Bioactivity of Fragaria vesca leaves through inflammation, proteasome and autophagy modulation.

abstract Ethnopharmacological relevance: Fragaria vesca leaves have been used in folk medicine for the treatmentof several diseases, namely gastrointestinal, cardiovascular and urinary disorders, which could be relatedwith the potential anti-inflammatory properties of the extract. This work aims to disclose the bioactivityand the underlying action mechanism of an extract from Fragaria vesca leaves in order to support itstraditional uses.Materials and methods: A hydroalcoholic extract was prepared from Fragaria vesca leaves and its anti-inflammatory potential was evaluated through inhibition of nitric oxide production and expression ofseveral pro-inflammatory proteins in lipopolysaccharide-triggered macrophages. Nitric oxide scavengeractivity was also assessed using a standard nitric oxide donor. Since numerous inflammatory proteins aretightly regulated by ubiquitination and proteasomal degradation, the putative effect of the extract onthese cellular proteolytic pathways was also disclosed. The phytochemical characterization wasperformed by HPLC-PDA-ESI/MSn and compared with an infusion prepared according to the traditionalmethod.Results: For non-cytotoxic concentrations (80 and 160 mg/mL) the extract inhibited nitrite production,probably due to a direct nitric oxide scavenging. Furthermore, inhibition of proteasome activity wasverified, leading to accumulation of ubiquitinated proteins. The extract also increased the conversion ofthe microtubule-associated protein light chain LC3-I to LC3-II, a marker of autophagy. Polyphenols,namely ellagitannins, proanthocyanidins, and quercetin and kaempferol glucuronide derivatives wereidentified in Fragaria vesca leaves extract. Most of the identified phenolic compounds matched withthose found in traditional preparation, the infusion.Conclusions: The extract has a direct nitric oxide scavenging activity giving support to the traditional useof this plant for the treatment of inflammatory disorders. Furthermore, the extract affects the proteolyticsystems but its role in cancer treatment requires further studies.& 2014 Elsevier Ireland Ltd. All rights reserved.