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Biomedical subjects

M Kojima

Publications and source records attributed to M Kojima.

At least 55 records · Page 3Linked to original sources
PubMed2001

Catecholamines and serotonin are differently regulated by tetrahydrobiopterin. A study from 6-pyruvoyltetrahydropterin synthase knockout mice.

(6R)-L-erythro-5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase (TH), tryptophan hydroxylase, phenylalanine hydroxylase, and nitric-oxide synthase. These enzymes synthesize neurotransmitters, e.g. catecholamines, serotonin, and nitric oxide (NO). We established mice unable to synthesize BH4 by disruption of the 6-pyruvoyltetrahydropterin synthase gene, the encoded protein of which catalyzes the second step of BH4 biosynthesis. Homozygous mice were born at the almost expected Mendelian ratio, but died within 48 h after birth. In the brain of homozygous mutant neonates, levels of biopterin, catecholamines, and serotonin were extremely low. The number of TH molecules was highly dependent on the intracellular concentration of BH4 at nerve terminals. Alteration of the TH protein level by modulation of the BH4 content is a novel regulatory mechanism. Our data showing that catecholaminergic, serotonergic, and NO systems were differently affected by BH4 starvation suggest the possible involvement of BH4 synthesis in the etiology of monoamine-based neurological and neuropsychiatric disorders.

Animals↗
PubMed2001

Molecular cloning of natriuretic peptide receptor A from bullfrog (Rana catesbeiana) brain and its functional expression.

A comparative study of natriuretic peptide receptor (NPR) was performed by cloning the NPR-A receptor subtype from the bullfrog (Rana catesbeiana) brain and analyzing its functional expression. Like other mammalian NPR-A receptors, the bullfrog NPR-A receptor consists of an extracellular ligand binding domain, a hydrophobic transmembrane domain, a kinase-like domain and a guanylate cyclase domain. Sequence comparison among the bullfrog and mammalian receptors revealed a relatively low ( approximately 45%) similarity in the extracellular domain compared to a very high similarity ( approximately 92%) in the cytoplasmic regulatory and catalytic domains. Expression of NPR-A mRNA was detected in various bullfrog tissues including the brain, heart, lung, kidney and liver; highest levels were observed in lung. Functional expression of the receptor in COS-7 cells revealed that frog atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) elicited cyclic guanosine 3'5'-monophosphate production by stimulating the receptor in a dose-dependent manner from 10(-10) M concentrations. Rat ANP was also effective in stimulating the frog receptor whereas rat BNP and porcine BNP were less responsive to the receptor. On the other hand, frog C-type natriuretic peptide (CNP) as well as porcine CNP stimulated the receptor only at high concentrations (10(-7) M). This clearly indicates that the bullfrog receptor is a counterpart of mammalian NPR-A, and is specific for ANP or BNP but not for CNP.

Amino Acid Sequence↗
PubMed2001

Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues.

Ghrelin is a 28-amino acid residue endogenous growth hormone secretagogue. Intensive investigations revealed that the N-terminus tetrapeptide, having octanoyl group at Ser(3), is the minimum active core. In this study, we further explored the structure-function relationships of the active N-terminus portion of ghrelin using a Ca(2+) mobilization assay. The smallest and most potent ghrelin derivative we have found so far is 5-aminopentanoyl-Ser(Octyl)-Phe-Leu-aminoethylamide, showing comparable activity to the natural molecule. In the process of modifying the active core, the ghrelin-derived short analogues emerged structurally close to peptidyl growth hormone secretagogues. The N-terminus modification suggested that Gly(1)-Ser(2) unit works as a spacer, forming adequate distance between N(alpha)-amino group and n-octanoyl group. Replacement of 3rd and 4th amino acid residues to D-isomer suggested that the N-terminal dipeptide contributes to shape the biologically active geometry by effecting conformation of residues in positions 3 and 4.

Amino Acid Sequence↗
PubMed2001

Inhibitory effect of oxcarbazepine on high-frequency firing in peripheral nerve fibers.

We assessed the effects of oxcarbazepine, an antiepileptic derivative of carbamazepine, on discharges in single cutaneous afferent fibers produced by repetitive high-frequency stimulation (mimicking the abnormal excitation of peripheral nerves in neuropathic pain and paresthesia). After intravenous administration of oxcarbazepine, the later responses in the train dropped out without the earlier ones being affected and, thus, the total number of spikes decreased. The latency of the responses to an individual pulse was unchanged. These results, which indicate that oxcarbazepine inhibits the generation of high-frequency firing without affecting impulse conduction, suggest that this drug may be useful against neuropathic pain and paresthesia.

Animals↗
PubMed2001

Correlation among crystal shape, absolute configuration, and circular dichroism spectrum of enantiomorphs of Tris[2-(((2-phenylimidazol-4-yl)methylidene)amino)ethyl]-aminemetal(II) nitrate-methanol (1/1).

A series of metal(II) complexes of a tripod-type ligand with the chemical formulas [M(H(3)L)](NO(3))(2).MeOH (M = Mn (1), Fe (2), Co (3), Ni (4), Zn (6)) and [Cu(H(3)L)](NO(3))(2).CH(3)CN.H(2)O (5) were synthesized and characterized (H(3)L = tris[2-(((2-phenylimidazol-4-yl)methylidene)amino)ethyl]amine). The crystal structures were determined, in which those of 1-4 and 6 are isomorphous and conglomerates, because they crystallize into the acentric space group P2(1)2(1)2(1). Each metal(II) ion of 1-4 and 6 assumes an octahedral coordination environment with the N(6) donor atoms of the tripod ligand and becomes either a C (clockwise) or an A (anticlockwise) enantiomorph because of the screw arrangement of the tripod-type ligand around the metal(II) ion. The crystals were divided into two groups, where their crystal shapes are mirror images and their CD spectra show enantiomeric patterns. The circular dichroism (CD) spectrum of the crystal used for the X-ray analysis was measured. The absolute configuration of the enantiomorph of the crystal used for the X-ray analysis was determined by the Flack parameter. The correlation among the crystal shape, the absolute configuration, and the CD spectral pattern was thus confirmed for 1-4 and 6. On the other hand, 5 assumes a square pyramidal coordination geometry with the N(5) donor atoms, and hence, there are no optical isomers.

Journal Article↗
PubMed2001

Biological characterization and optical imaging of brain-derived neurotrophic factor-green fluorescent protein suggest an activity-dependent local release of brain-derived neurotrophic factor in neurites of cultured hippocampal neurons.

To visualize the release dynamics of the brain-derived neurotrophic factor (BDNF) involved in neural plasticity, we constructed a plasmid encoding green fluorescent protein (GFP) fused with BDNF. First, several biological studies confirmed that this fusion protein (BDNF-GFP) mimics the biological functions and the release kinetics of unfused (native) BDNF. Second, when BDNF-GFP was expressed in cultured hippocampal neurons, we observed that this protein formed striking clusters in the neurites of mature neurons and colocalized with the PSD-95 immunoreactivity. Such a clustered BDNF-GFP rapidly disappeared in response to depolarization with KCl, as revealed by confocal microscopic studies. These data suggest that BDNF is locally and rapidly released at synaptic sites in an activity-dependent manner. Optical studies using BDNF-GFP may provide important evidence regarding the participation of BDNF in synaptic plasticity.

Animals↗
PubMed2001

Ghrelin acts in the central nervous system to stimulate gastric acid secretion.

Ghrelin is a novel acylated peptide that functions in the regulation of growth hormone release and energy metabolism. It was isolated from rat stomach as an endogenous ligand for growth hormone secretagogue receptor. Ghrelin is also localized in the arcuate nucleus of rat hypothalamus. Intracerebroventricular (ICV) administration increases food intake and body weight. We examined the effect of ghrelin on gastric acid secretion in urethane-anesthetized rats and found that ICV administration of ghrelin increased gastric acid output in a dose-dependent manner. Vagotomy and administration of atropine abolished the gastric acid secretion induced by ghrelin. ICV administration of ghrelin also induced c-fos expression in the neurons of the nucleus of the solitary tract and the dorsomotor nucleus of the vagus, which are key sites in the central nervous system for regulation of gastric acid secretion. Our results suggest that ghrelin participates in the central regulation of gastric acid secretion by activating the vagus system.

Animals↗
PubMed2001

Ynolate chemistry. Reaction of a silylynolate with aziridines leading to gamma-lactams.

A silylynolate, generated via the carbonylation of lithium silyldiazomethane, was reacted with N-tosyl aziridines to produce various five-membered lactams in good yields. The key step of this reaction involves the ring-opening ketenylation of aziridines by the silylynolate. The reaction proceeded in a highly stereoselective manner, and ketenylation took place at the less hindered carbon. When treated with aldehydes prior to protonation, the alpha-silylated lactam enolates gave alpha-vinylidene gamma-lactams. These reactions represent a unique path to the generation of and for controlling the reactivity of a rare class of reactive intermediates, namely, acyllithium derivatives and ynolates.

Journal Article↗
PubMed2001

A role for ghrelin in the central regulation of feeding.

Ghrelin is an acylated peptide that stimulates the release of growth hormone from the pituitary. Ghrelin-producing neurons are located in the hypothalamus, whereas ghrelin receptors are expressed in various regions of the brain, which is indicative of central-and as yet undefined-physiological functions. Here we show that ghrelin is involved in the hypothalamic regulation of energy homeostasis. Intracerebroventricular injections of ghrelin strongly stimulated feeding in rats and increased body weight gain. Ghrelin also increased feeding in rats that are genetically deficient in growth hormone. Anti-ghrelin immunoglobulin G robustly suppressed feeding. After intracerebroventricular ghrelin administration, Fos protein, a marker of neuronal activation, was found in regions of primary importance in the regulation of feeding, including neuropeptide Y6 (NPY) neurons and agouti-related protein (AGRP) neurons. Antibodies and antagonists of NPY and AGRP abolished ghrelin-induced feeding. Ghrelin augmented NPY gene expression and blocked leptin-induced feeding reduction, implying that there is a competitive interaction between ghrelin and leptin in feeding regulation. We conclude that ghrelin is a physiological mediator of feeding, and probably has a function in growth regulation by stimulating feeding and release of growth hormone.

Animals↗
PubMed2001

Frequent activation of the beta-catenin-Tcf signaling pathway in nonfamilial colorectal carcinomas with microsatellite instability.

It has been reported that wild-type APC protein forms a complex with beta-Catenin and GSK3beta, inducing degradation of beta-Catenin in normal cells. Both beta-Catenin and APC gene mutations have recently been shown to activate the same signaling pathway. Frequent mutations of beta-Catenin in hereditary nonpolyposis colorectal carcinomas have also been reported. It was, however, controversial whether the mutation of the beta-Catenin gene was frequent in nonfamilial colorectal carcinomas with high-frequency microsatellite instability (MSI-H). We analyzed the mutations of the APC and beta-Catenin genes in 56 nonfamilial colorectal carcinomas stratified according to the presence or absence of microsatellite instability (MSI). APC mutations were identified in 11 of 22 (50%) cases of MSI-H and 14 of 34 (41%) cases of microsatellite-stable (MSS)/low-frequency microsatellite instability (MSI-L). In contrast, the frequency of beta-Catenin mutations was significantly higher in MSI-H (6/22; 27%) than in MSS/MSI-L (1/34; 3%) (P = 0.01). beta-Catenin mutations were not detected in carcinomas with APC mutation. APC mutation occurred irrespective of MSI status. beta-Catenin mutation, however, occurred frequently in MSI-H carcinomas. Our data suggest that activation of the beta-Catenin-Tcf signaling pathway, through either beta-Catenin or APC mutation, frequently contributes to MSI-H nonfamilial colorectal carcinomas (17/22; 77%).

Cadherins↗
PubMed2001

Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration.

Ghrelin is a novel gut-brain peptide that binds to the growth hormone secretagogue receptor (GHS-R), thereby functioning in the regulation of growth hormone (GH) release and food intake. Ghrelin-producing cells are most abundant in the oxyntic glands of the stomach. The regulatory mechanism that governs the biosynthesis and secretion of ghrelin has not been clarified. We report that ghrelin mRNA expression in the gastric fundus was increased, but that ghrelin peptide content decreased after a 48-h fast. Both values returned to control levels after refeeding. The ghrelin plasma concentration in the gastric vein and systemic venous blood increased after 24- and 48-h fasts. Furthermore, des-octanoylated ghrelin and n-octanoylated ghrelin were found in rat stomach, with the ratio of des-octanoylated ghrelin to n-octanoylated ghrelin markedly increased after fasting. The ghrelin mRNA level in the stomach also increased after administration of insulin and leptin. Conversely, db/db mice, which are deficient in the leptin receptor, had lower ghrelin mRNA levels than control mice. These findings suggest that this novel gastrointestinal hormone plays a role in the regulation of energy balance.

Animals↗
PubMed2001

Peripheral T/natural killer-cell lymphoma involving the female genital tract: a clinicopathologic study of 5 cases.

Malignant lymphoma of the female genital tract (FGT) is rare. In this study, 5 peripheral T/natural killer (NK)-cell lymphomas (PTCLs) involving the FGT are reported. They include 2 from the uterus and 1 each from ovary, uterus and ovary, and vagina, and were detected between 1996 and 2000. One of the 2 ovarian tumors was bilateral. In all cases, the FGT was the initial site of clinical presentation of disease. Age at presentation ranged from 21 to 52 years (median, 36 years). One case was stage I disease, 2 were stage II, and 2 were stage IV. All 5 tumors were positive for CD3epsilon, and 3 harbored the Epstein-Barr virus, although the detailed immunophenotypic profiles varied. Three were diagnosed as nasal type T/NK-cell lymphoma, 1 as anaplastic large-cell lymphoma (anaplastic lymphoma kinase [ALK]-positive), and 1 as unspecified PTCL of cytotoxic phenotype, according to the forthcoming World Health Organization classification. Four of 5 patients received laparotomy and chemotherapy. Four patients (in stages II and IV) died of disease within 16 months of the initial diagnosis, whereas only 1 patient (in stage I) is alive without disease at 39 months of follow-up. Our experience in this series provided clinically relevant information on diagnosis, treatment, and outcome for extremely rare tumors of the FGT.

Adult↗
PubMed2001

Assignment of 64 genes expressed in 28-day-old pig embryo to radiation hybrid map.

A swine resource family was constructed at the National Institute of Animal Industry, Japan, in order to determine the genetic regions responsible for economically important traits, including fetus development. To identify genes expressed in the early stage of embryo development, we cataloged and mapped genes expressed in a 28-day-old normal pig embryo. In this effort, we have mapped 64 genes, which have map information in human genome onto a swine radiation hybrid (RH) map, IMpRH. These mappings provided additional chromosomal homologies between swine and human to improve the comparative map between the two species. The distribution of the genes assigned to swine chromosomes are as follows: 9 genes were assigned on SSC6; 6 genes each assigned on SSC5 and SSC14; 5 genes each assigned on SSC3, SSC4, and SSC8; 4 genes each assigned on SSC1, SSC7, SSC9, and SSC15; 3 genes each assigned on SSC2, SSC13 and SSCX; and 1 gene each assigned on SSC10, SSC11, and SSC16. Moreover, the present findings revealed 18 new chromosomal homologies between pig and human. Briefly, SSC3 regions were indicated to correspond with HSA1 and HSA10; SSC4 with HSA6; SSC5 with HSA2, HSA15, and HSA16; SSC6 with HSA3, HSA6, and HSA20; SSC7 with HSA11; SSC8 with HSA3, HSA6, and HSA7; SSC9 with HSA8; SSC13 with HSA1; SSC14 with HSA13; SSC15 with HSA19; SSC16 with HSA9.

Animals↗
PubMed2001

Obsessional personality features in employed Japanese adults with a lifetime history of depression: assessment by the Munich Personality Test (MPT).

BACKGROUND: Although a number of studies have reported on the association between obsessional personality features as measured by the Munich Personality Test (MPT) "Rigidity" scale and depression, there has been no examination of these relationships in a non-clinical sample. METHODS: The dimensional scores on the MPT were compared between subjects with and without lifetime depression, using a sample of employed Japanese adults. The odds ratio for suffering from lifetime depression was estimated by multiple logistic regression analysis. To diagnose a lifetime history of depression, the Inventory to Diagnose Depression, Lifetime version (IDDL) was used. RESULTS: The subjects with lifetime depression scored significantly higher on the "Rigidity" scale than the subjects without lifetime depression. In our logistic regression analysis, three risk factors were identified as each independently increasing a person's risk for suffering from lifetime depression: higher levels of "Rigidity", being of the female gender, and suffering from current depressive symptoms. CONCLUSION: The MPT "Rigidity" scale is a sensitive measure of personality features that occur with depression.

Adolescent↗
PubMed2001

Association of enhanced cyclooxygenase-2 expression with possible local immunosuppression in human colorectal carcinomas.

BACKGROUND: Prostaglandin (PG) E2 has an influence on antitumor lymphocyte reactions and causes local immunosuppression at tumor sites. The contribution of cyclooxygenase (COX), a key enzyme in PGE2 synthesis, to this effect is still unclear. We examined if cyclooxygenase (COX)-2 is involved in local immunosuppression in human colon carcinoma cell lines and in clinical tumor specimens. METHODS: PGE2 concentrations were measured in culture media from a highly COX-2-expressing human colon carcinoma cell line (CE-1) and other cell lines. Lymphocyte proliferation in response to a mitogen was used to evaluate immunosuppression in tumor cell-lymphocyte cocultures with and without selective COX-2 inhibitor NS-398. We also evaluated expression of COX-2 mRNA in surgical specimens of colorectal carcinoma by reverse transcription polymerase chain reaction (RT-PCR) and COX-2 protein by immunohistochemistry, correlating COX-2 expression with clinicopathologic features. RESULTS: CE-1 cells produced large amounts of PGE2, which was significantly inhibited by NS-398. The proliferation index of lymphocytes cocultured with CE-1 cells was significantly less than that of control lymphocytes; again, this effect was inhibited by NS-398. While human colorectal carcinoma tissue expressed more COX-2 mRNA and protein than nonneoplastic tissue, no significant correlation was found between COX-2 levels and clinicopathologic features. CONCLUSIONS: Overexpression of COX-2 in colon cancer may cause local immunosuppression, and COX-2 inhibitors might be therapeutically useful against these tumors.

Adenocarcinoma↗
PubMed2001

Low density lipoprotein receptor mRNA in rat liver is affected by resistant starch of beans.

The effects of resistant starches of beans on serum cholesterol and hepatic low density lipoprotein (LDL) receptor mRNA in rats were investigated. Rats were fed a cholesterol-free diet with 150 g/kg corn starch (CS), 150 g/kg adzuki (Vigna angularis) starch (AS), 150 g/kg kintoki (Phaseolus vulgaris, variety) starch (KS), or 150 g/kg tebou (P. vulgaris, variety) starch (TS) for 4 wk. There were no significant differences in body weight among groups through the experimental period. The liver weight in the CS group was 1.1-1.2 times higher than that in the AS, KS, and TS groups. The cecum weight in the TS was 1.4 times higher than that in the CS group, and the cecal pH in the CS group was significantly higher than in the other groups. The serum total cholesterol, very low density lipoprotein + intermediate density lipoprotein + LDL-cholesterol and high density lipoprotein (HDL)-cholesterol concentrations in the bean starch groups were significantly lower than those in the CS group through the feeding period. The total cholesterol/HDL-cholesterol ratio in the bean starch groups was also significantly lower than that in the CS group at the end of the 4-wk feeding period. The hepatic cholesterol concentration in the TS group was significantly higher than in the CS group at the end of the 4-wk feeding period. The relative quantity of hepatic apo B mRNA in the AS group was 1.2 times higher than that in the CS group, and the hepatic LDL receptor mRNA levels in the AS and TS groups were 1.8-2.0 times higher than that in the CS group. The results of this study demonstrate that AS, KS, and TS lowered the serum total cholesterol level by enhancing the hepatic LDL receptor mRNA level.

Animals↗
PubMed2001

Intracameral and Lenticular Penetration of Locally Applied Deuterium-Labeled Vitamin E in Rats.

Purpose: To confirm the intraocular dynamics of 1% deuterium (D) labeled alpha-tocopheral acetate (VEA) solution.Methods: The concentrations of D(3)-VEA and D(3)-alpha-tocopherol (VE) derived from D(3)-VEA in the aqueous humor and lens were measured after instilling 1% D(3)-VEA continuously into the cul-de-sac of rat eyes for one and three weeks. D(3)-VEA and D(3)-VE concentrations were determined by gas chromatograph/mass spectrometry.Results: D(3)-VEA and D(3)-VE concentrations in the aqueous humor after one and three weeks of continuous administration were 93.1 and 498.9, and 9.4 and 21.5 ng/mL, respectively. The concentrations in the lens were 15.0 and 6.1, and 9.8 and 4.8 ng/g, respectively.Conclusion: The penetration of VEA into the aqueous humor and lens by eyedrop application was confirmed.

Journal Article↗