Trimethylamine N-oxide (TMAO) is a biologically active gut microbiome-derived dietary metabolite. Recent studies have shown that high circulating plasma TMAO levels are closely associated with diseases such as atherosclerosis and hypertension, and metabolic disorders such as diabetes and hyperlipidemia, contributing to endothelial dysfunction. There is a growing interest to understand the mechanisms underlying TMAO-induced endothelial dysfunction in cardio-metabolic diseases. Endothelial dysfunction mediated by TMAO is mainly driven by inflammation and oxidative stress, which includes: (1) activation of foam cells; (2) upregulation of cytokines and adhesion molecules; (3) increased production of reactive oxygen species (ROS); (4) platelet hyperreactivity; and (5) reduced vascular tone. In this review, we summarize the potential roles of TMAO in inducing endothelial dysfunction and the mechanisms leading to the pathogenesis and progression of associated disease conditions. We also discuss the potential therapeutic strategies for the treatment of TMAO-induced endothelial dysfunction in cardio-metabolic diseases.

Nicotinamide (NAM), a NAM adenine dinucleotide precursor, is known for its benefits to skin health. Under standard culture conditions, NAM delays the differentiation and enhances the proliferation of human primary keratinocytes, leading to the maintenance of stem cells. In this study, we investigated the effects of NAM on photoaging in two-dimensional human primary keratinocyte cultures and three-dimensional organotypic epidermal models. In both models, we found that UVB irradiation and hydrogen peroxide induced human primary keratinocyte premature terminal differentiation and senescence. In three-dimensional organotypics, the phenotype was characterized by a thickening of the granular layer expressing filaggrin and loricrin, but thinning of the epidermis overall. NAM limited premature differentiation and ameliorated senescence, as evidenced by the maintenance of lamin B1 levels in both models, with decreased lipofuscin staining and reduced IL-6/IL-8 secretion in three-dimensional models, compared to those in UVB-only controls. In addition, DNA damage observed after irradiation was accompanied by a decline in energy metabolism, whereas both effects were partially prevented by NAM. Our data thus highlight the protective effects of NAM against photoaging and oxidative stress in the human epidermis and pinpoint DNA repair and energy metabolism as crucial underlying mechanisms.

Para-hydroxycinnamic acid (pHCA) is one of the most abundant naturally occurring hydroxycinnamic acids, a class of chemistries known for their antioxidant properties. In this study, we evaluated the impact of pHCA on different parameters of skin aging in in vitro skin models after H₂O₂ and UV exposure. These parameters include keratinocyte senescence and differentiation, inflammation, and energy metabolism, as well as the underlying molecular mechanisms. Here we demonstrate that pHCA prevents oxidative stress-induced premature senescence of human primary keratinocytes in both 2D and 3D skin models, while improving clonogenicity in 2D. As aging is linked to inflammation, referred to as inflammaging, we analyzed the release of IL-6, IL-8, and PGE₂, known to be associated with senescence. All of them were downregulated by pHCA in both normal and oxidative stress conditions. Mechanistically, DNA damage induced by oxidative stress is prevented by pHCA, while pHCA also exerts a positive effect on the mitochondrial and glycolytic functions under stress. Altogether, these results highlight the protective effects of pHCA against inflammaging, and importantly, help to elucidate its potential mechanisms of action.