Anti-inflammatory and antiophidic effects of extract of Hymenaea eriogyne Benth and structure-activity relationship prediction of the major markers in silico.

ETHNOPHARMACOLOGICAL RELEVANCE: Hymenaea eriogyne Benth (Fabaceae) is popularly known as "Jatobá". Despite its use in folk medicine to treat inflammatory disorders, there are no descriptions that show its anti-inflammatory potential. AIM OF THE STUDY: In this sense, this study aimed to evaluate the anti-inflammatory and antivenom action of bark and leaves extract of H. eriogyne. MATERIALS AND METHODS: The in vivo anti-inflammatory activity was conducted by carrageenan-induced paw edema and zymosan-induced air pouch models, evaluating the edematogenic effect, leukocyte migration, protein concentration, levels of pro-inflammatory cytokines, malondialdehyde (MDA) and MPO activity. The antivenom potential was investigated in vitro on the enzymatic action (proteolytic, phospholipase and hyaluronidase) of Bothrops brazili and B. leucurus venom, as well as in vivo on the paw edema model induced by B. leucurus. Furthermore, the influence of its markers (astilbin and rutin) on myeloperoxidase (MPO) activity was investigated in silico. For molecular docking, AutodockVina, Biovia Discovery Studio, and Chimera 1.16 software were used. RESULTS: The extracts and bark and leaves of H. eriogyne revealed a high anti-inflammatory effect, with a reduction in all inflammatory parameters evaluated. The bark extract showed superior results when compared to the leaf extract, suggesting the influence of the astilbin concentration, higher in the bark, on the anti-inflammatory action. In addition, only the H. eriogyne bark extract was able to reduce MDA, indicating an associated antioxidant effect. Regarding the in vitro antivenom action, the extracts (bark and leaves) revealed the ability to inhibit the proteolytic, phospholipase and hyaluronidase action of both bothropic venom, with a greater effect against B. leucurus venom. In vivo, extracts from the bark and leaves of H. eriogyne (50 - 200 mg/kg) showed antiedematogenic activity, reducing the release of MPO and pro-inflammatory cytokines, indicating the presence of bioactive components useful in controlling the inflammatory process induced by the venom. In the in silico assays, astilbin and rutin showed reversible interactions of 9 possible positions and orientations towards MPO, with affinities of -9.5 and -10.4 kcal/mol and interactions with Phe407, Gln91, His95 and Arg239, important active pockets of MPO. Rutin demonstrated more effective types of interactions with MPO. CONCLUSION: This approach reveals for the first time the anti-inflammatory action of H. eriogyne bark and leaf extracts in vivo, as well as its antiophidic potential. Moreover, the distinct effect of pharmacogens as antioxidant agents and distinct effect of astilbin and rutin under MPO sheds light on the different anti-inflammatory mechanisms of bioactive compounds present in H. eriogyne extracts, with high potential for the prospection of new pharmacological agents.

Metabolomics perspectives of the ecotoxicological risks of polycyclic aromatic hydrocarbons: A scoping review.

Polycyclic Aromatic Hydrocarbons (PAHs) represent persistent environmental pollutants ubiquitously distributed in the environment. Their presence alongside various other contaminants gives rise to intricate interactions, culminating in profound deleterious consequences. The combination effects of different PAH mixtures on biota remains a relatively unexplored domain. Recent studies have harnessed the exceptional sensitivity of metabolomic techniques to unveil the significant ecotoxicological perils of PAH pollution confronting both human populations and ecosystems. This article furnishes a comprehensive overview of current literature focused on the metabolic repercussions stemming from exposure to complex mixtures of PAHs or PAH-pollution sources using metabolomics approaches. These insights are obtained through a wide range of models, including in vitro assessments, animal studies, investigations on human subjects, botanical specimens, and soil environments. The findings underscore that PAH mixtures induce cellular stress responses and systemic effects, leading to metabolic dysregulations in amino acids, carbohydrates, lipids, and other key metabolites (e.g., organic acids, purines), with specific variations observed based on the organism and PAH compounds involved. Additionally, the ecological consequences of PAH pollutants on plant and soil microbial responses are emphasized, revealing significant changes in stress-related metabolites and nutrient cycling in soil ecosystems. The complex interplay of various PAHs and their metabolic effects on several models, as elucidated through metabolomics, highlight the urgency of further research and the need for comprehensive strategies to mitigate the risks posed by these widespread environmental pollutants.

Loss of RAS Mutations in Liquid Biopsies of Patients With Multi-Treated Metastatic Colorectal Cancer.

BACKGROUND: Liquid biopsy (LB) is a non-invasive tool to evaluate the heterogeneity of tumors. Since RAS mutations (RAS-mut) play a major role in resistance to antiepidermal growth factor receptor inhibitors (EGFR) monoclonal antibodies (Mabs), serial monitoring of RAS-mut with LB may be useful to guide treatment. The main aim of this study was to evaluate the prognostic value of the loss of RAS-mut (NeoRAS-wt) in LB, during the treatment of metastatic colorectal cancer (mCRC). METHODS: A retrospective study was conducted on patients with mCRC between January 2018 and December 2021. RAS-mut were examined in tissue biopsy, at mCRC diagnosis, and with LB, during treatment. RESULTS: Thirty-nine patients with RAS-mut mCRC were studied. LB was performed after a median of 3 lines (0-7) of systemic treatment including anti-vascular endothelial growth factor (anti-VEGF) Mabs. NeoRAS-wt was detected in 13 patients (33.3%); 9 (69.2%) of them received further treatment with anti-EGFR Mabs with a disease control rate of 44.4%. Median overall survival (OS), from the date of LB testing, was 20 months in the NeoRAS-wt group and 9 months in the persistent RAS-mut group (log-rank 2.985; P = .08), with a 12-month OS of 84.6% and 57.7%, respectively. NeoRAS-wt was identified as a predictor of survival (HR = 0.29; P = .007), with an 11-month improvement in median OS and a 71% decrease in risk of death, in heavily pretreated patients. CONCLUSIONS: In conclusion, monitoring clonal evolution in mCRC by LB may provide an additional treatment line for patients with NeoRAS-wt in advanced disease.

Temperature effect in the inhibition of PLA2 activity of Bothrops brazili venom by Rosmarinic and Chlorogenic acids, experimental and computational approaches.

Myotoxicity caused by snakebite envenoming emerges as one of the main problems of ophidic accidents as it is not well neutralized by the current serum therapy. A promising alternative is to search for efficient small molecule inhibitors that can act against multiple venom components. Phospholipase A2 (PLA2) is frequently found in snake venom and is usually associated with myotoxicity. Thus it represents an excellent target for the search of new treatments. This work reports the effect of temperature in the inhibition of catalytic properties of PLA2 from Bothrops brazili venom by Rosmarinic (RSM) and Chlorogenic (CHL) acids through experimental and computational approaches. Three temperatures were evaluated (25, 37 and 50 °C). In the experimental section, enzymatic assays showed that RSM is a better inhibitor in all three temperatures. At 50 °C, the inhibition efficiency decayed significantly for both acids. Docking studies revealed that both ligands bind to the hydrophobic channel of the protein dimer where the phospholipid binds in the catalytic process, interacting with several functional residues. In this context, RSM presents better interaction energies due to stronger interactions with chain B of the dimer. Molecular dynamics simulations showed that RSM can establish selective interactions with ARG112B of PLA2, which is located next to residues of the putative Membrane Disruption Site in PLA2-like structures. The affinity of RSM and CHL acids towards PLA2 is mainly driven by electrostatic interactions, especially salt bridge interactions established with residues ARG33B (for CHL) and ARG112B (RSM) and hydrogen bonds with residue ASP89A. The inability of CHL to establish a stable interaction with ARG112B was identified as the reason for its lower inhibition efficiency compared to RSM at the three temperatures. Furthermore, extensive structural analysis was performed to explain the lower inhibition efficiency at 50 °C for both ligands. The analysis performed in this work provides important information for the future design of new inhibitors.Communicated by Ramaswamy H. Sarma.

Impact of early memories and current experiences of warmth and safeness on adolescents' psychological distress.

A variable-centered and a person-centered approach were performed to examine the role of early memories of warmth and safeness (EMWS) and current experiences of warmth and safeness (CEWS) on depressive and anxious symptoms among adolescents from community and residential youth care (RYC) settings. Variable-centered results revealed EMWS were only indirectly (through CEWS) associated with depressive and anxious symptoms. Person-centered outcomes allowed to identify four different profiles based on EMWS and CEWS, which differed on depressive and anxious symptoms. EMWS and CEWS seem to play an important role in psychological distress during adolescence. CEWS seem to have a protective role on RYC adolescents' psychological distress, even when EMWS were poor.

Proposed Specifiers for Conduct Disorder (PSCD): Factor Structure and Validation of the Self-Report Version in Community and Forensic Samples of Portuguese Youth.

The Proposed Specifiers for Conduct Disorder (PSCD) was developed as a measure to assess the multifaceted model of psychopathic traits in children/youth (i.e., grandiose-manipulative [GM], callous-unemotional [CU], and daring-impulsive [DI] traits) in addition to Conduct Disorder (CD) symptoms. This study aims to test the psychometric properties of the PSCD-self-report version across community (n = 648; 52.9% female) and forensic male youth (n = 258) from the Portuguese population. Results supported a general factor and four specific factors (GM, CU, DI, CD), which was invariant across gender and sample type. Evidence for reliability, construct, and temporal validity were also found. Overall, the PSCD appears to be a promising measure for assessing psychopathic traits in youth from both community and forensic settings, which may contribute to the discussion around the conceptualization, assessment, predictive value, and clinical usefulness of the multifaceted model of psychopathy in youthful populations, particularly in its association with CD.

Warmer water, high light intensity, lithium and microplastics: Dangerous environmental combinations to zooplankton and Global Health?

Nowadays there is a high concern about the combined effects of global warming and emerging environmental contaminants with significant increasing trends of use, such as lithium (Li) and microplastics (MPs), both on wildlife and human health. Therefore, the effects of high light intensity (26,000 lx) or warmer water temperature (25 °C) on the long-term toxicity of Li and mixtures of Li and MPs (Li-MPs mixtures) were investigated using model populations of the freshwater zooplankton species Daphnia magna. Three 21-day bioassays were done in the laboratory at the following water temperatures and light intensities: (i) 20 °C/10830 lx; (ii) 20 °C/26000 lx (high light intensity); (iii) 25 °C/10830 lx (warmer temperature). Based on the 21-day EC50s on reproduction, high light intensity increased the reproductive toxicity of Li and Li-MPs mixtures by ~1.3 fold; warmer temperature increased the toxicity of Li by ~1.2 fold, and the toxicity of Li-MPs mixtures by ~1.4 fold based on the concentration of Li, and by ~2 fold based on the concentrations of MPs. At high light intensity, Li (0.04 mg/L) and Li-MPs mixtures (0.04 Li + 0.09 MPs mg/L) reduced the population fitness by 32 % and 41 %, respectively. Warmer temperature, Li (0.05 mg/L) and Li-MPs mixtures (0.05 Li + 0.09 MPs mg/L) reduced it by 63 % and 71 %, respectively. At warmer temperature or high light intensity, higher concentrations of Li and Li-MPs mixtures lead to population extinction. Based on the population growth rate and using data of bioassays with MPs alone done simultaneously, Li and MPs interactions were antagonistic or synergistic depending on the scenario. High light intensity and chemical stress generally acted synergistically. Warmer temperature and chemical stress always acted synergistically. These findings highlight the threats of long-term exposure to Li and Li-MPs mixtures to freshwater zooplankton and Global Health in a warmer world.

Synthetic Cannabinoids: A Pharmacological and Toxicological Overview.

Synthetic cannabinoids (SCs) are a chemically diverse group of new psychoactive substances (NPSs) that target the endocannabinoid system, triggering a plethora of actions (e.g., elevated mood sensation, relaxation, appetite stimulation) that resemble, but are more intense than, those induced by cannabis. Although some of these effects have been explored for therapeutic applications, anticipated stronger psychoactive effects than cannabis and reduced risk perception have increased the recreational use of SCs, which have dominated the NPS market in the United States and Europe over the past decade. However, rising SC-related intoxications and deaths represent a major public health concern and embody a major challenge for policy makers. Here, we review the pharmacology and toxicology of SCs. A thorough characterization of SCs' pharmacodynamics and toxicodynamics is important to better understand the main mechanisms underlying acute and chronic effects of SCs, interpret the clinical/pathological findings related to SC use, and improve SC risk awareness.

Promoting a compassionate motivation in detained youth: A secondary analysis of a controlled trial with the PSYCHOPATHY.COMP program.

This study aims to assess the efficacy of the PSYCHOPATHY.COMP in promoting a compassionate motivation among male detained youth, also testing its role as a potential mechanism of change on the reduction of psychopathic traits. A treatment group (n = 58) and a control group (n = 61) answered a set of self-report measures on psychopathic traits, shame, fears of compassion, social safeness, self-compassion, and compassion for others at three timepoints: baseline, posttreatment, and 6 months' follow-up. Treatment participants attended the PSYCHOPATHY.COMP. Controls received the treatment as usual delivered at juvenile detention facilities. The treatment effects were tested with latent growth curve models. At baseline, no significant differences between groups were found. Results from latent growth curve models showed that condition was a significant predictor of change over time observed in all outcome measures, even after controlling for psychopathic traits scores. When compared with the control group, the treatment group showed a significant decrease on shame and fears of compassion and a significant increase on social safeness, self-compassion, and compassion for others over time (medium-to-large effect sizes; growth modeling analysis d ranging from .57 to .96). It was also observed that increases in self-compassion and, in some cases, decreases in fears of receiving compassion, were crucial to the decrease of psychopathic traits. These findings suggest that the PSYCHOPATHY.COMP is a promising approach to promote a compassionate motivation in these youth, strengthening their rehabilitation odds. Increasing self-compassion and decreasing fears of receiving compassion should be considered when designing intervention programs for detained youth. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Toxicity of pesticides widely applied on soybean cultivation: Synergistic effects of fipronil, glyphosate and imidacloprid in HepG2 cells.

The transgenic soy monoculture demands supplementation with pesticides. The aim of this study was to evaluate the individual and mixture effects of fipronil, glyphosate and imidacloprid in human HepG2 cells. Cytotoxicity was evaluated after 48-h incubations through MTT reduction and neutral red uptake assays. Free radicals production, mitochondrial membrane potential, DNA damage, and release of liver enzymes were also evaluated. Data obtained for individual agents were used to compute the additivity expectations for two mixtures of definite composition (one equipotent mixture, based in the EC50 values achieved in the MTT assay; the other one based in the acceptable daily intake of each pesticide), using the models of concentration addition and independent action. The EC50 values for fipronil, glyphosate and imidacloprid were 37.59, 41.13, and 663.66 mg/L, respectively. The mixtures of pesticides elicited significant synergistic effects (p < 0.05), which were greater than the expected by both addictive predictions. Decreased in mitochondrial membrane potential and increased in the transaminases enzymatic activities were observed. As they occur simultaneously, interactions between pesticides, even at non-effective single levels, can reverberate in significant deleterious effects, justifying the need for a more realistic approach in safety evaluations to better predict the effects to human health.

Long-term effects of lithium and lithium-microplastic mixtures on the model species Daphnia magna: Toxicological interactions and implications to 'One Health'.

Environmental contamination with lithium (Li) and microplastics (MP) has been steadily increasing and this trend is expected to continue in the future. Many freshwater ecosystems, which are crucial to reach the United Nations Sustainable Development Goals, are particularly vulnerable to Li and MP contamination, and other pressures. The long-term effects of Li, either alone or combined with MP (Li-MP mixtures), were investigated using the freshwater zooplankton micro-crustacean Daphnia magna as model species. In the laboratory, D. magna females were exposed for 21 days to water concentrations of Li (0.02, 0.04, 0.08 mg/L) or Li-MP mixtures (0.02 Li + 0.04 MP, 0.04 Li + 0.09 MP mg/L, 0.08 Li + 0.19 MP mg/L). In the range of concentrations tested, Li and Li-MP mixtures caused parental mortality, and decreased the somatic growth (up to 20% and 40% reduction, respectively) and the reproductive success (up to 93% and 90% reduction, respectively). The 21-day EC50s of Li and Li-MP mixtures on D. magna reproduction were 0.039 mg/L and 0.039 Li + 0.086 MP mg/L, respectively. Under exposure to the highest concentration of Li (0.08 mg/L) and Li-MP mixtures (0.08 Li + 0.19 MP mg/L), the mean of D. magna population growth rate was reduced by 67% and 58%, respectively. Based on the population growth rate and using data from a bioassay testing the same concentrations of MP alone and carried simultaneously, the toxicological interaction between Li and MP was antagonism under exposure to the lowest and the highest concentrations of Li-MP mixtures, and synergism under exposure to the medium concentration of Li-MP mixtures. These findings highlight the need of further investigating the combined effects of contaminants, and the threat of long-term environmental contamination with Li and MP to freshwater zooplankton, biodiversity, ecosystem services and 'One Health'.

The burden of injury in Central, Eastern, and Western European sub-region: a systematic analysis from the Global Burden of Disease 2019 Study.

BACKGROUND: Injury remains a major concern to public health in the European region. Previous iterations of the Global Burden of Disease (GBD) study showed wide variation in injury death and disability adjusted life year (DALY) rates across Europe, indicating injury inequality gaps between sub-regions and countries. The objectives of this study were to: 1) compare GBD 2019 estimates on injury mortality and DALYs across European sub-regions and countries by cause-of-injury category and sex; 2) examine changes in injury DALY rates over a 20 year-period by cause-of-injury category, sub-region and country; and 3) assess inequalities in injury mortality and DALY rates across the countries. METHODS: We performed a secondary database descriptive study using the GBD 2019 results on injuries in 44 European countries from 2000 to 2019. Inequality in DALY rates between these countries was assessed by calculating the DALY rate ratio between the highest-ranking country and lowest-ranking country in each year. RESULTS: In 2019, in Eastern Europe 80 [95% uncertainty interval (UI): 71 to 89] people per 100,000 died from injuries; twice as high compared to Central Europe (38 injury deaths per 100,000; 95% UI 34 to 42) and three times as high compared to Western Europe (27 injury deaths per 100,000; 95%UI 25 to 28). The injury DALY rates showed less pronounced differences between Eastern (5129 DALYs per 100,000; 95% UI: 4547 to 5864), Central (2940 DALYs per 100,000; 95% UI: 2452 to 3546) and Western Europe (1782 DALYs per 100,000; 95% UI: 1523 to 2115). Injury DALY rate was lowest in Italy (1489 DALYs per 100,000) and highest in Ukraine (5553 DALYs per 100,000). The difference in injury DALY rates by country was larger for males compared to females. The DALY rate ratio was highest in 2005, with DALY rate in the lowest-ranking country (Russian Federation) 6.0 times higher compared to the highest-ranking country (Malta). After 2005, the DALY rate ratio between the lowest- and the highest-ranking country gradually decreased to 3.7 in 2019. CONCLUSIONS: Injury mortality and DALY rates were highest in Eastern Europe and lowest in Western Europe, although differences in injury DALY rates declined rapidly, particularly in the past decade. The injury DALY rate ratio of highest- and lowest-ranking country declined from 2005 onwards, indicating declining inequalities in injuries between European countries.

Cocaine: An Updated Overview on Chemistry, Detection, Biokinetics, and Pharmacotoxicological Aspects including Abuse Pattern.

Cocaine is one of the most consumed stimulants throughout the world, as official sources report. It is a naturally occurring sympathomimetic tropane alkaloid derived from the leaves of Erythroxylon coca, which has been used by South American locals for millennia. Cocaine can usually be found in two forms, cocaine hydrochloride, a white powder, or 'crack' cocaine, the free base. While the first is commonly administered by insufflation ('snorting') or intravenously, the second is adapted for inhalation (smoking). Cocaine can exert local anaesthetic action by inhibiting voltage-gated sodium channels, thus halting electrical impulse propagation; cocaine also impacts neurotransmission by hindering monoamine reuptake, particularly dopamine, from the synaptic cleft. The excess of available dopamine for postsynaptic activation mediates the pleasurable effects reported by users and contributes to the addictive potential and toxic effects of the drug. Cocaine is metabolised (mostly hepatically) into two main metabolites, ecgonine methyl ester and benzoylecgonine. Other metabolites include, for example, norcocaine and cocaethylene, both displaying pharmacological action, and the last one constituting a biomarker for co-consumption of cocaine with alcohol. This review provides a brief overview of cocaine's prevalence and patterns of use, its physical-chemical properties and methods for analysis, pharmacokinetics, pharmacodynamics, and multi-level toxicity.

The burden of mental disorders, substance use disorders and self-harm among young people in Europe, 1990-2019: Findings from the Global Burden of Disease Study 2019.

Background: Mental health is a public health issue for European young people, with great heterogeneity in resource allocation. Representative population-based studies are needed. The Global Burden of Disease (GBD) Study 2019 provides internationally comparable information on trends in the health status of populations and changes in the leading causes of disease burden over time. Methods: Prevalence, incidence, Years Lived with Disability (YLDs) and Years of Life Lost (YLLs) from mental disorders (MDs), substance use disorders (SUDs) and self-harm were estimated for young people aged 10-24 years in 31 European countries. Rates per 100,000 population, percentage changes in 1990-2019, 95% Uncertainty Intervals (UIs), and correlations with Sociodemographic Index (SDI), were estimated. Findings: In 2019, rates per 100,000 population were 16,983 (95% UI 12,823 - 21,630) for MDs, 3,891 (3,020 - 4,905) for SUDs, and 89·1 (63·8 - 123·1) for self-harm. In terms of disability, anxiety contributed to 647·3 (432-912·3) YLDs, while in terms of premature death, self-harm contributed to 319·6 (248·9-412·8) YLLs, per 100,000 population. Over the 30 years studied, YLDs increased in eating disorders (14·9%;9·4-20·1) and drug use disorders (16·9%;8·9-26·3), and decreased in idiopathic developmental intellectual disability (-29·1%;23·8-38·5). YLLs decreased in self-harm (-27·9%;38·3-18·7). Variations were found by sex, age-group and country. The burden of SUDs and self-harm was higher in countries with lower SDI, MDs were associated with SUDs. Interpretation: Mental health conditions represent an important burden among young people living in Europe. National policies should strengthen mental health, with a specific focus on young people. Funding: The Bill and Melinda Gates Foundation.

At the heart of change: Differences in young offenders' HRV patterns after the delivery of the PSYCHOPATHY.COMP program.

Introduction: Literature has pointed the need for intervention programs specifically tailored to target the treatment needs of young offenders, as well as the need to test the efficacy of such programs through physiological indexes of emotion regulation (e.g., heart rate variability; HRV), complementing self-reports typically used as outcome measures. The PSYCHOPATHY.COMP is a 20-session individual intervention program based on Compassion Focused Therapy aiming to reduce psychopathic traits and disruptive behavior among young offenders through the development of a compassionate motivation, while stimulating the soothing system as a strategy to improve emotion regulation. Previous research with young offenders has shown decreases in vagally mediated HRV (vmHRV) when the soothing system is activated. This physiological pattern seems to mirror threat-like responses that contrast with relaxed states. Methods: To test the efficacy of the PSYCHOPATHY.COMP, a clinical trial was implemented encompassing a treatment (n = 56) and a control group (n = 53). Treatment participants attended the PSYCHOPATHY.COMP, while controls received the Treatment As Usual (TAU) delivered in Portuguese juvenile detention facilities. HRV data was collected throughout a standardized procedure (encompassing resting, reactivity and recovery phases) specifically designed to trigger the soothing system. Participants were assessed at pre-treatment, post-treatment and 6-months follow-up. Results: Although treatment participants continued to process the soothing system as unpleasant (with decreased vmHRV), they seem to become able to adaptively recover from the stimuli without avoiding it or resorting to maladaptive coping strategies. The physiological pattern was in line with participants' decreases in difficulties in emotion regulation across the assessment periods. In contrast, controls seemed to have actively employed coping strategies associated with increases in vmHRV not only when the soothing system was triggered, but also when recovering from the stimuli. Congruently, for controls, increases in difficulties in emotion regulation were found, with increases in the lack of emotional clarity across the assessment periods. Discussion: Findings offer new evidence for the efficacy of the PSYCHOPATHY.COMP program in improving emotion regulation in young offenders, assessed through both self-report and physiological measures. Additionally, findings support the assessment of the autonomic balance as a treatment efficacy index in future research, targeting the rehabilitation of these youth. Clinical trial registration: ClinicalTrials.gov, identifier NCT03971682.

4-Fluoromethamphetamine (4-FMA) induces in vitro hepatotoxicity mediated by CYP2E1, CYP2D6, and CYP3A4 metabolism.

4-Fluoromethamphetamine (4-FMA) is an amphetamine-like psychoactive substance with recognized entactogenic and stimulant effects, but hitherto unclear toxicological mechanisms. Taking into consideration that the vast majority of 4-FMA users consume this substance through oral route, the liver is expected to be highly exposed. The aim of this work was to determine the hepatotoxic potential of 4-FMA using in vitro hepatocellular models: primary rat hepatocytes (PRH), human hepatoma cell lines HepaRG and HepG2, and resorting to concentrations ranging from 37 µM to 30 mM, during a 24-h exposure. EC50 values, estimated from the MTT viability assay data, were 2.21 mM, 5.59 mM and 9.57 mM, for each model, respectively. The most sensitive model, PRH, was then co-exposed to 4-FMA and cytochrome P450 (CYP) inhibitors to investigate the influence of metabolism on the toxicity of 4-FMA. Results show that CYP2E1, CYP3A4 and CYP2D6 have major roles in 4-FMA cytotoxicity. Inhibition of CYP2D6 and CYP3A4 led to left-geared shifts in the concentration-response curves of 4-FMA, hinting at a role of these metabolic enzymes for detoxifying 4-FMA, while CYP2E1 inhibition pointed towards a toxifying role of this enzyme in 4-FMA metabolism at physiologically-relevant concentrations. The drug also destabilised mitochondrial membrane potential and decreased ATP levels, increased the production of reactive oxygen and nitrogen species and compromised thiol antioxidant defences. 4-FMA further affected PRH integrity by interfering with the machinery of apoptosis and necrosis, increasing the activity of initiator and effector caspases, and causing loss of cell membrane integrity. Potential for autophagy was also observed. This research contributes to the growing body of evidence regarding the toxicity of new psychoactive substances, in particular regarding their hepatotoxic effects; the apparent influence of metabolism over the resulting cytotoxicity of 4-FMA shows that there is a substantial degree of unpredictability of the consequences for users that could be independent of the dose.

The efficacy of the PSYCHOPATHY.COMP program in reducing psychopathic traits: A controlled trial with male detained youth.

OBJECTIVE: To assess the efficacy of the PSYCHOPATHY.COMP program in reducing psychopathic traits among male detained youth. METHOD: In this controlled trial, a treatment group (n = 58) and a control group (n = 61) answered the Youth Psychopathic Traits Inventory-Short (YPIS) and the Proposed Specifiers for Conduct Disorder (PSCD) at baseline, posttreatment, and 6-month follow-up. Treatment participants attended the PSYCHOPATHY.COMP; controls only received Treatment As Usual (TAU). Treatment effects were tested with latent growth curve models (LGCM). RESULTS: At baseline, no significant differences between groups were found. Results from LGCM showed that condition was a significant predictor of change over time observed in almost all outcome measures. Concerning the YPIS, treatment participants presented a significant decrease both in the total score and in the YPIS factors scores when compared with the controls (medium/large effect sizes; growth modeling analysis-GMA d ranging from .58 to 1.12). Considering the PSCD, treatment participants also showed a significant decrease both in the total score and in the PSCD factors scores (except for the grandiose-manipulative factor) when compared with controls (medium effect sizes; GMA d ranging from .53 to .72). Results also showed that treatment effects were maintained 6 months after the PSYCHOPATHY.COMP completion. CONCLUSIONS: Findings indicate that the PSYCHOPATHY.COMP is a promising treatment approach to reduce psychopathic traits among male detained youth, suggesting that interventions targeting these traits should be considered in their rehabilitation, as the absence of tailored interventions may increase the levels of psychopathic traits and their associated risks. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Biosynthetic versatility of marine-derived fungi on the delivery of novel antibacterial agents against priority pathogens.

Despite the increasing number of novel marine natural products being reported from fungi in the last three decades, to date only the broad-spectrum cephalosporin C can be tracked back as marine fungal-derived drug. Cephalosporins were isolated in the early 1940s from a strain of Acremonium chrysogenum obtained in a sample collected in sewage water in the Sardinian coast, preliminary findings allowing the discovery of cephalosporin C. Since then, bioprospection of marine fungi has been enabling the identification of several metabolites with antibacterial effects, many of which proving to be active against multi-drug resistant strains, available data suggesting also that some might fuel the pharmaceutical firepower towards some of the bacterial pathogens classified as a priority by the World Health Organization. Considering the success of their terrestrial counterparts on the discovery and development of several antibiotics that are nowadays used in the clinical setting, marine fungi obviously come into mind as producers of new prototypes to counteract antibiotic-resistant bacteria that are no longer responding to available treatments. We mainly aim to provide a snapshot on those metabolites that are likely to proceed to advanced preclinical development, not only based on their antibacterial potency, but also considering their targets and modes of action, and activity against priority pathogens.

Overview of Synthetic Cannabinoids ADB-FUBINACA and AMB-FUBINACA: Clinical, Analytical, and Forensic Implications.

ADB-FUBINACA and AMB-FUBINACA are two synthetic indazole-derived cannabinoid receptor agonists, up to 140- and 85-fold more potent, respectively, than trans-∆9-tetrahydrocannabinol (∆9-THC), the main psychoactive compound of cannabis. Synthesised in 2009 as a pharmaceutical drug candidate, the recreational use of ADB-FUBINACA was first reported in 2013 in Japan, with fatal cases being described in 2015. ADB-FUBINACA is one of the most apprehended and consumed synthetic cannabinoid (SC), following AMB-FUBINACA, which emerged in 2014 as a drug of abuse and has since been responsible for several intoxication and death outbreaks. Here, we critically review the physicochemical properties, detection methods, prevalence, biological effects, pharmacodynamics and pharmacokinetics of both drugs. When smoked, these SCs produce almost immediate effects (about 10 to 15 s after use) that last up to 60 min. They are rapidly and extensively metabolised, being the O-demethylated metabolite of AMB-FUBINACA, 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamide)-3-methylbutanoic acid, the main excreted in urine, while for ADB-FUBINACA the main biomarkers are the hydroxdimethylpropyl ADB-FUBINACA, hydroxydehydrodimethylpropyl ADB-FUBINACA and hydroxylindazole ADB-FUBINACA. ADB-FUBINACA and AMB-FUBINACA display full agonism of the CB1 receptor, this being responsible for their cardiovascular and neurological effects (e.g., altered perception, agitation, anxiety, paranoia, hallucinations, loss of consciousness and memory, chest pain, hypertension, tachycardia, seizures). This review highlights the urgent requirement for additional studies on the toxicokinetic properties of AMB-FUBINACA and ADB-FUBINACA, as this is imperative to improve the methods for detecting and quantifying these drugs and to determine the best exposure markers in the various biological matrices. Furthermore, it stresses the need for clinicians and pathologists involved in the management of these intoxications to describe their findings in the scientific literature, thus assisting in the risk assessment and treatment of the harmful effects of these drugs in future medical and forensic investigations.

Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects.

Salvia divinorum Epling and Játiva is a perennial mint from the Lamiaceae family, endemic to Mexico, predominantly from the state of Oaxaca. Due to its psychoactive properties, S. divinorum had been used for centuries by Mazatecans for divinatory, religious, and medicinal purposes. In recent years, its use for recreational purposes, especially among adolescents and young adults, has progressively increased. The main bioactive compound underlying the hallucinogenic effects, salvinorin A, is a non-nitrogenous diterpenoid with high affinity and selectivity for the k-opioid receptor. The aim of this work is to comprehensively review and discuss the toxicokinetics and toxicodynamics of S. divinorum and salvinorin A, highlighting their psychological, physiological, and toxic effects. Potential therapeutic applications and forensic aspects are also covered in this review. The leaves of S. divinorum can be chewed, drunk as an infusion, smoked, or vaporised. Absorption of salvinorin A occurs through the oral mucosa or the respiratory tract, being rapidly broken down in the gastrointestinal system to its major inactive metabolite, salvinorin B, when swallowed. Salvinorin A is rapidly distributed, with accumulation in the brain, and quickly eliminated. Its pharmacokinetic parameters parallel well with the short-lived psychoactive and physiological effects. No reports on toxicity or serious adverse outcomes were found. A variety of therapeutic applications have been proposed for S. divinorum which includes the treatment of chronic pain, gastrointestinal and mood disorders, neurological diseases, and treatment of drug dependence. Notwithstanding, there is still limited knowledge regarding the pharmacology and toxicology features of S. divinorum and salvinorin A, and this is needed due to its widespread use. Additionally, the clinical acceptance of salvinorin A has been hampered, especially due to the psychotropic side effects and misuse, turning the scientific community to the development of analogues with better pharmacological profiles.