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Biomedical subjects

Y Ohmoto

Publications and source records attributed to Y Ohmoto.

At least 37 records · Page 2Linked to original sources

Noninvolvement of hypertriglyceridemia and hyperleptinemia in blood pressure increases induced by dietary lard in rats.

We investigated whether hypertriglyceridemia and hyperleptinemia are involved in the development of increases in blood pressure induced by dietary lard. Rats received either chow alone or chow in which 50% of the energy content was from substituted lard. Each group was divided into two groups according to whether the diet included bezafibrate or not. In another series of experiments, rats were fed either chow alone or chow in which 50% of the energy content was from substituted lard, safflower oil, or sucrose. Systolic blood pressure (SBP) was measured every week during each 7-week feeding period. A steady-state plasma glucose method was used to determine insulin sensitivity after lard substitution with or without bezafibrate. After the 7-week feeding period, the plasma levels of glucose, immunoreactive insulin, triglyceride and leptin were measured. In rats fed with a high lard diet, SBP, plasma levels of immunoreactive insulin, triglyceride, leptin and steady-state plasma glucose concentrations significantly increased, compared with levels of these substances in controls. Bezafibrate treatment completely reversed these effects. In rats fed with a high safflower oil or a high sucrose diet, no significant change was seen in SBP and plasma immunoreactive insulin levels. However, the plasma triglyceride levels were increased by dietary lard or sucrose. Moreover, the plasma leptin level was also increased by dietary lard and safflower oil. Neither dietary hypertriglyceridemia nor hyperleptinemia were involved in the development of increases in blood pressure induced by dietary lard.

Adipose Tissue↗

Rise in plasma leptin levels after stimulation of hypothalamic cholinoceptive neurons by neostigmine in rats.

To investigate the role of hypothalamic cholinergic neurons in the regulation of plasma leptin levels, we injected neostigmine, a cholinesterase inhibitor, or vehicle alone into the third cerebral ventricle in free moving male Wistar rats and then measured plasma leptin levels. The administration of neostigmine (5 x 10(-9) or 5 x 10(-8) mol) increased plasma leptin levels 3-6 h after stimulation in a dose-dependent manner, while intravenous injection of neostigmine (5 x 10(-8) mol) had no effect. Atropine (5 x 10(-8) mol) concomitantly injected with neostigmine (5 x 10(-8) mol) prevented neostigmine-induced increase in plasma leptin. The expression of leptin messenger ribonucleic acid (mRNA) in epididymal white adipose tissue was significantly increased at 4 and 6 h after neostigmine injection compared with that before the injection. Plasma levels of corticosterone were significantly increased at 30 min after stimulation with neostigmine and this increase was sustained for 6 h after stimulation. Furthermore, bilateral adrenalectomized rats showed no increase in plasma leptin levels after stimulation. In conclusion, stimulation of hypothalamic cholinoceptive neurons increased plasma leptin levels in rats by increasing leptin production in adipocytes. This increase may be due to an increase in glucocorticoids from the adrenal glands. These results suggest that plasma leptin levels can be regulated by hypothalamic cholinoceptive neurons.

Adipocytes↗

Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway.

BACKGROUND: Among the many adipocyte-derived endocrine factors, we found an adipocyte-derived plasma protein, adiponectin, that was decreased in obesity. We recently demonstrated that adiponectin inhibited tumor necrosis factor-alpha (TNF-alpha)-induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease (CIRCULATION: 1999;100:2473-2476). However, the intracellular signal by which adiponectin suppressed adhesion molecule expression was not elucidated. The present study investigated the mechanism of modulation for endothelial function by adiponectin. METHODS AND RESULTS: The interaction between adiponectin and human aortic endothelial cells (HAECs) was estimated by cell ELISA using biotinylated adiponectin. HAECs were preincubated for 18 hours with 50 microg/mL of adiponectin, then exposed to TNF-alpha (10 U/mL) or vehicle for the times indicated. NF-kappaB-DNA binding activity was determined by electrophoretic mobility shift assays. TNF-alpha-inducible phosphorylation signals were detected by immunoblotting. Adiponectin specifically bound to HAECs in a saturable manner and inhibited TNF-alpha-induced mRNA expression of monocyte adhesion molecules without affecting the interaction between TNF-alpha and its receptors. Adiponectin suppressed TNF-alpha-induced IkappaB-alpha phosphorylation and subsequent NF-kappaB activation without affecting other TNF-alpha-mediated phosphorylation signals, including Jun N-terminal kinase, p38 kinase, and Akt kinase. This inhibitory effect of adiponectin is accompanied by cAMP accumulation and is blocked by either adenylate cyclase inhibitor or protein kinase A (PKA) inhibitor. CONCLUSIONS: These observations raise the possibility that adiponectin, which is naturally present in the blood stream, modulates the inflammatory response of endothelial cells through cross talk between cAMP-PKA and NF-kappaB signaling pathways.

Adenylyl Cyclase Inhibitors↗

Humoral immune responses to adenovirus vectors in the brain.

We have investigated the humoral immune response to E1-deleted adenovirus vectors encoding the lacZ gene introduced into the brains of mice. Injection of these non-replicating vectors into the brain induced systemic antibody production to adenovirus vectors in dose dependent manner. Apparent antibody production to beta-galactosidase, the product of the lacZ gene, was detected later than anti-adenovirus antibody. Neutralizing antibody was not detected. This study demonstrates that E1-deleted adenovirus vectors injected into the brain trigger humoral immune responses to the adenovirus and its gene products, but they are not sufficient to block the infection of cells by adenovirus upon repeat injection.

Adenoviridae↗

Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFalpha and IL-1alpha.

We examined whether macrophage infiltration is associated with angiogenesis in cutaneous melanoma. The numbers of macrophages and microvessels increased significantly with increasing depth of tumor and with tumor angiogenesis. Macrophage infiltration thus appeared to provide a useful diagnostic marker for the progression of cutaneous melanoma. We further examined whether human melanoma cells produce angiogenic factors in response to macrophage-derived cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1 alpha (IL-1alpha). Treatment of melanoma cells with TNFalpha and IL-1alpha in vitro enhanced the production of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), and of basic fibroblast growth factor (bFGF) to a lesser degree, in human melanoma cells. Lipopolysaccharide (LPS)-activated human monocytes enhanced production of IL-8, VEGF, TNF alpha, as well as IL-1alpha, but not bFGF. Co-culture of human monocytes and human melanoma cells was also found to significantly enhance production of IL-8 and VEGF in the absence and presence of LPS, compared with either monocytes or melanoma cells alone. The production of IL-8 and VEGF from co-cultured melanoma cells and LPS-activated monocytes was blocked when anti-TNF-alpha antibody or anti-IL-1alpha antibody was co-administrated. This is direct evidence that production of the potent angiogenic factors IL-8 and VEGF from melanoma cells is up-regulated through TNFalpha and/or IL-1alpha secreted by activated monocytes/macrophages, influencing both tumor growth and angiogenesis in melanomas.

Adult↗

Allergen-induced mRNA expression of IL-5, but not of IL-4 and IFN-gamma, in peripheral blood mononuclear cells is a key feature of clinical manifestation of seasonal allergic rhinitis.

OBJECTIVES: To investigate the allergen-induced messenger RNA (mRNA) expression of interleukin (IL) 4, IL-5 and interferon gamma (IFN-gamma) in peripheral blood mononuclear cells from individuals sensitized by Japanese cedar (Cryptomeria japonica) pollens, and to elucidate the clinical role of IL-4, IL-5, and IFN-gamma in the allergen sensitization and clinical manifestation of allergic disorders. DESIGN: This study included 30 patients sensitized to the pollen and 14 nonatopic healthy volunteers. Peripheral blood mononuclear cells (1.0 x 10(6) cells/mL) of each individual were cultured at 37 degrees C for 24 hours in the presence of 10 microg/mL of Cry j 1, a major allergen of the pollens. Total cellular RNA was extracted from the peripheral blood mononuclear cells, and IL-4, IL-5, and IFN-gamma mRNA expression was determined with a reverse transcriptase polymerase chain reaction. RESULTS: From the results of a survey of symptom diary cards and interviews regarding nasal symptoms during the pollen season in 1998, we found that 20 patients (symptomatic group), but not 10 patients (asymptomatic group), had typical symptoms of seasonal allergic rhinitis. Interleukin 4 mRNA was not expressed in the nonatopic subjects but was expressed in 9 asymptomatic patients and in 17 symptomatic patients. Interleukin 5 mRNA was exclusively expressed in the symptomatic patients. Interferon gamma mRNA expression did not differ significantly among the nonatopic subjects, asymptomatic patients, and symptomatic patients. CONCLUSIONS: This study has clearly highlighted an interesting and new concept that IL-4 is implicated in allergen sensitization but not in clinical manifestation, and that IL-5 may not be a feature of atopy in itself but seems to be a hallmark of clinical manifestation of ongoing atopic diseases.

Adolescent↗

Triterpenoids from Tripterygium wilfordii.

The extract (T(II)) of Tripterygium wilfordii Hook f. afforded four triterpenoids: wilforic acid D (3beta,24-epoxy-2alpha-hydroxy-24R*-ethoxy-29-friedelanoic acid); (E) 3beta,24-epoxy-2-oxo-3alpha-hydroxy-29-friedelanoic acid; (F) 2beta-hydroxy-3-oxo-friedelan-29-oic acid; 29-hydroxy-3-oxo-olean-12-en-28-oic acid and 17 known triterpenoids. Their structures were established on the basis of spectroscopic studies. In a bioactivity analysis, only the known dulcioic acid compound showed a significant inhibitory effect on cytokine production.

Immunosuppressive Agents↗

Thyroid hormones influence serum leptin levels in patients with Graves' disease during suppression of beta-adrenergic receptors.

Leptin is a protein product of the ob gene, mainly produced by adipocytes. Leptin is thought to play an important role in the homeostasis of body weight by suppressing appetite and increasing energy consumption. The aim of this study was to investigate the possible effect of thyroid hormone on the regulation of the leptin system during suppression of beta-adrenergic receptors in Graves' patients. We studied 15 adult female patients with Graves' disease. Thyroid function, serum levels of leptin, and percent body fat (%BF) were examined at four different clinical conditions during therapy (A, untreated; B, beta-adrenergic antagonist only [A, B; hyperthyroid], C, beta-adrenergic antagonist and antithyroid drug; D, antithyroid drug only [C, D; euthyroid]). The use of beta-adrenergic antagonist significantly reduced heart rate in spite of hyperthyroid state, indicating sufficient suppression of beta-adrenergic receptors. During treatment with beta-adrenergic antagonist, leptin percentage of body fat (%BF) ratio significantly decreased in euthyroid state compared to that in hyperthyroid state (from 38.7 +/- 21.3 to 18.1 +/- 19.3, p = 0.003). Moreover, there was a significantly positive correlation between delta leptin/%BF and delta free thyroxine (FT4) (r = 0.51, p = 0.008). Under a euthyroid state induced by antithyroid drug treatment, leptin/%BF did not change in spite of withdrawal of beta-adrenergic antagonist. Our data indicate that thyroid hormones could increase serum leptin level during suppression of beta-adrenergic receptors in Graves' patients. Our data also suggest that the beta-adrenergic action of thyroid hormones might be partly mediated by regulation of leptin.

Adrenergic beta-Antagonists↗

Effect of grepafloxacin on cytokine production in vitro.

The effect of a new quinolone antibacterial agent, grepafloxacin, on the production of cytokines was investigated using lipopolysaccharide-stimulated human peripheral blood cells. Grepafloxacin 1-30 mg/L inhibited the production of interleukin 1alpha (IL-1alpha) and IL-1beta, and the expression of IL-1alpha, IL-1beta, tumour necrosis factor alpha (TNFalpha), IL-6 and IL-8 mRNA. These results suggest that the inhibitory effect of grepafloxacin is exerted, in part, at the gene transcription level.

Anti-Infective Agents↗

Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.

Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)-matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6+/-0.4 versus 7.9+/-0.5 microg/mL in men, 7.6+/-0.7 versus 11.7+/-1.0 microg/mL in women; P<0.001). The plasma adiponectin concentrations of diabetic patients with CAD were lower than those of diabetic patients without CAD (4.0+/-0.4 versus 6.6+/-0.4 microg/mL, P<0.001 in men; 6.3+/-0.8 versus 7.6+/-0. 7 microg/mL in women). In contrast, plasma levels of leptin did not differ between diabetic patients with and without CAD. The presence of microangiopathy did not affect the plasma adiponectin levels in diabetic patients. Significant, univariate, inverse correlations were observed between adiponectin levels and fasting plasma insulin (r=-0.18, P<0.01) and glucose (r=-0.26, P<0.001) levels. In multivariate analysis, plasma insulin did not independently affect the plasma adiponectin levels. BMI, serum triglyceride concentration, and the presence of diabetes or CAD remained significantly related to plasma adiponectin concentrations. Weight reduction significantly elevated plasma adiponectin levels in the diabetic subjects as well as the nondiabetic subjects. These results suggest that the decreased plasma adiponectin concentrations in diabetes may be an indicator of macroangiopathy.

Adiponectin↗

Effects of SSM (specific substance maruyama) on HBe antigen-positive chronic hepatitis B -clinical efficacy and modulation of cytokines.

Twenty-three patients with HBe antigen-positive chronic hepatitis B were treated with capitalite first letters Maruyama (SSM). HBe antigen turned negative in 15 patients. The levels of various cytokines in pre- and post-treatment frozen serum samples from six patients whose HBe antigen turned negative and from five whose HBe antigen did not were examined. Reduction of serum interleukin (IL) -10 level to below 20 pg/ml was observed after SSM treatment in four of the six patients whose HBe antigen turned negative. SSM was found to stimulate the production of interferon (IFN) -gamma in peripheral blood cells from two healthy volunteers. This stimulatory effect was confirmed in 12 out of 24 healthy volunteers. SSM augmented the production of IFN-gamma in eight out of 10 patients with chronic hepatitis B and nine of 10 with hepatitis C. These results demonstrate for the first time that SSM stimulates the production of IFN-gamma in human peripheral blood cells and also suggest that treatment of HBe antigen-positive chronic hepatitis B patients with SSM leads to the clearance of HBe antigen and normalization of serum aspartate aminotransferase levels through inhibition of IL-10 and stimulation of IFN-gamma.

Adult↗

Gender-related difference in relationship between insulin resistance and serum leptin level in Japanese type 2 diabetic and non-diabetic subjects.

It remains controversial whether or not a correlation exists between serum leptin levels and insulin resistance, and, if such a correlation does exist, whether it is independent of adiposity. To investigate the possible existence of an independent correlation, we have assessed serum leptin levels and insulin resistance in Japanese diabetic and non-diabetic subjects by means of Homeostatic Model Assessment (HOMA-R). Sixty-four Japanese patients with Type 2 diabetes mellitus (DM) (33 men and 31 women) and 53 sex-, age-, and body mass index (BMI)-matched non-diabetic adults (29 men and 24 women) were enrolled. The fasting plasma level of glucose (FPG) and the fasting serum levels of immunoreactive insulin (FIRI) and leptin were determined. Multiple linear regression analysis demonstrated that, in both male diabetic and male non-diabetic subjects, HOMA-R and BMI were independently correlated with serum leptin levels. In females, BMI, but not HOMA-R, was correlated to the serum levels of leptin in both groups. There was no statistically significant difference in the partial regression coefficients between male diabetic and male non-diabetic subjects. These results suggest that the correlation of HOMA-R to the serum levels of leptin in females is dependent on BMI. In males, the relationship between serum leptin levels and the insulin resistance was not affected by the extent of glucose intolerance.

Adult↗

Expression of interferon alpha/beta receptor in human hepatocellular carcinoma.

Interferon-alpha (IFNalpha) plays a crucial role in the antiproliferation and immunoregulatory activity through the specific cell surface receptor, interferon-alpha/beta receptor (IFNalpha/betaR). We examined the immunohistochemical expression of IFNalpha/betaR in 91 hepatocellular carcinoma (HCC), HCV-related chronic hepatitis (n=38) and cirrhosis (n=53), dysplastic nodules (n=5), and normal liver (n=9). The level of IFNalpha/betaR increased in chronic hepatitis and cirrhosis compared with normal liver. All the dysplastic nodules showed moderate or high expression. In HCCs, 26% (24/91) of patients showed high IFNalpha/betaR expression while the remaining 38% (35/91) showed moderate, and 35% (32/91) no or faint expression. Clinicopathological survey demonstrated a significant correlation between IFNalpha/betaR expression and differentiation of carcinoma (P=0.0008) although there was no correlation between IFNalpha/betaR expression in HCC and survival or disease-free survival. Thus, IFNalpha/betaR was expressed not only in chronic hepatitis or liver cirrhosis but in HCC and its expression was significantly correlated with tissue differentiation of carcinoma.

Blotting, Western↗

Regulation of disease-progression genes in human gastric carcinoma cells by interleukin 8.

The expression of interleukin 8 (IL-8) by human gastric carcinomas directly correlates with tumor vascularity and disease progression. To determine whether IL-8 can act in an autocrine manner to regulate the expression of other disease-progression genes, we examined the expression of IL-8 receptors IL-8RA (CXCR1) and IL-8RB (CXCR2) in six different human gastric carcinoma cell lines and 38 surgical specimens of human gastric carcinomas. All of the gastric carcinoma cell lines expressed mRNA and protein for IL-8RA and IL-8RB protein. In all surgical specimens, the majority of the tumor cells and small vessel endothelial cells stained positive for IL-8RA and IL-8RB protein. In vitro treatment of human gastric cancer MKN-1 cells with exogenous IL-8 enhanced the expression of epidermal growth factor receptor, type IV collagenase (metalloproteinase-9), vascular endothelial growth factor, and IL-8 mRNA. In contrast, treatment with exogenous IL-8 decreased expression of E-cadherin mRNA. IL-8 treatment increased invasive capacity of MKN-1 cells, which was associated with activity of metalloproteinase-9. Collectively, these results demonstrate that human gastric carcinoma cells express receptors for IL-8 and that IL-8 may play a role in the progressive growth of human gastric carcinoma by autocrine/paracrine mechanisms.

Cell Membrane↗

Increased incidence of autoantibodies to interleukin-1a in rheumatoid arthritis with interstitial lung disease.

OBJECTIVE: To clarify the clinical significance of autoantibodies (auto-Ab) to interleukin-1alpha (IL-1alpha) in rheumatoid arthritis (RA) with interstitial lung disease (ILD), we examined the IL-1alpha auto-Ab level in serum of patients with RA with/without ILD. METHODOLOGY: We investigated the level of IL-1alpha auto-Ab in serum of 70 patients with RA with/without ILD and 40 control patients (CP). Levels of IL-1alpha auto-Ab were measured by radioimmunoassay, and serum was regarded as IL-1alpha auto-Ab positive at an auto-Ab level of more than 5 ng/mL. RESULTS: Interleukin-1alpha auto-Ab was detected in the serum of 30 out of 70 RA patients (42.9%), and six out of 40 CP (15%) (P < 0.05). Interleukin-1alpha auto-Ab were detected in the serum of 18 out of 32 patients with RA with ILD (56.2%) and 12 out of 38 patients with RA without ILD (31.5%). The positive rate of these autoantibodies in RA with ILD was significantly higher than that in RA without ILD (P < 0.05). Although C-reactive protein, immunoglobulin G, rheumatoid factor and rheumatoid arthritis particle agglutination levels in serum from patients with RA with ILD were not significantly different between the IL-1alpha auto-Ab-positive and -negative groups, the lactate dehydrogenase level (LDH) and AaDO, in the IL-1alpha auto-Ab-positive group were significantly higher than those in the negative group (LDH: P < 0.001, AaDO2: P < 0.05). CONCLUSION: These results suggest that IL-1alpha auto-Ab are generated in response to the immunoinflammatory process of ILD in RA, and these autoantibodies may neutralize and regulate the IL-1alpha activity.

Adult↗

Interleukin-1beta level in gingival crevicular fluid of patients with active periodontitis.

Previous studies revealed that interleukin-1beta (IL-1beta) was detectable in gingival crevicular fluid (GCF) of patients with periodontitis, and the level was increased in level in gingival tissue extracts of active periodontal disease sites (defined as attachment loss > or = 2.5 mm over the preceding 2 months) compared to inactive sites or healthy sites. The present study evaluated the relationship of IL-1beta level in GCF and periodontal disease status. GCF was collected with Periopaper strips from 34 disease-active and 45 disease-inactive teeth in 11 untreated periodontitis patients and from 60 teeth in 15 healthy control subjects. Disease activity was defined as attachment loss of > or = 2.5 mm in at least one site of a tooth as determined by sequential probing. The absorbed GCF volume was determined using a Periotron 6000 and the crevicular IL-1beta level was determined using IL-1beta monoclonal antibody (Otsuka Pharmaceutical, Japan). IL-1beta was below the detection level of the assay (6 pg/ml) in the healthy control group but was detected in most teeth of the periodontitis group. However, disease-active teeth had higher IL-1beta level (Mann-Whitney U-test, p < 0.05) than disease-inactive teeth (mean total IL-1beta of 5.89 +/- 7.88 pg/tooth and 1.72 +/- 2.28 pg/tooth; mean concentration of 1.6 +/- 2.5 ng/ml and 0.6 +/- 0.83 ng/ml, respectively). The level of IL-1beta showed no correlation with probing depth, but had significant correlation (p < 0.05) with the extent of attachment loss. This study suggests that the level of IL-1beta in GCF may have a predictive value for determining active and inactive periodontal status.

Adult↗

Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.

We isolated the human adipose-specific and most abundant gene transcript, apM1 (Maeda, K., et al., Biochem. Biophys. Res. Commun. 221, 286-289, 1996). The apM1 gene product was a kind of soluble matrix protein, which we named adiponectin. To quantitate the plasma adiponectin concentration, we have produced monoclonal and polyclonal antibodies for human adiponectin and developed an enzyme-linked immunosorbent assay (ELISA) system. Adiponectin was abundantly present in the plasma of healthy volunteers in the range from 1.9 to 17.0 mg/ml. Plasma concentrations of adiponectin in obese subjects were significantly lower than those in non-obese subjects, although adiponectin is secreted only from adipose tissue. The ELISA system developed in this study will be useful for elucidating the physiological and pathophysiological role of adiponectin in humans.

Adiponectin↗

Presence and potent immunosuppressive role of interleukin-10 in malignant pleural effusion due to lung cancer.

The presence and possible role of interleukin (IL)-10 were examined in malignant pleural effusion due to lung cancer. In 37 out of 55 cases examined, IL-10 was detectable in pleural effusion and the mean level with standard error was 62.1+/-12.1 pg/ ml. Spontaneous and lipopolysaccharide-induced production of anti-tumor cytokines such as IL-1beta and tumor necrosis factor (TNF)-alpha, by pleural macrophages, obtained from five patients with malignant pleurisy, were suppressed by IL-10. These findings suggest that IL-10 is present in the tumor-growing site and acts as a suppressive factor of local anti-tumor immunity in humans.

Aged↗