研究者詳細 - 末松　誠

論文 - 末松　誠

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Myocardial fatty acid uptake through CD36 is indispensable for sufficient bioenergetic metabolism to prevent progression of pressure overload-induced heart failure

Umbarawan Y., Syamsunarno M.R.A.A., Koitabashi N., Obinata H., Yamaguchi A., Hanaoka H., Hishiki T., Hayakawa N., Sano M., Sunaga H., Matsui H., Tsushima Y., Suematsu M., Kurabayashi M., Iso T.

Scientific Reports （Scientific Reports） 8 （ 1 ） 12035 2018年12月

ISSN 2045-2322

© 2018, The Author(s). The energy metabolism of the failing heart is characterized by reduced fatty acid (FA) oxidation and an increase in glucose utilization. However, little is known about how energy metabolism-function relationship is relevant to pathophysiology of heart failure. Recent study showed that the genetic deletion of CD36 (CD36KO), which causes reduction in FA use with an increased reliance on glucose, accelerates the progression from compensated hypertrophy to heart failure. Here, we show the mechanisms by which CD36 deletion accelerates heart failure in response to pressure overload. CD36KO mice exhibited contractile dysfunction and death from heart failure with enhanced cardiac hypertrophy and interstitial fibrosis when they were subjected to transverse aortic constriction (TAC). The pool size in the TCA cycle and levels of high-energy phosphate were significantly reduced in CD36KO-TAC hearts despite an increase in glycolytic flux. De novo synthesis of non-essential amino acids was facilitated in CD36KO-TAC hearts, which could cause a further decline of the pool size. The ingestion of a diet enriched in medium-chain FA improved cardiac dysfunction in CD36KO-TAC hearts. These findings suggest that myocardial FA uptake through CD36 is indispensable for sufficient ATP production and for preventing an increased glycolytic flux-mediated structural remodeling during pressure overload-induced hypertrophy.

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Gold-nanofève surface-enhanced Raman spectroscopy visualizes hypotaurine as a robust anti-oxidant consumed in cancer survival

Shiota M., Naya M., Yamamoto T., Hishiki T., Tani T., Takahashi H., Kubo A., Koike D., Itoh M., Ohmura M., Kabe Y., Sugiura Y., Hiraoka N., Morikawa T., Takubo K., Suina K., Nagashima H., Sampetrean O., Nagano O., Saya H., Yamazoe S., Watanabe H., Suematsu M.

Nature Communications （Nature Communications） 9 （ 1 ） 1561 2018年12月

ISSN 2041-1723

© 2018 The Author(s). Gold deposition with diagonal angle towards boehmite-based nanostructure creates random arrays of horse-bean-shaped nanostructures named gold-nanofève (GNF). GNF generates many electromagnetic hotspots as surface-enhanced Raman spectroscopy (SERS) excitation sources, and enables large-area visualization of molecular vibration fingerprints of metabolites in human cancer xenografts in livers of immunodeficient mice with sufficient sensitivity and uniformity. Differential screening of GNF-SERS signals in tumours and those in parenchyma demarcated tumour boundaries in liver tissues. Furthermore, GNF-SERS combined with quantum chemical calculation identified cysteine-derived glutathione and hypotaurine (HT) as tumour-dominant and parenchyma-dominant metabolites, respectively. CD44 knockdown in cancer diminished glutathione, but not HT in tumours. Mechanisms whereby tumours sustained HT under CD44-knockdown conditions include upregulation of PHGDH, PSAT1 and PSPH that drove glycolysis-dependent activation of serine/glycine-cleavage systems to provide one-methyl group for HT synthesis. HT was rapidly converted into taurine in cancer cells, suggesting that HT is a robust anti-oxidant for their survival under glutathione-suppressed conditions.

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Aldosterone and 18-oxocortisol coaccumulation in aldosterone-producing lesions

Sugiura Y., Takeo E., Shimma S., Yokota M., Higashi T., Seki T., Mizuno Y., Oya M., Kosaka T., Omura M., Nishikawa T., Suematsu M., Nishimoto K.

Hypertension （Hypertension） 72 （ 6 ） 1345 - 1354 2018年12月

ISSN 0194911X

© 2018 American Heart Association, Inc. Primary aldosteronism is a secondary hypertensive disease caused by autonomous aldosterone production that often caused by an aldosterone-producing adenoma (APA). Immunohistochemistry of aldosterone synthase (CYP11B2) shows the presence of aldosterone-producing cell clusters (APCCs) even in non-primary aldosteronism adult adrenal cortex. An APCC-like structure also exists as possible APCC-to-APA transitional lesions (a speculative designation) in primary aldosteronism adrenals. However, whether APCCs produce aldosterone or 18-oxocortisol, a potential serum marker of APA, remains unknown because of lack of technology to visualize adrenocorticosteroids on tissue sections. To address this obstacle, in this study, we used highly sensitive Fourier transform ion cyclotron resonance mass spectrometry to image various adrenocorticosteroids, including 18-oxocortisol, in adrenal tissue sections from 8 primary aldosteronism patients with APCC (cases 1-4), possible APCC-to-APA transitional lesions (case 5), and APA (cases 6-8). Further analyses by tandem mass spectrometry imaging allowed us to differentially visualize aldosterone from cortisone, which share identical mass-to-charge ratio value (m/z). In conclusion, these advanced imaging techniques revealed that aldosterone and 18-oxocortisol coaccumulated within CYP11B2-expressing lesions. These imaging outcomes along with a growing body of aldosterone research led us to build a progressive development hypothesis of an aldosterone-producing pathology in the adrenal glands.

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Biochemical, metabolomic, and genetic analyses of dephospho coenzyme a kinase involved in coenzyme a biosynthesis in the human enteric parasite entamoeba histolytica

Nurkanto A., Jeelani G., Yamamoto T., Hishiki T., Naito Y., Suematsu M., Hashimoto T., Nozaki T.

Frontiers in Microbiology （Frontiers in Microbiology） 9 （ NOV ） 2902 2018年11月

ISSN 1664-302X

Copyright © 2018 Nurkanto, Jeelani, Yamamoto, Hishiki, Naito, Suematsu, Hashimoto and Nozaki. Coenzyme A (CoA) is an essential cofactor for numerous cellular reactions in all living organisms. In the protozoan parasite Entamoeba histolytica, CoA is synthesized in a pathway consisting of four enzymes with dephospho-CoA kinase (DPCK) catalyzing the last step. However, the metabolic and physiological roles of E. histolytica DPCK remain elusive. In this study, we took biochemical, reverse genetic, and metabolomic approaches to elucidate role of DPCK in E. histolytica. The E. histolytica genome encodes two DPCK isotypes (EhDPCK1 and EhDPCK2). Epigenetic gene silencing of Ehdpck1 and Ehdpck2 caused significant reduction of DPCK activity, intracellular CoA concentrations, and also led to growth retardation in vitro, suggesting importance of DPCK for CoA synthesis and proliferation. Furthermore, metabolomic analysis showed that suppression of Ehdpck gene expression also caused decrease in the level of acetyl-CoA, and metabolites involved in amino acid, glycogen, hexosamine, nucleic acid metabolisms, chitin, and polyamine biosynthesis. The kinetic properties of E. histolytica and human DPCK showed remarkable differences, e.g., the Km values of E. histolytica and human DPCK were 58–114 and 5.2 μM toward dephospho-CoA and 15–20 and 192 μM for ATP, respectively. Phylogenetic analysis also supported the uniqueness of the amebic enzyme compared to the human counterpart. These biochemical, evolutionary features, and physiological importance of EhDPCKs indicate that EhDPCK represents the rational target for the development of anti-amebic agents.

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Survey on patients with undiagnosed diseases in Japan: Potential patient numbers benefiting from Japan's initiative on rare and undiagnosed diseases (IRUD)

Adachi T., Imanishi N., Ogawa Y., Furusawa Y., Izumida Y., Izumi Y., Suematsu M.

Orphanet Journal of Rare Diseases （Orphanet Journal of Rare Diseases） 13 （ 1 ） 208 2018年11月

© 2018 The Author(s). Background: There is now an international partnership to establish global programs for patients with rare and undiagnosed diseases, involving interdisciplinary expert panels and phenotype-driven genetic analyses utilizing next-generation sequencing and analytics. Whereas it is crucial to have data such as the actual number of undiagnosed patients, to help inform the implementation plan with such programs, there have been no systematic studies to quantitate the numbers of patients principally because of the inherent difficulty in most health systems to identify patients whose condition has not yet been diagnosed and coded. Our national experience with a rare disease program, Nan-Byo which was established in 1972, and the more recently expanded Initiative on Rare and Undiagnosed Diseases (IRUD), provided a unique opportunity to design a cross-sectional study to ascertain the undiagnosed patients in Japan based on the IRUD referral criteria. Results: Two rounds of online surveys were performed: one survey targeting physicians affiliated with general hospitals (GH) and family clinics (FC) (the response rate: 30.6% (242/792)) and one nationwide survey targeting university hospitals (UH) in Japan (47.1% (839/1781)). A high percentage of doctors needing IRUD was seen in pediatrics at GH, FC, while there was a clear demand for IRUD in most departments at UH. We calculated the number of undiagnosed patients in Japan, as the "percentage of doctors needing IRUD" × "number of patients who would be referred to IRUD per doctor needing IRUD (cases/person)" × "total number of doctors in the relevant facilities in Japan (persons)", resulting in 3681 cases in pediatrics/pediatric surgery and 33,703 cases in other departments, for a total of 37,384 cases. Conclusions: Our study revealed the extant demand for IRUD in most departments and 37,000+ potential patients with undiagnosed diseases in the Japanese health system. These data inform the establishment of an equitable, sustainable, efficient and effective outpatient-based IRUD. These findings would serve as a valuable reference for undiagnosed diseases programs in different international jurisdictions and for countries and regions who also share vision(s) for societal implementation that help to advance international efforts to support patients with rare diseases who are direly waiting for diagnosis, subsequent treatment and care.

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Sodium–glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice

Tanaka S., Sugiura Y., Saito H., Sugahara M., Higashijima Y., Yamaguchi J., Inagi R., Suematsu M., Nangaku M., Tanaka T.

Kidney International （Kidney International） 94 （ 5 ） 912 - 925 2018年11月

ISSN 00852538

© 2018 International Society of Nephrology It is unclear whether long-term sodium–glucose cotransporter 2 (SGLT2) inhibition such as that during the treatment of diabetes has deleterious effects on the kidney. Therefore, we first sought to determine whether abnormal glucose metabolism occurs in the kidneys of 22-week-old BTBR ob/ob diabetic mice. Second, the cumulative effect of chronic SGLT2 inhibition by ipragliflozin and 30% calorie restriction, either of which lowered blood glucose to a similar extent, on renal glucose metabolism was evaluated. Mass spectrometry–based metabolomics demonstrated that these diabetic mice exhibited an abnormal elevation in the renal pools of tricarboxylic acid cycle metabolites. This was almost completely nullified by SGLT2 inhibition and calorie restriction. Moreover, imaging mass spectrometry indicated an increased level of the tricarboxylic acid cycle intermediate, citrate, in the cortex of the diabetic mice. SGLT2 inhibition as well as calorie restriction almost completely eliminated citrate accumulation in the cortex. Furthermore, imaging mass spectrometry revealed that the accumulation of oxidized glutathione in the cortex of the kidneys, prominent in the glomeruli, was also canceled by SGLT2 inhibition and calorie restriction. Effects of these beneficial interventions were consistent with improvements in glomerular damage, such as albuminuria, glomerular hyperfiltration, and mesangial expansion. Tubulointerstitial macrophage infiltration and fibrosis were ameliorated only by calorie restriction, which may have been due to autophagy activation, which was observed only with calorie restriction. Thus, chronic SGLT2 inhibition is efficient in normalizing the levels of accumulated tricarboxylic acid cycle intermediates and increased oxidative stress in the kidneys of diabetic mice.

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Development of a highly sensitive device for counting the number of disease-specific exosomes in human sera

Kabe Y., Suematsu M., Sakamoto S., Hirai M., Koike I., Hishiki T., Matsuda A., Hasegawa Y., Tsujita K., Ono M., Minegishi N., Hozawa A., Murakami Y., Kubo M., Itonaga M., Handa H.

Clinical Chemistry （Clinical Chemistry） 64 （ 10 ） 1463 - 1473 2018年10月

ISSN 00099147

© 2018 American Association for Clinical Chemistry BACKGROUND: Although circulating exosomes in blood play crucial roles in cancer development and progression, difficulties in quantifying exosomes hamper their application for reliable clinical testing. By combining the properties of nanobeads with optical disc technology, we have developed a novel device named the ExoCounter to determine the exact number of exosomes in the sera of patients with various types of cancer. METHOD: In this system, individual exosomes were captured in the groove of an optical disc coated with antibodies against exosome surface antigens. The captured exosomes were labeled with antibody-conjugated magnetic nanobeads, and the number of the labeled exosomes was counted with an optical disc drive. RESULTS: We showed that the ExoCounter could detect specific exosomes derived from cells or human serum without any enrichment procedures. The detection sensitivity and linearity with this system were higher than those with conventional detection methods such as ELISA or flow cytometry. In addition to the ubiquitous exosome markers CD9 and CD63, the cancer-related antigens CD147, carcinoembryonic antigen, and human epidermal growth factor receptor 2 (HER2) were also used to quantify cancer cell line-derived exosomes. Furthermore, analyses of a cross-sectional cohort of sera samples revealed that HER2-positive exosomes were significantly increased in patients with breast cancer or ovarian cancer compared with healthy individuals and those with noncancer diseases. CONCLUSIONS: The ExoCounter system exhibits high performance in the direct detection of exosomes in cell culture and human sera. This method may enable reliable analysis of liquid biopsies.

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FEBUXOSTAT EXERTED RENO-PROTECTIVE EFFECTS AFTER TRANSIENT ISCHEMIA BY PROMOTING ATP RECOVERY IN THE CORTEX: VISUALIZATION OF RENAL ADENINE NUCLEOTIDES BY AN IMAGING MASS-SPECTROMETRY TECHNIQUE

Miyashita Kazutoshi, Fujii Kentaro, Kubo Akiko, Sato Masaaki, Hagiwara Aika, Inoue Hiroyuki, Ryuzaki Masaki, Endo Sho, Uto Asuka, Suematsu Makoto, Itoh Hiroshi

JOURNAL OF HYPERTENSION 36 E72 - E73 2018年10月

ISSN 0263-6352

Optogenetic astrocyte activation evokes BOLD fMRI response with oxygen consumption without neuronal activity modulation

Takata N., Sugiura Y., Yoshida K., Koizumi M., Hiroshi N., Honda K., Yano R., Komaki Y., Matsui K., Suematsu M., Mimura M., Okano H., Tanaka K.F.

GLIA （GLIA） 66 （ 9 ） 2013 - 2023 2018年09月

ISSN 08941491

© 2018 Wiley Periodicals, Inc. Functional magnetic resonance imaging (fMRI) based on the blood oxygenation level-dependent (BOLD) signal has been used to infer sites of neuronal activation in the brain. A recent study demonstrated, however, unexpected BOLD signal generation without neuronal excitation, which led us to hypothesize the presence of another cellular source for BOLD signal generation. Collective assessment of optogenetic activation of astrocytes or neurons, fMRI in awake mice, electrophysiological measurements, and histochemical detection of neuronal activation, coherently suggested astrocytes as another cellular source. Unexpectedly, astrocyte-evoked BOLD signal accompanied oxygen consumption without modulation of neuronal activity. Imaging mass spectrometry of brain sections identified synthesis of acetyl-carnitine via oxidative glucose metabolism at the site of astrocyte-, but not neuron-evoked BOLD signal. Our data provide causal evidence that astrocytic activation alone is able to evoke BOLD signal response, which may lead to reconsideration of current interpretation of BOLD signal as a marker of neuronal activation.

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Overexpression of CAPZA1, a novel negative regulator of autophagy, develops CD44v9-expressing cancer stem-like cells in Helicobacter pylori-infected gastric mucosa

Tsugawa H., Matsuzaki J., Kato C., Mori H., Suematsu M., Suzuki H.

HELICOBACTER 23 2018年09月

ISSN 1083-4389

A method for determination of aldosterone in adrenal tributary venous serum by derivatization using Girard P reagent isotopologues followed by LC/ESI-MS/MS

Higashi T., Akaishi M., Yokota M., Suzuki T., Ogawa S., Sugiura Y., Nishikawa T., Nishimoto K., Suematsu M.

Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences （Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences） 1092 106 - 113 2018年08月

ISSN 15700232

© 2018 Elsevier B.V. The quantification of aldosterone (ALD) in adrenal tributary venous blood serum/plasma combined with the super-selective adrenal venous sampling (ssAVS) technique is recognized as a definitive procedure for differentiation of the forms of primary aldosteronism (PA), identification of the affected segment(s) and operating decision-making. In this study, an enhanced throughput and sensitive method was developed and validated for the quantification of ALD in ssAVS serum samples by liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) combined with derivatization using the Girard P reagent (GP) isotopologues (2H0- and 2H5-GP). The right and left adrenal serum samples were separately pretreated and derivatized with either isotopologue. The two samples were then combined and injected together for LC/ESI-MS/MS analysis. Based on the mass differences between the isotopologues, the derivatized ALD in the two samples were quantified within a single run. This method enabled the reproducible (intra- and inter-assay relative standard deviations, 6.6% or lower) and accurate (98.2–107.0%) quantification of the serum ALD using a 25-μL sample, and the lower limit of quantification was 1.0 ng/mL. The developed method was used for the analysis of 11 pairs of ssAVS serum samples (total of 22 samples) of patients with ALD-producing adenoma and proven to have a satisfactory applicability; this method enabled the identification of the affected adrenal and the determination of the laterality of PA, and reduced the analysis time to about 2/3 compared to the previous method for 22 samples.

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Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye

Sakurai T., Uruno T., Sugiura Y., Tatsuguchi T., Yamamura K., Ushijima M., Hattori Y., Kukimoto-Niino M., Mishima-Tsumagari C., Watanabe M., Suematsu M., Fuku Y.

Science Signaling （Science Signaling） 11 （ 541 ） 2018年07月

ISSN 19450877

© 2018 American Association for the Advancement of Science. All rights reserved. Although immune responses are essential to protect the body from infection, they can also harm tissues. Certain tissues and organs, including the eye, constitute specialized microenvironments that locally inhibit immune reactivity. Dedicator of cytokinesis protein 2 (DOCK2) is a Rac-specific guanine nucleotide exchange factor (GEF) that is predominantly found in hematopoietic cells. DOCK2 plays a key role in immune surveillance because it is essential for the activation and migration of leukocytes. DOCK2 mutations cause severe immunodeficiency in humans. We found that DOCK2-mediated Rac activation and leukocyte migration were effectively inhibited by cholesterol sulfate (CS), but not by cholesterol or other sulfated steroids. CS bound to the catalytic domain of DOCK2 and suppressed its GEF activity. Mass spectrometric quantification revealed that CS was most abundantly produced in the Harderian gland, which provides the lipids that form the oily layer of the tear film. Sulfation of cholesterol is mediated by the sulfotransferases SULT2B1b and, to a lesser extent, SULT2B1a, which are produced from the same gene through alternative splicing. By genetically inactivating Sult2b1, we showed that the lack of CS in mice augmented ultraviolet- And antigen-induced ocular surface inflammation, which was suppressed by administration of eye drops containing CS. Thus, CS is a naturally occurring DOCK2 inhibitor and contributes to the generation of the immunosuppressive microenvironment in the eye.

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Glucose is preferentially utilized for biomass synthesis in pressure-overloaded hearts: Evidence from fatty acid-binding protein-4 and-5 knockout mice

Umbarawan Y., Syamsunarno M.R.A.A., Koitabashi N., Yamaguchi A., Hanaoka H., Hishiki T., Nagahata-Naito Y., Obinata H., Sano M., Sunaga H., Matsui H., Tsushima Y., Suematsu M., Kurabayashi M., Iso T.

Cardiovascular Research （Cardiovascular Research） 114 （ 8 ） 1132 - 1144 2018年07月

ISSN 00086363

© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology. Aims The metabolism of the failing heart is characterized by an increase in glucose uptake with reduced fatty acid (FA) oxidation. We previously found that the genetic deletion of FA-binding protein-4 and-5 [double knockout (DKO)] induces an increased myocardial reliance on glucose with decreased FA uptake in mice. However, whether this fuel switch confers functional benefit during the hypertrophic response remains open to debate. To address this question, we investigated the contractile function and metabolic profile of DKO hearts subjected to pressure overload. Methods and results Transverse aortic constriction (TAC) significantly reduced cardiac contraction in DKO mice (DKO-TAC), although an increase in cardiac mass and interstitial fibrosis was comparable with wild-Type TAC (WT-TAC). DKO-TAC hearts exhibited enhanced glucose uptake by 8-fold compared with WT-TAC. Metabolic profiling and isotopomer analysis revealed that the pool size in the TCA cycle and the level of phosphocreatine were significantly reduced in DKO-TAC hearts, despite a marked increase in glycolytic flux. The ingestion of a diet enriched in medium-chain FAs restored cardiac contractile dysfunction in DKO-TAC hearts. The de novo synthesis of amino acids as well as FA from glycolytic flux was unlikely to be suppressed, despite a reduction in each precursor. The pentose phosphate pathway was also facilitated, which led to the increased production of a coenzyme for lipogenesis and a precursor for nucleotide synthesis. These findings suggest that reduced FA utilization is not sufficiently compensated by a robust increase in glucose uptake when the energy demand is elevated. Glucose utilization for sustained biomass synthesis further enhances diminishment of the pool size in the TCA cycle. Conclusions Our data suggest that glucose is preferentially utilized for biomass synthesis rather than ATP production during pressure-overload-induced cardiac hypertrophy and that the efficient supplementation of energy substrates may restore cardiac dysfunction caused by energy insufficiency.

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Quantitative imaging mass spectroscopy reveals roles of heme oxygenase-2 for protecting against transhemispheric diaschisis in the brain ischemia

Goto S., Morikawa T., Kubo A., Takubo K., Fukuda K., Kajimura M., Suematsu M.

Journal of Clinical Biochemistry and Nutrition （Journal of Clinical Biochemistry and Nutrition） 63 （ 1 ） 70 - 79 2018年07月

ISSN 09120009

© 2018 JCBN. Carbon monoxide-generating heme oxygenase-2 is expressed in neurons and plays a crucial role for regulating hypoxic vasodilation through mechanisms unlocking carbon monoxide-dependent inhibition of H2S-generating cystathionine β-synthase expressed in astrocytes. This study aims to examine whether heme oxygenase-2 plays a protective role in mice against stroke. Focal ischemia was induced by middle cerebral artery occlusion. Regional differences in metabolites among ipsilateral and contralateral hemispheres were analysed by quantitative imaging mass spectrometry equipped with an image-processing platform to optimize comparison of local metabolite contents among different animals. Under normoxia, blood flow velocity in precapillary arterioles were significantly elevated in heme oxygenase-2-null mice vs controls, while metabolic intermediates of central carbon metabolism and glutamate synthesis were elevated in the brain of heme oxygenase-2-null mice, suggesting greater metabolic demands to induce hyperemia in these mice. In response to focal ischemia, heme oxygenase-2-null mice exhibited greater regions of ischemic core that coincide with notable decreases in energy metabolism in the contralateral hemisphere as well as in penumbra. In conclusion, these findings suggest that heme oxygenase-2 is involved in mechanisms by which not only protects against compromised energy metabolism of the ipsilateral hemisphere but also ameliorates transhemispheric diaschisis of the contralateral hemisphere in ischemic brain.

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Function and structural regulation of the carbon monoxide (CO)-responsive membrane protein PGRMC1

Kabe Y., Handa H., Suematsu M.

Journal of Clinical Biochemistry and Nutrition （Journal of Clinical Biochemistry and Nutrition） 63 （ 1 ） 12 - 17 2018年07月

ISSN 09120009

© 2018 JCBN. Progesterone receptor membrance associated component 1 is a multifunctional heme-binding protein that plays a role in several biological processes such as tumor progression, metabolic regulation, and viability control of nerve cells. Notably, progesterone receptor membrane associated component 1 is highly expressed in various types of cancer cells, and facilitates cancer proliferation and chemoresistance. Recently, progesterone receptor membrane associated component 1 structure has been explored by X-ray crystallographic analysis. Interestingly, whereas apoprogesterone receptor membrane associated component 1 exists as a monomer, the heme-bound progesterone receptor membrane associated component 1 converts into a stable dimer by forming a unique heme-heme stacking structure, leading to activation of epidermal growth factor receptor signaling and chemoresistance in cancer cells. Furthermore, the gas mediator carbon monoxide inhibits progesterone receptor membrane associated component 1-mediated activation in cancer cells by dissociating the heme-stacking dimer of progesterone receptor membrane associated component 1. The dynamic structural regulation of progesterone receptor membrane associated component 1 will provide new insights for understanding the mechanisms underlying its various functions.

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A MASS IMAGING TECHNIQUE REVEALED A RENO-PROTECTIVE EFFECT OF THE XANTHINE OXIDASE INHIBITOR FEBUXOSTAT IN THE ISCHEMIC KIDNEY BY PROMOTING ATP RECOVERY IN THE CORTEX

Miyashita K., Fujii K., Kubo A., Sato M., Hagiwara A., Inoue H., Ryuzaki M., Endo S., Uto A., Suematsu M., Itoh H.

JOURNAL OF HYPERTENSION 36 E79 - E79 2018年06月

ISSN 0263-6352

Neuroprotective Role of Astroglia in Parkinson Disease by Reducing Oxidative Stress Through Dopamine-Induced Activation of Pentose-Phosphate Pathway

Mashima K., Takahashi S., Minami K., Izawa Y., Abe T., Tsukada N., Hishiki T., Suematsu M., Kajimura M., Suzuki N.

ASN Neuro （ASN Neuro） 10 1759091418775562 2018年05月

ISSN 1759-0914

© The Author(s) 2018. Oxidative stress plays an important role in the onset and progression of Parkinson disease. Although released dopamine at the synaptic terminal is mostly reabsorbed by dopaminergic neurons, some dopamine is presumably taken up by astroglia. This study examined the dopamine-induced astroglial protective function through the activation of the pentose-phosphate pathway (PPP) to reduce reactive oxygen species (ROS). In vitro experiments were performed using striatal neurons and cortical or striatal astroglia prepared from Sprague-Dawley rats or C57BL/6 mice. The rates of glucose phosphorylation in astroglia were evaluated using the [ 14 C]deoxyglucose method. PPP activity was measured using [1- 14 C]glucose and [6- 14 C]glucose after acute (60 min) or chronic (15 hr) exposure to dopamine. ROS production was measured using 2′,7′-dichlorodihydrofluorescein diacetate. The involvement of the Kelch-like ECH-associated protein 1 (Keap1) or nuclear factor-erythroid-2-related factor 2 (Nrf2) system was evaluated using Nrf2 gene knockout mice, immunohistochemistry, and quantitative reverse transcription polymerase chain reaction analysis for heme oxygenase-1. Acute exposure to dopamine elicited increases in astroglial glucose consumption with lactate release. PPP activity in astroglia was robustly enhanced independently of Na + -dependent monoamine transporters. In contrast, chronic exposure to dopamine induced moderate increases in PPP activity via the Keap1/Nrf2 system. ROS production from dopamine increased gradually over 12 hr. Dopamine induced neuronal cell damage that was prevented by coculturing with astroglia but not with Nrf2-deficient astroglia. Dopamine-enhanced astroglial PPP activity in both acute and chronic manners may possibly reduce neuronal oxidative stress.

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A SEMI-QUANTITAIVE IMAGING MASS SPECTROMETRY REVEALED THE RENO-PROTECTIVE EFFECT OF FEBUXOSTAT IN THE ISCHEMIC KIDNEY BY PROMOTING ATP RECOVERY IN THE CORTEX

Fujii Kentaro, Miyashita Kazutoshi, Kubo Akiko, Sato Masaaki, Hagiwara Aika, Inoue Hiroyuki, Ryuzaki Masaki, Endo Sho, Uto Asuka, Suematsu Makoto, Itoh Hiroshi

NEPHROLOGY DIALYSIS TRANSPLANTATION 33 2018年05月

ISSN 0931-0509

Japans initiative on rare and undiagnosed diseases patients: To bring their diagnostic odyssey to an end, and beyond

Adachi T., Imanishi N., Umehara S., Izumida Y., Matsumoto N., Kosaki K., Matsubara Y., Mizusawa H., Suematsu M.

JOURNAL OF INVESTIGATIVE DERMATOLOGY 138 （ 5 ） S126 - S126 2018年05月

ISSN 0022-202X

Characterization and validation of Entamoeba histolytica pantothenate kinase as a novel anti-amebic drug target

Nurkanto A., Jeelani G., Yamamoto T., Naito Y., Hishiki T., Mori M., Suematsu M., Shiomi K., Hashimoto T., Nozaki T.

International Journal for Parasitology: Drugs and Drug Resistance （International Journal for Parasitology: Drugs and Drug Resistance） 8 （ 1 ） 125 - 136 2018年04月

ISSN 2211-3207

© 2018 The Authors The Coenzyme A (CoA), as a cofactor involved in >100 metabolic reactions, is essential to the basic biochemistry of life. Here, we investigated the CoA biosynthetic pathway of Entamoeba histolytica (E. histolytica), an enteric protozoan parasite responsible for human amebiasis. We identified four key enzymes involved in the CoA pathway: pantothenate kinase (PanK, EC 2.7.1.33), bifunctional phosphopantothenate-cysteine ligase/decarboxylase (PPCS-PPCDC), phosphopantetheine adenylyltransferase (PPAT) and dephospho-CoA kinase (DPCK). Cytosolic enzyme PanK, was selected for further biochemical, genetic, and phylogenetic characterization. Since E. histolytica PanK (EhPanK) is physiologically important and sufficiently divergent from its human orthologs, this enzyme represents an attractive target for the development of novel anti-amebic chemotherapies. Epigenetic gene silencing of PanK resulted in a significant reduction of PanK activity, intracellular CoA concentrations, and growth retardation in vitro, reinforcing the importance of this gene in E. histolytica. Furthermore, we screened the Kitasato Natural Products Library for inhibitors of recombinant EhPanK, and identified 14 such compounds. One compound demonstrated moderate inhibition of PanK activity and cell growth at a low concentration, as well as differential toxicity towards E. histolytica and human cells.

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