Genotoxic properties of synthetic cannabinoids on TK6 human cells by flow cytometry

Novel Psychoactive Substances (NPS) include several classes of substances such as synthetic cannabinoids (SCBs), an emerging alternative to marijuana, easily purchasable on internet. SCBs are more dangerous than 069-Tetrahydrocannabinol as a consequence of their stronger affinities for the CB1 and CB2 receptors, which may result in longer duration of distinct effects, greater potency, and toxicity. The information on SCBs cytotoxicity, genotoxicity, mutagenicity, and long-term effects is scarce. This fact suggests the urgent need to increase available data and to investigate if some SCBs have an impact on the stability of genetic material. Therefore, the aim of the present study was the evaluation of the mutagenic effect of different SCBs belonging to indole-and indazole-structures. The analyzes were conducted in vitro on human TK6 cells and mutagenicity were measured as micronucleus fold increase by flow cytometry. Our results have highlighted, for the first time, the mutagenic capacity of four SCBs, in particular in terms of chromosomal damage induction. We underline the serious potential toxicity of SCBs that suggests the need to proceed with the studies of other different synthetic compounds. Moreover, we identified a method that allows a rapid but effective screening of NPS placed on the market increasingly faster

Psychostimulant effect of the synthetic cannabinoid JWH-018 and AKB48: Behavioral, neurochemical, and dopamine transporter scan imaging studies in mice

JWH-018 and AKB48 are two synthetic cannabinoids (SCBs) belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. In vivo studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB1 receptor blockade and dopamine (DA) D1/5 and D2/3 receptors inhibition. SPECT-CT studies on dopamine transporter (DAT) revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [123I]-FP-CIT binding in the mouse striatum. Conversely, in vitro competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc) shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [3H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health

Comprehensive evaluation of the pharmacological and toxicological effects of γ-valerolactone as compared to γ-hydroxybutyric acid: Insights from in vivo and in silico models

Γ-valerolactone (GVL), marketed online as "Tranquilli-G" and "excellent Valium", is used as a legal substitute for γ-hydroxybutyric acid (GHB); however, until now, GVL has only been connected to one Drug-Facilitated Sexual Assault (DFSA) case. Moreover, the pharmaco-toxicological effects of GVL are poorly studied. The aim of this study was to investigate the 1) in vivo effects of gavage administration of GVL (100-3000 mg/kg) on neurological (myoclonia, convulsions), sensorimotor (visual, acoustic, and overall tactile) responses, righting reflex, thermoregulation, motor activity (bar, drag, and accelerod test) and cardiorespiratory changes (heart rate, breath rate, oxygen saturation, and pulse distension) in CD-1 male mice and the 2) in silico ADMET profile of GVL in comparison to GHB and the open active form γ-hydroxyvaleric acid (GHV). The present study demonstrates that GVL inhibits, in a dose-dependent manner, sensorimotor and motor responses and induces cardiorespiratory depression (at a dose of 3000 mg/kg) in mice. The determination of the ED50 in sensorimotor and motor responses revealed that GVL is about 4-5 times less potent than GHB. In silico prediction of ADMET profiles revealed toxicokinetic similarities between GHB and GHV, and differences with GVL. These results suggest that GVL could be used as a substitute for GHB and should be added to forensic toxicology screenings

Towards an end-to-end analysis and prediction system for weather, climate, and marine applications in the Red Sea

Author Posting. © American Meteorological Society, 2021. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 102(1), (2021): E99-E122, https://doi.org/10.1175/BAMS-D-19-0005.1.The Red Sea, home to the second-longest coral reef system in the world, is a vital resource for the Kingdom of Saudi Arabia. The Red Sea provides 90% of the Kingdom’s potable water by desalinization, supporting tourism, shipping, aquaculture, and fishing industries, which together contribute about 10%–20% of the country’s GDP. All these activities, and those elsewhere in the Red Sea region, critically depend on oceanic and atmospheric conditions. At a time of mega-development projects along the Red Sea coast, and global warming, authorities are working on optimizing the harnessing of environmental resources, including renewable energy and rainwater harvesting. All these require high-resolution weather and climate information. Toward this end, we have undertaken a multipronged research and development activity in which we are developing an integrated data-driven regional coupled modeling system. The telescopically nested components include 5-km- to 600-m-resolution atmospheric models to address weather and climate challenges, 4-km- to 50-m-resolution ocean models with regional and coastal configurations to simulate and predict the general and mesoscale circulation, 4-km- to 100-m-resolution ecosystem models to simulate the biogeochemistry, and 1-km- to 50-m-resolution wave models. In addition, a complementary probabilistic transport modeling system predicts dispersion of contaminant plumes, oil spill, and marine ecosystem connectivity. Advanced ensemble data assimilation capabilities have also been implemented for accurate forecasting. Resulting achievements include significant advancement in our understanding of the regional circulation and its connection to the global climate, development, and validation of long-term Red Sea regional atmospheric–oceanic–wave reanalyses and forecasting capacities. These products are being extensively used by academia, government, and industry in various weather and marine studies and operations, environmental policies, renewable energy applications, impact assessment, flood forecasting, and more.The development of the Red Sea modeling system is being supported by the Virtual Red Sea Initiative and the Competitive Research Grants (CRG) program from the Office of Sponsored Research at KAUST, Saudi Aramco Company through the Saudi ARAMCO Marine Environmental Center at KAUST, and by funds from KAEC, NEOM, and RSP through Beacon Development Company at KAUST

Micro-Fabricated RTD Based Sensor for Breathing Analysis and Monitoring

The design, micro-fabrication, and characterization of a resistance temperature detector (RTD) based micro sensor for minimally invasive breathing analysis and monitoring is presented. Experimental results demonstrate that the change in air temperature while inhaling and exhaling can be transduced into a time varying electrical signal, which is subsequently used to determine the breathing frequency (respiratory rate). The RTD is placed into a Wheatstone bridge to simultaneously reduce the sensor’s output noise and improve overall system accuracy. The proposed design could potentially aid health care providers in the determination of respiratory rates, which is of critical importance during the current COVID-19 pandemic

Toxicity and behavioural effects of ocfentanil and 2-furanylfentanyl in zebrafish larvae and mice

The introduction of the so-called New Psychoactive Substances represents a problem of global concern due to several factors, including multiplicity of structures, poorly known activity, short half-life in the market, lack of pure standards etc. Among these problems, of the highest relevance is also the lack of information about metabolism , adverse effects, which must be faced using simple and low-cost animal models. On these grounds, the present work has been carried out on 5 days post fertilization zebrafish (Danio rerio) larvae in comparison with adult mice (Mus musculus). Ocfentanil and 2-furanylfentanyl were administered at different concentrations to zebrafish larvae (1, 10 mu M) and mice (0.1, 1, 6, 15 mg/kg). The behavioural assay showed a decrease in basal locomotor activity in zebrafish, whereas in mice this effect was evident only after the me-chanical stimulus. Larva extracts and mice urine were analysed by using liquid chromatography coupled to high resolution mass spectrometry to identify the metabolic pathways of the fentanyl analogs. For 2-furanylfentanyl, the most common biotransformations observed were hydroxylation, hydration and oxidation in zebrafish larvae, whereas mice produced mainly the dihydrodiol metabolite. Hydroxylation was the major route of metabolism for ocfentanil in zebrafish larvae, while in mice the O-demethylated derivative was the main metabolite. In addition, a study was conducted to evaluate morphological effects of the two drugs on zebrafish larvae. Malformations were noticeable only at the highest concentration of 2-furanylfentanyl, whereas no significant damage was observed with ocfentanil. In conclusion, the two animal models show similarities in behavioral response and in metabolism, considering the different biological investigated

Single exposure to the cathinones mdpv and α‐pvp alters molecular markers of neuroplasticity in the adult mouse brain

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone‐induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α‐PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward‐related brain regions. We found that a single, low dose of MDPV or α‐PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity

Novel Synthetic Opioids: The Pathologist's Point of View

New Psychoactive Substances (NPS) constitute a broad range of hundreds of natural and synthetic drugs, including synthetic opioids, synthetic cannabinoids, synthetic cathinones, and other NPS classes, which were not controlled from 1961 to 1971 by the United Nations drug control conventions. Among these, synthetic opioids represent a major threat to public health

Zebrafish larvae: A new model to study behavioural effects and metabolism of fentanyl, in comparison to a traditional mice model

In an effort to find alternatives to study in vivo the so-called New Psychoactive Substances (NPS), the present work was undertaken to investigate the use of zebrafish larvae as animal model in pharmaco-toxicology, providing behavioural and metabolism information. For this purpose, fentanyl, the progenitor of an extremely dangerous group of NPS, was administered at different doses to zebrafish larvae (1, 10, 50, 100 mu M) in comparison to mice (0.1, 1, 6, 15 mg/kg), as a well-established animal model. A behavioural assay was performed at the time of the peak effect of fentanyl, showing that the results in larvae are consistent with those observed in mice. On the other hand, several morphological abnormalities (namely yolk sac edema, abnormal pericardial edema, jaw defect and spinal curvature) were found in larvae mostly at high fentanyl doses (50, 100 mu M). Larva extract and mice urine were analyzed by using liquid chromatography coupled to high resolution mass spectrometry to identify the metabolic pathways of fentanyl. The main metabolites detected were norfentanyl and hydroxyfentanyl in both the tested models. In conclusion, the present study provides evidence that fentanyl effects on zebrafish larvae and metabolism are similar to rodents and consequently support the hypothesis of using zebrafish larvae as a suitable rapid screening tool to investigate new drugs, and particularly NPS

A Programmable Mode-Locked Fiber Laser Using Phase-Only Pulse Shaping and the Genetic Algorithm

A novel, programmable, mode-locked fiber laser design is presented and numerically demonstrated. The laser programmability is enabled by an intracavity optical phase-only pulse shaper, which utilizes the same linearly chirped fiber Bragg grating (LC-FBG) from its two opposite ends to perform real-time optical Fourier transformation. A binary bit-pattern generator (BPG) operating at 20-Gb/s and producing a periodic sequence of 32 bits every 1.6 ns, is subsequently used to drive an optical phase modulator inside the laser cavity. Simulation results indicate stable programmable intensity profiles for each optimized user defined 32 code words. The laser operated in the self-similar mode-locking regime, enabling wave-breaking free operation. The programmable 32 bit code word targeting a specific intensity profile was determined using 100 generations of the genetic algorithm. The control of ultrashort pulse intensity profiles on the picosecond and femtosecond time scales is difficult. The process of stretching and compressing the pulse in the time domain allows for a slower BPG to impose a predefined phase modulation prior to pulse compression. This results in control over the fine features of the intensity profile of the compressed pulse on a picosecond or femtosecond time scale inside the laser cavity. The stability of the proposed scheme depends on the consistency and accuracy of the BPG rise and fall times in practice