Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.3.1 (citrate synthase)
 4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The trends of novel AD therapeutics are focused on multitarget-directed ligands (MTDLs), which combine cholinesterase inhibition with additional biological properties such as antioxidant properties to positively affect neuronal energy metabolism as well as mitochondrial function. We examined the in vitro effects of 10 novel MTDLs on the activities of mitochondrial enzymes (electron transport chain complexes and citrate synthase), mitochondrial respiration, and monoamine oxidase isoform (MAO-A and MAO-B) activity. The drug-induced effects of 7-MEOTA-adamantylamine heterodimers (K1011, K1013, K1018, K1020, and K1022) and tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers (K1046, K1053, K1056, K1060, and K1065) were measured in pig brain mitochondria. Most of the substances inhibited complex I- and complex II-linked respiration at high concentrations; K1046, K1053, K1056, and K1060 resulted in the least inhibition of mitochondrial respiration. Citrate synthase activity was not significantly inhibited by the tested substances; the least inhibition of complex I was observed for compounds K1060 and K1053, while both complex II/III and complex IV activity were markedly inhibited by K1011 and K1018. MAO-A was fully inhibited by K1018 and K1065, and MAO-B was fully inhibited by K1053 and K1065; the other tested drugs were partial inhibitors of both MAO-A and MAO-B. The tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers K1046, K1053, and K1060 seem to be the most suitable molecules for subsequent in vivo studies. These compounds had balanced inhibitory effects on mitochondrial respiration, with low complex I and complex II/III inhibition and full or partial inhibition of MAO-B activity.
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PMID:Effects of Novel Tacrine Derivatives on Mitochondrial Energy Metabolism and Monoamine Oxidase Activity-In Vitro Study. 3308 24

Specimens of two endemic cyprinids, Squalius laietanus (Catalan chub) and Barbus meridionalis (Mediterranean barbel), were sampled from a reference site in a small stream of the Ripoll River (NW Mediterranean) outside of their reproductive season. Biomarkers involved in xenobiotic-mediated responses were individually contrasted in fish of both species and 17 perfluoroalkyl substances (PFASs) analysed in muscle to reveal bioaccumulation trends. The parameters were in muscle: cholinesterases, metabolic lactate dehydrogenase (LDH) and citrate synthase (CS); and in liver: cytochrome P450 dependent activities (EROD and BFCOD), carboxylesterase (CE), glutathione S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPX) and catalase (CAT). All markers are considered adaptive defence mechanism to face stress. Sensitivity to a model pesticide: dichlorvos was also contrasted in vitro in muscular acetylcholinesterase (AChE) and hepatic CE to reveal species sensitivity to neurotoxic chemicals. Enzymatic activities related to protective mechanisms such as butyrylcholinesterase (BuChE), CE and CAT were higher in chub whereas the antioxidant defences GR and GPX were higher in barbel. Aerobic CS was also higher in barbel while anaerobic LDH was so in chub. EROD activity did not differ between the two species but BFCOD activity was higher in barbel. Levels of PFAS were higher in barbel likely due to its benthic habitat. The in vitro tests revealed higher sensitivity to dichlorvos of muscular AChE in chub (lower IC50) which was probably compensated by a higher catalytic efficiency of CE. All these former biochemical particularities are discussed in terms of fish ecological performance in front of anthropogenic stressors.
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PMID:Biochemical aspects of susceptibility to stressors in two small cyprinids Squalius laietanus and Barbus meridionalis from the NW Mediterranean. 3317 Dec 99