Unmasking a growth factor/oncogene-activated S6 phosphorylation cascade.
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Amino Acid Sequence↗
Biomedical subjects
S Ferrari
Publications and source records attributed to S Ferrari.
Effects of an olive-oil-rich diet on erythrocyte membrane lipid composition and cation transport systems.
1. In this study we sought to test the possibility that an olive-oil-rich diet might influence the membrane lipid composition and cation transport mechanisms in erythrocytes. 2. To this end, 11 normotensive normolipidaemic healthy volunteers were given a standard relatively low fat diet (28% of total energy) for 3 weeks, followed by a high fat (38% of total energy), olive-oil (100 g/day)-enriched diet for the 3 subsequent weeks, in a metabolic ward. The two diets contained the same amount of cholesterol (400 mg), and the polyunsaturated fatty acid/saturated fatty acid ratio was similar and comparatively low (0.35 on the standard vs 0.36 on the olive oil diet). 3. At the end of the study the lipid composition of the erythrocyte membranes showed the following changes: the oleic acid content increased by 15.7% and the amount of saturated fatty acid decreased by 3.2%. The polyunsaturated fatty acid content tended to decrease, while the polyunsaturated fatty acid/saturated fatty acid ratio did not change significantly. The cholesterol/phospholipid molar ratio increased significantly by 7.8%, still remaining within the reference range. 4. At the same time, the mean values of the maximum rates of the cation fluxes mediated by the Na+ -K+ pump, and by Na+ -K+ co-transport rose significantly, while the maximal rate of Na+ -L+ countertransport showed a non-significant trend towards lower values. 5. Urinary excretion of Na+ and K+, body weight and blood pressure did not change significantly.
Adult↗
Steroid hormone sulphation in lead workers.
The metabolism of steroid hormones has been investigated in 10 workers exposed to lead and in 10 non-exposed subjects to determine whether lead interferes with the first or second phase reactions of steroid hormone biotransformation, or both. In the exposed workers blood lead concentrations (PbB) ranged from 45 to 69 micrograms/100 ml; in the controls PbB was less than 25 micrograms/100 ml. No statistical differences were found for the total amount of the urinary hormone metabolites, but a drop of about 50% was observed for the sulphated portion. It is suggested that lead interferes with the mechanisms of sulphoconjugation through an effect on the cytosol enzymes sulphotransferase and sulphokinase.
Adult↗
Plasma lipoproteins, tissue cholesterol overload, and skeletal muscle apolipoprotein A-I synthesis in the developing chick.
In the present study we investigated the changes of plasma lipids, lipoproteins, and tissue lipids that occur during the late embryonic life (5 days before hatching) and the postnatal period (0, 2, 7, 14, and 30 days after hatching) of the chick. The chick emerges from the egg with extreme hypercholesterolemia associated with a high level of cholesterol-rich VLDL + IDL. The density gradient profile of plasma lipoproteins showed that the concentrations of VLDL + IDL and LDL decreased during the first week of postnatal life, whereas HDL concentration increased sharply around hatching and remained stable afterwards. All plasma lipoprotein classes of the newborn chick (2 days from hatching) were enriched in cholesterol and cholesteryl esters; 2 weeks after hatching, the relative amount of cholesterol and cholesteryl esters decreased. In the newborn chick, plasma VLDL + IDL consisted of two populations of cholesteryl ester-rich lipoproteins: the main one (designated apoB-VLDL) contained apoB and no apoA-I; the other (designated apoA-I-VLDL) contained predominantly apoA-I. In the newborn chick there was an accumulation of free and esterified cholesterol in the liver and, to a lesser extent, in the skeletal muscle. These cholesterol deposits were depleted 2 to 7 days after hatching. The depletion in skeletal muscle was preceded by and associated with a striking increase in the synthesis of apoA-I in this tissue, as demonstrated by immunological methods and apoA-I mRNA measurements. In addition, apoA-I-containing HDL were secreted in vitro by explants of skeletal muscle of the newborn chick. The synthesis of apoA-I in the skeletal muscle decreased to the level found in the adult animal 1 week after hatching. It is likely that the rise of HDL and apoA-I in plasma observed 1-2 days after hatching reflects the production of apoA-I-containing HDL by skeletal muscle. We suggest that the cholesterol overload in skeletal muscle might stimulate the production of apoA-I which, in turn, would promote the removal of cholesterol from this tissue. The hypothesis that metabolic stimuli play a role in inducing apoA-I synthesis in skeletal muscle is supported by the observation that feeding the newborn chick a diet rich in proteins and lipids and free of carbohydrates delays the fall of apoA-I mRNA which normally occurs 1 week after hatching.
Animals↗
[Plasma dehydroepiandrosterone sulfate and urine steroid excretion in hepatic cirrhosis].
In the present study we evaluated the alterations of plasma levels of dehydroepiandrosterone sulphate (DHEA-S) and of steroid-derivatives urinary excretion in cirrhotic patients compared with normal controls. 107 patients have been studied: 45 affected by liver cirrhosis (22 males and 23 females) both in compensated and in ascitic state, and 62 healthy controls (32 males and 30 females). In all patients we assayed plasma DHEA-S by RIA as well as common liver function tests; moreover gaschromatographic profile of adrenal steroid excretion was performed in daily urine. Our findings show a significantly lower DHEA-S in cirrhotic patients compared with healthy controls, both males (451.7 SD 440.3 ng/ml vs 1438.3 SD 604.8, p less than 0.001) and females (225.5 SD 152.6 ng/ml vs 974.0 SD 405.7, p less than 0.001). Variance analysis confirmed that the difference was significant both for compensated and uncompensated ones. We also found some interesting relationships between DHEA-S and liver function tests, cholesterol and age. Urinary steroids were markedly low in both sexes, particularly adrenal sexual fraction. Our data show clear disfunction in DHEA-S metabolism in liver cirrhosis, partially related with the severity of the disease.
Adult↗
Expression of the myeloperoxidase gene in acute and chronic myeloid leukemias: relationship to the expression of cell cycle-related genes.
The expression of the myeloperoxidase (MPO) gene was studied, by means of Northern blot analysis in 14 cases of acute myeloid leukemia (AML), 11 cases of chronic myeloid leukemia (CML), and 6 cases of CML blast crisis, and in HL60 cells before and after induction of terminal differentiation with retinoic acid (RA), phorbol esters (TPA), or vitamin D. The expression of a panel of cell cycle-related genes, namely C-MYC, histone H3, ornithine decarboxylase, P53, vimentin, and calcyclin, was also studied in the same cell populations. Our results indicate that: (a) MPO gene expression (steady state mRNA levels) is strictly confined to the first stages of myeloid differentiation, reaching its peak at the promyelocyte stage and becoming undetectable in mature granulocytes and monocytes; (b) cells devoid of any detectable MPO enzymatic activity such as leukemic basophils have a high content of MPO mRNA; and (c) MPO gene expression is not related to the growth activity of the cell population. Finally, our results show that the pattern of expression of growth-regulated genes in the neoplastic myeloid disorders AML, CML, and CML blast crisis is remarkably different.
Blast Crisis↗
Increased erythrocyte membrane arachidonate and platelet malondialdehyde (MDA) production in psoriasis: normalization after fish-oil.
Evidence exists of platelet activation and increased thromboxane B2 production in psoriasis. In 13 patients suffering from psoriasis, we determined the lipid composition of erythrocyte membrane, erythrocyte and platelet glutathione peroxidase activity (E-GSH-Px; Plt-GSH-Px), platelet MDA production and bleeding time. Compared with normal controls, psoriatics showed a significant increase in erythrocyte membrane arachidonic acid (AA) (p less than 0.001) and polyunsaturated fatty acids (PUFA) (p less than 0.001), platelet MDA production (p less than 0.01) and E- and Plt-GSH-Px activity (p less than 0.01; p less than 0.01). After 8 weeks of fish-oil supplementation (20 ml/day) we observed the following changes: a) marked amelioration of skin lesions; b) normalization of membrane lipid pattern and platelet MDA production; c) a further increase in E- and Plt-GSH-Px activity (p less than 0.01; p less than 0.01); d) significant prolongation of bleeding time (p less than 0.05). Our data demonstrate: 1) a generalized perturbation of membrane lipid pattern in psoriasis, characterized by an excess of AA; 2) an activation of AA metabolism in platelets suggested by increased MDA production and GSH-Px activity; 3) dietary fish-oil may normalize membrane lipid pattern and reduce platelet hyperactivity in psoriasis.
Adult↗
Philadelphia-positive chronic myelogenous leukemia with typical bcr/abl molecular features and atypical, prolonged survival.
Despite the major breakthrough in the knowledge of the molecular events underlying the t(9;22) translocation, still no consistent data have been found on the evolution of Ph1 positive CML from the chronic to the accelerated or blastic phase of the disease. In most patients in fact the bcr/abl rearrangements are identical both in chronic phase and in blast crisis, and overall differences in chronic phase duration, related to different location of breakpoints inside the bcr region, were found to be marginal. We approached this problem by studying the molecular features of the bcr/abl abnormality in rare CML patients with very long, atypical chronic phase. The three patients studied, whose chronic phase duration is 17, 19, and 21 years, respectively, have typical genomic bcr rearrangements, and two of them show, hybridizing Northern blots to c-abl, the 8.5 kb mRNA, as that typically present in CML. It seems that genomic alterations within bcr and abl cannot account, alone, for the duration of the chronic phase of Ph1 positive CML and those quantitative and/or qualitative alterations of the p210 bcr/abl protein, unluckily awkward to prove, might be responsible for the atypical clinical features of these CML long survivors.
Adult↗
BclI RFLP for the human vimentin gene.
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Chromosomes, Human, Pair 10↗
Growth factor regulation of the promoter for calcyclin, a growth-regulated gene.
The steady-state levels of calcyclin mRNA are regulated by growth factors. Using deletion mutants of the 5'-flanking region and a linked reporter (the bacterial chloroamphenicol transferase gene), we have investigated the elements of the calcyclin gene's promoter that respond to growth factors. By a transient expression assay after transfection in BALB/c/3T3 cells, we have been able to show that the serum-inducible sequences are contained in a 164-base pair fragment just upstream of the cap site. This fragment also contains an enhancer, and responds to platelet-derived growth factor as well as to serum. The sequences from -1371 to -1194 upstream of the cap site contain an element which is negatively regulated by epidermal growth factor. These findings have been confirmed in hamster cell lines in which the deletion mutants of the calcyclin promoter controlled the expression of the cDNA for human thymidine kinase. These results indicate that, like in other growth-regulated genes the activity of the calcyclin promoter is modulated by both positive and negative elements. Even more intriguing, though, is the finding that some of these negative elements may be influenced by growth factors in the environment.
Animals↗
Nucleotide sequence of the promoter region of the gene encoding chicken calbindin D28K.
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Animals↗
Mechanism of Ca2+ and phospholipid-independent protein phosphorylation by protein kinase C: protamines and related peptides as substrates and inhibitors.
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Amino Acid Sequence↗
Expression of c-myc and induction of DNA synthesis by platelet-poor plasma in human diploid fibroblasts.
When WI-38 human diploid fibroblasts become confluent, they stop synthesizing DNA and dividing. Addition of serum causes the quiescent cell to reenter the cell cycle. Prolonged quiescence after confluence decreases and delays the response to serum. For a few days after reaching confluence, WI-38 cells also respond to platelet-poor plasma. During this period, although not cycling, WI-38 cells still express c-myc and other growth-regulated genes, as measured by steady-state RNA levels. If the quiescence is prolonged further, c-myc expression (and that of two other growth-regulated genes) is no longer detectable, and its disappearance coincides with a loss of response to platelet-poor plasma. These results suggest that, also under physiological conditions, the expression of c-myc and other growth-regulated genes can cooperate with platelet-poor plasma in inducing cellular DNA synthesis in human diploid fibroblasts.
Blood Platelets↗
Olive-oil-enriched diet: effect on serum lipoprotein levels and biliary cholesterol saturation.
The effect of diet enriched with a monounsaturated fatty acid (olive oil) on serum lipoproteins, biliary cholesterol saturation index, and gallbladder motility compared with a standard low-fat diet was evaluated in 11 young volunteers admitted to a metabolic ward. A significant decrease of mean total cholesterol (-9.5%), total apo B (-7.4%), LDL cholesterol (-12.2%), and total triglycerides (-25.5%) was observed after the olive-oil-enriched diet. Total HDL- and HDL-subfractions-cholesterol levels as well as serum apo A-I mean levels remained unchanged. Cholesterol saturation index of the bile and fasting and after-meal gallbladder volumes were unaffected by the enriched diet as compared with the low-fat diet. Olive oil may be a natural fat that can be used for the control of plasma and LDL cholesterol as a valid alternative to polyunsaturated fatty acids.
Adult↗
Myeloperoxidase gene expression in blast cells with a lymphoid phenotype in cases of acute lymphoblastic leukemia.
By using a cDNA clone of the myeloperoxidase (MPO) gene, we have studied, by Northern blot analysis, the level of MPO mRNA in eight cases of acute lymphoblastic leukemia (ALL). The blast cell populations studied were characterized by morphologic, cytochemical, immunochemical, and molecular criteria. With all the methods used the populations were found to be highly homogeneous and showed a typical lymphoid phenotype. In particular, the Ig heavy-chain gene rearrangement was largely prevalent, and the germ line configuration was almost absent. However, in three of eight cases, high levels of MPO mRNA were detected. The remarkable homogeneity of the cell populations examined suggests that the MPO mRNA observed was present in cellular elements certainly identified as lymphoid. The absence of contamination by myeloid cells was confirmed by the results of Western blot analysis of the proteins of the cell population studied: no MPO protein was detectable. The levels of mRNA observed were high enough to be comparable to those observed in a promyelocytic cell population.
Cell Transformation, Neoplastic↗
[Increased urinary excretion of methionine, cystathionine and cystine in adults during parenteral nutrition].
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Adult↗
[Possible effects of lead on various hormonal metabolic pathways].
After reviewing the principal studies on the interferences of lead on the endocrine system, this paper reports the results of a survey carried out on 30 subjects in which the effects of lead on serum FSH, LH and testosterone and on urinary steroid hormones excretion were examined. Statistically significant differences were not demonstrated between lead exposed subjects and control group for serum LH and testosterone (total and free) and for urinary steroids. A significant increase of FSH has been detected in lead exposed workers even if this increase remains between the "normal limits" of the laboratory which performed the determinations. The results are discussed in the light of the more recent knowledge about the endocrine effects of xenobiotics in general and heavy metals in particular and some interpretations to justify the detected FSH increase are proposed.
17-Hydroxycorticosteroids↗
Expression of oncogenes and cell cycle related genes in acute and chronic leukemias.
The authors have assayed the level of expression of several cell-cycle related genes in several populations of circulating myeloid leukemic blast cells. The genes explored included oncogenes such as c-myc, c-myb, p53, and cell-cycle-related genes such as vimentin, calcyclin, ornithine decarboxylase (ODC) and histone H3. Particular attention was given to analysis of the relationship existing between the mRNA levels of the histone H3 gene, which is expressed specifically in the S phase of the cell cycle, and the levels of other genes that are expressed in different stages of the G1 phase. Remarkable differences were observed among the different cases indicating that a differential expression of cell-cycle-related genes characterizes many acute leukemias. This differential expression is reflected in an altered ratio among G1-related genes and the H3 histone gene. The large fraction of leukemic cells which does not express histone H3 and therefore is functionally noncycling, shows a heterogeneous pattern of G1-related gene expression. This reflects the inability of most leukemic cells to progress through the G1 phase into the S phase of the cell cycle. This inability represents an abnormality of the cell cycle. It is concluded that the study of the expression of cell-cycle genes and protooncogenes in in understanding how leukemic cells enter a state of proliferation arrest, which appears to occur in a large fraction of leukemic cells.
Cell Cycle↗