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Biomedical subjects

M Fiore

Publications and source records attributed to M Fiore.

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

X-ray-induced chromosome aberrations in human lymphocytes in vitro are potentiated under simulated microgravity conditions (Clinostat).

The influence of simulated microgravity weightlessness on the outcome of radiation-induced chromosomal aberrations was investigated using the clinostat as a tool to simulate weightlessness conditions. Treatments were performed in the G0 phase of human lymphocytes with 1.5 Gy of X-rays alone or in combination with the DNA synthesis inhibitor of 1-beta-D-arabinofuranosylcytosine (ara-C) to check also for possible specific radiation-induced DNA repair processes impairment (excision repair caused by base damage) under microgravity conditions. The results obtained, which confirmed previous findings, showed significantly higher increases of aberrant cells and hence total number of aberrations compared to the parallel treatments performed 'on ground'. For what concern ara-C its contribution in terms of potentiation in the induction of aberrant cells was equivalent in absolute terms under simulated microgravity conditions and 'on ground' indicating that excision repair caused by base damage and inhibited by ara-C is not affected by simulated microgravity. A possible explanation for this outcome could quote two major factors: i) Enhanced probability that under simulated microgravity conditions the reactive DSB are spatially brought together to better interact, hence increasing the probability of mis-rejoining. ii) Alternatively chromatin structure could be modified under simulated microgravity conditions generating different quality and quantities of DNA lesions compared to treatments performed 'on ground'.

Antimetabolites, Antineoplastic↗
PubMed2000

Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis.

In this study we investigate the neurotoxic action of Cisplatin (6 micrograms/g body weight for 5 treatment cycles during 15 weeks with a total dose of 30 micrograms/g), an antitumor drug, and its effect on the level of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in peripheral tissues. We found that Cisplatin in adult rodents impairs peripheral sensory function and both sympathetic and sensory peripheral innervation as shown by the hot-plate response, catecholamine distribution and substance P immunoreactivity respectively. These changes are associated with decreased NGF in intestine, paws, and bladder while NGF increased in the spinal cord. Also BDNF decreased in bladder and paws and increased in spinal cord and intestine. To further investigate the role of NGF in the pathogenesis of Cisplatin-induced peripheral neuropathies a group of animals was injected with NGF (1 microgram/g every 4 days for 4 times) following Cisplatin treatment and evaluated for sensory function, sympathetic and sensory innervation and BDNF levels. Data demonstrated that exogenous NGF administration is able to restore biochemical, structural and functional changes induced by Cisplatin. These findings suggest that the reduction of NGF availability could be a cause of Cisplatin-induced peripheral neuropathies and that NGF exogenous administration could prevent or reduce Cisplatin neurotoxicity also in cancer patients, reducing the side effects of chemotherapy.

Animals↗
PubMed2000

Prolonged perinatal exposure to AZT affects aggressive behaviour of adult CD-1 mice.

RATIONALE: AZT is commonly administered to seropositive women and their neonates to prevent mother-to-child transmission of HIV. Recently, animal studies performed in monkeys and rodents have revealed that pre- and/or perinatal exposure to AZT induces age- and sex-dependent behavioural alterations in the offspring, possibly resulting from an action of this drug on CNS targets. Long-term effects of prenatal AZT treatment on social/aggressive behaviour of adult male mice have been previously described. Specifically, AZT has been shown to induce selective changes in the offensive components of agonistic interactions. OBJECTIVE: The aim of the present study was to extend previous findings, analysing the long-term effects of a more prolonged AZT exposure on intraspecific male mice agonistic behaviour. METHODS: AZT was given orally twice daily to pregnant CD- mice. The dosage selected for AZT was 160 mg/kg. Saline solution (0.9% NaCl) was used as vehicle. Starting on postnatal day (PND) 60 isolated males underwent five 15-min repeated encounters with an opponent of the same age and strain isolated for the same amount of time. Furthermore, a locomotor activity test (PND 67) and a hot-plate test (52 +/- 0.1 degrees C) (PND 74) were performed to assess AZT effects on, respectively, general activity and pain sensitivity. RESULTS: AZT perinatal exposure reduced attack behaviour of adult mice, while increasing the likelihood of them behaving as subordinates. Furthermore, long-term effects of AZT treatment on pain sensitivity were found in the hot-plate test, with AZT mice showing higher pain thresholds than controls. CONCLUSIONS: Overall, these data indicate that perinatal exposure to drugs such as AZT exerts selective effects on the developing CNS, resulting in long-term behavioural disturbances. Future studies will need to address the issue of the specific mechanisms underlying these effects.

Aggression↗
PubMed2000

Learning performances, brain NGF distribution and NPY levels in transgenic mice expressing TNF-alpha.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine involved in a variety of neurobiological activities including changing behavior and regulation of both neurotrophin and neuropeptide levels. In this study we used two lines of transgenic mice overexpressing brain TNF-alpha characterized by neurological deficits (line Tg6074) or phenotypically normal (line TgK3). We analyzed whether or not impairments in learning and memory processes due to TNF-alpha overexpression were associated with changes in endogenous brain NGF, NPY and beta-amyloid. The results indicate that full TNF-alpha transgene expression disrupted the learning capabilities of transgenic mice (both Tg6074 and TgK3). NGF decreased in the hippocampus of both transgenic mice whereas hippocampal NPY slightly potentiated in Tg6074. The decrease in NGF is correlated with deficits in spatial learning and memory whereas inflammation in the brain of Tg6074 could be responsible of the hippocampal increase in NPY. As a whole, these results show that transgenic mice overexpressing TNF-alpha in the brain represent a useful model for studying neuronal degeneration and brain inflammatory processes.

Amyloid beta-Peptides↗
PubMed2000

Data and hypotheses on the role of nerve growth factor and other neurotrophins in psychiatric disorders.

Nerve growth factor (NGF) was discovered and characterized for its role on the growth, differentiation and maintenance of specific neurons of the peripheral nervous system. Subsequent studies revealed that NGF is synthesized and released within the central nervous system and exerts a trophic and functional role on basal forebrain cholinergic neurons; it is involved in a protective role following brain insults induced by an epileptic status, seizure, as well as surgical and chemical lesions.More recently our collaborative studies provided evidence that NGF is implicated in neurobehavioral response including cerebral alterations associated with psychiatric disorders. In this brief review, ongoing and emerging data are presented and discussed.

Animals↗
PubMed2000

Clastogenic effects of two tyrosine kinase inhibitors, tyrphostin 23 and tyrphostin 46, on a transformed (CHO-K1) and on a primary embryonic chinese hamster cell line (CHE).

Protein tyrosine kinases (PTKs) play fundamental roles in signal transduction pathways. Many proliferative diseases are characterized by deregulation of PTK activity, therefore PTKs appear as promising targets in the design of anticancer drugs. Tyrphostins are a family of synthetic compounds which efficiently target specific PTKs without competing for ATP and thus are much less cytotoxic with respect to conventional therapeutic agents. We tested two tyrphostin derivatives, Tyrphostin 23 and Tyrphostin 46, on a transformed (CHO-K1) and on a primary embryonic Chinese hamster cell line (CHE) to determine whether these compounds had a genotoxic effect. We found that the tyrphostins increased sister chromatid exchange frequency in both cell lines, but induced chromosomal aberrations only in the transformed CHO-K1 cell line when treatment was in the S phase of the cell cycle, and not in primary CHE cells. Such a result could have important therapeutic implications: it could mean that deregulation of signal transduction pathways in cells which already have a deficit in cell cycle control could cause chromosomal aberrations.

Animals↗
PubMed2000

Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders.

Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are known to play a crucial role in growth, differentiation and function in a variety of brain neurons during development and in adult life. We have recently shown that environmental changes, aggressive behavior and anxiety-like responses alter both circulating and brain basal NGF levels. In the present review, we present data obtained using animal models which suggest that neurotrophic factors, particularly NGF and BDNF, might be implicated in mechanism(s) leading to a condition associated with schizophrenic-like behaviors. The hypothesis that neurotrophins of the NGF family can be implicated in some maldevelopmental aspects of schizophrenia is supported by findings indicating that the constitutive levels of NGF and BDNF are affected in schizophrenic patients.

Aggression↗
PubMed2000

Patients treated with antitumor drugs displaying neurological deficits are characterized by a low circulating level of nerve growth factor.

The aim of our study was to explore whether nerve growth factor (NGF) plays any role in the development of peripheral neuropathy induced by anticancer treatment. We measured the circulating NGF levels in 23 cancer patients before and after chemotherapy. We evaluated whether the development of peripheral neurotoxicity was associated with changes in basal NGF concentrations in patients studied with a comprehensive neurological and neurophysiological examination. The results of these studies showed that the circulating levels of NGF, which are about 20 pg/ml in plasma of controls, decrease during chemotherapy and in some cases completely disappeared after prolonged treatment with antitumor agents. The decrease in NGF levels seems to be correlated with the severity of neurotoxicity. These results clearly suggest that NGF might become a useful agent to prevent neuropathies induced by antineoplastic drugs and restore peripheral nerve dysfunction induced by these pharmacological compounds.

Aged↗
PubMed1999

Phyllanthus orbicularis aqueous extract: cytotoxic, genotoxic, and antimutagenic effects in the CHO cell line.

The present work evaluates the cytotoxic, genotoxic, and antimutagenic effects of Phyllanthus orbicularis (plant of genus Phyllantus) aqueous extract in Chinese hamster ovary (CHO) cells. P. orbicularis aqueous extracts are used in Cuban traditional medicine for their antiviral activity against Hepatitis B virus and A and B flu virus. The cytotoxicity of the extract was tested by means of colony-forming ability and growth-inhibition assays as well as by measuring the mitotic index. Apoptosis induction and cell-cycle kinetics were analyzed by cytofluorimetric methods. Chromosome aberration assays were performed to study the genotoxic and antimutagenic activity of the extract. Results show that doses of up to 100 microg/ml of the extract did not induce any cytotoxic effects. Cell survival and mitotic index decreased significantly at doses higher than 100 microg/ml as a function of dose as well as of treatment time. Moreover, continuous treatments of up to 18 h induced the appearance of a significant number of apoptotic cells. Following a 3-h exposure to a dose of 750 microg/ml, cells accumulated significantly in G(2)-M phase and remained blocked in G(1-) and G(2)-M phases after several posttreatments in fresh growth medium. The aqueous extract alone did not induce chromosome aberrations but, in combined treatment with H(2)O(2), significantly reduced H(2)O(2)-induced chromosome aberrations. Flow cytometric analysis of DCFH intracellular oxidation showed that the extract decreased the oxidizing power of H(2)O(2.) This ability could possibly explain the extract's antigenotoxic activity. Absence of cytotoxicity at the lower tested doses and the antimutagenic properties of the extract stimulate the interest in studying possible new pharmaceutical uses of P. orbicularis.

Animals↗
PubMed1999

Learning abilities, NGF and BDNF brain levels in two lines of TNF-alpha transgenic mice, one characterized by neurological disorders, the other phenotypically normal.

In this study we used two lines of transgenic mice overexpressing tumor necrosis factor alpha (TNF-alpha) in the central nervous system (CNS), one characterized by reactive gliosis, inflammatory demyelination and neurological deficits (Tg6074) the other showing no neurological or phenotypical alterations (TgK3) to investigate the effect of TNF-alpha on brain nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels and learning abilities. The results showed that the amount of NGF in the brain of Tg6074 and TgK3 transgenic mice is low in the hippocampus and in the spinal cord, increases in the hypothalamus of Tg6074 and showed no significant changes in the cortex. BDNF levels were low in the hippocampus and spinal cord of TgK3. BDNF increased in the hypothalamus of TgK3 and Tg6074 while in the cortex, BDNF increased only in Tg6074 mice. Transgenic mice also had memory impairments as revealed by the Morris Water Maze test. These findings indicate that TNF-alpha significantly influences BDNF and NGF synthesis, most probably in a dose-dependent manner. Learning abilities were also differently affected by overexpression of TNF-alpha, but were not associated with inflammatory activity. The possible functional implications of our findings are discussed.

Animals↗
PubMed1999

Dimethyl sulfoxide restores contact inhibition-induced growth arrest and inhibits cell density-dependent apoptosis in hamster cells.

Most nontransformed cell lines respond to confluence by arresting the cell cycle in a viable G(1) phase, whereas immortalized cell lines growing in monolayer do not stop cell cycle progression in response to high cell density and are subjected to density-dependent apoptosis. We have examined the effects, in terms of cell growth, apoptosis, and expression of adhesion molecules of culturing contact inhibition-deficient hamster cells in the presence of dimethyl sulfoxide (DMSO). Addition of 1.5% DMSO to the growth medium for 96 h arrested Chinese hamster ovary (CHO) cells in the G(1) phase as a confluent monolayer, associated with a remarkable increase in the expression of the cyclin-dependent kinase inhibitor p27. Cells cultured in DMSO-containing medium showed increased levels of cadherins and alpha5beta1 and beta1 integrin complexes. Cell exposure to DMSO also reduced both cell density-dependent apoptosis and necrosis and resulted in increased Bcl-2 expression. These results converge to indicate that DMSO restores contact inhibition-induced growth arrest and prevents high-density-dependent apoptosis and suggest that the effect of DMSO may be mediated by intracellular signaling triggered by cell-extracellular matrix and cell-cell interactions. Both p27 and bcl-2 appear to be involved in the resumption of growth control accompanying cell adhesion in DMSO-exposed CHO cells.

3T3 Cells↗
PubMed1999

Inducible expression of the cell surface heparan sulfate proteoglycan syndecan-2 (fibroglycan) on human activated macrophages can regulate fibroblast growth factor action.

Monocyte/macrophages play important roles in regulating tissue growth and angiogenesis through the controlled release of heparin-binding growth factors such as fibroblast growth factor (FGF), vascular endothelial growth factor, and heparin binding epidermal growth factor. The action of these potent growth mediators is known to be regulated by adsorption to heparan sulfate proteoglycans (HSPGs) on the surface and within the extracellular matrix of other neighboring cells, which respectively promote or restrict interactions with their signal-transducing receptors on target cells. Here we report on the nature of HSPGs inducibly expressed on the surface of macrophages that confer these cells with the capacity to regulate endogenous growth factor activity. We reveal that activated human macrophages express only a single major 48-kDa cell surface HSPG, syndecan-2 (fibroglycan) as the result of de novo RNA and protein synthesis. In addition, we demonstrate this macrophage HSPG selectively binds the macrophage-derived growth factors FGF-2, vascular endothelial growth factor and heparin binding EGF and can present FGF-2 in a form that transactivates receptor-bearing BaF32 cells. These results define a novel and unique proteoglycan profile for macrophages and imply a key role for syndecan-2 in the delivery of sequestered growth factors by inflammatory macrophages for productive binding to their appropriate target cells in vivo.

Angiogenesis Inducing Agents↗
PubMed1999

Overexpression of tumour necrosis factor alpha in the brain of transgenic mice differentially alters nerve growth factor levels and choline acetyltransferase activity.

Tumour necrosis factor alpha (TNF-alpha) is a pleiotrophic cytokine synthesized primarily by macrophages and monocytes, which exerts a variety of biological activities during inflammatory responses, immune reactions, and wound healing. Within the central nervous system (CNS), the basal levels of TNF-alpha are almost undetectable, but increase after neurological insults. Using transgenic mice expressing high levels of TNF-alpha in the CNS, we investigated the effect of this cytokine on the levels of brain nerve growth factor (NGF), a neurotrophin playing a crucial role in the development, maintenance and regeneration of basal forebrain cholinergic neurons. The immunoenzymatic assay and in situ hybridization revealed that the constitutive expression of NGF decreased in the hippocampus, increased in the hypothalamus, while remained unchanged in the cortex. Moreover, septal cholinergic neurons which receive trophic support from NGF produced in the hippocampus display loss of choline acetyltransferase immunoreactivity, suggesting that the reduced availability of NGF may influence negatively the synthesis of brain cholinergic neurons. These observations indicate that the basal level of brain NGF can be influenced negatively or positively by local expression of TNF-alpha and that this cytokine, through dose-dependent regulation of NGF synthesis and release, may be involved in neurodegenerative events associated with aging.

Age Factors↗
PubMed1999

Prenatal methylazoxymethanol acetate alters behavior and brain NGF levels in young rats: a possible correlation with the development of schizophrenia-like deficits.

It has been hypothesized that a deleterious key contribution to schizophrenia (SZ) development is a failure of migration and setting of young neurons into their appropriate cortical target sites, particularly in the entorhinal cortex (EC). To test this hypothesis in an animal model, we injected, in pregnant rats, on gestational day (GD) 9, or 10, or 11, or 12, the antimitotic compound methylazoxymethanolacetate (MAM) known to cause EC neuronal loss. We investigated whether or not EC disruption during prenatal development is able to affect behavior, including memory and learning, and brain nerve growth factor (NGF). Prenatally MAM treated young rats didn't display gross behavioral changes in social interaction, open-field and novel object investigation tests. By contrast, GD11 and GD12 MAM treated rats had a retardation in passive avoidance acquisition, while, in GD12 animals, pain sensitivity was reduced. GD12 animals also showed increased NGF in the EC and remaining cortex. MAM treated animals showed no changes in paw NGF or substance P levels suggesting that the altered nociceptive response is not related to local downregulation of these two molecules. The possibility that these behavioral and biochemical alterations might be associated with the onset of SZ is discussed.

Analysis of Variance↗
PubMed1999

Song behavior, NGF level and NPY distribution in the brain of adult male zebra finches.

The aim of the present study was to investigate the role of nerve growth factor (NGF) and neuropeptide Y (NPY) in the higher vocal center (HVC) on singing behavior of adult male zebra finches. The results of our studies show: (a) that NGF is present in the brain of these birds and it is higher in the HVC than in the other neostriatal tissues; (b) that exogenous administration of NGF or NGF-antibody had no discernible effect on singing behavior; and (c) that NGF enhances the NPY immunoreactivity in neurons and fibers localized in HVC and other areas of the neostriatum and hippocampus whereas anti-NGF decreased NPY stained cells in the hippocampus. These studies indicate that NGF is produced in the brain of zebra finch and that it plays a role in the regulation of NPY.

Animals↗
PubMed1999

Psychological and symptom distress in terminal cancer patients with met and unmet needs.

This study identified the needs of terminal cancer patients, investigated the factors associated with unmet needs, and assessed psychological and symptom distress associated with unsolved needs. Ninety-four patients were randomly selected from 324 patients admitted for palliative care in 13 Italian centers. Two self-administered questionnaires (the Symptom Distress Scale and the Psychological Distress Inventory) were administered to all the patients. Patients needs were identified using a semi-structured interview, aimed at exploring five areas: physiological needs, safety needs, love and belonging needs, self-esteem needs, self-fulfillment needs. A content analysis of the answers defined 11 needs, and identified patients with unmet needs. The most frequent unmet needs were symptom control (62.8%), occupational functioning (62.1%), and emotional support (51.7%). The less frequently reported needs were those related to personal care (14.6%), financial support (14.1%), and emotional closeness (13.8%). Low functional state was significantly associated with a high proportion of patients with unmet needs of personal care, information, communication, occupational functioning, and emotional closeness. Patients with unmet needs showed significantly higher psychological and symptom distress for most needs. This study provides some suggestions about the concerns that should be carefully considered during the late stage of cancer.

Aged↗
PubMed1999

Inhibitory action of melatonin on H2O2- and cyclophosphamide-induced DNA damage.

Melatonin, the pineal gland hormone known for its ability to modulate circadian rhythm, has recently been studied in its several functions. It is believed to inhibit cancer growth, to stimulate the immune system and to act as an antioxidant. In particular, this latter activity is ascribed to two different mechanisms: stimulation of radical detoxifying enzymes and scavenging of free radicals. We used this compound in mammalian cells in vitro to investigate its mechanism of action in modulating DNA damage. Cytogenetic and cytofluorimetric analyses were performed. We show that melatonin is able to modulate chromosome damage (chromosomal aberrations and sister chromatid exchanges) induced by cyclophosphamide. Conversely, its involvement in modulating oxidative processes, thereby reducing DNA damage, is less clear. In particular, melatonin is able to decrease H2O2-induced chromosomal aberrations but not sister chromatid exchanges and has been found to induce oxygen species in a cytofluorimetric test (DCFH assay).

Animals↗