1,721,120 research outputs found
Identificazione di nuovi bersagli molecolari per il fenotipo di resistenza al TRAIL nel carcinoma polmonare.
No full textDifetti nel programma di apoptosi cellulare si riscontrano frequentemente nel cancro, nell’uomo. Quindi, l’identificazione dei principali mediatori nel “pathway” apoptotico potrà garantire lo sviluppo di farmaci mirati su bersagli selettivi. Il TRAIL (ligando inducente l’apoptosi relato al TNF), ha da alcuni anni attirato un particolare interesse nella terapia delle neoplasie umane. Infatti, il TRAIL è in grado di indurre apoptosi solo nelle cellule trasformate e non in quelle normali. Tuttavia in alcuni casi, le cellule tumorali si mostrano resistenti al trattamento con il TRAIL. I meccanismi di questa resistenza non sono noti. Lo scopo di questo studio è quello di identificare nuove molecole che possono modulare la resistenza al TRAIL. In particolare, prenderà in esame uno dei carcinomi più diffusi nell’uomo, il carcinoma polmonare a non piccole cellule (NSCL). Le molecole identificate attraverso diversi approcci, saranno poi testate in sistemi cellulari e nell’animale. Attraverso l’utilizzo di due approcci complementari, lo studio si propone di isolare molecole biologicamente attive di piccoli RNA, come nuovi strumenti per inibire la resistenza al TRAIL nel carcinoma NSCLC. Il primo approccio, basato sulla selezione combinatoriale di nuove molecole permetterà di isolare attameri di RNA, attraverso la metodologia del SELEX integrata con identificazione mediante spettrometria di massa. Il secondo approccio, basato sul profiling di miRNA nelle cellule di NSCL resistenti al TRAIL, permetterà di identificare piccole molecole naturali di RNA attive coinvolte nella resistenza al TRAIL.
L’attività biologica di entrambi i tipi di molecole, sarà valutata sia in sistemi cellulari che in modelli animali di NSCLC, attraverso lo studio del recupero della sensibilità al TRAIL. Il prodotto finale di questo studio è rappresentato dalla generazione di molecole di RNA come strumenti per modulare e monitorare la sensibilità al TRAIL nelle cellule di NSCLC
A neutralizing RNA aptamer against PDGFR beta and the use thereof in the therapy and diagnosis of hyperproliferative diseases
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Contrast agents and renal cell apoptosis
No full textContrast media (CM) induce a direct toxic effect on renal tubular cells. This toxic effect may have a role in the pathophysiology of contrast nephropathy. I evaluated: (i) the cytotoxicity of CM [both low-osmolality (LOCM) and iso-osmolality (IOCM)], of iodine alone,and of an hyperosmolar solution (mannitol 8%) on human embryonic kidney (HEK 293), porcine proximal renal tubular (LLC-PK1), and canine Madin–Darby distal tubular renal (MDCK) cells; and (ii) the effectiveness of various antioxidant compounds [N-acetylcysteine (NAC), ascorbic acid and sodium bicarbonate] in preventing CM cytotoxicity. The cytotoxicity of CM was assessed at different time points, with different methods: cell viability,DNA laddering, flow cytometry, and caspase activation. Both LOCM and IOCM produced a concentration- and time-dependent increase in cell death as assessed by the different methods. On the contrary, iodine alone and hyperosmolar solution did not induce any significant cytotoxic effect. There was not any significant difference in the cytotoxic effect between LOCM and IOCM. Furthermore, both LOCM and IOCM caused a marked increase in caspase-3 and -9 activities and poly(ADP-ribose) fragmentation, while no effect on caspase-8/-10 was observed, thus indicating that the CM activated apoptosis mainly through the intrinsic pathway. Both CM induced an increase in protein expression levels of pro-apoptotic members of the Bcl2 family (Bim and Bad). NAC and ascorbic acid but not sodium bicarbonate had a dose-dependent protective effect on renal cells after 3 h incubation with high dose (200 mg iodine/mL) of both LOCM and IOCM. Both LOCM and IOCM induce a dose-dependent renal cell apoptosis. NAC and ascorbic acid but not sodium bicarbonate prevent this contrast-induced apoptosis
Multifunctional role of PED/PEA15 in cell death and cell motility in human non small cell lung cancer (NSCLC).
No full textPED (phosphoprotein enriched in diabetes) is a 15 KDa protein involved in many cellular pathways and human diseases, including type II diabetes and cancer. We recently reported its overexpression in breast and lung cancers, and B-cell chronic lymphocytic leukemia (B-CLL). Furthermore, PED mediated resistance to chemotherapic agents in breast cancer cell lines and TRAIL (TNF-Related Apoptosis Inducing Ligand) treatment in primary B-CLL cells and lung cancer cell lines. Then, we show that PED function and expression are reguated by vitamin D3. To better understand its role in cancer, we focused on PED interactome characterization in non small cell lung cancer (NSCLC) cell line, A459. By the Tandem Affinity Purification (TAP), we have identified Rac1, member of mammalian Rho GTPase proteins family, as a PED-interacting protein, which is involved in many cellular processes, such as migration and invasion. Here we show that PED stimulates migration and invasion in Rac1-dependent manner in non small cell lung cancer. In conclusion, this is teh first report showing that PED and Rac1 interact and that this interaction regulates cell migration/invasion process through ERK1/2 pathway
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