bluuebunny/crossref_metadata_2025 huggingface dataset:
Protective Effects of Vitamin E and Selenium on the Renal Morphology in Rats Fed High-Cholesterol Diets
Authors: Gonca Süheyla , Ceylan Süreyya , Yardimoglu Melda , Dalçık Hakkı , Yumbul Zühal , Köktürk Sibel , Filiz Serdar
Published: April 2003

The histopathological effects of cholesterol and the protective effects of vitamin E and selenium (Se) on renal histology were examined in Sprague-Dawley rats. Light-microscopic evaluation of the renal cortex revealed: glomerular fibrosis, cellular and mesangial proliferation, capillary obliteration and cholesterol crystals in the tubular lumina of the cholesterol-fed group. These results suggest that oxidated LDL (O-LDL) is a cytotoxic factor which stimulates mesangial cell and matrix proliferation. Ultrastructurally, small and large lipid vacuolization in intracapillary lumina, adhesion of epithelial foot processes, mesangial foam cells and polymorphonuclear leukocytes were seen in the cholesterol-fed group. In the groups fed cholesterol + vitamin E, cholesterol + Se and cholesterol + vitamin E + Se, morphological improvements were observed. It appeared that an excess in O-LDL, reactive oxygen species and growth factors might play an important role in the pathogenesis of glomerulosclerosis. In addition, it was concluded that antioxidant therapy may prevent LDL oxidation and generation of free radicals.
Pre-Eclampsia-Associated Differential Expression of Proteoglycans in the Umbilical Cord Arteries
Authors: Gogiel Tomasz , Bańkowski Edward , Jaworski Stefan
Published: April 2003

Objective: The role of proteoglycans (PGs) of the umbilical cord arteries (UCAs) in the pathomechanism of pre-eclampsia is not known. Therefore we decided to compare the PGs of normal (control) UCAs and those of newborns delivered by mothers with pre-eclampsia. Methods: PGs were extracted in dissociative conditions, purified by Q-Sepharose anion exchange chromatography and lyophilized. They were analyzed by gel filtration and SDS-PAGE before and after treatment with chondroitinase ABC. Results: It was found that the PG preparation from pre-eclamptic UCAs had a higher amount of sulphated glycosaminoglycans (in relation to protein) than in the case of control UCAs. The predominant PG fraction included small PGs with core proteins of 45 and 47 kD, immunologically related to biglycan (45 kD) and decorin (45 and 47 kD). The expression of decorin core proteins was increased and that of biglycan slightly decreased in pre-eclamptic UCAs. Some other putative small PG core proteins (56, 53, 49, 42, 38 and 34 kD) were also found. They were present in higher amounts in pre-eclamptic UCAs. Larger PGs (core proteins of 99–110 and >150 kD), were detected in lower amounts, both in control and particularly in pre-eclamptic material. Conclusion: Pre-eclampsia is associated with alterations in PG composition of the UCAs. They may affect the mechanical properties of this organ and disturb fetal blood circulation.
Effect of IL-2 and IL-6 on Parameters Related to Metastatic Activity in a Murine Melanoma
Authors: García de Galdeano A. , Cruz-Conde J.C. , Boyano M.D. , García-Vázquez M.D. , Cañavate M.L.
Published: April 2003

Previous results have shown that the metastatic colonization with B16F10 melanoma in vivo increased after in vitro treatment of the cells with IL-2 or IL-6. To further investigate the mechanisms underlying this effect, we have studied adhesion, invasion, and proliferation properties of B16 melanoma, using two sublines with different metastatic ability. Adhesion of tumor cells to Matrigel coats increased using IL-6, which also induced upregulation of VLA-4 expression in both sublines. Unexpectedly, invasion through Matrigel filters was almost completely inhibited by IL-6 and decreased in the presence of IL-2. Cell growth was not affected by these interleukins; however, IL-6 could partially overcome the proliferation blockade induced by stress conditions. Taken together, these results suggest that upregulation of adhesion properties and/or the protective effect induced by IL-6 could account for the enhancement of metastasis exerted by this interleukin.
Prednisolone Inhibits an IgE-Mediated Late-Phase Allergic Cutaneous Reactionby Interfering w ith the Activation of Mast Cells in Mice
Authors: Kimata Masahiro , Abe Toru , Yamaguchi Itaru , Mito Kanako , Tsunematsu Masako , Inagaki Naoki , Nagai Hiroichi
Published: April 2003

Epicutaneous antigen challenge in passively sensitized mice with IgE produces a biphasic cutaneous response which peaks 1 h (immediate-phase reaction) and 24 h (late-phase reaction; LPR) after the antigen challenge. In this model, anaphylactic degranulation and interleukin 6 (IL-6) expression between 4 and 8 h are observed in resident mast cells as the preceding stage of LPR. Prednisolone at a dose of 3 mg kg–1 clearly inhibited the LPR when administered 2 h before and 4 h after antigen challenge. Slight or no inhibition of LPR was observed by prednisolone administered 6–12 h after challenge. Histologically, prednisolone treatment 2 h before antigen challenge completely inhibited edema and inflammatory cell infiltration, while treatment at 6 h did not at all. In order to investigate the relationship between inhibition of LPR by prednisolone and mast cell activation, the effects of prednisolone on degranulation of mast cells and IL-6 expression in mast cells were investigated. 8 h after antigen challenge, prednisolone clearly inhibited the increase in the number of anaphylactic degranulated and IL-6-positive mast cells by administration 2 h before challenge, but did not affect it by administration 6 h after challenge. These data indicate that the inhibitory mechanism of prednisolone on LPR, at least, involves the inhibition of mast cell activation before LPR.
Stimulation of Hyaluronan Synthetase by Platelet-Derived Growth Factor bb in Human Prostate Smooth Muscle Cells
Authors: Pullen Mark A. , Thomas Katherine , Wu Hsiao-Ling , Nambi Ponnal
Published: April 2003

Hyaluronic acid (HA) is an important component of the extracellular matrix of prostate cells. Platelet-derived growth factor bb (PDGFbb) has a mitogenic effect on prostate stromal cells. The effect of PDGFbb on HA production by smooth muscle cells from normal and benign prostatic hyperplasia (BPH) tissue was studied to elucidate the role of these two factors in BPH. The basal level of HA released into the cell media was greater in BPH cells. PDGFbb increases HA production in normal and BPH smooth muscle cells. This is partly due to an increase in HA synthetase II mRNA expression. In prostate disease, PDGFbb may have a role that involves HA production.
Kynurenic Acid Influences the Respiratory Parameters of Rat Heart Mitochondria
Authors: Baran Halina , Staniek Katrin , Kepplinger Berthold , Gille Lars , Stolze Klaus , Nohl Hans
Published: April 2003

In the present study the effect of L-kynurenine, kynurenic acid and quinolinic acid on the heart mitochondrial function were investigated. Mitochondria were incubated with saturating concentrations of respiratory substrates glutamate/malate (5 mmol/l), succinate (10 mmol/l) or NADH (1 mmol/l), with and without kynurenines. The concentration of kynurenines varied between 1.25 µmol/l and 10 mmol/l. From all investigated kynurenines, only kynurenic acid affected dose-dependently the respiratory parameters of heart mitochondria. Respiratory control and P/O values were reduced significantly with glutamate/malate and moderately with succinate as substrates in the presence of 125 µmol/l to 10 mmol/l kynurenic acid. A known elevation of L-kynurenine in the blood of patients with ischemic heart disease or essential hypertension may suggest the involvement of L-kynurenine metabolites in the impairment of heart mitochondrial function, for example in cardiomyopathy.
Stimulatory and Protective Effects of Alkylating Agents Applied in Ultra-Low Concentrations
Authors: Pukhalsky Alexander L. , Shmarina Galina V.
Published: April 2003

Alkylating drugs belonging to the nitrogen mustard family are known as cytostatic and immunosuppressive agents. Ultra-low doses of these drugs may demonstrate pharmacological effects unlike this category of drugs. In the case of a gradual dose decrease, the number of targets for alkylation is also reduced and the drug switches from cytostatic to cell growth modifier. We postulate that application of ultra-low doses of alkylating drugs may result in a beneficial effect in the therapy of diseases associated with chronic inflammation of the mucosa, especially with the signs of epithelial atrophy.
Central Serotonergic Mechanisms on Head Twitch Response Induced by Benzodiazepine Receptor Agonists
Authors: Tadano T. , Hozumi M. , Satoh N. , Oka R. , Hishinuma T. , Mizugaki M. , Arai Y. , Yasuhara H. , Kinemuchi H. , Niijima F. , Nakagawasai O. , Tan-no K. , Kisara K.
Published: April 2003

Intraperitoneal injection of benzodiazepine receptor agonists (estazolam, zopiclone, triazolam: 0.03–0.24 mmol/kg) induces the head twitch response (HTR). The present study was undertaken to examine the possible participation of the serotonergic system in the mechanism of head twitches induced by benzodiazepine receptor agonists (BZ-RAs). The HTR induced by BZ-RAs was suppressed by pretreatment with ketanserine (1 mg/kg, i.p.), a selective 5-HT2 receptor antagonist. Pretreatment with fluoxetine (10 mg/kg, i.p.), a 5-HT reuptake inhibitor, and 8-hydroxy-2-(di-n-propylamino)tetralin, a 5-HT1A receptor agonist, also suppressed the HTR induced by BZ-RAs. These results suggest that the HTR induced by BZ-RAs may be the result of an activation of postsynaptic 5-HT2 receptors, probably due to direct action.
Antidiarrheal Activity of Wood Creosote: Inhibition of Muscle Contraction and Enterotoxin-Induced Fluid Secretion in Rabbit Small Intestine
Authors: Ogata Norio , Shibata Takashi
Published: April 2003

Wood creosote has long been used as an antidiarrheal agent, but its mechanism of action is not well understood. To elucidate the mechanism of its antidiarrheal activity, we have addressed questions whether it inhibits fluid secretion induced by Escherichia coli heat-stable enterotoxin (STa) in rabbit jejunum in vivo, and whether it inhibits muscle contraction of isolated rabbit ileum ex vivo. Wood creosote (10–100 mg/l) instilled in a ligated loop of jejunum inhibited STa-induced fluid secretion (p < 0.05). It also inhibited the spontaneous phasic, acetylcholine-induced tonic and Ba2+-induced tonic contractions of longitudinal and circular muscles of ileum dose-dependently with IC50 values of 130–530 mg/l. These data provide further evidence that the antidiarrheal activity of wood creosote is attributable to its antisecretory and antimotility effects.
Effects of Bergenin, the Major Constituent of Mallotus japonicus against D-Galactosamine-Induced Hepatotoxicity in Rats
Authors: Lim Hwa-Kyung , Kim Hack-Seang , Choi Hong-Serck , Choi Jongwon , Kim Seung-Hwan , Chang Myung-Jei
Published: April 2003

The hepatoprotective effects of bergenin, a major constituent of Mallotus japonicus, were evaluated against D-galactosamine (GalN)-induced liver damage in rats. Bergenin (50, 100 and 200 mg/kg) was given orally once daily for 7 successive days and then GalN 400 mg/kg was injected intraperitoneally to rats at 24 and 96 h after the final administration of bergenin. Pretreatment with bergenin reduced the increased enzyme activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase, γ-glutamyltransferase and the elevated level of malondialdehyde induced by GalN. Bergenin restored the decreased hepatic contents of glutathione as well as the decreased activities of glutathione S-transferase and glutathione reductase by GalN towards normalization, suggesting that the hepatoprotective effects of bergenin may consist in maintaining adequate levels of hepatic glutathione for the removal of xenobiotics. The present results indicate that bergenin has hepatoprotective effects against GalN-induced hepatotoxicity in rats.
In vitro and in vivo Activity of New Rhodium (III) Complexes against Leishmania donovani
Authors: Rodriguez-Cabezas M.N. , Mesa-Valle C.M. , Azzouz S. , Moraleda-Lindez V. , Craciunescu D. , Gutierrez-Rios M.T. , De Frutos M.I. , Osuna A.
Published: April 2003

The activities of 17 new rhodium drug complexes were determined against Leishmania donovani promastigotes. The five most active salts were selected: [RhIII(2-amino-6-ethoxybenzothiazole)4Br2]+Br–; [RhIII(2-bromothiazole)4(Br)2]+Br–; [RhIII(mefloquine)4(Cl)2]+Cl–; [RhIII(2-mepacrine)4(Cl)2]+Cl–, and [RhIII(oxamniquine)4(Cl)2]+Cl–, which induced growth-inhibition rates of more than 50% at 24 h of treatment and at the maximum dosage tested. The cytotoxicity assays on the macrophage cell line J-774 showed high cytotoxicity for the salts [RhIII (mefloquine)4(Cl)2]+Cl–, [RhIII(2-mepacrine)4(Cl)2]+Cl– and [RhIII(oxaminquine)4(Cl)2]+Cl– with a percentage of specific 15Cr release of 49.3, 64.8 and 53.2% at 24 h of incubation and 100 µg/ml. Meanwhile, assays of the other compounds showed practically no cytotoxicity. The ultrastructural studies in the flagellates treated with the salt [RhIII(2-amino-6-ethoxybenzothiazole)4Br2]+Br– showed some alterations in the nucleus of the parasites with a very condensed chromatin and an electrodense endosome. This compound showed a high in vivo activity in parasitized Wistar rats.
Evaluation of the Effects of Nicorandil on Experimentally Induced Gastric Ulcers
Authors: Patel Hetal M. , Santani Dev D. , Goswami Sunita S.
Published: April 2003

The present study was designed to evaluate the effects of a potassium channel opener, nicorandil, and to elucidate its possible mechanism of action in aspirin plus pylorus ligation induced and ethanol-induced gastric ulcers in rats. In an attempt to ascertain the involvement of KATP channels in the modulation of gastric ulcers, the effects of nicorandil alone as well as in the presence of the KATP channel blocker glibenclamide were studied. Nicorandil and glibenclamide were administered orally at a dose of 2 mg/kg throughout the study. Nicorandil showed significant protection in all the selected models that was evident from a significant reduction in the ulcer index. The results of nicorandil treatment were comparable with those of cimetidine treatment in both models. Glibenclamide was found to inhibit this effect of nicorandil. Further, glibenclamide showed proulcerogenic potential in ethanol and aspirin plus pylorus ligation models. In the aspirin plus pylorus ligation model, nicorandil showed a significant reduction in total acidity, pepsin activity, and protein content and a significant rise in mucin activity. The effect of nicorandil was also studied on gastric mucosal blood flow (GMBF). The GMBF was found to be more increased in the test group than in the control group, indicating enhancement of GMBF by nicorandil. Glibenclamide reversed this effect of nicorandil as well. It is concluded from our study that nicorandil possesses antiulcer activity in the models employed in the present study. This may be attributed to the opening of KATP channels, inhibition of acid secretion, enhancement of mucin activity, and improvement in GMBF.
The Inhibitory Mechanism of Rebamipide on the Mediator Release in the Guinea Pig Lung Mast Cells Activated with Specific Antigen-Antibody Reactions
Authors: Ro Jai Youl , Kim Ji Young , Kim Kyung Hwan
Published: April 2003

This study aim was to assess the effects of rebamipide on the mechanism of histamine release and biosynthesis and release of leukotrienes caused by mast cell activation. We purified mast cells from guinea pig lung tissues by the use of enzyme digestion, the rough and the discontinuous density percoll gradient method. Mast cells were sensitized with IgG1 (anti-OVA) antibody and challenged with ovalbumin. Mast cells were also stimulated with A23187 and the intracellular Ca2+ level was measured. Histamine and leukotrienes were measured by automated fluorometric analyzer and radioimmunoassay, respectively. The intracellular Ca2+ level was analyzed using a confocal laser scanning microscope. Protein kinase C (PKC) activity was determined by protein phosphorylated with [γ-32P]ATP. The phospholipase D activity was assessed by the labeled phosphatidylalcohol. Mass 1,2-diacylglycerol (DAG) was measured by the [3H]DAG produced when prelabeled with [3H]myristic acid. PLA2 activity was determined by measuring the arachidonic acid released from the labeled phospholipids. Rebamipide decreased the releases of histamine and leukotrienes, and completely blocked Ca2+ influx during mast cell activation by antigen-antibody reactions. It also decreased the release of histamine and leukotrienes during mast cell activation by A23187. The PKC and PLD activities were also decreased by rebamipide in a dose-dependent manner. Rebamipide inhibited the mass DAG production and PLA2 activity during mast cell activation. The data suggest that rebamipide inhibits intracellular signals and blocks Ca2+ influx in mast cells activated by specific antigen-antibody reactions, which in turn inhibits histamine release and leukotriene generation.
Effects of Silymarin MZ-80 on Hepatic Oxidative Stress in Rats with Biliary Obstruction
Authors: González-Correa J.A. , de la Cruz J.P. , Gordillo J. , Ureña I. , Redondo L. , Sánchez de la Cuesta F.
Published: April 2003

This study was designed to evaluate the effects of three pharmaceutical forms of silymarin (silymarin MZ-80, silybinin-β-cyclodextrin, and silybinin) on the liver oxidative status in vitro and after oral administration to rats with extrahepatic biliary obstruction (EBO) and sham-operated animals. We evaluated thiobarbituric acid-reactive substances (TBARS), glutathione (GSH + GSSG) and their related enzyme activities (GSH peroxidase, GSSG reductase and GSH transferase). All three compounds inhibited the in vitro production of TBARS (IC50 56–533 µmol/l). These compounds, mainly silymarin MZ-80, also increased GSH peroxidase and GSH transferase activities. In EBO rats we found increases in TBARS production which was inhibited by 50–70% after treatment. Glutathione was reduced by 55% and elevated by silymarin MZ-80. GSH transferase increased in the group given silymarin MZ-80. We conclude that all three derivatives of silymarin show a clear ability to reduce lipid peroxidation in the liver. Silymarin MZ-80 was the only compound that enhanced the glutathione antioxidant system.
Acetylcholine Attenuates Cardiomyocyte Oxidant Stress during Simulated Ischemia and Reoxygenation
Authors: McPherson Bradley C. , Zhu Xiangdong , Liu Huiping , Wang Bin , Baman Timir , McPherson Steven S. , Da Costa Mark L.A. , Jayakar David V. , Jeevanandam Valluvan , Yao Zhenhai
Published: April 2003

We wanted to determine whether oxygen radicals open the mitochondrial ATP-dependent potassium channels (KATP) during an ischemic period to reduce cell death and oxidant stress. Chick embryonic cardiomyocytes were used. Cell viability was quantified with propidium iodide (5 µM), and free radicals was measured using 2′,7′-dichlorofluorescin diacetate. Preconditioning was produced by 10 min of simulated ischemia followed by 10 min of reoxygenation. Acetylcholine (1 mM), infused for 10 min instead of preconditioning, reduced cell death similarly (24 ± 5%, n = 7 and 18 ± 2%, n = 7, respectively, vs. controls, 49 ± 6%, n = 8). In control series, 60 min of simulated ischemia and 3 h of reoxygenation generated free radicals more than 300% above the baseline (ischemia: 3.63 ± 0.58, reoxygenation: 3.66 ± 0.47, n = 8). Preconditioning and acetylcholine markedly attenuated the oxidant stress during simulated ischemia (1.18 ± 0.41, n = 6 and 1.34 ± 0.60, n = 7 vs. controls 3.63 ± 0.58, n = 8) and re-oxygenation (1.23 ± 0.36, n = 6 and 1.50 ± 0.59, n = 7 vs. controls 3.66 ± 0.47, n = 8). The protection of acetylcholine was abolished with pretreatment with the antioxidant thiol reductant 2-mercaptopropionyl glycine and posttreatment with 5-hydroxydecanoate, a selective mitochondrial KATP channel antagonist (37 ± 7%, n = 7). These results demonstrate that oxygen radicals open mitochondrial KATP channels, which mediates the acetylcholine-induced preconditioning effect, and that stimulation of this signaling pathway attenuates oxidant stress.
Assessment of ex vivo Pharmacodynamic Markers during Inhibition of Thrombosis by CI-1031 (ZK-807834), a Novel Direct Factor Xa Inhibitor
Authors: Chi Liguo , Pen Yun-Wen , Potoczak Ronald , Gibson Glenn , Hicks Gary , Mertz Thomas E. , Janiczek Nancy , Juneau Paul L. , Gallagher Kim , Leadley Robert
Published: April 2003

CI-1031 (ZK-807834) is a novel, synthetic factor Xa (FXa) inhibitor with a Ki of 0.11 nM against human FXa. In human plasma in vitro, CI-1031 doubled PT and aPTT at 0.23 and 0.49 µM, respectively. The in vivo antithrombotic effect of CI-1031 was evaluated in a veno-venous shunt model of thrombosis in anesthetized rabbits. After thrombus formation was verified in the first shunts, rabbits received either vehicle or CI-1031 intravenously (bolus injection of 60, 240, or 480 µg/kg followed by an infusion of 2, 8, or 16 µg/kg/min for 140 min, respectively). The second shunts were inserted after 20 min of infusion of CI-1031 or vehicle. CI-1031 dose-dependently prolonged time to occlusion (TTO) in the second shunts (35 ± 21, 62 ± 24, and 120 ± 0 min for the three dose groups, respectively, vs. 10 ± 1 min for vehicle). Thrombus mass (TM) was reduced in a dose-dependent manner by CI-1031 (42 ± 7, 27 ± 6, and 18 ± 4 mg vs. 50 ± 4 mg for vehicle). Maximal TM reduction was 70% with an IC50 of 0.6 µg/ml. Among all the coagulation parameters tested, PT had the best correlation with plasma CI- 1031 concentration (r = 0.97). Ex vivo plasma anti-FXa activity was also well correlated with plasma concentration of CI-1031 and with PT (r = 0.96 and 0.98, respectively). These results indicate that CI-1031, which is currently undergoing clinical evaluation, is an effective antithrombotic compound with a favorable efficacy-to-bleeding ratio. In addition, CI-1031 concentration in plasma can be monitored using PT or anti-Xa assays, thereby providing reliable methods to ensure safe and accurate dose titration of CI-1031.
Studies on the Expression and Function of Beta-3-Adrenoceptors in the Colon of Rats with Acetic Acid-Induced Colitis
Authors: Khan Islam , Hussein Shaima M.K. , Oriowo Mabayoje A.
Published: April 2003

Ulcerative colitis is characterized by dysfunctional motility. Our main objective in this investigation was to study the effect of an acetic acid-induced ulcerative colitis on the expression and function of β3-adrenoceptors in the rat colon. Inflammation was induced by administering acetic acid intrarectally into rats. Levels of myeloperoxidase activity and β3-adrenoceptor mRNA were measured in colon samples taken following acetic acid administration. Relaxation responses to β3-adrenoceptor agonists were also studied. Ulcerative colitis was associated with significantly elevated levels of myeloperoxidase activity in the colon segments. Levels of β3-adrenoceptor mRNA as well as the relaxation responses to isoprenaline and BRL 37344 were however not significantly different between inflamed and control tissue. Acetic acid-induced ulcerative colitis in rats was not associated with changes in the expression and/or function of β3-adrenoceptors in the rat colon. Therefore, the dysfunctional motility that is characteristic of ulcerative colitis, is not likely to be due to changes in β3-adrenergic mechanisms in this model.
Nefiracetam Improves the Impairment of Local Cerebral Blood Flow and Glucose Utilization after Chronic Focal Cerebral Ischemia in Rats
Authors: Jin Jingji , Watabe Shigeo , Yamamoto Tsuneyuki
Published: April 2003

In this study we investigated the effects of nefiracetam (DM-9384) on local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglc) in the chronic phase after middle cerebral artery (MCA) occlusion in rats. Nefiracetam (10 mg/kg) was administered orally once a day for 2 weeks from day 15 after MCA occlusion. On day 28 after MCA occlusion, LCBF and LCMRglc were measured by an autoradiographic image-processing method. In MCA-occluded rats, LCBF and LCMRglc in the ischemic side of seven regions including the frontal cortex were significant decreased compared with those of the nonischemic side. Nefiracetam significantly improved the impairment of LCBF in the frontal cortex, parietal cortex, caudate putamen, ventral thalamus, amygdaloid nucleus and hippocampus. It also improved the decrease of LCMRglc in the frontal cortex, ventral thalamus and hippocampus. These results suggested that nefiracetam has ameliorating effects on chronic disorders of LCBF and LCMRglc induced by MCA occlusion.
Relationship between Prostatic α1-Adrenoceptor Binding and Reduction in Intraurethral Pressure following Continuous Infusion of KMD-3213 in Rats
Authors: Akiyama Katsuyoshi , Tatemichi Satoshi , Katayama Susumu , Nakajima Mariko , Oki Tomomi , Okura Takashi , Yamada Shizuo , Kimura Ryohei
Published: April 2003

The relationship between α1-adrenoceptor binding in rat tissues and pharmacodynamic effects of continuous infusion of KMD-3213 was examined. In vivo specific binding of [3H]KMD-3213 after continuous intravenous infusion of the ligand (100 pmol/kg/min for 10 min, followed by 30 pmol/kg/min for 60 or 90 min) differed largely among the tissues examined. Specific binding of [3H]KMD-3213 in aorta, heart, lung, and kidney was not different in terms of infusion time in the case of continuous infusion for 10, 70 and 100 min, whereas the binding in prostate, vas deferens, and submaxillary gland by 70- and/or 100-min infusion was significantly greater than that by the 10-min infusion. A similar extent of specific binding in the prostate was observed by the infusion (100 min) of a three-fold higher dose of [3H]KMD- 3213. Continuous intravenous infusion of KMD-3213 (100 pmol/kg/min for 10 min, followed by 30 pmol/kg/min) for 70 or 100 min significantly reduced the phenylephrine-induced increase in the mean blood pressure and that in the intraurethral pressure of anesthetized rats. Extent and time course of the KMD-3213 effect reduction in the phenylephrine-induced increase in intraurethral pressure were closely associated with those in prostatic [3H]KMD-3213 binding after continuous infusion of the corresponding dosage of the radioligand. The reduction in the phenylephrine-induced increase by the infusion of a three-fold higher dose of KMD-3213 was significantly greater in the case of the intraurethral pressure than in that of the mean blood pressure, thereby suggesting a greater selectivity for the α1-adrenoceptor in the lower urinary tract than for that in the vascular tissue. In conclusion, the present study has shown that specific binding of [3H]KMD-3213 in the rat prostate after the continuous intravenous infusion of the radioligand may be closely associated with the pharmacological effect of this drug on the lower urinary tract.
Opposite Biological Effects of Arsenic Trioxide and Arsacetin Involve a Different Regulation of Signaling in Human Gastric Cancer MGC-803 Cells
Authors: Zhang Tong-Cun , Cao En-Hua , Qin Jing-Fen
Published: April 2003

Opposite biological effects of arsenic trioxide (As2O3) and arsacetin on the growth of human gastric cancer MGC-803 cells have been observed. Results show that As2O3 inhibited the growth of MGC-803 cells by triggering apoptosis, whereas arsacetin promoted the cell proliferation and seemed to stimulate the secretion of some growth factors at the same micromolar concentrations. Further studies showed that As2O3 could regulate protein tyrosine kinase activity, protein tyrosine phosphorylation, and Bcl-2 protein and upregulate p53 protein. The ability of arsacetin to promote cell proliferation is linked with causing the opposite effects on these factors. These results indicate that the opposite biological effects of As2O3 and arsacetin involve different regulations of molecular mechanisms in MGC-803 cells and that arsacetin may be a potential tumor promoter.
Effects of SM-20550, a New Na+/H+ Exchange Inhibitor, on Survival and Infarct Size in Rat Myocardial Infarction
Authors: Yamada Kazuto , Sasabe Masao , Matsui Kazuki , Yamamoto Setsuko , Ohashi Naohito
Published: April 2003

The effect of a novel potent Na+/H+ exchange inhibitor, SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid], on survival after myocardial infarction was studied. Anesthetized rats underwent occlusion of the coronary artery (30 min) followed by reperfusion (14 days). SM-20550 was administered intravenously before ischemia (1-day treatment group) or before ischemia and on the 2 days following (3-day treatment group). The infarct size was significantly reduced on the 14th day after surgery by approximately 17 and 20% in 1- and 3-day treatment groups, respectively. The survival rate on day 14 was significantly enhanced in both treatment groups (96%) compared with the vehicle-treated control group (70%). These results suggest that SM-20550 improved survival after myocardial infarction, at least due to its antinecrotic effect.
Effects of Y-27632, a Rho/Rho Kinase Inhibitor, on Leukotriene D4- and Histamine-Induced Airflow Obstruction and Airway Microvascular Leakage in Guinea Pigs in vivo
Authors: Tokuyama Kenichi , Nishimura Hideko , Iizuka Kunihiko , Kato Masahiko , Arakawa Hirokazu , Saga Reiko , Mochizuki Hiroyuki , Morikawa Akihiro
Published: April 2003

Recent in vitro studies have shown that the Rho/Rho kinase pathway is involved in the mechanism of not only airway smooth muscle contraction but also vascular endothelial permeability caused by certain stimuli. This suggests that Rho/Rho kinase inhibitors may become useful agents against asthma via reduction of increased airway microvascular leakage, one of the main features of this disease. Thus, we wanted to know the in vivo effect of Y-27632, a selective Rho kinase inhibitor, on airway microvascular leakage caused by leukotriene D4 (LTD4) and histamine, potent mediators of allergic airway inflammation, by comparing its effect against airflow obstruction. For comparison, the effects of procaterol, a β2-adrenoceptor agonist, on these responses were also studied. Tracheostomized guinea pigs were given either aerosolized Y-27632 (3 or 15 mmol/l), procaterol (6 µmol/l) or vehicle (0.9% NaCl) for 5 min under spontaneous breathing. After being mechanically ventilated, the animals were given intravenous Evans blue dye 15 min after the end of inhalation. One minute later, either 2 nmol/kg LTD4, 300 nmol/kg histamine or vehicle was administered intravenously. After measurements of lung resistance (RL) for 6 min, the lungs of animals were taken out, and the amount of extravasated Evans blue dye was examined as an index of leakage. Inhaled Y-27632 dose-dependently attenuated increases in RL caused by LTD4 and histamine. The degree of inhibition was almost similar between 15 mmol/l Y-27632 and 6 µmol/l procaterol. By contrast, only 15 mmol/l, but not 3 mmol/l, Y-27632 partially reduced LTD4-induced leakage. Histamine-induced Evans blue dye extravasation was not inhibited by 15 mmol/l Y-27632. Procaterol significantly inhibited the dye extravasation caused by either LTD4 or histamine. These results suggest that Y-27632 is not a useful agent in attenuating airway microvascular leakage which is seen in asthma, although it is potent in inhibiting airflow obstruction.
Effect of 17β-Estradiol Exposure on Vasorelaxation Induced by K+ Channel Openers and Ca2+ Channel Blockers
Authors: Tsang Suk Ying , Yao Xiaoqiang , Chan Hoi Yun , Chen Zhen Yu , Ming Wong Chi , Huang Yu
Published: April 2003

17β-Estradiol has been shown to relax blood vessels partly through inhibition of Ca2+ channels at supraphysiological concentrations; however, it is unknown whether acute exposure of the isolated artery rings to near physiological concentrations of sex steroid hormones could modulate the ionic channels that are involved in regulation of vascular tone. Brief incubation (20 min) with 17β-estradiol (1–3 nmol/l) did not alter the relaxant response to three blocking agents of L-type voltage-sensitive Ca2+ channels, nifedipine, diltiazem and verapamil in either endothelium-intact or endothelium-denuded rat mesenteric artery rings. In contrast, 17β-estradiol at 3 nmol/l significantly attenuated the relaxation induced by K+ channel openers, cromakalim and pinacidil in endothelium-denuded rings. Similarly, preincubation with progesterone (3 nmol/l) inhibited pinacidil-induced relaxation with much less effect on cromakalim-induced relaxation. It appears that 17β-estradiol and progesterone attenuated the cromakalim- and pinacidil-induced relaxation in a different manner. These results suggest that acute exposure to female sex steroid hormones at near physiological levels may reduce the activity of ATP-sensitive K+ channels in the rat arteries.
Effects of STA2, a Thromboxane A2 Mimetic, in Inducing Airflow Obstruction and Airway Microvascular Leakage in Guinea Pigs
Authors: Inoue Yoshinari , Tokuyama Kenichi , Nishimura Hideko , Arakawa Hirokazu , Kato Masahiko , Mochizuki Hiroyuki , Morikawa Akihiro
Published: April 2003

Background: U-46619, a thromboxane A2 (TXA2) mimetic, is shown to cause airway microvascular leakage, although the effects is weak when comparing with that to induce bronchoconstriction in guinea pigs. Objective: In order to know the airway effect of TXA2 more accurately, we have examined the effects of STA2, a TXA2 mimetic with higher affinity to TXA2 (TP) receptors than U-46619, to induce airway microvascular leakage and airflow obstruction. Methods: Anesthetized and ventilated guinea pigs were i.v. given STA2 (3–30 nmol/kg) or U-46619 (3–100 nmol/kg) 1 min after i.v. Evans blue dye. STA2- and U-46619-induced increases in lung resistance (RL) was measured for 6 min. The amount of extravasated Evans blue dye in the lower airways was, then, examined as an index of leakage. In selected animals, specific TP receptor antagonists (10 µg/kg S-1452 or 10 mg/kg ONO-3708) were pretreated i.v. Results: Both STA2 and U-46619 induced significant increases in leakage and airflow obstruction. However, STA2 induced a slow and significantly less increase in RL but caused a significantly greater increase in extravasation of Evans blue dye compared to U-46619. Specific TP receptor antagonists completely abolished both airway effects induced by STA2 and U-46619. Conclusion: Our present results have supported a possibility that TXA2 induces microvascular leakage as well as bronchoconstriction in the airways.
Effects of Morpheme Boundaries on Intergestural Timing: Evidence from Korean
Authors: Cho Taehong
Published: April 2003

This paper examines the effects of morpheme boundaries on intergestural timing, and demonstrates that low-level phonetic realization is influenced by morphological structure, i.e. compounding and affixation. It reports two experiments, one using electromagnetic midsagittal articulography (EMA) and one electropalatography (EPG), examining Korean data. The results of the EMA study show that intergestural timing is less variable for adjacent gestures across the word boundary inside a lexicalized compound than inside a nonlexicalized compound, and inside a monomorphemic word than across a morpheme boundary. The EPG study (which examined the timing in palatalization of a coronal) shows that both [ti] and [ni] have more variability in gestural timing when heteromorphemic than when tautomorphemic. Furthermore, the phonetic details of gestural overlap shed light on the asymmetry on palatalization between tautomorphemic and heteromorphemic gestural sequences (e.g. ni vs. n-i), presumably driven by paradigmatic contrast and preference of overlap. In short, what emerges from two experiments is that gestures are coordinated more stably within a single lexical item (a morpheme or a lexicalized compound) than across a boundary between lexical items. In accounting for the stability of intergestural timing within a lexical entry, several hypotheses were discussed including the Phase Window, Bonding Strength, Phonological Timing and Extended Phase Window model newly proposed here. The implication is that the morphological structure may be encoded in the phonetic realization, as is the case with other linguistic structure (e.g. prosodic structure).
Perception of Vowel-to-Vowel Transitions with Different Formant Trajectories
Authors: Carré R. , Ainsworth W.A. , Jospa P. , Maeda S. , Pasdeloup V.
Published: April 2003

In this paper, the perceptual effects of vowel-to-vowel transitions determined by different temporal variations of model parameters which specify the shapes of the vocal tract area function are investigated. It is shown that, (a) the method of deformation of the vocal tract area function between two targets can be perceptually important and (b) conversely, within certain limits, the time course of parameters from one state to another, and the precise synchronization of two parameters is not important for the correct identification of a vowel series. These characteristics are necessary but not sufficient to prove the existence of a phonetic gesture percept.
Lung Lining Liquid – The Hidden Depths
Authors: Walters Dafydd V.
Published: April 2003

The volume of liquid which lines the lumen of the lung is small and thus exists as an extremely thin layer. Nevertheless, it appears to have important functions which include contributing to the mechanical and chemical defences of the pulmonary epithelium and providing the correct ionic environment for surfactant function. Energy is expended by the epithelium to prevent excess liquid accumulating, a process involving active transport of sodium ions out of the lumen. Precisely how lung lining liquid (LLL) is formed and how its volume is controlled remain uncertain. Control of volume is important to prevent excess liquid interfering with gas exchange: yet too little liquid would inhibit efficient functioning of the airway ciliary escalator and thus removal of mucus, debris and pathogens. The chemical content of LLL is also controlled by the epithelium. LLL pH is acidic which favours calcium ionisation, important for surfactant function. Glucose is removed from LLL so decreasing the likelihood of bacterial growth and reducing extra-cellular glycosylation of proteins such as immunoglobulins and surfactant apoproteins which would destroy their function. LLL is rich in antioxidant species, protecting the lung from atmospheric oxygen and free radicals formed by inflammation. The physico-chemical properties of water itself may be important when the lining layer is very thin. The structure of water can be semi-crystalline under some circumstances which could impart another role to LLL – that of contributing to the structural integrity of the surfactant/LLL/epithelial complex.
The Future of Surfactant Therapy for Patients with Acute Lung Injury – New Requirements and New Surfactants
Authors: Spragg Roger G.
Published: April 2003

New requirements must be considered when designing trials of new lung surfactants for patients with acute lung injury (ALI). Radiographic inclusion criteria must be carefully applied if they are to generate reproducible patient groups. Strategies for ventilation are now known to significantly affect outcome and also must be clearly defined and applied. Similar mortality rates in patients with different degrees of gas exchange and radiographic abnormalities suggest that prior clinical distinctions should be re-examined. Current trials of surfactant therapy for ALI are examining the efficacy of a natural surfactant, a surfactant containing recombinant SP-C and a surfactant based on an SP-B-like peptide.
Aneuploidy in human sperm: a review of the frequency and distribution of aneuploidy, effects of donor age and lifestyle factors
Authors: Shi Q. , Martin R.H.
Published: April 2003

Application of fluorescence in situ hybridization (FISH) analysis has opened the way for comprehensive studies on numerical chromosome abnormalities in human sperm. During the last decade, more than five million sperm from approximately 500 normal men were analyzed by a number of laboratories from around the world by this approach. Except for chromosome 19 which has been analyzed in only one study, all other chromosomes have been examined by two or more studies with considerable differences in disomy frequency for an individual chromosome among studies. The mean disomy frequency is 0.15% for each of the autosomes and 0.26% for the sex chromosomes. Most chromosomes analyzed have an equal distribution of disomy with the exception of chromosomes 14, 21, 22 and the sex chromosomes, which display significantly higher disomy frequencies. Slight but significant increases in disomy frequency with advancing paternal age were observed for some chromosomes, in particular for the sex chromosomes. Some lifestyle factors such as smoking, alcohol drinking and caffeine consumption have been investigated and no consistent association between disomy frequency and any type of lifestyle factors has been established. The question of whether different geographic and ethnic groups of men have inherent differences in frequency of disomic sperm has been investigated by two studies with conflicting results.
Genomic organization and chromosome location of the murine Rpl23 gene
Authors: Kleiter N. , Artner I. , Copeland N.G. , Gilbert D.J. , Jenkins N.A. , Kratochwil K.
Published: April 2003

The mouse gene coding for ribosomal protein L23 (Rpl23) has been fully sequenced, including 580 bp of the 5′ upstream region. The 5-kb gene comprises 5 exons and contains an unusually long (3,153 bp) third intron. The gene was mapped to the distal region of mouse chromosome 11, homologous to human chromosome 17q21→q22.
Dog chromosome-specific paints reveal evolutionary inter- and intrachromosomal rearrangements in the American mink and human
Authors: Graphodatsky A.S. , Yang F. , Serdukova N. , Perelman P. , Zhdanova N.S. , Ferguson-Smith M.A.
Published: April 2003

Forty chromosome-specific paint probes of the domestic dog (Canis familiaris, 2n = 78) were used to delineate conserved segments on metaphase chromosomes of the American mink (Mustela vison, 2n = 30) by fluorescence in situ hybridisation. Half of the 38 canine autosomal probes each painted one pair of homologous segments in a diploid mink metaphase, whereas the other 19 dog probes each painted from two to five pairs of discrete segments. In total, 38 canine autosomal paints highlighted 71 pairs of conserved segments in the mink. These painting results allow us to establish a complete comparative chromosome map between the American mink and domestic dog. This map demonstrates that extensive chromosome rearrangements differentiate the karyotypes of the dog and American mink. The 38 dog autosomes could be reconstructed from the 14 autosomes of the American mink through at least 47 fissions, 25 chromosome fusions, and six inversions. Furthermore, comparison of the current dog/mink map with the published human/dog map discloses 23 cryptic intrachromosomal rearrangements in 10 regions of conserved synteny in the human and American mink genomes and thus further refined the human/mink comparative genome map.
Cell lines from the same cervical carcinomabut with different radiosensitivities exhibit different cDNA microarray patterns of gene expression
Authors: Achary M.P. , Jaggernauth W. , Gross E. , Alfieri A. , Klinger H.P. , Vikram B.
Published: April 2003

Combining chemotherapy with radiotherapy has improved the cure rate among patients with cancers of the cervix. Although one-half to two-thirds of the patients can be cured by radiation alone, such patients cannot be identified at present and must therefore suffer the burden of chemotherapy. Our long-range goal is to identify those cervical cancers that are radiosensitive and could be cured by radiotherapy alone. The advent of methods that permit the simultaneous analysis of expression patterns of thousands of genes, make it feasible to attempt to identify the molecular events related to radiosensitivity and the associated regulatory pathways. We hypothesize that the sensitivity of tumor cells to ionizing radiation (IR) is determined by the level of expression of specific genes that may be identified with the aid of cDNA microarrays. As the first step in testing this hypothesis, we determined the gene expression differences between two cell lines exhibiting different degrees of radiosensitivity. These were derived from the same tumor prior to treatment from a patient with squamous cell carcinoma of the cervix. The mRNA from these cells was subjected to cDNA analysis on a microarray of 5,776 known genes and ESTs. The expression of 52 genes of the total of 5,776 was elevated (maximum 4.1 fold) in the radioresistant cells as compared to the radiosensitive cells. Ten of the 52 sequences are known genes while 42 are ESTs. Conversely, the expression of 18 genes was elevated in the sensitive cells as compared to the resistant cells. Seven of these 18 are known genes while eleven are ESTs. Among the genes expressed differentially between the resistant and sensitive cells were several known to be associated with response to IR and many more genes and ESTs that had not previously been reported to be related to radiosensitivity. The genes that showed the greatest overexpression in the radioresistant cell line were metal-regulatory transcription factor-1, cytochrome P450 CYP1B1, adenomatosis polyposis coli, translation elongation factor-1, cytochrome-c oxidase, whereas in the sensitive cell line, transcription factor NF-kappa-B, metalloproteinase inhibitor-1 precursor, superoxide dismutase-2, insulin-like growth factor binding protein-3, guanine nucleotide-binding protein and transforming growth factor beta-induced protein were overexpressed.
Local mechanisms in sex specific morphogenesis
Authors: Drews U.
Published: April 2003

Sex determination in mammals occurs on three levels. Segregation of sex chromosomes determines the chromosomal sex. Sry on the Y chromosome induces formation of a testis which in turn regulates via AMH and testosterone the development of the genital tract and the external phenotype. Recently a number of new factors have been described, which affect sexual development but have not yet found a place in the above canonical scheme of sex determination. For the purpose of this review, the factors are aligned according to their quality as transcription factors, steroid hormones, or growth factors. In this web of regulatory factors, the classical sex determining factors have evolved as master mechanisms while others function as slaves, or were totally suppressed. In this context, androgens acquired a dominant role in mammalian development. Androgens determine the morphogenesis of the genital tract. The effects of androgens are mediated by local cellular interactions. In the cranial section of the Wolffian duct the androgen receptor appears in the epithelium and mediates maintenance of the duct via an epithelial factor. In the caudal section of the duct the androgen receptor is expressed in the embryonic mesenchyme. Vesicular glands are induced via a morphogenetically active mesenchymal condensation, while the epithelial buds are primarily AR androgen receptor negative. The dominant role of androgens and formation of a vagina evolved together at the transition to eutherian mammals. Under this aspect, the role of androgens in the development of the vagina is analyzed.
A second case of inv(4)pat with both recombinants in the offspring: rec dup(4q) in a girl with Wolf-Hirschhorn syndrome and rec dup(4p)
Authors: Dufke A. , Eggermann K. , Balg S. , Stengel-Rutkowski S. , Enders H. , Kaiser P.
Published: April 2003

In a girl presenting with features of Wolf-Hirschhorn syndrome, cytogenetic and molecular cytogenetic analysis revealed a rearranged chromosome 4 with monosomy of the distal bands 4pter→4p16.2 and trisomy of the distal bands 4q35.1→4qter [rec dup(4q)] due to a large, paternal pericentric inversion. In the following two pregnancies, prenatal diagnosis showed the same imbalance in one fetus and a reverse segmental imbalance [rec dup(4p)] in the other. We discuss the recombination risk of the given inversion with respect to the size of the inverted segment and the viability of the recombinants. The high frequency of recombinants in this family and others suggests a high recurrence risk in similar cases with large pericentric inversions comprising almost entire chromosomes.