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ABSTRACT A series of dietary ingredients and metabolites are able to induce an adaptive stress response either by generation of reactive oxygen species (ROS) and/or via activation of the Nrf2/Keap1 stress response network. Most of the molecules belong to activated Michael acceptors, electrophiles capable to S-alkylate redox sensitive cysteine thiols. This review summarizes recent advances in the (re)search of these compounds and classifies them into distinct groups. More than 60 molecules are described that induce the Nrf2 network, most of them found in our daily diet. Although known as typical antioxidants, a closer look reveals that these molecules induce an initial mitochondrial or cytosolic ROS formation and thereby trigger an adaptive stress response and hormesis, respectively. This, however, leads to higher levels of intracellular glutathione and increased expression levels of antioxidant enzymes such as glutathione peroxidase, thioredoxin reductase, and superoxide dismutase. According to this principle, the author suggests the term hormetics to describe these indirect antioxidants.

Complementary and alternative medicine (CAM) supplements are widely used by cancer patients. Dietary supplements, vitamins and minerals, herbal remedies, and antioxidants are especially popular. In a systematic literature review, 37 studies, each including more than 1000 participants, on CAM, dietary supplement, and vitamin use among cancer patients were identified. Accordingly, cancer patients use antioxidants such as vitamin C (from 2.6% (United Kingdom) to 41.6% (United States)) and vitamin E (from 2.9% (China) to 48% (United States)). Dietary supplements and vitamins are taken for different reasons, but often during conventional cancer treatment involving chemotherapy or radiotherapy and in a self-decided manner without seeking medical advice from healthcare professionals. Drug–drug interactions with dietary supplements or vitamins involving multiple signaling pathways are well described. Since most of the anticancer drugs generate reactive oxygen species (ROS), an adaptive stress response of healthy and malignant cells, mainly driven by the Nrf-2-Keap I network, can be observed. On the one hand, healthy cells should be protected from ROS-overproducing chemotherapy and radiotherapy; on the other hand, ROS production in cancer cells is a “desirable side effect” during anticancer drug treatment. We here describe the paradoxical use of antioxidants and supplements during cancer therapy, possible interactions with anticancer drugs, and the involvement of the Nrf-2 transcription factor.

Exercise promotes longevity and ameliorates type 2 diabetes mellitus and insulin resistance. However, exercise also increases mitochondrial formation of presumably harmful reactive oxygen species (ROS). Antioxidants are widely used as supplements but whether they affect the health-promoting effects of exercise is unknown. We evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) on insulin sensitivity as measured by glucose infusion rates (GIR) during a hyperinsulinemic, euglycemic clamp in previously untrained (n = 19) and pretrained (n = 20) healthy young men. Before and after a 4 week intervention of physical exercise, GIR was determined, and muscle biopsies for gene expression analyses as well as plasma samples were obtained to compare changes over baseline and potential influences of vitamins on exercise effects. Exercise increased parameters of insulin sensitivity (GIR and plasma adiponectin) only in the absence of antioxidants in both previously untrained (P < 0.001) and pretrained (P < 0.001) individuals. This was paralleled by increased expression of ROS-sensitive transcriptional regulators of insulin sensitivity and ROS defense capacity, peroxisomeproliferator-activated receptor gamma (PPARγ), and PPARγ coactivators PGC1α and PGC1β only in the absence of antioxidants (P< 0.001 for all). Molecular mediators of endogenous ROS defense (superoxide dismutases 1 and 2; glutathione peroxidase) were also induced by exercise, and this effect too was blocked by antioxidant supplementation. Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.

New techniques in genome editing have led to a controversial debate about the opportunities and uncertainties they present for agricultural food production and consumption. In July 2018, the Court of Justice of the European Union defined genome editing as a new process of mutagenesis, which implies that the resulting organisms count as genetically modified and are subject, in principle, to the obligations of EU Directive 2001/18/EG. This paper examines how key protagonists from academia, politics, and the economy strategically framed the debate around genome editing in agriculture in Germany prior to its legal classification by the Court of Justice. It is based on an analysis of 96 official statements, including position papers, press releases, and information brochures. Our study reveals eight strategic frames used in the discourse on genome editing and uncovers the strategies used to disconnect from or connect with the previous discourse on green genetic engineering in the 1970s, 1980s and 1990s. Building on competitive framing theory, the study provides explanations for the use and emergence of counter-framing strategies and their success or failure in the debate around genome editing.

The Nutrition and Health Claims Regulation (NHCR) has introduced a new regulatory perspective in food manufacturing, along with influencing consumers’ perception of health-related food claims. Since 2006, a new standard of science-based claims has significantly impacted the European health food market. Over the years, numerous additional decisions have been made, and the ongoing process remains challenging for policymakers striving to harmonize consumer protection and trade within and outside the European Union (EU). This paper presents the current state of the NHCR’s implementation, along with key events aimed at enhancing understanding among consumer organizations and food industry stakeholders, while also offering an insider perspective on relevant policy issues. Additionally, we address two pertinent policy issues to elucidate the associated challenges and opportunities, providing insights to support informed decision-making by policymakers. We use the nutrient profiles framework as a case study to illustrate considerations underpinning the objective of “consumer protection”, while the “probiotics” market serves as an example for exploring the goal of “facilitation of trade”. This historical perspective and reflection lead us to propose possible solutions for future food regulation.

Background: Our study presented a novel LC-MS/MS method for the simultaneous quantification of α-tocopherol (α-TOH) and its phase II metabolites, α-13′-COOH and α-13′-OH, in human serum using deuterium-labeled internal standards (d6-α-TOH, d6-α-13′-COOH, d6-α-13′-OH). Methods: The method addresses the analytical challenge posed by the significantly different concentration ranges of α-TOH (µmol/L) and its metabolites (nmol/L). Previous methods quantified these analytes separately, which caused an increase in workflow complexity. Results: Key features include the synthesis of stable isotope-labeled standards and the use of a pentafluorophenyl-based core-shell chromatography column for baseline separation of both α-TOH and its metabolites. Additionally, solid phase extraction (SPE) with a HybridSPE® material provides a streamlined sample preparation, enhancing analyte recovery and improving sensitivity. By utilizing deuterium-labeled standards, the method compensates for matrix effects and ion suppression. This new approach achieves precise and accurate measurements with limits of detection (LOD) and quantification (LOQ), similar to previous studies. Calibration, accuracy, and precision parameters align well with the existing literature. Conclusions: Our method offers significant advantages in the simultaneous analysis of tocopherol and its metabolites despite concentration differences spanning up to three orders of magnitude. In contrast to earlier studies, which required separate sample preparations and analytical techniques for tocopherol and its metabolites, our approach streamlines this process. The use of a solid-phase extraction procedure allows for parallel sample preparation. This not only enhances efficiency but also significantly accelerates pre-analytical workflows, making the method highly suitable for large-scale studies.

Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2 R )-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13′-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8–49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13′-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13′-COOH, potentially through inhibiting 5-lipoxygenase in immune cells. Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.

Nematodes define a new role for sirtuins in lifespan extension, in which the sirtuin product nicotinamide is converted to a substrate for aldehyde oxidase; turnover of this enzyme generates hydrogen peroxide, causing upregulation of defense mechanisms that promote longevity. Sirtuins, a family of histone deacetylases, have a fiercely debated role in regulating lifespan. In contrast with recent observations, here we find that overexpression of sir-2.1 , the ortholog of mammalian SirT1 , does extend Caenorhabditis elegans lifespan. Sirtuins mandatorily convert NAD + into nicotinamide (NAM). We here find that NAM and its metabolite, 1-methylnicotinamide (MNA), extend C. elegans lifespan, even in the absence of sir-2.1 . We identify a previously unknown C. elegans nicotinamide-N-methyltransferase, encoded by a gene now named anmt-1 , to generate MNA from NAM. Disruption and overexpression of anmt-1 have opposing effects on lifespan independent of sirtuins, with loss of anmt-1 fully inhibiting sir-2.1 –mediated lifespan extension. MNA serves as a substrate for a newly identified aldehyde oxidase, GAD-3, to generate hydrogen peroxide, which acts as a mitohormetic reactive oxygen species signal to promote C. elegans longevity. Taken together, sirtuin-mediated lifespan extension depends on methylation of NAM, providing an unexpected mechanistic role for sirtuins beyond histone deacetylation.

Natural chromanols and chromenols comprise a family of molecules with enormous structural diversity and biological activities of pharmacological interest. A recently published systematic review described more than 230 structures that are derived from a chromanol ortpd chromenol core. For many of these compounds structure-activity relationships have been described with mostly anti-inflammatory as well as anti-carcinogenic activities. To extend the knowledge on the biological activity and the therapeutic potential of these promising class of natural compounds, we here present a report on selected chromanols and chromenols based on the availability of data on signaling pathways involved in inflammation, apoptosis, cell proliferation, and carcinogenesis. The chromanol and chromenol derivatives seem to bind or to interfere with several molecular targets and pathways, including 5-lipoxygenase, nuclear receptors, and the nuclear-factor \"kappa-light-chain-enhancer\" of activated B-cells (NFκB) pathway. Interestingly, available data suggest that the chromanols and chromenols are promiscuitively acting molecules that inhibit enzyme activities, bind to cellular receptors, and modulate mitochondrial function as well as gene expression. It is also noteworthy that the molecular modes of actions by which the chromanols and chromenols exert their effects strongly depend on the concentrations of the compounds. Thereby, low- and high-affinity molecular targets can be classified. This review summarizes the available knowledge on the biological activity of selected chromanols and chromenols which may represent interesting lead structures for the development of therapeutic anti-inflammatory and chemopreventive approaches.

Vitamins E, A, D and K comprise the class of lipid-soluble vitamins. For vitamins A and D, a metabolic conversion of precursors to active metabolites has already been described. During the metabolism of vitamin E, the long-chain metabolites (LCMs) 13′-hydroxychromanol (13′-OH) and 13′-carboxychromanol (13′-COOH) are formed by oxidative modification of the side-chain. The occurrence of these metabolites in human serum indicates a physiological relevance. Indeed, effects of the LCMs on lipid metabolism, apoptosis, proliferation and inflammatory actions as well as tocopherol and xenobiotic metabolism have been shown. Interestingly, there are several parallels between the actions of the LCMs of vitamin E and the active metabolites of vitamin A and D. The recent findings that the LCMs exert effects different from that of their precursors support their putative role as regulatory metabolites. Hence, it could be proposed that the mode of action of the LCMs might be mediated by a mechanism similar to vitamin A and D metabolites. If the physiological relevance and this concept of action of the LCMs can be confirmed, a general concept of activation of lipid-soluble vitamins via their metabolites might be deduced.