Você está na página 1de 15

Nutrafoods (2014) 13:13-27

DOI 10.1007/s13749-014-0001-x

Review 13

The role of superoxide dismutase (SOD)

in skin disorders
A review
Sébastien Le Quéré, Dominique Lacan, Benoit Lemaire, Julie Carillon, Karine Schmitt

Correspondence to: Keywords:

Sébastien Le Quéré
skin, superoxide dismutase,
reactive oxygen species,
sebastien.lequere@bionov.fr UV radiation,
Received: 12 July 2013 / Accepted: 8 January 2014
© Springer – CEC Editore 2014

Abstract a protective envelope that is crucial for homeostasis.

Environmental stress factors attack body cells daily. On the other hand, the skin is a major target for
As skin is the first barrier to exogenous threats, such toxic insult by a broad spectrum of physical (i.e.,
as UV exposure, chemicals and pathogens, a proper ultraviolet radiation, UVR) and chemical (xenobi-
strategy to prevent skin inflammation is necessary. otic) agents able to release free radicals, thus altering
As the environment tends to strip away the nutrients the skin’s structure and function [1].
essential to maintain the skin’s hydrolipidic barrier, Reactive oxygen species (ROS) and free radicals
restoration of the skin’s natural antioxidant balance have been implicated in numerous diseases and
seems to be an alternative and convenient method disorders. Skin, due to its location, is exposed to
to maintain healthy skin. At the moment, many many environmental threats. Skin dysfunction
studies have considered superoxide dismutase (SOD) could result in injury to deeper tissues and activate
as a good agent for the prevention or the therapeutic an acute inflammatory response. Free radical scav-
treatment of skin inflammation. Therefore, we will engers and antioxidants have thus been proposed
discuss the mechanism of action of SOD in numer- as protective or therapeutic agents against ROS-
ous skin disorders and evaluate whether the use of a mediated injuries [1].
powerful antioxidant like SOD B can help deliver This article was thus designed to describe whether
benefits against skin alterations. superoxide dismutase (SOD B) can prevent and re-
sorb the development of skin inflammatory disor-
Introduction ders. In particular, the role of SOD B against UVR
Skin is the largest organ of the body and serves as damage will be discussed, as well as against some
an important environmental interface. It provides secondary effects due to inflammatory processes
such as healing, fibrosis, psoriasis and vitiligo.

Sébastien Le Quéré (•), Dominique Lacan, Benoit Lemaire,

Julie Carillon, Karine Schmitt
Skin alterations
Bionov – Site Agroparc, Bâtiment Orion Skin and oxidative stress
Chemin des Meinajaries, CS 80501 As human skin is responsible for protecting the in-
84908 Avignon 9, France
tel +33(0)787 979 866 ternal organs from the toxic external environment,
sebastien.lequere@bionov.fr skin is therefore the major target of ROS.

14 Nutrafoods (2014) 13:13-27

Exogenous Endogenous
Ultraviolet Radiation Environmental pollulants Xenobiotics Intracellular processes:
ATP generation
Phagocytic defense
Nucleotide degradation
UVB UVA Secondary messengers

Production of ROS (Figure 2)

Antioxidants defense system Oxidative Stress

(enzymatic, non-enzymatic)

Cellular substructure

DNA mutations Lipid peroxidation Protein peroxidation

Clinical effects

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.

Nutrafoods (2014) 13:13-27

Skin and inflammation of transforming growth factor-beta (TGF-β). TGF-β

There is overwhelming evidence that, by inducing is a major pro-fibrotic cytokine that downregulates
ROS production, endogenous and exogenous agents the inflammatory response. It is a major stimulus
activate several signalling pathways in the skin. In- for collagen deposition [2].
deed, ROS are both stress-inducing compounds and ROS production also involves the upregulation of
signalling molecules that control, among other hypoxia-inducible factors (HIFs), matrix metallo-
things, gene expression and cellular metabolic ac- proteinases (MMPs), cyclooxygenase-2 (COX-2) and
tivities [2]. Oxidising species released during skin inducible nitric oxide synthase (iNOS), which are
infiltration with inflammatory cells, or produced related to angiogenesis and inflammation in vitro
by keratinocytes in response to chemical and phys- and in vivo [4].
ical exposures, play an important role as second The upregulation of key MMPs associated with the
messengers in redox-sensitive signal transduction inhibition of TGF-β leads to enhanced collagen
processes and in gene expression leading to inflam- breakdown and increases the elastin production in
mation. the extracellular matrix (ECM). Imperfect repair of
That is why Reuter et al. [3] underlines that in- the dermal damage impairs the functional and
flammation is one of the manifestations of oxida- structural integrity of the ECM. Given that ECM is
tive stress and that the pathways that generate the essential for tissue homeostasis, any changes in its
mediators of inflammation are often induced by microenvironment can be detrimental to cell func-
oxidative stress. tion during inflammation. These molecular path-
The inflammation process includes a cascade of ways driven by ROS play important roles in diverse
events, which involve infiltration of inflammatory skin alterations (Fig. 2) [2]. The inflammatory cas-
blood leucocytes (macrophages and neutrophils). cade promotes the production of ROS, perpetuating
These peripheral blood leukocytes interact with oxidative damages and leading to numerous skin
vascular endothelium in various types of inflam- alterations.
matory reactions, which further produce ROS (via
the expression of NADPH oxidase) and increase ox-
idative stress. Reuter et al. [3] highlights that the BROS

relationship between oxidative stress and inflam-

BInflammatory cytokines & Growth factors,
mation results in a loop in which ROS cause in- Receptor activation

flammation, which in turn increases the produc-

tion of ROS. Nucleus

ROS, particularly O2•−, cause activation of cell sur-

face cytokines (tumour necrosis factor-alpha ?Inflammatory cytokines BMMP expression ?Procollagen synthesis BElastin expression

(TNF-α), interleukin-1 (IL-1) and IL-6) and growth

factor receptors (such as vascular endothelial ?Collagen production
growth factor (VEGF)), which contribute to the in- BCollagen breakdown
Extracellular BElastin accumulation
duction and maintenance of cutaneous inflamma- Matrix
tion [2, 4].
ROS activate various signalling pathways through Clinical signs of photoageing:
Solar elastosis, deep wrinkles,
oxidation of reactive cysteine residues on specific Skin coarse textures, telangiectasias,
target molecules such as redox-sensitive transcrip- pigmentation

tion factors, nuclear factor-κB (NF-κB) and activator

Figure 2 Role of ROS in inflammation and skin alterations [2]
protein 1 (AP-1). This leads to the downregulation

16 Nutrafoods (2014) 13:13-27

SOD: definition and mechanism of action RNS Oxidative

path damages
SOD: antioxidant properties NOS
L-arginine + O2 NOs ONOOn OHs + NO2
Superoxide dismutase (SOD) is an ubiquitous an-
tioxidant enzyme, naturally present in all aerobic Cu-Zn SOD
organisms, including mammals and plants, but also path Nox
Fe-SOD & GPx Primary
O2 O2sn H2O2 H2O + O2 antioxidants
+1sn Dismutation
in some anaerobic bacteria. SOD exists as different
isoforms that have similar functions but present
Fe2+; Cu+
differences in protein structure, metal cofactor re- Proteins & lipids H2O H+ + 1sn Fenton reaction
quirements and cellular compartmentalisation. OHs
SOD is defined as the first line of antioxidant de- H2O

fence of the body, known as a primary antioxidant. RH

Rs damages
As an enzyme, SOD exhibits a very high catalytic
rate of reaction and is constantly renewing itself.
This mode of action is radically different from the ROOs Secondary
so-called secondary antioxidants (vitamin C, vita-
min E, glutathione, carotenoids, polyphenols, min- ROH + H2O

eral, etc.), which are quickly exhausted with no

Figure 3 Oxidative damage cascade and antioxidant defences
possibility of renewal [5]. in the human body
SOD converts the extremely reactive superoxide
anion O2•− into hydrogen peroxide H2O2. By dis-
muting O2•−, SOD prevents the liberation of free SOD3, located in the ECM and specifically ex-
iron ions and, thus, the formation of harmful ROS pressed in the epidermis and dermis) in the inhibi-
such as OH•. At the same time, SOD protects the tion of inflammation. Unlike other SODs, SOD3
vascular signalisation from NO• by preventing its has a heparin-binding domain that interacts with
reaction with O2•− and the formation of peroxini- heparan sulphate proteoglycans on cell surfaces
trite ONOO–, a harmful reactive nitrogen species and in the ECM. Thus, the cleavage of SOD3 fol-
(RNS) (Fig. 3). lowing exposure to exogenous and endogenous
Evidence accumulated in recent years, including threats means that the enzyme is no longer in a
more than 50,000 scientific works published on position to protect against stimuli. In such a state,
SOD, has shown that SOD has a protective physio- an inflammatory reaction is initiated. These authors
logical function. added that SOD levels in skin were altered upon
the progression of inflammation.
SOD: anti-inflammatory properties Interestingly, Ookawara et al. [10] showed that the
In 1971, a link was established between SOD and heparin-binding domain of SOD3 can act as a nu-
Orgotein®, a protein isolated several years earlier clear localisation signal in certain cell types, sug-
by Huber and co-workers [6]. Since this date, nu- gesting that SOD3 may act not only as an antioxi-
merous studies have reported the anti-inflamma- dant, but also as a controller of signal propagation.
tory properties of this protein [7, 8]. Kim et al. [4] confirmed this hypothesis and as-
Considering that the skin is the primary contact sessed the involvement of redox-sensitive pathways
with the exogenous environment, it is necessary to determine the anti-angiogenic and anti-inflam-
to understand the role of SOD in the prevention matory properties of SOD in the skin. They found
or suppression of skin inflammation. that one mechanism of action of SOD against in-
Kwon et al. [9] studied the role of SOD (EC-SOD or flammation is related to modulation of the expres-

Nutrafoods (2014) 13:13-27

control T-cell-mediated immune diseases, including

SOD inflammatory diseases. This is why it seems that
O2 Inflammatory the SOD-mediated anti-inflammatory effect is not
cytokines simply due to its action against ROS.

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

18 Nutrafoods (2014) 13:13-27

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].

Nutrafoods (2014) 13:13-27

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.

20 Nutrafoods (2014) 13:13-27

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

Nutrafoods (2014) 13:13-27

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
SOD response women with cellulite aged between 31 and 50 years
Phenotype reversion
old with visible fat nodes on the stomach and/or
thighs [40]. Women were divided into two groups:
a group (n=21) supplemented orally with 40 mg
(560 IU SOD) per day of coated and bioactive SOD B
(14,000 IU/mg), and a group (n=20) supplemented
with a placebo, for 56 days. The aspect of the skin
was assessed, in terms of cellulite, by scoring fat
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

22 Nutrafoods (2014) 13:13-27

demonstrated that the ability of neutrophils to pro-

Placebo Coated SOD B
duce ROS is significantly enhanced in patients with
6.8 acne vulgaris. At the same time, Grange et al. [43]
* *
Anti-cellulite effect on thighs

showed that the production of ROS, and especially

–11.3% O2•−, is a very early event occurring almost immedi-
(mean of scores)

ately after the stimulation of keratinocytes with P. ac-

nes. These authors suggest that the burden of oxida-
tive stress may not be a mere consequence of acne,
but may be an early event that helps to drive the
acne process. To support this theory, Sarici et al. [44]
D0 D28 D56 and Al-Shobaili et al. [45] found lower SOD activity
Figure 6 Significant reduction of fat nodes on thighs at D28 in acne patients, which confirms that the antioxi-
and D56 compared to placebo (*p<0.05; n=41). dant defence system is damaged in acne vulgaris.
Values are mean of scores ±SD [40]
The disrupted balance between ROS and antioxi-
dants contributes to the promotion of inflammation.
supplementation with coated SOD B significantly Thirty percent of patients with inflammatory acne
reduced fat nodes on thighs by 9.5% (p=0.0152) are prone to significant scarring, which is disfigur-
and 11.3% (p=0.0217), respectively, at day 28 (D28) ing and difficult to treat. A scar is defined as a “fi-
and day 56 (D56) (Fig. 6) [40]. brous tissue that replaces normal tissue destroyed
These results are interesting because it is the first by injury or disease”. Indeed, scarring is a conse-
time that a 100% natural ingredient, supplemented quence of abnormal resolution or wound healing
orally, has been demonstrated to significantly re- after the damage that occurs in the sebaceous folli-
duce cellulite compared to a placebo. cle during acne inflammation [46]. This is why col-
Considering the real and huge consumer expecta- lagen and other tissue damage from the inflamma-
tion and the scientific evidence of SOD B’s efficacy tion of acne leads to permanent skin texture
against cellulite, we can state that SOD B represents changes and fibrosis. As hypertrophic scars contain
an active and efficient agent against a major cos- abundant myofibroblasts, it is conceivable that an
metic issue. alteration of the process of myofibroblast disap-
pearance in distinct locations may result in the
Acne pathological formation of acne lesions [47].
Affecting more than 80–90% of adolescents and SOD could act at different levels in acne. First of
young adults, acne is a disorder of childhood and all, SOD may prevent the development and the
adolescence which deeply impacts people physi- promotion of inflammation by inhibiting the pro-
cally and emotionally. Various pathophysiologic duction of ROS by inflammatory cells. Then, in
factors are involved in the development of acne le- case of prolonged inflammation and scarring, SOD,
sions, microcomedones, comedones and inflam- thanks to its anti-fibrotic properties, may resorb
matory lesions. These factors include follicular hy- the fibrosis state by inducing the phenotype rever-
perkeratosis, increased colonisation of follicles by sion of myofibroblasts into fibroblasts. Therefore
Propionibacterium acnes, and increased sebum pro- SOD could be efficient against both mild and severe
duction and inflammatory mediators [41]. acne. Overall, SOD B supplementation may be use-
ROS are responsible for the irritation and destruction ful in order to restore antioxidant defence levels,
of the follicular wall that ends with inflammation and counteract the acne process and these related
and progression of acne. Akamatsu and Horio [42] alterations.

Nutrafoods (2014) 13:13-27

Psoriasis the skin: melanocytes. Evidence has shown the role

Psoriasis is the most common chronic inflamma- of oxidative stress as the initial event in melanocyte
tory skin disorder, affecting about 2% of the general degeneration.
population. Psoriasis is a complex and multifacto- Whatever the originating causes of vitiligo, it has
rial skin disease that seems to be genetically pre- been observed that the epidermis undergoes ox-
disposed and immune-mediated. The exact aetio- idative stress that is believed to have a fundamental
logical factor for psoriasis is not yet clearly known, role in the pigment cell degeneration, characteristic
but trauma, skin infection, drugs, emotional stress, of this disorder. Schallreuter  et  al. [50] demon-
alcohol and smoking greatly influence its clinical strated in vitro and in vivo evidence for epidermal
development [48]. The symptoms of psoriasis are H2O2 accumulation in patients with active vitiligo.
erythema, itching, thickening and scaling of the This H2O2 overproduction can cause inactivation
skin. Histological examination of psoriatic plaques of catalase as well as vacuolation in epidermal
reveals three major pathogenic factors: abnormal melanocytes and keratinocytes. Dell’Anna et al. [51]
keratinocyte differentiation, hyperproliferation of observed an imbalance in the intracellular redox
keratinocytes and infiltration of inflammatory cells status and a significant depletion of enzymatic and
(macrophages and leukocytes) into the skin, leading non-enzymatic antioxidants in the epidermis of vi-
to the release of ROS and oxidative damage. tiligo patients. This represents a fingerprint of ab-
Pujari et al. [48] found that plasma lipid peroxida- normal oxidative stress, capable of injuring epider-
tion is significantly higher in psoriatic patients mal cells including keratinocytes and melanocytes.
than in controls. In addition, the same authors ob- These findings support the theory for the need for
served that the NO• concentrations in the serum restoration of antioxidant enzyme levels, in order
of psoriasis patients are significantly higher as com- to help counteract oxidative stress and prevent the
pared to control levels. These findings provide ev- development of vitiligo. It supports an adjuvant
idence of increased ROS production. Then, Gor- role of antioxidant treatments in vitiligo. Specifi-
nicki and Gutsze [49] determined the serum levels cally, supplementation with a complex of SOD/cata-
of SOD and its correlation with the severity of pso- lase appears to be the most efficient solution.
riasis. They noticed that activities of the antioxi- Sanclemente et al. [52] investigated the effect of a
dant enzymes, SOD but also catalase, decrease in topical complex of catalase/SOD applied twice daily
erythrocytes of psoriasis patients as compared to in vitiligo patients (n=25) for 10 months. At the
the control subject. end of the treatment, the percentage of skin repig-
These studies clearly indicate that the lower level mentation increased to 56.5% in the treated group
of enzymatic antioxidant defences and the higher compared to placebo.
level of oxidative damages observed in psoriatic Even though some studies reported that narrow-
patients are associated with the severity of psoriasis. band UV-B (nbUV-B) alone is as effective as when
SOD  B supplementation may thus be a new ap- added to SOD B [53], Yones et al. [54] showed that
proach to relieve angiogenic and inflammatory skin the addition of SOD B allows the repigmentation
disorders such as psoriasis. to be maintained over a long period after the treat-
ment. Faria  et  al.  [55] confirmed that supporting
Vitiligo the antioxidant system with formulations including
Vitiligo is a depigmenting skin disease which occurs SOD and catalase could increase the success of
in all skin types, with equal frequencies in men and nbUV-B treatment in vitiligo. These authors evalu-
women. Vitiligo results from a gradual disappear- ated the clinical response of treatment with coated
ance of the cells responsible for pigmentation of SOD B (applied topically) associated with sun ex-

24 Nutrafoods (2014) 13:13-27

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

Nutrafoods (2014) 13:13-27

many skin disorders are mainly caused by oxidative Human Rights

stress. Large amounts of ROS result in an acute in- All procedures followed were in accordance with the ethical
flammatory response characterised by the recruit- standards of the responsible committee on human experimen-
ment of numerous inflammatory cells. The release tation (institutional and national) and with the Helsinki Decla-
of pro-inflammatory mediators leads to the pro- ration of 1975, as revised in 2000.
motion of ROS production and the activation of
redox-sensitive activation pathways. These molec- Informed consent
ular pathways driven by ROS play important roles Informed consent was obtained from all patients for inclusion
in numerous skin alterations. This confirms the in the study.
close association between oxidative stress and in-
flammation. Animal studies
SOD B has a high capacity to remove free radicals, All institutional and national guidelines for the care and use of
one of the main causes of skin disorders. Thanks laboratory animals were followed.
to its powerful antioxidant potential, SOD  B ex-
hibits potent anti-inflammatory properties by in- References
1. Bickers DR, Athar M (2006) Oxidative stress in the patho-
hibiting the expression of ROS-sensitive transcrip-
genesis of skin disease. J Invest Dermatol 126(12):2565–2575
tion factors. These effects may be due to its ability 2. Chen L, Hu JY, Wang SQ (2012) The role of antioxidants in
to inhibit pro-inflammatory intermediates that fur- photoprotection: a critical review. J Am Acad Dermatol
ther damage skin homeostasis and accelerate its 67(5):1013–1024
3. Reuter S, Gupta S, Chaturvedi M, Aggarwal B (2010) Ox-
idative stress, inflammation, and cancer: how are they
Specifically, SOD has an anti-fibrotic action. This linked? Free Radic Biol Med 49(11):1603–1616
acts by reducing collagen accumulation in the der- 4. Kim Y, Kim BH, Lee H et al (2011) Regulation of skin in-
mis of irradiated skin and reactivating cellular func- flammation and angiogenesis by EC-SOD via HIF-1α and
NF-κB pathways. Free Radic Biol Med 51(11):1985–1995
tions in dermal fibroblasts and epidermal cells, as
5. Bafana A, Dutt S, Kumar A, Kumar S, Ahuja P (2011) The
demonstrated by phenotypic changes of myofibro- basic and applied aspects of superoxide dismutase. J Molec
blasts. These findings suggest that SOD  B supple- Catal B 68(2):129–138
mentation could play an efficient role in cutaneous 6. Huber W (1981) Orgotein—(bovine Cu-Zn superoxide dis-
mutase), an anti-inflammatory protein drug: discovery, tox-
wound healing and acne, which are characterised
icology and pharmacology. Eur J Rheumatol Inflamm
by a fibrosis process. It has also been demonstrated 4(2):173–182
that SOD B reduces cellulite in women. 7. Menander-Huber KB, Edsmyr F, Huber W (1978) Orgotein
It can be concluded that oxidative stress is largely (superoxide dismutase): a drug for the amelioration of ra-
diation-induced side effects. Urol Res 6(4):255–257
involved in skin disorders. Accumulated evidence
8. McIlwain H, Silverfield JC, Cheatum DE et al (1989) Intra-
has demonstrated that SOD  B, as a powerful an- articular orgotein in osteoarthritis of the knee: a placebo-
tioxidant, is a useful and natural solution to skin controlled efficacy, safety, and dosage comparison. Am J
disorders. Med 87(3):295–300
9. Kwon M-J, Kim B, Lee YS, Kim T-Y (2012) Role of superoxide
dismutase 3 in skin inflammation. J Dermatol Sci 67(2):81–87
Conflict of interest
10. Ookawara T, Imazeki N, Matsubara O et al (1998) Tissue
The authors Sébastien Le Quéré, Dominique Lacan, Benoit distribution of immunoreactive mouse extracellular super-
Lemaire and Julie Carillon work for the company Bionov as, re- oxide dismutase. Am J Physiol 275(3 Pt 1):C840–847
11. Shofian N, Hamid A, Osman A et al (2011) Effect of freeze-
spectively, products manager, R&D director, marketing and busi-
drying on the antioxidant compounds and antioxidant activity
ness director, and preclinical research manager. The author of selected tropical fruits. Int J Molec Sci 12(7):4678–4692
Karine Schmitt works for the company Activ’Inside as senior 12. Orak H, Aktas T, Yagar H, Isbilir S, Ekinci N, Sahin F (2011)
innovation projects manager. Antioxidant activity, some nutritional and colour properties

26 Nutrafoods (2014) 13:13-27

of vacuum dried strawberry tree (Arbutus unedo L.) fruit. 27. Rasik A, Shukla A (2000) Antioxidant status in delayed
Acta Scientiarum Polonorum 10(3):327–338 healing type of wounds. Int J Exp Pathol 81(4):257–263
13. Carillon J, Rouanet J, Cristol J, Brion R (2013) Superoxide 28. Vorauer-Uhl K, Furnschlief E, Wagner A, Ferko B, Katinger
dismutase administration, a potential therapy against ox- H (2001) Topically applied liposome encapsulated super-
idative stress related diseases: several routes of supplemen- oxide dismutase reduces postburn wound size and edema
tation and proposal of an original mechanism of action. formation. Eur J Pharm Sci 14(1):63–67
Pharm Res 30(11):2718–2728 29. Churgin S, Callaghan M, Galiano R, Blechman K, Ceradini
14. Cui Y, Robertson J, Maharaj S et al (2011) Oxidative stress D, Gurtner G (2005) Therapeutic administration of super-
contributes to the induction and persistence of TGF-beta1 oxide dismutase (SOD) mimetics normalizes wound healing
induced pulmonary fibrosis. Int J Biochem Cell Biol in diabetic mice. J Am Coll Surg 201(3, Suppl):S57
43(8):1122–1133 30. Gabbiani G (1994) Modulation of fibroblastic cytoskeletal
15. Andersen HR, Nielsen JB, Nielsen F, Grandjean P (1997) features during wound healing and fibrosis. Pathol Res
Antioxidative enzyme activities in human erythrocytes. Pract 190(9–10):851–853
Clin Chem 43(4):562–568 31. Vozenin-Brotons MC, Sivan V, Gault N et al (2001) Antifi-
16. Poljsak B, Dahmane R (2012) Free radicals and extrinsic brotic action of Cu/Zn SOD is mediated by TGF-beta1 re-
skin aging. Dermatol Res Pract (135206):4 pression and phenotypic reversion of myofibroblasts. Free
17. Jurkiewicz B, Buettner G (1994) Ultraviolet light-induced Radic Biol Med 30(1):30–42
free radical formation in skin: an electron paramagnetic 32. Delanian S, Martin M, Bravard A, Luccioni C, Lefaix JL (2001)
resonance study. Photochem Photobiol 59(1):1–4 Cu/Zn superoxide dismutase modulates phenotypic changes
18. Scharffetter-Kochanek K, Brenneisen P, Wenk J et al (2000) in cultured fibroblasts from human skin with chronic radio-
Photoaging of the skin from phenotype to mechanisms. therapy damage. Radiother Oncol 58(3):325–331
Exp Gerontol 35(3):307–316 33. Delanian S, Baillet F, Huart J, Lefaix JL, Maulard C, Housset
19. Takahashi H, Hashimoto Y, Aoki N, Kinouchi M, Ishida-Ya- M (1994) Successful treatment of radiation-induced fibrosis
mamoto A, Iizuka H (2000) Copper, zinc–superoxide dis- using liposomal Cu/Zn superoxide dismutase: clinical trial.
mutase protects from ultraviolet B-induced apoptosis of Radiother Oncol 32(1):12–20
SV40-transformed human keratinocytes: the protection is 34. Campana F, Zervoudis S, Perdereau B et al (2004) Topical
associated with the increased levels of antioxidant enzymes. superoxide dismutase reduces post-irradiation breast cancer
J Dermatol Sci 23(1):12–21 fibrosis. J Cell Mol Med 8(1):109–116
20. Filipe P, Emerit I, Vassy J et al (1997) Epidermal localization 35. Lefaix JL, Delanian S, Leplat JJ et al (1996) Successful treat-
and protective effects of topically applied superoxide dis- ment of radiation-induced fibrosis using Cu/Zn-SOD and
mutase. Exp Dermatol 6(3):116–121 Mn-SOD: an experimental study. Int J Radiat Oncol Biol
21. Sasaki H, Akamatsu H, Horio T (2000) Protective role of Phys 35(2):305–312
copper, zinc superoxide dismutase against UVB-induced 36. Martin M, Delanian S, Sivan V et al (2000) Fibrose superfi-
injury of the human keratinocyte cell line HaCaT. J Invest cielle radio-induite et TGF-β1. Cancer/Radiothérapie
Dermatol 114(3):502–507 4(5):369–384
22. Morel C, Lacan D (2000) Evaluation de l’activité protectrice 37. Goldman MP, Hexsel D (2009) Cellulite: pathophysiology
de SOD by Bionov® vis-à-vis du rayonnement UV sur kéra- and treatment (2nd ed.). Informa Healthcare
tinocytes humains normaux. 38. Nürnberger F, Müller G (1978) So-called cellulite: an in-
23. Di Mambro VM, Fonseca MJ (2007) Assessment of physical vented disease. J Dermatol Surg Oncol 4(3):221–229
and antioxidant activity stability, in vitro release and in 39. Mirrashed F, Sharp JC, Krause V, Morgan J, Tomanek B
vivo efficacy of formulations added with superoxide dis- (2004) Pilot study of dermal and subcutaneous fat structures
mutase alone or in association with alpha-tocopherol. Eur by MRI in individuals who differ in gender, BMI, and cel-
J Pharm Biopharm 66(3):451–459 lulite grading. Skin Res Technol 10(3):161–168
24. Lods LM, Dres C, Johnson C, Scholz DB, Brooks GJ (2000) 40. Schmitt K, Simoneau G, Lemaire B, Lacan D (2012) A dou-
The future of enzymes in cosmetics. Int J Cosmet Sci ble-blind, randomized placebo controlled clinical study
22(2):85–94 demonstrates Cellulight® activity on cellulite
25. Murakami K, Inagaki J, Saito M et al (2009) Skin atrophy in 41. Basak P, Gultekin F, Kilinc I (2001) The role of the antiox-
cytoplasmic SOD-deficient mice and its complete recovery idative defense system in papulopustular acne. J Dermatol
using a vitamin C derivative. Biochem Biophys Res Com- 28(3):123–127
mun 382(2):457–461 42. Akamatsu H, Horio T (1998) The possible role of reactive
26. Iuchi Y, Roy D, Okada F et al (2010) Spontaneous skin dam- oxygen species generated by neutrophils in mediating acne
age and delayed wound healing in SOD1-deficient mice. inflammation. Dermatology 196(1):82–85
Mol Cell Biochem 341(1):181–194 43. Grange P, Chereau C, Raingeaud J et al (2009) Production of

Nutrafoods (2014) 13:13-27

superoxide anions by keratinocytes initiates P. acnes-induced 53. Yuksel EP, Aydin F, Senturk N, Canturk T, Turanli AY (2009)
inflammation of the skin. PLoS Pathogens 5(7):e1000527 Comparison of the efficacy of narrow band ultraviolet B
44. Sarici G, Cinar S, Armutcu F, Altinyazar C, Koca R, Tekin N and narrow band ultraviolet B plus topical catalase-super-
(2010) Oxidative stress in acne vulgaris. J Eur Acad Dermatol oxide dismutase treatment in vitiligo patients. Eur J Der-
Venereol 24(7):763–767 matol 19(4):341–344
45. Al-Shobaili H, Alzolibani A, Al Robaee A, Meki A, Rasheed 54. Yones S, Palmer R, Garibaldinos T, Hawk J (2007) Random-
Z (2013) Biochemical markers of oxidative and nitrosative ized double-blind trial of treatment of vitiligo: efficacy of
stress in acne vulgaris: correlation with disease activity. J psoralen-UV-A therapy vs narrowband-UV-B therapy. Arch
Clin Lab Anal 27(1):45–52 Dermatol 143(5):578–584
46. Holland D, Jeremy A (2005) The role of inflammation in 55. Faria B, Contreras S, Ferreira F et al (2005) Vitiligo and Ex-
the pathogenesis of acne and acne scarring. Semin Cutan tramel therapeutic action. XLI Reunión Anual de la So-
Med Surg 24(2):79–83 ciedad Venezolana de Dermatología y Cirugía Dermatológ-
47. Ehrlich H, Desmouliere A, Diegelmann R et al (1994) Mor- ica: Dermatología Venezolana
phological and immunochemical differences between 56. Diehl C, Lipozencic J, Ledic-Drvar D (2009) The basis of
keloid and hypertrophic scar. Am J Pathol 145(1):105–113 topical superoxide dismutase antipruritic activity. Acta Der-
48. Pujari V, Suryakar A, Ireddy S (2009) Oxidants and antiox- matovenerol Croatica 17(1):25–39
idant status in psoriasis patients. Biochem Res 21:221–223 57. Blasing H, Hendrix S, Paus R (2005) Pro-inflammatory cy-
49. Gornicki A, Gutsze A (2001) Erythrocyte membrane fluidity tokines upregulate the skin immunoreactivity for NGF, NT-
changes in psoriasis: an EPR study. J Dermatol Sci 27(1):27–30 3, NT-4 and their receptor, p75NTR in vivo: a preliminary
50. Schallreuter KU, Moore J, Wood JM et al (1999) In vivo report. Arch Dermatol Res 296(12):580–584
and in vitro evidence for hydrogen peroxide (H2O2) accu- 58. Mohri D, Satomi F, Kondo E, Fukuoka T, Sakagami M,
mulation in the epidermis of patients with vitiligo and its Noguchi K (2001) Change in gene expression in facial nerve
successful removal by a UVB-activated pseudocatalase. J nuclei and the effect of superoxide dismutase in a rat model
Investig Dermatol Symp Proc 4(1):91–96 of ischemic facial paralysis. Brain Res 893(1–2):227–236
51. Dell’Anna ML, Maresca V, Briganti S, Camera E, Falchi M, 59. Tsukahara H, Shibata R, Ohshima Y et al (2003) Oxidative
Picardo M (2001) Mitochondrial impairment in peripheral stress and altered antioxidant defenses in children with
blood mononuclear cells during the active phase of vitiligo. acute exacerbation of atopic dermatitis. Life Sci 72(22):
J Investig Dermatol 117(4):908–913 2509–2516
52. Sanclemente G, Garcia JJ, Zuleta JJ, Diehl C, Correa C, Fal- 60. Niwa Y, Iizawa O (1994) Abnormalities in serum lipids and
abella R (2008) A double-blind, randomized trial of 0.05% leukocyte superoxide dismutase and associated cataract for-
betamethasone vs. topical catalase/dismutase superoxide mation in patients with atopic dermatitis. Arch Dermatol
in vitiligo. J Eur Acad Dermatol Venereol 22(11):1359–1364 130(11):1387–1392