研究者詳細 - 末松　誠

論文 - 末松　誠

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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年12月

© 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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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年12月

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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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年12月

© 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年12月

© 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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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年09月

© 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年09月

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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年09月

© 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年09月

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年08月

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年07月

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年06月

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年04月

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年04月

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年01月

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年01月

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年

© 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年

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年12月

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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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年12月

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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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年12月

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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