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Biomedical subjects

H Nagase

Publications and source records attributed to H Nagase.

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

Mechanism of hypergammaglobulinemia by HIV infection: circulating memory B-cell reduction with plasmacytosis.

The mechanism of hypergammaglobulinemia in patients infected with HIV has remained unclear in spite of the identification of a reduction of CD4+ T cells. The amounts of CD27+ memory B cells were remarkably reduced in the peripheral blood and immunoglobulin (Ig) production was diminished in HIV-infected patients. Some of the freshly isolated patients' T cells expressed the CD70 (CD27 ligand) on the surface and the CD70 expression on both of the CD4+ and CD8+ T cells was greatly enhanced by various stimuli. It was also striking that plasmacytosis was observed in patients' bone marrow. Thus, our findings suggest that CD70 expressed spontaneously or by activation on T cells of HIV-infected patients stimulates memory B cells via CD27 and promotes their differentiation into plasma cells, resulting in the elevation of serum Ig levels and the elimination of circulating memory B cells in HIV-infected patients.

Adult↗
PubMed2001

Inhibition of liver metastasis from orthotopically implanted colon cancer in nude mice by transfection of the TIMP-1 gene into KM12SM cells.

To determine whether the tissue inhibitor of metalloproteinases 1 (TIMP-1) can modulate in vivo tumor growth and metastasis, we transfected TIMP-1 cDNA into KM12SM human colon carcinoma cells and determined the implanted tumor volume and incidence of liver metastasis in orthotopically implanted colon cancer in nude mice. We also treated the implanted tumors with repeated intraperitoneal injections of recombinant human TIMP-1 (rTIMP-1), and compared the inhibitory efficacy on liver metastasis with that achieved by the TIMP-1 transfectants. The TIMP-1 transfectants had a significantly greater inhibitory effect, in association with TIMP-1 expression, on the growth of the primary tumor and on liver metastasis as compared with the controls. However, the intraperitoneal administration of rTIMP-1 did not decrease the rate of liver metastasis. In situ hybridization demonstrated that TIMP-1 mRNA in the cecal tumors implanted with the highly produced KM12SMT-2 cells with TIMP-1 was mainly expressed by the tumor cells. These results suggest that the increased expression of TIMP-1 in KM12SM cells was responsible for their decreased metastatic potential, and that the endogenous increase in TIMP-1 production by the tumor cells might be more effective for counteracting the matrix metalloproteinases (MMPs) in tumor tissue and for inhibiting liver metastasis from colon cancer than the exogenous administration of TIMPs.

Animals↗
PubMed2001

Different motivational effects induced by the endogenous mu-opioid receptor ligands endomorphin-1 and -2 in the mouse.

The present study was designed to investigate the motivational effects of the newly discovered endogenous mu-opioid receptor ligands, endomorphin-1 and endomorphin-2, using the conditioned place preference paradigm in mice. The binding properties of these peptides were first examined using an opioid binding assay. In membranes obtained from the mouse whole brain, the binding of [3H][D-Ala2, NMePhe4, Gly(ol)5]enkephalin (DAMGO; mu), but not of [3H][D-Phe2, D-Phe5]enkephalin (DPDPE; delta) or [3H]U69593 (kappa) selectively and concentration-dependently competed with that of endomorphin-1 and endomorphin-2, indicating that both endomorphin-1 and endomorphin-2 are specific ligands for mu-opioid receptors in the brain. Endomorphin-1 (1-30 nmol/mouse) given i.c.v. produced a dose-related place preference. This effect was abolished by pre-treatment with the mu-opioid receptor antagonist beta-funaltrexamine but not the delta-opioid receptor antagonist naltrindole or the kappa-opioid receptor antagonist nor-binaltorphimine. In contrast, endomorphin-2 (5.6 nmol/mouse) produced place aversion. This aversive effect was inhibited by nor-binaltorphimine as well as beta-funaltrexamine, but not by naltrindole. The place aversion produced by endomorphin-2 was also attenuated by pre-treatment with antiserum against the endogenous kappa-opioid receptor ligand dynorphin A (1-17). These findings indicate that endomorphin-1 may produce its rewarding effect via mu-opioid receptors. On the other hand, the aversive effect induced by endomorphin-2 may be associated with the stimulation of endomorphin-1-insensitive mu-opioid receptors and the activation of dynorphinergic systems in the mouse brain.

Animals↗
PubMed2001

Characterization of mouse mammary tumour virus-induced migration of lymphoid cells into lymph nodes.

We previously found that Mtv-2+ lymph nodes (LN) implanted into Mtv-2- mice underwent marked hyperplasia owing to the influx of lymphocytes. LN grafts infected with exogenous mouse mammary tumour viruses (MMTV), MMTV(FM) transmitted by FM mice and MMTV-2 produced by Mtv-2, also swelled in MMTV-free recipients. Mtv-3 and Mtv-7 also displayed this capability. Mtv-2-induced LN hyperplasia was earlier in onset and greater in extent when major histocompatibility complex (MHC) class II I-E was expressed than unexpressed. Mtv-3-induced LN hyperplasia was suppressed completely by Mtv-3 from a different mouse strain and partially by Mtv-6 slightly different from Mtv-3 in superantigen (SAg) Vbeta specificity. LN hyperplasia occurred bidirectionally in LN transplantation between mice carrying Mtv-2 and Mtv-3, which are different SAg Vbeta specificity. LN hyperplasia induced by MMTV-2 carrying SAg responsive to Vbeta14 alone and MMTV(FM) carrying SAg responsive to Vbeta14 and Vbeta8.2 was completely but partially suppressed by MMTV(FM) and MMTV-2, respectively. CD4+ T cells were essential for MMTV-induced LN hyperplasia. LN in situ also underwent significant hyperplasia when infected with MMTV. Thus, MMTV SAg may entice circulating lymphocytes into lymphoid organs and contribute to more efficient dissemination MMTV in vivo. Secondary lymphoid tissue chemokine (SLC) may not be directly involved in this event.

Animals↗
PubMed2001

Rhein, an active metabolite of diacerein, down-regulates the production of pro-matrix metalloproteinases-1, -3, -9 and -13 and up-regulates the production of tissue inhibitor of metalloproteinase-1 in cultured rabbit articular chondrocytes.

OBJECTIVE: Diacerein has proved to be effective in the treatment of osteoarthritis (OA). However, the precise action mechanism of diacerein on OA is not yet fully understood. Therefore, we investigated the effects of rhein, an active metabolite of diacerein, on the production of promatrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase-1 (TIMP-1) in rabbit articular chondrocytes. DESIGN: Confluent rabbit chondrocytes were treated for 24 or 48 h with rhein, naproxen or dexamethasone in the presence of recombinant human IL-1alpha (rhIL-1alpha). ProMMP-9/progelatinase B in the culture medium was monitored by gelatin zymography, and proMMP-1/procollagenase 1, proMMP-3/prostromelysin 1, proMMP-13/procollagenase 3 and TIMP-1 were analysed by Western blot analysis. The steady-state levels of proMMP mRNAs were examined by Northern blot analysis. Total MMPs activity was also determined using FITC-labeled casein. RESULTS: Rhein suppressed the rhIL-1alpha-induced production of proMMPs-1, -3, -9 and -13 in a dose-dependent manner (0.1-30 microM). The suppressed production of proMMPs-1 and -3 was accompanied by a decrease in the steady-state levels of their mRNAs. Interestingly, rhein increased the production of TIMP-1. These observations were further supported by the fact that rhein decreased the apparent total activity of MMPs in the culture medium. CONCLUSION: We have demonstrated that rhein, an active metabolite of diacerein down-regulates the gene-expression and production of proMMPs and up-regulates the TIMP-1 production. The therapeutic effects of diacerein on OA may be due, at least in part, to the chondroprotective effect of rhein, its active metabolite.

Animals↗
PubMed2001

Inhibitory effect of magnolol and honokiol from Magnolia obovata on human fibrosarcoma HT-1080. Invasiveness in vitro.

We investigated the inhibitory effect of Magnolia obovata Thunb. bark ethanol extracts on human fibrosarcoma HT-1080 cells invasion in a reconstituted basement membrane [Matrigel (MG)]. We found that the effective components of the bark ethanol extracts were magnolol and honokiol, two biphenyl compounds. The extracts, magnolol and honokiol, did not affect HT-1080 cells adhesion to MG, but did inhibit HT-1080 cells migration at a high concentration (100 microM). HT-1080 cells secrete matrix metalloproteinase (MMP)-9, which degrades the extracellular matrix as a part of the invasive process. Magnolol and honokiol inhibited the activity of MMP-9, which may have been responsible, in part, for the inhibition of tumor cell invasiveness.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Glucocorticoids induce basophil apoptosis.

BACKGROUND: Induction of apoptosis represents an important mechanism by which glucocorticoids (GCCs) exert their anti-inflammatory properties. The effects of GCCs on apoptosis have been determined in various immune cells and found to vary among different cell types. On the other hand, the effects of GCCs on apoptosis of basophils, active participants in allergic inflammation, have remained obscure. OBJECTIVE: The objective of this study was to investigate the effects of GCCs on basophil apoptosis. METHODS: Basophils were highly purified (purity, >97%) by Percoll density gradient centrifugation followed by negative selection. Cell status was determined by their ability to bind annexin V and exclude propidium iodide. DNA fragmentation was determined by flow cytometry. RESULTS: Dexamethasone (DEX) significantly accelerated the decrease in live cells and increased the number of apoptotic cells in a time-dependent fashion. Light microscopy as well as DNA fragmentation assay confirmed the induction of apoptosis by DEX. A half-maximal effect was observed in a DEX concentration range from 10(-9) to 10(-8) mol/L. Sex steroids did not induce basophil apoptosis at all. DEX also induced basophil apoptosis in the presence of low doses of IL-3. CONCLUSION: GCCs exert potent apoptogenic effects on basophils. GCC-mediated apoptogenic effects on basophils might have implications with respect to the mechanism of action of this class of drugs in allergic disorders.

Apoptosis↗
PubMed2001

Chemokine receptor expression profile of eosinophils at inflamed tissue sites: Decreased CCR3 and increased CXCR4 expression by lung eosinophils.

BACKGROUND: To date, most studies dealing with eosinophil chemokine receptors have used eosinophils isolated from peripheral blood. During the movement of eosinophils from the peripheral blood to inflamed tissue sites, microenvironmental signals might alter their expression of chemokine receptors. However, little is known about the profile of expression of chemokine receptors by eosinophils at inflamed tissue sites in human beings. OBJECTIVE: The purpose of this study was to determine whether eosinophils that have migrated into inflamed tissues exhibit a profile of chemokine receptor expression that is qualitatively and/or quantitatively different from that of eosinophils in peripheral locations. METHODS: We studied simultaneously the expression and function of chemokine receptors in eosinophils in both bronchoalveolar lavage fluid (BALF) and peripheral blood specimens of 7 patients with eosinophilic lung diseases. RESULTS: De novo expression of CCR2, CCR4, and CCR5 was not detected at either the protein or the mRNA level. However, surface expression of CCR3 was decreased and CXCR4 was conversely increased with statistical significance in BALF eosinophils. Moreover, the changes in CCR3 and CXCR4 expression were reflected in the altered migratory response to their ligands. On the other hand, the levels of CXCR1, CXCR2, CXCR3, and CCR1 were virtually unchanged in BALF eosinophils, and these receptors did not have functional significance. CONCLUSION: Eosinophils at inflamed tissue sites exhibited an expression profile qualitatively similar to that in peripheral locations, except for decreased CCR3 and increased CXCR4 expression. Our results suggest that CCR3 is primarily and CXCR4 is cooperatively involved in eosinophil accumulation at inflamed tissue sites.

Adult↗
PubMed2001

The expression and localization of membrane type-1 matrix metalloproteinase in human abdominal aortic aneurysms.

BACKGROUND AND OBJECTIVE: Matrix metalloproteinase-2 (MMP-2) degrades both fibrillar collagens and elastin. MMP-2 is secreted as a latent 72-kd proenzyme that must be proteolytically processed to the 62-kd active form. In our laboratory we demonstrated a significant increase of active, matrix-bound MMP-2 in abdominal aortic aneurysmal (AAA) tissue compared with nonaneurysmal aorta with arteriosclerotic occlusive disease and normal aortic tissue. This increase in active MMP-2 is considered to be important in aneurysm pathogenesis, but the mechanism of its activation in aortic tissue is unknown. Membrane type-1 MMP (MT-1 MMP) is known to be an activator of MMP-2. The purpose of this study was to determine MT-1 MMP expression and its involvement in pro-MMP-2 activation in human aneurysmal tissue. METHODS: Infrarenal aortic tissue was obtained during the surgical repair of AAAs or the bypass of aortoiliac occlusive disease, or from nondiseased aorta, and the expression of MT-1 MMP messenger RNA was determined with Northern blot analysis. MT-1 MMP protein was determined with immunoblot and immunohistochemistry. The ability of aortic tissue to activate pro-MMP-2 was analyzed by incubating aortic tissue with exogenous radiolabeled pro-MMP-2. RESULTS: MT-1 MMP messenger RNA and protein are increased in AAA (P <.05) compared with arteriosclerotic occlusive disease and normal aortic tissue. Immunohistochemical analysis localized MT-1 MMP to aortic smooth muscle cells and macrophages in aneurysmal tissue. AAA tissue demonstrated a greater capacity to activate exogenous pro-MMP-2 compared with atherosclerotic and normal aortic tissue (P <.05). CONCLUSION: These studies demonstrate that MT-1 MMP is increased in AAA tissue and suggest that it may be important in AAA pathogenesis through its ability to activate pro-MMP-2

Aorta, Abdominal↗
PubMed2001

Catalase catalyzes nitrotyrosine formation from sodium azide and hydrogen peroxide.

Sodium azide (NaN3) is known as an inhibitor of catalase, and a nitric oxide (NO) donor in the presence of catalase and H2O2. We showed here that catalase-catalyzed oxidation of NaN3 can generate reactive nitrogen species which contribute to tyrosine nitration in the presence of H2O2. The formation of free-tyrosine nitration and protein-bound tyrosine nitration by the NaN3/catalase/H2O2 system showed a maximum level at pH 6.0. Free-tyrosine nitration induced by peroxynitrite was inhibited by ethanol and dimethylsulfoxide (DMSO), and augmented by superoxide dismutase (SOD). However, free-tyrosine nitration induced by the NaN3/catalase/H2O2 system was not affected by ethanol, DMSO and SOD. NO2- and NO donating agents did not affect free-tyrosine nitration by the NaN3/catalase/H2O2 system. The reaction of NaN3 with hydroxyl radical generating system showed free-tyrosine nitration, but no formation of nitrite and nitrate. The generation of nitrite (NO2-) and nitrate (NO3-) by the NaN3/catalase/H2O2 system was maximal at pH 5.0. These results suggested that the oxidation of NaN3 by the catalase/H2O2 system generates unknown peroxynitrite-like reactive nitrogen intermediates, which contribute to tyrosine nitration.

Animals↗
PubMed2001

Protection of cardiac myocytes via delta(1)-opioid receptors, protein kinase C, and mitochondrial K(ATP) channels.

The objective of the present study was to investigate the role of delta(1)-opioid receptors in mediating cardioprotection in isolated chick cardiac myocytes and to investigate whether protein kinase C and mitochondrial ATP-sensitive K(+) (K(ATP)) channels act downstream of the delta(1)-opioid receptor in mediating this beneficial effect. A 5-min preexposure to the selective delta(1)-opioid receptor agonist (-)-TAN-67 (1 microM) resulted in less myocyte injury during the subsequent prolonged ischemia compared with untreated myocytes. 7-Benzylidenenaltrexone, a selective delta(1)-opioid receptor antagonist, completely blocked the cardioprotective effect of (-)-TAN-67. Naltriben methanesulfonate, a selective delta(2)-opioid receptor antagonist, had only a slight inhibitory effect on (-)-TAN-67-mediated cardioprotection. Nor-binaltorphimine dihydrochloride, a kappa-opioid receptor antagonist, did not affect (-)-TAN-67-mediated cardioprotection. The protein kinase C inhibitor chelerythrine and the K(ATP) channel inhibitors glibenclamide, a nonselective K(ATP) antagonist, and 5-hydroxydecanoic acid, a mitochondrial selective K(ATP) antagonist, reversed the cardioprotective effect of (-)-TAN-67. These results suggest that the delta(1)-opioid receptor is present on cardiac myocytes and mediates a potent cardioprotective effect via protein kinase C and the mitochondrial K(ATP) channel.

Adenosine Triphosphate↗
PubMed2001

Regulation of chemokine receptor expression in eosinophils.

Signals via chemokine receptors play an important role in the accumulation of eosinophils at allergic inflammatory sites. Eosinophils constitutively express CC chemokine receptor 3 (CCR3) and, to a lesser extent, CCR1. CCR3 is mainly responsible for migration of resting eosinophils, and its specific ligand, eotaxin, represents the most potent chemoattractant for eosinophils. Some reports also suggest the expression of CXC chemokine receptor 1 (CXCR1) and/or CXCR2 in eosinophils. In addition, we recently reported the functional expression of CXCR4. The ligand of CXCR4, stromal cell-derived factor-1 (SDF-1), was able to induce a strong migratory response comparable to that by eotaxin. In contrast to the CCR3/eotaxin system which is mainly regulated at the level of ligand production, the CXCR4/SDF-1 system is regulated at the level of receptor expression. CXCR4 expression was completely attenuated by IL-4 and IL-5 and upregulated by IFN-gamma and dexamethasone, while CCR3 expression was only marginally affected. The balance between the biological effects of these chemokine systems may affect the distribution and migration of eosinophils.

Animals↗
PubMed2001

Suppressive effect of aspirin on chromosome aberration induced by mitomycin C in mice.

Chromosome aberrations induced by mitomycin C (MMC) were suppressed by aspirin in a mouse micronucleus test with peripheral blood and bone marrow cells. Aspirin at doses of 0.5, 5, and 50 mg/kg was injected intraperitoneally or per administered orally 0.5, 6, or 24 h after administration of MMC and then peripheral blood and/or bone marrow cells were sampled 48 h after administration of MMC. The suppressive effect of aspirin was more pronounced in the aspirin-treated groups 24 h than 0.5 and 6 h after administration of MMC. In the aspirin-treated group at 24 h, the frequency of polychromatic erythrocytes with micronuclei was decreased by about 60-80% after intraperitoneal injection and by about 40-70% after oral administration. It is suggested that aspirin may directly act on MMC metabolites, but not on MMC itself.

Alanine Transaminase↗
PubMed2001

TRK-820, a selective kappa-opioid agonist, produces potent antinociception in cynomolgus monkeys.

TRK-820 ((-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride) has been shown to be a potent opioid kappa-receptor agonist with pharmacological properties different from those produced by kappa1-opioid receptor agonists in rodents. To ascertain whether or not these properties of TRK-820 would be extended to primates, the antinociceptive effect of TRK-820 was evaluated in cynomolgus monkeys by the hot-water tail-withdrawal procedure. TRK-820 given intramuscularly (i.m.) produced a potent antinociceptive effect that was 295- and 495-fold more potent than morphine with the 50 degrees C and 55 degrees C hot-water tests, respectively, and 40-fold more potent than U-50,488H and 1,000-fold more potent than pentazocine in the 50 degrees C hot-water test. The duration of antinociceptive effects of TRK-820 treatment (0.01 and 0.03 mg/kg, i.m.) lasted more than 6 h, which was much longer than those of U-50,488H. The antinociception produced by the higher dose (0.03 mg/kg, i.m.) of TRK-820 was not inhibited by nor-binaltorphimine (3.2 and 10 mg/kg, s.c.) or by naloxone (0.1 mg/kg, s.c.), although the antinociception induced by a lower dose of TRK-820 (0.01 mg/kg, i.m.) was inhibited by nor-binaltorphimine (10 mg/kg, s.c.). The same doses of nor-binaltorphimine and naloxone effectively inhibited the antinociception induced by the higher doses of U-50,488H (1.0 mg/kg, i.m.) and morphine (10 mg/kg, i.m.), respectively. These results indicate that the antinociception induced by TRK-820 is less sensitive to nor-binaltorphimine and suggest that it is mediated by the stimulation of a subtype of kappa-opioid receptor different from the kappa-opioid receptor in cynomolgus monkeys.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2001

[Structural analysis for psychosocial factors including health locus of control (HLC) and sense of coherence (SOC) associated with lifestyle-related diseases].

The purpose of this study was to clarify psychosocial characteristics associated with preventive health behavior for lifestyle-related diseases. The author performed objective health examinations and gave questionnaires to 289 men (39.7 +/- 11.8 years, mean +/- SD) and 80 women (32.8 +/- 10.4 years) engaged in office work. Psychosocial factors included lifestyle and perceived stress, as well as the health locus of control (HLC) and sense of coherence (SOC) as newly developed indicators for health behavior. The principal component analysis for men did not extract lifestyle from the psychosocial structures. Multiple regression analysis showed that internal HLC (IHLC), chance HLC (CHLC), professional HLC (PHLC) and stress significantly contributed to SOC. Principal component analysis using psychosocial factors in women showed two psychosocial structures, i.e. the second principal (high SOC, high lifestyle, and low stress) and the 4th principal components (high supernatural HLC, and high PHLC). Both components were negatively correlated with systolic blood pressure. SOC was recognized to be negatively associated with age, stress, and total cholesterol, and positively with IHLC, FHLC, lifestyle, and gamma-GTP using multiple regression analysis for women. These results indicated a distinguishable sex difference regarding the involvement of psychosocial factors including HLC and SOC in objective health. SOC seems likely to be involved not in objective health, but closely with stress, suggesting a direct influence on mental health. Lifestyle should be divided into more detailed categories such as smoking and salt intake. Structural analysis of women suggests that SOC is involved directly or indirectly through lifestyle in objective health, different from men. To further clarify causal relationships between psychosocial factors and risk factors for lifestyle-related diseases, a longitudinal study is necessary based on these results.

Adult↗
PubMed2001

Structural confirmation of 15-norlubiminol and 15-norepilubiminol, isolated from Solanum aethiopicum, by chemical conversion from lubimin and epilubimin, and their antifungal activity.

15-Norlubiminol and 15-norepilubiminol were obtained from Solanum aethiopicum as an inseparable 1:1 mixture in a relatively poor yield to that of the major phytoalexins, lubimin and epilubimin. Their structures were confirmed by chemical conversion starting from lubimin and epilubimin. Baeyer-Villiger oxidation of the protected lubimins with m-chloroperoxybenzoic acid provided the desired formates. Deoxygenation with triphenylphosphine selenide and subsequent methanolysis provided 15-norlubiminols, whose 1H-NMR spectra were respectively identical with that of the corresponding isomer in the natural 15-norlubiminol mixture. The antifungal activity of 15-norlubiminols would be weaker than that of lubimins.

Antifungal Agents↗
PubMed2001

Imbalance between matrix metalloproteinase 9 and tissue inhibitor of metalloproteinases 1 expression by tumor cells implicated in liver metastasis from colorectal carcinoma.

We have evaluated the degree of MMP-9 and TIMP-1 messenger RNA (mRNA) expressions according to cell types in tumor tissues, and evaluated the implication of balance between the MMP-9 mRNA and the TIMP-1 mRNA expression in liver metastasis using orthotopic-implanted colon cancer in nude mouse, and also in 47 patients with colorectal cancer. The grade of MMP-9 or TIMP-1 mRNA expression was classified into 4 categories according to positive cell ratio. A higher grade of MMP-9 mRNA expression in tumor cells was correlated with liver metastasis in the experimental colon cancer, but was not statistically correlated in the clinical colorectal cancer. In contrast, the expression of TIMP-1 mRNA in the stromal cells of human colorectal cancer was correlated with liver metastasis. In both experimental and clinical colorectal cancer, a balance between the expression of MMP-9 mRNA and that of TIMP-1 mRNA was correlated with the occurrence of liver metastasis. The imbalance of MMP-9 dominance in tumor cells was implicated in liver metastasis. However, there was no significant relationship between the incidence of liver metastasis and the expression patterns of MMP-9 and TIMP-1 mRNA in the stromal cells. These results suggest that the balance between the expressions of MMP-9 and TIMP-1 in the tumor cells is more closely related to tumor biological behavior rather than the balance in the stromal cells.

Adult↗