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Inflammation & Cell Signaling 2015; 2: e737.doi: 10.14800/ics.737; © 2015 by G. Fabbrocini, et al.
http://www.smartscitech.com/index.php/ics
REVIEW
Fragile Skin: Benefit of Cosmeceuticals based on Rhealba® Oat
plantlet in acne vulgaris
G. Fabbrocini1, M. Saint Aroman2, F. Schmitt3
1
Department of Dermatology and Venereology, University of Naples Federico II, 80100 Naples, Italy
A-DERMA, Pierre Fabre Dermo-Cosmétique, 81500 Lavaur, France
3
A-DERMA, Pierre Fabre Dermo-Cosmétique, 81500 Lavaur, France
2
Correspondence: M. Saint Aroman
E-mail: [email protected]
Received: March 19, 2015
Published online: May 07, 2015
Fragile skin is the state of unbalanced skin characterized by lower resistance to aggressions linked with impaired
barrier function of skin. Acneic skin becomes fragile due to its own pathophysiological mechanism. Indeed,
acneic skin differs from normal skin as it is subject to higher transepidermal water loss and lower stratum
corneum hydration. Moreover, acne vulgaris is also characterized by alterations in the lipid content of sebum
and an inflammation in the sebaceous gland. These alterations lead to hyperproliferation and to an increased
desquamation of keratinocytes within sebaceous follicles. Thus, the accumulation of keratinocytes can block the
pilosebaceous unit, preventing sebum drainage. This results in the formation of microcomedones, and further
acne lesions. Changes of the pilo-sebaceous environment favour the proliferation of Propionibacterium acnes (P.
Acnes). P. acnes exerts several pro-inflammatory activities which trigger the innate immune system by activating
toll-like receptor 2 and NLRP3-inflammasome, resulting in IL-1β secretion in human monocytes. Rhealba® Oat
Plantlets extract (Pierre Fabre Dermo-Cosmetique) has been reported to restore fragile skin, inhibit bacterial
adhesion of P. Acnes, and to be capable of reducing inflammation and irritation in acne. Moreover,
cosmeceuticals including Rhealba® Oat Plantlets extract and hydro-compensating actives, which can be
associated with anti-comedogenic agents (hydroxyl acids), may be usually used stand-alone or in addition to acne
treatments in order to treat acne vulgaris.
Keywords: Fragile skin; Acne vulgaris; Inflammasome; Toll Like Receptor; Rhealba® Oat
To cite this article: G. Fabbrocini, et al. Fragile Skin: Benefit of Cosmeceuticals based on Rhealba® Oat plantlet in acne
vulgaris.Inflamm Cell Signal 2015; 2: e737. doi: 10.14800/ics.737.
disruption of the immune system, including innate immunity
and adaptive immunity[1].
Introduction
The most important function of the skin is to provide a
protective barrier against external threats such as
microorganisms, mechanical impacts, physical insults and
chemicals. Fragile skin is the state of unbalanced skin
characterized by lower resistance to aggressions linked with
impaired barrier function of skin[1]. This impairment is
characterized by an excessive water loss and a reduced
capacitance. In addition, the ability to fend off potentially
invasive microorganisms is also reduced in fragile skin by a
Fragile skin can be categorized differently depending on
its origin. Four categories were established: Firstly, the
physiological fragile skin (age, location). Secondly, fragile
skin can be the results of external and internal factors, like
climate and stress. This type of fragile skin is therefore
classified as circumstantial fragile skin. Then, the fragile skin
caused by peeling or isotretinoin is referred to as iatrogenic
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fragile skin. Finally, the pathological fragile skin is
represented by atopic dermatitis and acne vulgaris[1].
Acne vulgaris is a chronic inflammatory skin disease of
the pilosebaceous unit[2, 3]. The acne pathophysiology is
multifactorial, with microbiological, immunological and
hormonal mechanisms. Propionibacterium acnes (P. acnes),
the predominant organism in the microbiome of facial skin,
has been identified in acne lesions and induces inflammatory
response and causes keratinocytes damage[4, 5]. These
different mechanisms lead to inflammasome activation, and
to an alteration of the epidermal barrier, and thus the acneic
skin becomes fragile.
Acne and epidermal barrier
The epidermal barrier is represented by multiple
physiologic activities occurring within the stratum corneum
(SC). These activities include maintaining skin water content,
protection against microbial organisms, protection from
effects of ultraviolet radiations, neutralization of reactive
oxygen species (ROS) and an immunologic role against
exogenous allergens and haptens[6]. Changes in the epidermal
barrier may participate or exacerbate the development of
acne[1]. Acneic skin differs from normal skin because of
higher transepidermal water loss (TEWL) and lower stratum
corneum hydration (decreased conductance), responsible of
skin dehydration[7]. The severity of acne appears to be
correlated with the increase in transepidermal water loss and
the decreased conductance[7, 8]. These impairments of the
integrity of the skin barrier can cause an accumulation of
corneocytes leading to skin thickening. This build-up of
corneocytes may block the release of sebum from the
pilosebaceous unit[1]. The hyperkeratosis of the follicular
epithelium may result in the formation of comedone[8].
Furthermore, total ceramides (lipid rich matrix) and free
sphingosine are significantly reduced. By causing
hyperkeratosis, the deficiency of intercellular lipid may also
contribute to the comedone formation[8]. Moreover,
inflammation in the pilosebaceous unit can lead to the
follicular wall rupture with subsequent leakage of sebum,
bacteria and keratin into the dermis. This event is
characterized by the occurrence of nodulocystic or nodular
acne lesions[1].
Filaggrin is a fundamental protein in the differentiation of
the epidermis and is involved in the functional and structural
integrity of the stratum corneum[9]. Filaggrin support
cytoskeletal aggregation and formation of the cornified cell
envelope, providing additional strength and structure to
epidermal barrier. Some skin diseases, and especially atopic
dermatitis, are associated with the alteration of filaggrin
expression, responsible for skin barrier impairment. However,
in cultured keratinocytes and human skin explants, P. acnes
causes an increase of filaggrin expression. Thereby, in acne
lesions, the expression of filaggrins in keratinocytes lining
the follicle wall is increased[10, 11]. Moreover, inflammatory
cytokines have been reported to contribute to the
overexpression of filaggrin in sebaceous gland explants[12].
These findings suggest that filaggrin expression would play a
significant role in acne lesions formation. Another study on
the filaggrin mutation in patients with xerosis comes
consolidate these findings[13]. This study suggested that some
patients may be protected against acne vulgaris whether they
present one copy of a null mutation in the filaggrin gene.
Nevertheless, a larger study specifically examining the
presence of filaggrin null mutations in acne sufferers did not
confirm these conclusions[14]. Actually, the filaggrin
expression is linked with the differentiation of keratinocytes
and alterations in the stratum corneum associated with acne
lesion.
Although in acne filaggrin expression seems to be
augmented, in acne affected skin we curiously find different
parameters typically associated with filaggrin function
impairment: Yamamato et al. observed that patients with
acne vulgaris exhibited markedly greater TEWL and lower
skin hydration with an evident permeability barrier
impairment. The decrease of skin hydration and increase of
TEWL were higher in patients with acne vulgaris of
moderate severity as compared to those with mild acne
severity and as compared to normal control subjects. This
suggests that the degree of the impairment of stratum
corneum permeability barrier is correlated directly with the
acne vulgaris severity. Another consideration: if filaggrin,
that is a protein with an important activity against bacterial
colonization, is augmented in acne, why do we observe in
acne affected skin an abnormal bacterial colonization? All
this apparent contradictions can be probably explained by
considering not only quantitative, but also qualitative
representation of filaggrin. It’s probable, in fact, that in acne
lesions augmented levels of filaggrin coexist with a
functional impairment of this protein, that could be unable or
less able to complete its natural maturation from
profilaggrine, trough filaggrin, to natural moisturizing factors
(NMFs), the final filaggrin products, essential to maintain
skin hydratation, normal TEWL and skin permeability, and
to contrast bacterial colonization. For these reasons, the use
of topical products containing functional filaggrin could be
an effective and innovative therapeutic option. It is also
important to consider that some medications, usually used in
the acne treatment, can be responsible for additional
alterations of the skin function and its integrity. The origin of
these additional alterations may be the active substance or the
vehicle, or both, but in any case specific skin care
recommendations are very important in the management of
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Figure 1. Pathophysiology of acne vulgaris. Keratinocyte hyperproliferation, increased desquamation, sebum accumulation, altered
sebum lipid composition and P. acnes growth into the pilo-sebaceous unit, lead to fragile skin, involving barrier impairment and
dehydration, and follicular rupture. TEWL, TransEpidermal Water Loss.
acne vulgaris in order to potentiate the efficacy of drugs in
the reduction of acne lesions[7].
severe cases, nodules and cysts. Acne lesions are distributed
essentially on face, chest, and back.
Indeed, systemic medications, topical medications, and
surgical and physical procedures used to treat acne and acne
scaring can cause impairment in stratum corneum barrier
function. Benzoyl peroxide and retinoids are particularly
responsible for fragile skin, as characterized by irritated skin
(burning and stinging), erythema, scaling, and xerosis[6]. The
mechanism of action of retinoids involves the increase of
epithelial cells turnover and the shedding of corneocytes[15].
Moreover, topical retinoids cause hypergranulosis,
acanthosis, desquamation, and a decrease in stratum corneum
thickness. “Retinoid dermatitis” is usually transitory, arising
after 2-4 weeks and vanishing afterwards. As for the
mechanism of action of benzoyl peroxide, reactive oxygen
species are produced and the cohesion of keratinocytes are
disrupted in the stratum corneum (keratolysis)[16].
Generally, the first lesions appear around 12 years old. In
fact, acne is often linked with puberty and less prevalent in
adulthood. Nevertheless, juvenile acne can still be found in
people between the ages of 20 and 30. It happens to 64% of
individuals for the former, and to 43% for the latter and lead
to a considerable psychological and social impact[3].
Although this skin disorder is most frequently not severe,
people with acne are often subject to anxiety in social
situations, and embarrassed with their appearance leading to
reduce their quality of life[17]. Formation of acne lesions is
well known to be associated with genetic and environmental
factors, and especially emotional stress[2, 3].
Pathology of acne: inflammatory role of P. acnes
Acne vulgaris is a chronic inflammatory disease of the
pilosebaceous unit. Acne is a common condition, with a
lifetime prevalence of 80% but it occurs more frequently
during the adolescence between 15 and 17 years old[17].
Features of acne include hyperseborrhoea (excessive sebum
production), non-inflammatory lesions (comedones),
inflammatory lesions characterized by papules, and pustules
associated with diverse degrees of scarring, and in the most
P. acnes has been identified as a contributing factor in
acne lesions by playing an important role in the pathogenesis
because of colonization of the pilosebaceous unit and
inflammation caused[3, 12, 18]. Acne lesions first develop in the
pilosebaceous unit as subclinical microcomedones and may
evolve into inflammatory (papules, pustules) and
non-inflammatory lesions[2, 19]. The overproduction of sebum
and increased follicular hyperkeratosis were thought to be
first events leading to establish an environment favourable
for the proliferation of P. acnes, and therefore responsible for
the appearance of the initial eruptions (microcomedones).
However, most recent evidence points that the inflammation
begins before the primary eruptions[18]. Indeed, inflammation
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Figure 2. Activation of the NLRP3-inflammasome by P. acnes. Infiltration by inflammatory cells within the pilo-sebaceous unit
allows contact between P. acnes and myeloid cells. The phagocytosis of P. acnes by macrophage and the activation of the TLR
result in the activation of the NLRP3-inflammasome, and therefore, the release of active IL-1 β. IL-1 β, Interleukin-1β; PAMPs,
Pathogen-associated molecular pattern; ROS, reactive oxygen species; TLR, Toll Like Receptor.
and the infiltration of perivascular lymphoid can precede
lymphoproliferation. Under normal circumstances, the
keratinocytes differentiate into corneocytes, which will then
desquamate and lost from the stratum corneum surface.[20] In
acne vulgaris, changes in the lipid content of sebum
associated with the inflammation in and around the
sebaceous gland result in keratinocytes hyperproliferation
and increased desquamation within sebaceous follicles[18, 9].
Inflammation of the pilosebaceous unit and the build-up of
keratinocytes prevent sebum drainage, and thus
microcomedones formation[6]. (figure1)
P. acnes is responsible for several pro-inflammatory
activities. This microorganism triggers the innate immune
system by activating toll-like receptor 2 (TLR2) and the
inflammasome pathway[21, 22]. The Toll Like Receptors
(TLRs) are transmembrane proteins activated by
pathogen-associated molecular patterns. The activation of
TLRs by exposure to microbial agent leads to the activation
of the NF-κB pathway which modulate expression of many
immune response genes[23, 24]. P. acnes induces the
production of monocyte cytokines, via a TLR2-dependent
pathway. Indeed, TLR2 activation leads to stimulate the
release of pro-inflammatory cytokines by the monocytes,
such as IL-12 and IL-8. It allows to recruit neutrophils to the
active lesion site. Through the release of lysosomal enzymes,
these neutrophils cause the rupture of follicular epithelium
triggering the inflammation[25]. TLR2 expression in acne
suggests that the activation of TLR2 by P. acnes can be
involved in the inflammatory lesion development[26].
Furthermore, P. acnes can also be phagocyted by myeloid
cells resulting in IL-1β release, responsible for the
inflammatory response by the neutrophils[22]. Indeed, in
human monocytes, P. acnes activates NLRP3-inflammasome
leading to maturation of pro-IL-1β to active IL-1β by means
of caspase 1[27]. The inflammasome is an intracellular and
molecular complex that has the function of initiate
inflammation. The danger- and pathogen-associated
molecular patterns (DAMPs/PAMPSs) activate the
inflammasome which will regulate the release of several
caspase-1 activation-dependent cytokines, and especially
IL-1β[28]. Overall, NLRP3-inflammasome activation requires
thephagocytosis of P. acnes, the release of cathepsin B by the
lysosomal rupture, K+ efflux and formation of reactive
oxygen species (ROS)[29]. (figure 2)
Rhealba® Oat plantlet extract
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The healing properties of oat have been known for
thousands of years. Since 400 BC, traditional medicine has
Figure 3. Chemical structure of isoorientin-2’’-O-arabinoside (1)
and isovitexin-2’’-O-arabinoside (2).
been using oat in the form of flour or gruel, for its emollient
and anti-inflammatory benefits. The healing virtues of oat are
frequently employed for several skin disorders, such as
pruritus, burns, ulcers as well as erythema[30]. Today,
Rhealba®
Oat
plantlet
extract
(Pierre
Fabre
DermoCosmetique) is usually used for treating fragile skin
due to its varied biochemical properties. Indeed, the
non-dietary aerial parts of Rhealba® Oat contain essentially
flavonoids and saponins, two molecular species which would
have interesting anti-inflammatory and immunomodulatory
activities. The active components of Rhealba® Oat Plantlets
extract were separated by reverse phase liquid
chromatography followed by semi-preparative reverse phase
HPLC. Two C-glycosylated flavonoids were isolated, one of
the apigenin type, isoorientin-2”-O-arabinoside, and the other
of the luteolin type, isovitexin-2”-O-arabinoside[1, 31]. (figure
3)
The immunomudulatory and anti-inflammatory activity of
Rhealba® Oat Plantlets extract and its purified active
substances were therefore studied in vitro in several cell
models mimicking the different pathways of activation of
inflammation[31]. The results suggest that Rhealba® Oat
Plantlets extract exerts interesting immunomodulatory
activity. In fact, Plantlets extract causes dose-dependent
inhibition in the secretion of pro-inflammatory Th1 and Th2
cytokines and particularly on IL-13 and IL-2 production,
cytokines that play a central role in controlling the immune
response. Moreover, Rhealba® Oat Plantlets extract has an
inhibitory effect on the capacity of dendritic cells to
stimulate T lymphocyte proliferation. This reduced efficacy
of dendritic cells might be due to the weaker expression of
the MHC I and II costimulatory molecules on their surface,
negatively regulated by the extract[31].
In addition, Rhealba® Oat Plantlets extract presents an
anti-inflammatory activity. Indeed, the extract inhibits
significantly the production of the prostacycline PG6KF1α, a
prostaglandin which is a major metabolite of arachidonic
acid resulting from the cyclo-oxygenase pathway in
keratinocytes. This effect appears to be exerted by directly
inhibiting the activity of the COX-2 enzyme and not by
reducing quantity of arachidonic acid[31].
Rhealba® Oat Plantlets extract has also been identified to
inhibit bacterial adhesion, especially Staphylococcus aureus,
enhance the production of ceramides, cerebrosides and free
acide both involved in cutaneous barrier homeostasis.
Moreover, the extract stimulates the proliferation of
keratinocytes and enhances the production of collagen IV,
hyaluronic acid, and sphingomyelin[1]. All of these findings
suggest that Rhealba® Oat Plantlets extract is capable of
reducing inflammation and irritation in acne.
Cosmeceuticals based on Rhealba® Oat plantlet extract
FDA identified colloidal oatmeal in 1989 as a skin
protectant drug available over the counter and offered to
classify it as a category I ingredient which means safe and
effective, while waiting for the standardization of its
formula[32].
Rhealba® Oat
plantlet
extract
(Pierre
Fabre
Dermo-Cosmetique) is an oat plantlet extract without protein
used to heal fragile skin and is an exclusive ingredient of
A-DERMA. This extract is also part of the Phys-AC range,
the product line of A-DERMA to treat acne. A-DERMA
products contain also hydro-compensating actives to restore
fragile skin and reduce irritation and inflammation[33, 34].
Indeed, acne is often associated with irritation and dry skin
and the symptoms can be aggravated by anti-acneic treatment
such as topical tretinoin or isotretinoin[32].
The Phys-AC range encompasses four products. The first,
Phys-AC Global, is employed as a stand-alone cream which
associates Rhealba® Oat plantlet extract, anti-comedogenic
agents and hydro-compensating actives. In Phys-AC Global,
the anti-comedogenic agents are represented by the hydroxy
acids. The main hydroxy acid used, is the glycolic acid, a
natural product from sugar cane, known to reduce the
cohesion of corneocytes, and favor desquamation[35, 36].
Lactic acid, another hydroxyl acid, is used to inhibit the
growth of P. acnes and promote keratinocyte
desquamation[11, 37]. The last anti-comedogenic agent is the
salicylic acid which has keratolytic activity[38]. Another
product of Phys-AC is the Hydra cream, which is composed
of Rhealba® Oat plantlet extract and hydro-compensating
actives. This cream is to be used in addition to anti-acneic
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treatments in order to lessen the irritation and restore fragile
skin. The last two Phys-AC products are the purifying
foaming gel and the purifying micellar water. They also
contain Rhealba® Oat plantlet extract as well as
hydro-compensating actives and can be used as daily
cleansers.
6.
Del Rosso JQ. Clinical relevance of skin barrier changes
associated with the use of oral isotretinoin: the importance of
barrier repair therapy in patient management. J Drugs Dermatol
2013; 12:626-631.
7.
Thiboulot D, Del Rosso JQ. Acne Vulgaris and the Epidermal
Barrier: Is acne Vulgaris Associated with Inherent Epidermal
Abnormalities that Cause Impairment of Barrier Functions? Do
any Topical Acne Therapies Alter the Structural and/or Functional
Integrity of the Epidermal Barrier? J ClinAesthetDermatol 2013;
6:18-24.
8.
Yamamoto A, Takenouchi K, Ito M. Impaired water barrier
function in acne vulgaris. Arch Dermatol Res 1995; 287:214-218.
9.
Harding CR, Aho S, Bosko CA. Filaggrin - revisited. Int J
CosmetSci 2013; 35:412-423.
Conclusions
In acne, fragile skin has two origins; the impairment of the
skin barrier and the inflammatory nature of this skin disease.
These events are mainly attributed to the proliferation of P.
acnes. Thanks to its anti-inflammatory, immunomodulatory
and barrier restoration properties, Rhealba® Oat plantlet
extract is able to reduce inflammation, inhibit adhesion of P.
acnes, and thus, restore the fragile skin. Therefore,
cosmeceuticals based on Rhealba® Oat plantlet extract
associated with hydro-compensating actives, which can be
associated with anti-comedogenic agents (hydroxyl acids),
may be usually used stand-alone or in addition to anti-acneic
treatment for acne vulgaris treatment.
10. Kurokawa I, Mayer-da-Silva A, Gollnick H, Orfanos CE.
Monoclonal antibody labeling for cytokeratins and filaggrin in the
human pilosebaceous unit of normal, seborrhoeic and acne skin. J
Invest Dermatol 1988; 91:566-571.
11. Jarrousse V, Castex-Rizzi N, Khammari A, Charveron M, Dreno
B. Modulation of integrins and filaggrin expression by
Propionibacterium acnes extracts on keratinocytes. Arch Dermatol
Res 2007; 299:441-447.
Conflict of interest
12. Guy R, Kealey T. The effects of inflammatory cytokines on the
isolated human sebaceous infundibulum. J Invest Dermatol 1998;
110:410-415.
GF declares no conflicts of interest. MSA is an employee
of Pierre Fabre and FS is a trainee of Medical Direction of
A-DERMA
13. Sergeant A, Campbell LE, Hull PR, Porter M, Palmer CN, Smith
FJ, et al. Heterozygous null alleles in filaggrin contribute to
clinical dry skin in young adults and the elderly. J Invest Dermatol
2009; 129:1042-1045.
Abbreviations
14. Common JE, Brown SJ, Haines RL, Goh CS, Chen H,
Balakrishnan A, et al. Filaggrin null mutations are not a protective
factor for acne vulgaris. J Invest Dermatol 2011; 131:1378-1380.
COX: Cyclooxygenase; IL: Interleukin; NMF: Natural
Moisturizing Factors; MHC: Major Histocompatibility
Complex; P. acnes: Propionibacterium acnes; PG6KF1α:
ProstaGlandin 6KF1α; ROS: Reactive Oxygen Species; SC:
stratum corneum; TEWL: TransEpidermal Water Loss; Th:
Lymphocyte T helper; TLR: Toll Like Receptor.
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