Biomedical subjects

T Okumoto

Publications and source records attributed to T Okumoto.

At least 19 recordsLinked to original sources

PubMed2004

Inhibition of endotoxin- and antigen-induced airway inflammation by fudosteine, a mucoactive agent.

We evaluated the effect of a mucoactive agent (-)-(R)-2-amino-3-(3-hydroxypropylthio) propionic acid (fudosteine), on airway inflammation using endotoxin- and antigen-induced models. Time courses of growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) production, neutrophil migration and goblet cell hyperplasia were examined in endotoxin-induced rat airway inflammation. GRO/CINC-1 in bronchoalveolar lavage fluid (BALF) increased in response to intratracheal instillation of endotoxin and peaked within 4 h. Neutrophils in BALF and goblet cells on trachea peaked 24 and 96 h after endotoxin instillation, respectively. Fudosteine significantly inhibited increases in GRO/CINC-1 at 10-100 mg/kg, and neutrophils and goblet cells at 30 and 100 mg/kg. These results suggest that inflammatory events including neutrophil chemoattractant production and neutrophil migration play important roles for goblet cell hyperplasia in endotoxin-induced airway inflammation, and fudosteine inhibits goblet cell hyperplasia by inhibiting GRO/CINC-1 production and/or neutrophil migration. Furthermore, fudosteine (100 mg/kg) inhibited ovalbumin-induced eosinophil infiltration into BALF, suggesting it attenuates asthmatic inflammation.

Animals↗

PubMed2002

Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis.

The triad of small vessel vasculitides (SVV) comprise Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CS). All three are associated with presence of circulating IgG antineutrophil cytoplasm antibodies (ANCA) which target autoantigens contained, primarily, within neutrophil azurophilic granules. The widely accepted model of pathogenesis suggests that ANCA activate cytokine-primed neutrophils within the microvasculature, leading to by-stander damage to endothelial cells, and rapid escalation of inflammation with recruitment of mononuclear cells. Activation may be initiated, in vitro, by the coligation of the PR3 or MPO antigen, translocated to the cell surface, and FcgammaRIIa/FcgammaRIIIb receptors. This suggests that the IgG subclass profile of ANCA and, possibly, its glycosylation status could influence the inflammatory mechanisms activated. The glycosylation status of total IgG isolated from the sera of patients with WG (13), MPA (6) and CSS (1) was determined by analysis of the released oligosaccharides. A deficit in IgG galactosylation is demonstrated for all patient samples, compared to controls. The mean percentage values for the agalactosylated (G0) oligosaccharides were 57% (SD +/- 9.71), 47% (SD +/- 4.25) and 28% (SD +/- 4.09) for WG, MPO and control samples, respectively. The G0 levels for polyclonal IgG isolated from the sera of both WG and MPA patients were significantly increased compared to controls (P < 0.0001). The major glycoform present therefore is agalactosylated (G0) IgG. In previous studies the G0 glycoform of IgG has been shown to bind and activate mannan binding lectin, and hence to activate the complement cascade, and to facilitate mannose receptor binding and the uptake of IgG complexes by macrophages and dendritic cells. Both of these activities could impact on the processing and presentation of self-antigens in autoimmune disease.

Adolescent↗

PubMed2000

Effect of FTY720, a novel immunosuppressant, on adjuvant-induced arthritis in rats.

OBJECTIVE AND DESIGN: Anti-arthritic effect of FTY720, a novel immunosuppressant, was compared with those of immunosuppressants cyclosporin A and tacrolimus in adjuvant-induced arthritis in rats. MATERIAL: Male LEW rats. TREATMENT: FTY720 (0.03-0.3 mg/kg), cyclosporin A (1-10 mg/kg) or tacrolimus (0.3-3 mg/kg) were orally administered to rats for 21 days beginning on the day (day 0) of adjuvant inoculation. In addition, the anti-arthritic effect of FTY720 (0.3 mg/kg) and cyclosporin A (10 mg/kg) were evaluated by administration to animals for 5 consecutive days (days 2-6, 6-10, and 10-14). METHODS: Adjuvant-induced arthritis was produced by intradermal injection of 0.5 mg heat-killed Mycobacterium tuberculosis. Hindpaw edema was measured plethysmographically. The day of arthritis onset was determined macroscopically. Bone degradation was determined by radiography. Peripheral blood leukocytes were classified microscopically. RESULTS: All test compounds inhibited the incidence of arthritis, hindpaw edema and bone destruction. In addition, FTY720 but not cyclosporin A or tacrolimus markedly decreased the number of peripheral blood lymphocytes. FTY720 treatment on days 6 to 10 inhibited the bone destruction and hindpaw edema. CONCLUSION: These results suggest that the anti-arthritic effect of FTY720 in this adjuvant-induced arthritic model was more potent than those of cyclosporin A and tacrolimus. FTY720 administered on days 6 to 10 showed the inhibitory effect on the bone destruction and hindpaw edema. FTY720 may be effective in the treatment of rheumatoid arthritis.

Animals↗

PubMed2000

Effect of FTY720, a novel immunosuppressant, on adjuvant- and collagen-induced arthritis in rats.

The anti-arthritic effect of FTY720, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride, a novel immunosuppressant which induces peripheral lymphocyte homing to peripheral lymph nodes, was compared with those of anti-rheumatic compounds, mizoribine and prednisolone in rat adjuvant-induced arthritis (AA) and collagen-induced arthritis (CIA). FTY720 at doses of 0.03-0.3 mg/kg, mizoribine at 3-30 mg/kg, and prednisolone at 1-10 mg/kg were orally administered to rats for 21 days from the day of inoculation with heat-killed Mycobacterium tuberculosis or type II collagen. Efficacy of FTY720 at 0.3 mg/kg was almost equal or higher as compared with those of mizoribine and prednisolone in both AA and CIA models. FTY720, but not mizoribine and prednisolone, decreased selectively lymphocyte counts in the peripheral blood in both models below the levels of the normal rats. Although FTY720 gave no other abnormal signs resulting in side effects, mizoribine was lethal to rats at 30 mg/kg and prednisolone inhibited body weight gain at 10 mg/kg, indicating that FTY720 has a wider margin of safety compared with these reference compounds. FTY720 also inhibited the production of anti-collagen antibody in CIA model, while neither mizoribine nor prednisolone did it. These results suggest that FTY720 is a promising compound for the treatment of arthritis with a unique profile.

Animals↗

PubMed2000

Plasma lactate concentration and muscle blood flow during dynamic exercise with negative-pressure breathing.

This study assessed the hypothesis that increasing cardiac filling pressure (CFP) would enhance contracting muscle blood flow (MBF) by stretching cardiopulmonary baroreceptors and attenuate the increase in plasma lactate concentration ([Lac(-)](p)) during dynamic exercise. Continuous negative-pressure breathing (CNPB) (-15 cmH(2)O) was used to increase the CFP by accelerating the venous return to the heart. In the first series of experiments, 10 men performed a graded exercise seated on a cycle ergometer with (N1) and without CNPB (C1). The increase in [Lac(-)](p) for N1 was attenuated at 60%, 90%, and 100% of maximal exercise intensity compared with that in C1 (P < 0.001). Also, the increases in mean arterial pressure (MAP) and plasma catecholamine concentrations were attenuated in N1 compared with those in C1 throughout the graded exercise (P < 0.05). However, heart rate and pulse pressure were not significantly influenced by CNPB. Second, we studied the impact of CNPB on forearm MBF during a rhythmic handgrip exercise in 5 of the 10 subjects. Forearm MBF was measured immediately after cessation of the exercise by venous occlusion plethysmography at rest, 30%, 50%, and 70% of maximal work load (WL(max)) with (N2) and without CNPB (C2). Forearm MBF and vascular conductance for both trials increased with the increase in intensity, but forearm skin blood flow measured by laser-Doppler flowmetry remained unchanged. MBF and vascular conductance in N2, however, increased more than in C2 at every intensity (P < 0.01) except for MBF at 70% WL(max), whereas the increase in MAP for N2 was attenuated compared with that in C2 (P < 0.05). Thus augmented active muscle vasodilation occurred in N2 with a lower increase in MAP compared with that in C2. These findings suggest that the stretch of intrathoracic baroreceptors, such as cardiopulmonary mechanoreceptors, by CNPB increased MBF by suppressing sympathetic nerve activity. The attenuation of the increase in [Lac(-)](p) might be caused, at least partially, by the increased MBF.

Adult↗

PubMed2000

[A case of breast cancer with multiple organ metastases responding remarkably to combination therapy of CAF (cyclophosphamide, adriamycin and 5-FU), 5'-DFUR and MPA (medroxyprogesterone acetate)].

A 52-year-old woman complaining of breast tumor was diagnosed as having advanced breast cancer (T4bN1M1-Stage IV), with metastasis of multiple organs (lung, liver, mediastinal and unilateral axillary lymph nodes) after which she underwent tumorectomy. Postoperative adjuvant therapy was performed using combined chemoendocrine therapy (CAF + 5'-DFUR + MPA). Following the endocrine therapy, the metastatic lesions of the liver and lung had disappeared. The adverse effects were not remarkable. Complete remission was continued for 2 years and 3 months, and the patient enjoyed a favorable quality of life.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Effects of Y-24180, a receptor antagonist to platelet-activating factor, on allergic cutaneous eosinophilia in mice.

We examined the effects of Y-24180, a potent and long-acting antagonist to platelet-activating factor (PAF), on allergic cutaneous eosinophilia and cytokine production in the skin of mice. Mice sensitized actively with ovalbumin (OA) were challenged by an intradermal injection of OA solution. The number of inflammatory cells, including eosinophils and eosinophil peroxidase (EPO) activity reflecting eosinophil infiltration into the tissue increased in OA-challenged skin 12 hr after the challenge. The levels of interleukin-4 (IL-4) and IL-5 also increased significantly in the challenged skin 12 hr and 3-24 hr, respectively, but that of interferon-gamma (IFN-gamma) did not change. Then, we evaluated the effects of Y-24180, ketotifen, suplatast and prednisolone on the increase in EPO activity, IL-4 and IL-5. These drugs were orally administered once a day for 5 days beginning 4 days before the challenge. Y-24180 (10 mg/kg) and prednisolone (5 mg/kg) significantly suppressed these parameters. Suplatast did not affect EPO activity, but significantly decreased the levels of IL-4 and IL-5. Ketotifen had no effect on them. These results indicate that the inhibition of IL-4, IL-5 and PAF are required to suppress the cutaneous eosinophilia and Y-24180 contributes to the treatment of allergic cutaneous eosinophilia.

Animals↗

PubMed1999

Age effect on expression of myosin heavy and light chain isoforms in suspended rat soleus muscle.

This study was designed to test the hypothesis that myosin heavy (MHC) and light chain (MLC) plasticity resulting from hindlimb suspension (HS) is an age-dependent process. By using an electrophoretic technique, the distribution of MHC and MLC isoforms was quantitatively evaluated in the soleus muscles from 3- or 12-wk-old rats after 1-3 wk of HS treatment was maintained. In normal 12- and 15-wk-old rats, the soleus muscles contained a predominance of MHCI ( approximately 94%) with small amounts of MHCIIa, but not MHCIId or MHCIIb. The suspended muscles of adult rats were characterized by the appearance of MHCIIb and MHCIId, the latter reaching approximately 6% after 3 wk of HS treatment. In contrast to changes in MHC, HS did not induce a transition in the MLC pattern in the soleus muscles from adult rats. Compared with adult rats, in juveniles HS had a much more pronounced effect on the shift toward faster MHC and MLC isoform expression. The soleus muscles of 6-wk-old rats after 3 wk of HS were composed of 37.0% MHCI, 19.1% MHCIIa, 23.7% MHCIId, and 20.2% MHCIIb. Changes in MLC isoforms consisted of an increase in MLC1f and MLC2f concomitant with a decrease in MLC2s. These results indicate the existence of a differential effect of HS on MHC and MLC transitions that appears to be age dependent. They also suggest that the suspended soleus muscles from young rats may acquire the intrinsic contractile properties that are intermediate between those in the normal soleus and typical fast-twitch skeletal muscles.

Aging↗

PubMed1998

Induction of apoptotic DNA fragmentation by nonsteroidal anti-inflammatory drugs in cultured rat gastric mucosal cells.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to cause apoptosis in several cell lines including transformed chicken embryo fibroblasts and human colon cancer cells. We herein report the apoptotic effect of NSAIDs in a non-transformed cell line derived from the rat gastric mucosa, RGMI (rat gastric mucosa cell first). 1-[p-Chlorobenzoyl]-5-methoxy-2-methylindole-3-acetic acid (indomethacin) and sodium 2-(2,6-dichloroanilino)phenylacetate (sodium diclofenac), potent and non-selective inhibitors of cyclooxygenase, were found to induce DNA fragmentation in RGM1 cells in a time- and concentration-dependent manner. The expression of mRNA for cyclooxygenase-2 was hardly detected in the intact cells but was clearly enhanced when the cells were incubated with the two NSAIDs. In contrast, the expression of mRNA for cyclooxygenase-1 was constitutive and was never affected by NSAIDs. The effect of [3,4-di(4-methoxyphenyl)-5-isoxazolyl] acetic acid (mofezolac), a potent and highly preferential inhibitor of cyclooxygenase-1, and N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulphonamide (NS-398), a selective inhibitor of cyclooxygenase-2, on DNA fragmentation and cyclooxygenase-2 mRNA expression was weak compared to the effect of indomethacin or sodium diclofenac. The DNA fragmentation induced by sodium diclofenac was hardly affected by the exogenous addition of 16,16-dimethyl prostaglandin E2 but was inhibited by caspase inhibitors such as Ac-YVAD-CHO and Ac-DEVD-CHO. The present data provide the first evidence that NSAIDs, such as indomethacin and sodium diclofenac, cause apoptotic DNA fragmentation in cultured gastric mucosal cells, and also indicate the involvement of caspases rather than the inhibition of cellular prostaglandin synthesis in the apoptotic process.

16,16-Dimethylprostaglandin E2↗

PubMed1998

Effect of Y-24180, an antagonist at platelet-activating factor (PAF) receptors, on IgE-mediated cutaneous reactions in mice.

OBJECTIVE AND DESIGN: We examined the effect of Y-24180, a potent platelet-activating factor (PAF) antagonist, on IgE-mediated cutaneous reactions in mice. MATERIALS: Female BALB/c mice were used. TREATMENT: Drugs were orally administered 1 h before a dinitrofluorobenzene (DNFB) challenge or 1 h before and 12 h after the challenge. METHODS: Biphasic increase in ear thickness, with peak responses at 1 h (immediate phase reaction, IPR) and 24 h (late phase reaction, LPR) after the DNFB challenge, were induced in mice which had been passively sensitized with monoclonal anti-dinitrophenyl IgE antibody 24 h before the DNFB challenge. Ear thickness was measured with a dial thickness gauge. RESULTS: Y-24180, WEB2086, ketotifen, and suplatast suppressed the IPR. Y-24180 also suppressed the LPR when administered once at 10 mg/kg or twice at 1 to 10 mg/kg. WEB2086 suppressed the LPR only when administered twice. However, ketotifen and suplatast did not suppress the LPR even when administered twice. Single administration of prednisolone significantly suppressed both the IPR and LPR. CONCLUSIONS: These results indicate that PAF may be involved in the induction of biphasic cutaneous reactions mediated by IgE, and Y-24180 is more effective compared with WEB2086 in this model. It is possible that the difference in the effectiveness between Y-24180 and WEB2086 depends on the persistence of those activities.

Animals↗

PubMed1998

Involvement of prostaglandins produced by cyclooxygenase-1 in murine visceronociception induced by phenylquinone.

Intraperitoneal injection of phenyl-p-benzoquinone (phenylquinone, PQ) induced writhing in mice for up to 30 min. During this time, the peritoneal content of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), a stable degradation product of PG12, was highest in the 15-min. sample. In the peritoneal cells, the mRNA expression for the constitutive cyclooxygenase-1 (COX-1) was unchanged by PQ administration. In contrast, little mRNA for COX-2 was detected in the peritoneal cells from unstimulated animals, and was induced 60-120 min. after PQ administration. PGs involved in the induction of writhing thus seem to be derived from a COX-1 reaction. Oral administration of mofezolac, a non-steroidal anti-inflammatory drug which potently inhibits COX-1, suppressed the PQ-induced writhing and peritoneal accumulation of PGs without affecting mRNA expression for both COX isoforms in mice.

6-Ketoprostaglandin F1 alpha↗

PubMed1998

Analgesic effect of mofezolac, a non-steroidal anti-inflammatory drug, against phenylquinone-induced acute pain in mice.

The oral administration of mofezolac, [3,4-di(4-methoxyphenyl)-5-isoxazolyl]acetic acid, resulted in the suppression of writhing induced by the intraperitoneal injection of phenyl-p-benzoquinone (phenylquinone, PQ) in mice. The analgesic activity of mofezolac was almost as potent as that of indomethacin, and more potent than that of sodium diclofenac, zaltoprofen, NS-398, and etodolac when their 50% effective doses were compared. The in vitro inhibitory activity of mofezolac against ovine cyclooxygenase (COX)-1 was also more potent than that of any other non-steroidal anti-inflammatory drugs (NSAIDs) tested, whereas the activity of mofezolac against COX-2 was relatively weak. A Western analysis revealed COX-1 to be constitutively expressed, whereas COX-2 was hardly expressed until 30 min after the PQ-injection in the peritoneal cells. Because the writhing terminated within 30 min after PQ-injection, the prostaglandins involved in the induction of writhing seem to be derived from COX-1. These data thus indicate that potent analgesic activity of mofezolac against the present model to be more closely related to its potent inhibitory activity against COX-1 but not against COX-2.

Analgesics↗

PubMed1998

Long-term follow-up of a patient with Romberg's disease reconstructed with free groin flaps.

Sixteen years ago the result of an operation that was performed on a 5-year-old boy with Romberg's disease was described in this journal. Nineteen years have passed since the first operation, and the authors now report the long-term follow-up. The volume of the transferred free groin flaps was maintained. Although these flaps covered the patient's atrophic tissues as vascularized tissues, these flaps could not normalize the atrophy of the surrounding tissues, especially the bone. As for the orbital content, bony atrophy was more remarkable than the other tissues.

Atrophy↗

PubMed1997

Principal involvement of cyclooxygenase-1-derived prostaglandins in the c-fos expression of the rat hind brain following visceral stimulation with acetic acid.

We investigated the relationship between c-fos expression in the hind brain and peritoneal prostaglandin (PG) synthesis after visceronociceptive stimulation with acetic acid in rats. Time-course studies on the mRNA expression for c-fos in the hind brain and cyclooxygenase (COX) isoforms in the peritoneal cells, as well as on the peritoneal 6-keto-PGF1alpha accumulation, after stimulation indicated that COX-1 but not COX-2 was responsible for the peritoneal synthesis of PGs which were suggested to evoke c-fos expression in the hind brain. Pharmacological experiments using mofezolac, a preferential inhibitor against COX-1, and NS-398, a selective inhibitor against COX-2, confirmed the involvement of COX-1 derived PGs in the induction of c-fos expression in the hind brain following the noxious stimulation.

Acetic Acid↗

PubMed1997

Effects of nonsteroidal anti-inflammatory drugs on interleukin-1 receptor antagonist production in cultured human peripheral blood mononuclear cells.

The effects of nonsteroidal anti-inflammatory drugs (NSAIDs), mofezolac, indomethacin, sodium diclofenac, and zaltoprofen, on the production of interleukin-1 receptor antagonist (IL-1ra) were examined in cultured human peripheral blood mononuclear cells (PBMC). Among the NSAIDs tested, mofezolac and sodium diclofenac were found to stimulate the mRNA expression for IL-1ra without affecting the mRNA expression for IL-1 beta. These two drugs also stimulated the secretion of IL-1ra by PBMC in the absence of bacterial lipopolysaccharide (LPS), however, the stimulatory effect of sodium diclofenac diminished in the presence of LPS. Mofezolac suppressed the mRNA expression for IL-1 beta in PBMC stimulated with exogenous IL-1 beta, indicating the secreted IL-1ra in the presence of mofezolac to be biologically active. Since IL-1ra suppresses the function of IL-1, a pro-inflammatory cytokine, the stimulatory effect of such NSAIDs as mofezolac on IL-1ra production could also be one of the mechanisms involved in its anti-inflammatory and antinociceptive actions.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1996

Cell kill kinetics of an antineoplastic nucleoside, 1-(2-deoxy-2-methylene-beta-D-erythro-pentofuranosyl)cytosine.

The cytotoxic properties of 1-(2-deoxy-2-methylene-beta-D-erythro-pentofuranosyl)cytosine (DMDC) were compared with those of 1-beta-D-arabinofuranosylcytosine (ara-C), using SK-MEL-28(P-36) human melanoma cells. DMDC and ara-C were most cytotoxic to cells in the S phase of the cell cycle. Cell cycle progression in S phase was blocked by both compounds. Treatment with DMDC (1 microgram/mL) or ara-C (1 and 30 micrograms/mL) did not increase cytotoxicity against asynchronous cells when the exposure time was prolonged from 1 to 6 hr, but did increase cytotoxicity thereafter. These findings suggest that cells in S phase are rapidly killed by the treatment but are temporarily prevented or delayed entry into the drug-sensitive S phase. On the other hand, DMDC treatment at a higher concentration (30 micrograms/mL) increased cytotoxicity in a time-dependent manner. Intracellular DMDC 5'-triphosphate (DMDCTP) increased in proportion to exogenous DMDC concentration, which was not saturated by treatment with a maximum concentration of the compound at 80 micrograms/mL. In contrast, intracellular ara-C 5'-triphosphate reached peak level when the cells were treated with ara-C at 8 micrograms/mL. The cytotoxicity of DMDC treatment for 4 hr increased relative to the intracellular DMDCTP accumulated during the period. These findings suggest that in cells treated with DMDC at a high concentration, an effective DMDCTP level is maintained for an extended period after washing out the compound from the medium. Consequently, the cells would be killed in the same way as in the case of extended exposures over 6 hr to DMDC at low concentration or to ara-C, in addition to acute S-phase-specific cytotoxicity.

Antineoplastic Agents↗

PubMed1996

Alterations of c-fos gene methylation in the processes of aging and tumorigenesis in human liver.

The state of DNA methylation in the c-fos gene was examined in human livers of different ages, cirrhosis and hepatocellular carcinoma. The degree of methylation in the intron 1 to exon 4 region increased with age, whereas all of the 10 cirrhosis samples revealed a decrease in methylation when compared to normal livers of similar ages. The 11 hepatocellular carcinomas showed varied alterations suggesting that the alteration of the c-fos gene methylation is related to aging as well as to early-step of hepatocarcinogenesis.

Adolescent↗

PubMed1996

Expression of hybrid isomyosins in human skeletal muscle.

Myosin of human skeletal muscles was analyzed by means of several electrophoretic techniques. Myosin heavy chain (HC)-IIa-and HC-IIb-based isomyosins were identified by pyrophosphate-polyacrylamide gel electrophoresis (PP-PAGE). The electrophoretic mobilities of these fast-twitch muscle isomyosins differed in the order HC-IIa triplets < HC-IIb triplets. To determine the subunit composition of myosin molecules that function in intact muscle, two-dimensional electrophoresis in which the first and second dimensions were PP-PAGE and sodium dodecyl sulfate-PAGE, respectively, was also performed. Slow-twitch muscle isomyosin contained, in addition to slow-twitch light chain (LC) and HC-I isoforms, appreciable amounts of LC-2f, HC-IIa, and HC-IIb isoforms, and fast-twitch muscle isomyosin consisted of LC-2s and HC-I isoforms as well as fast-twitch LC and HC isoforms. Without consideration of HC- and slow-twitch alkali LC heterodimers, at least 31 possible isomyosins are derived from these findings on the subunit composition of isomyosins in human skeletal muscle.

Diphosphates↗