Antioxidant capacity of simplified oxygen heterocycles and proposed derivatives by theoretical calculations.

CONTEXT: Some structural properties can be involved in the antioxidant capacity of several polyphenol derivatives, among them their simplified structures. This study examines the contribution of simplified structure for the antioxidant capacity of some natural and synthetic antioxidants. The resonance structures were related to the π-type electron system of carbon-carbon double bonds between both phenyl rings. Trans-resveratrol, phenyl-benzofuran, phenyl-indenone, and benzylidene-benzofuranone are the best basic antioxidant templates among the simplified derivatives studied here. Additionally, the stilbene moiety was found on the molecules with the best antioxidant capacity. Furthermore, our investigation suggests that these compounds can be used as antioxidant scaffold for designing and developing of new promising derivatives. METHODS: To investigate the structure-antioxidant capacity for sixteen simplified natural and proposed derivatives we have employed density functional theory and used Gaussian 09. Our DFT calculations were performed using the B3LYP functional and the 6-31+G(d,p) basis set. All electron transfer mechanisms were investigated by using values of HOMO, ionization potential, energy affinity, stabilization energies, and spin density distributions.

Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy.

Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.

Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.

Deficiency in peroxisome proliferator-activated receptor gamma coactivator 1-alpha. (PGC-1α) expression or function is implicated in numerous neurological and psychiatric disorders. PGC-1α is required for the expression of genes involved in synchronous neurotransmitter release, axonal integrity, and metabolism, especially in parvalbumin-positive interneurons. As a transcriptional coactivator, PGC-1α requires transcription factors to specify cell-type-specific gene programs; while much is known about these factors in peripheral tissues, it is unclear if PGC-1α utilizes these same factors in neurons. Here, we identified putative transcription factors controlling PGC-1α-dependent gene expression in the brain using bioinformatics and then validated the role of the top candidate in a knockout mouse model. We transcriptionally profiled cells overexpressing PGC-1α and searched for over-represented binding motifs in the promoters of upregulated genes. Binding sites of the estrogen-related receptor (ERR) family of transcription factors were enriched, and blockade of ERRα attenuated PGC-1α-mediated induction of mitochondrial and synaptic genes in cell culture. Localization in the mouse brain revealed enrichment of ERRα expression in parvalbumin-expressing neurons with tight correlation of expression with PGC-1α across brain regions. In ERRα null mice, PGC-1α-dependent genes were reduced in multiple regions, including neocortex, hippocampus, and cerebellum, though not to the extent observed in PGC-1α null mice. Behavioral assessment revealed ambulatory hyperactivity in response to amphetamine and impairments in sensorimotor gating without the overt motor impairment characteristic of PGC-1α null mice. These data suggest that ERRα is required for normal levels of expression of PGC-1α-dependent genes in neurons but that additional factors may be involved in their regulation.

A comparative theoretical mechanism on simplified flavonoid derivatives and isoxazolone analogous as Michael system inhibitor.

Flavonoids are a big class of natural product and have a wide range of biological activities. Some of these applications depend on its antioxidant capacity. Nevertheless, another mechanism can be involved by means of alkylation reaction on α,ß-unsaturated carbonyl system. This study aimed to evaluate the antioxidant capacity and the chemical reactivity among simplified flavonoid derivatives and isoxazolone analogous as Michael system by using B3LYP functional and 6-311 g(d,p) basis set. Frontier molecular orbital, ionization potential (IP), spin density contributions, and Fukui index explain the antioxidant capacity and reactivity index on isoxazolone and its related derivatives. The best contribution at ß-alkene moiety is related to better reactivity of α,ß-unsaturated carbonyl group. A decrease in antioxidant capacity is related to an increase in the chemical reactivity index. The frontier molecular orbitals show that aurone is more reactive than isoxazolone. In accordance with Fukui index, isoxazolone can be better inhibitor as Michael system when compared to flavonoid derivatives. Graphical abstract.

Evaluation and theoretical study on the anti-inflammatory mechanism of 1-nitro-2-phenylethane.

In this study, 1-nitro-2-phenylethane was evaluated with respect to its effects in edema models of acute inflammation induced with carrageenan, dextran, and croton oil. 1-Nitro-2-phenylethane produced inhibition of rat paw edema induced by carrageenan and dextran at the doses of 25 and 50 mg/kg. The same doses caused an inhibition of croton oil-induced ear edema in mice. Our results suggest that 1-nitro-2-phenylethane has anti-inflammatory activity, probably of peripheral origin, acting in the synthesis and/or release of inflammatory mediators. A conformational study of 1-nitro-2-phenylethane was carried out using density functional theory calculations, showing three different groups of conformers corresponding to energy minimum geometries. The stereoelectronic repulsions are responsible for conformational preferences and the one most stable conformer. The prostaglandin endoperoxide synthase mechanism is related more to electrophilic than nucleophilic properties.

Design and evaluation of 4-aminophenol and salicylate derivatives as free-radical scavenger.

This theoretical and experimental study describes the design and evaluation of the free-radical scavenging effect for the molecular association of 4-aminophenol and salicylate derivatives. For this purpose, we employed theoretical methods for the selection of antioxidant drugs and the rapid methods of evaluation: the 1,1-diphenyl-2-picrylhydrazyl radical and the thiobarbituric acid reactive substances in the lipid peroxidation initiated by Fe(2+) and ascorbic acid in human erythrocytes. The associate derivatives exhibited a more potent inhibition than the salicylic acid, while the benzoyl compound exhibited a more potent inhibition than paracetamol. The molecular parameters related to the electron distribution and structure (ionization potential and energy of the highest occupied molecular orbital) correlated very well with the antioxidant action of the compounds studied here in different tests.

Neonatal goitrogen treatment increases adult testis size and sperm production in the mouse.

Male rats made hypothyroid during neonatal life show unprecedented increases in adult testis size and daily sperm production (DSP). To determine if this effect was unique to the rat or could also be demonstrated in other species, we examined the effects of neonatal treatment with the reversible goitrogen 6-propyl-2-thiouracil (PTU) on adult testis size and function in the mouse. Male Swiss-Webster mice were untreated (control) or given PTU by adding 0.1% (w/v) to their mother's water from birth to day 25 postpartum. All pups were then weaned and given no further treatment. Sertoli cell proliferation was examined using tritiated thymidine autoradiography in some control and treated mice at 0, 5, 10, 15, 20, and 25 days, while the remainder were killed at 90 days to determine a variety of reproductive parameters. Neonatal PTU treatment decreased growth; body weight of treated mice at 4 weeks of age was 57% less than controls. Treated mice grew rapidly following cessation of PTU treatment, although their weights never equalled controls, remaining 17% smaller at 90 days of age. At 90 days of age, testis weight and DSP were increased by approximately 30% and 50%, respectively, in PTU-treated mice compared to controls. Despite the increased testis weight and function, serum testosterone concentrations were not different in control and treated mice. Testicular and epididymal histology in treated mice was similar to controls, while epididymal sperm in treated mice were motile and morphologically normal. Sertoli cell proliferation was altered in treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)