MTOR blocking peptide

Rationale: Traumatic brain injury (TBI) leads to neurological impairment, with no satisfactory treatments available. Classical ketogenic diets (KD), which reduce reliance on carbohydrates and provide ketones as fuel, have neuroprotective potential, but their high fat content reduces compliance, and experimental evidence suggests they protect juvenile brain against TBI, but not adult brain, which would strongly limit their applicability in TBI. Methods: We designed a new-KD with a fat to carbohydrate plus protein ratio of 2:1, containing medium chain triglycerides (MCT), docosahexaenoic acid (DHA), low glycaemic index carbohydrates, fibres and the ketogenic amino acid leucine, and evaluated its neuroprotective potential in adult TBI. Adult male C57BL6 mice were injured by controlled cortical impact (CCI) and assessed for 70 days, during which they received a control diet or the new-KD. Results: The new-KD, that markedly increased plasma Beta-hydroxybutyrate (beta-HB), significantly attenuated sensorimotor deficits and corrected spatial memory deficit. The lesion size, perilesional inflammation and oxidation were markedly reduced. Oligodendrocyte loss appeared to be significantly reduced. TBI activated the mTOR pathway and the new-KD enhanced this increase and increased histone acetylation and methylation. Conclusion: The behavioural improvement and tissue protection provide proof of principle that this new formulation has therapeutic potential in adult TBI.

In the last few decades, studies on autophagy regulation and its potential role in cancer therapeutics have expanded to include detailed mechanisms. Since apoptosis exhibits drug resistance in some cancers, efforts have focused on searching for compounds with autophagy modulating properties. Numerous natural compounds have been used in cancer treatment and are considered a significant research area due to their remarkable anti-cancer properties. Celastrol, a quinone methide triterpene, derived from Tripterygium wilfordii, has recently drawn much attention because of its anticancer potential. It enhances tumor suppression and induces autophagy in cancer cells by regulating signaling pathways such as Beclin-1, Akt/mTOR, ROS, NF-kappa B, MAPK, HSP90, and the proteasome. In the current study, we address the anticancer potential of celastrol, its effect on various cellular pathways, and describe how it functions as an autophagy modulator in cancer therapeutics and helps diminish multidrug resistance in cancer cells.