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Milk is not only a composite of nutrients but emerged as a source of exosomes acting as a promising drug delivery vehicle for small interfering RNA (siRNA). siRNA is known for its immense therapeutic potential but has various physiological limitations, including stable delivery. To investigate the suitability of siRNA for physiological stability and oral delivery, we encapsulated scrambled Alexa Fluor (AF)-488 siRNA in milk whey exosomes using lipofection and evaluated stability against the digestive processes along with its uptake and transepithelial transport by intestinal epithelial cells. Milk exosomal siRNA were found resistant to different digestive juices, including saliva, gastric, bile, and pancreatic juices, in vitro and were internalized by Caco-2 cells. The stable delivery of exosomal AF-488 siRNA along with its transepithelial transport was confirmed by fluorescence microscopy and fluorescence intensity measurements. In summary, the encapsulation of siRNA in milk exosomes resists harsh digestive processes, improving intestinal permeability and payload protection.

Several bioactive compounds are in use for the treatment of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. Historically, willow (salix sp.) bark has been an important source of salisylic acid and other natural compounds with anti-inflammatory, antipyretic and analgesic properties. Among these, picein isolated from hot water extract of willow bark, has been found to act as a natural secondary metabolite antioxidant. The aim of this study was to investigate the unrevealed pharmacological action of picein. In silico studies were utilized to direct the investigation towards the neuroprotection abilities of picein. Our in vitro studies demonstrate the neuroprotective properties of picein by blocking the oxidative stress effects, induced by free radical generator 2-methyl-1,4-naphthoquinone (menadione, MQ), in neuroblastoma SH-SY5Y cells. Several oxidative stress-related parameters were evaluated to measure the protection for mitochondrial integrity, such as mitochondrial superoxide production, mitochondrial activity (MTT), reactive oxygen species (ROS) and live-cell imaging. A significant increase in the ROS level and mitochondrial superoxide production were measured after MQ treatment, however, a subsequent treatment with picein was able to mitigate this effect by decreasing their levels. Additionally, the mitochondrial activity was significantly decreased by MQ exposure, but a follow-up treatment with picein recovered the normal metabolic activity. In conclusion, the presented results demonstrate that picein can significantly reduce the level of MQ-induced oxidative stress on mitochondria, and thereby plays a role as a potent neuroprotectant.

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