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Skin Cancer, Free Radicals and Antioxidants



Human skin is constantly directly exposed to the air, solar radiation, other environmental pollutants or other mechanical and chemical insults, which are capable of inducing the generation of free radicals as well as reactive oxygen species (ROS) of our own metabolism. Extrinsic skin damage develops due to several factors: ionizing radiation, severe physical and psychological stress, alcohol intake, poor nutrition, overeating, environmental pollution, and exposure to UV radiation (UVR). It is estimated that among all these environmental factors, UVR contributes up to 80%. UV-induced generation of ROS in the skin develops oxidative stress, when their formation exceeds the antioxidant defence ability of the target cell. The primary mechanism by which UVR initiates molecular responses in human skin is via photochemical generation of ROS mainly formation of superoxide anion (O 2 -˙), hydrogen peroxide (H2O2), hydroxyl radical (OH˙), and singlet oxygen (1 O 2). Oxidative phosphorylation in the mitochondria is an important energy-producing process for eukaryotic cells, but this process can also result in producing potentially cell-damaging side products, e.g. free radicals and other ROS. The only protection of our skin is its endogenous protection (melanin and enzymatic antioxidants) and antioxidants we consumed with the food (vitamin A, C, E, etc.). Dietary antioxidants thus play a major role in maintaining the homeostasis of the oxidative balance. Vitamin C (ascorbic acid), vitamin E (tocopherol), beta-carotene and other micronutrients such as carotenoids, polyphenols and selenium have been evaluated as antioxidant constituents in the human diet. The most important strategy to reduce the risk of sun UVR damage is to avoid the sun exposure and the use of sunscreens. The next step is the use of exogenous antioxidants orally or by topical application and interventions in preventing oxidative stress and in enhanced DNA repair.
International Journal of Cancer Research and Prevention ISSN: 1554-1134
Volume 4, Number 3 © 2011 Nova Science Publishers, Inc.
Skin Cancer, Free Radicals and Antioxidants
B. Poljsak, U. Glavan, and R. Dahmane
Laboratory for Oxidative Stress Research, Faculty of Health Sciences,
University of Ljubljana, Slovenia
Human skin is constantly directly exposed to the air, solar radiation, other environmental
pollutants or other mechanical and chemical insults, which are capable of inducing the
generation of free radicals as well as reactive oxygen species (ROS) of our own metabolism.
Extrinsic skin damage develops due to several factors: ionizing radiation, severe physical and
psychological stress, alcohol intake, poor nutrition, overeating, environmental pollution, and
exposure to UV radiation (UVR). It is estimated that among all these environmental factors,
UVR contributes up to 80%. UV-induced generation of ROS in the skin develops oxidative
stress, when their formation exceeds the antioxidant defence ability of the target cell. The
primary mechanism by which UVR initiates molecular responses in human skin is via
photochemical generation of ROS mainly formation of superoxide anion (O2-˙), hydrogen
peroxide (H2O2), hydroxyl radical (OH˙), and singlet oxygen (1O2). Oxidative
phosphorylation in the mitochondria is an important energy-producing process for eukaryotic
cells, but this process can also result in producing potentially cell-damaging side products, e.g.
free radicals and other ROS. The only protection of our skin is its endogenous protection
(melanin and enzymatic antioxidants) and antioxidants we consumed with the food (vitamin
A, C, E, etc.). Dietary antioxidants thus play a major role in maintaining the homeostasis of
the oxidative balance. Vitamin C (ascorbic acid), vitamin E (tocopherol), beta-carotene and
other micronutrients such as carotenoids, polyphenols and selenium have been evaluated as
antioxidant constituents in the human diet. The most important strategy to reduce the risk of
sun UVR damage is to avoid the sun exposure and the use of sunscreens. The next step is the
use of exogenous antioxidants orally or by topical application and interventions in preventing
oxidative stress and in enhanced DNA repair.
Human skin is naked and is constantly directly exposed to the air, solar radiation, other
environmental pollutants or other mechanical and chemical insults, which are capable of
inducing the generation of free radicals as well as reactive oxygen species (ROS) of our own
metabolism. Reactive oxygen species are usually of little harm if intracellular mechanisms
that reduce their damaging effects work properly. Most important mechanisms include
antioxidative enzymatic and non-enzymatic defences as well as repair processes. But the
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B. Poljsak, U. Glavan, and R. Dahmane 194
problem arises with age, when endogenous antioxidative mechanisms and repair processes do
not work anymore in the effective way.
The identification of free radical reactions as initiators and promoters of the cancer
process implies that interventions aimed at limiting or inhibiting these factors should be able
to reduce the rate of cancer incidence. There still remains the answer regarding controversial
data on the use of synthetic antioxidants in cancer prevention and cancer treatment.
1. Free Radicals and Oxidative Stress
A free radical is a chemical species possessing an unpaired electron (Cheeseman and
Slater, 1993). It can also be considered a fragment of a molecule. Excess generation of free
radicals may overwhelm natural cellular antioxidant defences, leading to oxidation and
further cellular functional impairment. In reality, the oxidative damage potential is greater,
and thus there is a constant small amount of toxic free radical formation, which escapes the
defense of the cell. Oxidative stress is proportional to the concentration of free radicals which
depends on both processes (formation and quenching). The degree of oxidative stress
experienced by a cell will be a function of the activity of free radical generating reactions on
one hand, and the activity of the free radical scavenging system on the other.
UV-induced generation of ROS in the skin develops oxidative stress, when their
formation exceeds the antioxidant defence ability of the target cell (Katiyar and Mukhtar,
2001). Although the skin possesses an elaborate antioxidant defence system to deal with UV-
induced oxidative stress and immunotoxicity, excessive and chronic exposure to UV light can
overwhelm the cutaneous antioxidant and immune response capacity, leading to oxidative
damage and immunotoxicity, premature skin aging, and skin cancer. Acute exposure to UV
irradiation depletes the catalase activity in the skin and increases protein oxidation (Sander et
al., 2002).
2. Oxidative Damage
Oxidative damage to both nuclear and mitochondrial DNA has detrimental effects,
leading to uncontrolled cell proliferation or accelerated cell death (Evans et al., 2004).
Furthermore, redox modification of transcriptional factors leads to the activation or
inactivation of signalling pathways, which will subsequently produce changes in gene
expression profiles (Martindale et al., 2002), including those affecting cellular proliferation,
differentiation, senescence and death (Kregel and Zhang, 2007). Damage to human skin due
to ultraviolet light from the sun (photoaging) and damage occurring as a consequence of the
passage of time (chronologic or natural aging) were considered to be distinct entities. The
findings of the study performed by Varani et al., (2000) indicate that naturally aged sun-
protected skin and photoaged skin share important molecular features including connective
tissue damage, elevated matrix metalloproteinase levels, and reduced collagen production.
The intrinsic (genetically determined) and the extrinsic (UV- and toxic exposure mediated)
skin damage processes are thus overlapped and are strongly related to the increased
generation of free radicals in the skin.
Skin Cancer, Free Radicals and Antioxidants 195
3. Beneficial Role of ROS
Oxidant agents, including reactive oxygen species (ROS), and reactive nitrogen species
(RNS) are recognized to play a dual role as both malefic and beneficial species, being
sometimes compared with fire, which is dangerous, but nonetheless useful to humans (De
Magalhaes and Church, 2006). The "two-faced" character of ROS is substantiated by growing
body of evidence that ROS within cells act as secondary messengers in intracellular signalling
cascades, which induce and maintain the oncogenic phenotype of cancer cells, however, ROS
can also induce cellular senescence and apoptosis and can therefore function as anti-
tumorigenic species. Low amounts of these ROS are important for cellular-signalling
pathways. In general, the balance between the production and scavenging of ROS leads to
homeostasis (Wittgen and van Kempen, 2007). But it seems that there is always a bit more
free radicals produced leading to constant oxidative stress and cell damage which
accumulates with time.
4. Extrinsic Skin Damage
Extrinsic skin damage develops due to several factors: ionizing radiation, severe physical
and psychological stress, alcohol intake, poor nutrition, overeating, environmental pollution,
and exposure to UV radiation (UVR). It is estimated that among all these environmental
factors, UV radiation contributes up to 80%. UV radiation is the most important
environmental factor in the development of skin cancer and skin aging (Poljsak, 2010).
4.1. UVR and ROS formation
UVR increases the ROS formation in the skin cells. The primary mechanism by which
UVR initiates molecular responses in human skin is via photochemical generation of ROS
mainly formation of superoxide anion (O2-˙), hydrogen peroxide (H2O2), hydroxyl radical
(OH˙), and singlet oxygen (1O2) (Hanson and Clegg, 2002). UVR penetrates the skin, reaches
the cells and is absorbed by DNA, leading to the formation of photoproducts that inactivate
the functions of DNA. UVA radiation acts mostly indirectly through the generation of ROS,
producing high amounts of singled oxygen which can further initiate lipid peroxidation,
oxidation of proteins or generation of DNA strand breaks (Scharffetter-Kochanek et al.,
2000). UVB action is mostly by direct interaction with DNA via the induction of DNA
damage. The epidermis and dermis are both affected by UVB, but the dermis is also affected
to a significant extent by UVA. UVA radiation constitutes an oxidant stress that involves the
generation of active species including singlet oxygen and hydroxyl radicals. Hydrogen
peroxide can be generated by UVA irradiation of tryptophan (McCormick et al., 1976), and
superoxide can be produced by UVA irradiation of NADH and NADPH (Cunningham et al.,
1985). The skin-damaging effects of UVA appear to result from type II, oxygen-mediated
photodynamic reactions in which UVA or near-UV radiation in the presence of certain
photosensitizing chromophores (e.g., riboflavin, porphyrins, nicotinamide adenine
dinucleotide phosphate (NADPH), etc.) leads to the formation of reactive oxygen species
B. Poljsak, U. Glavan, and R. Dahmane 196
(1O2, O2.-, .OH) (Dalle Carbonare and Pathak, 1992). As well as causing permanent genetic
changes involving protooncogenes and tumour suppressor genes, ROS activate cytoplasmic
signal transduction pathways that are related to growth differentiation, senescence,
transformation and tissue degradation (Scharffetter-Kochanek et al., 1997).
4.2. UV-Induced Skin Damage
According to Pattison and Davies (2006) UV radiation can mediate damage via two
different mechanisms: (a) direct absorption of the incident light by the cellular components,
resulting in excited state formation and subsequent chemical reaction, and (b)
photosensitization mechanisms, where the light is absorbed by endogenous (or exogenous)
sensitizers that are excited to their triplet states. The excited photosensitisers can induce
cellular damage by two mechanisms: (a) electron transfer and hydrogen abstraction processes
to yield free radicals (Type I); or (b) energy transfer with O2 to yield the reactive excited
state, singlet oxygen (Type II) (Pattison and Davies, 2006). Oxidation of DNA can produce
different types of DNA damage: strand breaks, sister chromatid exchange, DNA-protein
crosslinks, sugar damage, abasic sites, and base modifications. Cell death, chromosome
changes, mutation and morphological transformations are observed after UV exposure of
prokaryotic and eukaryotic cells. Numerous types of UV induced DNA damage have now
been recognized that include stand breaks (single and double), cyclobutane-type pyrimidine
dimers, 6-4 pyo photoproducts and the corresponding Dewar isomer, thymine glycols, 8-
hydroxy guanine, and many more. Additionally, the specific lesions in DNA which can be
induced by UVA radiation include pyrimidine dimmers, single-strand breaks (both not
thought to be the critical lesions in UVA radiation-induced cellular lethality), and, perhaps
more importantly, DNA protein crosslinks (Peak et al., 1987; Rosenstein and Ducore 1983;
Peak et al., 1988; Peak et al., 1985). The number of different DNA modifications that OH˙ is
capable of producing appears to be over 100 (Hutchinson, 1985). In addition, DNA-protein
cross-links are produced during UV exposure. Larger scale genetic alterations include
chromosome breakage, sister chromatid exchanges and chromatid aberrations. Although
partial UV action spectra are now available for many of these lesions, the most studied have
been the different types of pyrimidine dimers (International programme on chemical safety,
Environmental health criteria 160).
Besides oxidation of nuclear DNA, UVR can induce also oxidative damage to
mitochondrial DNA (mtDNA). It has been suggested that sunlight passing through the skin
can even cause DNA damage in white cells circulating through skin capillaries (Yang et al.,
2004) but the greatest damage is within the skin cells, including the damage to dermal
mitochondrial DNA (Wang et al., 2004). Singlet oxygen produced by UVA light has been
shown to cause strand breaks in the mitochondrial DNA, which has resulted in mtDNA
deletions. Mitochondrial DNA is believed to be the most critical target of endogenous ROS
production since it lies in the inner mitochondrial membrane, in close proximity to the
electron transport chain where the most free radicals are formed. In the past it was believed
that mitochondria lack DNA repair capacity but this is not true. However, it is true that
mitochondria do not remove UV induced DNA damage which might be important in
photodamage and skin cancer formation. There have been observed greater accumulation of
Skin Cancer, Free Radicals and Antioxidants 197
mtDNA found in sun exposed skin compared to protected skin (Berneburg et al., 1999; Birch-
Machin et al., 1998). The most frequent mutation is a 4,977-base pair deletion also called the
common deletion, which is increased in photoaged skin.
5. Intrinsic Skin Damage
The changes in our skin cells occur partially as the result of cumulative endogenous
damage due to the continuous formation of reactive oxygen species (ROS), which are
generated by oxidative cellular metabolism. Oxidative phosphorylation in the mitochondria is
an important energy-producing process for eukaryotic cells, but this process can also result in
producing potentially cell-damaging side products, e.g. free radicals and other ROS. Oxygen
is the final proton acceptor in this cascade of electron/proton transfer and results in harmless
water. The electron transfer, however, is not completely efficient and oxygen is not totally
reduced to water. It is estimated that approximately 1-3% oxygen is reduced to superoxide
instead to water.
There are two main sources of ROS: mitochondrial sources (which play the principal role
in aging) and non-mitochondrial sources (which have different, sometimes specific, roles
especially in the pathogenesis of age-related diseases). Most estimates suggest that the
majority of intracellular ROS production is derived from mitochondria. Mitochondrial
sources are represented by the electron transport chain and the nitric oxide synthase reaction.
The rate of mitochondrial respiration is responsible for the rate of generation of ROS. Fenton
reaction is an example of the non-mitochondrial source of ROS. The H2O2 degrading Fenton
reaction is catalyzed by the free iron bivalent ions and leads to the generation of OH˙. It
should be taken into account that body's content of iron increases with age (Koster and
Sluiter, 1995; Vercellotti, 1996). Sources of H2O2 could be mitochondria superoxide
dismutase reaction, peroxisomes (acyl-CoA oxidase reaction) and amyloid β of senile plaques
(superoxide dismutase-like reactions) (Rottkamp et al., 2001). Sources of superoxide (O2-˙)
are mitochondria, microsomes which contain the cytochrome P450 enzymes, the respiratory
burst of phagocytic cells and others. Estimates of how much oxygen reacts directly to
generate free radicals vary (Speakman, 2003). However, typically cited values are around
1.5–5% of the total consumed oxygen (Beckman and Ames, 1998b; Casteilla et al., 2001).
These estimates have been questioned by Hansford et al. (1997) and Staniek and Nohl (1999,
2000), which suggested that H2O2 production rates were less than 1% of consumed O2. Yet,
even if we accept a conservative value of 0.15%, this still represents a substantial amount of
free radicals (Speakman, 2003). Also the skin cells are constantly exposed to ROS and
oxidative stress from exogenous and endogenous sources. It has been found that in aged rat
skin the oxidized lipid phosphatidylcholine hydroperoxide (PCOOH) increases from 3.46
±1.02 μmol/PC mol at 6 months to 7.14 ±1.63 μmol/PC mol at 24 months. The free 7-hydro-
peroxycholesterol (ChOOH) content also increased from 22.83 ±3.97 at 6 month to 42.58 ±
16.59 μmol/ free Ch mol at 24 months. The TBARS (ThioBarbituric Acid Reactive
Substances, harmful substances formed by lipid peroxidation, and detected by the TBARS
assay, using thiobarbituric acid as a reagent) content increases from 4.71 ± 1.53 nmol/ mg
protein at 6 months to 11.10 ± 2.05 nmol/ mg protein at 30 months. The oxidized DNA in rat
skin also increases with age and reaches the level of 2.04 ± 0.27 8-oxoG/ 105 dG at 30 months
B. Poljsak, U. Glavan, and R. Dahmane 198
of age compared to 1.67 ± 0.16 8-oxoG/ 105 dG at 6 months of age. Results suggest that
chronic accumulation of oxidative damage occurs also in skin cells with age (Sivonova et al.,
2007; Tahara et al., 2001; Lasch et al., 1997)
The energy demand of skin cells comes from three sources: mitochondrial oxidative
phosphorylation, glycolysis and creatine/phosphocreatine system. All three major energy
sources are affected by intrinsic and extrinsic skin aging and offer potential entry points for
intervention strategies to decelerate the skin aging process (Blatt et al., 2010). Due to
impaired mitochondria with age, less energy is produced by mitochondrial oxidative
phosphorylation although the number of mitochondria does not change with age. Higher
energy demand needs higher energy production via non-mitochondrial pathways, such as
glycolysis. With advancing age energy production is mostly anaerobic. Primary keratinocytes
derived from old donors show a higher glucose uptake and the increased lactate production
which indicates a suboptimal utilization of glucose and a shift in metabolism towards an
increased glycolysis (Blatt et al., 2010).
Mostly skin tissues engage in, and derive energy using aerobic glycolysis. Despite the
presence of oxygen there is preferential conversion of glucose to lactate via the glycolytic
cycle (Krebs, 1972; Philpott and Kealey, 1991). This results in the production of substantial
amounts of lactate, which is carried to the liver by the bloodstream and converted back to
glucose (the Cory cycle). Skin tissues have a strong preference for the metabolism of glucose
rather than fatty acids or ketone bodies, though alternative citric acid cycle intermediates such
as glutamine are also actively utilized (Williams et al., 1993). Interestingly, of the relatively
small amount of oxygen that is metabolized by skin the majority is supplied to the epidermis
and upper dermis by diffusion from the atmosphere (Stucker et al., 2000). ROS and RNS are
constitutively produced also by endogenous sources in most cell types, including epidermal
keratinocytes and dermal fibroblasts (Fuchs, 1992; Darr and Fridovich, 1994). In addition to
stimulated ROS/RNS production by resident epidermal and dermal cells, these species as well
as reactive halogen species (RHS) can be produced and released into skin by invading
macrophages as well as polymorphonuclear and eosinophilic leukocytes.
6. Skin Antioxidant Defenses
Although the skin possesses an elaborate antioxidant defense system to deal with
oxidative stress, excessive and chronic exposure to UV light or cigarette smoke can
overwhelm the cutaneous antioxidant and immune response capacity, leading to oxidative
damage and immunotoxicity, premature skin aging, and skin cancer.
A biological antioxidant has been defined as any substance that when present at low
concentrations compared to those of an oxidizable substrate, significantly delays or prevents
oxidation of that substrate (Halliwell and Gutterigde, 1999). Antioxidant functions are
associated with lowering oxidative stress, DNA damage, malignant transformation, and other
parameters of cell damage in vitro as well as epidemiologically with lowered incidence of
certain types of cancer and degenerative diseases. Antioxidants attenuate the damaging effects
of ROS and can impair and/or reverse many of the events that contribute to epidermal toxicity
and disease. However, increased or prolonged free radical action can overwhelm ROS
defense mechanisms, contributing to the development of cutaneous diseases, disorders and
Skin Cancer, Free Radicals and Antioxidants 199
skin aging. The two main categories of antioxidant defences are those whose role is to prevent
the generation of ROS, and those that intercept any radicals that are generated (Cheeseman
and Slater, 1993). The defence system exists in aqueous and membrane compartments of cells
and can be enzymatic and non-enzymatic. A second category of natural antioxidants are
repair processes, which remove the damaged biomolecules before they accumulate to cause
altered cell metabolism or viability (Cheeseman and Slater, 1993).
The skin is equipped with a network of protective antioxidants. They include enzymatic
antioxidants such as glutathione peroxidase, superoxide dismutase and catalase, and
nonenzymatic low-molecular-weight antioxidants such as vitamin E isoforms, vitamin C,
glutathione (GSH), uric acid, and ubiquinol (Shindo et al., 1993).Various other components
present in skin are potent antioxidants including ascorbate, uric acid, carotenoids and
sulphydrils. Water-soluble antioxidants in plasma include glucose, pyruvate, uric acid,
ascorbic acid, bilirubin and glutathione. Lipid soluble anti-oxidants include alpha-tocopherol,
ubiquinol-10, lycopene, ß-carotene, lutein, zeaxanthin and alpha-carotene. In general, the
outer part of the skin, the epidermis, contains higher concentrations of antioxidants than the
dermis (Shindo et al., 1994a,b,c). In the lipophilic phase, α-tocopherol is the most prominent
antioxidant, while vitamin C and GSH have the highest abundance in the cytosol. On molar
basis, hydrophilic non-enzymatic antioxidants including L-ascorbic acid, GSH and uric acid
appear to be the predominant antioxidants in human skin (Thiele et al., 2006). Their overall
dermal and epidermal concentration are more than 10- to 100-fold greater than those found
for vitamin E or ubiquinol.
The antioxidant capacity of the human epidermis is far greater than that of dermis. This
was demonstrated in the study by Shindo et al., (1994a,b,c) where enzymic and non-enzymic
antioxidants in human epidermis and dermis from six healthy volunteers undergoing surgical
procedures was measured. A similar study was done by Shindo et al. (1993) where enzymic
and non-enzymic antioxidants in epidermis and dermis of hairless mice were compared.
Catalase, glutathione peroxidase, and glutathione reductase were higher in epidermis than
dermis. Lipophilic antioxidants (alpha-tocopherol, ubiquinol 9, and ubiquinone 9) and
hydrophilic antioxidants (ascorbic acid, dehydroascorbic acid, and glutathione) were also
higher in epidermis than in dermis. The stratum corneum (SC) was found to contain both
hydrophilic and lipophilic antioxidants. Vitamins C and E (both αγ and α-tocopherol) as well
as GSH and uric acid were found to be present in the SC (Weber et al., 1999; Thiele et al.,
1998). Surprisingly, they were not distributed evenly, but in gradient fashion, with low
concentrations on the outer layers and increasing concentrations toward the deeper layers of
the SC. This phenomenon may be explained by the fact that O2 partial pressure is higher in
the upper SC, which already causes a mild oxidative stress resulting in the partial depletion of
All the major antioxidant enzymes are present in skin but their role in protecting cells
against oxidative damage generated by UV radiation has not been elucidated. In response to
the attack of reactive oxygen species, the skin has developed a complex antioxidant defence
system including among others the manganese-superoxide dismutase (MnSOD). The study of
Poswig et al. (1999) revealed that adaptive antioxidant response of manganese-superoxide
dismutase following repetitive UVA irradiation can be induced. The authors provide evidence
for the increasing induction of MnSOD upon repetitive UVA irradiation that may contribute
to the effective adaptive UVA response of the skin during light hardening in phototherapy.
The study of Fuchs et al., (1989a,b) on mouse skin showed that acute UV exposures lead also
B. Poljsak, U. Glavan, and R. Dahmane 200
to changes in glutathione reductase and catalase activity in mouse skin but insignificant
changes in superoxide dismutase and glutathione peroxidase (Fuchs et al., 1989a,b). The
study of Sander et al. (2002) confirmed that chronic and acute photodamage is mediated by
depleted antioxidant enzyme expression and increased oxidative protein modifications.
DNA Repair Systems
Generation of ROS and the activity of antioxidant defence appear more or less balanced
in vivo. In fact, as already mentioned, the balance may be slightly tipped in favor of the ROS
so that there is continuous low-level oxidative damage in the human body. This creates a need
for a second category of endogenous antioxidant defence system, which removes or repairs
damaged biomolecules before they can accumulate and before their presence results in altered
cell metabolism. DNA is the most critical target for damage by UVA, UVB and UVC
radiations. Measurable DNA damage is induced in human skin cells in vivo after exposures to
UVA, UVB and UVC radiation, including doses in the range commonly experienced by
humans. A number of different DNA repair mechanisms have been established (Freifelder
1987), the best known being photoreactivation, excision repair, postreplication repair and sos
repair. Most of the DNA damage after a single exposure is repaired within 24 h. The
majorities of DNA lesions are repaired by BER (Base Excision Repair), NER (Nucleotide
Excision Repair), and MMR (Mismatch Repair) (Norbury and Hickson, 2001). DNA repair
capacity has been found to decrease with age. For example, decrease in the level of proteins
that participate in nucleotide excision repair was reported to occur for aged dermal fibroblasts
(Goukassian et al., 2000). The aging and survival of endothelial cells are linked to molecular
mechanisms that control cell proliferation, quiescence, apoptosis and senescence.
Hormesis effect activates the synthesis of melanin and antioxidant protection and
damaged lipids are cleaved and replaced. Irreparably cells are removed by apoptosis (Yarosh,
2003). However, these repair mechanisms are not 100% effective. The damaged components
are not always completely repaired. The problem arises in the cases of intensive acute sun
exposure or in the cases of chronical sun exposures over longer decades which manifests as
skin photoaging. Despite the fact that biological species, including man, are exposed to
potentially harmful levels of solar UVR, mechanisms have evolved to protect cells and to
repair damaged molecules
Apoptosis is a cellular end point of the stress response. Apoptosis removes damaged cells
from UV-irradiated tissues. If the cell damage cannot be repaired before the next cell division
the cell rather decides to “commit a suicide” than to spread mutations to its daughter cells.
Activation of apoptosis is associated with generation of reactive oxygen species. Superoxide
is produced by mitochondria isolated from apoptotic cells due to a switch from the normal 4-
electron reduction of O2 to a 1-electron reduction when cytochrome c is released from
mitochondria. Apoptosis is stimulated through release of mitochondrial cytochrome c, which
results in activation of death protease (caspase-3) and increased free radical generation due to
uncoupled respiration (Cai and Jones, 1998; Cai et al., 1998). Antioxidant treatment could
sometimes possess anti-apoptotic properties and for this reason antioxidants should be
consumed before exposure to the factors that increase oxidative stress and not after. The
genes that control apoptosis in the epidermis, such as the bcl-2 gene, are disregulated during
Skin Cancer, Free Radicals and Antioxidants 201
aging. The decreased efficiency of apoptosis may contribute to chronological aging and
extrinsic skin aging (Rocquet and Bonte, 2002). Differentiation, proliferation, and cell death
are coordinated tightly within the epidermis. Alterations within keratinocytes that disrupt
these processes are believed to contribute to the development of nonmelanoma skin cancers.
8. ROS and Cancer
Increasing evidence has implicated a role for free radicals and oxidative stress in all three
stages of the carcinogenic process. Radicals may be involved in the initiation step, either in
the oxidative activation of a procarcinogen to its carcinogenic form or in the binding of the
carcinogenic species to DNA, or both (Guyton and Kensler, 1993; Trush and Kensler, 1991;
Pryor, 1997), thus making oxidative stress an important cofactor for carcinogen activation.
Promotion always involves radicals, at least to some extent (Cerutti, 1985; Troll and Wiesner,
1985; Marks and Fu¨rstenberger, 1985; Kensler and Taffe, 1986; Crawford et al., 1988; Sun,
1990; Cheng et al., 1992; Agarwal and Mukhtar, 1993; Feig et al., 1994; Kensler et al., 1995;
Slaga, 1998), while their role in progression is controversial (Pryor, 1997).
8.1. Skin Cancer
The target organ of UV radiation is the skin. Sun exposure is the major known
environmental factor associated with the development of skin cancer of all types. Skin cancer
is a malignant growth on the skin which can have many causes. There are various types of
skin cancer. One main class is formed by the cutaneous melanocytes - melanoma. The other
main types are basal cell carcinomas and squamous cell carcinomas, cancers of the epithelial
cells. These carcinomas of the skin (basal cell and squamous cell carcinomas) are sometimes,
collectively, called "non-melanoma skin cancers". UV exposure appears to promote the
induction of skin cancer by two mechanisms. The first involves direct mutagenesis of
epidermal DNA, which promotes the induction of neoplasia. The second is associated with
immune suppression, which allows the developing tumor to escape immune surveillance and
grow progressively (Katiyar and Mukhtar, 2001). It has been proposed that if unrepaired
damage occurs to regulatory genes (e.g. tumour suppressor genes), this may be involved in
the process of carcinogenesis. In this context mutations to and activation of genes may be
important. Other responses likely to result from UV exposure of cells include increased
cellular proliferation, which could have a tumor promoting effect on genetically altered cells,
as well as changes in components of the immune system present in the skin (International
programme on chemical safety, Environmental health criteria 160).
8.2 The Importance of Antioxidants in Decreasing ROS Formation
and Skin Cancer Prevention
It is estimated that ¾ of sun exposure is non-intentional. Our skin is exposed to majority
of UV-radiation when we are outdoor working, walking, etc. and not when we are
B. Poljsak, U. Glavan, and R. Dahmane 202
intentionally exposed to the sun on the beach. At this time we also do not use sun-creams
with UVA/UVB protection. The only protection of our skin is its endogenous protection
(melanin and enzymatic antioxidants) and antioxidants we consumed with the food (vitamin
A, C, E, etc.). Dietary antioxidants thus play a major role in maintaining the homeostasis of
the oxidative balance. Vitamin C (ascorbic acid), vitamin E (tocopherol), beta-carotene and
other micronutrients such as carotenoids, polyphenols and selenium have been evaluated as
antioxidant constituents in the human diet. UVR exposure affects the skin antioxidants.
Ascorbate, GSH, SOD, catalase and ubiquinol are depleted in UV-B exposed skin, both
dermis and epidermis. Levels of electron paramagnetic resonance (EPR)-detectable ascorbyl
radical rise on UV exposure of skin. Studies of cultured skin cells and murine skin in vivo
have indicated that UVR-induced damage involves the generation of reactive oxygen species
and depletion of endogenous antioxidant systems (McArdle, et al., 2002). For example, the
study by Shindo et al. (1993) where enzymatic and non-enzymiatic antioxidants in epidermis
and dermis and their responses to ultraviolet light of hairless mice were compared. After
irradiation epidermal and dermal catalase and superoxide dismutase activities were greatly
decreased. α-Tocopherol, ubiquinol 9, ubiquinone 9, ascorbic acid, dehydroascorbic acid, and
reduced glutathione decreased in both epidermis and dermis by 26-93%. Oxidized glutathione
showed a slight, non-significant increase (Shindo et al., 1993). Many other studies confirmed
that acute exposure of human skin to UVR in vivo leads to oxidation of cellular biomolecules
that could be prevented by prior antioxidant treatment. There have been many studies
performed where different antioxidants or combinations of antioxidants and different
phytochemicals were tested in order to find evidence against ROS induced damage.
8.3. Vitamin C
Oral vitamin C supplements (500 mg/day) were taken by 12 volunteers for 8 weeks
resulting in significant rises in plasma and skin vitamin C content (McArdle et al., 2002).
Supplementation had no effect on the UVR-induced erythemal response. The skin
malonaldehyde content was reduced by vitamin C supplementation, but surprisingly,
reductions in the skin content of total glutathione and protein thiols were also seen. Authors
speculate that this apparently paradoxical effect could be due to regulation of total reductant
capacity by skin cells, such that vitamin C may have been replacing other reductants in these
Ascorbic Acid was a photoprotectant in clinical human UV studies at doses well above
the minimal erythema dose (MED). An opaque cream containing 5% Ascorbic Acid did not
induce dermal sensitization in 103 human subjects. A product containing 10% Ascorbic Acid
was non-irritant in a 4-day minicumulative patch assay on human skin and a facial treatment
containing 10% Ascorbic Acid was not a contact sensitizer in a maximization assay on 26
humans (McArdle, 2002). Many other studies have found that vitamin C can increase
collagen production, protect against damage from UVA and UVB rays, correct pigmentation
problems, and improve inflammatory skin conditions (Poljsak, 2011).
Skin Cancer, Free Radicals and Antioxidants 203
8.4. Vitamin E
Skin exposure to UV and ozone alone and in combination resulted in a significant
potentiation of the UV-induced vitamin E depletion (Packer and Valacchi, 2002), which
means that vitamin E is efficiently quenching ROS during O3 and UVR skin exposure.
Depletion of SC vitamin E is one of the earliest oxidative stress markers in human skin
exposed to UVR and other environmental stress (Thiele 2001). One study showed that the
number of sunburn to cells was decreased by treatment with the antioxidant tocopherol, and
may result from both direct protection from free radicals and indirect protection by means of
increased epidermal thickness. (Ritter et al., 1997). Additionally, Packer et al., (2001) showed
that vitamin E has skin barrier-stabilizing properties. In a study by Werninghaus and
coworkers (1994), a relatively small group of 12 healthy volunteers received 295 mg (400 IU)
-tocopherol acetate or a placebo daily for 6 months along with their regular diet. Mean
MEDs were similar in both groups before supplementation, but increased in some subjects
and decreased in others after supplementation. Plasma concentrations of α-tocopherol
increased during the study, but no parallel increase was detected in the skin. A study revealed
that topical application of alpha-tocopherol inhibits ultraviolet (UV) B-induced
photocarcinogenesis and DNA photodamage in C3H mice in vivo. This study also suggests
that incorporation of tocopherol compounds into sunscreen products confers protection
against procarcinogenic DNA photodamage and that cellular uptake and distribution of
tocopherol compounds is necessary for their optimal photoprotection (McVean and Liebler,
1999). Vitamin E provides protection against UV-induced skin photodamage through a
combination of antioxidant and UV absorptive properties. Topical application of alpha-
tocopherol on mouse skin inhibits the formation of cyclobutane pyrimidine photoproducts.
However, topically applied alpha-tocopherol is rapidly depleted by UVB radiation in a dose-
dependent manner (Krol et al., 2000).
8.5. β-Carotene
β-carotene is a major constituent of commercially available products administered for
systemic photoprotection. β-carotene supplements are frequently used as so-called oral sun
protectants, but studies proving a protective effect of oral treatment with β-carotene against
skin responses to sun exposure are scarce and conflicting results have been reported (Stahl et
al., 2006). Studies on the systemic use of β-carotene provide evidence that 15-30 mg/d over a
period of about 10-12 wk produces a protective effect against UV-induced erythema. Similar
effects have been attributed to mixtures of carotenoids or after long-term intake of dietary
products rich in carotenoids. Supplementation with carotenoids contributes to basal protection
of the skin but is not sufficient to obtain complete protection against severe UV irradiation
(Stahl and Krutmann 2006). Studies showed that the efficacy of β-carotene in systemic
photoprotection depends on the duration of treatment and on the dose (Stahl, 2000). For
successful intervention, treatment with carotenoids is needed for a period of at least ten weeks
(Sies and Stahl, 2004). A study by Stahl et al., (2000) was performed where carotenoids and
tocopherols antioxidant effect was investigated against scavenging reactive oxygen species
generated during photooxidative stress. It was investigated whether antioxidant oral
B. Poljsak, U. Glavan, and R. Dahmane 204
supplementation may protect the skin from ultraviolet light-induced erythema. The
antioxidants used in this study provided protection against erythema in humans and may be
useful for diminishing sensitivity to ultraviolet light. Heinrich et al., (2003) additionally
compared the erythema-protective effect of beta-carotene (24 mg/d from an algal source) to
that of 24 mg/d of a carotenoid mix consisting of the three main dietary carotenoids, beta-
carotene, lutein and lycopene (8 mg/d each). In a placebo-controlled, parallel study design,
volunteers with skin type II (n = 12 in each group) received beta-carotene, the carotenoid mix
or placebo for 12 weeks. Serum beta-carotene concentration increased three- to fourfold in the
beta-carotene group, whereas in the mixed carotenoid group, the serum concentration of each
of the three carotenoids increased one- to threefold. No changes occurred in the control group.
The intensity of erythema 24 h after irradiation was diminished in both groups that received
carotenoids and was significantly lower than baseline after 12 wk of supplementation. Long-
term supplementation for 12 weeks with 24 mg/d of a carotenoid mix supplying similar
amounts of beta-carotene, lutein and lycopene ameliorates UV-induced erythema in humans.
According to the authors, the effect is comparable to daily treatment with 24 mg of beta-
carotene alone.Carotenoids have been shown to inhibit UV-induced epidermal damage and
tumor formation in mouse models (Mathews-Roth and Krinsky, 1987). The use of sunscreens
on the skin can prevent sunburn but whether long-term use can prevent skin cancer is not
known. Also, there is evidence that oral beta-carotene supplementation lowers skin-cancer
rates in animals, but there is limited evidence of its effect in human beings (Green et al.,
1999). In a community-based randomized trial performed by Green et al., (1999) with a 2 by
2 factorial design, individuals were assigned to four treatment groups: daily application of a
sun protection factor 15-plus sunscreen to the head, neck, arms, and hands, and beta-carotene
supplementation (30 mg per day); sunscreen plus placebo tablets; beta-carotene only; or
placebo only. The endpoints after 4.5 years of follow-up were the incidence of basal-cell and
squamous-cell carcinomas both in terms of people treated for newly diagnosed disease and in
terms of the numbers of tumours that occurred. There were no significant differences in the
incidence of first new skin cancers between groups randomly assigned daily sunscreen and no
daily sunscreen. Similarly, there was no significant difference between the beta-carotene and
placebo groups in incidence of either cancer. In terms of the number of tumours, there was no
effect on incidence of basal-cell carcinoma by sunscreen use or by beta-carotene but the
incidence of squamous-cell carcinoma was significantly lower in the sunscreen group than in
the no daily sunscreen group (1115 vs. 1832 per 100,000). The authors concluded that there
was no harmful effect of daily use of sunscreen in this medium-term study. Cutaneous
squamous-cell carcinoma, but not basal-cell carcinoma seems to be amenable to prevention
through the routine use of sunscreen by adults for 4.5 years. There was no beneficial or
harmful effect on the rates of either type of skin cancer, as a result of beta-carotene
supplementation (Green et al. 1999).
A randomized, placebo-controlled clinical trial on the efficacy of oral β-carotene (50
mg/day over 5 years) in prevention of skin cancer in patients with recent nonmelanoma skin
cancer showed no significant effect of β-carotene on either number or time of occurrence of
new nonmelanoma skin cancer (Greenberg et al., 1990). In a separate trial among healthy
men, 12 years of supplementation with β-carotene (50 mg on alternate days) produced no
reduction of the incidence of malignant neoplasms, including nonmelanoma skin cancer
(Hennekenset al., 1996). It must be pointed out that these intervention trials were conducted
with patients whose skin cancer was primarily UV-induced and it remains to be seen whether
Skin Cancer, Free Radicals and Antioxidants 205
antioxidants are clinically effective in prevention of cutaneous chemocarcinogenesis (Fuch et
al., 2001).
Another study investigated the effects of oral vitamin E and beta-carotene
supplementation on ultraviolet radiation-induced oxidative stress in human skin (McArdle et
al., 2004). Results revealed that vitamin E or beta-carotene supplementation had no effect on
skin sensitivity to UVR. Although vitamin E supplements significantly reduced the skin
malondialdehyde concentration, neither supplement affected other measures of UVR-induced
oxidative stress in human skin, which suggested no photoprotection of supplementation.
In a study by Wolf et al (1988), 23 healthy volunteers received 150 mg of an oral
carotenoid preparation containing 60 mg ß-carotene and 90 mg canthaxanthin daily for 4 wk.
No differences in MEDs were shown in a comparison of values before and after carotenoid
supplementation. Concentrations in serum increased during treatment, but concentrations in
the skin were not reported. Additionally, no effects of ß-carotene were detected when UV
irradiation–induced unscheduled DNA synthesis was investigated, suggesting that carotenoids
were not protective against DNA lesions repairable by excision repair.
Although the photoprotective effects of beta-carotene are thought to originate from its
antioxidant properties, some studies documented pro-oxidant effects of beta-carotene.
8.6. Retinoids
A study was done to compare the effects of dietary administration of a vitamin A drug
(13-cis-retinoic acid) to the natural form of vitamin A (retinyl palmitate).
Female mice were administered a chemical carcinogen to evaluate the incidence and
severity on mouse skin tumour promotion. The results showed that retinyl palmitate inhibited
the number and weight of tumours, whereas 13-cis-retinoic acid resulted in a decrease in
weight, but not in number of tumours promoted (Gensler et al., 1987).
In another study, tumours were chemically induced in a group of Swiss mice over a 23-
week period. The topical application of 13-cis-retinoic acid was compared to natural vitamin
A (retinyl palmitate). This study showed that both retinyl palmitate and 13-cis-retinoic acid
inhibited the development of skin papillomas and also had a marked effect on skin cancers
(Abdel-Galil et al., 1984).
8.7. Coenzyme Q10
It was recently reported that Coenzyme Q10 protects against oxidative stress-induced cell
death and enhances the synthesis of basement membrane components in dermal and
epidermal cells (Muta-Takada et al., 2009).
Coenzyme Q10 (CoQ10) was reported to reduce ROS production and DNA damage
triggered by UVA irradiation in human keratinocytes in vitro. Further, CoQ10 was shown to
reduce UVA-induced MMPs in cultured human dermal fibroblasts (Inui et al., 2008). It was
reported that it is considered that CoQ10 appears to have also a cutaneous healing effect in
vivo (Choi et al., 2009).
B. Poljsak, U. Glavan, and R. Dahmane 206
8.8. Glutathione
In cell culture models using human skin cells, it has been clearly shown that glutathione
depletion leads to a large sensitization to UVA (334 nm, 365 nm) and near-visible (405 nm)
wavelengths as well as to radiation in the UVB (302 nm, 313 nm) (Tyrrell and Pidoux,
There is a direct correlation between the levels of sensitisation and cellular glutathione
content. Additional evidence that glutathione is a photoprotective agent in skin cells is
derived from experiments which have demonstrated that glutathione levels in both dermis and
epidermis are depleted by UVA treatment (Connor and Wheeler, 1987).
8.9. Green Tea
In vitro and in vivo animal and human studies suggest that green tea polyphenols are
photoprotective in nature, and can be used as pharmacological agents for the prevention of
solar UVB light-induced skin disorders including photoaging, melanoma and nonmelanoma
skin cancers after more clinical trials in humans. Topical treatment or oral consumption of
green tea polyphenols (GTP) inhibits chemical carcinogen- or UV radiation-induced skin
carcinogenesis in different laboratory animal models. Topical application of GTP and EGCG
prior to exposure of UVB protects against UVB-induced local as well as systemic immune
suppression in laboratory animals, which was associated with the inhibition of UVB-induced
infiltration of inflammatory leukocytes (Katiyar, 2003).
Another study of Vayalil et al., (2003) demonstrated that topical application of green tea
polyphenols reduced UVB-induced oxidation of lipids and proteins and depletion of
antioxidant enzymes.
Other protective effects include the reduced production of ROS and lipid peroxidation
products, a reduced depletion of Langerhans cells and of endogenous antioxidant systems as
reported by Afaq and Mukhtar (2002).
9. Pro-Oxidant Effects of Antioxidants
Antioxidants that are reducing agents can also act as pro-oxidants. Antioxidants, which
are reducing agents, are capable of reacting with molecular oxygen (e.g. ascorbic acid) and
will generate superoxide radicals under aerobic conditions. This will dismutate to H2O2 that
can enter cells and react with superoxide or reduced metal ions to form highly damaging
hydroxyl radicals. The presence of redox cycling metal ions with antioxidants might result in
a synergistic effect, resulting in increased free radical formation or the so called pro-oxidant
effect. For example, vitamin C or glutathione have antioxidant activity when they reduce
oxidizing substances such as hydrogen peroxide, however, they can also reduce metal ions
which leads to the generation of free radicals through the Fenton reaction. Both vitamin C and
E possess pro-oxidant properties, at least in vitro, depending on their concentration, the
existence of regenerating co-antioxidants and traces of metal ions.
Skin Cancer, Free Radicals and Antioxidants 207
The results of epidemiologic studies where people were treated with synthetic
antioxidants are inconclusive and contradictory: from the proven beneficial effect, proven no
difference, to the proven harmful effect of synthetic antioxidant supplements. None of the
major clinical studies using mortality or morbidity as an end point has found positive effects
of supplementation with antioxidants such as vitamin C, vitamin E or β-carotene.
There are several possible explanations for the potential negative effect of antioxidant
supplements. Reactive oxygen species in moderate concentrations are essential mediators of
defense against unwanted cells. Thus, if administration of antioxidant supplements decreases
free radicals, (it may interfere with essential defensive mechanisms for ridding the organism
of damaged cells, including those that are precancerous and cancerous (Salganik, 2001).
Thus, antioxidant supplements may actually cause some harm (Vivekananthan et al.,
2003; Bjelakovic et al., 2004a; Bjelakovic et al., 2004b; Miller et al., 2005; Bjelakovic et al.,
2007; ; Caraballoso et al., 2003). Our diets typically contain safe levels of vitamins, but high-
level antioxidant supplements could potentially upset an important physiologic balance
(Vivekananthan et al., 2003; Bjelakovic et al., 2004a; Bjelakovic et al., 2004b; Miller et al.,
2005; Bjelakovic et al., 2007; Caraballoso et al., 2003). Additionally, consuming antioxidant
molecules such as polyphenols and vitamin E will produce changes in other parts of the
metabolism, and these other non-antioxidant effects may be the real reason for their
importance in human nutrition (Azzi, 2007; Aggarwal and Shishodia, 2006) and their positive
effect on aging and chronical degenerative diseases prevention. There seems to be an effect
between exogenous antioxidants that tends to depress endogenous antioxidant levels.
Changing the level of one antioxidant causes a compensatory change in others, while the
overall antioxidant capacity remains unaffected. Dosing cells with exogenous antioxidants
might decrease the rate of synthesis or uptake of endogenous antioxidants, so that the total
“cell antioxidant potential” remains unaltered.
Thus, the key to the future success of dietary antioxidant supplementation should be the
suppression of oxidative damage without disruption of the well-integrated antioxidant defense
network. Increasing cellular viability with antioxidants prior to toxic compound-induced
toxicity (e.g. Cr(VI), UV-radiation, ionizing radiation) might not always be beneficial
(Poljsak et al., 2006). Carcinogen-induced growth arrest and apoptosis are at the molecular
decision point between carcinogen toxicity and carcinogen carcinogenesis (Carlisle, 2000).
When normal growing cells come in contact with carcinogens, they may respond by
undergoing growth arrest, apoptosis and necrosis.
A population of genetically damaged cells may also emerge, which exhibits either
intrinsic or induced resistance to apoptosis (Carlisle 2000). Such cells may be predisposed to
neoplasia as a result of their altered growth/death ratio, disrupted cell cycle control, or
genomic instability. This, however, raises the question of whether decreasing carcinogen
toxicity with antioxidants might actually increase the incidence of cancer by allowing the
inappropriate survival of genetically damaged cells. This hypothesis was recently confirmed
also by the study of Schafer et al. (2009) which revealed an unanticipated mechanism for cell
survival in altered matrix environments by antioxidant restoration of ATP generation.
Antioxidant activity may promote the survival of pre-initiated tumor cells in unnatural matrix
environments, and thus enhance malignancy.
At low glutathione concentrations, UVB-induced mtDNA deletions have been prevented,
but at high levels of glutathione, when it acts as an electron donor the pro-oxidative properties
reveal and the mtDNA deletions return (Ji et al., 2006). A number of experimental studies
B. Poljsak, U. Glavan, and R. Dahmane 208
indicate protective effects of beta-carotene against acute and chronic manifestations of skin
photodamage. However, most clinical studies have failed to convincingly demonstrate its
beneficial effects so far. Nevertheless, intake of oral β-carotene supplements before sun
exposure has been recommended on a population-wide basis. Studies on skin cells in culture
have revealed that beta-carotene acts not only as an antioxidant but also has unexpected
prooxidant properties (Biesalski and Obermueller-Jevic, 2001). Lycopene was reported to
enhance UVA-induced oxidative stress in C3H cells, and authors of the study suggest that
under UVA irradiation, lycopene may produce also oxidative products that are responsible for
the prooxidant effects (Yeh et al., 2005).
Skin DNA molecules are constantly “bombarded” by ROS originating from endogenous
processes as well as from environmental agents and from radiation sources. Damaged DNA is
being constantly repaired by many cellular repair systems. If the frequency of damaging
events exceeds the repair capacity, damaged DNA is not repaired in time and can pass to
daughter cells and thus trigger tumor initiation and progression process. Although DNA
damage due to ROS is not a rare event since it is estimated that human cell sustains an
average of 105 oxidative hits per day due to cellular oxidative metabolism (Fraga et al., 1991),
DNA is functionally very stable, so that the incidence of cancer is much lower than one
would expect, taking into account the high frequency of oxidative hits. Nevertheless,
avoidance of excessive cumulative and sporadic sun exposure is important in reducing the
risk of skin cancer and skin aging. Additionally, antioxidants might act by enhancing the
DNA enzyme repair systems through a post-transcriptional gene regulation of transcription
factors (Xanthoudakis et al., 1992; Hirota et al., 1997; Schenk et al., 1994). The repair
capacity of human skin cells therefore directly relates to the probability of initiation of the
carcinogenesis process and eventually tumor formation. Cellular antioxidant defense
mechanisms are therefore crucial for the prevention or removal of the damage caused by the
oxidizing component of UV radiation. Evidence is accumulating that dietary changes and
special nutrients may help to reduce oxidative stress, free radical formation and thereby slow
down the skin damage process. Foods rich in antioxidants and other phytochemicals, such as
fruits, vegetables, wine and green tea help protect against oxidative damage and free radical
attack of all body cells including the skin. The primary treatment of photoaging is
photoprotection but secondary treatment could be achieved with the use of antioxidants and
some novel compounds such as polyphenols. Exogenous antioxidants like vitamin C, E, and
many others cannot be synthesized by the human body and must be taken up by the diet. They
have been shown to prevent exogenous free radical formation (e.g. UVA and UVB). They
could also possess beneficial effects in endogenous ROS prevention. Antioxidants can
regulate the transfer of electrons or quench free radicals escaping from electron transport
chain. Since the effectiveness of endogenous antioxidant system is diminished during aging,
the exogenous supplementation of antioxidants might be a protective strategy against age-
associated skin oxidative damage. It can be concluded that oxidative stress is a problem of
skin cells and endogenous as well as exogenous antioxidants could play an important role in
decreasing it. However, it is important to pre-treat the skin with antioxidants before sun
Skin Cancer, Free Radicals and Antioxidants 209
exposure. Animal and human studies have convincingly demonstrated pronounced photo-
protective effects of 'natural' and synthetic antioxidants when applied topically before UVR
exposure. No significant protective effect of melatonin or the vitamins when applied alone or
in combination were obtained when antioxidants were applied after UVR exposure. UVR-
induced skin damage is a rapid event, and antioxidants possibly prevent such damage only
when present in relevant concentration at the site of action beginning and during oxidative
stress (Dreher et al., 1999). Treatment of the skin with antioxidants after the damage was
caused by UVR might cause additional harmful effects on cell cycle control and apoptosis
process. The photoprotective effects of antioxidants are significant when applied in distinct
mixtures in appropriate vehicles.
The most important strategy to reduce the risk of sun UV radiation damage is to avoid the
sun exposure and the use of sunscreens. The next step is the use of exogenous antioxidants
orally or by topical application and interventions in preventing oxidative stress and in
enhanced DNA repair. The laboratory studies conducted in animal models suggest that many
plant compounds have the ability to protect the skin from the adverse effects of UV radiation,
including the risk of skin cancers. It is suggested that antioxidants may favourably
supplement sunscreens protection, and may be useful for skin diseases associated with solar
UV radiation-induced inflammation, oxidative stress and DNA damage. At this point, it
should be stressed that extrapolation of in vitro data to the in vivo situation is often difficult.
Moreover, in vivo studies of the effects of nutrients on human skin have mainly focused on
indirect measures of skin function after supplementation. Many more placebo-controlled
human studies are required to support food and supplement product claims regarding skin
beneficial effects. The controversy in beneficial vs. harmful synthetic antioxidant properties
may also reflect a misinterpretation of epidemiology. Fruits, grains and vegetables contain
multiple components that might exert protective effects against disease. It could be any or any
combination of those factors that is a true protective agent. For example, high plasma
ascorbate levels or high ascorbate intake could simply be a marker of a good diet rather than a
true protective factor (Rietjens et al., 2001). Antioxidants may thus have dichotomous
activities with respect to tumorigenesis, namely, suppressing tumorigenesis by preventing
oxidative damage to DNA (Gao, 2007; Narayanan, 2006) and promoting tumorigenesis by
allowing survival of cells that are metabolically impaired (e.g. in altered matrix
Besides the compounds mentioned in our review, many recent studies showed potentially
interesting effects of some naturally occurring, less well investigated compounds that may
improve skin conditions. This area of research is constantly emerging and new antioxidants
are reported. Nevertheless, endogenous skin protection with the use of selected antioxidants
or plant extracts contributes to the protection of sensitive dermal target sites beyond those
reached with sunscreens and especially because of lifelong exposure to sunlight which mainly
occurs under everyday circumstances, when no topical protection is applied. According to
Stahl et al., (2006) endogenous photoprotection is complementary to topical photoprotection,
and these two forms of prevention clearly should be considered mutually exclusive. We have
to realize that the use of synthetic vitamin supplements is not an alternative to regular
consumption of fruit and vegetables. It is probable that many antioxidants are still
undiscovered; furthermore the combination of antioxidants in fruit and vegetables causes their
reciprocal regeneration and consecutively intensifies their defense from free radicals. Given
B. Poljsak, U. Glavan, and R. Dahmane 210
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... Four potential mechanisms that account for the harmful effects of air pollution on skin have been identified: generation of free radicals, induction of inflammatory cascade and disruption of skin barrier, activation of the aryl hydrocarbon receptor, and alterations to skin microflora [19,20]. The presence of free radicals, in particular, increases the risk of skin cancer through mechanisms such as the promotion of oxidative stress and a proinflammatory environment in the skin and DNA damage [21,22]. In addition, ambient ozone's unstable characteristics cause it to be highly reactive, directly targeting the skin's surface, and oxidizing with molecules in the outermost layer of the epidermis (stratum corneum). ...
... In addition, ambient ozone's unstable characteristics cause it to be highly reactive, directly targeting the skin's surface, and oxidizing with molecules in the outermost layer of the epidermis (stratum corneum). This causes skin barrier alterations and dysfunction as well as oxidative stress and inflammation [21,22]. ...
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Climate change is associated with shifts in global weather patterns, especially an increase in ambient temperature, and is deemed a formidable threat to human health. Skin cancer, a non-communicable disease, has been underexplored in relation to a changing climate. Exposure to solar ultraviolet radiation (UVR) is the major environmental risk factor for skin cancer. South Africa is situated in the mid-latitudes and experiences relatively high levels of sun exposure with summertime UV Index values greater than 10. The incidence of skin cancer in the population group with fair skin is considered high, with cost implications relating to diagnosis and treatment. Here, the relationship between skin cancer and several environmental factors likely to be affected by climate change in South Africa are discussed including airborne pollutants, solar UVR, ambient temperature and rainfall. Recommended strategies for personal sun protection, such as shade, clothing, sunglasses and sunscreen, may change as human behaviour adapts to a warming climate. Further research and data are required to assess any future impact of climate change on the incidence of skin cancer in South Africa.
... Excessive exposure to UV radiation can lead to DNA (deoxyribonucleic acid) damage (mutation or chromosomal rearrangements) in skin cells using two ways [12]: a) the direct absorption of UVB by DNA skin cells and b) the indirect generation of reactive oxygen species (free radicals) induced by UVA. DNA damages lead to the formation of two common types of skin cancers: malignant melanoma and non-melanoma cancers (basal cell carcinoma and squamous cell carcinoma) [20,21]. ...
Nowadays, there is a growing demand for effective cosmetic skincare products that can address the specific skin problems of consumers. Delivery systems play an important role in the effective action of cosmetic skincare formulations. Delivery systems are attractive and smart technologies used as carriers for cosmetic ingredients, which are sensitive to various physical factors such as light, oxygen, pH and temperature. Delivery systems offer several advantages: transport and protection of sensitive active compounds, controlled and targeted release of active ingredients. Several delivery systems, varying in chemical composition, with adaptable physicochemical characteristics (size, morphology, zeta potential, structure) as well as great advantages as carriers, are developed and described in the literature. This article reviews the current cosmetic active ingredients used in skincare products due to their beneficial properties such as antioxidant, anti-aging, photo-protective, anti-inflammatory, anti-microbial, etc.). In addition, the main advantages of several classes of delivery systems (emulsions, lipid nanoparticles, polymeric particles) are described, as well as some recent approaches used to ensure their efficacy (long-term stability, controlled release of the active, skin penetration/permeation) are reviewed. Finally, new trends to be considered for the development of delivery systems and cosmetic formulations are discussed.
... Antioxidants decrease ROS accumulation and attenuate their damaging effects. UV radiation exposure can overcome the endogenous skin protection, which is why the application of endogenous antioxidants is crucial to overcome the oxidative stress caused by an imbalance between ROS and defense mechanisms [8][9][10][11]. Natural compounds (NCs) are gaining increased attention due to their pharmacological health-benefitting properties, including antioxidant activity. ...
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Oxidative stress, triggered by UV radiation, is one of the major causes of free radical-associated disorders, such as skin cancer. The application of natural compounds (NCs) with antioxidant effects can attenuate free radicals’ accumulation and, therefore, provide a strategy for skin care and cancer prevention. In this work, three natural compounds, naringenin, nordihydroguaiaretic acid (NDGA), and kaempferol, were encapsulated into nanostructured lipid carriers (NLCs) aiming for the development of a formulation for cutaneous application with antioxidant properties. For the experiments, different formulation parameters were evaluated to optimize the NLCs that showed a diameter around 200 nm, which is an adequate particle size for incorporation in cosmetics. Transmission electron microscopy (TEM) analysis confirmed the NLCs’ typical spherical morphology. Encapsulation efficiency (EE) and loading capacity (LC) values revealed an effective production process, with EEs over 90% and LCs near the maximum value. The developed NLCs revealed a prolonged in vitro release of the natural compounds. The NLCs were stable under storage conditions, maintaining their psychochemical characteristics for 30 days. Additionally, they did not show any physical instability in accelerated stability studies, which also suggests long-term stability. Finally, the NCs antioxidant activity was evaluated. Interestingly, the NDGA and kaempferol mixture provided an antioxidant synergic effect. The NLC formulations’ cytotoxicity was tested in vitro in immortalized human keratinocytes (HaCaT). In addition, putative antioxidant effects of the developed NLC formulations against tert-butyl hydroperoxide (t-BHP)-induced oxidative stress were studied, and the NDGA-loaded NLC was revealed to be the one with the most protective effect. Therefore, we concluded that the naringenin, NDGA, and kaempferol incorporation into NLCs constitutes a promising strategy to increase their bioavailability and delivery to the skin.
... Antioxidants carry out their function during biological processes including inflammation by balancing and stabilizing generated free radicals. 28,29 Antioxidants adopt different mechanisms in achieving their defence function. They impede the reaction of free radicals with proteins by sequestering them with transition metals, they make provision for free radical scavenging molecules as well as specific mechanisms for repairing DNA damage induced by ROS. 30 Worthy of note is the fact that A. muricata extract contains polyphenols, flavonoids, steroids, glycosides, alkaloids and tannins. ...
... Diets rich in fruits and vegetables have been reported to have a protective effect against cardiovascular disease and cancer [1][2][3][4] . The nutrients thought to provide protection by fruits and vegetables are antioxidants 5,6 . Oxidative stress is the basic etiology of disease and can be viewed as an imbalance between antioxidants and prooxidants in the body. ...
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This review article is focused on the impact of antioxidants and prooxidants on health with emphasis on the type of antioxidants that should be taken. Medical researchers suggest that diet may be the solution for the control of chronic diseases such as cardiovascular complications, hypertension, diabetes mellitus, and different cancers. In this survey, we found scientific evidence that the use of antioxidants should be limited only to the cases where oxidative stress has been identified. This is often the case of specific population groups such as postmenopausal women, the elderly, infants, workers exposed to environmental pollutants, and the obese. Before starting any supplementation, it is necessary to measure oxidative stress and to identify and eliminate the possible sources of free radicals and thus increased oxidative stress.
... Air, harsh sun rays, other environmental pollutants or other mechanical and chemical insults, induce the generation of free radicals (FR) as well as reactive oxygen species (ROS) of our own metabolism when human being exposed to it. Thus, skin aging is divided into these two categories: Natural or sequential and extraneous or photo-aging into common terms [2,3]. ...
Objective: The aim of this research article is to develop and evaluate herbal antiaging cream using Annona squamosa leaf extract because of its antioxidant potential. Method: Free radical scavenging activity of Annona squamosa aqueous was determined by DPPH method. 0.5 ml of each solution of concentration of sample was added to 3 ml of 0.004% ethanolic DPPH free radical solution. After 30 minutes the absorbance of the preparations were taken at 517 nm by a UV spectrophotometer which was compared with the corresponding absorbance of standard ascorbic acid. The qualitative phytochemical analysis of Annona squamosa (custard apple) leaf extract shows the presence of flavonoids, tannins, alkaloids and phenols and absence of terpenoids and steroids Results: Formulation A3 shows good DPPH scavenging activity as compare to formulation A1 and A2 and ascorbic acid. Formulation A3 is stable for 3 months. Conclusion: Due to high antioxidant values of Annona squamosa it is concluded that it is possible to develop anti-aging cream using aqueous extract of Annona squamosa leaf.
... It plays a key role in protecting the body from daily toxic aggressions due to environmental pollutants by generating reactive oxygen species (ROS) (Valacchi et al., 2012). This overproduction of ROS unbalances the antioxidant defense system of the human body (Poljšak et al., 2011) leading to oxidative stress that can create skin damage like premature skin aging (Rinnerthaler et al., 2015) but also skin cancer risks (Baudouin et al., 2002). Among the environmental sources responsible for skin damage (Krutmann et al., 2017), UV radiations were unambiguously shown to cause skin cancers (Valacchi et al., 2012). ...
This study aims to prove the value of the polyoxazolines polymer family as surfactant in formulations for topical application and as an alternative to PEG overuse. The amphiphilic polyoxazolines (POx) were demonstrated to have less impact on cell viability of mice fibroblasts (NIH3T3) than their PEG counterparts. Mixed micelles, made of POx and phosphatidylcholine, were manufactured using thin film and high pressure homogenizer process. The mixed micelles were optimized to produce nanosized of vesicles about 20 nm with a spherical shape and stable over 28 days. The natural lipophilic antioxidant, quercetin, was successfully encapsulated (encapsulation efficiency 94±4 % and drug loading 3.6±0.17 %) in the mixed micelles with no morphological variation. Once loaded in the formulation, the quercetin impact on cell viability of NIH3T3 was decreased while its antioxidant activity remained unchanged. This work highlights the capacity of amphiphilic POx to create, in association with phospholipids, stable nanoformulations which show promise for topical delivery of antioxidant and ensuring skin protection against oxidative stress.
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Hyptis spicigera is a plant with reported anti-diabetic and antioxidant properties. The aim of this study is to determine the in vitro antidiabetic and free radical potentials of methanolic extract of Hyptis spicigeraleaf (HSL). The HSL was obtained fromZone C Area ElekoYangan, Moro Local Government Kwara State, air dried at room temperature, soaked in methanol (1:20) for 48 hours and filtered using The alpha amylase inhibitory, alpha glucosidase inhibitory, glucose uptake modulatory, haemoglobin glycosylation inhibitory and free radical scavenging activities of the extract and standards were determined at five concentrations (62.5, 125, 250, 500, and 1000 µg/ml). While acarbose was used as standard for the alpha amylase and alpha glucosidase inhibitory potentials, metformin and ascorbic acid (and/or butylatedhydrotoluene BHT) were employed as standard for the glucose uptake and free radical scavenging assays respectively.The therapeutic efficacy of the experimental result is appreciable: The effect of the sample (H. spicigera) to inhibit Alpha amylase and Alpha glucosidase, increases according to the increase in concentration and seems more effective compare to the standard (but more elevated than the sample) indicating the required dose for therapeutic effect and stabilization of physiological functions, the effect of the sample (H. spicigera) increases according to the increase in concentration but seems more effective compared to the standard and therefore it is able to scavenge free radicals than the standard (Ascorbic acid and/or butylatedhydrotoluene). Hyptis spicigeraleaf (HSL). In glucose uptake modulation, the higher the glucose level the lower the efficiency of the sample or standard i.e the lower the glucose the yeast is able to uptake. Therefore the efficiency increases according to the level of concentration. Therefore the studied plant possesses antihyperglycemic and antioxidant activities and could be useful in the management of hyperglycemia and oxidative stress.
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تضمنت الدراسة الحالية تقييم فاعلية خمسة أنواع من المساحيق الخاملة وهي مسحوق السربنتينيت Serpintinite ، البيتايتAlbitite ، اللايمستون Limeston ، الصلصال Marl و الإردواز Slate وثلاثة أنواع من المساحيق النباتية وهي مسحوق الثوم Allium sativum, الفلفل الأسود Piper nigrum والكمونCuminum cyminum وخمسة أنواع من الزيوت النباتية وهي زيت الحبة السوداء Nigella sativa , الخروع Ricinus communis , زهرة الشمس Helianthus annuus , الكتان Linum usitatissimum و الخردل Brassica juncea في خنفساء اللوبيا الجنوبية Callosobruchus maculatus أظهرت النتائج الدراسة ان فاعلية مسحوق الصلصال ومسحوق ثمار الكمون وزيت الخردل تفوقت معنويا على بقية المساحيق الخاملة والنباتية والزيوت النباتية وبنسب قتل بلغت نسبة 29.76, 55.31% , 34.53% على التوالي. وبالنسبة لتقليل عدد البيض وزيادة نسبة الطرد المئوية أيضا تفوقت مسحوق الصلصال على بقية المساحيق الخاملة فقد بلغت 163.0, 65.42% على التوالي ومسحوق الكمون على بقية المساحيق النباتية فقد بلغت 84.5, 95.14% على التوالي وزيت الخردل على بقية الزيوت فقد بلغت 161.13, 64.4% على التوالي. أما بالنسبة لزيادة الفترة اللازمة لخروج أفراد الجيل الأولF1 فبلغت 21 يوما مع المساحيق الخاملة عند التراكيز 10, 20, 30غم/كغم, بينما تفوقت مسحوق الكمون على بقية المساحيق النباتية فقد بلغت 22.63 يوما, وزيت الخردل على بقية الزيوت النباتية فبلغت 28.08يوما, وبالنسبة لتقليل عدد الحشرات البازغة وزيادة النسبة المئوية لخفض أفراد الجيل الأولF1 تفوقت مسحوق الإردواز على بقية المساحيق الخاملة فقد بلغت 105.75, 58.92% على التوالي, ومسحوق الكمون على بقية المساحيق النباتية حيث بلغت 47.25, 95.15% على التوالي وزيت الكتان على بقية الزيوت النباتية فقد بلغت 48.5, 97.43% على التوالي. أما بالنسبة لتقليل النسبة المئوية للضرر ودليل ثقب السوس تفوقت مسحوق السربنتين على بقية المساحيق الخاملة فقد بلغت 65.31, 69.86% على التوالي ومسحوق الكمون على بقية المساحيق النباتية فقد بلغت 26.38, 10.64% على التوالي وزيت الكتان على بقية الزيوت النباتية فقد بلغت 24.90%, 6.00% على التوالي وبالنسبة لتقليل النسبة المئوية للفقد في الوزن تفوقت مسحوق الإردواز ومسحوق الكمون وزيت الخردل على بقية المساحيق الخاملة والنباتية والزيوت النباتية فقد بلغت 30.75, 17.2% , 16.88% على التوالي. ولم يكن هناك فروق معنوية بين جميع المساحيق الخاملة والسيطرة من حيث النسبة المئوية للإنبات اذ تفوقت مسحوق ثمار الفلفل الأسود والكمون على مسحوق الثوم فقد بلغت نسبة الإنبات معهما 95.00%, بينما تفوقت زيت زهرة الشمس على بقية الزيوت النباتية فقد بلغت 95.83% مقارنة بالسيطرة حيث بلغت 96.66%,و كانت العلاقة عكسية بين التركيز وكل من عدد البيض, عدد الحشرات البازغة , النسبة المئوية للضرر ,دليل ثقب السوس, الفقد في الوزن والإنبات لبذور اللوبيا المعاملة وطردية مع قتل الكاملات, نسبة الطرد المئوية, الفترة اللازمة لخروج أفراد الجيل الأولF1 والنسبة المئوية لخفض أفراد الجيل الأولF1. عموماً أظهرت نتائج الدراسة الحالية ان المساحيق النباتية تفوقت معنوياً على الزيوت النباتية والمساحيق الخاملة في نسب قتل الكاملات وبالنسبة لتقليل عدد البيض وزيادة نسبة الطرد المئوية تفوقت المساحيق النباتية معنوياً على المساحيق الخاملة والزيوت النباتية, أما لزيادة الفترة اللازمة لخروجF1 تفوقت الزيوت النباتية معنوياً على المساحيق النباتية والخاملة و لتقليل عدد الحشرات البازغة وزيادة النسبة المئوية لخفضF1 تفوقت الزيوت النباتية معنوياً على المساحيق النباتية و الخاملة ولتقليل النسبة المئوية للضرر والفقد في الوزن تفوقت الزيوت النباتية معنوياً على المساحيق النباتية والخاملة وبالنسبة لإنبات بذور اللوبيا المعاملة بهذه المواد فقد تفوقت المساحيق الخاملة معنوياً على المساحيق والزيوت النباتية.
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أجريت الدراسة في البيت الحيواني التابع لكلية للعلوم/ جامعة كركوك للفترة من1/3/2019 الى 15/5/2019 ولمدة عشرة أسابيع. شملت الدراسة 50 جرذاً من الذكور البالغة وزعت عشوائياً الى 10 مجاميع (كل مجموعة 5 ) غذيت الحيوانات السليمة على العليقة الاعتيادية طوال مدة التجربة والبالغة ثمانية اسابيع , أما الحيوانات عالية الدهون غذيت على العليقة التي تحتوي على الكولسترول بنسبة 2% لمدة أسبوعين ثم تجرع بزيت الزيتون المحلي و هايدروكسي تايروزول وعقار الاتورفاستاتين لمدة ستة أسابيع مع الاستمرار على العليقة الغنية بالكولسترول وكما يلي: المجموعة الأولى وهي مجموعة السيطرة التي أعطيت عليقة قياسية وجرعت بالماء المقطر, المجاميع الثانية , الثالثة , الرابعة والخامسة أعطيت عليقة قياسية وجرعت بزيت الزيتون المحلي فقط بتركيز (0.5 مل/كغم) , مادة الهايدروكسي تايروزول فقط بتركيز (50 مايكرولتر / كغم) , زيت الزيتون المحلي بتركيز (0.5 مل/كغم) + مادة الهايدروكسي تايروزول بتركيز (50 مايكرولتر / كغم) وعقار الاتورفاستاتين بتركيز (2.06 ملغم/كغم) على التوالي. المجموعة السادسة عالية الدهون أعطيت عليقة عالية الكوليسترول بنسبة 2% من وزن العليقة القياسية وجرعت بالماء المقطر , المجاميع السابعة , الثامنة , التاسعة والعاشرة أعطيت عليقة عالية الكوليسترول وجرعت بزيت الزيتون المحلي فقط بتركيز (0.5 مل/كغم) , مادة الهايدروكسي تايروزول فقط بتركيز (50 مايكرولتر / كغم) , زيت الزيتون المحلي بتركيز (0.5 مل/كغم) + مادة الهايدروكسي تايروزول بتركيز (50 مايكرولتر / كغم) وعقار الاتورفاستاتين بتركيز (2.06 ملغم/كغم) على التوالي . صممت الدراسة الحالية للبحث في دور كل من زيت الزيتون المحلي و مادة الهايدروكسي تايروزول في خفض وتحسين عوامل الخطورة على الجهاز القلبي الوعائي والحد من الاجهاد التأكسدي في ذكور الجرذان البيض نوع Sprague Dawley المصابة بفرط الدهون التجريبي، باستخدام الكولسترول بنسبة 2% ضمن العليقة ومقارنة النتائج مع عقار الأتورفاستاتين المعروف بدوره كمخفض للكوليسترول . لذا فقد تم تقدير تراكيز متغيرات مرتسم الدهون ، وكذلك متغيرات ميزان الأكسدة - مضادات الأكسدة, في مصل الدم ومستخلص الكبد لحيوانات التجربة. وفضلاً عن ذلك فقد تم تقدير تركيز أنزيم HMG-CoA reductase ومستوى الكلوكوز و ايون الحديد وهرمون الهبسيدين وفعالية إنزيم GGT في مصل الدم , فضلاً عن الدراسة النسجية للشريان الأبهر و القلب و الكبد والكلى ودور زيت الزيتون ومادة الهايدروكسي تايروزول في خفض مستوى الحديد النسجي . تضمنت الدراسة أيضاً قياس أوزان الحيوانات عند بداية ونهاية التجربة ومؤشر القلب والكبد والكلى. أظهرت نتائج الدراسة الآتي :- أظهرت نتائج المتغيرات الكيموحيوية ارتفاعاً معنوياً (0.05≥P) في متغيرات الدهون في مصل دم ومستخلص نسيج الكبد في المجموعة عالية الدهون مقارنة مع مجموعة السيطرة , أما في حال المجاميع عالية الدهون المجرعة فقد أظهر زيت الزيتون + مادة الهايدروكسي تايروزول معاً دوراً أكثر فاعلية في الوقاية من فرط الدهون مقارنةَ مع المعاملات الاخرى في تحسين متغيرات الدهون. أظهرت الدراسة ايضاً انخفاضاً معنوياً (0.05≥P) في تركيز أنزيم HMG-CoA reductase في المجموعة عالية الدهون مقارنة مع مجموعة السيطرة، في حين ارتفع تركيزها في المجاميع عالية الدهون المعالجة مقارنةً مع المجموعة عالية الدهون . كما اظهرت ارتفاعاً معنوياً (0.05≥P) في مستوى الكلوكوز وهورمون الهبسيدين وانخفاضاً معنوياً في تركيز ايون الحديد في مصل الدم للمجموعة عالية الدهون مقارنةً مع مجموعة السيطرة , أما في حال المجاميع عالية الدهون الجرعة فقد أظهرت زيت الزيتون + مادة الهايدروكسي تايروزول دوراً أكثر فاعلية في تحسن تركيز الكلوكوز وهرمون الهبسيدين وايون الحديد مقارنةً مع المعاملات الاخرى. وبالنسبة للإجهاد التأكسدي ومضادات الأكسدة فقد أظهرت ارتفاعاً معنوياً (0.05≥P) في مستويات المالون ثنائي الالديهايد وانخفاضاً معنوياً في مستويات كلوتاثيون GSH وفعالية الكتاليزCAT في كل من مصل الدم ومستخلص أنسجة الكبد في المجموعة عالية الدهون مقارنة مع مجموعة السيطرة, أما في حال المجاميع المصابة المعالجة فقد أظهر زيت الزيتون + مادة الهايدروكسي تايروزول دوراً أكثر فاعلية كمضاد أكسدة مقارنة مع المعاملات الاخرى في تحسين ميزان الاكسدة في مصل الدم و مستخلص الكبد. وبالنسبة لفعالية أنزيم الكبدGGT في مصل الدم فقد أظهرت ارتفاعاً معنوياً (0.05≥P) في المجموعة عالية الدهون مقارنة مع مجموعة السيطرة, أما في حال المجاميع عالية الدهون المجرعة فقد أظهر زيت الزيتون + مادة الهايدروكسي تايروزول دوراً أكثر فاعلية في تطبيع فعالية GGT مقارنة مع المعاملات الاخرى. كما أظهرت النتائج ارتفاعاً معنوياً (0.05≥P) في النسبة المئوية للتغير في الوزن وموشر القلب ومؤشر الكبد في حيوانات المجموعة عالية الدهون مقارنة مع مجموعة السيطرة في حين لم يكن هناك اختلاف معنوي في مؤشر الكلى بين جميع المعاملات ، أما في حال المجاميع عالية الدهون المجرعة فقد أظهر زيت الزيتون + مادة الهايدروكسي تايروزول دوراً أكثر فاعلية في خفض النسبة المئوية للتغير في الوزن ومؤشر الكبد ومؤشر القلب مقارنة مع المعاملات الاخرى . اما بالنسبة للدراسة النسجية للمجموعة المصابة فقد وجد في الشريان الابهر ترسب بلورات الكولسترول وتشكل لويحات تصلب العصيدي بنسبة مرتفعة (+++) ضمن الغلالة البطانية وارتشاح خلايا التهابية بنسبة منخفضة (+) مع زيادة في سمك جدار الشريان الأبهر وترسب الحديد بنسبة مرتفعة (+++), واظهرت زيت الزيتون + مادة الهايدروكسي تايروزول دوراً أكثر فاعلية في تطبيع الآفات النسجية تليها عقار الاتورفاستاتين ثم مادة الهايدروكسي تايروزول و زيت الزيتون كلاً على حدى. كما لوحظ في القلب وجود التليف ضمن عضلة القلب وتسمك جدار الوعاء التاجي وتضخم الالياف العضلية القلبية بنسبة متوسطة (++) مع ارتشاح الخلايا الالتهابية و تحلل الدم بين الالياف العضلية القلبية وتنكس الالياف العضلية القلبية بنسبة منخفضة (+) وتفكك الالياف العضلية القلبية بنسبة مرتفعة (+++) , واظهر زيت الزيتون + مادة الهايدروكسي تايروزول دوراً أكثر فاعلية في تطبيع الآفات النسجية تليها مادة الهايدروكسي تايروزول لوحده ثم عقار الاتورفاستاتين و زيت الزيتون لوحده. كما اظهر في الكبد وجود تليف كبدي و تسمك جدار الوريد المركزي وارتشاح للخلايا الالتهابية بنسبة مرتفعة (+++) مع حصول تصلب الشريان الكبدي وتحلل الدم بنسبة متوسطة (++) وملاحظة تنكس بنسبة منخفضة (+) واظهر زيت الزيتون + مادة الهايدروكسي تايروزول دوراً أكثر فاعلية في تطبيع الآفات النسجية تليها مادة الهايدروكسي تايروزول ثم زيت الزيتون كل على حدى واخيراَ العقار اتورفاستاتين . كما لوحظ في الكلى وجود تليف ضمن نسيج الكلى , تسمك جدار محفظة بومان و ارتشاح للخلايا الالتهابية بنسبة مرتفعة (+++) وانكماش الكبيبات و تحطم النبيبات و تسمك جدار الاوعية الكلوية و الانسلاخ بنسبة متوسطة (++) و انسداد تجويف النبيبات و احتقان دموي بنسبة منخفضة (+)واظهر زيت الزيتون + مادة الهايدروكسي تايروزول دوراً أكثر فاعلية في تطبيع الآفات النسجية يليه زيت الزيتون لوحدها ثم مادة الهايدروكسي تايروزول لوحدها و عقار الاتورفاستاتين. يستنتج من الدراسة الحالية بان لزيت الزيتون ومادة الهايدروكسي تايروزول دوراً اساسياً في تحسين جميع الصفات الكيموحيوية والنسجية المدروسة التي تأثرت سلبياً بفرط الدهون المستحث بإضافة 2% من الكولسترول الى العليقة وقد يأتي ذلك من خلال دورهما الفعال كمضادات للأكسدة , فضلاً عن ذلك كان للفعل التازري بين زيت الزيتون ومادة الهايدروكسي تايروزول أثراً واضح في تحسين الصفات المدروسة مقارنةً بالمعاملات الأخرى.
Dermatology is a complex and puzzling world of itching bumps, pim­ ples, and rashes. The multitude of clinically distinct skin diseases, their frequently unresolved pathogenesis, and the exponentially in­ creasing amount of scientific information add to the confusion about skin diseases. The great prevalence of skin diseases makes them an urgent priority for intensive research effort, and although many scientists and academic clinicians are vigorously trying to uncover we are only at the very brink of understanding the etiol­ their secrets, ogy of most dermatoses. The principle mechanisms of general organ pathology (physical, chemical, microbial, ischemic, degenerative, and neoplastic disturb­ ances) are believed to be relatively well understood. In contrast to skin pathomorphology, however little is known regarding the bio­ chemistry and physiology of dermatoses. The difficulty in under­ standing skin diseases may be overcome partially by finding biome­ dical simplifications, and the concept of "oxidative injury in dermatopathology" is just such a simplification. It should, of course, always be kept in mind that no single mechanism alone can explain the pathogenesis of a disease and that there may be a danger of over­ looking other important biological determinants.
Aging is understood as the result of a complex interaction of biological processes that are caused by both environmental processes (extrinsic aging) and genetic processes (intrinsic aging). Research into the biology of aging has provided detailed insight into the molecular mechanisms of age-related changes in organs, tissues, and cells. Most information relating to intrinsic aging processes comes from tissues other than the skin. This is in part due to the fact that clinically manifest diseases such as Type-2 diabetes or neurodegenerative disease are often correlated with aging of cells. In part it is also due to the fact that substantial amounts of primary cells and organelles for biochemical analyses can be more easily isolated from other organs such as muscle, brain, or liver, as compared with skin. Nevertheless, intrinsic aging is based on general biological processes that apply more or less to all proliferating cells and terminally differentiated cells as well. Therefore, general intrinsic aging processes seen in a liver cell, muscle cell, or neuron can be expected also to apply more or less to skin cells. In fact, most of the aging processes identified and studied with other cells could also be confirmed with keratinocytes or dermal fibroblasts, even though some downstream details may be different.
There is considerable evidence that increased concentrations of active oxygen, organic-peroxides and organic-radicals (prooxidant states), can promote initiated cells to neoplastic growth. Prooxidant states can be caused by different classes of agents, including, hyperbaric oxygen, ionizing radiation, xenobiotic metabolites, Fenton-type reagents, modulators of cytochrome P450 electron transport, peroxisome proliferators, inhibitors of the antioxidant defense, and membrane-active agents. Many of these agents cause chromosomal damage by indirect action, but the role of this damage in carcinogenesis remains unclear. Prooxidant states can be prevented or suppressed by the enzymes of the cellular antioxidant defense and low molecular weight scavenger molecules. Many antioxidants are antipromoters and anticarcinogens. Prooxidant states may modulate the expression of a family of “prooxidant genes ” which are related to cell growth and differentiation by inducing alterations in DNA structure or by epigenetic mechanisms, e. g., by poly ADP-ribosylation of chromosomal proteins (1).
As our body's envelope, the skin acts as a biosensor with the environment and reflects our personality. Skin ageing is therefore an important and interesting topic of study. It results from the combination of intrinsic ageing and photoageing, which is due to the environmental influence, such as reactive oxygen species (ROS). The more recent data are gathered here to remind current knowledge about skin ageing, from a molecular level to the clinical signs, wrinkles and spots mainly. Because knowledge of the preferential biological targets of ageing has recently been making progress, it is possible to delay the manifestation of ageing, by acting on key biological processes.
The human organism depends on an adequate energy supply provided by major dietary components, protein, carbohydrates and lipids. However, minor constituents such as vitamins, minerals and specific fatty acids are required in a healthy diet as well. Secondary plant compounds are ingested with food and enter the systemic circulation. These are not essential in the strict sense of a vitamin, but some of these compounds exhibit distinct biological activities. Among them are terpenoids and polyphenols such as carotenoids, tocopherols, and fla-vonoids [1-3] which are known to be efficient antioxidant micronutrients. As the exterior barrier of the body, the skin is in direct contact with the environment. This organ is exposed to oxygen and light, conditions under which reactive oxygen species (ROS) are generated. Photooxidative stress is involved in processes of photoaging and photocarcinogen-esis, and plays a major role in the pathogenesis of photodermatoses [4]. As any other tissue, skin depends on an optimal supply of nutritive compounds. Skin benefits from dietary antioxidants capable of scavenging reactive intermediates generated under the condition of photooxidative stress [5-7]. Micronutrients may also act as UV absorbers, or modulate signaling pathways elicited upon UV exposure [8-10]. In plants, minor constituents play an important role in protection against excess light. Besides acting as accessory pigments, carotenoids are associated with photoprotection [11], being involved in the dissipation of excess light energy through the xanthophyll cycle, quenching excited triplet state molecules and singlet oxygen. Based on their structural features which determine their physicochemical properties, carot-enoids, flavonoids, and vitamins E and C are also suitable compounds for photoprotection in humans [6].