Fiore A.,University of Florence |
Fiore A.,Instituto Toscano Tumori |
Carraresi L.,University of Florence |
Morabito A.,University of Florence |
And 13 more authors.
Cancer Medicine | Year: 2013
The human ether-à-go-go-related gene (hERG)1 K+ channel is upregulated in human colorectal cancer cells and primary samples. In this study, we examined the role of hERG1 in colorectal carcinogenesis using two mouse models: adenomatous polyposis coli (Apcmin/+) and azoxymethane (AOM)-treated mice. Colonic polyps of Apcmin/+ mice overexpressed mERG1 and their formation was reverted by the hERG1 blocker E4031. AOM was applied to either hERG1-transgenic (TG) mice, which overexpress hERG1 in the mucosa of the large intestine, or wild-type mice. A significant increase of both mucin-depleted foci and polyps in the colon of hERG1-TG mice was detected. Both the intestine of TG mice and colonic polyps of Apcmin/+ showed an upregulation of phospho-Protein Kinase B (pAkt)/vascular endothelial growth factor (VEGF-A) and an increased angiogenesis, which were reverted by treatment with E4031. On the whole, this article assigns a relevant role to hERG1 in the process of in vivo colorectal carcinogenesis. © 2013 The Authors.
Ricciarelli R.,University of Genoa |
Puzzo D.,University of Catania |
Bruno O.,Section of Pharmacology and Toxicology |
Canepa E.,University of Genoa |
And 10 more authors.
Annals of Neurology | Year: 2014
Cyclic adenosine monophosphate (cAMP) regulates long-term potentiation (LTP) and ameliorates memory in healthy and diseased brain. Increasing evidence shows that, under physiological conditions, low concentrations of amyloid β (Aβ) are necessary for LTP expression and memory formation. Here, we report that cAMP controls amyloid precursor protein (APP) translation and Aβ levels, and that the modulatory effects of cAMP on LTP occur through the stimulation of APP synthesis and Aβ production. Ann Neurol 2014;75:602-607 © 2014 American Neurological Association.
Luccini E.,Section of Pharmacology and Toxicology |
Romei C.,Section of Pharmacology and Toxicology |
Di Prisco S.,Section of Pharmacology and Toxicology |
Raiteri M.,Section of Pharmacology and Toxicology |
And 3 more authors.
Journal of Neurochemistry | Year: 2010
Energy deprivation during ischemia causes dysregulations of ions, particularly sodium, potassium and calcium. Under these conditions, release of neurotransmitters is often enhanced and can occur by multiple mechanisms. The aim of this work was to characterize the modes of exit of glycine and GABA from nerve endings exposed to stimuli known to reproduce some of the ionic changes typical of ischemic conditions. Their approach was chosen instead of application of ischemic conditions because the release evoked during ischemia is mechanistically too heterogeneous. Mouse hippocampus and spinal cord synaptosomes, pre-labeled with [3H]glycine or [3H]GABA, were exposed in superfusion to 50 mM KCl or to 10 M veratridine. The evoked overflows differed greatly between the two transmitters and between the two regions examined. Significant portions of the K+- and the veratridine-evoked overflows occurred by classical exocytosis. Carrier-mediated release of GABA, but not of glycine, was evoked by high K+; GABA and, less so, glycine were released through transporter reversal by veratridine. External calcium-dependent overflows were only in part sensitive to -conotoxins; significant portions occurred following reversal of the plasmalemmal Na +Ca2+ exchanger. Finally, a relevant contribution to the overall transmitter overflows came from cytosolic calcium originating through the mitochondrial Na+Ca2+ exchanger. To conclude, ionic dysregulations typical of ischemia cause neurotransmitter release by heterogeneous mechanisms that differ depending on the transmitters and the CNS regions examined. © 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.
Bakke M.J.,Section of Pharmacology and Toxicology |
Nahrgang J.,University of Tromsø |
Ingebrigtsen K.,Section of Pharmacology and Toxicology
Polar Biology | Year: 2015
The Arctic is an important sink for organic pollutants such as polycyclic aromatic hydrocarbons (PAHs) long-range transported from industrial regions. With the retreat of sea ice and increasing anthropogenic activities such as the oil and gas industries, local sources of PAHs are expected to increase both through operational and accidental discharges. There is a need to increase our knowledge concerning the uptake and distribution of organic pollutants, in particular PAHs, to evaluate the risk these toxic compounds may represent for Arctic species. The absorption and tissue distribution of 14C-benzo(a)pyrene (BaP) and 14C-phenanthrene (Phen) were studied in the polar cod (Boreogadus saida), a key Arctic species. After a single oral dose of BaP (1.15 ± 0.36 mg/kg fish) or Phen (0.40 ± 0.12 mg/kg fish), corresponding to 0.12 ± 0.03 mCi/kg fish, the tissue distribution was followed through 30 days by means of whole-body autoradiography and liquid scintillation counting of liver and bile. For both compounds, radiolabeling was mainly present in the bile and the intestines throughout the study period. Phen-derived radioactivity, however, appeared to be more systemically distributed compared to BaP. Furthermore, a far higher amount of irreversibly bound BaP-derived radioactivity was present in the intestinal mucosa compared to Phen, indicating a more extensive formation of reactive intermediates from the former compared with the latter. Liquid scintillation counting confirmed that radioactivity was present in the liver at all time points for both groups although the levels were low in the BaP group. These results strongly indicated that both compounds and/or their metabolites undergo enterohepatic circulation. © 2015 The Author(s)
Nonga H.E.,Sokoine University of Agriculture |
Sandvik M.,National Veterinary Institute |
Miles C.O.,National Veterinary Institute |
Lie E.,Section of Pharmacology and Toxicology |
And 5 more authors.
Hydrobiologia | Year: 2011
Frequent mortality of Lesser Flamingo (Phoeniconaias minor) in East African alkaline saline lakes is a tragedy to the conservation of this nearly threatened species of birds. The objective of this study was to investigate the cause of Lesser Flamingo mortality in Lake Manyara during August 2008 and to determine if microcystins were involved. Pathological, microbiological and microcystin analysis was done to 11 Lesser Flamingo carcasses using standard procedures. It was found that carcasses were emaciated, the visceral organs were enlarged, haemorrhagic and the livers had nodular lesions. Tissue histopathological sections revealed that there was diffuse chronic inflammation, perisinusoidal haemorrhages, portal mononuclear cell infiltrations, necrosis and degenerative changes in the liver. Corynebacteria spp., Pasteurella multocida, Proteus spp. and Escherichia coli were isolated from the visceral organs in all carcasses. All the Lesser Flamingo carcasses contained detectable levels of microcystins. Three microcystin variants: MC-LR, -YR and -RR were detected with MC-LR having a concentration of 22 ± 16 μg/g wet weight in livers. Low concentrations of microcystins were detected in the kidneys, lungs and heart samples. Simultaneously, the high concentrations of microcystins in the livers together with the opportunistic bacterial infections could synergistically have caused effects to the stressed Lesser Flamingo which lead to their mortality. © 2011 Springer Science+Business Media B.V.
Arciuli M.,Sezione di Biologia Medica |
Fiocco D.,University of Foggia |
Cicero R.,Sezione di Biologia Medica |
Maida I.,Sezione di Biologia Medica |
And 5 more authors.
Biochemistry and Cell Biology | Year: 2012
Melanogenesis is mostly studied in melanocytes and melanoma cells, but much less is known about other pigment cell systems. Liver, spleen, kidney, and other organs of lower vertebrates harbour a visceral pigment cell system with an embryonic origin that differs from that of melanocytes. In teleosts, melanin-containing cells occur in the reticulo-endothelial system and are mainly in the kidney and spleen. The Atlantic salmon (Salmo salar L.) is an ichthyic breeding species of considerable economic importance. The accumulation of pigments in salmon visceral organs and musculature adversely affects the quality of fish products and is a problem for the aquaculture industry. With the aim to reveal novel functions and behaviour of the salmonid extracutaneous pigment system, we investigated aspects of the melanogenic systems in the tissues of Atlantic salmon, as well as in SHK-1 cells, which is a long-term cell line derived from macrophages of the Atlantic salmon head-kidney. We demonstrate that a melanogenic system is present in SHK-1 cells, head-kidney, and spleen tissues. As teleosts lack lymph nodes and Peyer's patches, the head-kidney and spleen are regarded as the most important secondary lymphoid organs. The detection of tyrosinase activity in lymphoid organs indicates that a link exists between the extracutaneous pigmentary system and the immune system in salmon. © 2012 Published by NRC Research Press.
PubMed | Section of Pharmacology and Toxicology
Type: Journal Article | Journal: Journal of neurochemistry | Year: 2011
Glycine release provoked by ion dysregulations typical of some neuropathological conditions was analyzed in cerebellar synaptosomes selectively pre-labelled with [H]glycine through GlyT2 transporters and exposed in superfusion to KCl, 4-aminopyridine (4-AP) or veratridine. The overflows caused by relatively low concentrations of the releasers were largely external Ca-dependent. Higher concentrations of KCl (50 mM) or veratridine (10 M), but not of 4-AP (1 mM), involved also external Ca-independent mechanisms. GlyT1-mediated release could not be observed; only the external Ca-independent veratridine-evoked overflow occurred significantly by GlyT2 reversal. None of the three depolarizing agents activated store-operated or transient receptor potential or L-type Ca channels. The overflows caused by KCl or 4-AP occurred in part by N- and P/Q-type voltage-sensitive calcium channel-dependent exocytosis. Significant portions of the external Ca-dependent overflow evoked by KCl or 4-AP (and all that caused by veratridine) were mediated by reverse plasmalemmal Na/Ca exchangers. Significant contribution to the overflows evoked by KCl or veratridine came from Ca originated through mitochondrial Na/Ca exchangers. Ca-induced Ca release (CICR) mediated by inositoltrisphosphate receptors (InsPRs) represents the final trigger of the glycine release evoked by high KCl. The overflows evoked by 4-AP or, less so, by veratridine also involved InsPR-mediated CICR and, in part, CICR mediated by ryanodine receptors. To conclude, ionic dysregulations typical of ischemia and epilepsy caused glycine release in cerebellum by multiple differential mechanisms that may represent potential therapeutic targets.
Bercsenyi K.,Cancer Research UK Research Institute |
Giribaldi F.,Section of Pharmacology and Toxicology |
Schiavo G.,Cancer Research UK Research Institute
Current Topics in Microbiology and Immunology | Year: 2013
Axonal transport ensures long-range delivery of essential components and signals between proximal and distal areas of the neuron, and it is crucial for neuronal homeostasis and survival. Several pathogens and virulence factors use this route to gain access to the central nervous system, exploiting the complex and still poorly understood trafficking mechanisms that regulate the dynamics of their cellular receptors. Studying the intracellular transport of neurotropic pathogens is therefore instrumental to glean new insights into these important molecular events. Botulinum (BoNT) and tetanus (TeNT) neurotoxins bind with high affinity to a variety of neurons and are internalised by specialised endocytic pathways leading to specific intracellular fates. Whereas BoNT trafficking is largely confined to the neuromuscular junction, TeNT is internalised in signalling endosomes shared with neurotrophins and their receptors, which are recruited to the fast axonal retrograde transport pathway. Recently, important paradigms regarding the mechanisms by which BoNT and TeNT interact with their cellular targets and are transported in neurons have been challenged. In this review, we summarise new findings concerning the uptake and intracellular trafficking of these neurotoxins, and discuss their implications in terms of the physiological effects of BoNT and TeNT in the central nervous system. © Springer-Verlag Berlin Heidelberg 2013.