Androgen Receptor and Cardiovascular Disease:A Potential Risk for the Abuse of Supplements Containing Selective Androgen Receptor Modulators

The androgen receptor (AR) is a member of the family of ligand-activated transcription factors. Selective androgen receptor modulators (SARMs) exert their biological function through complex interactions with the AR. It has been speculated that overexertion of AR signaling cascades as a result of SARM abuse can be a risk factor for the development of various cardiovascular diseases. The present literature review explores the implications of the interaction between SARMs and the AR on cardiovascular health by focusing on the AR structure, function, and mechanisms of action, as well as the current clinical literature on various SARMs. It is shown that SARMs may increase the risk of cardiovascular diseases through implications on the renin-angiotensin system, smooth muscle cells, sympathetic nervous system, lipid profile, inflammation, platelet activity, and various other factors. More research on this topic is necessary as SARM abuse is becoming increasingly common. There is a noticeable lack of clinical trials and literature on the relationship between SARMs, cardiovascular diseases, and the AR. Future in vivo and in vitro studies within this field are vital to understand the mechanisms that underpin these complex interactions and risk factors

Inter-individual differences in pharmacokinetics of vitamin B6:A possible explanation of different sensitivity to its neuropathic effects

The use of vitamin B6 supplements has gained lots of attention over the past years as they have been related to the development of peripheral neuropathy. The present study focused on the pharmacokinetics of vitamin B6. Twelve healthy volunteers were daily supplemented with either 50 mg pyridoxine or pyridoxal-phosphate for one week. On days 1, 3 and 7, blood samples were taken after oral intake of the supplements. Plasma levels of different vitamers of B6 were determined with ultra-performance liquid chromatography-tandem mass spectrometry. Additionally, reported adverse reactions related to polyneuropathy and vitamin B6 supplements were analyzed. At day 1, pyridoxine only increased after supplementation with pyridoxine during the 4 h analysis. At days 3 and 7, average plasma pyridoxal-phosphate and pyridoxal concentrations significantly increased after supplementation with both vitamers. Average plasma pyridoxine concentrations only significantly increased after 3 and 7 days of supplementation with pyridoxine. Large individual differences in plasma levels of B6 vitamers were seen at all days. Also, individual differences concerning dose and plasma levels were determined in the reported complaints. Our results show that there is a clear inter-individual difference in kinetics of vitamin B6, potentially explaining differences in sensitivity to vitamin B6 toxicity

Toxicological risks of dairy proteins produced through cellular agriculture: Current state of knowledge, challenges and future perspectives

The growing population and the associated increasing demand for high-protein meals are the main drivers of the protein transition. To meet demand, the food industry has turned to new technologies, such as food production through cell culture methods, also known as cellular agriculture. The interest in cellular agriculture is rising, and more products produced this way are seeking regulatory approval, including cell-based dairy products.This review explores the potential toxicological challenges that may arise from cell-based dairy production, in regards to human consumption. The purpose is to identify knowledge gaps and elucidate an inscrutable field. The major production routes are described and analyzed regarding potential safety concerns and the current state of the industry. An in-depth look into the EU regulatory requirements concerning these foods is offered, along with a detailed overview of the potential risks and ways to assess them, focused on new approach methodologies (NAMs).Cellular agriculture presents novel advantages and disadvantages in regard to food safety. To assess these novel risks, both regulatory and toxicological sciences need to adapt in order to keep up with innovations in food production. The advancement and integration of NAMs in food safety assessment is a crucial step to achieving this goal

Gastrointestinal digestion of dietary advanced glycation endproducts using an in vitro model of the gastrointestinal tract (TIM-1)

Protein- and sugar-rich food products processed at high temperatures contain large amounts of dietary advanced glycation endproducts (dAGEs). Our earlier studies have shown that specifically protein-bound dAGEs induce a pro-inflammatory reaction in human macrophage-like cells. To what extent these protein-bound dAGEs survive the human gastrointestinal (GI) tract is still unclear. In this study we analysed gastric and small intestinal digestion of dAGEs using the validated, standardised TNO in vitro gastroIntestinal digestion model (TIM-1), a dynamic in vitro model which mimics the upper human GI tract. This model takes multiple parameters into account, such as: dynamic pH curves, peristaltic mixing, addition of bile and pancreatic digestive enzymes, and passive absorption. Samples of different digested food products were collected at different time points after (i) only gastric digestion and (ii) after both gastric plus small intestinal digestion. Samples were analysed for dAGEs using UPLC-MS/MS for the lysine derived Nε-carboxymethyllysine (CML) and Nε-carboxyethyllysine (CEL), and the arginine derived methylglyoxal-derived hydroimidazolone-1 (MG-H1), and glyoxal-derived hydroimidazolone-1 (G-H1). All AGEs were quantified in their protein-bound and free form. The results of this in vitro study show that protein-bound dAGEs survive gastrointestinal digestion and are additionally formed during small intestinal digestion. In ginger biscuits, the presence MG-H1 in the GI tract increased with more than 400%. This also indicates that dAGEs enter the human GI tract with potential pro-inflammatory characteristics.</p

Dietary advanced glycation endproducts induce an inflammatory response in human macrophages in vitro

Advanced glycation endproducts (AGEs) can be found in protein-and sugar-rich food products processed at high temperatures, which make up a vast amount of the Western diet. The effect of AGE-rich food products on human health is not yet clear and controversy still exists due to possible contamination of samples with endotoxin and the use of endogenous formed AGEs. AGEs occur in food products, both as protein-bound and individual molecules. Which form exactly induces a pro-inflammatory effect is also unknown. In this study, we exposed human macrophage-like cells to dietary AGEs, both in a protein matrix and individual AGEs. It was ensured that all samples did not contain endotoxin concentrations > 0.06 EU/mL. The dietary AGEs induced TNF-alpha secretion of human macrophage-like cells. This effect was decreased by the addition of N(ε)-carboxymethyllysine (CML)-antibodies or a receptor for advanced glycation endproducts (RAGE) antagonist. None of the individual AGEs induce any TNF-alpha, indicating that AGEs should be bound to proteins to exert an inflammatory reaction. These findings show that dietary AGEs directly stimulate the inflammatory response of human innate immune cells and help us define the risk of regular consumption of AGE-rich food products on human health.</p

The shifting perception on antioxidants: The case of vitamin E and β-carotene

Antioxidants are vital for aerobic life, and for decades the expectations of antioxidants as health promoting agents were very high. However, relatively recent meta-analyses of clinical studies show that supplementation of antioxidants does not result in the presumed health benefit, but is associated with increased mortality. The dilemma that still needs to be solved is: what are antioxidants in the end, healthy or toxic? We have evaluated this dilemma by examining the presumed health effects of two individual antioxidants with opposite images i.e. the “poisonous” β-carotene and the “wholesome” vitamin E and focused on one aspect, namely their role in inducing BPDE-DNA adducts. It appears that both antioxidants promote DNA adduct formation indirectly by inhibition of the protective enzyme glutathione-S-transferase π (GST π). Despite their opposite image, both antioxidants display a similar type of toxicity. It is concluded that, in the appreciation of antioxidants, first their benefits should be identified and substantiated by elucidating their molecular mechanism. Subsequently, the risks should be identified including the molecular mechanism. The optimal benefit–risk ratio has to be determined for each antioxidant and each individual separately, also considering the dose

<i>In Vitro</i> Activation of Human Adrenergic Receptors and Trace Amine-Associated Receptor 1 by Phenethylamine Analogues Present in Food Supplements

Pre-workout supplements are popular among sport athletes and overweight individuals. Phenethylamines (PEAs) and alkylamines (AA) are widely present in these supplements. Although the health effects of these analogues are not well understood yet, they are hypothesised to be agonists of adrenergic (ADR) and trace amine-associated receptors (TAARs). Therefore, we aimed to pharmacologically characterise these compounds by investigating their activating properties of ADRs and TAAR1 in vitro. The potency and efficacy of the selected PEAs and AAs was studied by using cell lines overexpressing human ADRα1A/α1B/α1D/α2a/α2B/β1/β2 or TAAR1. Concentration–response relationships are expressed as percentages of the maximal signal obtained by the full ADR agonist adrenaline or the full TAAR1 agonist phenethylamine. Multiple PEAs activated ADRs (EC50 = 34 nM–690 µM; Emax = 8–105%). Almost all PEAs activated TAAR1 (EC50 = 1.8–92 µM; Emax = 40–104%). Our results reveal the pharmacological profile of PEAs and AAs that are often used in food supplements. Several PEAs have strong agonistic properties on multiple receptors and resemble potencies of the endogenous ligands, indicating that they might further stimulate the already activated sympathetic nervous system in exercising athletes via multiple mechanisms. The use of supplements containing one, or a combination of, PEA(s) may pose a health risk for their consumers