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Biomedical subjects

H Nagase

Publications and source records attributed to H Nagase.

At least 235 records · Page 13Linked to original sources
PubMed1996

Multigenic control of skin tumour development in mice.

Different inbred mouse strains vary greatly in their susceptibility to tumour development in a variety of tissues. Intraspecific and interspecific crosses can, therefore, be used to map the loci that control this predisposition. Crosses of Mus musculus with Mus spretus are highly resistant to tumour development in the skin, liver, lung and lymphoid system. M. spretus, therefore, has dominantly acting resistance loci, which we have attempted to map. More than 350 interspecific backcross mice were followed for 18 months to assess susceptibility to development of chemically induced papillomas and carcinomas. The results were analysed using a combination of MAPMAKER/QTL analysis and multiple regression analysis for the determination of linkage in multigenic quantitative traits. The results showed clearly that at least three genes on chromosomes 5 and 7 control resistance to tumour development. Importantly, some genes confer resistance to benign tumours but they have relatively little effect on malignant progression. This suggests the existence of different classes of benign tumours: those that are capable of tumour progression and those that have only a very low probability of becoming malignant. Identification of these genes will improve our understanding of mechanisms of carcinogenesis and may provide a novel route to the identification of "low-penetrance' human tumour susceptibility genes.

Animals↗
PubMed1996

Change in digital blood flow with simultaneous reduction in plasma endothelin induced by hand-arm vibration.

Involvement of endothelium-derived relaxing factor (EDRF) or endothelium-derived constricting factor (EDCF) has been proposed as the pathophysiologic mechanism of vibration-induced white finger (VWF). Recent evidence that endothelin is a potent vasoconstrictor peptide indicates that it may play a role in vasoregulation during vibration exposure through the local actions of EDRF or EDCF. Therefore, we examined the effects of grasping (50 N) and hand-arm vibration (50 m/s2 rms, 120 Hz, x-axis) on digital blood flow (DBF) and on the level of plasma endothelin in seven healthy male office workers. Grasping decreased DBF without affecting endothelin, and vibration increased DBF with a simultaneous reduction in endothelin. The grasping-induced decrease in DBF seemed to be due to mechanical compression of the vessels. The negative correlation between DBF and endothelin during vibration exposure suggests that a reduction in release of endothelin from smooth muscle into the vessel cavity during vibration leads to vasodilatation, possibly attributable to the local axon reflex.

Arm↗
PubMed1996

Uterine circulatory dysfunction induced by whole-body vibration and its endocrine pathogenesis in the pregnant rat.

Effects of whole-body vibration on normal pregnancy were studied in the rat. Uterine blood flow and five endocrine functions corticosterone (CS), estradiol (E2), progesterone (P), prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) concentration were measured in rats exposed to whole-body vibration with an acceleration of 10 m.s-2 at a frequency of 8 Hz. While no change in uterine blood flow was observed in control rats, uterine blood flow was significantly decreased 75 and 90 min after exposure to vibration. The uterine blood flow at 15 and 30 min was increased by pretreatment with intraperitoneal injections of angiotensin II (AII). In contrast, in AII pretreated rats exposed to the vibration, uterine blood flow was significantly reduced 90 min after exposure. The CS concentration was increased by vibration independently of the pretreatment with AII. Neither E2 nor PGF2 alpha concentration were changed by the vibration with or without AII administration. The P and PGE2 concentrations were both decreased by vibration in the absence of AII, while the decrease in PGE2 induced by the vibration was also found in AII-treated rats. The present results indicated that the pregnant rats subjected to whole-body vibration responded with changes in uterine and ovarian function. The observed decrease in uterine blood flow may have been the result of reduced PGE2 concentration resulting from an indirect effect of vibration.

Animals↗
PubMed1996

The effects of dopamine D1 and D2 receptor antagonists on the rewarding effects of delta 1 and delta 2 opioid receptor agonists in mice.

The effects of the dopamine D1 antagonist SCH23390 and the D2 antagonist sulpiride on the rewarding effects of delta opioid receptor agonists were examined in mice. Both [D-Pen2, Pen5]enkephalin (DPDPE, 1-15 nmol, ICV), a selective delta 1 opioid receptor agonist, and [D-Ala2]deltorphin II (DELT, 0.5-5 nmol, ICV), a selective delta 2 opioid receptor agonist, produced a dose-dependent place preference in mice. The DPDPE (15 nmol, ICV)-induced place preference was abolished by BNTX (0.5 mg/kg, SC), a delta 1 opioid receptor antagonist, but not by NTB (0.5 mg/kg, SC), a delta 2 opioid receptor antagonist. In contrast, the DELT (5 nmol, ICV)-induced place preference was antagonized by NTB, but not BNTX. Pretreatment with SCH23390 (3 micrograms/kg, SC) abolished the DPDPE-induced place preference, but not affect the DELT-induced place preference. Moreover, pretreatment with sulpiride (40 mg/kg, SC) did not modify the place preference induced by DPDPE or DELT. In the present study, we found that the activation of both central delta 1 and delta 2 opioid receptors produced rewarding effects. Furthermore, these results suggest that the rewarding effects of delta 1 opioid receptor agonist may be produced through activation of the central dopaminergic system, especially dopamine D1 receptors, whereas the rewarding effects of delta 2 opioid receptor agonists may be produced by some other mechanism(s).

Animals↗
PubMed1996

Use of antisense oligodeoxynucleotide to determine delta-opioid receptor involvement in [D-Ala2]deltorphin II-induced locomotor hyperactivity.

Intracerebroventricularly (i.c.v.)-administered [D-Ala2]deltorphin II (20 micrograms) produced a marked locomotor hyperactivity in male ICR mice. The locomotor hyperactivity induced in response to i.c.v. [D-Ala2]deltorphin II (20 micrograms) was suppressed by pretreatment with naltriben (NTB, 10 micrograms) but not 7-benzylidene naltrexone (BNTX, 1 microgram) and D-Phe-Cys-Tyr-D-Try-Orn-Thr-Phe-Thr-NH2 (CTOP, 100 ng). The influence of antisense oligodeoxynucleotide to delta-opioid receptor mRNA (delta-AS oligo) or a mismatch oligodeoxynucleotide (MM oligo) on the locomotor hyperactivity induced by [D-Ala2]deltorphin II was determined. Groups of mice pretreated i.c.v. with delta-AS oligo (1 microgram), MM oligo (1 microgram) or saline (4 microliters) once a day for 3 days, were injected i.c.v. [D-Ala2]deltorphin II (10 or 20 micrograms) and the locomotor response to [D-Ala2]deltorphin II was measured. The locomotor hyperactivity of i.c.v. [D-Ala2]deltorphin II (10 or 20 micrograms) were significantly suppressed by i.c.v. pretreatment with delta-AS oligo but not MM oligo. The present results indicate that pretreatment with delta-AS oligo suppresses mouse locomotor hyperactivity produced by stimulation of delta 2-opioid receptors in the brain.

Amino Acid Sequence↗
PubMed1996

Effects of pyruvate and lactate on food intake in rat strains sensitive and resistant to dietary obesity.

We have investigated the effects of peripherally administered pyruvate and lactate on the intake of high fat (HF) and low fat (LF) diets by a strain of rat either sensitive (Osborne-Mendel, OM) or resistant (SSB/Pl) to high fat-induced obesity. Both pyruvate and lactate inhibited the intake of HF and LF diets by OM rats and these effects were blocked by selective hepatic vagotomy. In contrast, in S5B/Pl rats fed an LF diet the responses to pyruvate and lactate were attenuated and were absent in S5B/Pl rats fed the HF diet. These data suggest that OM and S5B/Pl rats differ either in their metabolism of pyruvate and lactate or in their responses to these metabolites.

Animals↗
PubMed1996

Matrix metalloproteinase (stromelysin-1) increases the albumin permeability of isolated rat glomeruli.

Matrix metalloproteinases (MMPs) secreted by connective tissue cells are capable of acting on extracellular matrix components of glomerular basement membrane at a slow rate and thus may play a role in the control of protein permeability and in the progression of certain kinds of glomerulonephritis. We have used an in vitro assay to measure the direct effect of three MMPs and human neutrophil elastase on glomerular albumin permeability (Palbumin). Glomeruli were isolated from normal male Sprague-Dawley rats and suspended in isolation medium with or without interstitial collagenase, gelatinase-A, stromelysin-1, or elastase and were incubated at 37 degrees C for up to 4 hours. A tissue-specific inhibitor of matrix metalloproteinases (TIMP-1) and a plasma proteinase inhibitor, alpha2-macroglobulin (alpha2M), were used to block the activity of MMPs. Palbumin was calculated from the change in glomerular volume in response to an applied oncotic gradient. In this study stromelysin-1 (10 microg/ml) and elastase (5 microg/ml) increased Palbumin significantly. Stromelysin-1 increased Palbumin after 4 hours, whereas elastase had an effect after 2 hours. Lower concentrations of stromelysin-1 or shorter incubation time had no effect on Palbumin. Incubation for up to 4 hours with interstitial collagenase (10 microg/ml) or gelatinase-A (10 microg/ml) had no effect on Palbumin. Coincubation with TIMP-1 and alpha2M blocked the stromelysin-1-mediated increase in Palbumin. We conclude that stromelysin-1 is capable of affecting the glomerular filtration barrier directly and that it may play an important role in causing proteinuria in glomerular diseases.

Albumins↗
PubMed1996

Possible involvement of mu 2-opioid receptor-mediated mechanisms in morphine-induced enhancement of the pentobarbital-induced loss of the righting reflex in the mouse.

The effects of pretreatment with selective mu-, delta- and kappa-opioid receptor antagonists on the enhancement of the pentobarbital-induced loss of the righting reflex by morphine were examined in mice. Mice injected with pentobarbital (50 mg/kg, i.p.) showed an increased duration for the loss of the righting reflex after administration of morphine. This enhancement of the pentobarbital-induced loss of the righting reflex produced by morphine (10 mg/kg, s.c.) was significantly antagonized by pretreatment with beta-funaltrexamine, a selective mu-opioid receptor antagonist, but not by pretreatment with naloxonazine, a selective mu 1-opioid receptor antagonist. Furthermore, neither naltrindole, a selective delta-opioid receptor antagonist, nor nor-binaltorphimine, a selective kappa-opioid receptor antagonist, had a significant effect on the enhancement of the pentobarbital-induced loss of the righting reflex by morphine. These results suggest that mu 2-, rather than mu 1-, delta- and kappa-, opioid receptor-mediated mechanisms are involved in the morphine-induced enhancement of the pentobarbital-induced loss of the righting reflex.

Animals↗
PubMed1996

Enhanced invasiveness of tumour cells after host exposure to heavy metals.

The invasiveness of tumour cells to heavy metal-exposed host cells or tissues was investigated. Human fibrosarcoma cell invasion of heavy metal-treated fibroblast or endothelial cell was enhanced in a treatment-time-dependent manner although tumour cell attachment to host cells was not affected. This enhancement was correlated with an increase in metallothioneins in the cytosol of fibroblasts or endothelial cells. Mouse melanoma cell invasion of organ samples obtained from syngeneic mice who had been administered heavy metals was also enhanced. The results suggest that heavy metal-induced metallothioneins serve as a host-derived factor in malignant disease and closely relate to metastasis.

Animals↗
PubMed1996

Matrix metalloproteinases and TIMPS in cultured C57BL/6J-cpk kidney tubules.

Restructuring of basement membranes is a hallmark of the pathology of renal cystic disorders. Here, we present findings consistent with the view that basement membrane degradation by matrix metallo-proteinases (MMPs) may contribute to abnormal basement membrane structure in polycystic kidney disease. Cells from cystic kidney tubules embedded in collagen gels appeared to migrate through the gel. This migration through collagen indicated that these cells could degrade the matrix. To examine this activity, we cultured cystic kidney tubules derived from the C57BL/6J cpk/cpk mouse, a hereditary model of polycystic kidney disease, and assayed conditioned medium for the presence of MMPs and tissue inhibitors of metalloproteinases (TIMPs). The conditioned medium from the cystic tubules contained higher than normal levels of MMP-9, MMP-2, and MMP-3 as well as TIMP-1 and TIMP-2. A 101 kDa protease was present equally in cystic and control cultures and although inhibited by EDTA, it was not inhibited by TIMPs, nor activated by the mercurial compound APMA. These data suggest that cystic kidney tubules synthesize and secrete high levels of MMPs which may then participate in the restructuring of the tubular basement membrane.

Animals↗
PubMed1996

Effect of depolymerized holothurian glycosaminoglycan (DHG) on the activation of factor VIII and factor V by thrombin.

Our previous study has shown that depolymerized holothurian glycosaminoglycan (DHG) has two different inhibitory activities in the blood coagulation cascade: heparin cofactor II-dependent thrombin inhibition; and antithrombin III- and heparin cofactor II-independent inhibition of the intrinsic factor Xase complex [Nagase et al. (1995) Blood 85, 1527-1534]. In the present study, the effect of DHG on the activation of factor VIII and factor V by thrombin was examined with purified human components. DHG inhibited the activation of factor VIII by thrombin at concentrations exceeding 80 nM, but not the activation of factor V by thrombin at concentrations of up to 8 mu M. On Western blot analysis, DHG inhibited the cleavage of factor VIII light chain at concentrations exceeding 0.8 mu M. The interaction between DHG and factors VIII and V and thrombin was examined with a DHG-cellulofine column. DHG had strong affinity for factor V and thrombin, but slight affinity for factor VIII. The interaction of DHG with thrombin was analyzed, using fluorescein isothiocyanate-labeled DHG. One mole of DHG bound 2 mol of thrombin, with a dissociation constant (Kd) of 3.04 x 10(-6) M. These results suggest that DHG interferes with the interaction between thrombin and factor VIII, probably by making a binary complex through the anionic binding exosite II of thrombin.

Animals↗
PubMed1996

Family history-related risk of gastric cancer in Japan: a hospital-based case-control study.

In Japan, there have been a few reports on the familiar factors of gastric cancer (GC) and on the GC risk related to family history (FH) at other cancer sites. We analyzed the association between GC occurrence and a positive FH of cancer of the stomach and of other sites in a hospital-based case-control study. The subjects included cases histologically confirmed as incident cancer of the stomach (n = 136; 86 male and 50 female patients) and sex and age (+/- 1 year)-matched controls. GC risk was high when a subject had a parental history of GC [Mantel-Haenszel odds ratio adjusted for sex and age (OR)=2.3; 95% confidence interval (95% CI):1.1-5.0]. GC risk was almost unity for a cancer FH of any other cancer site, even among closer relatives, suggesting little or no contribution to GC occurrence. The familial occurrence of GC found in this study suggests the existence of a genetic susceptibility to cancer of the stomach. Further, females tended to show higher GC risks than males, when reporting an affected mother (OR=6.0; 95% CI:1.1-31.4 and OR= 1.4; 95% CI:0.4-4.8, respectively), whereas males showed a slightly higher risk than females when reporting an affected father (OR=2.4; 95% CI:0.8-7.5 and OR=2.3; 95% CI:0.4-15.6, respectively). This suggests a possible gender difference in how environmental factors influence GC occurrence. The development of gastric tumors seems to be due to a complex and unknown interaction between environmental and genetic factors.

Aged↗
PubMed1996

Pyruvate and hepatic pyruvate dehydrogenase levels in rat strains sensitive and resistant to dietary obesity.

This study compared the effects of exogenous pyruvate and lactate on the serum levels of pyruvate, lactate, glucose, alanine, and insulin, as well as the activity of hepatic pyruvate dehydrogenase (PDH) in strains of rat that were either sensitive [Osborne-Mendel (OM)] or resistant (S5B/Pl) to high-fat diet-induced obesity. Serum pyruvate and lactate were significantly higher and glucose lower in ad libitum-fed OM rats, but these differences disappeared after an 18-h fast. The increase in pyruvate and lactate after exogenous pyruvate administration was significantly greater in S5B/Pl rats than OM rats. There were no differences in serum alanine with strain or diet. The total PDH activity was similar across strains and diets but the proportion of PDH in its activated form (PDHa) was decreased in ad libitum-fed S5B/Pl rats. Pyruvate injection increased insulin and hepatic PDHa activity in OM rats fed both high- and low-fat diets, but these responses were greatly attenuated or absent in S5B/Pl rats. The data are consistent with the hypothesis that modulation of carbohydrate oxidation by PDH may be related to susceptibility to obesity when rats are fed a high-fat diet.

Animals↗
PubMed1996

Translational augmentation of pro-matrix metalloproteinase 3 (prostromelysin 1) and a tissue inhibitor of metalloproteinases (TIMP)-1 mRNAs by epidermal growth factor and transforming growth factor alpha, but not by interleukin 1 alpha or 12-O-tetradecanoylphorbol 13-acetate in human uterine cervical fibroblasts: the possible involvement of an atypical protein kinase C.

We have previously reported that epidermal growth factor (EGF) augments the translation of pro-matrix metalloproteinase 3 (proMMP-3/prostromelysin 1) and tissue inhibitor of metalloproteinases (TIMP)-1 mRNAs during the first 1-h treatment of human uterine cervical fibroblasts (Hosono, T. et al., FEBS Lett., 381, 115-118, (1996)). In this report, we have investigated the effect of interleukin 1 alpha (IL-1 alpha) and 12-O-tetradecanoylphorbol 13-acetate (TPA), potent stimulators of proMMPs and TIMP-1 production, on the translation of proMMP-3 and TIMP-1 mRNAs. When human uterine cervical fibroblasts were treated with IL-1 alpha or TPA for 2h, their translations were not augmented, whereas the steady-state levels of proMMP-3 and TIMP-1 mRNAs in the cells treated with these stimuli for 24 h were increased 13.3- and 1.3-fold by IL-1 alpha and 52.5- and 5.7-fold by TPA, respectively. By contrast, transforming growth factor alpha(TGF alpha), which also binds to EGF-receptor, enhanced their production as early as 2 h after treatment, indicating that growth factors that bind to EGF-receptor are likely to be involved in the translational enhancement of proMMP-3 and TIMP-1 mRNAs. EGF partially translocated cytoplasmic protein kinase C (PKC) to plasma membrane, but the PKC down-regulation induced by 100nM TPA did not diminish the EGF-mediated translational augmentation of proMMP-3 and TIMP-1 mRNAs. In contrast, the PKC inhibitor of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) effectively suppressed the translational regulation of proMMP-3 and TIMP-1 in a dose-dependent manner during the first 2-h treatment with EGF. These results suggest that EGF and TGF alpha, but not IL-1 alpha and TPA, specifically augment the translation of proMMP-3 and TIMP-1 mRNAs and accelerate their accumulation without modifying their transcripts during the first 1-2 h treatment of human uterine cervical fibroblasts. This translational augmentation is suggested to be mediated by a TPA-insensitive atypical PKC subclass in the PKC family.

Cervix Uteri↗
PubMed1996

Immunolocalization of the matrix metalloproteinases gelatinase B and stromelysin 1 in human endometrium throughout the menstrual cycle.

Immunolocalization techniques were used to examine the distribution of the matrix metalloproteinases gelatinase B and stromelysin 1 in human endometrial specimens, taken across the normal menstrual cycle. Gelatinase B was produced by glandular epithelial cells for approximately 7 days during the proliferative phase, with polymorphonuclear leucocytes, macrophages and eosinophils providing most of this enzyme at menstruation. There was no evidence that gelatinase B is produced by stromal cells or mast cells during the cycle. Immunoreactive gelatinase B in glandular epithelial cells was greatest during the late proliferative phase and just after ovulation; its presence in glandular secretion and the uterine fluid was optimal during the peri-implantation phase. Gelatinase B was clearly associated with an influx of polymorphonuclear leucocytes, macrophages and eosinophils just before, and during, menstruation. In contrast, immunostaining for stromelysin 1 was much weaker than that for gelatinase B, and was present only around stromal cells and limited to microfocal locations at times coincident with stromal oedema (days 8-10 and 21-22). Both enzymes were widely distributed in specimens just before and during menstruation, and were particularly prominent in connective tissue stroma and vascular basement membranes. Specimens at the early proliferative stage were devoid of both enzymes. The data provide further evidence supporting a role for metalloproteinases in endometrial biology, not only in matrix remodelling during the cycle, but also in glandular secretions potentially relevant to blastocyst recognition and implantation. Our observations emphasize the functional importance of specific cell types and the temporal regulation of gelatinase B and stromelysin 1 throughout the normal menstrual cycle.

Collagenases↗
PubMed1996

Effect of matrix glycation on expression of type IV collagen, MMP-2, MMP-9 and TIMP-1 by human mesangial cells.

Human mesangial cells grown in either 5 or 25 mM glucose were cultured on type IV collagen which had been previously control-incubated or in vitro glycated. Northern blot analysis revealed that after 3-7 days in culture mesangial cells on glycated type IV collagen expressed approximately 25-200% more alpha 1 (IV), approximately 20-50% less matrix metalloproteinase 2 (MMP-2), and 65-75% more tissue inhibitor of metalloproteinase 1 (TIMP-1). Decreased immunoreactivity (approximately 30-40%) and collagenolytic activity (approximately 10-40%) corresponding to MMP-2 was also detected in media conditioned during the third day of culture on glycated type IV collagen. These effects on cell function were related to the extent of type IV collagen modification and were similar for cells cultured in 5 or 25mM glucose. Elevated glucose (25 vrs 5 mM) increased expression of alpha 1 (IV) mRNA (approximately 40-70%) and in conjunction with matrix glycation resulted in detectable levels of MMP-9 message by northern blot although collagenolytic activity corresponding to MMP-9 was not detectable by zymography. We conclude that glucose and matrix glycation may each alter mesangial cell function, perhaps leading to an imbalance in mesangial matrix synthesis and degradation which could contribute to mesangial expansion characteristic of diabetic renal disease.

Blotting, Northern↗
PubMed1996

Effect of the highly selective and nonpeptide delta opioid receptor agonist TAN-67 on the morphine-induced place preference in mice.

The effect of 2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12a alpha-octahydroquinolino [2,3,3,-g]isoquinoline (TAN-67), a selective non-peptide delta opioid receptor agonist, on the morphine-induced place preference was examined in mice. Morphine (1-5 mg/kg, s.c.) produced a dose-related place preference in mice. In contrast, administration of TAN-67 (5-20 mg/kg, s.c.) did not result in a preference for either the drug- or vehicle-associated place. When TAN-67 (5-20 mg/kg, s.c.) was coadministered with morphine (1 mg/kg, s.c.), the morphine-induced place preference was enhanced dose dependently, and this effect of TAN-67 was suppressed by the pretreatment with naltrindole (1 mg/kg, s.c.), a nonselective delta opioid receptor antagonist, 7-benzylidenenaltrexone (0.05 and 0.5 mg/kg, s.c.), a selective delta 1 opioid receptor antagonist, and naltriben (0.05 and 0.5 mg/kg, s.c.), a selective delta 2 opioid receptor antagonist. In biochemical study, morphine (1 mg/kg, s.c.) or TAN-67 (20 mg/kg, s.c.) alone did not modify dopamine turnover in the limbic forebrain. Coadministration of TAN-67 (20 mg/kg, s.c.) with morphine (1 mg/kg, s.c.) increased DA turnover in the limbic forebrain. This increase in DA turnover in the limbic forebrain was suppressed by pretreatment with naltrindole (1 mg/kg, s.c.) or 7-benzylidenenaltrexone (0.5 mg/kg, s.c.), but not by naltriben (0.5 mg/kg, s.c.). Our results demonstrate that coadministration of TAN-67 with morphine enhances the morphine-induced place preference via activation of both delta 1 and delta 2 opioid receptors, suggesting that both delta 1 and delta 2 opioid receptors may modulate the morphine-induced rewarding effect. In addition, we also found that although both delta 1 and delta 2 opioid receptors may be implicated in the modulation of rewarding effect of morphine, the mechanisms involved may be different for each receptor subtypes, i.e., mu-delta 1 interaction may mainly modulate the rewarding effect of morphine by enhancing neurotransmission of mesolimbic dopamine neurons, although modulation by mu-delta 2 opioid receptor interaction may involve some other dopamine-independent mechanisms.

Analgesics↗