TY - JOUR T1 - The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases. JF - Int J Mol Sci Y1 - 2018 A1 - Bernardi, Stella A1 - Marcuzzi, Annalisa A1 - Piscianz, Elisa A1 - Tommasini, Alberto A1 - Fabris, Bruno KW - Anti-Inflammatory Agents KW - Cardiovascular Diseases KW - Humans KW - Hypolipidemic Agents KW - Immune System KW - Inflammation KW - Interleukins KW - Lipid Metabolism KW - Lipids KW - Metabolic Diseases AB -

Lipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response-and interleukins-had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed.

VL - 19 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30558209?dopt=Abstract ER - TY - JOUR T1 - Association between thyroid hormones and TRAIL. JF - Clin Biochem Y1 - 2017 A1 - Bernardi, Stella A1 - Bossi, Fleur A1 - Toffoli, Barbara A1 - Giudici, Fabiola A1 - Bramante, Alessandra A1 - Furlanis, Giulia A1 - Stenner, Elisabetta A1 - Secchiero, Paola A1 - Zauli, Giorgio A1 - Carretta, Renzo A1 - Fabris, Bruno KW - Aged KW - Female KW - Gene Expression Regulation KW - Humans KW - Hyperthyroidism KW - Hypothyroidism KW - Leukocytes, Mononuclear KW - Male KW - Middle Aged KW - Thyroxine KW - TNF-Related Apoptosis-Inducing Ligand KW - Triiodothyronine AB -

INTRODUCTION: Recent studies suggest that a circulating protein called TRAIL (TNF-related apoptosis-inducing ligand) might have a role in the regulation of body weight and metabolism. Interestingly, thyroid hormones seem to increase TRAIL tissue expression. This study aimed at evaluating whether overt thyroid disorders affected circulating TRAIL levels.

METHODS: TRAIL circulating levels were measured in euthyroid, hyperthyroid, and hypothyroid patients before and after thyroid function normalization. Univariate and multivariate analyses were performed to evaluate the correlation between thyroid hormones and TRAIL. Then, the stimulatory effect of both triiodothyronine (T3) and thyroxine (T4) on TRAIL was evaluated in vitro on peripheral blood mononuclear cells.

RESULTS: Circulating levels of TRAIL significantly increased in hyperthyroid and decreased in hypothyroid patients as compared to controls. Once thyroid function was restored, TRAIL levels normalized. There was an independent association between TRAIL and both fT3 and fT4. Consistent with these findings, T3 and T4 stimulated TRAIL release in vitro.

CONCLUSION: Here we show that thyroid hormones are associated with TRAIL expression in vivo and stimulate TRAIL expression in vitro. Given the overlap between the metabolic effects of thyroid hormones and TRAIL, this work sheds light on the possibility that TRAIL might be one of the molecules mediating thyroid hormones peripheral effects.

VL - 50 IS - 16-17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28551332?dopt=Abstract ER - TY - JOUR T1 - Circulating osteoprotegerin is associated with chronic kidney disease in hypertensive patients. JF - BMC Nephrol Y1 - 2017 A1 - Bernardi, Stella A1 - Toffoli, Barbara A1 - Bossi, Fleur A1 - Candido, Riccardo A1 - Stenner, Elisabetta A1 - Carretta, Renzo A1 - Barbone, Fabio A1 - Fabris, Bruno KW - Aged KW - Animals KW - Biomarkers KW - Case-Control Studies KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension KW - Male KW - Mice KW - Mice, Inbred C57BL KW - Middle Aged KW - Osteoprotegerin KW - Random Allocation KW - Renal Insufficiency, Chronic AB -

BACKGROUND: Osteoprotegerin (OPG) is a glycoprotein that plays an important regulatory role in the skeletal, vascular, and immune system. It has been shown that OPG predicts chronic kidney disease (CKD) in diabetic patients. We hypothesized that OPG could be a risk marker of CKD development also in non-diabetic hypertensive patients.

METHODS: A case-control study was carried out to measure circulating OPG levels in 42 hypertensive patients with CKD and in 141 hypertensive patients without CKD. A potential relationship between OPG and the presence of CKD was investigated and a receiver-operating characteristic (ROC) curve was designed thereafter to identify a cut-off value of OPG that best explained the presence of CKD. Secondly, to evaluate whether OPG increase could affect the kidney, 18 C57BL/6J mice were randomized to be treated with saline or recombinant OPG every 3 weeks for 12 weeks.

RESULTS: Circulating OPG levels were significantly higher in hypertensive patients with CKD, and there was a significant inverse association between OPG and renal function, that was independent from other variables. ROC analysis showed that OPG levels had a high statistically predictive value on CKD in hypertensive patients, which was greater than that of hypertension. The OPG best cut-off value associated with CKD was 1109.19 ng/L. In the experimental study, OPG delivery significantly increased the gene expression of pro-inflammatory and pro-fibrotic mediators, as well as the glomerular nitrosylation of proteins.

CONCLUSIONS: This study shows that OPG is associated with CKD in hypertensive patients, where it might have a higher predictive value than that of hypertension for CKD development. Secondly, we found that OPG delivery significantly increased the expression of molecular pathways involved in kidney damage. Further longitudinal studies are needed not only to evaluate whether OPG predicts CKD development but also to clarify whether OPG should be considered a risk factor for CKD.

VL - 18 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28683789?dopt=Abstract ER - TY - JOUR T1 - TRAIL modulates the immune system and protects against the development of diabetes. JF - J Immunol Res Y1 - 2015 A1 - Bossi, Fleur A1 - Bernardi, Stella A1 - Zauli, Giorgio A1 - Secchiero, Paola A1 - Fabris, Bruno KW - Animals KW - Diabetes Mellitus KW - Humans KW - Immune System KW - Receptors, TNF-Related Apoptosis-Inducing Ligand KW - Signal Transduction AB -

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.

VL - 2015 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25759846?dopt=Abstract ER - TY - JOUR T1 - Osteoprotegerin increases in metabolic syndrome and promotes adipose tissue proinflammatory changes. JF - Mol Cell Endocrinol Y1 - 2014 A1 - Bernardi, Stella A1 - Fabris, Bruno A1 - Thomas, Merlin A1 - Toffoli, Barbara A1 - Tikellis, Christos A1 - Candido, Riccardo A1 - Catena, Cristiana A1 - Mulatero, Paolo A1 - Barbone, Fabio A1 - Radillo, Oriano A1 - Zauli, Giorgio A1 - Secchiero, Paola KW - Adipose Tissue KW - Adult KW - Animals KW - Blood Glucose KW - Body Mass Index KW - C-Reactive Protein KW - Case-Control Studies KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diet, High-Fat KW - Female KW - Humans KW - Inflammation KW - Insulin KW - Insulin Resistance KW - Male KW - Metabolic Syndrome X KW - Mice KW - Mice, Inbred C57BL KW - Middle Aged KW - Obesity KW - Osteoprotegerin KW - Triglycerides AB -

BACKGROUND: Inflammation is believed to link obesity to insulin resistance, as in the setting of metabolic syndrome (MetS). Osteoprotegerin (OPG) is a soluble protein that seems to exert proatherogenic and prodiabetogenic effects. This study aims at determining OPG levels in MetS and whether OPG might contribute to MetS development and progression.

METHODOLOGY/PRINCIPAL FINDINGS: Circulating OPG was measured in 46 patients with MetS and 63 controls, and was found significantly elevated in those with MetS. In addition, circulating and tissue OPG was significantly increased in high-fat diet (HFD) fed C57BL6 mice, which is one of the animal models for the study of MetS. To evaluate the consequences of OPG elevation, we delivered this protein to C57BL6 mice, finding that it promoted systemic and adipose tissue proinflammatory changes in association with metabolic abnormalities.

CONCLUSIONS/SIGNIFICANCE: These data suggest that OPG may trigger adipose tissue proinflammatory changes in MetS/HFD-induced obesity.

VL - 394 IS - 1-2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24998520?dopt=Abstract ER - TY - JOUR T1 - Patients affected by metabolic syndrome show decreased levels of circulating platelet derived growth factor (PDGF)-BB. JF - Clin Nutr Y1 - 2013 A1 - Tisato, Veronica A1 - Toffoli, Barbara A1 - Monasta, Lorenzo A1 - Bernardi, Stella A1 - Candido, Riccardo A1 - Zauli, Giorgio A1 - Secchiero, Paola KW - Adolescent KW - Adult KW - Aged KW - Case-Control Studies KW - Cell Line, Tumor KW - Chemokine CXCL10 KW - Endothelial Cells KW - Female KW - Humans KW - Interleukin-6 KW - Linear Models KW - Male KW - Metabolic Syndrome X KW - Middle Aged KW - Obesity KW - Pilot Projects KW - Proto-Oncogene Proteins c-sis KW - RNA, Messenger KW - Young Adult AB -

BACKGROUND & AIMS: The development and/or progression of metabolic syndrome (MetS) in overweight and obese individuals have been associated to low-grade inflammation, but few studies have simultaneously analyzed the circulating levels of several cytokines.

METHODS: In this pilot study, a group of 27 cytokines and growth factors was analyzed in the serum of obese patients (n=40) diagnosed for MetS in comparison with sex- and age-matched control subjects without MetS (n=53) by using a multiplex immunoassay. Release of cytokines was measured in culture supernatants of human primary endothelial cells, THP-1 macrophagic cells and HuH-7 hepatoma cells upon exposure to a high fat mixture.

RESULTS: While the majority of cytokines did not show significant differences between the investigated groups, the circulating levels of CXCL10/IP-10 and IL-6 were higher in the MetS group versus overweight control group. In contrast, PDGF-BB serum levels were significantly decreased in MetS patients. The in vitro addition of a high fat mixture increased the release of IL-6 and/or CXCL10/IP-10 in the culture supernatant of human primary endothelial cells and THP-1 macrophagic cells, while the same mixture significantly decreased the release of PDGF-BB by human THP-1 macrophagic and HuH-7 hepatoma cells.

CONCLUSIONS: The current demonstration that MetS is associated with decrease of the pro-fibrotic PDGF cytokine is a completely novel finding, which adds complexity to the interplay between inflammation and fibrosis in patients affected by MetS.

VL - 32 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22840561?dopt=Abstract ER - TY - JOUR T1 - Potential role of TRAIL in the management of autoimmune diabetes mellitus. JF - Curr Pharm Des Y1 - 2012 A1 - Bernardi, Stella A1 - Norcio, Alessia A1 - Toffoli, Barbara A1 - Zauli, Giorgio A1 - Secchiero, Paola KW - Animals KW - Autoimmunity KW - Diabetes Mellitus, Type 1 KW - Humans KW - Hypoglycemic Agents KW - Insulin KW - Insulin-Secreting Cells KW - Islets of Langerhans KW - TNF-Related Apoptosis-Inducing Ligand AB -

Type 1 diabetes mellitus (T1DM) is an autoimmune disease, due to the immune-mediated destruction of pancreatic β-cells, whose incidence has been steadily increasing during the last decades. Insulin replacement therapy can treat T1DM, which, however, is still associated with substantial morbidity and mortality. For this reason, great effort is being put into developing strategies that could eventually prevent and/or cure this disease. These strategies are mainly focused on blocking the immune system from attacking β-cells together with functional islet restoration either by regeneration or transplantation. Recent experimental evidences suggest that TNFrelated apoptosis-inducing ligand (TRAIL), which is an immune system modulator protein, could represent an interesting candidate for the cure for T1DM and/or its complications. Here we review the evidences on the potential role of TRAIL in the management of T1DM.

VL - 18 IS - 35 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22726118?dopt=Abstract ER - TY - JOUR T1 - State of art and recent developments of anti-cancer strategies based on TRAIL. JF - Recent Pat Anticancer Drug Discov Y1 - 2012 A1 - Bernardi, Stella A1 - Secchiero, Paola A1 - Zauli, Giorgio KW - Animals KW - Antineoplastic Agents KW - Antineoplastic Combined Chemotherapy Protocols KW - Apoptosis KW - Clinical Trials as Topic KW - Humans KW - Mice KW - Neoplasms KW - Receptors, Death Domain KW - TNF-Related Apoptosis-Inducing Ligand AB -

Multicellular organisms require apoptosis whereby the human body eliminates unnecessary and/or damaged cells. Apoptosis, or programmed cell death, can indeed be considered as a constitutive anti-cancer mechanism that seems to be defective in more than 50% of cancers. Molecular insights on the biology of the apoptotic process have led to the development of new anti-cancer strategies aiming at recovering and stimulating this process. Preclinical and clinical studies of our and other groups have demonstrated that targeting the extrinsic apoptotic pathway by various death receptors agonists is a safe and effective anti-cancer strategy, which thus may become a new cornerstone of cancer therapy. Here, we review the most recent acquisitions and patents on TRAIL or TRAIL mimetics, as well as the combination therapies that could be used with them.

VL - 7 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22114983?dopt=Abstract ER - TY - JOUR T1 - TNF-related apoptosis-inducing ligand significantly attenuates metabolic abnormalities in high-fat-fed mice reducing adiposity and systemic inflammation. JF - Clin Sci (Lond) Y1 - 2012 A1 - Bernardi, Stella A1 - Zauli, Giorgio A1 - Tikellis, Christos A1 - Candido, Riccardo A1 - Fabris, Bruno A1 - Secchiero, Paola A1 - Cooper, Mark E A1 - Thomas, Merlin C KW - Adiposity KW - Animals KW - Apoptosis KW - Calorimetry KW - Cytokines KW - Dietary Fats KW - Energy Intake KW - Glucose Tolerance Test KW - Hyperglycemia KW - Hyperinsulinism KW - Inflammation KW - Inflammation Mediators KW - Male KW - Mice KW - Mice, Inbred C57BL KW - Oxidation-Reduction KW - Palmitic Acid KW - Real-Time Polymerase Chain Reaction KW - TNF-Related Apoptosis-Inducing Ligand AB -

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).

VL - 123 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22616837?dopt=Abstract ER - TY - JOUR T1 - TRAIL as biomarker and potential therapeutic tool for cardiovascular diseases. JF - Curr Drug Targets Y1 - 2012 A1 - Bernardi, Stella A1 - Milani, Daniela A1 - Fabris, Bruno A1 - Secchiero, Paola A1 - Zauli, Giorgio KW - Biological Markers KW - Cardiovascular Diseases KW - Humans KW - Prognosis KW - TNF-Related Apoptosis-Inducing Ligand AB -

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.

VL - 13 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22676911?dopt=Abstract ER - TY - JOUR T1 - TRAIL shows potential cardioprotective activity. JF - Invest New Drugs Y1 - 2012 A1 - Toffoli, Barbara A1 - Bernardi, Stella A1 - Candido, Riccardo A1 - Zacchigna, Serena A1 - Fabris, Bruno A1 - Secchiero, Paola KW - Animals KW - Apolipoproteins E KW - Apoptosis KW - Cardiotonic Agents KW - Diabetes Mellitus, Experimental KW - Diabetes Mellitus, Type 1 KW - Diabetic Cardiomyopathies KW - Fibrosis KW - Male KW - Mice KW - Mice, Knockout KW - Recombinant Proteins KW - TNF-Related Apoptosis-Inducing Ligand AB -

Recent clinical trials carried out in patients with advanced cancer have shown that recombinant TRAIL administration is usually safe and well tolerated when used either alone or in association with chemotherapeutic drugs. Notably, anticancer chemotherapy can be associated to cardiomiopathy. We have here demonstrated that TRAIL (administrated as either recombinant soluble TRAIL or as AAV-TRAIL expression viral vector) reduced the development of cardiomyopathy in the ApoE(-/-) diabetic mouse model. These data suggest, for the first time, that therapeutically administration of TRAIL might have a cardioprotective effect.

VL - 30 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21197620?dopt=Abstract ER - TY - JOUR T1 - Osteoprotegerin induces morphological and functional alterations in mouse pancreatic islets. JF - Mol Cell Endocrinol Y1 - 2011 A1 - Toffoli, Barbara A1 - Bernardi, Stella A1 - Candido, Riccardo A1 - Sabato, Nicoletta A1 - Carretta, Renzo A1 - Corallini, Federica A1 - Secchiero, Paola A1 - Zauli, Giorgio A1 - Fabris, Bruno KW - Animals KW - Apoptosis KW - Blood Glucose KW - Blood Pressure KW - Body Weight KW - Cell Lineage KW - Cell Movement KW - Chemokine CCL2 KW - Connective Tissue Growth Factor KW - Fibrosis KW - Gene Expression Regulation KW - Humans KW - Insulin KW - Islets of Langerhans KW - Macrophages KW - Mice KW - Monocytes KW - Organ Size KW - Osteoprotegerin KW - Peptidyl-Dipeptidase A KW - Receptor, Angiotensin, Type 1 KW - Systole KW - Transforming Growth Factor beta KW - Vascular Cell Adhesion Molecule-1 AB -

Although serum osteoprotegerin (OPG) is significantly increased in diabetic subjects, its potential role in beta cell dysfunction has not been investigated. This study aimed to assess the effect of full-length OPG administered in vivo in mice on pancreatic islet structure and function and its interaction with the renin-angiotensin system (RAS). OPG-treated mice showed increased islet monocyte/macrophage infiltration, fibrosis and apoptosis with reduction of islet function. The remodeling of islet architecture was associated with increased pancreatic expression of components of the RAS, growth factor genes (transforming growth factor β and connective tissue growth factor) and inflammatory molecules (monocyte chemotactic protein-1 and vascular adhesion molecule type 1). Prevention of these changes with improvement of insulin secretion was observed in ramipril treated animals. Our data suggest that OPG might play an important role in promoting beta cell dysfunction and that the upregulation of the local RAS represents one possible mechanism responsible for the OPG-induced beta cell dysfunction.

VL - 331 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20832449?dopt=Abstract ER - TY - JOUR T1 - Osteoprotegerin promotes vascular fibrosis via a TGF-β1 autocrine loop. JF - Atherosclerosis Y1 - 2011 A1 - Toffoli, Barbara A1 - Pickering, Raelene J A1 - Tsorotes, Despina A1 - Wang, Bo A1 - Bernardi, Stella A1 - Kantharidis, Phillip A1 - Fabris, Bruno A1 - Zauli, Giorgio A1 - Secchiero, Paola A1 - Thomas, Merlin C KW - Animals KW - Apolipoproteins E KW - Cell Proliferation KW - Collagen KW - Fibronectins KW - Fibrosis KW - Gene Expression Regulation KW - Humans KW - Mice KW - Mice, Inbred C57BL KW - Mice, Transgenic KW - Muscle, Smooth, Vascular KW - Myocytes, Smooth Muscle KW - Osteoprotegerin KW - Platelet-Derived Growth Factor KW - Transforming Growth Factor beta1 AB -

BACKGROUND: This study was designed to evaluate the potential role of osteoprotegerin (OPG) in arterial fibrosis.

METHODS: Aortic samples were analyzed after in vivo treatment of ApoE(-/-) mice with recombinant human OPG. Mouse vascular smooth muscle cells (VSMC) were exposed in vitro to recombinant OPG and analyzed for markers of inflammation and fibrosis, such as fibronectin, collagen I, III, IV and transforming growth factor-β1 (TGF-β1). Conversely, the potential modulation of endogenous OPG expression and release by VSMC was analyzed in response to different pro-atherosclerotic cytokines, TGF-β1, platelet derived growth factor (PDGF) and angiogensin II (Ang II).

RESULTS: In vivo treatment with human OPG induced signs of fibrosis and up-regulated the arterial expression of TGF-β1. Consistently, in vitro treatment of VSMC with human OPG induced the expression of fibronectin, collagen type I, III, IV, metalloprotein-2 (MMP-2) and MMP-9, as well as of TGF-β1. On the other hand, exposure to recombinant TGF-β1 promoted the expression/release of endogenous OPG and mediated the increase of OPG release induced by PDGF and Ang II in VSMC.

CONCLUSIONS: Taken together, these data support a pathogenic role for OPG in the development and progression of atherosclerotic lesions and suggest the existence of a vicious circle between TGF-β1 and OPG.

VL - 218 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21679949?dopt=Abstract ER -