PSIV-B-22 Comparative effects of nanoparticle-selenium, selenium-enriched yeast and sodium selenite antagonize cadmium-induced cardiotoxicity in chicken (Gallus gallus) via modulating AHR/CAR/PXR/Nrf2 pathways

Selenium (Se), a nutritionally essential mineral for human and animals, has a significant antagonistic effect on heavy metal cadmium (Cd) biotoxicity. Still, the impact of different Se source on alleviating Cd toxicity has received only limited attention. Therefore, the purpose of the current study was to assess the mitigation level of Cd-induced cardiotoxicity by different sources such as nanoparticles of selenium (Nano-Se), selenium-rich yeast (SY) and sodium selenite (SS). Two hundred of male, 1-day old Hy-Line Variety White chickens were randomly, equally divided into five groups (n = 25). These chicken groups were assigned to (1) basal diet (Con), (2) 140 mg/kg CdCl[2] of basal diet Cd (Cd), (3) 1 mg/kg Nano-Se plus 140 mg/kg CdCl[2] of basal diet (Nano-Se + Cd), (4) 3 mg/kg selenium-enriched yeast plus 140 mg/kg CdCl[2] of basal diet (SY + Cd group), and (5) 3 mg/kg sodium selenite plus 140 mg/kg CdCl[2] of basal diet (SS+ Cd group). The results evidenced that presence of Cd led to a significant increase in biochemical parameters such as lactate dehydrogenase (LDH) and creatine kinase (CK), as well as histopathological lesions in the heart of chickens. Cd exposure also resulted in more extensive effects on phase I metabolism enzymes and transcript CYP isoforms, elevated the levels of MDA and H[2]O[2] and depressed total superoxide dismutase (T-SOD), Cu-Zn SOD, total antioxidant capacity (T-AOC) and catalase (CAT) activities. The expression of nuclear receptors (NRs), AHR, CAR and PXR was declined, down-regulated Nrf2 and its downstream targets in the Cd-treat group. Notably, Se sources application alleviated Cd toxicity by triggering AHR/CAR/PXR/Nrf2 signaling pathway to promote restoring antioxidant defense system and phase I metabolism enzymes system. However, when compared the effectiveness of antagonism, the Nano-Se was superior in relieving Cd-induced cardiotoxicity via AHR/CAR/PXR/Nrf2 pathway activation than other Se- sources.

The Novel Psychoactive Substance Cumyl-CH-MEGACLONE: Human Phase-I Metabolism, Basic Pharmacological Characterization and Comparison to Other Synthetic Cannabinoid Receptor Agonists with a γ-Carboline-1-One Core

Synthetic cannabinoids (SC) remain one of the largest groups of new psychoactive substances on the European drug market. In December 2018, Cumyl-CH-MEGACLONE, a novel SC based on a γ-carboline-1-one core structure, was firstly identified in Hungary and later also other European countries. This work aims to reveal the pharmacological characteristics and phase-I metabolism of Cumyl-CH-MEGACLONE and compare the data to its analogs Cumyl-PEGACLONE and 5F-Cumyl-PEGACLONE. The purified substance was characterized by means of gas chromatography–mass spectrometry (GC–MS), liquid chromatography–quadrupole time-of-flight mass spectrometry (LC–QToF-MS), attenuated total reflection infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance spectroscopy. Phase-I metabolites were identified by LC–QToF-MS analysis combined with a scheduled precursor ion list of authentic urine samples and confirmed by comparison with metabolites built in vitro by pooled human liver microsome assays. Pharmacological data were obtained in a competitive ligand binding assay and a receptor activation assay at the human cannabinoid receptor 1 (hCB1). The structure of 5-cyclohexylmethyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (semisystematic name: Cumyl-CH-MEGACLONE) was identified in a herbal blend as the main active ingredient. Investigation of phase-I biotransformation of Cumyl-CH-MEGACLONE led to three monohydroxylated metabolites (M08, M10 and M13) as reliable urinary markers for proof of consumption. At the hCB1, Cumyl-CH-MEGACLONE shows high binding affinity with Ki = 1.01 nM (2.5-fold higher than JWH-018), an EC50 of 1.22 nM and high efficacy with EMAX = 143.4% above constitutive activity of the receptor (1.13-fold higher than JWH-018). Comparison to the analogs 5F-Cumyl-PEGACLONE and Cumyl-PEGACLONE (both are hCB1 full agonists carrying a 5-fluoropentyl or pentyl chain instead of the cyclohexylmethyl moiety) suggests that Cumyl-CH-MEGACLONE is more likely to resemble the pharmacologic profile of the latter one.