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Biomedical subjects

M Obata

Publications and source records attributed to M Obata.

At least 37 records · Page 2Linked to original sources
PubMed1996

Identification of the Par2 (Pulmonary adenoma resistance) locus on mouse chromosome 18, a major genetic determinant for lung carcinogen resistance in BALB/cByJ mice.

The A/J mouse strain is 14 times more susceptible to urethane-induction of lung carcinogenesis than the BALB/cByJ strain (BALB). The relative resistance of BALB is dominant over the high sensitivity of A/J, since (BALBxA/J)F1 mice are phenotypically similar to the parental BALB mice. BALB mice must thus possess modifier genes suppressing phenotypic expression of the Pas (Pulmonary adenoma susceptibility) genes, which are known to be dominant genetic determinants for lung carcinogenesis in A/J mice. In order to genetically dissect the dominant resistance of the BALB mouse, we performed a linkage analysis to chromosomally map modifier genes by using 130 (A/JxBALB)F1xA/J backcross mice. Each backcross mouse was injected i.p. with urethane (1 mg/g bw) at 6 weeks of age and lung tumors were enumerated after 120 days. When the backcross mice were genotyped at multiple simple sequence repeat marker loci distributed on all the chromosomes, a significant linkage between the presence of a BALB allele and resistance to lung tumor induction was found on distal chromosome 18 (maximum LOD = 12.2). Thus, distal chromosome 18 of the BALB mouse contains a modifier gene for lung carcinogenesis: The locus, designated Par2 (Pulmonary adenoma resistance), accounted for 38% of the phenotypic variance in the backcross population, indicating a major role in protection against lung tumor development.

Adenoma↗
PubMed1996

Role of urinary trypsin inhibitor in the maintenance of pregnancy in mice.

OBJECTIVE: To investigate the mechanisms whereby urinary trypsin inhibitor prevents lipopolysaccharide-induced preterm delivery in mice. METHODS: On day 15 of pregnancy, C3H/HeNCrg female mice impregnated by Crg:B6D2F1 male mice were treated intraperitoneally with lipopolysaccharide (50 micrograms/kg, twice at a 3-hour interval) to induce preterm delivery. Urinary trypsin inhibitor (2.5 x 10(4), 7.5 x 10(4), or 25 x 10(4) units/kg, ten times at 1-hour intervals) or saline solution was administered intraperitoneally to the animals. RESULTS: The incidence of preterm delivery was significantly decreased on a dose-related basis by urinary trypsin inhibitor treatment. Urinary trypsin inhibitor prevented the morphologic and functional changes in fetal membranes and cervical ripening preceding the onset of preterm delivery. Urinary trypsin inhibitor also suppressed the increase in plasma and amniotic fluid concentrations of interleukin-1 alpha, interleukin-6, and tumor necrosis factor-alpha after the lipopolysaccharide dosing in this animal model for preterm delivery. CONCLUSION: Urinary trypsin inhibitor prevents the pathogenicity of preterm delivery through the suppression of cytokine production.

Animals↗
PubMed1996

Detection by polymerase chain reaction of wild-type measles virus genome in the cerebrospinal fluid of a patient with SSPE who had received measles vaccine.

BACKGROUND: Previous studies have reported that approximately 4-5% of patients with subacute sclerosing panencephalitis (SSPE) were given measles vaccination but had no history of natural measles. However, in the case who received measles vaccine, it has been extremely difficult to determine whether the actual cause of SSPE is the inoculated vaccine virus or not. OBJECTIVES: To detect the measles virus genome in a patient with SSPE and to analyze its nucleotide and deduced amino acid sequence. STUDY DESIGN: We applied the polymerase chain reaction (PCR) to detect the measles virus genome in specimens from a 12-year-old boy with SSPE who had received measles vaccine 10 years before and had no history of apparent natural measles. The oligonucleotide primers for PCR were prepared based on the nucleotide sequence of the F and NP genes of the measles virus Edmonston strain. RESULTS: F and NP genes were detected in both the cerebrospinal fluid and peripheral blood lymphocytes. Nucleotide and deduced amino acid sequence analysis of the F gene showed that the patient's virus was different from that of the vaccine strain. Judging from these results, it was likely that the SSPE-associated strain in this case was derived from the wild-type rather than the vaccine strain. CONCLUSIONS: PCR is a useful method to establish a definitive diagnosis of SSPE and to study the nature of the SSPE-associated virus.

Journal Article↗
PubMed1996

Repeated administration of low-dose lipopolysaccharide induces preterm delivery in mice: a model for human preterm parturition and for assessment of the therapeutic ability of drugs against preterm delivery.

OBJECTIVE: Our purpose was to establish a new animal model for human preterm delivery for assessment of the protective effect of drugs against preterm delivery. STUDY DESIGN: C3H/HeN, C3H/HeN, and BALB/c female mice impregnated by C3H/HeN, B6D2F1, and B6D2F1 male mice, respectively, were treated intraperitoneally with Escherichia coli lipopolysaccharide (0 to 100 microgram/kg, single dose or repeated doses at 1- to 6-hour intervals) on days 12 through 17 of pregnancy. On day 15 of pregnancy, the C3H/HeN females that had been impregnated by B6D2F1 males and administered lipopolysaccharide were treated intraperitoneally with indomethacin (1000 microgram/kg), ritodrine hydrochloride (1000 microgram/kg), urinary trypsin inhibitor (25 x 10(4) units/kg), or gabexate mesylate (100 mg/kg); preterm or term delivery was recorded for these mice. RESULTS: C3H/HeN females impregnated by B6D2F1 males revealed the highest (100%) incidence of preterm delivery when the females were treated with 50 microgram/kg lipopolysaccharide twice at a 3-hour interval on day 15 or 17 of pregnancy. Indomethacin and urinary trypsin inhibitor used separately significantly decreased the incidence of preterm delivery, but only urinary trypsin inhibitor, and not any of the other drugs, significantly increased the incidence of term delivery in the mice. CONCLUSION: A new animal model for investigation of preterm delivery was established, and its usefulness for assessment of the protective effect of drugs against preterm delivery was demonstrated.

Animals↗
PubMed1996

Usefulness of a new tactile sensor for measurement of uterine cervical ripening in mice in a quantitative and noninvasive manner.

OBJECTIVE: The purpose of this study was to establish a method with a new tactile sensor for determining in a quantitative and noninvasive manner the extent of uterine cervical ripening. STUDY DESIGN: We used a newly designed tactile sensor to measure the softness of the cervix in untreated nonpregnant, pregnant, parturient, and nursing mice and then on day 15 of gestation in pregnant mice treated with dehydroepiandrosterone sulfate or Escherichia coli lipopolysaccharide. Additionally, to elucidate the correlation between the extent of cervical softness and its morphologic changes, we observed microscopically the uterine cervices. RESULTS: The hardness of the murine cervix decreased with the progression of pregnancy and became minimal at delivery. We demonstrated for the first time with a tactile sensor for measuring hardness that dehydroepiandrosterone sulfate and lipopolysaccharide significantly decreased the stiffness of the murine cervix. These findings were supported by the morphologic observations on the cervices. CONCLUSIONS: These results show that the tactile sensor for measuring hardness makes it possible to determine the extent of cervical ripening quantitatively rather than qualitatively. We consider that cervical ripening determined objectively in this manner is a good parameter to predict the onset of preterm delivery.

Animals↗
PubMed1992

Polymorphonuclear leukocyte function and serum opsonic activity in surgical patients.

Thirty-six patients who underwent major surgery were studied in order to clarify the perioperative changes in polymorpho - nuclear leukocyte (PMNL) function and serum opsonic activity. In patients without postoperative infection, the PMNL phagocytic-bactericidal capacity and plasma elastase levels significantly increased, while the serum opsonic index remarkably decreased just after surgery, however, all returned to the preoperative levels within 1 or 2 weeks. Conversely, in patients with postoperative infection, the PMNL bactericidal capacity and plasma elastase levels remained at high levels even after 1 or 2 weeks, while the PMNL phagocytic capacity and serum opsonic index substantially decreased after 2 weeks compared with the patients without postoperative infection. Plasma leukotriene B4, which is a potent chemo-attractant for PMNL, noticeably decreased in the patients with postoperative infection on the first postoperative day compared with that in the patients without postoperative infection. Our data suggests that the most important predisposing factors to postoperative infection may be a depressed PMNL phagocytic capacity and a lower serum opsonic activity after surgery, and that the increased PMNL bactericidal capacity and high plasma elastase levels during postoperative infection may contribute to the susceptibility to multiple organ failure.

Adult↗
PubMed1992

Functional assessment of the stratum corneum under the influence of oral aromatic retinoid (etretinate) in guinea-pigs and humans. Comparison with topical retinoic acid treatment.

Clinically we have noted that the skin of patients treated with long-term oral etretinate becomes uniformly soft and smooth to touch, like facial skin that becomes smoother and less wrinkled following treatment with topical tretinoin. This suggests that retinoids, whether used systemically or topically, alter the physical properties of the skin, particularly of the stratum corneum (SC). To study the influence of retinoids on the SC, we serially assessed the functional properties of the SC non-invasively in retinoid-treated humans and experimental animals. SC hydration and barrier function were assessed by measurement of high-frequency conductance and transepidermal water loss (TEWL), respectively. Daily application of topical retinoic acid creams was found to rapidly induce a time- and dose-dependent, linear increase in SC hydration of the forearm skin of healthy adults over a 2-week period and to compromise its water barrier function in a similar fashion. Systemic administration of high-dosage etretinate, 4 or 8 mg/kg/day, to guinea-pigs also induced dose-dependent increases in both SC hydration and TEWL measured on the plantar skin after 1 month. Moreover, in the animals given etretinate 4 mg/kg/day we confirmed a slight but significant decrease in the number of cell layers of the plantar SC. Likewise, patients with various dermatoses began to show similar functional changes of the SC in the uninvolved skin of the flexor surface of the forearms 3 weeks after the start of oral etretinate treatment, consisting of 50 mg daily for 2 weeks, followed by gradual dose tapering.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Synthesis and biological activities of optical isomers of 2-(4-chlorophenyl)-5,6-dihydro-(1)benzothiepino[5,4-c]pyridazin-3(2H)-o ne 7-oxide.

Two enantiomers of 2-(4-chlorophenyl)-5,6-dihydro-(1)benzothiepino[5,4- c]pyridazin-3(2H)-one 7-oxide ((+/-)-1: Y-23684) were synthesized in high yields by asymmetric oxidation of the synthetic precursor (2) using modified Sharpless reagent. Among the oxidants tested, cumene hydroperoxide (CHP) gave the highest optical and chemical yields, while tert-butyl, tert-amyl, and 1,1,3,3-tetramethylbutyl hydroperoxides did not show such high enantio-selectivities. The absolute configuration of (+)-1 enantiomer synthesized from 2, Ti(O-iso-Pr)4, (-)-diethyl tartarate, and CHP was determined to be S by X-ray crystallographic analysis. Both enantiomers, S-(+)-1 and R-(-)-1, and (+/-)-1 had approximately equivalent in vivo activities to antibicuculline test in mice and anticonflict test in rats, although S-( + )-1 showed about three times higher affinity to benzodiazepine receptor than R-(-)-1 in [3H]diazepam binding assay.

Animals↗
PubMed1992

[Investigation of lipid peroxidation in regenerating rat liver].

The purpose of this study was to estimate the effects of lipid peroxidation in regenerating rat liver. Partial 70% hepatectomy was performed in rat according to Higgings and Anderson. EPC (alpha Toc: Ascorbic acid = 6:4, radical scavenger) was injected intravenously (5mg/kg weight) one hour before operation. Lipid peroxidation in regenerating liver reached a peak at 24 hours after operation. The administration of EPC markedly suppressed the increase of lipid peroxide in the plasma and remnant liver and that of GPT after hepatectomy, with subsequent good liver regeneration ratio. Moreover, the pretreatment with EPC remarkably elevated the activity of thymidine kinase (index of DAN synthesis). The EPC administration had not notable effects on the level of plasma ketone body ratio in animal but pathologically caused early advent of glycogen granule in the remnant liver tissue after partial hepatectomy, which reflected restoration of mitochondrial energy level. The results of the present study suggest that scavenger may be useful not only for impairment of liver dysfunction but also for recovery of mitochondrial energy level and DNA synthesis after liver resection.

Alanine Transaminase↗
PubMed1991

Vertebrate collagenase inhibitor. II. Tetrapeptidyl hydroxamic acids.

To develop a potent and specific collagenase inhibitor, a series of tetrapeptidyl hydroxamic acids were synthesized, based on the previous findings with tripeptidyl derivatives (Chem. Pharm. Bull., 38, 1007-1011, 1990). Among the series of tetrapeptidyl derivatives synthesized, R-Gly-Pro-Leu-Ala-NHOH and R-Gly-Pro-D-Leu-D-Ala-NHOH were found to be highly specific and potent inhibitors against vertebrate collagenase with an IC50 of 10(-6) M order, where R stands for Boc or acyl group. Analysis of their structure-activity relationships showed a characteristic feature of the substrate-binding site of collagenase as follows: 1) the S1 subsite forms a shallow hydrophobic pocket, although glycine residue corresponds to the subsite of the natural collagen substrate: 2) the S2 subsite constitutes a bulky pocket with less requirement for hydrophobicity: 3) the S3 subsite preferentially accommodates Pro residue: and 4) the accommodation of the P4-P1 subsites of peptidyl collagenase inhibitor to the S4-S1 subsites is required to form a tight binding of its hydroxamic acid moiety to the zinc ion at the catalytic site of the enzyme. The introduction of an enantiometric dipeptide unit, D-Leu-D-Ala, to the P2-P1 subsites demonstrated an increased binding capacity to the extended S4-S1 subsites of collagenase, thus providing proteinase-resistant inhibitor.

Amino Acid Sequence↗
PubMed1991

Studies on the synthesis of condensed pyridazine derivatives. IV. Synthesis and anxiolytic activity of 2-aryl-5,6-dihydro-(1)benzothiepino[5,4- c]pyridazin-3(2H)-ones and related compound.

A series of 2-aryl-5,6-dihydro-(1)benzothiepino[5,4-c]pyridazin-3(2H)- ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo. Compounds with a 4'-methoxyphenyl (36) or 4'-chlorophenyl group (37, 39--42) as 2-aryl substituents showed prominent activities in both the in vitro and in vivo tests. Among them, 2-(4'-chlorophenyl)-5,6-dihydro- (37) and 2-(4'-chlorophenyl)-5,6-dihydro-10-fluoro-(1)benzothiepino[5,4-c]+ ++pyridazin- 3(2H)-one 7-oxides (41) showed activity twice as potent as diazepam in an anticonflict test (Vogel type, rats) while exhibiting less muscle relaxation (rotarod test, mice) and augmentation of gamma-aminobutyric acid-induced chloride current (Icl) in isolated frog sensory neurones than diazepam. Compound 37 (Y-23684) was selected from this series as a candidate for further development. The structure-activity relationships are discussed.

Animals↗
PubMed1990

Vertebrate collagenase inhibitor. I. Tripeptidyl hydroxamic acids.

A series of tripeptidyl analogues carrying hydroxamic acid residue at the C-terminus of the molecule were synthesized, and their inhibitory activities against vertebrate collagenase and other metalloenzymes including bacterial collagenase were examined. Both Z-Pro-Leu-Ala-NHOH and Z-Pro-D-Leu-D-Ala-NHOH showed highly specific and potent inhibitory activity against tadpole and human skin collagenases with an IC50 of 10(-6) M order.

Amino Acid Sequence↗
PubMed1990

[Studies on the synthesis of condensed pyridazine derivatives. II. Synthesis and anxiolytic activities of 2-aryl-4,4a,5,6-tetrahydropyridazino[4,3-c]quinolin-3(2H)-ones, 2-aryl-4a,5-dihydro-2H-(1)benzothiopyrano[4,3-c]pyridazin-3(4H)-ones, and related compounds].

A series of 2-aryl-4,4a,5,6-tetrahydropyridazino[4,3-c]quinolin-3(2H)- ones, 2-aryl-4a,5-dihydro-2H-(1)benzothiopyrano[4,3-c]pyridazin-3( 4H)-ones, and related compounds were synthesized and tested for their ability to displace [3H]diazepam from rat brain membranes in vitro, and to prevent bicuculline-induced convulsions in mice in vivo. Among them, 2-(4-chlorophenyl)-4a,5-dihydro-2H-(1)benzothiopyrano[4,3-c]pyr idazin-3(4H)- one (16b) showed remarkable activities both in vitro (Ki 48 nM) and in vivo (ED50 12.4 mg/kg, p.o.). The trans sulfoxide (19a) of 16b exhibited anxioselective pharmacological activities. Compound 19a was equipotent with diazepam in the anticonflict assay (Vogel type, rat, MED 10 mg/kg, p.o.) while exhibiting reduced muscle relaxation (rotarod test) and narcotic potentiation. The structure-activity relationships are discussed.

Animals↗
PubMed1990

Immunogenetic analysis of beta-cell autoimmunity in NOD mice. Relationship of insulitis to T-lymphocyte-receptor beta nod and A beta nod genes.

An early molecular event in the evolution of insulin-dependent diabetes in humans and NOD mice appears to involve the interaction of MHC class II molecules, beta-cell autoantigen-derived peptides, and receptor molecules of helper T lymphocytes. To examine the influence of T-lymphocyte-receptor beta-genes on the development of beta-cell autoimmunity, (NOD x NZW)F1 x NOD backcrossed (BC) mice were studied for the development of insulitis, because insulitis is the pathognomonic histological lesion of autoimmune diabetes. Heterozygosity for H-2nod was permissive for the development of pancreatic interstitial inflammation and peri-islet insulitis, whereas homozygosity for H-2nod was highly associated with insulitis. However, (NOD x NZW)F1 x NOD BC mice developed insulitis regardless of homozygosity or heterozygosity for T-lymphocyte receptor beta nod. Therefore, in our study, T-lymphocyte receptor beta nod did not function as an autosomal-recessive beta-cell autoimmunity gene.

Animals↗