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Marutani, Eizo

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Marutani

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Eizo

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Marutani, Eizo
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    An Engineered Enzyme That Targets Circulating Lactate to Alleviate Intracellular NADH:NAD+ Imbalance
    (Springer Science and Business Media LLC, 2020-01-13) Patgiri, Anupam; Skinner, Owen; Miyazaki, Yusuke; Schleifer, Grigorij; Marutani, Eizo; Shah, Hardik; Sharma, Rohit; Goodman, Russell; To, Tsz-Leung; Bao, Xiaoyan; Ichinose, Fumito; Zapol, Warren; Mootha, Vamsi
    An elevated intracellular NADH/NAD+ ratio, or “reductive stress,” has been associated with multiple diseases, including disorders of the mitochondrial electron transport chain (ETC). As the intracellular NADH/NAD+ ratio can be in near-equilibrium with the circulating lactate/pyruvate ratio, we hypothesized that reductive stress could be alleviated by oxidizing extracellular lactate into pyruvate. We engineered LOXCAT, a fusion of bacterial lactate oxidase (LOX) and catalase (CAT), which irreversibly converts lactate and oxygen to pyruvate and water. Addition of recombinant LOXCAT to the media of cultured human cells with a defective ETC was able to decrease the extracellular lactate/pyruvate ratio, normalize the intracellular NADH/NAD+ ratio, upregulate glycolytic ATP production, and restore cellular proliferation. In mice, tail-vein injected LOXCAT reduced circulating lactate/pyruvate ratio, blunted a metformin-induced rise in blood lactate/pyruvate, and improved NADH/NAD+ balance in heart and brain. Our study lays the groundwork for a class of injectable therapeutic enzymes that alleviate intracellular redox imbalances by directly targeting circulating redox-coupled metabolites.
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    Trapping Hydrogen Sulfide (H2S) with Diselenides: The Application in the Design of Fluorescent Probes
    (American Chemical Society, 2015) Peng, Bo; Zhang, Caihong; Marutani, Eizo; Pacheco, Armando; Chen, Wei; Ichinose, Fumito; Xian, Ming
    Here we report a unique reaction between phenyl diselenide-ester substrates and H2S to form 1,2-benzothiaselenol-3-one. This reaction proceeded rapidly under mild conditions. Thiols could also react with the diselenide substrates. However, the resulted S–Se intermediate retained high reactivity toward H2S and eventually led to the same cyclized product 1,2-benzothiaselenol-3-one. Based on this reaction two fluorescent probes were developed and showed high selectivity and sensitivity for H2S. The presence of thiols was found not to interfere with the detection process.
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    Thiosulfate Mediates Cytoprotective Effects of Hydrogen Sulfide Against Neuronal Ischemia
    (John Wiley and Sons Inc., 2015) Marutani, Eizo; Yamada, Marina; Ida, Tomoaki; Tokuda, Kentaro; Ikeda, Kohei; Kai, Shinichi; Shirozu, Kazuhiro; Hayashida, Kei; Kosugi, Shizuko; Hanaoka, Kenjiro; Kaneki, Masao; Akaike, Takaaki; Ichinose, Fumito
    Background: Hydrogen sulfide (H2S) exhibits protective effects in various disease models including cerebral ischemia–reperfusion (I/R) injury. Nonetheless, mechanisms and identity of molecules responsible for neuroprotective effects of H2S remain incompletely defined. In the current study, we observed that thiosulfate, an oxidation product of H2S, mediates protective effects of an H2S donor compound sodium sulfide (Na2S) against neuronal I/R injury. Methods and Results: We observed that thiosulfate in cell culture medium is not only required but also sufficient to mediate cytoprotective effects of Na2S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (SH‐SY5Y) and murine primary cortical neurons. Systemic administration of sodium thiosulfate (STS) improved survival and neurological function of mice subjected to global cerebral I/R injury. Beneficial effects of STS, as well as Na2S, were associated with marked increase of thiosulfate, but not H2S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating “carrier” molecule of beneficial effects of H2S. Protective effects of thiosulfate were associated with inhibition of caspase‐3 activity by persulfidation at Cys163 in caspase‐3. We discovered that an SLC13 family protein, sodium sulfate cotransporter 2 (SLC13A4, NaS‐2), facilitates transport of thiosulfate, but not sulfide, across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of Na2S and STS. Conclusions: The protective effects of H2S are mediated by thiosulfate that is transported across cell membrane by NaS‐2 and exerts antiapoptotic effects via persulfidation of caspase‐3. Given the established safety track record, thiosulfate may be therapeutic against ischemic brain injury.