Unifying Electrostatic Mechanism for Metal Cations in Receptors and Cell Signaling

Resveratrol (RVT) is a naturally occurring trihydroxy stilbene that displays a wide spectrum of physiological activity. Its ability to behave therapeutically as a component of red wine has attracted wide attention. The phenol acts as a protective agent involving various body constituents. Most attention has been given to beneficial effects in insults involving cancer, aging, cardiovascular system, inflammation and the central nervous system. One of the principal modes of action appears to be as antioxidant. Other mechanistic pathways entail cell signaling, apoptosis and gene expression. There is an intriguing dichotomy in relation to pro-oxidant property. Also discussed are metabolism, receptor binding, rationale for safety and suggestions for future work. This is the first comprehensive review of RVT based on a broad, unifying mechanism.

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“…Discussion is present in recent reviews on receptor-ligand activity,108 phosphates and sulfates109 and metal cations 110…”

Section: Cell Signalingmentioning

confidence: 99%

Multifaceted Approach to Resveratrol Bioactivity: Focus on Antioxidant Action, Cell Signaling and Safety

Kovacic

Somanathan

2010

Oxidative Medicine and Cellular Longevity

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“…Metals such as iron, copper, chromium, manganese and cobalt are capable of redox cycling in which a single electron may be accepted or donated by the metal. These actions catalyse reactions that play critical roles in the function of many organisms but may also produce reactive radicals and reactive oxygen species [31][32][33][34].…”

Section: Divalent Metal Cationsmentioning

confidence: 99%

The interplay between iron, haem and manganese in Porphyromonas gingivalis

Butler

Dashper

Khan

et al. 2015

Journal of Oral Biosciences

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a b s t r a c tBackground: Transition metals including iron and manganese are necessary for life because of their ability to donate and accept electrons. Approximately one-third of all proteins require essential transition metal ions to perform catalytic, structural and regulatory functions. These essential metal ions react differently to the presence of oxygen radicals with iron directly involved in the formation of toxic reactive oxygen species, whilst manganese can protect against oxidative stress. Highlight: Anaerobic bacterial species have been poorly studied with regard to transition metal homoeostasis and behave differently in many respects when compared with aerobic or aerotolerant species. To optimise catabolism whilst protecting themselves from unwanted reactions bacterial cells must maintain intracellular metal levels in a very narrow range that varies, dependent on the environment. To maintain metal ion homoeostasis, bacteria have evolved complex regulatory mechanisms of metal uptake, secretion and storage. In this review we examine how iron, haem and manganese availability dictate the lifestyle and virulence of the anaerobic Gram-negative, periodontal pathogen Porphyromonas gingivalis. Conclusion: P. gingivalis has novel haem, iron and manganese transporters and metalloregulatory proteins that enable it to switch rapidly between an energy efficient iron-dependent virulent phase and a protective manganese-dependent survival phase.

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“…Energetics and bridging may be important actors. Application is also made to phosphate and sulfate anions in cell signaling,18 as well as to metal cations, such as Ca, Mg, Zn, Fe and Cu 19. There is appreciable research dealing with MEP in relation to DNA chemistry 20.…”

Section: Introductionmentioning

confidence: 99%

Zolpidem, A Clinical Hypnotic that Affects Electronic Transfer, Alters Synaptic Activity Through Potential Gaba Receptors in the Nervous System Without Significant Free Radical Generation

Kovacic

Somanathan

2009

Oxidative Medicine and Cellular Longevity

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Zolpidem (trade name Ambien) has attracted much interest as a sleep-inducing agent and also in research. Attention has been centered mainly on receptor binding and electrochemistry in the central nervous system which are briefly addressed herein. A novel integrated approach to mode of action is presented. The pathways to be discussed involve basicity, reduction potential, electrostatics, cell signaling, GABA receptor binding, electron transfer (ET), pharmacodynamics, structure activity relationships (SAR) and side effects. The highly conjugated pyridinium salt formed by protonation of the amidine moiety is proposed to be the active form acting as an ET agent. Extrapolation of reduction potentials for related compounds supports the premise that zolpidem may act as an ET species in vivo. From recent literature reports, electrostatics is believed to play a significant role in drug action.The pyridinium cation displays molecular electrostatic potential which may well play a role energetically or as a bridging mechanism. An SAR analysis points to analogy with other physiologically active xenobiotics, namely benzodiazepines and paraquat in the conjugated iminium category. Inactivity of metabolites indicates that the parent is the active form of zolpidem. Absence of reactive oxygen species and oxidative stress is in line with minor side effects. In contrast, generally, the prior literature contains essentially no discussion of these fundamental biochemical relationships. Pharmacodynamics may play an important role. Concerning behavior at the blood-brain barrier, useful insight can be gained from investigations of the related cationic anesthetics that are structurally related to acetyl choline. Evidently, the neutral form of the drug penetrates the neuronal membrane, with the salt form operating at the receptor. The pathways of zolpidem have several clinical implications since the agent affects sedation, electroencephalographic activity, oxidative metabolites and receptors in the central nervous system. The drug acts at the GABA(A) receptor benzodiazepine site, displaying high and intermediate affinities to various receptor regions. Structural features for tight binding were determined. The sedative and anticonvulsant activities are due to its action on the alpha-1-GABA(A) receptors. One of the common adverse responses to zolpidem is hallucinations. Proposed mechanisms comprise changes in the GABA(A) receptor, pharmacodynamic interactions involving serotonin and neuronal-weak photon emission processes entailing redox phenomena. Reports cite cases of abuse with cravings based on anxiolytic and stimulating actions. It is important to recognize that insight concerning processes at the fundamental, molecular level can translate into beneficial results involving both positive and adverse side effects. In order for this to occur, interdisciplinary interaction is necessary. Suggestions are made for future research aimed at testing the various hypotheses.

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Unifying Electrostatic Mechanism for Metal Cations in Receptors and Cell Signaling

Cited by 17 publications

References 47 publications

Multifaceted Approach to Resveratrol Bioactivity: Focus on Antioxidant Action, Cell Signaling and Safety

Multifaceted Approach to Resveratrol Bioactivity: Focus on Antioxidant Action, Cell Signaling and Safety

The interplay between iron, haem and manganese in Porphyromonas gingivalis

Zolpidem, A Clinical Hypnotic that Affects Electronic Transfer, Alters Synaptic Activity Through Potential Gaba Receptors in the Nervous System Without Significant Free Radical Generation

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