Publications by authors named "Yuki Sugiura"

126 Publications

Restoring metabolism of myeloid cells reverses cognitive decline in ageing.

Nature 2021 Feb 20;590(7844):122-128. Epub 2021 Jan 20.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease. Systemically, circulating pro-inflammatory factors can promote cognitive decline, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E (PGE), a major modulator of inflammation. In ageing macrophages and microglia, PGE signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
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http://dx.doi.org/10.1038/s41586-020-03160-0DOI Listing
February 2021

Distribution of inhaled volatile β-caryophyllene and dynamic changes of liver metabolites in mice.

Sci Rep 2021 Jan 18;11(1):1728. Epub 2021 Jan 18.

Department of Applied Biological Chemistry, Graduate School of Agriculture, Kindai University, 204-3327 Nakamachi, Nara, Nara, 631-8505, Japan.

β-caryophyllene (BCP), an essential oil component of many herbs and spices, has various biological activities as a functional food factor. A distinct feature of BCP is its volatile double-ring sesquiterpene structure. Orally administered BCP is reportedly detected in its intact form in mice serum; however, the distribution of inhaled volatile BCP throughout the body remains unknown. This study aimed to estimate the distribution properties of inhaled volatile BCP and to investigate its effects on metabolism. After mice were exposed to volatile BCP, it was detected in the lung, olfactory bulb, brain, serum, heart, liver, kidney, epididymal fat, and brown adipose tissue. BCP was further detected in the brain, liver, and brown adipose tissue 24 h after exposure. Metabolites related to glutathione metabolism were significantly altered in the liver. These results suggest that inhaled volatile BCP is widely distributed in murine tissues and affects the dynamics of metabolites in the liver.
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http://dx.doi.org/10.1038/s41598-021-81181-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813867PMC
January 2021

Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders.

Science 2021 01;371(6526):265-270

Division of Cancer Cell Biology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 () as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.
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http://dx.doi.org/10.1126/science.abb5916DOI Listing
January 2021

Adolescent Kawasaki disease shock syndrome with inflammatory cell infiltration into the myocardium: a case report.

Eur Heart J Case Rep 2020 Oct 9;4(5):1-7. Epub 2020 Sep 9.

Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan.

Background: Kawasaki disease (KD) is a self-limiting form of systemic vasculitis. KD usually occurs in infants and young children and is rarely seen in adolescents. On rare occasions, KD is accompanied with reduced organ perfusion due to systolic hypotension, a condition known as Kawasaki disease shock syndrome (KDSS). The multifactorial causes of KDSS may include intensive vasculitis with capillary leak, myocardial dysfunction, and release of proinflammatory cytokines. However, the mechanisms underlying the pathophysiology of KDSS have not been fully elucidated.

Case Summary: A febrile 17-year-old male with cervical lymphadenopathy developed extreme shock with rapid cardiac dysfunction and reduced organ perfusion. Electrocardiogram revealed ST elevation in the precordial leads and increased serum levels of cardiac enzyme levels. Endomyocardial biopsy at the acute phase revealed CD3, CD4 or CD8, and CD20 lymphocytes and CD68 macrophages within infiltrates in the myocardium with mild interstitial fibrosis. He was treated with intravenous immunoglobulin (IVIG) and followed by glucocorticoids with mechanical circulatory support. His cardiac function recovered rapidly with no apparent adverse effects.

Discussion: Our results suggest that KDSS may be a form of myocarditis, a condition in which inflammatory cells infiltrate the myocardium. Early immunosuppressive therapy, including IVIG and glucocorticoid therapy, may limit the severity of disease and improve the prognosis. As shown by this case, an accurate diagnosis of KD and KDSS will lead to early intervention and improved prognosis even among those in an older cohort.
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http://dx.doi.org/10.1093/ehjcr/ytaa304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649480PMC
October 2020

Aesthetic Silver-Doped Octacalcium Phosphate Powders Exhibiting Both Contact Antibacterial Ability and Low Cytotoxicity.

ACS Omega 2020 Sep 14;5(38):24434-24444. Epub 2020 Sep 14.

Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 2217-14, Hayashi-cho, Takamatsu 761-0895, Kagawa, Japan.

Since the introduction of biomaterials, infection has been a serious problem in clinical operations. Although several studies have introduced hybrid materials of calcium phosphate and Ag nanoparticles (NPs) that exhibit antibacterial activity, released Ag ions and Ag NPs are highly cytotoxic and the materials require complex fabrication techniques such as laser irradiation. In this study, we introduce a simple one-pot synthesis method based on crystal-engineering techniques to prepare Ag-substituted octacalcium phosphate (OCP-Ag) powder that simultaneously exhibits antibacterial activity, little change in color, and low cytotoxicity, thereby overcoming the shortcomings of calcium phosphate as a biomaterial. We used AgNO-containing (NH)HPO aqueous solutions as reaction solutions in which Ag forms soluble complex [Ag(NH)] ions that are stable at Ag concentrations less than ∼30 mmol/L. Hydrolysis of soluble calcium phosphate in this solution led to pure OCP-Ag when the Ag concentration was less than ∼30 mmol/L. Crystallographic analysis showed that Ag substituted at the 5 PO-conjugated sites and was uniformly distributed. When the concentration of Ag in the reaction solution was varied, the Ag content of the OCP-Ag could be controlled. The obtained OCP-Ag exhibited little color change or Ag release when immersed in various media; however, it exhibited contact antibacterial ability toward resident oral bacteria. The prepared OCP-Ag showed no substantial cytotoxicity toward undifferentiated and differentiated MC3T3-E1 cells in assays. Notably, when the Ag content in OCP-Ag was optimized (Ag: ∼1 at %), it simultaneously exhibited contact antibacterial ability, little color change, and low cytotoxicity.
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http://dx.doi.org/10.1021/acsomega.0c02868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528307PMC
September 2020

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

PLoS Biol 2020 09 29;18(9):e3000813. Epub 2020 Sep 29.

Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.

Short-chain fatty acids (SCFAs) produced by gastrointestinal microbiota regulate immune responses, but host molecular mechanisms remain unknown. Unbiased screening using SCFA-conjugated affinity nanobeads identified apoptosis-associated speck-like protein (ASC), an adaptor protein of inflammasome complex, as a noncanonical SCFA receptor besides GPRs. SCFAs promoted inflammasome activation in macrophages by binding to its ASC PYRIN domain. Activated inflammasome suppressed survival of Salmonella enterica serovar Typhimurium (S. Typhimurium) in macrophages by pyroptosis and facilitated neutrophil recruitment to promote bacterial elimination and thus inhibit systemic dissemination in the host. Administration of SCFAs or dietary fibers, which are fermented to SCFAs by gut bacteria, significantly prolonged the survival of S. Typhimurium-infected mice through ASC-mediated inflammasome activation. SCFAs penetrated into the inflammatory region of the infected gut mucosa to protect against infection. This study provided evidence that SCFAs suppress Salmonella infection via inflammasome activation, shedding new light on the therapeutic activity of dietary fiber.
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http://dx.doi.org/10.1371/journal.pbio.3000813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524008PMC
September 2020

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

Commun Biol 2020 Sep 4;3(1):479. Epub 2020 Sep 4.

Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

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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http://dx.doi.org/10.1038/s42003-020-01202-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473863PMC
September 2020

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

iScience 2020 Jul 31;23(9):101426. Epub 2020 Jul 31.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Asagi Saito, Ibaraki-city, Osaka 567-0085, Japan; Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Kobe-city, Hyogo 650-0017, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita-city, Osaka 565-0871, Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Graduate School of Medicine and Graduate School of Dentistry, Osaka University, Yamadaoka, Suita-city, Osaka 565-0871, Japan. Electronic address:

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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http://dx.doi.org/10.1016/j.isci.2020.101426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452312PMC
July 2020

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

J Exp Med 2020 11;217(11)

Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

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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http://dx.doi.org/10.1084/jem.20192230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596812PMC
November 2020

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

Front Immunol 2020 21;11:1405. Epub 2020 Jul 21.

Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

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 and sensitization of tumor cells 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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http://dx.doi.org/10.3389/fimmu.2020.01405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385076PMC
July 2020

Role of cytotoxic T lymphocytes and interferon-γ in coronavirus infection: Lessons from murine coronavirus infections in mice.

J Vet Med Sci 2020 Oct 5;82(10):1410-1414. Epub 2020 Aug 5.

Laboratory of Biomedical Science, Department of Veterinary Medical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyou-ku, Tokyo 113-8657, Japan.

Murine coronavirus (CoV) is a beta-CoV that infects mice by binding to carcinoembryonic antigen-related cell adhesion molecule 1. Intraperitoneal infection with the murine CoV strain JHM (JHMV) induces acute mild hepatitis in mice. While both innate and acquired immune responses play a significant role in the protection against murine CoV infection in mice, CD8 cytotoxic T lymphocytes (CTLs) and interferon-γ are essential for viral clearance in JHMV-induced hepatitis. In addition, CoVs are characterized by high diversity, caused by mutations, recombination, and gene gain/loss. 25V16G is an immune-escape JHMV variant, which lacks a dominant CTL epitope. By evading immune responses, 25V16G establishes persistent infections, leading to granulomatous serositis in interferon-γ-deficient mice. These examples of CoV-associated pathogenesis in mice might provide useful information on other CoV infections, including coronavirus disease 2019 (COVID-19).
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http://dx.doi.org/10.1292/jvms.20-0313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653326PMC
October 2020

[Monoamine Mapping Using Mass Spectrometry Identified New Monoamine-rich Brain Nuclei].

Yakugaku Zasshi 2020 ;140(8):979-983

Department of Biochemistry, Keio University School of Medicine.

Monoamine neurotransmitters are released by specialized neurons that regulate behavioral and cognitive functions. Although localization of monoaminergic neurons in the brain is well known, the distribution, concentration, and kinetics of monoamines remain unclear. We used mass spectrometry imaging (MSI) for simultaneous and quantitative imaging of endogenous monoamines to generate a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels. We observed several nuclei rich in both 5-HT and a catecholamine (DA or NE). Additionally, we analyzed de novo monoamine synthesis or fluctuations in those nuclei. We propose that MSI is a useful tool to gain deeper understanding of associations among the localization, levels, and turnover of monoamines in different brain areas and their role in inducing behavioral changes.
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http://dx.doi.org/10.1248/yakushi.20-00012-3DOI Listing
September 2020

Leukotriene B receptor 1 exacerbates inflammation following myocardial infarction.

FASEB J 2020 06 8;34(6):8749-8763. Epub 2020 May 8.

Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Leukotriene B receptor 1 (BLT1), a high-affinity G-protein-coupled receptor for leukotriene B4 (LTB ), is expressed on various inflammatory cells and plays critical roles in several inflammatory diseases. In myocardial infarction (MI), various inflammatory cells are known to be recruited to the infarcted area, but the function of BLT1 in MI is poorly understood. Here, we investigated the role of BLT1 in MI and the therapeutic effect of a BLT1 antagonist, ONO-4057, on MI. Mice with infarcted hearts showed increased BLT1 expression and LTB levels. BLT1-knockout mice with infarcted hearts exhibited attenuated leukocyte infiltration, proinflammatory cytokine production, and cell death, which led to reduced mortality and improved cardiac function after MI. Bone-marrow transplantation studies showed that BLT1 expressed on bone marrow-derived cells was responsible for the exacerbation of inflammation in infarcted hearts. Furthermore, ONO-4057 administration attenuated the inflammatory responses in hearts surgically treated for MI, which resulted in reduced mortality and improved cardiac function after MI. Our study demonstrated that BLT1 contributes to excessive inflammation after MI and could represent a new therapeutic target for MI.
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http://dx.doi.org/10.1096/fj.202000041RDOI Listing
June 2020

Pathological changes of the myocardium in reworsening of anthracycline-induced cardiomyopathy after explant of a left ventricular assist device.

Nagoya J Med Sci 2020 Feb;82(1):129-134

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

We herein report the long-term changes in cardiac function and pathological findings after successful explantation of a left ventricular assist device in a 42-year-old patient with anthracycline-induced cardiomyopathy with reworsening heart failure. Endomyocardial biopsy samples revealed that the cardiomyocyte diameter decreased and collagen volume fraction increased just after left ventricular assist device explantation. The collagen volume fraction decreased after 6 months, despite preserved systolic function. At 5 years after left ventricular assist device explantation, the systolic function markedly decreased and cardiomyocyte diameter increased. Pathological changes of the myocardium may enable the identification of cardiac dysfunction prior to echocardiographic changes in patients with reworsening heart failure after left ventricular assist device explantation.
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http://dx.doi.org/10.18999/nagjms.82.1.129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103868PMC
February 2020

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

Biol Open 2020 04 7;9(4). Epub 2020 Apr 7.

Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan

The teleost fish, medaka (), 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 , a critical gene for male development, was suppressed by starvation, and a (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 under starvation.
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http://dx.doi.org/10.1242/bio.050054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132775PMC
April 2020

Comparative histological studies on properties of polysaccharides secreted by vomeronasal glands of eight Laurasiatheria species.

Acta Histochem 2020 Apr 18;122(3):151515. Epub 2020 Feb 18.

Department of Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11 Inada-cho, Obihiro, Hokkaido, 080-8555, Japan; Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, 232-3 Yomogida, Naruko-onsen, Osaki, Miyagi, 989-6711, Japan.

Most mammalian species have a vomeronasal organ that detects specific chemical substances, such as pheromones. Mucous fluid covering the vomeronasal sensory epithelium is secreted by vomeronasal glands, and the properties of these fluids have been suggested to be involved in chemical detection. Histological studies using periodic acid-Schiff (PAS) and Alcian blue pH 2.5 (AB) stains, which respectively detect natural and acidic polysaccharides, have suggested variations in the nature of the vomeronasal glands among species. Here, we investigated the responsivity of the vomeronasal glands to PAS and AB stains in eight Laurasiatheria species. All species studied herein possessed vomeronasal glands that stained positive for PAS, like other many reported species. The vomeronasal glands of dogs and minks - like rodents, were AB-negative, whereas those of cows, goats, sika deer, musk shrews and two bat species were positive. Considering the present findings and previous reports, the vomeronasal glands in most of Laurasiatheria species appear to be fundamentally abundant in acidic polysaccharides, whereas those in carnivores essentially contains neutral polysaccharides.
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http://dx.doi.org/10.1016/j.acthis.2020.151515DOI Listing
April 2020

In situ imaging of monoamine localization and dynamics.

Pharmacol Ther 2020 04 10;208:107478. Epub 2020 Jan 10.

Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address:

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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http://dx.doi.org/10.1016/j.pharmthera.2020.107478DOI Listing
April 2020

Biological responses of MC3T3-E1 on calcium carbonate coatings fabricated by hydrothermal reaction on titanium.

Biomed Mater 2020 03 4;15(3):035004. Epub 2020 Mar 4.

Department of Biomaterials, Faculty of Dental Science, Kyushu University, Japan. School of Materials Science and Engineering, Hanoi University of Science and Engineering, Vietnam.

Titainum (Ti) implants have been successfully used in orthopaedic and dental surgery. However, poor early bone tissue integration is still a common cause of implant failure. This could be modulated by improving the material bonding or adhesion directly to the bone by surface roughening and/or a bioresorbable and osteoconductive coating. In this study, we report on the biological behaviours of the Ti substrate with modified surface roughness and/or a calcium carbonate (CaCO) coating. The roughened Ti surface was prepared using an acid etching reaction, and the CaCO coating on the substrates was synthesized by the hydrothermal treatment of Ti in calcium citrate complexes. This study demonstrates that surface roughening of Ti alone does not improve the biological response of the MC3T3-E1 cells, but a CaCO coating on the smooth Ti surface increases cell responses, and these effects are further enhanced by the combination of coating a roughened Ti surface with CaCO. The larger the cell area, the greater the cell proliferation and increased bone-like nodule formation were observed on the CaCO coating of the roughened Ti surface. This observation was also supported by a higher ALP value. The cell behaviours found in the current study further support the development of CaCO coatings towards clinical application.
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http://dx.doi.org/10.1088/1748-605X/ab6939DOI Listing
March 2020

Loss of autophagy impairs physiological steatosis by accumulation of NCoR1.

Life Sci Alliance 2020 01 26;3(1). Epub 2019 Dec 26.

Department of Physiology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan

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 , 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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http://dx.doi.org/10.26508/lsa.201900513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932742PMC
January 2020

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

iScience 2019 Oct 27;20:359-372. Epub 2019 Sep 27.

Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. Electronic address:

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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http://dx.doi.org/10.1016/j.isci.2019.09.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818351PMC
October 2019

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

J Pharm Biomed Anal 2020 Jan 4;178:112912. Epub 2019 Oct 4.

Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba, 278-8510, Japan. Electronic address:

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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http://dx.doi.org/10.1016/j.jpba.2019.112912DOI Listing
January 2020

Identification of Initial Colonizing Bacteria in Dental Plaques from Young Adults Using Full-Length 16S rRNA Gene Sequencing.

mSystems 2019 Sep 3;4(5). Epub 2019 Sep 3.

Section of Preventive and Public Health Dentistry, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka, Japan

Development of dental plaque begins with the adhesion of salivary bacteria to the acquired pellicle covering the tooth surface. In this study, we collected dental plaque formed on hydroxyapatite disks for 6 h from 74 young adults and identified initial colonizing taxa based on full-length 16S rRNA gene sequences. A long-read, single-molecule sequencer, PacBio Sequel, provided 100,109 high-quality full-length 16S rRNA gene sequence reads from the early plaque microbiota, which were assigned to 90 oral bacterial taxa. The microbiota obtained from every individual mostly comprised the 21 predominant taxa with the maximum relative abundance of over 10% (95.8 ± 6.2%, mean ± SD), which included species as well as nonstreptococcal species. A hierarchical cluster analysis of their relative abundance distribution suggested three major patterns of microbiota compositions: a / sp. HMT-423-dominant profile, a //-dominant profile, and a complex profile with high diversity. No notable variations in the community structures were associated with the dental caries status, although the total bacterial amounts were larger in the subjects with a high number of caries-experienced teeth (≥8) than in those with no or a low number of caries-experienced teeth. Our results revealed the bacterial taxa primarily involved in early plaque formation on hydroxyapatite disks in young adults. Selective attachment of salivary bacteria to the tooth surface is an initial and repetitive phase in dental plaque development. We employed full-length 16S rRNA gene sequence analysis with a high taxonomic resolution using a third-generation sequencer, PacBio Sequel, to determine the bacterial composition during early plaque formation in 74 young adults accurately and in detail. The results revealed 21 bacterial taxa primarily involved in early plaque formation on hydroxyapatite disks in young adults, which include several streptococcal species as well as nonstreptococcal species, such as // and Given that no notable variations in the microbiota composition were associated with the dental caries status, the maturation process, rather than the specific bacterial species that are the initial colonizers, is likely to play an important role in the development of dysbiotic microbiota associated with dental caries.
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http://dx.doi.org/10.1128/mSystems.00360-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722423PMC
September 2019

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

Nat Cell Biol 2019 08 1;21(8):1003-1014. Epub 2019 Aug 1.

Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

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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http://dx.doi.org/10.1038/s41556-019-0363-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686884PMC
August 2019

leaf extract facilitates oligodendrocyte development.

R Soc Open Sci 2019 Jun 26;6(6):190266. Epub 2019 Jun 26.

Department of Integrative Biosciences, University of Brain Education, Cheonan 31228, Republic of Korea.

Treatment of multiple sclerosis is effective when anti-inflammatory, neuroprotective and regenerative strategies are combined. () has anti-inflammatory, anti-oxidative properties, which may be beneficial for multiple sclerosis. However, there have been no reports on the effects of on myelination, which is critical for regenerative processes. To know whether benefits myelination, we checked differentiation and myelination of oligodendrocytes (OLs) in various primary culture systems treated with leaf EtOH extracts or control. extracts increased the OL membrane size in the mixed glial and pure OL precursor cell (OPC) cultures and changed OL-lineage gene expression patterns in the OPC cultures. Western blot analysis of -treated OPC cultures showed upregulation of MBP and phosphorylation of ERK1/2. In myelinating cocultures, extracts enhanced OL differentiation, followed by increased axonal contacts and myelin gene upregulations such as Myrf, CNP and PLP. Phytochemical analysis by LC-MS/MS identified multiple components from extracts, containing bioactive molecules such as quercetin, cannabidiol, etc. Our results suggest extracts enhance OL differentiation, followed by an increase in membrane size and axonal contacts, thereby indicating enhanced myelination. In addition, we found that extracts contain multiple bioactive components, warranting further studies in relation to finding effective components for enhancing myelination.
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http://dx.doi.org/10.1098/rsos.190266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599778PMC
June 2019

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

Neurochem Int 2019 10 21;129:104494. Epub 2019 Jun 21.

Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan. Electronic address:

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 (CN-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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http://dx.doi.org/10.1016/j.neuint.2019.104494DOI Listing
October 2019

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

Anal Chem 2019 07 26;91(14):8918-8925. Epub 2019 Jun 26.

Department of Biotechnology, Graduate School of Engineering , Osaka University , 2-1 Yamadaoka , Suita , Osaka 565-0871 , Japan.

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 (MS) 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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http://dx.doi.org/10.1021/acs.analchem.9b00619DOI Listing
July 2019

Prognostic impact of mitral L-wave in patients with hypertrophic cardiomyopathy without risk factors for sudden cardiac death.

Heart Vessels 2019 Dec 31;34(12):2002-2010. Epub 2019 May 31.

Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.

Hypertrophic cardiomyopathy (HCM) with severe diastolic dysfunction is a major cause of heart failure and sudden cardiac death (SCD) associated with lethal arrhythmia. Although various risk factors for cardiac events have been reported in HCM patients, previous studies have reported that some HCM patients exhibit either no risk or a low risk of SCD experienced cardiac events. The mid-diastolic transmitral flow velocity curve (mitral L-wave) is an echocardiographic index of left ventricular compliance, and it has been reported as one of the parameters of advanced diastolic dysfunction assessed noninvasively. However, little is known about the association between the mitral L-wave and long-term clinical outcomes in HCM patients without SCD risk factors. Between July 2005 and February 2016, 112 patients were diagnosed with HCM and 96 patients without risk factors were enrolled. After excluding 3 patients whom we could not detect L-wave more than once, 93 patients (mean age 57.7 ± 13.1 years, 33 females) were divided into the following two groups, according to the presence or absence of the mitral L-wave: Group L (+) (with the mitral L-wave) and Group L (-) (without the mitral L-wave). The correlations between the mitral L-wave and rates of cardiac events were investigated. The mitral L-wave was present in 14 (15.1%) patients [Group L]. During the follow-up period [4.7 (2.9-7.5) years], patients experienced 7 cardiac events. Kaplan-Meier survival analysis showed that the event-free rate was significantly lower in Group L (+) than in Group L (-) (log-rank P = 0.002). Additionally, in multivariate analysis, L-wave positivity was identified as independent predictors of cardiac events. Existence of the mitral L-wave can predict cardiac events, even in HCM patients without SCD risk factors.
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http://dx.doi.org/10.1007/s00380-019-01440-yDOI Listing
December 2019

Autophagy regulates lipid metabolism through selective turnover of NCoR1.

Nat Commun 2019 04 5;10(1):1567. Epub 2019 Apr 5.

Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, 951-8510, Japan.

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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http://dx.doi.org/10.1038/s41467-019-08829-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450892PMC
April 2019

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

Sci Rep 2019 03 5;9(1):3559. Epub 2019 Mar 5.

Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

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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http://dx.doi.org/10.1038/s41598-019-39087-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401014PMC
March 2019

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

Sci Rep 2019 03 5;9(1):3559. Epub 2019 Mar 5.

Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

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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http://dx.doi.org/10.1038/s41598-019-39087-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401014PMC
March 2019