An Essential Difference between the Flavonoids MonoHER and Quercetin in Their Interplay with the Endogenous Antioxidant Network

Antioxidants can scavenge highly reactive radicals. As a result the antioxidants are converted into oxidation products that might cause damage to vital cellular components. To prevent this damage, the human body possesses an intricate network of antioxidants that pass over the reactivity from one antioxidant to another in a controlled way. The aim of the present study was to investigate how the semi-synthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER), a potential protective agent against doxorubicin-induced cardiotoxicity, fits into this antioxidant network. This position was compared with that of the well-known flavonoid quercetin. The present study shows that the oxidation products of both monoHER and quercetin are reactive towards thiol groups of both GSH and proteins. However, in human blood plasma, oxidized quercetin easily reacts with protein thiols, whereas oxidized monoHER does not react with plasma protein thiols. Our results indicate that this can be explained by the presence of ascorbate in plasma; ascorbate is able to reduce oxidized monoHER to the parent compound monoHER before oxidized monoHER can react with thiols. This is a major difference with oxidized quercetin that preferentially reacts with thiols rather than ascorbate. The difference in selectivity between monoHER and quercetin originates from an intrinsic difference in the chemical nature of their oxidation products, which was corroborated by molecular quantum chemical calculations. These findings point towards an essential difference between structurally closely related flavonoids in their interplay with the endogenous antioxidant network. The advantage of monoHER is that it can safely channel the reactivity of radicals into the antioxidant network where the reactivity is completely neutralized

Connecting West and East

Despite their similarities, Western medicine and Eastern medicine are very different because they are built on different fundamentals. The general idea has arisen that we will benefit by connecting Western and Eastern medicine. First, both the merits as well as the limitations of both types of medicine are discussed. It was concluded that to create a bridge, we should focus on similarities that inspire the further unravelling of the molecular mechanism of the mode of action and toxicity of Traditional Chinese Medicine. It is suggested that the energy perspective provides a basis to integrate Eastern and Western medicine

Competition between Ascorbate and Glutathione for the Oxidized Form of Methylated Quercetin Metabolites and Analogues: Tamarixetin, 4'O-Methylquercetin, Has the Lowest Thiol Reactivity

Quercetin (Q) is a bioactive compound with excellent antioxidant activity. However, the thiol reactivity of its oxidation product (oxQ) forms a disadvantage. The aim of the present study was to decrease this thiol toxicity. We found that methylated Q metabolites displayed lower thiol reactivity than Q. The most effective was tamarixetin, 4'O-methylquercetin (4'MQ), that has a corresponding oxidation product (ox4'MQ) with thiol reactivity 350 times lower than oxQ. The endogenous metabolism of Q to 4'MQ might be a physiological way to safely benefit from the antioxidant potential of Q in vivo. Our results were explained with Pearson's HSAB concept and corroborated by quantum molecular calculations that revealed a strong correlation between the relative thiol reactivity and the lowest unoccupied molecular orbital (LUMO). The polarity of the molecule and the pi-pi interaction between the AC- and the B-ring appeared to determine the LUMO and the thiol reactivity of the oxidation product

Delocalization of the Unpaired Electron in the Quercetin Radical: Comparison of Experimental ESR Data with DFT Calculations

In the antioxidant activity of quercetin (Q), stabilization of the energy in the quercetin radical (Q(center dot)) by delocalization of the unpaired electron (UE) in Q(center dot) is pivotal. The aim of this study is to further examine the delocalization of the UE in Q(center dot), and to elucidate the importance of the functional groups of Q for the stabilization of the UE by combining experimentally obtained spin resonance spectroscopy (ESR) measurements with theoretical density functional theory (DFT) calculations. The ESR spectrum and DFT calculation of Q(center dot) and structurally related radicals both suggest that the UE of Q(center dot) is mostly delocalized in the B ring and partly on the AC ring. The negatively charged oxygen groups in the B ring (3 ' and 4 ') of Q(center dot) have an electron-donating effect that attract and stabilize the UE in the B ring. Radicals structurally related to Q(center dot) indicate that the negatively charged oxygen at 4 ' has more of an effect on concentrating the UE in ring B than the negatively charged oxygen at 3 '. The DFT calculation showed that an OH group at the 3-position of the AC ring is essential for concentrating the radical on the C2-C3 double bond. All these effects help to explain how the high energy of the UE is captured and a stable Q(center dot) is generated, which is pivotal in the antioxidant activity of Q

Slippage of a porphyrin macrocycle over threads of varying bulkiness: Implications for the mechanism of threading polymers through a macrocyclic ring

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Flavonoids Seen through the Energy Perspective

In all life forms, opposing forces provide the energy that flows through networks in an organism, which fuels life. In this concept, health is the ability of an organism to maintain the balance between these opposing forces, which creates resilience, and a deranged flow of energy is the basis for diseases. Treatment should focus on adjusting the deranged flow of energy, e.g., by the redox modulating activity of antioxidants. A major group of antioxidants is formed by flavonoids, a group of polyphenolic compounds abundantly present in our diet. The objective here is to review how the redox modulation by flavonoids fits in the various concepts on the mode of action of bioactive compounds, so we can ‘see’ where there is overlap and where the missing links are. Based on this fundament, we should choose our research path aiming to ‘understand’ the redox modulating profile of specific flavonoids, so we can ultimately rationally apply the redox modulating power of flavonoids to improve our health

An essential difference in the reactivity of the glutathione adducts of the structurally closely related flavonoids monoher and quercetin

During the scavenging of free radicals flavonoids are oxidized to electrophilic quinones. Glutathione (GSH) can trap these quinones, thereby forming GSH-flavonoid adducts. The aim of this study was to compare the stability of the GSH-flavonoid adduct of 7-mono-O-(beta-hydroxyethyl)rutoside (monoHER) with that of quercetin. It was found that GSH-quercetin reacts with the thiol N-acetyl-l-cysteine (NAC) to form NAC-quercetin, whereas GSH-monoHER does not react with NAC. In addition, the adduct of the monoHER quinone with the dithiol dithiothreitol (DTT) is relatively stable, whereas the DTT-quercetin adduct is readily converted into quercetin and DTT disulfide. These differences in reactivity of the thiol-flavonoid adducts demonstrate that GSH-monoHER is much more stable than GSH-quercetin. This difference in reactivity was corroborated by molecular quantum chemical calculations. Thus, although both flavonoid quinones are rapidly scavenged by GSH, the advantage of monoHER is that it forms a stable conjugate with GSH, thereby preventing a possible spread of toxicity. These findings demonstrate that even structurally comparable flavonoids behave differently, which will be reflected in the biological effects of these flavonoids