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T Nonaka

Publications and source records attributed to T Nonaka.

At least 73 records · Page 4Linked to original sources
PubMed1997

Potency of truncated secretory leukoprotease inhibitor assessed in acute lung injury models in hamsters.

We evaluated the potency of truncated secretory leukoprotease inhibitor (truncated SLPI) in a human sputum elastase (HSE)-induced lung injury model and in a specific neutrophil-mediated acute lung injury model in hamsters. Intratracheal administration of HSE induced acute lung hemorrhage that could be measured by determination of the hemoglobin content in the bronchoalveolar lavage fluid. Intratracheal administration of truncated SLPI 1 hr before HSE administration inhibited acute lung hemorrhage in a dose-dependent manner (ED50 = 46.8 microg/kg), as did i.v. injection of the inhibitor given 2 min before HSE administration (ED50 = 14.7 mg/kg). Intratracheal administration of endotoxin (lipopolysaccharide) induced pulmonary neutrophilia. Twenty-four hours after lipopolysaccharide administration, the addition of formyl-methionyl-leucyl-phenylalanine resulted in a neutrophil-dependent acute lung injury that expressed an increase in hemoglobin content and in elastase-like activity in bronchoalveolar lavage fluids. In this model, lung injury was significantly attenuated by i.v. and intratracheal administration of truncated SLPI. These results suggest that truncated SLPI appears to be a good candidate inhibitor for the treatment of destructive lung diseases due to neutrophils.

Animals↗
PubMed1996

Crystal structures of the binary and ternary complexes of 7 alpha-hydroxysteroid dehydrogenase from Escherichia coli.

7 alpha-Hydroxysteroid dehydrogenase (7 alpha-HSDH;1 EC 1.1.1.159) is an NAD+-dependent oxidoreductase belonging to the short-chain dehydrogenase/reductase (SDR) 1 family. It catalyzes the dehydrogenation of a hydroxyl group at position 7 of the steroid skeleton of bile acids. The crystal structure of the binary (complexed with NAD+) complex of 7 alpha-HSDH has been solved at 2.3 A resolution by the multiple isomorphous replacement method. The structure of the ternary complex [the enzyme complexed with NADH, 7-oxoglycochenodeoxycholic acid (as a reaction product), and possibly partially glycochenodeoxycholic acid (as a substrate)] has been determined by a difference Fourier method at 1.8 A resolution. The enzyme 7 alpha-HSDH is an alpha/beta doubly wound protein having a Rossmann-fold domain for NAD (H) binding. Upon substrate binding, large conformation changes occur at the substrate binding loop (between the beta F strand and alpha G helix) and the C-terminal segment (residues 250-255). The variable amino acid sequences of the substrate-binding loop appear to be responsible for the wide variety of substrate specificities observed among the enzymes of the SDR family. The crystal structure of the ternary complex of 7 alpha-HSDH, which is the only structure available as the ternary complex among the enzymes of the SDR family, indicates that the highly conserved Tyr159 and Ser146 residues most probably directly interact with the hydroxyl group of the substrates although this observation cannot be definite due to an insufficiently characterized nature of the ternary complex. The strictly conserved Lys163 is hydrogen-bonded to both the 2'- and 3'-hydroxyl groups of the nicotinamide ribose of NAD(H). We propose a new catalytic mechanism possibly common to all the enzymes belonging to the SDR family in which a tyrosine residue (Tyr159) acts as a catalytic base and a serine residue (Ser146) plays a subsidiary role of stabilizing substrate binding.

Amino Acid Sequence↗
PubMed1996

The crystal structure of ribonuclease Rh from Rhizopus niveus at 2.0 A resolution.

The three-dimensional structure of ribonuclease Rh (RNase Rh), a new class of microbial ribonuclease from Rhizopus niveus, has been determined at 2.0 A resolution. The overall structure of RNase Rh is completely different from those of other previously studied RNases, such as RNase A from bovine pancreas and RNase T1 from Aspergillus oryzae. In the structure of RNase Rh, two histidine residues (His46 and His109) and one glutamic acid residue (Glu105), which were predicted to be critical to the activity from the chemical modification and mutagenesis experiments, are found to be located close together, constructing the active site. The indole ring of Trp49 plays an important role in preserving the active site structure by its stacking interactions with the imidazole ring of His 109, and by hydrogen bonding with the carboxyl group of Glu105. There exists a hydrophobic pocket around the active site, which contains the aromatic side-chain of Trp49 and Tyr57. The results of mutagenesis studies suggest that this pocket is the base binding site of the substrate.

Amino Acid Sequence↗
PubMed1996

Crystal structure of the ternary complex of mouse lung carbonyl reductase at 1.8 A resolution: the structural origin of coenzyme specificity in the short-chain dehydrogenase/reductase family.

BACKGROUND: Mouse lung carbonyl reductase (MLCR) is a member of the short-chain dehydrogenase/reductase (SDR) family. Although it uses both NADPH and NADH as coenzymes, the structural basis of its strong preference for NADPH is unknown. RESULTS: The crystal structure of the ternary complex of MLCR (with NADPH and 2-propanol) has been determined at 1.8 A resolution. This is the first three-dimensional structure of a carbonyl reductase, and MLCR is the first member of the SDR family to be solved in complex with NADPH (rather than NADH). Comparison of the MLCR ternary complex with three structures reported previously for enzymes of the SDR family (all crystallized as complexes with NADH) reveals a pair of basic residues (Lys17 and Arg39) making strong electrostatic interactions with the 2'-phosphate group of NADPH. This pair of residues is well conserved among the NADPH-preferring enzymes of the SDR family, but not among the NADH-preferring enzymes. In the latter, an aspartate side chain occupies the position of the two basic side chains. The aspartate residue, which would come into unacceptably close contact with the 2'-phosphate group of the adenosine moiety of NADPH, is replaced by a threonine or alanine in the primary sequences of NADPH-preferring enzymes of the SDR family. CONCLUSIONS: The cofactor preferences exhibited by the enzymes of the SDR family are mainly determined by the electrostatic environment surrounding the 2'-hydroxyl (or phosphate) group of the adenosine ribose moiety of NADH (or NADPH). Thus, positively charged and negatively charged environments correlate with preference for NADPH and NADH respectively.

1-Propanol↗
PubMed1996

Crystallization and preliminary X-ray crystallographic studies of 7alpha-hydroxysteroid dehydrogenase from Escherichia coli.

Crystals of 7alpha-hydroxysteroid dehydrogenase from E. coli, which is a tetramer in its active form, have been obtained by a hanging-drop vapor-diffusion method in the presence of the coenzyme NAD(+). Crystals as large as 0.25 x 0.25 x 0.75 mm could be grown within a month at pH 8.5 with polyethylene glycol as precipitating agent. Preliminary X-ray crystallographic analysis revealed that they belong to one of the enantiomorphic space groups P4(1)2(1)2 or P4(3)2(1)2 with dimensions a = b = 81.66 and c = 214.6 A, having two subunits in an asymmetric unit. The crystals diffract to at least 2.3 A resolution.

Journal Article↗
PubMed1996

Involvement of two basic residues (Lys-17 and Arg-39) of mouse lung carbonyl reductase in NADP(H)-binding and fatty acid activation: site-directed mutagenesis and kinetic analyses.

Mouse lung carbonyl reductase, a member of the short-chain dehydrogenase/reductase (SDR) family, shows a strong coenzyme preference for NADP(H) over NAD(H), and is uniquely activated by fatty acids. Previous chemical modification and X-ray crystallography studies show that interactions responsible for the coenzyme specificity include salt linkages between the 2'-phosphate of NADPH and side-chains of Lys-17 and Arg-39 of the enzyme. Although Arg-39 is highly conserved in NADP(H)-dependent enzymes of the SDR family, Lys-17 is substituted with Arg in about half of the NADP(H)-dependent enzymes. The present study shows that mutations of Lys-17 to His (K17H) or Ser (K17S) and of Arg-39 to Ala (R39A) bring about decreases (from 5 to 90-fold) of the affinities for NADP(H), but minor changes in the affinity for NAD+. The binding energy arising from the mutations on the binding of the 2'-phosphate of NADP+ was decreased by 38-66% from the value of 4.8 kcal/mol calculated for the wild-type enzyme. In contrast, the mutation of Lys-17 to Arg (K17R) had little effect on the kinetic or thermodynamic properties. The activation by fatty acids was completely attenuated by the mutations of K17H and K17S, but not by K17R or R39A. These results indicate that the 2'-phosphate group of NADP(H) is recognized by both Lys-17 and Arg-39, of which Lys-17 is a component of the binding site for the activator, probably interacting with the negatively charged carboxylate group of fatty acids, and also suggest that the existence of a positively charged residue (either Lys or Arg) at position 17 is required for both NADP(H) specificity of the SDR family enzymes and fatty acid activation of the pulmonary carbonyl reductase.

Alcohol Oxidoreductases↗
PubMed1996

Administration of truncated secretory leukoprotease inhibitor ameliorates bleomycin-induced pulmonary fibrosis in hamsters.

The purposes of this study were to investigate the effect of our recently developed truncated secretory leukoprotease inhibitor (SLPI) on bleomycin (BLM)-induced lung injury and fibrosis in hamsters, which is widely used as a model of interstitial pulmonary fibrosis, and to assess the possible involvement of neutrophil elastase in the pathogenesis of pulmonary fibrosis. The fibrosis model was prepared by administration of BLM (10 mg/kg) intratracheally to hamsters. The truncated SLPI was administered at a dose 5 or 15 mg/kg intraperitoneally twice a day only for 10 d starting from the time of BLM administration. BLM administration resulted in decreases in body weight and survival rate. Elastase activity in the supernatant of bronchoalveolar lavage (BAL) fluids was increased at 3 and 7 d after BLM administration in parallel with the increase in the number of neutrophils in the fluids. Histopathologically, at 14 and 28 d after BLM administration, diffuse thickening and fibrosis of alveolar walls with marked cell infiltration and severe distortion of alveolar structure, including honeycomb lung, were observed to have occurred. In this model, the decreases in body weight and survival rate and the increase in elastase activity were inhibited by the truncated SLPI dose-dependently, and pulmonary fibrosis was significantly ameliorated by the administration of this shortened form of SLPI. These results suggest that neutrophil elastase may be implicated in the pathogenesis of BLM-induced pulmonary fibrosis and that the truncated SLPI might be a promising therapeutic in the treatment of interstitial pulmonary fibrosis.

Animals↗
PubMed1996

The significance of artificial cerebrospinal fluid as perfusate and endoneurosurgery.

To compare the benefits of physiological saline solution and artificial cerebrospinal fluid (CSF) as perfusates, we investigated 12 patients with presumed symptomatic aqueductal stenosis by clinical course and CSF analysis. In all patients, endoneurosurgical third ventriculostomy and cine magnetic resonance imaging confirmed the patency of ventriculostomy. After endoneurosurgery, patients who received the saline solution experienced high fever, headaches, and elevated cell count in lumbar CSF. Saline solution provoked a striking inflammatory reaction in the CSF. In contrast, the artificial CSF reduced these conditions to a minimum. Artificial CSF used as a physiological perfusate during endoneurosurgery can suppress host reactions within the CSF pathway and is also available for routine neurosurgical procedures.

Adult↗
PubMed1996

[Distinctions of petroclival meningioma with perifocal edema on adjacent brain stem].

Although the most frequent benign tumor of the central nervous system, meningioma may be associated with extensive peritumoral edema. Whereas, peritumoral edema in the brain stem along the tumor in the infratentorial region has not been given sufficient recognition. Among 44 meningiomas attached to the petrous bone, 25 cerebellopontine angle meningiomas and 17 petroclival meningiomas, peritumoral edema in the brain stem along the tumor were clearly demonstrated on T2 weighted images of MRI in three petroclival meningiomas (6.8% of all clival and 17.6% of petroclival meningiomas). Attempts were made to surgically remove all of these tumors. However, during surgery an arachnoid/pial layer between the tumor and brain stem was destroyed completely and small perforating arteries were found to be encased in the tumor at the level of the associated edema. So surgical dissection of the tumors from the brain stem was quite difficult. By attempting radical removal of the tumor in the first case, even meticulous dissections caused direct surgical damage in the brain stem due to the obliteration of small perforating vessels. In the second case, a thin layer of the tumor remnant beside the brain stem was left intentionally, but a severe damage of the brain stem also occurred due to the obliteration of small perforating vessels. In the third case, only bulk reduction of the tumor was attempted to minimize the mass effect to the brain stem and the tumor located beside the brain stem with edema and encasing the cranial nerves and the perforating arteries from the vertebrobasilar artery was left untouched. This surgical attempt caused a transient worsening of a swallowing disturbance, but was not associated with the brain stem damage in this case. In meningiomas attached to the clivus, existence of associated peritumoral edema in the adjacent brain stem on T2 weighted images on MRI may be caused by the destruction of a arachnoid/pial layer and the encasement of small perforating vessels. The attempt at tumor dissection from the brain stem at the level of the edema was very difficult and led to serious surgical complications due to direct damage to the brain stem. In such cases, the surgery should aim at achieving a simple bulk reduction and the tumor beside the brain stem with edema should be left untouched.

Aged↗
PubMed1996

[Report of a case of intraosseous meningioma: a review of the literature and diagnostic value using MRI study].

A 40-year-old woman with intraosseous meningioma is reported. She was admitted because of a slowly growing, bony hard, fixed mass in the temporal area that was covered by the normal scalp. The neurological examination on admission was negative. Plain skull radiogram demonstrated an area of hyperostotic change in the temporal region. Bone-targeted CT demonstrated irregularity in the structure of the skull bone. Selective external carotid angiogram showed a homogeneous tumor stain in the region of the skull thickening. Macroscopically complete tumor resection (Simpson's grade 1) was carried out. Her postoperative course was uneventful. The skull tumor had the typical feature of meningotheliomatous meningioma. MRI showed a mass lesion of the temporal bone on T1- and T2-weighted images, and a well-enhanced mass lesion of the outer dura and outer table of the skull bone on Gd-DTPA enhanced T1 images. The findings of the preoperative MRI study using Gd-DTPA were identical with the tumor area on histological study. Therefore, MRI with Gd-DTPA enhancement was considered a useful diagnostic modality.

Adult↗
PubMed1996

[Characteristics of visual impairment complicated with planum sphenoidale and tuberculum sellae meningiomas and their surgical results].

It is well known that it is difficult to remove the planum sphenoidale and tuberculum sellae meningioma without damaging the optic nerves. The visual outcome after this operation has been unacceptable in such tumors, especially in large ones. This review propounds a strategy to secure visual acuity through operation. A total of eight cases are summarized. In five midline symmetrical meningiomas, the tumors compressed the nerves at the portion of the optic chiasma, causing a typical bitemporal hemianopsia. Four large tumors were resected by the frontobasal interhemispheric approach to minimize the intraoperative damage to the optic chiasma, and a small one was removed by the pterional approach. Visual deficits were recovered immediately after the operation in all cases without any surgical complications. Three meningiomas were attached to the lateral part of the planum sphenoidale or tuberculum sella. Although the sizes were relatively small in all cases, they caused ipsilateral severe visual loss by direct compression to optic nerves. MRI and three-dimensional CT angiography showed the tumor extension into the optic canal. The ipsilateral pterional approach was selected in these cases. To avoid additional nerve damage, we tried to reduce the tension of nerves which were compressed by the tumors. We removed the anterior clinoid process and opened the optic canal before surgical manipulation of the tumor. In two cases, tumors severely compressed the optic nerves from the medial side, and nerves were stretched laterally. Great care was required to separate the optic nerves from tumors in those two cases. In contrast, the resection seemed to be very easy in one of the cases where the optic nerve was displaced infero-medially. Visual symptoms were improved in all cases, although one case became worse temporarily. Although planum sphenoidale and tuberculum sellae meningiomas are still troublesome, appropriate preoperative management would allow us to expect an excellent visual outcome. Especially, selection of the surgical approach should be based on the anatomical analysis of the nerve displacement.

Adult↗
PubMed1996

[Obstruction of the true lumen by retrograde perfusion during repair of DeBakey type I aortic dissection: a case report].

Retrograde femoral perfusion is often used during the repair of DeBakey type I aortic dissections, however, it may cause serious ischemic damage of vital organs even though the arterial cannula is properly placed. A 58-year-old woman with chest pain was admitted to our hospital. She was operated on urgently because chest computed tomograms revealed that she suffered from a DeBakey type I aortic dissection. A ringed graft, 22 mm in diameter, was implanted into the ascending aorta using retrograde perfusion through the right femoral artery. Following the removal of the aortic cross-clamp and rewarming, the prosthetic graft remained flaccid and the heart failed to resume beating. We speculated that retrograde femoral perfusion caused the true lumen obstruction while distending the false lumen. This resulted in blocking reperfusion of the coronary arteries. After antegrade perfusion was initiated through an 8 mm Dacron graft which was anastmosed to the ringed graft, the heart soon resumed beating. During the repair of DeBakey type I aortic dissections, this serious complication should be anticipated. If it occurs, retrograde femoral perfusion must be exchanged for antegrade aortic perfusion before irreversible changes occur.

Aortic Dissection↗
PubMed1995

Effect of cyclic AMP on urokinase-type plasminogen activator receptor and fibrinolytic factors in a human osteoblast-like cell line.

We investigated the effect of cyclic AMP (cAMP) on the pericellular fibrinolytic system in NY cells. Dibutyryl cAMP (dbcAMP) or forskolin increased the level of urokinase-type plasminogen activator (u-PA) mRNA and enhanced the secretion of u-PA antigen into the conditioned medium. These agents also increased u-PA antigen on the cell surface. PA inhibitor-1 (PAI-1) antigen was inhibited by dbcAMP or forskolin. Butyrate had no effect on the production and secretion of u-PA and PAI-1. A binding assay of 125I-DFP-u-PA to NY cells revealed a single class of binding sites with a Kd of 3.85 nM and Bmax of 0.89.10(5) binding sites/cell. The Bmax was increased by dbcAMP (1 mM or 10 mM), forskolin (2 microM or 20 microM) of 1.0-, 1.4-, 1.2- and 1.8-fold, respectively. However, the Kd value was not changed. Furthermore, the level of mRNA for the u-PA receptor (u-PAR) was increased by these agents 1.2-, 1.7-, 1.8- and 2.5-fold, respectively. However, butyrate did not alter either the Bmax or the u-PAR mRNA level. These results indicated that the pericellular fibrinolytic activity induced by u-PA/u-PAR is modulated by cAMP in osteoblast-like cells.

Bucladesine↗
PubMed1995

Monovalent cation selective channel in the apical membrane of rat inner medullary collecting duct cells in primary culture.

Ion channels in the apical membrane of rat inner medullary collecting duct (IMCD) were investigated by the patch clamp technique. Owing to the histological heterogeneity of IMCD, cells were cultured from the lower half of the inner medulla of Wistar rat kidney. Channel activity was rarely seen in cell attached patch, but membrane excision activated multiple units of 28.2 +/- 0.7 pS cation selective channel. A Na or K selective channel was not found. The 28 pS channel showed membrane voltage dependency, no rectification, almost equal permeability to monovalent cations (Na/K/Li/Cs/Rb/NH4 = 1:1.00:0.82:0.97:1.10:1.71) and no significant permeation to anions or divalent cations. Calcium of the cytoplasmic side from 10(-7) M to 10(-4) M affected the mean number of open channels (nPo) dose-dependently in excised patch (IC50 = 5 x 10(-6) M). 1 mM of ATP, ADP, AMP and gadolinium reversibly suppressed nPo to near zero whereas amiloride, cAMP or cGMP had no effect. Multiple conductance substates were frequently observed. These results suggested that this channel belongs to the nonselective cation channels which has been identified in other epithelia and is not responsible for amiloride sensitive Na transport through IMCD cells.

Amiloride↗
PubMed1995

Characterization of a thermostable lysine-specific metalloendopeptidase from the fruiting bodies of a basidiomycete, Grifola frondosa.

A zinc-metalloendopeptidase, MEP, capable of catalyzing specific cleavage of acyl-lysine bonds (-X-Lys-) in polypeptides has been purified 212-fold in a yield of 24.7% from the fruiting bodies of Grifola frondosa, which is a popular edible mushroom called "MAITA-KE" in Japan. The purified enzyme consists of a single polypeptide chain with an apparent molecular mass of 20 kDa and a pI value of 7.46, contains 1 atom of zinc/molecule and can be inactivated with EDTA or 1,10-phenanthroline. Treatment of MEP with EDTA affords an apoenzyme, whose activity can be fully restored by the addition of Mn2+, Zn2+, Ca2+, or Co2+. Prominent features of MEP are its remarkable heat stability and its high affinity for beta-D-glucans and chitin. It hydrolyzes proteins maximally at pH 9-10, liberating only lysylpeptides. Polylysine and lysine copolymers with alanine, phenylalanine, or glutamic acid can serve as good substrates. Lysylalanine was liberated from bovine insulin and its oxidized B chain by the action of MEP. Mass spectrometric analysis by Frit-FAB MS of the fragments generated from horse heart cytochrome c presented unambiguous evidence to corroborate the specificity of MEP for acyl-lysine bonds.

Amino Acid Sequence↗
PubMed1995

Crystallization of mouse lung carbonyl reductase complexed with NADPH and analysis of symmetry of its tetrameric molecule.

Mouse lung carbonyl reductase (MLCR), which belongs to the short-chain dehydrogenase/reductase family, is an oxidoreductase involved in the metabolism of biogenic and xenobiotic carbonyl compounds. The crystals of MLCR complexed with its cofactor NADPH belong to a monoclinic space group P2(1) with dimensions a = 79.73 A, b = 105.5 A, c = 60.87 A, and beta = 91.43 degrees. X-ray diffraction data were collected up to 1.8 A resolution using a macromolecule-oriented Weissenberg camera at the Photon Factory synchrotron radiation source. Studies using a self-rotation function revealed the presence of a twofold rotational symmetry relating the subunits. This suggests that the tetrameric MLCR molecule has the 222 point group symmetry.

Alcohol Oxidoreductases↗