Serino, Elena (2024) Food Plants Secondary Metabolites Active on Metabolic Syndrome. [Tesi di dottorato]

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Abstract

Metabolic syndrome (MetS) is a group of obesity-related symptoms that often occur together and significantly increase the risk of developing cardiovascular complications such as stroke and type 2 diabetes mellitus. In 2019, cardiovascular disease was responsible for about 9.6 million deaths in men and 8.9 million deaths in women, accounting for about one-third of all deaths worldwide. In the same year, diabetes and diabetes-related kidney disease contributed to an estimated 2 million deaths worldwide. In the early stages, in order to limit the worsening of MetS symptoms and its pathological development, it is recommended to reduce the risk factors, not through drug therapy, but by changing the patient's daily habits. In this phase, the use of nutraceuticals can be helpful and provide significant health benefits. During my PhD, I focused my research on several food plants that had been reported in the literature for their anti-diabetic potential and whose phytochemical characterisation had not been described. The isolated secondary metabolites were therefore tested against targets involved in MetS to validate the use of the plants and identify the bioactive ingredients. This manuscript is divided into four parts, each of which is divided into chapters. The first part is an introduction discussing the main characteristics of MetS and the targets on which the isolated secondary metabolites were tested (Chapter 1), while the second part describes the main techniques I have used in my research (Chapter 2). The second part describes the phytochemical characterisation of three different Centaurea species, C. kotschyi, C. sicula and C. patula. The isolation and structural characterisation (HR-MS, 1D and 2D NMR) of 58 pure secondary metabolites are reported, including different structural families of sesquiterpene lactones, lignans and polyphenols. In particular, these analyses lead to the isolation of 14 unprecedented compounds. In addition, the antidiabetic potential of the isolated secondary metabolites was evaluated on GLUT transporters and on the α-glucosidase enzyme, thanks to our collaboration with Professor Mariano Stornaiuolo of the University Federico II and Professor Sonia Piacente of the University of Salerno. The NMR spectra of the previously undescribed metabolites are given in Appendices A, B and C respectively. This research was partly funded by Ministry of Education, Universities and Research, PRIN 2022 PNRR: P2022PPH4C. The third part of this manuscript describes the analyses of two different food plants: Glycyrrhiza foetida and Aglianico grape pomace. In the first chapter of Part 3, the phytochemical composition of the aerial parts of G. foetida is reported, where a total of 29 pure compounds were isolated and characterised, including 12 previously unreported metabolites. The isolated compounds were tested against various targets related to MetS; in particular, the amorfrutins were tested against PPARs targets thanks to our collaboration with Dr Rosa Maria Vitale at the Institute of Biomolecular Chemistry (IBC) in Pozzuoli, while both the amorfrutins and the other polyphenols were tested in prof. Mariano Stornaiuolo's laboratory as GLUT promoters and as mitochondrial stimulators. This project was partly funded by the Ministry of Education, Universities and Research, PRIN 2022 PNRR: P2022PPH4C. The second chapter of Part 3 reports on the phytochemical analysis of Aglianico grape pomace and the anti-diabetic potential of oleanolic acid, its main component. This project was carried out in collaboration with Professor Martino Forino of the Department of Agronomy of the University Federico II. The NMR spectra of G. foetida are reported in Appendix D. The fourth part of this manuscript deals with the analytical analyses of tropical dietary plants with anti-diabetic potential: a less studied species of the genus Piper and Annona sp. plants. The first chapter presents the previously unknown composition of P. borbonense, which was investigated using a metabolomic approach and different analytical techniques, including Feature-Based Molecular Networking analysis. Furthermore, the analyses led to the isolation of two unprecedented compounds. This project was carried out in collaboration with Professor Giovanni Appendino at the Università degli Studi del Piemonte Orientale and partly at the École Polytechnique during my stay abroad. The second chapter deals entirely with my stay in Gif-sur-Yvette, near Paris, at the Centre National de la Recherche Scientifique (CNRS) under the supervision of prof. Véronique Eparvier and in collaboration with prof. David Touboul at the École Polytechnique. Here, thanks to the collaboration of 'Herbier IRD de Guyane', I studied different species of Annona genus from French Guyana and developed an LCMS-based chemotaxonomic classification methodology. Then I have focused on acetogenins, a class of specialised metabolites present in the Annonaceae family, developing and optimizing an analytical LC-MS/MS procedure for the detection of these secondary metabolites by performing post-column infusions of different salts to induce a specific fragmentation pattern. I also had the opportunity to carry out ion mobility analyses. Appendices E and F contain the supplementary data for P. borbonense and the MS data for acetogenins, respectively.

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