Valeria Bergonzini

University of Padova, Padua, Veneto, Italy

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Publications (7)27.7 Total impact

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    ABSTRACT: Patients treated with amiodarone accumulate lysobisphosphatidic acid (LBPA), also known as bis(monoacylglycero)phosphate, in airway secretions and develop in different tissues vacuoles and inclusion bodies thought to originate from endosomes. To clarify the origin of these changes, we studied in vitro the effects of amiodarone on endosomal activities like transferrin recycling, Shiga toxin processing, ESCRT-dependent lentivirus budding, fluid phase endocytosis, proteolysis and exosome secretion. Furthermore, since the accumulation of LBPA might point to a broader disturbance in lipid homeostasis, we studied the effect of amiodarone on the distribution of LBPA, unesterified cholesterol, sphingomyelin and glycosphyngolipids. Amiodarone analogues were also studied, including the recently developed derivative dronedarone. We found that amiodarone does not affect early endosomal activities, like transferrin recycling, Shiga toxin processing and lentivirus budding. Amiodarone, instead, interferes with late compartments of the endocytic pathway, blocking the progression of fluid phase endocytosis and causing fusion of organelles, collapse of lumenal structures, accumulation of undegraded substrates and amassing of different types of lipids. Not all late endocytic compartments are affected, since exosome secretion is spared. These changes recall the Niemann-Pick type-C phenotype (NPC), but originate by a different mechanism, since, differently from NPC, they are not alleviated by cholesterol removal. Studies with analogues indicate that basic pKa and high water-solubility at acidic pH are crucial requirements for the interference with late endosomes/lysosomes and that, in this respect, dronedarone is at least as potent as amiodarone. These findings may have relevance in fields unrelated to rhythm control.
    Biochemical pharmacology 08/2011; 82(9):1234-49. · 4.25 Impact Factor
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    ABSTRACT: Inhibitor of differentiation-1 (Id-1) is a member of helix-loop-helix (HLH) family of proteins that regulate gene transcription through their inhibitory binding to basic-HLH transcription factors. Similarly to other members of this family, Id-1 is involved in the repression of cell differentiation and activation of cell growth. The dual function of Id-1, inhibition of differentiation, and stimulation of cell proliferation, might be interdependent, as cell differentiation is generally coupled with the exit from the cell cycle. Fibroblast growth factor-2 (FGF-2) has been reported to play multiple roles in different biological processes during development of the central nervous system (CNS). In addition, FGF-2 has been described to induce "neuronal-like" differentiation and trigger apoptosis in neuroblastoma SK-N-MC cells. Although regulation of Id-1 protein by several mitogenic factors is well-established, little is known about the role of FGF-2 in the regulation of Id-1. Using human neuroblastoma cell line, SK-N-MC, we found that treatment of these cells with FGF-2 resulted in early induction of both Id-1 mRNA and protein. The induction occurs within 1 h from FGF-2 treatment and is mediated by ERK1/2 pathway, which in turn stimulates expression of the early growth response-1 (Egr-1) transcription factor. We also demonstrate direct interaction of Egr-1 with Id-1 promoter in vitro and in cell culture. Finally, inhibition of Id-1 expression results in G(2) /M accumulation of FGF-2-treated cells and delayed cell death.
    Journal of Cellular Physiology 07/2011; 226(7):1763-70. · 4.22 Impact Factor
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    ABSTRACT: To date, almost one and a half million cases of cancer are diagnosed every year in the US and nearly 560,000 Americans are expected to die of cancer in the current year, more than 1,500 people a day (data from the American Cancer Society at http://www.cancer.org/). According to the World Health Organization (WHO), roughly 20% of all cancers worldwide results from chronic infections; in particular, up to 15% of human cancers is characterized by a viral aetiology with higher incidence in Developing Countries. The link between viruses and cancer was one of the pivotal discoveries in cancer research during the past Century. Indeed, the infectious nature of specific tumors has important implications in terms of their prevention, diagnosis, and therapy. In the 21st Century, the research on viral oncology field continues to be vigorous, with new significant and original studies on viral oncogenesis and translational research from basic virology to treatment of cancer. This review will cover different viral oncology aspects, starting from the history of viral oncology and moving to the peculiar features of oncogenic RNA and DNA viruses, with a special focus on human pathogens.
    Infectious Agents and Cancer 01/2010; 5:11.
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    ABSTRACT: Although the introduction of highly active antiretroviral therapy (HAART) has resulted in a significant decrease of acquired immunodeficiency syndrome (AIDS) morbidity and mortality, the prevalence of human immunodeficiency virus (HIV)-associated dementia (HAD) has actually risen, due to the increasing life expectancy of the infected subjects. To date, several aspects of the HAD pathogenesis remain to be dissected. In particular, the viral-cellular protein interplay is still under investigation. Given their specific features, two viral proteins, Tat and Nef, have been mainly hypothesized to play a role in HIV neuropathology. Here we show that HIV-1 Nef has an effect on the transcriptional levels of a cellular protein, anaplastic lymphoma kinase (ALK), that is preferentially expressed in the central and peripheral nervous system at late embryonic stages. By its overexpression along with Nef, the authors demonstrate ALK ability to influence, at least in the U87MG astrocytic glioma cells, the mytogen-activated protein kinase (MAP-K)-dependent pathway. Moreover, although in the absence of a physical direct interaction, Nef and ALK activate matrix metalloproteinases (MMPs), which are likely to contribute to blood-brain barrier (BBB) damage in HAD. Finally, in the in vitro model of glioblastoma cells adopted, Nef and ALK show similar effects by increasing different cytochines/chemokines that may be relevant for HAD pathogenesis. If confirmed in vivo, these data may indicate that, thanks to its ability to interfere with specific cellular pathways involved in BBB damage and in central nervous system (CNS) integrity, Nef, along with specific cellular counterparts, could be one of the viral players implicated in HAD development.
    Journal of NeuroVirology 06/2009; 15(3):238-48. · 2.85 Impact Factor
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    ABSTRACT: HIV-associated dementia (HAD) is a serious neurological disorder affecting about 7% of people with AIDS. In the brain, HIV-1 infects a restricted number of cell types, being primarily present in macrophages and microglial cells, less abundant in astrocytes, and rarely seen in oligodendrocytes and neurons. Lack of a productive HIV-1 infection of neuronal cells suggests the presence of an indirect pathway by which the virus may determine the brain pathology and neuronal dysfunction seen in AIDS patients. Among the participants in this event, viral proteins including gp120 and Tat, along with host factors including cytokines, chemokines, and several signaling pathways have received considerable attention. In this article, we discuss the most recent concepts pertaining to the mechanisms of HIV-1-induced neuronal dysfunction by highlighting the interplay between signal transduction pathways activated by viral and host factors and their consequences in neuronal cell function.
    Brain Research Reviews 01/2006; 50(1):114-25. · 7.82 Impact Factor
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    ABSTRACT: Id1 is a helix-loop-helix transcriptional factor that controls growth and survival of neuronal cells. Downregulation of Id1 expression is required to initiate differentiation and cell-cycle withdrawal in primary neuronal culture as well as in PC12 cells. The HIV-1 transactivating factor, Tat, has been suspected of causing neuronal dysfunction that often leads to the development of HIV-associated dementia in AIDS patients. We found that the expression of Tat in PC12 cells promotes serum-independent growth, formation of large colonies in soft agar, and the acceleration of tumor growth in nude mice. In addition, Tat showed the ability to inhibit the nerve growth factor (NGF)-induced neuronal differentiation of PC12 cells. Our results show that the Tat-mediated signaling events, which lead to serum-independent growth and the inhibition of NGF-induced differentiation, have a common cellular target: the upregulation of Id1 expression. In the absence of NGF, expression of Id1 is required to promote serum-independent proliferation of PC12/Tat cells, as the inhibition of Id1 by antisense DNA restored the serum-dependent growth of PC12/Tat cells. In the presence of NGF, Tat utilizes an additional pathway that involves phosphorylation of Stat5a, to upregulate Id1 expression and block neuronal cell differentiation. Suppression of Stat5a by use of its dominant-negative mutant reversed the transient expression of Id1 and the blockage of NGF-mediated differentiation in PC12/Tat cells. Finally, the treatment of PC12 cells with recombinant Tat also enhanced the NGF-induced Id1 expression, further pointing to Id1 as a target for Tat. Taken together, these studies suggest additional targets for Tat action in neuronal cells and provide new insights into the mechanisms involved in the dysregulation of neuronal functions.
    Oncogene 11/2004; 23(46):7701-11. · 8.56 Impact Factor
  • Valeria Bergonzini
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    ABSTRACT: During HIV-1 associated dementia (HAD), a variety of HIV-1-induced lesions of the central nervous system (CNS) has been described, including neuronal loss, but very little is known about the mechanisms that lead to this process. Among HIV-1 proteins, we analysed the role of Nef since it could alter some signal transduction pathways related to cellular proteins involved in neuronal differentiation, such as ALK (Anaplastic Lymphoma Kinase), thus contributing to explain some of the HAD features. Our data show that Nef alters ALK expression and interferes with the ALK signal transduction pathway, in particular by modifying the MMP-9 (Matrix MetalloProteinase-9) and MMP-2 (Matrix MetalloProteinase-2) pathways. Furthermore, Nef and ALK show a cumulative effect in the modulation of cytochines/chemokines and of proteins involved in their common transduction pathways, such as MAP-K.