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Biomedical subjects

E Alesse

Publications and source records attributed to E Alesse.

At least 19 recordsLinked to original sources
PubMed2003

Human pituitary tumours express the bHLH transcription factors NeuroD1 and ASH1.

Among the transcription factors involved in pituitary ontogenesis and physiology, basic helix-loop-helix (bHLH) have been poorly studied. Members of bHLH family include NeuroD1 and ASH1, both involved in neuroendocrine differentiation. We evaluated their mRNA expression patterns, by semi-quantitative RT-PCR analysis (sq-RT-PCR) and/or Northern blot, in a series of 33 pituitary adenomas (PA), anterior pituitaries, and pituitary cell lines. Immunohistochemistry for NeuroD1 was also performed in 25 PA. Low levels of NeuroD1 were observed in normal pituitaries and in the somatomammotroph cell lines GH3/GH4C1, contrasting with high levels in corticotroph AtT20 cells. NeuroD1 mRNA was widely expressed in PA (82%), with measurable levels found especially in those derived from Pit-1 independent lineages, i.e. corticotroph (5/5) and clinically non-secreting (CNS) adenomas (9/11). According to sq-RT-PCR analysis, overexpression of NeuroD1 compared to normal pituitaries was frequent. Variable nuclear NeuroD1 immunopositivity was also present in about 70% of studied cases. ASH1 mRNA was widely detected in normal pituitaries, in all tumour cell lines and in most PA (84%), with measurable levels in corticotroph (5/5) and CNS (9/11) adenomas, and in a significant subset of PA derived from Pit-1 dependent lineages (9/16). We conclude that: a) NeuroD1 is differentially expressed in PA and its possible ontogenetic and/or pathogenetic implications in non-corticotroph PA are discussed; b) ASH1 is a neuroendocrine marker whose expression is largely conserved in normal and neoplastic pituitary cells.

Adult↗
PubMed2001

EGF regulates a complex pattern of gene expression and represses smooth muscle differentiation during the neurotypic conversion of the neural-crest-derived TC-1S cell line.

EGF, known to sustain CNS neuronal progenitors, also promotes a neurotypic response in the thymic neural-crest-derived TC-1S cell line. We report here the use of TC-1S cells as a model to identify the genetic programs regulated during the neurotypic response induced by EGF and to isolate 23 EGF-responsive genes. Among them 5 represent novel cDNAs, while 18 are known genes, whose regulation by EGF is associated with the mitogenic or differentiating effects of the growth factor. The repression of smooth muscle alpha-actin and SM22alpha genes by EGF and their increase by TGFbeta suggest that the TC-1S line includes neural crest multipotent cells whose smooth muscle differentiation is repressed upon EGF treatment and stimulated by TGFbeta. Therefore, we identified a complex pattern of EGF-target genes and propose EGF as a novel signal able to recruit postmigratory neural-crest-derived cells along proliferation and cell lineage choice pathways.

Animals↗
PubMed2001

Two familial giant pituitary adenomas associated with overweight: clinical, morphological and genetic features.

OBJECTIVE: Pituitary adenomas are usually sporadic, although rare familial cases have been described. Here we report two first degree female cousins with giant pituitary adenoma and overweight. Both presented with secondary amenorrhoea, occasional headache and weight gain. MATERIALS AND METHODS: In both patients clinical, morphological and genetic studies were performed. Both patients underwent surgery and post-operative medical therapy with somatostatin analogues and dopamine agonist, followed by a conventional radiotherapy course. RESULTS: Clinical examination at presentation revealed an acromegaloid habitus only in the second patient. Basal and dynamic hormonal evaluation showed high serum GH and serum IGF-I values, higher in the second than in the first patient, and a mild hyperprolactinaemia only in the first patient. On optical and electron microscopy, both tumours were oncocytic adenomas, immunopositive for GH in the first patient and GH/prolactin in the second. The genetic analysis for germ-line mutations of the multiple endocrine neoplasia type 1 gene was negative. Two years after radiotherapy a remarkable shrinkage of both tumours was observed, whereas the overweight worsened in both patients, accompanied by high plasma leptin values. CONCLUSION: To our knowledge, this is the first report of familial pituitary adenomas including one case of a clinically silent GH-secreting adenoma. In addition, it provides further evidence that familial pituitary tumours can occur as a multiple endocrine neoplasia type 1 unrelated disease.

Adenoma↗
PubMed2000

Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice.

The multiplicity of Notch receptors raises the question of the contribution of specific isoforms to T-cell development. Notch3 is expressed in CD4(-)8(-) thymocytes and is down-regulated across the CD4(-)8(-) to CD4(+)8(+) transition, controlled by pre-T-cell receptor signaling. To determine the effects of Notch3 on thymocyte development, transgenic mice were generated, expressing lck promoter-driven intracellular Notch3. Thymuses of young transgenics showed an increased number of thymocytes, particularly late CD4(-)8(-) cells, a failure to down-regulate CD25 in post-CD4(-)8(-) subsets and sustained activity of NF-kappaB. Subsequently, aggressive multicentric T-cell lymphomas developed with high penetrance. Tumors sustained characteristics of immature thymocytes, including expression of CD25, pTalpha and activated NF-kappaB via IKKalpha-dependent degradation of IkappaBalpha and enhancement of NF-kappaB-dependent anti-apoptotic and proliferative pathways. Together, these data identify activated Notch3 as a link between signals leading to NF-kappaB activation and T-cell tumorigenesis. The phenotypes of pre-malignant thymocytes and of lymphomas indicate a novel and particular role for Notch3 in co-ordinating growth and differentiation of thymocytes, across the pre-T/T cell transition, consistent with the normal expression pattern of Notch3.

Animals↗
PubMed2000

Apoptosis and apoptosis-associated perturbations of peripheral blood lymphocytes during HIV infection: comparison between AIDS patients and asymptomatic long-term non-progressors.

This study was designed to compare the degree of lymphocyte apoptosis and Fas-Fas ligand (FasL) expression in AIDS patients and long-term non-progressors (LTNPs) and correlate these parameters with apoptosis-associated perturbations in lymphocyte function. LTNPs had a lower frequency of apoptotic CD4+ and CD8+ T cells compared with subjects with AIDS. This correlated with a lower frequency of cells expressing Fas and FasL. The frequency of selected lymphocyte populations exhibiting a disrupted mitochondrial transmembrane potential (DeltaPsim) and increased superoxide generation was lower in LTNPs than in patients with AIDS; these abnormalities were associated with lower levels of caspase-1 activation in LTNPs. The results indicate a significantly reduced level of apoptosis and apoptosis-associated parameters in LTNPs than in patients developing AIDS. Based on these findings, a crucial role for mitochondria can be predicted in the process of lymphocyte apoptosis during the evolution of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Angiotensin II stimulates intercellular adhesion molecule-1 (ICAM-1) expression by human vascular endothelial cells and increases soluble ICAM-1 release in vivo.

BACKGROUND: We evaluated whether angiotensin II (Ang II) influenced intercellular adhesion molecule (ICAM)-1 expression by human vascular endothelial cells derived from umbilical cord veins (HUVECs) and plasma soluble ICAM-1 levels in vivo. METHODS AND RESULTS: Cultured HUVECs were incubated with Ang II (from 10(-9) to 10(-6) mol/L) with or without candesartan and PD12319 (inhibitors of Ang II AT(1) and AT(2) receptors, respectively) for various times up to 4 hours. Total RNA was then extracted from HUVECs, and Northern blots were probed with a 1.9-kb ICAM-1 cDNA fragment. HUVEC supernatants were used to assess soluble ICAM-1 release by ELISA. Northern blot analysis detected a strong increase of ICAM-1 mRNA after 2-hour incubation with Ang II. The response was inhibited by candesartan. Soluble ICAM-1 release by HUVECs also increased (P<0. 002) after 2-hour Ang II stimulation. In vivo, Ang II (at an initial rate of 1.0 ng. kg(-1). min(-1), to be increased each 30 minutes by 2.0 ng. kg(-1). min(-1) to the final rate of 7.0 ng. kg(-1). min(-1)) was infused in 8 normotensive and 12 essential hypertensive individuals. In the latter, Ang II was reinfused after 4 weeks on either placebo (n=3), losartan (50 mg UID, n=5), or atenolol (50 mg UID, n=4) treatment. Plasma soluble ICAM-1 levels increased after Ang II infusion in hypertensives and normotensives (P<0.0001 after 90 minutes). Losartan reduced baseline soluble ICAM-1 levels (P<0.05) and Ang II-related ICAM-1 increments. CONCLUSIONS: Ang II upregulates ICAM-1 expression by HUVECs and stimulates in vitro and in vivo soluble ICAM-1 release. AT(1) receptor blockade inhibits such endothelial effects of Ang II.

Adult↗
PubMed1999

Acetyl-L-carnitine administration increases insulin-like growth factor 1 levels in asymptomatic HIV-1-infected subjects: correlation with its suppressive effect on lymphocyte apoptosis and ceramide generation.

The aim of this study was to investigate the impact of long-term acetyl-L-carnitine administration on CD4 and CD8 absolute counts, apoptosis, and insulin-like growth factor-1 (IGF-1) serum levels in HIV-1-infected subjects. The generation of cell-associated ceramide and HIV-1 viremia were also investigated. Eleven asymptomatic, HIV-1-infected subjects were treated daily with acetyl-L-carnitine (3 g) for 5 months. Immunologic and virologic measures and safety were monitored at the start of the treatment and then on days 90 and 150. Altogether our findings suggest that acetyl-L-carnitine administration has a substantial impact on the main immunologic abnormality associated with HIV infection, the loss of CD4 cells, by reducing the rate of apoptotic lymphocyte death. The reduction of ceramide generation and the increase of the serum levels of IGF-1, a major survival factor able to protect cells from apoptosis by different stimuli and conditions, could represent two important mechanisms underlying the observed anti-apoptotic effects of acetyl-L-carnitine.

Acetylcarnitine↗
PubMed1999

Reduction of glutamate levels in HIV-infected subjects treated with acetylcarnitine.

The excitotoxic amino acid glutamate, which is elevated in blood and cerebrospinal fluid from subjects with AIDS dementia complex, is crucially implicated in the neurotoxicity of HIV infection. We describe a subject with AIDS dementia complex who showed a significant motor and cognitive improvement after a course of intravenous acetylcarnitine therapy. The clinical improvement was paralleled by a significant reduction of glutamate concentrations in both blood and cerebrospinal fluid. A prospective pilot study confirmed that acetylcarnitine administration resulted indeed to reduce the blood levels of glutamate in AIDS patients treated with acetylcarnitine therapy in order to prevent the neurotoxicity of nucleoside analogs. Even though the mechanisms responsible for the reduction of glutamate concentrations remain to be established, we suggest that acetylcarnitine should be added to the list of drugs under investigation for the treatment of AIDS dementia complex. The anti-apoptotic activity of carnitines and their safety profile further support this view.

AIDS Arteritis, Central Nervous System↗
PubMed1999

Combined antiviral therapy reduces HIV-1 plasma load and improves CD4 counts but does not interfere with ongoing lymphocyte apoptosis.

The progression of HIV-1 disease appears associated with an unregulated Fas-mediated apoptosis of lymphocytes that involves the activation of ICE protease and ceramide generation and antiviral therapy may not be fully effective in the absence of a relevant impact on apoptosis. Six drug-naive HIV-1-infected symptomless patients with advanced immunodeficiency were treated with combined AZT and ddl for 4 months; plasma HIV-1 RNA levels, the counts of CD4 cells, CD4 and CD8 apoptotic lymphocytes, Fas-positive cells and ICE-positive cells, and intracellular ceramide levels were measured at base-line and after 7, 45 and 120 days of treatment. There was a prompt reduction in plasma viremia and a secondary increase in CD4 counts, but the treatment had no impact on apoptotic CD4 and CD8 lymphocytes, Fas-positive cells and ICE-positive cells, and on the intracellular levels of ceramide. A discrepancy exists between the positive impact of combined AZT and ddl treatment on plasma viral load and CD4 counts and the lack of any effect on the process of lymphocyte apoptosis. We suggest to use the measurement of apoptotic lymphocytes as a surrogate marker to predict, in combination with viral load and CD4 counts, a large proportion of the clinical effect of antiviral therapy.

Adult↗
PubMed1998

Effect of L-carnitine on human immunodeficiency virus-1 infection-associated apoptosis: a pilot study.

The Fas/Fas ligand system is involved in uncontrolled apoptosis, which ultimately leads to the loss of T lymphocytes in human immunodeficiency virus (HIV)-infected individuals. The signal transduced by Fas receptor involves the activation of an acidic sphingomyelinase, sphingomyelin breakdown, and ceramide production. Our recent reports have shown that L-carnitine inhibits Fas-induced apoptosis and ceramide production both in vitro and in vivo. The aim of this study was to study, in a preliminary fashion, the impact of long-term L-carnitine administration on CD4 and CD8 absolute counts, rate, and apoptosis in HIV-1-infected subjects. The generation of cell-associated ceramide and HIV-1 viremia was also investigated. Eleven, asymptomatic, HIV-1-infected subjects, who refused any antiretroviral treatment despite experiencing a progressive decline of CD4 counts, were treated with daily infusions of L-carnitine (6 g) for 4 months. Immunologic and virologic measures and safety were monitored at the start of the treatment and then on days 15, 30, 90, and 150. L-carnitine therapy resulted in an increase of absolute CD4 counts, which was statistically significant on day 90 and 150 (P = . 010 and P = .019, respectively). A positive, not significant trend was also observed even in the change in absolute counts of CD8 lymphocytes. L-carnitine therapy also led to a drop in the frequency of apoptotic CD4 and CD8 lymphocytes. This reduction occurred gradually, but changes in actual values between each time point and baseline were strongly significant (P = .001 at the end of the study compared with the baseline). A strong reduction (P = .001) in cell-associated ceramide levels was found at the end of the study. In general, HIV-1 viremia increased slightly. No toxicity related to L-carnitine therapy was observed and dose reductions were not necessary. In HIV-1-infected subjects, long-term infusions of L-carnitine produced substantial increases in the rate and absolute counts of CD4 and, to a lesser degree, of CD8 lymphocytes. This was paralleled by a reduced frequency of apoptotic cells of both subgroups and a decline in the levels of ceramide. No clinically relevant change of HIV-1 viremia was observed.

Adult↗
PubMed1998

The growth arrest and downregulation of c-myc transcription induced by ceramide are related events dependent on p21 induction, Rb underphosphorylation and E2F sequestering.

Ceramide is an intracellular lipid mediator generated through the sphingomyelin cycle in response to several extracellular signals. Ceramide has been shown to induce growth inhibition, c-myc downmodulation and apoptosis. In this paper we examined the mechanism by which ceramide induces growth suppression and the role of the G1-CDK/pRb/E2F pathway in this process. The addition of exogenous, cell-permeable C2-ceramide to the Hs 27 human diploid fibroblast cell line resulted in a dose-dependent induction of the p21WAF1/CIP1/Sdi1 kinase inhibitor with reduction of cyclin-D1 associated kinase activity. Furthermore, significant dephosphorylation of pRb was observed, with increased association of pRb and the E2F transcription factor into a transcriptionally inactive complex. Ceramide was also capable of inhibiting the transcriptional activity of a CAT reporter vector driven by E2F binding sites containing c-myc promoter transfected into Hs 27 cells. The requirement of the pRb protein for ceramide-induced c-myc downregulation was supported by the failure of ceramide to inhibit promoter activity in HeLa cells, in which pRb function is abrogated by the presence of the E7 Papilloma virus oncoprotein, and in pRb-deleted SAOS2 AT cells. Ceramide-induced downregulation of the c-myc promoter was restored in SAOS2 #1 cells in which a functional Rb gene was reintroduced. Our studies demonstrate that pRb dephosphorylation, induced by ceramide, is at least partly necessary for c-myc downregulation, and therefore the CDK-Rb-E2F pathway appears to be a target for the ceramide-induced modulation of cell cycle regulated gene transcription.

Apoptosis↗
PubMed1997

2-Aminopurine unravels a role for pRB in the regulation of gene expression by transforming growth factor beta.

Transforming growth factor type beta (TGFbeta) is a pleiotropic factor that regulates different cellular activities including cell growth, differentiation, and extracellular matrix deposition. All the known effects of TGFbeta appear to be mediated by its interaction with cell surface receptors that possess a serine/threonine kinase activity. However, the intracellular signals that follow receptor activation and lead to the different cellular responses to TGFbeta are still largely unknown. On the basis of the different sensitivity to the protein kinase inhibitor 2-aminopurine and the phosphatase inhibitor okadaic acid, we identified two distinct pathways through which TGFbeta activates a genomic response. Consistently, 2-aminopurine prevented and okadaic acid potentiated the induction of JE by TGFbeta. The induction of PAI-1 and junB was instead potentiated by 2-aminopurine, after a transient inhibition and was unaffected by okadaic acid. The superinducing effect of 2-aminopurine required the presence of a functional RB protein since it was abolished in SV40 large T antigen-transfected cells, absent in the BT549 and Saos-2 RB-defective cell lines, and restored in BT549 and Saos-2 cells after reintroduction of pRB. The effects of 2-aminopurine on the TGFbeta inducible junB expression occur in all the cell lines examined suggesting that junB, and possibly other genes, can be regulated by TGFbeta through a distinct pRB-dependent pathway.

2-Aminopurine↗
PubMed1997

Effect of L-carnitine treatment in vivo on apoptosis and ceramide generation in peripheral blood lymphocytes from AIDS patients.

Lymphocyte apoptosis in HIV-infected individuals may play a role in T-cell depletion and therefore favor progression to AIDS. In this study, we examined the effects of a short-term (5-day) intravenous treatment with L-carnitine (6 g/day) on apoptosis of CD4 and CD8 cells from 10 AIDS patients. L-carnitine administration has been shown to induce a strong reduction in the percentage of both CD4 and CD8 cells undergoing apoptosis. Interestingly, the L-carnitine treatment, which did not show relevant side effects in four patients, led to a strong and significant reduction of peripheral blood mononuclear cell-associated ceramide, an intracellular messenger of apoptosis, that positively correlated with the decrease of apoptotic CD4- and CD8-positive cells. These results suggest that L-carnitine could be an effective antiapoptotic drug in the treatment of AIDS patients.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Influence of L-carnitine on CD95 cross-lining-induced apoptosis and ceramide generation in human cell lines: correlation with its effects on purified acidic and neutral sphingomyelinases in vitro.

Recently, we examined the effects of a short-term (5-days) intravenous L-carnitine (6 g/die) treatment on apoptosis of CD4 and CD8 cells from 10 AIDS patients. Without inducing side effects, L-carnitine administration has been shown to induce a potent reduction in the percentage of cells undergoing apoptosis, paralleled by a significant increase of CD4 an CD8 cells. Interestingly, L-carnitine treatment led to a significant reduction of peripheral blood mononuclear cell-associated ceramide (an intracellular messenger for apoptosis) that correlated with the decrease of apoptotic CD4- and CD8-positive cells. These results suggest that L-carnitine could be an effective antiapoptotic drug use with AIDS patients. In this article we report the results of in vitro studies performed to better characterize the effects of L-carnitine on cell apoptosis. Previously, a high expression of the Fas (CD95/APO-1)/Fas ligand system in peripheral blood mononuclear cells from HIV-positive individuals has been reported and could be responsible for the observed relevant apoptosis of both infected and uninfected cells. Thus, we investigated the in vitro effects of L-carnitine on CD95 cross-linking-induced apoptosis through an anti-CD95 mAb in Fas-sensitive cell lines (HuT78 and U937). The results strongly support the in vivo observations. Our data indicate that L-carnitine is able to inhibit CD95-induced apoptosis of these cells, most likely by preventing sphingomyelin breakdown and consequent ceramide synthesis. The effect of L-carnitine seems to be specific for acidic sphingomyelinase as shown by experiments performed in vitro and using purified neutral or acidic sphingomyelinases.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Expression of trKB neurotrophin receptor during T cell development. Role of brain derived neurotrophic factor in immature thymocyte survival.

The relationships between the nervous and the immune systems raise the question of whether neurotrophic factors, in addition to the regulation of neural cell ontogeny, may influence lymphocyte development. We report in this work that the pattern of neurotrophin receptor expression depends on the developmental stage of T cells. The presence of nerve growth factor receptor trkA could not be detected in any of the thymocyte subsets, whereas brain-derived neurotrophic factor (BDNF) receptor trkB was expressed in all thymocyte subpopulations. Interestingly, both trkB mRNA and protein expression inversely correlated with the maturation stage and the differentiation potential of thymocytes, being more expressed in CD4-8- immature thymocytes and progressively declining in CD8+ and CD4+ single-positive and CD4+8+ more mature thymocytes. The developmentally regulated expression of trkB is further shown by the inhibition or enhancement of trkB expression induced by signals that either trigger or impair the transition from immature to more differentiated stages of the thymocyte developmental pathway. Signals generated following the interaction of BDNF with trkB receptor resulted in the stimulation of trkB autophosphorylation and in the up-regulation of the expression of the c-fos gene in CD4-8- cells and enhanced thymocyte survival. Finally, BDNF is expressed in thymic stroma and is further up-regulated by signals generated by the thymocyte/stromal cell interaction. These data suggest that BDNF may be a novel survival factor for thymocyte precursors and support the presence of developmentally regulated feedback mechanisms based on autocrine/paracrine neurotrophin/receptor interactions that may be involved in the thymocyte differentiation process.

Animals↗
PubMed1996

Prostaglandin E2 inhibits the interleukin-2 promoter activity through down-regulation of the Oct-dependent transcription of the octamer motif.

Prostaglandins, mainly those of the E series (PGE), are modulators of immune responses. Indeed PGE2 inhibits T cell activation and the transcription of the interleukin-2 (IL-2) gene, the major T cell growth factor. We observed that PGE2 inhibits IL-2 promoter transcription activity by interfering with signals activating the (-96 to -66 bp) octamer motif. This motif binds Oct-1 and Oct-2 as well as the phorbol ester and calcium ionophore-inducible jun and fos AP-1 factors. The PGE2-dependent down-modulation is observed in the presence of either the endogenous transacting factor Oct-1 or the exogenously expressed Oct-2. PGE2 does not regulate octamer function by influencing the jun and fos mRNA or Oct-1 protein levels or their DNA-binding abilities. Functional dissection of the octamer motif, through mutations of either the AP-1 or the octamer sites, revealed that the AP-1 site is dispensable for PGE2-dependent inhibition which instead may occur through the interference with the Oct-mediated transactivation of the octamer element. Our data suggest that the Oct-octamer interaction is a novel target of the PGE2-induced down-regulation of the IL-2 promoter.

DNA-Binding Proteins↗