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Biomedical subjects

G Schettini

Publications and source records attributed to G Schettini.

159 records · Page 9Linked to original sources
PubMed1977

Increased plasma corticosterone and decreased plasma thyroid-stimulating hormone levels in rats treated with vincristine.

A single i.p. injection of vincristine (1000 microgram/kg) into rats increased the plasma concentration of corticosterone after a latent period of 4 hr; the effect lasted for 48 hr. The response was dose related with the threshold dose being 100 microgram/kg and the maximal effect occurring after 250 microgram/kg. Vincristine also increased plasma corticosterone levels in hypophysectomized rats, suggesting that the drug may have a direct action on the adrenal gland. The injection of 500 or 1000 microgram/kg also reduced the plasma concentration of thyroid-stimulating hormone. Twelve and 18 hr after the injection of vincristine (1000 microgram/kg), the plasma concentration of thyroid-stimulating hormone was reduced, whereas the hypothalamic content of norepinephrine, a neurotransmitter involved in the regulation of thyrotropin-releasing hormone-thyroid-stimulating hormone secretion, remained unchanged. The adrenocortical stimulation produced by vincristine may play some role in the antineoplastic effects of this drug.

Adrenal Cortex↗
PubMedDate not supplied

Cabergoline modulation of alpha-subunits and FSH secretion in a gonadotroph adenoma.

Most non-functioning pituitary adenomas respond poorly to medical therapy. We describe the case of a 62-year-old man who presented with clinical features of an invasive macroadenoma. Baseline hormonal evaluation revealed increased FSH and alpha-subunit (alpha-SU) levels. Transsphenoidal exeresis followed by radiotherapy (RT) was performed. Almost all neoplastic cells were intensely immunoreactive for alpha-SU. On PCR analysis, specific amplification products were observed for somatostatin 2, 3 and 5 receptors as well as for both short and long isoforms of the dopamine D2 receptor. In vitro, alpha-SU and FSH were released into the medium by adenoma cells and increased after TRH stimulation. After surgery, alpha-SU and FSH levels were still elevated. Short-term slow-release lanreotide treatment did not modify either alpha-SU or FSH levels. Cabergoline was started and a fast and long-lasting decrease in alpha-SU and, to a lesser extent, in FSH was observed. The tumor remnant was unmodified on magnetic resonance imaging 3 years after surgery and RT. This case report shows that the in vitro expression of somatostatin receptors may not be directly associated to the in vivo response of alpha-SU and FSH to lanreotide, probably because of a functional uncoupling of the receptors. Cabergoline should be considered as an effective therapy for hormonal, and perhaps proliferative, control of gonadotroph adenoma remnants before the effects of RT are fully effective.

Adenoma↗
PubMedDate not supplied

Fipexide improvement of cognitive functions in rat: behavioural and neurochemical studies.

Dopamine neurotransmission plays a role in learning, memory and related cognitive processes. We evaluated the effect of a nootropic drug, fipexide, a parachloro-phenossiacetic acid derivative, both on behavioural and biochemical parameters. The compound was able to cause an improved performance on active avoidance test, when administered just before the trial, being also effective on memory retention and recall experiments. Fipexide was also able to revert the impairment of the acquired behaviour caused by sulpiride in pretrained rats, while it failed to be effective on the haloperidol deconditioning effect. Striatal adenylate cyclase activity, from fipexide pretreated rats, was significantly reduced both in basal and dopamine stimulated conditions. Furthermore, fipexide, directly added to membrane preparations, was able to inhibit striatal adenylate cyclase activity. These results, along with our previous reports on fipexide effect on locomotor activity, allow us to hypothesize that the positive effect of this drug on cognitive performance seems to be mediated, at least partially, by dopaminergic neurotransmission.

Adenylyl Cyclase Inhibitors↗
PubMedDate not supplied

Intracellular mechanisms mediating the neuronal death and astrogliosis induced by the prion protein fragment 106-126.

Prion encephalopathies include fatal diseases of the central nervous system of men and animals characterized by nerve cell loss, glial proliferation and deposition of amyloid fibrils into the brain. During these diseases a cellular glycoprotein (the prion protein, PrP(C)) is converted, through a not yet completely clear mechanism, in an altered isoform (the prion scrapie, PrP(Sc)) that accumulates within the brain tissue by virtue of its resistance to the intracellular catabolism. PrP(Sc) is believed to be responsible for the neuronal loss that is observed in the prion disease. The PrP 106-126, a synthetic peptide that has been obtained from the amyloidogenic portion of the prion protein, represents a suitable model for studying the pathogenic role of the PrP(Sc), retaining, in vitro, some characteristics of the entire protein, such as the capability to aggregate in fibrils, and the neurotoxicity. In this work we present the results we have recently obtained regarding the action of the PrP 106-126 in different cellular models. We report that the PrP 106-126 induces proliferation of cortical astrocytes, as well as degeneration of primary cultures of cortical neurons or of neuroectodermal stable cell lines (GH(3) cells). In particular, these two opposite effects are mediated by the same attitude of the peptide to interact with the L-type calcium channels: in the astrocytes, the activity of these channels seems to be activated by PrP 106-126, while, in the cortical neurons and in the GH(3) cells, the same treatment causes a blockade of these channels causing a toxic effect.

Amino Acid Sequence↗
PubMedDate not supplied

Somatostatin receptor 1 (SSTR1)-mediated inhibition of cell proliferation correlates with the activation of the MAP kinase cascade: role of the phosphotyrosine phosphatase SHP-2.

The mitogen activated protein (MAP) kinase cascade represents one of the major regulator of cell growth by hormones and growth factors. However, although the activation of this intracellular pathway has been often regarded as mediator of cell proliferation, in many cell types the increase in MAP kinase (also called extra-cellular signal regulated kinase: ERK) activity may result in cell growth arrest, depending on the length or the intensity of the stimulation. In this review we examine recent data concerning the effects of somatostatin on the MAP kinase cascade through one of its major receptor subtype, the somatostatin receptor 1 (SSTR1), stably expressed in CHO-K1 cells. Somatostatin inhibits the proliferative effects of basic FGF (bFGF) in CHO-SSTR1 cell line. However, in these cells, somatostatin robustly activates the MAP kinase and augments bFGF-induced stimulation of ERK. We show that the activation of ERK via SSTR1 is mediated by the betagamma subunit of a pertussis toxin-sensitive G-protein and requires both the small G protein Ras and the serine/threonine kinase Raf-1. Moreover the phosphatidyl inositol-3kinase and the cytosolic tyrosine kinase c-src participate in the signal transduction regulated by SSTRI to activate ERK, as well as it is involved the protein tyrosine phosphatase (PTP) SHP-2. Previous studies have suggested that somatostatin-stimulated PTP activity mediates the growth inhibitory actions of somatostatin, in CHO-SSTR1 cells. Thus, the activation of SHP-2 by SSTR1 may mediate the antiproliferative activity of somatostatin. SHP-2 may. in turn, regulate the activity of kinases upstream of ERK that require tyrosine dephosphorylation to be activated, such as c-src. Finally, the synergism between somatostatin and bFGF in the activation of ERK results in an increased expression of the cyclin-dependent kinase inhibitor p21cip/WAF1 as molecular effector of the antiproliferative activity of somatostatin.

Animals↗
PubMedDate not supplied

Identification of a conserved N-capping box important for the structural autonomy of the prion alpha 3-helix: the disease associated D202N mutation destabilizes the helical conformation.

Peptides corresponding to three alpha helices present in the C-terminal region of the human prion protein have been synthesized and their structural autonomy analyzed by circular dichroism (CD) and NMR spectroscopy. The results obtained indicate that the protein fragment corresponding to the alpha 3-helix, in contrast to alpha 1 and alpha 2 peptides, shows a complete structural autonomy. The chemical shifts values found for NH and CHalpha resonance of the isolated alpha 3 peptide, formed by 30 aminoacid residues, were markedly and surprisingly similar to the corresponding values of the alpha 3-helix in the protein. The structural autonomy of the alpha 3-helix is profoundly determined by the presence of the conserved capping box and, in part, by the ionic bond formed between Glu200 and Lys204. On the basis of these observations a novel PrP consensus pattern, centered on the alpha 3-helix region, has been defined. The data indicate that this autonomous and highly conserved region of the PrPc likely plays a critical role in folding and stability. This gives an explanation of why many of pathogenic mutations occur in this part of the molecule, sharing relevant effects on the overall protein conformation. In particular the D202N capping mutation almost completely destabilizes the isolated alpha 3 peptide. While it is well known that the D202N substitution is associated with a GSS disease, the possible structural basis of this fatal pathology has never been investigated. We propose that a lower alpha 3-helical propensity leading to a major destabilization of the PrPc molecule initiates the pathogenic process associated with D202N capping mutation.

Amino Acid Sequence↗
PubMedDate not supplied

Conformation dependent pro-apoptotic activity of the recombinant human prion protein fragment 90-231.

The transition of prion protein from a mainly alpha-structured isoform (PrPC) to a beta sheet-containing protein (PrPSc) represents a major pathogenetic mechanism in prion diseases. To study the role of PrP structural conformation in prion-dependent neurodegeneration, we analysed the neurotoxicity of PrP in alpha and beta conformations, using a recombinant protein encompassing amino acids 90-231 of the human PrP (hPrP90-231). Using controlled thermal denaturation (53 degrees C, 1h) we converted hPrP90-231 in a structural isoform displaying PrPSc-related characteristics: high beta sheet content, increased aggregability and a slight increase in the resistance to protease K. In virtue of these structural changes, hPrP90-231 powerfully affected the survival of SH-SY5Y cells, inducing a caspase-3 and p38- dependent apoptosis. Conversely, in the native alpha-helix-rich conformation, hPrP90-231 did not show significant cell toxicity. The relationship between the structural state of hPrP90-231 and its neurotoxicity was demonstrated, inducing the thermal denaturation of the peptide in the presence of Congo red that prevented both the transition of hPrP90-231 into a beta-rich isoform and the acquisition of toxic properties. In conclusion, we report that the toxicity of hPrP90-231 is dependent on its three-dimensional structure, as is supposed to occur for the pathogen PrP during TSE.

Amyloid↗