Biomedical subjects

H Fukasawa

Publications and source records attributed to H Fukasawa.

At least 19 recordsLinked to original sources

PubMed1997

Inhibition of IL-1-induced IL-6 production by synthetic retinoids.

The effects of retinoids and retinoid antagonists on IL-6 production in MC3T3-E1 cells were investigated. None of the synthetic retinoids examined stimulated IL-6 production, but all of them strongly inhibited IL-6 production induced by mouse IL-1 alpha. Their inhibitory activities correlated well with their differentiation-inducing activities in HL-60 assay or their binding affinities to nuclear retinoic acid receptors (RARs). Among three retinoid antagonists, two weak antagonists exhibited similar inhibition of mouse IL-1 alpha-induced IL-6 production, whereas a potent retinoid antagonist, 4-(13H-10,11,12,13-tetrahydro-10,10,13,13,15-pentamethyl-dinaph tho[2,3-b] [1,2-e]diazepin-7-yl)benzoic acid (LE540, 14), enhanced IL-6 production under the same conditions.

3T3 Cells↗

PubMed1997

Photoaffinity labeling of tumor promoter-binding protein (CN-TPBP) and preparation of affinity sorbent gels.

Cytosolic-nuclear tumor promoter-specific binding protein (CN-TPBP) was photoaffinity-labeled with a specific ligand, 3beta,5alpha-dihydroxycholestan-6-one (YS-64). Analysis by ODS-HPLC of peptide fragments obtained from the labeled CN-TPBP by trypsinization indicated the existence of a single specifically labeled site. Affinity gels for the purification of CN-TPBP were then prepared. As ligands for the affinity gels, 12-O-tetradecanoylphorbol 13-acetate (TPA), a typical phorbol-type tumor promoter, and benzolactam-V8-310 (BL-V8-310), a structural/biological mimic of teleocidin-class tumor promoters, were adopted. The use of these gels afforded a protein that showed a single band of 58 kDa on SDS-PAGE.

Affinity Labels↗

PubMed1996

Nerve function and blood flow in Otsuka Long-Evans Tokushima Fatty rats with sucrose feeding: effect of an anticoagulant.

To investigate the pathogenesis of diabetic neuropathy in non-insulin-dependent diabetes mellitus, Otsuka Long-Evans Tokushima Fatty rats, an animal model of non-insulin-dependent diabetes mellitus, and non-diabetic Long-Evans Tokushima Otsuka rats were fed with or without sucrose and/or cilostazol, an anticoagulant, for 8 weeks. Sucrose-fed diabetic rats showed a delayed motor nerve conduction velocity, decreased R-R interval variability of electrocardiogram, reduced sciatic nerve blood flow, increased platelet aggregability and a decreased erythrocyte 2,3-diphosphoglycerate concentration compared with non-sucrose-fed diabetic rats and non-diabetic rats. These abnormalities were significantly prevented by treatment with cilostazol without changes in the nerve tissue levels of polyols. These findings indicate that sucrose-fed Otsuka Long-Evans Tokushima Fatty rats may be a useful animal model of neuropathy in non-insulin-dependent diabetes mellitus, and that cilostazol may prevent the development of diabetic neuropathy by modifying vascular factors.

2,3-Diphosphoglycerate↗

PubMed1996

Effect of propionyl-L-carnitine on oscillatory potentials in electroretinogram in streptozotocin-diabetic rats.

The effect of propionyl-L-carnitine, an analogue of L-carnitine, and insulin on the oscillatory potentials of the electroretinogram was determined in rats with streptozotocin-induced diabetes. Propionyl-L-carnitine was administered at a daily dose of 0.5 g/kg by gavage for 4 weeks, while other rats were treated with subcutaneous injections of insulin (8-10 U/day). Both treatments shortened the peak latencies of the oscillatory potentials in the electroretinogram, which were significantly prolonged in untreated diabetic rats (O1, O2 and O3, and sigma (O1 + O2 + O3)) (P < 0.0001 vs. untreated normal rats). A significant decrease in the erythrocyte free carnitine level in diabetic rats was prevented by both treatments. Insulin produced a significant reduction of retinal glucose, sorbitol and fructose levels in diabetic rats, while propionyl-L-carnitine failed to do so. However, both treatments markedly reduced serum lipids levels in the diabetic rats. These findings provide information on the pathogenesis of diabetic retinopathy as well as suggesting the potential therapeutic value of propionyl-L-carnitine for retinopathy.

Analysis of Variance↗

PubMed1996

Effects of propionyl-L-carnitine and insulin on the electroretinogram, nerve conduction and nerve blood flow in rats with streptozotocin-induced diabetes.

The effect of an analogue of L-carnitine, propionyl-L-carnitine, on the electroretinogram, motor nerve conduction velocity and nerve blood flow was determined in rats with streptozotocin-induced diabetes, and was compared with the effects of insulin alone or combined therapy. Oral administration of propionyl-L-carnitine (3 g/kg daily for 4 weeks) significantly increased caudal nerve motor conduction velocity and sciatic nerve blood flow in diabetic rats. There were no differences in the effects of insulin (8-10 U daily for 4 weeks), propionyl-L-carnitine and combined therapy. Although propionyl-L-carnitine significantly shortened the peak latency of the electroretinogram b-wave in diabetic rats, its effect was far weaker than that of insulin or combined therapy, with combined therapy producing the greatest improvement. These effects of propionyl-L-carnitine were accompanied by a decrease of serum lipid levels, an increase of the sciatic nerve carnitine content, and no changes of the tissue (nerve and retinal) sorbitol and myo-inositol concentrations. In contrast, insulin significantly reduced the tissue sorbitol content and markedly increased myo-inositol. These findings suggest that propionyl-L-carnitine may improve diabetic neuropathy and retinopathy without influencing the polyol pathway, and that this beneficial effect may be mediated through the amelioration of microcirculation and tissue carnitine content, thus probably increasing fatty acid oxidation.

Animals↗

PubMed1996

Effect of acarbose on blood glucose profiles and plasma 1,5-anhydro-d-glucitol in type 2 diabetes poorly controlled by sulfonylurea therapy.

Sixteen patients with type 2 diabetes poorly controlled by glibenclamide (7.5-10.0 mg/day) were treated with acarbose (100 mg tds) for one week and the effect on the blood glucose profile, 24-hour urinary glucose excretion, plasma fructosamine, and plasma 1,5-anhydro-D-glucitol (1,5-AG) level was determined. The blood glucose profile was more stable and levels were lower during acarbose administration. In some patients, this improvement was maintained after discontinuing acarbose. The M-value, an indicator of blood glucose fluctuations, decreased significantly from 33.2 +/- 3.0 (mean +/- SEM) in the run-in period to 13.4 +/- 2.4 during acarbose therapy (P < 0.001), and rose again to 26.5 +/- 4.4 (P < 0.001) in the follow-up period. The 24-hour urinary glucose excretion and plasma fructosamine decreased similarly (P < 0.001 and P < 0.01, respectively) during and after acarbose therapy. Plasma 1,5-AG levels did not change significantly during acarbose therapy, but increased markedly afterwards (from 19.3 +/- 3.1 mumol 1(-1) to 25.0) +/- 3.1 mumol l-1, P < 0.001). Plasma 1,5-AG levels were significantly correlated with urinary glucose excretion one week earlier (r = 0.513, P < 0.006). These findings suggest that acarbose may improve glycemic control in type 2 diabetic patients poorly controlled by sulfonylurea therapy and that plasma 1,5-AG might be used as a marker of glycemic control cooperating with other markers such as fructosamine and urinary glucose determination for monitoring the short-term response to antidiabetic therapy.

Acarbose↗

PubMed1996

Anatomic study of anterior frontal cortical bridging veins with special reference to the frontopolar vein.

Anatomic variations of the frontopolar vein were investigated in 21 cadaver brains to improve the preservation rate of this vein in interhemispheric surgery for anterior communicating aneurysms. Most of the frontopolar vein has been considered to drain the outer convex side of the frontal lobe, but in reality, the area of its venous drainage was found to cover a large part of the frontal lobe, including its medial and basal surfaces. This observation suggests that sacrifice of the vein during surgery carries a risk of venous infarction. Therefore, care must be taken to not injure the vein during surgery. The mean distance between the frontopolar vein and the most anterior point of the frontal lobe was 31.1 mm. Although the vein became smaller close to the frontal tip, the mean diameter of the vein was 1.9 mm. Morphologically, approximately two-thirds of the frontopolar veins was found to have a "main trunk." The frontopolar vein can be spared during surgery by using a flexible surgical technique incorporating vein dissection or additional craniotomy.

Aged↗

PubMed1996

Evaluation of differentiation-inducing activity of retinoids on human leukemia cell lines HL-60 and NB4.

Retinoids, including all-trans-retinoic acid (ATRA), its isomers, and fifty synthetic retinoids (retinobenzoic acids), were tested for differentiation-inducing activity on human leukemia cell lines HL-60 and NB4. Binding activity of typical retinoids to nuclear retinoic acid receptors (RARs) was also investigated. A good linear correlation between the ED50 values of differentiation-inducing activity towards HL-60 cells and those towards NB4 cells was found. Binding activities of retinoids to RAR alpha and RAR beta also correlated well to the differentiation-inducing activities.

Benzoates↗

PubMed1996

Location of two photoaffinity-labeled sites on the ligand-binding domain of retinoic acid receptor alpha.

Retinoic acid receptors (RARs) consist of six domain structures. The C-terminal region (D/E/F-domains) is involved in ligand binding, dimerization, and ligand-dependent transactivation. Structural information about RARs is required for understanding its complex function. A photoreactive retinoid denoted as ADAM-3, which was designed as the result of comparison of two fluorescent retinoids (DAM-3 and DAM-15), was synthesized and used for photoaffinity labeling of recombinant protein MBP-RAR alpha/E. The photoaffinity-labeled site was determined by an endoprotease combination method which utilizes four endoproteinases in a two-phase digestion procedure. Two major labeled fragments were detected in each digestion, and the results of two-phase digestion allowed identification of the labeled residues as being located within residues 492-510 and 585-594, which correspond to 288-306 and 381-390 in human RAR alpha, respectively.

Affinity Labels↗

PubMed1996

[Retinoid antagonists].

Retinoids, retinoic acid and its bioisosters, regulate many biological functions such as cell differentiation, proliferation and embryonic development in vertebrates, through binding to and activating their specific nuclear receptors. There are two classes of nuclear receptors for retinoids, retinoic acid receptors (RAR alpha, beta, gamma) and retinoid X receptors (RXR alpha, beta, gamma). Several retinoid antagonists, which bind to but not activate RARs, have been reported. Among them, 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10-pentamethylbenzo[e]naphtho [2,3-b][1,4]diazepin-13-yl)benzoic acid (LE135, 20) is a RAR beta-selective retinoid antagonist. Structure-activity relationships of LE135 (20) showed that the naphthalenyl analogs [LE540 (21) and LE550 (22)] are more potent retinoid antagonists in HL-60 assay. Contrary to the antagonistic activity of LE135 (20), an isomer of LE135 (20), 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo- [b,e][1,4]diazepin-11-yl)benzoic acid (HX600, 39) enhanced the activities of retinoids. Although the synergistic activity of HX600 (39) can be explained by the binding to RXRs and the further activation of RAR/RXR heterodimer activated by retinoid (RAR ligand), the significantly different biological character of HX600 (39) from the typical RXR-selective ligand suggested the possibility of the participation of other nuclear receptors or cofactors in the retinoid synergism.

Animals↗

PubMed1996

Protective effect of nilvadipine on focal cerebral ischemia in spontaneously hypertensive rats.

The protective effect of nilvadipine, a Ca2+ antagonist, on cerebral ischemia was investigated in spontaneously hypertensive rats. The 12-week-old animals were treated for 7 days with either nilvadipine or vehicle using osmotic pumps implanted subcutaneously. Group 1 animals (n = 10) received the vehicle, and Group 2 (n = 10) and 3 animals (n = 10) received 1 and 3 mg/kg/day nilvadipine, respectively. The left middle cerebral artery was occluded under halothane anesthesia on the 6th day of treatment, and neuropathological outcomes were quantified 24 hours later. The systolic blood pressure measured before occlusion decreased to 137 +/- 9 mmHg (Group 2) and 130 +/- 9 mmHg (Group 3), compared to 189 +/- 12 mmHg for Group 1 (p < 0.05). The percentage infarct volumes in Groups 1-3 were 39 +/- 3%, 37 +/- 2%, and 34 +/- 3%, respectively (p < 0.05, Groups 1 vs. 3). Therefore, nilvadipine decreased the infarct size dose-dependently. Nilvadipine has a protective effect against cerebral ischemia in rats with chronic hypertension. Neuropathological findings suggest that nilvadipine may act at the ischemic penumbra. Nilvadipine may have the additional benefit of reducing the consequences of a possible later stroke in patients with hypertension (one of the risk factors for stroke).

Animals↗

PubMed1996

Effects of beraprost sodium and insulin on the electroretinogram, nerve conduction, and nerve blood flow in rats with streptozotocin-induced diabetes.

The effect of a prostacyclin analog, beraprost sodium, on the electroretinogram, motor nerve conduction velocity, and nerve blood flow was determined in rats with streptozotocin-induced diabetes and was compared with the effect of insulin. Beraprost sodium (0.01 mg x kg-1 x day-1 for 8 weeks) significantly shortened the peak latency of the electroretinogram b-wave, increased tail nerve conduction velocity, and increased sciatic nerve blood flow in diabetic rats (P < 0.0003, 0.0001, and 0.0001 vs. untreated diabetic rats, respectively). This was accompanied by a significant increase in the 6-keto-prostaglandin F1alpha content of the thoracic aorta and a marked increase in the cAMP content of the sciatic nerve. Beraprost sodium had no effect on the sorbitol and fructose contents of the sciatic nerve and retina, but insulin (8-10 U/day) significantly reduced both parameters. These findings suggest that beraprost sodium may be useful for prevention of vascular and neural dysfunction in the retina and peripheral nerve.

6-Ketoprostaglandin F1 alpha↗

PubMed1995

Determination of the photoaffinity-labeled site on the ligand-binding domain of retinoic acid receptor alpha.

The ligand-binding domain of human retinoic acid receptor alpha (hRAR alpha) was photoaffinity-labeled with a fluorescent retinoid, ADAM-3, by the use of a recombinant fused protein constructed from a maltose-binding protein and the E/F-domain of hRAR alpha (MBP-RAR alpha/E), which was expressed in E. coli. The labeled site was identified as Arg-589 (this corresponds to amino acid residue 385 of hRAR alpha) or a residue in its vicinity.

Affinity Labels↗

PubMed1995

Correlation of differentiation-inducing activity of retinoids on human leukemia cell lines HL-60 and NB4.

Retinoids, including all-trans-retinoic acid, its isomers, and fifty synthetic retinoids (retinobenzoic acids), were tested for differentiation-inducing activity on human leukemia cell lines HL-60 and NB4. A good linear correlation, with an r value of 0.91, between the ED50 values for the differentiation-inducing activity towards HL-60 cells and that towards NB4 cells was found.

Cell Differentiation↗

PubMed1995

Lymphadenectomy in stage-III serous cystadenocarcinoma of the ovary.

OBJECTIVE: To elucidate the effects of lymphadenectomy on the prognosis for ovarian cancer. METHOD: A retrospective study of 69 patients with stage-III serous cystadenocarcinoma was performed. RESULTS: Among the 69 patients, 36 were not treated by lymphadenectomy. Both pelvic and para-aortic lymphadenectomies were performed on 13 patients at the initial operation and on 11 at the second operation. The group (n = 13) treated by both pelvic and para-aortic lymphadenectomies at the initial operation had a disease-free survival rate that was significantly higher than the non-lymphadenectomy group (n = 36) or the group (n = 5) treated by pelvic or para-aortic lymphadenectomy alone (P < 0.04). These 54 patients were subjected to multivariate analysis for lymphadenectomy at the initial operation, and a significant correlation was found between disease-free survival rate and both pelvic and para-aortic lymphadenectomies (P < 0.05). CONCLUSION: These results suggest that systematic lymphadenectomy can reduce the rate of recurrence.

Adult↗

PubMed1995

Effect of a potent new aldose reductase inhibitor, (5-(3-thienyltetrazol-1-yl)acetic acid (TAT), on diabetic neuropathy in rats.

(5-(3-Thienyl)tetrazol-1-yl)acetic acid (TAT), a novel potent aldose reductase inhibitor, was administered for 4 weeks to rats with streptozotocin-induced diabetes. Physiological and biochemical studies were subsequently conducted on rat nerve tissue and erythrocyte sorbitol content was estimated. Sciatic nerve blood flow (SNBF) was markedly lower (about 43.4%) in untreated diabetic (DC) rats than in non-diabetic controls (NC). A significant delay in caudal motor nerve conduction velocity (MNCV) and significantly higher glucose, sorbitol and fructose values were observed in the sciatic nerve, accompanied by a markedly higher sorbitol concentration in erythrocytes. In contrast, TAT-treated diabetic groups (DT-10, DT-40 and DT-200) had significantly higher SNBF, MNCV and sciatic nerve myo-inositol values and lower sciatic nerve sorbitol and fructose levels and erythrocyte sorbitol concentration than the DC group. There were good correlations between SNBF and MNCV (r = 0.672, P < 0.001) and between SNBF and erythrocyte sorbitol (r = 0.455, P < 0.003). These findings suggest that both vascular and metabolic factors play an important role in diabetic neuropathy and the effect of aldose reductase inhibitors on diabetic neuropathy may be mediated by at least these two factors.

Aldehyde Reductase↗

PubMed1995

An aldose reductase inhibitor, TAT, prevents electroretinographic abnormalities and ADP-induced hyperaggregability in streptozotocin-induced diabetic rats.

Rats with streptozotocin-induced diabetes were oral given TAT, a potent aldose reductase inhibitor, at a dose of 10 mg kg-1 day-1 or 40 mg kg-1 day-1 for 30 days. Prolongation of the peak latency of oscillatory potentials in the b-wave of the electroretinogram (ERG), which is associated with retinal Müller cell dysfunction, was significantly improved by treatment with TAT as compared with untreated diabetic rats [sigma(O1 + O2 + O3) was 106.8 +/- 1.8 ms in normal controls (NC), 118.2 +/- 1.1 ms in diabetic controls (DC) (P < 0.001 vs. NC), 110.8 +/- 1.5 ms with 10 mg kg-1 TAT (P < 0.001 vs. DC) and 111.4 +/- 1.6 ms with 40 mg kg-1 TAT (P < 0.01 vs. DC)]. The improvement in ERG abnormalities in diabetic rats was accompanied by partial reduction of elevated sorbitol levels in the retina and erythrocytes, and by correction of platelet hyperaggregability. The authors' findings suggest that a better understanding of the mechanism by which TAT acts may provide new insights into the pathogenesis of hyperglycaemic retinal dysfunction and contribute to establishing effective therapy for diabetic retinopathy.

Adenosine Diphosphate↗

PubMed1995

Synergists for retinoid in cellular differentiation of human promyelocytic leukemia cells HL-60.

4-[5H-2,3-(2,5-Dimethyl-2,5-hexano)-5-methyldibenzo[b, e]diazepin-11-yl]benzoic acid (4) enhanced the differentiation-inducing activity of retinoic acid (1) and of a synthetic retinoid Am80 (2) toward human promyelocytic leukemia cells HL-60, although 4 alone did not induce differentiation. The synergistic effect of 4 on the activities of retinoids was also seen in suppression of proliferation of HL-60 cells.

Cell Differentiation↗