Evaluación de la efectividad terapéutica de extractos funcionales obtenidos de Brasicáceas

Résumé

Colon cancer and obesity are two non-communicable diseases with a high prevalence in society. Obesity is defined as an abnormal or excessive accumulation of fat due to an energy imbalance between calories ingested and calories consumed. The WHO estimates that a quarter of the European adult population suffers from obesity that is responsible for more than 1.2 million deaths per year. Colorectal cancer (CRC) is caused by cellular alterations that lead to a loss of control of the proliferation process, resulting in excessive cell division and the ability of these malignant cells to spread to other tissues. It is the third type of cancer by incidence in the population worldwide, and the second type in number of associated deaths. Although they are two distinct entities, it should be noted that obesity per se is an important risk for the development of different types of cancer, including colorectal cancer. Both pathologies involve an imbalance in the individual's redox state, a chronic inflammatory state, metabolic alterations and intestinal dysbiosis. In this context, plant extracts are a great tool to improve these parameters due to their content of bioactive compounds which have been shown to have a beneficial effect on human health by reducing or preventing these alterations. The plant species of the Brassicaceae family provide numerous health benefits due to their nutritional value and their high content of bioactive compounds. Among them, the isothiocyanates stand out, to which most of the physiological effects on human health are attributed. However, phenolic compounds attracted great interest in this doctoral thesis due to their antioxidant, anti-inflammatory, anticancerogenic, antiaggregation and detoxifying enzyme induction capacity. Physical exercise also plays a fundamental role in the prevention of these diseases. The beneficial effects of regular exercise are mediated by anti-inflammatory mechanisms, stimulation of the immune system response, modulation of metabolism and improvement of the cardiovascular system. The general objective of this PhD is to obtain functional extracts derived from Brassicaceae and other plant species, which can be used for the treatment of obesity and associated disorders and the prevention of colorectal cancer, administered alone or in combination with a physical exercise protocol. For this purpose, a screening in terms of plant species and extraction methods was carried out in order to select those plant extracts with the highest antioxidant capacity in various chemical tests. In addition, in the case of Brassicaceae plant extracts, the capacity to induce detoxifying enzymes was evaluated. Based on the screening results, two nutraceuticals were formulated combining different plant species and extraction methods. These were subjected to an in vitro digestion process and tested for antioxidant, antiproliferative and anti-inflammatory capacity in HT- 29, T84 and J774A1 cell lines, respectively. High performance liquid chromatography was used to identify their specific bioactive compounds. Finally, the functionality of each nutraceutical was evaluated in two animal experimental assays in C57BL/6J mice: i) high-fat diet-induced obesity model and ii) AOM/DSS-induced colorectal cancer model. A model of obesity and metabolic alterations in experimental animals was established from the 3rd week of the experimental by consuming a high fat and fructose in the drinking water period. The administration of the nutraceutical in combination with a physical exercise protocol not only managed to reverse the body weight of the animals, but also improved plasma parameters related to glycemic and lipid metabolism, decreased the accumulation of fat in the liver, and managed to reverse the inflammatory, oxidative, and intestinal dysbiosis state derived from obesity. On the other hand, it was possible to develop tumor polyps in the colon of mice without affecting other organs. The daily administration of the nutraceutical developed from plant extracts at 500mg/kg body weight was able to reduce the development of these polyps, an effect that was further enhanced when combined with the physical exercise protocol. In addition, it was able to improve the endogenous antioxidant and anti-inflammatory activities and correct the gut dysbiosis derived from tumor development. The increasing prevalence of obesity and related metabolic disorders requires the development of effective strategies to combat the health and social problems associated with these pathologies. Caloric restriction is an effective strategy for weight loss and our results highlight that the combination of nutraceutical administration with an exercise protocol may provide the ideal treatment synergy in combination with the former intervention to be tested in population-based studies to enhance the effects of caloric restriction on different metabolic and inflammatory parameters derived from the development of obesity. Furthermore, these results confirm the beneficial effects of brassica extracts on health and encourage their use as a dietary supplement in the prevention/treatment of those pathological conditions where inflammation and oxidative stress play a fundamental role. The consumption of brassicas, or the bioactive compounds derived from this family, may decrease the risk and incidence of CRC by being able to eliminate unstable molecules such as ROS that can initiate the process of carcinogenesis.