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Biomedical subjects

M Eda

Publications and source records attributed to M Eda.

At least 19 recordsLinked to original sources
PubMed2002

Demonstration of the optic pathway in large pituitary adenoma on heavily T2 weighted MR images.

The objective of the investigation was to understand preoperatively the detailed anatomical relationship of large pituitary adenomas to surrounding structures, using the heavily T2-weighted reversed (T2R) MR images. This study consisted of 28 patients with pituitary adenoma, presenting with visual disturbance. The MRI scanner used was a Gyroscan ACSNT 1.5T and the slice thickness of the image was 3 mm with 0.5 mm interslice gap. The relation of pituitary adenoma to optic pathway and to the degree of visual field defect was assessed. Relations of the optic chiasm to adenoma were classified into three types: anterior, superior and posterior. The optic chiasm was directly visualized and identifiable in all patients studied. It was located anterior in four cases, superior in 22 and posterior in two in relation to the adenoma. Its location was further confirmed by the anatomical delineation of surrounding structures such as anterior commissure and lamina terminalis. Optic nerve or tract was unidentifiable in one case, for each category. Detectability of each optic component was higher on T2R images than on conventional T1-weighted images. The adenoma extended into and in front of the third ventricle in anterior and posterior types, respectively. The anterior communicating artery complex and the optic pathway were relocated together in anterior and superior types, and were separated in the posterior type. In a case of the posterior type, the complex was sectioned to obtain a wider surgical field during anterior interhemispheric approach. While degrees of visual field defect were proportional to tumour size in the superior type, they were unrelated in the anterior and posterior types. On choosing a transcranial approach, the transcallosal route is unsuitable for an adenoma of posterior type, which extends in front of the third ventricle. This preoperative MRI information makes it possible to visualize directly the optic pathway even in huge adenomas, and is useful in predicting surgical anatomy and selecting a proper surgical approach.

Adenoma↗
PubMed2001

Synthesis, structure-activity relationships, and pharmacokinetic profiles of nonpeptidic difluoromethylene ketones as novel inhibitors of human chymase.

Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P3-P2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K(i) of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.

Animals↗
PubMed2001

Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds.

The flavonoid genistein and the benzo[c]quinolizinium MPB-07 have been shown to activate the cystic fibrosis transmembrane conductance regulator (CFTR), the protein that is defective in cystic fibrosis. Lead-based combinatorial and parallel synthesis yielded 223 flavonoid, quinolizinium, and related heterocyclic compounds. The compounds were screened for their ability to activate CFTR at 50 microm concentration by measurement of the kinetics of iodide influx in Fisher rat thyroid cells expressing wild-type or G551D CFTR together with the green fluorescent protein-based halide indicator YFP-H148Q. Duplicate screenings revealed that 204 compounds did not significantly affect CFTR function. Compounds of the 7,8-benzoflavone class, which are structurally intermediate between flavones and benzo[c]quinoliziniums, were effective CFTR activators with the most potent being 2-(4-pyridinium)benzo[h]4H-chromen-4-one bisulfate (UCcf-029). Compounds of the novel structural class of fused pyrazolo heterocycles were also strong CFTR activators with the most potent being 3-(3-butynyl)-5-methoxy-1-phenylpyrazole-4-carbaldehyde (UCcf-180). A CFTR inhibitor was also identified. The active compounds did not induce iodide influx in null cells deficient in CFTR. Short-circuit current measurements showed that the CFTR activators identified by screening induced strong anion currents in the transfected cell monolayers grown on porous supports. Compared with genistein, the most active compounds had up to 10 times greater potency in activating wild-type and/or G551D-CFTR. The activators had low cellular toxicity and did not elevate cellular cAMP concentration or inhibit phosphatase activity, suggesting that CFTR activation may involve a direct interaction. These results establish an efficient screening procedure to identify CFTR activators and inhibitors and have identified 7,8-benzoflavones and pyrazolo derivatives as novel classes of CFTR activators.

Animals↗
PubMed2001

Energetic feasibility of hydrogen abstraction and recombination in coenzyme B(12)-dependent diol dehydratase reaction.

Coenzyme B(12) serves as a cofactor for enzymatic radical reactions. The essential steps in all the coenzyme B(12)-dependent rearrangements are two hydrogen abstraction steps: hydrogen abstraction of the adenosyl radical from substrates, and hydrogen back-abstraction (recombination) of a product-derived radical from 5'-deoxyadenosine. The energetic feasibility of these hydrogen abstraction steps in the diol dehyratase reaction was examined by theoretical calculations with a protein-free, simplified model at the B3LYP/6-311G* level of density functional theory. Activation energies for the hydrogen abstraction and recombination with 1,2-propanediol as substrate are 9.0 and 15.1 kcal/mol, respectively, and essentially not affected by coordination of the substrate and the radical intermediate to K+. Since these energies can be considered to be supplied by the substrate-binding energy, the computational results with this simplified model indicate that the hydrogen abstraction and recombination in the coenzyme B(12)-dependent diol dehydratase reaction are energetically feasible.

Aldehydes↗
PubMed2001

Rho-dependent transfer of Citron-kinase to the cleavage furrow of dividing cells.

Citron-kinase (Citron-K) is a Rho effector working in cytokinesis. It is enriched in cleavage furrow, but how Rho mobilizes Citron-K remains unknown. Using anti-Citron antibody and a Citron-K Green Fluorescence Protein (GFP)-fusion, we monitored its localization in cell cycle. We have found: (1) Citron-K is present as aggregates in interphase cells, disperses throughout the cytoplasm in prometaphase, translocates to cell cortex in anaphase and accumulates in cleavage furrow in telophase; (2) Rho colocalizes with Citron-K in the cortex of ana- to telophase cells and the two proteins are concentrated in the cleavage furrow and to the midbody; (3) inactivation of Rho by C3 exoenzyme does not affect the dispersion of Citron-K in prometaphase, but prevented its transfer to the cell cortex, and Citron-K stays in association with the midzone spindles of C3 exoenzyme-treated cells. To clarify further the mechanism of the Rho-mediated transfer and concentration of Citron-K in cleavage furrow, we expressed active Val14RhoA in interphase cells expressing GFP-Citron-K. Val14RhoA expression transferred Citron-K to the ventral cortex of interphase cells, where it formed band-like structures in a complex with Rho. This structure was localized at the same plane as actin stress fibers, and they exclude each other. Disruption of F-actin abolished the band and dispersed the Citron-K-Rho-containing patches throughout the cell cortex. Similarly, in dividing cells, a structure composed of Rho and Citron-K in cleavage furrow excludes cortical actin cytoskeleton, and disruption of F-actin disperses Citron-K throughout the cell cortex. These results suggest that Citron-K is a novel type of a passenger protein, which is dispersed to the cytoplasm in prometaphase and associated with midzone spindles by a Rho-independent signal. Rho is then activated, binds to Citron-K and translocates it to cell cortex, where the complex is then concentrated in the cleavage furrow by the action of actin cytoskeleton beneath the equator of dividing cells.

ADP Ribose Transferases↗
PubMed2000

The solid-phase Zincke reaction: preparation of omega-hydroxy pyridinium salts in the search for CFTR activation.

A study of structural modifications of MPB-07 was undertaken as part of a synthetic program aimed at discovering small molecules with CFTR activation potential. Solid-phase synthesis techniques were used to prepare derivatives of MPB-07 employing the Zincke reaction for the construction of aromatic, quaternary ammonium salts such as those found in 2 or 3. In this transformation, primary amines react with highly electrophilic N-2,4-dinitrophenylpyridinium (DNP) salt 4 to afford pyridinium salt 8 with release of 2,4-dinitroaniline 6. Thus, the reaction of 1-(2,4-dinitrophenyl)pyridinium salts with various polymer-bound amino ethers, followed by cleavage from the resin, delivers the desired salts in good yield and high purity.

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed2000

Citron, a Rho target that affects contractility during cytokinesis.

The small GTPase Rho, which regulates cell shape, is thought to contribute to cytokinesis. Recently, Citron was characterized as a Rho target. This large protein contains a Ser/Thr kinase domain related to that of ROCK, another Rho effector. Both endogenous Citron and recombinant Citron localize to the cleavage furrow in dividing cells and to the midbody in post-mitotic cells. Moreover, overexpression of Citron deleted from its C-terminal sequence caused abnormal contractions specifically during cytokinesis, resulting in the formation of multinucleated cells. Cell shape, F-actin, intermediate filaments, and microtubules appeared essentially normal in these cells during interphase. Thus, Citron is a Rho effector that appears to function during cytokinesis, modulating its contractile process. In brain, however, Citron is highly expressed in a subset of neurons as a brain-specific isoform that lacks a kinase domain, Citron-N. This protein accumulates in synapses and associates to the NMDA receptor via interaction with the adaptor protein PSD95, suggesting that the function of Citron is specialized in the neurons.

Animals↗
PubMed1999

MRI of growth hormone-secreting pituitary adenomas: factors determining pretreatment hormone levels.

Preoperative serum growth hormone (GH) level is one of the most important determinants of outcome. Our aim was to assess MRI findings which may correlate with pretreatment GH levels in GH-secreting adenomas. We retrospectively studied 29 patients with acromegaly caused by a pituitary adenoma. Tumor size (height, width, thickness and volume), suprasellar extension, sphenoid or cavernous sinus invasion, signal intensity and contrast enhancement were studied. Linear regression analysis or Fisher's exact probability test was used for statistical analysis. Factors related to high GH levels were the maximum dimension of the tumour (r = 0.496, P < 0. 01), its volume (r = 0.439, P < 0.05), spenoid sinus invasion (P < 0. 01) and intracavernous carotid artery (encasement (P < 0.01). The other items were not related to serum GH levels. Since we believe surgery is the first choice of treatment and the cavernous sinus is difficult of access with a conventional surgical approach, preoperative assessment of invasion into the cavernous sinus is critical for predicting the surgical outcome. Low GH levels (5-50 ng/ml) were found with tumours medial to the intercarotid line and high levels (more than 101 ng/ml) with invasive tumours with carotid artery encasement. Variable GH levels were noted with tumours extending beyond the intercarotid line. Because functioning adenomas invading the cavernous sinus tend to have markedly high hormone levels, and only patients with carotid artery encasement showed markedly elevated GH levels, we believe carotid artery encasement a reliable MRI indicator of cavernous sinus invasion.

Acromegaly↗
PubMed1999

Direct participation of potassium ion in the catalysis of coenzyme B(12)-dependent diol dehydratase.

The direct ion-dipolar interactions between potassium ion (K(+)) and the two hydroxyl groups of the substrate are the most striking feature of the crystal structure of coenzyme B(12)-dependent diol dehydratase. We carried out density-functional-theory computations to determine whether K(+) can assist the 1,2-shift of the hydroxyl group in the substrate-derived radical. Between a stepwise abstraction/recombination reaction proceeding via a direct hydroxide abstraction by K(+) and a concerted hydroxyl group migration assisted by K(+), only a transition state for the latter concerted mechanism was found from our computations. The barrier height for the transition state from the complexed radical decreases by only 2.3 kcal/mol upon coordination of the migrating hydroxyl group to K(+), which corresponds to a 42-fold rate acceleration at 37 degrees C. The net binding energy upon replacement of the K(+)-bound water for substrate was calculated to be 10.7 kcal/mol. It can be considered that such a large binding energy is at least partly used for the substrate-induced conformational changes in the enzyme that trigger the homolytic cleavage of the Co-C bond of the coenzyme and the subsequent catalysis by a radical mechanism. We propose here a new mechanism for diol dehydratase in which K(+) plays a direct role in the catalysis.

Catalysis↗
PubMed1998

Role of citron kinase as a target of the small GTPase Rho in cytokinesis.

During mitosis, a ring containing actin and myosin appears beneath the equatorial surface of animal cells. This ring then contracts, forms a cleavage furrow and divides the cell, a step known as cytokinesis. The two daughter cells often remain connected by an intercellular bridge which contains a refringent structure known as the midbody. How the appearance of this ring is regulated is unclear, although the small GTPase Rho, which controls the formation of actin structures, is known to be essential. Protein kinases are also thought to participate in cytokinesis. We now show that a splice variant of a Rho target protein, named citron, contains a protein kinase domain that is related to the Rho-associated kinases ROCK14 and ROK, which regulate myosin-based contractility. Citron kinase localizes to the cleavage furrow and midbody of HeLa cells; Rho is also localized in the midbody. We find that overexpression of citron mutants results in the production of multinucleate cells and that a kinase-active mutant causes abnormal contraction during cytokinesis. We propose that citron kinase regulates cytokinesis at a step after Rho in the contractile process.

Alternative Splicing↗
PubMed1998

Peptidyl human heart chymase inhibitors. 2. Discovery of highly selective difluoromethylene ketone derivatives with Glu at P3 site.

Appropriate structural modification of the difluoromethylene ketone derivatives at both P3 and P' positions led us to the discovery of peptidyl human heart chymase inhibitor 12h which shows potent activity with Ki = 6 nM and high selectivity against closely related serine protease bovine alpha-chymotrypsin (chymotrypsin Ki = > 100 microM). Using the compound 12b, a docking study with human heart chymase was carried out to presume probable interactions.

Animals↗
PubMed1998

Effects of repeated hand instrumentation on the marginal portion of a cast gold crown.

A study was conducted to evaluate the effects of repeated hand instrumentation on the marginal portion of a cast gold crown. Seven extracted periodontally diseased premolars were used. The finishing line of the preparation was placed on the root surface and then the crown was cast and cemented in the usual manner. One proximal surface of each sample was divided into 2 areas: root planing (RP) area and RP plus polishing (RPP) area. The marginal portion of the crown was measured to give a baseline value using a surface roughness- and profile-analyzing system. Then, the marginal portion was painted with a waterproof pen. RP was performed to remove paint in the RP area with the curets. In the RPP area, RP followed by polishing was done by silicone polishing points and a rubber cup with polishing paste. The relevant procedures and measurements were repeated 3 times in each area. Changes in the sample roughness and profile were evaluated and compared between the 2 techniques. The results showed that repeated instrumentation altered the surface of the marginal portion of the cast gold crown, resulting in increased roughness in both areas (P < 0.01). However, the roughness of the RPP area was considerably restored to the baseline value by polishing after RP. Therefore, it is suggested that polishing after RP smoothes the marginal portion of the cast gold crowns and appears to be an efficient prophylactic system.

Bicuspid↗
PubMed1996

AL0671, a new potassium channel opener, inhibits nonenzymatic glycation of protein and LDL oxidation.

1. The effects of AL0671, a novel potassium channel opener, on protein glycation and low-density lipoprotein (LDL) oxidation were tested. 2. AL0671 dose-dependently inhibited both fluorescence development of bovine serum albumin and cross-linking of lysozyme. These inhibitory effects for glycation were no less potent than aminoguanidine. 3. AL0671 dose-dependently inhibited both increase in negative charge and apo B-100 fragmentation during incubation of LDL with Cu2+. In addition, AL0671 significantly decreased the LDL degradation in rat peritoneal macrophages. 4. Neither pinacidil nor levcromakalim inhibited protein glycation and LDL oxidation. 5. Antioxidant properties of AL0671 might be due to its potent electron-donating ability, and this agent is expected to be useful for hypertensive diabetes.

Animals↗
PubMed1996

Synthesis and pharmacological evaluation of N-(6-functionalized-amino-3-pyridyl)-N'-bicycloalkyl-N''-cyanoguanidine s as antihypertensive agents.

A series of amino acid conjugates of N-(6-amino-3-pyridyl)-N'-[exo-bicyclo[2.2.1]hept-2-yl]-N''- cyanoguanidine (4) were prepared and evaluated as antihypertensive agents. The parent compound 4 showed potent potassium channel-opening and antihypertensive activities, but with undesirable changes of the urinary balance of electrolytes. However, alanine and histidine congeners (9,19) reduced this undesirable side effect of 4 through improved pharmacokinetics without loss of antihypertensive activity. They also provided additional information on the structural requirements for pinacidil-type potassium channel openers.

Animals↗
PubMed1994

Novel potassium-channel openers: preparation and pharmacological evaluation of racemic and optically active N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives.

The previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induced contraction of rat aorta, hypotensive activity in normotensive rats, and diuretic activity in spontaneously hypertensive rats. This led to further evaluation of compound (+/-)-10 and selection of (+)-N-(6-amino-3-pyridyl)-N'- [(1S,2R,4R)-bicyclo- [2.2.1]hept-2-yl]-N"-cyanoguanidine ((+)-10) (AL0670) for development as an antihypertensive agent. Although AL0670 is regarded as a pinacidil-type K(+)-channel opener, it showed different pharmacological and conformational profiles from pinacidil.

Animals↗
PubMed1994

Novel potassium channel openers: synthesis and pharmacological evaluation of new N-(substituted-3-pyridyl)-N'-alkylthioureas and related compounds.

This report describes the synthesis and pharmacological evaluation of a series of novel potassium channel openers related to the pinacidil-type compounds. Thioureas, cyanoguanidines, and pyridine N-oxides were systematically evaluated for their effects on both the inhibition of spontaneous mechanical activity in rat portal vein (in vitro) and their antihypertensive activity (in vivo), and the structure-activity relationship for this series of compounds was discussed. Good correlation between in vitro and iv antihypertensive activity was observed for these compounds. Among them, cyanoguanidines bearing a conformationally rigid unit such as a norbornyl group generally possessed potent activity in both in vitro and in vivo studies. Especially, N-(6-amino-3-pyridyl)-N'-cyano-N"-(1-methyl-2-norbornyl)guanidine (23d) was identified as a more potent potassium channel opener in vitro (EC100 = 3 x 10(-8) M) than pinacidil (EC100 = 10(-7) M).

4-Aminopyridine↗
PubMed1994

A possible mechanism of action of a new potassium channel opener, AL0671, on lipid metabolism in obese Zucker rats.

Antihypertensive drugs are expected to have a lipid-lowering effect for use in treating ischemic heart disease. We evaluated the effect of (+)-N-(6-amino-3-pyridil)-N'-[(1S,2R,4R)-bicyclo-[2.2.1]hept-2-yl] -N"- cyanoguanidine hydrochloride (AL0671), a newly synthesized cyanoguanidine-derivative potassium channel opener, on serum lipid and lipoprotein levels in obese Zucker rats, a genetically engineered model of type IV hyperlipidemia. AL0671 dose-dependently decreased systolic blood pressure in obese Zucker rats. Serial administration (for 1 or 2 weeks) of AL0671 (5 mg/kg/day) significantly decreased serum total triglyceride, chylomicron and very-low-density lipoprotein levels with increasing high-density lipoprotein cholesterol, whereas low-density lipoprotein levels did not change. AL0671 (5 mg/kg/day) increased lipoprotein lipase activities 4-fold and hepatic triglyceride lipase activities 3-fold in postheparin plasma. Another urea-derivative compound, AL0674, whose potassium channel-opening activity is diminished, did not affect serum lipid and lipoprotein levels. These results suggested that AL0671 activates both lipoprotein lipase and hepatic triglyceride lipase activities through its potassium channel-opening activity followed by decreasing triglyceride-rich lipoproteins in genetically obese hyperlipemic rats. Therefore, AL0671 might be beneficial in the treatment of hypertensive patients with hypertriglyceridemia (probably with insulin resistance).

Animals↗