Mario Arciello

Publications (10)30.55 Total impact

• Article: Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer’s disease patients

  Concetta R. Capo, Mario Arciello, Rosanna Squitti, Emanuele Cassetta, Paolo Maria Rossini, Lilia Calabrese, Luisa Rossi
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  ABSTRACT: The level of the apo-form of the copper enzyme ceruloplasmin (CP) is an established peripheral marker in diseases associated with copper imbalance. In view of the proposal that disturbances of copper homeostasis may contribute to neurodegeneration associated with Alzheimer’s disease (AD), the present work investigates, by Western blot and non-reducing SDS-PAGE followed by activity staining, the features of CP protein, and the copper/CP relationship in cerebrospinal fluid (CSF) and serum of AD patients. Results show that only a fraction of total copper is associated with CP in the CSF, at variance with serum, both in affected and in healthy individuals. Furthermore, a conspicuous amount of apo-ceruloplasmin and a decrease of CP oxidase activity characterize the CSF of the affected individuals, and confirm that an impairment of copper metabolism occurs in their central nervous system. In the CSF of AD patients the decrease of active CP, associated with the increase in the pool of copper not sequestered by this protein, may play a role in the neurodegenerative process.
  BioMetals 04/2012; 21(3):367-372. · 2.82 Impact Factor
• Article: Focal adhesion kinase (FAK) mediates the induction of pro-oncogenic and fibrogenic phenotypes in hepatitis C virus (HCV)-infected cells.

  Anna Alisi, Mario Arciello, Stefania Petrini, Beatrice Conti, Gabriele Missale, Clara Balsano
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  ABSTRACT: Hepatitis C Virus (HCV) infection is one of the most common etiological factors involved in fibrosis development and its progression to hepatocellular carcinoma (HCC). The pivotal role of hepatic stellate cells (HCSs) and extracellular matrix (ECM) in fibrogenesis is now certainly accepted, while the network of molecular interactions connecting HCV is emerging as a master regulator of several biological processes including proliferation, inflammation, cytoskeleton and ECM remodeling. In this study, the effects of HCV proteins expression on liver cancer cells, both pro-invasive and pro-fibrogenic phenotypes were explored. As a model of HCV infection, we used permissive Huh7.5.1 hepatoma cells infected with JFH1-derived ccHCV. Conditioned medium from these cells was used to stimulate LX-2 cells, a line of HSCs. We found that the HCV infection of Huh7.5.1 cells decreased adhesion, increased migration and caused the delocalization of alpha-actinin from plasma membrane to cytoplasm and increased expression levels of paxillin. The treatment of LX-2 cells, with conditioned medium from HCV-infected Huh7.5.1 cells, caused an increase in cell proliferation, expression of alpha-smooth muscle actin, hyaluronic acid release and apoptosis rate measured as cleaved poly ADP-ribose polymerase (PARP). These effects were accompanied in Huh7.5.1 cells by an HCV-dependent increasing of FAK activation that physically interacts with phosphorylated paxillin and alpha-actinin, and a rising of tumor necrosis factor alpha production/release. Silencing of FAK by siRNA reverted all effects of HCV infection, both those directed on Huh7.5.1 cells, and those indirect effects on the LX-2 cells. Moreover and interestingly, FAK inhibition enhances apoptosis in HCV-conditioned LX-2 cells. In conclusion, our findings demonstrate that HCV, through FAK activation, may promote cytoskeletal reorganization and a pro-oncogenic phenotype in hepatocyte-like cells, and a fibrogenic phenotype in HSCs.
  PLoS ONE 01/2012; 7(8):e44147. · 4.09 Impact Factor
• Article: Inverse correlation between plasma oxysterol and LDL-cholesterol levels in hepatitis C virus-infected patients.

  Mario Arciello, Salvatore Petta, Valerio Leoni, Gino Iannucci, Giancarlo Labbadia, Carlo Cammà, Antonio Craxì, Clara Balsano
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  ABSTRACT: Hepatitis C virus infection is characterised by enhanced oxidative stress, which can be measured quantitatively by plasma oxysterol concentration. These molecules may affect lipid metabolism through the activation of Liver X Receptors. Hepatitis C virus exploits host lipid metabolism to facilitate its replication and diffusion. In our study we aimed to evaluate and highlight the potential pathogenetic role of oxysterols, 7-ketocholesterol and 7-β-hydroxycholesterol, in hepatitis C virus-related lipid dysmetabolism. The study was performed in 42 patients with chronic hepatitis C (93% genotype 1b) and 38 non-alcoholic fatty liver disease patients. Plasma oxysterols 7-ketocholesterol and 7-β-hydroxycholesterol were determined by isotope dilution gas chromatography/mass spectrometry. Gas chromatography/mass spectrometry revealed higher 7-ketocholesterol (71.2 ± 77.3 vs 30.4 ± 14.5; p<0.005) and 7-β-hydroxycholesterol (23.7 ± 20.6 vs 11.5 ± 4.9; p<0.001) plasma levels in hepatitis C virus patients. Furthermore, multivariate regression analysis highlighted an inverse independent correlation between high oxysterol levels and low low-density lipoprotein cholesterol (p=0.01 for 7-β-hydroxycholesterol; p=0.02 for 7-ketocholesterol) in the hepatitis C virus group; in contrast, the non-alcoholic fatty liver disease group showed a direct correlation between oxysterol levels and low-density lipoprotein-cholesterol (p<0.001 for 7-β-hydroxycholesterol; p=0.002 for 7-ketocholesterol). These different correlations reveal profound differences in lipid dysmetabolism between chronic hepatitis C and non-alcoholic fatty liver disease patients.
  Digestive and Liver Disease 12/2011; 44(3):245-50. · 3.05 Impact Factor
• Article: Regarding: epithelial-mesenchymal transition induced by hepatitis C virus core protein in cholangiocarcinoma.

  Clara Balsano, Beatrice Conti, Mario Arciello
  Annals of Surgical Oncology 03/2011; 18(3):896; author reply 897. · 4.17 Impact Factor
• Article: Copper depletion increases the mitochondrial-associated SOD1 in neuronal cells.

  Mario Arciello, Concetta Rosa Capo, Sara D'Annibale, Mauro Cozzolino, Alberto Ferri, Maria Teresa Carrì, Luisa Rossi
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  ABSTRACT: The role of copper in the toxicity of mutant copper-dependent enzyme superoxide dismutase (SOD1) found in patients affected with the familial form of amyotrophic lateral sclerosis (fALS) is widely debated. Here we report that treatment of human neuroblastoma cells SH-SY5Y with a specific copper chelator, triethylene tetramine (Trien) induces the decrease of intracellular copper level, paralleled by decreased activity of SOD1. A comparable effect is observed in mouse NSC-34-derived cells, a motoneuronal model, transfected for the inducible expression of either wild-type or G93A mutant human SOD1, one of the mutations associated with fALS. In both cell types, the drop of SOD1 activity is not paralleled by the same extent of decrease in SOD1 protein content. This discrepancy can be explained by the occurrence of a fraction of copper-free SOD1 upon copper depletion, which is demonstrated by the partial recovery of the enzyme activity after the addition of copper sulphate to homogenates of SH-SY5Y cells. Furthermore, copper depletion produces the enrichment of the physiological mitochondrial fraction of SOD1 protein, in both cells models. However, increasing the fraction of mitochondrial, possibly copper-free, mutant human SOD1 does not further alter mitochondrial morphology in NSC-34-derived cells. Thus, copper deficiency is not a factor which may worsen mitochondrial damage, which is one of the earliest events in fALS associated with mutant SOD1.
  Biology of Metals 12/2010; 24(2):269-78. · 3.17 Impact Factor
• Article: Inactivation of cytochrome c oxidase by mutant SOD1s in mouse motoneuronal NSC‐34 cells is independent from copper availability but is because of nitric oxide

  Mario Arciello, Concetta Rosa Capo, Mauro Cozzolino, Alberto Ferri, Monica Nencini, Maria Teresa Carrì, Luisa Rossi
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  ABSTRACT: J. Neurochem. (2010) 112, 183–192.AbstractThe copper-enzyme cytochrome c oxidase (Cytox) has been indicated as a primary molecular target of mutant copper, zinc superoxide dismutase (SOD1) in familial amyotrophic lateral sclerosis (fALS); however, the mechanism underlying its inactivation is still unclear. As the toxicity of mutant SOD1s could arise from their selective recruitment to mitochondria, it is conceivable that they might compete with Cytox for the mitochondrial copper pool causing Cytox inactivation. To investigate this issue, we used mouse motoneuronal neuroblastoma × spinal cord cell line-34, stably transfected for the inducible expression of low amounts of wild-type or mutant (G93A, H46R, and H80R) human SOD1s and compared the effects observed on Cytox with those obtained by copper depletion. We demonstrated that all mutants analyzed induced cell death and decreased the Cytox activity, but not the protein content of the Cytox subunit II, at difference with copper depletion that also affected subunit II protein. Copper supplementation did not counteract mutant hSOD1s toxicity. Otherwise, the treatment of neuroblastoma × spinal cord cell line-34 expressing G93A, H46R, or H80R hSOD1 mutants, and showing constitutive expression of iNOS and nNOS, with either a NO scavenger, or NOS inhibitors prevented the inhibition of Cytox activity and rescued cell viability. These results support the involvement of NO in mutant SOD1s-induced Cytox damage, and mitochondrial toxicity.
  Journal of Neurochemistry 12/2009; 112(1):183 - 192. · 4.06 Impact Factor
• Article: 7-ketocholesterol and 5,6-secosterol modulate differently the stress-activated mitogen-activated protein kinases (MAPKs) in liver cells.

  Simona Anticoli, Mario Arciello, Adriano Mancinetti, Massimo De Martinis, Lia Ginaldi, Luigi Iuliano, Clara Balsano
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  ABSTRACT: Enhanced oxidative stress is a common feature of liver diseases and contributes to chronic liver disease (CLD) progression by inducing fibrogenesis during liver regeneration. Peroxidation products of cholesterol metabolism, named oxysterols, are new and reliable markers of oxidative stress in vivo. Patients affected by CLDs present high plasma levels of oxysterols, raising the question of the origin and biological relevance of these compounds in the pathophysiology of chronic liver damage. The aim of this study was to examine the molecular basis of the biological effects of oxysterols on liver-derived cells, HepG2 and Huh7. Cells were treated with different concentrations (10(-9) to 10(-5) M) of 7-ketocholesterol used as a reference, and 5,6-secosterol, a recently discovered oxysterol. FACS investigations, caspase-3 activation, and Sytox Green immunofluorescent assay showed that pathological concentrations of oxysterols induced necrosis (30-50%) after 48 h of treatment. The two analyzed compounds displayed a similar, but not identical, behavior. In fact, 5,6-secosterol, but not 7-ketocholesterol, induced cell senescence. Notably, low concentrations of 5,6-secosterol caused a sustained activation of ERK1/2, inducing cell proliferation, this unexpected behavior should be better characterized by further studies. Since enhanced oxidative stress is known to worsen liver chronic hepatitis and frequently results in overall decreased cellular survival, our data suggest the important and different role oxysterols may have in interfering with physiological liver tissue regeneration in injured human liver. Antioxidant treatment may provide a highly specific and effective mean to counteract the common consequences of oxidative stress on chronic hepatitis, such as fibrosis/cirrhosis and liver failure.
  Journal of Cellular Physiology 11/2009; 222(3):586-95. · 3.87 Impact Factor
• Article: Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer's disease patients.

  Concetta R Capo, Mario Arciello, Rosanna Squitti, Emanuele Cassetta, Paolo Maria Rossini, Lilia Calabrese, Luisa Rossi
  [show abstract] [hide abstract]
  ABSTRACT: The level of the apo-form of the copper enzyme ceruloplasmin (CP) is an established peripheral marker in diseases associated with copper imbalance. In view of the proposal that disturbances of copper homeostasis may contribute to neurodegeneration associated with Alzheimer's disease (AD), the present work investigates, by Western blot and non-reducing SDS-PAGE followed by activity staining, the features of CP protein, and the copper/CP relationship in cerebrospinal fluid (CSF) and serum of AD patients. Results show that only a fraction of total copper is associated with CP in the CSF, at variance with serum, both in affected and in healthy individuals. Furthermore, a conspicuous amount of apo-ceruloplasmin and a decrease of CP oxidase activity characterize the CSF of the affected individuals, and confirm that an impairment of copper metabolism occurs in their central nervous system. In the CSF of AD patients the decrease of active CP, associated with the increase in the pool of copper not sequestered by this protein, may play a role in the neurodegenerative process.
  BioMetals 07/2008; 21(3):367-72. · 2.82 Impact Factor
• Article: Copper-dependent toxicity in SH-SY5Y neuroblastoma cells involves mitochondrial damage.

  Mario Arciello, Giuseppe Rotilio, Luisa Rossi
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  ABSTRACT: Treatment of SH-SY5Y human neuroblastoma cells with copper sulphate (50-300microM) in complete medium for 24h caused an increase in the level of the metal both in whole cells and in isolated mitoplasts. Toxic effects of copper resulted in the impairment of the capability of mitochondrial dehydrogenases to reduce a tetrazolium salt, and, to a lesser extent, in the loss of the integrity of the plasma membrane. The mechanism of toxicity involved the production of reactive oxygen species, amplified by the presence of ascorbate. Decreases in the levels of several mitochondrial proteins (subunits of complex I, complex V, and of the pyruvate dehydrogenase complex) were observed. These findings demonstrate that mitochondria are an early and susceptible target of copper-mediated oxidative stress in neuronal cells and support the hypothesis that mitochondrial damage triggers the neurodegenerative processes associated with copper overload in Wilson's disease.
  Biochemical and Biophysical Research Communications 03/2005; 327(2):454-9. · 2.48 Impact Factor
• Article: Copper imbalance and oxidative stress in neurodegeneration.

  Luisa Rossi, Mario Arciello, Concetta Capo, Giuseppe Rotilio
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  ABSTRACT: Much experimental evidence demonstrates that the increased production of free radicals and oxidative damage due to alterations in copper homeostasis (because of either deficit or excess or aberrant coordination of the metal) are involved in the neurodegenerative processes occurring in many disorders of the central nervous system. This review outlines the systems that are involved in copper homeostasis and in the control of copper redox reactivity. The mechanisms underlying neurodegeneration in the acknowledged genetic disturbances of copper homeostasis, namely Menkes' and Wilson's diseases, and the involvement of copper in the aetiology of the major neurodegenerative disease of the aging brain, Alzheimer's disease, will be described, with particular focus on oxidative stress.
  The Italian journal of biochemistry 55(3-4):212-21.