Minipigs are recognized as a relevant non-rodent species for nonclinical safety assessment in drug development, although their use remains considerably less common than that of dogs and non-human primates. Historically cited barriers to broader adoption have included increased test article requirements due to their larger size, limited historical control data, technical challenges, and limited experience with their use in nonclinical safety assessment. However, some of these limitations have been mitigated in recent years. While minipigs are most often used for dermally administered drugs due to similarities in skin structure, they are also considered a highly relevant model for cardiovascular research due to similarities in anatomy and physiology with the human cardiovascular system. In this review, we evaluate the advantages and limitations of using minipigs in nonclinical safety assessment for predicting human cardiovascular effects. We summarize current knowledge of porcine cardiovascular anatomy, electrophysiology, hemodynamics, and pharmacokinetics, and discuss how these parameters influence the translational relevance of the minipig model.
The pharmaceutical exposome encompasses human exposure to non-biological contaminants associated with medicinal products, including microplastics (MPs) and nanoplastics (NPs) potentially released from primary packaging. Materials such as high-density polyethylene, polyvinyl chloride, and polyethylene terephthalate may contribute particles during storage, transport, and handling, particularly in liquid formulations. Experimental and preclinical studies suggest that MPs/NPs can alter gut microbiota composition, reduce beneficial bacterial populations, impair short-chain fatty acid production, and promote inflammatory responses. Reported cellular effects include oxidative stress, mitochondrial dysfunction, disruption of intestinal tight junctions, and lysosomal damage. MPs/NPs may also provide surfaces for biofilm formation and interact with active pharmaceutical ingredients through proposed "Trojan Horse" mechanisms, although the pharmaceutical relevance of these processes remains uncertain. Chemical constituents associated with packaging, including phthalates and residual catalysts, may provide additional exposure pathways with potential inflammatory or endocrine-disrupting effects. Pediatric patients, individuals receiving long-term medications, and patients with pre-existing gastrointestinal dysbiosis may warrant particular attention because of potential biological susceptibility or repeated exposure. Analytical characterization remains challenging because pharmaceutical matrices are complex and highly susceptible to contamination, requiring complementary spectroscopic and mass-spectrometric approaches with rigorous quality control. Importantly, direct human evidence specifically linking pharmaceutical packaging-derived MPs/NPs to clinically relevant exposure or adverse health outcomes remains sparse. Current evidence should therefore be interpreted cautiously, with greater emphasis on source-specific human exposure assessment, standardized analytical methods, longitudinal studies, evidence-based risk evaluation, and harmonized regulatory frameworks.
P53-mutant colorectal cancer stem cells (CRCSCs) are characterized by multidrug-resistance, high self-renewal, and limited differentiation potential, which necessitates the development of novel compounds capable of targeting the molecular drivers of differentiation and stemness maintenance in CRCSCs, independent of p53 status. Given this, docosahexaenoic acid (DHA) was selected as a promising therapeutic candidate and its ability to modulate differentiation marker genes and stemness maintenance in CRC stem-like cells was evaluated.P53-mutant (E204X) Caco2 cells, serving as a well-established model of CRCSCs, were treated with 50-150 μM DHA for 48 h. We then evaluated multiple parameters including cell number, metabolic activity, proliferation rates, and LDH release. Additionally, the expression of stemness (CD133) and intestinal differentiation marker genes (Muc-2 and CK-20) as well as clonogenic capacity were assessed. Bioinformatic analysis was performed to predict p53-binding sites within the promoters of CD133, Muc-2, and CK-20 for wild-type p53 and its mutant form.DHA significantly decreased cell numbers, metabolic activities, and proliferation rates after 48 h of treatment. Concurrently, DHA treatment disrupted cell membrane integrity, as evidenced by a marked increase in LDH release into the supernatant. The initially low expression levels of Muc-2 and CK-20 increased dramatically, whereas significant decreases were observed in CD133 gene expression. This was confirmed by significant reductions in self-renewal, plating efficiency, and survival fraction after 2 weeks. Bioinformatics analyses showed that while wild-type p53 binds to the promoters of three differentiation marker genes, the mutant-p53 (E204X) lacks such binding.DHA disrupts cell membrane integrity, modulates stemness and differentiation marker genes, and targets stemness maintenance through a p53-independent pathway, highlighting its cytotoxic and therapeutic potential against p53-mutant CRCSCs.
The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Hydroxyacetophenone as used in cosmetic formulations. This ingredient is reported to function in cosmetics as an antioxidant and skin-conditioning agent. The Panel reviewed relevant data related to the safety of this ingredient in cosmetic formulations, and concluded that Hydroxyacetophenone is safe in cosmetics in the present practices of use and concentration described in this safety assessment.
