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Biomedical subjects

M Itakura

Publications and source records attributed to M Itakura.

At least 163 records · Page 9Linked to original sources
PubMed1990

Increased de novo purine synthesis by insulin through selective enzyme induction in primary cultured rat hepatocytes.

The proliferative effect of insulin on de novo purine synthesis and on the expression of various enzymes of purine metabolism were studied in primary cultured rat hepatocytes. Insulin greater than 1.5 x 10(-8) M increased DNA and de novo purine synthesis to 260-390 and 270-420%, respectively, 24 and 8 h after the administration. Insulin at 1.5 x 10(-7) M increased the specific activity of amidophosphoribosyltransferase (ATase) to 154-180%, hypoxanthine-guanine phosphoribosyltransferase to 129%, and adenine phosphoribosyltransferase (APRT) to 205%, in contrast to unchanged xanthine dehydrogenase at 80%. Enzyme induction was supported by the results of kinetic analysis and the inhibition of the insulin-induced increase in enzyme activities by protein synthesis inhibitors. Insulin increased ATP to 127% and decreased AMP, ADP, 5'-guanylic acid (GMP), and guanosine 5'-diphosphate (GDP), respectively, to 73, 69, 73, and 69%. Insulin increased adenylate energy charge from 0.83 to 0.90 without changing total feedback inhibitory potential on ATase. No obvious increase of 5-phosphoribosyl-1-pyrophosphate supply was suggested, although its apparent availability for purine ribonucleotide synthesis was increased to 208-245%, reflecting mainly induced APRT activity to 205%. It is concluded that hepatocyte proliferation by insulin, as evidenced by purine metabolism, is mediated by the selective gene activation of anabolic enzymes and increased ATP as the basis to activate multiple metabolic pathways without remarkable changes of substrate availability or feedback inhibition.

Adenine Phosphoribosyltransferase↗
PubMed1990

Successful treatment of a metastatic hormone-producing adrenal cancer by a combination of mitotane, tegafur and surgical resection.

A 34-year-old man had a huge hormone-producing adrenal cancer with multiple lung metastases, direct liver invasion and a tumor thrombus in the inferior vena cava. Initial treatment was mitotane alone. The dose of mitotane was 2 g/day initially and gradually increased to 15 g/day in combination with 600 mg of tegafur per day. During the initial phase of chemotherapy, the serum mitotane level was relatively low (2.9-4.6 micrograms/ml) and the pulmonary metastases tended to grow in size in spite of a gradual decline in urinary 17-KS and 17-OHCS and a regression of the primary tumor. A seemingly marked increase in serum mitotane (20.5-34.5 micrograms/ml) was coincident with the addition of tegafur. Rapid and consistent regression of the primary tumor occurred. This excellent response to the chemotherapy made the primary tumor with liver invasion and the metastases resectable. The adverse effect of mitotane, central nervous toxicity, appeared to be serum mitotane level dependent. The present results, together with previous reports in the literature, seem to recommend the following therapeutic approaches to advanced adrenal cancer: monitoring of the serum level may be useful in predicting the efficacy as well as the occurrence of side effects of mitotane, surgical treatment of the lesions should be performed whenever possible, even though it may be only palliative, and the combination of mitotane and tegafur is a choice of chemotherapy which should be evaluated in future studies.

17-alpha-Hydroxypregnenolone↗
PubMed1989

[Clinical investigation of plasma prostaglandin levels in patients with digestive cancers].

Plasma PGE2 level of 45 patients with digestive cancers, 10 patients with digestive benign diseases and 10 healthy controls were examined. Some patients were also examined plasma levels of TXB2, 6-keto-PGF1 alpha and PGF2 alpha. Plasma PGE2 level of digestive cancer patients (53.5 +/- 69.1 pg/ml, mean +/- SD) were about 10 times higher compared to healthy controls (5.2 +/- 3.8 pg/ml, p less than 0.01). Patients with digestive benign diseases also revealed elevated level of plasma PGE2, but the change of value were smaller than those of digestive cancer patients. Furthermore, in the case of digestive cancer patients, significantly elevated levels of TXB2 (49.7 +/- 60.3 pg/ml, p less than 0.05) and 6-keto-PGF1 alpha (33.9 +/- 31.5 pg/ml, p less than 0.01), and significantly reduced levels of PGF2 alpha (246 +/- 63 pg/ml, p less than 0.01) were noted. The changes in plasma prostaglandin levels of digestive cancer patients may reflect, even though prostaglandins are present in normal human body and are inactivated rapidly, the biological characteristics of tumors and in vivo reactions of the host.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Inorganic phosphate accelerates hemoglobin A1c synthesis.

The effects of inorganic phosphate (Pi), 2,3-diphosphoglycerate (2,3-DPG) and glucose-6-phosphate (G-6-P) on labile and stable hemoglobin A1c (HbA1c) synthesis were studied. After a 75 gram oral glucose administration, the rate of labile or stable HbA1c synthesis decreased in parallel to the decrease in plasma Pi concentrations. In in vitro incubations of red blood cell suspensions or hemoglobin preparations with glucose, Pi proportionally increased the rate of labile or stable HbA1c synthesis. The increase in 2,3-DPG caused by Pi explained only one fiftieth of the increased rate of labile HbA1c synthesis, and G-6-P did not affect HbA1c synthesis. The kinetic analysis of the effect of Pi showed the unchanged rate constant [K1], the decreased rate constant [K-1], and the increased rate constant [K2]. Based on these data it is concluded that Pi in its physiological range directly increases hemoglobin glycation by decreasing labile HbA1c dissociation and accelerating the Amadori rearrangement for stable HbA1c synthesis, and that Pi should be taken into account when using HbA1c to evaluate diabetic control.

2,3-Diphosphoglycerate↗
PubMed1989

[In vivo and in vitro studies on PGE2 production and function in human hepatocellular carcinoma].

In order to investigate the production of PGE2 and its' function in human hepatocellular carcinoma, the effects of indomethacin and PGE2 on tumor growth were examined using in vivo and in vitro techniques. HH2-6 cells produced PGE2 in the culture media, and the inverse relationship was observed in between the cell proliferation and the culture supernatant PGE2 levels. While in vivo, plasma and tumor tissue PGE2 levels of tumor bearing nude mice were significantly increased for 1 or 2 weeks after tumor inoculation. In the case of which indomethacin was injected daily into the abdominal cavity (4 mg/kg body weight), the elevation of plasma and tissue PGE2 levels was remarkably suppressed, and the latent time of tumor growth was also prolonged. On the other hand, another case of which PGE2 was injected (10 micrograms or 0.1 microgram i.p.) at first 10 days revealed shortened latent time. These results indicate the intimate relation between PGE2 and latent time on tumor growth. Furthermore, histological findings suggest that tumor derived PGE2 might play an important role in tumor angiogenesis.

Animals↗
PubMed1989

[A study of microproteinuria in patients with diabetes mellitus].

In order to investigate the early renal damage in diabetes mellitus, 89 diabetics without proteinuria by dipsticks and 67 normal control subjects were examined by means of SDS-PAGE. The relationships between electrophoretic patterns of urinary protein and duration of diabetes, age of patients, metabolic controls and stages of retinopathy were examined. 1) The percentage of higher molecular weight (MW) proteins (67,000 less than or equal to MW) was larger in diabetics than that in controls. Especially the percentage of proteins with MW between 67,000 and 94,000, which include transferrin was 13.9 +/- 6.9% in diabetics, significantly higher than that in controls (10.3 +/- 5.1%) (P less than 0.01). On the contrary, the percentage of low MW proteins (MW less than 67,000) was relatively small in diabetics. 2) The excretion of higher MW proteins increased until 16 years of diabetic duration, however that decreased after 16 years. Especially in the group with duration longer than 20 years, excretion of low MW proteins increased. 3) Electrophoretic patterns of urinary proteins in patients with good metabolic control were similar to those in normal controls. 4) Excretion of higher MW proteins increased in patients with retinopathic complication suggesting the progression to microangiopathy. From the above results, we concluded that increased excretion of higher MW proteins in diabetics may be the results of GBM damages in protein selectivity. In patients with longer history of diabetes, predominant excretion of urinary low MW proteins may be the result of tubular dysfunction due to macroangiopathy.

Adult↗
PubMed1988

Assessment of the relationship between serum thyroid hormone levels and peripheral metabolism in patients with anorexia nervosa.

It has been observed that basal and/or TRH-stimulated serum TSH levels occasionally conflict with the actual values of circulating thyroid hormones in patients with anorexia nervosa. In the present study sixteen female patients with anorexia nervosa during self-induced starvation displayed clinical findings suggesting hypothyroidism, e.g., cold intolerance, constipation, bradycardia, hypothermia and hypercholesterolemia in association with decreased serum total T3 (62.8 +/- 5.2 ng/dl) and T4 (6.6 +/- 0.3 micrograms/dl). Markedly decreased T3 correlated positively with average heart rate (r = 0.5655, P less than 0.025) and negatively with total cholesterol (r = -0.7413, P less than 0.005). This result may suggest that peripheral metabolic state of the underweight anorexics depends considerably upon the serum T3 concentration. Despite decreased total thyroid hormones, free T4 assayed by radioimmunoassay was normal in all five cases examined (1.4 +/- 0.2 ng/dl) and the free T4 index in fifteen cases was normal except in one case. Basal TSH was not increased and TSH response to exogenous TRH was not exaggerated in any. These results may be compatible with a theory that free T4 has a dominant influence on pituitary TSH secretion. Furthermore, glucocorticoids may also have some influence on depressed TSH response, because an inverse correlation between increased plasma cortisol and the sum of net TSH increase after TRH was observed in twelve cases examined. In conclusion, it is suggested that normal sensitivity of peripheral tissues and pituitary thyrotroph to different circulating thyroid hormones is maintained in anorexia nervosa patients even during severe self-induced starvation, and that the metabolic state in these patients is considerably under the influence of circulating T3.

Adolescent↗
PubMed1987

Increased adenylate energy charges in rat liver or primary cultured rat hepatocytes by diisopropyl 1,3-dithiol-2-ylidenemalonate.

Six hours after oral administration in rat liver, diisopropyl 1,3-dithiol-2-ylidenemalonate (malotilate) decreased AMP concentrations by 60% with unchanged total adenine nucleotide concentrations and significantly increased adenylate energy charges of 0.87 in comparison to those of 0.81 in vehicle administered control animals. Twelve hours after incubation in primary cultured rat hepatocytes, malotilate decreased AMP concentrations by 18% and increased ATP and GTP concentrations by 13 and 18% respectively with significantly increased adenylate energy charges of 0.89 in comparison to 0.87 in vehicle control. Increased adenylate energy charges by malotilate coincided with the initiation of increases in protein and de novo purine synthesis in vivo, and are associated with the increased rate of de novo purine synthesis in vitro.

Adenine Nucleotides↗
PubMed1987

Glucagon infusion increases rate of purine synthesis de novo in rat liver.

Based on the parallel increases of glucagon, the second peak of hepatic cAMP, and the rate of purine synthesis de novo in the prereplicative period in regenerating rat liver after a 70% hepatectomy, it was hypothesized that glucagon is responsible for the increased rate of purine synthesis de novo. To test this hypothesis, the effect of glucagon or dibutyryl cAMP infusion on the rate of purine synthesis de novo in rat liver was studied. Glucagon infusion but not insulin or glucose infusion increased the rate of purine synthesis de novo, which was assayed by [14C]glycine or [14C]formate incorporation, by 2.7- to 4.3-fold. Glucagon infusion increased cAMP concentrations by 4.9-fold and 5-phosphoribosyl-1-pyrophosphate concentrations by 1.5-fold in liver but did not change the specific activity of amidophosphoribosyltransferase (EC 2.4.2.14) or purine ribonucleotide concentrations. Dibutyryl cAMP infusion also increased the rate of purine synthesis de novo by 2.2- to 4.0-fold. Because glucagon infusion increased the rate of purine synthesis de novo in the presence of unchanged purine ribonucleotide concentrations, it is concluded that glucagon after infusion or in animals after a 70% hepatectomy is playing an anabolic role to increase the rate of purine synthesis de novo by increasing cAMP and 5-phosphoribosyl-1-pyrophosphate concentrations.

Amidophosphoribosyltransferase↗
PubMed1987

Effect of ethanol on sialidase activity of peripheral lymphocytes.

Sialidase activity of peripheral mononuclear cells, which are mostly lymphocytes, was found to be increased by lectin stimulations in in vitro experiments, but this induction was suppressed in the presence of 50 mM ethanol. This increasing change and its suppressive effect by lectins and ethanol were parallel to blastogenic change of the cells determined by 3H-thymidine uptake. In in vivo, sialidase activity of peripheral MNC prepared from patients with alcoholic liver disease was found to be decreased or not increased in 50% of the cases, in contrast to the marked increase of the activity in non-alcoholic liver diseases observed in our previous study.

Alcoholism↗
PubMed1986

Mechanism of increased rate of de novo purine biosynthesis in rat liver after bilateral adrenalectomy.

The incorporation of [14C]glycine to hepatic purines increased proving the increased rate of de novo purine biosynthesis in rat liver after bilateral adrenalectomy in comparison to sham-operated controls. In the liver of adrenalectomized animals 24 hours after adrenalectomy when the rate of de novo purine biosynthesis is increased above control by 70% there was a 200% increase of 5-phosphoribosyl 1-pyrophosphate (PRPP) concentration. The concentrations of purine ribonucleotides showed a 33 and a 24% decrease of ATP and GTP, and 245 and 38% increase of AMP and ADP respectively associated with the unchanged total adenine and guanine nucleotide concentration and a 18% decrease of adenylate energy charge. The specific activity of amidophosphoribosyltransferase (ATase) was not changed. The replacement with corticosterone acetate to adrenalectomized animals for 24 hours partially restored the rate of de novo purine biosynthesis and the concentrations of purine ribonucleotides. These results suggest that the increased rate of de novo purine biosynthesis in adrenalectomized rat liver is compensatory against the increased catabolism of purine ribonucleotides as a result of the increased AMP concentration and that it is mediated by the increased concentration of PRPP. Our study has demonstrated the importance of the physiological amount of adrenocortical hormone to sustain the normal concentrations and the metabolism of purine ribonucleotides in liver.

Adrenalectomy↗