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

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

The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function.

Vitamin B6 is a water-soluble vitamin that functions as a coenzyme in many reactions involved in amino acid, carbohydrates and lipid metabolism. Since 2014, >50 cases of sensory neuronal pain due to vitamin B6 supplementation were reported. Up to now, the mechanism of this toxicity is enigmatic and the contribution of the various B6 vitamers to this toxicity is largely unknown. In the present study, the neurotoxicity of the different forms of vitamin B6 is tested on SHSY5Y and CaCo-2 cells. Cells were exposed to pyridoxine, pyridoxamine, pyridoxal, pyridoxal-5-phosphate or pyridoxamine-5-phosphate for 24h, after which cell viability was measured using the MTT assay. The expression of Bax and caspase-8 was tested after the 24h exposure. The effect of the vitamers on two pyridoxal-5-phosphate dependent enzymes was also tested. Pyridoxine induced cell death in a concentration-dependent way in SHSY5Y cells. The other vitamers did not affect cell viability. Pyridoxine significantly increased the expression of Bax and caspase-8. Moreover, both pyridoxal-5-phosphate dependent enzymes were inhibited by pyridoxine. In conclusion, the present study indicates that the neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to pyridoxine. The inactive form pyridoxine competitively inhibits the active pyridoxal-5'-phosphate. Consequently, symptoms of vitamin B6 supplementation are similar to those of vitamin B6 deficiency

Mixture effects of tetrodotoxin (TTX) and drugs targeting voltage-gated sodium channels on spontaneous neuronal activity in vitro

Tetrodotoxin (TTX) potently inhibits TTX-sensitive voltage-gated sodium (NaV) channels in nerve and muscle cells, potentially resulting in depressed neurotransmission, paralysis and death from respiratory failure. Since a wide range of pharmaceutical drugs is known to also act on NaV channels, the use of medicines could predispose individuals to a higher susceptibility towards TTX toxicity. We therefore first assessed the inhibitory effect of selected medicines that act on TTX-sensitive (Riluzole, Chloroquine, Fluoxetine, Valproic acid, Lamotrigine, Lidocaine) and TTX-resistant (Carbamazepine, Mexiletine, Flecainide) NaV channels on spontaneous neuronal activity of rat primary cortical cultures grown on microelectrode arrays (MEA). After establishing concentration-effect curves, binary mixtures of the medicines with TTX at calculated NOEC, IC20 and IC50 values were used to determine if pharmacodynamic interactions occur between TTX and these drugs on spontaneous neuronal activity. At IC20 and IC50 values, all medicines significantly increased the inhibitory effect of TTX on spontaneous neuronal activity of rat cortical cells in vitro. Subsequent experiments using human iPSC-derived neuronal co-cultures grown on MEAs confirmed the ability of selected medicines (Carbamazepine, Flecainide, Riluzole, Lidocaine) to inhibit spontaneous neuronal activity. Despite the need for additional experiments using human iPSC-derived neuronal co-cultures, our combined data already highlight the importance of identifying and including vulnerable risk groups in the risk assessment of TTX