Designer Cathinones N-Ethylhexedrone and Buphedrone Show Different In Vitro Neurotoxicity and Mice Behaviour Impairment.

N-Ethylhexedrone (NEH) and buphedrone (Buph) are emerging synthetic cathinones (SC) with limited information about their detrimental effects within central nervous system. Objectives: To distinguish mice behavioural changes by NEH and Buph and validate their differential harmful impact on human neurons and microglia. In vivo safety data showed the typical induced behaviour of excitation and stereotypies with 4-64 mg/kg, described for other SC. Buph additionally produced jumping and aggressiveness signs, while NEH caused retropulsion and circling. Transient reduction in body-weight gain was obtained with NEH at 16 mg/kg and induced anxiolytic-like behaviour mainly with Buph. Both drugs generated place preference shift in mice at 4 and 16 mg/kg, suggestive of abuse potential. In addition, mice withdrawn NEH displayed behaviour suggestive of depression, not seen with Buph. When tested at 50-400 µM in human nerve cell lines, NEH and Buph caused neuronal viability loss at 100 µM, but only NEH produced similar results in microglia, indicating different cell susceptibilities. NEH mainly induced microglial late apoptosis/necrosis, while Buph caused early apoptosis. NEH was unique in triggering microglia shorter/thicker branches indicative of cell activation, and more effective in increasing microglial lysosomal biogenesis (100 µM vs. 400 µM Buph), though both produced the same effect on neurons at 400 µM. These findings indicate that NEH and Buph exert neuro-microglia toxicities by distinct mechanisms and highlight NEH as a specific inducer of microglia activation. Buph and NEH showed in vivo/in vitro neurotoxicities but enhanced specific NEH-induced behavioural and neuro-microglia dysfunctionalities pose safety concerns over that of Buph.

A new Cu(II)-O-Carvacrotinate complex: Synthesis, characterization and biological activity.

Herein, we report the first example of the synthesis of a novel type of Cu(II) complex based on a natural product ligand derived from carvacrol. The copper(II) complex [Cu(DCA)2(EtOH)]2·2EtOH (1, HDCAO-carvacrotinic acid) has been synthesized and characterized by elemental analysis, IR spectroscopy, ESI-MS and single crystal X-ray analysis. Complex 1 and the carvacrotinic acid (2, HDCA) have been studied towards their antimicrobial and antiproliferative activities. For both compounds the antimicrobial activity was assessed against a panel of Gram-positive and Gram-negative bacteria and yeasts. The microdilution method allowed the determination of their Minimum Inhibitory Concentration (MIC) and minimum bactericidal concentration (MBC). Interestingly, both compounds seem to be more effective on yeasts rather than bacteria especially against C. albicans. Regarding the antimicrobial properties, the compounds appear to present a bacteriostatic behaviour, rather than bactericide. The antiproliferative effect of complex 1, O-carvacrotinic acid (HDCA) 2 and carvacrol (CA) 3 used as a reference to compare their antitumoral activity, was examined in 4 human tumor cell lines (ovarian carcinoma (A2780), colorectal carcinoma (HCT116), lung adenocarcinoma (A549) and breast adenocarcinoma (MCF7)) and in normal human primary fibroblasts. Complex 1 exhibits a moderate cytotoxic activity against ovarian carcinoma cells (A2780), with no cytotoxicity in normal primary human fibroblasts. The moderate cytotoxicity observed in A2780 cells was due to an increase of cell apoptosis.

Mixed ligand aroylhydrazone and N-donor heterocyclic Lewis base Cu(II) complexes as potential antiproliferative agents.

A series of four mixed ligand aroylhydrazone and N-donor heterocyclic Lewis base Cu(II) complexes [CuL(X)]2 [L refers to the dianionic form of (5-bromo-2-hydroxybenzylidene)-2-hydroxybenzohydrazide; X=pyrazine (Pz; 1), pyridine (Py; 2), imidazole (Imz; 3) and 3-pyridinecarbonitrile (3-PyCN; 4)] has been synthesized and characterized by elemental analysis, various spectroscopic techniques and X-ray crystallography (for 1, 2 and 4). The antiproliferative effect of complexes 1-4 was examined in 4 human tumor cell lines (ovarian carcinoma (A2780), colorectal carcinoma (HCT116), lung adenocarcinoma (A549) and breast adenocarcinoma (MCF7)) and in normal human primary Fibroblasts. Complex 4 exhibits a high cytotoxic activity against ovarian and colorectal carcinoma cells (A2780, HCT116 respectively), with IC50 much lower than those for normal primary fibroblasts. Complex 4 could induce cell death via apoptosis but not autophagy in colorectal carcinoma cells.

Tumor Microenvironment Modulation via Gold Nanoparticles Targeting Malicious Exosomes: Implications for Cancer Diagnostics and Therapy.

Exosomes are nanovesicles formed in the endosomal pathway with an important role in paracrine and autocrine cell communication. Exosomes secreted by cancer cells, malicious exosomes, have important roles in tumor microenvironment maturation and cancer progression. The knowledge of the role of exosomes in tumorigenesis prompted a new era in cancer diagnostics and therapy, taking advantage of the use of circulating exosomes as tumor biomarkers due to their stability in body fluids and targeting malignant exosomes' release and/or uptake to inhibit or delay tumor development. In recent years, nanotechnology has paved the way for the development of a plethora of new diagnostic and therapeutic platforms, fostering theranostics. The unique physical and chemical properties of gold nanoparticles (AuNPs) make them suitable vehicles to pursuit this goal. AuNPs' properties such as ease of synthesis with the desired shape and size, high surface:volume ratio, and the possibility of engineering their surface as desired, potentiate AuNPs' role in nanotheranostics, allowing the use of the same formulation for exosome detection and restraining the effect of malicious exosomes in cancer progression.