Free radical-mediated lipid peroxidation and systemic nitric oxide bioavailability:implications for postexercise hemodynamics

The metabolic vasodilator mediating postexercise hypotension (PEH) is poorly understood. Recent evidence suggests an exercise-induced reliance on pro-oxidant-stimulated vasodilation in normotensive young human subjects, but the role in the prehypertensive state is not known.

Asymmetric Total Synthesis of (+)-Inthomycin C Via O-Directed Free Radical Alkyne Hydrostannation with Ph3SnH and Catalytic Et3B: Reinstatement of the Zeeck-Taylor (3R)-Structure for (+)-Inthomycin C

A new pathway to (+)-inthomycin C is reported that exploits an O-directed free radical hydrostannation reaction on (−)-12 and a Stille cross-coupling as key steps. Significantly, the latter process was effected on 19 where a gauche-pentane repulsive interaction could interfere. Our stereochemical studies on the alkynol (−)-12 and the enyne (+)-7 confirm that Ryu and Hatakeyama’s (3S)-stereochemical revision of (+)-inthomycin C is invalid and that Zeeck and Taylor’s original (3R)-stereostructure for (+)-inthomycin C is correct.

Synthesis of the C(7)-C(22)-Sector of (+)-Acutiphycin Via O-Directed Double Free Radical Alkyne Hydrostannation with Ph3SnH/Et3B, Double I-Sn Exchange and Double Stille Coupling

Abstract Image

Herein a new double O-directed free radical hydrostannation reaction is reported on the structurally complex dialkyldiyne 11. Through our use of a conformation-restraining acetal to help prevent stereocenter-compromising 1,5-H-atom abstraction reactions by vinyl radical intermediates, the two vinylstannanes of 10 were concurrently constructed with high stereocontrol using Ph3SnH/Et3B/O2. Distannane 10 was thereafter elaborated into the bis-vinyl iodide 9 via O-silylation and double I–Sn exchange; double Stille coupling of 9, O-desilylation, and oxidation thereafter furnished 8.

The validation of Fibit ZipTM physical activity monitor as a measure of free-living physical activity

BACKGROUND: The new generation of activity monitors allow users to upload their data to the internet and review progress. The aim of this study is to validate the Fitbit Zip as a measure of free-living physical activity.

FINDINGS: Participants wore a Fitbit Zip, ActiGraph GT3X accelerometer and a Yamax CW700 pedometer for seven days. Participants were asked their opinion on the utility of the Fitbit Zip. Validity was assessed by comparing the output using Spearman's rank correlation coefficients, Wilcoxon signed rank tests and Bland-Altman plots. 59.5% (25/47) of the cohort were female. There was a high correlation in steps/day between the Fitbit Zip and the two reference devices (r = 0.91, p < 0.001). No statistically significant difference between the Fitbit and Yamax steps/day was observed (Median (IQR) 7477 (3597) vs 6774 (3851); p = 0.11). The Fitbit measured significantly more steps/day than the Actigraph (7477 (3597) vs 6774 (3851); p < 0.001). Bland-Altman plots revealed no systematic differences between the devices.

CONCLUSIONS: Given the high level of correlation and no apparent systematic biases in the Bland Altman plots, the use of Fitbit Zip as a measure of physical activity. However the Fitbit Zip recorded a significantly higher number of steps per day than the Actigraph.

Synthesis and biological activities of polyphenolic hybrids - evaluation of anti-cancer, anti-inflammatory and antioxidant activities

Os compostos polifenólicos constituem uma classe de metabolitos secundários de plantas, mas existe também uma enorme quantidade de derivados sintéticos ou semi-sintéticos contendo múltiplas unidades fenólicas. Estes compostos apresentam importantes características biológicas, que dependem das suas estruturas básicas. Certos derivados desta família de compostos, tais como flavonoides, cromonas e cumarinas contribuem para os benefícios da dieta humana, e partilham o núcleo de benzopiran-(2 e 4)-ona ou benzofuran-3-ona. A presente dissertação inclui uma introdução geral e três capítulos que descrevem as novas rotas sintéticas estabelecidas para a preparação de novos híbridos de diversos compostos polifenólicos, assim como a sua elucidação estrutural e termina com a presentação dos resultados da avaliação biológica desses mesmos compostos. No segundo capítulo discute-se a preparação de híbridos de pirimidina- e imidazolidina-polifenóis, especialmente a síntese diastereoseletiva de novos híbridos benzofuran-3-ona-hidantoína e derivados de uracilo. A rota sintética envolve a ação de carbodiimidas sobre os ácidos cromona-(2- e 3)-carboxílicos num só passo ou em dois passos sequenciais, catalisada por uma base orgânica ou inorgânica. O terceiro capítulo descreve reações do tipo adições conjugadas 1,4 - hetero-ciclisações em cascata de compostos 1,3-dicarbonílicos em ácido cromona-3-carboxílico catalisadas por uma base orgânica, que originaram novas cromonas, cromanonas e flavonas polissubstituídas. As bispiranonas [bispiran-2 e 4)-onas] foram elaboradas numa reacção de acoplamento da 4-hidroxicumarina ou da lactona do ácido triacético com o ácido cromona-3-carboxílico ou precursores formil-funcionalizados (ω-formil-2’-hydroxy acetofenonas e cromona-3-carbaldeídos) utilizando organocatálise básica. Finalmente, alargou-se o estudo das adições conjugadas 1,4 para uma variedade de 4-hidroxipiran-2-onas e cetonas α,β-insaturadas para originar novos análogos de warfarina. Obteve-se uma variedade de estruturas complexas por hibridação das unidades de 4-hidroxicumarina ou da lactona do ácido triacético com os novos derivados de cromonas polissubstituídas. Todos as reações foram executadas em condições suaves e ambientalmente favoráveis, utilizando a 4-pirrolidinopiridina como organocatalisador básico. As estruturas dos novos híbridos polifenólicos foram caracterizados por técnicas espectroscópicas de alta resolução, incluindo espectroscopia de ressonância magnética nuclear (1D e 2D) e por difractometria de raios-X, que nos permitiram resolver o complexidade estrutural dos compostos sintetizados. O quarto capítulo apresenta os resultados da avaliação biológica obtidos com os híbridos polifenólicos sintetizados neste trabalho, mostrando a possibilidade de seu envolvimento na terapia do cancro. A maioria dos compostos foram avaliados quanto ao seu efeito sobre a citotoxicidade e proliferação de células leucémicas e ao seu envolvimento na regulação de via pró-inflamatória NF-kB, na qual, os híbridos de biscumarinas exibiram actividades elevadas (IC50 = 6-19 μM para inibição de NF-kB depois de 8 horas de incubação e IC50 = 15-39 μM para efeitos citotóxicos em células cancerosas, após 24 horas de incubação). Uma inibição moderada das enzimas HDAC e Cdc25 foi induzida pelos derivados de benzofuran-3-ona-hidantoína. Catorze dos novos derivados polifenólicos polissubstituídos, tendo como estrutura básica a benzopiran-4-ona, foram avaliados pela sua actividade quimiopreventiva do cancro mediada pela indução de sinalização citoprotectora Nrf2 (fator 2 relacionado com o fator nuclear da proteína E2) e capacidade para inibir a proliferação das células de cancro da mama. Os derivados da classe das cromanonas foram identificados como os indutores mais potentes da actividade Nrf2. As concentrações necessárias para aumentar a actividade de luciferase em 10 vezes (C10) foram de 2,8-21,3 μM. Todos os novos híbridos polifenólicos que apresentam atividade citotóxica e anti-proliferativa não afectam o crescimento de células saudáveis periféricas do sangue (PBMC) (IC50 > 50 μM), indicando a sua seletividade para as células cancerosas e sugerindo que alguns deles são estruturalmente interessantes para posteriores análises. A avaliação da atividade antioxidante utilizando os testes do radical livre DPPH e o poder redutor do ião férrico FRAP foram realizados em algumas estruturas híbridas polifenólicas.

Effects of antioxidant enzyme inhibitors on free radical levels in mice and possible clinical applications for decreasing ROS damage in the cochlea

This paper examines an experiment to determine if impairment of antioxident protective agents resulted in elevated ROS levels in mice.

Antioxidant activity and protective effects of green and dark coffee components against human low density lipoprotein oxidation

The in vitro antioxidant activity and the protective effect against human low density lipoprotein oxidation of coffees prepared using different degrees of roasting was evaluated. Coffees with the highest amount of brown pigments (dark coffee) showed the highest peroxyl radical scavenging activity. These coffees also protected human low-density lipoprotein (LDL) against oxidation, although green coffee extracts showed more protection. In a different experiment, coffee extracts were incubated with human plasma prior to isolation of LDL particles. This showed, for the first time, that incubation of plasma with dark, but not green coffee extracts protected the LDL against oxidation by copper or by the thermolabile azo compound AAPH. Antioxidants in the dark coffee extracts must therefore have become associated with the LDL particles. Brown compounds, especially those derived from the Maillard reaction, are the compounds most likely to be responsible for this activity.

Sulfation of genistein alters its antioxidant properties and its effect on platelet aggregation and monocyte and endothelial function

Soy isoflavones have been extensively studied because of their possible benefits to human health. Genistein, the major isoflavone aglycone, has received most attention; however, it undergoes extensive metabolism (e.g. conjugation with sulfuric acid) in the gut and liver, which may affect its biological proper-ties. This study investigated the antioxidant activity and free radical-scavenging properties of genistein, genistein-4'-sulfate and genistein-4'-7-disulfate as well as their effect on platelet aggregation and monocyte and endothelial function. Electron spin resonance spectroscopy (ESR) and spin trapping data and other standard antioxidant assays indicated that genistein is a relatively weak antioxidant compared to quercetin and that its sulfated metabolites are even less effective. Furthermore, genistein-4'-sulfate was less potent than genistem, and genistein-4'-7-disulfate even less potent, at inhibiting collagen-induced platelet aggregation, nitric oxide (NO) production by macrophages, and secretion by primary human endothelial cells of monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). The current data suggest that sulfation of genistein, with the associated loss of hydroxyl groups, decreases its antioxidant activity and its effect on platelet aggregation, inflammation, cell adhesion and chemotaxis. (C) 2004 Elsevier B.V All rights reserved.

Sulfation of genistein alters its antioxidant properties and its effect on platelet aggregation and monocyte and endothelial function

Soy isoflavones have been extensively studied because of their possible benefits to human health. Genistein, the major isoflavone aglycone, has received most attention; however, it undergoes extensive metabolism (e.g. conjugation with sulfuric acid) in the gut and liver, which may affect its biological proper-ties. This study investigated the antioxidant activity and free radical-scavenging properties of genistein, genistein-4'-sulfate and genistein-4'-7-disulfate as well as their effect on platelet aggregation and monocyte and endothelial function. Electron spin resonance spectroscopy (ESR) and spin trapping data and other standard antioxidant assays indicated that genistein is a relatively weak antioxidant compared to quercetin and that its sulfated metabolites are even less effective. Furthermore, genistein-4'-sulfate was less potent than genistem, and genistein-4'-7-disulfate even less potent, at inhibiting collagen-induced platelet aggregation, nitric oxide (NO) production by macrophages, and secretion by primary human endothelial cells of monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). The current data suggest that sulfation of genistein, with the associated loss of hydroxyl groups, decreases its antioxidant activity and its effect on platelet aggregation, inflammation, cell adhesion and chemotaxis. (C) 2004 Elsevier B.V All rights reserved.

Effects of copper on the antioxidant activity of olive polyphenols in bulk oil and oil-in-water emulsions

The antioxidant activity and interactions with copper of four olive oil phenolic compounds, namely oleuropein, hydroxytyrosol, 3,4- dihydroxyphenylethanol- elenolic acid ( 1), and 3,4- dihydroxyphenyl-ethanolelenolic acid dialdehyde ( 2), in olive oil and oil- in- water emulsions stored at 60 degrees C were studied. All four phenolic compounds significantly extended the induction time of lipid oxidation in olive oil with the order of activity being hydroxytyrosol > compound 1 > compound 2 > oleuropein > alpha- tocopherol; but in the presence of Cu( II), the stability of oil samples containing phenolic compounds decreased by at least 90%, and the antioxidant activity of hydroxytyrosol and compounds 1 and 2 became similar. In oil- in- water emulsions prepared from olive oil stripped of tocopherols, hydroxytyrosol enhanced the prooxidant effect of copper at pH 5.5 but not at pH 7.4. The stability of samples containing copper at pH 5.5 was not significantly different if oleuropein was present from that of the control. Oleuropein at pH 7.4, and compounds 1 and 2 at both pH values tested, reduced the prooxidant effect of copper. The lower stability and the higher reducing capacity of all compounds at pH 7.4 could not explain the higher stability of emulsions containing phenolic compounds at this pH value. However, mixtures containing hydroxytyrosol or oleuropein with copper showed higher 1,1-diphenyl- 2- picrylhydrazyl radical scavenging activity at pH 7.4 than at pH 5.5. Moreover, the compound 2- copper complex showed higher radical scavenging activity then the uncomplexed compound at pH 5.5. It can be concluded that the formation of a copper complex with radical scavenging activity is a key step in the antioxidant action of the olive oil phenolic compounds in an emulsion containing copper ions.

Characterization of the phytochemicals and antioxidant properties of extracts from Teaw (Cratoxylum formosum Dyer)

The leaves of the Thai vegetable, Teaw (Cratoxylum formosum Dyer) were extracted with ethanol to provide an extract that had antioxidant properties. The composition of the extract was studied by high-performance liquid chromatography with a diode array detector, and by electrospray ionization mass spectrometry. The main antioxidant component (peak 1) was chlorogenic acid, which was present at 60% of the extract. Three minor components were present at 7%, 3% and 2%, and other components that were present at lower concentrations were also observed. Treatment of the Teaw extract with 2,2-diphenyl-1-picrylhydrazyl radical (DPPH center dot) caused a similar reduction in peak area of 55.2-58.1% for chlorogenic acid and the three minor components, indicating that these components had common structural features. Component 2 was identified as dicaffeoylquinic acid, and compounds 3 and 4 were identified as ferulic acid derivatives. The radical-scavenging activity of the Teaw extract was compared with alpha-tocopherol, BHT and chlorogenic acid, using the DPPH center dot and 2,2'-azinobis (3-ethylbenzothialozinesulfonic acid) radical cation (ABTS(center dot+)) assays. The Teaw extract scavenged both free radicals more strongly than did a-tocopherol and BHT, and the activity of the extract was consistent with the concentration of chlorogenic acid that was present, confirming that this component is a major contributor to the antioxidant activity. The acute toxicity of the Teaw leaf extract was investigated in mice, and it was found that the LD50 of the extract was > 32 g/kg. Consequently, this plant is a promising source of a natural food antioxidant. (c) 2006 Elsevier Ltd. All rights reserved.

Electron spin resonance study of puff-resolved free radical formation in mainstream cigarette smoke

Puff-by-puff resolved gas phase free radicals were measured in mainstream smoke from Kentucky 2R4F reference cigarettes using ESR spectroscopy. Three spin-trapping reagents were evaluated: PBN, DMPO and DEPMPO. Two procedures were used to collect gas phase smoke on a puff-resolved basis: i) the accumulative mode, in which all the gas phase smoke up to a particular puff was bubbled into the trap (i.e., the 5th puff corresponded to the total smoke from the 1st to 5th puffs). In this case, after a specified puff, an aliquot of the spin trap was taken and analysed; or, ii) the individual mode, in which the spin trap was analysed and then replaced after each puff. Spin concentrations were determined by double-integration of the first derivative of the ESR signal. This was compared with the integrals of known standards using the TEMPO free radical. The radicals trapped with PBN were mainly carbon-centred, whilst the oxygen-centred radicals were identified with DMPO and DEPMPO. With each spin trap, the puff-resolved radical concentrations showed a characteristic pattern as a function of the puff number. Based on the spin concentrations, the DMPO and DEPMPO spin traps showed better trapping efficiencies than PBN. The implication for gas phase free radical analysis is that a range of different spin traps should be used to probe complex free radical reactions in cigarette smoke.

Constituents of the Leaves of Magnolia ovata

Two new lignans, magnovatins A (1) and B (2), along with nine known compounds, were isolated from the leaves of Magnolia ovata. The known compounds were identified as acuminatin (3), licarin A (4), kadsurenin M, 4-O-demethylkadsurenin M, oleiferin A, oleiferin C, spathulenol, parthenolide, and 11,13-dehydrocompressanolide. In addition, compounds I and 2 yielded four new derivatives (1a, 1b, 2a, and 2b). The structures of the new compounds were established on the basis of spectrometric data evaluation. Free-radical scavenging and antimicrobial activities of the major compounds 1, 3, and 4 were investigated.