The increase of chronic diseases, such as cardiovascular diseases, is leading to a high burden on the healthcare system. Moreover, the rise in life expectancy determined a demographic change accompanied by a boost of noncommunicable diseases and a corresponding demand for healthy aging. Diet is a well-established modifiable lifestyle factor able to reduce the risk of chronic diseases, but also the complications associated with an overall beneficial impact on health status. In the last years, evidence has been increasing on the protective role of dietary bioactives, non-nutritive substances mainly found in plants. In particular, (poly)phenols are the most studied compounds over the last 20 years. Several clinical trials showed a protective effect of these bioactives through the modulation of different health outcomes. However, it is less clear the mechanisms through which (poly)phenols may exert their beneficial effect. This is mainly due to their wide diversity, their extensive and complex metabolism, but also to the paucity of reliable, sensitive and validated biomarkers able to bridge the gap between the intake of (poly)phenols and the different endpoints under investigation. Thus, there is a need of more evidence based nutrition able to fill this gap. Within this context, the aim of the present PhD thesis was to evaluate the role of different (poly)phenolic compounds in the modulation of several functional and metabolic biomarkers, through in vivo and in vitro approaches. The first part of the thesis was dedicated to assessing the effect of different (poly)phenols and their metabolites on cardiovascular risk biomarkers by using two different in vitro models of atherosclerosis. Specifically, the first model was a co-culture model of human vascular endothelial cells (HUVECs) and THP-1 used to study the capacity of different (poly)phenols in counteracting THP-1 adhesion process and resolve a TNF-alpha mediated pro-inflammatory process through the modulation of different adhesion molecules. The second in vitro model consisted in a monoculture of monocytes (THP-1) derived macrophages used to study the capacity of (poly)phenolic compounds to reduce lipid accumulation (pivotal step of atherogenesis) and modulate the expression of different genes involved in lipid metabolism. The results obtained have shown the capacity of different (poly)phenols and their metabolites to reduce the THP-1 adhesion to HUVEC, the inflammatory process, including the production of adhesion molecules. In addition, (poly)phenols have shown to reduce lipid accumulation in macrophages and this reduction was accompanied by a modulation of lipid metabolism related genes. The second part of the thesis was carried out at the Departments of Nutrition and Environmental Toxicology, University of California (Davis, USA) and devoted to investigate the role of certain phenolic compounds in the modulation of metabolic features of the adipose tissue, critically involved in the reduction of cardiovascular risk through both in vivo and in vitro models. Specifically, by using 3T3-L1 pre-adipocytes cell line, it has been studied the effect of anthocyanins and their metabolites in the promotion of mitochondrial function and differentiation from white to brown adipocytes. Furtherly, the effect of anthocyanins and metabolites was also investigated in vivo by using an animal model of C57BL/6J mice fed with a high-fat diet. The results obtained documented the capacity of anthocyanins and their metabolites to promote mitochondrial biogenesis and beiging of white adipose tissue via regulation of mitochondrial dynamics both in 3T3-L1 adipocytes cell line and in mice fed with a high fat diet. In the third part of the thesis, the study was devoted to the evaluation of markers able to provide more insight on a novel hypothesis about the effect of (poly)phenols on intestinal permeability and related markers. Specifically, the effect of a polyphenol-rich diet (PR-diet) was evaluated on markers of oxidative stress and vascular function in a group of older subjects with increased intestinal permeability. This last part was carried out in the context of the MaPLE (Microbiome mAnipulation through Polyphenols for managing Leakiness in the Elderly) European project, in which a positive modulation of intestinal permeability was documented. The analysis performed failed to show an effect of the intervention on markers of oxidative stress (e.g. cell resistance to DNA damage and endogenous DNA damage) and vascular function (e.g. serum levels of sVCAM-1 and sICAM-1) in this target vulnerable subjects. In conclusion, this PhD thesis contributed to increase evidence about the beneficial effects of (poly)phenolic compounds through the exploitation of different biomarkers in in vitro and in vivo models. In particular, the in vitro studies contributed to elucidate several biological mechanisms (i.e. related to inflammation, oxidative stress and lipid accumulation/metabolism) of single metabolites and parent compounds also at physiological relevant concentrations. Finally, the studies performed on the animal model and in humans, contributed to demonstrate the potential impact of dietary polyphenols in vivo where more factors can affect and/or interfere on the final effect. The overall results seem to further support the potential benefit of these dietary bioactives even if depending on marker/outcome under study. Future in vitro, but above all, in vivo studies should be designed to better clarify the effectiveness of (poly)phenols by considering the actual dose, their complex pharmacokinetics and extensive metabolism. However, the selection, analysis, exploitation and combination of traditional and candidate biomarkers is highlighted as a critical aspect to address.
ROLE OF (POLY)PHENOLS IN THE MODULATION OF METABOLIC AND FUNCTIONAL MARKERS: IN VIVO AND IN VITRO APPROACHES / M. Marino ; Tutor: M. Porrini ; Co-tutors: P. Riso, C. Del Bo' ; Cooordinator: L. Pinotti. - Milano : Università degli studi di Milano. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2020 Dec 09. ((33. ciclo, Anno Accademico 2020.
|Titolo:||ROLE OF (POLY)PHENOLS IN THE MODULATION OF METABOLIC AND FUNCTIONAL MARKERS: IN VIVO AND IN VITRO APPROACHES|
|Supervisori e coordinatori interni:||PINOTTI, LUCIANO|
|Data di pubblicazione:||9-dic-2020|
|Settore Scientifico Disciplinare:||Settore MED/49 - Scienze Tecniche Dietetiche Applicate|
|Citazione:||ROLE OF (POLY)PHENOLS IN THE MODULATION OF METABOLIC AND FUNCTIONAL MARKERS: IN VIVO AND IN VITRO APPROACHES / M. Marino ; Tutor: M. Porrini ; Co-tutors: P. Riso, C. Del Bo' ; Cooordinator: L. Pinotti. - Milano : Università degli studi di Milano. Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, 2020 Dec 09. ((33. ciclo, Anno Accademico 2020.|
|Appare nelle tipologie:||Tesi di dottorato|