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Biomedical subjects

A Karasik

Publications and source records attributed to A Karasik.

At least 37 records · Page 2Linked to original sources
PubMed1996

Necrobiosis lipoidica and diabetic control revisited.

Necrobiosis lipoidica diabeticorum is a rare skin disorder, usually considered a marker for diabetes mellitus. More than half of the patients with necrobiosis lipoidica diabeticorum have diabetes mellitus, but less than one per cent of diabetes mellitus patients have necrobiosis lipoidica diabeticorum. In the diabetes and dermatology literature, we find the position that there is no effect of glucose control on either the appearance of necrobiosis lipoidica diabeticorum or the clinical course of the lesion. We base our challenge to this position on a critical review of the original data. And conclude on the contrary, that necrobiosis lipoidica diabeticorum is usually associated with poor glucose control and that tighter glucose control, as currently practised, might improve or prevent the disorder.

Blood Glucose↗
PubMed1996

Increased insulin-like growth factor binding protein-2 (IGFBP-2) gene expression and protein production lead to high IGFBP-2 content in malignant ovarian cyst fluid.

Expression of insulin-like growth factor-I (IGF-I), its receptor and IGF-binding proteins (IGFBPs) by ovarian cancer cells and its mitogenic effect on these cells in vitro, suggest that IGF-I may have a role in regulation of human ovarian cancer. We have recently shown IGFBP-2 to be markedly elevated in malignant ovarian cyst fluid in vivo. To identify the origin of increased IGFBP-2 in these cyst fluids, the gene expression and protein content of IGFBP-2 were investigated in 14 malignant and four benign epithelial ovarian neoplasms. IGFBP-2 mRNA was detected in all ovarian specimens and was 2- to 30-fold higher in malignant than in benign neoplasms. Within the malignant tissues IGFBP-2 mRNA levels correlated with the aggressiveness of the tumour and were higher in invasive tumours than in those with borderline pathology. Southern blot analysis revealed no amplification of IGFBP-2 gene in the DNA samples from ovarian tumours regardless of their nature. IGFBP-2 was the major binding protein in tissue extracts, as measured by both Western ligand blotting and immunoblotting, and was significantly higher in malignant than in benign neoplasms. These findings were further supported by immunohistochemical detection of IGFBP-2 in tumour sections. Our data suggest that increased local production by the tumour in vivo is responsible for the increased IGFBP-2 levels in the cyst fluid bathing the ovarian malignancy. This may represent an autocrine regulatory mechanism for IGF-I proliferative effect of ovarian cancer.

Blotting, Northern↗
PubMed1996

Induction of apoptosis in MDA-231 cells by protein synthesis inhibitors is suppressed by multiple agents.

In the present study we investigated the ability of several diverse agents to inhibit MDA-231 cell death induced by two different protein synthesis inhibitors, cycloheximide (CHX) and ricin. Cell death was evaluated by several techniques: trypan blue staining, determination of the released lactic dehydrogenase, transmission electron microscopy, and DNA fragmentation. Results from DNA gel electrophoresis and electron microscopy suggest a mechanism of death by apoptosis which terminates in necrosis. Approximately 60% of cell death was induced either by a continuous exposure to 30 micrograms/ml CHX for 48 hr or by a 1-hr exposure to 250 pg/ml ricin followed by a subsequent incubation of 48 hr in the absence of the drug. Cell survival, in the protein synthesis-inhibited cells, was enhanced by the following diverse agents: the growth factors EGF (20 ng/ml) and IGF-1 (20 ng/ml), the protein kinase C activator 12-0-tetradecanoyl-phorbol-13-acetate (5 ng/ml), the protein kinase A activator 8-bromoadenosine 3':5'-cyclic monophosphate (650 micrograms/ml), the nuclease inhibitor aurintricarboxylic acid (100 micrograms/ml), and fetal bovine serum (5%). The survival agents that stimulated protein synthesis in the control untreated cells had no effect on the CHX-inhibited protein synthesis, which indicates that new protein synthesis is not required for cell survival. The same survival agents attenuated the continuous decrease in protein synthesis in the ricin-exposed cells; therefore, the involvement of new protein synthesis in the survival mechanism could not be excluded. The protein kinase C inhibitor staurosporine blocked, in a dose-dependent manner, the survival effect of 12-0-tetradecanoyl-phorbol-13-acetate and EGF, but not that of aurintricarboxyclic acid or fetal bovine serum, in the protein synthesis-inhibited cells. These results provide evidence for several distinctive pathways, the activation of which inhibits MDA-231 cell death induced by protein synthesis inhibitors. Some of these pathways involved activation of protein kinases, probably protein kinase C.

Alkaloids↗
PubMed1996

Insulin-like growth factor I and its binding proteins 3 and 4 are increased in Human inflammatory synovial fluid.

OBJECTIVE: To measure insulin-like growth factor I (IGF-I) and its binding proteins (IGFBP) in human synovial fluid (SF), as IGF-I resistance in the chondrocyte was implicated in the pathogenesis of inflammatory arthritis. METHODS: Ten patients with inflammatory arthritis and 7 controls were evaluated. IGF-I and IGFBP-3 were measured by radioimmunoassay while all IGFBP were evaluated by Western ligand blotting. RESULTS: Serum IGF-I did not differ between patients and controls (22.3 +/- 2.9 vs 22.0 +/- 3.0 nmol/l), while significantly higher values were found in inflammatory SF compared with noninflammatory SF (14.7 +/- 1.5 vs 10.2 +/- 1.2 nmol/l; p = 0.05). IGFBP-3 and IGFBP-4 were the most prominent bands found in inflammatory SF by Western ligand blotting. The 24 kDa IGFBP-4 band appeared faintly in 2 noninflammatory effusions and was nearly absent in others. IGFBP-3 levels in sera from the 2 groups did not differ (2.9 +/- 0.3 vs 2.5 +/- 0.3 mg/l), but were significantly higher in inflammatory compared with noninflammatory effusions (1.5 +/- 0.2 vs 0.9 +/- 0.2 mg/l; p = 0.05). CONCLUSION: The pattern of IGFBP in SF differs in inflammatory versus noninflammatory joints.

Adult↗
PubMed1996

Insulin-like growth factor-I and IGF binding protein-3 remain high after GnRH analogue therapy in girls with central precocious puberty.

OBJECTIVE: IGF-I rises in normal adolescence and in central precocious puberty (CPP), secondary to a rise in sex steroids and GH. The aim of this study was to examine changes in serum IGF-I and its major binding protein IGFBP-3 after pharmacological arrest of puberty. PATIENTS AND MEASUREMENTS: Ten girls diagnosed for CPP were evaluated before and during the first 3 months of GnRH analogue (GnRHa) therapy aimed at suppression of the gonadal axis. Serum IGF-I was measured by immunoradiometric assay (IRMA) and IGFBP-3 by both IRMA and Western ligand blotting (WLB). RESULTS: Serum IGF-I was markedly higher in patients with CPP as compared with age matched controls (48.8 +/- 6.5 vs 23.1 +/- 4.9 nmol/l, P < 0.01). While GnRHa therapy caused serum oestradiol levels to return to prepubertal levels in all 10 patients, serum IGF-I levels decreased only minimally after 1, 2 or 3 months of therapy (43.2 +/- 5.6, 42.3 +/- 6.4 and 44.1 +/- 7.2 nmol/l respectively). Serum IGFBP-3 levels as determined using IRMA were also higher in CPP compared with age matched controls (4.70 +/- 0.37 vs 3.71 +/- 0.42 mg/l, P < 0.01). These differences were also evident when measured by WLB. GnRHa therapy caused a small and insignificant decrease in serum IGFBP-3 levels after 1, 2 or 3 months of therapy (4.57 +/- 0.33, 4.48 +/- 0.4 and 4.42 +/- 0.3 mg/l respectively). CONCLUSIONS: The lack of suppression of both IGF-I and IGFBP-3, despite therapy which halts puberty and slows growth velocity, suggests that steroids may be involved in the induction of changes in the GH/IGF-I axis but not in their subsequent maintenance.

Blotting, Western↗
PubMed1995

Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1.

Tumor necrosis factor-alpha (TNF) has been suggested to be the mediator of insulin resistance in infection, tumor cachexia, and obesity. We have previously shown that TNF diminishes insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1). The current work examines potential mechanisms that mediate this event. TNF effect on IRS-1 in Fao hepatoma cells was not associated with a significant reduction in insulin receptor tyrosine kinase activity as measured in vitro but impaired the association of IRS-1 with phosphatidylinositol 3-kinase, localizing TNF impact to IRS-1. TNF did not increase protein-tyrosine phosphatase activity and protein-tyrosine phosphatase inhibition by vanadate did not change TNF effect on IRS-1 tyrosine phosphorylation, suggesting that protein-tyrosine phosphatases are not involved in this TNF effect. In contrast, TNF increased IRS-1 phosphorylation on serine residues, leading to a decrease in its electrophoretic mobility. TNF effect on IRS-1 tyrosine phosphorylation was not abolished by inhibiting protein kinase C using staurosporine, while inactivation of Ser/Thr phosphatases by calyculin A and okadaic acid mimicked it. Our data suggest that TNF induces serine phosphorylation of IRS-1 through inhibition of serine phosphatases or activation of serine kinases other than protein kinase C. This increased serine phosphorylation interferes with insulin-induced tyrosine phosphorylation of IRS-1 and impairs insulin action.

Alkaloids↗
PubMed1995

Multiple pathways are involved in protection of MCF-7 cells against death due to protein synthesis inhibition.

Previously we have shown that IGF-I protected MCF-7 cells against death induced by the protein synthesis inhibitor cycloheximide (CHX). In the present study we investigated the ability of protein kinase C activator 12-0-tetradecanoyl-phorbol-13-acetate (TPA), the protein kinase A activator 8-bromoadenosine 3'5'-cyclic monophosphate (Br-cAMP), and the enzyme inhibitor aurintricarboxylic acid (ATA) to protect MCF-7 cells against death, due to a continuous presence of CHX. Cell death was evaluated after 48 h of incubation by several techniques (trypan blue staining, release of lactic dehydrogenase, cellular ATP content, transmission electron microscopy, and DNA fragmentation). Apoptosis which terminates in necrosis, characterized this mode of cell death. TPA and ATA at optimal concentrations of 40 ng/ml and 100 micrograms/ml, respectively, reduced cell death to the control level (without CHX), while Br-cAMP at an optimal concentration of 650 micrograms/ml reduced cell death only partially. IGF-1, TPA, and ATA, which stimulated protein synthesis in the control MCF-7 cells, had no effect on protein synthesis in the CHX-treated cells, indicating that the survival effect is not due to new protein synthesis. The protein kinase C inhibitor staurosporine blocked the survival effect of TPA and IGF-1 in a dose-dependent manner, however did not affect the survival effect of ATA. The tyrosine kinase inhibitor genistein blocked the survival effect of IGF-1, but not that of TPA and ATA. Our results provide evidence for several distinctive pathways, the activation of which protects MCF-7 cells against death, due to protein synthesis inhibition.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Glyburide crosses the placenta in vivo in pregnant rats.

Non-insulin-dependent diabetes mellitus (NIDDM) is normally treated by oral hypoglycaemic agents, but their use is excluded during pregnancy because of their potential teratogenic and hypoglycaemic effects on the fetus. This caveat was recently questioned as glyburide was shown to cross an isolated cotyledon in vitro in insignificant amounts. In the present study, placental transport of glyburide in vivo was examined as an indispensable step towards clinical trials. Tritiated glyburide, C14 albumin or C14-labelled diazepam were injected into 13, 9 and 11 pregnant rats, respectively and the radioactivity was measured thereafter in maternal blood and in whole fetal extracts. The ratios between radioactivity in fetal tissue to that in maternal blood for glyburide (0.535 +/- 0.068) were similar to those of diazepam (0.641 +/- 0.057) which readily crosses the placenta. However, they differed significantly from those for albumin (0.048 +/- 0.0004) which does not cross. Moreover, glyburide in fetal tissue consistently reflected its concentration in maternal blood when measured at consecutive intervals after intravenous injection in the mother. In contrast, albumin in fetal tissue was low at all time points regardless of its levels in maternal blood when measured at different times after injection. These data suggest that glyburide crosses the placenta of pregnant rats and should therefore be considered with caution as a hypoglycaemic agent in the treatment of gestational diabetes.

Animals↗
PubMed1995

Controlled trial of high spermatic vein ligation for varicocele in infertile men.

OBJECTIVE: To determine whether high ligation is an effective treatment for infertile men with clinical varicocele. DESIGN: A randomized, controlled trial of high spermatic vein ligation was carried out. The patients were treated and observed for 3 years. SETTING: Infertility treatment clinic and andrology laboratory in a hospital. PATIENTS: Infertile men with abnormal semen analysis because of varicocele only. INTERVENTION: High ligation 1 year postrecruitment (group A) and at the beginning of the study (group B). RESULTS: Among the 20 couples in group A, 2 pregnancies (10%) were achieved within the 1st year of observation period. During the year after high ligation, there were 8 pregnancies (44.4%), and during the 2nd year after high ligation, there were 4 more pregnancies (22.2%). In group B, 15 pregnancies (60%) occurred within the 1st year after operation. Three pregnancies (12%) and 1 pregnancy (4%) occurred during the 2nd and 3rd year, respectively. After operation in all patients of both groups, there was significant improvement in semen parameters, regardless of pregnancy occurrence. The difference in pregnancy rate (PR) between the operated group B and nonoperated group A during the 1st year of study was found to be highly significant. CONCLUSIONS: It is concluded that in a population of infertile men presenting varicocele as the only demonstrable factor of infertility, the varicocele is clearly associated with infertility and reduced testicular function, and its correction by ligation improves sperm parameters and fertility rate. Furthermore, the highest PR in both groups occurred during the 1st year postoperation.

Adult↗
PubMed1995

Familial prolactinoma.

BACKGROUND: Apart from the rare association with type I multiple endocrine neoplasia (MEN-1), familial types of prolactinoma have not been reported. PATIENTS AND MEASUREMENTS: Eight hyperprolactinaemic patients in four families and 18 of their first and second-degree relatives (parents, children and grandchildren) were examined. Hormone levels were measured, as well as other biochemical parameters. RESULTS: Prolactinoma was diagnosed in more than one member of each of the four families. CONCLUSION: Familial prolactinoma is a distinct entity which is probably due to a genetic mutation promoting lactotroph proliferation.

Adolescent↗
PubMed1995

A cytosolic protein tyrosine kinase activity is induced by follicle stimulating hormone and insulin like growth factor-I in human granulosa cells.

Follicle stimulating hormone (FSH) induces estradiol (E2) production in rat, porcine and human granulosa cells with a concomitant increase in cAMP. In human granulosa cells insulin like growth factor-I (IGF-I) induces E2 production without cAMP accumulation. In the current study we report that IGF-I and FSH effects on aromatase activity both involve activation of a cytosolic soluble protein tyrosine kinase (CytPTK). This FSH and IGF-I stimulated CytPTK activity was blocked by AG-82 (a tyrosine kinase inhibitor) and by staurosporine (STS) (a non specific protein kinase inhibitor) at concentrations which inhibited E2 production. These new findings strengthen the concept of fail-safe mechanism in E2 production in human granulosa cells by an involvement of tyrosine kinase(s) activity downstream of cAMP formation and protein kinase A (PKA) activation.

Alkaloids↗
PubMed1995

Insulin-like growth factor-1 inhibits cell death induced by anticancer drugs in the MCF-7 cells: involvement of growth factors in drug resistance.

The involvement of growth factors in cell survival in the presence of anticancer drugs was investigated. Cell death was induced in the human breast cancer cell line MCF-7, by the structurally and mechanistically unrelated chemotherapeutic drugs puromycin, actinomycin D, 5-fluorouracil, cisplatin, and adriamycin. The effect of insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and insulin on cell death was evaluated by two different methods: (1) trypan blue dye exclusion test and (2) lactic dehydrogenase release into the culture medium. IGF-1 inhibited cell death induced by each of the diverse drugs in a concentration-dependent manner reaching a maximal effect at 40 ng/ml. Insulin mimicked the effect of IGF-1 only at supraphysiological concentration with an optimal effect at 10,000 ng/ml. EGF had no effect on cell death up to 100 ng/ml. Our finding that IGF-1 specifically enhanced MCF-7 cell survival in the presence of different anticancer drugs suggests the involvement of growth factors in the mechanism of drug resistance.

Antineoplastic Agents↗
PubMed1994

Effect of dexamethasone on the carbohydrate chains of the insulin receptor.

Dexamethasone treatment of IM-9 lymphocytes and Fao hepatoma cells resulted in an increase in synthesis of the insulin receptor. The receptors synthesized after stimulation with the glucocorticoid had altered carbohydrate structure. The carbohydrate side chains of the insulin receptor were less branched on the dexamethasone-treated cells; i.e., the ratio of saccharides with three and four branches to those bearing only two branches was decreased. The predominant polymannose oligosaccharide after dexamethasone treatment was Man9GlcNAc (vs Man6GlcNAc in the control cell). Both of these changes are consistent with a less complete processing of the N-linked carbohydrate units and were not observed for the total cellular glycoproteins, whereas all glycoproteins manifested an increased sialylation in Fao cells after dexamethasone treatment. These data indicate that glucocorticoid treatment results in alterations in branching of carbohydrate side chains, in the size of polymannose chains and in sialylation of the insulin receptor.

Animals↗
PubMed1994

Hyperinsulinemia induces a reversible impairment in insulin receptor function leading to diabetes in the sand rat model of non-insulin-dependent diabetes mellitus.

The insulin receptor was evaluated at different disease stages in the sand rat (Psammomys obesus), a model for nutrition-induced diabetes. Nondiabetic sand rats showed markedly low receptor number in liver compared with albino rats. Their receptor had an intact tyrosine kinase activity but a higher Km for ATP in the phosphorylation reaction of exogenous substrates. The initial effects of overeating (i.e., development of hyperinsulinemia without hyperglycemia) were associated in the sand rat with a dramatic decrease in in vitro and in vivo insulin-induced receptor tyrosine kinase activity in both liver and muscle. In muscle, this coincided with a decrease in receptor number and an increase in basal tyrosine kinase activity. Similar changes were observed upon development of hyperinsulinemia with hyperglycemia. Upon recovery from the diabetic state by diet restriction, the impaired receptor kinase activation was corrected. Complete restoration occurred only in animals that fully recovered from the diabetic state and became normoinsulinemic. These observations indicate that loss and gain of receptor tyrosine kinase activity were dependent on insulin levels. Thus, overeating may lead to the development of hyperinsulinemia through ineffective extraction of excess insulin by the scarce liver receptors. Hyperinsulinemia, in turn, causes a reversible reduction in receptor kinase activity, leading to insulin resistance. This sequence of events may be relevant to diet-related changes in human non-insulin-dependent diabetes mellitus.

Animals↗
PubMed1994

Epidermal growth factor and insulin-like growth factor-1 protect MDA-231 cells from death induced by actinomycin D: the involvement of growth factors in drug resistance.

In the present study, we investigated the ability of epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and insulin to protect the human breast cancer cell line MDA-231 from death induced by the antitumor drug actinomycin D (ACT-D). ACT-D is an inhibitor of RNA and protein synthesis, and its cytotoxicity may result due to continuous depletion in some vital protein molecules. Cell death was induced in the MDA-231 cells by either continuous exposure to a low dose of ACT-D (0.2 microgram/ml), or by a short-time exposure to a high dose of ACT-D (2 micrograms/ml) and further culturing in the absence of the drug. Cell death was evaluated by the trypan blue dye exclusion test, the release of lactic dehydrogenase into the culture medium, and the depletion in the cellular ATP content. EGF and IGF-1, each at an optimal concentration of 20 ng/ml, enhanced substantially survival of cells exposed either to a low or a high dose of ACT-D. The combination of EGF (10 ng/ml) and IGF-1 (10 ng/ml) had an additive survival effect, which proposes that each of the growth factors enhanced survival by a distinct pathway. Insulin up to 40 ng/ml had no effect on cell survival. Pretreatment of the cells for 1 to 5 h with EGF and IGF-1 protected cells from the cytotoxic effect of ACT-D. Exposure of the cells to 2 micrograms/ml of ACT-D for 1 h resulted in a drastic inhibition in uridine incorporation and only in a slight inhibition in leucine incorporation.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1994

Epidermal growth factor, phorbol esters, and aurintricarboxylic acid are survival factors for MDA-231 cells exposed to adriamycin.

The ability of epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin, 12-O-tetradecanoylphorbol-13-acetate (TPA), and aurintricarboxylic acid (ATA) to protect the human breast cancer cell line MDA-231 from death induced by the anticancer drug adriamycin was investigated. Cell death was induced in the MDA-231 cells either by a short-time exposure to a high dose of adriamycin (2 micrograms.ml-1.1h-1) and further culturing in the absence of the drug, or by continuous exposure to a low dose of adriamycin (0.3 micrograms/ml). Cell death was evaluated after 48 h of incubation by several techniques (trypan blue dye exclusion, lactic dehydrogenase activity, cellular ATP content, transmission electron microscopy, and DNA fragmentation). EGF, TPA, and ATA, each at an optimal concentration of 20 ng/ml, 5 ng/ml, and 100 micrograms/ml respectively, substantially enhanced survival of cells exposed either to a high or low dose of adriamycin. Neither IGF-1 nor insulin, each at concentrations of 20 ng/ml, had an effect on cell survival. The three survival factors enhanced protein synthesis in the untreated cells and attenuated the continuous decrease in protein synthesis in the adriamycin-treated cells. Moreover, the three survival factors protected the MDA-231 cells from death in the absence of protein synthesis (cycloheximide 30 micrograms/ml). These results suggest that EGF, TPA, and ATA promote survival of adriamycin pretreated cells by at least two mechanisms: enhancement of protein synthesis and by a protein synthesis independent process, probably a posttranslational modification effect.

Adenosine Triphosphate↗
PubMed1994

Vanadate has no effect on insulin-extraction by the rat liver.

The mechanism(s) responsible for the insulin-like effects of vanadate are still unclear, although several possible explanations have been raised. However, the possibility that vanadate induces inhibition of insulin degradation in the liver was not examined yet. Therefore, in the present study we examined the effect of vanadate on the extraction of insulin by the perfused rat liver using an open, non-recycling system. Baseline insulin extraction (44 +/- 2% and 37 +/- 3%) was not affected by the administration of 1 and 5 microM vanadate (decreased to 42 +/- 2% and 36 +/- 1, respectively, p = NS). Vanadate had no adverse effects on liver viability, and the bile flow remained stable during and after vanadate administration (0.87 +/- 0.08 microliter/min/g liver prior to Vs. 0.084 +/- 0.11 microliter/min/g liver following vanadate administration). This study shows that vanadate does not inhibit insulin extraction by the perfused liver, and that does of vanadate that effectively inhibit hepatic glucose production possess no adverse effects on liver viability.

Animals↗