[Chemotherapy of relapsed AML and ALL].
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
K Nishikawa
Publications and source records attributed to K Nishikawa.
[A role of inhaled disodium cromoglycate in child asthma].
Inhalation of disodium clomoglycate (DSCG) is main therapy for childhood asthma in Japan. Regular inhalation of both DSCG and beta 2 stimulant is recommended for the treatment of severe asthma in the guideline which was made in 1993. Characteristic of childhood asthma such as retardation of growth and exercise-induced asthma is considered as an important view point in Japanese pediatric field. On the other hand inhalation of beclomethasone dipropionate (BDP) is used for the treatment of adult-hood asthma in Japan and WHO global storategy. In the future new treatment will be developed using both DSCG and BDP.
Administration, Inhalation↗
[Early liver cancer].
There is no definition for early liver cancers. However, solitary liver cancers smaller than 2 cm in diameter are defined as small liver cancers and this term is often used as the meaning of early cancers. Small liver cancers are diagnosed by US, US-guided biopsies, computed tomography (CT), magnetic resonance imaging (MRI), and angiography. They are successfully treated by percutaneous ethanol injection (PEI), subsegmental transcatheter arterial embolization (TAE), operations and percutaneous microwave coagulation therapy (PMCT), 3-years survival rates being more than 70%. The choice of treatments depends on the techniques available in each institute and liver function, since most cases are complicated with liver cirrhosis.
Electrocoagulation↗
[Tricuspid and mitral regurgitation due to congenital hypoplasia of atrioventricular valves in the aged: a case report].
A 76-year-old woman with a history of repeated right-sided cardiac failure during the past 2 years presented with tricuspid and mitral regurgitation due to congenital hypoplasia of atrioventricular valves. Two-dimensional echocardiography demonstrated enlarged right atrium and right ventricle, and discoaptation between the leaflets. Color Doppler echocardiography revealed severe tricuspid regurgitation through the gap between the leaflets. Autopsy showed congenital hypoplasia of the leaflets and the chordae tendineae in the tricuspid and mitral valvular apparatus.
Aged↗
Mutation in aspartic acid residues modifies catalytic and haemolytic activities of Bacillus cereus sphingomyelinase.
Four aspartic acid residues (Asp126, Asp156, Asp233 and Asp295) of Bacillus cereus sphingomyelinase (SMase) in the conservative regions were changed to glycine by in vitro mutagenesis, and the mutant SMases [D126G (Asp126-->Gly etc.), D156G, D233G and D295G] were produced in Bacillus brevis 47, a protein-producing strain. The sphingomyelin (SM)-hydrolysing activity of D295G was completely abolished and those of D126G and D156G were reduced by more than 80%, whereas that of D233G was not so profoundly affected. Two mutant enzymes (D126G and D156G) were purified and characterized further. The hydrolytic activities of D126G and D156G toward four phosphocholine-containing substrates with different hydrophobicities, SM, 2-hexadecanoylamino-4-nitrophenylphosphocholine(HNP), lysophosphatidylcholine (lysoPC) and p-nitro-phenylphosphocholine (p-NPPC), were compared with those of the wild-type. The activity of D126G toward water-soluble p-NPPC was comparable with that of the wild-type. On the other hand, D156G catalysed the hydrolysis of hydrophilic substrates such as HNP and p-NPPC more efficiently (> 4-fold) than the wild-type. These results suggested that Asp126 and Asp156, located in the highly conserved region, may well be involved in a substrate recognition process rather than catalytic action. Haemolytic activities of the mutant enzymes were found to be parallel with their SM-hydrolysing activities. Two regions, including the C-terminal region containing Asp295, were found to show considerable sequence identity with the corresponding regions of bovine pancreatic DNase I. Structural predictions indicated structural similarity between SMase and DNase I. An evolutionary relationship based on the catalytic function was suggested between the structures of these two phosphodiesterases.
Amino Acid Sequence↗
Molecular-dynamics studies on the shock-induced phase transition of a MgF2 crystal.
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Journal Article↗
Influence of spontaneous portosystemic collateral pathways on portal hemodynamics in living-related liver transplantation in children. Doppler ultrasonographic study.
We investigated the influence of spontaneous portosystemic collateral pathways on the portal hemodynamics and examined the necessity for ligating these vessels in pediatric liver transplantation from living donors. We assessed portal blood flow before, during, and after surgery in 82 pediatric recipients (mean age, 4.2 years), using Doppler ultrasonography. When blood flow in the reconstructed portal vein was decreased (< 10 ml/min/kg body weight) and portosystemic collaterals persisted during surgery, those vessels were ligated and Doppler flowmetry was examined again. Spontaneous portosystemic collaterals were detected at one or more sites in 67 patients before transplantation. These collaterals had been ligated in 17 patients before intraoperative flowmetry. Among the remaining 50 patients, initial Doppler studies revealed a decrease in portal blood flow in 22 patients. Nine patients had hepatofugal splenic venous flow and 6 had no significant flow signals from the intrahepatic portal vein. Ligation of collaterals resulted in a remarkable increase in portal blood flow in 20 patients, all of whom are alive. The remaining 2 patients died of graft failure due in part to portal hypoperfusion. On the other hand, the collaterals were not ligated in 24 patients because adequate portal blood flow was confirmed by intraoperative flowmetry. Postoperatively, flow signals from the unligated collateral vessels gradually diminished, but they still persisted in 3 patients at 12 months after transplantation. Hepatofugal blood flow through the portosystemic collateral pathways may persist after implantation of a normal graft. If the patent collaterals significantly reduce the effective portal blood flow, these vessels should be ligated in order to avoid graft failure.
Adolescent↗
Beneficial effect of CV-4151 (Isbogrel), a thromboxane A2 synthase inhibitor, in a rat middle cerebral artery thrombosis model.
Effects of thromboxane A2 (TXA2) synthase inhibitors (CV-4151 and ozagrel) on cerebral thrombosis and cerebral damage were examined in a rat middle cerebral artery (MCA) thrombosis model and their potencies were compared with the conventional antithrombotic agents, aspirin and ticlopidine. CV-4151 significantly inhibited photochemically induced MCA thrombosis by oral (1 and 10 mg/kg) and intravenous (1 mg/kg) administration. Ozagrel (10 mg/kg, p.o.) also inhibited it. The potency of CV-4151 was about 10 times stronger than that of ozagrel, being comparable with the inhibition of blood TXA2 generation. Aspirin (100 mg/kg, p.o.) and ticlopidine (300 mg/kg, p.o.) showed an inhibitory tendency on MCA thrombosis. Twenty-four h after photochemical stimulation, cerebral edema and cerebral infarction were observed, and the lactate content in the brain increased. CV-4151 and ozagrel prevented this edema, and the antiedema effects of the drugs were correlated with the antithrombotic effect on thrombotic MCA occlusion. CV-4151 (10 mg/kg, p.o.), furthermore, significantly reduced the infarct size and inhibited the increase in lactate content. These results indicate that TXA2 synthase inhibitors inhibit cerebral damage by inhibition of MCA occlusion with thrombosis, probably resulting from the inhibition of TXA2 generation, and their effects are superior to those of aspirin and ticlopidine. TXA2 might play an important role in cerebral damage in the MCA thrombosis model. CV-4151 might be a useful drug for the treatment of cerebral thrombosis and for the prevention of cerebral infarction.
Animals↗
Side-chain structure is critical for the transport of sterols from lysosomes to cytoplasm.
Macrophages take up and metabolize negatively charged liposomes containing free cholesterol efficiently, resulting in a massive accumulation of cholesteryl esters and triacylglycerols in their cytoplasm (Nishikawa, K., Arai, H. and Inoue, K. (1990) J. Biol. Chem. 265, 5226-5231). This system was used to assess the effects of structural variation of sterol on the intracellular transport and the metabolism of endocytosed sterols by the cells. Liposomes containing phytosterols with an extra one (campesterol) or two (beta-sitosterol, stigmasterol, fucosterol) carbons at the C-24 position of the cholesterol side-chain were endocytosed as efficiently as those containing cholesterol without exhibiting any apparent toxicity on the cells. Esterification of endocyotosed phytosterols was, however, extremely low; campesterol esterification was only 20% that of cholesterol and either beta-sitosterol or stigmasterol was not esterified appreciably. A morphological study showed that the endocytosed phytosterols were accumulated in the phagolysosomes of the cells. Blocking of esterification of endocytosed cholesterol by an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor did not lead to cholesterol accumulation in the phagolysosomes. These data suggest that accumulation of endocytosed phytosterols in phagolysosomes is not a consequence of the inability of the cell to esterify sterols in the endoplasmic reticulum. In the light of these observations, we conclude that cultured macrophages can discriminate between sterols that differ only by a methyl or ethyl group at the C-24 position at their lysosomal compartment.
Animals↗
Desk-top analysis of the structural stability of various point mutations introduced into ribonuclease H.
The structural stability of Escherichia coli ribonuclease HI mutants was analyzed by a pseudo-energy potential developed for evaluating structure-sequence compatibility. From the structure profile, the energy changes of the folding of mutant proteins relative to that of the wild-type, which correspond to the changes of free energy differences, were estimated. They are weakly but significantly correlated with the experimentally determined changes in the melting temperature between the mutant proteins and the wild-type. The correlation coefficient between the experimental data and the computation, estimated for all the known data (96 point mutations) and for the buried site data (32 point mutations), are -0.51 and -0.68, respectively. Experimentally known mechanisms to increase the structural stability are explained by the method: the main contributor to the stability in mutations of Val74 to either Ile or Leu is the side-chain packing energy, and that of Lys95 to Gly is the local conformational energy. This analysis is easy to do on a desk-top computer, and allows one to consider all the sites of possible candidates for point mutations. From the profile, new promising sites to increase the structural stability are suggested.
Computer Simulation↗
Highly specific and efficient cleavage of squid tRNA(Lys) catalyzed by magnesium ions.
Two lysine isoacceptor tRNAs corresponding to the codons AAA and AAG, respectively, were isolated from squid (Loligo bleekeri), and their nucleotide sequences were determined. During this analysis, we discovered that the tRNA with the anticodon CUU was efficiently cleaved at a specific site in the presence of magnesium ions, whereas the tRNA with the anticodon UUU was not. Cleavage occurred almost exclusively at the phosphodiester linkage between G15 and D16 (p16). The most remarkable feature of this cleavage reaction is that the end product was not a 2',3'-cyclic phosphate but was mainly a 3'-phosphate. Thus, this reaction was distinct from the well characterized cleavage of yeast tRNA(Phe) by lead and from reactions catalyzed by various other metalloribozymes. The presence of a cytidine residue at position 60 was required for efficient cleavage but was not crucial for the reaction, and the entire tRNA molecule had to be intact for this specific and efficient cleavage reaction. The present study provides evidence that there exists a new catalytic mechanism for cleavage of tRNA that exploits biologically ubiquitous ions rather than toxic, nonessential ions such as lead.
Animals↗
Exclusive expression of C. elegans osm-3 kinesin gene in chemosensory neurons open to the external environment.
In Caenorhabditis elegans three genetic loci osm-3, unc-104 and unc-116 have been identified, which encode anterograde motor kinesin. Here we show that osm-3 encodes a 672 amino acid long kinesin-like protein (KLP) that contains all three functional domains similar to the kinesin heavy chain, including a globular motor region, an alpha-helical coiled-coil rod, and a globular tail region. OSM-3 shows homology in both the motor and rod domains with kinesins from divergent species such as mouse KIF3, and sea urchin KRP95, and also with the rod domains of several non-kinesin proteins, such as myosin, ezrin, outer membrane proteins alpha precursor OMPA, yeast intracellular protein transport USO1, and the rat neurofilament NF-H. Temporal and spatial expression of the osm-3::lacZ fusion gene during development is limited to an exclusive set of 26 chemosensory neurons whose dendritic endings are exposed to the external environment, including six IL2 neurons of the inner labial sensilla, eight pairs of amphid neurons (ADF, ADL, ASE, ASG, ASH, ASI, ASJ, ASK) in the head, and two pairs of phasmid neurons (PHA and PHB) in the tail. Our data are consistent with the known structural defects in the amphid and phasmid sensilla in osm-3 mutants and also show the expression of the gene in IL2 neurons. Temporally, the gene is differentially expressed in all three types of chemosensory sensilla. Further work on osm-3, unc-104 and unc-116 mutants should give insight into the in vivo functions of the kinesin family during C. elegans neurogenesis.
Amino Acid Sequence↗
Effects of thromboxane A2 synthase inhibitors (CV-4151 and ozagrel), aspirin, and ticlopidine on the thrombosis caused by endothelial cell injury.
The antiplatelet and antithrombotic effects of CV-4151 (isbogrel), a potent selective thromboxane A2 (TXA2) synthase inhibitor, were compared with those of ozagrel (OKY-046), aspirin, and ticlopidine in rats. Two hours after oral administration, CV-4151, ozagrel and aspirin inhibited blood TXA2 generation with ID50 values of 0.04, 0.3 and 6.4 mg/kg, respectively. These values were similar to the oral ID50 values of CV-4151 (0.06 mg/kg), ozagrel (0.92 mg/kg) and aspirin (7.0 mg/kg) for arachidonic acid (AA)-induced platelet aggregation ex vivo. Two hours after p.o. administration, CV-4151 and ozagrel inhibited femoral vein platelet-rich thrombosis caused by endothelial injury with ID50 values of 2.46 and 13.7 mg/kg, respectively. However, aspirin (100 mg/kg, p.o.) only slightly inhibited the thrombosis. Ticlopidine (300 mg/kg, p.o.) slightly but significantly inhibited AA-induced and ADP-induced platelet aggregation, however, it potently inhibited the thrombosis. CV-4151 and ozagrel given by i.v. injection showed therapeutic effects on the thrombosis with ED50 values of 0.026 and 0.066 mg/kg, respectively. These values were similar to the i.v. ED50 values of CV-4151 (0.0056 mg/kg) and ozagrel (0.042 mg/kg) for blood TXA2 generation. However, aspirin (30 mg/kg, i.v.) only moderately reduced the thrombosis. CV-4151 (> 0.3 mg/kg, p.o.), ozagrel (> 3 mg/kg, p.o.) and ticlopidine (300 mg/kg, p.o.) all significantly prolonged tail bleeding time. Aspirin (100 mg/kg, p.o.) tended to prolong the bleeding time. The antiplatelet and antithrombotic effects of CV-4151 are more potent than those of ozagrel, aspirin and ticlopidine in rats. CV-4151 may therefore be a useful drug for the treatment of thrombotic diseases.
Animals↗
Trifluoroethanol-induced stabilization of the alpha-helical structure of beta-lactoglobulin: implication for non-hierarchical protein folding.
Trifluoroethanol (TFE) is known to stabilize the alpha-helical structure in proteins and their fragments. However, the relationship between the TFE-induced structures and the native structure is not clear. Here we show that beta-lactoglobulin, which consists predominantly of beta-sheets, exhibited a markedly high propensity to form an alpha-helical structure in the presence of TFE, as measured by far-UV circular dichroism. A cooperative transformation from the beta-sheet structure to an alpha-helical structure occurred at a TFE concentration between 10% and 20%. These results were in contrast to a gradual beta-sheet to alpha-helix transition of the constant fragment of the immunoglobulin light chain, which is also a beta-sheet protein. To understand the significance of the high helical propensity of beta-lactoglobulin, we measured the TFE-induced conformational transition of more than 20 proteins of various secondary structural types. Whereas the alpha-helical proteins showed a propensity to form an extensive helical structure in TFE, the helical propensity of proteins with a low helical content in the native state varied. The helical content in TFE was correlated more with the helical content predicted by a secondary structure prediction than with the helical content of the native structure, suggesting that the stability of the helical structure in TFE is determined by local interactions between nearby amino acid residues. Our results suggest that an alpha-helical intermediate can accumulate during the refolding process of beta-lactoglobulin and that a hierarchical model of protein folding is not necessarily true for some beta-sheet proteins including beta-lactoglobulin.
Animals↗
Evaluation of protective effects of prostaglandin E1 on ischemic liver damage with in vivo 31P-MR spectroscopy.
The cytoprotective effect of prostaglandins (PG) was evaluated by in vivo 31P MR spectroscopy. Twenty rabbits were divided into two groups; the control group given physiological saline, and the PG group given prostaglandin E1 (0.5 microgram/kg/min). Each solution was infused for 8 min, after which complete hepatic ischemia was induced for 20 min, followed by reperfusion for 40 min. During ischemia, beta-ATP decreased to 23.6% and 42.3%, phosphomonoester increased to 260% and 200% of their initial values in the control and the PG groups, respectively. Inorganic phosphate also increased. After reperfusion, beta-ATP recovered to 65.2% and 96.5%, phosphomonoester to 130% and 110%, inorganic phosphate to 140% and 120% in the control and PG groups, respectively. The changes during ischemia were significantly smaller and the recoveries during reperfusion were more complete in the PG group. These results may confirm the cytoprotective effect of prostaglandins by in vivo 31P-MR spectroscopy.
Adenosine Triphosphate↗
Assessment of a protein fold recognition method that takes into account four physicochemical properties: side-chain packing, solvation, hydrogen-bonding, and local conformation.
A protein fold recognition method was tested by the blind prediction of the structures of a set of proteins. The method evaluates the compatibility of an amino acid sequence with a three-dimensional structure using the four evaluation functions: side-chain packing, solvation, hydrogen-bonding, and local conformation functions. The structures of 14 proteins containing 19 sequences were predicted. The predictions were compared with the experimental structures. The experimental results showed that 9 of the 19 target sequences have known folds or portions of known folds. Among them, the folds of Klebsiella aerogenes urease beta subunit (KAUB) and pyruvate phosphate dikinase domain 4 (PPDK4) were successfully recognized; our method predicted that KAUB and PPDK4 would adopt the folds of macromomycin (Ig-fold) and phosphoribosylanthranilate isomerase:indoleglycerol-phosphate synthase (TIM barrel), respectively, and the experimental structure revealed that they actually adopt the predicted folds. The predictions for the other targets were not successful, but they often gave secondary structural patterns similar to those of the experimental structures.
Amino Acid Sequence↗
Mechanisms of biliary excretion of lithocholate-3-sulfate in Eisai hyperbilirubinemic rats (EHBR).
Biliary excretion of lithocholate-3-sulfate is markedly impaired in EHBR. To examine the mechanism of biliary lithocholate-3-sulfate excretion in EHBR, the effects of colchicine treatment, a vesicular transport inhibitor, and infusion of taurocholate and organic anions were studied in EHBR and Sprague-Dawley rats. Colchicine treatment and taurocholate infusion had no effect of biliary lithocholate-3-sulfate excretion in EHBR, suggesting that biliary lithocholate-3-sulfate excretion is not mediated by the vesicular transport or by the bile acid excretory pathway. In control Sprague-Dawley rats, both sulfobromophthalein and dibromosulfophthalein infusion inhibited biliary lithocholate-3-sulfate excretion. In contrast, in EHBR dibromosulfophthalein infusion inhibited biliary lithocholate-3-sulfate excretion but BSP infusion did not. Indocyanine green and pravastatin infusion did not affect biliary lithocholate-3-sulfate excretion but pravastatin infusion had no effect in EHBR. These findings indicate that, whether physiologically important or not, two of more excretory pathways for organic anions exist at the canalicular membrane other than the ATP-dependent one.
Animals↗
Two flavone 2'-glucosides from Scutellaria baicalensis.
Two new flavone glucosides, 5,2',6'-trihydroxy-6,7,8-trimethoxyflavone 2'-O-glucoside and 5,2',6'-trihydroxy-6,7-dimethoxyflavone 2'-O-glucoside were isolated from the aqueous methanol extract of the roots of Scutellaria baicalensis. From the extract, seven phenolics, 5,7,2',6'-terahydroxyflavone, 5,7,2',5'-tetrahydroxy-8,6'-dimethoxyflavone, skullcapflavone II, baicalin, baicalin methyl ester, wogonin 7-glucuronide and 3,5,7,2',6'-pentahydroxyflavanone were also isolated.
Flavonoids↗