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1.
J Hered ; 108(3): 280-287, 2017 Apr 01.
Article in English | MEDLINE | ID: mdl-28164229

ABSTRACT

Lotic dragonflies and damselflies are expected to be more affected by vicariance than lentic sister species. We demonstrated that severe vicariant speciation acted on lotic Coeliccia in contrast to lentic Copera damselflies, which are both included in the family Platycnemididae. We constructed maximum likelihood and Bayesian inference trees of these Platycnemididae species from the continental islands of Ryukyu (Amami, Okinawa, and Yaeyama islands), Taiwan, and Japan relative to Chinese species using raxmlGUI and BEAST, based on the mitochondrial COI gene (682 bp), COII gene (494 bp), 16SrRNA (478 bp), and the nuclear 28SrRNA gene (807 bp). In BEAUti, we calibrated the splitting age of the MRCA of all the Coeliccia species as 1.55-0.15 million years ago (Ma), a date that corresponds to a geologic constraint: the Okinawa trough and associated straits, including the Yilan basin in Taiwan, began to rift at 1.55 Ma, isolating the Ryukyu-Taiwan islands from the Chinese continent. The vicariance split Coeliccia into the Ryukyu-side clade of Coeliccia ryukyuensis (Coe. r. ryukyuensis in Okinawa and Coe. r. amamii in Amami) and Coeliccia flavicauda (Coe. f. masakii in Yaeyama and Coe. f. flavicauda in southern Taiwan), and the Chinese-side clade of Coeliccia cyanomelas (northern Taiwan and China), separated by the Okinawa trough. These Coeliccia species were further deeply differentiated to form local populations on the major islands and some of the minor islands. The Copera clade constituted a sister of the lotic Coeliccia clade, but genetic differentiation was not recognizable in lentic Copera between China, Taiwan, and Japan. Base substitution rates applying a strict clock model were estimated for COI: 0.0783, COII: 0.0803, 18SrRNA: 0.0186, 28SrRNA: 0.00577, and combined: 0.0408 substitutions/site/myr, and these rates are relatively high.


Subject(s)
Genetic Speciation , Insecta , Animals , Environment
2.
Asian J Psychiatr ; 24: 33-40, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27931903

ABSTRACT

A deterioration in information-processing performance is commonly recognized in patients with chronic schizophrenia. Although the enhancement of cognitive skills in patients with schizophrenia is important, the types of external stimuli that influence performance have not received much attention. The aim of present study was to clarify the effects of spatial and affordance compatibility in patients with schizophrenia, compared with those in healthy people. The subjects (25 patients with schizophrenia and 25 healthy controls) participated in two experiment examining the effects of the spatial location of stimuli and the action-relevance of objects. The results showed that the effect of spatial compatibility was similar in both the patients and the controls, whereas the influence of action-relevant objects was not highlighted in either patients with chronic schizophrenia or healthy controls. These findings provide important evidence of a normal spatial compatibility effect in patients with chronic schizophrenia. However, further research examining the affordance compatibility effect is needed, taking into consideration the symptomatology and the severity of the social functioning level in patients with schizophrenia.


Subject(s)
Pattern Recognition, Visual/physiology , Psychomotor Performance/physiology , Schizophrenia/physiopathology , Space Perception/physiology , Adult , Female , Humans , Male , Middle Aged
3.
Arzneimittelforschung ; 59(2): 79-85, 2009.
Article in English | MEDLINE | ID: mdl-19338138

ABSTRACT

The renoprotective effect of cilnidipine ((+/-)-2-methoxyethyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate, CAS 132203-70-4), a L/N-type calcium channel antagonist, on puromycin aminonucleoside (PAN)-induced nephrosis was investigated in rats. In the Experiment I, rats were given an intravenous injection of PAN (70 mg/kg). Cilnidipine (3 mg/kg/day) and enalapril (CAS 75847-73-3, 5 mg/kg/day) were administered orally from 6 days after treatment with PAN (day 6) to day 26, and urinary analysis was performed on days 9, 15, 20 and 27. In the Experiment II, nephrosis was also induced by intravenous injection of PAN (70 or 100 mg/kg) in rats which were treated with cilnidipine and enalapril from days 6 to 10. Systolic blood pressure was measured on day 7 and urinary analysis was performed on day 10. On day 11, serum was collected and the kidneys were removed for immunofluorescence staining for nephrin and podocin proteins. In PAN-treated rats, the daily urinary protein excretion was dramatically elevated on day 5, reached a peak on day 9 and gradually returned to a normal level from days 15 to 27. Cilnidipine (3 mg/kg/ day) significantly suppressed the increase in proteinuria on day 9 and also improved the decrease in creatinine clearance without evident effect on the blood pressure. Furthermore, the elevations in serum total cholesterol and triglyceride tended to be suppressed by cilnidipine. The expression of nephrin and podocin proteins in PAN-treated rats showed the granular pattern in the glomeruli, while the intensity of staining seemed to be dependent on the urinary protein excretion level in the cilnidipine-treated rats. The results obtained in this study suggest a renoprotective effect of cilnidipine in PAN-induced nephrosis in rats.


Subject(s)
Antimetabolites, Antineoplastic/toxicity , Calcium Channel Blockers/therapeutic use , Dihydropyridines/therapeutic use , Nephrosis/chemically induced , Nephrosis/prevention & control , Protective Agents , Puromycin Aminonucleoside/toxicity , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Blood Pressure/drug effects , Calcium Channels, L-Type/drug effects , Calcium Channels, N-Type/drug effects , Creatinine/blood , Creatinine/urine , Enalapril/therapeutic use , Fluorescent Antibody Technique , Male , Membrane Proteins/biosynthesis , Nephrosis/pathology , Proteinuria/prevention & control , Rats , Rats, Sprague-Dawley
4.
J Pharmacol Sci ; 105(1): 48-56, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17827869

ABSTRACT

This study explores the effects of the anti-allergic and anti-fibrotic agent tranilast on adjuvant- and streptococcal cell wall-induced arthritis in rats, animal models of rheumatoid arthritis in humans. Tranilast (150 or 300 mg/kg, twice daily) or vehicle only was administered orally to the two arthritis models, from 17 days before sensitization. As a comparative control, methotrexate (0.1 mg/kg, once daily) was given to another group. Tranilast suppressed the increase in foot volumes, paw thicknesses, clinical scores, and histopathological scores of the ankle joints in both models dose-dependently. In addition, the fibrosis indices of the ankles were dramatically decreased by tranilast in both of the models. Compared to the effects of methotrexate, tranilast seemed to work more effectively in the streptococcal cell wall-induced arthritis model than in the adjuvant-induced arthritis model. From these observations, it can be concluded that tranilast suppresses the development of arthritis in multiple models and is potentially a novel therapeutic agent for human rheumatoid arthritis.


Subject(s)
Ankle Joint/drug effects , Arthritis, Experimental/prevention & control , Cell Wall/immunology , ortho-Aminobenzoates/pharmacology , Administration, Oral , Analysis of Variance , Animals , Ankle Joint/pathology , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/pharmacology , Antirheumatic Agents/therapeutic use , Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , Calcaneus/drug effects , Calcaneus/pathology , Cell Wall/chemistry , Dose-Response Relationship, Drug , Female , Humans , Image Processing, Computer-Assisted , Male , Methotrexate/administration & dosage , Methotrexate/pharmacology , Methotrexate/therapeutic use , Rats , Rats, Inbred Lew , Rhamnose/immunology , Severity of Illness Index , Streptococcus/chemistry , Streptococcus/immunology , Time Factors , ortho-Aminobenzoates/administration & dosage , ortho-Aminobenzoates/therapeutic use
5.
Atherosclerosis ; 191(2): 290-7, 2007 Apr.
Article in English | MEDLINE | ID: mdl-16820149

ABSTRACT

BACKGROUND: Acyl-coenzyme A:cholesterol O-acyltransferase-1 (ACAT-1), a major ACAT isozyme in macrophages, plays an essential role in foam cell formation in atherosclerotic lesions. However, whether pharmacological inhibition of macrophage ACAT-1 causes exacerbation or suppression of atherosclerosis is controversial. METHODS AND RESULTS: We developed and characterized a novel ACAT inhibitor, K-604. The IC(50) values of K-604 for human ACAT-1 and ACAT-2 were 0.45 and 102.85 micromol/L, respectively, indicating that K-604 is 229-fold more selective for ACAT-1. Kinetic analysis indicated that the inhibition was competitive with respect to oleoyl-coenzyme A with a K(i) value of 0.378 micromol/L. Exposure of human monocyte-derived macrophages to K-604 inhibited cholesterol esterification with IC(50) of 68.0 nmol/L. Furthermore, cholesterol efflux from THP-1 macrophages to HDL(3) or apolipoprotein A-I was enhanced by K-604. Interestingly, administration of K-604 to F1B hamsters on a high-fat diet at a dose of >or=1mg/kg suppressed fatty streak lesions without affecting plasma cholesterol levels. CONCLUSIONS: K-604, a potent and selective inhibitor of ACAT-1, suppressed the development of atherosclerosis in an animal model without affecting plasma cholesterol levels, providing direct evidence that pharmacological inhibition of ACAT-1 in the arterial walls leads to suppression of atherosclerosis.


Subject(s)
Atherosclerosis/prevention & control , Benzimidazoles/pharmacology , Cholesterol/metabolism , Enzyme Inhibitors/pharmacology , Macrophages/drug effects , Sterol O-Acyltransferase/antagonists & inhibitors , Animals , Atherosclerosis/chemically induced , Atherosclerosis/metabolism , Atherosclerosis/pathology , Benzimidazoles/therapeutic use , Binding, Competitive , CHO Cells , Cell Differentiation , Cholesterol/blood , Cricetinae , Cricetulus , Dietary Fats , Disease Models, Animal , Enzyme Inhibitors/therapeutic use , Esterification , Humans , Kinetics , Macrophages/cytology , Macrophages/metabolism , Male , Monocytes/cytology , Sterol O-Acyltransferase/genetics , Sterol O-Acyltransferase/metabolism , Transfection , Sterol O-Acyltransferase 2
6.
J Atheroscler Thromb ; 13(6): 295-307, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17192694

ABSTRACT

Although statins are prescribed as relatively safe and effective drugs for hypercholesterolemic patients, it has been reported that a significant side effect, myopathy, occurs infrequently during medication. Moreover, because statins decrease cardiac ubiquinone levels, the risk of cardiac dysfunction has been suggested. This study sought to evaluate and compare the cytotoxicity of statins (cerivastatin, pitavastatin, fluvastatin, simvastatin, atorvastatin and pravastatin) in cultured human skeletal muscle cells (HSkMCs) and the effects on ubiquinone levels in statin-treated rat skeletal muscle and heart. Cerivastatin, the most potent inhibitor of HMG-CoA reductase, showed the strongest cytotoxicity (over 10-fold) among the statins examined, while the effects of the others were in a similar range. In rat experiments, neither pitavastatin nor cerivastatin decreased ubiquinone levels in skeletal muscle, but both dose-dependently lowered ubiquinone levels in the heart. As the rates of reduction by pitavastatin (9.6% at 30 mg/kg) and cerivastatin (9.7% at 0.3 mg/kg) were almost equal, it was estimated that cerivastatin reduced ubiquinone levels in the rat heart approximately 100-fold more strongly than pitavastatin, based on the effective doses. We found that cerivastatin showed the most potent cytotoxicity in HSkMCs and strongly lowered ubiquinone levels in the rat heart.


Subject(s)
Cholesterol/biosynthesis , Heart/drug effects , Muscle, Skeletal/drug effects , Ubiquinone/metabolism , Animals , Cell Survival/drug effects , Cells, Cultured , Cholesterol/metabolism , Enzymes/blood , Enzymes/drug effects , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Lipids/blood , Male , Muscle Proteins/drug effects , Muscle Proteins/metabolism , Muscle, Skeletal/cytology , Muscle, Skeletal/metabolism , Myocardium/metabolism , Rats , Rats, Wistar
7.
Nihon Yakurigaku Zasshi ; 123(5): 349-62, 2004 May.
Article in Japanese | MEDLINE | ID: mdl-15118259

ABSTRACT

Today 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most often prescribed drugs among the therapeutics for hypercholesterolemia. Pitavastatin is a novel statin that has been developed entirely in Japan from the biological screening to clinical studies persuing more efficatious statin than hitherto known. Preclinical studies on drug metabolism revealed that pitavastatin is distributed selectively to the liver, excreted into bile without metabolic modification, and efficiently re-circulates to the liver to show a prolonged plasma half-life. In guinea pigs, pitavastatin enhanced hepatic LDL receptor activity and reduced VLDL secretion in a liver perfusion study, and it lowered plasma total cholesterol (TC) levels at 0.3 mg/kg and triglyceride (TG) levels at 1 mg/kg, respectively, and more. From these results, pitavastatin is assumed to lower LDL cholesterol (LDL-C) by promoting LDL receptor expression and further potentiate the cholesterol-lowering effect and exert TG-lowering effect by reducing VLDL secretion. (14)C-Pitavastatin is metabolized with CYP2C9 to 8-hydroxy derivative, but its Vmax /Km was about 2 micro l/min/mg, about 1/8 to 1/100 in comparison to the reported values of other statins, indicating that pitavastatin is hardly metabolized. Also, other human P450 species were not inhibited by pitavastatin. Therefore, pitavastatin is considered to have little interaction with drugs through P450. In the summarized clinical results with 862 patients, pitavastatin lowered TC and LDL-C by 28% and 40%, respectively. There was no difference in the frequency of side effects and no serious adverse effect was observed for pitavastatin. Pitavastatin possesses superior plasma lipid-improving effects, induces little drug interaction, and is expected to make a good contribution to the medication of hypercholesterolemia.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Quinolines/pharmacology , Animals , Arteriosclerosis/drug therapy , Arteriosclerosis/prevention & control , Cholesterol/biosynthesis , Cholesterol, VLDL/metabolism , Citrus paradisi , Clinical Trials as Topic , Cytochrome P-450 Enzyme System/physiology , Drug Interactions , Drug Therapy, Combination , Fenofibrate/therapeutic use , Food-Drug Interactions , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Quinolines/chemistry , Quinolines/pharmacokinetics , Quinolines/therapeutic use , Receptors, LDL/metabolism , Triglycerides/metabolism
8.
Arzneimittelforschung ; 53(5): 351-6, 2003.
Article in English | MEDLINE | ID: mdl-12854362

ABSTRACT

The influence of pitavastatin (CAS 147526-32-7), a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, exerted on fecal and biliary excretion of sterols and bile acids was investigated using guinea pigs. The cumulative amount of [3H] bile acid in bile 0 to 6 h after the injection of high density lipoprotein (HDL), which was labeled with [3H] cholesteryl ester (CE), was slightly decreased with atorvastatin (30 mg/kg, CAS 134523-00-5) and simvastatin (30 mg/kg, CAS 79902-63-9), and the same level as the control was maintained with pitavastatin (3 mg/kg). The amount of excretion of [3H] sterol into bile was significantly increased with atorvastatin and simvastatin, and exhibited a tendency to decline with pitavastatin. The [3H] bile acid/[3H] sterol ratios were significantly lowered with atorvastatin and simvastatin by 41% and 29%, respectively, as compared to the control, and exhibited an upward tendency with pitavastatin (22%). The total amounts of fecal [3H] bile acid from 0 to 7 days were significantly decreased with atorvastatin and simvastatin by 30% and 32%, respectively, and slightly increased with pitavastatin by 8% Furthermore, mRNA expression of the hepatic microsomal cytochrome P-450 enzyme, cholesterol-NADPH: oxygen oxidoreductase (cholesterol 7 alpha-hydroxylase; CYP7A), which is a late limiting enzyme with a bile acid composition, was also decreased with atorvastatin and simvastatin by 54% and 38%, respectively, and slightly increased with pitavastatin (14%). The change in CYP7A mRNA expression was well correlated with the amount of the fecal [3H] bile acid. The bile acid excreting efficacy of pitavastatin was relatively high as compared with atorvastatin or simvastatin. It is suggested that this action may contribute to the powerful cholesterol lowering action of pitavastatin.


Subject(s)
Anticholesteremic Agents/pharmacology , Bile Acids and Salts/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Quinolines/pharmacology , Sterols/metabolism , Animals , Atorvastatin , Cholesterol 7-alpha-Hydroxylase/metabolism , Cholesterol, HDL/blood , Feces/chemistry , Guinea Pigs , Heptanoic Acids/pharmacology , Male , Pyrroles/pharmacology , RNA, Messenger/biosynthesis , Simvastatin/pharmacology
9.
J Atheroscler Thromb ; 10(2): 109-16, 2003.
Article in English | MEDLINE | ID: mdl-12740485

ABSTRACT

This study investigated the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA ) reductase inhibitor with strong cholesterol-lowering activity, on the composition of atherosclerotic plaque. Pitavastatin ( 0.5mg/kg ) was administered to Watanabe heritable hyperlipidemic ( WHHL ) rabbits for 16 weeks, with the result that plasma total cholesterol ( TC ), very low density lipoprotein ( VLDL )-C, intermediate density lipoprotein ( IDL )-C and low density lipoprotein ( LDL )-C decreased by 28.6, 60.0, 42.3 and 21.7%, respectively. In the aorta, pitavastatin reduced the area of the lesion by 38.6%. In the pitavastatin group, the macrophage-positive area in the aortic plaque was reduced by 39.4%, and the areas occupied by collagen and a-smooth muscle actin ( alpha-SMA )-positive area increased by 66.4 and 91.7%, respectively. In the aortic arch, pitavastatin increased the average thickness of alpha-SMA in the plaque by 96.7% and reduced the vulnerability index by 76.0%. Furthermore, pitavastatin reduced the positive areas of monocyte chemoattractant protein ( MCP )-1, matrix metalloproteinase ( MMP )-3 and MMP-9 by 39.1, 40.6 and 52.3%, respectively. These results indicated that pitavastatin had an excellent lipid-lowering effect in WHHL rabbits, suppressing the progression of atherosclerosis and stabilizing atherosclerotic plaque.


Subject(s)
Aorta/drug effects , Arteriosclerosis/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hyperlipidemias/metabolism , Quinolines/pharmacology , Animals , Aorta/pathology , Arteriosclerosis/pathology , Chemokine CCL2/metabolism , Lipid Metabolism , Lipoproteins/metabolism , Matrix Metalloproteinase 3/metabolism , Matrix Metalloproteinase 9/metabolism , Rabbits
10.
Arzneimittelforschung ; 53(3): 154-8, 2003.
Article in English | MEDLINE | ID: mdl-12705169

ABSTRACT

The triglyceride (TG)-lowering effect of pitavastatin (CAS 147526-32-7), a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was investigated in a guinea pig model of post-prandial lipemia. Plasma TG levels started to rise 2 h after the fat load, reached the maximum at 8 h and then gradually decreased. A 14-day dose of pitavastatin at 3 mg/kg decreased the 8 h plasma TG levels by 59%, and the 0-12 h area under the curve (AUC) of TG levels above the initial levels, by 77%. This effect was also shown with 30 mg/kg of atorvastatin (CAS 134523-00-5), and the same dose of simvastatin (CAS 79902-63-9). The intensity of the action was equivalent for pitavastatin and atorvastatin, but weaker with simvastatin. In order to clarify the mechanism of this action, the effect of pitavastatin exerted on the activity of microsomal triglyceride transfer protein (MTP), which participates in the secretion to the lymph vessel of chyromicron (CM)-TG in the small intestine, and the activity of lipoprotein lipase (LPL), which is the hydrolysis enzyme of the very low density lipoprotein (VLDL)-TG and CM-TG, was examined. However, an influence on the activity of MTP or LPL by pitavastatin was not shown. These results suggested that pitavastatin lowered the postprandial TG levels in guinea pigs by accelerating the remnant clearance, probably through the enhancement of the low density lipoprotein (LDL) receptor. This effect is expected to improve postprandial lipemia.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hypolipidemic Agents , Lipids/blood , Postprandial Period/drug effects , Quinolines/pharmacology , Triglycerides/blood , Animals , Anticoagulants/pharmacology , Atorvastatin , Carrier Proteins/metabolism , Guinea Pigs , Heparin/pharmacology , Heptanoic Acids/pharmacology , Intestinal Mucosa/metabolism , Lipoproteins/blood , Male , Pyrroles/pharmacology , Simvastatin/pharmacology
11.
Eur J Pharmacol ; 444(1-2): 107-13, 2002 May 24.
Article in English | MEDLINE | ID: mdl-12191589

ABSTRACT

The triglyceride-lowering effect of pitavastatin, a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was investigated in a rat model of postprandial lipemia. Plasma triglyceride levels started to increase 4 h after the fat load, reached the maximum at 6 h and then gradually decreased. A single dose of pitavastatin (1 mg/kg) significantly suppressed chylomicron-triglyceride secretion into the lymph by 40% and delayed the elevation of plasma triglyceride. Pitavastatin at 1 mg/kg decreased the 6-h plasma triglyceride levels by 53% and at 0.5 mg/kg decreased the 0-12 h area under the curve (AUC) of triglyceride levels by 56%. Atorvastatin also caused decreases, but to a lesser extent. Pitavastatin, and atorvastatin to a lesser extent, reduced the activity of the intestinal microsomal triglyceride transfer protein (MTP) at 6 h. These results suggested that a single dose of pitavastatin lowered postprandial triglyceride levels in rats by decreasing chylomicron-triglyceride secretion, probably through a reduction of intestinal MTP activity and triglyceride droplet formation in the endoplasmic reticulum.


Subject(s)
Hyperlipidemias/drug therapy , Quinolines/therapeutic use , Triglycerides/blood , Animals , Chylomicrons/drug effects , Male , Postprandial Period , Rats , Rats, Wistar
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