A combined toxicokinetic and metabolic approach to investigate deschloro-N-ethylketamine exposure in a multidrug user.

The use of new psychoactive substances derived from ketamine is rarely reported in France. A chronic GHB, 3-MMC, and methoxetamine consumer presented a loss of consciousness in a chemsex context and was referred to the intensive care unit with a rapid and favorable outcome. To investigate the chemicals responsible for the intoxication, a comprehensive analysis was conducted on the ten plasma samples collected over a 29.5-hour period, urine obtained upon admission, a 2-cm hair strand sample, and a seized crystal. These analyses were performed using liquid chromatography hyphenated to high resolution tandem mass spectrometry operating in targeted and untargeted modes. Additionally, analyses using gas chromatography coupled to mass spectrometry and nuclear magnetic resonance were conducted to probe the composition of the seized crystal. The molecular network-based approach was employed for data processing in non-targeted analyses. It allowed to confirm a multidrug exposure encompassing GHB, methyl-(aminopropyl)benzofuran (MAPB), (aminopropyl)benzofuran (APB), methylmethcathinone, chloromethcathinone, and a new psychoactive substance belonging to the arylcyclohexylamine family namely deschloro-N-ethyl-ketamine (O-PCE). Molecular network analysis facilitated the annotation of 27 O-PCE metabolites, including phase II compounds not previously reported. Plasma kinetics of O-PCE allowed the estimation of the elimination half-life of ∼5 hours. Kinetics of O-PCE metabolites was additionally characterized, possibly useful as surrogate biomarkers of consumption. We also observed marked alterations in lipid metabolism related to poly consumption of drugs. In conclusion, this case report provides a comprehensive analysis of exposure to O-PCE in a multidrug user including kinetic and metabolism data in human.

Lin28a induces SOX9 and chondrocyte reprogramming via HMGA2 and blunts cartilage loss in mice.

Articular cartilage has low regenerative capacity despite permanent stress. Irreversible cartilage lesions characterize osteoarthritis (OA); this is not followed by tissue repair. Lin28a, an RNA binding protein, is detected in damaged cartilage in humans and mice. We investigated the role of LIN28a in cartilage physiology and in osteoarthritis. Lin28a-inducible conditional cartilage deletion up-regulated Mmp13 in intact mice and exacerbated the cartilage destruction in OA mice. Lin28a-specific cartilage overexpression protected mice against cartilage breakdown, stimulated chondrocyte proliferation and the expression of Prg4 and Sox9, and down-regulated Mmp13. Lin28a overexpression inhibited Let-7b and Let-7c miRNA levels while RNA-sequencing analysis revealed five genes of transcriptional factors regulated by Let-7. Moreover, Lin28a overexpression up-regulated HMGA2 and activated SOX9 transcription, a factor required for chondrocyte reprogramming. HMGA2 siRNA knockdown inhibited the cartilage protective effect of Lin28a overexpression. This study provides insights into a new pathway including the Lin28a-Let7 axis, thus promoting chondrocyte anabolism in injured cartilage in mice.