Current Pharmaceutical Design

Early Pathogenesis of Atherosclerosis: The Childhood Obesity

Luigi Amati1*, Marisa Chiloiro1, Emilio Jirillo1,2 and Vito Covelli3

‘IRCCS ‘S. De Bellis’, Gastellana Grotte (Bari, Italy, 2Immunology, University of Bari, Italy and3Neurology, Policlinico, Bari, Italy

Abstract: Obesity represents a chronic inflammatory status and adipocytes release either cytokines or an array of adipokines such as leptin, endowed with immunomodulating and systemic activities. The involvement of cytokines in obesity as well as of the adipokine leptin is supported by the notion that weight reduction normalizes mediators of inflammation.
In this framework, we will demonstrate that in obese children, subjected for a period of six months to a hypocaloric diet, reduction of ma¬jor biochemical and anthropometric parameters correlates with a normalization of immune status. Infact, absolute numhers of CD4+ cells and CD4/CD8 ratio increase, while leptin values fluctuate within normal ranges, being this adipokine involved in the modulation of either innate or adaptive immune responses.
In the discussion, the immune abnormalities detected in obesity will be pointed out and emphasis will be placed on the increased fre¬quency of infectious episodes occurring in obese adolescent and adults. Finally, the infectious etiology of obesity will be illustrated in the sense that adipocytes interacting with infectious agents may cause obesity.
Taken together, the bulk of available data indicate that childhood obesity should be prevented or reduced to avoid more serious complica¬tions in adulthood.
Key Words: Atherosclerosis, adipokines, cytokines, leptin, obesity.

Hereditary Haeniorrhagic Telangiectasia: A Rare Disease As A Mode! for the Study of Human Atherosclerosis

G.M. Lenato1, P. Suppressa1, P. Giordano2, G. Guanti3, E. Guastamacchiaa, V. Triggianib, L. Amati4,
F. Resta5, V. CoveIIi6, E. Jirillo4’5 and C. Sabbà1,*

‘Clinic of Internal Medicine and Public Health, University of Bari and Interdepartmental HHT Center, Bari, Ilaly, 2Deparhnent of Pediatrics. University of Bari, Bari, Itaiv, 3Medica! Genetics Unit, University of Bari, Bari, Italy, 4National Institute for Digestive Diseases, Castellana Grotte, Bari, Italy, 5Department of Internal Medicine, Immunology and Infectious Disease, University of Bari Bari, Italy, 6Neurolog.y Polyclinic Hospital, Bari, Italy, Endocrinology Unit, DETO, University of Bari, Bari, italy and 3Endocinology Unit, DACTI, University of Bari, Bari, Italy

Abstract: Hereditary Haemorrhagic Telangiectasia (HHT) or Rendu-Osler-Weber syndrome is an autosomal dominant disease character¬ized by local angiodysplasia affecting different organisrn districts. From a clinical viewpoint, HHT patients suffer from epistaxis, muco¬cutaneous telangiectases and arteriovenous malformations in various organs. Mutations in two known genes (ENG and ALK1) account for the majority of HHT patients. Additional loci are predicted, but the underiying genes are stili to be identified. Moreover, SMAD4 mu¬tations have been reported to cause JP-HHT combined syndrome.

Both endoglin and ALK-1 bind to various growth factors in the context of the Transforming Growth Factors (TGF)-beta superfamily and their expression is restricted to vascular endothelial cells and verv few other cells types, such as activated monocytes. Endoglin and ALK1 mutations are thought to affect endothelial cells metabolism, angiogenesis and vascular remodelling, even if the precise mechanism lead¬ing to the HHT lesions is still obscure. Endoglin is also overexpressed in smooth muscle cells of atherosclerotic plaques, suggesting a role for this protein in atherogenesis and plaque progression, as well as in other cardiovascular diseases. Recently, we demonstrated that HHT adult patients display several deficits of both innate and adaptive immune system. Here, we investigated the function of immune cells in iHHT pediatric patients. Our results clearly show that HHT children have a normal functionally immune system, and suggest that HHT patients become immunocompromised host during their lifetime, likely due to a precocious immunosenescence. Moreover, the rela¬tionship between immune responsiveness in HUT and atherosclerosis are discussed.

Keywords: Atherosclerosis, Endoglin, Endothelial cells, Hereditaiy Haemorrhagic Telangiectasia, Trasforming Growth Faetor-beta.

Red Wine Consumption and Prevention of Atherosclerosis: An In Vitro Model Using Human Peripheral Blood Mononuclear Cells
T. Magronet, A. Tafar&, F. Jirillo’, M.A. Panaro2, P. Cuzzuol3, A.C. Cuzzuol1, V. Pugliese’, L. Amati4,
E. Jiri1lol~4,* and V. Covellit

‘Immunology, Faculty of Medicine, University of Bari, Bari, Italy, 2Human Anatomy, Faculty of Medicine, Bari, Bari, Italy, 3Cantina Sociale “Pliniana” Mandano, Taranto, Italy, 4National Institute for Digestive Diseases, Castellano Grotte (Bari), Italy, Neurologv, Policlinic Hospital, Bari, ftaly

Abstract: Evidence has been provided that red wine possesses antiatherogenic activities in virtue of its content in poiyphenols (flavon¬oids and non-flavonoids substances).
Here, some red wines (Negroamaro, Primitivo and Lambrusco) were tested far their ability to trigger nitric oxide (NO) production from human healthy peripheral blood mononuclear cells (PBMC). Negroamaro was the strongest inducer of NO from PBMC and deprivation of polyphenols did not influence its NO generation capacily. This fact supports the involvement of polyphenols in the NO production even in the absence of alcohal, which also per se does not exert any significant activity. These results are also corroborated by the evi¬dence that PBMC inducible-nitric oxide synthase (iNOS) expression occured by the effect of samples containing polyphenols bui this cx¬pression was very weak when polyphenols were removed from the whole Negroamaro.

In synthesis, flavonoids and resveratrol, major constitutents of red wine, once absorbed at intestinal level, enter circulation and trigger monocytes for NO production. To the best of our knowledge, this is the first demonstration of a direct effect at red wine on monocytes far NO release te occur. On the other hand, also the macrophage contingent from gut-associated lymphoid tissue can contribute te NO generation, besides the aliquot produced by endothelial cells, as previously demanstrated by various authors. Taken together, these results support the concept that moderate intake of red wine can prevent atherosclerosis via production of NO, a potent vasodilator of terminaI vessels.

KeyWords: Antiinflammatory, Atherosclerosis, Flavonoids, inducible Nitrie Oxide Synthase, Nitric Oxide, Peripheral Blood Mononuclear Cells, Polyphenols, Red wine.

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