Perinatal High-Fat Diet Influences Ozone-Induced Responses on Pulmonary Oxidant Status and the Molecular Control of Mitophagy in Female Rat Offspring.

Previous research has shown that a perinatal obesogenic, high-fat diet (HFD) is able to exacerbate ozone-induced adverse effects on lung function, injury, and inflammation in offspring, and it has been suggested that mitochondrial dysfunction is implicated herein. The aim of this study was to investigate whether a perinatal obesogenic HFD affects ozone-induced changes in offspring pulmonary oxidant status and the molecular control of mitochondrial function. For this purpose, female Long-Evans rats were fed a control diet or HFD before and during gestation, and during lactation, after which the offspring were acutely exposed to filtered air or ozone at a young-adult age (forty days). Directly following this exposure, the offspring lungs were examined for markers related to oxidative stress; oxidative phosphorylation; and mitochondrial fusion, fission, biogenesis, and mitophagy. Acute ozone exposure significantly increased pulmonary oxidant status and upregulated the molecular machinery that controls receptor-mediated mitophagy. In female offspring, a perinatal HFD exacerbated these responses, whereas in male offspring, responses were similar for both diet groups. The expression of the genes and proteins involved in oxidative phosphorylation and mitochondrial biogenesis, fusion, and fission was not affected by ozone exposure or perinatal HFD. These findings suggest that a perinatal HFD influences ozone-induced responses on pulmonary oxidant status and the molecular control of mitophagy in female rat offspring.

Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System.

Titanium dioxide (TiO2) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO2 and recent insights into its potentially hazardous properties, there are concerns about its application in commercially available products. Especially the nano-sized particle fraction (<100 nm) of TiO2 warrants a more detailed evaluation of potential adverse health effects after ingestion. A workshop organized by the Dutch Office for Risk Assessment and Research (BuRO) identified uncertainties and knowledge gaps regarding the gastrointestinal absorption of TiO2, its distribution, the potential for accumulation, and induction of adverse health effects such as inflammation, DNA damage, and tumor promotion. This review aims to identify and evaluate recent toxicological studies on food-grade TiO2 and nano-sized TiO2 in ex-vivo, in-vitro, and in-vivo experiments along the gastrointestinal route, and to postulate an Adverse Outcome Pathway (AOP) following ingestion. Additionally, this review summarizes recommendations and outcomes of the expert meeting held by the BuRO in 2018, in order to contribute to the hazard identification and risk assessment process of ingested TiO2.

Gene expression and DNA methylation as mechanisms of disturbed metabolism in offspring after exposure to a prenatal HF diet.

Exposure to a prenatal high-fat (HF) diet leads to an impaired metabolic phenotype in mouse offspring. The underlying mechanisms, however, are not yet fully understood. Therefore, this study investigated whether the impaired metabolic phenotype may be mediated through altered hepatic DNA methylation and gene expression. We showed that exposure to a prenatal HF diet altered the offspring's hepatic gene expression of pathways involved in lipid synthesis and uptake (SREBP), oxidative stress response [nuclear factor (erythroid-derived 2)-like 2 (Nrf2)], and cell proliferation. The downregulation of the SREBP pathway related to previously reported decreased hepatic lipid uptake and postprandial hypertriglyceridemia in the offspring exposed to the prenatal HF diet. The upregulation of the Nrf2 pathway was associated with increased oxidative stress levels in offspring livers. The prenatal HF diet also induced hypermethylation of transcription factor (TF) binding sites upstream of lipin 1 (Lpin1), a gene involved in lipid metabolism. Furthermore, DNA methylation of Lpin1 TF binding sites correlated with mRNA expression of Lpin1 These findings suggest that the effect of a prenatal HF diet on the adult offspring's metabolic phenotype are regulated by changes in hepatic gene expression and DNA methylation.

Cigarette Filter Ventilation and Smoking Protocol Influence Aldehyde Smoke Yields.

The WHO study group on tobacco product regulation (TobReg) advised regulating and lowering toxicant levels in cigarette smoke. Aldehydes are one of the chemical classes on the TobReg smoke toxicants priority list. To provide insight in factors determining aldehyde yields, the levels of 12 aldehydes in mainstream cigarette smoke of 11 Dutch brands were quantified. Variations in smoking behavior and cigarette design affecting human exposure to aldehydes were studied by using four different machine testing protocols. Machine smoking was based on the International Standardization Organization (ISO) and Health Canada Intense (HCI) regime, both with and without taping the filter vents. The 11 cigarette brands differed in (i) design and blend characteristics; (ii) tar, nicotine, and carbon monoxide (TNCO) levels; (iii) popularity; and (iv) manufacturer. Cigarette smoke was trapped on a Cambridge filter pad and carboxen cartridge. After being dissolved in methanol/CS2 and derivatization with DNPH, the aldehyde yields were determined using HPLC-DAD. Using an intense smoking regime (increased puff volume, shorter puff interval) significantly increased aldehyde yields, following the pattern: ISO < ISO-taped < HCI-untaped < HCI. For all of the regimes, acetaldehyde and acrolein yields were strongly correlated ( r = 0.804). The difference in TNCO and aldehyde levels between regular and highly ventilated low-TNCO cigarettes (as measured using ISO) diminished when smoking intensely; this effect is stronger when combined with taping filter vents. The highly ventilated low-TNCO brands showed six times more aldehyde production per mg nicotine for the intense smoking regimes. In conclusion, acetaldehyde and acrolein can be used as representatives for the class of volatile aldehydes for the different brands and smoking regimes. The aldehyde-to-nicotine ratio increased when highly ventilated cigarettes were smoked intensely, similar to real smokers. Thus, a smoker of highly ventilated low-TNCO cigarettes has an increased potential for higher aldehyde exposures compared to a smoker of regular cigarettes.

In Vitro 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/ß1/ß2 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.

Alterations in the molecular control of mitochondrial turnover in COPD lung and airway epithelial cells.

Abnormal mitochondria have been observed in bronchial- and alveolar epithelial cells of patients with chronic obstructive pulmonary disease (COPD). However, it is unknown if alterations in the molecular pathways regulating mitochondrial turnover (mitochondrial biogenesis vs mitophagy) are involved. Therefore, in this study, the abundance of key molecules controlling mitochondrial turnover were assessed in peripheral lung tissue from non-COPD patients (n = 6) and COPD patients (n = 11; GOLDII n = 4/11; GOLDIV n = 7/11) and in both undifferentiated and differentiated human primary bronchial epithelial cells (PBEC) from non-COPD patients and COPD patients (n = 4-7 patients/group). We observed significantly decreased transcript levels of key molecules controlling mitochondrial biogenesis (PPARGC1B, PPRC1, PPARD) in peripheral lung tissue from severe COPD patients. Interestingly, mRNA levels of the transcription factor TFAM (mitochondrial biogenesis) and BNIP3L (mitophagy) were increased in these patients. In general, these alterations were not recapitulated in undifferentiated and differentiated PBECs with the exception of decreased PPARGC1B expression in both PBEC models. Although these findings provide valuable insight in these pathways in bronchial epithelial cells and peripheral lung tissue of COPD patients, whether or not these alterations contribute to COPD pathogenesis, underlie changes in mitochondrial function or may represent compensatory mechanisms remains to be established.

Disruption of the Molecular Regulation of Mitochondrial Metabolism in Airway and Lung Epithelial Cells by Cigarette Smoke: Are Aldehydes the Culprit?

Chronic obstructive pulmonary disease (COPD) is a devastating lung disease for which cigarette smoking is the main risk factor. Acetaldehyde, acrolein, and formaldehyde are short-chain aldehydes known to be formed during pyrolysis and combustion of tobacco and have been linked to respiratory toxicity. Mitochondrial dysfunction is suggested to be mechanistically and causally involved in the pathogenesis of smoking-associated lung diseases such as COPD. Cigarette smoke (CS) has been shown to impair the molecular regulation of mitochondrial metabolism and content in epithelial cells of the airways and lungs. Although it is unknown which specific chemicals present in CS are responsible for this, it has been suggested that aldehydes may be involved. Therefore, it has been proposed by the World Health Organization to regulate aldehydes in commercially-available cigarettes. In this review, we comprehensively describe and discuss the impact of acetaldehyde, acrolein, and formaldehyde on mitochondrial function and content and the molecular pathways controlling this (biogenesis versus mitophagy) in epithelial cells of the airways and lungs. In addition, potential therapeutic applications targeting (aldehyde-induced) mitochondrial dysfunction, as well as regulatory implications, and the necessary required future studies to provide scientific support for this regulation, have been covered in this review.

Habitual Intake of Dietary Dicarbonyls is Associated with Greater Insulin Sensitivity and Lower Prevalence of Type 2 Diabetes: The Maastricht Study.

BACKGROUND: Dicarbonyls are reactive precursors of advanced glycation end-products (AGEs). Dicarbonyls are formed endogenously, but also during food processing. Circulating dicarbonyls are positively associated with insulin resistance and type 2 diabetes, but the consequences of dietary dicarbonyls are unknown. OBJECTIVES: We aimed to examine the associations of dietary intake of dicarbonyls with insulin sensitivity, ß-cell function, and the prevalence of prediabetes or type 2 diabetes. METHODS: In 6282 participants (aged 60 ± 9 y; 50% men, 23% type 2 diabetes [oversampled]) of the population-based cohort the Maastricht Study, we estimated the habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) using food frequency questionnaires. Insulin sensitivity (n = 2390), ß-cell function (n = 2336), and glucose metabolism status (n = 6282) were measured by a 7-point oral glucose tolerance test. Insulin sensitivity was assessed as the Matsuda index. Additionally, insulin sensitivity was measured as HOMA2-IR (n = 2611). ß-cell function was assessed as the C-peptidogenic index, overall insulin secretion, glucose sensitivity, potentiation factor, and rate sensitivity. Cross-sectional associations of dietary dicarbonyls with these outcomes were investigated using linear or logistic regression adjusting for age, sex, cardiometabolic risk factors, lifestyle, and dietary factors. RESULTS: Higher dietary MGO and 3-DG intakes were associated with greater insulin sensitivity after full adjustment, indicated by both a higher Matsuda index (MGO: Std. ß [95% CI] = 0.08 [0.04, 0.12]; 3-DG: 0.09 [0.05, 0.13]) and a lower HOMA2-IR (MGO: Std. ß = -0.05 [-0.09, -0.01]; 3-DG: -0.04 [-0.08, -0.01]). Moreover, higher MGO and 3-DG intakes were associated with a lower prevalence of newly diagnosed type 2 diabetes (OR [95% CI] = 0.78 [0.65, 0.93] and 0.81 [0.66, 0.99]). There were no consistent associations of MGO, GO, and 3-DG intakes with ß-cell function. CONCLUSION: Higher habitual consumption of the dicarbonyls MGO and 3-DG was associated with better insulin sensitivity and lower prevalence of type 2 diabetes, after excluding individuals with known diabetes. These novel observations warrant further exploration in prospective cohorts and intervention studies.

Maternal fatty acid status during pregnancy versus offspring inflammatory markers: a canonical correlation analysis of the MEFAB cohort.

The development of inflammatory lung disorders in children may be related to maternal fatty acid intake during pregnancy. We therefore examined maternal fatty acid (FA) status during pregnancy and its associations with inflammatory markers and lung conditions in the child by analyzing data from the MEFAB cohort using multivariate canonical correlation analysis (CCA). In the MEFAB cohort, 39 different phospholipid FAs were measured in maternal plasma at 16, 22 and 32 weeks of pregnancy, and at day of birth. Child inflammatory markers and self-reported doctor diagnosis of inflammatory lung disorders were assessed at 7 years of age. Using CCA, we found that maternal FA levels during pregnancy were significantly associated with child inflammatory markers at 7 years of age and that Mead acid (20:3n-9) was the most important FA for this correlation. To further verify the importance of Mead acid, we examined the relation between maternal Mead acid levels at the day of birth with the development of inflammatory lung disorders in children at age 7. After stratification for the child's sex, maternal Mead acid levels at day of birth were significantly related with self-reported doctor diagnosis of asthma and lung infections in boys, and bronchitis and total number of lung disorders in girls. Future studies should investigate whether the importance of Mead acid in the relation between maternal FA status and inflammation and lung disorders in the child is due to its role as biomarker for essential fatty acid deficiency or due to its own biological function as pro-inflammatory mediator.

Dysregulated mitochondrial metabolism upon cigarette smoke exposure in various human bronchial epithelial cell models.

Exposure to cigarette smoke (CS) is the primary risk factor for developing chronic obstructive pulmonary disease. The impact of CS exposure on the molecular mechanisms involved in mitochondrial quality control in airway epithelial cells is incompletely understood. Undifferentiated or differentiated primary bronchial epithelial cells were acutely/chronically exposed to whole CS (WCS) or CS extract (CSE) in submerged or air-liquid interface conditions. Abundance of key regulators controlling mitochondrial biogenesis, mitophagy and mitochondrial dynamics was assessed. Acute exposure to WCS or CSE increased the abundance of components of autophagy and receptor-mediated mitophagy in all models. Although mitochondrial content and dynamics appeared to be unaltered in response to CS, changes in both the molecular control of mitochondrial biogenesis and a shift toward an increased glycolytic metabolism were observed in particular in differentiated cultures. These alterations persisted, at least in part, after chronic exposure to WCS during differentiation and upon subsequent discontinuation of WCS exposure. In conclusion, smoke exposure alters the regulation of mitochondrial metabolism in airway epithelial cells, but observed alterations may differ between various culture models used. This article has an associated First Person interview with the joint first authors of the paper.

Higher habitual intake of dietary dicarbonyls is associated with higher corresponding plasma dicarbonyl concentrations and skin autofluorescence: the Maastricht Study.

BACKGROUND: Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown. OBJECTIVES: To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs. METHODS: In 2566 individuals of the population-based Maastricht Study (age: 60 ± 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in > 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using the AGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle. RESULTS: Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (ß: 0.08; 95% CI: 0.02, 0.13) and SAF (ß: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (ß: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF. CONCLUSIONS: Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).

Habitual intake of dietary methylglyoxal is associated with less low-grade inflammation: the Maastricht Study.

BACKGROUND: Dicarbonyls are major reactive precursors of advanced glycation endproducts (AGEs). Dicarbonyls are formed endogenously and also during food processing. Circulating dicarbonyls and AGEs are associated with inflammation and microvascular complications of diabetes, but for dicarbonyls from the diet these associations are currently unknown. OBJECTIVES: We sought to examine the associations of dietary dicarbonyl intake with low-grade inflammation and microvascular function. METHODS: In 2792 participants (mean ± SD age: 60 ± 8 y; 50% men; 26% type 2 diabetes) of the population-based cohort the Maastricht Study, we estimated the habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by linking FFQ outcome data to our food composition database of the MGO, GO, and 3-DG content of >200 foods. Low-grade inflammation was assessed as six plasma biomarkers, which were compiled in a z score. Microvascular function was assessed as four plasma biomarkers, compiled in a zscore; as diameters and flicker light-induced dilation in retinal microvessels; as heat-induced skin hyperemic response; and as urinary albumin excretion. Cross-sectional associations of dietary dicarbonyls with low-grade inflammation and microvascular function were investigated using linear regression with adjustments for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle and dietary factors. RESULTS: Fully adjusted analyses revealed that higher intake of MGO was associated with a lower z score for inflammation [standardized ß coefficient (STD ß): -0.05; 95% CI: -0.09 to -0.01, with strongest inverse associations for hsCRP and TNF-α: both -0.05; -0.10 to -0.01]. In contrast, higher dietary MGO intake was associated with impaired retinal venular dilation after full adjustment (STD ß: -0.07; 95% CI: -0.12 to -0.01), but not with the other features of microvascular function. GO and 3-DG intakes were not consistently associated with any of the outcomes. CONCLUSION: Higher habitual intake of MGO was associated with less low-grade inflammation. This novel, presumably beneficial, association is the first observation of an association between MGO intake and health outcomes in humans and warrants further investigation.

Smoking-Associated Exposure of Human Primary Bronchial Epithelial Cells to Aldehydes: Impact on Molecular Mechanisms Controlling Mitochondrial Content and Function.

Chronic obstructive pulmonary disease (COPD) is a devastating lung disease primarily caused by exposure to cigarette smoke (CS). During the pyrolysis and combustion of tobacco, reactive aldehydes such as acetaldehyde, acrolein, and formaldehyde are formed, which are known to be involved in respiratory toxicity. Although CS-induced mitochondrial dysfunction has been implicated in the pathophysiology of COPD, the role of aldehydes therein is incompletely understood. To investigate this, we used a physiologically relevant in vitro exposure model of differentiated human primary bronchial epithelial cells (PBEC) exposed to CS (one cigarette) or a mixture of acetaldehyde, acrolein, and formaldehyde (at relevant concentrations of one cigarette) or air, in a continuous flow system using a puff-like exposure protocol. Exposure of PBEC to CS resulted in elevated IL-8 cytokine and mRNA levels, increased abundance of constituents associated with autophagy, decreased protein levels of molecules associated with the mitophagy machinery, and alterations in the abundance of regulators of mitochondrial biogenesis. Furthermore, decreased transcript levels of basal epithelial cell marker KRT5 were reported after CS exposure. Only parts of these changes were replicated in PBEC upon exposure to a combination of acetaldehyde, acrolein, and formaldehyde. More specifically, aldehydes decreased MAP1LC3A mRNA (autophagy) and BNIP3 protein (mitophagy) and increased ESRRA protein (mitochondrial biogenesis). These data suggest that other compounds in addition to aldehydes in CS contribute to CS-induced dysregulation of constituents controlling mitochondrial content and function in airway epithelial cells.

Harm potential of magic mushroom use: a review.

In 2007, the Minister of Health of the Netherlands requested the CAM (Coordination point Assessment and Monitoring new drugs) to assess the overall risk of magic mushrooms. The present paper is an updated redraft of the review, written to support the assessment by CAM experts. It summarizes the literature on physical or psychological dependence, acute and chronic toxicity, risk for public health and criminal aspects related to the consumption of magic mushrooms. In the Netherlands, the prevalence of magic mushroom use was declining since 2000 (last year prevalence of 6.3% in 2000 to 2.9% in 2005), and further declined after possession and use became illegal in December 2008. The CAM concluded that the physical and psychological dependence potential of magic mushrooms was low, that acute toxicity was moderate, chronic toxicity low and public health and criminal aspects negligible. The combined use of mushrooms and alcohol and the quality of the setting in which magic mushrooms are used deserve, however, attention. In conclusion, the use of magic mushrooms is relatively safe as only few and relatively mild adverse effects have been reported. The low prevalent but unpredictable provocation of panic attacks and flash-backs remain, however, a point of concern.

Quantification of dicarbonyl compounds in commonly consumed foods and drinks; presentation of a food composition database for dicarbonyls.

Dicarbonyls are reactive precursors of advanced glycation endproducts. They are formed endogenously and during food processing. Currently, a comprehensive database on dicarbonyls in foods that covers the entire range of food groups is lacking, limiting knowledge about the amount of dicarbonyls that is ingested via food. The aim of this study was to analyze the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) in commonly-consumed products in a Western diet. We validated a UHPLC-MS/MS method to quantify MGO, GO, and 3-DG. We present a dietary dicarbonyl database of 223 foods and drinks. Total dicarbonyl concentrations were highest in dried fruit, Dutch spiced cake, and candy bars (>400 mg/kg). Total dicarbonyl concentrations were lowest in tea, dairy, light soft drinks, and rice (<10 mg/kg). The presented database of MGO, GO, and 3-DG opens the possibility to accurately estimate dietary exposure to these dicarbonyls, and explore their physiological impact on human health.

Ranking the harm of alcohol, tobacco and illicit drugs for the individual and the population.

Drug policy makers continuously face a changing pattern of drug use, i.e. new drugs appear on the market, the popularity of certain drugs changes or drugs are used in another way or another combination. For legislative purposes, drugs have mostly been classified according to their addictive potency. Such classifications, however, lack a scientific basis. The present study describes the results of a risk assessment study where 19 recreational drugs (17 illicit drugs plus alcohol and tobacco) used in the Netherlands have been ranked by a Dutch expert panel according to their harm based on the scientific state of the art. The study applies a similar approach as recently applied by Nutt et al. [Lancet 2007;369:1047-1053], so that the results of both studies could be compared. The harm indicators scored are acute and chronic toxicity, addictive potency and social harm. The aim of this study is to evaluate whether the legal classification of drugs in the Netherlands corresponds with the ranking of the drugs according to their science-based ranking of harm. Based on the results, recommendations are formulated about the legal classification of recreational drugs at national and international level which serves a rational approach for drug control.

Adverse health effects of anabolic-androgenic steroids.

Anabolic-androgenic steroids (AAS) are synthetic drugs derived from testosterone. Illegally, these drugs are regularly self-administered by body builders and power lifters to enhance their sportive performance. Adverse side effects of AAS include sexual dysfunction, alterations of the cardiovascular system, psyche and behavior, and liver toxicity. However, severe side effects appear only following prolonged use of AAS at high dose and their occurrence is limited. Occasionally, AAS abuse may be linked to certain social and psychological traits of the user, like low self-esteem, low self-confidence, suffered hostility, childhood conduct disorder, and tendency to high-risk behavior. The overwhelming stereotype about AAS is that these compounds cause aggressive behavior in males. However, the underlying personality traits of a specific subgroup of the AAS abusers, who show aggression and hostility, may be relevant, as well. Use of AAS in combination with alcohol largely increases the risk of violence and aggression. The dependence liability of AAS is very low, and withdrawal effects are relatively mild. Based on the scores for acute and chronic adverse health effects, the prevalence of use, social harm and criminality, AAS were ranked among 19 illicit drugs as a group of drugs with a relatively low harm.

Dietary Advanced Glycation Endproducts and the Gastrointestinal Tract.

The prevalence of inflammatory bowel diseases (IBD) is increasing in the world. The introduction of the Western diet has been suggested as a potential explanation of increased prevalence. The Western diet includes highly processed food products, and often include thermal treatment. During thermal treatment, the Maillard reaction can occur, leading to the formation of dietary advanced glycation endproducts (dAGEs). In this review, different biological effects of dAGEs are discussed, including their digestion, absorption, formation, and degradation in the gastrointestinal tract, with an emphasis on their pro-inflammatory effects. In addition, potential mechanisms in the inflammatory effects of dAGEs are discussed. This review also specifically elaborates on the involvement of the effects of dAGEs in IBD and focuses on evidence regarding the involvement of dAGEs in the symptoms of IBD. Finally, knowledge gaps that still need to be filled are identified.

Dietary Advanced Glycation Endproducts Decrease Glucocorticoid Sensitivity In Vitro.

Glucocorticoids are very effective anti-inflammatory drugs and widely used for inflammatory bowel disease (IBD) patients. However, approximately 20% of IBD patients do not respond to glucocorticoids and the reason for this is largely unknown. Dietary advanced glycation endproducts (AGEs) are formed via the Maillard reaction during the thermal processing of food products and can induce a pro-inflammatory reaction in human cells. To investigate whether this pro-inflammatory response could be mitigated by glucocorticoids, human macrophage-like cells were exposed to both LPS and AGEs to induce interleukin-8 (IL8) secretion. This pro-inflammatory response was then modulated by adding pharmacological compounds interfering in different steps of the anti-inflammatory mechanism of glucocorticoids: rapamycin, quercetin, and theophylline. Additionally, intracellular reactive oxygen species (ROS) were measured and the glucocorticoid receptor phosphorylation state was assessed. The results show that AGEs induced glucocorticoid resistance, which could be mitigated by quercetin and rapamycin. No change in the phosphorylation state of the glucocorticoid receptor was observed. Additionally, intracellular ROS formation was induced by AGEs, which was mitigated by quercetin. This suggests that AGE-induced ROS is an underlying mechanism to AGE-induced glucocorticoid resistance. This study shows for the first time the phenomenon of dietary AGE-induced glucocorticoid resistance due to the formation of ROS. Our findings indicate that food products with a high inflammatory potential can induce glucocorticoid resistance; these results may be of great importance to IBD patients suffering from glucocorticoid resistance.

Haemodynamic effects of the flavonoid quercetin in rats revisited.

BACKGROUND AND PURPOSE: The flavonoid quercetin increased the in vitro potency of the α1 -antagonist tamsulosin to reduce phenylephrine-dependent arterial contractions by 10-fold. To examine if this supplement-drug interaction luxates hypotensive and orthostatic events in vivo, several set of studies were conducted in spontaneously hypertensive (SHR) and normotensive (Wistar Kyoto [WKY]) rats. EXPERIMENTAL APPROACH: First, in rats pretreated with quercetin or its vehicle, responses to phenylephrine and tamsulosin were examined. Second, tamsulosin-induced changes in renal, mesenteric, hindquarter and carotid conductance were compared in quercetin- and vehicle-treated rats instrumented with Doppler flow probes. Animals were also placed on a tilt table to record regional haemodynamic changes to orthostatic challenges. Third, adult SHR were instrumented with telemeters to measure 24-hr patterns of BP. Recordings were made before and during a 5-week oral treatment of quercetin. Finally, pre-hypertensive SHR were treated with quercetin from 4 to 8 weeks of age and arterial pressure was measured at 8 and 12 weeks. KEY RESULTS: Pretreatment with quercetin did not influence the responses to phenylephrine and tamsulosin, in neither WKY nor SHR. While tamsulosin treatment and tilting lowered BP and increased conductance in all vascular beds, effect size was not influenced by pretreatment with quercetin. Prolonged treatment with quercetin, in either prehypertensive SHR or adult SHR with established hypertension did not lower BP. CONCLUSIONS AND IMPLICATIONS: Cumulatively, these data demonstrate that quercetin does not amplify haemodynamic effects of tamsulosin or tilting in vivo in rats and has no effect on BP development in SHR.