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Possible Mechanisms of Fullerene C60 Antioxidant Action

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Possible Mechanisms of Fullerene C60 Antioxidant Action

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Novel mechanism of antioxidant activity of buckminsterfullerene C60 based on protons absorbing and mild uncoupling of mitochondrial respiration and phosphorylation was postulated. In the present study we confirm this hypothesis using computer modeling based on Density Functional Theory. Fullerene's geroprotective activity is sufficiently higher than those of the most powerful reactive oxygen species scavengers. We propose here that C60 has an ability to acquire positive charge by absorbing inside several protons and this complex could penetrate into mitochondria. Such a process allows for mild uncoupling of respiration and phosphorylation. This, in turn, leads to the decrease in ROS production.
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BioMed Research International
Volume , Article ID , pages
http://dx.doi.org/.//
Research Article
Possible Mechanisms of Fullerene C60 Antioxidant Action
V. A. Chistyakov,1Yu. O. Smirnova,2,3 E. V. Prazdnova,1and A. V. Soldatov2
1Research Institute of Biology, Southern Federal University, Rostov-on-Don 344090, Russia
2Research Center for Nanoscale Structure of Matter, Southern Federal University, Rostov-on-Don 344090, Russia
3Department of Physics, Purdue University, West Lafayette, IN 47907, USA
Correspondence should be addressed to Yu. O. Smirnova; ysmirnov@purdue.edu
Received  June ; Revised  August ; Accepted  September 
Academic Editor: Claiton Leonetti Lencina
Copyright ©  V. A. Chistyakov et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Novel mechanism of antioxidant activity of buckminsterfullerene C60 based on protons absorbing and mild uncoupling of
mitochondrial respiration and phosphorylation was postulated. In the present study we conrm this hypothesis using computer
modeling based on Density Functional eory. Fullerenes geroprotective activity is suciently higher than those of the most
powerful reactive oxygen species scavengers. We propose here that C60 has an ability to acquire positive charge by absorbing inside
several protons and this complex could penetrate into mitochondria. Such a process allows for mild uncoupling of respiration and
phosphorylation. is, in turn, leads to the decrease in ROS production.
1. Introduction
Reactive oxygen species (ROS) are able to cause oxidative
damage to DNA, lipids, and proteins and are known to
be the key regulators of cellular signaling. In spite of the
criticismfromanumberofresearchers[] free-radical theory
occupies a pivotal position in modern biological concepts
of aging []. e ability to retard senescence is typical for
many antioxidants []. Well-known ability of fresh vegeta-
bles, fruits, red wines, and spices to stimulate longevity is
largely determined by the existence of compounds such as
deprotonated xanthones [], carotenoids [], anthocyanins
and pyranoanthocyanins [], and avonoids and terpenoids
[]. ese compounds exhibit a broad spectrum of oxyradical
quenching activity based on reactions of single electron
transfer, hydrogen atom transfer, sequential electron proton
transfer, proton coupled electron transfer, radical adduct
formation, and iron chelation [,].
IntherecentstudyBaatietal.[] showed that the oral
administration of the fullerene C60 suspension in olive oil
retards senescence of rats. Herewith, median and maximum
life span increase approximately twice. Moreover, it was
shown that rats treated with fullerene C60 demonstrated high
resistance to carbon tetrachloride. Toxicity of this substance
is mediated by ROS generation []. According to this fact and
results of biochemical tests fullerene C60 was proposed to be
of high antioxidant activity in vivo. Due to the free-radical
theory of aging, highly active antioxidant activity can be the
basis for unique antiaging (geroprotective) properties.
Fullerene C60 isknowntobeabletoinactivatehydroxyl
radicals by attaching to double bonds []. However, this
mechanism cannot explain sucient (near two times) incre-
ase in lifespan of rats. Such kind of antioxidative activity is
also attributed to natural phenolic antioxidants that do not
possess high senescence retarding activity []. We propose
that there is an additional mechanism involved in fullerene
anti-aging activity. Respiratory chain located in the inner
mitochondrial membrane is the main source of superoxide
anion radicals, which lead to a cascade of other toxic ROS.
In this connection mitochondrial-targeted antioxidants like
lipophilic cations (Skulachev ions) with antioxidant load
[] are the most eective antiaging agents (geroprotectors)
among synthetic compounds.
Accumulation of Skulachev ions in the mitochondria is
based on the transmembrane potential dierence generated
asaresultofelectrontransportchainactivity.eouterside
of inner membrane of mitochondria has positive charge and
the inner side has negative charge. So, lipophilic cations are
concentrating in mitochondria via electric eld forces [].
BioMed Research International
(a) (b)
F : e results of DFT geometry optimization for one (a) and six (b) protons and fullerene. Initially protons were placed outside the
fullerene and then the conguration that has the minimum value of total energy was found as a result of DFT geometry optimization. As a
result, all protons appeared to be inside the fullerene. For the simulation, GGA-BLYP exchange-correlation potential was used. Carbon atoms
are shown in grey and protons are shown in black.
e lipophilic properties of fullerene C60 are well known [].
In addition, Wong-Ekkabut et al. showed using molecular
dynamics simulations []thatC
60 fullerene is capable of
penetrating into membrane and accumulates in the middle
of lipid bilayer. However, the simulation does not consider
the possible presence of fullerene and/or membrane charge.
We suppose that fullerene is capable of absorbing protons and
obtaining positive charge, which allows it to be delivered into
the mitochondria. us, superoxide anion-radical generation
is decreased by mild uncoupling of respiration and phos-
phorylation []. In the present study we perform theoretical
analysis of the fullerene C60 ability to acquire positive charge
and to absorb protons to prove that the proposed mechanism
indeed may take place.
2. Methods
All the computer simulations were performed within the
framework of Density Functional eory (DFT) for solving
Schr¨
odinger equation [], which has been used for the
investigation of antioxidants previously []. In the present
work, DFT implemented in ADF  code was used [].
Initially from one up to seven protons were placed outside the
fullerene and then the most probable atomic conguration
was found by minimizing the total energy of the system
during the process of geometry optimization, that is, nding
a stable conguration of the system that corresponds to
the minimum of total energy. For the exchange-correlation
part of molecule potential General Gradient Approximation
(GGA) was used in both GGA-BLYP [] and GGA-BLYP-
D [,] forms, but all nal results were obtained using
GGA-BLYP potential. Basis sets are DZ (double-𝜁)withinthe
calculations including water molecules around C60 and TZP
(triple-𝜁) within the calculations without taking into account
the water molecules around “C60 plus-protons” system.
3. Results
At rst step an interaction between single proton and
fullerene was simulated. e proton was placed outside the
C60 above one of the pentagons at the distance about  ˚
A
from the pentagon plane. As a result, the proton transfers
intothefullereneandnallyappearedtobeinsidethe
fullerene at a distance about . ˚
A from the nearest carbon
atom (Figure (a)). Next, more protons were added to this
system; some of them were initially placed above pentagons,
but most were placed above hexagons. e rst two protons
were placed at maximum possible distance from each other.
All others were equally distributed around the fullerene. In all
cases protons were “absorbed” by the fullerene, and it was so
until the seventh proton was added to the system—it repulsed
from the fullerene. So, the maximum amount of protons
inside the fullerene consists of six protons (Figure (b)).
It is crucial to know the distribution of charge over C60 for
each conguration of protons. Figure  shows the distribu-
tion for two, four, and six protons inside the fullerene. It can
be seen that when there are two protons inside the surface of
thefullerenehasalmostnocharge.Whenfourtosixprotons
are added the fullerene surface obtains positive charge.
Table  provides information about binding energies and
VDD charges [] for each proton added to the system. Both
charges on protons and relatively big C-H distances allow us
to suppose that protons interact with fullerene according to
donor-acceptor mechanism and do not form strong chemical
bonds.
It is important to know whether the presence of other
molecules near fullerene will impact the ability of protons
to penetrate into fullerene or not. For this purpose we
performed a simulation involving water molecules which are
themostcommoninorganisms.oughitisknownthat
in the presence of both protons and water hydronium ions
will appear, water molecules can be chosen. An exchange
of protons between hydronium ions takes place in such
environment, so for some small period of time protons are
free.
e simulation was carried out for a fullerene with single
proton placed above a pentagon and  water molecules
randomly distributed around the fullerene. It was shown
that solvent molecules do not inuence the capability of a
fullerene to absorb the proton.
BioMed Research International
0.200
0.150
0.100
0.0500
0.000
MDC-d charge
F : e distribution of charge for two, four, and six protons inside the fullerene. e charge of fullerene with two protons inside is
about zero (red color) while fullerenes that have four or six protons inside obtain positive charge (green and blue color). Protons lose their
positive charge starting from positive charge (blue color) to almost zero (orange color).
T : Binding energies and VDD charges for dierent amounts
of protons added to fullerene.
Number of
protons
Binding energy
values, eV
e Voronoi Deformation
Density (VDD)
 . .
..
.
 .
.
.
.
 .
.
.
.
.
 .
.
.
.
.
.
4. Discussion
AccordingtoourmodelfullereneC
60 accumulating in
mitochondria provides high radical scavenging activity in
this subcellular compartment, called by Skulachev the “dirt-
iest place in the cell” []. Another eective antioxidant
mechanism is based on mild uncoupling of respiration and
phosphorylation. Respiratory chain obtains electrons from
NADHandsuccinate.eyareusedforharmlessfour-
electron reduction of oxygen. But the transfer of one or two
electrons could produce the radicals that are dangerous to
cells (such as superoxide or peroxide anions).
e specic feature attributable to the generation of
ROS by mitochondria is related to the fact that the higher
is the membrane potential (the larger is the dierence in
the concentration of protons inside and outside the mito-
chondria), the higher is the level of the superoxide anion
production. As it was shown [], there is steep depen-
dence of mitochondrial superoxide-anion-radical generation
on transmembrane potential (Δ𝜓). Even a small (–%)
decline of Δ𝜓 resulted in tenfold lowering of ROS production
rate.
erefore, the so-called mild uncouplers of oxidative
phosphorylation are the substances which can move some
of the protons inside the mitochondria and can possess
an excellent oxygen-protective eect, although they are not
antioxidants in terms of chemistry [].
DFT simulations allowed us to propose the following
mechanism. C60 fullerene molecules enter the space between
inner and outer membranes of mitochondria, where the
excess of protons has been formed by diusion. In this com-
partment fullerenes are loaded with protons and acquire
positive charge distributed over their surface. Such “charge-
loaded” particles can be transferred through the inner mem-
brane of the mitochondria due to the potential dierence
generated by the inner membrane, using electrochemical
mechanism described in detail by Skulachev et al. [,]. In
this case the transmembrane potential is reduced, which in
turn signicantly reduces the intensity of superoxide anion-
radical production.
5. Conclusion
e proposed ability of C60 fullerenes to acquire positive
charge allows ascribing them to the mitochondrial-targeted
compounds. e key role of mitochondria in the cellular
regulation makes such “charge-loaded” fullerenes be of great
interest along the route for novel classes of drugs develop-
ment.
Authors’ Contribution
V. A. Chistyakov and Yu. O. Smirnova contributed equally to
this work.
Acknowledgments
e authors are grateful to Dr. V. S. Lysenko and Dr. Igor
Alperovich for valuable comments that improved the paper.
BioMed Research International
e support by Southern Federal University of Russia grants
is acknowledged.
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... Excess free radicals and oxidative stress are generally known to be detrimental to human health [11], and several diseases have been associated with increased levels of oxidative stress, including cancer, Alzheimer's disease, Parkinson's disease, inflammatory disorders, and asthma [6,12,13]. The antioxidant activities of fullerene C60 have been demonstrated in previous reports, showing that the antioxidant capacity of C60 is 125 times that of vitamin C, and the mechanism may be the REDOX reaction between ROS and fullerene molecules through direct electron transfer, such that ROS is finally decomposed [14,15]. It has been reported that fullerene-C60-treated rats have high resistance to CCl4, the toxicity of which is mediated by ROS production [16]. ...
... It has been reported that fullerene-C60-treated rats have high resistance to CCl4, the toxicity of which is mediated by ROS production [16]. Studies have shown that another mechanism of fullerene oxidation resistance is based on the mild decoupling of the respiratory chain and phosphorylation in the mitochondrial inner membrane [14]. ...
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Due to its unique redox chemistry, nanoceria is considered as potent free radical scavenger and antioxidant. However, their protective capacity in aging organisms remains controversial. To detect the anti-aging effects associated with the redox activity of 2 and 10 nm nano-CeO2, different test systems were used, including in vitro analysis, in situ assay of mitochondria function and in vivo studies of suitable nano-CeO2 on aging of male Wistar rats from 22 months-old to the end of life. The 2 nm nanoparticles exhibited not only antioxidant (·OH scavenging; chemiluminescence assay; decomposition of H2O2, phosphatidylcholine autooxidation) but also prooxidant properties (reduced glutathione and reduced nicotinamide adenine dinucleotide phosphate oxidation) as well as affected mitochondria whereas in most test systems 10 nm nano-CeO2 showed less activity or was inert. Prolonged use of the more redox active 2 nm nano-CeO2 (0.25–0.3 mg/kg/day) in vivo with drinking water resulted in improvement in physiological parameters and normalization of the prooxidant/antioxidant balance in liver and blood of aging animals. Survival analysis using Kaplan–Meier curve and Gehan tests with Yates' correction showed that by the time the prooxidant-antioxidant balance was assessed (32 months), survival rates exceeded the control values most considerably. The apparent median survival for the control rats was 900 days, and for the experimental rats—960 days. In general, the data obtained indicate the ability of extra-small 2 nm nano-CeO2 to improve quality of life and increase the survival rate of an aging organism.
... Another characteristic observed for CNMs is that they display strong antioxidant activity (Samadi et al., 2020). For example, sphereshaped fullerene C 60 is known to exhibit a robust antioxidant capacity and rich redox properties (Chistyakov et al., 2013;Injac et al., 2013). The analogs of fullerene, fullerols, were shown to be an excellent compound to trigger defense system of maize (Liu et al., 2016). ...
Article
Nanomaterial fullerene (FLN) has different responses called hormesis effect against stress conditions. The favorable/adverse impacts of hormesis on crop quality and productivity are under development in agrotechnology. In this study, the effect of FLN administration (100-250-500 mg L-1 for FLN1-2-3, respectively) on growth, water management, gas exchange, chlorophyll fluorescence kinetics and cobalt (Co)-induced oxidative stress in Zea mays was investigated. The negative alterations in relative growth rate (RGR), water status (relative water content, osmotic potential and proline content) and gas exchange/stomatal regulation were removed by FLNs. FLNs were shown to protect photosynthetic apparatus and preserve the photochemistry of photosystems (PSI-PSII) in photosynthesis, chlorophyll fluorescence transients and energy flux damaged under Co stress. The maize leaves exposed to Co stress exhibited a high accumulation of hydrogen peroxide (H2O2) due to insufficient scavenging activity, which was confirmed by reactive oxygen species (ROS)-specific fluorescence visualization in guard cells. FLN regulated the gene expression of ribulose-1,5-bisphosphate carboxylase large subunit (rbcL), nodulin 26-like intrinsic protein1-1 (NIP1-1) and tonoplast intrinsic protein2-1 (TIP2-1) under stress. After stress exposure, FLNs successfully eliminated H2O2 content produced by superoxide dismutase (SOD) activity of catalase (CAT) and peroxidase (POX). The ascorbate (AsA) regeneration was achieved in all FLN applications together with Co stress through the elevated monodehydroascorbate reductase (MDHAR, under all FLNs) and dehydroascorbate reductase (DHAR, only FLN1). However, dose-dependent FLNs (FLN1-2) provided the induced pool of glutathione (GSH) and GSH redox state. Hydroponically applied FLNs removed the restrictions on metabolism and biological process induced by lipid peroxidation (TBARS content) and excessive ROS production. Considering all data, the modulation of treatment practices in terms of FLN concentrations and forms of its application will provide a unique platform for improving agricultural productivity and stress resistance in crops. The current study provided the first findings on the chlorophyll a fluorescence transient and localization of ROS in guard cells of Zea mays exposed to FLN and Co stress.
... Thus, researchers are now trying to functionalize fullerenes with hydrophilic moieties to improve the water solubility for their potential applications such as antimicrobial, antiviral, and antioxidant agents. Fullerene is well known for its antioxidant activity [46,47]. Fullerene can scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS), which expand their usage in biomedical sector. ...
Chapter
Carbon is one of the essential elements in our world and is also one of the main building blocks of our body. From centuries, several forms of carbon-based materials such as carbon black, graphite, and coke have been used for drawing and writing. Other than these, carbon-based materials are also a key power source in the form of fossil fuel. However in the last two decades, researchers have explored various novel forms of carbon-based materials, especially in nanodimensions. These carbon-based nanomaterials (CBNs) include fullerene, carbon nanotubes, graphene, carbon nanodiamond, carbon quantum dots, etc. These CBNs have been considered as a novel class of material due to their exceptional physical and chemical properties, including mechanical, electrical, thermal, optical, and structural diversity. As a consequence, these CBNs have been extensively used in various industrial sectors, including catalysis, energy, electronics, sensing as well as biology. Especially in the last couple of years, a significant number of studies have been focused on biomedical applications of these CBNs. In this chapter, we have focused on various biomedical applications of these CBNs, including drug/gene delivery, bioimaging, tissue engineering, and biosensing. We also highlighted the biocompatibility of these CBNs both in vitro and in vivo. In conclusion, we also outlined the current challenges and future directions of these CBNs for bioapplications.
... Antioxidant effects of water-soluble carboxyfullerene have been proved in vivo [14]. The possibility of fullerenes acting as mitochondria protonophores allows them to be considered anti-aging antioxidants [15,16]. Hydroxylated Gd@C 82 has antineoplastic activity simultaneously with low toxicity [17,18]. ...
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Background: Fullerenes and metallofullerenes can be considered promising nanopharmaceuticals themselves and as a basis for chemical modification. As reactive oxygen species homeostasis plays a vital role in cells, the study of their effect on genes involved in oxidative stress and anti-inflammatory responses are of particular importance. Methods: Human fetal lung fibroblasts were incubated with aqueous dispersions of C60, C70, and Gd@C82 in concentrations of 5 nM and 1.5 µM for 1, 3, 24, and 72 h. Cell viability, intracellular ROS, NOX4, NFκB, PRAR-γ, NRF2, heme oxygenase 1, and NAD(P)H quinone dehydrogenase 1 expression have been studied. Results & conclusion: The aqueous dispersions of C60, C70, and Gd@C82 fullerenes are active participants in reactive oxygen species (ROS) homeostasis. Low and high concentrations of aqueous fullerene dispersions (AFD) have similar effects. C70 was the most inert substance, C60 was the most active substance. All AFDs have both "prooxidant" and "antioxidant" effects but with a different balance. Gd@C82 was a substance with more pronounced antioxidant and anti-inflammatory properties, while C70 had more pronounced "prooxidant" properties.
... Such charge-loaded particles could be transferred through the inner membrane of mitochondria. In this case, the transmembrane potential is reduced [33], significantly reducing SAR production [34]. Furthermore, C 60 is capable of penetrating an artificial lipid bilayer [35]. ...
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The antioxidant potential (capacity and activity) of aqueous fullerene dispersions (AFD) of non-functionalized C60, C70, and Gd@C82 endofullerene (in micromolar concentration range) was estimated based on chemiluminescence measurements of the model of luminol and generation of organic radicals by 2,2′-azobis(2-amidinopropane) dihydrochloride (ABAP). The antioxidant capacity was estimated by the TRAP method, from the concentration of half-suppression, and from the suppression area in the initial period. All three approaches agree and show that the antioxidant capacity of AFDs increased in the order Gd@C82 < C70 < C60. Mathematical modeling of the long-term kinetics data was used for antioxidant activity estimation. The effect of C60 and C70 is found to be quenching of the excited product of luminol with ABAP-generated radical and not an actual antioxidant effect; quenching constants differ insignificantly. Apart from quenching with a similar constant, the AFD of Gd@C82 exhibits actual antioxidant action. The antioxidant activity in Gd@C82 is 300-fold higher than quenching constants.
... Fullerenes and their derivatives are among one of the early developed nanozymes because in 1990s, itself fullerene was found as nuclease mimic (Maiti et al. 2019). Subsequently, many beneficial features of fullerene were discovered including antioxidant behavior (ability to scavenge free radicals) (Chistyakov et al. 2013;Hu et al. 2012). ...
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Such carbon structures as fullerenes, endofullerenes, nanotubes, nanodiamonds, and graphenes, which were discovered over recent decades, possess a number of unique properties and can become the basis for the design of a new class of neuroprotective agents; however, despite years of research, this has not happened yet. In the first part of the review, the significance of the functionalization of carbon nanoparticles for their use in biology and medicine is described, and the data on their toxicity are also discussed. The second part presents the works of Russian and foreign scientists demonstrating the neuroprotective properties of carbon nanoparticles and the possibilities of their application in neurobiology and neurology. The successful experience of such experiments is described and the existing problems are indicated.
Chapter
Basically the antioxidants activity follows mechanism based on the redox reactions. Redox reactions are very common in our day-to-day life. During the occurrence of various physiological reactions in our body, free radicals are also generated as inevitable by-products which may cause damage to our cells. Free radicals are generated through many pathways and promulgate through chain initiation to chain termination by the butting action of antioxidants. Neutralization of free radicals, ROS or RNS checks the oxidative damage and may operate in number of ways such as direct scavenging of free radicals, activating antioxidant enzymes, chelating metal catalysts, and inhibiting oxidases. At the molecular level, the operations are done through five known antioxidant mechanisms that can be used to describe the basis of various electron–proton transfer theories involving thermodynamic operators to describe antioxidant reactions.
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Background: Fullerenes and metallofullerenes can be considered promising nanopharmaceuticals themselves and as a basis for chemical modification. As reactive oxygen species homeostasis plays a vital role in cells, the study of their effect on genes involved in oxidative stress and anti-inflammatory response is of particular importance. Methods: Human fetal lung fibroblasts were incubated with aqueous dispersions of C60, C70, and Gd@C82 in concentrations of 5 nM and 1.5 µM for 1, 3, 24, and 72 hours. Cell viability, intracellular ROS, NOX4, NFκB, PRAR-γ, NRF2, heme oxygenase 1, and NAD(P)H quinone dehydrogenase 1 expression have been studied. Results & conclusion: The aqueous dispersions of C60, C70, and Gd@C82 fullerenes are active participants in ROS homeostasis. Low and high concentrations of AFDs have similar effects. C70 was the most inert substance, C60 was the most active substance. All AFDs have both a “prooxidant” and “antioxidant” effect, but with a different balance. Gd@C82 was a substance with more pronounced antioxidant and anti-inflammatory properties, while C70 had more pronounced “prooxidant” properties.
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Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated with decyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, is specifically targeted to mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. The respiratory chain also regenerates reduced SkQ1H2 from its oxidized form that appears as a result of the antioxidant activity of SkQ1H2. SkQ1H2 prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive to attack by reactive oxygen species (ROS). In cell cultures, SkQ1 and its analog plastoquinonyl decylrhodamine 19 (SkQR1) arrest H2O2-induced apoptosis. When tested in vivo, SkQs (i) prolong the lifespan of fungi, crustaceans, insects, fish, and mice, (ii) suppress appearance of a large number of traits typical for age-related senescence (cataract, retinopathies, achromotrichia, osteoporosis, lordokyphosis, decline of the immune system, myeloid shift of blood cells, activation of apoptosis, induction of β-galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissue damage and save the lives of young animals after treatments resulting in kidney ischemia, rhabdomyolysis, heart attack, arrhythmia, and stroke. We suggest that the SkQs reduce mitochondrial ROS and, as a consequence, inhibit mitochondriamediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast “biochemical suicide” of an organism after a severe metabolic crisis.
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Many insights into the mechanisms and signaling pathways underlying aging have resulted from research on the nematode Caenorhabditis elegans. In this paper, we discuss the recent findings that emerged using this model organism concerning the role of reactive oxygen species (ROS) in the aging process. The accrual of oxidative stress and damage has been the predominant mechanistic explanation for the process of aging for many years, but reviewing the recent studies in C. elegans calls this theory into question. Thus, it becomes more and more evident that ROS are not merely toxic byproducts of the oxidative metabolism. Rather it seems more likely that tightly controlled concentrations of ROS and fluctuations in redox potential are important mediators of signaling processes. We therefore discuss some theories that explain how redox signaling may be involved in aging and provide some examples of ROS functions and signaling in C. elegans metabolism. To understand the role of ROS and the redox status in physiology, stress response, development, and aging, there is a rising need for accurate and reversible in vivo detection. Therefore, we comment on some methods of ROS and redox detection with emphasis on the implementation of genetically encoded biosensors in C. elegans.
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We present a density functional theory (DFT) and time-dependent density functional theory (TD-DFT) study on the stability, antioxidant properties with respect to the single electron transfer mechanism, and electronic absorption spectra of some isomers (9-cis, 13-cis, and 15-cis) of carotenoids such as astaxanthin, lycopene, and those present in virgin olive oil (lutein, β-carotene, neoxanthin, antheraxanthin, violaxanthin, neochrome, luteoxanthin, mutatoxanthin, and violaxanthin). In general, the calculated relative stability of the cis isomers appears to be in line with experimental observations. It is predicted that the above-mentioned carotenoids (cis and trans isomers) will transfer one electron to the (•)OH radical. However, this transference is not plausible with radicals such as (•)OOH, (•)OC2H5, (•)OOC2H5, (•)NO2, and (•)OOCH2CH═CH2. On the other hand, some carotenoids (β-carotene, lycopene, lutein, astaxanthin, violaxanthin, and antheraxanthin) will likely accept, in a medium of low polarity, one electron from the radical (•)O2(-). However, neoxanthin, auroxanthin, mutatoxanthin, luteoxanthin, and neochrome would not participate in such an electronic transfer mechanism. The TD-DFT studies show that neutral species of the cis and trans isomers maintain the same color. On the contrary, the ionic species undergo a "bleaching" process where the absorption wavelengths shift to longer values (>700 nm). Additionally, the formation of a complex between astaxanthin and Cu(2+) is explored as well as the effect that the metal atom will have in the UV-vis spectrum.
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Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging. Somatic mitochondrial DNA (mtDNA) mutations and respiratory chain dysfunction accompany normal aging, but the first direct experimental evidence that increased mtDNA mutation levels contribute to progeroid phenotypes came from the mtDNA mutator mouse. Recent evidence suggests that increases in aging-associated mtDNA mutations are not caused by damage accumulation, but rather are due to clonal expansion of mtDNA replication errors that occur during development. Here we discuss the caveats of the traditional mitochondrial free radical theory of aging and highlight other possible mechanisms, including insulin/IGF-1 signaling (IIS) and the target of rapamycin pathways, that underlie the central role of mitochondria in the aging process.
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Oxovitisin is a natural antioxidant present in aged wine and comes from the chemical transformation undergone by anthocyanins and pyranoanthocyanins. Its antioxidant radical scavenging capacity was theoretically explored by density functional theory (DFT)/B3LYP methods. The O–H bond dissociation energy (BDE), the ionization potential (IP), the proton affinity (PA), and the metal–oxovitisin binding energy (BE) parameters were computed in the gas-phase and in water and benzene solutions. Results provided molecular insight into factors that influence radical scavenging potential of this new class of anthocyanins.
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Most dermatologists agree that antioxidants help fight free radical damage and can help maintain healthy skin. They do so by affecting intracellular signaling pathways involved in skin damage and protecting against photodamage, as well as preventing wrinkles and inflammation. In today's modern world of the rising nutraceutical industry, many people, in addition to applying topical skin care products, turn to supplementation of the nutrients missing in their diets by taking multivitamins or isolated, man-made nutraceuticals, in what is known as the Inside-Out approach to skin care. However, ingestion of large quantities of isolated, fragmented nutrients can be harmful and is a poor representation of the kind of nutrition that can be obtained from whole food sources. In this comprehensive review, it was found that few studies on oral antioxidants benefiting the skin have been done using whole foods, and that the vast majority of current research is focused on the study of compounds in isolation. However, the public stands to benefit greatly if more research were to be devoted toward the impact that physiologic doses of antioxidants (obtained from fruits, vegetables, and whole grains) can have on skin health, and on health in general.
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We present the theoretical and technical foundations of the Amsterdam Density Functional (ADF) program with a survey of the characteristics of the code (numerical integration, density fitting for the Coulomb potential, and STO basis functions). Recent developments enhance the efficiency of ADF (e.g., parallelization, near order-N scaling, QM/MM) and its functionality (e.g., NMR chemical shifts, COSMO solvent effects, ZORA relativistic method, excitation energies, frequency-dependent (hyper)polarizabilities, atomic VDD charges). In the Applications section we discuss the physical model of the electronic structure and the chemical bond, i.e., the Kohn–Sham molecular orbital (MO) theory, and illustrate the power of the Kohn–Sham MO model in conjunction with the ADF-typical fragment approach to quantitatively understand and predict chemical phenomena. We review the “Activation-strain TS interaction” (ATS) model of chemical reactivity as a conceptual framework for understanding how activation barriers of various types of (competing) reaction mechanisms arise and how they may be controlled, for example, in organic chemistry or homogeneous catalysis. Finally, we include a brief discussion of exemplary applications in the field of biochemistry (structure and bonding of DNA) and of time-dependent density functional theory (TDDFT) to indicate how this development further reinforces the ADF tools for the analysis of chemical phenomena. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 931–967, 2001