Adipokines and their Involvement as a target of new drugs

Globesity is referred to a global epidemic of obesity, affecting millions of individuals. Molecules released by the enlarged adipose tissue, most of which are pro-inflammatory, have been named adipokines. The present review deals with function, molecular targets and the potential clinical relevance of adipokines. Currently, more than 600 adipokines have been identified, many of them, including leptin, visfatin, resistin as well as Retinol Binding Protein4 may serve as informative markers for metabolic and cardiovascular diseases and play important roles in glucose homeostasis, insulin sensitivity as well as metabolic regulation of energy expenditure. Adiponectin on the contrary exerts anti-inflammatory and insulin sensitizing activity. Adiponectin has additional anti-atherogenic effects and low adiponectin serum concentrations are associated with increased risk for cardiovascular diseases. The understanding of the role of adipokines has provided a wealth of information that has opened great opportunities for new therapeutic advances. Adiponectin may be the most prominent example for the potential use of an adipokine in the treatment of obesity and obesity-associated metabolic diseases. In many studies, administration of recombinant adiponectin results in improved insulin sensitivity, increased insulin secretion and beneficial effects on body weight and hyperglycemia. Up-regulation of adiponectin/adiponectin receptors or enhancing adiponectin receptor function may be an interesting therapeutic strategy for obesity-linked insulin resistance. Moreover, the therapeutic use of combined amylin/leptin agonism (with pramlintide and metreleptin) demonstrated a significant weight-lowering effect in obese subjects. Therefore, adipokines may be clinically relevant either as therapeutic tools or as target in the treatment of obesity related diseases

Expression of phospholipase C genes in cultured endothelial cells.

During inflammation, endothelial cells (EC) are the first elements to be exposed to mediators circulating in the bloodstream. EC react with finely tuned responses mediated by different pathways, including the Phosphoinositide (PI) signal transduction system. The PI pathway contributes to a variety of cell functions, including hormone secretion, neurotransmitter signal transduction, cell growth, membrane trafficking, ion channel activity, cytoskeleton regulation, cell cycle control, apoptosis, embryonic development, organogenesis, and cell/tissue polarity. The Phosphoinositide-specific phospholipase C (PI-PLC) enzymes contribute to the regulation of the spatio-temporal balance of molecules belonging to the PI system. Thirteen mammalian PI-PLC enzymes have been identified, divided into six sub-families on the basis of amino acid sequence, domain structure and mechanism of recruitment. Isoforms within sub-families share sequence similarity, common domain organization, and general regulatory mechanism. The expression of PI-PLCs is strictly tissue specific, and evidences suggest that it varies under different conditions, such as tumor progression or cell activation. We obtained the complete panel of expression of PI-PLC isoforms in human umbilical vein endothelial cells (HUVEC), a widely used experimental model for EC. Then, we analyzed the mRNA concentration of PI-PLCs in LPS treated HUVEC by using the multiliquid bioanalyzer methodology after 3, 6, 24 48 and 72 hours from LPS administration. Marked differences in the expression of most PI-PLC codifying genes were evident

Immunolocalization of Interleukin-17 and Interleukin-23 within human aortic aneurysms

STUDY OBJECTIVE: Much recent experimental evidence suggests that inflammatory reactions are involved in aneurysm formation and progression. Vessel wall weakening has been attributed to the infiltration of a variety of cells, which leads to the upregulation of multiple cytokines. A growing interest is currently focused in the definition of cytokines associated with the final stage of the disease that precedes the rupture. MATERIALS AND METHODS: In the present study full aortic segments were collected from patients with thoracic aortic aneurysms, according to the declaration of Helsinki. Control aorta tissue from organ donors was included as reference. Microtome sections of paraffin embedded samples were analyzed for the presence of IL-17 and IL-23 positivity. Aortic sections were also stained with hematoxylin and eosin and Verhoeff-Van Gieson for elastin. RESULTS: Immunohistochemistry detected IL-17 and IL-23 positive cells at the level of adventitia and muscle cell layer. CONCLUSION: Our data reinforce previous results showing that IL-17 plays a central role in the promotion of vascular inflammation. The identification of main cytokines released during inflammatory processes underlying aneurysm formation and progression may lead to the set up of pharmaceutic strategies that may prove effective for the stabilization of aortic aneurysms

IL-23 involvement in human carotid atherosclerosis progression

Atherosclerosis is now considered an autoimmune-inflammatory disease associated with lipoprotein metabolism alterations. Atheroma begins with the accumulations of oxidized low-density lipoprotein in the subendothelial matrix and the recruitment of monocytes which then differentiate to different functional phenotypes depending on the surrounding microenvironment. Plaque macrophages represent the majority of leukocytes in the atherosclerotic lesions, and their secretory activity, including proinflammatory cytokines and matrix-degrading proteases, is related to the progression as well as to the fragilization and rupture of the plaque (1). The balance between pro- and anti-inflammatory molecules is a major determinant of disease progression (2). In this connection an important role is played by cytokines secreted by 2 major populations of macrophages: M1 or classically activated and M2 or alternatively activated (3). Advanced plaques contain a majority of pro-inflammatory cells and processes leading to plaque rupture are probably dependent on mediators released by these cells in the close proximity of the fibrous cap. The identification of molecules involved in such a mechanism should provide new target for an effective prevention of main tromboembolic complications. Recently, among the many inflammatory cells and cytokines involved in atherosclerosis, an emerging role has been assigned to Th17 and IL-17 cytokine family. IL-23, a heterodimeric cytokine, member of IL-12 family of cytokines, represents the most important cytokine for maintaining and expanding Th17 cells and contributes to local inflammation. Interestingly, very recent meta-analysis correlated autoimmune diseases with excessive cardiovascular events (4), and previous studies have shown the presence of autoantibodies directed to autoantigens of the plaque in patients with carotid atherosclerosis (5,6). Aim of our study was to localize IL-23- and IL-23 receptor-positive cells within human carotid atherosclerotic plaques and to determine the levels of this cytokine in plaque supernatants and in sera from patients with carotid atherosclerosis. We investigated the presence of IL-23 and IL-23 receptor in human carotid atherosclerotic plaques by immunohistochemistry (30 samples), fluorescent in situ hybridization (FISH) (10 samples) and western blot (11 samples). 53% of the supernatant of cultered carotid plaques (19 samples) as well as 60% of carotid atherosclerosis patient sera (25 samples) have shown to contain discrete amounts of IL-23, as measured by enzyme-linked immunosorbent assay (ELISA). In particular our results demonstrated the presence of CD 68 and IL-23-double positive cells at the border and within the fibrous cap of complicated plaques. Moreover IL-23 receptor was detected at the surface of T lymphocytes distributed within the inflammatory infiltrate of the plaque. Of note, only human M1 pro-inflammatory macrophages obtained in vitro from monocytes induced to differentiate in the presence of granulocyte-macrophage colony stimulating factor were able to release IL-23, in response to toll-like receptor 2 and 4 agonists. In addition 53% of the supernatant of cultured carotid plaques (19 samples) as well as 60% of patient sera (25 samples) contained detectable amounts of IL-23, as measured by ELISA. All these findings suggest a relevant role for IL-23 in the inflammatory processes of atherosclerosis, identifying a new potential therapeutic target for immune modulation of atherosclerosis. 1) Businaro R. J Neuroimmune Pharmacol. 2013;8:15-27. 2) Businaro R. et al. Ann N Y Acad Sci. 2012;1262:134-41. 3) Taghavie-Moghadam et al. Ann N Y Acad Sci. 2014;1319:19-37. 4) Amaya-Amaya et al.Biomed Res Int. 2014;2014:367359. 5) Riganò R. et al. Ann N Y Acad Sci. 2007;1107:1-10 6) Businaro R. et al Atherosclerosis. 2009;207:74-8

La civilt\ue0 del latte. Fonti, simboli e prodotti dal Tardoantico al Novecento

Attraverso un percorso interdisciplinare si pubblicano gli atti del convegno nazionale del 2008 svoltosi a Brescia sul latte e i suoi derivati dall'et\ue0 antica al Novecento; un corredo di indici aiuta la consultazione e l'uso multidisciplinare del volumeThe proceedings of the national convention of 2008, in Brescia, about milk and dairy products, are published: the study shows a research, characterized by an interdisciplinary way, from ancient times to the twentieth century: a set of indices also helps the reading and the multidisciplinary stud