Molecular docking and oxidation kinetics of 3-phenyl coumarin derivatives by human CYP2A13

CYP2A13 enzyme is expressed in human extrahepatic tissues, while CYP2A6 is a hepatic enzyme. Reactions catalysed by CYP2A13 activate tobacco-specific nitrosamines and some other toxic xenobiotics in lungs. To compare oxidation characteristics and substrate-enzyme active site interactions in CYP2A13 vs CYP2A6, we evaluated CYP2A13 mediated oxidation characteristics of 23 coumarin derivatives and modelled their interactions at the enzyme active site. CYP2A13 did not oxidise six coumarin derivatives to corresponding fluorescent 7-hydroxycoumarins. The K-m-values of the other coumarins varied 0.85-97 mu M, V-max-values of the oxidation reaction varied 0.25-60 min(-1), and intrinsic clearance varied 26-6190 kL/min*mol CYP2A13). K-m of 6-chloro-3-(3-hydroxyphenyl)-coumarin was 0.85 (0.55-1.15 95% confidence limit) mu M and V-max 0.25 (0.23-0.26) min(-1), whereas K-m of 6-hydroxy-3-(3-hydroxyphenyl)-coumarin was 10.9 (9.9-11.8) mu M and V-max 60 (58-63) min(-1). Docking analyses demonstrated that 6-chloro or 6-methoxy and 3-(3-hydroxyphenyl) or 3-(4-trifluoromethylphenyl) substituents of coumarin increased affinity to CYP2A13, whereas 3-triazole or 3-(3-acetate phenyl) or 3-(4-acetate phenyl) substituents decreased it. The active site of CYP2A13 accepts more diversified types of coumarin substrates than the hepatic CYP2A6 enzyme. New sensitive and convenient profluorescent CYP2A13 substrates were identified, such as 6-chloro-3-(3-hydroxyphenyl)-coumarin having high affinity and 6-hydroxy-3-(3-hydroxyphenyl)-coumarin with high intrinsic clearance

“Notame”: Workflow for non-targeted LC-MS metabolic profiling

Metabolomics analysis generates vast arrays of data, necessitating comprehensive workflows involving expertise in analytics, biochemistry and bioinformatics in order to provide coherent and high-quality data that enable discovery of robust and biologically significant metabolic findings. In this protocol article, we introduce notame, an analytical workflow for non-targeted metabolic profiling approaches, utilizing liquid chromatography-mass spectrometry analysis. We provide an overview of lab protocols and statistical methods that we commonly practice for the analysis of nutritional metabolomics data. The paper is divided into three main sections: the first and second sections introducing the background and the study designs available for metabolomics research and the third section describing in detail the steps of the main methods and protocols used to produce, preprocess and statistically analyze metabolomics data and, finally, to identify and interpret the compounds that have emerged as interesting. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Increased steroid hormone dehydroepiandrosterone and pregnenolone levels in post-mortem brain samples of alcoholics

Intra-tissue levels of steroid hormones (e.g., dehydroepiandrosterone [DHEA], pregnenolone [PREGN], and testosterone [T]) may influence the pathological changes seen in neurotransmitter systems of alcoholic brains. Our aim was to compare levels of these steroid hormones between the post-mortem brain samples of alcoholics and non-alcoholic controls. We studied steroid levels with quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) in post-mortem brain samples of alcoholics (N = 14) and non-alcoholic controls (N = 10). Significant differences were observed between study groups in DHEA and PREGN levels (p values 0.0056 and 0.019, respectively), but not in T levels. Differences between the study groups were most prominent in the nucleus accumbens (NAC), anterior cingulate cortex (ACC), and anterior insula (AINS). DHEA levels were increased in most alcoholic subjects compared to controls. However, only a subgroup of alcoholics showed increased PREGN levels. Negative Spearman correlations between tissue levels of PREGN and previous reports of [H-3]naloxone binding to mu-opioid receptors were observed in the AINS, ACC, NAC, and frontal cortex (R values between -0.6 and -.8; p valuesPeer reviewe

Comparison of the level of allostatic load between patients with major depression and the general population

Objective: We compared the level of allostatic load (AL) between patients with major depressive disorder (MDD) and non-depressed controls using two definitions of AL: continuous AL scores (AL index) and clinically significant high AL (>4). We examined whether MDD was associated with AL independent of basic socioeconomic (age, sex, cohabiting status and level of education) and lifestyle factors (smoking and alcohol use). Methods: The MDD patient sample consisted of 177 psychiatric outpatients (mean age 33.7, SD 10.7 years), who were recruited from the Department of Psychiatry at Kuopio University Hospital, Finland, in 2016?19. The nondepressed controls (n = 228, mean age 49.8, SD 10.1 years) lived in the municipality of Lapinlahti, Finland. Ten biomarkers were used to construct the two AL variables. These indicators were systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, glucose, creatinine, waist circumference, body mass index (BMI) and C-reactive protein (CRP). Results: The mean AL scores did not significantly differ between MDD patients (2.97) and non-depressed controls (3.12), thus it was not associated with MDD in univariate analysis. In multivariate models a higher AL index was associated with a 1.42 to 1.82 times higher likelihood of belonging to the MDD group. Furthermore, we found that high AL (i.e. AL > 4) was associated with MDD, with the likelihood ranging between 2.27 and 2.96 compared with the non-depressed controls in multivariate models. Conclusions: Even young adult patients with MDD appear to display clinically significant, high AL compared with non-depressed controls. Thus, it is important to pay attention to the somatic health of depressed patients in addition to their mental health.Peer reviewe

Specific gut microbial, biological, and psychiatric profiling related to binge eating disorders: A cross-sectional study in obese patients.

BACKGROUND & AIMS: Binge eating disorder (BED) is a frequent eating disorder associated with obesity and co-morbidities including psychiatric pathologies, which represent a big health burden on the society. The biological processes related to BED remain unknown. Based on psychological testing, anthropometry, clinical biology, gut microbiota analysis and metabolomic assessment, we aimed to examine the complex biological and psychiatric profile of obese patients with and without BED. METHODS: Psychological and biological characteristics (anthropometry, plasma biology, gut microbiota, blood pressure) of 101 obese subjects from the Food4Gut cohort were analysed to decipher the differences between BED and Non BED patients, classified based on the Questionnaire for Eating Disorder Diagnosis (Q-EDD). Microbial 16S rDNA sequencing and plasma non-targeted metabolomics (liquid chromatography-mass spectrometry) were performed in a subcohort of 91 and 39 patients respectively. RESULTS: BED subjects exhibited an impaired affect balance, deficits in inhibition and self-regulation together with marked alterations of eating behaviour (increased emotional and external eating). BED subjects displayed a lower blood pressure and hip circumference. A decrease in Akkermansia and Intestimonas as well as an increase in Bifidobacterium and Anaerostipes characterized BED subjects. Interestingly, metabolomics analysis revealed that BED subjects displayed a higher level of one food contaminants, Bisphenol A bis(2,3-dihydroxypropyl) ether (BADGE.2H(2)O) and a food derived-metabolite the Isovalerylcarnitine. CONCLUSIONS: Non-targeted omics approaches allow to select specific microbial genera and two plasma metabolites that characterize BED obese patients. Further studies are needed to confirm their potential role as drivers or biomarkers of binge eating disorder. Food4gut, clinicaltrial.gov:NCT03852069, https://clinicaltrials.gov/ct2/show/NCT03852069

Manifesto for an international digital mental health network

Current mental health services across the world remain expert-centric and are based on traditional workflows, mostly using impractical and ineffective electronic record systems or even paper-based documentation. The international network for digital mental health (IDMHN) is comprised of top-level clinicians, regulatory and ICT experts, genetic scientists, and support organizations. The IDMHN has been formed to enable the implementation of digital innovations in clinical practice, hereby facilitating the transformation of current mental health services to be more personalized and more responsive to patients and healthcare needs. This consensus statement summarizes the consortium’s vision and strategy for further development of digital mental health