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Biomedical subjects

Y Higashi

Publications and source records attributed to Y Higashi.

At least 37 records · Page 2Linked to original sources
PubMed2001

Tacrolimus suppressed the production of cytokines involved in atopic dermatitis by direct stimulation of human PBMC system. (Comparison with steroids).

Tacrolimus (FK506) ointment showed remarkable efficacy against atopic dermatitis in animal models and clinical trials. The suppressive effect of tacrolimus on the production of the cytokines involved in atopic dermatitis (IL-2, IL-3, IL-4, IL-5, IFN-gamma and GM-CSF) from human peripheral blood mononuclear cells (PBMC) was investigated. We constructed a new cytokine production system in which T cells are activated by direct stimulation in vitro with anti-CD3/CD2 or anti-CD3/CD28 antibody combination. Tacrolimus inhibited the production of these cytokines by both stimulations. In a comparative study with steroids (alclometasone dipropionate and betamethason valerate) in anti-CD3/CD2 system, tacrolimus and both steroids inhibited Th1 cytokines (IL-2, IFN-gamma), Th2 cytokines (IL-4, IL-5) and IL-3, GM-CSF (produced by both Th1 and Th2). The suppressive effect of tacrolimus on cytokine production was stronger than that of alclometasone dipropionate and equal to or stronger than that of betamethason valerate. The effective dose of tacrolimus (IC50, 0.02-0.11 ng/ml) is almost the same as for Th1 and Th2 cytokines, and 1 ng/ml of tacrolimus suppressed all cytokines completely. These results suggest that tacrolimus suppresses the allergic cytokines from T cells, and that tacrolimus ointment is effective against atopic dermatitis through the inhibition of cytokine production.

Betamethasone↗
PubMed2001

Endoscopic treatment of a long fibroepithelial ureteral polyp.

A case is reported of a 30-year-old woman with a long fibroepithelial polyp in the middle ureter treated with the Ho-YAG laser endoscopically. She presented with an intermittent macroscopic hematuria and lower abdominal pain lasting for 1 year. The filling defect on urography occupying one-third of the ureter was migratory depending on the patient position. Transurethral flexible ureterorenoscopy showed a large pedunculated tumor with a small base at the middle ureter. About 1 month after the endoscopic irradiation of the Ho-YAG laser to the base of tumor, the tumor was spontaneously discharged and pathologic examination revealed it to be a fibroepithelial polyp without malignant component. Postoperatively, the patient remained asymptomatic and follow-up excretory urographs showed no abnormal findings.

Adult↗
PubMed2001

Calorie restriction reduced blood pressure in obesity hypertensives by improvement of autonomic nerve activity and insulin sensitivity.

Association between obesity and hypertension has been well recognized. A reduction in the body weight of over-weight hypertensive patients is a recommended lifestyle modification. The purpose of our study is to examine the relationship of insulin sensitivity and autonomic nervous activity with reduction of blood pressure by the calorie restriction. We evaluated the heart rate variability, nocturnal change of blood pressure and insulin resistance before and after a short-term low-calorie diet in 12 overweight essential hypertensives. After a week of standard diet (2000 kcal), 2 weeks of low-calorie diet (800 kcal) with normal sodium content induced a significant reduction in body mass index, triglyceride, fasting immunoreactive protein, homeostasis model assessment as an index of insulin resistance, and urinary excretion of sodium and potassium. Systolic blood pressure was significantly reduced both in daytime and night-time after the low-calorie diet (daytime, 134.5+/-6.0 to 122.0+/-4.1 mmHg; night-time, 126.8+/-5.2 to 113.4+/-7.2 mmHg). In daytime, diastolic blood pressure was also reduced (90.3+/-2.1 to 88.1+/-4.8 mmHg). Although heart rate was not significantly reduced, a rise of high frequency in night-time (346+/-82 to 572+/-108 ms2) and a fall of low frequency/high frequency in day-time (3.5+/-0.4 to 2.6+/-0.1) was significant after a low-calorie diet. In conclusion, weight loss by low-calorie diet with a constant intake of sodium, reduced blood pressure in obese hypertensives by improvement of vagal nervous activity and insulin resistance.

Adult↗
PubMed2001

Molecular significance of excess body weight in postmenopausal breast cancer patients, in relation to expression of insulin-like growth factor I receptor and insulin-like growth factor II genes.

A number of epidemiological and clinical studies have revealed that excess body weight increases the risk of postmenopausal breast cancer and also adversely affects subsequent malignant progression. To elucidate the molecular mechanisms underlying these observations, we examined mRNA expression of various genes in normal (non-cancerous) mammary gland and cancer tissue of Japanese patients with primary breast cancer, in association with their body mass index (BMI). On the basis of analysis of 106 breast cancer patients, we found that mRNA expression of insulin-like growth factor I receptor (IGF-IR) and insulin-like growth factor II (IGF-II) in the normal mammary gland showed a significant and positive association with increased BMI among postmenopausal patients. Furthermore, the positive association of increased BMI with IGF-IR mRNA expression was also found in postmenopausal breast cancer tissue, while this association was not observed among premenopausal patients. In addition, increased mRNA expression of cyclin D1 and bcl-2 was observed in association with increased mRNA levels of IGF-IR among the patients regardless of menopausal status. These findings suggest that the molecular consequence of the increased BMI is the increased expression of IGF-II and IGF-IR, resulting in development of postmenopausal breast cancer and its progression mediated through modulation of the cell cycle and apoptosis.

Adult↗
PubMed2001

The transcriptional repressor ZEB regulates p73 expression at the crossroad between proliferation and differentiation.

The newly discovered p73 gene encodes a nuclear protein that has high homology with p53. Furthermore, ectopic expression of p73 in p53(+/+) and p53(-/-) cancer cells recapitulates some of the biological activities of p53 such as growth arrest, apoptosis, and differentiation. p73(-/-)-deficient mice exhibit severe defects in proper development of the central nervous system and pheromone sensory pathway. They also suffer from inflammation and infections. Here we studied the transcriptional regulation of p73 at the crossroad between proliferation and differentiation. p73 mRNA is undetectable in proliferating C2C12 cells and is expressed at very low levels in undifferentiated P19 and HL60 cells. Conversely, it is upregulated during muscle and neuronal differentiation as well as in response to tetradecanoyl phorbol acetate-induced monocytic differentiation of HL60 cells. We identified a 1-kb regulatory fragment located within the first intron of p73, which is positioned immediately upstream to the ATG codon of the second exon. This fragment exerts silencer activity on p73 as well as on heterologous promoters. The p73 intronic fragment contains six consensus binding sites for transcriptional repressor ZEB, which binds these sites in vitro and in vivo. Ectopic expression of dominant-negative ZEB (ZEB-DB) restores p73 expression in proliferating C2C12 and P19 cells. Thus, transcriptional repression of p73 expression by ZEB binding may contribute to the modulation of p73 expression during differentiation.

Animals↗
PubMed2001

Atopic dermatitis-like skin lesions induced by topical application of mite antigens in NC/Nga mice.

BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing inflammation usually observed in patients with an individual or a familial history of atopic diseases, precipitated by environmental factors including mite antigens (Ag). However, the exact etiology of AD is unclear. To further explore the pathogenesis and treatment of AD, a suitable animal model is necessary. In this study, we developed a new animal model of AD induced by mite Ag in NC/Nga mice. METHODS: We injected the extracts of mite Ag intradermally at the ventral side of the ear of SPF NC/Nga mice on days 0, 2, 4, 7, 9, 11, 14 and 16, and measured the clinical symptoms and the ear thickness. On day 18, we collected blood and submandibular lymph nodes (LN) of the immunized ear to perform a histochemical analysis, and to measure the plasma immunoglobulins and cytokines. RESULTS: The NC/Nga mice immunized with mite Ag suffered from AD-like skin lesions including erythema followed by edema, excoriation and scaling. The histological and immunohistochemical examinations of the affected skin showed epidermal hyperplasia with hyperkeratosis, severe infiltration of CD4+ T lymphocytes, eosinophils and macrophages, and degranulation of mast cells. The total plasma IgE level was markedly elevated in mite Ag-treated mice. LN cells of mice immunized with mite Ag synthesized IgE in an Ag-dependent manner and secreted interleukin-4 (IL-4) and IL-5 but not interferon-gamma. CONCLUSIONS: NC/Nga mice treated with mite Ag manifest clinical and immunological aspects similar to patients with AD, suggesting that this model is suitable for exploring the pathogenesis of human AD.

Allergens↗
PubMed2001

Effect of estrogen replacement therapy on endothelial function in peripheral resistance arteries in normotensive and hypertensive postmenopausal women.

Both menopause and hypertension are associated with endothelial dysfunction and are risk factors for coronary heart disease. We evaluated forearm resistance artery endothelial function in hypertensive postmenopausal women (HPW, n=57) and compared it with endothelial function in normotensive postmenopausal women (NPW, n=67). In addition, we evaluated the effects of long-term estrogen replacement therapy (ERT, conjugated equine estrogen at a dose of 0.625 mg daily for 12 weeks) on endothelial function in HPW (n=10) and NPW (n=35). Forearm blood flow (FBF) was measured by strain-gauge plethysmography during reactive hyperemia to assess endothelium-dependent vasodilation and after sublingual nitroglycerin (NTG) administration to assess endothelium-independent vasodilation. Basal FBF was similar in the NPW and HPW groups. The FBF in the HPW group during reactive hyperemia was significantly lower than that in the NPW group. Increases in FBF after NTG were similar in the 2 groups. ERT decreased the LDL cholesterol concentration and circulating ACE activity and increased estradiol and HDL cholesterol in both groups. Basal blood pressures, heart rate, FBF, and body weight did not change with ERT. After 12 weeks of ERT, the maximal FBF response during reactive hyperemia increased significantly in both groups. The improvement in reactive hyperemia after ERT was significantly greater in the HPW group than in the NPW group (49+/-8 versus 17+/-5%, P<0.05). Changes in FBF after sublingual NTG administration were similar before and after 12 weeks of ERT. These findings suggest that continued ERT improves forearm resistance artery endothelial function in postmenopausal women and that this beneficial effect is greater in patients that are hypertensive.

Blood Pressure↗
PubMed2001

Effects of angiotensin-(1-7) on forearm circulation in normotensive subjects and patients with essential hypertension.

Previous animal studies have shown that angiotensin (Ang)-(1-7) is a biologically active component of the renin-angiotensin system, acting as a vasoactive agent, and may play a role in the blood pressure regulation. There is little information, however, on the effect of Ang-(1-7) on human circulation or the mechanism of its action. To investigate the effect of Ang-(1-7) on forearm circulation and to determine whether this effect is altered in patients with essential hypertension, we measured change in forearm blood flow using venous occlusion plethysmography in response to intra-arterial infusion of Ang-(1-7) (10(-10), 10(-9), and 10(-8) mol/min; for 5 minutes) in normotensive control subjects (n=8) and patients with essential hypertension (n=8). Infusion of Ang-(1-7) significantly increased the forearm blood flow response in a dose-dependent manner in both normotensive control subjects (28.7+/-9.7%, at 10(-8) mol/min; P<0.05) and hypertensive patients (31.8+/-15.2%, at 10(-8) mol/min; P<0.05). The vasodilatory effect of Ang-(1-7) was similar in the two groups. Intra-arterial infusion of N(G)-monomethyl-L-arginine, a nitric oxide synthesis inhibitor, did not alter the forearm blood flow response to Ang-(1-7) in either group. These findings suggest that Ang-(1-7) causes vasodilation in forearm circulation of normotensive subjects and patients with essential hypertension through a pathway that is independent of nitric oxide synthesis.

Analysis of Variance↗
PubMed2001

Selective delivery of estradiol to bone by aspartic acid oligopeptide and its effects on ovariectomized mice.

We have developed a novel osteotropic prodrug of estradiol (E(2)) conjugated with L-Asp-hexapeptide (E(2).3D(6)), which has very low affinity for estrogen receptors, and in this study, we examined its pharmacokinetic behavior and pharmacological potential. After a single iv injection of E(2) x 3D(6) to mice, the half-time for elimination from plasma was about 100 min; however, E(2) was selectively delivered to the bone and eliminated very slowly, declining to the endogenous level at about 7 days. After a single iv injection of E(2), the half-time in plasma was about 70 min, whereas E(2) was highly distributed to the uterus, and the bone concentration of E(2) was only slightly increased at 6 h. When E(2) (0.37 micromol/kg, sc, every third day) or E(2) x 3D(6) (0.11 to 1.1 micromol/kg, sc, every seventh day) was administered to OVX mice for 4 weeks, E(2) increased the bone mineral density (BMD) together with weights of liver and uterus, whereas E(2) x 3D(6) increased only the BMD, in a dose-dependent manner. E(2) x 3D(6) enhanced the expression of messenger RNAs of bone matrix proteins (osteopontin, bone sialoprotein, type I collagen alpha) of OVX mice at 4 h after administration, but E(2) did very slightly. These results indicate that the E(2) prodrug was delivered to the bone, where it gradually released E(2), thereby ameliorating bone loss. This acidic oligopeptide appears to be a good candidate for selective drug delivery to bone.

Animals↗
PubMed2001

Effect of gamma-butyrobetaine on fatty liver in juvenile visceral steatosis mice.

We pharmacokinetically examined the effect of gamma-butyrobetaine, a precursor of L-carnitine, on the change of fatty acid metabolism in juvenile visceral steatosis (JVS) mice, which have systemic L-carnitine deficiency due to lack of L-carnitine transporter activity. The concentrations of total free fatty acid (FFA), palmitic acid and stearic acid in the liver of JVS mice were significantly higher than those in wild-type mice. After intravenous administration of gamma-butyrobetaine (50 mg kg(-1)), the concentration of L-carnitine in the plasma of JVS mice reached about twice that of the control level and levels in the brain, liver and kidney were also significantly increased, whereas those in wild-type mice hardly changed. Although the plasma concentrations of FFA in both types of mice were unchanged after administration of gamma-butyrobetaine, the concentrations of palmitic acid and stearic acid were significantly decreased. In particular, the liver concentration of FFA in JVS mice was decreased to the wild-type control level, accompanied by significant decreases in long-chain fatty acids, palmitic acid and stearic acid, whereas those in wild-type mice were not changed. These results suggest that gamma-butyrobetaine can be taken up into organs, including the liver, of JVS mice, and transformed to L-carnitine. Consequently, administration of gamma-butyrobetaine may be more useful than that of L-carnitine itself for treatment of primary deficiency of carnitine due to a functional defect of the carnitine transporter.

Animals↗
PubMed2001

Sodium chloride loading does not alter endothelium-dependent vasodilation of forearm vasculature in either salt-sensitive or salt-resistant patients with essential hypertension.

The purpose of this study was to determine whether a high NaCl intake impairs endothelium-dependent and -independent vasodilation of forearm circulation in salt sensitive (SS) patients with essential hypertension. We evaluated the effects of intra-arterial acetylcholine (ACh) and isosorbide dinitrate (ISDN) on forearm hemodynamics in 29 patients with essential hypertension, while consuming a low NaCl (50 mmol/d) or high Na Cl (340 mmol/d) diet for 1 week. The forearm blood flow (FBF) was measured by strain-gauge plethysmography. Patients were classified as SS (n=12) or salt resistant (SR; n=17) based on salt-induced changes in blood pressures. The FBF responses of ACh and ISDN were similar in the SS and SR patients while on either NaCl diet, and was not altered by salt loading (ACh, SS: low NaCl 22.8+/-4.3 vs. high NaCl 21.1+/-3.6 ml/min per 100 ml, SR: low NaCl 22.5+/-4.0 vs. high NaCl 23.3+/-4.1 ml/min per 100 ml; ISDN, SS: low NaCl 13.9+/-2.1 vs. high NaCl 14.1+/-2.2 ml/min per 100 ml, SR: low NaCl 13.8+/-2.3 vs. high NaCl 14.0+/-2.2 ml/min per 100 ml). There were no significant differences in the vascular responses to ACh and ISDN in the presence of N(G)-monomethyl-L-arginine, a nitric oxide synthase inhibitor, in either group for either NaCl diet. These findings suggest that forearm resistance artery endothelial function may not be influenced by salt loading in either SS patients which finding may play a role in determining salt sensitivity in patients with essential hypertension or SR patients.

Diet, Sodium-Restricted↗
PubMed2001

Novel drug delivery system to bone using acidic oligopeptide: pharmacokinetic characteristics and pharmacological potential.

We synthesized fifteen oligopeptides consisting of Asp or Glu conjugated with a fluorescent probe, 9- fluorenylmethylchloroformate (Fmoc). In the in vitro binding assay to putative hydroxyapatite (HA), the affinities of these conjugates depended only on the number of amino acid residues, not on their optical characters (L or D) or their species (Asp or Glu). In an in vivo experiment involving a single i.v. injection of Fmoc-D-Asp oligopeptides into mice, peptides consisting of over six Asp residues were selectively distributed to the bone. Then, we synthesized estradiol-17 beta-succinate-(L-Asp)6 [E2-(L-Asp)6] and studied its pharmacokinetic characteristics and its antiosteoporotic effects on ovariectomized (OVX) mice. Although the distribution volume of E2-(L-Asp)6 was significantly smaller than that of E2, E2-(L-Asp)6 was selectively distributed in the bone after i.v. injection and gradually decreased during 7 days. E2-(L-Asp)6 effectively prevented OVX-induced bone loss, without altering the uterine weight, in the dosage range of 0.11 to 1.1 mumol/kg once a week, while E2 increased both the bone mineral density and uterine weight at 0.37 mumol/kg every third day. The results suggest that acidic oligopeptide may be useful for drug delivery to bone and E2-(L-Asp)6 is a good candidate as an anti-osteoporosis drug without the adverse side effects of E2.

Acids↗
PubMed2001

[A case of lung and pleural metastases from breast cancer responding to toremifene].

A patient with lung and pleural metastases from breast cancer treated effectively with toremifene is reported. A 62-year-old woman underwent mastectomy for breast cancer, and had high levels of estrogen and progesterone receptor. After 2-years of adjuvant UFT therapy, lung and pleural metastases were seen on a chest x-ray. The patient received a high-dose of toremifene (120 mg/day). After five months with toremifene, a chest x-ray and CT scan showed the disappearance of lung and pleural metastases. No recurrence or metastases have been detected for twenty months to date. No serious side effects were noticed. High-dose toremifene might be an effective therapy for cases of postmenopausal metastatic breast cancer, with high levels of estrogen and progesterone receptor.

Antineoplastic Agents, Hormonal↗
PubMed2001

Oral estrogen replacement therapy increases forearm reactive hyperemia accompanied by increases in serum levels of nitric oxide in postmenopausal women.

The present study sought to determine the correlation between the vasodilator response of forearm resistance vessels and the circulating levels of nitric oxide (NO) after the administration of oral estrogen for 12 weeks to postmenopausal women. We classified postmenopausal women into two groups: those treated with conjugated equine estrogen (0.625 mg daily) orally for 12 weeks (n = 24) or those who received no treatment (control group, n = 8). Forearm blood flow was measured using strain-gauge plethysmography during hyperemia to evaluate endothelium-dependent vasodilation, and after sublingual nitroglycerin administration to evaluate endothelium-independent vasodilation. Serum levels of nitrite/nitrate (metabolites of NO) and lipid parameters were measured. Basal forearm blood flow, body weight and heart rate were similar in each group. After 12 weeks of estrogen administration, the maximal forearm blood flow response during reactive hyperemia and the serum level of nitrite/nitrate each showed a significant increase from 26.9 +/- 1.9 to 37.9 +/- 3.5 ml/min per 100 ml tissue (p < 0.01), and from 25.2 +/- 2.2 to 37.5 +/- 3.7 mumol/l (p < 0.05), respectively. No increases were seen in controls. The changes in forearm blood flow after sublingual nitroglycerin were similar before and after 12 weeks of estrogen administration. The increase in maximal forearm blood flow with reactive hyperemia was significantly correlated with the increase in nitrite/nitrate in the group administered estrogen (r = 0.48, p < 0.05). There was no significant correlation between maximal forearm blood flow with reactive hyperemia, nor any change in serum lipids, blood pressure or other parameters. In conclusion, the 12-week administration of oral estrogen increased forearm reactive hyperemia in postmenopausal women, probably via an increase in the production of NO.

Body Weight↗
PubMed2001

Cyclooxygenase-2 expression and prostaglandin E2 biosynthesis are enhanced in scleroderma fibroblasts and inhibited by UVA irradiation.

OBJECTIVE: We and others reported on the beneficial effects of combined therapy using 8-methoxypsoralen and long wave ultraviolet light (PUVA therapy) in the treatment of scleroderma. We now investigate the mechanism by which PUVA therapy is effective by comparing interleukin 1beta (IL-1beta) mediated signal transduction in scleroderma fibroblasts and those from normal skin. METHODS: Prostaglandin E2 (PGE2) production and expression of cytosolic phospholipase A2 (cPLA2), cyclooxygenase (COX)-1, and COX-2 (enzymes that regulate PGE2 production) were examined in untreated and IL-1beta treated fibroblasts from scleroderma involved and normal skin. The effect of UVA irradiation on enzyme expression and PGE2 production was examined. PGE2 was measured by a competitive radioimmunoassay and enzyme expression was analyzed by Western immunoblotting and Northern blotting. RESULTS: Constitutive PGE2 production was significantly upregulated and IL-1beta induced PGE2 production was increased by the enhancing expression of both COX-2 mRNA and protein in fibroblasts from scleroderma involved skin; PGE2 production and COX-2 expression were inhibited by UVA irradiation. CONCLUSION: Enhanced PGE2 production regulated by COX-2 expression in scleroderma fibroblasts may contribute to the development of this disorder. PUVA therapy might exhibit its beneficial effect, at least in part, by inhibiting COX-2 expression transcriptionally and translationally, with subsequent inhibition of PGE2 production.

Adult↗
PubMed2001

Foam cell formation containing lipid droplets enriched with free cholesterol by hyperlipidemic serum.

A monoclonal antibody, ASH1a/256C (256C), which binds to atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbit (WHHL) aorta in vivo, recognizes complex structures of phosphatidylcholine mixed with neutral lipids. In the present study, a cell culture system is described in which foam cells express 256C-positive lipid droplets. J774.1 macrophages were incubated in the presence of a small volume of WHHL serum for 24 h to produce foam cells, which were then incubated without the WHHL serum for 3 days. Oil red O-positive lipid droplets appeared on day 1, and were present in the cells during the whole incubation period. The lipid droplets in the cells were positively immunostained with antibody 256C on day 4, although they were negative on day 1. Expression of the antigenic lipid droplets was also induced by the addition of acetylated LDL or sera from patients with hyperlipidemia. When foam cells were induced by the addition of WHHL serum, cellular content of cholesteryl ester was greatly increased but then decreased to near basal levels by day 4. Concomitantly, cellular free cholesterol increased during the culture period, indicating that the cholesteryl ester changes to free cholesterol by day 4. The lipid droplets in the foam cells on day 4 were positively stained with filipin, a fluorescent probe for free cholesterol, as well as with 256C antibody, indicating that free cholesterol is enriched in antigenic lipid droplets. These observations suggest that hydrolysis and rearrangement of cellular cholesterol take place in foam cells to form complex structures of phosphatidylcholine and free cholesterol in lipid droplets.

Animals↗
PubMed2000

Inhibitory effects of 9-cis-retinoic acid and pyrrolidinedithiocarbamate on cyclooxygenase (COX)-2 expression and cell growth in human skin squamous carcinoma cells.

We recently demonstrated that the constitutive expression of cyclooxygenase (COX)-2 protein and prostaglandin E(2) (PGE(2)) biosynthesis were significantly enhanced in human skin epidermal cancer cells and that cancer cell growth was effectively inhibited by the suppression of COX-2 expression by transfection with COX-2 antisense oligonucleotide. The purpose of this study was to search for agents which suppress COX-2 expression and examine their effects on cell growth. Since retinoids and antioxidants have been used for chemoprevention of cancers in several tissues, the effects of these agents on COX-2 expression and PGE(2) biosynthesis in skin squamous carcinoma cells were investigated. Treatment with a retinoid (9-cis-retinoic acid (9-cis-RA)) or an antioxidant (pyrrolidinedithiocarbamate (PDTC)) suppressed COX-2 expression and PGE(2) biosynthesis in a concentration-dependent manner. Cell growth was significantly inhibited by 9-cis-RA and PDTC. These results suggest that 9-cis-RA and PDTC may be useful in preventing skin cancer growth and that COX-2 is involved in their protective effects on skin carcinogenesis.

Acetylcysteine↗