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Biomedical subjects

Junichi Takahashi

Publications and source records attributed to Junichi Takahashi.

16 recordsLinked to original sources

Structural basis for the phase switching of bisaminecopper(II) cations at the thermal limits of lattice stability.

The structural grounds of the decrease of point and lattice symmetries coupled with switching of the exchange interaction in single crystals of a highly strained, coordinationally unsaturated bisdiaminecopper(II) cation are described. The combined magnetic susceptibility and X-ray diffraction results indicate that the interplay between the inherent vibronic instability and ligand-field strain imposed by moderately flexible, coordinationally shielding ligands enables effective switching of the pseudo-Jahn-Teller d9 centers between states with different exchange interaction in the low-temperature regime and valence orbital orientation and coordination geometry in the high-temperature regime. Within the low-temperature hysteresis region, the phase transition can also be induced by excitation of the ligand-to-metal charge-transfer bands, resulting in overall shrinkage of the lattice. The compound is a prototype of weakly electronically coupled one-dimensional Jahn-Teller systems, which can undergo phase transitions induced by light, in addition to heating, cooling, and change of pressure, and it represents a prospective basis for the design of switching materials capable of multimode external control.

Journal Article↗

Adipose-specific effect of rosiglitazone on vascular permeability and protein kinase C activation: novel mechanism for PPARgamma agonist's effects on edema and weight gain.

PPARgamma agonists, thiazolidinediones, cause fluid retention and edema due to unknown mechanisms. We characterized the effect of rosiglitazone (RSG), a thiazolidinedione, to induce vascular permeability, vascular endothelial growth factor (VEGF) expression, and protein kinase C (PKC) activation with edema and wt gain. In lean, fatty and diabetic Zucker rats, and endothelial insulin receptor knockout mice, RSG increased wt and vascular permeability, selectively in fat and retina, but not in heart or skeletal muscle. H2O content and wt of epididymal fat were increased by RSG and correlated to increases in capillary permeability in fat and body wt. RSG induced VEGF mRNA expression and PKC activation in fat and retina up to 2.5-fold. Ruboxistaurin, a PKCbeta isoform inhibitor, in the latter 2 wk of a 4-wk study, normalized vascular permeability in fat and decreased total wt gain, H2O content, and wt of fat vs. RSG alone but did not decrease VEGF expression, basal permeability, or food intake. Finally, RSG did not increase wt or vascular permeability in PKCbeta knockout vs. control mice. Thus, thiazolidinedione's effects on edema and wt are partially due to an adipose tissue-selective activation of PKC and vascular permeability that may be prevented by PKCbeta inhibition.

Adipose Tissue↗

Myofibroblasts in the stroma of metastatic pulmonary calcification in a patient with chronic renal failure.

We present a case of metastatic pulmonary calcification. Histologically, deposition of hematoxyphilic materials was seen along the alveolar and vessel walls. Fibrous tissues were also seen within the alveolar lumens, resulting in intra-alveolar fibrous pneumonia. Immunohistochemically, CD34-positive perivascular adventitial fibroblasts were seen in normal alveolar septa, whereas no myofibroblasts were observed. In contrast, perivascular adventitial fibroblasts were absent in the alveolar septa of the lesion of metastatic calcification, whereas many myofibroblasts were present in the fibrous tissue within alveolar lumens. No positive cells for TGF-(beta1) were observed in the lesion of metastatic calcification, but positive cells for PDGF-BB were focally seen in adveolar epithelial cells. Finally, many myofibroblasts appear in the alveolar lumens of metastatic pulmonary calcification, and we suggest that these myofibroblasts may be derived from CD34-positive perivascular adventitial fibroblasts and PDGF-BB may be involved in the pathogenesis of surrounding fibrosis.

Becaplermin↗

Intramolecular nitro-assisted proton transfer in photoirradiated 2-(2',4'-dinitrobenzyl)pyridine: polarized optical spectroscopic study and electronic structure calculations.

The nitro-assisted proton transfer (NAPT), responsible for the photoactivity of ortho-nitrobenzylpyridines and a model for the nitro-based caged compounds, is studied along with the parent compound 2-(2',4'-dinitrobenzyl)pyridine (DNBP) with polarized optical spectroscopy and theoretical calculations. The transition dipole moments of a DNBP single-crystal identified oriented molecules of the long-lived enamine tautomer (NH), rather than of the aci-nitro tautomer (OH), as carriers of the photoinduced blue coloration. It is clarified that the blue second singlet transition owes to intramolecular charge transfer from the allyl-pyridinium part to the dinitrophenyl fragment of NH. The theoretical modeling of the ground-state potential energy surface showed that while NH and OH can interconvert by means of direct proton transfer, such a process between the initial form CH and either OH and NH would require significant rotation of the aromatic rings. In the ground state, OH is less stable but the kinetically preferred product over NH. Once created, regardless of whether via ground-state or excited-state routes, the aci-nitro group of OH undergoes energetically inexpensive rotation to deliver the proton to the nitrogen acceptor. The "softening" of the energy surface around OH due to its structural flexibility, that is, mediation of the proton transfer by the nitro group, is crucial to overcome the high barrier for a direct proton jump from CH to NH, even in cases of unfavorable donor-acceptor geometry. The very small structural change experienced by the surrounding of a molecule undergoing NAPT is promising for the design of photoactive systems which retain their crystallinity during a prolonged operation.

Journal Article↗

Adenosine agonist regulation of outward active transport of fluorescein across retinal pigment epithelium in rabbits.

To investigate the effect of an adenosine agonist, 2-5'-N-ethylcarboxamidoadenosine (NECA), on the outward active transport of fluorescein across the retinal pigment epithelium (RPE) in rabbits. High (5x10(-4)-2x10(-3) M) and low (1x10(-5)-1x10(-4) M) concentrations of NECA or phosphate buffered saline (PBS) were intravitreously injected into Dutch-belted rabbits. Sodium fluorescein was injected intravenously 180 min after NECA. Differential vitreous fluorophotometry was performed 3 hr after the sodium fluorescein injection and the vitreal fluorescein/fluorescein monoglucuronide (F/FG) ratio then was calculated. The F/FG ratios are inversely proportional to the outward active transport of fluorescein across the RPE. Retinal detachments were induced by injection of PBS into the subretinal space after the intravitreous injection of low- or high-dose NECA or PBS, and the size of the blebs was monitored. In eyes that received a low-dose injection of NECA, the F/FG ratio was higher compared with controls (P<0.05); in eyes that received a high-dose intravitreal injection, the F/FG ratio was significantly lower compared with controls (P<0.05). The effect of low-dose NECA on the F/FG ratio was suppressed by the A2 receptor antagonist, ZM241385, and the effect of high-dose NECA was suppressed by the A1 receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthine. The A3 receptor antagonist MRS1191 did not influence the effect of low- or high-dose NECA. Intravitreal injection of high-dose NECA enhanced the reabsorption of subretinal fluid compared with PBS; however, low-dose NECA inhibited reabsorption of subretinal fluid (P<0.02 and 0.05, respectively). Intravitreous injection of high-dose NECA accelerates the active outward transport across the RPE via A1 receptors and low-dose NECA decelerates it via A2 receptors.

Adenosine↗

Effect of nucleotide P2Y2 receptor agonists on outward active transport of fluorescein across normal blood-retina barrier in rabbit.

BACKGROUND: To evaluate the effect of nucleotide P2Y(2) receptor agonists INS542 and uridine 5'-triphosphate (UTP) on the outward active transport of fluorescein across rabbit blood-retina barrier (BRB) in vivo. METHODS: Injection (0.1 ml) of INS542 (0.1 or 1mM), phosphate buffered solution, or UTP (1 or 10mM) was made in Dutch-belted rabbits. Differential vitreous fluorophotometry (DVF) was performed 3hr later and the fluorescein (F)/fluorescein monoglucuronide (FG) ratio was then calculated. F/FG ratios are inversely proportional to outward active transport of F across BRB at the level of the retinal pigment epithelium (RPE). In another set of experiments, the effect of 0.1 ml vitreous injection of INS542 (1mM) on F/FG ratios was evaluated at different time points ranging from 0.5 to 48hr before conducting DVF. RESULTS: F/FG ratios obtained 3hr after intravitreal injection were as follows (mean+/-standard error): 0.49+/-0.14 (0.1mM INS542), 0.19+/-0.04 (1mM INS542), 0.48+/-0.09 (PBS), 0.40+/-0.08 (1mM UTP) and 0.36+/-0.05 (10mM UTP). The F/FG ratio for 1mM INS542 was significantly lower than in the other groups (P<0.05). In the time course experiments, a significant decrease in the F/FG ratios was observed between 1 and 12hr following administration of INS542 when compared with F/FG ratios obtained in the contralateral (untreated) eye. CONCLUSION: Intravitreal administration of INS542 (but not UTP) enhances outward active transport of F across RPE in intact rabbit eye, indicating that activation of P2Y(2) receptors in vivo directly stimulates RPE active transport.

Animals↗

Analysis of lead in tooth enamel by laser ablation-inductively coupled plasma-mass spectrometry.

Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to determine the Pb/Ca ratios in the enamel of deciduous incisors, a biomarker of in utero Pb exposure, using pelletized bone certified reference materials (CRMs) as calibrants. The detection limit for Pb by LA-ICP-MS was 11 microg kg(-1) demonstrating an adequate sensitivity for Pb in the teeth of unexposed individuals (0.1-10 mg kg(-1)). The precision for the Pb/Ca ratios in NIST SRM 1486 Bone Meal was 3.4%. The correlation between Pb/Ca ratios obtained by LA-ICP-MS and those obtained by a digestion method was highly significant. We found one point calibration by a CRM was applicable for the quantification of Pb in tooth enamel. This method will be valuable for the assessment of in utero Pb exposure levels.

Adult↗

Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation.

Increases in leukostasis/monocyte adhesion to the capillary endothelium (leukostasis) and decreases in retinal blood flow may be causally associated and are implicated in the pathogenesis of diabetic retinopathy. In this study, we demonstrate that increases in leukostasis are observed in insulin-resistant states without diabetes, whereas decreases in retinal blood flow require diabetes and hyperglycemia. Microimpaction studies using beads mimicking retinal capillary obstruction by leukocytes did not affect retinal blood flow. In diabetic rats, treatment with the antioxidant alpha-lipoic acid normalized the amount of leukostasis but not retinal blood flow. In contrast, treatment with D-alpha-tocopherol and protein kinase-C beta-isoform inhibition (LY333531) prevented the increases in leukostasis and decreases in retinal blood flow in diabetic rats. Serum hydroxyperoxide, a marker of oxidative stress, was increased in diabetic rats, but normalized by treatment with antioxidants alpha-lipoic acid and D-alpha-tocopherol and, surprisingly, PKC beta-isoform inhibition. These findings suggest that leukostasis is associated with endothelial dysfunction, insulin resistance, and oxidative stress but is not related to retinal blood flow and is not sufficient to cause diabetic-like retinopathy. Moreover, treatment with PKC beta inhibition is effective to normalize diabetes or hyperglycemia-induced PKC beta-isoform activation and oxidative stress.

Animals↗

[A patient of recurrent orbital myositis with good response to high-dose intravenous immunoglobulin (i.v.-i.g.) therapy].

We report a 62-year old woman with orbital myositis who had a favorable response to intravenous immunoglobulin (i.v.-IG) administration in preventing disease recurrence. She had been suffering from frequent relapses of swelling and redness of the left eye with increasing pain and diplopia caused by restricted eye movement of the left eyeball. T2-weighted magnetic resonance image of the orbit showed enlargement of the left medial rectus muscle. She was treated with 1 g of methylprednisolone per day for 3 days. One mg/kg per day of oral prednisolone was subsequently started with non-steroid anti-inflammatory drugs, which resulted in improvement. However, her symptoms were aggravated while the drug was tapered off even though she used a high dose of oral prednisolone. High dose of i.v.-IG (400 mg/kg per day) was then administered for five days. Since the treatment, she has been free from recurrences of the disease for over one year, suggesting that i.v.-IG can prevent the recurrence of orbital myositis. Some reports have suggested that i.v.-IG treatment is useful to prevent recurrence of other forms of inflammatory myositis, such as dermatomyositis or polymositis. Overproduction of the pro-inflammatory cytokines (IL-1, IL-1 beta, INF-alpha) and Th1 cytokines (INF-gamma, IL-2) are related to the deterioration of these diseases. I.v.-IG treatment suppresses the production of the pro-inflammatory cytokines. In our case, serum levels of the pro-inflammatory cytokines were all normal, but the IL-4 level was elevated after the i.v.-IG treatment, suggesting that orbital myositis was probably related to the Th1 dominant disease that was suppressed by IL-4.

Dose-Response Relationship, Drug↗

Inhibitory effect of bucillamine on the increased leukocyte entrapment in the retinal microcirculation of diabetic rats.

PURPOSE: To evaluate quantitatively the effects of bucillamine on the entrapment of leukocytes in the retinal microcirculation of diabetic rats. METHODS: 13 male Brown Norway rats were injected with streptozotocin (STZ). After the animals developed diabetes, they were divided into two groups. Group 1 (n=7) received fresh drinking water without bucillamine, and group 2 (n=6) received fresh drinking water supplemented with bucillamine (200 mg/kg per day). Rats that were not injected with STZ and received water without bucillamine served as controls (n=6). Four weeks after the injection of STZ, the leukocytes in the retina were observed by acridine orange digital fluorography. The number of leukocytes trapped in the retinal vessels was compared among the three groups. RESULTS: In the untreated diabetic rats, the number of trapped leukocytes was significantly higher than in control rats or bucillamine-treated diabetic rats (P<0.05). CONCLUSIONS: We demonstrated an inhibitory effect of bucillamine on leukocyte entrapment in the retinal vessels of diabetic rats. Bucillamine may have therapeutic efficacy in preventing the development of diabetic retinopathy.

Animals↗

Effects of latanoprost on blood-retinal barrier permeability in rabbits.

PURPOSE: To investigate the effect of latanoprost (LP) on the inward and outward permeability (Pin and Pout) of the blood-retinal barrier (BRB). METHODS: Four New Zealand white rabbits received topical LP (0.005%) once daily for 3 weeks in one eye and phosphate-buffered saline (PBS) in the fellow eye (topical group). Five New Zealand white rabbits were injected intravitreously with LP (0.1 ml, 0.005%) in one eye and PBS (0.1 ml) in the fellow eye (injection group). In the injection group, vitreous fluorophotometry (VFP) to estimate the Pin and differential vitreous fluorophotometry (DVF) to estimate the Pout were performed 60 min after LP was injected. After the baseline measurements, VFP and DVF were performed 60 and 180 min after intravenous injection of sodium fluorescein, respectively. Fluorescein (F) and fluorescein monoglucuronide (FG) concentrations were obtained by DVF, and the F/FG ratio was calculated as an index of the Pout. RESULTS: In the topical group, there were no significant differences in the Pin or F/FG ratio between the LP- and the PBS-treated eyes. In the injection group, the Pin in the LP-treated eyes was significantly higher than in PBS-treated eyes (p < 0.05). There was no significant difference in the F/FG ratio between the two groups. CONCLUSION: Although we cannot exclude the effect of differences in species, the physiologic effect of LP, which increased the Pin, was seen in experimental studies. Because antiglaucoma drugs are generally used over an extended period, further clinical studies of the effect of LP on the BRB should be performed in patients who have BRB breakdown, such as in uveitis, and in patients who are pseudophakic and aphakic.

Administration, Topical↗