Salerno, Italy
Salerno, Italy

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Basile A.,University of Salerno | Basile A.,BIOUNIVERSA srl | Zeppa R.,University of Salerno | Pasquino N.,University of Naples Federico II | And 12 more authors.
Journal of Cellular Physiology | Year: 2011

The expression of the anti-apoptotic protein BAG3 is induced in several cell types by exposure to high temperature, oxidants, and other stressful agents. We investigated whether exposure to 50Hz electromagnetic fields raised BAG3 levels in the human melanoma cell line M14, in vitro and in orthotopic xenografts. Exposure of cultured cells or xenografts for 6h or 4 weeks, respectively, produced a significant (P<0.01) increase in BAG3 protein amounts. Interestingly, at the same times, we could not detect any significant variation in the levels of HSP70/72 protein or cell apoptosis. These results confirm the stressful effect of exposure to ELF in human cells, by identifying BAG3 protein as a marker of ELF-induced stress. Furthermore, they suggest that BAG3 induction by ELF may contribute to melanoma cell survival and/or resistance to therapy. © 2011 Wiley-Liss, Inc.


Basile A.,University of Salerno | Basile A.,BIOUNIVERSA Srl | Pascale M.,University of Salerno | Pascale M.,BIOUNIVERSA Srl | And 7 more authors.
Journal of Cellular Physiology | Year: 2012

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent Cl- channel located in the plasma membrane, and its malfunction results in cystic fibrosis (CF), the most common lethal genetic disease in Caucasians. Most CF patients carry the deletion of Phe508 (ΔF508 mutation); this mutation prevents the delivery of the CFTR to its correct cellular location, the apical (lumen-facing) membrane of epithelial cells. Molecular chaperones play a central role in determining the fate of ΔF508-CFTR. In this report, we show that the Matrine, a quinolizidine alkaloid, downregulates the expression of the molecular chaperone HSC70 and increases the protein levels of ΔF508-CFTR in human alveolar basal epithelial cells (A549 cell line), stably transfected with a ΔF508-CFTR-expressing construct. Moreover, Matrine induced ΔF508-CFTR release from endoplasmic reticulum to cell cytosol and its localization on the cell membrane. Interestingly, downregulation of HSC70 resulted in increased levels of ΔF508-CFTR complexes with the co-chaperone BAG3 that in addition appeared to co-localize with the mutated protein on the cell surface. These results shed new light on ΔF508-CFTR interactions with proteins of the chaperones/co-chaperones system and could be useful in strategies for future medical treatments for CF. © 2011 Wiley Periodicals, Inc.


Rosati A.,University of Salerno | Rosati A.,BIOUNIVERSA Srl | Graziano V.,University of Chieti Pescara | De Laurenzi V.,BIOUNIVERSA Srl | And 5 more authors.
Cell Death and Disease | Year: 2011

Bcl2-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that interacts with the ATPase domain of the heat shock protein (Hsp) 70 through BAG domain (110-124 amino acids). BAG3 is the only member of the family to be induced by stressful stimuli, mainly through the activity of heat shock factor 1 on bag3 gene promoter. In addition to the BAG domain, BAG3 contains also a WW domain and a proline-rich (PXXP) repeat, that mediate binding to partners different from Hsp70. These multifaceted interactions underlie BAG3 ability to modulate major biological processes, that is, apoptosis, development, cytoskeleton organization and autophagy, thereby mediating cell adaptive responses to stressful stimuli. In normal cells, BAG3 is constitutively present in a very few cell types, including cardiomyocytes and skeletal muscle cells, in which the protein appears to contribute to cell resistance to mechanical stress. A growing body of evidence indicate that BAG3 is instead expressed in several tumor types. In different tumor contexts, BAG3 protein was reported to sustain cell survival, resistance to therapy, and/or motility and metastatization. In some tumor types, down-modulation of BAG3 levels was shown, as a proof-of-principle, to inhibit neoplastic cell growth in animal models. This review attempts to outline the emerging mechanisms that can underlie some of the biological activities of the protein, focusing on implications in tumor progression. © 2011 Macmillan Publishers Limited All rights reserved.


Palma G.,Instituto Nazionale dei Tumori | Palma G.,University of Naples Federico II | De Laurenzi V.,University of Chieti Pescara | De Laurenzi V.,Biouniversa Srl | And 7 more authors.
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2012

Dendritic cells (DCs) are immunological sentinels of the organism acting as antigen-presenting cells (APC) and are critical for induction of innate and adaptive immunity. Traditionally they are divided in myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs), a rare population of circulating cells that selectively express Toll-like receptors (TLR) 7 and TLR9 and have the capacity to produce large amounts of type I interferons (IFNs) in response to pathogenic agents or danger signals. It has been demonstrated that pDCs can coordinate events during the course of viral infections, allergic and autoimmune diseases and cancer. Through the production of type I IFNs, pDCs initiate protective immunity by activating classical DCs, T cells, natural killer cells and B cells. Upon activation, pDCs also differentiate into mature DCs and may contribute to the contraction of T-cell response. Human pDCs preferentially express immunoglobulin-like transcript 7 (ILT7; LILRA4), which couples with a signaling adapter to activate a prominent immune-receptor tyrosine-based activation motif (ITAM)-mediated signaling pathway. The interaction between ILT7 and bone marrow stromal cell antigen 2 (BST2, CD317) assures an appropriate TLR response by pDCs during viral infections and likely participates in pDCs tumor crosstalk. Moreover these cells seem to play a crucial role in the initiation of the pathological process of autoimmune diseases such as lupus or psoriasis. Despite the fact that their function within a tumor context is still controversial they represent an attractive target for therapeutic manipulation of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies. © 2012.


Patent
Biouniversa Srl | Date: 2014-07-23

The present invention relates to the use of BAG3 receptor-binding molecules as a medicament, in particular for use in the treatment of diseases of an immune, inflammatory, cardiovascular, neoplastic and/or degenerative nature.


Patent
Biouniversa Srl | Date: 2013-12-25

The present disclosure concerns the field of diagnostic serum and tissue markers. Specifically the disclosure relates to anti-BAG3 antibodies for use as serum markers of a pathological state. Furthermore, the disclosure involves specific ELISA methods and kits, for detecting and evaluating, anti-BAG3 antibodies or BAG3/antibody complexes in a biological sample. The disclosure further relates to an immunohistochemistry kit to detect and evaluate intracellular BAG3, in specific physiopathological states (heart diseases, pancreatic cancer, bladder carcinoma). Furthermore the disclosure involves BAG3-specific antibodies, their modified derivatives, and peptides for modulation of macrophage activation.


Patent
Biouniversa Srl | Date: 2014-03-04

The present invention relates to the use of BAGS antibodies as a medicament, in particular for use in the treatment of pancreatic tumours or other pathologies of an immune, inflammatory, neoplastic and/or degenerative nature.


Patent
Biouniversa Srl | Date: 2014-12-16

The present invention concerns the field of diagnostic biological markers. Specifically the invention relates to anti-BAG3 antibodies for use as biological markers for the diagnosis of a pathological state. Furthermore, the invention involves specific ELISA methods and kits, for detecting and evaluating, anti-BAG3 antibodies or BAG3/antibody complexes in a biological sample.


Patent
Biouniversa Srl | Date: 2014-12-16

The present invention concerns the field of diagnostic biological markers. Specifically the invention relates to BAG3 RNA or a fragment thereof for use as biological markers for the diagnosis of a pathological state. Furthermore, the invention involves specific kits and methods, for detecting and/or evaluating the levels of BAG3 RNA or a fragment thereof in a biological sample.


PubMed | University of Amsterdam, Calixar Inc., Instituto Nazionale Tumouri Fondazione G Pascale, Ss Annunziatahospital and 8 more.
Type: | Journal: Nature communications | Year: 2015

The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.

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