Bar adsorptive microextraction and liquid chromatography-diode array detection of synthetic cannabinoids in oral fluid.

In recent years, synthetic cannabinoids (SCs) have become a major public health issue. For this reason, there is a need for innovative analytical methods that allow its monitoring in biological matrices. In this work, we propose a novel methodology to screen eight SCs (AM-694, cumyl-5F-PINACA, MAM-2201, 5F-UR-144, JWH-018, JWH-122, UR-144 and APINACA) in oral fluids. A bar adsorptive microextraction method followed by microliquid desorption combined with high-performance liquid chromatography with diode array detection (BAµE-µLD/HPLC-DAD) was developed to monitor the target SCs. The main factors affecting the BAµE technology were fully optimized for oral fluid analysis. Under optimized experimental conditions, the proposed methodology showed good linear dynamic ranges from 20.0 to 2000.0 µg L-1 (r2 > 0.99, relative residuals < 15%), limits of detection between 2.0 and 5.0 µg L-1 and suitable average recovery yields (87.9-100.5%) for the eight studied SCs. The intra- and interday accuracies (bias ≤ ± 14.7%) and precisions (RSD ≤ 14.9%) were also evaluated at three spiking levels. The validated methodology was then assayed to oral fluid samples collected from several volunteers. The proposed analytical approach showed remarkable performance and could be an effective alternative for routine monitoring of the target compounds in oral fluid.

Evaluation of polygenic prediction methodology within a reference-standardized framework.

The predictive utility of polygenic scores is increasing, and many polygenic scoring methods are available, but it is unclear which method performs best. This study evaluates the predictive utility of polygenic scoring methods within a reference-standardized framework, which uses a common set of variants and reference-based estimates of linkage disequilibrium and allele frequencies to construct scores. Eight polygenic score methods were tested: p-value thresholding and clumping (pT+clump), SBLUP, lassosum, LDpred1, LDpred2, PRScs, DBSLMM and SBayesR, evaluating their performance to predict outcomes in UK Biobank and the Twins Early Development Study (TEDS). Strategies to identify optimal p-value thresholds and shrinkage parameters were compared, including 10-fold cross validation, pseudovalidation and infinitesimal models (with no validation sample), and multi-polygenic score elastic net models. LDpred2, lassosum and PRScs performed strongly using 10-fold cross-validation to identify the most predictive p-value threshold or shrinkage parameter, giving a relative improvement of 16-18% over pT+clump in the correlation between observed and predicted outcome values. Using pseudovalidation, the best methods were PRScs, DBSLMM and SBayesR. PRScs pseudovalidation was only 3% worse than the best polygenic score identified by 10-fold cross validation. Elastic net models containing polygenic scores based on a range of parameters consistently improved prediction over any single polygenic score. Within a reference-standardized framework, the best polygenic prediction was achieved using LDpred2, lassosum and PRScs, modeling multiple polygenic scores derived using multiple parameters. This study will help researchers performing polygenic score studies to select the most powerful and predictive analysis methods.

Wound healing potential and anti-inflammatory action of extracts and compounds of Myrciaria plinioides D. Legrand leaves.

Wounds or chronic injuries are associated with high medical costs so, develop healing-oriented drugs is a challenge for modern medicine. The identification of new therapeutic alternatives focuses on the use of natural products. Therefore, the main goal of this study was to evaluate the healing potential and anti-inflammatory mechanism of action of extracts and the main compounds derived from Myrciaria plinioides D. Legrand leaves. The antimicrobial activity of leaf extracts was analyzed. Cell viability, cytotoxicity and genotoxicity of plant extracts and compounds were also assessed. Release of pro- and anti-inflammatory cytokines and TGF-ß by ELISA, and protein expression was determined by Western Blot. The cell migration and cell proliferation of ethanol and aqueous leaf extracts and p-coumaric acid, quercetin and caffeic acid compounds were also evaluated. The aqueous extract exhibited antibacterial activity and, after determining the safety concentrations in three assays, we showed that this extract induced p38-α MAPK phosphorylation and the same extract and the p-coumaric acid decreased COX-2 and caspase-3, -8 expression, as well as reduced the TNF-α release and stimulated the IL-10 in RAW 264.7 cells. In L929 cells, the extract and p-coumaric acid induced TGF-ß release, besides increasing the process of cell migration and proliferation. These results suggested that the healing properties of Myrciaria plinioides aqueous extract can be associated to the presence of phenolic compounds, especially p-coumaric acid, and/or glycosylated metabolites.

Synthesis of emerging cathinones and validation of a SPE GC-MS method for their simultaneous quantification in blood.

Over the past 15 years, synthetic cathinones have emerged as an important class of new psychoactive substances (NPS) worldwide. The proliferation of these psychostimulants and their sought-after effects among recreational drug users pose a serious threat to public health and enormous challenges to forensic laboratories. For forensic institutions, it is essential to be one step ahead of covert laboratories, foreseeing the structural changes possible to introduce in the core skeleton of cathinones while maintaining their stimulating activity. In this manner, it is feasible to equip themselves with standards of possible new cathinones and validated analytical methods for their qualitative and quantitative detection. Therefore, the aim of the work herein described was to synthesize emerging cathinones based on the evolving patterns in the illicit drug market, and to develop an analytical method for their accurate determination in forensic situations. Five so far unreported cathinones [4'-methyl-N-dimethylbuphedrone (4-MDMB), 4'-methyl-N-ethylbuphedrone (4-MNEB), 4'-methyl-N-dimethylpentedrone (4-MDMP), 4'-methyl-N-dimethylhexedrone (4-MDMH), and 4'-methyl-N-diethylbuphedrone (4-MDEB)] and a sixth one, 4'-methyl-N-ethylpentedrone, already reported to EMCDDA and also known as 4-MEAP, were synthesized and fully characterized by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). An analytical method for the simultaneous quantification of these cathinones in blood, using solid phase extraction (SPE) combined with gas chromatography-mass spectrometry (GC-MS) was developed and validated. The results prove that this methodology is selective, linear, precise, and accurate. For all target cathinones, the extraction efficiency was higher than 73%, linearity was observed in the range of 10 (lower limit of quantification, LLOQ) to 800 ng/mL, with coefficients of determination higher than 0.99, and the limits of detection (LODs) were 5 ng/mL for all target cathinones. The stability of these cathinones in blood matrices is dependent on the storage conditions; 4-MNEB is the most stable compound and 4-MDMH is the least stable compound. The low limits obtained allow the detection of the compounds in situations where they are involved, even if present at low concentrations.

Marine-Derived Components: Can They Be a Potential Therapeutic Approach to Parkinson's Disease?

The increase in the life expectancy average has led to a growing elderly population, thus leading to a prevalence of neurodegenerative disorders, such as Parkinson's disease (PD). PD is the second most common neurodegenerative disorder and is characterized by a progressive degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). The marine environment has proven to be a source of unique and diverse chemical structures with great therapeutic potential to be used in the treatment of several pathologies, including neurodegenerative impairments. This review is focused on compounds isolated from marine organisms with neuroprotective activities on in vitro and in vivo models based on their chemical structures, taxonomy, neuroprotective effects, and their possible mechanism of action in PD. About 60 compounds isolated from marine bacteria, fungi, mollusk, sea cucumber, seaweed, soft coral, sponge, and starfish with neuroprotective potential on PD therapy are reported. Peptides, alkaloids, quinones, terpenes, polysaccharides, polyphenols, lipids, pigments, and mycotoxins were isolated from those marine organisms. They can act in several PD hallmarks, reducing oxidative stress, preventing mitochondrial dysfunction, α-synuclein aggregation, and blocking inflammatory pathways through the inhibition translocation of NF-kB factor, reduction of human tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6). This review gathers the marine natural products that have shown pharmacological activities acting on targets belonging to different intracellular signaling pathways related to PD development, which should be considered for future pre-clinical studies.

Bromoditerpenes from the Red Seaweed Sphaerococcus coronopifolius as Potential Cytotoxic Agents and Proteasome Inhibitors and Related Mechanisms of Action.

Seaweeds are a great source of compounds with cytotoxic properties with the potential to be used as anticancer agents. This study evaluated the cytotoxic and proteasome inhibitory activities of 12R-hydroxy-bromosphaerol, 12S-hydroxy-bromosphaerol, and bromosphaerol isolated from Sphaerococcus coronopifolius. The cytotoxicity was evaluated on malignant cell lines (A549, CACO-2, HCT-15, MCF-7, NCI-H226, PC-3, SH-SY5Y, and SK-MEL-28) using the MTT and LDH assays. The ability of compounds to stimulate the production of hydrogen peroxide (H2O2) and to induce mitochondrial dysfunction, the externalization of phosphatidylserine, Caspase-9 activity, and changes in nuclear morphology was also studied on MCF-7 cells. The ability to induce DNA damage was also studied on L929 fibroblasts. The proteasome inhibitory activity was estimated through molecular docking studies. The compounds exhibited IC50 values between 15.35 and 53.34 µM. 12R-hydroxy-bromosphaerol and 12S-hydroxy-bromosphaerol increased the H2O2 levels on MCF-7 cells, and bromosphaerol induced DNA damage on fibroblasts. All compounds promoted a depolarization of mitochondrial membrane potential, Caspase-9 activity, and nuclear condensation and fragmentation. The compounds have been shown to interact with the chymotrypsin-like catalytic site through molecular docking studies; however, only 12S-hydroxy-bromosphaerol evidenced interaction with ALA20 and SER169, key residues of the proteasome catalytic mechanism. Further studies should be outlined to deeply characterize and understand the potential of those bromoditerpenes for anticancer therapeutics.

Antiulcerogenic Potential of the Ethanolic Extract of Ceiba speciosa (A. St.-Hil.) Ravenna Evaluated by In Vitro and In Vivo Studies.

Gastrointestinal diseases, such as peptic ulcers, are caused by a damage in the gastric mucosa provoked by several factors. This stomach injury is regulated by many inflammatory mediators and is commonly treated with proton-pump inhibitors, histamine H2 receptor blockers and antacids. However, various medicinal plants have demonstrated positive effects on gastric ulcer treatment, including plants of the Ceiba genus. The aim of this study was to evaluate the antiulcer and anti-inflammatory activities of the stem bark ethanolic extract of Ceiba speciosa (A. St.-Hil.) Ravenna. We performed a preliminary quantification of phenolic compounds by high-performance liquid chromatography-diode array detection (HPLC-DAD), followed by the prospection of other chemical groups through nuclear magnetic resonance (NMR) spectroscopy. A set of in vitro assays was used to evaluate the extract potential regarding its antioxidant activity (DPPH: 19.83 ± 0.34 µg/mL; TPC: 307.20 ± 6.20 mg GAE/g of extract), effects on cell viability and on the release of TNF-α in whole human blood. Additionally, in vivo assays were performed to evaluate the leukocyte accumulation and total protein quantification in carrageenan-induced air pouch, as well as the antiulcerogenic effect of the extract on an ethanol-induced ulcer in rats. The extract contains flavonoids and phenolic compounds, as well as sugars and quinic acid derivatives exhibiting potent antioxidant activity and low toxicity. The extract reduced the release of TNF-α in human blood and inhibited the activity of p38α (1.66 µg/mL), JAK3 (5.25 µg/mL), and JNK3 (8.34 µg/mL). Moreover, it reduced the leukocyte recruitment on the pouch exudate and the formation of edema, reverting the effects caused by carrageenan. The extract presented a significant prevention of ulcer formation and a higher reduction than the reference drug, Omeprazole. Therefore, C. speciosa extract has demonstrated relevant therapeutic potential for the treatment of gastric diseases, deserving the continuation of further studies to unveil the mechanisms of action of plant bioactive ingredients.

Saccorhiza polyschides-A Source of Natural Active Ingredients for Greener Skincare Formulations.

The growing knowledge about the harmful effects caused by some synthetic ingredients present in skincare products has led to an extensive search for natural bioactives. Thus, this study aimed to investigate the dermatological potential of five fractions (F1-F5), obtained by a sequential extraction procedure, from the brown seaweed Saccorhiza polyschides. The antioxidant (DPPH, FRAP, ORAC and TPC), anti-enzymatic (collagenase, elastase, hyaluronidase and tyrosinase), antimicrobial (Staphylococcus epidermidis, Cutibacterium acnes and Malassezia furfur), anti-inflammatory (nitric oxide, tumor necrosis factor-α, interleukin-6 and interleukin-10) and photoprotective (reactive oxygen species) properties of all fractions were evaluated. The ethyl acetate fraction (F3) displayed the highest antioxidant and photoprotective capacity, reducing ROS levels in UVA/B-exposed 3T3 fibroblasts, and the highest anti-enzymatic capacity against tyrosinase (IC50 value: 89.1 µg/mL). The solid water-insoluble fraction (F5) revealed the greatest antimicrobial activity against C. acnes growth (IC50 value: 12.4 µg/mL). Furthermore, all fractions demonstrated anti-inflammatory potential, reducing TNF-α and IL-6 levels in RAW 264.7 macrophages induced with lipopolysaccharides. Chemical analysis of the S. polyschides fractions by NMR revealed the presence of different classes of compounds, including lipids, polyphenols and sugars. The results highlight the potential of S. polyschides to be incorporated into new nature-based skincare products.

A major role for common genetic variation in anxiety disorders.

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank.

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

Disclosing the potential of eleganolone for Parkinson's disease therapeutics: Neuroprotective and anti-inflammatory activities.

The treatment of Parkinson´s disease (PD) has benefited from significant advances resulting from the increasing research efforts focused on new therapeutics. However, the current treatments for PD are mostly symptomatic, alleviating disease symptoms without reversing or retarding disease progression. Thus, it is critical to find new molecules that can result in more effective treatments. Within this framework, this study aims to evaluate the neuroprotective and anti-inflammatory effects of three compounds (eleganolone, eleganonal and fucosterol) isolated from the brown seaweed Bifurcaria bifurcata. In vitro neuroprotective effects were evaluated on a PD cellular model induced by the neurotoxin 6-hydroxydopamine (6-OHDA) on SH-SY5Y human cells, while lipopolysaccharide (LPS) - stimulated RAW 264.7 macrophages were used to evaluate the anti-inflammatory potential. Additionally, the underlying mechanisms of action were also investigated. Compounds were isolated by preparative chromatographic methods and their structural elucidation attained by NMR spectroscopy. Among the tested compounds, eleganolone (0.1-1 µM; 24 h) reverted the neurotoxicity induced by 6-OHDA in about 20%. The neuroprotective effects were mediated by mitochondrial protection, reduction of oxidative stress, inflammation and apoptosis, and inhibition of NF-kB pathway. The results suggest that eleganolone may provide advantages in the treatment of neurodegenerative conditions and, therefore, should be considered for future preclinical studies.

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.

Unravelling the Anti-Inflammatory and Antioxidant Potential of the Marine Sponge Cliona celata from the Portuguese Coastline.

Inflammation is a double-edged sword, as it can have both protective effects and harmful consequences, which, combined with oxidative stress (OS), can lead to the development of deathly chronic inflammatory conditions. Over the years, research has evidenced the potential of marine sponges as a source of effective anti-inflammatory therapeutic agents. Within this framework, the purpose of this study was to evaluate the antioxidant and the anti-inflammatory potential of the marine sponge Cliona celata. For this purpose, their organic extracts (C1-C5) and fractions were evaluated concerning their radical scavenging activity through 2,2-diphenyl-1-picrylhydrazyl radical (DPPH), ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), and anti-inflammatory activity through a (lipopolysaccharides (LPS)-induced inflammation on RAW 264.7 cells) model. Compounds present in the two most active fractions (F5 and F13) of C4 were tentatively identified by gas chromatography coupled to mass spectrometry (GC-MS). Even though samples displayed low antioxidant activity, they presented a high anti-inflammatory capacity in the studied cellular inflammatory model when compared to the anti-inflammatory standard, dexamethasone. GC-MS analysis led to the identification of n-hexadecanoic acid, cis-9-hexadecenal, and 13-octadecenal in fraction F5, while two major compounds, octadecanoic acid and cholesterol, were identified in fraction F13. The developed studies demonstrated the high anti-inflammatory activity of the marine sponge C. celata extracts and fractions, highlighting its potential for further therapeutic applications.

Unravelling the Dermatological Potential of the Brown Seaweed Carpomitra costata.

The ever-increasing interest in keeping a young appearance and healthy skin has leveraged the skincare industry. This, coupled together with the increased concern regarding the safety of synthetic products, has boosted the demand for new and safer natural ingredients. Accordingly, the aim of this study was to evaluate the dermatological potential of the brown seaweed Carpomitra costata. The antioxidant, anti-enzymatic, antimicrobial, photoprotective and anti-inflammatory properties of five C. costata fractions (F1-F5) were evaluated. The ethyl acetate fraction (F3) demonstrated the most promising results, with the best ability to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals (EC50 of 140.1 µg/mL) and the capacity to reduce reactive oxygen species (ROS) production promoted by UVA and UVB radiation in 3T3 cells, revealing its antioxidant and photoprotective potential. This fraction also exhibited the highest anti-enzymatic capacity, inhibiting the activities of collagenase, elastase and tyrosinase (IC50 of 7.2, 4.8 and 85.9 µg/mL, respectively). Moreover, F3 showed anti-inflammatory potential, reducing TNF-α and IL-6 release induced by LPS treatment in RAW 264.7 cells. These bioactivities may be related to the presence of phenolic compounds, such as phlorotannins, as demonstrated by NMR analysis. The results highlight the potential of C. costata as a source of bioactive ingredients for further dermatological applications.

Loliolide, a New Therapeutic Option for Neurological Diseases? In Vitro Neuroprotective and Anti-Inflammatory Activities of a Monoterpenoid Lactone Isolated from Codium tomentosum.

Parkinsons Disease (PD) is the second most common neurodegenerative disease worldwide, and is characterized by a progressive degeneration of dopaminergic neurons. Without an effective treatment, it is crucial to find new therapeutic options to fight the neurodegenerative process, which may arise from marine resources. Accordingly, the goal of the present work was to evaluate the ability of the monoterpenoid lactone Loliolide, isolated from the green seaweed Codium tomentosum, to prevent neurological cell death mediated by the neurotoxin 6-hydroxydopamine (6-OHDA) on SH-SY5Y cells and their anti-inflammatory effects in RAW 264.7 macrophages. Loliolide was obtained from the diethyl ether extract, purified through column chromatography and identified by NMR spectroscopy. The neuroprotective effects were evaluated by the MTT method. Cells' exposure to 6-OHDA in the presence of Loliolide led to an increase of cells' viability in 40%, and this effect was mediated by mitochondrial protection, reduction of oxidative stress condition and apoptosis, and inhibition of the NF-kB pathway. Additionally, Loliolide also suppressed nitric oxide production and inhibited the production of TNF-α and IL-6 pro-inflammatory cytokines. The results suggest that Loliolide can inspire the development of new neuroprotective therapeutic agents and thus, more detailed studies should be considered to validate its pharmacological potential.

Cytotoxic Mechanism of Sphaerodactylomelol, an Uncommon Bromoditerpene Isolated from Sphaerococcus coronopifolius.

Marine natural products have exhibited uncommon chemical structures with relevant antitumor properties highlighting their potential to inspire the development of new anticancer agents. The goal of this work was to study the antitumor activities of the brominated diterpene sphaerodactylomelol, a rare example of the dactylomelane family. Cytotoxicity (10-100 µM; 24 h) was evaluated on tumor cells (A549, CACO-2, HCT-15, MCF-7, NCI-H226, PC-3, SH-SY5Y, SK-ML-28) and the effects estimated by MTT assay. Hydrogen peroxide (H2O2) levels and apoptosis biomarkers (membrane translocation of phosphatidylserine, depolarization of mitochondrial membrane potential, Caspase-9 activity, and DNA condensation and/or fragmentation) were studied in the breast adenocarcinoma cellular model (MCF-7) and its genotoxicity on mouse fibroblasts (L929). Sphaerodactylomelol displayed an IC50 range between 33.04 and 89.41 µM without selective activity for a specific tumor tissue. The cells' viability decrease was accompanied by an increase on H2O2 production, a depolarization of mitochondrial membrane potential and an increase of Caspase-9 activity and DNA fragmentation. However, the DNA damage studies in L929 non-malignant cell line suggested that this compound is not genotoxic for normal fibroblasts. Overall, the results suggest that the cytotoxicity of sphaerodactylomelol seems to be mediated by an increase of H2O2 levels and downstream apoptosis.

Self-reported medication use as an alternate phenotyping method for anxiety and depression in the UK Biobank.

The requirement for large sample sizes for psychiatric genetic analyses necessitates novel approaches to derive cases. Anxiety and depression show substantial genetic overlap and share pharmacological treatments. Data on prescribed medication could be effective for inferring case status when other indicators of mental health are unavailable. We investigated self-reported current medication use in UK Biobank participants of European ancestry. Medication Status cases reported using antidepressant or anxiolytic medication (n = 22,218), controls did not report psychotropic medication use (n = 168,959). A subset, "Medication Only," additionally did not meet criteria for any other mental health indicator (case n = 2,643, control n = 107,029). We assessed genetic overlap between these phenotypes and two published genetic association studies of anxiety and depression, and an internalizing disorder trait derived from symptom-based questionnaires in UK Biobank. Genetic correlations between Medication Status and the three anxiety and depression phenotypes were significant (rg  = 0.60-0.73). In the Medication Only subset, the genetic correlation with depression was significant (rg  = 0.51). The three polygenic scores explained 0.33% - 0.80% of the variance in Medication Status and 0.07% - 0.19% of the variance in Medication Only. This study provides evidence that self-reported current medication use offers an alternate or supplementary anxiety or depression phenotype in genetic studies where diagnostic information is sparse or unavailable.

Drug Targetor: a web interface to investigate the human druggome for over 500 phenotypes.

SUMMARY: Results from hundreds of genome-wide association studies (GWAS) are now freely available and offer a catalogue of the association between phenotypes across medicine with variants in the genome. With the aim of using this data to better understand therapeutic mechanisms, we have developed Drug Targetor, a web interface that allows the generation and exploration of drug-target networks of hundreds of phenotypes using GWAS data. Drug Targetor networks consist of drug and target nodes ordered by genetic association and connected by drug-target or drug-gene relationship. We show that Drug Targetor can help prioritize drugs, targets and drug-target interactions for a specific phenotype based on genetic evidence. AVAILABILITY AND IMPLEMENTATION: Drug Targetor v1.21 is a web application freely available online at drugtargetor.com and under MIT licence. The source code can be found at https://github.com/hagax8/drugtargetor. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals.

Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with a study comparing 1247 individuals with mean IQ ~170 to 8185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems.

Adverse outcome pathways induced by 3,4-dimethylmethcathinone and 4-methylmethcathinone in differentiated human SH-SY5Y neuronal cells.

Cathinones (ß-keto amphetamines), widely abused in recreational settings, have been shown similar or even worse toxicological profile than classical amphetamines. In the present study, the cytotoxicity of two ß-keto amphetamines [3,4-dimethylmethcathinone (3,4-DMMC) and 4-methylmethcathinone (4-MMC)], was evaluated in differentiated dopaminergic SH-SY5Y cells in comparison to methamphetamine (METH). MTT reduction and NR uptake assays revealed that both cathinones and METH induced cytotoxicity in a concentration- and time-dependent manner. Pre-treatment with trolox (antioxidant) partially prevented the cytotoxicity induced by all tested drugs, while N-acetyl-L-cysteine (NAC; antioxidant and glutathione precursor) and GBR 12909 (dopamine transporter inhibitor) partially prevented the cytotoxicity induced by cathinones, as evaluated by the MTT reduction assay. Unlike METH, cathinones induced oxidative stress evidenced by the increase on intracellular levels of reactive oxygen species (ROS), and also by the decrease of intracellular glutathione levels. Trolox prevented, partially but significantly, the ROS generation elicited by cathinones, while NAC inhibited it completely. All tested drugs induced mitochondrial dysfunction, since they led to mitochondrial membrane depolarization and to intracellular ATP depletion. Activation of caspase-3, indicative of apoptosis, was seen both for cathinones and METH, and confirmed by annexin V and propidium iodide positive staining. Autophagy was also activated by all drugs tested. Pre-incubation with bafilomycin A1, an inhibitor of the vacuolar H+-ATPase, only protected against the cytotoxicity induced by METH, which indicates dissimilar toxicological pathways for the tested drugs. In conclusion, the mitochondrial impairment and oxidative stress observed for the tested cathinones may be key factors for their neurotoxicity, but different outcome pathways seem to be involved in the adverse effects, when compared to METH.