Redox cycling of quinones reduced by ascorbic acid.

In aqueous solutions containing ascorbic acid and O2, many quinones undergo reduction to the semiquinone followed by reoxidation. This redox cycling mediates the oxidation of ascorbic acid and the reduction of O2 to superoxide and ultimately hydrogen peroxide. For that reason, redox cycling has attracted attention as a source of reactive oxygen species. This redox cycling is paradoxical, however, because the one-equivalent reduction potentials of the reactants are unfavorable, so the concentrations of the products, monodehydroascorbate and superoxide, must be kept extremely low. Disproportionation is not fast enough to eliminate these products. We have investigated the mechanism of ascorbate-driven redox cycling by monitoring the redox status of the quinone and the rate of redox cycling in parallel. Evidence is presented for a mechanism in which monodehydroascorbate is oxidized by the semiquinone. The result is that cycling of the semiquinone and hydroquinone mediates a rapid disproportionation of monodehydroascorbate. This mechanism accounts for the dependence of the redox cycling rate on quinone and ascorbate concentrations as well as on the reduction potential of the quinone. Therefore, it predicts how fast ascorbate-driven redox cycling will generate hydrogen peroxide under a variety of conditions and with different quinones.

Manganese-stimulated redox cycling of dopamine derivatives: Implications for manganism.

Manganism, the condition caused by chronic exposure to high levels of manganese, selectively targets the dopamine-rich basal ganglia causing a movement disorder with symptoms similar to Parkinson's disease. While the basis for this specific targeting is unknown, we hypothesize that it may involve complexation of Mn by dopamine derivatives. At micromolar concentrations, MnCl2 accelerates the two-equivalent redox cycling of a dopamine-derived benzothiazine (dopathiazine) by an order of magnitude. In the process, O2 is reduced to superoxide and hydrogen peroxide. This effect is unique to Mn and is not shared by Fe, Cu, Zn, Co, Ca or Mg. Notably, the effect of Mn requires the presence of inorganic phosphate, suggesting that phosphate may stabilize a Mn/catecholate complex, which reacts readily with O2. This or similar endogenous dopamine derivatives may exacerbate Mn-dependent oxidative stress accounting for the neurological selectivity of manganism.

Ascorbic acid: The chemistry underlying its antioxidant properties.

Ascorbic acid (vitamin C) is an unusual antioxidant in that it donates a single reducing equivalent, and the radical it forms, monodehydroascorbate, reacts preferentially with radicals instead of with non-radical compounds. This happens because removal of an electron from monodehydroascorbate would create a tricarbonyl structure that is energetically unfavored. Instead of forming this structure, ascorbic acid oxidizes only to monodehydroascorbate, and monodehydroascorbate reacts with other radicals, oxidizing by mechanisms that may circumvent formation of this unfavored structure. Ironically, this tricarbonyl compound, which we suggest be called pseudodehydroascorbate, is commonly and mistakenly cited as the real product of ascorbic acid oxidation. In fact, it has been known for over 40 years that dehydroascorbate has a bicyclic hemiketal structure, and kinetic considerations suggest that it may be produced and reduced without forming pseudodehydroascorbate as an intermediate. This and other significant questions about the chemical basis of the antioxidant properties of ascorbic acid are obscured by this misconception about its oxidation product, dehydroascorbate.

Are Proteinopathy and Oxidative Stress Two Sides of the Same Coin?

Parkinson's disease, like other neurodegenerative diseases, exhibits two common features: Proteinopathy and oxidative stress, leading to protein aggregation and mitochondrial damage respectively. Because both protein aggregates and dysfunctional mitochondria are eliminated by autophagy, we suggest that inadequate clearance may couple the two phenomena. If a neuron's autophagy machinery is overwhelmed, whether by excessive oxidative stress or by excessive protein aggregation, protein aggregates and dysfunctional mitochondria will both accumulate. Parkinson's disease may provide a unique window into this because there is evidence that both sides contribute. Mutations amplifying the aggregation of α-synuclein are associated with Parkinson's disease. Likewise, mutations in Parkin and PINK1, proteins involved in mitophagy, suggest that impaired mitochondrial clearance is also a contributing factor. Many have suggested that dopamine oxidation products lead to oxidative stress accounting for the dopaminergic selectivity of the disease. We have presented evidence for the specific involvement of hypochlorite-oxidized cysteinyl-dopamine (HOCD), a redox-cycling benzothiazine derivative. While toxins like 6-hydroxydopamine and 1-methyl-4-phenyl pyridinium (MPP+) have been used to study mitochondrial involvement in Parkinson's disease, HOCD may provide a more physiologically relevant approach. Understanding the role of mitochondrial dysfunction and oxidative stress in Parkinson's disease and their relation to α-synuclein proteinopathy is important to gain a full picture of the cause, especially for the great majority of cases which are idiopathic.

A theoretical study of ascorbic acid oxidation and HOO˙/O2˙- radical scavenging.

Ascorbic acid is a well-known antioxidant and radical scavenger. It can be oxidized by losing two protons and two electrons, but normally loses only one electron at a time. The reactivity of the ascorbate radical is unusual, in that it can either disproportionate or react with other radicals, but it reacts poorly with non-radical species. To explore the oxidation mechanism of ascorbic acid, the pKa's and reduction potentials have been calculated using the B3LYP/6-31+G(d,p) and CBS-QB3 levels of theory with the SMD implicit solvent model and explicit waters. Calculations show that the most stable form of dehydroascorbic acid in water is the bicyclic hydrated structure, in agreement with NMR studies. The possible oxidation reactions at different pH conditions can be understood by constructing a potential-pH (Pourbaix) diagram from the calculated pKa's and standard reduction potentials. At physiological pH disproportionation of the intermediate radical is thermodynamically favored. The calculations show that disproportionation proceeds via dimerization of ascorbate radical and internal electron transfer, as suggested by Bielski. In the dimer, one of the ascorbate units cyclizes. Then protonation and dissociation yields the fully reduced and bicyclic fully oxidized structures. Calculations show that this mechanism also explains the reaction of the ascorbic acid radical with other radical species such as superoxide. Ascorbate radical combines with the radical, and intramolecular electron transfer followed by cyclization and hydrolysis yields dehydroascorbic acid and converts the radical to its reduced form.

Hypochlorite converts cysteinyl-dopamine into a cytotoxic product: A possible factor in Parkinson's Disease.

The dopamine oxidation product cysteinyl-dopamine has attracted attention as a contributor to the death of dopaminergic neurons in Parkinson's disease. Treatment of cysteinyl-dopamine with hypochlorite yields an even more cytotoxic product. This product has potent redox-cycling activity and initiates production of superoxide in PC12 cells. Taurine, which scavenges hypochlorite, protects PC12 cells from cysteinyl-dopamine but not from the hypochlorite product, suggesting that the product, not cysteinyl-dopamine itself, is toxic. Furthermore, rotenone, which enhances expression of the hypochlorite-producing enzyme myeloperoxidase, increases the cytotoxicity of cysteinyl-dopamine but not of the hypochlorite product. This suggests that dopamine oxidation to cysteinyl-dopamine followed by hypochlorite-dependent conversion to a cytotoxic redox-cycling product leads to the generation of reactive oxygen species and oxidative stress and may contribute to the death of dopaminergic neurons.

Religious identification as a moderator of evolved sexual strategies of men and women.

Buss and Schmitt (1993) found empirical support for their Sexual Strategies Theory hypothesis of evolved sex differences in mating attitudes. This study hypothesized that religiosity would moderate those sex differences. Specifically, it was predicted that men high and low in religiosity would differ in mating attitudes, but it was expected that there would be fewer differences between women high and low in religiosity because of evolved preferences for longer term, more committed relationships. In Study 1, 219 college students completed questionnaires that included a single-item indicator of religiosity and short-term and long-term mating desires. Religiosity moderated sex differences in some mating preferences. In Study 2, 234 college student participants (mean age, 19.1 years) completed measures from Study 1 plus a measure of three types of religiosity: intrinsic (religion as a valuable end in itself), extrinsic (religion as a means to an end), and quest (religion as a means of questioning and doubting; Revised Religious Life Inventory-Hills, Francis, & Robbins, 2005). Intrinsic religiosity, but not extrinsic or quest, moderated sex differences in mating attitudes, especially attitudes regarding number of sexual partners in the short term. These results provide evidence that intrinsic religiosity is an individual difference variable that qualifies the differences in mating strategies hypothesized in Sexual Strategies Theory.

Need for cognition as a predictor of psychosocial identity development.

The authors examined the hypothesis that psychosocial identity development is related to need for cognition (NFC), a social-cognitive individual-difference variable defined as the desire to engage in effortful thinking (J. T. Cacioppo, R. E. Petty, J. Feinstein, & W. Jarvis, 1996). They administered 2 measures of psychosocial identity-a scale from the Extended Objective Measure of Ego Identity Status 2 (EOMEIS-2; G. R. Adams, L. Bennion, & K. Huh, 1989) and the Identity subscale of the Erikson Psychosocial Stage Inventory (EPSI; D. A. Rosenthal, R. M. Gurney, & S. M. Moore, 1981)-and the NFC scale to 200 incoming college students and approximately half of those students about 15 months later. Results indicate that people with higher psychosocial identity levels had higher NFC scores at both time periods. In addition, higher Time 1 NFC scores were related to higher Time 2 EOMEIS-2 achieved scores and lower Time 2 foreclosure and diffusion scores, and changes in NFC over the course of the study were positively correlated with EPSI changes and negatively correlated with changes in EOMEIS-2 foreclosure and diffusion scores. Results provide support for the importance of a cognitive and motivational individual-difference variable in the development of a unique and cohesive identity.

The epinephrine assay for superoxide: why dopamine does not work.

Superoxide oxidizes epinephrine to a semiquinone, initiating a series of reactions leading to the colored product adrenochrome. This popular assay for superoxide is more sensitive at higher pH, and it does not work if dopamine is used instead of epinephrine. A kinetic analysis shows that these effects can be explained by competing reactions that lower the yield of the observed product. The catecholamine quinone may cyclize to form the absorbing product, or it may be reduced back to the semiquinone by superoxide. For epinephrine, the quinone cyclizes quickly and adrenochrome formation dominates, but for dopamine, the quinone cyclizes slowly and the back reaction prevails. The yield of adrenochrome increases if the epinephrine semiquinone reacts with O(2) to form more superoxide, but this reaction competes with disproportionation of the semiquinone. Because disproportionation slows as pH increases, both superoxide formation and the yield of adrenochrome increase at higher pH.

Oxidation of 4-methylcatechol: implications for the oxidation of catecholamines.

At alkaline pH, 4-methylcatechol oxidizes more rapidly than the related catecholamines: dopamine, norepinephrine, and epinephrine. This oxidation is not inhibited by superoxide dismutase or catalase, indicating that O2 itself is the oxidant, but the reduction potential of O2/O2-* is too low for it to oxidize 4-methylcatechol directly. Instead, O2 oxidizes the 4-methylcatechol semiquinone, which is formed by comproportionation of 4-methylcatechol and its o-quinone. Aniline reacts very quickly with the o-quinone and thus stops the comproportionation reaction that oxidizes 4-methylcatechol to the semiquinone. Oxidation of 4-methylcatechol then requires superoxide, and in the presence of aniline, oxidation of 4-methylcatechol by O2 is inhibited by superoxide dismutase. When catecholamines oxidize, the side chain amine inserts into the catechol o-quinone, forming a bicyclic compound. By eliminating the quinone, this ring closure prevents comproportionation and the consequent oxidation of catecholamines by O2. It also prevents reaction of the quinone with other compounds and the formation of potentially toxic products.

Clicker evolution: seeking intelligent design.

Two years after the first low-cost radio-frequency audience response system using clickers was introduced for college classrooms, at least six different systems are on the market. Their features and user-friendliness are evolving rapidly, driven by competition and improving technology. The proliferation of different systems is putting pressure on universities to standardize or otherwise limit the number of different clickers a student is expected to acquire. To facilitate that choice, the strengths and weaknesses of six systems (eInstruction Classroom Performance System, Qwizdom, TurningPoint, Interwrite PRS, iClicker, and H-ITT) are compared, and the factors that should be considered in making a selection are discussed. In our opinion, the selection of a clicker system should be driven by the faculty, although students and the relevant teaching and technology support units of the university must also participate in the dialogue. Given the pace of development, it is also wise to reconsider the choice of a clicker system at regular intervals.

Imidazole facilitates electron transfer from organic reductants.

In cyclic voltammetry studies at pH 8, imidazole facilitates oxidation of organic compounds that normally lose hydrogen atoms. High concentrations of imidazole shift the oxidizing wave of ascorbic acid, 2,3-dimethoxy-5-methyl-1,4-hydroquinone, and the vitamin E analogue Trolox toward lower potentials. By contrast, imidazole has no effect on the cyclic voltammogram of methyl viologen, which undergoes electron rather than hydrogen-atom transfer. The effect of imidazole is observed at pH 8.0 but only to a lesser extent at pH 5.5 indicating that imidazole must be unprotonated to facilitate oxidation. Digital simulation shows that these results are consistent with a mechanism in which imidazole acts as a proton acceptor permitting concerted proton/electron transfer by the organic reductant.