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Biomedical subjects

Y Nagata

Publications and source records attributed to Y Nagata.

At least 343 records · Page 19Linked to original sources
PubMed1994

Effect of newly synthesized indole derivatives on multidrug resistance in human cancer cells.

Twenty indole derivatives were investigated for their ability to reverse multidrug resistance (MDR), for their ability to compete with [3H]azidopine in binding to P-glycoprotein (P-gp) and for their hydrophobicity. Six derivatives almost completely reversed the resistance to vincristine (VCR) in multidrug-resistant KB-C2 cells, and other derivatives partially overcame the resistance. The ability of the derivatives to enhance vincristine cytotoxicity did not significantly correlate with the inhibition of [3H]azidopine binding to P-gp or with their hydrophobicity. However, all the derivatives that inhibited > 50% of the photolabeling completely reversed VCR resistance. The 2-pyridyl group with a basic nitrogen atom attached at position 3 of indole in an appropriate spatial orientation seems to be an important feature for the interaction of the indole derivatives with P-gp. One of the derivatives, 1, which has low cytotoxicity and hydrophobicity, completely reversed the resistance of KB-C2 cells to Adriamycin, actinomycin D and VCR. Our data indicate that MDR-reversing indole derivatives with low cytotoxicity and hydrophobicity exist. These characteristics will surely be profitable for clinical use.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

[Simultaneous determination of catecholamines, serotonin, and their precursors and metabolites in body fluid by an HPLC system with multi-electrode electrochemical detector].

We have developed two HPLC systems for the simultaneous determination of CA, 5-HT and their precursors and metabolites in human body fluid. One system consisted of two reversed-phase columns, a column switching device, a pair of electrodes for elimination of interferents and two sets of new electrochemical detectors with four electrodes. Using this system, adequate separation of peaks for 17 kinds of CA, 5-HT and their related metabolites in a standard solution required only 17 min. NE, MHPG, DOPAC, 5-HIAA, HVA and TRP levels in cerebrospinal fluid (CSF) were determined without any pretreatment of the CSF samples. The concentrations of DOPAC, 5-HIAA and HVA in CSF were significantly lower in Alzheimer's disease, vascular dementia and Parkinson's disease than in the controls. The other system was developed for determination of CA acidic metabolites and 5-HIAA in human urine. This system consisted of a mixed-mode column (C18/anion) and 8-channel electrochemical detector with isocratic elution of citrate buffer. Detection limits, precision and analytical recoveries of this method were satisfactory for clinical use.

Aged↗
PubMed1994

Effects of dietary fat levels on the absorption and tissue accumulation of probucol in the rat.

The effects of dietary fat level on the absorption and tissue accumulation of probucol (PB, CAS 23288-49-5) were studied in male Wistar rats. Addition of 1% PB (w/w) to the diets as compared to the diets without an addition (P) resulted in a decrease in the concentration of both serum and high-density lipoprotein (HDL) cholesterol as well as TBA-reactive substances (TBARS), without influencing food intake or growth. When rats were fed with the PB diet, the apparent intestinal absorption of PB was 7.9%, while the serum PB level was 5 micrograms/ml. The tissue distribution of PB, when expressed per g of tissue, was highest in the adrenal glands, followed by the liver, heart, epididymal adipose tissues, kidneys, lung, spleen, and testes. The addition of 10% olive oil (PBO) to the PB diet (w/w) appeared to double the PB diet-induced increase in apparent intestinal absorption and the serum concentration of PB. Furthermore, compared with the PB diet, the PBO diet caused 3- to 4-fold higher accumulation of PB in the liver and its subcellular fractions and 2-fold higher accumulation in the spleen. However, there was no further accumulation of the drug in the heart, kidneys, lungs, and testes. Incorporation of the drugs into adipose tissues was significantly lower with the PBO diet than with the PB diet. These results suggest that dietary manipulation leads to changes in the intestinal absorption and serum level of PB.

Animals↗
PubMed1994

[Clinical results of breast conservation therapy; a radiotherapeutical viewpoint].

Between November 1987 and March 1993, 244 breasts in 243 patients underwent breast conserving therapy at Kyoto University Hospital. Clinically, there were 159 stage I and 85 stage II tumors. Pathological staging showed 216 stage I, 24 stage II, and 4 stage III tumors. All except 10 tumors were invasive ductal carcinomas. Eleven tumors were margin--positive by histopathological examinations. As surgical treatment, quadrantectomy or wide excision with complete axillary dissection was performed. Radiation therapy consisted of 50 Gy delivered to the whole breast by opposed tangential fields over 5 weeks using 60Co gamma rays. For patients with a positive margin, boost electron irradiation was given to a total of 10 Gy. We used the CT simulator for individualized optimization of the tangential fields. Prompt and accurate determination of the tangential portals was possible by using the simulator to determine various parameters, including beam angle and the head rotation angle. During follow-up for 2-66 months (median, 20 months), unrelated death occurred in 2 patients and distant metastases developed in 5 patients (bone 4, lung 1). However, neither local recurrence nor symptomatic radiation pneumonitis has occurred. The cumulative survival rate and the disease--free survival rate at five years were 95.2% and 91.8%, respectively. These promising clinical results of breast conservation therapy encourage further clinical trials.

Breast Neoplasms↗
PubMed1994

[Foscarnet for cytomegalovirus retinitis in a patient with acquired immunodeficiency syndrome].

A 41-year-old man with acquired immunodeficiency syndrome (AIDS) developed cytomegalovirus (CMV) retinitis. Intravenous administration of ganciclovir arrested progression of the retinitis, but it was discontinued due to side effects of severe anemia, neutropenia, and thrombocytopenia. Reactivation of CMV retinitis occurred two weeks after stopping ganciclovir, and then forscarnet was given intravenously. The response was prompt with resolution of the retinitis. There was no progression of retinitis during the treatment. The patient experienced renal dysfunction as a side effect of foscarnet, but it was reversible. As with ganciclovir, foscarnet appeared to be an effective drug for CMV retinitis associated with AIDS. Both drugs have severe adverse events: foscarnet causes renal dysfunction and ganciclovir causes myelosuppression, that necessitated discontinuation of the therapy. We suggest that alternating ganciclovir and foscarnet administration, switching to other treatment on the basis of the clinical response and side effects of the drugs, is an efficacious regimen for the treatment of CMV retinitis associated with AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1994

[Urinary extravasation: report of five cases and review of the Japanese literature].

We studied the etiology, diagnosis and management of 201 cases of urinary extravasation reported in the Japanese literature along with our five cases. Most of them were caused by urolithiasis and malignant tumors. Four of our five cases also presented with a ureter stone; two being cured by spontaneous stone passage within several days and the others being treated by ureterolithotomy or nephrectomy. The other case involving a ureter tumor was treated by nephroureterectomy with partial cystectomy. The clinical manifestations of urinary extravasation were distinguished as spontaneous peripelvic extravasation and spontaneous rupture of the renal pelvis and ureter. Performing an accurate and differential diagnosis of these cases, however, was difficult. We therefore propose a set of clinical diagnostic criteria based on our findings of X-ray examination and the macroscopic appearance seen during surgical treatment. We review the 201 reported cases along with our five cases of urinary extravasation and discuss their diagnostic procedures and treatment approaches.

Adult↗
PubMed1994

[Surgical treatment of arteriovenous malformations in the brain stem].

The authors report the surgical removal of four arteriovenous malformations (AVM's) in the brain stem causing hemorrhage. These included two intra-axial and two extra-axial AVM's. Three of the four were situated at the pons, and the remaining one in the posterior medullary velum. Complete surgical removal was obtained in the two extra-axial cases and in one of the intra-axial cases. The patient in whom complete removal was not obtained received partial embolization therapy with the remaining feeder being coagulated surgically. No patient was made permanently worse after surgery. One patient, in a comatose state on admission, died, while the remaining three patients showed useful recovery. These data indicate that surgical therapy with or without endovascular surgery appears to be possible for some AVM's and can be performed at an acceptable risk.

Adult↗
PubMed1994

Intraarterial infusion of autologous lymphocytes for the treatment of refractory lymphoedema. Preliminary report.

OBJECTIVE: To evaluate the results of the treatment of lymphoedema by intra-arterial infusion of autologous lymphocytes. DESIGN: Open study. SETTING: University Hospital. SUBJECTS: 13 patients with refractory lymphoedema. INTERVENTIONS: Lymphocytes were separated from the patient's own blood using a blood cell separator; about 100 cc of lymphocyte dominant blood separated from this blood was immediately infused into the proximal artery of the affected limb. Infusion was practiced once a week, and repeated 4 to 6 times. MAIN OUTCOME MEASURES: Change in size of the affected limb (defined as the difference between the affected limb and the normal limb after treatment), and softening of the edema (measured with a tension gauge). RESULTS: In all 13 patients there was softening of the affected hard limb followed by a reduction in the size of the limb (mean 64%), and the ache and sensation of heat in the limb lessened. The reduction in size was maintained in 9 of the 13 patients for three months, despite returning to their normal activities. CONCLUSION: Intra-arterial infusion of autologous lymphocytes is a promising treatment for refractory lymphoedema.

Adolescent↗
PubMed1993

Induction of erythroid-specific gene expression in lymphoid cells.

Erythropoietin (Epo) is a cytokine which specifically regulates differentiation and proliferation of erythroid progenitor cells. We report here that Epo receptor expressed in interleukin 3-dependent lymphoid Ba/F3 cells transmits both differentiation and growth signals. Epo stimulation of these cells leads to activation of transcription and/or translation of the erythroid-specific transcription factors GATA-1 and SCL, followed by the accumulation of both alpha- and beta-globin chains. These results suggest that expression and activation of the Epo receptor regulates erythroid-specific gene expression and might play a role in determining a cell lineage in vivo and that GATA-1 and SCL may exert their effects after Epo binds to its receptor. It was further found that chimeric receptors composed of extracellular domains of Epo receptor and cytoplasmic domains of interleukin 2 or interleukin 3 receptors could also induce erythroid-specific gene expression in Ba/F3 cells. Taking these data together with previous observations, we conclude that interaction of the extracellular domains of the Epo receptor with other membrane components is essential for transmission of both the erythroid differentiation and the growth signals.

Animals↗
PubMed1993

Acrodysostosis associated with spinal canal stenosis.

An adult case of acrodysostosis with striking lumbar spinal canal stenosis is reported. She complained of numbness on the right arm, intermittent claudication with numbness on both legs and pain and weakness on the left leg. Although the reduced lumbar interpedicular distance has been reported, no adult case with neurologic symptoms has been reported.

Adult↗
PubMed1993

Effects of NB-598, a potent squalene epoxidase inhibitor, on the apical membrane uptake of cholesterol and basolateral membrane secretion of lipids in Caco-2 cells.

Caco-2 cells grown on membrane filters were used as a model to study the effects of NB-598, an inhibitor of squalene epoxidase, on cholesterol absorption from the intestinal epithelia. NB-598 (10 microM) inhibited the synthesis of sterol and sterol ester from [14C]acetate without affecting the synthesis of other lipids such as phospholipids (PL), free fatty acids (FFA) and triacylglycerol (TG). When labeled lipid was apically loaded as a micellar lipid solution into Caco-2 cell cultures, NB-598 reduced basolaterally secreted radioactivity in cholesterol, cholesterol ester, PL and TG. Furthermore, NB-598 suppressed the basolateral secretion of apolipoprotein (apo) B. When microsomes prepared from control Caco-2 cells were incubated with 10 microM NB-598, acyl CoA:cholesterol acyltransferase (ACAT) activity was inhibited slightly. After incubating Caco-2 cells with 10 microM NB-598, a slight reduction in cellular ACAT activity was also observed. These results suggest that suppression of the secretion of particles containing apo B and reduction of cellular ACAT activity in the intestinal epithelia are part of the mechanism of the cholesterol-lowering effect of NB-598.

Anticholesteremic Agents↗
PubMed1993

Plasma glutathione peroxidase reduces phosphatidylcholine hydroperoxide.

The reducing activity of rat plasma glutathione peroxidase on phosphatidylcholine hydroperoxide (PC-OOH) and cholesteryl ester hydroperoxide (CE-OOH) was examined since these hydroperoxides are the major oxidation products of plasma. PC-OOH was reduced by the enzyme while CE-OOH was not. The reduction of PC-OOH by the enzyme ceased when all thiol was consumed, but the activity was recovered by the addition of glutathione, suggesting glutathione is important to keep the enzyme in the reduced form. These results are consistent with the findings that CE-OOH is present in human and rat plasmas while PC-OOH is undetectable and suggest that one of the physiological roles of the enzyme is to reduce PC-OOH.

Animals↗
PubMed1993

An inhibitor of squalene epoxidase, NB-598, suppresses the secretion of cholesterol and triacylglycerol and simultaneously reduces apolipoprotein B in HepG2 cells.

NB-598, a specific inhibitor of squalene epoxidase, suppressed the secretion of cholesterol and triacylglycerol from HepG2 cells into the medium. L-654,969, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, inhibited the secretion of cholesterol as potently as NB-598, but did not suppress the secretion of triacylglycerol. Both compounds decreased the intracellular cholesterol content almost equally, and neither of the compounds reduced the intracellular triacylglycerol content. The suppression of lipid secretion by NB-598 was associated with a significant reduction in apolipoprotein (apo) B secretion into the medium. Therefore, the suppression of lipid secretion by NB-598 may be caused by a reduction in the number of triacylglycerol-rich lipoprotein particles. In contrast, the suppression of cholesterol secretion by L-654,969 may be due to a modulation of lipoprotein lipid composition, since this agent did not reduce the secretion of apo B or triacylglycerol. The secretion of apo A-I was unaffected by either NB-598 or L-654,969. Pulse chase studies using [35S]methionine showed that the suppression of apo B secretion by NB-598 depended on an enhancement of intracellular degradation of apo B. These results indicate that the secretion of apo B from HepG2 cells is not regulated by the lipid synthesis alone, and suggest that the mechanism of the hypolipidemic effect of NB-598 involves the suppression of triacylglycerol-rich lipoprotein secretion from the liver as well as an inhibition of cholesterol synthesis in the liver.

Anticholesteremic Agents↗
PubMed1993

Erythropoietin receptor binds to Friend virus gp55 through other membrane components.

Direct interactions of Friend spleen focus-forming virus glycoprotein gp55 with either erythropoietin receptor (EpoR) or interleukin (IL)2 receptor beta chain (IL2R) (but not with IL3 receptor) have been reported to induce factor-independent prolonged proliferation of erythroid or lymphoid cells. In order to clarify the molecular mechanism by which EpoR-gp55 complex transmits an aberrant growth signal in the absence of erythropoietin, various chimeric receptors constituted with IL2R, EpoR or IL3 receptor were constructed. It was found that coexpression of gp55 and the chimeric receptors containing the cytoplasmic domains of EpoR and the extracellular domains of IL3 (or IL2) receptor in IL3-dependent Ba/F3 cells results in factor-independent growth. Since gp55 in cell membrane has only a two amino acid tail in the cytoplasmic domains and thus cannot interact with EpoR in cytoplasm, our data suggest that gp55 does not bind EpoR directly but interacts with EpoR through third membrane component(s).

Animals↗
PubMed1993

Relationship between the anti-HTLV-1 antibody level, the number of abnormal lymphocytes and the viral-genome dose in HTLV-1-infected individuals.

Two distinct diseases, adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), develop in a minor population of HTLV-1 carriers. We examined the relationship between the viral genome dose in the peripheral-blood mononuclear cells and the serological response in HTLV-1 carriers and patients with HAM/TSP. The antibody titer to HTLV-1 gag and env proteins, as well as the frequency of an antibody response to viral protein p40tax and the titer, increased with increasing viral genome dose. However, the number of abnormal lymphocytes was not directly related to the host viral load. Patients with HAM/TSP generally showed a higher genome dose than healthy carriers and also had higher antibody titers than healthy carriers with the same HTLV-1 load, supporting the existence of an augmented immune response in these patients. These findings suggest that the antibody titer to HTLV-1 genome products, and not the number of abnormal lymphocytes, intimately reflects the approximate viral load in HTLV-1-infected individuals.

Adolescent↗
PubMed1993

Tyrosine kinase activation through the extracellular domains of cytokine receptors.

Interaction of cytokines with their membrane receptors induces the proliferation and differentiation of a specific lineage of haematopoietic progenitors. The molecular mechanism of cytokine receptor-mediated signal transduction is unclear because these receptors do not have tyrosine kinase activity. Interleukin-3 and erythropoietin, however, induce transient tyrosine phosphorylation of a common set of proteins as a growth signal, and interleukin-2 induces phosphorylation of an overlapping but distinct set of proteins. Here we show that chimaeric receptors consisting of the extracellular domains of the erythropoietin receptor and the cytoplasmic domains of the interleukin-2 (or interleukin-3) receptor induce an erythropoietin-dependent tyrosine phosphorylation in interleukin-3-dependent Ba/F3 cells; however, chimaeric receptors composed of the extracellular domains of the interleukin-2 receptor and the cytoplasmic domains of the erythropoietin (or interleukin-3) receptor apparently transmit an interleukin-2-dependent signal. Our results indicate that these cytokines transmit distinct signals for activation of specific tyrosine kinases through the extracellular rather than cytoplasmic domains of the receptors.

Amino Acid Sequence↗