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1.
J Diabetes Res ; 2014: 672590, 2014.
Article in English | MEDLINE | ID: mdl-25215304

ABSTRACT

PURPOSE: To evaluate the effect of ranirestat, a new aldose reductase inhibitor (ARI), on diabetic retinopathy (DR) in Spontaneously Diabetic Torii (SDT) rats. METHODS: The animals were divided into six groups, normal Sprague-Dawley rats (n = 8), untreated SDT rats (n = 9), ranirestat-treated SDT rats (0.1, 1.0, and 10 mg/kg/day, n = 7, 8, and 6, resp.), and epalrestat-treated SDT rats (100 mg/kg/day, n = 7). Treated rats received oral ranirestat or epalrestat once daily for 40 weeks after the onset of diabetes. After the eyes were enucleated, the retinal thickness and the area of stained glial fibrillary acidic protein (GFAP) were measured. RESULTS: The retinas in the untreated group were significantly thicker than those in the normal and ranirestat-treated (0.1, 1.0, and 10 mg/kg/day) groups. The immunostained area of GFAP in the untreated group was significantly larger than that in the normal and ranirestat-treated (1.0 and 10 mg/kg/day) groups. There were no significant differences between the untreated group and epalrestat-treated group in the retinal thickness and the area of stained GFAP. CONCLUSION: Ranirestat reduced the retinal thickness and the area of stained GFAP in SDT rats and might suppress DR and have a neuroprotective effect on diabetic retinas.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Diabetic Retinopathy/prevention & control , Enzyme Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Pyrazines/pharmacology , Retina/drug effects , Spiro Compounds/pharmacology , Administration, Oral , Aldehyde Reductase/metabolism , Animals , Blood Glucose/metabolism , Body Weight , Diabetic Retinopathy/enzymology , Diabetic Retinopathy/pathology , Disease Models, Animal , Drug Administration Schedule , Enzyme Inhibitors/administration & dosage , Glial Fibrillary Acidic Protein/metabolism , Glycated Hemoglobin/metabolism , Male , Neuroprotective Agents/administration & dosage , Pyrazines/administration & dosage , Rats , Rats, Sprague-Dawley , Retina/enzymology , Retina/pathology , Rhodanine/analogs & derivatives , Rhodanine/pharmacology , Spiro Compounds/administration & dosage , Thiazolidines/pharmacology , Time Factors
2.
J Diabetes Res ; 2013: 175901, 2013.
Article in English | MEDLINE | ID: mdl-23671855

ABSTRACT

We evaluated ranirestat, an aldose reductase inhibitor, in diabetic cataract and neuropathy (DN) in spontaneously diabetic Torii (SDT) rats compared with epalrestat, the positive control. Animals were divided into groups and treated once daily with oral ranirestat (0.1, 1.0, 10 mg/kg) or epalrestat (100 mg/kg) for 40 weeks, normal Sprague-Dawley rats, and untreated SDT rats. Lens opacification was scored from 0 (normal) to 3 (mature cataract). The combined scores (0-6) from both lenses represented the total for each animal. DN was assessed by measuring the motor nerve conduction velocity (MNCV) in the sciatic nerve. Sorbitol and fructose levels were measured in the lens and sciatic nerve 40 weeks after diabetes onset. Cataracts developed more in untreated rats than normal rats (P < 0.01). Ranirestat significantly (P < 0.01) inhibited rapid cataract development; epalrestat did not. Ranirestat significantly reversed the MNCV decrease (40.7 ± 0.6 m/s) in SDT rats dose-dependently (P < 0.01). Epalrestat also reversed the prevented MNCV decrease (P < 0.05). Sorbitol levels in the sciatic nerve increased significantly in SDT rats (2.05 ± 0.10 nmol/g), which ranirestat significantly suppressed dose-dependently, (P < 0.05, <0.01, and <0.01); epalrestat did not. Ranirestat prevents DN and cataract; epalrestat prevents DN only.

3.
J Nanosci Nanotechnol ; 11(4): 2823-8, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21776638

ABSTRACT

The electronic structures of lanthunum (La) incorporated hafnium (Hf)-based oxides (HfLaO) and their silicate (HfLaSiO) films were investigated by the Near Edge X-ray Absorption Fine Structure (NEXAFS) technique. The oxygen (O) K-edge spectra, which reflected the hybridized Hf 5d state with the O 2p orbital, were found to reveal features of the unoccupied state of the metal oxides, as well as the conduction-band edge. We also found that, while La incorporation into the Hf-based oxides simply changed the features of the conduction-band structure, subsequent thermal annealing of the La-incorporated films led to a conduction-band edge shift due to an interface silicate reaction and/or local bond rearrangement depending on the La concentration and annealing temperature. The impact of La incorporation into the Hf-based high-k materials on the electronic structure is discussed by taking into account the intrinsic nature of these metal oxides.


Subject(s)
Hafnium/chemistry , Lanthanum/chemistry , Nanostructures/chemistry , Nanostructures/ultrastructure , X-Ray Diffraction/methods , Electric Conductivity , Materials Testing
4.
Vascul Pharmacol ; 50(1-2): 40-4, 2009.
Article in English | MEDLINE | ID: mdl-18854227

ABSTRACT

Estrogens are known to contribute to endothelial function and sympathetic activity, both of which are strongly associated with the pathogenesis of ischemic heart disease. In addition, estrogens improve impaired lipid profile, a risk factor of endothelial dysfunction. In this study, we investigated the effects of OS-0544, a structurally new selective estrogen receptor modulator (SERM), on endothelial function, sympathetic activity, and plasma cholesterol level in ovariectomized (OVX) rats. Female Sprague-Dawley rats were ovariectomized and orally treated with OS-0544 (or OS-0689, the (R)-enantiomer of OS-0544), or 17beta-estradiol (E2) for 4 weeks, starting the next days after ovariectomy or for 1 week, starting 6 weeks after ovariectomy. Ovariectomy significantly increased vasopressin-induced mean blood pressure (AVP-MBP) (57+/-3.3 mm Hg vs. 46+/-3.5 mm Hg, P<0.05) and decreased acetylcholine (Ach)-induced maximum vasorelaxation response (69+/-5.6% vs. 81+/-4.0%, P<0.05). OS-0544 significantly inhibited AVP-MBP elevation (46+/-3.5 mm Hg vs. 57+/-3.3 mm Hg, P<0.05) and decreased Ach-induced maximum vasorelaxation response (90+/-3.3% vs. 69+/-5.6%, P<0.05) in OVX rats. In addition, OS-0689 as well as E2 significantly reduced (up to 67%) the increase in sympathetic activity in OVX rats. Moreover, like E2, OS-0544 significantly decreased plasma cholesterol level in OVX rats. These results demonstrate that OS-0544 has vascular protective effect on vascular function after ovariectomy. It is therefore believed that OS-0544 has vascular protective effect in postmenopausal woman.


Subject(s)
Endothelium, Vascular/drug effects , Endothelium, Vascular/physiology , Indans/pharmacology , Ovariectomy , Piperidines/pharmacology , Selective Estrogen Receptor Modulators/pharmacology , Spiro Compounds/pharmacology , Sympathetic Nervous System/drug effects , Acetylcholine/pharmacology , Animals , Blood Pressure/drug effects , Cholesterol/blood , Female , Rats , Rats, Sprague-Dawley , Sympathetic Nervous System/physiology , Vasodilation/drug effects , Vasopressins/pharmacology
5.
Anal Sci ; 21(7): 779-81, 2005 Jul.
Article in English | MEDLINE | ID: mdl-16038494

ABSTRACT

The Li 1s XPS (X-ray Photoelectron Spectroscopy) spectra of LiMn2O4, which is one of the major positive-electrode materials in lithium-ion rechargeable batteries, and MnO2 as a reference material, were measured by a laboratory-type XPS spectrometer. The Li 1s peak was not observed in the spectra excited by the Mg Kalpha line (1253.6 eV), because the Li 1s peak overlapped the background of the Mn 3p peak of LiMn2O4. The photoionization cross section of Mn 3p was larger than that of Li 1s for Mg Kalpha excitation. Therefore, the XPS measurement of LiMn2O4 by soft X-ray synchrotron excitation was carried out at beamline BL-7B on NewSUBARU synchrotron facility. Excitation energies of 110, 120, 130, 140, 150 and 151.4 eV were selected. The Li 1s peak was clearly observed in these XPS spectra. In order to investigate the excitation energy dependence, the area ratio of the Li 1s and Mn 3p peaks in the XPS spectra was plotted against the excitation energy. As a result, when the excitation energy was 110 eV, the area ratio had the maximum value.

6.
Maturitas ; 51(4): 434-41, 2005 Aug 16.
Article in English | MEDLINE | ID: mdl-16039418

ABSTRACT

OBJECTIVE: We have previously shown that OS-0689 attenuates the rise in tail skin temperature of ovariectomized rats, which is believed to be relevant to human symptoms of hot flush. In this study, we elucidate the mechanism underlying the ameliorating effects of OS-0689 on elevated tail skin temperature. METHODS: Female Sprague-Dawley rats were ovariectomized and orally treated with OS-0544 (1 mg/kg), OS-0689 (3 mg/kg; (+)-enantiomer of OS-0544) or 17beta-estradiol (3 mg/kg; E2) for 1 week. At 1, 3 or 6 weeks after ovariectomy, the vasoconstrictions and vasorelaxations induced by periarterial nerve stimulation (PNS), l-noradrenaline (NA), and rat calcitonin gene-related peptide (CGRP) in isolated tail arteries were compared between OVX and sham-operated rats. RESULTS: Three weeks after ovariectomy, vasoconstrictions in response to PNS and NA in the arteries of OVX rats were markedly less than those in the arteries of sham-operated rats. However, at 1 and 6 weeks after ovariectomy the stimuli-induced vasoconstrictions in the arteries of OVX rats were greater than those of sham-operated rats. Moreover, NA reactivity was not attenuated in the mesenteric arteries at 3 weeks after ovariectomy. OS-0544, OS-0689 and E2 prevented the decrease in vasoconstrictions in the tail arteries. Vasorelaxations in response to PNS and rat CGRP were significantly greater in the arteries of OVX rats than in those of the sham-operated rats. OS-0689 inhibited the increase in vasorelaxation induced by both stimuli, whereas E2 had no effects. CONCLUSIONS: Ovariectomy not only decreases adrenergic function but also enhances CGRPergic function in rats' tail arteries. OS-0689 improves both impairments and thereby improves on rat hot flush.


Subject(s)
Climacteric/drug effects , Indans/pharmacology , Piperidines/pharmacology , Selective Estrogen Receptor Modulators/pharmacology , Skin Temperature/drug effects , Spiro Compounds/pharmacology , Vasoconstriction/drug effects , Vasodilation/drug effects , Analysis of Variance , Animals , Arteries/drug effects , Arteries/innervation , Calcitonin Gene-Related Peptide/pharmacology , Climacteric/blood , Estradiol/pharmacology , Female , Ovariectomy , Rats , Rats, Sprague-Dawley , Stereoisomerism , Tail/blood supply
7.
Bioorg Med Chem Lett ; 15(5): 1361-6, 2005 Mar 01.
Article in English | MEDLINE | ID: mdl-15713387

ABSTRACT

We have previously reported that (4R,5R)-5-ethyl-2-imino-4-methylthiazolidine (3) strongly inhibits inducible nitric oxide synthase (iNOS). In a successive search for strong and selective iNOS inhibitors, we, herein, describe the synthesis of the selenium analogue of 3 (4: ES-2133) and its related optically active compounds and examine their in vitro and in vivo inhibitory activity against iNOS. In addition, an alternative synthetic method to the selected compound 4 and its pharmacokinetic profile is also reported.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Nitric Oxide Synthase/antagonists & inhibitors , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/pharmacokinetics , Arginine/antagonists & inhibitors , Biological Availability , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Kinetics , Molecular Conformation , Nitric Oxide Synthase Type II , Organoselenium Compounds/chemistry , Selenium/chemistry , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 13(24): 4317-20, 2003 Dec 15.
Article in English | MEDLINE | ID: mdl-14643317

ABSTRACT

In the structure-activity relationships of spiro[indene-1,1'-indane] series, the 4-(4-alkylpiperazin-1-yl)phenyl group was found to be functionally equipotent to the 4-(1-piperidinoethoxy)phenyl group, the most widely used basic side chain in selective estrogen receptor modulators.


Subject(s)
Alkanes/chemical synthesis , Alkanes/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Receptors, Estrogen/antagonists & inhibitors , Alkanes/chemistry , Animals , Cholesterol/blood , Female , Humans , Kinetics , Models, Molecular , Molecular Conformation , Piperazines/chemistry , Rats , Structure-Activity Relationship , Uterus/drug effects , Uterus/physiology
9.
J Med Chem ; 46(19): 3961-4, 2003 Sep 11.
Article in English | MEDLINE | ID: mdl-12954049

ABSTRACT

In our studies of the development of a novel class of selective estrogen receptor modulators, (+)-3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1'-indane]-5,5'-diol hydrochloride (1) was found to be an estrogen receptor ligand with beneficial effects in rat models for human hot flush. Moreover, 1 was found to have beneficial effects on lipid and bone metabolism while maintaining marginal effects on the uterus and breasts. These findings suggest that 1 would provide a new treatment for hot flush.


Subject(s)
Hot Flashes/drug therapy , Indans/chemistry , Indans/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptors, Estrogen/agonists , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Animals , Bone Density/drug effects , Breast Neoplasms/metabolism , Cholesterol/blood , Drug Evaluation, Preclinical , Estradiol/analogs & derivatives , Estradiol/pharmacology , Female , Indans/metabolism , Male , Morphine Dependence/metabolism , Naloxone/pharmacology , Piperidines/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/metabolism , Skin Temperature/drug effects , Spiro Compounds/metabolism , Stereoisomerism , Tumor Cells, Cultured , Uterus/drug effects
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