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Free iron: a forgotten target in
skin aging prevention
Iron
Iron is essential for aerobic life, oxygen transport,
energy production, red blood cell function
But (free) iron is also involved at various steps of
the oxidation processes, increasing the production
of the more toxic hydroxyl radicals
Fenton reaction:
H2O2 + Fe2+
.OH
Haber-Weiss reaction: H2O2 + O2.- + Fe2+
+ Fe3+ + -OH
.OH
+
-OH
+ O2 + Fe3+
O2
molecular oxygen
Fe2+
O2.superoxide anion
H2O2
.OH
hydrogen peroxide
hydroxyl radical
sugar
DNA
glycation
nucleus
strand breaks
membrane lipids
mitochondria
dysfuntion of the
respiratory chain
proteins
functional
alterations
cellular senescence
Damages induced by hydroxyl radical (Polla BS et al 2013)
lipid
peroxidation
Iron
Free iron also activates transcription factors
involved at different steps of pro-inflammatory
processes such as NFκB
UV plays a role in the release of free iron from
proteins to which iron is normally bound such as
ferritin
Iron and inflammation
UV
ferritin
Fe2+
Fe2+
O2.-
Fe2+
lysosomal
enzyme
.OH
H2O2
Fe3+
Fe2+
Fe2+
NF-κB
activation
Fe2+
ferritin
lysosome
cellular
damages
inflammation
fibroblast
Lysosomal enzymes damage ferritin that releases free iron thus indirectly
causing cellular damages (Polla BS et al 2013)
Iron
-The
aging process is accelerated by oxidation
→iron increases oxidation damage → affects the
aging process
-The aging process is modulated by inflammation
→ iron modulates inflammation → affects the aging
process
Haemochromatosis
-0.3% of individuals: common metabolic disorder
-genetically determined: HFE gene on chromosome
6
-this gene intervenes in the control of
gastrointestinal iron absorption
-spontaneous pathology of iron accumulation in
the internal organs as well as in the skin
Haemochromatosis
-skin has a gray appearance and presents
accelerated signs of aging: role of iron in
photoaging
-iron levels in the circulation are generally higher
than the binding capacity of iron to transferrin
-publications on hemochromatosis and skin aging
are however rare; skin histology appears to be
missing
Haemochromatosis
Picture: Cutaneous pigmentation in haemochromatosis (greyish hue and
brown hue) (Hemochromatosis, Genetics, pathophysiology, diagnosis and
treatment, Ed JC Barton and CQ Edwards, 2000)
Clinical / pathological models for iron overload and
free iron excess
-Haemochromatosis
-UV exposure
In both cases :
-excess free iron
-accelerated aging
Iron and UV
-UV radiations remove the iron from its protective
envelopes (Pourzand et al 1999)
-skin iron: three times higher in the skin exposed
to UV light (forehead, cheeks) than in non-exposed
areas (buttocks, thighs) (Bissett et al 1991)
Iron and UV
UV
Fe2+
storage proteins
Fe2+
Fe2+
storage proteins
Fe2+
O2.-
UV
Fe2+
Fe2+
Fe2+
Fe3+
H2O2
.OH
cellular damages
cellular aging
fibroblast
UV radiations remove the iron from its protective envelope (Polla BS et al
2013)
Protection against free iron:
depletion, storage and chelation
-ROS-induced lesions are inhibited by a reduction
in free iron
-depletion has also been shown to be efficient in
various animal models such as Duchenne’s
myopathy were oxidation at the cellular level plays
an important role in the progressive muscle lesions
(Clark 1984) as well as in an animal models
(Bornman et al, 1998)
-iron linked to transport proteins and stored
Chele
Chelation
UV
ferritin
ferritin
Fe2+ Fe2+
A
Fe2+
Fe2+
B
Fe2+
Fe2+ Fe2+
iron chelator
C
Figure A: ferritin scavenges iron
Figure B: UV damages ferritin which releases iron
Figure C: iron chelator scavenges iron with same manner as ferritin (Polla
BS et al 2013)
Chelation: works by Bissett et al
Topical treatment
( = 5)
Average wrinkles
Onset time
(W)
Vehicle control*
5.8 ± 0.8
5% FDO 5%
16. 6 ± 3.1
5% Padimate O
22.8 ± 4.1
5% Padimate O
+
5% FDO
74.3 ± 7.1
Time of onset of wrinkles in mouse skin treated with 2-furildioxime (FDO),
sunscreen and their combination before UV exposure. *ethanol/prop.glycol
(Bissett et al 1996)
Chelation from the Greek chele, which describes the crab
claw
Chelation: works by Bissett et al
2.5
Erythema Score
2
1.5
1
0.5
0
-UV
+UV
Vehicle
-UV
+UV
FDO
Suppression of UV-induced human skin erythema 24 hours after 3 MED by 2furildioxime (FDO) (Bissett et al 1994)
Chelation: works by Bissett et al
Sunburn Cells per mm
8
6
4
2
0
-UV
+UV
Vehicle
-UV
+UV
FDO
Inhibition of sunburn cell formation in human skin 24 hours after 3 MED by 2furildioxime (FDO) (Bissett et al 1994)
Synthetic chelators
-desferrioxamine effects on liver ischaemiareperfusion injury → decrease in oxidative and
inflammatory serum markers and in hepatocellular
damage (Arkadopoulos et al 2010)
-combination with desferrioxamine, deferipone and
deferasirox → improve cardiac and hepatic iron
load in beta-thallassemia (Berdoukas et al 2009)
Synthetic chelators
-Parkinson’s disease: abnormal accumulation of
iron in affected neurons in the substantia nigra.
Desferrioxamine/desferal/ deferiprone: new use in
neurodegenerative diseases (Mounsey and
Teismann 2012)
-Different types of iron chelators have
neuroprotective effects, preventing neural
apoptosis and activating cellular protective
pathways against oxidative stress (Oshiro et al
2011)
Natural chelators
-quercetine, genisteine, kaempferol,…
-”iron-binding motif”: iron chelating agent which
may modulate the bioactivity and bioavailability of
iron in the body (Guo M et al 2007)
OH
OH
O
HO
OH
OH
chelation
site
O
quercetin molecule with chelation site
Natural chelators
-shuttle for labile iron : effective in loading the
metal into the iron-transport protein transferrin
(Baccan MM et al 2012)
-association between antioxidants and iron
chelators in topical approaches
Conclusion
Modulation of iron levels appears as a very
attractive approach in the management of diseases
and conditions associated with excess oxidation
and in antiaging
The skin could provide an excellent model to
investigate the preventive effects of iron chelation
in inflammation and aging
However we are missing clinical research on the
effects of iron chelation including in dermatology
>> back to work !
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