Ιωάννης Π. Τρουγκάκος, Καθηγητής Βιολογίας Ζωικού Κυττάρου και Ηλεκτρονικής Μικροσκοπίας, Τομέας Βιολογίας Κυττάρου και Βιοφυσικής, Τμήμα Βιολογίας, ΕΚΠΑ
The integrity of proteome homeodynamics, which is called proteostasis, is vital for the cellular homeostasis and the organism’s survival and heath. Thus, cells have developed a quality control system, namely the proteostasis network, which is responsible for the maintenance of proteome functionality and stability. Key components of the proteostasis network are the molecular chaperones, the ubiquitin-proteasome and the autophagy-lysosome pathways, as well as the antioxidant responses pathway NRF2/KEAP1. Deregulation of proteostasis is one of the hallmarks of ageing and contributes to the ageing phenotype.
It is well established that both health- and life-span can be improved and prolonged by genetic, dietary and/or pharmacological interventions. However, given the fact that genetic interventions and caloric restriction cannot be applied in humans, many studies have been devoted to the identification of natural products that can improve healthspan and/or prolong lifespan. Natural products, extracts or pure compounds, can be isolated from different sources of the biosphere, like plants, marine organisms or microorganisms. Several natural products have been studied and found to activate the proteostasis network and, likely, exert anti-ageing properties both in vitro and in vivo.
Following an extensive high-throughput screening of natural products in order to identify bioactive molecules against cellular senescence, the aim of this thesis was the study of the effect of selected natural products on proteostatic modules. Our study was focused on the extract XTMm223-S2-BM and the pure compound TM1-S3 LAEMB T89-100 P1, which have been isolated from microbial symbionts of invertebrates that live in marine mesophotic coral ecosystems. Furthermore, we studied four extracts from the plant Cichorium intybus, each one isolated with a different method of extraction.
Our findings support that the extract XTMm223-S2-BM is a positive modulator of the proteostasis network and of antioxidant responses. Furthermore, we observed that the extract reduces intracellular oxidative load and protects cells from oxidative and genotoxic stress. Regarding the compound TM1-S3 LAEMB T89-100 P1, we found that cancer cell lines overexpressing key kinases-targets of the molecule are more sensitive to it than normal or immortalized cell lines, indicating its potential anti-cancer activity. Therefore, this compound could be used as a scaffold for the design and development of molecules with potential anti-cancer activity. Finally, with reference to the study of the extracts of the plant Cichorium intybus, only one of them, the extract which was isolated with the accelerated solvent extraction method, tended to reduce the oxidative load and increase the main proteasome enzytic activity in human immortalized keratinocytes.
In conclusion, the natural products presented in the current work could be investigated more extensively in the future, in order to find out the mechanisms of their action in cells and the beneficial properties that they may possess.
Proteostasis network, proteasome, autophagy, ageing, natural products