Professional Documents
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DOI 10.1007/s13749-014-0001-x
Review 13
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Exogenous Endogenous
Ultraviolet Radiation Environmental pollulants Xenobiotics Intracellular processes:
ATP generation
Phagocytic defense
Nucleotide degradation
UVB UVA Secondary messengers
(photosensitisers)
Cellular substructure
Clinical effects
Photoaging
Immunosuppression
Photocarcinogenesis
Figure 1 ROS induction by exogenous and endogenous sources and skin alterations [2]
Many exogenous factors such as environmental pol- matic (also called secondary antioxidants) and en-
lutants, UVR, drugs, physical and psychological zymatic molecules (also called primary antioxidants),
stress, alcohol, poor nutrition and xenobiotics are which function as potent antioxidants or oxidant-
able to catalyse the production of ROS directly or degrading systems. Unfortunately, these homeostatic
indirectly. The endogenous sources include enzymes defences, although highly effective, have limited ca-
such as xanthine oxidase (XO), nicotinamide ade- pacity and can be overwhelmed, thereby leading to
nine dinucleotide phosphate-oxidase (NADPH oxi- increased ROS production in the skin [1].
dase/Nox) and nitric oxide synthase (NOS), which ROS are involved in the pathogenesis of a number
can produce, respectively, superoxide anions (O2•−) of skin disorders such as skin erythema, inflamma-
and nitric oxide (NO•) directly in the skin. Inflam- tion, phototoxicity, photoageing, tumours and oth-
matory cells, including leukocytes and macrophages, ers. These negative effects are compounded by in-
represent an additional source of free radicals. creasingly poor diets and lifestyle habits, which are
Skin is easily exposed to oxidative stress caused by not conducive to maintaining the skin’s natural
ROS accumulation, leading to cutaneous oxidative repair process and antioxidant network. This is why
attacks. ROS can target lipid-rich membranes as well one approach to prevent or treat these ROS-medi-
as cellular DNA and proteins to produce an array of ated disorders is based on the administration of
toxic effects, leading to inflammatory changes and antioxidants in an effort to restore homeostasis [1].
to aberrant cell proliferation responses (Fig. 1). As “Beauty from within” or “improved skin condition
skin is rich in lipids, proteins and DNA, it is ex- through nutrition and supplements” is a worldwide
tremely sensitive to the oxidation process. trend that is on the increase. Therefore, there is an
The skin possesses an array of antioxidant defence opportunity for natural ingredients to improve
mechanisms that interact with toxicants to obviate long-term skin health management through nutri-
their deleterious effects. These include non-enzy- tional supplementation.
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What is SOD B?
Figure 4 Anti-inflammatory action of SOD
SOD B is a SOD-rich freeze-dried melon juice con-
centrate obtained from a unique selected French
variety of Cantaloupe melon (Cucumis melo L.). To-
sion and distribution of angiogenic factors and in- day, melon is the richest plant source of SOD com-
flammatory mediators. pared to other sources such as microalgae SOD.
Overall, Kim et al. [4] showed that the anti-angio- Shofian et al. [11] studied the effect of freeze-drying
genic and anti-inflammatory effects of SOD might on the antioxidant activity of selected muskmelon
be due to suppression of hypoxia-inducible factor- (C. melo L.). They determined the antioxidant ac-
1a (HIF-1α), protein kinase C (PKC) and NF-κB ex- tivity in terms of lipid peroxidation inhibition by
pression (Fig. 4). In fact, SOD decreased phospho- conjugated diene assay. This measurement is useful
rylation of PKC and both expression and nuclear to assess the antioxidant activity of plant materials
translocation of NF-κB. Thanks to this specific and allows quantification of the ability of antioxi-
mechanism of action, SOD is able to inhibit expres- dants to inhibit the peroxidation of linoleic acid.
sion of VEGF, MMPs (by increasing the expression The authors found that, interestingly, freeze-dried
of tissue inhibitor of matrix metalloproteinases samples of muskmelon had significantly (p<0.05)
(TIMP)) and other pro-angiogenic and pro-inflam- higher antioxidant activity than fresh samples.
matory mediators. Consistently, NF-κB-dependent Orak et al. [12] investigated the antioxidant activity
expression of pro-inflammatory enzymes such as and nutritional properties of freeze-dried strawberry
COX-2 and iNOS was also decreased in the skin [9]. tree (Arbutus unedo L.). They concluded that freeze-
Kim et al. [4] and Kwon et al. [9] also demonstrated drying is the best drying method to keep the nutri-
that SOD participates in the immune response by tional value, antioxidant activity and sensory prop-
blocking immune cell infiltration and inhibiting erties of fruits.
leukocyte–endothelium adhesion. Specifically, SOD
acts by suppressing hyaluronic acid fragments SOD B: original mechanism of action
(HAF), which are able to directly activate leuko- Several studies have demonstrated that SOD B sup-
cytes, leading to the production of pro-inflamma- plementation could induce endogenous antioxi-
tory cytokines. Indeed, HAF activates NADPH oxi- dant enzyme (SOD, glutathione peroxidase (GPx)
dase and produces ROS, which translocates toll-like and catalase (CAT)) expression, without reaching
receptor 4 (TLR4) to initiate signalling. SOD blocks the target organs [13]. The induction of an endoge-
this cascade by inhibiting NADPH oxidase activity nous antioxidant defence system naturally allows
and the subsequent O2•− production. Consequently, a decrease in oxidative stress and inflammation.
TLR4-mediated NF-kB trans-activation and the ex- The induction of all antioxidant enzymes avoids
pression of inflammatory cytokines is impaired, al- an imbalance in the ratio of SOD to CAT and GPx,
leviating skin inflammation. which could be involved in some disorders. Indeed,
Kwon et al. [9] added that SOD (SOD3) may control CAT and GPx remove the H2O2 produced after the
the adaptative immune response by inhibiting den- dismutation of O2•− by SOD (Fig. 3).
dritic cell maturation. It is likely that SOD may Thanks to this original mechanism of action, SOD B
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contributes to maintaining a healthy balance of O2•−, UV-B irradiation induces an impairment of the epi-
preventing the formation of oxidative products. dermal antioxidant defence system and a decrease
Based on its antioxidant properties, SOD B could be of the epidermal SOD activity [19, 20]. As the ef-
able to regulate inflammation initiation by quench- fectiveness of the endogenous antioxidant system
ing O2•− and by inhibiting the NF-kB activation path- is diminished after an UV exposure, an exogenous
way [4, 14]. Therefore, SOD B could play an effective supplementation in antioxidants, including SOD B,
role in numerous inflammatory skin disorders. might be a protective strategy against skin oxidative
However, SOD activity in the skin is 5–10 times damages [16].
lower than in other tissues and does not signifi- Several studies indicate a protective effect of SOD B
cantly differ from dermis to epidermis. Some au- against UV-induced cutaneous damage.
thors reported an age-related decrease in SOD ac-
tivity. This, associated with the strong exposure of SOD B and keratinocyte apoptosis
skin to exogenous threats, could explain the bene- Sasaki et al. [21] examined the possible role of en-
ficial effect of SOD B supplementation [15]. dogenous Cu,Zn-SOD against UV-B-mediated ker-
atinocyte injury in vitro. They demonstrated that
SOD efficiency in skin oxidative disorders Cu,Zn-SOD plays a primary protective role against
UV radiation UV-B-induced injury on human keratinocytes.
Extensive evidence supports the notion that the Takahashi et al. [19] confirmed these findings by
whole solar spectrum (UV, visible and infrared showing that a transfection of Cu,Zn-SOD expres-
wavelengths) participates in skin cell damage. How- sion vector suppresses the UV-B-induced apoptosis
ever, UV wavelengths are regarded as the most haz- of keratinocytes. Morel and Lacan [22] demon-
ardous and most toxic. Among exogenous sources strated that SOD B (30 IU SOD/ml) reduces ker-
that can induce ROS production, UV is the most atinocyte apoptosis with a maximal protective ef-
important factor for the skin, contributing to 80% fect when administered 24 h before UV exposure.
of ROS production [16].
UVR affecting the skin are composed of two types SOD B and pro-inflammatory cytokine production
of waves: UV-A (320–400 nm) and UV-B (290– SOD has also been studied for its role in the pre-
320 nm). Although it is well accepted that low levels vention and inhibition of inflammation induced
of ROS are continuously produced and are involved by UV exposure. Filipe et al. [20] demonstrated
in physiological processes, there is accumulating that topical application of a highly purified Cu,Zn-
evidence of the damaging effects of higher concen- SOD from bovine erythrocytes (specific activity at
trations of ROS generated in vitro and in vivo after 5000 units/mg protein) is able to inhibit the acute
UV-A and UV-B irradiation of the skin [17, 18]. UVR inflammatory response induced by UV-A irradiation
increase activities of both NADPH oxidase and XO on human skin.
in human keratinocytes, increasing production of Morel and Lacan [22] showed that the protective
O2•−. At the same time, both UV-A and UV-B activate effect of SOD B against cutaneous inflammation is
NOS in the skin, increasing levels of NO•. due to the inhibition of pro-inflammatory media-
Cellular antioxidant defence mechanisms are cru- tors. Stimulation of human keratinocytes by UV
cial for the prevention or removal of the damage induces the production of TNF-α, IL-6 and NO• via
caused by the oxidising component of UVR. There activation of inducible NOS in these cells. A signif-
have been many reports on the antioxidant defence icant reduction in the production of these cytokines
mechanisms of the skin in response to UV irradia- is observed when SOD B is administered 24 h before
tion. These reports show that a single exposure to irradiation and at the time of irradiation [22].
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Kim et al. [4] studied the mechanism of action of This confirms the capacity of SOD to reduce UVR-
SOD in angiogenesis and inflammation. They ex- induced damage such as erythema. The ability to
posed the dorsal skin of mice to high doses of UV- reduce erythema is a measure of anti-irritant capa-
B irradiation. UV-B-irradiated wild-type mice show bilities, which highlights free radical-scavenging
markedly increased epidermal hyperplasia, hyper- ability.
keratinisation and inflammatory cell infiltration. All these studies show that the antioxidant and
These changes are significantly decreased in SOD anti-inflammatory effects of SOD B could be inter-
transgenic mice. Overall, the anti-angiogenic and esting against UV light-induced cutaneous damage.
anti-inflammatory effects of SOD might be due to These findings suggest that SOD B could be efficient
suppression of HIF-1α, PKC and NF-κB expression. against UV radiation side effects such as ageing,
These results highlight the anti-inflammatory prop- photocarcinogenesis and immunosuppression.
erties of SOD B and confirm its mechanism of ac-
tion against the expression of redox-sensitive pro- Wound healing
tein kinases and transcription factors. As ROS play Reduced collagen deposition could explain the de-
an important role as second messengers able to ac- velopment of dermal atrophy and would be related
tivate these pathways, SOD B is able to prevent the to poor wound healing in the elderly. Impaired
development and promotion of UV-induced in- wound healing is indeed one of the clinical char-
flammation. This results in the inhibition of pro- acteristics of photoageing [18]. Skin-wound healing
inflammatory cytokines. starts immediately after injury and consists of three
phases: inflammation, proliferation and matura-
SOD and erythema tion. The wound is continually stimulated to pro-
As SOD exhibits potent anti-inflammatory activity, duce inflammatory mediators, resulting in a pro-
some authors investigated whether it could prevent longed inflammatory phase.
and inhibit the development of inflammatory re- Excessive production of ROS causes tissue damage
sponses such as erythema. and impairs the wound healing process. Increased
Activation of NF-κB leads to the expression of pro- levels of ROS, during excessive contamination of
inflammatory enzymes such as cyclooxygenase-2 the wound, can inhibit cell migration and prolifer-
(COX-2). This enzyme is responsible for the for- ation and can even cause severe tissue damage.
mation of important inflammatory mediators Cu,Zn-SOD-deficient mice have been reported to
called prostaglandins (PG), including PGE2, an es- suffer skin atrophy due to collagen and elastin de-
sential fatty acid derivative which mediates the in- generation [25]. These data are consistent with
flammatory response conducing to erythema [4]. those of Iuchi et al. [26], who confirm that the re-
Di Mambro and Fonseca [23] examined the ability dox system in mice is dysfunctional and may cause
of SOD (applied topically) to reduce UV-induced the facial inflammation and the delayed healing
erythema and showed that SOD is effective in in- process. Rasik and Shukla [27] showed that SOD
hibiting UVB-induced skin erythema for 48 h after activity is reduced upon skin injury and is not fully
a single application. recovered within 14 days. They add that low levels
Lods et al. [24] reported that SOD was able to reduce of SOD accompanied by raised levels of markers of
the production of PGE2 in vitro. hese results high- free radical damage play a significant role in delay-
light the anti-inflammatory properties of SOD and ing wound healing. This suggests that efficient an-
confirm its mechanism of action against the ex- tioxidant treatment with increased SOD activity
pression of redox-sensitive protein kinases and tran- could play an important role in impaired wound
scription factors. healing.
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Topically applied, SOD (human recombinant actin. This results in a rapid increase in the amount
Cu,Zn-SOD encapsulated in liposomes) reduces the of collagen detected in the wound, as well as in in-
size of post-burn wounds and the formation of cisional tensile strength. This amplified response
oedema in rabbits. Results suggest that local treat- leads to the histological modifications that charac-
ment of burn wounds with enzymatic radical scav- terise radiation-induced fibrosis (RIF).
engers, such as SOD, has a beneficial effect on the Fibrosis is characterised by the deposition of newly
extent of the post-burn damage [28]. formed ECM components resulting from an altered
To confirm this theory, the therapeutic potential of balance between connective tissue production and
an SOD mimetic (MnTBAP, applied IP) on the dia- degradation and the accumulation of myofibro-
betic wound healing process was examined [29]. blasts in the late phases. Authors observed that
MnTBAP significantly accelerates diabetic wound myofibroblasts have a depleted antioxidant system
closure and increases vascular density in treated and a deficiency of endogenous Mn-SOD, resulting
mice (n=12, 10 mg/kg), possibly by restoring local in cell proliferation [32]. Thus, an association be-
levels of VEGF. VEGF protein and mRNA expression tween an imbalance of the redox state of the tissue
are significantly increased (65±0.5%) in treated mice. and accumulation of ECM appears to be a common
As neovascularisation is essential for the synthesis, parameter of chronic inflammatory processes lead-
deposition and organisation of a new ECM, the ing to the development of fibrosis. Hence, protective
improvement of VEGF expression explains the ef- enzymes like SOD could be used to prevent the pro-
ficient mechanism of action of SOD. duction of ROS and its consequences for fibrosis.
These studies confirm that ROS play an important SOD exhibits potent anti-inflammatory properties
role in the failure of ischaemic wound healing and and is the best candidate to fight fibrosis, since
that SOD B could improve healing in skin wounds. anti-fibrosis properties of SOD have been studied,
with more than 130 scientific studies published.
Fibrosis In the 1990s, SOD was already used as a powerful
During normal wound healing, inflammation anti-fibrotic therapeutic agent to prevent and resorb
processes are stopped once the filling is ensured. radiotherapy-induced fibrosis [31]. Therefore, in
However, in several pathological cases, the infiltra- the treatment of various fibrotic skin diseases, mod-
tion by inflammatory cells is permanent, leading to ulation of skin SOD activity to inhibit some oxida-
the generation of continuous mediators such as ROS tive stress damage has been described with clinical
growth factors or cytokines. This provokes fibroblast success [33, 34].
recruitment, proliferation and differentiation into The anti-fibrotic properties of SOD imply the re-
myofibroblasts, improving the inflammatory re- duction of the fibrotic block. Lefaix et al. [35]
sponse. Gabbiani [30] first described the existence demonstrated that both Cu,Zn-SOD and Mn-SOD
of a particular cell type during wound healing: the isoforms induce 70% regression of a well estab-
myofibroblasts. These cells have contractile proper- lished fibrotic tissue in vivo (n=10) [35].
ties and are directly involved in many inflammatory Clinical studies confirm the capacity of SOD to re-
and fibroproliferative diseases such as scleroderma duce and counteract the fibrosis process. Delanian et
and Crohn’s disease, and in all fibrosis. al. [33] showed that systemic injections of liposomal
The cytokine TGF-β seems to be a key element re- Cu,Zn-SOD (3300 units/mg) for 3 weeks signifi-
sponsible for initiating, developing and maintain- cantly and durably reduced long-standing fibrosis
ing myofibroblast stimulation [31]. The formation following radiation therapy. Campana et al. [34]
of these cells in the wound generates a constrictive observed that Cu,Zn-SOD (3600 units/mg twice a
force thanks to the expression of α-smooth muscle day) applied topically in 44 patients with clinical
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radio-fibrosis is effective in decreasing the fibrotic tion, SOD leads not only to the arrest of fibrosis
area size in half of the cases after 6 months of sup- aggravation, but also to the dissolution of the pre-
plementation. existing matrix network.
The reduction of the fibrotic block implies the elim- This supports the theory that SOD B could repre-
ination of myofibroblasts. The molecular mecha- sent an efficient anti-fibrotic agent. This has been
nisms underlying this regression were elucidated confirmed in the paragraph discussed below.
in the early 2000s. In vitro studies conducted by
Delanian et al. [32] and Vozenin-Brotons et al. [31] Cellulite
demonstrate that treatment with SOD affects the Cellulite is a connective tissue disorder affecting
homeostasis of myofibroblasts by inducing the phe- more than 90–95% of women, representing 1.7 bil-
notypic reversion of myofibroblasts into normal lion women around the world. It results from a
fibroblasts. These authors showed that this pheno- chronic inflammatory process secondary to the
typic reversion is correlated with the inhibition of hormonal activity of the menstrual cycle, provok-
TGF-β1 (Fig. 5) [31]. ing continuous collagen destruction [37]. Nürn-
This mechanism of action explains the breaking of berger and Müller [38] argued in favour of the im-
the chronic stimulation of the fibrotic process. portance of connective tissue degradation in the
Thanks to this specific effect, it is postulated that cellulite evolution, as part of the normal ageing
SOD contributes to the regeneration of fibrotic tis- process. This theory was later confirmed by Mir-
sues. Lefaix et al. [35] confirmed this theory by rashed et al. [39], who studied the link between
demonstrating that Mn-SOD (10 mg/10 kg for connective tissue density and degree of cellulite.
3 weeks at 3300 units/mg) reverses the radiation- They found that low density of connective tissues
induced fibrotic process in experimental animals in women with cellulite leads to fat accumulation,
(n=10) and permits the regeneration of fibrotic tis- causing connective damage. These alterations lead
sues in a zone of well established post-irradiation to a consequent increase in collagen production
fibrosis. characteristic of a fibrosclerotic condition in the
Overall, these findings support the conclusion that abdomen, thighs and flanks [37].
anti-fibrotic properties of SOD allow the phenotype As fibrosis is one of the main mechanisms involved
reversion of myofibroblasts and restore the dis- in cellulite, SOD may reduce and counteract the
turbed balance between ECM synthesis and degra- cellulite process thanks to its anti-fibrotic proper-
dation. Thanks to this specific mechanism of ac- ties. A double-blind randomised placebo-controlled
clinical study on women presenting cellulite was
conducted. This study was performed on 41 healthy
Myofibroblast
Fibroblast
SOD response women with cellulite aged between 31 and 50 years
Phenotype reversion
old with visible fat nodes on the stomach and/or
Apoptosis?
thighs [40]. Women were divided into two groups:
a group (n=21) supplemented orally with 40 mg
SOD
(560 IU SOD) per day of coated and bioactive SOD B
Irradiation
TGF-`1
(14,000 IU/mg), and a group (n=20) supplemented
Inflammation/cicatrisation
with a placebo, for 56 days. The aspect of the skin
was assessed, in terms of cellulite, by scoring fat
Fibroblast
Stress response Myofibroblast nodes, without pinching, according to the linear
non-structured scale ranging from 8 to 10. When
Figure 5 The anti-fibrotic action of SOD [36]
compared with the basal value (day 0, D0), oral
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posure in vitiligo patients (n=45); 60% of vitiligo ates its effects by downregulating TNF-α, IL-1, IL-6
patients repigment after application of SOD B, com- and NO•.
pared to placebo. These findings demonstrate a significant antipru-
To conclude, the use of a SOD B in association with ritic effect of SOD and suggest that SOD B supple-
nbUV-B is as effective as the use of nbUV-B alone. mentation could be efficient against this disorder.
SOD B helps to support the beneficial effect of the
nbUV-B treatment. More precisely, the addition of SOD and atopic dermatitis
SOD B allows the repigmentation process to be Clinically, SP is claimed to be involved in several
maintained even after a long period following pho- pruritic diseases, including atopic dermatitis (AD).
totherapy treatment, and thus represents a useful AD is a chronic inflammatory skin disease charac-
and safe solution for vitiligo patients. terised by typical distributed eczematous skin le-
sions with lichenification, pruritic excoriations, dry
Pruritus skin and a susceptibility to skin infections. Inflam-
Pruritus is one of the most common symptoms of matory cell activation and dysregulated cytokine
skin diseases. Pruritus is an unpleasant cutaneous production appear to play a critical role in the
sensation that provokes a desire to scratch. It can pathogenesis of AD.
affect equally patients of all ages and both sexes. Its Tsukahara et al. [59] observed that impaired home-
intensity can be mild, moderate, severe and even ostasis of ROS and RNS participates in the develop-
distressing with sleep disturbances, loss of weight, ment and progression of inflammatory process in
discomfort, increased irritability, problems in daily childhood AD. This indicates that oxidative stress
activities and even stress [56]. Keratinocytes express and altered antioxidant defences are involved in the
a range of neuropeptide mediators and receptors pathophysiology of acute exacerbation of AD. This
that appear to be involved in pruritus, including theory is also supported by Niwa and Iizawa [60],
opioids, nerve growth factor (NGF), calcitonin gene- who showed that SOD activity is markedly less in-
related peptide (CGRP) and the pro-inflammatory ducible in serum of AD patients complicated by
neuropeptide substance P (SP) [56]. Each neuropep- cataracts. Thus, the suppression of oxidative stress
tide alone or in coordination with one another can might be a potentially useful strategy for the treat-
cause significant increases in IL-1β and TNF-α pro- ment of AD.
duction, leading to the promotion of inflammation. As SOD provides potent anti-pruritic properties, it
As accumulated evidence demonstrates the anti-in- could also be efficient against atopic AD. SOD B
flammatory properties of SOD, Diehl et al. [56] eval- supplementation may thus be helpful against this
uated the antipruritic effect of topical SOD in a ran- disorder.
domised study including 15 volunteers. They
observed that topical SOD seems to possess a strong Conclusion
antipruritic activity, even in anti-histamine-resistant Skin is a highly metabolic tissue with the largest
pruritus. The antipruritic activity of SOD involves surface area in the body. It serves as the protective
the downregulation of numerous pruritic factors: layer for internal organs. The skin tissue is exposed
• Levels of NGF can be indirectly downregulated to a variety of damaging threats coming from the
by SOD through its activity on various pro-in- outer environment, the skin itself and various en-
flammatory cytokines [57]. dogenous sources. Skin exposure to these endoge-
• There is clearly a regulatory role of SOD in CGRP nous and environmental pro-oxidant agents leads
production and expression [58]. to the harmful generation of ROS, which damages
• Although not acting directly on SP, SOD attenu- proteins, lipids and DNA. Evidence indicates that
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