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Biomedical subjects

A Lev-Ran

Publications and source records attributed to A Lev-Ran.

At least 37 records · Page 2Linked to original sources
PubMed1990

Epidermal growth factor in serum, urine, submandibular glands and kidneys of diabetic mice.

Levels of epidermal growth factor (EGF) in serum were significantly decreased in streptozotocin (STZ)-diabetic mice (446 +/- 168 pg/ml after 1 week and 423 +/- 52 after 4 weeks vs 766 +/- 162 pg/ml in controls, P.002 and less than .001. respectively) and in genetically diabetic ob/ob mice (455 +/- 285 vs 962 +/- 453 pg/ml in nondiabetic ob/+ controls, P.043). The urinary excretion of EGF was significantly increased in STZ mice (104 +/- 53 vs 51 +/- 23 ng/h, P.013) but unchanged in ob/ob mice (33 +/- 9 vs 45 +/- 16 ng/h, P.134). However, when expressed per mg creatinine it was decreased in both cases: in STZ mice to 680 +/- 250 ng/mg at 1 week and 684 +/- 211 at 4 weeks vs 1250 +/- 303 ng/mg in controls (P less than .01); and in the ob/ob mice to 552 +/- 117 vs 1237 +/- 300 ng/mg in ob/+ controls (P less than .01). EGF content of the submandibular glands of STZ mice remained unchanged at 1 week (13.1 +/- 2.9 vs 11.0 +/- 1.8 micrograms/mg protein, P.170) but dropped by 4 weeks (4.7 +/- 1.2 micrograms/mg, P less than .001); in the ob/ob mice it was less than 20% that of controls (2.1 +/- 0.8 vs 12.2 +/- 3.6 micrograms/mg protein). In kidneys, the EGF content was not altered in either ob/ob (524 +/- 50 vs 571 +/- 33 pg/mg protein) or STZ mice (652 +/- 183 vs 665 +/- 80 pg/mg). The preproEGF mRNA level in STZ-treated mice was reduced after 4 weeks in submandibular glands but not in kidneys. The results show that diabetes affects EGF production, utilization and/or excretion in mice and that kidneys are spared from suppression of EGF synthesis that is pronounced in the submandibular glands.

Animals↗
PubMed1990

Hepatotoxicity induced by diethylnitrosamine causes no significant disturbances of systemic glucose homeostasis in rats.

In rats, a moderately hepatotoxic single dose of diethylnitrosamine (DEN) 100 mg/kg causing depletion of liver glycogen, elevation of aspartate aminotransferase and decreased liver uptake of 3-O-methylglucose, resulted in substantial changes in insulin and glucagon balance. Two days after DEN, insulin binding to liver membranes and insulin removal by the liver were sharply reduced whereas its binding to muscle and adipocyte membranes remained unaltered. Serum insulin (random and after an overnight fast) remained normal. Intravenous (I.V.) insulin (10 U/kg) caused the usual degree of hypoglycemia that, however, lasted longer than in the control animals. Removal of glucagon by liver was also depressed in spite of its normal binding to hepatocytes, and peripheral serum glucagon was increased three-fold. I.V. glucagon (40 micrograms/kg) resulted in a blunted response of plasma glucose. I.V. glucose tolerance test (1 g/kg) remained normal in spite of the insulin increase to a level twice as high as in the controls, and in spite of nonsuppressed glucagon. These changes were still present after 1-3 months, but disappeared by 6 months. The results demonstrate remarkable ability of homeostatic mechanisms to preserve normal plasma glucose and glucose tolerance in spite of dramatic changes in insulin and glucagon.

Animals↗
PubMed1990

Human serum and plasma have different sources of epidermal growth factor.

Epidermal growth factor (EGF) was determined by radioimmunoassay in serum, plasma, and urine of 23 patients undergoing ablative therapy followed by bone marrow transplantation. The difference between the serum and plasma values reflected the amount of EGF released from the platelets at the time of blood coagulation. Platelet-derived EGF strongly correlated with platelet count (r + 0.850, P less than 0.0001), and the intercept of the regression line was very close to zero; one platelet contained approximately 2.5 x 10(-18) g EGF. Correspondingly, when the platelet count dropped after bone marrow ablation from 222 +/- 97 to 33 +/- 13 x 10(9)/l, the serum EGF decreased from 603 +/- 222 to 65 +/- 41 pg/ml (P less than 0.0001). Plasma EGF content did not correlate with the platelet count and did not change significantly after bone marrow ablation (before and after the ablation, correspondingly, 290 +/- 80 and 332 +/- 99 pg/ml, P = 0.194). High-performance liquid chromatographic fractionation of serum and plasma showed different molecular mass distribution of EGF-immunoreactive fractions. The main molecular mass components of the plasma EGF did not change after bone marrow ablation. Urine excretion remained unchanged (320 +/- 133 and 314 +/- 173 pmol EGF/mmol creatinine). We conclude that whereas platelets are the source of serum EGF, the origin of plasma EGF is different and the search of its origin is warranted.

Adult↗
PubMed1990

Epidermal growth factor and platelet-derived growth factor in blood in diabetes mellitus.

Epidermal and platelet-derived growth factors are potent mitogens for many types of cells, including smooth muscle cells. Epidermal growth factor in blood of humans is present both in platelets (as reflected in its serum level) and in plasma, the source(s) of which remains unknown. We assayed its level in 82 diabetic patients and 53 age-matched controls. In diabetes, epidermal growth factor level was increased in serum (191 +/- 43 vs 155 +/- 64 pmol/l, p = 0.0002) and plasma (53 +/- 9 vs 38 +/- 14 pmol/l, p less than 0.0001), without any difference between the patients with and without complications. Platelet-derived growth factor level was assayed only in serum of 19 patients with uncomplicated diabetes and found elevated (222 +/- 47) as compared with 13 controls (160 +/- 26 pmol/l), (p = 0.0002). Type of diabetes, its duration, mode of therapy, control, presence of retinopathy or albuminuria (in case of epidermal growth factor), as well as C-peptide age and sex did not correlate with epidermal or platelet-derived growth factor levels. Serum but not plasma epidermal and platelet-derived growth factor were negatively correlated with serum creatinine (correspondingly, r = -0.373, p = 0.0008 and r = -0.564, p = 0.0285). It is concluded that diabetes itself and not its complications cause increased levels of epidermal growth factor in plasma and serum and of platelet-derived growth factor in serum.

Adult↗
PubMed1990

Epidermal growth factor in blood and urine of athyreotic adults.

The total contribution of the thyroid to epidermal growth factor (EGF) levels in blood and urine was determined in 18 patients cured from thyroid cancer at the time of thyroxine treatment and 6 weeks off it in the state of athyroidism. As compared to the euthyroid state, the athyrodism was associated with a drop in the urinary EGF excretion from 24.8 +/- 8.4 to 11.8 +/- 4.6 ng/mg creatinine (p less than 0.0001) and some increase in the EGF level in blood serum from 159.5 +/- 55.0 to 191.2 +/- 41.0 pM (p = 0.023). We conclude that the thyroid affects the synthesis and/or blood delivery of EGF and is responsible for approximately one half of its urinary excretion.

Adult↗
PubMed1990

Megakaryocyte synthesis is the source of epidermal growth factor in human platelets.

Epidermal growth factor (EGF) is known to be present in the alpha granules of human platelets; however the source of this EGF, ie, whether it is taken up by the platelets from the circulation, or whether it is packaged into the platelets from the megakaryocyte during thrombopoiesis, is unknown. To determine whether EGF is taken up by platelets, platelets for EGF receptors were assayed and it was attempted to detect uptake of EGF by the platelets from culture medium. Platelets were found to lack EGF receptors, and no uptake of EGF from the culture medium was detected. To assess whether EGF is packaged into platelets from the megakaryocyte, megakaryocytes in frozen section bone marrow cores were stained for EGF protein by immunohistochemistry, and it was demonstrated that EGF is present in megakaryocytes. In addition, staining of megakaryocytes by in situ hybridization for EGF mRNA demonstrated its presence in these cells. Therefore it is concluded that the source of EGF in human platelets is the megakaryocyte and that this EGF is synthesized in the megakaryocyte rather than being taken up from its environment.

Base Sequence↗
PubMed1989

Epidermal growth factor excretion and receptor binding in diabetic rats.

Urinary epidermal growth factor (EGF) excretion was calculated as ng EGF per mg creatinine and ng EGF per 24 hr. It was increased 4-9 fold in rats with genetic (BB) or streptozotocin-induced diabetes. It decreased to 2-3 fold control values in insulin-treated animals. In contrast, EGF concentration in serum was lower in diabetic than in control rats (360 +/- 72 vs 524 +/- 150 pg/ml, P .086); EGF level in plasma was unchanged (319 +/- 67 vs 313 +/- 96 pg/ml). In diabetic rats EGF content was increased in submaxillary glands (1018 +/- 259 vs 738 +/- 122 pg/mg protein, P .060) but unchanged in the kidneys (70 +/- 18 vs 65 +/- 6 pg/mg protein in controls). EGF binding to the liver microsomes in diabetic rats was decreased by 30-40% and was not restored by insulin therapy. Binding to the kidneys also showed a tendency to decrease in diabetic animals. The EGF excretion and receptor binding were normal in obese normoglycemic Zucker fa/fa rats. We suggest that hyperglycemia and/or glucosuria may affect EGF synthesis and/or excretion in the kidneys and EGF synthesis or accumulation in the megakaryocytes. The mechanism of decreased EGF receptor binding remains to be clarified.

Animals↗
PubMed1987

Hepatocarcinogens induce decrease in mRNA transcripts of receptors for insulin and epidermal growth factor in the rat liver.

Gene expression of the receptors for insulin and epidermal growth factor (EGF) was studied in the livers of rats after a single injection of a hepatocarcinogen diethylnitrosamine (DEN) 100 mg/kg or after feeding the animals N-acetylaminofluorene (AAF) 0.02% w/w. DEN induced a time-dependent decrease in mRNA transcription of the receptors for insulin (10.3 and 8.5 Kb) and EGF (10.0, 5.8 and 2.8 Kb), evident already after 4 hours, reaching a nadir of 10-20% of the initial level between 16 and 24 hours and returning to normal by 10 days. In rats fed AAF, transcription of both receptor genes decreased to less than 20% of the control values after 2 days. In the livers of rats treated with DEN, that developed hepatocellular carcinomas one year later, expression of both receptors was also very low. DNA showed no changes. The results suggest that the hepatocarcinogens or their metabolites decrease RNA transcription or destabilize the steady state RNA level of both receptors in the early phase of toxic effect and that some tumor-derived products may be involved in the same phenomenon in the later stage of tumor development.

Animals↗
PubMed1987

Insulin-like activity of chromium-binding fractions from brewer's yeast.

51CrCl3 was added to the incubation medium of Saccharomyces cerevisiae for up to 48 hr. After repeated freezing and thawing, lysing in 9 M urea with 1% NP-40 detergent, and dialysis against water, the lower molecular weight (Mr less than 3500) dialysate was retained on a SE53 cationic exchange column, eluted with 0.25 M NH4OH and fractionated on a Bio-gel P-2 column. The insulin-like biological activity of the fractions was measured by the 14C-glucose oxidation in isolated rat adipocytes. The biological activity that was found in two of nine fractions did not correspond to their chromium content. Moreover, identical findings were obtained when chromium was added not to the live yeast but to the yeast extract, which showed that its binding was a chemical process not requiring cellular activity. No fraction demonstrated insulin-potentiating activity on rat adipocytes.

Adipose Tissue↗
PubMed1986

Expression of epidermal growth factor receptors in human lung tumors.

Using the adjacent histologically normal tissues obtained from the same patients as controls, six human lung tumors were studied for the activities of epidermal growth factor (EGF) receptor binding, and receptor autophosphorylation. There was a 1.2- to 2.8-fold increase in EGF receptor activities in lung tumors due to an increase in the number of receptors without changes in their affinity. The increase had no direct correlation with the degree of differentiation or the type of lung tumors. The elevated expression of EGF receptor may be one of the characteristics in lung tumors. Epidermal growth factor and its receptor also may play a role in the regulatory mechanisms during tumorigenesis.

Adenocarcinoma↗
PubMed1986

Chromium-associated 32P-labeling of proteins.

The incubation of proteins with chromium (Cr3+ or Cr6+) in the presence of 32P ([gamma-32P]ATP or H3(32)PO4) at room temperature for 10-30 min resulted in the labeling of these proteins with 32P. The 32P-labeled proteins could be separated by SDS-polyacrylamide gel electrophoresis and identified by exposure to X-ray film. The characteristics of this procedure included: the optimal chromium concentration was 100 microM; the minimum requirement of each protein was 1 microgram; the optimal pH value was between 6 and 8; metal ions such as V5+, Mn2+ and Fe3+ strongly inhibited the effect of chromium, whereas Ca2+ and Mg2+ had little effect. It was concluded that chromium binds to the proteins and forms a complex with 32P to achieve the 32P-labeling of the proteins. This technique can be applied for the rapid preparation of 32P labels on protein markers for gel electrophoresis and for the identification of unknown protein species.

Autoradiography↗
PubMed1986

Decreased expression of liver epidermal growth factor receptors in rats with alloxan and streptozotocin diabetes.

Male rats (200 g) were rendered diabetic with one intraperitoneal injection of alloxan (150 mg/kg) or streptozotocin (60 mg/kg). In hyperglycemic animals within 3 hours after the injection, the binding of EGF to liver membranes decreased by 43-52%; the maximal drop was by 70% and persisted for the 20 days of the experiment. EGF receptors decreased in number with almost no changes in their affinity. Autophosphorylation of the receptors decreased parallel to the ligand binding. In animals that received lower doses and did not develop diabetes and in animals in whom diabetes was prevented by the injections of glucose (before alloxan) or nicotinamide (before streptozotocin) the binding of EGF to liver receptors remained normal. We conclude that the decreased expression of EGF receptors was caused by diabetes and not by the toxic effects of the diabetogenic compounds on the liver.

Animals↗
PubMed1986

Chronic treatment with phenobarbital decreases the expression of rat liver EGF and insulin receptors.

In male F-344 rats fed phenobarbital 0.05% with chow the binding of EGF to microsomal and Golgi liver fractions decreased after 2 weeks, dropped by more than 60% after one month and remained low for the following five months of the experiment. The binding of insulin remained stable for 2 weeks after which it decreased by half. In both cases the receptors decreased in number without changes in their affinity. Autophosphorylation of the receptors showed changes parallel to those of the binding of the ligands.

Animals↗
PubMed1986

In vitro effects of ethanolamine on insulin secretion.

The effects of ethanolamine on insulin secretion by the perfused rat pancreas were examined. During the second phase of glucose-induced insulin secretion 5-minute perfusions of ethanolamine at final concentrations of 0.1, 1 and 10 mM inhibited insulin release in a dose-related manner. When given throughout the experiment the highest dose of ethanolamine markedly suppressed both phases of glucose-induced insulin release. The inhibitory effect of ethanolamine was blunted in the presence of phentolamine. It is concluded that ethanolamine inhibits glucose-induced insulin secretion by the perfused rat pancreas and that alpha-adrenergic receptors play a role in its actions on insulin output.

Animals↗
PubMed1986

Binding of growth hormone to rat liver during experimental chemical hepatocarcinogenesis.

Male F-344 rats (180-200 g) received either a single injection of diethylnitrosamine (DEN) or continuous feeding with 2-acetylaminofluorene (AAF). DEN induced a decrease in the binding of human GH (hGH) to its hepatic Golgi receptors in a dose-dependent manner; the changes were due to a decrease in the number of hGH receptors without significant changes in their affinity. Thirty days after DEN, the binding of hGH returned to normal. After the administration of AAF, the binding of hGH increased owing to the greater number of binding sites, and this effect persisted for the 30-day period of the continuous AAF feeding. In three separate hepatocellular carcinomas, the hGH binding to the Golgi fraction of the tumors was only one quarter of the binding to the peritumorous tissues. We conclude that DEN and AAF, administered acutely for a short time, affect hepatic hGH receptors in a different way, but that hepatocellular carcinomas bind much less hGH than peritumorous or normal tissues. The results show that hepatocarcinogenesis encompasses changes in receptors belonging to different classes.

2-Acetylaminofluorene↗
PubMed1986

Insulin and epidermal growth factor receptors in rat liver after administration of the hepatocarcinogen 2-acetylaminofluorene: ligand binding and autophosphorylation.

The livers of male F344 rats which were fed 0.02% 2-acetylaminofluorene (2-AAF) for two days or more had decreased binding of insulin and epidermal growth factor (EGF) to their hepatic receptors in microsomal and Golgi fractions. Hepatic receptors which were partially purified from carcinogen-fed rats by Triton X-100 solubilization and wheat germ agglutinin affinity column chromatography also had decreased binding activity compared to receptors from normal rats. Scatchard analysis indicated that the decrease in insulin receptor binding was due to decreased receptor number whereas the change in EGF receptor binding was attributed to decreased receptor affinity. Insulin receptor phosphokinase activity was also decreased in 2-AAF-fed rats and correlated with the decrease in receptor binding. EGF receptor phosphokinase activity was unchanged in 2-AAF-fed rats when stimulated with a high concentration (1 microM) of EGF but was decreased when stimulated with low concentrations (0.01-0.1 microM) of EGF. No EGF or insulin competing activity for receptor binding was found using acid-ethanol extracts of 2-AAF-altered liver. These results suggest that 2-AAF causes different alterations in the insulin and EGF receptors of the rat liver.

2-Acetylaminofluorene↗
PubMed1986

Effects of diethylnitrosamine on hepatic receptor binding and autophosphorylation of epidermal growth factor and insulin in rats.

Carcinogen-mediated alterations in hepatic membrane growth factor receptor activity were investigated with the use of the hepatocarcinogen diethylnitrosamine [(DENA) CAS: 55-18-5]. For the separate assessment of carcinogen-induced acute membrane receptor changes from changes associated with carcinogen-mediated alterations in growth, the receptor activity was measured both acutely after, and several months after, a single ip dose of DENA in male F344 rats. An acute dose-dependent decrease was observed in ligand binding and autophosphorylation of the epidermal growth factor (EGF) and insulin receptor. Binding decreased sharply by 36 hours and recovered by 30 days in Golgi fractions and more slowly in plasma membranes. Scatchard analysis revealed a decrease in receptor number but not affinity. Chronic DENA administration also decreased insulin and EGF binding. Hepatocellular carcinomas, induced by single DENA injections 1 year previously, had decreased EGF receptor binding and autophosphorylation compared to those seen in age-matched controls and also less extensive insulin receptor changes. Single DENA doses thus have two effects: an acute reversible receptor change and a delayed, apparently permanent change associated with altered growth.

Animals↗