Details of a Researcher - Suematsu, Makoto

Papers - Suematsu, Makoto

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Progesterone receptor membrane associated component 1 enhances obesity progression in mice by facilitating lipid accumulation in adipocytes

Furuhata R., Kabe Y., Kanai A., Sugiura Y., Tsugawa H., Sugiyama E., Hirai M., Yamamoto T., Koike I., Yoshikawa N., Tanaka H., Koseki M., Nakae J., Matsumoto M., Nakamura M., Suematsu M.

Communications Biology (Communications Biology) 3 ( 1 ) 479 2020.12

© 2020, The Author(s). Progesterone receptor membrane associated component 1 (PGRMC1) exhibits haem-dependent dimerization on cell membrane and binds to EGF receptor and cytochromes P450 to regulate cancer proliferation and chemoresistance. However, its physiological functions remain unknown. Herein, we demonstrate that PGRMC1 is required for adipogenesis, and its expression is significantly enhanced by insulin or thiazolidine, an agonist for PPARγ. The haem-dimerized PGRMC1 interacts with low-density lipoprotein receptors (VLDL-R and LDL-R) or GLUT4 to regulate their translocation to the plasma membrane, facilitating lipid uptake and accumulation, and de-novo fatty acid synthesis in adipocytes. These events are cancelled by CO through interfering with PGRMC1 dimerization. PGRMC1 expression in mouse adipose tissues is enhanced during obesity induced by a high fat diet. Furthermore, adipose tissue-specific PGRMC1 knockout in mice dramatically suppressed high-fat-diet induced adipocyte hypertrophy. Our results indicate a pivotal role of PGRMC1 in developing obesity through its metabolic regulation of lipids and carbohydrates in adipocytes.

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Annexin A1 accounts for an anti-inflammatory binding target of sesamin metabolites

Kabe Y., Takemoto D., Kanai A., Hirai M., Ono Y., Akazawa S., Horikawa M., Kitagawa Y., Handa H., Rogi T., Shibata H., Suematsu M.

npj Science of Food (npj Science of Food) 4 ( 1 ) 4 2020.12

© 2020, The Author(s). Sesamin [(7α,7′α,8α,8′α)-3,4:3′,4′-bis(methylenedioxy)-7,9′:7′,9-diepoxylignane] is a major lignan in sesame seeds. Sesamin is converted to the catechol metabolite, SC1 [(7α,7′α,8α,8′α)-3′,4′-methylenedioxy-7,9′:7′,9-diepoxylignane-3,4-diol] with anti-inflammatory effects after oral administration. However, its molecular target remains unknown. Analysis using high-performance affinity nanobeads led to the identification of annexin A1 (ANX A1) as an SC1-binding protein. SC1 was found to bind to the annexin repeat 3 region of ANX A1 with a high-affinity constant (Kd = 2.77 μmol L−1). In U937 cells, SC1 exhibited an anti-inflammatory effect dependent on ANX A1. Furthermore, administration of sesamin or SC1 attenuated carbon tetrachloride-induced liver damage in mice and concurrently suppressed inflammatory responses dependent on ANX A1. The mechanism involved SC1-induced ANX A1 phosphorylation at serine 27 that facilitates extracellular ANX A1 release. Consequently, the ANX A1 released into the extracellular space suppressed the production of tumor necrosis factor α. This study demonstrates that ANX A1 acts as a pivotal target of sesamin metabolites to attenuate inflammatory responses.

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2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche

Koike N., Kota R., Naito Y., Hayakawa N., Matsuura T., Hishiki T., Onishi N., Fukada J., Suematsu M., Shigematsu N., Saya H., Sampetrean O.

Communications Biology (Communications Biology) 3 ( 1 ) 450 2020.12

© 2020, The Author(s). Under hypoxic conditions, nitroimidazoles can replace oxygen as electron acceptors, thereby enhancing the effects of radiation on malignant cells. These compounds also accumulate in hypoxic cells, where they can act as cytotoxins or imaging agents. However, whether these effects apply to cancer stem cells has not been sufficiently explored. Here we show that the 2-nitroimidazole doranidazole potentiates radiation-induced DNA damage in hypoxic glioma stem cells (GSCs) and confers a significant survival benefit in mice harboring GSC-derived tumors in radiotherapy settings. Furthermore, doranidazole and misonidazole, but not metronidazole, manifested radiation-independent cytotoxicity for hypoxic GSCs that was mediated by ferroptosis induced partially through blockade of mitochondrial complexes I and II and resultant metabolic alterations in oxidative stress responses. Doranidazole also limited the growth of GSC-derived subcutaneous tumors and that of tumors in orthotopic brain slices. Our results thus reveal the theranostic potential of 2-nitroimidazoles as ferroptosis inducers that enable targeting GSCs in their hypoxic niche.

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Identification and local manipulation of bone marrow vasculature during intravital imaging

Morikawa T., Tamaki S., Fujita S., Suematsu M., Takubo K.

Scientific Reports (Scientific Reports) 10 ( 1 ) 6422 2020.12

ISSN 2045-2322

© 2020, The Author(s). Physiological regulation of blood flow in bone marrow is important to maintain oxygen and glucose supplies but also the physiological hypoxic state of the hematopoietic stem cell (HSC) niche. However, regulatory mechanisms underlying microcirculation in the bone marrow (BM) niche remain unclear. Here, we identify vessels functioning in control of blood flow in bone marrow and assess their contractility. To evaluate contractile potential of Alexa Fluor 633 (AF633; an arterial marker)-positive vessels, we performed immunohistochemistry for α-smooth muscle actin (α-SMA) and found it expressed around AF633+ vessels in the femoral and calvarial marrow. To validate AF633+ vessel contractility, we developed a simple system to locally administer vasoactive agents that penetrate BM through transcalvarial vessels. After exposure of the calvarial surface to FITC-dextran (70 kDa), FITC intensity in calvarial bone marrow gradually increased. When we evaluated the effect of transcalvarial administration (TCA) of norepinephrine (NE) on vascular tone of AF633+ arteries and behavior of transplanted blood cells, NE administration decreased artery diameter and transendothelial migration of transplanted cells, suggesting that adrenergic signaling regulates the HSC niche microcirculation and blood cell migration into the BM via effects on BMarteries. We conclude that TCA is a useful tool for bone marrow research.

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Vitamin B1 Supports the Differentiation of T Cells through TGF-β Superfamily Production in Thymic Stromal Cells

Hirata S.i., Sawane K., Adachi J., Isoyama J., Sugiura Y., Matsunaga A., Hosomi K., Tomonaga T., Suematsu M., Nagatake T., Kunisawa J.

iScience (iScience) 23 ( 9 ) 101426 2020.09

© 2020 The Authors Homeostatic generation of T cells, which occurs in the thymus, is controlled at least in part by endogenous cytokines and ligands. In addition, nutritional factors are other key regulators for the homeostasis of host immunity, but whether and how nutrition affects the homeostatic generation of thymocytes remains to be established. Here, we showed that vitamin B1 deficiency resulted in a bias toward the maturation of γδ thymocytes accompanied by decreased differentiation into double-positive thymocytes during thymic involution. These events were mediated through the increased production of TGF-β superfamily members due to the accumulation of branched-chain α-keto acids in thymic stromal cells. These findings revealed essential roles of vitamin B1 in the appropriate differentiation of T cells through the metabolism of thymic stromal cells.

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Fatty Acid Synthesis Is Indispensable for Survival of Human Pluripotent Stem Cells

Tanosaki S., Tohyama S., Fujita J., Someya S., Hishiki T., Matsuura T., Nakanishi H., Ohto-Nakanishi T., Akiyama T., Morita Y., Kishino Y., Okada M., Tani H., Soma Y., Nakajima K., Kanazawa H., Sugimoto M., Ko M.S.H., Suematsu M., Fukuda K.

iScience (iScience) 23 ( 9 ) 2020.09

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O-glycan-altered extracellular vesicles: A specific serum marker elevated in pancreatic cancer

Yokose T., Kabe Y., Matsuda A., Kitago M., Matsuda S., Hirai M., Nakagawa T., Masugi Y., Hishiki T., Nakamura Y., Shinoda M., Yagi H., Abe Y., Oshima G., Hori S., Nakano Y., Honda K., Kashiro A., Morizane C., Nara S., Kikuchi S., Shibahara T., Itonaga M., Ono M., Minegishi N., Koshiba S., Yamamoto M., Kuno A., Handa H., Sakamoto M., Suematsu M., Kitagawa Y.

Cancers (Cancers) 12 ( 9 ) 1 - 17 2020.09

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Pancreatic cancer (PC) is among the most lethal malignancies due to an often delayed and difficult initial diagnosis. Therefore, the development of a novel, early stage, diagnostic PC marker in liquid biopsies is of great significance. In this study, we analyzed the differential glycomic profiling of extracellular vesicles (EVs) derived from serum (two cohorts including 117 PC patients and 98 normal controls) using lectin microarray. The glyco-candidates of PC-specific EVs were quantified using a high-sensitive exosome-counting system, ExoCounter. An absolute quantification system for altered glycan-containing EVs elevated in PC serum was established. EVs recognized by O-glycan-binding lectins ABA or ACA were identified as candidate markers by lectin microarray. Quantitative analyses using ExoCounter revealed that the ABA-or ACA-positive EVs were significantly increased in the culture of PC cell lines or in the serum of PC patients including carbohydrate antigen 19-9 negative patients with high area under curve values. The elevated numbers of EVs in PC serum returned to normal levels after pancreatectomy. Histological examination confirmed that the tumors stained with ABA/ACA. These specific EVs with O-glycans recognized by ABA/ACA are elevated in PC sera and can act as potential biomarkers in a liquid biopsy for PC patients screening.

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Short-chain fatty acids bind to apoptosis-associated speck-like protein to activate inflammasome complex to prevent Salmonella infection.

Tsugawa H, Kabe Y, Kanai A, Sugiura Y, Hida S, Taniguchi S, Takahashi T, Matsui H, Yasukawa Z, Itou H, Takubo K, Suzuki H, Honda K, Handa H, Suematsu M

PLoS biology 18 ( 9 ) e3000813 2020.09

ISSN 1544-9173

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C-type lectin Mincle mediates cell death-triggered inflammation in acute kidney injury

Tanaka M., Saka-Tanaka M., Ochi K., Fujieda K., Sugiura Y., Miyamoto T., Kohda H., Ito A., Miyazawa T., Matsumoto A., Aoe S., Miyamoto Y., Tsuboi N., Maruyama S., Suematsu M., Yamasaki S., Ogawa Y., Suganami T.

Journal of Experimental Medicine (Journal of Experimental Medicine) 217 ( 11 ) 2020.08

ISSN 00221007

© 2020 Rockefeller University Press. All rights reserved. Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia-reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death-triggered, sustained inflammation after acute kidney injury.

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Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells

Okuno D., Sugiura Y., Sakamoto N., Tagod M.S.O., Iwasaki M., Noda S., Tamura A., Senju H., Umeyama Y., Yamaguchi H., Suematsu M., Morita C.T., Tanaka Y., Mukae H.

Frontiers in Immunology (Frontiers in Immunology) 11 1405 2020.07

ISSN 1664-3224

© Copyright © 2020 Okuno, Sugiura, Sakamoto, Tagod, Iwasaki, Noda, Tamura, Senju, Umeyama, Yamaguchi, Suematsu, Morita, Tanaka and Mukae. Increasing attention has been paid to human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) in the field of cancer immunotherapy. We have previously demonstrated that a novel bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA), efficiently expands peripheral blood Vγ2Vδ2 T cells to purities up to 95–99% in 10–11 days. In the present study, we first examined the effect of PTA on farnesyl diphosphate synthase (FDPS) using liquid chromatography mass spectrometry (LC-MS) to analyze the mechanism underlying the PTA-mediated expansion of Vγ2Vδ2 T cells. We find that the prodrug induced the accumulation of both isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), direct upstream metabolites of FDPS. This indicates that not only IPP but also DMAPP plays an important role in PTA-mediated stimulation of Vγ2Vδ2 T cells. We next analyzed TCR-independent cytotoxicity of Vγ2Vδ2 T cells. When human lung cancer cell lines were challenged by Vγ2Vδ2 T cells, no detectable cytotoxicity was observed in 40 min. The lung cancer cell lines were, however, significantly killed by Vγ2Vδ2 T cells after 4–16 h in an effector-to-target ratio-dependent manner, demonstrating that Vγ2Vδ2 T cell-based cell therapy required a large number of cells and longer time when tumor cells were not sensitized. By contrast, pulsing tumor cell lines with 10–30 nM of PTA induced significant lysis of tumor cells by Vγ2Vδ2 T cells even in 40 min. Similar levels of cytotoxicity were elicited by ZOL at concentrations of 100–300 μM, which were much higher than blood levels of ZOL after infusion (1–2 μM), suggesting that standard 4 mg infusion of ZOL was not enough to sensitize lung cancer cells in clinical settings. In addition, Vγ2Vδ2 T cells secreted interferon-γ (IFN-γ) when challenged by lung cancer cell lines pulsed with PTA in a dose-dependent manner. Taken together, PTA could be utilized for both expansion of Vγ2Vδ2 T cells ex vivo and sensitization of tumor cells in vivo in Vγ2Vδ2 T cell-based cancer immunotherapy. For use in patients, further studies on drug delivery are essential because of the hydrophobic nature of the prodrug.

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Comparative Glycomic Analysis of Exosome Subpopulations Derived from Pancreatic Cancer Cell Lines

Matsuda A., Kuno A., Yoshida M., Wagatsuma T., Sato T., Miyagishi M., Zhao J., Suematsu M., Kabe Y., Narimatsu H.

Journal of Proteome Research (Journal of Proteome Research) 19 ( 6 ) 2516 - 2524 2020.06

ISSN 15353893

Copyright © 2020 American Chemical Society. Extracellular vesicles such as exosomes are generally covered with an array of glycans, which are controlled by the host-cell glyco-synthetic machinery, similar to secreted and membrane glycoproteins. Several exosome subpopulations classified by their tetraspanin expression have been investigated in the context of diseases. However, a comparative analysis of their glycomics has never been attempted. Herein, we report a method for the comparative glycomic analysis of exosome subpopulations among pancreatic cancer cell lines. Glycomic profiles were obtained for extracellular vesicles, secreted glycoproteins, and membrane glycoproteins from eight cell lines. Statistical analyses revealed high populations of PHA-L-binding proteins in the vesicles. The surfaces of extracellular vesicles were labeled with Cy3 and captured by magnetic beads with antibodies against tetraspanins (CD9, CD63, and CD81). The coprecipitated vesicles were lysed and subjected to a lectin microarray analysis. A hierarchical clustering analysis using 19 glycomic profiles confirmed that most subpopulations, except CD81-positive exosomes, could be distinguished according to the host-cell species. Principal component analysis and subsequent lectin-affinity capturing of intact exosomes highlighted that CD81-positive exosomes preferentially expressed not PHA-L- but LEL-binding proteins on their surfaces. These data suggested that exosomal glycomics depended on the host-cell type and subpopulation.

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Starvation causes female-to-male sex reversal through lipid metabolism in the teleost fish, medaka (Olyzias latipes)

Sakae Y., Oikawa A., Sugiura Y., Mita M., Nakamura S., Nishimura T., Suematsu M., Tanaka M.

Biology Open (Biology Open) 9 ( 4 ) 2020.04

ISSN 2046-6390

© 2020 Company of Biologists Ltd. All rights reserved. The teleost fish, medaka (Oryzias latipes), employs the XX/XY genetic sex determination system. We show here that the phenotypic sex of medaka is affected by changes in lipid metabolism. Medaka larvae subjected to 5 days of starvation underwent female-to-male sex reversal. Metabolomic and RT-qPCR analyses indicated that pantothenate metabolism was suppressed by starvation. Consistently, inhibiting the pantothenate metabolic pathway caused sex reversal. The final metabolite in this pathway is coenzyme A, an essential factor for lipogenesis. Inhibiting fatty acid synthesis, the first step of lipogenesis, also caused sex reversal. The expression of dmrt1, a critical gene for male development, was suppressed by starvation, and a dmrt1 (Δ13) mutant did not show sex reversal under starvation. Collectively, these results indicate that fatty acid synthesis is involved in female-to-male sex reversal through ectopic expression of male gene dmrt1 under starvation.

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In situ imaging of monoamine localization and dynamics

Sugiyama E., Skelly A.N., Suematsu M., Sugiura Y.

Pharmacology and Therapeutics (Pharmacology and Therapeutics) 208 107478 2020.04

ISSN 01637258

© 2020 Recent advances in sample preparation protocols and instrumentation allow current imaging mass spectrometry (IMS) to enable the visualization of small molecule tissue localization, including that of monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine. Although monoamine-producing neurons, and their projections and synaptic connections, have been thoroughly characterized, in situ monoamine localization within these circuits remains unclear. Moreover, studying the fluctuations in local monoamine concentration in response to physiological stimuli, drug administration, and neurodegenerative disease progression is worthwhile, and can be achieved by analyzing the in situ concentration maps afforded by coupling IMS with on-tissue derivatization protocols. Recent reports have shown that monoamines localize within cell bodies and also translocate to distant nerve terminals, indicating active transport along axons and/or local synthesis at the terminals. Moreover, IMS can reveal regionally segregated monoamine fluctuations, such as rapid dopamine fluctuation within the nucleus accumbens (NAc) subregion during pain sensation. Furthermore, since exogenous drug pharmacokinetics can also be visualized by IMS, this technique could provide powerful methodologies enabling the simultaneous imaging of monoamines and drugs that selectively regulate monoamine signaling, such as serotonin reuptake inhibitors (SSRIs). Therefore, IMS could reveal where SSRIs administered over the long-term accumulate and how they affect local monoamine metabolism.

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Small molecules assisting eggshell calcium dissolution for embryonic bone formation

Ito T., Kato S., Kubo A., Suematsu M., Nakata M., Saikawa Y.

Tetrahedron (Tetrahedron) 76 ( 5 ) 2020.01

ISSN 00404020

© 2019 Elsevier Ltd Calcium carbonate in avian eggshell is used as a calcium source for bone formation during embryonic development. We studied ostrich eggshells as a representative avian egg and found that the calcium reserve assembly (CRA) region, eventually dissolving for bone formation, consists of nano-granules comprising amorphous calcium carbonate (ACC) by careful microscopic observation. ACC is unstable phase of calcium carbonate with high solubility and is stabilized by additives. As such a stabilizer, we found small molecules from eggshell internal region. Particularly, the ACC was recreated by the formation of calcium carbonate in the presence of D-myo-inositol 4,5-bisphosphate (Ins(4,5)P2), isolated from ostrich eggshell for the first time in this study. Further mass spectrometric imaging technique revealed that Ins(4,5)P2 is localized at the CRA region, suggesting that this compound could play a major role that makes it easier to dissolve and internalize eggshell calcium during embryogenesis.

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Quantitative MALDI-MS/MS assay for serum cortisol through charged derivatization

Nakamura M., Moritsuna M., Yuda K., Fujimura S., Sugiura Y., Shimma S., Nishimoto K., Nishikawa T., Suematsu M., Ogawa S., Higashi T.

Journal of Pharmaceutical and Biomedical Analysis (Journal of Pharmaceutical and Biomedical Analysis) 178 112912 2020.01

ISSN 07317085

© 2019 Elsevier B.V. Cortisol (CRT), the main glucocorticoid in humans, plays a crucial role in many physiological processes, therefore, the measurement of its serum level is of great clinical significance. Matrix-assisted laser desorption/ionization-tandem mass spectrometry (MALDI-MS/MS) might be an effective approach for the quantification of CRT in serum due to its attractive properties, i.e., high specificity, ease of use, ruggedness and rapid analysis. In this study, we developed a method to quantify the serum CRT by MALDI-MS/MS. This method employed the derivatization using a Girard-type reagent, 1-(hydrazinocarbonylmethyl)isoquinolinium chloride, which compensated for the lack of sensitivity. This method enabled the reproducible quantification of the serum CRT using a 20-μL sample (intra- and inter-assay relative standard deviations, 7.4% or lower), and the measurable range was 25–500 ng/mL. The serum CRT concentrations determined by the newly-developed MALDI-MS/MS method agreed well with those by liquid chromatography/electrospray ionization-MS/MS or electrochemiluminescence immunoassay. The MALDI-MS/MS method was used for the analysis of peripheral venous serum samples of healthy subjects and adrenal venous serum samples of patients with primary aldosteronism, and satisfactory results were obtained.

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Loss of autophagy impairs physiological steatosis by accumulation of NCoR1

Takahashi S.s., Sou Y.S., Saito T., Kuma A., Yabe T., Sugiura Y., Lee H.C., Suematsu M., Yokomizo T., Koike M., Terai S., Mizushima N., Waguri S., Komatsu M.

Life Science Alliance (Life Science Alliance) 3 ( 1 ) 2020

© 2019 Takahashi et al. Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, such as after a meal. LDs serve as an energy reservoir during fasting and have a buffering capacity that prevents lipotoxicity. Autophagy and the autophagic machinery have been proposed to play a role in LD biogenesis, but the underlying molecular mechanism remains unclear. Here, we show that when nuclear receptor co-repressor 1 (NCoR1), which inhibits the transactivation of nuclear receptors, accumulates because of autophagy suppression, LDs decrease in size and number. Ablation of ATG7, a gene essential for autophagy, suppressed the expression of gene targets of liver X receptor α, a nuclear receptor responsible for fatty acid and triglyceride synthesis in an NCoR1-dependent manner. LD accumulation in response to fasting and after hepatectomy was hampered by the suppression of autophagy. These results suggest that autophagy controls physiological hepatosteatosis by fine-tuning NCoR1 protein levels.

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DESI-based imaging mass spectrometry in forensic science and clinical diagnosis

Sugiura Yuki, Sugiyama Eiji, Suematsu Makoto

AMBIENT IONIZATION MASS SPECTROMETRY IN LIFE SCIENCES: PRINCIPLES AND APPLICATIONS 107 - 118 2020

ISSN 978-0-12-817220-9

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A thin layer of sucrose octasulfate protects the oesophageal mucosal epithelium in reflux oesophagitis

Hayakawa T., Kawasaki S., Hirayama Y., Tsutsui T., Sugiyama E., Adachi K., Kon R., Suematsu M., Sugiura Y.

Scientific Reports (Scientific Reports) 9 ( 1 ) 3559 2019.12

ISSN 2045-2322

© 2019, The Author(s). Sucralfate is effective for the treatment of gastric and duodenal ulcers owing to its protective gel-forming ability. However, the mechanism by which sucralfate protects the oesophageal mucosa against reflux oesophagitis has not been clarified. We aimed to investigate the mechanisms of action of sucralfate and sucrose octasulfate (SOS), a component of sucralfate. SOS and sucralfate were administered to oesophagitis-induced rats, and the ulcer lesion size was macroscopically examined and scored. Effective pepsin activity in the gastric juices obtained from the animal model was evaluated by a casein digestion test. Sucralfate and SOS improved the pathology scores in a dose-dependent manner, whereas gastric juice pepsin activity was not impaired by therapeutic doses of SOS. As SOS lacks the ability to form a thick gel layer by polymerisation, we examined the distribution of SOS in the mucosal lumen by imaging mass spectrometry (IMS) to determine whether SOS directly adheres to the mucosal surface. A clear homogeneous thin-layer SOS film (>100 μm thick) was visualized on the oesophageal mucosal surface. Moreover, this SOS film formation was enhanced at ulcer lesion sites. Taken together, SOS appears to protect oesophageal mucosa against reflux oesophagitis via thin-layer formation on the mucosal surface.

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Autophagy regulates lipid metabolism through selective turnover of NCoR1

Saito T., Kuma A., Sugiura Y., Ichimura Y., Obata M., Kitamura H., Okuda S., Lee H.C., Ikeda K., Kanegae Y., Saito I., Auwerx J., Motohashi H., Suematsu M., Soga T., Yokomizo T., Waguri S., Mizushima N., Komatsu M.

Nature Communications (Nature Communications) 10 ( 1 ) 1567 2019.12

ISSN 2041-1723

© 2019, The Author(s). Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production.

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Identification of a binding protein for sesamin and characterization of its roles in plant growth

Tera M., Koyama T., Murata J., Furukawa A., Mori S., Azuma T., Watanabe T., Hori K., Okazawa A., Kabe Y., Suematsu M., Satake H., Ono E., Horikawa M.

Scientific Reports (Scientific Reports) 9 ( 1 ) 8631 2019.12

ISSN 2045-2322

© 2019, The Author(s). Sesamin is a furofuran-type lignan that is found abundantly in seeds of Sesamum indicum (sesame) and has been widely accepted as a dietary supplement with positive effects on human health. The biological activity of sesamin in human cells and organs has been analysed extensively, although comparatively few studies show biological functions for sesamin in planta. Herein we screened sesamin-binding proteins (SBP) from sesame seedling extracts using sesamin-immobilized nano-beads. In subsequent peptide mass fingerprinting analyses, we identified a SBP, Steroleosin B, which is one of the membrane proteins found in oil bodies. In addition, pull-down assays and saturation transfer difference-nuclear magnetic resonance (STD-NMR) experiments demonstrated that sesamin binds directly to recombinant Steroleosin B in vitro. Finally, ectopic accumulations of sesamin and Steroleosin B in transgenic Arabidopsis thaliana plants induced severe growth defects including suppression of leaf expansion and root elongation. Collectively, these results indicate that sesamin influences tissue development in the presence of Steroleosin B.

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Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides

Fujii K., Kubo A., Miyashita K., Sato M., Hagiwara A., Inoue H., Ryuzaki M., Tamaki M., Hishiki T., Hayakawa N., Kabe Y., Itoh H., Suematsu M.

JCI Insight (JCI Insight) 4 ( 22 ) 2019.11

© 2019, American Society for Clinical Investigation. Although oxidative stress plays central roles in postischemic renal injury, region-specific alterations in energy and redox metabolism caused by short-duration ischemia remain unknown. Imaging mass spectrometry enabled us to reveal spatial heterogeneity of energy and redox metabolites in the postischemic murine kidney. After 10-minute ischemia and 24-hour reperfusion (10mIR), in the cortex and outer stripes of the outer medulla, ATP substantially decreased, but not in the inner stripes of the outer medulla and inner medulla. 10mIR caused renal injury with elevation of fractional excretion of sodium, although histological damage by oxidative stress was limited. Ischemia-induced NADH elevation in the cortex indicated prolonged production of reactive oxygen species by xanthine oxidase (XOD). However, consumption of reduced glutathione after reperfusion suggested the amelioration of oxidative stress. An XOD inhibitor, febuxostat, which blocks the degradation pathway of adenine nucleotides, promoted ATP recovery and exerted renoprotective effects in the postischemic kidney. Because effects of febuxostat were canceled by silencing of the hypoxanthine phosphoribosyl transferase 1 gene in cultured tubular cells, mechanisms for the renoprotective effects appear to involve the purine salvage pathway, which uses hypoxanthine to resynthesize adenine nucleotides, including ATP. These findings suggest a novel therapeutic approach for acute ischemia/reperfusion renal injury with febuxostat through salvaging high-energy adenine nucleotides.

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Mutant ASXL1 Promotes Expansion of the Phenotypic Hematopoietic Stem Cell Compartment

Fujino Takeshi, Goyama Susumu, Sugiura Yuki, Inoue Daichi, Yamasaki Satoshi, Matsumoto Akiko, Sato Naru, Morinaga Hironobu, Shikata Shiori, Fukuyama Tomofusa, Tanaka Yosuke, Asada Shuhei, Fukushima Tsuyoshi, Honda Hiroaki, Nishimura Emi K., Shibata Tatsuhiro, Suematsu Makoto, Kitamura Toshio

BLOOD 134 2019.11

ISSN 0006-4971

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Hydrogen sulfide bypasses the rate-limiting oxygen activation of heme oxygenase

Matsui T., Sugiyama R., Sakanashi K., Tamura Y., Iida M., Nambu Y., Higuchi T., Suematsu M., Ikeda-Saito M.

Journal of Biological Chemistry (Journal of Biological Chemistry) 293 ( 43 ) 16931 - 16939 2019.10

ISSN 00219258

© 2018 Matsui et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. Discovery of unidentified protein functions is of biological importance because it often provides new paradigms for many research areas. Mammalian heme oxygenase (HO) enzyme catalyzes the O2-dependent degradation of heme into carbon monoxide (CO), iron, and biliverdin through numerous reaction intermediates. Here, we report that H2S, a gaseous signaling molecule, is part of a novel reaction pathway that drastically alters HO's products, reaction mechanism, and catalytic properties. Our prediction of this interplay is based on the unique reactivity of H2S with one of the HO intermediates. We found that in the presence of H2S, HO produces new linear tetrapyr-roles, which we identified as isomers of sulfur-containing biliverdin (SBV), and that only H2S, but not GSH, cysteine, and polysulfides, induces SBV formation. As BV is converted to bilirubin (BR), SBV is enzymatically reduced to sulfur-containing bilirubin (SBR), which shares similar properties such as antioxidative effects with normal BR. SBR was detected in culture media of mouse macrophages, confirming the existence of this H2S-induced reaction in mammalian cells. H2S reacted specifically with a ferric verdoheme intermediate of HO, and verdoheme cleavage proceeded through an O2-independent hydrolysis-like mechanism. This change in activation mode diminished O2 dependence of the overall HO activity, circumventing the rate-limiting O2 activation of HO. We propose that H2S could largely affect O2 sensing by mammalian HO, which is supposed to relay hypoxic signals by decreasing CO output to regulate cellular functions. Moreover, the novel H2S-induced reaction identified here helps sustain HO's heme-degrading and antioxidant-generating capacity under highly hypoxic conditions.

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Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging

Sugiyama E., Guerrini M.M., Honda K., Hattori Y., Abe M., Källback P., Andrén P.E., Tanaka K.F., Setou M., Fagarasan S., Suematsu M., Sugiura Y.

iScience (iScience) 20 359 - 372 2019.10

© 2019 The Author(s) Monoamine neurotransmitters are released by specialized neurons regulating behavioral, motor, and cognitive functions. Although the localization of monoaminergic neurons in the brain is well known, the distribution and kinetics of monoamines remain unclear. Here, we generated a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels using mass spectrometry imaging (MSI). We found several nuclei rich in both 5-HT and a catecholamine (DA or NE) and identified the paraventricular nucleus of the thalamus (PVT), where 5-HT and NE are co-localized. The analysis of 5-HT fluctuations in response to acute tryptophan depletion and infusion of isotope-labeled tryptophan in vivo revealed a close kinetic association between the raphe nuclei, PVT, and amygdala but not the other nuclei. Our findings imply the existence of a highly dynamic 5-HT-mediated raphe to PVT pathway that likely plays a role in the brain monoamine system.

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Mechanical allodynia induced by optogenetic sensory nerve excitation activates dopamine signaling and metabolism in medial nucleus accumbens

Sugiyama E., Kondo T., Kuzumaki N., Honda K., Yamanaka A., Narita M., Suematsu M., Sugiura Y.

Neurochemistry International (Neurochemistry International) 129 104494 2019.10

ISSN 01970186

© 2019 The Authors The mesolimbic dopaminergic signaling, such as that originating from the ventral tegmental area (VTA) neurons in the medial part of the nucleus accumbens (mNAc), plays a role in complex sensory and affective components of pain. To date, we have demonstrated that optogenetic sensory nerve stimulation rapidly alters the dopamine (DA) content within the mNAc. However, the physiological role and biochemical processes underlying such rapid and regional dynamics of DA remain unclear. In this study, using imaging mass spectrometry (IMS), we observed that sensitized pain stimulation by optogenetic sensory nerve activation increased DA and 3-Methoxytyramine (3-MT; a post-synaptic metabolite obtained following DA degradation) in the mNAc of the experimental mice. To delineate the mechanism associated with elevation of DA and 3-MT, the de novo synthesized DA in the VTA/substantia nigra terminal areas was evaluated using IMS by visualizing the metabolic conversion of stable isotope-labeled tyrosine (13C15N-Tyr) to DA. Our approach revealed that at steady state, the de novo synthesized DA occupied >10% of the non-labeled DA pool in the NAc within 1.5 h of isotope-labeled Tyr administration, despite no significant increase following pain stimulation. These results suggested that sensitized pain triggered an increase in the release and postsynaptic intake of DA in the mNAc, followed by its degradation, and likely delayed de novo DA synthesis. In conclusion, we demonstrated that short, peripheral nerve excitation with mechanical stimulation accelerates the mNAc-specific DA signaling and metabolism which might be associated with the development of mechanical allodynia.

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Molecular characterization of the gastric commensal bacteria progressing gastric carcinogenesis in H. pylori-infected gastric mucosa

TsugaWa H., Matsuzaki J., Mori H., Suematsu M., Suzuki H.

HELICOBACTER 24 2019.09

ISSN 1083-4389

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

Kofuji S., Hirayama A., Eberhardt A.O., Kawaguchi R., Sugiura Y., Sampetrean O., Ikeda Y., Warren M., Sakamoto N., Kitahara S., Yoshino H., Yamashita D., Sumita K., Wolfe K., Lange L., Ikeda S., Shimada H., Minami N., Malhotra A., Morioka S., Ban Y., Asano M., Flanary V.L., Ramkissoon A., Chow L.M.L., Kiyokawa J., Mashimo T., Lucey G., Mareninov S., Ozawa T., Onishi N., Okumura K., Terakawa J., Daikoku T., Wise-Draper T., Majd N., Kofuji K., Sasaki M., Mori M., Kanemura Y., Smith E.P., Anastasiou D., Wakimoto H., Holland E.C., Yong W.H., Horbinski C., Nakano I., DeBerardinis R.J., Bachoo R.M., Mischel P.S., Yasui W., Suematsu M., Saya H., Soga T., Grummt I., Bierhoff H., Sasaki A.T.

Nature Cell Biology (Nature Cell Biology) 21 ( 8 ) 1003 - 1014 2019.08

ISSN 14657392

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

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Tandem Mass Spectrometry Imaging Reveals Distinct Accumulation Patterns of Steroid Structural Isomers in Human Adrenal Glands

Takeo E., Sugiura Y., Uemura T., Nishimoto K., Yasuda M., Sugiyama E., Ohtsuki S., Higashi T., Nishikawa T., Suematsu M., Fukusaki E., Shimma S.

Analytical Chemistry (Analytical Chemistry) 91 ( 14 ) 8918 - 8925 2019.07

ISSN 00032700

© 2019 American Chemical Society. Visualizing tissue distribution of steroid hormones is a promising application of MALDI mass spectrometry imaging (MSI). On-tissue chemical derivatization using Girard's T reagent has enhanced the ionization efficiency of steroids. However, discriminating between structural isomers with distinct bioactivities remains a challenge. Herein, we used ion trap MS/tandem MS (MS3) to distinguish a mineralcorticoid aldosterone (Aldo) and a glucocorticoid cortisol (F), from their structural isomers. Our method is also useful to detect hybrid steroids (18-hydroxycortisol [18-OHF] and 18-oxocortisol) with sufficient signal-to-noise ratio. The clinical applicability of the tandem MS method was evaluated by analyzing F, Aldo, and 18-OHF distributions in human adrenal glands. In such clinical specimens, small Aldo-producing cell clusters (APCCs) were identified and were first found to produce a high level of Aldo and not to contain F. Moreover, a part of APCCs produced 18-OHF, presumably converted from F by APCC-specific CYP11B2 activity. Catecholamine species were also visualized with another derivatization reagent (TAHS), and those profiling successfully discriminated pheochromocytoma species. These tandem MSI-methods, coupled with on-tissue chemical derivatization has proven to be useful for detecting low-abundance steroids, including Aldo and hybrid steroids and thus identifying steroid hormone-producing lesions.

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Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cells Ex Vivo

Kobayashi H., Morikawa T., Okinaga A., Hamano F., Hashidate-Yoshida T., Watanuki S., Hishikawa D., Shindou H., Arai F., Kabe Y., Suematsu M., Shimizu T., Takubo K.

Cell Reports (Cell Reports) 28 ( 1 ) 145 - 158.e9 2019.07

ISSN 2211-1247

© 2019 The Authors Hematopoietic stem cells (HSCs) maintain lifelong hematopoiesis by remaining quiescent in the bone marrow niche. Recapitulation of a quiescent state in culture has not been achieved, as cells rapidly proliferate and differentiate in vitro. After exhaustive analysis of different environmental factor combinations and concentrations as a way to mimic physiological conditions, we were able to maintain engraftable quiescent HSCs for 1 month in culture under very low cytokine concentrations, hypoxia, and very high fatty acid levels. Exogenous fatty acids were required likely due to suppression of intrinsic fatty acid synthesis by hypoxia and low cytokine conditions. By contrast, high cytokine concentrations or normoxia induced HSC proliferation and differentiation. Our culture system provides a means to evaluate properties of steady-state HSCs and test effects of defined factors in vitro under near-physiological conditions. Maintaining quiescent HSCs under physiological conditions facilitates evaluation of the properties of steady-state HSCs. Kobayashi et al. report that low cytokine concentrations, hypoxia, and high fatty acid levels mimicking the bone marrow microenvironment enable maintenance of engraftable quiescent HSCs for 1 month in culture.

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Maintenance of tissue stiffness via metabolism in Presbyopia

Hayano Motoshi, Nagashima Hayato, Amano Sachie, Sakuma Atsushi, Hishiki Takako, Suematsu Makoto, Tsubota Kazuo

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 60 ( 9 ) 2019.07

ISSN 0146-0404

Research on decrease of lens elasticity in mice and rats during aging

Nagashima Hayato, Hayano Motoshi, Amano Sachie, Sakuma Atsushi, Hishiki Takako, Suematsu Makoto, Tsubota Kazuo

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 60 ( 9 ) 2019.07

ISSN 0146-0404

The Fundamental Characteristics of a Translational Scientist.

Gilliland CT, White J, Gee B, Kreeftmeijer-Vegter R, Bietrix F, Ussi AE, Hajduch M, Kocis P, Chiba N, Hirasawa R, Suematsu M, Bryans J, Newman S, Hall MD, Austin CP

ACS pharmacology & translational science 2 ( 3 ) 213 - 216 2019.06

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Application of high-performance magnetic nanobeads to biological sensing devices

Kabe Y., Sakamoto S., Hatakeyama M., Yamaguchi Y., Suematsu M., Itonaga M., Handa H.

Analytical and Bioanalytical Chemistry (Analytical and Bioanalytical Chemistry) 411 ( 9 ) 1825 - 1837 2019.03

ISSN 16182642

© 2019, The Author(s). Nanomaterials have extensive applications in the life sciences and in clinical diagnosis. We have developed magnetic nanoparticles with high dispersibility and extremely low nonspecific binding to biomolecules and have demonstrated their application in chemical biology (e.g., for the screening of drug receptor proteins). Recently, the excellent properties of nanobeads have made possible the development of novel rapid immunoassay systems and high-precision technologies for exosome detection. For immunoassays, we developed a technology to encapsulate a fluorescent substance in magnetic nanobeads. The fluorescent nanobeads allow the rapid detection of a specific antigen in solution or in tissue specimens. Exosomes, which are released into the blood, are expected to become markers for several diseases, including cancer, but techniques for measuring the absolute quantity of exosomes in biological fluids are lacking. By integrating magnetic nanobead technology with an optical disc system, we developed a novel method for precisely quantifying exosomes in human serum with high sensitivity and high linearity without requiring enrichment procedures. This review focuses on the properties of our magnetic nanobeads, the development of novel biosensors using these nanobeads, and their broad practical applications. [Figure not available: see fulltext.].

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Increased cytotoxicity of herpes simplex virus thymidine kinase expression in human induced pluripotent stem cells

Iwasawa C., Tamura R., Sugiura Y., Suzuki S., Kuzumaki N., Narita M., Suematsu M., Nakamura M., Yoshida K., Toda M., Okano H., Miyoshi H.

International Journal of Molecular Sciences (International Journal of Molecular Sciences) 20 ( 4 ) 2019.02

ISSN 16616596

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Human induced pluripotent stem cells (iPSCs) hold enormous promise for regenerative medicine. The major safety concern is the tumorigenicity of transplanted cells derived from iPSCs. A potential solution would be to introduce a suicide gene into iPSCs as a safety switch. The herpes simplex virus type 1 thymidine kinase (HSV-TK) gene, in combination with ganciclovir, is the most widely used enzyme/prodrug suicide system from basic research to clinical applications. In the present study, we attempted to establish human iPSCs that stably expressed HSV-TK with either lentiviral vectors or CRISPR/Cas9-mediated genome editing. However, this task was difficult to achieve, because high-level and/or constitutive expression of HSV-TK resulted in the induction of cell death or silencing of HSV-TK expression. A nucleotide metabolism analysis suggested that excessive accumulation of thymidine triphosphate, caused by HSV-TK expression, resulted in an imbalance in the dNTP pools. This unbalanced state led to DNA synthesis inhibition and cell death in a process similar to a “thymidine block”, but more severe. We also demonstrated that the Tet-inducible system was a feasible solution for overcoming the cytotoxicity of HSV-TK expression. Our results provided a warning against using the HSV-TK gene in human iPSCs, particularly in clinical applications.

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CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy

Tsugawa H., Mori H., Matsuzaki J., Sato A., Saito Y., Imoto M., Suematsu M., Suzuki H.

Autophagy (Autophagy) 15 ( 2 ) 242 - 258 2019.02

ISSN 15548627

© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Helicobacter pylori-derived CagA, a type IV secretion system effector, plays a role as an oncogenic driver in gastric epithelial cells. However, upon delivery into gastric epithelial cells, CagA is usually degraded by macroautophagy/autophagy. Hence, the induction of autophagy in H. pylori-infected epithelial cells is an important host-protective ability against gastric carcinogenesis. However, the mechanisms by which autophagosome-lysosome fusion is regulated, are unknown. Here, we report that enhancement of LAMP1 (lysosomal associated membrane protein 1) expression is necessary for autolysosome formation. LAMP1 expression is induced by nuclear translocated LRP1 (LDL receptor related protein 1) intracellular domain (LRP1-ICD) binding to the proximal LAMP1 promoter region. Nuclear translocation of LRP1-ICD is enhanced by H. pylori infection. In contrast, CAPZA1 (capping actin protein of muscle Z-line alpha subunit 1) inhibits LAMP1 expression via binding to LRP1-ICD in the nuclei. The binding of CAPZA1 to LRP1-ICD prevents LRP1-ICD binding to the LAMP1 proximal promoter. Thus, in CAPZA1-overexpressing gastric epithelial cells infected with H. pylori, autolysosome formation is inhibited and CagA escapes autophagic degradation. These findings identify CAPZA1 as a novel negative regulator of autolysosome formation and suggest that deregulation of CAPZA1 expression leads to increased risk of gastric carcinogenesis. Abbreviations: CagA: cytotoxin-associated gene A; CAPZA1: capping actin protein of muscle Z-line alpha subunit 1; ChIP: chromatin immunoprecipitation; GTF2I: general transcription factor IIi; HDAC: histone deacetylase; LAMP1: lysosomal associated membrane protein 1; LRP1: LDL receptor related protein 1; LRP1-ICD: CagA intracellular domain; qPCR: quantitative polymerase chain reaction; VacA: vacuolating cytotoxin.

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A defined commensal consortium elicits CD8 T cells and anti-cancer immunity

Tanoue T., Morita S., Plichta D.R., Skelly A.N., Suda W., Sugiura Y., Narushima S., Vlamakis H., Motoo I., Sugita K., Shiota A., Takeshita K., Yasuma-Mitobe K., Riethmacher D., Kaisho T., Norman J.M., Mucida D., Suematsu M., Yaguchi T., Bucci V., Inoue T., Kawakami Y., Olle B., Roberts B., Hattori M., Xavier R.J., Atarashi K., Honda K.

Nature (Nature) 565 ( 7741 ) 600 - 605 2019.01

ISSN 00280836

© 2019, Springer Nature Limited. There is a growing appreciation for the importance of the gut microbiota as a therapeutic target in various diseases. However, there are only a handful of known commensal strains that can potentially be used to manipulate host physiological functions. Here we isolate a consortium of 11 bacterial strains from healthy human donor faeces that is capable of robustly inducing interferon-γ-producing CD8 T cells in the intestine. These 11 strains act together to mediate the induction without causing inflammation in a manner that is dependent on CD103 + dendritic cells and major histocompatibility (MHC) class Ia molecules. Colonization of mice with the 11-strain mixture enhances both host resistance against Listeria monocytogenes infection and the therapeutic efficacy of immune checkpoint inhibitors in syngeneic tumour models. The 11 strains primarily represent rare, low-abundance components of the human microbiome, and thus have great potential as broadly effective biotherapeutics.

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Fatty acid β-oxidation-dependent and -independent responses and tumor aggressiveness acquired under mild hypoxia

Wakui M., Kawai K., Mizushima T., Nishime C., Serizawa A., Suemizu H., Asakura K., Yamauchi Y., Hayashida T., Suematsu M., Murata M.

Anticancer Research (Anticancer Research) 39 ( 1 ) 191 - 200 2019.01

ISSN 02507005

© 2019 International Institute of Anticancer Research. All Rights Reserved. Background/Aim: The present study assessed whether and how tumor cells undergoing hypoxia contribute to disease progression after moving to areas with different oxygen conditions. Materials and Methods: Human colorectal carcinoma HCT116 cells cultured under mild hypoxia were subjected to in vivo experiments using transfer to immunodeficient murine recipients and to in vitro experiments using pharmacological inhibition of fatty acid β-oxidation (FAO). Results: Bone involvement and hepatic metastases were accelerated in transfer models of hypoxically cultured HCT116 cells. Hypoxic HCT116 cells exhibited FAO-dependent glycogen synthesis. FAO-dependent and -independent induction of gene expression also occurred under hypoxia. The distribution of glucose transporter 1 expression compared with heme oxygenase 1 expression in HCT116 cell spheroids seemed consistent with differential dependence of hypoxic expression of these molecules on FAO. Conclusion: These results provide insights into the contribution of hypoxia to tumor progression and the relevance of FAO.

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Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori–Infected CAPZA1-Overexpressing Cells

Tsugawa H., Kato C., Mori H., Matsuzaki J., Kameyama K., Saya H., Hatakeyama M., Suematsu M., Suzuki H.

Cellular and Molecular Gastroenterology and Hepatology (Cellular and Molecular Gastroenterology and Hepatology) 8 ( 3 ) 319 - 334 2019

ISSN 2352-345X

© 2019 The Authors Background & Aims: CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain. Methods: CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells. Results: CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori–infected gastric mucosa. Conclusions: CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells.

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Brief exposure of skin to near-infrared laser modulates mast cell function and augments the immune response

Kimizuka Y., Katagiri W., Locascio J., Shigeta A., Sasaki Y., Shibata M., Morse K., Sirbulescu R., Miyatake M., Reeves P., Suematsu M., Gelfand J., Brauns T., Poznansky M., Tsukada K., Kashiwagi S.

Journal of Immunology (Journal of Immunology) 201 ( 12 ) 3587 - 3603 2018.12

ISSN 00221767

©2018 by The American Association of Immunologists,Inc. The treatment of skin with a low-power continuous-wave (CW) near-infrared (NIR) laser prior to vaccination is an emerging strategy to augment the immune response to intradermal vaccine, potentially substituting for chemical adjuvant, which has been linked to adverse effects of vaccines. This approach proved to be low cost, simple, small, and readily translatable compared with the previously explored pulsed-wave medical lasers. However, little is known on the mode of laser-tissue interaction eliciting the adjuvant effect. In this study, we sought to identify the pathways leading to the immunological events by examining the alteration of responses resulting from genetic ablation of innate subsets including mast cells and specific dendritic cell populations in an established model of intradermal vaccination and analyzing functional changes of skin microcirculation upon the CW NIR laser treatment in mice. We found that a CW NIR laser transiently stimulates mast cells via generation of reactive oxygen species, establishes an immunostimulatory milieu in the exposed tissue, and provides migration cues for dermal CD103+ dendritic cells without inducing prolonged inflammation, ultimately augmenting the adaptive immune response. These results indicate that use of an NIR laser with distinct wavelength and power is a safe and effective tool to reproducibly modulate innate programs in skin. These mechanistic findings would accelerate the clinical translation of this technology and warrant further explorations into the broader application of NIR lasers to the treatment of immune-related skin diseases. The Journ Al of Immunology, 2018, 201: 3587-3603.

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Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese

Okada Y., Momozawa Y., Sakaue S., Kanai M., Ishigaki K., Akiyama M., Kishikawa T., Arai Y., Sasaki T., Kosaki K., Suematsu M., Matsuda K., Yamamoto K., Kubo M., Hirose N., Kamatani Y.

Nature Communications (Nature Communications) 9 ( 1 ) 1631 2018.12

ISSN 2041-1723

© 2018 The Author(s). Understanding natural selection is crucial to unveiling evolution of modern humans. Here, we report natural selection signatures in the Japanese population using 2234 high-depth whole-genome sequence (WGS) data (25.9×). Using rare singletons, we identify signals of very recent selection for the past 2000-3000 years in multiple loci (ADH cluster, MHC region, BRAP-ALDH2, SERHL2). In large-scale genome-wide association study (GWAS) dataset (n = 171,176), variants with selection signatures show enrichment in heterogeneity of derived allele frequency spectra among the geographic regions of Japan, highlighted by two major regional clusters (Hondo and Ryukyu). While the selection signatures do not show enrichment in archaic hominin-derived genome sequences, they overlap with the SNPs associated with the modern human traits. The strongest overlaps are observed for the alcohol or nutrition metabolism-related traits. Our study illustrates the value of high-depth WGS to understand evolution and their relationship with disease risk.

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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 2018.12

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 2018.12

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 2018.12

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 2018.11

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 2018.11

© 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 2018.11

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 2018.10

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 2018.10

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 2018.09

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 2018.09

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 2018.08

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 ) 2018.07

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 2018.07

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 2018.07

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 2018.07

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 2018.06

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 2018.05

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 2018.05

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 2018.05

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 2018.04

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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PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

Morita M., Sato T., Nomura M., Sakamoto Y., Inoue Y., Tanaka R., Ito S., Kurosawa K., Yamaguchi K., Sugiura Y., Takizaki H., Yamashita Y., Katakura R., Sato I., Kawai M., Okada Y., Watanabe H., Kondoh G., Matsumoto S., Kishimoto A., Obata M., Matsumoto M., Fukuhara T., Motohashi H., Suematsu M., Komatsu M., Nakayama K.I., Watanabe T., Soga T., Shima H., Maemondo M., Tanuma N.

Cancer Cell (Cancer Cell) 33 ( 3 ) 355 - 367.e7 2018.03

ISSN 15356108

© 2018 Elsevier Inc. Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRASG12D-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs. The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation.

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Utilizing mass spectrometry imaging to map the thyroid hormones triiodothyronine and thyroxine in Xenopus tropicalis tadpoles

Goto-Inoue N., Sato T., Morisasa M., Kashiwagi A., Kashiwagi K., Sugiura Y., Sugiyama E., Suematsu M., Mori T.

Analytical and Bioanalytical Chemistry (Analytical and Bioanalytical Chemistry) 410 ( 4 ) 1333 - 1340 2018.02

ISSN 16182642

© 2017, Springer-Verlag GmbH Germany, part of Springer Nature. Thyroid hormones are not only responsible for thermogenesis and energy metabolism in animals, but also have an important role in cell differentiation and development. Amphibian metamorphosis provides an excellent model for studying the remodeling of the body. This metamorphic organ remodeling is induced by thyroid hormones, and a larval body is thus converted into an adult one. The matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry (MS) imaging technology is expected to be a suitable tool for investigating small bioreactive molecules. The present study describes the distribution of the thyroid hormones, i.e., triiodothyronine (T3) and thyroxine (T4) and their inactive form reverse T3 (rT3) in Xenopus tropicalis tadpoles using two different types of imaging techniques, MS/MS and Fourier transform (FT)-MS imaging. As a result of MS/MS imaging, we demonstrated that T3 was mainly distributed in the gills. T4 was faintly localized in the eyes, inner gills, and intestine during metamorphosis. The intensity of T3 in the gills and the intensity of T4 in the body fluids were increased during metamorphosis. Moreover, the localization of the inactive form rT3 was demonstrated to be separate from T3, namely in the intestine and muscles. In addition, FT-MS imaging could utilize simultaneous imaging including thyroid hormone. This is the first report to demonstrate the molecular distribution of thyroid hormones themselves and to discriminate T3, T4, and rT3 in animal tissues.

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Plant hormone cytokinins control cell cycle progression and plastid replication in apicomplexan parasites

Andrabi S.B.A., Tahara M., Matsubara R., Toyama T., Aonuma H., Sakakibara H., Suematsu M., Tanabe K., Nozaki T., Nagamune K.

Parasitology International (Parasitology International) 67 ( 1 ) 47 - 58 2018.02

ISSN 13835769

© 2017 The Authors Cytokinins are plant hormones that are involved in regulation of cell proliferation, cell cycle progression, and cell and plastid development. Here, we show that the apicomplexan parasites Toxoplasma gondii and Plasmodium berghei, an opportunistic human pathogen and a rodent malaria agent, respectively, produce cytokinins via a biosynthetic pathway similar to that in plants. Cytokinins regulate the growth and cell cycle progression of T. gondii by mediating expression of the cyclin gene TgCYC4. A natural form of cytokinin, trans-zeatin (t-zeatin), upregulated expression of this cyclin, while a synthetic cytokinin, thidiazuron, downregulated its expression. Immunofluorescence microscopy and quantitative PCR analysis showed that t-zeatin increased the genome-copy number of apicoplast, which are non-photosynthetic plastid, in the parasite, while thidiazuron led to their disappearance. Thidiazuron inhibited growth of T. gondii and Plasmodium falciparum, a human malaria parasite, suggesting that thidiazuron has therapeutic potential as an inhibitor of apicomplexan parasites.

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Future of Rare Diseases Research 2017–2027: An IRDiRC Perspective

Austin C.P., Cutillo C.M., Lau L.P.L., Jonker A.H., Rath A., Julkowska D., Thomson D., Terry S.F., de Montleau B., Ardigò D., Hivert V., Boycott K.M., Baynam G., Kaufmann P., Taruscio D., Lochmüller H., Suematsu M., Incerti C., Draghia-Akli R., Norstedt I., Wang L., Dawkins H.J.S.

Clinical and Translational Science (Clinical and Translational Science) 11 ( 1 ) 21 - 27 2018.01

ISSN 17528054

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Identification of outer mitochondrial membrane cytochrome b₅ as a modulator for androgen synthesis in leydig cells

Ogishima Tadashi, Kinoshita Junya, Mitani Fumiko, Suematsu Makoto, Ito Aki

Journal of biological chemistry 278 ( 23 ) 21204-21211 2003.06

Research paper (scientific journal), Joint Work

An Inverse Correlation between Expression of a Preprocathepsin B-related Protein with Cysteine-rich Sequences and Steroid 11beta-Hydroxylase in Adrenocortical Cells

Mukai Kuniaki, Mitani Fumiko, Nagasawa Hideko, Suzuki Reiko, Suzuki Tsuneharu, Suematsu Makoto, Ishimura Yuzuru

Journal of biological chemistry 278 ( 19 ) 17084-17092 2003.05

Research paper (scientific journal), Joint Work

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Kajimura Mayumi, Shimoyama Masaru, Tsuyama Shingo, Suzuki Tsuneharu, Kozaki Shinji, Takenaka Shingo, Tsubota Kazuo, Oguchi Yoshihisa, Suematsu Makoto

FASEB journal 17 ( 3 ) 506-508 2003.03

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Peyer’s patch is the essential site in initiating murine acute and lethal graft-versus-host reaction

Murai Masako, Yoneyama Hiroyuki, Ezaki Taichi, Suematsu Makoto, Terashima Yuya, Harada Akihisa, Hamada Hiromasa, Asakura Hitoshi, Ishikawa Hiromichi, Matsushima Kouji

Nature immunology 4 ( 2 ) 154-160 2003.02

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The undifferentiated cell zone is a stem cell zone in adult rat adrenal cortex

Mitani Fumiko, Mukai Kuniaki, Miyamoto H, Suematsu Makoto, Ishimura Yuzuru

Biochimica biophysica acta 1619 ( 3 ) 317-324 2003.02

Research paper (scientific journal), Joint Work

Human serum albumin incorporating synthetic heme: red blood cell substitute without hypertension by nitric oxide scavenging

Tsuchida Eishun, Komatsu Teruyuki, Matsukawa Yasuko, Nakagawa Akito, Sakai Hiromi, Kobayashi Koichi, Suematsu Makoto

J Journal of biomedical materials research 64A ( 2 ) 257-261 2003.02

Research paper (scientific journal), Joint Work

Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction

Murai Masako, Yoneyama Hiroyuki, Ezaki Taichi, Suematsu Makoto, Terashima Yuya, Harada Akihisa, Hamada Hiromasa, Asakura Hitoshi, Ishikawa Hiromichi, Matsushima Kouji

Nature immunology 4 ( 2 ) 154-160 2003.02

Research paper (scientific journal), Joint Work

Expression of heme oxygenase-1 in rat ontogeny.

SUEMATSU MAKOTO

Arch. Histol. Cytol. 66 ( 1 ) 155-162 2003

Research paper (scientific journal), Single Work

Human serum albumin incorporating synthetic heme: Red blood cell substitute without hypertension by nitric oxide scavenging.

SUEMATSU MAKOTO

J Biomed Mater Res. 64 ( A ) 257-261 2003

Research paper (scientific journal), Single Work

Subendothelial dome of gut Peyer’s patches is the essential anatomical site in initiating acute graft-versus-host disease.

SUEMATSU MAKOTO

Nat. Immunol. 4 ( 1 ) 154-160 2003

Research paper (scientific journal), Single Work

The undifferentiated cell zone is a stem cell zone in adult rat adrenal cortex.

SUEMATSU MAKOTO

Biochim Biophys Acta. 1619 ( 1 ) 317-324 2003

Research paper (scientific journal), Single Work

An inverse correlation between expression of a preprocathepsin B-related protein with cysteine-rich sequences and steroid 11-hydroxylase in adrenocortical cells.

SUEMATSU MAKOTO

J. Biol. Chem. 278 ( 1 ) 17084-17092 2003

Research paper (scientific journal), Single Work

Identification of outer mitochondrial membrane cytochrome b5 as a modulator for androgen synthesis in Leydig cells.

SUEMATSU MAKOTO

J. Biol. Chem. 278 ( 1 ) 21204-21211 2003

Research paper (scientific journal), Single Work

Bilirubin rinse: A simple protectant against the rat liver graft injury mimicking heme oxygenase-1 preconditioning.

SUEMATSU MAKOTO

Hepatology 38 ( 1 ) 364-373 2003

Research paper (scientific journal), Single Work

Suppressed apoptosis in the inflamed gastric mucosa of Helicobacter pylori-colonized iNOS-knockout mice.

SUEMATSU MAKOTO

Free Radic. Biol. Med. 34 ( 1 ) 121-1630 2003

Research paper (scientific journal), Single Work

Quartet signal transducers in gas biology.

SUEMATSU MAKOTO

Antioxid. Redox Signal. 5 ( 1 ) 435-437 2003

Research paper (scientific journal), Single Work

Mechanistic probing of gaseous signal transduction in microcirculation.

SUEMATSU MAKOTO

Antioxid. Redox Signal. 5 ( 1 ) 485-492 2003

Research paper (scientific journal), Single Work

Carbon monoxide stimulates mrp2-dependent excretion of bilirubin-IX into bile in the perfused rat liver.

SUEMATSU MAKOTO

Antioxid. Redox Signal. 5 ( 1 ) 449-456 2003

Research paper (scientific journal), Single Work

Aberrant utilization of nitric oxide and regulation of soluble guanylate cyclase in rat diabetic retinopathy.

SUEMATSU MAKOTO

Antioxid. Redox Signal. 5 ( 1 ) 457-466 2003

Research paper (scientific journal), Single Work

Kinetic and spectroscopic characterization of hydroperoxy compound in the reaction of native myoglobin with hydrogen peroxide.

SUEMATSU MAKOTO

J. Biol. Chem. 278 ( 1 ) 41597-41606 2003

Research paper (scientific journal), Single Work

Infrared spectroscopic and mutational studies on putidaredoxin-induced conformational changes in ferrous CO-P450cam.

SUEMATSU MAKOTO

Biochemistry 42 ( 1 ) 14507-14514 2003

Research paper (scientific journal), Single Work

Nonendothelial source of nitric oxide in arterioles but not in venules. Alternative source revealed in vivo by diaminofluorescein microfluorography

Kashiwagi Satoshi, Kajimura Mayumi, Yoshimura Yasunori, Suematsu Makoto

Circulation research 91 ( 12 ) e55-e64 2002.12

Research paper (scientific journal), Joint Work

Nonendothelial source of nitric oxide in arterioles but not in venules:alternative source revealed in vivo by diaminofluorescein microfluorography

Kashiwagi Satoshi, Kajimura Mayumi, Yoshimura Yasuhiro, Suematsu Makoto

Circuration research 91 ( 12 ) 55-64 2002.12

Research paper (scientific journal), Joint Work

Gas Biology：ガス分子による生体制御の生物学

Suematsu Makoto

生化学 74 ( 11 ) 1317-1328 2002.11

Research paper (scientific journal), Single Work

Stabilization of mast cells by heme oxygenase-1: an anti-inflammatory role

Takamiya Rina, Murakami Makoto, Kajimura Mayumi, Goda Nobuhito, Makino Nobuya, Takamiya Yoshihiro, Yamaguchi Tokio, Ishimura Yuzuru, Hozumi Nobumichi, Suematsu Makoto

American journal of Physiology. Heart and circulutory physiology 283 ( 3 ) 861-870 2002.09

Research paper (scientific journal), Joint Work

Carbon monoxide modulates endotoxin-induced microvascular leukocyte adhesion through platelet-dependent mechanisms

Morisaki Hiroshi, Katayama Tomihiro, Kotake Yoshifumi, Ito Masaharu, Handa Makoto, Ikeda Yasuo, Takeda Junzo, Suematsu Makoto

Anesthesiology 97 ( 3 ) 701-709 2002.09

Research paper (scientific journal), Joint Work

Carbon monoxide modulates endotoxin-induced microvascular leukocyte adhesion through platelet-dependent mechanisms

Morisaki Hiroshi, Katayama Tomihiro, Kotake Yoshifumi, Ito Masaharu, Handa Makoto, Ikeda Yasuo, Takeda Junzo, Suematsu Makoto

Anesthesiology 97 ( 3 ) 701-709 2002.09

Research paper (scientific journal), Joint Work

The inflammatory aspect of the microcirculation in hypertension: oxidative stress, leukocytes/endothelial interaction, apoptosis

Suematsu Makoto, Suzuki Hidekazu, Delano Frank A, Schmid-Schonbein Geere W

Microcirculation 9 ( 4 ) 259-276 2002.09

Research paper (scientific journal), Joint Work

Related Articles, Links Organ design for generation and reception of CO: lessons from the liver

Kajimura Mayumi, Goda Nobuhiko, Suematsu Makoto

Antioxidants & redox signalling 4 ( 4 ) 633-637 2002.08

Research paper (scientific journal), Joint Work

The protective role of Kupffer cells in the ischemia-reperfused rat liver

Kobayashi T, Hirano K, Yamamoto T, Hasegawa G, Hatakeyama K, Suematsu Makoto, Naito M

Archives of histology and cytology 65 ( 3 ) 251-261 2002.08

Research paper (scientific journal), Joint Work

H.pylori 感染動物モデルによる胃粘膜炎症の遷延と前癌性変化の検討―宿主の反応性から疾患機序を考える―

Suzuki Hidekazu, Miyazawa Masaharu, Masaoka Tatsuhiro, Suzuki Masayuki, Suematsu Makoto, Nagata Hiroshi, Miura Souichirou, Ishii Hiromasa

実験潰瘍 29 ( 1 ) 24-27 2002.05

Research paper (scientific journal), Joint Work

Related Articles, Links COHb: a stress-induced marker reflecting surgical insults?

Suematsu Makoto

J gastroenterol hepatol. 17 ( 5 ) 519-520 2002.05

Research paper (scientific journal), Single Work

No difference in the level of gastric mucosal cell apoptosis and proliferation in Helicobacter pylori-colonized p53 heterozygous knockout mice

Suzuki H, Miyazawa M, Kai A, Suzuki M, Suematsu Makoto, Miura S, Ishii H

Alimentary pharmacology & therapeutics 16 ( Suppl2 ) 158-166 2002.04

Research paper (scientific journal), Joint Work

Inflammatory aspects of the microcirculation in hypertension: oxidative stress, leukocytes/endothelial interaction, apoptosis

Suematsu, Makoto, Suzuki Hidekazu, DeLano, Frank A, Schmid-Schonbein, Geert W

Microcirculation 9 ( 4 ) 259-276 2002.04

Research paper (scientific journal), Joint Work

From O_{#DR to H#D}S: a landscape view of gas biology

Kashiba M, Kajimura M, Goda N, Suematsu M

The keio Journal of Medicine 51 ( 1 ) 1-10 2002.03

Research paper (scientific journal), Joint Work

Leydig cell-derived heme oxygenase-l regulates apoptosis of premeiotic germin response to stress

Ozawa Nobuaki, Goda Nobuhito, Makino Nobuya, Yamaguchi Tokio, Yoshimura Yasunori, Suematsu Makoto

The Journal of Clinical Investigation 109 ( 4 ) 457-467 2002.02

Research paper (scientific journal), Joint Work

Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress

Ozawa N, Goda N, Makino N, Yamaguchi T, Yoshimura Y, Suematsu M

The Journal of Clinical Investigation 109 ( 4 ) 457-467 2002.02

Research paper (scientific journal), Joint Work

Conditionally immortalized adrenocortical cell lines at undifferentiated states exhibit inducible expression of glucocorticoid-synthesizing genes

Mukai K, Nagasawa H, Agake-Suzuki R, Mitani F, Totani K, Yanai N, Obinata M, Suematsu M, Ishimura Y

European Journal of Biochemistry 269 ( 1 ) 69-81 2002.01

Research paper (scientific journal), Joint Work

Conditionally immortalized adrenocortical cell lines at undifferentiated states exhibit inducible expression of glucocorticoid-synthesizing genes

Mukai Kuniaki, Nagasawa Hideko, Agake-Suzuki Reiko, Mitani Fumiko, Totani Keiko, Yanai Nobuaki, Obinata Masuo, Suematsu Makoto, Ishimura Y,

European journal of biochemistry 269 ( 1 ) 69-81 2002.01

Research paper (scientific journal), Joint Work

Gene transfection of H25A mutant heme oxygenase-1 protects cells against hydroperoxide-induced cytotoxicity

Hori R, Kashiba M, Toma T, Yachie A, Goda N, Makino N, Soejima A, Nagasawa T, Nakabayashi K, Suematsu M

The Journal of Biological Chemistry 277 10712-10718 2002

Research paper (scientific journal), Joint Work

Carbon monoxide modulates endotoxin-induced microvascular leukocyte adhesion through platelet-dependent mechanisms

Morisaki H, Katayama T, Kotake Y, Handa Makoto, Ikeda Yasuo, Takeda J, Suematsu M

Anesthesiology 97 ( 3 ) 701-709 2002

Research paper (scientific journal), Joint Work

Carbon monoxide modulates endotoxin-induced microvascular leukocyte adhesion through platelet-dependent mechanisms

Morisaki H, Katayama T, Kotake Y, Handa M, Ikeda Y, Takeda J, Suematsu M

Anesthesiology 97 ( 3 ) 701-709 2002

Research paper (scientific journal), Joint Work

Kupffer cell-mediated recruitment of rat dendritic cells to the liver: roles of N-acetylgalactosamine-specific sugar receptors

Uwatoku R, Suematsu M, Ezaki T, Saiki T, Tsujii M, Irimura T, kawada N, Suganuma T, Naito M, Ando M, Matsuno K

Gastroenterology 121 ( 6 ) 1460-1472 2001.12

Research paper (scientific journal), Joint Work

Activated platelets and endothelial cell interaction with neutrophils under flow conditions

Mine S, Fujisaki T, Suematsu M, Tanaka Y

Internal Medicine 40 ( 11 ) 1085-1092 2001.11

Research paper (scientific journal), Joint Work

Organic phosphates as a new class of soluble guanylate cyclase inhibitors

Suzuki T, Suematsu M, Makino R

FEBS Letters 507 ( 1 ) 49-53 2001.10

Research paper (scientific journal), Joint Work

ERK and p38 MAPK, but not NF-κB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts

Sano Motoaki, Fukuda Keiichi, Sato Toshihiko, Kawaguchi Haruko, Suematsu Makoto, Matsuda Satoshi, Koyasu Shigeo, Matsui Hideo, Yamauchi-Takihara Keiko, Harada Masaki, Saito Yoshihiko, Ogawa Satoshi

Circulation Research 89 ( 8 ) 661-669 2001.10

Research paper (scientific journal), Joint Work

ERK and p38 MAPK, but not NF-_kB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts

Sano Motoaki, Fukuda Keiichi, Sato Toshihiko, Kawaguchi H, Suematsu Makoto, Matsuda Satoshi, Koyasu Shigeo, Matsui Hideo, Yamauchi-Takihara Keiko, Harada M,Saito Y, Ogawa Satoshi

Circulation Research 89 ( 8 ) 661-669 2001.10

Research paper (scientific journal), Joint Work

ERK and p38 MAPK, but not NF-kB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts

Sano M, Fukuda K, Sato T, Kawaguchi H, Suematsu M, Matsuda S, Koyasu S, Matsui H, Yamauchi-Takihara K, Harada M, Saito Y, Ogawa S

Circulation Research 89 ( 8 ) 661-669 2001.10

Research paper (scientific journal), Joint Work

Increased expression of heme oxygenase 1 and bilirubin accumulation in foam cells of rabbit atherosclerotic lesions

Nakayama M, Takahashi K, Komaru T, Fukuchi M, Shioiri H, Sato K, Kitamuro T, Shirato K, Yamaguchi T, Suematsu M, Shibahara S

Arteriosclerosis, Thrombosis and Vascular Biology 21 ( 8 ) 1373-1377 2001.08

Research paper (scientific journal), Joint Work

Relaxation effects of clustered particles

Tanimoto A, Oshio K, Suematsu M, Pouliquen D, Stark D

Journal of Megnetic Resonance Imaging 14 ( 1 ) 72-77 2001.07

Research paper (scientific journal), Joint Work

Roles of carbon monoxide in leukocyte and platelet dynamics in rat mesentery during sevoflurane anesthesia

Morisaki H, Katayama T, Kotake Y, Ito M, Tamatani T, Sakamoto S, Ishimura Y, Takeda J, Suematsu M

Anesthesiology 95 ( 1 ) 192-199 2001.07

Research paper (scientific journal), Joint Work

Roles of carbon monoxide in leukocyte and platelet dynamics in rat mesentery during sevoflurane anesthesia

Morisaki Hiroshi, Katayama Tomihiro, Kotake Yosifummi, Ito Masaharu, Sakamoto Shinichi, Ishimura Yuzuru, Takeda Junzo, Suematsu Makoto

Anesthesiology 95 ( 1 ) 192-199 2001.07

Research paper (scientific journal), Joint Work

Vascular smooth muscle cell-directed overexpression of heme oxygenase-1 elevates blood pressure through attenuation of nitric oxide-induced vasodilation in mice

Imai T, Morita T, Shindo T, Nagai R, Yazaki Y, Kurihara H, Suematsu M, Katayama S

Circulation Research 89 ( 1 ) 55-62 2001.07

Research paper (scientific journal), Joint Work

Relaxation effects of clustered particles

Tanimoto Akihiro, Oshio Koichi, Suematsu Makoto, Pouliquen Daniel, Stark David D

Journal of Magnetic Resonance Imaging 14 ( 7 ) 72-77 2001.07

Research paper (scientific journal), Joint Work

Professor Toshio Ito: a clairvoyant in pericyte biology

Suematsu M, Aiso S

The keio Journal of Medicine 50 ( 2 ) 66-71 2001.06

Research paper (scientific journal), Joint Work

Professor Toshio Ito:a clairvoyant in pericyte biology

Suematsu Makoto, Aiso Sadakazu

The Keio Journal of Medicine 50 ( 2 ) 66-71 2001.06

Research paper (scientific journal), Joint Work

Role of heme oxygenase-1 and Kupffer cells in the production of bilirubin in the rat liver

Hirano K, Kobayashi T, Watanabe T, Yamamoto T, Hasegawa G, Hatakeyama K, Suematsu M, Naito M

Archives of Histology and Cytology 64 ( 2 ) 169-78 2001.05

Research paper (scientific journal), Joint Work

Polaprezinc attenuates the Helicobacter pylori-induced gastric mucosal leucocyte activation in Mongolian gerbils - a study using intravital videomicroscopy

Suzuki H, Mori M, Seto K, Miyazawa M, Kai A, Suematsu M, Yoneta T, Miura S, Ishii H

Alimentary Pharmacology and Therapentics 15 ( 5 ) 715-725 2001.05

Research paper (scientific journal), Joint Work

Polaprezinc attenuates the H.pylori-induced gastric mucosal leukocyte activation in Mongolian gerbils.-a study using intravital videomicroscopy

Suzuki Hidekazu, Mori Mikiji, Seto Koichi, Miyazawa Masaharu, Kai Akemi, Suematsu Makoto, Yoneta Tomoyuki, Miura Soichiro, Ishii Hiromasa

Alimentary Pharmacology and Therapeutics 15 ( 5 ) 715-725 2001.05

Research paper (scientific journal), Joint Work

Endothelin B receptor-mediated protection against anoxia-reoxygenation injury in perfused rat liver: nitric oxide-dependent and-independent mechanisms.

Taniai H, Suematsu M, Suzuki T, Hori R, Ishimura Y, Nimura Y

Hepatology 33 ( 4 ) 894-901 2001.04

Research paper (scientific journal), Joint Work

Carbon monoxide from heme catabolism protects against hepatobiliary dysfunction in endotoxin-treated rat liver

Kyokane T, Norimizu S, Taniai H, Yamaguchi T, Takeoka S, Tsuchida E, Naito M, Nimura Y, Ishimura Y, Suematsu M

Gastroenterology 120 ( 5 ) 1227-1240 2001.04

Research paper (scientific journal), Joint Work

Altered expression of heme oxygenase-1 in the livers of patients with portal hypertensive diseases

Makino N, Suematsu Makoto, Sugiura Y, Morikawa H, Shiomi H, Goda N, Sano T, Nimura Y, Sugimachi K, Ishimura Y

Hepatology 33 ( 1 ) 32-42 2001.01

Research paper (scientific journal), Joint Work

An ELISA assay for heme oxygenase-1

Kitchin KT, Anderson WL, Suematsu Makoto

Journal of Immunological Methods 247 ( 1-2 ) 153-161 2001.01

Research paper (scientific journal), Joint Work

Carbon monoxide reception in biological systems

Kashiba M, Ishimura Y, Suematsu M

Porphyrins 9 150-157 2001

Research paper (scientific journal), Joint Work

微小循環機能恒常性維持を考慮した人工酸素運搬体の開発研究

Suematsu Makoto，Kashiba Misato，Ishimura Yuzuru

医学のあゆみ 195 ( 13 ) 997-1000 2000.12

Research paper (scientific journal), Joint Work

Daily regeneration of rat adrenocortical cells: circadian and zonal variations in cytogenesis

Miyamoto Hirokuni, Mitani Fumiko, Mukai Kuniaki, Suematsu Makoto, Ishimura Yuzuru

Endocrine Research 26 ( 4 ) 899-904 2000.11

Research paper (scientific journal), Joint Work

ヘム分解の生化学から見た人工酸素運搬体の設計戦略

Suematsu Makoto，Kyoukane Takanori，Nimura Yuuji，Ishimura Yuzuru

人工血液 8 ( 2 ) 40-42 2000.07

Research paper (scientific journal), Joint Work

H.pylori感染胃粘膜細胞のアポトーシスレベルの宿主特異性について

Nagahashi Shouichi，Suzuki Hidekazu，Seto Kouichi，Mori Mikiji，Miyazawa Masaharu，

実験潰瘍 27 ( 1 ) 16-19 2000.05

Research paper (scientific journal), Joint Work

Roles of ICAM-1 for abnormal leukocyte recruitment in the microcirculation of bleomycin-induced fibrotic lung injury

Sato N, Suzuki Y, Nishio K, Suzuki K, Naoki K, Takeshita K, Kudo H, Miyao N, Tsumura H, Serizawa H, Suematsu M, Yamaguchi K

American Journal of Respiratory and Critical Care Medicine 161 ( 5 ) 1681-1688 2000.05

Research paper (scientific journal), Joint Work

Roles of ICAM-1 for abnormal leukocyte recruitment in the microcirculation in bleomycin-induced fibrotic lung injury

Sato Nagato, Suzuki Yukio, Nishio Kazumi, Suzuki Koichi, Naoki Katsuhiko, Takeshita Kei, Kudo Hiroyasu, Miyao Naoki, Tsumura Harukuni, Serizawa Hiroshi, Suematsu Makoto, Yamaguchi Kazuhiro

American Journal of Respiratory and Critical Care Medicine 161 ( 5 ) 1681-1688 2000.05

Research paper (scientific journal), Joint Work

Immunoneutralization of glycoprotein Iba attenuates endotoxin-induced interactions of platelets and leukocytes with rat venular endothelium in vivo

Katayama T, Ikeda Y, Handa M, Tamatani T, Sakamoto S, Ito M, Ishimura Y, Suematsu Makoto

Circulation Research 86 ( 10 ) 1031-1037 2000.05

Research paper (scientific journal), Joint Work

Immunoneutralization of glycoprotein Ibα attenuates endoxin-induced interactions of platelets and leukocytes with rat venular endothelium in vivo

Katayama Tomihiro, Ikeda Yasuo, Handa Makoto, Tamatani Takuya, Sakamoto Shinji, Ito Masaharu, Ishimura Yuzuru, Suematsu Makoto

Circulation Research 86 ( 10 ) 1031-1037 2000.05

Research paper (scientific journal), Joint Work

Immunoneutralization of glycoprotein Iba attenuates endotoxin-induced interactions of platelets and leukocytes with rat venular endothelium in vivo

Katayama Tomihiro, Ikeda Yasuo, Handa Makoto, Tamatani Takuya, Sakamoto Shinji, Ito Masaharu, Ishimura Yuzuru, Suematsu Makoto

Circulation Research 86 ( 10 ) 1031-1037 2000.05

Research paper (scientific journal), Joint Work

Increased sensitivity to the C-X-C chemokine CINC/gro in a model of chronic inflammation

Johnston B, Burns AR, Suematsu Makoto, Watanabe K, Issekutz TB, Kubes P

Microcirculation 7 ( 2 ) 109-118 2000.04

Research paper (scientific journal), Joint Work

Stage-Specific Expression of Mucosal Addressin Cell Adhesion Molecule-1 During Embryogenesis in Rats

Iizuka Toshihiko, Tanaka Toshiyuki, Suematsu Makoto, Miura Souichiro, Watanabe Toshiyuki, Koike Ryuji, Ishimura Yuzuru, Ishii Hiromasa, Miyasaka Nobuyuki, Miyasaka Masayuki

The Jounal of Immunology 164 2463-2471 2000.03

Research paper (scientific journal), Joint Work

Protective role of endogenous carbon monoxide in neointimal development elicited by arterial injury

Togane Yuko, Morita Toshisuke, Suematsu Makoto, Ishimura Yuzuru, Yamazaki Junichi, Katayma Shigehiro

American Jounal of Physiology Heart and Circulatory Physiology 278 ( 2 ) H623-H632 2000.02

Research paper (scientific journal), Joint Work

The Heme oxygenase-carbon monoxide system: a regulator of hepatobiliary function

Suematsu Makoto, Ishimura Yuzuru

Hepatorogy 31 ( 1 ) 3-6 2000.01

Research paper (scientific journal), Joint Work

Fate of adrenocortical cells: Distribution of degenerating cells and macrophages in the rat adrenal cortex

Mitani Fumiko, Mukai Kuniaki, Suematsu Makoto, Miyamoto Hirokuni, Ishimura Yuzuru

Molecular Steroidogenesis 231-232 2000.01

Research paper (scientific journal), Joint Work

A Low-Sodium Diet Affects The Proliferation and Migration of Rat Adrenocortex Cells in vivo

Miyamoto Hirokuni, Mitani Fumiko, Mukai Kuniaki, Suematsu Makoto, Ishimura Yuzuru

Molecular Steroidogenesis 227-228 2000.01

Research paper (scientific journal), Joint Work

Metyrapone, an Inhibitor of Glucocorticoid Synthesis, Had Two Opposite Effects on the Cells Proliferation in Rat Adrenal Cortex

Miyamoto Hirokuni, Mitani Fumiko, Mukai Kuniaki, Suematsu Makoto, Ishimura Yuzuru

Moleculer Steroidogenesis 229-230 2000.01

Research paper (scientific journal), Joint Work

Microvascular oxidative stress, immune reaction and apoptosis in hypertensives.

Suzuki Hidekazu, Suematsu Makoto, Schmid-Sch嗜bein Geert W

Clinical Hemorheology and Microcirculation 21 ( 12 ) 161-168 1999.12

Research paper (scientific journal), Joint Work

Studies on Cytogenesis in Adult Rat Adrenal Cortex: Circadian and Zonal Variations and Their Modulation by Adrenocorticotropic Hormone

Miyamoto Hirokuni, Mitani Fumiko, Mukai Kuniaki, Suematsu Makoto, Ishimura Yuzuru

The Journal of Biochemistry 126 ( 6 ) 1175-1183 1999.12

Research paper (scientific journal), Joint Work

Kupffer Cell-Independent Acute Hepaticellular Oxidative Stress and decreased Bile Formation in Post-Cold-Ischemic Rat Liver

Kumamoto Yusuke, Suematsu Makoto, Shimazu Motohide, Kato Yutaro, Sano Tsuyoshi, Makino Nobuya, Hirano Ken-ichiro, Naito Makoto, Wakabayashi Go, Ishimura Yuzuru, Kitajima Masaki

Hepatology 30 ( 6 ) 1454-1463 1999.12

Research paper (scientific journal), Joint Work

Kupffer cell-independent acute hepatocellular oxidative stress and decreased bile formation in post-cold-ischemic rat liver

Kumamoto Yusuke, Suematsu Makoto, Shimazu Motohide, Kato Yutaro, Sano Tsuyoshi, Makino Nobuya, Hirano Kenichiro, Naito Makoto, Wakabayashi Go, Ishimura Yuzuru, Kitajima Masaki

Hepatology 30 ( 6 ) 1454-1463 1999.12

Research paper (scientific journal), Joint Work

Ethanol intake preceding H.pylori inoculation promotes gastric mucosal inflammation in Mongolian gerbils.

Suzuki Hidekazu, Mori Mikiji, Seto Koichi, Nagahashi Shoichi, Kawaguchi Chizuko, Kai Akemi, Akiba Yasutada, Suzuki Masayuki, Suematsu Makoto, Miura Soichiro, Ishii Hiromasa

Journal of Gastroenterology and Hepatology 14 ( 11 ) 1062-1069 1999.11

Research paper (scientific journal), Joint Work

Ethanol intake preceding Helicobacter pylori inoculation promotes gastric mucosal inflammation in Mongolian gerbils

Suzuki Hidekazu, Mori Mikiji, Seto K, Nagahashi , Kawaguchi C, Akiba Y, Suzuki M, Suematsu M, Miura Soichiro, Ishii Hiromasa

Journal of Gastroenterology and Hepatology 14 ( 11 ) 1062-1069 1999.11

Research paper (scientific journal), Joint Work

In vivo leukocyte-endothelial interaction under different levels of wall shear rate

Suzuki H, Schmid-Schoenbein GW, Suematsu Makoto, Mori Mikiji, Nagata Hiroshi, Ishii Hiromasa

Microcirculation Annual 1999 15 21-22 1999.11

Research paper (scientific journal), Joint Work

Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress-role of bilirubin generated by the enzyme

Hayashi Shinobu, Takamiya Rina, Yamaguchi Tokio, Matsumoto Kenji, Shinichiro J. Tojo, Tamatani Takuya, Kitajima Masaki, Makino Nobuya, Ishimura Yuzuru, Suematsu Makoto

Circulation Reserch 85 ( 8 ) 663-671 1999.10

Research paper (scientific journal), Joint Work

Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of billirubin generated by the enzyme

Hayashi Shinobu, Takamiya Rina, Yamaguchi Tokio, Matsumoto Kenji, Tojo Shiichiro.J, Tamatani Takuya, Kitajima Masaki, Makino Nobuya, Ishimura Yuzuru, Suematsu Makoto

Circulation Research 85 ( 8 ) 663-671 1999.10

Research paper (scientific journal), Joint Work

ヘムオキシゲナーゼの誘導による微小循環の酸素ストレス耐性獲得と白血球接着の抑制：ビリルビンの役割

Hayashi Shinobu, Suematsu Makoto, Matsumoto Kenji, Ishimura Yuzuru, Kitajima Masaki

G.I.Reserch 7 ( 4 ) 87(323) 1999.08

Research paper (scientific journal), Joint Work

Carbon monoxide-mediates alterations in paracellular permeability and vesicular transport in acetaminophen-treated perfused rat liver

Mori Mikiji, Suematsu Makoto, Kyokane Takanori, Sano Tsuyoshi, Suzuki Hidekazu, Yamaguchi Tokio, Ishimura Yuzuru, Ishii Hiromasa

Hepatology 30 ( 1 ) 160-168 1999.07

Research paper (scientific journal), Joint Work

H.pylori感染マウス胃粘膜上皮細胞アポトーシスと好中球浸潤

Mori Mikiji, Suzuki Hidekazu, Nagahashi Shouichi, Seto Kouichi, Suzuki Masayuki, Suematsu Makoto, Miura Souichirou, Ishii Hiromasa

実験潰瘍 26 1-4 1999.07

Research paper (scientific journal), Joint Work

Recent developments in hepatic circulatory physiology

Suematsu Makoto

Hepatogastroenterology 46 ( Suppl 2 ) 1406-1408 1999.06

Research paper (scientific journal), Single Work

Carbon monoxide mediated alterations in paracellular permeability and vesicular transport in acetaminophen-treated perfused rat liver.

Mori Mikiji, Suematsu Makoto, Kyokane Takeshi, Sano Tsuyoshi, Suzuki Hidekazu, Yamaguchi Tokio, Ishimura Yuzuru, Ishii Hiromasa

Hepatology 30 ( 6 ) 160-168 1999.06

Research paper (scientific journal), Joint Work

【活性酸素と臓器保存】肝保存におけるラジカル発生と肝の微小循環障害

Kumamoto Yuusuke, Shimazu Motohide, Wakabayashi Gou, Katou Yuutarou, Suematsu Makoto, Ishimura Yuzuru, Kitajima Masaki

低温医学 25 ( 2 ) 92-96 1999.06

Research paper (scientific journal), Joint Work

Nitric oxide inhibits microvascular protein leakage induced by leukocyte adhesion-independent and adhesion-dependent inflammatory mediators

Johnston Brent, Gaboury JP, Suematsu Makoto, Kubes Paul

Microcirculation 6 ( 2 ) 153-162 1999.06

Research paper (scientific journal), Joint Work

H.pylori （Sydney株）感染マウス胃粘膜病変形成に対するrebamipideの効果

Suzuki Hidekazu, Mori Mikiji, Nagahashi Shouichi, Kai Akemi, Watanabe Katsushi, Suzuki Masayuki, Jou Takashi, Suematsu Makoto, Itou Makoto, Miura Souichirou, Ishii Hiromasa

Progress in Medicine 19 ( 5 ) 1323-1329 1999.05

Research paper (scientific journal), Joint Work

Chronic inflamation upregulates chemokine receptors and induces neutrophil migration to monocyte chemoattractant protein-1

Johnston Brent, Burns Alan R, Suematsu Makoto, Issekutz Thomas B, Woodman Richard C, Kubes Paul

Journal of Clinical Investigation 103 ( 9 ) 1269-1276 1999.05

Research paper (scientific journal), Joint Work

H.pylori-associated gastric pro- and anti-oxidant formation in Mongolian gerbils.

Suzuki Hidekazu, Mori Mikiji, Seto Koichi, Kai Akemi, Kawaguchi Chizuko, Suzuki Masayuki, Suematsu Makoto, Yoneta Tomoyuki, Miura Soichiro, Ishii Hiromasa

Free Radical Biology and Medicine 26 ( 4 ) 679-684 1999.04

Research paper (scientific journal), Joint Work

H.pylori-associated gastric pro - and antioxidant formation in Mongolian gerbils

Suzuki H, Mori M, Seto K, Kai A, Kawaguchi C, Suzuki M, Suematsu M, Yoneta T, Miura S, Ishii H

Free Radical Biology and Medicine 26 679-684 1999.03

Research paper (scientific journal), Joint Work

ガス状メデイエーターとヘム蛋白の相互作用と臓器機能制御

Suematsu Makoto, Makino Nobuya, Ishimura Yuzuru

医学のあゆみ 188 ( 13 ) 1105-1112 1999.03

Research paper (scientific journal), Joint Work

Paracrine upregulation of VEGF recepter mRNA in endothelial cells by hypoxia-exposed HepG₂ cells

Suzuki H, Seto K, Shinoda Y, Mori M, Ishimura Y, Suematsu M, Ishii H

American Journal of Physiology 276 G92-G97 1999.01

Research paper (scientific journal), Joint Work

肝類洞循環調節制御機構の新展開：Heme oxygenase-CO系の役割

Suematsu Makoto, Makino Nobuya, Ishimura Yuzuru

肝胆膵 38 13-18 1999.01

Research paper (scientific journal), Joint Work

Paracrine upregulation of VEGF receptor mRNA in endothelial cells by hypoxia-exposed hep G2 cells

Suzuki H, Seto K, Shinoda Yuichi, Mori M, Ishimura Y, Suematsu M, Ishii H

American Journal of Physiolosy 276 ( 1 ) 92-97 1999.01

Research paper (scientific journal), Joint Work

Paracrine upregulation of VEGF receptor mRNA in endothelial cells by hypoxia exposed hep G2 cells

Suzuki Hidekazu, Suematsu Makoto

American Journal of Physiology 276 ( 1 ) G92-G97 1999.01

Research paper (scientific journal), Joint Work

Microvascular oxidative stress, immune reaction and apoptosis in hypertensives.

Suzuki Hidekazu, Suematsu Makoto, Schmid-schonbein GW.

Clinical Hemorheology and Microcirculation 21 ( 3-4 ) 161-168 1999

Research paper (scientific journal), Joint Work

ガス状メデイエータ（NO, CO)による臓器微小循環機能の制御

Suematsu Makoto, Ishimura Yuzuru

現代医療 30 3117-3123 1998.12

Research paper (scientific journal), Joint Work

Discontinuous total parenteral nutrition prevents postischemic mitochondrial dysfunction in rat liver

Morikawa Nobuyuki, Suematsu Makoto, Goda Nobuhito, Okitsu Taro, Kumamoto Yusuke, Ishimura Yuzuru, Kitajima Masaki

Hepatology 28 ( 5 ) 289-299 1998.11

Research paper (scientific journal), Joint Work

人工酸素運搬体と微小循環機能

Suematsu Makoto, Takeoka Shinji, Tsuchida Eishun, Ishimura Yuzuru

医学のあゆみ 184 ( 10 ) 821-825 1998.10

Research paper (scientific journal), Joint Work

Nitric oxide modulates T-lymphocytes migration in Peyer's patches and villous submucosa of rat small intestine

Hokari R, Miura S, Fujimori H, Tsuzuki Y, Shigematsu T, Higuchi H, Kimura H, Serizawa H, Suematsu M, Yagita H, Granger D N, Ishii H

Gastroenterology 115 ( 3 ) 618-627 1998.09

Research paper (scientific journal), Joint Work

Nitric oxide modulates T-lymphocyte migration in Peyer's patches and villous submucosa of rat small intestine

Hokari Ryota, Miura Soichiro, Suematsu Makoto

Gastroenterology 115 ( 3 ) 618-627 1998.09

Research paper (scientific journal), Joint Work

Kupffer 細胞と肝微小循環：ヘム代謝と血流調節の接点

Suematsu Makoto, Kyoukane Takanori, Wakabayashi Yoshiyuki, Ishimura Yuzuru

病理と臨床 16 ( 9 ) 1089-1094 1998.09

Research paper (scientific journal), Joint Work

Effect of rebamipide on H. pylori-associated gastric mucosal injury in Mongolian gerbils

Suzuki Hidekazu, Suematsu Makoto

Digestive Disease and Sciences 43 ( 9 ) 181S-187S 1998.09

Research paper (scientific journal), Joint Work

Effect of rebamipide on H.pylori-associated gastric mucosal injury in Mongolian gerbils

Suzuki H, Mori M, Kai A, Suzuki M, Suematsu M, Miura S, Ishii H

Digeseive Diseace and Science 43 ( 9 ) 181S-187S 1998.09

Research paper (scientific journal), Joint Work

The heme oxygenaze system : A determinant of oxidative impact on microcirculation

Hayashi Shinobu, Matsumoto Kenji, Kitajima Masaki, Takamiya Rina, Ishimura Yuzuru, Suematsu Makoto

Microcirculation Annual 14 9-10 1998.08

Research paper (scientific journal), Joint Work

Carbon monoxide as an endogenous mediator of bile canalicular contractility in cultured rat hepatocytes

Shinoda Yuichi, Suematsu Makoto, Wakabayashi Yoshiyuki, Goda Nobuhito, Saito Shuji, Yamaguchi Tokio, Ishimura Yuzuru

Hepatology 28 ( 2 ) 612-618 1998.08

Research paper (scientific journal), Joint Work

誘導型ヘムオキシゲナーゼのプレコンディショニングによる微小循環の酸素ストレス耐性獲得と白血球接着の抑制

Hayashi Shinobu, Suematsu Makoto, Matsumoto Kenji, Takamiya Rina, Ishimura Yuzuru, Kitajima Masaki

Journal of Gastrointestinal Research 6 ( 4 ) 319 1998.08

Research paper (scientific journal), Joint Work

Carbon monoxide as a regulator of bile canalicular contractility in cultured rat hepatocytes

Shinoda Yuichi, Suematsu Makoto, Wakabayashi Yoshiyuki, Suzuki Tuneharu, Goda Nobuhito, Saito Shinji, Yamaguchi Tokio, Ishimura Yuzuru

Hepatology 28 ( 2 ) 286-295 1998.08

Research paper (scientific journal), Joint Work

肝小葉内における活性酸素の生成と代謝の特性

Suematsu Makoto, Wakabayashi Yoshiyuki, Makino Nobuya, Ishimura Yuzuru

肝胆膵 36 ( 6 ) 763-769 1998.06

Research paper (scientific journal), Joint Work

Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats

Suzuki H, Delano Fa, Parks Da, Jamshidi N, Granger Dn, Ishii H, Suematu M, Zweifacf Bw, Schmid-schonbein Gw

Proceedings of National Academy of Science USA 95 ( 4 ) 4754-4759 1998.04

Research paper (scientific journal), Joint Work

Behavior of stimulated leukocytes in the pulmonary microcirculation of perfused rat lungs

Aoki Takuya, Yamaguchi Kazuhiro, Suematsu Makoto

Advances in Experimental Medicine and Biology 428 355-362 1998.04

Research paper (scientific journal), Joint Work

Xanthine oxidase activity associated with arterial blood pressure in spontanously hypertensive rats

Suzuki Hidekazu, Delano Fa, Parks Da, Jamshidi N, Granger Dn, Ishii Hiromasa, Suematsu Makoto, Zweifach Bw

Proceedings of National Academy of Sciences in the United State of America 95 ( 8 ) 4754-4759 1998.04

Research paper (scientific journal), Joint Work

人工酸素運搬体と微小循環機能/ガス状血管拡張物質とヘモグロビンの相互作用

Suematsu Makoto, Ishimura Yuzuru

医のあゆみ 184 ( 10 ) 821-826 1998.03

Research paper (scientific journal), Joint Work

ヘムオキシゲナーゼ/一酸化炭素系による臓器機能制御機構

Suematsu Makoto, Wakabayashi Yoshiyuki, Makino Nobuya, Takamiya Rina, Gouda Nobuhito, Ishimura Yuzuru

血管 21 ( 1 ) 19-26 1998.02

Research paper (scientific journal), Joint Work

Differential contribution of various adhesion molecules to leukocyte kinetics in pulmonary microvessels of hyperoxia-exposed rat lungs

Nishio Kazumi, Suzuki Yukio, Aoki Takuya, Suzuki Koichi, Sato Nagato, Naoki Katsuhiko, Miyata Atsushi, Kudo Hiriyasu, Serizawa Hiroshi, Tsumura Harukuni, Morooka S, Ishimura Yuzuru, Suematsu Makoto, Yamaguchi Kazuhiro

Am J Respir Crit Care Med 157 599-609 1998.02

Research paper (scientific journal), Joint Work

Differential contribution of various adhesion molecules to leukocyte kinetics in pulmonary microvessels of hyperoxia-exposed rat lungs

Nishio Kazumi, Yamaguchi Kazuhiro, Suematsu Makoto

Am J Respir Crit Care Med 157 599-609 1998.02

Research paper (scientific journal), Joint Work

ヘムオキシゲナーゼーCO系による臓器機能制御

Suematsu Makoto, Gouda Nobuhito, Suzuki Tsuneharu, Wakabayashi Yoshiyuki, Ishimura Yuzuru

細胞工学 17 ( 2 ) 224-229 1998.02

Research paper (scientific journal), Joint Work

Distribution of heme oxygenase isoforms in rat liver : Topographic basis for carbon monoxide-mediated microvascular relaxation

Goda Nobuhito, Ishimura Tatsumi, Suematsu Makoto

J Clin Invest 101 ( 3 ) 604-612 1998.02

Research paper (scientific journal), Joint Work

一酸化炭素による微小血管機能の制御

Suematsu Makoto, Suzuki Tsuneharu, Makino Shinya, Wakabayashi Yoshiyuki, Kashiwagi Satoshi, Ishimura Yuzuru

組織培養工学 24 ( 1 ) 19-23 1998.01

Research paper (scientific journal), Joint Work

Nitric oxide suppression reversibly attenuates mitochondrial dysfunction and cholestasis in endotoxemic rat liver

Shiomi Masaya, Wakabayashi Yoshiyuki, Shinoda Yuichi, Ishimura Yatsumi, Suematsu Makoto

Hepatology 27 108-115 1998.01

Research paper (scientific journal), Joint Work

Leukocyte kinetics in the microcirculation of bleomycin-induced pulmonary fibrosis in the rat

Sato N, Suzuki Y, Nishio K, Naoki K, Takeshita K, Kudo H, Aoki T, Suzuki K, Tsumura H, Suematsu M, Yamaguchi K

Microcirculation Annual 14 91-92 1998

Research paper (scientific journal), Joint Work

Differential contribution of various adhesion molecules to leukocyte kinetics in pulmonary microvessels of hyperoxia-exposed rat lungs

Nishio K, Sato N, Aoki T, Suzuki K, Naoki K, Kudo H, Miyata A, Suzuki Y, Tsumura H, Serizawa H, Morooka S, Suematsu M, Ishimura Y, Yamaguchi K

American Journal of Respiratory and Critical Care Medicine 157 ( 2 ) 599-609 1998

Research paper (scientific journal), Joint Work

Role of CD18-ICAM-1 in the entrapment of stimulated leukocytes in alveolar capillaries of perfused rat lungs

Aoki Takuya, Suzuki Yukio, Nishio Kazumi, Suzuki Koichi, Miyata Atsushi, Mori Masaaki, Takasugi Tomoaki, Fujita Hirofumi, Tsumura Harukuni, Ishimura Yuzuru, Suematsu Makoto, Yamaguchi Kazuhiro

Am J Physiol (Heart and Circulatory Physiology) 273 H2361-H2371 1997.12

Research paper (scientific journal), Joint Work

Endothelial-derived nitric oxide preserves anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells

Irokawa Masahiro, Suematsu Makoto, Goda Nobuhito, Ishimura Yatsumi, Shinoda Yuichi

Atherosclerosis 135 9-17 1997.12

Research paper (scientific journal), Joint Work

活性化Tリンパ球の腸粘膜におけるmigration動態

Hokari Ryouta, Miura Souichirou, Fujimari Hitoshi, Hirokawa Masahiko, Shigematsu Takeharu, Kimura Hiroyuki, Takeuchi Tetsu, Yoshida Hideo, Higuchi Hajime, Kurose Iwao, Tsuzuki Yoshikazu, Serizawa Hiroshi, Inagaki Hiroyuki, Suematsu Makoto, Ishii Hiromasa

Prog Med 17 1956-1958 1997.10

Research paper (scientific journal), Joint Work

Enhanced lymphocyte interaction in postcapillary venules of Peyer's patches during fat absorption

Miura Soichiro, Suematsu Makoto

Gastroenterology 112 ( 3 ) 813-825 1997.09

Research paper (scientific journal), Joint Work

Leukocyte-endothelial interaction in the rat mesenteric microcirculation during halothane or cevoflurane anesthesia

Morisaki Hiroshi, Suematsu Makoto, Wakabayashi Yoshiyuki, Ishimura Tatsumi, Takeda Junzo

Anesthesiology 87 ( 3 ) 591-598 1997.09

Research paper (scientific journal), Joint Work

Leukocyte-endothelium interaction in the rat mesenteric microcirculation during halothane or sevoflurane anesthesia

Morisaki Hiroshi, Suematsu Makoto, Wakabayashi Y, Moro-oka S, Fukushima Kazuaki, Ishimura Yuzuru, Takeda Junzo

Anesthesiology 87 ( 3 ) 591-598 1997.09

Research paper (scientific journal), Joint Work

Role of CD18-ICAM-1 in the entrapment of stimulated leukocytes in alveolar capillaries of perfused rat lungs

Aoki Takuya, Suematsu Makoto, Ishimura Yuzuru, Yamaguchi Kazuhiro

Am J Physiol (Heart Circ Physiol) 273 H2361-H2371 1997.08

Research paper (scientific journal), Joint Work

Migration of activated T lymphocytes to hepatic sinusoid

Fujimori Hitoshi, Miura Soichiro, Hokari Ryota, Hirokawa Masahiko, Kimura Hiroyuki, Takeuchi Tetsu, Yoshida Hidehiko, Higuchi Hajime, Kurose Iwao, Suzuki Hidekazu, Tsuzuki Yoshikazu, Serizawa Hiroshi, Suematsu Makoto, Ishii Hiromasa

Microcirculation Annual 1997 165-166 1997.07

Research paper (scientific journal), Joint Work

In vivo constitutive expression of ICAM-1 in the rat microcirculation

Iigou Yutaka, Suematsu Makoto, Wakabayashi Yoshiyuki, Ishimura Y

Am J Physiol (Heart Circ Physiol) 273 H138-H147 1997.07

Research paper (scientific journal), Joint Work

臓器毛細血管機能を見る--低分子モノオキシドによる臓器機能制御機構

Suematsu Makoto, Wakabayashi Yoshiyuki, Ishimura Yuzuru

蛋核酵 42 ( 7 ) 1075-1079 1997.07

Research paper (scientific journal), Joint Work

Enhanced lymphocyte interaction in postcapillary venules of Peyer's patches during fat absorption in rats

Tsuzuki Yoshikazu, Miura Soichiro, Kurose Iwao, Suematsu Makoto, Higuchi Hajime, Shigematsu Takeharu, Kimura Hiroyuki, Serizawa Hiroshi, Hokari Ryota, Akiba Yasutada, Yagita Hideo, Okumura Ko, Tso Patrick, Granger D Neil, Ishii Hiromasa

Gastroenterology 112 ( 3 ) 813-825 1997.05

Research paper (scientific journal), Joint Work

Electrophysiological characterization of cultured hepatic stellate cells in rats

Kashiwagi Satoshi, Suematsu Makoto, Wakabayashi Yoshiyuki, Kawada Norihumi, Tachibana Masaaki, Koizumi Amane, Inoue Masayasu, Ishimura Yuzuru, Kaneko Akimichi

Am J Physiol 272 742-750 1997.05

Research paper (scientific journal), Joint Work

Endogenous carbon monoxide suppression stimulates bile acid-dependent biliary transport in perfused rat liver

Sano Tsuyoshi, Suematsu Makoto, Wakabayashi Yoshiyuki, Shinoda Yuichi, Ishimura Yuzuru

Am J Physiol (Gastrointest Liver Physiol) 272 G1268-G1275 1997.05

Research paper (scientific journal), Joint Work

CO(一酸化炭素):新しいガス状血管作動物質

Suematsu Makoto, Ishimura Yuzuru

医のあゆみ 181 ( 9 ) 612-612 1997.05

Research paper (scientific journal), Joint Work

Electrophysiological characterization of cultured hepatic stellate cells in rats

Kashiwagi Satoshi, Suematsu Makoto, Wakabayashi Yoshiyuki, Ishimura Yuzuru

Am J Physiol (Gastrointest Liver Physiol) 272 G742-G750 1997.04

Research paper (scientific journal), Joint Work

Electrophysiological characterization of cultured hepatic stellate cells in rats

Kashiwagi Satoshi, Suematsu Makoto, Wakabayashi Yoshiyuki, Kawada Norifumi, Tachibana Masaaki, Koizumi Amane, Inoue Masayasu, Ishimura Yuzuru, Kaneko Akimichi

Am J Physiol 272 G742-G750 1997.04

Research paper (scientific journal), Joint Work

高濃度酸素暴露の肺微小循環系に及ぼす影響--共焦点レーザー顕微鏡を用いた検討--

Suzuki Yukio, Aoki Takuya, Suzuki Kohichi, Miyata Atsushi, Nishio Kazumi, Tsumura Harukuni, Takasugi Tomoaki, Mori Masaoki, Suematsu Makoto, Yamaguchi Kazuhiro

日胸疾会誌 35 ( 2 ) 137-143 1997.01

Research paper (scientific journal), Joint Work

Vasoactive intestinal peptide modulates T lymphocyte migration in Peyer's patches of rat small intestine

Miura Soichiro, Serizawa Hiroshi, Tsuzuki Yoshikazu, Kurose Iwao, Suematsu Makoto, Higuchi Hajime, Shigematsu T, Hokari Ryouta, Hirokawa M, Kimura H, Ishii H

Am J Physiol 272 ( 35 ) G92-G99 1997.01

Research paper (scientific journal), Joint Work

Bile-acid-induced depolarization of mitochondrial membrane potential preceding cell injury in cultured gastric mucosal cells

Miura M, Fukumura D, Shiozaki H, Suzuki M, Kurose I, Suematsu M, Tsuchiya M, Ishii H

J Gastroenterol Hepatol 10 ( 6 ) 621-626 1996.11

Research paper (scientific journal), Joint Work

Endogenous nitric oxide production modulates mitochondrion-dependent oxidative stress in cultured human placental trophoblastic cells

Goda Nobuhito, Suematsu Makoto, Mukai Makio, Kiyokawa Kaoru, Natori Michiya, Nozawa Shiro, Ishimura Yuzuru

Am J Physiol 272 ( 40 ) H1893-H1899 1996.11

Research paper (scientific journal), Joint Work

Modulation of mitochondorion-mediated oxidative stress by nitric oxide in human placental trophoblastic cells

Goda Nobuhito, Suematsu Makoto, Mukai Makio, Kiyokawa Kaoru, Natori Michiya, Nozawa Shiro, Ishimura Yuzuru

Am J Physiol 271 H1893-H1899 1996.11

Research paper (scientific journal), Joint Work

Omeprazole attenuates oxygen-derived free radical production from human neutrophils

Suzuki Masayuki, Mori Mikiji, Miura Soichiro, Suematsu Makoto, Fukumura Dai, Kimura Hiroyuki, Ishii Hiromasa

Free Rad Biol Med 21 ( 5 ) 727-731 1996.11

Research paper (scientific journal), Joint Work

Subthreshold UV Light-induced peroxide formation in cultured corneal epithelial cells

Shimmura Shigeto, Suematsu Makoto, Shimoyama M, Tsubota Kazuo, Oguchi Y, Ishimura Yuzuru

Exp Eye Res 63 ( 1 ) 519-526 1996.11

Research paper (scientific journal), Joint Work

微小循環における接着分子

Suzuki Hidekazu, Mori Mikiji, Suematsu Makoto, Tsuchiya Masaharu, Ishii Hiromasa

現代医療 28 ( 10 ) 2671-2676 1996.10

Research paper (scientific journal), Joint Work

Gaseous monoxides: A novel regulator of microvascular function in the liver

Suematsu Makoto, Wakabayashi Yoshiyuki, Ishimura Yuzuru

Cardiovasc Res 32 ( 1 ) 679-686 1996.10

Research paper (scientific journal), Joint Work

Omeprazole attenuates oxygen-derived free radical production from human neutrophils

Suzuki Masayuki, Mori Mikiji, Miura Soichiro, Suematsu Makoto, Fukumura Dai, Kimura Hajime, Ishii Hiromasa

Free Rad Biol Med 21 ( 5 ) 727-731 1996.10

Research paper (scientific journal), Joint Work

Endotoxin stimulates lymphocyte-endothelial interactions in rat intestinal Peyer's patches and villus mucosa

Miura Soichiro, Tsuzuki Yoshikazu, Kurose Iwao, Suematsu Makoto, Shigematsu Takeharu, Kimura Hiroyuki, Higuchi Hajime, Serizawa Hiroshi, Yagita Hideo, Okumura Ko, Granger DN, Ishii Hiromasa

Am J Physiol 271 ( Gastrointest Liver Physiol 34(2) ) G282-G292 1996.10

Research paper (scientific journal), Joint Work

Bile-acid-induced depolarization of mitochondrial membrane potential preceding cell injury in cultured gastric mucosal cells

Miura Soichiro, Fukumura Dai, Shiozaki Hiroshi, Suzuki Masayuki, Kurose Iwao, Suematsu Makoto, Tsuchiya Masaharu, Ishii H

J Gastroenterol Hepatol 10 621-626 1996.07

Research paper (scientific journal), Joint Work

Taurocholate is necessary for directional excretion bilirubin into bile in the perfused rat liver

Yamaguchi Tokio, Wakabayashi Yoshiyuki, Tanaka Makiko, Sano Tsuyoshi, Ishikawa Hiromi, Nakajima Hiroshi, Suematsu Makoto, Ishimura Yuzuru

Am J Physiol 270 ( 33 ) G1028-G1032 1996.06

Research paper (scientific journal), Joint Work

Vasoactive intestinal peptide modulates T lymphocyte migration in Peyer's patches of rat small intestine

Miura Soichiro, Serizawa Hiroshi, Tsuzuki Yoshikazu, Kurose Iwao, Suematsu Makoto, Higuchi Hajime, Shigematsu Takeharu, Hokari Ryota, Hirokawa Masahiko, Kimura Hiroyuki, Ishii Hiromasa

Am J Physiol 272 ( Gastrointest Liver Physiol 35 ) G92-G99 1996.05

Research paper (scientific journal), Joint Work

Oxygen-derived metabolites and hepatic microciruclation

Suematsu Makoto, Sano Tsuyoshi, Ishimura Yuzuru

J Surg Hep Bil Pancr Surg 3 ( 1 ) 154-160 1996.04

Research paper (scientific journal), Joint Work

Alpha4 integrin plays a critical role in early stages of T lymphocyte migration in Peyer's patches

Tsuzuki Y, Miura S, Suematsu M, Kurose I, Shigematsu T, Kimura H, Higuchi H, Serizawa H, Yagita H, Okumura K, Ishii H

Int Immunol 8 ( 3 ) 287-295 1996.03

Research paper (scientific journal), Joint Work

脂肪吸収に伴うリンパ球接着分子発現とPeyer板血管内皮への接着反応の変化

Tsuzuki Yoshikazu

消化と吸収 18 ( 2 ) 27-31 1996.01

Research paper (scientific journal), Joint Work

Modulation of mitochondrion-mediated oxidative stress by nitric oxide human placental trophoblastic cells

Goda Nobuhito, Suematsu Makoto, Mukai Makio, Kiyokawa Kaoru, Natori Michiya, Nozawa Shiroh, Ishimura Yuzuru

Am J Physiol 271 1893-1899 1996

Research paper (scientific journal), Joint Work

ラット肝冷保存再灌流障害におけるミトコンドリア機能と胆汁産生能の検討

Kumamoto Yusuke, Suematsu Makoto, Shimazu Motohide, Wakabayashi Go, Shirasugi Nozomu, Kawachi Shigeyuki, Karahashi Tsuyoshi, Yoshida Masashi, Ishimura Yuzuru, Kitajima Masaki

Cyto-protect Biology 13 77-79 1995.12

Research paper (scientific journal), Joint Work

Bile acid-induced depolarization of mitochondrial membrane potential preceding cell injury in cultured gastric mucosal cells

Miura S, Fukumura D, Shiozaki H, Suzuki M, Kurose I, Suematsu M, Tsuchiya M, Ishii H

J Gastroenterol Hepatol 10 ( 6 ) 621-626 1995.11

Research paper (scientific journal), Joint Work

An endogenous modulator of sinusoidal tone in the perfused rat liver

Suematsu M, Goda N, Sano T, Kashiwagi S, Egawa T, Shinoda Y, Ishimura Y

J Clin Invest 96 ( 5 ) 2431-2437 1995.11

Research paper (scientific journal), Joint Work

Blood cell dynamics in pulmonary microcirculation・・Influence of oxygen toxicity・・

Aoki T, Suzuki Y, Suzuki K, Miyata A, Takasugi T, Oyamada K, Soejima K, Fujita H, Suematsu M, Yamaguchi K

Microcirc Annual 11 ( 1 ) 135-136 1995.11

Research paper (scientific journal), Joint Work

Impairment of selectin-mediated leukocyte adhesion to venular endothelium in spontaneously hypertensive rats

Suematsu M, Suzuki H, Tamatani T, Iigou Y, Delano FA, Miyasaka M, Forrest MJ, Kannagi R, Zweifach BW, Ishimura Y, Schmid-Scho^^ィenbein GW

J. Clin. Invest. 96 ( 4 ) 2009-2016 1995.10

Research paper (scientific journal), Joint Work

Recoginition of consensus carbohydrate structure in ligands for selectins by novel antibody against sialyl Lewis X

Tamatani T, Suematsu M, Tezuka K, Hanazawa N, Tsuji T, Ishimura Y

Am J Physiol 269 ( 4 ) H1282-H1287 1995.10

Research paper (scientific journal), Joint Work

Intravital demonstration of sequential migration process of lymphocyte subpopulations in rat・　Peyer's patches

Miura S, Tsuzuki Y, Fukumura D, Serizawa H, Suematsu M, Kurose I, Imaeda H, Kimura H, Nagata H, Tsuchiya M, Ishii H

Gastroenterolgy 109 ( 4 ) 1113-1119 1995.10

Research paper (scientific journal), Joint Work

Impairment of selectin-mediated leukocyte adhesion to venular endogenous in spontaneously hypertensive rats

Suematsu M, Suzuki H, DeLano FA, Tamatani T, Miyasaka M, Forrest M, Zweifach BW, Ishimura Y, Schmid-Schoenbein GW

J Clin Invest 96 ( 4 ) 2009-2016 1995.10

Research paper (scientific journal), Joint Work

微小循環障害

Suzuki Hidekazu, Miyai Katsumi, Suematsu Makoto, Tsuchiya Masaharu, Ishii Hiromasa

血栓と循環 3 ( 3 ) 257-263 1995.09

Research paper (scientific journal), Joint Work

肝微小循環障害時のreductive stressの解析・・Prostaglandin E1（PGE1）の効果・・

Suzuki Hidekazu, Suematsu Makoto, Kato Shinzo, Mori Mikiji, Miura Souichirou, Tsuchiya Masaharu, Ishii Hiromasa

過酸化脂質研究 18 ( 2 ) 148-151 1995.08

Research paper (scientific journal), Joint Work

微小循環障害とフリーラジカル

Suzuki Hidekazu

活性酸素，フリーラジカル 6 ( 2 ) 158-165 1995.07

Research paper (scientific journal), Joint Work

血管内皮細胞におけるoxidative stressの生体内観察・・一酸化窒素に関連して・・

Suzuki Hidekazu

GI Res 3 ( 1 ) 53-58 1995.06

Research paper (scientific journal), Joint Work

内皮―白血球相互反応からみた移植肝不全の病態とその予防

Shimazu Motohide, Wakabayashi Go, Tanabe Minoru, Shirasugi Nozomu, Kawachi Shigeyuki, Kumamoto Yusuke, Yoshida Masashi, Karahashi Tsuyoshi, Suematsu Makoto, Kitajima Masaki

脈管学 35 ( 5 ) 285-289 1995.05

Research paper (scientific journal), Joint Work

Alteration in mitochondrial re-energization during cold storage followed by reperfusion in the rat perfused liver

Kumamoto Y, Suematsu M, Shimazu M, Wakabayashi G, Sano T, Ishimura Y, Kitajima M

Organ Microcirculation 11 83-84 1995

Research paper (scientific journal), Joint Work

Microcirculation ・ Past, present and future in Japan・・20th Anniversary of our Microcirculatory Society・・

Tsuchiya M, Miura S, Akiba Y, Suematsu M

Microcirc Annual 1995 11 1-7 1995

Research paper (scientific journal), Joint Work

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