Preclinical studies on innovative approaches for targeting diet-related disorders

Lifestyle-associated disorders are nowadays severe concerns for their impact on social and healthcare systems. Over the past decades, the investigation of the multi-faceted molecular mechanisms beneath these disturbances has unveiled the detrimental role played by the low-grade chronic inflammation (metaflammation) and suggested the targeting of its components of as one the promising approaches for defining new strategies for counteracting its delirious consequences. The objective of this doctoral thesis was to explore and assess the involvement of two of these detrimental mediators, namely the Advanced Glycation End Products (AGEs) and casein kinase II (CK2) in the onset of chronic inflammation associated with a 12-week murine models of high-fat high- sugar diet consumption (HFHS). We evinced, for the first time, the innovative antiglycation property of Arthrospira Platensis enriched in zinc (Zn-SP) and its beneficial effects in ameliorating the systemic inflammation and glycaemic abnormalities linked to the HFHS chronic intake. Our findings suggest a new mechanism of action of Zn-SP, responsible of a reduction in AGEs endogenous formation and consequent activation of AGE/RAGE axis alongside to NFκB/NLRP3 cascades, and of boosting AGEs detoxifying defences. On the second set of experiments, we evaluated the effect of pharmacological inhibition of casein kinase II (CK2), a pleiotropic enzyme involved in the onset of different pathological contexts, with 4,5,6,7 tetrabromobenzotriazole (TBB), recording the overactivation of this kinase in the context of diet-related disturbances and the protective effects of its pharmacological inhibition in blunting the simultaneous activation of NFκB/NLRP3 cascades at hepatic level, in parallel to the systemic amelioration of both inflammatory and metabolic profiles. Overall, the experimental results presented in this doctoral thesis showed two different approaches for counteracting metabolic disturbances, strengthening the key role of metaflammation in diet-induced disorders, and propose innovative compounds, the Zn-SP and the CK2 inhibitor, as fascinating approaches to halt metabolic inflammation.