Details of a Researcher - Tomi, Masatoshi

Papers - Tomi, Masatoshi

Division display 21 - 40 of about 86 ／ All the affair displays >>

Hypotaurine Is a Substrate of GABA Transporter Family Members GAT2/Slc6a13 and TAUT/Slc6a6

Nishimura Tomohiro, Higuchi Kei, Yoshida Yuko, Sugita-Fujisawa Yuki, Kojima Kazuaki, Sugimoto Maiko, Santo Marie, Tomi Masatoshi, Nakashima Emi

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 41 ( 10 ) 1523 - 1529 2018.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 09186158

Hypotaurine is a precursor of taurine and a physiological antioxidant that circulates in adult and fetal plasma. The purpose of the present study was to clarify whether hypotaurine is a substrate of Slc6a/gamma-aminobutyric acid (GABA) transporter family members. Radiolabeled hypotaurine was synthesized from radiolabeled cysteamine and 2-aminoethanethiol dioxygenase. The uptakes of [3H]GABA, [3H]taurine, and [14C]hypotaurine by HEK293 cells expressing mouse GAT1/Slc6a1, TAUT/Slc6a6, GAT3/Slc6a11, BGT1/Slc6a12, and GAT2/Slc6a13 were measured. TAUT and GAT2 showed strong [14C]hypotaurine uptake activity, while BGT1 showed moderate activity, and GAT1 and GAT3 showed slight but significant activity. Mouse TAUT and GAT2 both showed Michaelis constants of 11 µM for hypotaurine uptake. GAT2-expressing cells pretreated with hypotaurine showed resistance to H2O2-induced oxidative stress. These results suggest that under physiological conditions, TAUT and GAT2 would be major contributors to hypotaurine transfer across the plasma membrane, and that uptake of hypotaurine via GAT2 contributes to the cellular resistance to oxidative stress.

Gene expression of A6-like subgroup of ATP-binding cassette transporters in mouse brain parenchyma and microvessels

Tachikawa M., Toki H., Watanabe M., Tomi M., Hosoya K., Terasaki T.

Anatomical Science International (Anatomical Science International) 93 ( 4 ) 456 - 463 2018.03

Research paper (scientific journal), Accepted, ISSN 1447-6959

© 2018, Japanese Association of Anatomists. The A-subclass of ATP-binding cassette (ABC) transporters is a highly conserved superfamily of potent lipid transporters. Although the ABCA1-like subgroup of ABCA1-4, and A7 have been shown to mediate the transport of endogenous lipids, the roles of the ABCA6-like subgroup transporters, which have been identified as a unique gene cluster on human chromosome 17q24 (ABCA5, A6, A8, A9, and A10) and mouse chromosome 11 (Abca5, a6, a8a, a8b, and a9), remains largely unknown. The purpose of the present study was to clarify the spatial and temporal expression profiles of Abca6-like subgroup transporters in embryonic and postnatal mouse brains by a combination of in situ hybridization and quantitative polymerase chain reaction (PCR) using magnetically isolated brain vascular endothelial cells. In embryonic brains, the transcripts of Abca5, a8a and a8b were detected predominantly in the mantle zone, where postmitotic neurons differentiate. At the postnatal stages, they were expressed in various nuclei and neuronal layers. Abca9 mRNA was detected diffusely in the embryonic and postnatal brains and sequential and/or strong spotted signals were detected in the leptomeninges on the brain surface. PCR detected expression of Abca8a and Abca9 mRNAs in isolated vascular endothelial cells. Expression signals for Abca6 mRNA were hardly observed at any stages examined. These distinct spatio-temporal expression patterns of Abca6-like subgroup transporters may reflect their functional significance and diversity to regulate lipid transport, particularly in neurons, leptomeningeal cells, and vascular endothelial cells.

Access to Document (DOI)

Effect of serotonin transporter genotype on self-reported efficacy and activity changes of brain prefrontal area in response to placebo

Isawa M., Tashiro R., Naruse C., Yamaguchi Y., Itoh H., Nishimura T., Tomi M., Shimada H., Saito H., Mochizuki M., Nakashima E.

Pharmazie (Pharmazie) 73 ( 1 ) 35 - 41 2018.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0031-7144

Patients benefit from drug therapy not only through pharmacological mechanisms, but also through non-pharmacological action (placebo effect), which may be mediated in part by the prefrontal area of the brain. We consider that the difference between responders and non-responders to placebo might be related to polymorphisms in the serotonin transporter-linked polymorphic region (5-HTTLPR). To study this idea, we performed a randomized double-blind clinical trial using caffeine and lactose (placebo). Activity in the prefrontal area of the brain was measured in terms of blood flow by means of near-infrared spectroscopy (NIRS) as an objective indicator. Self-reported feelings of drowsiness on established scales were used as subjective indicators. Twenty-one subjects in block A took caffeine on the first day and placebo on the third day, and 21 in block B took placebo on the first day and placebo on the third day. After placebo administration, improvement of sleepiness was significantly enhanced, a similar extent to that after caffeine medication. Among the 42 subjects, 22 showed S/S type polymorphism in the serotonin transporter (52.4 %), 17 showed S/L type (40.5 %) and 3 showed L/L type (7.10 %). Statistical analysis of the results indicate that subjects with L/L genotype showed a significantly greater placebo response in terms of both self-reported feeling of drowsiness and blood flow in the prefrontal area of the brain associated with working memory (46 area). Our results indicate that the L/L genotype of 5-HTTLPR, which is rare in Japanese (3.2 %) but common in Americans (32.2 %), may be associated with a greater placebo effect.

Access to Document (DOI)

Cellular Uptake of Levocetirizine by Organic Anion Transporter 4

Noguchi S., Nishimura T., Mukaida S., Benet L., Nakashima E., Tomi M.

Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences) 106 ( 9 ) 2895 - 2898 2017.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022-3549

© 2017 American Pharmacists Association® The pharmacokinetics of cetirizine, a nonsedating antihistamine, is profoundly affected by transporter-mediated membrane transport in the kidney. In this study, we aimed to investigate the transport mechanism of levocetirizine, the pharmacologically active enantiomer of cetirizine, via human organic anion transporter 4 (OAT4) expressed in the apical membrane of renal proximal tubules and the basal plasma membrane of placental syncytiotrophoblasts. In cells expressing human OAT4 under the control of tetracycline, levocetirizine uptake was increased by tetracycline treatment. On the other hand, OAT4 expression did not facilitate efflux of preloaded levocetirizine from the cells, either in the presence or absence of extracellular Cl−. The OAT4-mediated levocetirizine uptake was concentration-dependent with a Km of 38 μM. The uptake rate of levocetirizine via OAT4 was approximately twice that of racemic cetirizine, indicating stereoselective uptake of levocetirizine. On the other hand, OAT4-mediated [3H]dehydroepiandrosterone sulfate uptake was inhibited by dextrocetirizine and levocetirizine. Overall, our findings indicate that OAT4 mediates levocetirizine uptake but is unlikely to mediate the efflux.

Access to Document (DOI)

Co-localization of microsomal prostaglandin E synthase-1 with cyclooxygenase-1 in layer II of murine placental syncytiotrophoblasts

Inagaki M., Nishimura T., Akanuma S., Nakanishi T., Tachikawa M., Tamai I., Hosoya K., Nakashima E., Tomi M.

Placenta (Placenta) 53 76 - 82 2017.04

Research paper (scientific journal), Accepted, ISSN 01434004

© 2017 Elsevier Ltd The placenta is an organ that secretes prostaglandin (PG) E2 into the fetal-placental circulation to regulate both vascular tone and remodeling of the fetal ductus arteriosus. Placental PGE2 synthesis might be mediated by microsomal PGE synthase-1 (mPGES-1), in addition to cyclooxygenase (COX) isoforms. Thus, the purpose of this study is to clarify the temporal and spatial expression patterns of mPGES-1, together with COX-1 and COX-2, in murine placenta. We found that mPGES-1 and COX-1 protein levels continuously increased in the placental labyrinth from gestational day (GD) 13.5 to GD19.5, becoming higher than in the decidua or the junctional zone by GD17.5. The PGE2 level at GD17.5 was also highest in the labyrinth. Immunofluorescence stainings for mPGES-1 and COX-1 in the labyrinth at GD17.5 overlapped and were located on the fetal side of the signals for connexin 26, which forms gap junctions between maternal-facing (SynT-I) and fetal-facing (SynT-II) syncytiotrophoblast layers, and on the maternal side of the signals for glucose transporter 1 on the basal plasma membrane of SynT-II. On the other hand, the signals for COX-2 did not overlap with those for mPGES-1. These results indicate that COX-1 and mPGES-1 are co-localized in murine placental SynT-II, facing the fetal-placental circulation. Therefore, SynT-II could contribute to placental synthesis of PGE2 for release into the fetal-placental circulation.

Access to Document (DOI)

Contribution of equilibrative nucleoside transporter (ENT) 2 to fluorouracil transport in rat placental trophoblast cells

Takagi A., Nishimura T., Akashi T., Tomi M., Nakashima E.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 32 ( 2 ) 151 - 156 2017.04

Research paper (scientific journal), Accepted, ISSN 1347-4367

© 2016 The Japanese Society for the Study of Xenobiotics Fluorouracil is used for treatment of breast cancer even in pregnant women, except during fetal organogenesis. The purpose of this study was to clarify the transport mechanism of fluorouracil at the rat placental barrier. Maternal-to-fetal transfer of [3H]fluorouracil in rats at gestational day 19.5 was saturable and much higher than that of [14C]sucrose. The uptake of [3H]fluorouracil was also saturable in rat placental trophoblast TR-TBT 18d-1 cells, which express both equilibrative nucleoside transporter (ENT) 1 and ENT2. Nitrobenzylthioinosine (NBMPR) at 0.1 μM had no effect on [3H]fluorouracil uptake by TR-TBT 18d-1 cells, but 100 μM NBMPR almost completely inhibited the saturable component, suggesting involvement of ENT2, rather than ENT1 in the transport. Rat ENT2 cRNA-injected oocytes showed significantly increased [3H]fluorouracil uptake compared with water-injected oocytes, while rat ENT1 cRNA-injected oocytes did not show an increase of [3H]fluorouracil uptake. The Michaelis–Menten constant for rat ENT2-mediated uptake of [3H]fluorouracil was 4.21 mM. The expression profile of ENT2 mRNA in rat placenta during pregnancy was almost constant from 13.5 to 21.5 days of gestation. In conclusion, ENT2 appears to be the mediator of fluorouracil transport in rat placental trophoblast cells.

Access to Document (DOI)

Sex-specific life course changesin the neuro-metabolic phenotype of glut3 null heterozygous mice: Ketogenic diet ameliorates electroencephalographic seizures and improves sociability

Dai Y., Zhao Y., Tomi M., Shin B.C., Thamotharan S., Mazarati A., Sankar R., Wang E.A., Cepeda C., Levine M.S., Zhang J., Frew A., Alger J.R., Clark P.M., Sondhi M., Kositamongkol S., Leibovitch L., Devaskar S.U.

Endocrinology (Endocrinology) 158 ( 4 ) 936 - 949 2017.04

Research paper (scientific journal), Accepted, ISSN 0013-7227

© 2017 Endocrine Society. We tested the hypothesis that exposure of glut3 +/- mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma-cerebrospinal fluid (CSF)-brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3 +/- male but not femalemice (5months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3 +/- males alone. Higher plasma-CSF ketones (β-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid β1-40 deposition in an age-dependent manner in glut3 +/- males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learningandmemory, andreducedseizure events.We concludethat (1) sexspecific and age-dependent perturbations underlie the phenotype of glut3 +/- mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3 +/- male mice.

Access to Document (DOI)

Contributions of system A subtypes to α-methylaminoisobutyric acid uptake by placental microvillous membranes of human and rat

Takahashi Y., Nishimura T., Maruyama T., Tomi M., Nakashima E.

Amino Acids (Amino Acids) 49 ( 4 ) 795 - 803 2017.04

Research paper (scientific journal), Accepted, ISSN 0939-4451

© 2017, Springer-Verlag Wien. System A consists of three subtypes, sodium-coupled neutral amino acid transporter 1 (SNAT1), SNAT2, and SNAT4, which are all expressed in the placenta. The aim of this study was to evaluate the contributions of each of the three subtypes to total system A-mediated uptake in placental MVM of human and rat, using betaine and l-arginine as subtype-selective inhibitors of SNAT2 and SNAT4, respectively. Appropriate concentrations of betaine and l-arginine for subtype-selective inhibition in SNAT-overexpressing cells were identified. It was found that 10 mM betaine specifically and almost completely inhibited human and rat SNAT2-mediated [14C]α-methylaminoisobutyric acid ([14C]MeAIB) uptake, while 5 mM l-arginine specifically and completely inhibited [3H]glycine uptake via human SNAT4, as well as [14C]MeAIB uptake via rat SNAT4. In both human and rat placental MVM vesicles, sodium-dependent uptake of [14C]MeAIB was almost completely inhibited by 20 mM unlabeled MeAIB. l-Arginine (5 mM) partly inhibited the uptake in humans, but hardly affected that in rats. Betaine (10 mM) partly inhibited the uptake in rats, but hardly affected it in humans. These results suggest that SNAT1 is most likely the major contributor to system A-mediated MeAIB uptake by human and rat MVM vesicles and that the remaining uptake is mainly mediated by SNAT4 in humans and SNAT2 in rats. Thus, inhibition studies using betaine and l-arginine are useful to characterize the molecular mechanisms of system A-mediated transport.

Access to Document (DOI)

Layer II of placental syncytiotrophoblasts expresses MDR1 and BCRP at the apical membrane in rodents

Akashi T., Nishimura T., Takaki Y., Takahashi M., Shin B.C., Tomi M., Nakashima E.

Reproductive Toxicology (Reproductive Toxicology) 65 375 - 381 2016.10

Research paper (scientific journal), Accepted, ISSN 0890-6238

The purpose of this study is to clarify the subcellular localizations of multidrug resistance protein 1 (MDR1)/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2 in the rodent placental SynT bilayer, i.e., a maternal-facing (SynT-I) layer and a fetal-facing (SynT-II) layer. In double immunofluorescence staining, the signals of MDR1 and BCRP appeared midway between the signals of glucose transporter 1 on the apical membrane of SynT-I and the basal plasma membrane of SynT-II, and mostly overlapped with signals of connexin 26, which forms gap junctions between SynT-I and SynT-II. In detail, median intensities (pixels) of the MDR1 and BCRP signals were significantly closer to the fetal circulation as compared to the location of connexin 26 signals. In double in situ hybridization studies, the signals of Mdr1b mRNA mostly overlapped with those of Syncytin-B, a SynT-II marker. In conclusion, MDR1 and BCRP are expressed on apical membranes of the rodent placental SynT-II layer.

Access to Document (DOI)

Influence of Counseling Intervention on the Stress-Reducing Effect of Bergamot Oil and on the Concentration-Improving Effect of Rosemary Oil in Aromatherapy

ISAWA Minae, KOH Risako, ITOH Hiroshi, NISHIMURA Tomohiro, TOMI Masatoshi, SHIMADA Hideyo, SAITO Hidetsugu, NAKASHIMA Emi

Journal of Japanese Cosmetic Science Society (Japanese Cosmetic Science Society) 40 ( 2 ) 79 - 86 2016.06

Research paper (scientific journal), Accepted, ISSN 1880-2532

There is growing evidence that aromatherapy can improve patients' stress and refreshment levels. Also, an explanation to patients of the anticipated pharmacological effects of drugs may serve to improve compliance and to enhance subjective treatment benefit. Here, we aimed to examine the effectiveness of counseling as a means of improving the stress-reducing efficacy of bergamot oil and the concentration-improving effect of rosemary oil in 23 healthy young women. Efficacy was evaluated by using a self-reported questionnaire and multi-dimensional fatigue inventory-20 (MFI-20) as subjective indicators, together with near-infrared spectroscopy (NIRS)-evaluated blood flow in the inferior frontal cortex and amylase concentration in saliva as objective indicators. Counseling combined with bergamot aromatherapy significantly improved physical fatigue and mental fatigue and also improved sleepiness, concentration, and activity (p<0.01, p<0.05). Counseling combined with rosemary aromatherapy significantly improved motivation (p<0.05). Regional blood flow in the inferior frontal cortex was decreased totally. Especially partial right field of the prefrontal cortex area was decreased significantly by exposure to bergamot oil with counseling. By contrast, rosemary oil with counseling was decreased significantly in partial left of the prefrontal cortex area. Interestingly, we found that levels of salivary amylase (a sensitive biological marker of stress) were increased by counseling in subjects with low scores for resilience (capacity of individuals to resist stress). This finding may indicate that counseling was stressful to these subjects. Overall, our results indicate that counseling intervention increased the effectiveness of aromatherapy. Focused counseling taking account of behavioral differences between individuals may be a promising strategy to maximize patients' benefit.

Organic Anion Transporter 4-Mediated Transport of Olmesartan at Basal Plasma Membrane of Human Placental Barrier

Noguchi S., Nishimura T., Fujibayashi A., Maruyama T., Tomi M., Nakashima E.

Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences) 104 ( 9 ) 3128 - 3135 2015.09

Research paper (scientific journal), Accepted, ISSN 0022-3549

Mechanisms regulating fetal transfer of olmesartan, an angiotensin-II receptor type 1 antagonist, are important as potential determinants of life-threatening adverse fetal effects. The purpose of this study was to examine the olmesartan transport mechanism through the basal plasma membrane (BM) of human syncytiotrophoblasts forming the placental barrier. Uptake of olmesartan by human placental BM vesicles was potently inhibited by dehydroepiandrosterone sulfate (DHEAS), estrone 3-sulfate, and bromosulfophthalein, which are all typical substrates of organic anion transporter (OAT) 4 localized at the BM of syncytiotrophoblasts, and was increased in the absence of chloride. In tetracycline-inducible OAT4-expressing cells, [3H]olmesartan uptake was increased by tetracycline treatment. Olmesartan uptake via OAT4 was concentration dependent with a K<inf>m</inf> of 20 μM, and was increased in the absence of chloride. [3H]Olmesartan efflux via OAT4 was also observed and was trans-stimulated by extracellular chloride and DHEAS. Thus, OAT4 mediates bidirectional transport of olmesartan and appears to regulate fetal transfer of olmesartan at the BM of syncytiotrophoblasts. Efflux transport of olmesartan via OAT4 from syncytiotrophoblasts to the fetal circulation might be facilitated in the presence of an inwardly directed physiological chloride gradient and extracellular DHEAS.

Access to Document (DOI)

Role of OAT4 in uptake of estriol precursor 16α-hydroxydehydroepiandrosterone sulfate into human placental syncytiotrophoblasts from fetus

Tomi M., Eguchi H., Ozaki M., Tawara T., Nishimura S., Higuchi K., Maruyama T., Nishimura T., Nakashima E.

Endocrinology (Endocrinology) 156 ( 7 ) 2704 - 2712 2015.07

Research paper (scientific journal), Accepted, ISSN 0013-7227

Estriol biosynthesis in human placenta requires the uptake of a fetal liver-derived estriol precursor, 16α-hydroxydehydroepiandrosterone sulfate (16α-OH DHEAS), by placental syncytiotrophoblasts at their basal plasma membrane (BM), which faces the fetal circulation. The aim of this work is to identify the transporter(s) mediating 16α-OH DHEAS uptake at the fetal side of syncytiotrophoblasts by using human placental BM-enriched vesicles and to examine the contribution of the putative transporter to estriol synthesis at the cellular level, using choriocarcinoma JEG-3 cells. Organic anion transporter (OAT)-4 and organic anion transporting polypeptide 2B1 proteins were enriched in human placental BM vesicles compared with crude membrane fraction. Uptake of [3H]16α-OH DHEAS by BM vesicles was partially inhibited in the absence of sodium but was significantly increased in the absence of chloride and after preloading glutarate. Uptake of [3H]16α-OH DHEAS by BM vesicles was significantly inhibited by OAT4 substrates such as dehydroepiandrosterone sulfate, estrone-3-sulfate, and bromosulfophthalein but not by cyclosporin A, tetraethylammonium, p-aminohippuric acid, or cimetidine. These characteristics of vesicular [3H]16α-OH DHEAS uptake are in good agreement with those of human OAT4-transfected COS-7 cells as well as forskolin-differentiated JEG-3 cells. Estriol secretion from differentiated JEG-3 cells was detected when the cells were incubated with 16α-OH DHEAS for 8 hours but was inhibited in the presence of 50 μM bromosulfophthalein. Our results indicate that OAT4 at the BM of human placental syncytiotrophoblasts plays a predominant role in the uptake of 16α-OH DHEAS for placental estriol synthesis.

Access to Document (DOI)

Protective effect of hypotaurine against oxidative stress-induced cytotoxicity in rat placental trophoblasts

Nishimura T., Duereh M., Sugita Y., Yoshida Y., Higuchi K., Tomi M., Nakashima E.

Placenta (Placenta) 36 ( 6 ) 693 - 698 2015.06

Research paper (scientific journal), Accepted, ISSN 0143-4004

Introduction Hypotaurine is a precursor of taurine and an antioxidant, and is concentrated in fetal plasma compared to maternal plasma. Hypotaurine is significantly decreased in fetal plasma of ezrin (Vil2) knock-out mice, and fetuses show intrauterine growth retardation. The aim of this study was to characterize the mechanism through which cellular hypotaurine level is maintained in placental trophoblasts, and the effect of hypotaurine on oxidative stress induced by hydrogen peroxide (H<inf>2</inf>O<inf>2</inf>). Methods Hypotaurine transfer from extracellular fluid and antioxidant effect of hypotaurine were analyzed in rat placental trophoblast TR-TBT 18d-1 cells. Results We found that hypotaurine is concentrated into rat placental trophoblast TR-TBT 18d-1 cells, and the level of hypotaurine was markedly reduced by culture in medium supplemented with dialyzed fetal bovine serum (FBS) instead of normal FBS. The hypotaurine level recovered almost completely when hypotaurine was added to the culture medium, indicating that intracellular hypotaurine is predominantly supplied by transport across the plasma membrane from extracellular fluid rather than by biosynthesis. Hypotaurine showed a cytoprotective effect against H<inf>2</inf>O<inf>2</inf>-induced oxidative damage in TR-TBT 18d-1 cells. Hypotaurine treatment of TR-TBT 18d-1 cells increased antioxidant capacity against hydroxyl radical and peroxyl radical. The concentration of intracellular hydroxyl radical induced by H<inf>2</inf>O<inf>2</inf> in TR-TBT 18d-1 cells was significantly reduced by hypotaurine treatment. Discussion These results indicate that intracellular hypotaurine is mainly supplied to placental trophoblasts by transfer from extracellular fluid across the plasma membrane, and may play a role in cell protection by scavenging reactive oxygen species.

Access to Document (DOI)

Influence of Counseling Intervention on the Effectiveness of a Revitalizing Medicinal Product in Healthy Volunteers, Using a Brain Monitoring System

Isawa Minae, Shimizu Ayako, Miyashita Eri, Itoh Hiroshi, Nishimura Tomohiro, Tomi Masatoshi, Shimada Hideyo, Saito Hidetsugu, Nakashima Emi

Japanese Journal of Pharmaceutical Health Care and Sciences (Japanese Society of Pharmaceutical Health Care and Sciences) 40 ( 10 ) 558 - 566 2014.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

The purpose of this research was to examine whether the fatigue-relieving efficacy of a revitalizing medicinal product would be increased by counseling (advice to subjects regarding its expected efficacy), using both subjective and objective indicators. Twenty participants took the revitalizing medicinal product (drinkable product: 50 mL, once) on separate occasions, once with and once without counseling, with a 1-week interval. They completed a self-reported questionnaire (covering motivation, feeling of drowsiness, and general fatigue) and multi-dimensional fatigue inventory-20 (MFI-20) as subjective indicators, and blood flow in the inferior frontal cortex was evaluated by means of near-infrared spectroscopy (NIRS) as an objective indicator. The self-reported questionnaire showed that the revitalizing drink with counseling significantly improved general fatigue, as compared to the drink alone. MFI-20 showed no significant difference. Regional blood flow in the inferior frontal cortex was significantly increased by administration of the revitalizing drink with counseling, compared to without counseling (P < 0.05). Overall, the results indicated that counseling intervention increased the effectiveness of the revitalizing medicinal product.

Fetal growth retardation and lack of hypotaurine in ezrin knockout mice

Nishimura T., Higuchi K., Sai Y., Sugita Y., Yoshida Y., Tomi M., Wada M., Wakayama T., Tamura A., Tsukita S., Soga T., Nakashima E.

PLoS ONE (PLoS ONE) 9 ( 8 ) e105423 2014.08

Research paper (scientific journal), Accepted

Ezrin is a membrane-associated cytoplasmic protein that serves to link cell-membrane proteins with the actin-based cytoskeleton, and also plays a role in regulation of the functional activities of some transmembrane proteins. It is expressed in placental trophoblasts. We hypothesized that placental ezrin is involved in the supply of nutrients from mother to fetus, thereby influencing fetal growth. The aim of this study was firstly to clarify the effect of ezrin on fetal growth and secondly to determine whether knockout of ezrin is associated with decreased concentrations of serum and placental nutrients. Ezrin knockout mice (Ez-/-) were confirmed to exhibit fetal growth retardation. Metabolome analysis of fetal serum and placental extract of ezrin knockout mice by means of capillary electrophoresis-time-of-flight mass spectrometry revealed a markedly decreased concentration of hypotaurine, a precursor of taurine. However, placental levels of cysteine and cysteine sulfinic acid (precursors of hypotaurine) and taurine were not affected. Lack of hypotaurine in Ez-/- mice was confirmed by liquid chromatography with tandem mass spectrometry. Administration of hypotaurine to heterogenous dams significantly decreased the placenta-to-maternal plasma ratio of hypotaurine in wild-type fetuses but only slightly decreased it in ezrin knockout fetuses, indicating that the uptake of hypotaurine from mother to placenta is saturable and that disruption of ezrin impairs the uptake of hypotaurine by placental trophoblasts. These results indicate that ezrin is required for uptake of hypotaurine from maternal serum by placental trophoblasts, and plays an important role in fetal growth. © 2014 Nishimura et al.

Access to Document (DOI)

Role of protein kinase A in regulating steroid sulfate uptake for estrogen production in human placental choriocarcinoma cells

Tomi M., Miyata Y., Noguchi S., Nishimura S., Nishimura T., Nakashima E.

Placenta (Placenta) 35 ( 8 ) 658 - 660 2014.08

Research paper (scientific journal), Accepted, ISSN 0143-4004

The purpose of this study is to assess the role of the protein kinase A (PKA) in regulating uptake of dehydroepiandrosterone sulfate (DHEAS), an estrogen precursor, by syncytiotrophoblasts. Forskolin, a PKA activator, significantly increased [³H]DHEAS uptake and the mRNA expression levels of organic anion transporter (OAT) 4 and CYP19A1 in choriocarcinoma JEG-3 cells, while other steroid sulfate transporters present in the placenta showed no change in expression level. KT5720, a PKA inhibitor, attenuated these effects of forskolin. Accordingly, the PKA pathway appears to play an important role in estrogen synthesis by cooperatively regulating OAT4 and steroidogenic enzymes in syncytiotrophoblasts. © 2014 Elsevier Ltd. All rights reserved.

Access to Document (DOI)

Influence of Counseling Intervention on the Effectiveness of Aromatherapy with Bergamot Oil in Healthy Women Volunteers Measured with a Brain Monitoring System

ISAWA Minae, INOUE Shio, ITOH Hiroshi, NISHIMURA Tomohiro, TOMI Masatoshi, SHIMADA Hideyo, SAITO Hidetsugu, NAKASHIMA Emi

Journal of Japanese Cosmetic Science Society (Japanese Cosmetic Science Society) 38 ( 2 ) 81 - 86 2014.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 1880-2532

There is growing evidence that aromatherapy can improve mood. Since pharmacists may be requested to counsel patients about aromatherapy, this study was designed to evaluate the influence of counseling on the effectiveness of aromatherapy in 14 healthy young women. Participants completed a self-reported questionnaire (motivation, feeling of drowsiness and general fatigue) and multi-dimensional fatigue inventory-20 (MFI-20) in a room filled with the fragrance of bergamot, with or without counseling. Further, as an objective measure of changes in stress, blood flow in the inferior frontal cortex was evaluated by means of near-infrared spectroscopy (NIRS). MFI-20 showed that aromatherapy with counseling significantly improved activity and motivation, as compared to aromatherapy only. The self-reported questionnaire showed no significant difference. Regional blood flow in the inferior frontal cortex was significantly decreased by exposure to aromatherapy with counseling, compared to aromatherapy alone (p<0.01, p<0.05). The value of the laterality index (LI) derived from NIRS measurements, which is considered to be a measure of stress, was decreased by aromatherapy with counseling, indicating that bergamot oil reduces stress. Overall, the results indicated that counseling intervention markedly increased the effectiveness of aromatherapy.

System A amino acid transporter SNAT2 shows subtype-specific affinity for betaine and hyperosmotic inducibility in placental trophoblasts

Nishimura T., Yagi R., Usuda M., Oda K., Yamazaki M., Suda S., Takahashi Y., Okazaki F., Sai Y., Higuchi K., Maruyama T., Tomi M., Nakashima E.

Biochimica et Biophysica Acta - Biomembranes (Biochimica et Biophysica Acta - Biomembranes) 1838 ( 5 ) 1306 - 1312 2014.05

Research paper (scientific journal), Accepted, ISSN 0005-2736

Betaine uptake is induced by hypertonic stress in a placental trophoblast cell line, and involvement of amino acid transport system A was proposed. Here, we aimed to identify the subtype(s) of system A that mediates hypertonicity-induced betaine uptake. Measurement of [¹⁴C]betaine uptake by HEK293 cells transiently transfected with human or rat sodium-coupled neutral amino acid transporters (SNATs), SNAT1, SNAT2 and SNAT4 revealed that only human and rat SNAT2 have betaine uptake activity. The Michaelis constants (K_m) of betaine uptake by human and rat SNAT2 were estimated to be 5.3 mM and 4.6 mM, respectively. Betaine exclusively inhibited the uptake activity of SNAT2 among the rat system A subtypes. We found that rat SNAT1, SNAT2 and SNAT4 were expressed at the mRNA level under isotonic conditions, while expression of SNAT2 and SNAT4 was induced by hypertonicity in TR-TBT 18d-1 cells. Western blot analyses revealed that SNAT2 expression on plasma membrane of TR-TBT 18d-1 cells was more potently induced by hypertonicity than that in total cell lysate. Immunocytochemistry confirmed the induction of SNAT2 expression in TR-TBT 18d-1 cells exposed to hypertonic conditions and indicated that SNAT2 was localized on the plasma membrane in these cells. Our results indicate that SNAT2 transports betaine, and that tonicity-sensitive SNAT2 expression may be involved in regulation of betaine concentration in placental trophoblasts. © 2014 Elsevier B.V.

Access to Document (DOI)

Estrogen receptor α induction by mitoxantrone increases Abcg2 expression in placental trophoblast cells

Oda K., Nishimura T., Higuchi K., Ishido N., Ochi K., Iizasa H., Sai Y., Tomi M., Nakashima E.

Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences) 102 ( 9 ) 3364 - 3372 2013.09

Research paper (scientific journal), Accepted, ISSN 0022-3549

Substrate-induced upregulation of ATP-binding cassette subfamily G member 2 (ABCG2) has been well studied in cancer cells, but it is also important to understand whether ABCG2 is upregulated by its substrates in tissues in which it is constitutively expressed. In the present study, we aimed to clarify the regulatory mechanism of Abcg2 expression by its substrate, mitoxantrone, in placental cells. Abcg2 mRNA expression in rat placental TR-TBT 18d-1 cells treated with 10μM mitoxantrone for 24h was increased, compared with that in nontreated cells, whereas 10μM pheophorbide-a had no effect. Methylated CpG level in the promoter region of the Abcg2 gene was low and was not altered by mitoxantrone. On the contrary, mitoxantrone markedly increased the expression of estrogen receptor (ER) α and progesterone receptor (PR) B. Fulvestrant, an ER antagonist, attenuated the mitoxantrone-induced increase of Abcg2 mRNA expression, whereas mifepristone, a PR antagonist, had little effect. 17β-estradiol, an ER ligand, positively regulated the mitoxantrone-induced increase of Abcg2 expression. DNA demethylation by 5-aza-2-deoxycytidine treatment increased ERα expression, but mitoxantrone failed to facilitate the demethylation of ERα promoter in TR-TBT 18d-1 cells. In conclusion, Abcg2 expression is induced by mitoxantrone via the induction of ERα in TR-TBT 18d-1 cells. © 2013 Wiley Periodicals, Inc.

Access to Document (DOI)

Evaluation of rat in vivo fetal-to-maternal transfer clearances of various xenobiotics by umbilical perfusion

Nishimura T., Takanohashi T., Tomi M., Horikoshi M., Higuchi K., Sai Y., Nakashima E.

Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences) 102 ( 9 ) 3356 - 3363 2013.09

Research paper (scientific journal), Accepted, ISSN 0022-3549

It is important to address the tissue permeability of drugs, particularly in tissues that have a blood-tissue barrier, in terms of both lipophilicity and the contribution of transporters. Here, we employed umbilical perfusion in rats to evaluate in vivo fetal-to-maternal transfer clearances of various xenobiotics. We measured fetal-to-maternal clearance (CL_fm) of 23 compounds, which have a broad range of lipophilicity. Drugs for which CL_fm was more than 300 μL/(mL min) belonged exclusively to Biopharmaceutical Drug Disposition Classification System (BDDCS) class 1 (highly permeable) and those for which CL_fm was less than 50 μL/(mL min) belonged exclusively to BDDCS class 3 (poorly permeable). For most drugs, CL_fm values were broadly consistent with lipophilicity. However, CL_fm of digoxin was saturable and was inhibited by verapamil, suggesting that P-glycoprotein (P-gp)-mediated efflux has a substantially effect on measured clearance. CL_fm of mitoxantrone continued to increase slightly at high concentrations of mitoxantrone, but placental-to-maternal clearance of mitoxantrone was saturable, implying that Bcrp1 contributes to mitoxantrone efflux across the placenta. Thus, we measured CL_fm by umbilical perfusion and examined the relationship between CL_fm and lipophilicity of xenobiotics. Fetal-to-maternal transport clearances measured in this study will be helpful to understand the characteristics of the blood-placental barrier. © 2013 Wiley Periodicals, Inc.

Access to Document (DOI)

　 Previous page - Next page 　