ABSTRACT
The liver is the primary organ responsible for the detoxification and metabolism of drugs. To date, a lack of preclinical models that accurately emulate drug metabolism by the human liver presents a significant challenge in the drug development pipeline, particularly for predicting drug efficacy and toxicity. In recent years, emerging microfluidic-based organ-on-a-chip (OoC) technologies, combined with human induced pluripotent stem cell (hiPSC) technology, present a promising avenue for the complete recapitulation of human organ biology in a patient-specific manner. However, hiPSC-derived organoids and liver-on-a-chip models have so far failed to sufficiently express cytochrome P450 monooxygenase (CYP450) enzymes, the key enzymes involved in first-pass metabolism, which limits the effectiveness and translatability of these models in drug metabolism studies. This review explores the potential of innovative organoid and OoC technologies for studying drug metabolism and discusses their existing drawbacks, such as low expression of CYP450 genes. Finally, we postulate potential approaches for enhancing CYP450 expression in the hope of paving the way toward developing novel, fully representative liver drug-metabolism models.
ABSTRACT
The human brain grows rapidly in early life which requires adequate nutrition. Human milk provides optimal nutrition for the developing brain, and breastfeeding significantly improves the cognition development of infants. These benefits have been largely attributed to human milk oligosaccharides (HMOS), associated with sialic acid (Sia). Subsequently, sialylated HMOS present a vital source of exogenous Sia to infants. Sialic acid is a key molecule essential for proper development of gangliosides, and therefore critical in brain development and function. Recent pre-clinical studies suggest dietary supplementation with Sia or sialylated oligosaccharides enhances intelligence and cognition performance in early and later life. Furthermore, emerging evidence suggests the involvement of Sia in brain homeostasis and disbalance correlates with common pathologies such as Alzheimer's disease (AD). Therefore, this review will discuss early brain health and development and the role of Sia in this process. Additionally, studies associating breastfeeding and specific HMOS to benefits in cognitive development are critically assessed. Furthermore, the review will assess studies implying the potential role of HMOS and microbiota in brain development via the gut-brain axis. Finally, the review will summarize recent advances regarding the role of Sia in neurodegenerative disease in later life and potential roles of dietary Sia sources.