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Transcript of Antioxidants
The International School of Vitiligo & Pigmentary Disorders
Barcelona, 2-5 November 2011
Antioxidants for
vitiligo and
photoprotection:
new insights and
possible
therapeutic
implications.Linda Tognetti, MD
Division of Clinical, Preventive and Oncologic Dermatology Department of Critical Care Medicine and Surgery
University of Florence (Italy)
‘‘
THE ROLE OF OXIDATIVE STRESS IN CUTANEOUS PHOTO-DAMAGE
UV light
Photochemic reaction in the skin
Proteins and lipids peroxidation
Extracellular accumulation
PHOTO-CARCINOGENESISMelanoma; BCC and SCC
PHOTO-AGINGwrinkles, dryness, telangiectasia,
pigmentary abnormalities
CROMOPHORES
1O2 singlet oxygen> Urocanic acid
> DNA
SKIN filaggrin breakdown
(high concentrations superficially in the epidermis)UV
absorption
Cell membrane damage
Reactive oxygen species (ROS)
changes between adjacent pyrimidine bases
φ photon
Strand breaks + nucleic acids oxidation
Mutagenic lesions
Masaki H. Role of antioxidants in the skin: anti-aging effects. J Dermatol Sci 2010;58(2):85-90.
Inflammation
Dermal matrix alteration
Sander CS et al. Oxidative stress in malignant melanoma and non-melanoma skin cancer. Br J Dermatol 2003;148(5):913-22.
THE ROLE OF OXIDATIVE STRESS IN THE PATHOGENESIS OF VITILIGO
Significantly higher
levels of indicators of
oxidative stress:
malondialdehyde
and xanthine oxidase
Significantly lower levels of: - vitamins C - vitamin E- superoxidedismutase- glutathione peroxidase- catalase- total antioxidant ativity
ROS cause lipid peroxidation of cellular membrane of melanocytes
Imbalance of ROS scavenging
system in vitiligo melanocytes
Oxidative damage is the initial pathogenic event in melanocyte degeneration
H2O2 transfered from
keratinocytes to
melanocytes
ROS alter melanocytes’ specific factors to produce neo-antigens amplify antigen presentation
promote autoimmune destruction of melanocytes
Haider N et al. Oxidative Stress and Antioxidant Status in Vitiligo Patients.Dhaka Univ J Pharm Sci 2010; 9(2): 103-8. Pelle E et al. Keratinocytes act as a source of reactive oxygen species by transferring hydrogen peroxide to melanocytes. J Invest Dermatol 2005;124:793–797.
Sravani PV et al. Determination of oxidative stress in vitiligo by measuring superoxide dismutase and catalase levels in vitiliginous and non-vitiliginous skin. Ind J Dermatol Venereol Leprol 2009;75:268–271. Koca R et al. Oxidant-antioxidant enzymes and lipid peroxidation in generalized vitiligo. Clin Exp Dermatol 2004; 29(4): 406-9.
Khan R et al. Circulatory levels of antioxidants and lipid peroxidation in Indian patients with generalized and localized vitiligo. Arch Dermatol Res 2009; 301(10):731-7Namazi MR. Neurogenic dysregulation, oxidative stress, autoimmunity, and melanocytorrhagy in vitiligo: Can they be interconnected? Pigment Cell Res 2007;20:360-3.
in the skin and blood of vitiligo patients, compared with controls
Increased oxidative
stress
High metabolic demands
Depletion of antioxidants reserves
Physiologic antioxidant systems
are insufficient
SKINOXIDATIVE DAMAGE
Environmental factors (smoking, pollution)
ANTIOXIDANTS ADMINISTRATIO
N: It may prevent
and/or limit photo-damage
and vitiligo pathogenesis?
Masaki H. Role of antioxidants in the skin: anti-aging effects. J Dermatol Sci 2010;58(2):85-90.
Gonzalez S et al. A New Generation of Oral Photoprotectors. The Open Dermatology Journal 2011; 5:6-14.
ORALDiet,
supplementation
TOPICALSunscreen
creams
TOPICAL ANTIOXIDANTS
Gonzalez S et al. Current Trends in Photoprotection - A New Generation of Oral Photoprotectors. Open Dermat J 2011; 5:6-14.
Wang SQ et al. Photoprotection: a review of the current and future technologies. Dermatol Ther 2010;23(1):31-47.
TOPICAL AOs are a supplement to the physiological
antioxidant protection present in the skin.
They augment photoprotection provided by
sunscreens lotions/creams.
Direct application to the skin has the advantage of targeting a specific
skin
area needing photoprotection.
Once penetrated through the stratum corneum, they may remain
active for
several days.
Topical AOs exert their effect inside the cells: by regenerating
each other, they provide an ontioxidants’ reservoir. Pinnell SR. Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol 2003;48:1-19.
ORAL ANTIOXIDANTS
Epstein HA. The effect of diet and nutrition on the skin. Prime 2011;1:4 : 46-51.
Physiologic processes related to absorption, solubility and transport of oral AOs are
not
fully known, but they seem to limit the quote of oral OAs that can be delivered into
the skin.
An AO molecule is more stable when incorporated by nutrition in the skin, where it
accumulates in a mixture with different AOs molecules, compared with single
topically
applied AO.
Oral AOs increase the basal threshold of systemic AOs,
actively collaborating in refreshing skin natural AO systems.
Toghether with Topical AOs, Oral AOs can prevent
photoaging and photocarcinogenesis, in both animal
and human models.
Oral AOs administration helps preventing skin alterations,
(e.g., uneven skin tone and atopic dermatitis) and correlates
with a lower incidence of wrinkles.Gonzalez S, et al. Current Trends in Photoprotection - A New Generation of Oral Photoprotectors. Open Dermatol Journ 2011; 5:6-14.
Namazi MR, et al. Vitiligo and diet: a theoretical molecular approach with practical implications. Indian J Dermatol Venereol Leprol 2009;75(2):116-8.
VITAMIN C
VITAMIN E
VITAMIN A
RESVERATROL
QUERCETIN
TEA POLYPHENOLS
SOY ISOFLAVONES
Polypodium leucotomos extract
POLYUNSATURED FATTY ACIDS
CURCUMIN
CAPSAICIN
GLUTATHIONE
MELATONIN
13 Antioxidants
Flavonoids
VITAMIN C
Topical administration of L-ascorbate and its derivates (with greater
cutaneous penetration) augments photo-protection (sunscreen
component),
improves epidermal barrier function and provides anti-aging effects
(moisturizing creams component).
Oral combination of vitamins C and E in high doses provide protection
against UV-induced erythema.
Ascorbic acid plasma levels are often lowered in patients with vitiligo.
Oral administration of vit C, in association with vit E/ vit A/ vit B12/
folic acid +/- broadband UVB, has been followed by definite
repigmentation without side effects in vitiligo patients.
Don P et al.Treatment of vitiligo with broadband ultraviolet B and vitamins. Int J Dermatol. 2006;45(1):63-5.
Montes LF, et al. Folic acid and vitamin B12 in vitiligo: a nutritional approach. Cutis 1992;50(1):39-42.
Darr D et al. Effectiveness of antioxidants (vitamin C and E) with and without sunscreens as topical photoprotectants. Acta Derm Venereol 1996;76(4):264-8.
SOURCES :papayastrawberryorangekalelemonmelonauliflowergarlicgrapefruitraspberrykiwimandarinpassion fruitspinachlimemangoblackberrypotatomeloncranberrytomatoblueberrypineapple
Eberlein-Konig B et al. Protective effect against sunburn of combined systemic ascorbic acid (vitamin C) and d-alpha-tocopherol (vitamin E). J Am Acad Dermatol 1998;38:45-8.
Vitamin C or L-ascorbic acid is the predominant
AO in
the skin and it is an essential cofactor for collagen
synthesis.
Vitamin E exists in 8 forms, 4 tocopherols and 4 tocotrienols,
being α-tocopherol the most represented in humans.
Topical application of α-tocopherol reduces photo-aging
and
photo-carcinogenesis, and prevents UV-induced erythema,
lipid
peroxidation and immunosuppression.
Oral administration of vit E combined with vit C and/or vit A
demonstrated to increase protection against UV-induced
damage.
Oral 3 months-therapy with α-tocopherol plus ubiquinone,
selenomethionine, methionine stopped the progression of
vitiligo
and induced repigmentation of the most recent lesions.
Oral vit E has shown to increase narrow band-UVB
effectiveness
in vitiligo patients.
Lin JY et al. UV photoprotection by combination topical antioxidants vitamin C and vitamin E. J Am Acad Dermatol 2003: 48: 866–874.
Elgoweini M et al. Response of vitiligo to narrowband ultraviolet B and oral antioxidants. J Clin Pharmacol 2009;49(7):852-5.
Yuen KS, et al. Alpha-tocopherol, an inhibitor of epidermal lipid peroxidation, prevents ultraviolet radiation from suppressing the skin immune system. Photochem Photobiol 1997;65:587-92.
Picardo M et al. Antioxidant treatment in vitiligo? Pigment Cell Res 1997;10:360.
SOURCES :wheat germ oilsunflower oilsafflower oilnuts, nut oilsgreen leafy vegetablestomato productspumpkinsweet potato rockfishmangoesasparagusbroccolipapayasavocados
VITAMIN E
VITAMIN A
Jalel A et al. Vitiligo treatment with vitamins, minerals and polyphenol supplementation. Indian J Dermatol 2009;54(4):357-60.
Oral supplementation with vit A plus vit C and vit E, and
minerals
promoted vitiligo lesion repigmentation in the mice settings.
SOURCES : Liver (beef, pork, chicken, turkey, fish) carrot broccoli leaf sweet potato butter kale spinach pumpkin collard greens cheddar cheese cantaloupe melon egg apricot papaya mango pea broccoli milk
Vitamin A includes retinol and carotenoids (α/β/γ-
carotene,
lycopene and the xanthophylls lutein and zeaxanthin).
Daily oral β-carotene (30mg) can prevent and repair
photoaging
and increases synthesis of procollagen type I.
Topical β-carotene (2mg/cm2) provides protection against ROS
in the
human skin exposed to infra-red radiation.
Vit A is fat-soluble and can be stored in keratinocytes as retinyl esters.
Cho S et al. Differential effects of low-dose and high-dose beta-carotene supplementation on the signs of photoaging and type I procollagen gene expression in human skin in vivo. Dermatology. 2010;221:160-71.
Darvin ME et al. Topical beta-carotene protects against infra-red-light-induced free radicals. Exp Dermatol 2011;20:125-9.
Carotenoids are useful to protect against UV-induced damage:
Lycopene concentration in skin correlates significantly with
roughness.
Camera E et al. Astaxanthin, canthaxanthin and beta-carotene differently affect UVA-induced oxidative damage and expression of oxidative stress-responsive enzymes. Exp Dermatol 2009; 18:222–231.
QUERCETIN
SOURCES :applesonions (++red onion)red grapescitrus fruittomatobroccolileafy green vegetablesraspberrywhortleberrylingonberrycranberrychokeberryrowanberrycaperslovagerootslegumes
Quercetin is a very potent AO,
member
of the flavonoids family. Topical quercetin has successfully inhibited UVB-
induced skin damage in rodent models.
Casagrande R et al. Protective effect of topical formulations containing quercetin against UVB-induced oxidative stress in hairless mice. J Photochem Photobiol B 2006; 84(1): 21-7.
Topical application of the quercetin aglycone has been shown
to
prevent UVC-induced liposome peroxidation, UVB-induced
myeloperoxidase activity and glutathione depletion.
Vicentini FT et al. Quercetin in w/o microemulsion: in vitro and in vivo skin penetration and efficacy against UVB-induced skin damages evaluated in vivo. Eur J Pharm Biopharm 2008; 69(3): 948-57.
Fahlman BM et al. UVA and UVB radiation-induced oxidation products of quercetin. J Photochem Photobiol B. 2009; 97: 123-31.
In vitro studies demonstrated that quercetin can efficiently
contrast
keratinocytes oxidative damage induced by H2O2 exposure.
Wang X, et al.Quercetin in combating H2O2 induced early cell apoptosis and mitochondrial damage to normal human keratinocytes Chin Med J 2010;123(5):532-536
GREEN TEA POLYPHENOLS
Green tea polyphenols definition is used to refer to several potent
antioxidants
that appear in green tea leaves.
The most abundant (60-80%) polyphenols contained in green tea leaves
are
cathechins: epicatechin
epicatechin-3-gallate
epigallocatechin
epigallocatechin-3-gallate (EGCG) most important molecule
As antioxidant, cathehins are more potent than vitamins C and E.
Cathechins are able to regenerate oxidized vitamin E.
Harbowy ME et al. Tea chemistry. Crit Rev Plant Sci 1997;16:415-80.
Jeon HY et al. Effects of oral epigallocatechin gallate supplementation on the minimal erythema dose and UV-induced skin damage. Skin Pharmacol Physiol 22; 2009:137–141.
EGCG has photo-protective, anti-inflammatory,
anti-carcinogenic effects (promotes rapid repair of UVB-
induced DNA damage) and can inhibit collagenase activity.
Several studies assessed that oral administration of EGCG significantly
increases
the minimal erythema dose to UV, prevents disruption of the epidermal
barrier
function, improves microcirculation and modulates skin properties of
women.
Topical application of EGCG inhibits carcinogenesis and selectively
increases
apoptosis in UVB-induced skin tumors, in both animal and human model.
Oral supplementation of green tea decoction in association with vit A/E/C
and
minerals (selenium, zinc) has promoted vitiligo lesions repigmentation in
mice.
Katiyar SK. Green tea prevents non-melanoma skin cancer by enhancing DNA repair. Arch Biochem Biophys. 2011; 508: 152-158.
Jalel A et al. Vitiligo treatment with vitamins, minerals and polyphenol supplementation. Indian J Dermatol 2009;54(4):357-60.
Lu YP et al. Topical applications of caffeine or (-)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice. Proc Natl Acad Sci U S A 2002: 99: 12455–60. Camouse MM et al. Topical application of green and white tea extracts provides protection from solar-simulated ultraviolet light in human skin. Exp Dermatol. 2009; 18: 522-526.
Heinrich U, et al. Green tea polyphenols provide photoprotection, increase microcirculation, and modulate skin properties of women. J Nutr 2011; 141: 1202-8.
GREEN TEA POLYPHENOLS
TEA POLYPHENOLS
QUERCETIN VITAMIN C
Jeong Y-M et al. Cytoprotective Effect of Green Tea Extract and Quercetin against Hydrogen Peroxide-Induced Oxidative Stress. Arch Pharm Res 2005; 28(11):1251-56.
Green tea extract, quercetin and vitamin C have
demonstrated strong cytoprotective effects on H202
treated Mel-Ab melanocytes (immortalized mouse
melanocyte cell line), preventing H202-induced cell
death.
The triple combination green tea
extract/quercetin/folic acid prevented the cellular
damage induced by H202 in a synergistic manner.
This suggests that effective combinations of AOs
may be of importance, and that co-treatment with
AOs offers a possible means of treating vitiligo.
Jeong Y-M et al. Cytoprotective Effect of Green Tea Extract and Quercetin against Hydrogen Peroxide-Induced Oxidative Stress. Arch Pharm Res 2005; 28(11):1251-56.
RESVERATROL
Topical adsorbption of resveratrol has been investigated,
and its topical use on hairless mice before UVB irradiation
decreased erythema, ROS production and inflammation.
Resveratrol is a polyphenolic phytoalexin.
SOURCES :
Grapes/wines
(red,rose,white,
pinot noir)
peanuts
mulberries
blueberries
apples
cocoa powder
baking chocolate
dark chocolate
Its benifical effects (anti-oxidant, anti-inflammatory, anti-
cancer,
blood sugar-lowering) are currently a topic of numerous animal
and
human studies.
Oral resveratrol can prevent UV-induced tumorigenesis,
increases
cell survival and contrast cutaneous inflammatory disorders.
Nichols JA et al. Skin photoprotection by natural polyphenols: anti-inflammatory, antioxidant and DNA repair mechanisms. Arch Dermatol Res 2010; 302(2): 71-83.
Aziz MH et al. Longley BJ, Ahmad N. Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease? Faseb J 2005; 19(9): 1193-5.
Ndiaye M et al. Ahmad N. The grape antioxidant resveratrol for skin disorders: promise, prospects, and challenges. Arch Biochem Biophys 2011;508(2):164-70. Hung CF et al. Delivery of resveratrol, a red wine polyphenol, from solutions and hydrogels via the skin. Cancer Prev Res 2010;3(2):170-8.
SOY ISOFLAVONES Soybeans and their associated food products are a rich source of
flavonoids called isoflavones, the most abundant being genistein.
Topical genistein reduces erythema and histologic inflammation induced by PUVA in
mice.
Oral genistein decreases UVB-induced skin photoaging, carcinogenesis,
inflammation and immunosuppression in a rodent model.
Wei H et al. Isoflavone genistein: photoprotection and clinical implications in dermatology. J Nutr 2003; 133(11s1): 3811S-3819S.
SOURCES :
Soy
red clover
ginkgo biloba
Genistein has collagen-stimulating effects, by increasing collagen (COL1A2) gene expression.
Greenwel P et al. Tyrosine dephosphorylation of nuclear proteins mimics transforming growth factor beta-1 stimulation of alpha-2 (I) collagen gene expression. Mol Cell Biol 1995;15:6813-9.
Shyong EQ et al. Effects of the isoflavone 4 ’, 5,7-trihydroxyisoflavone (genistein) on psoralen plus ultraviolet A radiation (PUVA)-inducedphotodamage. Carcinogenesis 2002; 23:317-21.
Widyarini S, et al. Isoflavonoid compounds from red clover (Trifolium pratense) protect from inflammation and immune suppression induced by UV radiation. Photochem Photobiol 2001: 74: 465–470.
In animal studies, oral soy or genistein protected against several
cancers including bladder, breast, colon, liver, lung, prostate and skin.
Barnes S. Effect of genistein on in vitro and in vivo models of cancer. J Nutr 1995;125:S777-83.
A recent study has reported an association between daily ingestion of Ginko biloba
with a
significant improvement in total VASI (Vitiligo Area Scoring Index) and VETF (Vitiligo
European Task Force) staging in vitiligo patients.
Szczurko O. Ginkgo biloba for the treatment of vitilgo vulgaris: an open label pilot clinical trial. BMC Complement Altern Med 2011;11:21.
CURCUMIN
Curcumin, a low-molecular-weight polyphenol derived
from
Curcuma longa, is an active ingredient in the spice
tumeric,
to which curcumin gives the yellow color.
Curcumin has anti-oxidant (induction of glutathione S-
transferase enzymes), anti-proliferative,
anti-inflammatory (inhibition on cytokines and
prostaglandines synthesis),
antiviral, antibacterial and antifungal properties.
It reduces wound-healing time, improves collagen
deposition
and increases fibroblast and vascular density in wounds.
Rowe DL, et al. Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin. Breast Cancer: Basic and Clinical Research 2009; 3: 61–75.
Koeberte A, et al Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1. Molecul Cancer Therapeut 2009; 8:2348-2355
Potentially, curcumin could be employed in treatment
of different skin diseases.
Phototoxic dermatitis Melanoma Vitiligo Psoriasis Morphea Chronic inflammatory diseases Primary cutaneous T-cell
lymphoma NM skin cancer Cosmetics
Cho JW et al.. Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. Int J Mol Med 2007; 19: 469-474.
Phototoxic dermatitis
Ishizaki C et al. Enhancing effect of ultraviolet A on ornithine decarboxylase induction and dermatitis evoked by 12-o-tetradecanoylphorbol-13-acetate and its inhibition by curcumin in mouse skin.Dermatol 1996; 193: 311-317.
Melanoma
Curcumin at higher doses induces apoptosis in relatively resistant malignant
human melanoma cell lines, and its combination with tamoxifen provides a
non-toxic option for combinatorial chemotherapy.
Chatterjee S et al. Chemo-resistant melanoma sensitized by tamoxifen to low dose Curcumin treatment through induction of apoptosis and autophagy. Cancer Biol Ther 2011; 11: 216-228.
Vitiligo
A recent clinical trial has demonstrated that the association with topical
tetrahydrocurcuminoid cream increases the effectiveness of targeted
narrowband UVB phototherapy for induction of repigmentation in vitiligo
patients.
Asawanonda P, Klahan S. Tetrahydrocurcuminoid cream plus targeted narrowband UVB phototherapy for vitiligo: a preliminary randomized controlled study. Photomed Laser Surg 2010; 28: 679-684.
It has been showed that topical pretreatment with curcumin
significantly inhibited the pro-inflammatory effect of topically-applied tumor
promoter 12-o-tetradecanoylphorbol-13-acetate (TPA) in combination with
UVA .
Becatti M, Prignano F, et al. The involvment of Smac/DIABLO, p53, NF-kB, and MAPK pathways in apoptosis of keratinocytes from perilesional vitiligo skin: Protective effects of curcumin and capsaicin. Antiox Redox Signal 2010;13(1309-1321.
Vitiligo
• A recent in vitro study has evaluated the protective effects of
combinatorial therapy with curcumin and capsaicin
supplementation in cultured cells from lesional, perilesional and
healthy skin of selected vitiligo patients.
• Total antioxidant capacity and mitochondrial membran
depolarization has markers of scavenging activity and
mitochondrial integrity have been considered.
• The supplement of curcumin and capsaicin can improve the
resistance of cultured cells to oxidative stress.
CAPSAICIN
Capsaicin is a natural irritant of the vanilloid family, and represents
the main capsaicinoid of chilli peppers and other capsicum
preparations (chilli, cayenne pepper, red pepper) obtained
from the fruits of the Solanaceae plants, of the genus Capsicum.
Capsaicin is a potent anti-inflammatory agent which has been used for :
pain and itch relief, because of its desensitization property (it produces a
long-lasting refractory period after the initial excitation of sensory neurons);
cancer prevention; cardiovascular diseases; weight reduction.
High antioxidant and anti-apoptotic potential of capsaicin have been recently
described.
Pre-treatment with capsaicin inhibits keratinocytes apoptosis in peri-lesional
vitiligo skin, increases cellular total antioxidant capacity, contrasts ROS
generation and
lipid peroxidation and improves mitochondrial activity and cell metabolism.
Becatti M et al. The involvement of Smac/DIABLO, p53, NF-kB, and MAPK pathways in apoptosis of keratinocytes form perilesional vitiligo skin: protective effects of curcumin and capsaicin. Antioxid Redox Signal 2010;13(9):1309-21.
Oyagbemi AA et al. Capsaicin: A novel chemopreventive molecule and its underlying molecular mechanisms of action. Indian J Cancer 2010;47(1):53-8
POLIPODYUM LEUCOTOMOS EXTRACT P. leucotomos (PL) extract is obtained from the fern P. leucotomos.
Middelkamp-Hup MA et al. Orally administered Polypodium leucotomos extract decreases psoralen-UVA-induced phototoxicity, pigmentation, and damage of human skin. J. Am. Acad. Dermatol. 2004; 50(1): 41-49.
PL prevents oxidative DNA damage by accelerateing repair of thymine
dimers and
inhibiting trans-urocanic acid photoinduced isomerization and inactivation.
Capote R et al. Polypodium leucotomos extract inhibits trans-urocanic acid photoisomerization and photodecomposition. J Photochem Photobiol B 2006; 82(3): 173-9.
PL can potentiate the endogenous antioxidant response and inhibits photo-
immunosupression.
Brieva A, et al. Immunomodulatory properties of an hydrophilic extract of Polypodium leucotomos. Inflammopharmacol 2002;9:361-71.
Topical application of PL showed to inhibit UVB- and PUVA
therapy-
induced erythema, in vivo, and to contrast photocarinogenesis.
Gonzalez S et al. Topical or oral administration with an extract of Polypodium leucotomos prevents acute sunburn and psolaren-inducedphototoxic reactions as well as depletion of Langerhans cells in human skin. Photodermatol. Photoimmunol Photomed 1997; 13: 50-60.
Oral administration provides photoprotection and significantly decreases
Langerhans cells depletion.
Ω3-POLYUNSATURED FATTY ACIDS Ω -3 polyunsatured fatty acids (PFA) are well-documented
antioxidants
and inhibitors of pro-inflammatory cytokines (e.g.,TNF-α) and free
radicals.
Ω-3 PFA in the presence of AOs supplement appears to exert
protection
against auto-immunity by enhancing antioxidant enzymes.
The enrichment of cell membranes with Ω-3 PFA has been reported
to
increase the glutathione (GSH) peroxidase activity.
High doses of Ω-3 PFA have been shown to decrease UVB-induced
erythema and flogsis.
Moreover, Ω-3 PFA seem to favorably influence the vulnerability and
outcome in depressive disorders, that affect many patients with
vitiligo.
The diet of vitiligo patients should include large use of Ω-3 PFA.
Joulain C . Increased glutathione peroxidase activity in human blood mononuclear cells upon in vitro incubation with n-3 fatty acids. Biochem Pharmacol 1994;47:1315-23.
Namazi MR et al. Vitiligo and diet: A theoretical molecular approach with practical implications. Indian J Dermatol Venereol Leprol 2009;75:116-8
Logan AC. Omega-3 fatty acids and major depression: A primer for the mental health professional. Lipids Health Dis 2004;3:25.
Fernandez G. Dietary lipids and risk of autoimmune disease. Clin Immunol Immunopathol 1994;72:193-7.
Rhodes LE et al. Dietary fishoil supplementation in humans reduces UVB-erythemal sensitivity but increases epidermal lipid peroxidation. J Invest Dermatol 1994; 103(2): 151-4.
SOURCES:cold water oily fish (salmon, herring, mackerel, anchovies, sardines)fish oil,flaxseeds,nuts, eggs,Brussel sprouts,black raspberry,cowberry
GLUTATHIONE Glutathione (GSH) is a tripeptide ( γ-L-glutamyl-L-cysteinyl-glycine)
and represents one of the major contributor to the functional
vitality and morphological integrity of cells, where it controls redox-equilibrium.
GSH provides efficient protection against UVB-rays damages, by
inactivating different
ROS and regulating several genes involved in DNA repair and cell cycle regulation. Suprabasal keratinocytes employ high GSH quotes to absorb and neutralize UVB radiation, and
paracrine GSH secretion might mediate basal cells protection.
GSH paracrine stimulation of basal keratinocytes decreases the rate of cyclobutane
dimers formation
and p53-positive cells.
Schäfer M et al. Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis. Genes Dev 2010; 24:1045-58.
Zhu M et al. Molecular mechanisms for UV-B irradiation-induced glutathione depletion in cultured human keratinocytes. Photochem Photobiol 2004; 80: 191-6.
A severe GSH depletion has been documented inside keratinocytes after UV
irradiation. The rationale of GSH supplementation is providing intrinsic wide-spectrum photo
protection,
cancer prevention and anti-aging effect.
Steenvoorden DP et al.The use of endogenous antioxidants to improve photoprotection. J Photochem Photobiol 1997; 41:1-10.
Sekhar RV et al. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr 2011
Various studies assessed low levels of glutathione peroxidase activity
and total antioxidant status in vitiligo patients with or without
diabetes and thyreopathy.
It has been demonstrated that this depletion in antioxidant processes is involved
in vitiligo pathogenesis.
Reduced erythrocytic or systemic GSH levels constitute a distinctive feature in
vitiligo
patients regardless of disease activity.
Anti-oxidant supplementation with GSH-precursor may be helpful in vitiligo
treatment.
Consuming high protein foods, rich in sulphur-containing amino acids can help
boost
glutathione levels.
Shin JW et al. Erythrocyte malondialdehyde and glutathione levels in vitiligo patients. Ann Dermatol 2010;22(3):279-83.
Jalel A, et al. Study of total antioxidant status and glutathione peroxidase activity in Tunisian vitiligo patients. Indian J Dermatol 2009;54(1):13-6.
Khan R et al. Circulatory levels of antioxidants and lipid peroxidation in Indian patients with generalized and localized vitiligo. Arch Dermatol Res 2009; 301(10):731-7
Lu SC. Regulation of glutathione synthesis. Mol Aspects Med 2009; 30: 42-59.
Haider N et al. Oxidative Stress and Antioxidant Status in Vitiligo Patients.Dhaka Univ J Pharm Sci 2010; 9(2): 103-8.
GLUTATHIONE
MELATONIN Melatonin (MN) is one of the most ancient and phylogenetically
conserved hormones, occurring in unicellular, plants and animals.
MN is a potent scavenger of oxygen (OH, O2−), and NO radicals:
it has an higher reduction potential than Vitamin C
It is fivefold better than glutathione at neutralizing hydroxyl radicals, and twofold more
effective
than vitamin E at inactivating peroxyl radicals
Tan DX et al.Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2002; 2: 181-97.
Direct antioxidant
MN enhances gene expression of the main antioxidants enzymes:
superoxide dismutase (SOD), catalase, glutathione peroxidase Indirect antioxidant
MN contributes to the preservation of the epidermal barrier
contrasts solar radiation and other physico-chemical stressors
activates the pigmentary system to further prevent solar damage
stimulates fibroblasts and endoteliocytes to maintain a functional dermis
structure
enhances immune system response against pathogens.
Fischer TW et al. Melatonin as a major skin protectant: from free radical scavenging to DNA damage repair. Exp Dermatol 2008;17:713-30.
Bonnefont-Rousselot D et al. Melatonin: action as antioxidant and potential applications in human disease and aging. Toxicology 2010; 278:55-67.
Dreher F et al. Topical melatonin in combination with vitamins E and C protects skin from ultraviolet-induced erythema: a human study in vivo. Br J Dermatol 1998;139:332-9.
In the past, overactive melatonin receptor was thought to have a key role in vitiligo
pathogenesis.
Recent evidences on the prominent antioxidative actions of MN have then
suggested a
revision of that hypothesis.
According to these evidences, an insufficient intracutaneous synthesis and buffering
of MN
would lead to development of vitiligo when oxidative stress, cellular ⁄ subcellular or
DNA
damages occur because of insufficient scavenging and ⁄ or buffering activity.
In the skin, MN controls the dispersion and aggregation of melanin
throughout melanocytes, causing the skin to change color
(these variations follow MN circadian secretion cycle).
Fischer T et al. Melatonin in dermatology. Experimental and clinical aspects. Hautarzt 1999;50:5-11.
Slominski A et al. View point 4: melatonin hypothesis on the vitiligo pathogenesis. Exp Dermatol 2008; 17: 149-52
• Melanoma/carcinoma
• Psoriasis vulgaris
• Radioprotection
• Sarcoidosis
• Solar erythema
• Vitiligo
• Wound healing
MELATONIN
Slominski A et al. Hypothesis: possible role for the melaton'in- receptor in vitiligo: discussion paper. J Royal Soc Med 1989: 82: 539–541.
Skin disorders which could benefit from melatonin administration
• Aging
• Alopecia
• Atopic eczema
• Diabetic foot syndrome
• Hair greying
• Itching
Benefical effects of AOs molecules have been
investigated during last two decades.
Large part of these studies have used in
vitro models or animal models (mouse setting).
Few studies have been performed
on human beings, almost all based on limited
study group and without adequate controls.
Further investigations on human model, including randomized double-blind
trials
on large population groups, are necessary :
> to obtain statistically significant data
> to test different treatment modalities (oral vs topical,
alone vs combined) of the various AOs molecules.
AOs represents a natural tool for contrasting photo-damage
(photo-aging and photo-carcinogenesis) and vitiligo patogenesis.
Take home message
Thank you for the attention.