[Show abstract][Hide abstract] ABSTRACT: Caryocar coriaceum Wittm. (pequi) has been popularly used in Northeastern Brazil in the treatment of inflammation, pain and respiratory affections. This study evaluated the topical anti-inflammatory activity of C. coriaceum hydroethanolic extract (CCHE) and methanolic fraction (CCMF) from pequi tree leaves against different skin sensitizer agents (arachidonic acid, croton oil, phenol and histamine), as well their antioxidant activity and phenolic compound profile. High performance liquid chromatography with diode array detection (HPLC-DAD) analysis pointed the presence of chlorogenic acid, rutin, quercetin and lower concentrations of caffeic and gallic acids. Both CCHE and CCMF 1 mg/ear demonstrated significant topical anti-inflammatory effect against arachidonic acid, phenol and histamine single application (antiedematous effect ranging from 48 to 69% for CCHE and 36 to 64% for CCMF; P < 0.05 vs. negative control). In contrast, both extracts did not antagonize the croton oil single application-induced ear edema when compared with the control group (P > 0.05). Additionally, both extracts exhibited strong DPPH • free radical scavenging activity in vitro (EC 50 = 5.02 ± 4.37 μg/ml for CCMF and 6.06 ± 4.03 μg/ml for CCHE). Together, the results give important support that CCHE and CCMF (and their phenolic compounds, according to previous data from literature) could exert topical anti-inflammatory activity by possibly modulate the local production of inflammatory mediators including histamine, arachidonic acid metabolites and reactive oxygen species.
African journal of pharmacy and pharmacology 01/2014; 8:629-637. · 0.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: δ-Aminolevulinic acid dehydratase (δ-ALAD) is a metalloprotein that catalyzes porphobilinogen formation. This enzyme is sensitive to pro-oxidants and classically used as a biomarker of lead (Pb) intoxication. Diphenyl diselenide [(PhSe)₂] and analogs bis(4-chlorophenyl) diselenide [(pCl₃PhSe)₂], bis(4-methoxyphenyl)diselenide [(pCH₃OPhSe)₂], and bis[3-(trifluoromethy)phenyl] diselenide [(mCF₃PhSe)₂] inhibit mammalian δ-ALAD by oxidizing enzyme cysteinyl residues, which are involved in diselenide-induced toxicity. 2-Cysteinyl residues from δ-ALAD are believed to sequentially interact with (PhSe)₂. Thus this study utilized protein-ligand docking analyses to determine which cysteinyl residues might be involved in the inhibitory effect of (PhSe)₂ and analogs toward δ-ALAD. All diselenides that interact in a similar manner with the active site of δ-ALAD were examined. Docking simulations indicated an important role for π-π interactions involving Phe208 and cation-π interactions involving Lys199 and Arg209 residues with the aromatic ring of (PhSe)₂ and analogs. Based upon these interactions an approximation between Se atoms and -SH of Cys124, with distances ranging between 3.3 Å and 3.5 Å, was obtained. These data support our previous postulations regarding the mechanism underlying δ-ALAD oxidation mediated by (PhSe)₂ and analogs. Based on protein-ligand docking analyses, data indicated that -SH of Cys124 attacks one of the Se atoms of -SH of (PhSe)₂ releasing one PhSeH (selenophenol). Subsequently, the -SH of Cys132 attacks the sulfur atom of Cys124 (from the bond of E-S-Se-Ph indermediate), generating the second PhSe⁻, and the oxidized and inhibited δ-ALAD. In conclusion, AutoDock Vina 1.1.1 was a useful tool to search for diselenides inhibitors of δ-ALAD, and, most importantly, it provided insight into molecular mechanisms involved in enzyme inhibition.
Journal of Toxicology and Environmental Health Part A 08/2012; 75(16-17):1012-22. · 1.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Methamidophos is one of the most toxic organophosphorus (OP) compounds. It acts via phosphorylation of a serine residue in the active site of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), leading to enzyme inactivation. Different oximes have been developed to reverse this inhibition. Thus, our work aimed to test the protective or reactivation capability of pralidoxime and obidoxime, as well as two new oximes synthesised in our laboratory, on human and rat cholinesterases inhibited by methamidophos. In addition, we performed molecular docking studies in non-aged methamidophos-inhibited AChE to understand the mechanisms involved. Our results suggested that pralidoxime protected and reactivated methamidophos-inhibited rat brain AChE. Regarding human erythrocyte AChE, all oximes tested protected and reactivated the enzyme, with the best reactivation index observed at the concentration of 50 μM. Concerning BChE, butane-2,3-dionethiosemicarbazone oxime (oxime 1) was able to protect and reactivate the methamidophos-inhibited BChE by 45% at 50 μM, whereas 2(3-(phenylhydrazono)butan-2-one oxime (oxime 2) reactivated 28% of BChE activity at 100 μM. The two classical oximes failed to reactivate BChE. The molecular docking study demonstrated that pralidoxime appears to be better positioned in the active site to attack the O-P moiety of the inhibited enzyme, being near the oxyanion hole, whereas our new oximes were stably positioned in the active site in a manner similar to that of obidoxime. In conclusion, our work demonstrated that the newly synthesised oximes were able to reactivate not only human erythrocyte AChE but also human plasma BChE, which could represent an advantage in the treatment of OP compounds poisoning.