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Biomedical subjects

R Haraguchi

Publications and source records attributed to R Haraguchi.

18 recordsLinked to original sources
PubMed2001

Effects of suplatast tosilate (IPD Capsules) on the production of active oxygen by neutrophils and of IL-8 by mononuclear cells.

In bronchial asthma, eosinophils and neutrophils are activated, so that the production of active oxygen species increases, causing airway epithelial injury. Suplatast tosilate (IPD Capsules) is a novel immunomodulating antiallergic drug that acts against bronchial asthma through a new mechanism. To evaluate the effects of suplatast tosilate on mononuclear cell-mediated IL-8 production, and neutrophil-mediated active oxygen species production at sites of inflammation, we collected peripheral blood from healthy subjects and separated the neutrophils as well as mononuclear cells. Suplatast tosilate was added at a concentration of 1 x 10(-6), 1 x 10(-7) or 1 x 10(-8) M, and cells were incubated for 10 min at 37 degrees C. Then, the neutrophils were stimulated with fMLP, and luminol-dependent chemiluminescence (LDCL) was measured, while IL-8 production was determined with an ELISA kit. Suplatast tosilate (1 x 10(-6) M) inhibited neutrophil-mediated active oxygen species production by 12.4% in terms of the peak, and by 16% in terms of the integral value. Moreover, it significantly inhibited mononuclear cell-mediated IL-8 production at concentrations of 1 x 10(-6), 1 x 10(-7) and 1 x 10(-8) M, in a concentration-dependent manner. This study indicated that suplatast tosilate may inhibit neutrophil infiltration by suppressing monocyte-mediated IL-8 production, and it may also inhibit the activation of neutrophils at sites of inflammation. These results suggest the possibility that suplatast tosilate may not only be of benefit for asthma, but may also prevent or control pulmonary fibrosis or emphysema, for which no effective treatment is presently available.

Adjuvants, Immunologic↗
PubMed2001

Role of chemical mediators in airway hyperresponsiveness in an asthmatic model.

BACKGROUND: Airway hyperresponsiveness (AHR) is one of the characteristic features of human asthma. The presence of AHR and the precise mechanisms immediately after establishment of sensitization in guinea pigs are unclear, although there are many reports showing allergen exposure that causes an increase in bronchial responsiveness associated with eosinophil influx into the airway in sensitized guinea pigs. OBJECTIVE: We investigated the inhibitory effects on AHR to histamine of ONO-1078, a leukotriene antagonist; indomethacin, a cyclooxygenase inhibitor; S-145, a thromboxane A(2) (TXA(2)) antagonist, and Y-24180, a platelet-activating factor (PAF) antagonist, to assess the involvement of chemical mediators in AHR employing ovalbumin (OA) sensitized guinea pig models. METHODS: Male Hartley guinea pigs were used. Each group comprised 4-7 animals. The animals were sensitized to OA, injecting intraperitoneally 30 mg of cyclophosphamide and 2,000 microg of OA together with 100 mg of aluminum hydroxide as the adjuvant. The guinea pigs were artificially ventilated via a cannula using a small-animal respirator after intraperitoneal anesthesia with pentobarbital sodium for tracheotomy. The pressure at the airway opening (PAO) was measured using a differential pressure transducer, and a differential pressure of peak PAO (peak DeltaPAO) at inspiratory phase as an overall index of bronchial response to bronchoactive agents was used. While being artificially ventilated, the animals were exposed to physiological saline solution containing various concentrations of histamine (4.9, 9.8, 20, 39, 78, and 156 microg/ml) by inhalation for 30 s at 3-min intervals. Determinations were made at 1 min after each inhalation. The chemical mediators were each (30 mg/kg of ONO-1078, 3 mg/kg of S-1452, and 1 mg/kg of Y-24180) administered orally to sensitized guinea pigs, and the airway response to histamine was assessed. Each group comprised 4-7 animals. RESULTS: The airway response to histamine was significantly greater in the sensitized group than in the nonsensitized group at histamine concentrations of 36 (p < 0.05), 78, and 156 mg/ml (p < 0.01). Leukotrienes C(4) and D(4): 30 mg/kg of ONO-178 did not show any inhibitory effect on airway response to inhaled histamine. Cyclooxygenase: 5 mg/kg of indomethacin did not show any inhibitory effect on the airway response to inhaled histamine. TXA(2): the AHR to inhaled histamine at doses of 9.8, 39, 78, and 156 microg/ml was significantly inhibited by prior administration of 3 mg/kg of S-1452. PAF: the AHR to inhaled histamine at doses of 9.8, 39, and 78 microg/ml was significantly inhibited by prior administration of 1 mg/kg of Y-24180. CONCLUSIONS: S-1452 (3 mg/kg) and Y-24180 (1 mg/kg) significantly inhibited AHR to histamine, while ONO-108 (30 mg/kg) and indomethacin (5 mg/kg) did not. The results suggest that TXA(2) and PAF are involved in AHR in OA-sensitized guinea pigs.

Airway Resistance↗
PubMed2001

Unique functions of Sonic hedgehog signaling during external genitalia development.

Coordinated growth and differentiation of external genitalia generates a proximodistally elongated structure suitable for copulation and efficient fertilization. The differentiation of external genitalia incorporates a unique process, i.e. the formation of the urethral plate and the urethral tube. Despite significant progress in molecular embryology, few attempts have been made to elucidate the molecular developmental processes for external genitalia. The sonic hedgehog (Shh) gene and its signaling genes have been found to be dynamically expressed during murine external genitalia development. Functional analysis by organ culture revealed that Shh could regulate mesenchymally expressed genes, patched 1 (Ptch1), bone morphogenetic protein 4 (Bmp4), Hoxd13 and fibroblast growth factor 10 (Fgf10), in the anlage: the genital tubercle (GT). Activities of Shh for both GT outgrowth and differentiation were also demonstrated. Shh(-/-) mice displayed complete GT agenesis, which is compatible with such observations. Furthermore, the regulation of apoptosis during GT formation was revealed for the first time. Increased cell death and reduced cell proliferation of the Shh(-/-) mice GT were shown. A search for alterations of Shh downstream gene expression identified a dramatic shift of Bmp4 gene expression from the mesenchyme to the epithelium of the Shh mutant before GT outgrowth. Regulation of mesenchymal Fgf10 gene expression by the epithelial Shh was indicated during late GT development. These results suggest a dual mode of Shh function, first by the regulation of initiating GT outgrowth, and second, by subsequent GT differentiation.

Animals↗
PubMed2001

External genitalia formation: role of fibroblast growth factor, retinoic acid signaling, and distal urethral epithelium.

The process of fetal external genitalia development might be divided into two processes. The first process accomplishes the initial outgrowth of the anlage, genital tubercle (GT). Previous analysis suggests that the distal urethral epithelium (DUE) of the GT, the Fgf8-expressing region, regulates the outgrowth of the GT. The second process eventually generates the sexually dimorphic development of the external genitalia, which is dependent on the action of steroid hormones. Several key genes, for example, RARs, RXRs, RALDH2, and CYP26, were dynamically expressed during GT development. The teratogenic dose of RA at 9.0 d.p.c. induced a drastic malformation of the urethral plate during GT formation, but did not show gross abnormalities in its outgrowth. In RA-treated embryos, Fgf8 expression was still detected in the distal GT regions. Possible regulatory roles of the FGF and RA signaling systems in external genitalia formation are discussed.

Abnormalities, Drug-Induced↗
PubMed2000

Molecular analysis of external genitalia formation: the role of fibroblast growth factor (Fgf) genes during genital tubercle formation.

The molecular mechanisms underlying the development of the external genitalia in mammals have been very little examined. Recent gene knockout studies have suggested that the developmental processes of its anlage, the genital tubercle (GT), have much in common with those of limb buds. The Fgf genes have been postulated as regulating several downstream genes during organogenesis. Fgf8 was expressed in the distal urethral plate epithelium of the genital tubercle (GT) together with other markers such as the Msx1, Fgf10, Hoxd13 and Bmp4 expressed in the mesenchyme. To analyze the role of the FGF system during GT formation, an in vitro organ culture system was utilized. It is suggested that the distal urethral plate epithelium of GT, the Fgf8-expressing region, regulates the outgrowth of GT. Ectopic application of FGF8 beads to the murine GT induced mesenchymal gene expression, and also promoted the outgrowth of the GT. Experiments utilizing anti-FGF neutralizing antibody suggested a growth-promoting role for FGF protein(s) in GT outgrowth. In contrast, despite its vital role during limb-bud formation, Fgf10 appears not to be primarily essential for initial outgrowth of GT, as extrapolated from Fgf10(-/-) GTs. However, the abnormal external genitalia development of Fgf10(-/-) perinatal mice suggested the importance of Fgf10 in the development of the glans penis and the glans clitoridis. These results suggest that the FGF system is a key element in orchestrating GT development.

Animals↗
PubMed1999

Effects of ONO-1078 (pranlukast) on cytokine production in peripheral blood mononuclear cells of patients with bronchial asthma.

BACKGROUND: ONO-1078 (pranlukast) is a leukotriene receptor antagonist developed in Japan. This drug has been shown to be useful in oral treatment of bronchial asthma. The present study was undertaken to assess the effects of this drug on the production of cytokines in the peripheral blood mononuclear cells of patients with asthma under stimulation with specific antigens. METHODS: Peripheral blood mononuclear cells from mite antigen-positive asthmatic patients (immunoglobulin E RAST score > 3) were incubated for 72 h in the presence of mite antigen (10 microg/mL). The supernatant of the culture was subjected to enzyme-linked immunosorbent assay (ELISA) to quantify interleukin (IL) -4, IL-3, IL-5, and granulocyte macrophage-colony stimulating factor (GM-CSF). Other peripheral blood mononuclear cells from the same patients were incubated for 72 h in the presence of both mite antigen (10 microg/mL) and ONO-1078 (0.5, 1, or 10 microg/mL), followed by ELISA of the supernatant to quantify the cytokines. RESULTS: Production of IL-4, IL-5, and GM-CSF by mononuclear cells under stimulation with mite antigen was markedly suppressed when they were exposed to ONO-1078 at a concentration of 10 microg/mL. CONCLUSION: The results suggest that ONO-1078 acts directly on peripheral blood mononuclear cells and that blockade of leukotriene receptors on blood mononuclear cells by the cysteinyl-leukotriene receptor antagonist (LTRA) pranlukast (ONO-1078) can dose-dependently inhibit release of immunoreactive TH2-type cytokines (IL-3, IL-4, GM-CSF, and possibly IL-5), but not of the TH1-type cytokine IL-2, when stimulated by mite allergen in vitro. The data may provide clues to the mechanism by which a number of LTRA including zafirulukast and montelukast can reduce airway, sputum and blood eosinophil counts in clinical asthma. It supports animal studies showing that anti-IL-5 antibodies partially block cys-LT-induced airway eosinophilia, suggesting that cys-LTs may cause secondary release of IL-5 from an unknown cell-type. These findings indicate that ONO-1078 suppresses the production of IL-4 (a cytokine that affects IgG antibody production), IL-5, and GM-CSF (cytokines that affect eosinophil activation) by peripheral blood mononuclear cells under stimulation with specific antigens in patients with bronchial asthma. Because of its anti-inflammatory effects, ONO-1078 should be useful in the treatment of bronchial asthma.

Adult↗
PubMed1999

Effects of saiboku-to on the survival of human eosinophils.

In recent years, bronchial asthma has come to be regarded as a chronic inflammatory disease of the respiratory tract, with mast cells, lymphocytes and eosinophils playing important roles in its pathogenesis. Proteins contained in eosinophil granules, especially major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPO), can cause tissue injury. When stimulated, eosinophils release mediators such as leukotriene C4 (LTC4) and platelet activating factors (PAF). Thus, they are recognized as effector cells that are actively involved in the development of allergic inflammation. In this study, eosinophils from healthy volunteers were used to investigate the effects of Saiboku-to on eosinophils whose survival had been prolonged through stimulation with eosinophil-activating cytokines such as interleukin (IL)-3, IL-5 and granulocyte macrophage colony stimulating factors (GM-CSF). As a result, the cytokine-enhanced survival of eosinophils was significantly shortened by the addition of Saiboku-to. These findings suggest that Saiboku-to has the potential to inhibit allergic responses by directly affecting eosinophils which are related to allergic inflammation.

Cell Survival↗
PubMed1999

Middle ear defects associated with the double knock out mutation of murine goosecoid and Msx1 genes.

A number of developmental regulatory genes, including homeobox genes, are dynamically expressed in the mammalian cephalic ectomesenchyme during craniofacial morphogenesis. Owing to the vast amount of gene knock out experiments, functions of such genes are now being revealed in the mammalian skeletal patterning process. The murine goosecoid (Gsc) and Msx1 genes are expressed during craniofacial development and each mutant mouse displays intriguing facial abnormalities including those of middle ear ossicles, suggesting that both genes play roles in spatial programming of craniofacial regions. In order to examine whether these genes could function in concert to direct particular craniofacial morphogenesis, double knock out mice were analyzed. The phenotype of the double mutant mice was restricted to the first arch derivatives and was apparently additive of the single gene mutant mice, implying region specific genetic interactions of these homeobox genes expressed in overlapping regions of middle ear forming ectomesenchyme. Our results also suggested that the patterning of distal portions of the malleus depends on the tympanic membrane, for which normal expressions of both the genes are prerequisite.

Animals↗
PubMed1998

Roles of histamine receptor in a guinea pig asthma model.

Histamine plays an important role in bronchoconstriction mediated by histamine receptors which provoke bronchial asthma attack. In this study, we measured H1 and H2 receptors in the guinea pig lung membrane fraction and obtained the following results. The maximum binding (Bmax) of H1 receptors in the guinea pig lung membrane fraction was significantly higher in the OA-sensitized group than that in the non-sensitized group, but affinity (Kd) did not differ between the groups. Otherwise, the maximum binding (Bmax) of H2 receptors in the guinea pig lung membrane fraction was significantly lower in the OA-sensitized group than that in the non-sensitized group. But affinity (Kd) did not differ between the groups. These findings suggest a close association of Histamine receptors both H1 and H2 in the pathology of asthma.

Animals↗
PubMed1998

Aberrant regulation of bone trace elements in motheaten and osteopetrosis mutant mice.

Increasing numbers of genetic diseases involving bone development and models for these diseases have been identified recently. Analysis of these bone diseases have revealed that regulated action of multiple growth factors and subsequent signal transduction are essential for normal bone formation. In this paper, two murine mutant mice viable motheaten and osteopetrosis are analyzed. Mice with the recessive 'viable motheaten' mutation express a severe immunodeficiency syndrome and bone defects. Mutations at the motheaten locus were shown to be the result of aberrant splicing of the gene encoding hematopoietic cell phosphatase (Hcph). Mice homozygous for the osteopetrosis mutation develop congenital osteopetrosis due to a severe deficiency of osteoclasts. It has been recognized that bone trace element composition analysis helps to define bone-related physiological conditions. We have analyzed bone trace element composition in viable motheaten and osteopetrosis mutant animal models in this study. In order to gain insights into the effects of particular genetic defects on bone trace element composition, inductively coupled plasma atomic emissions spectrometry (ICP-AES) analysis was performed. Marked changes in bone trace element levels were found in limb bones of viable motheaten and osteopetrosis mutant mice. An assessment of these trace element spectrum in the two mutant models with respect to each genetic defects are discussed in this paper.

Animals↗
PubMed1998

Dysregulation of trace element composition in ovariectomized cynomolgus monkey bones.

One of the challenging issues in modern biomedical science is the increasing number of osteoporosis patients due to the expansion of elderly populations. Among aging-related pathogenic changes, alterations in bone function and skeletal pathogenesis is a particularly important issue of concern. Osteoporosis is one of the most serious bone-related pathogenic states, as it causes serious loss of quality of life. Alterations in estrogen levels in accordance with aging are one of the key risk factors for osteoporosis. Complexed estrogen actions on bones can be traced by analyzing bone mineral components, as those elements accumulate as mineral complexes, reflecting the context of multiple cellular reactions such as bone resorption/osteogenesis. We have analyzed bone trace element composition in ovariectomized (OVX-treated) Cynomolgus monkey models in this study. In order to gain insights into the effects of such defects on bone trace element composition, inductively coupled plasma atomic emissions spectrometry (ICP-AES) analysis was performed. Marked changes in bone trace element levels were found in vertebral bones of OVX-treated Cynomolgus monkeys. An assessment of these trace element spectra in OVX model animals is discussed. These results could provide useful markers for understanding the physiological states of bones in postmenopausal women.

Animals↗
PubMed1991

[The inhibitory effect of oxatomide on oxygen radical products from human eosinophils and an eosinophilic cell line].

Recently, much attention has been paid to the role played by the allergic inflammatory reaction in the role of asthma. Eosinophils are considered to be major inflammatory cells in bronchial asthma. Therefore, in this study, eosinophil-mediated oxygen radicals were examined by means of luminol-dependent chemiluminescence. Also, the effect of oxatomide, an anti-allergic agent, which has an inhibitory effect on eosinophil-mediated natural cytotoxicity against bronchial epithelial cells, on the production of oxygen radicals from eosinophils was studied. The results revealed the inhibitory effects of oxatomide on eosinophil-mediated oxygen radicals products. Furthermore, the inhibitory effect of this agent on oxygen radical products from eosinophilic cell-line named EoL-3, which has been established recently, was observed. We concluded from these results that oxatomide not only has anti-allergic activity but also anti-inflammatory properties for eosinophils.

Anti-Inflammatory Agents↗
PubMed1991

[Study of prognostic factors of survival in patients with unresectable non-small cell lung cancer].

We studied prognostic factors of survival in 121 patients unresectable non-small cell lung cancer treated between March 1983 and November 1988 at forth department of internal medicine, Kinki university school of medicine, about histology, clinical stage, age, sex, performance status, Brinkman Index, hemoglobin, serum TP, serum Alb, serum LDH, pulmonary function and chemotherapy. The prognostic factors were studied using survival rate by Kaplan-Meier method, univariate analysis by Log-rank test and generalized Wilcoxon test and multivariate analysis by proportional hazard model of Cox. The prognostic factors of pretreatment were age, serum Alb, serum LDH, pulmonary dysfunction of mixed type and performance status. In the classified study according to histology, age and pulmonary dysfunction of mixed type were prognostic importance in patients with squamous cell lung cancer. Hemoglobin in patients with squamous cell lung cancer was important, too. The chemotherapy given good response improved patient's prognosis.

Adenocarcinoma↗
PubMedDate not supplied

Microphthalmia (mi) mice display an aberrant bone trace element composition.

It has been recognized that bone trace element composition analysis provides clues when analyzing bone-related physiological conditions. Increasing numbers of bone-related genetic diseases have been identified recently. In this study, we have analyzed bone trace element composition in a genetic mutant animal model. Mutations in the mouse microphthalmia (mi) gene affect the development of a number of cell types, including melanocytes, mast cells, and osteoclasts. Previous studies have shown that different alleles of the mi locus show osteopetrosis. In order to gain insights into the effects of a particular genetic defect on bone trace element composition and bone structure, we performed bone trace element composition analysis using inductively coupled plasma atomic emissions spectrometry (ICP-AES). Marked changes in bone trace element levels were found in vertebrate bones of mi mutant mice. The implications and possible applications of bone trace element analysis will be discussed in this article.

Animals↗
PubMedDate not supplied

Effects of saiboku-to on dual-phase bronchoconstriction in asthmatic guinea pigs.

In recent years, bronchial asthma has come to be regarded pathologically as a chronic inflammatory disease of the respiratory tract. Inhalational steroids and antiinflammatory drugs are recognized as being effective against bronchial asthma. In this study, the effects of Saiboku-to, a Chinese herbal (Kampo) formulation, were investigated on asthmatic guinea pigs sensitized to ovalbumin (OA). Following 7-day administration of Saiboku-to (500 micrograms/kg), the late asthmatic response (LAR) to an antigen challenge was found to be inhibited. The number of eosinophils in fluid obtained by bronchoalveolar lavage (BAL) 4 h after antigen challenge was decreased while the infiltration of eosinophils and T-lymphocytes into the lung parenchyma was inhibited. These findings suggest that Saiboku-to has the potential to become a useful drug in the treatment of bronchial asthma.

Animals↗
PubMedDate not supplied

Dual-phase response model for bronchial asthma.

The authors have successfully developed an animal model of dual-phase bronchial responses and very high IgG titer by sensitizing Hartley-strain male guinea pigs. Specific airway resistance, which was determined in a two-chamber body plethysmograph, was elevated to sevenfold during immediate response, followed by a late phase response with a smaller but marked elevation in resistance. Furthermore, hematological and histological examinations revealed that the total cell count increased in BAL obtained during both immediate and late bronchial responses as compared to pre-OVA challenges. A significant increase in BAL eosinophils was present only for the late bronchial samples, and this finding was supported by histological examination.

Airway Resistance↗