Valeria Bertagnolo - Academia.edu (original) (raw)

Papers by Valeria Bertagnolo

Antioxidants

Voghiera garlic is an Italian white garlic variety which obtained in 2010 the Protected Designati... more Voghiera garlic is an Italian white garlic variety which obtained in 2010 the Protected Designation of Origin. It is widely used for culinary purposes or as an ingredient for supplement production due to its phytochemical compositions. The storage conditions seem to be crucial to retain the high quality of garlic bulbs and their by-products, taking into account the high importance of organosulfur and phenolic compounds for the bioactive potency of garlic and its shelf-life. This study aims to examine the effect of storage on the phytochemical composition, biological effects, and shelf-life of Voghiera garlic PDO. In detail, we considered (i) −4 °C (industrial storage) for 3, 6, and 9 months; (ii) +4 °C for 3 months (home conservation), and (iii) −4 °C for 3 months, plus +4 °C for another 3 months. We focused our attention on the organosulfur compounds, total condensed tannins, flavonoids, phenolic compounds, and related antioxidant activity changes during the storage period. To eval...

Italian journal of anatomy and embryology, 2016

Ductal carcinoma in situ (DCIS), which represents the most frequently diagnosed tumor in women in... more Ductal carcinoma in situ (DCIS), which represents the most frequently diagnosed tumor in women in industrialized countries, may be a crucial step in the progression of breast lesions to invasive ductal carcinoma (IDC) (1). Among the signaling molecules deregulated in breast tumors, the beta2 isoform of the phosphoinositide-dependent phospholipase C (PLC-b2) strongly correlates with malignancy of invasive tumors and breast tumor-derived cells (2, 3). In breast tumor-derived cell lines cultured under hypoxia, PLC-b2 regulates the levels of cancer stem cell and epithelial-to-mesenchymal transition (EMT) markers (4), suggesting its involvement in breast cancer progression. By using archival FFPE breast tumor samples, we demonstrated that PLC-β2 is up-regulated in DCIS, in which it inversely correlates to the levels of miR-146a, known to act as a tumor suppressor in breast cancer (5). By using the MCF10DCIS cell line, a well-established model of DCIS-derived cells, we demonstrated that the de-regulation of miR-146a is sufficient to modulate the expression of PLC-β2, in turn able to affect the epithelial-to-mesenchymal shift as well as the number of cells expressing CD133. These data indicate that miR-146a and PLC-β2 are members of an intracellular network able to ensure the maintenance of the non-invasive phenotype of DCIS and suggest that alterations in their levels can determine the appearance of an invasive phenotype. The potential prognostic relevance of PLC-β2/miR-146a relationship was investigated in primary DCIS from patients who developed an invasive ductal carcinoma in the contralateral breast. The PLC-β2/miR-146a correlation was found negative in primary DCIS from patients who did not recur and strongly positive in DCIS from patients who developed a contralateral IDC. We propose that the assessment of the correlation between the levels of PLC-β2 and miR-146a in primary DCIS at diagnosis could be beneficial to identify patients with either low or high propensity to develop invasive recurrence. Since a major problem in the management of patients with DCIS is the lack of reliable prognostic markers, our results might be of value in selecting the most appropriate therapies for individual women with non-invasive breast neoplasia.

Cell Biology International Reports, May 1, 1991

Journal of Cellular and Molecular Medicine, Mar 13, 2018

It has been recently demonstrated that high pre-treatment levels of miR-29b positively correlated... more It has been recently demonstrated that high pre-treatment levels of miR-29b positively correlated with the response of patients with acute myeloid leukaemia (AML) to hypomethylating agents. Upmodulation of miR-29b by restoring its transcriptional machinery appears indeed a tool to improve therapeutic response in AML. In cells from acute promyelocytic leukaemia (APL), miR-29b is regulated by PU.1, in turn upmodulated by agonists currently used to treat APL. We explored here the ability of PU.1 to also regulate miR-29b in non-APL cells, in order to identify agonists that, upmodulating PU.1 may be beneficial in hypomethylating agents-based therapies. We found that PU.1 may regulate miR-29b in the non-APL Kasumi-1 cells, showing the t(8;21) chromosomal rearrangement, which is prevalent in AML and correlated with a relatively low survival. We demonstrated that the PU.1-mediated contribution of the 2 miR-29b precursors is cell-related and almost completely dependent on adequate levels of Vav1. Nuclear PU.1/Vav1 association accompanies the transcription of miR-29b but, at variance with the APL-derived NB4 cells, in which the protein is required for the association of PU.1 with both miRNA promoters, Vav1 is part of molecular complexes to the PU.1 consensus site in Kasumi-1. Our results add new information on the transcriptional machinery that regulates miR-29b expression in AML-derived cells and may help in identifying drugs useful in upmodulation of this miRNA in pre-treatment of patients with non-APL leukaemia who can take advantage from hypomethylating agent-based therapies.

International Journal of Immunopathology and Pharmacology, Apr 1, 2006

Protein kinase Cs (PKCs) belong to a serine/threonine kinase family, ubiquitously expressed and c... more Protein kinase Cs (PKCs) belong to a serine/threonine kinase family, ubiquitously expressed and claimed to be involved in physiological processes including apoptosis, cell growth and differentiation. The question of the subcellular localization and activity of PKCs remains to be clarified. Here we report that nuclear PKC-o cooperates to regulate the S-G2/M phase transition of cell cycle, apparently being associated to chromosome condensation and alignment on the metaphase plate. MATERIALS AND METHODS Cell Culture and treatment Jurkat cells were grown in RPMI-1640 medium (Mascia Brunelli, Milano, Italy) containing 10% fetal calf serum (FCS, Mascia Brunelli), 2 mM L-glutamine

Cellular oncology, Aug 1, 2016

Purpose Reduced expression of miR-142-3p has been found to be associated with the development of ... more Purpose Reduced expression of miR-142-3p has been found to be associated with the development of various subtypes of myeloid leukemia, including acute promyelocytic leukemia (APL). In APLderived cells, miR-142-3p expression can be restored by all-trans retinoic acid (ATRA), which induces the completion of their maturation program. Here, we aimed to assess whether PU.1, essential for ATRA-induced gene transcription, regulates the expression of miR-142-3p in APLderived cells and, based on the established cooperation between PU.1 and Vav1 in modulating gene expression, to evaluate the role of Vav1 in restoring the expression of miR-142-3p. Methods ATRA-induced increases in PU.1 and Vav1 expression in APL-derived NB4 cells were counteracted with specific siRNAs, and the expression of miR-142-3p was measured by quantitative real-time PCR (qRT-PCR). The recruitment of PU.1 and/or Vav1 to the regulatory region of miR-142 was assessed by quantitative chromatin immunoprecipitation (Q-ChIP). Synthetic inhibitors or mimics for miR-142-3p were used to assess whether this miRNA plays a role in regulating the expression of PU.1 and/or Vav1. Results We found that the expression of miR-142-3p in differentiating APL-derived NB4 cells is dependent on PU.1, and that Vav1 is essential for the recruitment of this transcription factor to its cis-binding element on the miR-142 promoter. In addition, we found that in ATRA-treated NB4 cells miR-142-3p sustains agonist-induced increases in both PU.1 and Vav1. Conclusions Our results suggest the existence of a Vav1/PU.1/miR-142-3p network that supports ATRA-induced differentiation in APL-derived cells. Since selective regulation of miRNAs may play a role in the future treatment of hematopoietic malignancies, our results may provide a basis for the development of new therapeutic strategies to restore the expression of miR-142-3p.

Cell Biology International Reports, Sep 1, 1990

Subcellular distribution of inositol lipids has been studied in Friend Erythroleukemia Cells foll... more Subcellular distribution of inositol lipids has been studied in Friend Erythroleukemia Cells following induction to erythroid differentiation with hexamethylenebisacetamide, after labelling with ["Hlmyo-inositol. In situ autoradiography indicated that inositol-derived molecules were present also in the nuclear compartment of uninduced and induced cells. Fractionation studies showed that the nuclear polyphosphoinositides were deeply changed after short induction times, while the whole cell inositol lipids resulted only slightly modified by the inducer. The nuclear recovery of phosphatidylinositol 4,5-bisphosphate was largely increased after 2 hrs of induction, sugge sting that inositol lipid metabolism is involved in the early differentiation events occurring at the nuclear level.

Italian journal of anatomy and embryology, 2015

Italian journal of anatomy and embryology, 2010

PubMed, Mar 25, 2005

Differentiation and functional response of mature myeloid cells require cytoskeleton remodelling ... more Differentiation and functional response of mature myeloid cells require cytoskeleton remodelling in a dynamic system that involves subcellular organization and regional signalling. Within the myeloid lineage, neutrophils constitute a cell type in which different cell compartments, and predominantly the nucleus, undergo distinctive large changes involving actin reorganization. In the context of the progressive elucidation of the nuclear structure and composition that has been achieved in the last two decades, it is now clear that the nucleus possesses an ordered and dynamic skeletal structure which shares many properties with the cytoskeleton, and the full set of substrates and enzymes that participate in the inositol lipid metabolism. Consolidated evidence indicate that the changes in cytoskeleton assembly are regulated also by phosphoinositides in a way dependent on their local concentration and availability. Indeed, enzymes able to affect the amount and phosphorylation of inositol lipids can play fundamental roles in determining the architectural transitions of the cell. The expression pattern and the changes of activity of PLC and PI 3-K in the nucleus during differentiation of tumoral myeloid precursors suggest that these enzymes play a crucial role in modifying the intranuclear pool of phosphoinositides, which in turn induce the changes in nucleoskeleton associated to granulocytic maturation. It can be speculated that defective control of nucleoskeleton assembly is one of the causes of dysregulated cell maturation or differentiative block in the course of myeloid leukemias. Inositide modifying enzymes can thus be regarded as potential targets for molecularly designed therapeutic intervention on hematological malignancies.

Acute promyelocytic leukemia (APL), the M3 subtype of acute myeloid leukemia, is one of the most ... more Acute promyelocytic leukemia (APL), the M3 subtype of acute myeloid leukemia, is one of the most successful examples of translational research in medicine, since the coordinated combination of laboratory and clinical studies has transformed this leukemia from a fatal into a curable disease. In particular, the introduction of alltrans retinoic acid (ATRA) in APL therapy opened a new page in the history of tumor treatment, since this agonist is capable of inducing morphologic and functional maturation of APL blasts. In both APL blasts and APLderived cell lines, ATRA-induced progression of promyelocytes to a more mature state is mediated through a complex regulation of gene transcription. The events mediated by proteins codified by ATRA target genes that account for the complex and integrated network of intracellular signaling pathways responsible of the completion of maturation, are still largely unknown. In the last few years, the application of siRNA procedures to the study of molecular mechanisms that lead tumoral myeloid precursors to maturate along the granulocytic lineage has permitted to establish the specific role of a number of intracellular signaling molecules in a wide range of cell functions, including cell cycle regulation and control of gene expression. In particular, for some of these, as PLC-β β2 and Vav1, it was established a role in promoting maturation of APL-derived promyelocytes and in regulating the modifications of the cytoskeleton

Diagnostics, Sep 2, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Molecular Carcinogenesis, Jan 16, 2019

Molecular Oncology, May 16, 2018

Targeting different members of the Akt pathways is a promising therapeutic chance in solid tumors... more Targeting different members of the Akt pathways is a promising therapeutic chance in solid tumors including breast cancer. The variable expression levels of Akt isoforms with opposite effects on tumor growth and metastasis, however, make it difficult to select the inhibitors to be used for specific breast tumor subtypes. Using in vitro and in vivo models, we demonstrated here that Vav1, ectopically expressed in invasive breast tumors derived cells, downmodulates Akt acting at expression and/or activation levels depending on tumor subtype. The decreased p-Akt1 (Ser473) levels are a common effect of Vav1 upmodulation, suggesting that, in breast tumorderived cells and independently of their phenotype, Vav1 interferes with signaling pathways ended to specifically recruit Akt1. Only in ER-negative cell lines, the silencing of Vav1 induced the expression but not the activation of Akt2. A retrospective analysis of early invasive breast tumors allowed to establish the prognostic significance of the p-Akt/Vav1 relationship. In particular, low Vav1 levels negatively influence the follow-up of patients with low p-Akt in their primary tumors and subjected to adjuvant chemotherapy. As the use of specific or pan Akt inhibitors may not be sufficient or may even be detrimental, increasing the levels of Vav1 could be a new approach to improve breast cancer outcomes. This might be particularly relevant for tumors with a triple-negative phenotype, for which target-based therapies are not currently available.

Journal of Leukocyte Biology, Jun 1, 2002

In this study, we have investigated the expression of phospholipase C-␤2 during the course of gra... more In this study, we have investigated the expression of phospholipase C-␤2 during the course of granulocytic differentiation of normal and malignant progenitors. As a model system, we used the NB4 cell line, a reliable in vitro model for the study of acute promyelocytic leukemia (APL), a variety of acute myeloid leukemia (AML) that responds to pharmacological doses of all transretinoic acid (ATRA) by differentiating in a neutrophil-like manner. We found that PLC-␤2, virtually absent in untreated NB4 cells, was strongly upregulated after ATRA-induced granulocytic differentiation. Remarkably, using primary blasts purified from bone marrow of patients affected by APL successfully induced to remission by treatment with ATRA, we showed a striking correlation between the amount of PLC-␤2 expression and the responsiveness of APL blasts to the differentiative activity of ATRA. An increase of PLC-␤2 expression also characterized the cytokine-induced granulocytic differentiation of CD34 ؉ normal hematopoietic progenitors. Taken together, these data show that PLC-␤2 represents a sensitive and reliable marker of neutrophil maturation of normal and malignant myeloid progenitors. Moreover, PLC-␤2 levels can predict the in vivo responsiveness to ATRA of APL patients.

BMC Cancer, Nov 29, 2018

Background: The presence of hypoxic areas is common in all breast lesions but no data clearly cor... more Background: The presence of hypoxic areas is common in all breast lesions but no data clearly correlate low oxygenation with the acquisition of malignant features by non-invasive cells, particularly by cells from ductal carcinoma in situ (DCIS), the most frequently diagnosed tumor in women. Methods: By using a DCIS-derived cell line, we evaluated the effects of low oxygen availability on malignant features of non-invasive breast tumor cells and the possible role of all-trans retinoic acid (ATRA), a well-known anti-leukemic drug, in counteracting the effects of hypoxia. The involvement of the β2 isoform of PI-PLC (PLC-β2), an ATRA target in myeloid leukemia cells, was also investigated by specific modulation of the protein expression. Results: We demonstrated that moderate hypoxia is sufficient to induce, in DCIS-derived cells, motility, epithelialto-mesenchymal transition (EMT) and expression of the stem cell marker CD133, indicative of their increased malignant potential. Administration of ATRA supports the epithelial-like phenotype of DCIS-derived cells cultured under hypoxia and keeps down the number of CD133 positive cells, abrogating almost completely the effects of poor oxygenation. We also found that the mechanisms triggered by ATRA in non-invasive breast tumor cells cultured under hypoxia is in part mediated by PLC-β2, responsible to counteract the effects of low oxygen availability on CD133 levels. Conclusions: Overall, we assigned to hypoxia a role in increasing the malignant potential of DCIS-derived cells and we identified in ATRA, currently used in treatment of acute promyelocytic leukemia (APL), an agonist potentially useful in preventing malignant progression of non-invasive breast lesions showing hypoxic areas.

Stem cell reviews and reports, Nov 9, 2020

All-trans retinoic acid (ATRA) promotes the development and the function of insulin producing cel... more All-trans retinoic acid (ATRA) promotes the development and the function of insulin producing cells and induces partial differentiation of pancreatic tumor cells. A number of evidences clearly indicate that the ATRA mediated signaling may have a substantial role in therapeutic approaches based on restoration of functional β-cells. Among the proteins up-regulated by ATRA, Vav1 is involved in maturation and function of haematopoietic cells and is essential for retinoids induced differentiation of tumor promyelocytes. The presence of Vav1 in solid tissues, including pancreas, is considered ectopic and no role in the differentiation of human epithelial cells has so far been described. We demonstrated here that Vav1 sustains the maturation to β-cells of the normal precursors human Biliary Tree Stem/progenitor Cells (hBTSCs) induced by a differentiation medium containing ATRA and that, in the mature normal pancreas, insulin-producing cells express variable levels of Vav1. Using pancreatic ductal adenocarcinoma (PDAC)-derived cells, we also revealed that the ATRA induced up-modulation of Vav1 is essential for the retinoid-induced trans-differentiation of neoplastic cells into insulin producing cells. The results of this study identify Vav1 as crucial molecule in ATRA induced maturation of insulin producing cells and suggest this protein as a marker for new strategies ended to restore functional β-cells. Keywords Vav1. Insulin producing cells. Human biliary tree stem/progenitor cells (hBTSCs). Pancreatic ductal adenocarcinoma (PDAC) cells. All-trans retinoic acid (ATRA)

Cell Biochemistry and Function, Sep 1, 1994

The possibility that inositol lipid metabolism is related to nuclear events accompanying steroid ... more The possibility that inositol lipid metabolism is related to nuclear events accompanying steroid hormone action has been investigated by comparing lipid phosphorylation and breakdown in normal rat liver nuclei and in hypo-and hypercortisolemic conditions. Lipid phosphorylation in vitro showed the presence of diacylglycerol (DAG)-, phosphatidylinositol (PI)-and phosphatidylinositol-4-phosphate (PIP)-kinase activity, with differences between total tissue homogenates and isolated nuclei, relevant to the treatment in vivo. Administration of hydrocortisone (HC) produced a marked decrease in the phosphorylated nuclear products without influencing the homogenate kinase activity. Under conditions which were optimal for the kinase activities, nuclear PIP-kinase was strongly increased in presence of a high blood level of HC whereas PI-kinase activity was reduced. From these observations it appears that the observed differences were due to specific modulation of kinase activities rather than to changes in the availability of substrates. The phosphoinositide-specific phospholipase C (PLC) activity was also investigated. In the presence of a high HC blood level, the phosphodiesteratic cleavage of PIP strongly increased, while that of phosphatidylinositol bisphosphate (PIP2) was similar in normal and hypercortisolemic conditions. Nuclear phosphoinositide hydrolysis was affected by PLC, p and y isoforms, which were equally represented in all the conditions investigated, indicating that the observed changes of activity were due to a modulation rather than to a change in the amount of enzyme. These results suggest that inositol lipid metabolism plays a role in the nuclear modifications accompanying steroid hormone induction of transcriptional activity.

Molecular Carcinogenesis, Jan 19, 2016

Limited oxygen availability plays a critical role in the malignant progression of breast cancer b... more Limited oxygen availability plays a critical role in the malignant progression of breast cancer by orchestrating a complex modulation of the gene transcription largely dependent on the tumor phenotype. Invasive breast tumors belonging to different molecular subtypes are characterized by over-expression of PLC-b2, whose amount positively correlates with the malignant evolution of breast neoplasia and supports the invasive potential of breast tumor cells. Here we report that hypoxia modulates the expression of PLC-b2 in breast tumor cells in a phenotype-related manner, since a decrease of the protein was observed in the BT-474 and MCF7 cell lines while an increase was revealed in MDA-MB-231 cells as a consequence of low oxygen availability. Under hypoxia, the down-modulation of PLC-b2 was mainly correlated with the decrease of the EMT marker E-cadherin in the BT-474 cells and with the up-regulation of the stem cell marker CD133 in MCF7 cells. The increase of PLC-b2 induced by low oxygen in MDA-MB-231 cells supports the hypoxia-related reorganization of actin cytoskeleton and sustains invasion capability. In all examined cell lines, but with an opposite role in the ER-positive and ER-negative cells, PLC-b2 was involved in the hypoxia-induced increase of HIF-1a, known to affect both EMT and CD133 expression. Our data include PLC-b2 in the complex and interconnected signaling pathways induced by low oxygen availability in breast tumor cells and suggest that the forced modulation of PLC-b2 programmed on the basis of tumor phenotype may prevent the malignant progression of breast neoplasia as a consequence of intra-tumoral hypoxia.

Journal of Oncology, Sep 16, 2019

Initially correlated with hematopoietic precursors, the surface expression of CD133 was also foun... more Initially correlated with hematopoietic precursors, the surface expression of CD133 was also found in epithelial and nonepithelial cells from adult tissues in which it has been associated with a number of biological events. CD133 is expressed in solid tumors as well, including breast cancer, in which most of the studies have been focused on its use as a surface marker for the detection of cells with stem-like properties (i.e., cancer stem cells (CSCs)). Differently with other solid tumors, very limited and in part controversial are the information about the significance of CD133 in breast cancer, the most common malignancy among women in industrialized countries. In this review, we summarize the latest findings about the implication of CD133 in breast tumors, highlighting its role in tumor cells with a triple negative phenotype in which it directly regulates the expression of proteins involved in metastasis and drug resistance. We provide updates about the prognostic role of CD133, underlining its value as an indicator of increased malignancy of both noninvasive and invasive breast tumor cells. e molecular mechanisms at the basis of the regulation of CD133 levels in breast tumors have also been reviewed, highlighting experimental strategies capable to restrain its level that could be taken into account to reduce malignancy and/or to prevent the progression of breast tumors.