrease in EPR signal intensity in the blood in vivo, as a result of their higher cell permeability, rapid clearance from the bloodstream and/or transportation in the surrounding tissues. The hydrophilic Nitroxyls persist in the bloodstream (in their radical form) for a comparatively long time. The data suggest that the hydrophobic cell-permeable Nitroxyl derivatives are most appropriate for evaluation of cell and tissue oxidation/reduction status, while the hydrophilic Nitroxyls (impermeable for cell membranes or with very slow cell permeability) are most appropriate for evaluation of oxidation/reduction status of blood using EPR imaging.
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Modification of Nitroxyl contrast agents with multiple spins and their proton T1 relaxivity
Magnetic Resonance Imaging, 2008Co-Authors: Ken-ichiro Matsumoto, Kazunori Anzai, Haruko Yakumaru, Michiko Narazaki, Hidehiko Nakagawa, Hiroo Ikehira, Nobuo IkotaAbstract:Abstract The purpose of this study is to test the performance of multispin Nitroxyl contrast agents in improving the sensitivity of MR detection for Nitroxyl contrast agents. The relation between T 1 relaxivity and the number of paramagnetic centers in a molecule was investigated. Compound 1 is a single molecule of methoxycarbonyl-PROXYL (MC-PROXYL). Two and three MC-PROXYL molecules were chemically coupled to obtain Compounds 2 and 3, which have two and three Nitroxyl spins in the molecule, respectively. A good linear relation, the slope of which increased depending on the number of Nitroxyl spins in the molecule, was obtained between T 1 -weighted (fast low-angle shot) MR image contrast enhancement at 7 T and the concentration of Nitroxyl contrast agents. T 1 -weighted MR image contrast enhancement and T 1 relaxivity levels of Nitroxyl contrast agents were increased depending on the number of Nitroxyl spins in the molecule. Multicoupling Nitroxyl molecules can enhance the T 1 -weighted contrast effect while maintaining the quantitative behavior of the molecule for up to three spins.
Murali C Krishna - One of the best experts on this subject based on the ideXlab platform.
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comparative studies with epr and mri on the in vivo tissue redox status estimation using redox sensitive Nitroxyl probes influence of the choice of the region of interest
Free Radical Research, 2018Co-Authors: Ken-ichiro Matsumoto, James B Mitchell, Murali C KrishnaAbstract:AbstractIn vivo decay rates of a Nitroxyl contrast agent were estimated by a MR redox imaging (MRRI) technique and compared with the decay rates obtained by the electron paramagnetic resonance spectroscopy (EPRS) and imaging (EPRI). MRRI is a dynamic imaging technique employing T1-weighted pulse sequence, which can visualise a Nitroxyl-induced enhancement of signal intensity by T1-weighted contrast. EPR techniques can directly measure the paramagnetic Nitroxyl radical. Both the squamous cell carcinoma (SCC) tumour-bearing and normal legs of a female C3H mouse were scanned by T1-weighted SPGR sequence at 4.7 T with the Nitroxyl radical, carbamoyl-proxyl (CmP), as the contrast agent. Similarly, the time course of CmP in normal muscle and tumour tissues was obtained using a 700-MHz EPR spectrometer with a surface coil. The time course imaging of CmP was also performed by 300 MHz CW EPR imager. EPRS and EPRI gave slower decay rates of CmP compared to the MRRI. Relatively slow decay rate at peripheral region o...
Matsumoto Kenichiro - One of the best experts on this subject based on the ideXlab platform.
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Comparison of Blood-Brain-Barrier Permeable Nitroxyl Contrast Agents for Magnetic Resonance Brain RedOx Imaging
2019Co-Authors: Matsumoto Kenichiro, Ueno Megumi, Nakanishi Ikuo, Yamada Ken-ichi, Aoki IchioAbstract:Redox imaging technique is one of functional imaging method to visualize and estimate tissue redox status in living experimental animals, which can be achieved using magnetic resonance based imaging modalities, i.e. EPRI, OMRI and/or MRI. Nitroxyl radicals have been used as redox sensitive contrast agents. The redox imaging techniques can be applicable to brain by employing a blood-brain-barrier (BBB) permeable contrast agent. TEMPOL, which is one of most popular Nitroxyl radical, is an amphiphilic molecule. Therefore, TEMPOL can easily permeate BBB and is highly redox sensitive, however; it has relatively high toxicity and shows quite fast in vivo decay. Several new Nitroxyl radicals, which have lower toxicity, adequate in vivo decay rate, and good BBB permeability, have been developed for brain redox contrast agent. In this presentation, distributions and decay profiles of several different Nitroxyl based contrast agents in a mouse brain were compared for optimizing brain redox imaging technique on MRI.SFRBM\u27s 19th Annual Meetin
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Reaction of Nitroxyl radicals and GSH; pH deendence
2019Co-Authors: Matsumoto Kenichiro, Nakanishi Ikuo, Krishna MuraliAbstract:Nitroxyl radicals were utilized as redox probe in a field of in vivo EPR spectroscopy and imaging. Recently, utility of Nitroxyl radicals as redox sensitive contrast agents for functional MRI were proposed and were getting interests. Detail reaction of Nitroxyl radicals with each biological molecule, such as glutathione (GSH), were however not enough investigated. We have investigated temperature dependent reaction of Nitroxyl radical with coexisting GSH. GSH can react with 2 molecules of a Nitroxyl radical, and can eliminate EPR signal completely. Addition of K3Fe(CN)6 to the reaction mixture can not recover EPR signal of Nitroxyl radical after the reaction with GSH. In this study, pH dependence of reduction of several Nitroxyl radicals (TEMPO, TEMPOL, TEMPONE, carboxy-PROXYL, and carbamoyl-PROXYL) with coexisting glutathione at 37[deg]C was tested. The decay profiles of Nitroxyl radicals were depending on pH. The reduction of Nitroxyl radicals become faster in pH6 compared with pH7, except carboxy-PROXYL was not react in lower pH. Almost no reduction of Nitroxyl radicals occurred in pH8. However, mechanism of reaction of Nitroxyl radical and GSH is still in progress.SFRBM\u27s 17th Annual Meeting/SFRRI\u27s XV Biennial Meetin
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pH dependent reaction of Nitroxyl radicals and glutathione
2019Co-Authors: Matsumoto Kenichiro, Nakanishi Ikuo, Krishna MuraliAbstract:Nitroxyl radicals were utilized as redox probe in a field of in vivo EPR spectroscopy and imaging. Recently, utility of Nitroxyl radicals as redox sensitive contrast agents for functional MRI were proposed and were getting interests. Detail reaction of Nitroxyl radicals with each biological molecule, such as glutathione (GSH), were however not enough investigated. In this study, pH dependence of reaction of Nitroxyl radicals with GSH was investigated. Five deferent Nitroxyl radicals, i.e. TEMPO, TEMPOL, TEMPONE, carbamoyl-PROXYL, and carboxy-PROXYL, were tested for comparison. It was appeared that reaction of Nitroxyl radicals and GSH were faster at pH5.8 and slower at pH8.0 compared with pH7.0, except that carboxy-PROXYL did not show reduction at pH5.8.Introduction.International Symposium on Free Radical Research: Contribution to Medicin
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Modification of Nitroxyl contrast agents with multiple spins on the molecules and its proton T1-relaxivities
2019Co-Authors: Matsumoto Kenichiro, Narazaki Michiko, Yakumaru Haruko, Nagata Katsura, Anzai Kazunori, Ikehira Hiroo, Ikota NobuoAbstract:Paramagnetic Nitroxyl radicals have been proposed as a redox sensitive MR contrast agent. A time-sequence of the T1-weighted MR images at 4.7 T showed a readily visible enhancement of image intensity in mice due to paramagnetic Nitroxyl contrast agent and then sequentially showed gradual decrement of the image enhancement level. The dose 1.5 umol/g b.w. of the carbamoyl-PROXYL, which was a Nitroxyl contrast agent used in the previous report, was enough lower than its maximum tolerated dose (MTD) level for mice. However, the dose 1.5 umol/g b.w. is near to the MTD of TEMPOL for mice, which is reported as 275 mg/kg b.w. (1.6 umol/g b.w.). In addition the dose 1.5 umol/g b.w. is lager than dose levels of common medicines (< 1 umol/g b.w.). Although the dose of the Nitroxyl contrast agent used in future clinical trial should be decreased, the relatively small T1-relaxivity of the Nitroxyl radicals (= 0.2 mM-1s-1) makes difficult to detect low concentration levels. Higher magnetic field, such as 7 T, may increase the percentage of signal enhancement and the signal to noise ratio (SNR), while most clinical machines were worked at lower magnetic field, such as 3 T or 1.5 T. To obtain enough detectable T1-image enhancements quantitatively using lower dose, modification of T1-relaxivity of the Nitroxyl based contrast agents was tested. In this paper, the several Nitroxyl contrast agents which have different number of spins in the molecule were chemically synthesized. The relaxivity of those Nitroxyl contrast agents were measured. The suitable concentration range gave a linear relation with the image enhancement was observed for each Nitroxyl contrast agent. The availability of the multi-spin Nitroxyl contrast agent for MR-based redox imaging was described. The T1-relaxivity of Nitroxyl contrast agents were increased depending on the number of spins on the molecule. The suitable linear relation between image enhancement and concentration of the contrast agent was obtained for a Nitroxyl contrast agent in this paper.SFRBM\u27s 13th Annual Meetin
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Redox Sensitive MR Contrast Agent
2019Co-Authors: Matsumoto Kenichiro, Nakanishi Ikuo, Anzai KazunoriAbstract:Nitroxyl radicals (also known as nitroxide) have been used as in vitro and in vivo redox probes in fields of electron paramagnetic resonance (EPR) spectroscopy and imaging. Nitroxyl radicals are paramagnetic species, which also can be detected using T1-weighted MRI. Reactive oxygen species (ROS) react with Nitroxyl radicals to lose paramagnetism. The time course of in vivo MRI intensity induced by a Nitroxyl radical can give tissue redox information, which is the so called the redox imaging technique. Employing a membrane permeable Nitroxyl radical, redox information in tissues could be available. A brief theory of redox imaging techniques and applications of redox imaging techniques are introduced.Experimental Biology 201
Nakanishi Ikuo - One of the best experts on this subject based on the ideXlab platform.
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Presence of X-ray induced high concentrated hydrogen peroxide clusters
2019Co-Authors: Ueno Megumi, Nakanishi Ikuo, Ken-ichiro MatsumotoAbstract:Presence of high concetntrated hydrogen peroxide (H2O2) clusters in an aqueous solution during X-ray irradiation was demonstrated. A method to measure the distance between the clusters was attempted. X-ray induced H2O2 generation in the sample solution is related to the hydrogen-donor-independent reduction of Nitroxyl radical, however the reaction mechanisms are still in progress. In this study, the relation of H2O2 concentraion and hydrogen-donor-independent reduction of Nitroxyl radical was tested, and then the distance between localyzed H2O2 clusters was estimated.Reaction mixtures containing 0.1 mM of a Nitroxyl redox probe, TEMPOL or Carbamoyl-PROXYL, were prepared with containing several different concentrations (1.0 mM‒9.8 M) of H2O2. The reaction mixture was irradiated by 12000 μW/cm2 UVB for 2 min, and the reduction of the EPR signal of the nitorxyl radical was measured. An aliquot (2 µL) of 200 mM K3[Fe(CN)6] solution was added to 200 µL of the reaction mixture, and the time course of the EPR signal of the nitorxyl radical was measured. A series of Nitroxyl radical solutions with several different concentrations (0.06 μM‒2.28 mM) was irradiated with X-ray, and then the amount of reduction of Nitroxyl radical in each sample was measured by EPR. The UV induced EPR signal loss of the nitorxyl radical was increased with H2O2 higher than 10 mM. The EPR signal of nitorxyl radicals were decreased in the solution containing 1 M of H2O2, when K3[Fe(CN)6] was added to the reaction mixture. Oxidative stimulation by UVB irradiation or addition of K3[Fe(CN)6] could cause nitorxyl radical reduction in a high concentration H2O2 environment. This result suggests that ionizing radiations could prepare a high concentration H2O2 environment, which may be localized. Plotting reduction amount with density of Nitroxyl radical showed that the high concentration H2O2 clusters are with 43‒44 nm separation.The Society for Redox Biology and Medicine\u27s 26th Annual Conference (SfRBM 2019
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Comparison of Blood-Brain-Barrier Permeable Nitroxyl Contrast Agents for Magnetic Resonance Brain RedOx Imaging
2019Co-Authors: Matsumoto Kenichiro, Ueno Megumi, Nakanishi Ikuo, Yamada Ken-ichi, Aoki IchioAbstract:Redox imaging technique is one of functional imaging method to visualize and estimate tissue redox status in living experimental animals, which can be achieved using magnetic resonance based imaging modalities, i.e. EPRI, OMRI and/or MRI. Nitroxyl radicals have been used as redox sensitive contrast agents. The redox imaging techniques can be applicable to brain by employing a blood-brain-barrier (BBB) permeable contrast agent. TEMPOL, which is one of most popular Nitroxyl radical, is an amphiphilic molecule. Therefore, TEMPOL can easily permeate BBB and is highly redox sensitive, however; it has relatively high toxicity and shows quite fast in vivo decay. Several new Nitroxyl radicals, which have lower toxicity, adequate in vivo decay rate, and good BBB permeability, have been developed for brain redox contrast agent. In this presentation, distributions and decay profiles of several different Nitroxyl based contrast agents in a mouse brain were compared for optimizing brain redox imaging technique on MRI.SFRBM\u27s 19th Annual Meetin
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Reduction of TEMPOL in Highly Concentrated Hydrogen Peroxide caused by Oxidative Stimulation
2019Co-Authors: Matsumoto Ken-ichiro, Nakanishi IkuoAbstract:ABSTRACTRadiation exposure to an aqueous solution containing a Nitroxyl radical and glutathione (GSH) or other hydrogen donors, such as NAD(P)H, produces a dose-dependent EPR signal loss of the Nitroxyl radical [1, 2]. Radiation induced EPR signal loss of TEMPOL in water without coexisting hydrogen-donor, such as GSH or NAD(P)H, observed by relatively high dose has been also reported [3]. This hydrogen-donor-independent reduction of TEMPOL is partly depend on the generation of hydrogen peroxide (H2O2), since the reaction was partly suppressed by catalase. However, TEMPOL does not react with H2O2 directly. The detail mechanism of this hydrogen-donor-independent reduction of TEMPOL was in progress.A water solution of TEMPOL or Carbamoyl-PROXYL (0.1 mM) was irradiated by several doses (0, 16, 32, 64, 128 Gy) of X-ray, and the reduction of the X-band EPR signal of the nitorxyl radical was measured. A reaction mixture containing 0.1 mM TEMPOL or Carbamoyl-PROXYL and several concentration (1.0 mM‒9.8 M) of H2O2 was prepared, and then time course of X-band EPR signal intensity of the nitorxyl radical at room temperature was measured. A reaction mixture containing 0.1 mM TEMPOL or Carbamoyl-PROXYL and several concentration (1.0 mM‒9.8 M) of H2O2 was irradiated by 128 Gy of X-ray, and the reduction of the EPR signal of the nitorxyl radical was measured. An aliquot (2 µL) of 200 mM K3Fe(CN)6 solution was added to 200 µL of the reaction mixture containing 0.1 mM TEMPOL or Carbamoyl-PROXYL and several concentration (1.0 mM‒9.8 M) of H2O2, and the time course of the EPR signal of the nitorxyl radical was measured.When a water solution of a nitorxyl radical was irradiated by X-ray, EPR signal loss of the nitorxyl radical in the sample was decreased dose dependently. This X-ray induced EPR signal loss of the nitorxyl radical could be suppressed partly by adding catalase. On the other hand, nitorxyl radicals were quite stable in the solution containing H2O2. The X-ray induced EPR signal loss of the nitorxyl radical was slightly increased with H2O2 existing in the reaction mixture H2O2-concentration-dependently. The EPR signal of nitorxyl radicals were decreased in the solution containing quite high concentration (M level) of H2O2, when Fe3+ was added to the reaction mixture. However, in the solution containing lower H2O2 concentration (< mM level), the EPR signal intensity of the nitorxyl radical was stable even when the Fe3+ was added. Oxidative stimulation by X-ray irradiation or addition of Fe3+ could cause nitorxyl radical reduction in a very high concentration H2O2 environment.\nREFERENCES[1] K. Matsumoto, A. Okajo, K. Nagata, et al., Biol. Pharm. Bull. 32 (2009) 542[2] K. Matsumoto, K. Nagata, H. Yamamoto, et al., Magn. Reson. Med. 61 (2009) 1033[3] K. Matsumoto, I. Aoki, I. Nakanishi, et al., Magn. Reson. Med. Sci. 9 (2010) 131International Conference 2018 Modern Trends in Natural Sciences and Advanced Technologies in Science Educatio
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Reaction of Nitroxyl radicals and GSH; pH deendence
2019Co-Authors: Matsumoto Kenichiro, Nakanishi Ikuo, Krishna MuraliAbstract:Nitroxyl radicals were utilized as redox probe in a field of in vivo EPR spectroscopy and imaging. Recently, utility of Nitroxyl radicals as redox sensitive contrast agents for functional MRI were proposed and were getting interests. Detail reaction of Nitroxyl radicals with each biological molecule, such as glutathione (GSH), were however not enough investigated. We have investigated temperature dependent reaction of Nitroxyl radical with coexisting GSH. GSH can react with 2 molecules of a Nitroxyl radical, and can eliminate EPR signal completely. Addition of K3Fe(CN)6 to the reaction mixture can not recover EPR signal of Nitroxyl radical after the reaction with GSH. In this study, pH dependence of reduction of several Nitroxyl radicals (TEMPO, TEMPOL, TEMPONE, carboxy-PROXYL, and carbamoyl-PROXYL) with coexisting glutathione at 37[deg]C was tested. The decay profiles of Nitroxyl radicals were depending on pH. The reduction of Nitroxyl radicals become faster in pH6 compared with pH7, except carboxy-PROXYL was not react in lower pH. Almost no reduction of Nitroxyl radicals occurred in pH8. However, mechanism of reaction of Nitroxyl radical and GSH is still in progress.SFRBM\u27s 17th Annual Meeting/SFRRI\u27s XV Biennial Meetin
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pH dependent reaction of Nitroxyl radicals and glutathione
2019Co-Authors: Matsumoto Kenichiro, Nakanishi Ikuo, Krishna MuraliAbstract:Nitroxyl radicals were utilized as redox probe in a field of in vivo EPR spectroscopy and imaging. Recently, utility of Nitroxyl radicals as redox sensitive contrast agents for functional MRI were proposed and were getting interests. Detail reaction of Nitroxyl radicals with each biological molecule, such as glutathione (GSH), were however not enough investigated. In this study, pH dependence of reaction of Nitroxyl radicals with GSH was investigated. Five deferent Nitroxyl radicals, i.e. TEMPO, TEMPOL, TEMPONE, carbamoyl-PROXYL, and carboxy-PROXYL, were tested for comparison. It was appeared that reaction of Nitroxyl radicals and GSH were faster at pH5.8 and slower at pH8.0 compared with pH7.0, except that carboxy-PROXYL did not show reduction at pH5.8.Introduction.International Symposium on Free Radical Research: Contribution to Medicin
Kazunori Anzai - One of the best experts on this subject based on the ideXlab platform.
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Nitroxyl radicals for labeling of conventional therapeutics and noninvasive magnetic resonance imaging of their permeability for blood brain barrier relationship between structure blood clearance and mri signal dynamic in the brain
Molecular Pharmaceutics, 2009Co-Authors: Zhivko Zhelev, Ken-ichiro Matsumoto, Veselina Gadjeva, Rumiana Bakalova, Ichio Aoki, Kazunori Anzai, Iwao KannoAbstract:The present study describes a novel nonradioactive methodology for in vivo noninvasive, real-time imaging of blood−brain barrier (BBB) permeability for conventional drugs, using Nitroxyl radicals as spin-labels and magnetic resonance imaging (MRI). Two TEMPO-labeled analogues (SLENU and SLCNUgly) of the anticancer drug lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] were synthesized, using a substitution of the cyclohexyl part with Nitroxyl radical. Nonmodified Nitroxyl radical TEMPOL was used for comparison. The Nitroxyl derivatives were injected intravenously in healthy mice via the tail vein, and MR imaging of the brain was performed on a 7.0 T MRI. The MRI signal dynamic of SLENU and SLCNUgly followed the same kinetics as nonmodified TEMPO radical. SLENU and SLCNUgly were rapidly transported and randomly distributed in the brain tissue, which indicated that the exchange of cyclohexyl part of lomustine with TEMPO radical did not suppress the permeability of the anticancer drug for BBB. The sel...
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EPR signal reduction kinetic of several Nitroxyl derivatives in blood in vitro and in vivo
General Physiology and Biophysics, 2009Co-Authors: Zhivko Zhelev, Ken-ichiro Matsumoto, Veselina Gadjeva, Rumiana Bakalova, Ichio Aoki, Antoaneta Zheleva, Kazunori AnzaiAbstract:The present study is focused on the mechanism(s) of electron-paramagnetic resonance (EPR) signal reduction kinetic of several Nitroxyl radicals and Nitroxyl-labeled anticancer drugs in physiological solutions in the context of their application for evaluation of oxidation/reduction status of blood and tissues--an important step in biomedical diagnostics and planning of therapy of many diseases. The Nitroxyl derivatives were characterized with different size and water-solubility. Some of them are originally synthesized. In buffer, in the absence of reducing and oxidizing equivalents, the EPR signal intensity of all Nitroxyls was constant with the time. In serum and cell cultured medium, in an absence of cells and in a negligible amount of reducing and oxidizing equivalents, there was no significant EPR signal reduction, too. In vitro (in freshly isolated blood samples), the EPR signal intensity was characterized with slow decrease within 30 min, presumably as a result of interaction between the Nitroxyl derivative and blood cells. The EPR spectrum of hydrophobic Nitroxyls showed a slight anisotropy in cell-containing solutions and it did not changed in non-cell physiological solutions. This suggests for a limited motion of more hydrophobic Nitroxyls through their preferable location in cell membranes. In vivo (in the bloodstream of mice under anesthesia), the EPR signal reduction kinetic was characterized by two phases: i) a rapid enhancement within 30 s as a result of increasing of Nitroxyl concentration in the bloodstream after its intravenous injection, followed by ii) a rapid decrease (approximately 80-100%) within 2-5 min, presumably as a result of transportation of Nitroxyl in the tissues. The hydrophobic Nitroxyls were characterized with stronger and faster decrease in EPR signal intensity in the blood in vivo, as a result of their higher cell permeability, rapid clearance from the bloodstream and/or transportation in the surrounding tissues. The hydrophilic Nitroxyls persist in the bloodstream (in their radical form) for a comparatively long time. The data suggest that the hydrophobic cell-permeable Nitroxyl derivatives are most appropriate for evaluation of cell and tissue oxidation/reduction status, while the hydrophilic Nitroxyls (impermeable for cell membranes or with very slow cell permeability) are most appropriate for evaluation of oxidation/reduction status of blood using EPR imaging.
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Modification of Nitroxyl contrast agents with multiple spins and their proton T1 relaxivity
Magnetic Resonance Imaging, 2008Co-Authors: Ken-ichiro Matsumoto, Kazunori Anzai, Haruko Yakumaru, Michiko Narazaki, Hidehiko Nakagawa, Hiroo Ikehira, Nobuo IkotaAbstract:Abstract The purpose of this study is to test the performance of multispin Nitroxyl contrast agents in improving the sensitivity of MR detection for Nitroxyl contrast agents. The relation between T 1 relaxivity and the number of paramagnetic centers in a molecule was investigated. Compound 1 is a single molecule of methoxycarbonyl-PROXYL (MC-PROXYL). Two and three MC-PROXYL molecules were chemically coupled to obtain Compounds 2 and 3, which have two and three Nitroxyl spins in the molecule, respectively. A good linear relation, the slope of which increased depending on the number of Nitroxyl spins in the molecule, was obtained between T 1 -weighted (fast low-angle shot) MR image contrast enhancement at 7 T and the concentration of Nitroxyl contrast agents. T 1 -weighted MR image contrast enhancement and T 1 relaxivity levels of Nitroxyl contrast agents were increased depending on the number of Nitroxyl spins in the molecule. Multicoupling Nitroxyl molecules can enhance the T 1 -weighted contrast effect while maintaining the quantitative behavior of the molecule for up to three spins.
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Comparisons of EPR imaging and T1-weighted MRI for efficient imaging of Nitroxyl contrast agents.
Journal of Magnetic Resonance, 2007Co-Authors: Ken-ichiro Matsumoto, Kazunori Anzai, Michiko Narazaki, Hiroo Ikehira, Nobuo IkotaAbstract:Abstract The resolution and signal to noise ratio of EPR imaging and T 1 -weighted MRI were compared using an identical phantom. Several solutions of Nitroxyl contrast agents with different EPR spectral shapes were tested. The feasibility of T 1 -weighted MRI to detect Nitroxyl contrast agents was described. T 1 -weighted MRI can detect Nitroxyl contrast agents with a complicated EPR spectrum easier and quicker; however, T 1 -weighted MRI has less quantitative ability especially for lipophilic Nitroxyl contrast agents, because T 1 -relaxivity, i.e. accessibility to water, is affected by the hydrophilic/hydrophobic micro-environment of a Nitroxyl contrast agent. The less quantitative ability of T 1 -weighted MRI may not be a disadvantage of redox imaging, which obtains reduction rate of a Nitroxyl contrast. Therefore, T 1 -weighted MRI has a great advantage to check the pharmacokinetics of newly modified and/or designed Nitroxyl contrast agents.
