Prion diseases are transmissible encephalopathies associated with the conversion of the physiological form of the prion protein (PrPC) to the disease-associated (PrPSc). Despite intense research, no therapeutic or prophylactic agent is available. The catechol-type diterpene Carnosic acid (CA) and its metabolite Carnosol (CS) from Rosmarinus officinalis have well-documented anti-oxidative and neuroprotective effects. Since oxidative stress plays an important role in the pathogenesis of prion diseases, we investigated the potential beneficial role of CA and CS in a cellular model of prion diseases (N2a22L cells) and in a cell-free prion amplification assay (RT-QuIC). The antioxidant effects of the compounds were confirmed when N2a22L were incubated with CA or CS. Furthermore, CA and CS reduced the accumulation of the disease-associated form of PrP, detected by Western Blotting, in N2a22L cells. This effect was validated in RT-QuIC assays, indicating that it is not associated with the antioxidant effects of CA and CS. Importantly, cell-free assays revealed that these natural products not only prevent the formation of PrP aggregates but can also disrupt already formed aggregates. Our results indicate that CA and CS have pleiotropic effects against prion diseases and could evolve into useful prophylactic and/or therapeutic agents against prion and other neurodegenerative diseases.

Ubiquitin-conjugating enzyme E2T (UBE2T) has been implicated in many types of cancer including hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) process plays a fundamental role during tumor metastasis and progression. However, the molecular mechanisms underlying EMT in HCC in accordance with UBE2T still remain unknown. In this study, we showed that UBE2T overexpression augmented the oncogenic properties and specifically EMT in HCC cell lines, while its silencing attenuated them. UBE2T affected the activation of EMT-associated signaling pathways: MAPK/ERK, AKT/mTOR, and Wnt/b-catenin. In addition, we revealed that the epithelial protein complex of E-cadherin/b-catenin, a vital regulator of signal transduction in tumor initiation and progression, was totally disrupted at the cell membrane. In particular, we observed that UBE2T overexpression led to E-cadherin loss accompanied by a simultaneous elevation of both cytoplasmic and nuclear b-catenin, while its silencing resulted in a strong E-cadherin turnover at the cell membrane. Interestingly, chemical inhibition of the MAPK/ERK, AKT/mTOR, and Wnt/bcatenin signaling pathways demonstrated that the nuclear translocation of b-catenin and subsequent EMT was enhanced mainly by MAPK/ERK. Collectively, our findings demonstrate the UBE2T/MAPK-ERK/b-catenin axis as a critical regulator of cell state transition and EMT in HCC.

The genotoxic activity of 15 essential oil constituents used as flavouring agents or cosmetic ingredients was assessed at four concentrations (2.5, 5.0, 7.5 and 10 µl/ml) using the Drosophila melanogaster (Meigen) somatic mutation and recombination test, also known as the wing spot test. Ten of the compounds tested here, namely d‐neomenthol, nerol, 1‐octen‐3‐ol, α‐terpineol, neryl acetate, terpinyl acetate, p‐cymene, α‐pinene, β‐pinene, α‐terpinene were found free of mutagenic or recombinogenic activity, at the applied concentrations. On the other hand, for (1R)‐(−)‐myrtenol and linalyl acetate, weak positive effects were exhibited even at the lowest concentration. For myrtenyl acetate, weakly positive effects were recorded at the high but not at the low concentrations. The two hydrocarbons, γ‐terpinene and terpinolene, showed no genotoxic activity at the low concentrations, but at the high ones they significantly increased the frequency of mutant clones. Results clearly demonstrate differences in activity of positional isomers such as α‐ and γ‐terpinene and terpinolene. Our data suggest the need for re‐evaluating the safety of suspect compounds with cross‐checked genotoxicity studies and at a range of different concentrations. Copyright © 2013 John Wiley & Sons, Ltd.

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