@article {7727, title = {TNF-related apoptosis inducing ligand in ocular cancers and ocular diabetic complications.}, journal = {Biomed Res Int}, volume = {2015}, year = {2015}, month = {2015}, pages = {424019}, abstract = {

TNF-related apoptosis inducing ligand (TRAIL) is an intensively studied cytokine, in particular for its anticancer activity. The discovery that conjunctival sac fluid contains extremely high levels of soluble TRAIL as compared to other body fluids suggested important implications in the context of the immunological surveillance of the eye, in particular of the anterior surface. In this review, we discuss the potential physiopathologic and therapeutic role of the TRAIL/TRAIL receptor system in a variety of ocular cancers. Moreover, since an increasing amount of data has indicated the important biological activities of the TRAIL/TRAIL receptor systems also in a completely different pathologic context such as diabetes mellitus, in the second part of this review we summarize the currently available data on the involvement of TRAIL in the ocular complications of diabetes mellitus as modulator of the inflammatory and angiogenic response in the eye.

}, keywords = {Apoptosis, Diabetes Complications, Diabetes Mellitus, Eye Neoplasms, Humans, Receptors, TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand}, issn = {2314-6141}, doi = {10.1155/2015/424019}, author = {Perri, Paolo and Zauli, Giorgio and Gonelli, Arianna and Milani, Daniela and Celeghini, Claudio and Lamberti, Giuseppe and Secchiero, Paola} } @article {7730, title = {TRAIL modulates the immune system and protects against the development of diabetes.}, journal = {J Immunol Res}, volume = {2015}, year = {2015}, month = {2015}, pages = {680749}, abstract = {

TRAIL or tumor necrosis factor (TNF) related apoptosis-inducing ligand is a member of the TNF superfamily of proteins, whose best characterized function is the induction of apoptosis in tumor, infected, or transformed cells through activation of specific receptors. In nontransformed cells, however, the actions of TRAIL are less well characterized. Recent studies suggest that TRAIL may be implicated in the development and progression of diabetes. Here we review TRAIL biological actions, its effects on the immune system, and how and to what extent it has been shown to protect against diabetes.

}, keywords = {Animals, Diabetes Mellitus, Humans, Immune System, Receptors, TNF-Related Apoptosis-Inducing Ligand, Signal Transduction}, issn = {2314-7156}, doi = {10.1155/2015/680749}, author = {Bossi, Fleur and Bernardi, Stella and Zauli, Giorgio and Secchiero, Paola and Fabris, Bruno} } @article {7728, title = {Triple Akt inhibition as a new therapeutic strategy in T-cell acute lymphoblastic leukemia.}, journal = {Oncotarget}, volume = {6}, year = {2015}, month = {2015 Mar 30}, pages = {6597-610}, abstract = {

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder in which chemotherapy resistance and refractory relapses occur, with a poorer prognostic outcome.Constitutively active PI3K/Akt/mTOR pathway is a common feature of T-ALL upregulating cell proliferation, survival and drug resistance. This pathway is currently under clinical trials with small molecules inhibitors (SMI).To verify whether a multi-inhibition treatment against Akt protein could enhance the efficacy of individual drug administration and overcome drug resistance as well as to obtain a decrease in single drug concentration, we tested on T-ALL cell lines the effects of combined treatments with three Akt inhibitors with different mode of action, GSK690693, MK-2206 and Perifosine.In cells with hyperactivated Akt, combined administration of the drugs displayed a significant synergistic and cytotoxic effect and affected PI3K/Akt/mTOR pathway at much lower concentration than single drug use. Highest synergistic effect for full inhibition of Akt was also related to the timing of every drug administration. Furthermore the triple treatment had greater efficacy in inducing cell cycle arrest in G0/G1 phase and both apoptosis and autophagy.Targeting Akt as a key protein of PI3K/Akt/mTOR pathway with multiple drugs might represent a new and promising pharmacological strategy for treatment of T-ALL patients.

}, issn = {1949-2553}, doi = {10.18632/oncotarget.3260}, author = {Cani, Alice and Simioni, Carolina and Martelli, Alberto M and Zauli, Giorgio and Tabellini, Giovanna and Ultimo, Simona and McCubrey, James A and Capitani, Silvano and Neri, Luca M} } @article {8028, title = {Two-gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome results.}, journal = {Mol Med Rep}, volume = {12}, year = {2015}, month = {2015 Oct}, pages = {6128-32}, abstract = {

Next-generation sequencing (NGS) has generated a large amount of sequence data with the requirement of frequent critical revisions of reported mutations. This innovative tool has proved to be effective in detecting pathogenic mutations; however, it requires a certain degree of experience to identify incidental findings. In the present study, whole exome sequencing analysis was performed for the molecular diagnosis and correct genotype/phenotype correlation between parents and a patient presenting with an atypical phenotype. In addition, mevalonic acid quantification and frequency analysis of detected variants in public databases and X-chromosome inactivation (XCI) studies on the patient{\textquoteright}s mother were performed. V377I as well as the S135L mutations were identified on the mevalonate kinase deficiency gene and the levels of mevalonic acid in the patient were 5,496 {\textmu}g/ml. A D59G variation, reported in ESP6500 in two healthy individuals, was found on the Martin Probst syndrome gene (RAB40AL). Based on XCI studies on the patient{\textquoteright}s mother, it is likely that RAB40AL escapes XCI, while still remaining balanced. In conclusion, the results of the present study indicated that the Martin Probst syndrome is an X-linked condition, which is probably not caused by RAB40AL mutations. Although NGS is a powerful tool to identify pathogenic mutations, the analysis of genetic data requires expert critical revision of all detected variants.

}, issn = {1791-3004}, doi = {10.3892/mmr.2015.4215}, author = {Bianco, Anna Monica and Faletra, Flavio and Vozzi, Diego and Girardelli, Martina and Knowles, Alessandra and Tommasini, Alberto and Zauli, Giorgio and Marcuzzi, Annalisa} } @article {1911, title = {TNF-related apoptosis-inducing ligand significantly attenuates metabolic abnormalities in high-fat-fed mice reducing adiposity and systemic inflammation.}, journal = {Clin Sci (Lond)}, volume = {123}, year = {2012}, month = {2012 Nov}, pages = {547-55}, abstract = {

TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] has recently been shown to ameliorate the natural history of DM (diabetes mellitus). It has not been determined yet whether systemic TRAIL delivery would prevent the metabolic abnormalities due to an HFD [HF (high-fat) diet]. For this purpose, 27 male C57bl6 mice aged 8 weeks were randomly fed on a standard diet, HFD or HFD+TRAIL for 12 weeks. TRAIL was delivered weekly by intraperitoneal injection. Body composition was evaluated; indirect calorimetry studies, GTT (glucose tolerance test) and ITT (insulin tolerance test) were performed. Pro-inflammatory cytokines, together with adipose tissue gene expression and apoptosis, were measured. TRAIL treatment reduced significantly the increased adiposity associated with an HFD. Moreover, it reduced significantly hyperglycaemia and hyperinsulinaemia during a GTT and it improved significantly the peripheral response to insulin. TRAIL reversed the changes in substrate utilization induced by the HFD and ameliorated skeletal muscle non-esterified fatty acids oxidation rate. This was associated with a significant reduction of pro-inflammatory cytokines together with a modulation of adipose tissue gene expression and apoptosis. These findings shed light on the possible anti-adipogenic and anti-inflammatory effects of TRAIL and open new therapeutic possibilities against obesity, systemic inflammation and T2DM (Type 2 DM).

}, keywords = {Adiposity, Animals, Apoptosis, Calorimetry, Cytokines, Dietary Fats, Energy Intake, Glucose Tolerance Test, Hyperglycemia, Hyperinsulinism, Inflammation, Inflammation Mediators, Male, Mice, Mice, Inbred C57BL, Oxidation-Reduction, Palmitic Acid, Real-Time Polymerase Chain Reaction, TNF-Related Apoptosis-Inducing Ligand}, issn = {1470-8736}, doi = {10.1042/CS20120176}, author = {Bernardi, Stella and Zauli, Giorgio and Tikellis, Christos and Candido, Riccardo and Fabris, Bruno and Secchiero, Paola and Cooper, Mark E and Thomas, Merlin C} } @article {1973, title = {TRAIL, a new weapon against neointimal hyperplasia.}, journal = {Cardiology}, volume = {123}, year = {2012}, month = {2012}, pages = {94-6}, keywords = {Coronary Restenosis, Drug-Eluting Stents, Female, Humans, Male, Neointima, TNF-Related Apoptosis-Inducing Ligand}, issn = {1421-9751}, doi = {10.1159/000342983}, author = {Secchiero, Paola and Zauli, Giorgio} } @article {1939, title = {TRAIL administration down-modulated the acute systemic inflammatory response induced in a mouse model by muramyldipeptide or lipopolysaccharide.}, journal = {Cytokine}, volume = {60}, year = {2012}, month = {2012 Oct}, pages = {43-6}, abstract = {

The potent inducer of apoptosis TRAIL/Apo2 ligand is now under considerations in clinical trials for the treatment of different types of cancer. Since the natural history of cancer is often characterized by microbial infections, we have investigated the effect of recombinant human TRAIL in a mouse model of systemic acute inflammation of microbial origin represented by BALB/c mice treated with either bacterial muramyldipeptide (MDP) or lipopolysaccharide (LPS). When administered intraperitoneally (i.p.), these inflammatory bacterial compounds triggered a severe systemic inflammatory response within 2h, represented by body temperature elevation, increase of circulating serum amyloid-A (SAA) and of the number of leukocytes in the peritoneal cavity. Moreover, both MDP and LPS induced a significant elevation of the circulating levels of several inflammatory cytokines and chemokines. Noteworthy, pre-treatment with recombinant human TRAIL 48 and 72 h before administration of either MDP or LPS, significantly counteracted all acute inflammatory responses, including the elevation of key pro-inflammatory cytokines/chemokines such as IL-1α, IL-6, G-CSF, MCP-1. These data demonstrate for the first time that TRAIL has a potent anti-inflammatory activity, which might be beneficial for the anti-tumoral activity of TRAIL.

}, keywords = {Acetylmuramyl-Alanyl-Isoglutamine, Acute Disease, Animals, Chemokine CCL2, Cytokines, Disease Models, Animal, Down-Regulation, Granulocyte Colony-Stimulating Factor, Humans, Immunoassay, Inflammation, Inflammation Mediators, Interleukin-1alpha, Interleukin-6, Lipopolysaccharides, Male, Mice, Mice, Inbred BALB C, Recombinant Proteins, Serum Amyloid A Protein, TNF-Related Apoptosis-Inducing Ligand}, issn = {1096-0023}, doi = {10.1016/j.cyto.2012.06.001}, author = {Marcuzzi, Annalisa and Secchiero, Paola and Crovella, Sergio and Zauli, Giorgio} } @article {1917, title = {TRAIL as biomarker and potential therapeutic tool for cardiovascular diseases.}, journal = {Curr Drug Targets}, volume = {13}, year = {2012}, month = {2012 Aug}, pages = {1215-21}, abstract = {

This review focuses on TNF-related apoptosis-inducing ligand (TRAIL), also called Apo2 ligand, a protein belonging to the TNF superfamily. TRAIL can be found either in its transmembrane or circulating form, and its mostly studied peripheral effect is the induction of cellular apoptosis. Here, we discuss the evidences supporting the use of TRAIL as biomarker of cardiovascular diseases as well as the evidences showing the potential beneficial therapeutic effects of TRAIL on cardiovascular diseases and diabetes.

}, keywords = {Biological Markers, Cardiovascular Diseases, Humans, Prognosis, TNF-Related Apoptosis-Inducing Ligand}, issn = {1873-5592}, author = {Bernardi, Stella and Milani, Daniela and Fabris, Bruno and Secchiero, Paola and Zauli, Giorgio} } @article {1817, title = {Trail down-regulates the release of osteoprotegerin (OPG) by primary stromal cells.}, journal = {J Cell Physiol}, volume = {226}, year = {2011}, month = {2011 Sep}, pages = {2279-86}, abstract = {

The soluble member of the TNF-R superfamily osteoprotegerin (OPG) is abundantly released under basal conditions by both mesenchymal stem cells (MSC) and fibroblasts and by endothelial cells upon stimulation with inflammatory cytokines. Since MSC, fibroblasts and endothelial cells represent key elements of the normal and tumor microenvironment and express detectable levels of surface TRAIL receptors, we investigated the effect of TRAIL on OPG release. Unexpectedly, recombinant TRAIL decreased the spontaneous OPG release in all cell types examined. Moreover, TRAIL decreased OPG release also in stromal cells co-cultured with lymphoma cells and counteracted the OPG induction by TN-alpha in HUVEC and MSC. Such down-regulation was not due to a masking effect in the ELISA quantification of the OPG released in the culture supernatants due to binding of OPG to its ligands (TRAIL and RANKL), as demonstrated by competition experiments with recombinant TRAIL and by the lack of RANKL release/induction. In addition, OPG down-regulation was not due to induction of cytotoxic effects by TRAIL, since the degree of apoptosis in response to TRAIL was negligible in all primary cell types. With regards to the possible molecular mechanism accounting for the down-regulation of OPG release by TRAIL, we found that treatment of MSC with TRAIL significantly decreased the phosphorylation levels of p38/MAPK. There is a suggestion that this pathway is involved in the stabilization of OPG mRNA. In this respect, the ability of TRAIL to decrease the release of OPG, in the absence of cell cytotoxicity, was mimicked by the p38/MAPK inhibitor SB203580.

}, keywords = {Bone Marrow Cells, Cell Death, Cells, Cultured, Coculture Techniques, Down-Regulation, Endothelial Cells, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Fibroblasts, Humans, MAP Kinase Signaling System, Mesenchymal Stromal Cells, Osteoprotegerin, p38 Mitogen-Activated Protein Kinases, Protein Binding, Recombinant Proteins, Stromal Cells, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor-alpha}, issn = {1097-4652}, doi = {10.1002/jcp.22564}, author = {Corallini, Federica and Celeghini, Claudio and Rimondi, Erika and di Iasio, Maria Grazia and Gonelli, Arianna and Secchiero, Paola and Zauli, Giorgio} } @article {1718, title = {Treatment with recombinant tumor necrosis factor-related apoptosis-inducing ligand alleviates the severity of streptozotocin-induced diabetes.}, journal = {Diabetes}, volume = {59}, year = {2010}, month = {2010 May}, pages = {1261-5}, abstract = {

OBJECTIVE: To evaluate the potential therapeutic effect of recombinant human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) treatment in a model of type 1 diabetes.

RESEARCH DESIGN AND METHODS: Recombinant TRAIL was added in vitro to primary human and mouse peripheral blood mononuclear cells (PBMCs) and isolated human islets to evaluate the expression of the immunoregulatory gene SOCS1. Diabetes was induced by five consecutive daily injections of low-concentration (50 mg/kg) streptozotocin (STZ) in C57 black mice (n = 24). A group of these mice (n = 12) was co-injected with recombinant TRAIL (20 microg/day) for 5 days, and the diabetic status (glycemia and body weight) was followed over time. After 6 weeks, circulating levels of insulin, TNF-alpha, and osteoprotegerin (OPG) were measured, and animals were killed to perform the histological analysis of the pancreas.

RESULTS: The in vitro exposure of both PBMCs and human islets to recombinant TRAIL significantly upregulated the expression of SOCS1. With respect to STZ-treated animals, mice co-injected with STZ+TRAIL were characterized by 1) lower levels of hyperglycemia, 2) higher levels of body weight and insulinemia, 3) a partial preservation of pancreatic islets with normal morphology, and 4) a lower expression of both systemic (TNF-alpha and OPG) and pancreatic (vascular cell adhesion molecule [VCAM]-1) inflammatory markers.

CONCLUSIONS: Overall, these data demonstrate that the administration of recombinant TRAIL ameliorates the severity of STZ-induced type 1 diabetes, and this effect was accompanied by the upregulation of SOCS1 expression.

}, keywords = {Animals, Cells, Cultured, Diabetes Mellitus, Experimental, Gene Expression, Humans, Islets of Langerhans, Leukocytes, Mononuclear, Mice, Recombinant Proteins, Suppressor of Cytokine Signaling Proteins, TNF-Related Apoptosis-Inducing Ligand}, issn = {1939-327X}, doi = {10.2337/db09-1771}, author = {Zauli, Giorgio and Toffoli, Barbara and di Iasio, Maria Grazia and Celeghini, Claudio and Fabris, Bruno and Secchiero, Paola} }