A hundred years have passed since vitamin E was identified as an essential micronutrient for mammals. Since then, many biological functions of vitamin E have been unraveled in both cell and animal models, including antioxidant and anti-inflammatory properties, as well as regulatory activities on cell signaling and gene expression. However, the bioavailability and physiological functions of vitamin E have been considerably shown to depend on lifestyle, genetic factors, and individual health conditions. Another important facet that has been considered less so far is the endogenous interaction with other nutrients. Accumulating evidence indicates that the interaction between vitamin E and other nutrients, especially those that are enriched by supplementation in humans, may explain at least some of the discrepancies observed in clinical trials. Meanwhile, increasing evidence suggests that the different forms of vitamin E metabolites and derivates also exhibit physiological activities, which are more potent and mediated via different pathways compared to the respective vitamin E precursors. In this review, possible molecular mechanisms between vitamin E and other nutritional factors are discussed and their potential impact on physiological and pathophysiological processes is evaluated using published co-supplementation studies.

α-Tocopherol-13′-carboxychromanol (α-T-13′-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert lipid metabolism-regulatory, pro-apoptotic, and anti-tumoral properties at micromolar concentrations. The mechanisms underlying these cell stress-associated responses are, however, poorly understood. Here, we show that the induction of G₀/G₁ cell cycle arrest and apoptosis in macrophages triggered by α-T-13′-COOH is associated with the suppressed proteolytic activation of the lipid anabolic transcription factor sterol regulatory element-binding protein (SREBP)1 and with decreased cellular levels of stearoyl-CoA desaturase (SCD)1. In turn, the fatty acid composition of neutral lipids and phospholipids shifts from monounsaturated to saturated fatty acids, and the concentration of the stress-preventive, pro-survival lipokine 1,2-dioleoyl-sn-glycero-3-phospho-(1′-myo-inositol) [PI(18:1/18:1)] decreases. The selective inhibition of SCD1 mimics the pro-apoptotic and anti-proliferative activity of α-T-13′-COOH, and the provision of the SCD1 product oleic acid (C18:1) prevents α-T-13′-COOH-induced apoptosis. We conclude that micromolar concentrations of α-T-13′-COOH trigger cell death and likely also cell cycle arrest by suppressing the SREBP1-SCD1 axis and depleting cells of monounsaturated fatty acids and PI(18:1/18:1).

Over the past century, research on vitamin E has evolved from its initial identification as a fertility factor to the recognition of α-tocopherol (α-TOH) as an essential micronutrient with antioxidant and gene regulatory functions. Despite extensive investigation, controversies persist regarding its precise biological role, clinical efficacy, and classification as a vitamin. This review summarizes scientific milestones in vitamin E (tocochromanol) research. It highlights recent advances in understanding the absorption, metabolism, and molecular mechanisms of vitamin E. The review also outlines unresolved questions and methodological challenges. The focus is on α-TOH and its metabolites, which exhibit biological activities beyond classical antioxidant effects, such as the regulation of inflammation, lipid metabolism, and immune responses. Evidence from genetic, biochemical, and clinical studies supports the essentiality of α-TOH in humans, as demonstrated by ataxia with vitamin E deficiency (AVED). Other tocochromanols and their metabolites exhibit promising biological activities that suggest potential therapeutic applications. However, their physiological relevance must be confirmed. Advances in metabolomic profiling and molecular modeling now allow for a more comprehensive characterization of vitamin E metabolism and function. Understanding the molecular pathways and biological roles of vitamin E and its derivatives is crucial for refining its definition, establishing evidence-based dietary recommendations, and evaluating its potential in disease prevention and therapy.

Excessive inflammation in cells are a common cause of inflammation-related diseases such as cardiometabolic diseases. The cellular multiprotein complex nucleotide-binding domain and leucine-rich repeat pyrin domain 3 (NLRP3) inflammasome is a cellular key modulator of inflammatory processes. In addition to classic medications, phytochemicals are known for their anti-inflammatory potential. In African folk medicine the seeds of Garcinia kola are used to support the treatment of inflammatory diseases. Of particular interest is the phytochemical garcinoic acid (GA, trans -13′-carboxy-δ-tocotrienol), which is isolated from the Garcinia kola seeds. This derivative and potential metabolite of the vitamin E congener δ-tocotrienol (T3) shows anti-inflammatory properties in vitro. However, the underlying mechanisms are largely unknown. To get better insights into the molecular mode of action, murine J774A.1 macrophages were stimulated with lipopolysaccharides (LPS) only or in combination with adenosine triphosphate (ATP), which led to canonical activation of the NLRP3 inflammasome and subsequent pyroptosis. A combined treatment with GA resulted in significantly reduced stimulation of the transcription factor nuclear factor 'ĸ-light-chain-enhancer' of activated B-cells (NF-ĸB), decreased expression of inflammasome-related genes and marked downregulation of autoproteolytic cleavage of caspase-1 (Casp-1). Consequently, GA had an inhibitory effect on pyroptosis. The results have been validated using the well-known NLRP3 inflammasome inhibitor MCC950. In conclusion, GA was shown to have relevant effects on the regulation of the NLRP3 inflammasome and pyroptosis in vitro. Our study provides new mechanistic insights into the anti-inflammatory mode of action of GA and highlights its relevance as a potential phytochemical drug for the treatment of inflammation.

Caspase‐1 is a central component of the cellular inflammatory response, in particular with respect to its key role in the activation of the NLRP3 inflammasome pathway. Activation of caspase‐1 ensures the cleavage and release of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18, as well as the initiation of pyroptosis, that is a distinct form of programmed cell death. Hence, a wide‐ranging analysis of caspase‐1 in cellular systems is of special interest. To meet this requirement, we improved a commercial luminescence‐based caspase‐1 activity assay and combined it with the determination of the expression and release of caspase‐1 protein, using murine J774A.1 macrophages as a model system for in vitro studies. The presented assay procedure offers additional options over commercially available caspase‐1 activity assays as it allows for: (i) The simultaneous analysis of caspase‐1 activity and protein expression (both intracellular as well as secreted protein in supernatant) out of the same cell sample. (ii) A more economical use of valuable compounds and materials and improves the informative value of each measurement, since all results are generated from the same cell sample. Our optimized assay is therefore suitable for an efficient and reliable screening of modulatory effects of compounds of interest at various regulatory stages of the caspase‐1 system.