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Biomedical subjects

S Miyamoto

Publications and source records attributed to S Miyamoto.

At least 109 records · Page 6Linked to original sources
PubMed2001

Protein structure-based de novo design and synthesis of aldose reductase inhibitors.

Aldose reductase has been implicated in the etiology of diabetic complications. Due to the limited number of currently available drugs for the treatment of diabetic complications, we have carried out a structure-based de novo design and synthesis in an attempt to identify new aldose reductase inhibitors. With the LEGEND program, we have designed 200 chemical structures that fit into the ligand binding site of the crystal structure of the enzyme. After their visual inspection and assessment of synthetic feasibility, four compounds were chosen to be synthesized. These compounds were all found to have reasonable inhibitory activities (IC50 = 17-91 microM), indicating the first successful generation of nonpeptide drug leads that have been obtained using a rational de novo design approach.

Aldehyde Reductase↗
PubMed2000

Effects of posture on sympathetic nervous modulation in patients with chronic heart failure.

We investigated which recumbent position is preferred by patients with chronic heart failure (CHF) and whether sympathetic nervous modulation differs in three recumbent positions. We assessed 12 patients with CHF by spectral analysis of heart-rate variability and measurement of plasma norepinephrine concentrations. The right lateral decubitus position was preferred for significantly longer periods than the left lateral decubitus and supine positions. Sympathetic nervous modulation was most attenuated in the right lateral decubitus position. The right lateral decubitus position preferred by patients with CHF may be a self-protective mechanism to control increased sympathetic nervous modulation.

Heart Failure↗
PubMed2000

Signal transduction pathways that contribute to increased protein synthesis during T-cell activation.

Protein synthesis rates were maximally stimulated in human lymphocytes by ionomycin and the phorbol ester PMA (I+P), which promotes proliferation, whereas PMA alone, which does not promote proliferation, stimulated protein synthesis to a lesser degree. Three translation-associated activities, eIF4E phosphorylation, eIF2B activity and 4E-BP1 phosphorylation also increased with stimulation by I+P and PMA, but only 4E-BP1 phosphorylation was differentially stimulated by these conditions. Correspondingly, signaling pathways activated in T cells were probed for their connection to these activities. Immunosuppressants FK506 and rapamycin partially blocked the protein synthesis rate increases by I+P stimulation. FK506 had less of an inhibitory effect with PMA stimulation suggesting that its mechanism mostly affected ionomycin-activated signals. I+P and PMA equally stimulated phosphorylation of ERK1/2, but I+P more strongly stimulated Akt, and p70(S6K) phosphorylation. An inhibitor that blocks ERK1/2 phosphorylation only slightly reduced protein synthesis rates stimulated by I+P or PMA, but greatly reduced eIF4E phosphorylation and eIF2B activity. In contrast, inhibitors of the PI-3 kinase and mTOR pathways strongly blocked early protein synthesis rate stimulated by I+P and PMA and also blocked 4E-BP1 phosphorylation and release of eIF4E suggesting that these pathways regulate protein synthesis activities, which are important for proliferation in T cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

The Influence of Corneal Thickness and Curvature on the Difference Between Intraocular Pressure Measurements Obtained with a Non-contact Tonometer and Those with a Goldmann Applanation Tonometer.

Purpose: The influence of corneal thickness and curvature on the difference between intraocular pressure (IOP) measurements obtained with a non-contact tonometer (NCT) and those with a Goldmann applanation tonometer (GAT) was studied.Methods: The corneal thickness and curvature were obtained in 230 eyes of 115 subjects. The correlation between them and ratios of measurement with NCT to that with GAT ([NCT/GAT]) were examined.Results: [NCT/GAT] and corneal thickness showed a significant positive correlation (r = 0.556, P <.01), but, the correlation between [NCT/GAT] and the radius of corneal curvature was not statistically significant (r = -0.035, P =.30).Conclusion: The thick cornea has more influence on the measurement with NCT than GAT, because IOP is measured with NCT over a wider applanation area. The corneas with steeper curvature also cause higher corneal rigidity and produce more overestimation of NCT measurement, while they have stronger capillary attraction of the precorneal tear film for the GAT tip and also produce overestimation of GAT measurement. As a result, [NCT/GAT] was believed to be not influenced by the corneal curvature.

Journal Article↗
PubMed2000

Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor.

Negative transcriptional regulation or cross-coupling between NF-kappa B (RelA) and the glucocorticoid receptor (GR) is proposed to play a regulatory role in human physiology and disease. Despite previous advances, the biochemical basis of this phenomenon remains a subject of controversy. We show here that the inhibition of GR activity by RelA does not require the RelA DNA binding, transactivation, or nuclear localization domains. Surprisingly, RelA repression of GR is abolished by mutation of the conserved protein kinase A (PKA) site at amino acid residue 276 of RelA. We show that GR associates in vivo and in vitro with the catalytic subunit of PKA (PKAc) in a ligand-independent manner and that GR transcription depends on PKA signaling. Indeed, we demonstrated that GR-mediated inhibition of NF-kappa B transactivation is PKAc-dependent. In contrast to previous models, we suggest that the cross-coupling requires a cytoplasmic step and is regulated by a PKAc-associated signaling.

Catalytic Domain↗
PubMed2000

Prognostic value of plasma levels of secretory type II phospholipase A2 in patients with unstable angina pectoris.

Plasma levels of secretory nonpancreatic type II phospholipase A2 (sPLA2) are increased in various chronic inflammatory diseases; this increase is correlated with disease severity. sPLA2 plays a possible role in atherogenesis and is highly expressed in atheromatous plaques. Thus, this study prospectively examined whether plasma levels of sPLA2 may have a prognostic value in patients with unstable angina, which is known to have inflammatory features. Plasma levels of sPLA2 were measured in 52 patients with unstable angina, in 107 patients with stable angina, and in 96 control subjects by radioimmunoassay. sPLA2 levels were significantly higher in patients with unstable angina than in those with stable angina and in control subjects. sPLA2 remained elevated after stabilization of disease. The levels were not increased in the blood in the coronary sinus. Kaplan-Meier analysis demonstrated that patients with unstable angina and with the higher sPLA2 levels had a significantly higher probability of developing clinical coronary events during a follow-up period of 2 years compared with those with the lower levels. In multivariate Cox hazard analysis, the higher levels of sPLA2 were a significant predictor of developing coronary events in patients with unstable angina, independent of other risk factors, including C-reactive protein levels, an established inflammatory predictor. In conclusion, the increase in circulating levels of sPLA2 predicts clinical coronary events independently of other risk factors in patients with unstable angina. sPLA2 levels were persistently elevated but the elevated levels may not be derived from coronary circulation.

Aged↗
PubMed2000

Bidirectional function of coronary collateral channels in humans.

To investigate the bidirectional functional adequacy of collateral perfusion, we performed percutaneous transluminal coronary angioplasty (PTCA) on highly stenosed or occluded coronary arteries visualized by the collateral circulation,which were fed by the contralateral coronary artery with severe stenosis. After successful PTCA in all three patients, the contralateral artery was reversely filled by good collateral circulation originating from the dilated coronary artery. These findings indicated that dilation of the receiving coronary artery reversed the pressure gradient across the collateral network, establishing collateral flow in the opposite direction. It was concluded that human collateral channels serve as a bidirectionally functional conduit.

Aged↗
PubMed2000

Nonconvulsive focal inhibitory seizure: subdural recording from motor cortex.

The authors obtained an ictal electrocorticogram with chronically implanted subdural electrodes from a 30-year-old man with a low grade glioma in the right postcentral gyrus who had a focal inhibitory seizure of the left arm. During the ictal paresis, the authors observed epileptic discharges in the positive arm motor area of the right precentral gyrus and in its rostral area, but not in the negative motor area. The epileptic activity probably inhibited the spinal motoneuron pool without eliciting excitatory activity in the corticospinal pathway.

Adult↗
PubMed2000

Spirophostins: conformationally restricted analogues of adenophostin A.

The synthesis, biological evaluation, and molecular modeling of two conformationally restricted analogues of adenophostinA (1), denominated as spirophostin (3R)-10 and (3S)-11, as novel ligands for the D-myo-inositol 1,4,5-trisphosphate receptor (IP3R), is presented. These diastereoisomeric spiroketals are synthesized by spiroketalization of D-glucose derivatives (2S)-15 and (2R)-16, separation of the protected isomers (3R)-19 and (3S)-20, followed by phosphorylation and deprotection. The spirophostins (3R)-10 and (3S)-11 display comparable biological activity, with a 3H-IP3-displacing and Ca2+-releasing potency less than IP3 and adenophostin A.

Adenosine↗
PubMed2000

QT-prolonging class I drug, disopyramide, does not aggravate but suppresses adrenaline-induced arrhythmias. Comparison with cibenzoline and pilsicainide.

We investigated the effects of class I antiarrhythmic drugs on corrected QT (QTc) interval and adrenaline-induced arrhythmias in halothane-anaesthetized, closed-chest dogs. For this purpose, we plotted a dose-response curve for adrenaline by calculating the arrhythmic ratio, which is the number of ventricular ectopic beats induced by adrenaline divided by the total heart rate, and observed the changes in the arrhythmic ratio-adrenaline dose relation before and after administration of class I drugs. Disopyramide and cibenzoline decreased the arrhythmic ratio induced by adrenaline. Disopyramide prolonged the QTc interval by 20% (P<0.01), but cibenzoline did not. Pilsicainide prolonged the QTc interval (12%), but this drug did not change the arrhythmic ratio. These results indicate that in contrast to the class III drugs which we have reported earlier, i.e. 1, 3-dimethyl-6-2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)-propylamino]eth ylamino-2,4 (1H,3H)-pyrimidinedione hydrochloride (MS-551), 1-(2-amino-4-methanesulfonamidophenoxy)2-[N-(3, 4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride (KCB-328) and E-1-[(5-(4-chlorophenyl)-2-furanyl)methylene]amino-3-[4-(4-methyl-1 -piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride (azimilide), class I drugs do not aggravate adrenaline-induced arrhythmias even though some drugs prolong the QTc interval.

Animals↗
PubMed2000

Autosomal dominant temporal lobe epilepsy in a Japanese family.

We described autosomal dominant familial temporal lobe epilepsy in a Japanese family in which three individuals (one man and his two children) were affected. Their seizures commonly consisted of auditory symptoms and infrequent nocturnal generalized seizures. Repeated EEGs did not provide confirmative epileptiform discharges, but cranial MRI in one patient showed mild left hippocampal atrophy, and decreased glucose metabolism in the left temporal area was demonstrated by 18F-deoxyglucose positron emission tomography (FDG-PET). A confirmative diagnosis in one of the patients by FDG-PET was helpful for diagnosis in other patients in the same family. Seizure onset was adolescent commonly among the three patients, but better seizure control was achieved in the father as compared with the two children.

Adult↗
PubMed2000

Negative inotropic effect of endothelin-1 in the mouse right ventricle.

Effects of endothelin-1 on the contraction and cytosolic Ca(2+) concentrations (¿Ca(2+)(i)) of the mouse right ventricle were investigated. Endothelin-1 (1-300 nM) elicited a negative inotropic effect in a concentration-dependent manner. The endothelin-1-induced negative inotropy was antagonized by a selective endothelin ET(A) receptor antagonist, BQ-123 (cyclo ¿Asp-Pro-Val-Leu-Trp-; 3, 10 microM). Endothelin-1 reduced the peak amplitudes of both the ¿Ca(2+)(i) transient and contraction without changing inward Ca(2+) current. The relationship between peak amplitude of ¿Ca(2+)(i) and peak force generated by changing the extracellular Ca(2+) concentration (¿Ca(2+)(o)) was not affected by endothelin-1. In addition, the trajectory of the ¿Ca(2+)(i)-contraction phase plane diagram obtained at 2 mM ¿Ca(2+)(o) in the absence of endothelin-1 was superimposable on that obtained at 4 mM ¿Ca(2+)(o) in the presence of endothelin-1 (300 nM). Endothelin-1 (300 nM) translocated protein kinase C from cytosol to membrane, suggesting activation of protein kinase C. Further, a selective protein kinase C inhibitor, bisindolylmaleimide I (10 microM), inhibited the endothelin-1-induced negative inotropy. These results suggest that endothelin-1 elicits negative inotropy by reducing the amplitude of the ¿Ca(2+)(i) transient without changing inward Ca(2+) current through the activation of the endothelin ET(A) receptor followed by protein kinase C activation in the mouse right ventricle.

Animals↗
PubMed2000

A switch in distinct I kappa B alpha degradation mechanisms mediates constitutive NF-kappa B activation in mature B cells.

Inducible activation of cytoplasmic NF-kappa B/Rel transcription factors occurs via proteasome-dependent degradation of an associated inhibitor, termed I kappa B alpha. Mature B lymphocytes constitutively express nuclear NF-kappa B, which is important for their long-term survival. The intrinsic mechanisms by which B cells constitutively activate NF-kappa B are unknown. In this paper we demonstrate that maintenance of NF-kappa B activity in primary B cells is mediated by a novel calcium-dependent, but proteasome-independent, mechanism. Moreover, we show that differentiation of conditionally transformed pre-B cells is accompanied by a switch from proteasome-dependent to proteasome-independent degradation of I kappa B alpha. Our findings indicate that I kappa B alpha degradation mechanisms are dynamic during B cell development, and ultimately establish constitutive NF-kappa B activity in mature B lymphocytes.

Animals↗
PubMed2000

NF-kappaB activation by camptothecin. A linkage between nuclear DNA damage and cytoplasmic signaling events.

Activation of the transcription factor NF-kappaB by extracellular signals involves its release from the inhibitor protein IkappaBalpha in the cytoplasm and subsequent nuclear translocation. NF-kappaB can also be activated by the anticancer agent camptothecin (CPT), which inhibits DNA topoisomerase (Topo) I activity and causes DNA double-strand breaks during DNA replication to induce S phase-dependent cytotoxicity. Here we show that CPT activates NF-kappaB by a mechanism that is dependent on initial nuclear DNA damage followed by cytoplasmic signaling events. NF-kappaB activation by CPT is dramatically diminished in cytoplasts and in CEM/C2 cells expressing a mutant Topo I protein that fails to bind CPT. This response is intensified in S phase cell populations and is prevented by the DNA polymerase inhibitor aphidicolin. In addition, CPT activation of NF-kappaB involves degradation of cytoplasmic IkappaBalpha by the ubiquitin-proteasome pathway in a manner that depends on the IkappaB kinase complex. Finally, inhibition of NF-kappaB activation augments CPT-induced apoptosis. These findings elucidate the progression of signaling events that initiates in the nucleus with CPT-Topo I interaction and continues in the cytoplasm resulting in degradation of IkappaBalpha and nuclear translocation of NF-kappaB to attenuate the apoptotic response.

Apoptosis↗
PubMed2000

Biosynthesis and post-translational processing of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1). N-linked glycosylation affects cell-surface expression and ligand binding.

LOX-1 (lectin-like oxidized low density lipoprotein receptor-1) is a type II membrane protein belonging to the C-type lectin family that can act as a cell-surface receptor for atherogenic oxidized low density lipoprotein (Ox-LDL) and may play crucial roles in atherogenesis. In this study, we show, by pulse-chase labeling and glycosidase digestion, that LOX-1 is synthesized as a 40-kDa precursor protein with N-linked high mannose carbohydrate chains (pre-LOX-1), which is subsequently further glycosylated and processed into the 48-kDa mature form within 40 min. Furthermore, when treated with an N-glycosylation inhibitor, tunicamycin, both tumor necrosis factor-alpha-activated bovine aortic endothelial cells and CHO-K1 cells stably expressing bovine LOX-1 (BLOX-1-CHO) exclusively produced a 32-kDa deglycosylated form of LOX-1. Cell enzyme-linked immunosorbent assay, flow cytometry, and immunofluorescence confocal microscopy demonstrated that the deglycosylated form of LOX-1 is not efficiently transported to the cell surface, but is retained in the endoplasmic reticulum or Golgi apparatus in tumor necrosis factor-alpha-activated bovine aortic endothelial cells, but not in BLOX-1-CHO cells. Radiolabeled Ox-LDL binding studies revealed that the deglycosylated form of LOX-1 expressed on the cell surface of BLOX-1-CHO cells has a reduced affinity for Ox-LDL binding. Taken together, N-linked glycosylation appears to play key roles in the cell-surface expression and ligand binding of LOX-1.

Amidohydrolases↗
PubMed2000

Formation of platelet aggregates after attacks of coronary spastic angina pectoris.

Using a novel laser-light scattering method, we examined platelet aggregability, especially small-sized platelet aggregates, at baseline and after spontaneous coronary spastic attacks in 14 patients with coronary spastic angina, and before and after anginal attacks during an exercise test in 11 patients with stable exertional angina. The number of small-sized platelet aggregates after coronary spastic anginal attacks increased significantly, but not in patients with stable exertional angina. These results imply that an increase in the number of small-sized platelet aggregates from coronary spasm may be a trigger for coronary thrombosis via medium- and large-sized platelet aggregates.

Acetylcholine↗
PubMed2000

Bone regeneration by transforming growth factor beta1 released from a biodegradable hydrogel.

This paper describes the sustained release of transforming growth factor beta1 (TGF-beta1) from a biodegradable hydrogel based on polyion complexation for the enhancement of bone regeneration activity. Basic TGF-beta1 was adsorbed onto the biodegradable hydrogel of acidic gelatin with an isoelectric point of 5.0 by an electrostatic interaction. The TGF-beta1 could not be adsorbed onto basic gelatin. When acidic gelatin hydrogels incorporating 125I-labeled TGF-beta1 were implanted into the back subcutis of mice, the radioactivity decreased with time and the in vivo retention of TGF-beta1 was prolonged with a decrease in the water content of hydrogels. The higher the water content of hydrogels, the faster their biodegradation. The in vivo retention of TGF-beta1 correlated well with that of gelatin hydrogels, indicating that TGF-beta1 was released from the gelatin hydrogel as a result of hydrogel biodegradation. The ability of TGF-beta1-incorporated into acidic gelatin hydrogels to induce bone regeneration was evaluated in a rabbit calvarial defect model. Eight weeks after treatment, the gelatin hydrogels with water contents of 90 and 95 wt% induced significantly high bone regeneration compared with those with lower and higher water contents and free TGF-beta1. This indicates that the sustained release of TGF-beta1 from the hydrogel with suitable in vivo degradability is necessary to effectively enhance its osteoinductive function. Rapid hydrogel degradation will result in a retention time of TGF-beta1 which is too short to induce bone regeneration. It is possible that the slow degradation of the hydrogel physically blocked TGF-beta1-induced bone regeneration at the skull defect. It can be concluded that the gelatin hydrogel is a promising matrix of TGF-beta1 release to induce skull bone regeneration.

Absorbable Implants↗