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Pancotti F.,University of Bologna | Roncuzzi L.,University of Bologna | Roncuzzi L.,Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine | Maggiolini M.,University of Calabria | Gasperi-Campani A.,University of Bologna
Cellular Signalling | Year: 2012

Cav-1 is an essential structural constituent of caveolae implicated in mitogenic signaling, oncogenesis, angiogenesis, neurodegenerative diseases and senescence. Its role as a tumor suppressor gene or as a tumor promoter seems to strictly depend on cell type and tumor stage/grade. The high expression of Cav-1 in some tumors in vivo, amongst which lung adenocarcinoma, is associated with increased tumor aggressiveness, metastatic potential and suppression of apoptosis. In the present study we investigated the role of Cav-1 in metastatic lung cancer proliferation. Cell lines were from metastatic lesions of lung adenocarcinoma (RAL) and of small cell lung carcinoma (SCLC-R1), in which we found Cav-1 expressed at high levels. Results show that siRNA-mediated down-regulation of Cav-1 caused stable arrest of proliferation in both cell lines. A marked reduction of cyclin D1 and of CDK4 expression was evident in the cells transfected with Cav-1 siRNA and consequently of phospho-Rb on ser795 and ser780. Furthermore, a significant decrease of the expression of phosphorylated AKT and of its down-stream effectors phosphorylated ERK and STAT3 was evident. Together, these findings indicate that Cav-1 silencing induces an arrest of human metastatic lung proliferation in vitro by a new inhibitory pathway in lung cancer and provide new insights into the molecular mechanisms underlying the pro-survival and tumor-promoting functions of Cav-1. © 2012 Elsevier Inc.. Source

Gandolfi M.G.,University of Bologna | Taddei P.,University of Bologna | Siboni F.,University of Bologna | Modena E.,University of Bologna | And 2 more authors.
Dental Materials | Year: 2011

Aim: An innovative light-curable calcium-silicate cement containing a HEMA-TEGDMA-based resin (lc-MTA) was designed to obtain a bioactive fast setting root-end filling and root repair material. Methods: lc-MTA was tested for setting time, solubility, water absorption, calcium release, alkalinizing activity (pH of soaking water), bioactivity (apatite-forming ability) and cell growth-proliferation. The apatite-forming ability was investigated by micro-Raman, ATR-FTIR and ESEM/EDX after immersion at 37 °C for 1-28 days in DPBS or DMEM + FBS. The marginal adaptation of cement in root-end cavities of extracted teeth was assessed by ESEM/EDX, and the viability of Saos-2 cell on cements was evaluated. Results: lc-MTA demonstrated a rapid setting time (2 min), low solubility, high calcium release (150-200 ppm) and alkalinizing power (pH 10-12). lc-MTA proved the formation of bone-like apatite spherulites just after 1 day. Apatite precipitates completely filled the interface porosities and created a perfect marginal adaptation. lc-MTA allowed Saos-2 cell viability and growth and no compromising toxicity was exerted. Significance: HEMA-TEGDMA creates a polymeric network able to stabilize the outer surface of the cement and a hydrophilic matrix permeable enough to allow water absorption. SiO -/Si-OH groups from the mineral particles induce heterogeneous nucleation of apatite by sorption of calcium and phosphate ions. Oxygen-containing groups from poly-HEMA-TEGDMA provide additional apatite nucleating sites through the formation of calcium chelates. The strong novelty was that the combination of a hydraulic calcium-silicate powder and a poly-HEMA-TEGDMA hydrophilic resin creates the conditions (calcium release and functional groups able to chelate Ca ions) for a bioactive fast setting light-curable material for clinical applications in dental and maxillofacial surgery. The first and unique/exclusive light-curable calcium-silicate MTA cement for endodontics and root-end application was created, with a potential strong impact on surgical procedures. © 2011 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved. Source

Checchi V.,The Second University of Naples | Savarino L.,Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine | Montevecchi M.,University of Bologna | Felice P.,University of Bologna | Checchi L.,University of Bologna
International Journal of Oral and Maxillofacial Surgery | Year: 2011

After tooth extraction the healing process involves bone resorption and soft tissue contraction, events that can compromise the ideal implant placement with functional and aesthetic limitations. Following tooth extraction, a socket preservation technique can limit bone resorption. This study evaluated two different types of hydroxyapatite (HA) grafting materials placed into fresh extraction sockets, 6 months after tooth extraction, histologically, clinically and radiographically. Ten extraction sockets from 10 patients were divided in two groups: 5 sockets received a biomimetic HA and 5 received nanocrystalline HA. After 6 months, before implant placement, samples from the grafted area were harvested and evaluated clinically, radiographically and histologically. The percentages of bone, osteoid areas and residual material in the two groups were not statistically different. All samples showed great variability with extensive bone formation and total material resorption or amounts of osteoid tissue that filled the spaces between the residual material particles. The authors did not find any differences between biomimetic and nanocrystalline HA and assume that, within the limits of this study, both these materials could be applied into fresh extraction sockets to limit bone resorption. A control material and a much larger sample size are needed to confirm these findings. © 2011 International Association of Oral and Maxillofacial Surgeons. Source

Roncuzzi L.,Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine | Pancotti F.,Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine | Baldini N.,Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine | Baldini N.,University of Bologna
Oncology Reports | Year: 2014

Osteosarcoma is the most common primary bone cancer in children and adolescents. Despite aggressive treatment regimens, survival outcomes remain unsatisfactory, particularly in patients with metastatic and/or recurrent disease. Unfortunately, treatment failure is commonly due to the development of chemoresistance, for which the underlying molecular mechanisms remain unclear. The aim of the present study was to investigate the role of hypoxia-inducible factor 1α (HIF-1α) and its signalling pathways as mediators of drug-resistance in human osteosarcoma. Toward this aim, we established two osteosarcoma cell lines selected for resistance to doxorubicin, a drug of choice in the treatment of this tumour. Our results showed that the multidrug resistance (MDR) phenotype was also mediated by HIF-1α, the most important regulator of cell adaptation to hypoxia. Our data showed that this transcription factor promoted the outward transport of intracellular doxorubicin by activating the P-glycoprotein (P-gp) expression in osteosarcoma cells maintained in normoxic conditions. In addition, it hindered doxorubicin-induced apoptosis by regulating the expression of c-Myc and p21. Finally, we observed that the doxorubicin-resistant cells maintained for 2 months of continuous culture in a drug-free medium, lost their drug-resistance and this effect was associated with the absence of HIF-1α expression. The emerging role of HIF-1α in osteosarcoma biology indicates its use as a valuable therapeutic target. Source

Avnet S.,Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine | Di Pompo G.,Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine | Lemma S.,Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine | Salerno M.,Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine | And 6 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Suppression of oxidative phosphorylation combined with enhanced aerobic glycolysis and the resulting increased generation of protons are common features of several types of cancer. An efficient mechanism to escape cell death resulting from intracellular acidification is proton pump activation. In Ewing sarcoma (ES), although the tumor-associated chimeric gene EWS-FLI1 is known to induce the accumulation of hypoxia-induced transcription factor HIF-1α, derangements in metabolic pathways have been neglected so far as candidate pathogenetic mechanisms. In this paper, we observed that ES cells simultaneously activate mitochondrial respiration and high levels of glycolysis. Moreover, although the most effective detoxification mechanism of proton intracellular storage is lysosomal compartmentalization, ES cells show a poorly represented lysosomal compartment, but a high sensitivity to the anti-lysosomal agent bafilomycin A1, targeting the V-ATPase proton pump. We therefore investigated the role of V-ATPase in the acidification activity of ES cells. ES cells with the highest GAPDH and V-ATPase expression also showed the highest acidification rate. Moreover, the localization of V-ATPase was both on the vacuolar and the plasma membrane of all ES cell lines. The acidic extracellular pH that we reproduced in vitro promoted high invasion ability and clonogenic efficiency. Finally, targeting V-ATPase with siRNA and omeprazole treatments, we obtained a significant selective reduction of tumor cell number. In summary, glycolytic activity and activation of V-ATPase are crucial mechanisms of survival of ES cells and can be considered as promising selective targets for the treatment of this tumor. © 2013 Elsevier B.V. Source

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