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Biomedical subjects

M Alemany

Publications and source records attributed to M Alemany.

At least 37 records · Page 2Linked to original sources
PubMed2001

Effect of oleoyl-estrone treatment on the expression of beta1- beta2- and beta3-adrenoreceptors in rat adipose tissues.

Adult female rats received a constant i.v. infusion of oleoyl-estrone (3.5 pmol/kg day) in a lipidic suspension for 14 days. On days 0 (no treatment), 3, 6, 10 and 14, as well as on day 14 for controls (receiving only the lipid); the rats were killed and the expression of the beta1-, beta2- and beta3-adrenoceptor genes, in brown adipose tissue and in subcutaneous and periovaric white adipose tissue, were measured by RNA protection assay, and compared with that of cyclophyllin. The beta3-adrenoceptor was the most expressed in all adipose tissues, whereas beta2 was the less expressed in brown adipose tissue. Oleoyl-estrone significantly, but moderately, increased the expression of beta-adrenoceptors in the three adipose tissues: beta1 increased in subcutaneous, beta2 and beta3 in periovaric and beta3 in brown adipose tissue. Oleoyl-estrone also decreased beta3 expression in subcutaneous white adipose tissue. On day 10, adipocytes isolated from periovaric white adipose tissue of oleoyl-estrone-treated rats showed higher cAMP response to an isoproterenol challenge than the controls. The mechanism by which oleoyl-estrone elicits the wasting of fat reserves could be mediated by adrenergic pathways, at least in part.

Adipose Tissue↗
PubMed2001

Modulation by leptin, insulin and corticosterone of oleoyl-estrone synthesis in cultured 3T3 L1 cells.

Preadipocytes (3T3 L1) were used between 7 and 14 days after differentiation; they were incubated with 44 nM 3H-esterone. The medium was supplemented with 1 microM recombinant murine leptin, 10 nM recombinant human insulin, or 1 microM corticosterone for up to 72 hr. In a second series of experiments, cells were incubated for 48 hr with different concentrations of leptin, insulin or corticosterone, and compared with controls (plain medium). Cells were harvested, washed in buffer and homogenized, and protein was measured. Lipid extracts of cell homogenates were used for HPLC; the label distribution in free and acylestrone peaks was measured. Overall uptake of estrone (i.e., the sum of free and acylestrone) by cells was not affected by leptin or corticosterone, but strongly reduced by insulin. Leptin and corticosterone increased the synthesis of acyl-esterone in a dose- and time-dependent way. Insulin decreased acyl-estrone synthesis at low concentrations and with little change over time. The results suggest that control of oleoyl-estrone deposition in adipocytes is modulated in at least two distinct steps: (a) estrone uptake, affected by insulin in the physiological range; and (b) synthesis of oleoyl-estrone from cell estrone. The latter may be affected by insulin, but leptin and corticosterone enhance the process.

3T3 Cells↗
PubMed2001

Daily oral oleoyl-estrone gavage induces a dose-dependent loss of fat in Wistar rats.

OBJECTIVE: To establish whether single daily oral doses of oleoyl-estrone result in dose-dependent slimming effects on normal weight rats, and to determine the changes in energy parameters induced by this treatment. RESEARCH METHODS AND PROCEDURES: The effects of a daily oral gavage of oleoyl-estrone (0, 0.2, 0.5, 1, 2, 5, 10, and 20 micromol/kg per day) in 0.2 ml of sunflower oil given over a 10-day period were studied in groups, each of which contained six adult female Wistar rats initially weighing 190 to 230 g. A group of intact control rats receiving no gavage was included for comparison. Body weight and food intake were measured daily. Rats were killed on day 10 of treatment, and body composition (protein nitrogen, lipids, and water), liver lipids, and plasma parameters (glucose, triacylglycerols, total cholesterol, free fatty acids, 3-hydroxybutyrate, urea, aspartate, alanine transaminases, insulin, leptin, and free and acyl-estrone) were measured. RESULTS: The administration of oleoyl-estrone resulted in a dose-dependent loss of body fat, because of a partly maintained energy expenditure combined with decreased food intake. The differences in the energy budget were met by internal fat pools. The changes recorded did not affect the levels of the main plasma energy homeostasis indicators: unaltered glucose, triacylglycerols, free fatty acids, 3hydroxybutyrate, and urea. Protein was accrued even under conditions of severe lipid store drainage. There were no changes in transaminases. No lipid accumulation was recorded in the liver. Plasma insulin and leptin levels decreased with increased oleoyl-estrone doses, whereas the levels of free and esterified estrone increased with treatment, although not in proportion to the dose received. DISCUSSION: Oral treatment with oleoyl-estrone resulted in the specific dose-related loss of fat reserves with little change to other metabolic parameters. These results agree with the postulated role of oleoyl-estrone as a ponderostat signal.

Adipose Tissue↗
PubMed2001

Short-term effects of a hypocaloric diet on nitrogen excretion in morbid obese women.

OBJECTIVE: To determine whether the daily pattern of urine excretion of N wastes is affected by obesity and very low-calorie diets (VLCD). DESIGN: The plasma amino acid, urea and other energy parameters, as well as the urinary excretion of total nitrogen, urea and creatinine were studied in obese and normal-weight women. The obese women's data were obtained under hospital basal controlled conditions (8.1 MJ/day) and after 3 days of VLCD diet (1.9 MJ/day) controls were studied only once (5.8 MJ/day). The hourly excretion patterns of total N, urea and creatinine were determined from the composition of each bladder voiding. SUBJECTS: Twenty morbidly obese and 10 age-matched normal-weight control women. RESULTS: Plasma amino acid levels were higher in obese women, which showed a limited ability to metabolize amino acid hydrocarbon skeletons. Neither differences in the patterns between groups nor total 24 h values for urine volume were found. Total N and urea excretion diminished under VLCD diet. Hourly creatinine excretion showed a flat pattern and was higher in obese women than in the controls, VLCD diet diminished the amount of creatinine excreted in 24 h. CONCLUSIONS: The early change in energy availability that the creatinine excretion figures reflect may result from the energy conservation mechanisms induced in response to energy restriction. The early onset of this effect (3 days, and the extent of decrease (approximately 19%) also suggest that the impact of VLCD on the muscle energy budget of the obese is more marked than usually assumed.

Adult↗
PubMed2001

Anomalous lipoproteins in obese Zucker rats.

AIMS: Obesity is characterized by dislipoproteinaemia with increased cholesterol and triacylglycerol levels and lower chylomicra disposal rates. We studied here whether these alterations were related to lipoprotein number and/or size and composition. METHODS: Plasma from lean and obese Zucker rats was fractionated into lipoprotein classes (chylomicra, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL)) by differential centrifugation. The apoprotein and lipid composition of each fraction were measured. Lipoprotein particle size was estimated by dynamic light scattering and used to tabulate the mean diameter and volume of lipoprotein micelles. Particle mass was calculated from the density and volume. The mass of lipids and protein in each fraction/ml of plasma allowed the estimation of mean particle concentration and then the number of molecules of lipid and protein/unit of lipoprotein micelle. RESULTS: A large part of hyperlipidaemia of obese rats is due to the accumulation of chylomicra: 1.3 +/- 0.2 mg/ml in lean rats [LR] (34% of all lipoproteins) and 8.2 +/- 0.9 mg/ml in the obese rats [OR] (66% of all lipoproteins). Lipid percentage composition of lipoproteins was similar in both groups. The particle size of LDL and HDL was much higher in OR than in LR: LDLs weighed 31.1 +/- 7.5 ag (LR) vs. 273 +/- 81 ag (OR), and HDLs weighed 31.7 +/- 12.6 ag (LR) and 375 +/- 103 ag (OR). In chylomicra and VLDL there was a relative scarcity of apoproteins in OR compared with LR. The whole architecture of LDLs is altered in OR, with a predominance of surface lipids: phospholipid and free cholesterol, and lower amounts of core lipids: triacylglycerols and cholesterol esters, with surface/core lipids ratios of 0.74 (LR) and 1.89 (OR). The consequences of anomalous LDL and HDL composition, size and overall structure may result in magnified lipoprotein metabolism alterations that hamper their ability to transfer apolipoproteins to larger chylomicra and VLDL, and to alter cholesterol transfer and binding of their apoproteins to cell surface receptors. The smaller number of LDL and HDL particles may further compound these difficulties and thus change the free to esterified cholesterol ratios observed in OR. CONCLUSIONS: The main conclusions of this study are the key importance of chylomicron analysis for a better understanding of the transfer of lipids, and the altered lipoprotein size and apoprotein distribution in obese rats, which seriously hamper cholesterol interchange, resulting in hypercholesterolaemia, and thus triggering even more far-reaching consequences for the well-being of the obese.

Analysis of Variance↗
PubMed2001

Oral gavage of oleoyl-oestrone has a stronger effect on body weight in male Zucker obese rats than in female.

This study was carried out to determine the effect of sex and oral administration of oleoyl-oestrone on body weight of 12-week-old female and male Zucker obese (fa/fa) rats initially weighing 350-380 g and 405-420 g, respectively. The rats were maintained in standard conditions and given a daily oral gavage of 0.2 ml oleoyl-oestrone dissolved in sunflower oil at a dose of 10 micromol/kg/day for 10 days, and their body weight and food intake was monitored. They were then killed, and their carcass composition (water, lipid, protein and total energy), liver lipids and glycogen and plasma chemistry, insulin, free and total oestrone were measured. Oral administration of oleoyl-oestrone via gavage resulted in significant losses of fat, energy and-ultimately-weight. Treatment with oleoyl-oestrone decreased food intake; the energy expenditure was kept close to that of controls at the expense of internal fat stores. Nevertheless, body protein and plasma metabolite homeostasis were preserved. The slimming effects were more marked in males than in females. Treatment increased circulating acyl-oestrone and reduced to normal levels the high insulin observed in controls. Treatment of genetically obese rats with a daily oral gavage of oleoyl-oestrone resulted in the loss of fat reserves with little modification of other metabolic parameters, except for lower plasma glucose and insulin levels. The results suggest that oleoyl-oestrone, in addition to its slimming effects may be effective as an antidiabetic agent in type 2 diabetes.

Administration, Oral↗
PubMed2001

Modulation of corticosterone availability to white adipose tissue of lean and obese Zucker rats by corticosteroid-binding globulin.

Corticosterone-binding (CB) capacity was determined in periovarian and subcutaneous white adipose tissue (WAT), as well as in plasma of lean and obese Zucker rats. In lean rats, plasma CB was twice the level of obese rats. In lean rat WAT, dexamethasone binding accounted for only 0.05-0.09% of corticosterone binding, and aldosterone bound even less; in the obese rats, dexamethasone accounted for 0.2 - 0.3 % of corticosterone binding. Scatchard plots showed that KD for corticosterone was 3.1 nM (WAT) or 3.4 nM (plasma) in lean rats and 1.8 nM (WAT) or 1.5 nM (plasma) in obese rats. The total CB capacity in WAT was lower in the obese than in lean rats (47-50%). Plasma non-esterified fatty acid levels were higher in obese rats. The results suggest that CBG may limit the access of glucocorticoids to adipocytes more weakly in obese rats because of the lower CBG. Fatty acids may increase the affinity of CBG for corticosterone, which would make WAT cells less accessible to circulating glucocorticoids. The modulation of CBG by fatty acids may protect fat reserves by decreasing the sensitivity of WAT to glucocorticoids.

Adipose Tissue↗
PubMed2001

Lipoprotein lipase and cholesterol transfer activities of lean and obese Zucker rats.

Adult female lean and obese Zucker rats maintained under standard conditions were used for the estimation of plasma, liver and white adipose tissue (WAT) activity of lipoprotein lipase, plasma and liver hepatic lipase and plasma lecithin-cholesterol acyltransferase. No differences in plasma or tissue levels of lipoprotein lipase between lean and obese rats were detected, but the larger WAT size of the obese rats resulted in higher lipase activity per unit of rat weight. Hepatic lipase levels in plasma were higher in the obese, but in liver, the higher activity was found in lean rats. No significant differences were found for lecithin-cholesterol acyltransferase activity, except when the levels in the HDL fraction were expressed per unit of protein weight, showing lower activity in the obese rats. In conclusion, the essentially maintained enzyme activities in obese rat tissues suggest that they cannot explain the deficient lipoproteins processing of obese rats, and, consequently their dislipidaemia.

Adipose Tissue↗
PubMed2001

Leptin concentrations do not correlate with fat mass nor with metabolic risk factors in morbidly obese females.

AIMS: To investigate the determinants of leptinemia in a cohort of morbid obese females compared to those of normal weight and mild-to-moderate obesity, and the relationships between leptin and metabolic derangements associated with obesity. METHODS: Recruited females were: moderately obese [n=44; body mass index (BMI) 25-40 kg/m2], morbidly obese (n=34; BMI > or = 40 kg/m2) and normal weight volunteers (n=12; BMI 19-25 kg/m2). Fat mass assessed by bioelectrical impedance and fat distribution by waist-to-hip ratio (WHR) were determined in all subjects. Biochemical determinations included plasma leptin, lipoprotein profile, fasting insulin and cortisol. RESULTS: Plasma leptin values were significantly increased in morbid obese patients (54.95 +/- 1.8 ng/ml) compared to those moderately obese (30.2 +/- 1.7 ng/ml; p<0.001) and to controls (9.77 +/- 1.4 ng/ml; p<0.001). Fat and age-adjusted leptin values were not different between groups. When subjects with a BMI <40 kg/m2 were considered, plasma leptin was significantly and positively related to anthropometric variables (BMI, percentage body fat and WHR), total cholesterol, LDL-cholesterol, plasma triglycerides, AST, ALT and uric acid; and negatively with HDL-cholesterol. In contrast, when morbidly obese patients were analyzed separately, no relationships were observed between leptin concentrations and BMI, percentage of adiposity or biochemical variables. For obese patients no significant differences were observed in the adjusted leptin values with respect to the presence of diabetes, dyslipidemia or hypertension. CONCLUSIONS: In morbidly obese women, the plasma leptin concentrations, although increased, do not reflect the amount of adipose stores, and as such, factors other than simply adiposity need to be invoked to explain the variation in leptin values.

Adipose Tissue↗
PubMed2001

Comparison of the effects of human erythrocyte ghosts and intact erythrocytes on platelet interactions with subendothelium in flowing blood.

We investigated whether ghosts behaved similarly to intact erythrocytes to maintain regular primary hemostasis under flow conditions. To this end we performed perfusion experiments with whole blood in which erythrocytes were replaced by pink ghosts, and platelet interaction with the subendothelial surface of a damaged vessel was morphometrically evaluated. The same objective was sought by means of studies with a platelet function analyzer (PFA-100(TM) instrument). Perfusions performed with control blood reconstituted with intact erythrocytes gave rise to 0.4+/-0.2% contact but not spread platelets, 10.8+/-3.4% adhering and spread platelets, 16.3+/-4.6% platelets in thrombi, with 27.5+/-7.4% of the surface covered. Even though the average diameter of the ghosts was smaller than that of intact erythrocytes (5.3 microm vs. 7.7 microm), the values obtained in perfusions performed with ghosts were similar to those of the erythrocyte controls. Studies performed with the PFA-100(TM) analyzer were consistent with those observed in perfusion studies. The viscosity of control blood was compared with that of blood reconstituted with ghosts. At shear rates lower than 450 s(-1), the viscosity of the ghost samples was higher than that of the controls, but the difference progressively decreased as shear rate increased up to 750 s(-1) (3.61+/-0.15 and 3.71+/-0.17 cP, respectively). In conclusion, the results of our study showed that ghosts behaved similarly to intact erythrocytes in maintaining a normal platelet interaction with digested subendothelium, under conditions of moderate shear rate and constant hematocrit (40%). The rheological activity of ghosts, bodies that are metabolically less active, was sufficient for them to satisfactorily act as substitutes for intact erythrocytes in our system.

Blood Viscosity↗
PubMed2000

Dual structural requirements for multilineage hematopoietic-suppressive activity of chemokine-derived peptides.

Many chemokines have direct suppressive activity in vitro and in vivo on primitive hematopoietic cells. However, few chemokine-derived peptides have shown a significant activity in inhibiting hematopoiesis. Interestingly, a peptide derived from the 34-58 sequence of the CXC chemokine platelet factor 4 (PF4) produced a 30-40% inhibition of proliferation of murine hematopoietic progenitors (CFU-MK, CFU-GM, and BFU-E) in vitro, at concentrations of 30-60-fold lower than PF4. The aim of the present work was to define the structural parameters and motifs involved in conferring biological activity to the peptide PF4(34-58). Both structural predictions and determinations revealed a new helical motif that was further localized between residues 38 and 46. This helix was necessary for binding of the peptide and for permitting the functional DLQ motif at position 54-56 to activate the putative receptor site. Peptides lacking either the helical or the DLQ motif were devoid of inhibitory activity on the hematopoietic progenitors in vitro. However, among inactive peptides, only those having the helical motif counteracted the inhibition induced by the active peptide PF4(34-58). This suggested that the helix might be required for peptide interactions with a putative receptor site, whereas the DLQ motif would be implicated in the activation of this receptor. These results identify for the first time the dual requirements for the design of chemokine-derived peptides with high suppressive activity on hematopoiesis, as well as for the design of molecules with antagonistic action.

Amino Acid Motifs↗
PubMed2000

Oleoyl-estrone induces the massive loss of body weight in Zucker fa/fa rats fed a high-energy hyperlipidic diet.

To test whether oleoyl-estrone plus a hyperlipidic diet affects body weight in Zucker fa/fa rats, 13-week-old male Zucker obese (fa/fa) rats initially weighing 440-470 g were used. They were fed for 15 days with a powdered hyperlipidic diet (16.97 MJ/kg metabolizable energy) in which 46.6% was lipid-derived and 16.1% was protein-derived energy and containing 1.23 +/- 0.39 µmol/kg of fatty-acyl esters of estrone. This diet was supplemented with added oleoyl-estrone to produce a diet with 33.3 µmol/kg of fatty-acyl estrone. Oral administration of oleoyl-estrone in a hyperlipidic diet (at a mean dose of 0.5 µmol. kg(-1).d(-1)) resulted in significant losses of fat, energy and, ultimately, weight. Treatment induced the maintenance of energy expenditure combined with lower food intake, creating an energy gap that was filled with internal fat stores while preserving body protein, in contrast with the marked growth of controls fed the hyperlipidic diet. Treatment of genetically obese rats with a hyperlipidic diet containing additional oleoyl-estrone resulted in the loss of fat reserves with scant modification of other metabolic parameters, except for lower plasma glucose and insulin levels. The results agree with the postulated role of oleoyl-estrone as a ponderostat signal.

Journal Article↗
PubMed2000

Oral oleoyl-estrone induces the rapid loss of body fat in Zucker lean rats fed a hyperlipidic diet.

OBJECTIVE: To test whether oleoyl-estrone affects body weight when given orally, which may help curtail the secondary growth-boosting effects of derived estrone. DESIGN: The rats were fed for 15 days with a powdered hyperlipidic diet (16.97 MJ/kg metabolizable energy) in which 46.6% was lipid-derived and 16.1% protein-derived energy (HL group), containing 1.23+/-0.39micromol/kg of fatty-acyl esters of estrone. This diet was supplemented with additional oleoyl-estrone to produce diets with 2.5 micromol/kg (diet OE2.5), 4.4 micromol/kg (diet OE4.4), and 33.3 micromol/kg content in fatty-acyl estrone (diet OE33). SUBJECTS: Twelve-week old female Zucker lean (Fa/?) rats initially weighing 200-235g. MEASUREMENTS: Food intake and body weight changes; urine and droppings production and nitrogen content. Body composition (water, lipid, protein) and total energy. Energy and nitrogen balances. Plasma chemistry including free amino acids. RESULTS: Oral administration of oleoyl-estrone in a hyperlipidic diet resulted in significant losses of fat, energy and, ultimately, weight, which were dependent on the dose of oleoyl-estrone ingested. Treatment induced the maintenance of energy expenditure combined with lower food intake, creating an energy gap that was filled with internal fat stores whilst preserving body protein. The decrease in food intake was not a consequence of food aversion but of diminished appetite. Energy expenditure was practically constant for all groups except for the OE33, which showed values about 25% lower than the controls. In most of the groups studied, there was a net protein deposition in spite of severe lipid and energy drainage. Amino acid levels agreed with this N-sparing shift. In spite of lowered energy intake, the N balance was positive or near zero in all groups, with a sizeable N-gap in controls and in lower-dose groups that disappeared in the OE33 group. CONCLUSION: Treatment of rats with a hyperlipidic diet containing added oleoyl-estrone resulted in the dose-related loss of fat reserves with scant modification of other metabolic parameters and preservation of body protein. The results agree with the postulated role of oleoyl-estrone as a ponderostat signal and open the way for its development as anti-obesity drug.

Adipose Tissue↗
PubMed2000

Oleoyl-estrone lowers the body weight of both ob/ob and db/db mice.

Homozygous obese db/db (BKS-Lepr(db) and ob/ob (B6-Lep(ob)) mice were treated for 14 days with a continuous infusion of a fat emulsion (controls) or loaded with oleoyl-estrone at doses of 12.5 and 50 nmol/g x d using surgically inserted osmotic minipumps. Treatment with oleoyl-estrone resulted in a marked decrease in body weight in both strains, compared with the unchecked growth of controls. In db/db mice, plasma urea and insulin, as well as liver lipid decreased with treatment. In ob/ob mice, the effect on insulin was more marked, in parallel with higher plasma lipids pointing to increased fat mobilisation. The results suggest that oleoyl-estrone effects on body fat reserves and insulin resistance are not mediated by leptin, since ob/ob mice lack this hormone and in the db/db it is present but cannot induce effects because of defective leptin receptors; in both cases oleoyl-estrone treatment lowers body weight.

Animals↗
PubMed2000

Plasma acyl-estrone levels are altered in obese women.

A group of obese women (BMI>27 kg/m2; N=73) was studied together with lean controls (BMI <27 kg/m2; N=25). Three groups were defined by the compliance with: BMI lower than 27 kg/m2, glycaemia lower than 5.5 mM and insulinaemia lower than 0.2 nM (controls, group 1, N=19). The subjects with BMI>27 kg/m2, glucose >5.5 mM and insulin >0.2 nM constituted group 3 (N=41), and those with BMI>27 with glycaemia and/or insulinaemia lower than the limits set constituted group 2 (N=32). The women in group 3 had higher fat content, BMI and fat-free mass than those in group 2 and the controls. There were no changes in most plasma parameters, such as free estrone and beta-estradiol. Leptin levels were higher in groups 2 and 3 than in controls. In controls, leptin and acyl-estrone levels were well correlated with BMI and fat content; this correlation was not found in groups 2 and 3 for acyl-estrone, although it was found for leptin. Acyl-estrone levels were lower than expected in most obese women when compared to those of controls, suggesting an altered availability or function of this hormone. In obese women, acyl-estrone levels -and probably function- are lower than expected, contrasting with maintained leptin-BMI correlations. The role of insulin in the control of body weight, perhaps through acyl estrone-mediated effects, should be re-evaluated.

Acylation↗
PubMed2000

The effects of arsenic trioxide (As2O3) on human megakaryocytic leukemia cell lines. With a comparison of its effects on other cell lineages.

Arsenic trioxide (As2O3) has been demonstrated to be effective for the treatment of acute promyelocytic leukemia (APL) and to inhibit proliferation and produce apoptosis in the APL cell line NB4. The effect of this newly utilized chemotherapeutic agent on other lineages is currently under study to evaluate its efficacy for the treatment of other human malignancies and myeloproliferative syndromes. A recent study described the effects of As2O3 upon viability, proliferation, and induction of apoptosis in four different megakaryocytic leukemia cell lines. At pharmacological concentrations (0.5-2 microM) As2O3 selectively inhibits growth and causes apoptosis in the megakaryocytic leukemia cell lines HEL, Meg-01, UT7 and M07e. Pertinently, these concentrations of As2O3 resulted in identical changes in the characteristics of the APL cell line NB4, suggesting that As2O3 could produce its effects in both cellular lineages via a common mechanism of action. Various mechanisms have been proposed for the As2O3-induced changes in NB4 (including modulation of promyelocytic leukemia proteins (PML) and Bcl-2, modification of the glutathione redox system, caspase activation, and cell cycle arrest) and are currently under investigation in the megakaryocytic leukemia cell lines. Recent preliminary results indicate that As2O3 downregulates Bcl-2 expression and induces cell cycle arrest in megakaryocytic cell lines. The use of As2O3 for the treatment of malignant megakaryocytic disorders also has been considered. The in vitro effects of As2O3 on a chronic megakaryocytic proliferative disorder. i.e., Essential Thrombocythemia (ET), have been analyzed and megakaryocyte progenitors have shown an unexpectedly higher resistance to As2O3, in comparison to normal megakaryocyte colony-forming cells. The effects of As2O3 on ET and other megakaryocytic disorders need to be fully examined, in order to determine the clinical efficacy of As2O3 in the treatment of syndromes affecting the megakaryocytic lineage.

Antineoplastic Agents↗
PubMed1999

Inhibition of in vitro angiogenesis by platelet factor-4-derived peptides and mechanism of action.

In this study, we examined in detail the interaction of platelet factor-4 (PF-4) with fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) and the effect of PF-4-derived synthetic peptides. We show that a peptide between amino acids 47 and 70 that contains the heparin-binding lysine-rich site inhibits FGF-2 or VEGF function. This is based on the following observations: PF-4 peptide 47-70 inhibited FGF-2 or VEGF binding to endothelial cells; it inhibited FGF-2 or VEGF binding to FGFRs or VEGFRs in heparan sulfate-deficient CHO cells transfected with FGFR1 (CHOFGFR1) or VEGFR2 (CHOmVEGFR2) cDNA; it blocked proliferation or tube formation in three-dimensional angiogenesis assays; and, finally, it competed with the direct association of (125)I-PF-4 with FGF-2 or VEGF, respectively, and inhibited heparin-induced FGF-2 dimerization. A shorter C-terminal peptide (peptide 58-70), which still contained the heparin-binding lysin-rich site, had no effect. Peptide 17-58, which is located in the central part of the molecule, although it does not inhibit FGF-2 or VEGF binding or biologic activity in endothelial cells, inhibited heparin-dependent binding of (125)I-FGF-2 or (125)I-VEGF to CHOmFGFR1 or CHOmVEGFR2 cells, respectively. Shorter peptides (peptides 34-58 and 47-58) did not show any of these effects.

Animals↗