Review Article Ultraviolet Radiation-Induced Skin …downloads.hindawi.com/journals/sci/2016/7370642.pdfDNA damage and gives skin and hair their distinctive colors []. Microenvironment

Review ArticleUltraviolet Radiation-Induced Skin AgingThe Role of DNA Damage and Oxidative Stress in EpidermalStem Cell Damage Mediated Skin Aging

Uraiwan Panich Gunya Sittithumcharee Natwarath Rathviboonand Siwanon Jirawatnotai

Laboratory for Systems Pharmacology Department of Pharmacology Faculty of Medicine Siriraj HospitalMahidol University Bangkok 10700 Thailand

Correspondence should be addressed to Siwanon Jirawatnotai siwanonjirmahidolacth

Received 1 December 2015 Accepted 14 March 2016

Academic Editor Hung-Fat Tse

Copyright copy 2016 Uraiwan Panich et alThis is an open access article distributed under theCreative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Skin is the largest human organ Skin continually reconstructs itself to ensure its viability integrity and ability to provide protectionfor the body Some areas of skin are continuously exposed to a variety of environmental stressors that can inflict direct and indirectdamage to skin cell DNA Skin homeostasis is maintained bymesenchymal stem cells in inner layer dermis and epidermal stem cells(ESCs) in the outer layer epidermis Reduction of skin stem cell number and function has been linked to impaired skin homeostasis(eg skin premature aging and skin cancers) Skin stem cells with self-renewal capability and multipotency are frequently affectedby environment Ultraviolet radiation (UVR) a major cause of stem cell DNA damage can contribute to depletion of stem cells(ESCs and mesenchymal stem cells) and damage of stem cell niche eventually leading to photoinduced skin aging In this reviewwe discuss the role of UV-induced DNA damage and oxidative stress in the skin stem cell aging in order to gain insights into thepathogenesis and develop a way to reduce photoaging of skin cells

1 Introduction

Skin serves as the major protective organ of the bodyThis protection can be compromised by aging of the skina condition normally associated with skin inflammationimpaired wound repair and increased risk of skin cancers[1 2] Skin aging is defined as a continuous loss of certaincharacteristics present in juvenile skin including decreasedskin elasticity and pigmentation and loss of ESCs [3ndash5] Skinaging is a multifactorial process that involves genetic andenvironmental factors A variety of environmental stressesparticularly UV light can damage sun-exposed areas of theskin such as the face and neck and accelerate prematureaging [6] Skin aging that is associated with UVR exposureis referred to as photoaging

Adult tissues including skin epidermis gastrointestinalepithelium and the hematopoietic system have a high rateof cell turnover To maintain their functions and integritythe physiological process ofmaintaining tissue homeostasis is

attributed to a constant number of cells in renewing organsESCs are essential for the maintenance and regeneration ofskin tissues [7]

Adult skin is composed of a diverse organized array ofcells emanating from different embryonic origins Duringdevelopment skin is derived from embryonic origins ofcell types from different germ layers Epidermis and dermisare developed from ectoderm and mesoderm respectivelyThe epidermis develops from embryonic surface ectodermwhich starts as a single layer of unspecified progenitorcells covering the embryo after neurulation and becomesthe epidermal basal layer [8] The epidermal basal layer isenriched with ESCs Thus cells in this layer give rise to allepidermal structures including a stratified epidermis (alsocalled interfollicular epidermis) and epidermal appendagessuch as hair follicles sebaceous glands and sweat glandsThe underlying dermis is derived primarily from mesodermunder the ectoderm The mesoderm is the major source ofmesenchymal stem cells that give rise to collagen-producing

Hindawi Publishing CorporationStem Cells InternationalVolume 2016 Article ID 7370642 14 pageshttpdxdoiorg10115520167370642

2 Stem Cells International

fibroblasts (a component of blood vessels that provide nutri-ents to skin) subcutaneous adipocytes and immune cells inthe skin

Dermal fibroblasts are the main mesenchymal cell typein dermis Substructurally they were shown to be derivedfrom the upper dermis and lower dermisThefibroblasts fromthe former contribute to hair follicle formation while thefibroblasts from the later produce fibril extracellular matrix(ECM) ECM from dermal fibroblasts plays a crucial role instructural integrity and repair of the skin and wound healing[9]

Skin is also populated by specialized cells includingmelanocytes and sensory nerve endings of the skin that arederived from neural crest cells Overall approximately 20different cell types reside within the skin [8 10]

ESCs are defined by their ability to self-renew and differ-entiate into different cell lineages belonging to the skin [11]ESCs are capable of differentiating into the entire set of cellsthat comprise the skin Thus the epidermis is used for skingraft to replace damaged or missing skin [12] ESCs wereshown to be able to develop into three distinct layers of epi-dermis spinous layer granular layer and cornified layer (orstratum corneum composed of dead flattened and anucle-ated cells) ESCswere also shown to be capable of differentiat-ing intomultiple skin cell lineages includingmature and spe-cialized keratinocytes sebocytes or pigmented melanocytes[13 14]

In addition to the interfollicular stem cell ESCs includestem cells in hair follicles the hair follicle stem cells (HFSCs)that reconstitute hair follicles and play role in wound healing[15] Another type of stem cells in the epidermis ismelanocytestem cells (MSCs) which are intermingled withHFSCs in thehair bulge MSCs generate mature melanocytes that producemelanin which absorbs ultraviolet (UV) light to preventDNA damage and gives skin and hair their distinctive colors[16]

Microenvironment within skin is important for mainte-nance of stem cells The microenvironment provided fromthe complex structure of ECM and basement membraneform integral stem cell niches for the ESCs [17] Adult ESCsresiding within the niches remain there for self-renewalwhereas their progeny committed to differentiation leave thebasal call layer and migrate towards the epidermal surface[13] This made it relatively useful to track each lineage alongthe steps of differentiation Thus skin has served as oneof the ideal models for studying stem cell differentiationand the interaction between stem cells and their respectivemicroenvironments [18]

Because of their exposure to DNA damaging conditionsskin stem cells are innately highly resistant to the agingprocess andDNAdamage and carry highly activeDNA repairmechanisms [19ndash21] Nevertheless ESCs can be impaired inadvanced age [22] and are vulnerable to repetitive exposure toUVR [23ndash25] If not repaired properly damaged DNA mayresult in mutation or chromosomal rearrangements whichnegatively influences self-renewal and potency of stem cellsand promotes skin aging andor cancer formation [26]

To prevent photoaging and skin cancers reduced expo-sure to DNA damaging agent (UVR) and well-controlled

DNA repair mechanisms in ESCs are required to preventphotoaging and DNA damage-associated skin diseases suchas cutaneous basal cell and squamous cell carcinoma (BCCsand SCCs) [27]

While the role of UVR-induced DNA damage and oxida-tive stress in the skin aging involving ESC changes will be thefocus of this review it should also be noted that other factorsmay also contribute to this process Skin in the area notnormally exposed to UVR also can exhibit aging phenotypeFactors such as chronological shortening of skin cell telomere[28] increased inflammatory responses and accumulation ofsenescent cells could contribute to skin aging by impairingstem cell function and homeostasis [29]

2 UV-Induced DNA Damage in Skin Cells

Repetitive exposure to solar UVR is among the principalenvironmental factors that can hasten the aging process of theskin accompanied by progressive impairment of epidermalstem cell function [30] UVR is a natural component ofsunlight and is invisible to human eye Three types of UVare categorized according to their wavelength UV-A (315ndash400 nm) UV-B (280ndash315 nm) and UV-C (100ndash280 nm) UV-C is completely filtered out by the ozone layer of the Earthrsquosstratosphere Only UV-A and UV-B can reach the earthsurface However climate change and depletion of the ozonelayer may lead to increases in UV radiation at ground-levelUVR is known to be a mutagen long-term overexposureto sunlight is associated with photoaging and formation ofskin cancers [31] Interestingly both photoaging and cancer-inducing effects of UVR are mediated through UVRrsquos directand indirect toxicity to the DNA [32]

The direct effect of UV irradiation occurs when DNAabsorbs photons from UV-B This results in structural rear-rangement of nucleotides that then leads to defects in theDNA strand Cyclobutane pyrimidine dimers (CPD) andpyrimidine (6-4) pyrimidone (6-4 photoproducts 6-4 PPs)are the major products of UV-B-induced DNA damage [32]Direct absorption of UV-B photons induces cycloadditionbetweenC5-C6 of two adjacent pyrimidine bases and changesthem into CPD Meanwhile covalent bond formation ofC6-C4 of two adjacent pyrimidine bases generates 6-4 PPsphotoproduct which further converts to its Dewar valenceisomer upon UV excitation at 314 nm The hotspot withinthese UV-induced DNA lesions is where tandem pyrimidineresidues form (TT TC CT and CC) [33] At this pointcells will respond by promptly halting cell division to preventfurther DNA damage and allow the DNA repair mechanismto start In lower species photolyase enzyme is employedto repair DNA by removal of UV-induced DNA lesionsin a specific manner The enzyme binds CPD or 6-4 PPsat lesion sites and splits the dimers back to undamagedbases However human and othermammalian cells no longerpossess this enzyme The main UV-induced DNA damageresponse in humans is the nucleotide excision repair (NER)pathway There are 9 major proteins that function as NERin mammalian cells RAD23s RPA ERCC1 proteins andothers also participate in nucleotide excision repair [34 35]

Stem Cells International 3

Deficiencies of these proteins lead to diseases associated withDNA damage and premature skin aging [36]

NER starts when XPC forms complex with CETN2 andRAD23 at distorted DNA sites and DNA is unwound by XPBThe damaged DNA is then stabilized by XPA XPB XPD andRPA (single-stranded DNA binding proteins) RPA will thenactivate structure-specific endonucleases that contain XPGand ERCC1-XPF followed by base excisions Gaps are filledby DNA polymerase and fragments are sealed by DNA ligaseIn addition to DNA repair pathway defects mutations arealso caused by error-prone DNA polymerase which tendsto add a residue at the position where the specific base ismissing thus creating ldquoUV signaturerdquomutations of CrarrT andCCrarrTT transition as a result of UV irradiation [37]

UV radiation also indirectly damages DNA Absorp-tion of UV-A photons drives electrons and energy transferfrom cellular photosensitizers such as porphyrins bilirubinmelanin and pterins to oxygen molecules creating the radi-cal singlet oxygen (1O

2) anion [32] Consequently the singlet

oxygen anion induces guanine moiety oxidation followed bystructural rearrangement and 8-oxo-78-dihydroguanine (8-oxo-G) and 8-oxo-78-dihydro-21015840-deoxyguanosine (8-oxo-dG) formation which is the biochemical marker of UV-A-induced DNA damage 8-oxo-G and 8-oxo-dG tend topair with adenine instead of cytosine leading to C-T tran-sition mutation [38 39] Protective mechanisms againstUV-induced oxidative damage acquire both antioxidativepathway and base excision repair (BER) pathway Removalof 8-oxo-dG by BER is performed by a key enzyme human8-oxoguanine DNA glycosylase (hOGG1) which specificallyrecognizes and cleaves glycosidic bond from the DNAstrand creating abasic (AP) sites Subsequently missingnucleotides are restored by DNA polymerase and gaps aresealed by DNA ligase Accordingly depletion of hOGG1 bymicroRNA inhibits the repair of UV-A-induced 8-oxo-dG inkeratinocyte HaCaT cells [40]

3 UV-Induced Depletion of Skin Stem CellsA Multipronged Attack on Skin Stem Cells

Several studies have investigated the role of DNA damageon function and genetic instability of ESCs [27 41 42]Human ESCs are sensitive to DNA damaged lesions Ionizingradiation-mediated DNA damage reduced colony-formingpotential and viability of skin stem cells and destabilized thestem cell microenvironment in the bulge region of hair folli-cles As a consequence MSCs aging with related hair grayingwas observed [43] It was shown that damage to ESC DNAby low-dose ionizing radiation significantly induced DSBs-mediated chromatinmodifications and thatDSBsmay also bepassed on to their differentiated cell lineages [44] Persistentexposure to UVR also increased DNA damaged lesions andmutations and led to premature aging or carcinogenesis of theskin [45]

Links between UVR exposure and skin aging can beobserved when the DNA repair mechanism becomes dys-functional Quite often defects in DNA repair systems ofstem cells accelerate the accumulation of genome instability

in lineage-primed progenitor cells during aging [46] Asdescribed previously NER is one of the most versatile DNArepair systems for eliminating a variety of helix-distortingDNA lesions induced by UVR [47] Aberrance in this path-way contributes to UV hypersensitivity

Mouse models genetically engineered to contain nullallele of XPC shared skin aging phenotypes [48] Geneticcorrection of keratinocyte SCs from NER-deficient XPCpatients was observed to restore DNA repair capacity andcell survival following UVR as well as providing long-termgrowth potential of stem cells [49] Studies of human geneticdisorders collectively known as progeroid syndromes (PS)(characterized by conditions that resemble premature aging)foundmutations in the germ cell line or stem cells of genes inDNA repair pathways PS-associated premature aging affectsall tissues including the skin causing skin atrophy hairgraying and abnormal pigmentation [36] Patients with PSalso develop other systemic diseases such as atherosclerosisosteoporosis and diabetes mellitus at an early age [50] SomeDNA repair defects implicated in PS are found in Wernerrsquossyndrome (WS) Hutchinson-Gilford progeria syndrome(HGPS) dyskeratosis congenita xeroderma pigmentosum(XP) and Cockayne syndrome (CS) [51 52] All of these raresyndromes associate with depletion and dysfunction of adultstem cells and their progenies in various tissues including theskin The most well-studied inherited disorder among theseis XP involving themutation of XPs genes and defectiveNERXP patients whose genome harbors XPs gene mutations aregenerally hypersensitive to solar UVR accumulate increasedlevel ofmutations anddevelop skin aging and skin carcinomaby an early age with an approximate 1000-fold increased risk[53 54]

In addition evidence of NER role in skin aging isobserved in physiological aging Decline in NER functionassociated with increasing age is speculated to contribute tothe onset of aging manifested in various tissues including theskin

Telomeres are nucleoprotein complexes that cap and savethe ends of chromosomes from degradation and abnormalrecombination Telomeres shortenwith each cell division andprogressive telomere shortening ultimately results in cellularsenescence It is thus suggested that telomere dysfunction inassociation with p53-dependent premature cell senescence ispossibly responsible for the aging of human stem cells

Telomere shortening and dysfunction are a cause ofgenomic instability inWS (classic premature aging) resultingfrom a mutation in a gene coding the RecQ helicase WRNrequired for telomere maintenance during DNA replication[55]

Previous studies in the role of telomeres in epidermalstem cells observed that deletion of protein binding to telom-eric DNA adversely affects skin homeostasis and develop-ment at embryonic stages in association with enhanced DNAdamage response [56] In addition decline in function ofESCs was observed in association with shortened telomereswhich reduced proliferative potential in response to stimulithatmay be implicated in the premature skin aging phenotypeobserved in mice [57] Conversely ESCs from aged skin werefound to contain elevated levels of chromatin rearrangements


and epigenetic changes and indicated that aging might belargely the attribution of structural changes to chromatinpotentially leading to epigenetically induced transcriptionalderegulation [58] Finally a connection between UVR andtelomere attrition has recently been emphasized A reportby Stout and Blasco showed that telomere length is at leastpartly maintained by the same NER pathway that protectsDNA from UVR damage UVR treatment on mouse119883119875119862minusminusepidermis resulted in telomere shortening in stem cells [59]

Taken together these results argue for a strong connec-tion between skin photoaging and DNA damage-inducedstem cell exhaustion (Figure 1)

4 ESC Exhaustion as a Consequence of CellCycle Checkpoint Activation

DNA damage normally triggers activation of checkpointpathways simultaneously with the activation of DNA repairmechanisms Checkpoint proteins such as p53 and ATM areactivated upon UVR exposure and they elicit cell cycle arrestsignaling to allow properDNA repair [60] Deficiencies in thecheckpoint pathways result in accumulation of DNA damagelesions resembling the phenotypes of DNA repair deficien-cies Protein product of ataxia-telangiectasia mutated (ATM)gene a checkpoint protein that acts as a detecting sensorfor DNA damage in a cell triggers cell cycle arrestDNArepair Mutations of theATM gene cause ataxia telangiectasia(AT) an inherited disease associated with premature agingparticularly at the skin Although not a bona fide DNArepair gene defects in ATM lead to accumulation of genomicdamage and premature exhaustion of the stem cell pool invarious tissues including the skin [46]

A gene downstream of ATM p53 is a transcriptionfactor which primarily functions as a gatekeeper for DNAmutations [61] Timely expression of wild-type p53 is crucialin preventing deregulated or stressed cells from turninginto cancer cells [62] p53 does this by transactivatingexpressions of gene sets that initiate cell cycle arrest DNArepair senescence or apoptosis Examples of genes activatedby p53 include XPEDDB2 (a gene in the NER pathway)[63] p21 (a cell cycle inhibitor) BCL2-associated X protein(BAX) and TNF receptor subfamily member 6 (FAS) (bothproapoptotic proteins) [64ndash66] Upon UV irradiation p53is phosphorylated by several kinases namely ATM ATR(ATM-related kinase) andCHK12 UV-induced phosphory-lation at Serine 15 increased p53 stability and protein levelthat associated with DNA damage [61] Inhibition of p53phosphorylation duringUV-inducedDNAdamage increasedsensitivity to UV-induced skin tumor development [67]indicating that p53 activation after DNA damage effectivelyhalts the expansion of cells with damaged DNA in order toprevent cancer formation

Interestingly overactivation or prolonged activation ofcheckpoint proteins will also result in the diminishing of self-renewal potential of ESCs Skin of the mouse lacking thenegative regulatory protein of p53MDM2 elicited increasedbasal p53 level and premature aging skin phenotypesincluding thinning of the epidermis reduced wound healingand progressive hair loss [68]

In agreement with the negative role of prolonged p53expression on stem cell potency it was shown that p53restricted the stem cell gene expression program [69] Sup-pression of p53 by viral protein or siRNA facilitated repro-graming of iPS [70 71] In vivo p53minusminus mice showed markedstem cell expansion and were prone to teratoma [72] LastlyUV-damaged DNA binding proteins 1 (DDB1) and 2 (DDB2)cooperate with p53 in DNA damage response Deletion ofDDB1 in mouse resulted in genomic instability and loss ofepidermis which could be partially rescued by deletion ofp53 [73] Deletion of DDB2 another gene regulated by p53resulted in UV-induced skin cancer [74]

p63 a p53-related gene is well accepted as a protein thatmaintains ESCs Expression of p63 selectively distributed inthe basal cells of both stratified and glandular epithelia bothof which contained ESCs suggested its critical role in theregulation of stemness p63 and its isoforms are regardedas a marker of ESCs [75] The transactivating isoform ofp63 (TAp63) functions to suppress hyperproliferation of skinstemprogenitor cells that result in exhaustion of the ESCpoolor DNA damage TAp63-null mouse skin demonstrates cellswith terminal cell cycle arrest (senescence) phenotypes andpremature skin aging [76] Since p63was shown to respond tostress signals similar to p53 and is upregulated in prolongedcultured cells it might be reasonable to expect that p63works inDNAdamage response and contributes tomediatingUV-induced ESC exhaustion [77] However there is still noevidence to support this notion

Checkpoint proteins also triggered DNA repair In addi-tion to those already mentioned a mouse model for BRCA1deficiency emphasized the significance of unrepaired DNAin stem cell depletion Deficiency of BRCA1 a central proteinin single-stranded and double-stranded DNA repair in epi-dermis is associated with increased DNA damage genomeinstability loss of hair follicle stem cells (HFSCs) and hairfollicles Defects appeared to be the result of activated p53since deletion of p53 offset the effects of BRCA1 loss [78]BRCA1 plays a role in UV-induced DNA damage responseUV-induced DNA damage produced BRCA1-positive foci aspart of the damage response [79] Interestingly BRCA1 dele-tion in skin epidermis using K14-Cre did not affect stem cellsin sebaceous grand and interfollicular epidermis suggestingthat BRCA1 is only indispensable for some populations ofstem cells

5 DNA Damage Promotes Photoaging byDepriving Stem Cells of Their Niche

Maintenance and repair of many adult tissues rely on stemcells to produce numerous differentiated cells that replaceor repair the tissue [80ndash82] Stem cells in the pool spendrelatively long period of time in a quiescent state and thepool is to be used throughout the life of the organismESCs in the pool will exit from the quiescent stage to divideto produce more stem cells or committed progeny cellswhich will then eventually differentiate into various cellularcomponents of skin Maintenance of the pool relies onextrinsic factors such as signaling fromneighboring cells and


UVR

DNA damage

Activation ofcell cyclecheckpoints

Activation ofDNA repair(NER BER)

Damage ofstem cell niche

Damage ofdermal

Overactivationof checkpoints

Defects in Loss of nicheMMPs upregulation

accumulation of glycation

Loss of ECM integrity

ESC depletion

Skin aging

ROS

fibroblasts

DDR contact

UV-A UV-B

Figure 1 Skin aging induced by UVR-induced DNA damage to ESCs UVR is the major skin stressor capable of damaging ESCDNA (UV-B)or promoting production of the DNA toxic ROS (UV-A) DNA damaging effects of UVR result in activation of cell cycle arrest (checkpointactivation) and DNA repair proteins damaged stem cell niche and dermal fibroblastsThese facilitate ESC depletion and loss of extracellularmatrix (ECM) integrity leading to premature skin aging

surrounding environment (microenvironment) that make upthe stem cell niche and cell autonomous regulations [80 83]Irradiated quiescent MSCs prematurely differentiate in theniche upon their activation without sufficiently renewingthemselves These data suggest that tissue radiosensitivitymay be dependent on the state of somatic stem cells in theirlocal microenvironment [84]

UV-induced DNA damage was also reported to inter-fere with skin stem cell pool by causing changes in thestem cell niche ESCs are surrounded and maintained by amicroenvironment of various cell types and substances [85]The homeostasis of stem cells is influenced by cross talkbetween ESCs and mesenchyme cells and the interactionbetween stem cells and extracellular matrix (ECM laminintype IV collagen nidogen and perlecan) the constituents ofthe basement membrane of skin Communication between

ECM components is mediated by integrins a family of trans-membrane proteins on the ESCs surface Integrins contactother cells or the ECM Such connections trigger signaltransduction pathways which result in biological responsessuch as cell proliferation or cell motility The notion thatESCs express abundant levels of integrins indicates thatcommunication with the niche environment is fundamentalto ESC stemness (high level of 1205726-integrin is considered oneof the hallmarks of ESCs) Fibronectin vitronectin collagenand laminin are all ligands for integrins and have beenreported to play an intricate role in ESC homeostasis It wasdemonstrated in a study of HFSCs that the mesenchymalniche of the hair follicle provides molecular signals that aresufficient to induce hair growth [86] Interaction betweenintegrins and ECM is required for stem cell maintenanceLoss of contact from the ECMdecreases potency of stem cells


[87] and 1205731 integrin-mediated adhesion signaling is essentialfor epidermal progenitor cell expansion

DNA damage appears to also activate expression of genesthat are not directly implicated in DNA damage response butthat play a role in skin stem cell homeostasis Transcriptionfactor c-Myc is one of the genes found to be activated byUVRc-Myc overexpression was detected approximately 5 hoursafter UV irradiation of the skin cells [88] c-Myc expressionwas shown to correlate with reduced potency of skin cellsDeregulated c-Myc expression was shown to deplete ESCs bymaking the ESCs overproliferate move out of their nicheand then differentiate [89 90] c-Myc could also induceESC differentiation as mediated by c-Myc in the c-Myc-Miz1complex which supposedly suppresses genes critical for skincell stemness [91] In fact 1205731 integrin was reported to be agene target for repression by the c-Myc-Miz1 complex in stemcell depleted skin [91] These results indicated that stem cellsfavor low level of c-Myc to stay in undifferentiated statuswithDNAdamage triggering untimely c-Myc overexpressionresulting in ESC exhaustion

In addition long-term UVR exposure can cause restruc-turing of the extracellular matrix Proteins in extracellularmatrix components contain UV-absorbing chromophoreswhich are vulnerable to the UV-induced structural changes[92] UV-induced changes in ECM are well characterizedUVRexposure not only upregulates the expression ofMMP-1MMP-2 MMP-3 MMP-7 MMP-9 and MMP-12 [93] butalso promotes a prooxidative environment in human skinby which the structure of the skin will be further damagedAlthough this restructuring of the extracellular matrix likelydisturbs the ESC pool detailed studies are needed to identifyand elucidate the effects

6 UV-Induced Oxidative StressA Major Assault on Skin and a PotentialPreventive and Therapeutic Target forAntioxidants in Skin Photoaging

UV-A-induced ROS is to a major degree responsible forESCs DNA damage Normally reactive oxygen species (ROS)are endogenously produced in the cell fromvariousmetabolicprocesses including cellular respiration which takes placein mitochondria and is the primary source of intracellularROS [94]However ROS production can also be a by-productof cell exposure to the environment including exposure toUVR ionizing radiation pollutants cigarette smoke alcoholheavy or transition metals and certain drugs [95ndash97] ROSinclude not only free radicals such as superoxide anion radi-cal (O

2

∙minus) and hydroxyl radical (OH∙) but also nonradicalslike singlet oxygen (1O

2) and hydrogen peroxide (H

2O2)

ROS play a dual role as both harmful and useful moleculesin the cell as such an appropriate level of ROS is neededfor normal physiological function of mammalian cells andtherefore is essential for life Phagocytic ROS act as weaponsfor the immune system to kill pathogenic microorganismsthat cause infection ROS also take physiological roles in theregulation of several cellular functions and signaling cascadesinvolved in proliferation differentiation and survival of

various types of cells such as endothelial cells fibroblastssmooth muscle cells cardiac myocytes neuronal cells andskin keratinocytes [98ndash101]

While ESCs appear capable of adequate responsiveness tochanges in their environment accumulated oxidative dam-age to biomolecules in the cells including lipids proteinsand DNA caused by repetitive exposure to environmentalinsults in particular UVR may compromise their self-renewal capacity and promote loss of ESC numbers resultingin premature aging [42 102] Although the mechanisms bywhich ROS act on molecular changes in ESCs in the processof skin aging are not well understood it has been shownthat elevated ROS is responsible for premature aging of thestem cells of the skin Wang et al observed that persistentelevation of ROS and oxidative DNA damage are associatedwith increased senescence and decreased clonogenic capacityof hematopoietic stem cells (HSC) [103]

Thus it is very important to understand the role of ROSin ESC DNA damage and disturbed ESC homeostasis inparticular in association with DNA damage In many casesthe models that contained defect in antioxidation pathwaysor DNA repair helped to explain the significance of ROS-induced DNA damage during ESC exhaustion process

7 ROS in DNA Damage andDefective DNA Repair Systems Implicatedin Loss of Epidermal Stemness

Beyond DNA repair mechanisms protection of skin cellsagainst UV-induced DNA damage includes enzymatic an-tioxidants [104] It has been suggested that stem cell DNAdamage is often accompanied by oxidative stress which is anaccountable factor for stem cell senescence and aging [105106] Excessive ROS can result in single-strand break prod-ucts Oxidative DNA damage is continuously accumulatedthroughout the lifespan of a living cell During physiologicalaging DNA is constantly exposed to intracellular ROS asby-products of metabolic process ROS can introduce DNAbase or sugar damage resulting in formation of approximately5000 single-strand breaks in each cell in the human bodydaily [107 108]

ROS similarly damage both nuclear and mitochondrialDNA (mtDNA) It was recently reported that aging of theskin was observed to be associated with mtDNA damageand mutations mtDNA mutations were suggested as beinga sensitive biomarker of UVR exposure and oxidative stressin human skin [109] Additionally our study previouslydemonstrated that induction of oxidative DNA damage anddefects in DNA repair hOGG1 that could be responsiblefor photocarcinogenesis were associated with patients withBCC [110] Another report showed that overproduction ofROS (generated during ionizing radiation) was involved withMSC depletion in graying hair an obvious sign of agingDetailed study showed that ROS-induced DNA damage ledto MSC attrition and discontinued renewal of MSCs in miceby enhancing MSC differentiation into mature melanocytesThe same study proposed that ATM was the sensor ofROS-induced DNA damage and acted as a checkpoint for


the stemness Deficiency of ATM from MSCs stimulatedMSC differentiation [111] In another study ROS-induceddepletion of HSC was shown to be mediated by p38 MAPKphosphorylation in the 119860119879119872minusminus cells [112]

Integrity of chromosomes is determined by the lengthof the telomere Cellular aging is associated with shortenedtelomere Adequate telomerase (TERT) activity is required tomaintain telomere length DNA damage in association withtelomere dysfunction and shortening precipitates prematureaging and shortened lifespan leading to depletion of almostall tissue stem cell reserves and dysfunction of stem cellsincluding self-renewal and repair capacity of ESCs andmelanocytes of the follicle during the hair growth process[113 114] Interestingly high telomerase expression which isassociated with long telomeres is commonly found in adultstemprogenitor cell compartments including the stem cellsin hair follicles whereas low telomerase expression has beendetected in human fibroblasts and epithelial cells [115 116]

ROSmay also activate the p53-p21 axis Akt-MAPKATMpathways [117] and forkhead homeobox type O (FOXO)transcription factors in various types of stemcells by influenc-ing telomere length [118] Moreover the reduced proliferativepotency of stem cells was induced by ROS-activating p53stabilization [119] Skin aging associated with ROS accumu-lation thus was found to be rescued in the skin of late-generation p53 knockout mice [120] In these mice therewere improvedwound healing hair growth and skin renewalto levels comparable to those of wild-type mice as well asincreased ESC numbers and improved mobilization capacity[120]

Effects of ROS on supportive cell types have also beenstudied Exposure of human skin fibroblasts an importantcellular component of skin microenvironment to UVR hasbeen shown to result in oxidative stress and enhanced expres-sion of cell cycle inhibitors p16INK4A and p53p21WAF1CIP1 Upregulations were predictably followed by prematuresenescence of fibroblasts [121 122] which unavoidably dis-turbed stem cell-niche cross talk [123] High level of ROSwas also reported to induce skin fibroblasts to secrete highlevels of matrix metalloproteinases (MMPs) which causedextensive ECM remodeling in dermal layers [124ndash126]

In addition to the direct DNA damage caused by UVRROS a by-product of UV-A exposure also plays prominentrole as a DNA damaging agent that damages DNA in anequally extensive manner However due to the transientnature of ROS it is possible to ameliorate its effect andprotect the skin from premature aging PharmacologicallyROS has been considered as a potential target for photoagingprevention and therapies

8 Preventive and TherapeuticImplications of Antioxidants in Photoagingthrough Preservation of Stemness

Regarding the importance of stem cells several protectivemechanisms have been detected in different stem cell typesfor protecting against ROS and UV-induced DNA damage[127 128]

At present strategies to potentiate DNA repair pathwayor to restore functions of defective NER proteins are underinvestigation Gene therapies for the XP might be possiblewith the emergence of gene editing technologies [129 130]

Currently prevention and treatment strategies for pho-toaged skin mostly center on strengthening antioxidantdefense for the cells Mammalian tissues are equipped withan array of nonenzymatic and enzymatic antioxidant systemsthat work in a complex network to maintain the optimal levelof ROS in the cells or a redox balance by several mechanismsThesemechanismswork to neutralize oxidants inhibit oxida-tive damage and regulate transcription factors involved inredox and scavenging reactions [131] Proliferation and differ-entiation of human cells underlie a delicate control of severalsignaling pathways [132] The balance of redox homeostasisand regulation of ROS-mediated signaling are part of thecentral regulation involved in self-renewal proliferation anddifferentiation of normal stem and progenitor cells in humantissues including the skin [133]

Since skin cells can be exposed to environmental sourcesof ROS particularly UVR endogenous antioxidants functionas a crucial defense system to preserve redox balance requiredfor regulation of epidermal homeostasis and prevent ROS-induced skin damage [134] Important endogenous antiox-idants include enzymatic antioxidants such as superoxidedismutase (SOD) catalase (CAT) glutathione peroxidase(GPx) glutathione reductase and thioredoxin reductase andnonenzymatic antioxidants or low molecular weight antioxi-dants such as ascorbate or vitamin C glutathione (GSH)and 120572-tocopherol or vitamin E [135] SOD is an importantantioxidant enzyme that converts O

2

∙minus into H2O2 which is

finally degraded into water by CAT and GPxHowever when generated in excess ROS promote oxida-

tive stress that can damage cellular structures and biomolecu-les including lipids proteins and DNA as well as interferingwith normal signaling cascades It has been proposed thatan imbalance between ROS production and antioxidantdefense would occur as a consequence of overwhelmingROS production and the substantial reduction in antioxidantlevels that occurs with advanced aging [136 137] On theother hand the effect of excessive ROS on total lifespanwas implicated in a study which showed that whole bodydeletion of the SOD1 gene caused a reduced lifespan in micethat died by ldquoaging deadrdquo suggesting that the physiologicallevel of SOD1 is required to prevent premature aging [138]Mitochondrial ROS has also been suggested to be a drivingforce of accelerated aging caused by ROS damage in adultstem cells [139] Lastly oxidative stress may also have animpact on the aging process by causing biochemical andphysiological changes that accelerate age-related diseases[140]

ROS may be the leading cause of physiological change inskin stem cells It has been proposed that the maintenance ofself-renewal and differentiation capacity of ESCs into old ageand their resistance to cellular agingmay be attributed to theirability to control levels of intracellular ROS by antioxidantdefenses Consistent with this theory prevention of oxidativestress thus is the key to prevent stem cell exhaustion in theskin [141] In nature SOD may be an important antioxidant


Vitamins C and Eplant extracts

phytochemicalsSunscreen

Photoaging

ROS

UVR

Antioxidant interventionor upregulation ofantioxidant defences

Antioxidant proteinsCAT SOD GCL HO-1GST NQO1 GSH

Figure 2 Anti-ROS as a potential anti-skin aging intervention Possible interventions that delay ESC DNA damage by preventing UVRexposure using sunscreen anti-ROS or upregulation of antioxidant proteins

enzyme that is responsible for the tolerance of ESCs to ROS-mediated aging process because the SOD gene was observedto be highly expressed in ESCs isolated from both youngadult mice and old adult mice and its expression remainedunchanged in the ESCs from old mice [20]

Stem cells undergo a self-renewal process that produceslow levels of intracellular ROS as by-products Although theseROS are endogenous and low in amount they are still harm-ful to stem cells In order to maintain redox homeostasisantioxidant defense systems are transcriptionally upregulatedin response to ROS formation As such attempts have beenmade to explore the role of transcription factors that canserve as redox regulators in the self-renewal of stem cellsin particular FOXO family and nuclear factor erythroid-2-related factor 2 (Nrf2) [142] Activated FOXOs translocateinto the nucleus and mediate transcription of target antiox-idant genes including CAT and SOD [143] Disruption ofFOXO proteins which are key downstream components ofthe PI(3)K pathway was associated with depletion of tissuestem cells without external stimulation [144 145]

Nrf2 has been widely accepted as the key regulator ofredox homeostatic genes involved in human skin adaptionto oxidative stress which can stimulate its translocation intothe nucleus to bind to the antioxidant response element(ARE) a cis-acting enhancer sequence in the region ofseveral genes encoding antioxidantdetoxification enzymesincluding glutamate cysteine ligase (GCL) heme oxygenase-1 (HO-1) glutathione transferase (GST) and NAD(P)Hquinine oxidoreductase-1 (NQO1) [146ndash148] Depletion ofNrf2 can compromise the abilities of various cells (such asmouse embryonic and human primary skin fibroblasts andkeratinocyte HaCaT cells) to protect against photooxidative

damage [149ndash152] Moreover Nrf2 which may be a targetof keratinocyte growth factor was observed to play a rolein cutaneous wound repair in mice in association withan increase in mRNA expressions of collagen and VEGF(vascular endothelial growth factor) a main regulator ofangiogenesis [153] UV-B-induced apoptosis of basal ker-atinocytes in murine epidermis was blocked by suprabasalkeratinocytes capable of controlling their survival throughNrf2-regulated antioxidant defenses including GSH [154]

While melanin and enzymatic antioxidants serve asendogenous defense of the skin against UVR accumulativeexposure to UVR can overwhelm the ROS defense mech-anism Exogenous and dietary antioxidants such as vitaminC (ascorbic acid) vitamin E (120572-tocopherol) beta-carotenesand different phytochemicals particularly polyphenolsderived from plants-based food and beverages as well asherbal products that play a crucial role in maintaining redoxhomeostasis and antioxidant intervention are thus proposedas being useful in delaying skin photoaging and helping toprevent skin cancer [104 155] (Figure 2)

As UV-mediated oxidative stress can adversely affectESCs enhancing capacity of cellular antioxidant defensesto counteract oxidative stress would represent a promisingstrategy for inhibition of photoaged skin A number ofstudies using skin cell culture reconstructed skin and animalmodels have reported protective roles of natural and syntheticantioxidants aswell asmedicinal plants againstUV-mediatedskin photoaging through modulation of antioxidant defensesystem For example compounds capable of activating Nrf2were able to prevent UV-B-dependent cell death in primarykeratinocytes [156] and tanshinones derived from medicinalplant S miltiorrhiza which acted as Nrf2 inducer suppressed


UV-induced damage of human skin cells and reconstructedhuman skin through upregulation of Nrf2 and its targetantioxidants including GCL and NQO1 [157] Purified Tparthenium extracts inhibited UV-mediated DNA damagethrough activation of Nrf2-ARE signaling in primary humankeratinocytes [158] Eckstolonol isolated from E cava wasshown to protect keratinocyte HaCaT cells against UV-B-mediated photooxidative stress cytotoxicity and DNA dam-age possibly through induction of CAT and SOD activities[159] 18120573-glycyrrhetinic acid the major active ingredientin licorice root inhibited UV-induced skin photoaging ina mouse model by induction in skin collagen content anddownregulation of MMP-1 and MMP-3 associated withincreased activities of SOD and GPx [160] Furthermorethe mechanisms by which oral administration of Polypodiumleucotomos delayed skin tumor development in hairless micemight involve improvement in antioxidant defense status[161] K parviflora (black ginger) extracts orally adminis-trated to hairless mice exerted antiphotoaging effects onUV-B-irradiated hairless mice by suppression of MMPs andupregulation of collagen genes in association with inductionof CAT expression [162]We have also reported the protectiveroles of antioxidant phytochemicals such as caffeic acidferulic acid and gallic acid which are ubiquitously presentin plants-based food and beverages against UV-A-inducedmelanogenesis in different melanoma cell lines and MMP-1upregulation in HaCaT cells in association with promotionof Nrf2-related antioxidant defenses including CAT andGSH antioxidant system (GST and GPx) at the cellularand molecular levels [163ndash166] Nevertheless few studieshave addressed whether targeting ROS and antioxidantmechanisms could be a promising strategy for the delay ofpremature skin aging by promoting the capacity of skin stemcells for skin repair and rejuvenation

Choi et al suggested that redox status is essential forstemness in skin equivalents and demonstrated that vita-min C plant extracts (G lucidum and R sachalinensis)and a novel tripeptide ldquoACQ alanine-cysteine-glutaminerdquohaving high antioxidant activities promoted stemness andthe proliferative capacity of epidermal basal cells by improv-ing microenvironment through regulation of integrins themain receptors for ECM [167 168] In addition to variousantioxidant compounds reported as having beneficial effectson stemness of the skin the use of adult stem cells andtheir niches to contribute to regeneration and repair ofdamaged tissues has been proposed as a promising strategyin cell-based therapy in tissue injuryMesenchymal stem cellswithin the stromal-vascular fraction of subcutaneous adiposetissue successfully employed to substitute dermal fibroblastsfor skin construction were demonstrated to improve UV-B-induced wrinkles in hairless mice and exert antiapoptoticeffects on dermal fibroblasts through antioxidant mecha-nisms including upregulation of various antioxidant proteins[3 169]

Notably pharmacologic agents with antioxidant actionsand tissue engineering approaches have been proposed topromote stemness of the skin although their efficacy andsafety for clinical application in prevention and treatment ofskin photoaging warrant further investigation

Competing Interests

The authors hereby declare no personal or professionalcompeting interests regarding any aspect of this study

Acknowledgments

This work was supported by Thailand Research Fund(RSA5580012 and RSA5580018) Siriraj Research Fund Fac-ulty ofMedicine Siriraj Hospital Mahidol University and theAdvanced Research on Pharmacology Fund Siriraj Founda-tion (D003421) Uraiwan Panich and Siwanon Jirawatnotaiwere supported by a Chalermphrakiat Grant Faculty ofMedicine Siriraj Hospital Mahidol University

References

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[2] G B Maru K Gandhi A Ramchandani and G Kumar ldquoTherole of inflammation in skin cancerrdquo Advances in ExperimentalMedicine and Biology vol 816 pp 437ndash469 2014

[3] MMimeault and S K Batra ldquoRecent advances on skin-residentstemprogenitor cell functions in skin regeneration aging andcancers and novel anti-aging and cancer therapiesrdquo Journal ofCellular and Molecular Medicine vol 14 no 1-2 pp 116ndash1342010

[4] E C Naylor R E B Watson and M J Sherratt ldquoMolecularaspects of skin ageingrdquo Maturitas vol 69 no 3 pp 249ndash2562011

[5] C Lopez-Otın M A Blasco L Partridge M Serrano and GKroemer ldquoThe hallmarks of agingrdquoCell vol 153 no 6 pp 1194ndash1217 2013

[6] JWenk P Brenneisen CMeewes et al ldquoUV-induced oxidativestress and photoagingrdquo Current Problems in Dermatology vol29 pp 83ndash94 2001

[7] P A Sotiropoulou and C Blanpain ldquoDevelopment and home-ostasis of the skin epidermisrdquo Cold Spring Harbor Perspectivesin Biology vol 4 no 7 Article ID a008383 2012

[8] S Liu H Zhang and E Duan ldquoEpidermal development inmammals key regulators signals from beneath and stem cellsrdquoInternational Journal of Molecular Sciences vol 14 no 6 pp10869ndash10895 2013

[9] R R Driskell B M Lichtenberger E Hoste et al ldquoDistinctfibroblast lineages determine dermal architecture in skin devel-opment and repairrdquoNature vol 504 no 7479 pp 277ndash281 2013

[10] C Blanpain and E Fuchs ldquoEpidermal stem cells of the skinrdquoAnnual Review of Cell and Developmental Biology vol 22 pp339ndash373 2006

[11] GMascre S Dekoninck B Drogat et al ldquoDistinct contributionof stem and progenitor cells to epidermalmaintenancerdquoNaturevol 489 no 7415 pp 257ndash262 2012

[12] L Alonso and E Fuchs ldquoStem cells in the skin waste not WntnotrdquoGenes andDevelopment vol 17 no 10 pp 1189ndash1200 2003

[13] C Blanpain and E Fuchs ldquoEpidermal homeostasis a balancingact of stem cells in the skinrdquo Nature Reviews Molecular CellBiology vol 10 no 3 pp 207ndash217 2009

[14] I L Weissman ldquoStem cells units of development units ofregeneration and units in evolutionrdquo Cell vol 100 no 1 pp157ndash168 2000


[15] L Yang and R Peng ldquoUnveiling hair follicle stem cellsrdquo StemCell Reviews and Reports vol 6 no 4 pp 658ndash664 2010

[16] Y-C Hsu L Li and E Fuchs ldquoEmerging interactions betweenskin stem cells and their nichesrdquoNature Medicine vol 20 no 8pp 847ndash856 2014

[17] K A Moore and I R Lemischka ldquoStem cells and their nichesrdquoScience vol 311 no 5769 pp 1880ndash1885 2006

[18] C Grillon A Matejuk M Nadim N Lamerant-Fayel and CKieda ldquoNews on microenvironmental physioxia to revisit skincell targeting approachesrdquo Experimental Dermatology vol 21no 10 pp 723ndash729 2012

[19] D Racila and J R Bickenbach ldquoAre epidermal stem cells uniquewith respect to agingrdquo Aging vol 1 no 8 pp 746ndash750 2009

[20] M M Stern and J R Bickenbach ldquoEpidermal stem cells areresistant to cellular agingrdquo Aging Cell vol 6 no 4 pp 439ndash4522007

[21] A Giangreco M Qin J E Pintar and F M Watt ldquoEpidermalstem cells are retained in vivo throughout skin agingrdquo AgingCell vol 7 no 2 pp 250ndash259 2008

[22] A Giangreco S J Goldie V Failla G Saintigny and FMWattldquoHuman skin aging is associated with reduced expression of thestem cellmarkers1205731 integrin andMCSPrdquo Journal of InvestigativeDermatology vol 130 no 2 pp 604ndash608 2010

[23] E Makrantonaki and C C Zouboulis ldquoWilliam J Cunliffescientific awards Characteristics and pathomechanisms ofendogenously aged skinrdquo Dermatology vol 214 no 4 pp 352ndash360 2007

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[25] P Janich K Toufighi G Solanas et al ldquoHuman epidermal stemcell function is regulated by circadian oscillationsrdquo Cell StemCell vol 13 no 6 pp 745ndash753 2013

[26] T Sperka J Wang and K L Rudolph ldquoDNA damage check-points in stem cells ageing and cancerrdquo Nature Reviews Molec-ular Cell Biology vol 13 no 9 pp 579ndash590 2012

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[30] C C Zouboulis J Adjaye H Akamatsu G Moe-Behrens andC Niemann ldquoHuman skin stem cells and the ageing processrdquoExperimental Gerontology vol 43 no 11 pp 986ndash997 2008

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thymine-thymine dipyrimidines and correlate with the muta-tion spectrum in rodent cellsrdquo Nucleic Acids Research vol 31no 11 pp 2786ndash2794 2003

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[77] X Su M Paris Y J Gi et al ldquoTAp63 prevents premature agingby promoting adult stem cell maintenancerdquo Cell Stem Cell vol5 no 1 pp 64ndash75 2009

[78] P A Sotiropoulou A E Karambelas M Debaugnies et alldquoBrca1 deficiency in skin epidermis leads to selective loss of hairfollicle stem cells and their progenyrdquo Genes and Developmentvol 27 no 1 pp 39ndash51 2013

[79] J DunnM Potter A Rees and TM Runger ldquoActivation of theFanconi anemiaBRCA pathway and recombination repair inthe cellular response to solar ultraviolet lightrdquo Cancer Researchvol 66 no 23 pp 11140ndash11147 2006

[80] N Li and H Clevers ldquoCoexistence of quiescent and active adultstem cells in mammalsrdquo Science vol 327 no 5965 pp 542ndash5452010

[81] K W Orford and D T Scadden ldquoDeconstructing stem cellself-renewal genetic insights into cell-cycle regulationrdquo NatureReviews Genetics vol 9 no 2 pp 115ndash128 2008


[82] B D Simons and H Clevers ldquoStrategies for homeostatic stemcell self-renewal in adult tissuesrdquo Cell vol 145 no 6 pp 851ndash862 2011

[83] S J Morrison and A C Spradling ldquoStem cells and nichesmechanisms that promote stem cell maintenance throughoutliferdquo Cell vol 132 no 4 pp 598ndash611 2008

[84] M Ueno T Aoto Y Mohri H Yokozeki and E K NishimuraldquoCoupling of the radiosensitivity of melanocyte stem cellsto their dormancy during the hair cyclerdquo Pigment Cell ampMelanoma Research vol 27 no 4 pp 540ndash551 2014

[85] S Ozbek P G Balasubramanian R Chiquet-Ehrismann R PTucker and J C Adams ldquoThe evolution of extracellularmatrixrdquoMolecular Biology of the Cell vol 21 no 24 pp 4300ndash4305 2010

[86] V Greco T Chen M Rendl et al ldquoA two-step mechanism forstem cell activation during hair regenerationrdquo Cell Stem Cellvol 4 no 2 pp 155ndash169 2009

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[88] S Takahashi A D Pearse and R Marks ldquoThe acute effectsof ultraviolet-B radiation on c-myc and c-Ha ras expression innormal human epidermisrdquo Journal of Dermatological Sciencevol 6 no 2 pp 165ndash171 1993

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[90] A Gandarillas and F M Watt ldquoc-Myc promotes differentiationof human epidermal stem cellsrdquo Genes amp Development vol 11no 21 pp 2869ndash2882 1997

[91] A Gebhardt M Frye S Herold et al ldquoMyc regulates ker-atinocyte adhesion and differentiation via complex formationwith Miz1rdquo The Journal of Cell Biology vol 172 no 1 pp 139ndash149 2006

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[94] B Chance H Sies andA Boveris ldquoHydroperoxidemetabolismin mammalian organsrdquo Physiological Reviews vol 59 no 3 pp527ndash605 1979

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[99] C Caliceti P Nigro P Rizzo and R Ferrari ldquoROS Notch andWnt signaling pathways crosstalk between three major regula-tors of cardiovascular biologyrdquo BioMed Research Internationalvol 2014 Article ID 318714 8 pages 2014

[100] B Su S Mitra H Gregg et al ldquoRedox regulation of vascularsmooth muscle cell differentiationrdquo Circulation Research vol89 no 1 pp 39ndash46 2001

[101] A Van Laethem K Nys S Van Kelst et al ldquoApoptosis signalregulating kinase-1 connects reactive oxygen species to p38MAPK-induced mitochondrial apoptosis in UVB-irradiatedhuman keratinocytesrdquo Free Radical Biology amp Medicine vol 41no 9 pp 1361ndash1371 2006

[102] Q Shen H Jin and X Wang ldquoEpidermal stem cells andtheir epigenetic regulationrdquo International Journal of MolecularSciences vol 14 no 9 pp 17861ndash17880 2013

[103] YWang L Liu S K PazhanisamyH Li AMeng andD ZhouldquoTotal body irradiation causes residual bone marrow injury byinduction of persistent oxidative stress inmurine hematopoieticstem cellsrdquo Free Radical Biology amp Medicine vol 48 no 2 pp348ndash356 2010

[104] A Godic B Poljsak M Adamic and R Dahmane ldquoTherole of antioxidants in skin cancer prevention and treatmentrdquoOxidative Medicine and Cellular Longevity vol 2014 Article ID860479 6 pages 2014

[105] R A J Signer and S J Morrison ldquoMechanisms that regulatestem cell aging and life spanrdquo Cell Stem Cell vol 12 no 2 pp152ndash165 2013

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[107] M M Vilenchik and A G Knudson ldquoEndogenous DNAdouble-strand breaks Production fidelity of repair and induc-tion of cancerrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 100 no 22 pp 12871ndash128762003

[108] J H J Hoeijmakers ldquoDNA damage aging and cancerrdquo NewEngland Journal of Medicine vol 361 no 15 pp 1475ndash14852009

[109] M A Birch-Machin E V Russell and J A Latimer ldquoMito-chondrial DNA damage as a biomarker for ultraviolet radiationexposure and oxidative stressrdquoThe British Journal of Dermatol-ogy vol 169 supplement 2 pp 9ndash14 2013

[110] L Chaisiriwong R Wanitphakdeedecha P Sitthinamsuwan etal ldquoA case-control study of involvement of oxidative DNAdamage and alteration of antioxidant defense system in patientswith basal cell carcinoma modulation by tumor removalrdquoOxidative Medicine and Cellular Longevity vol 2016 Article ID5934024 12 pages 2016

[111] K Inomata T Aoto N T Binh et al ldquoGenotoxic stress abro-gates renewal of melanocyte stem cells by triggering their dif-ferentiationrdquo Cell vol 137 no 6 pp 1088ndash1099 2009

[112] K Ito A Hirao F Arai et al ldquoReactive oxygen species actthrough p38 MAPK to limit the lifespan of hematopoietic stemcellsrdquo Nature Medicine vol 12 no 4 pp 446ndash451 2006

[113] E Sahin and R A Depinho ldquoLinking functional decline oftelomeres mitochondria and stem cells during ageingrdquo Naturevol 464 no 7288 pp 520ndash528 2010

[114] I Flores M L Cayuela andM A Blasco ldquoEffects of telomeraseand telomere length on epidermal stem cell behaviorrdquo Sciencevol 309 no 5738 pp 1253ndash1256 2005


[115] S Y Rha E Izbicka R Lawrence et al ldquoEffect of telomere andtelomerase interactive agents on human tumor and normal celllinesrdquo Clinical Cancer Research vol 6 no 3 pp 987ndash993 2000

[116] W C Hahn CM Counter A S Lundberg R L BeijersbergenMW Brooks and R AWeinberg ldquoCreation of human tumourcells with defined genetic elementsrdquo Nature vol 400 no 6743pp 464ndash468 1999

[117] Y Peng M Xuan V Y L Leung and B Cheng ldquoStem cells andaberrant signaling of molecular systems in skin agingrdquo AgeingResearch Reviews vol 19 pp 8ndash21 2015

[118] Z Tothova R Kollipara B J Huntly et al ldquoFoxOs are criticalmediators of hematopoietic stem cell resistance to physiologicoxidative stressrdquo Cell vol 128 no 2 pp 325ndash339 2007

[119] C Richardson S Yan and C G Vestal ldquoOxidative stress bonemarrow failure and genome instability in hematopoietic stemcellsrdquo International Journal of Molecular Sciences vol 16 no 2pp 2366ndash2385 2015

[120] I Flores and M A Blasco ldquoA p53-dependent response limitsepidermal stem cell functionality and organismal size in micewith short telomeresrdquo PLoS ONE vol 4 no 3 Article ID e49342009

[121] W Chen J Kang J Xia et al ldquop53-related apoptosis resistanceand tumor suppression activity in UVB-induced prematuresenescent human skin fibroblastsrdquo International Journal ofMolecular Medicine vol 21 no 5 pp 645ndash653 2008

[122] D Volonte Z Liu P M Musille et al ldquoInhibition of nuclearfactor-erythroid 2-related factor (Nrf2) by caveolin-1 promotesstress-induced premature senescencerdquoMolecular Biology of theCell vol 24 no 12 pp 1852ndash1862 2013

[123] V Pekovic and C J Hutchison ldquoAdult stem cell maintenanceand tissue regeneration in the ageing context the role for a-typelamins as intrinsic modulators of ageing in adult stem cells andtheir nichesrdquo Journal of Anatomy vol 213 no 1 pp 5ndash25 2008

[124] N Philips T Keller C Hendrix et al ldquoRegulation of theextracellular matrix remodeling by lutein in dermal fibroblastsmelanoma cells and ultraviolet radiation exposed fibroblastsrdquoArchives of Dermatological Research vol 299 no 8 pp 373ndash3792007

[125] J Varani M K Dame L Rittie et al ldquoDecreased collagenproduction in chronologically aged skin roles of age-dependentalteration in fibroblast function and defective mechanical stim-ulationrdquo The American Journal of Pathology vol 168 no 6 pp1861ndash1868 2006

[126] T Quan and G J Fisher ldquoRole of age-associated alterations ofthe dermal extracellular matrix microenvironment in humanskin agingrdquo Gerontology vol 61 no 5 pp 427ndash434 2015

[127] M Orciani S Gorbi M Benedetti et al ldquoOxidative stressdefense in human-skin-derived mesenchymal stem cells versushuman keratinocytes different mechanisms of protection andcell selectionrdquo Free Radical Biology and Medicine vol 49 no 5pp 830ndash838 2010

[128] S Maynard A M Swistowska J W Lee et al ldquoHumanembryonic stem cells have enhanced repair of multiple formsof DNA damagerdquo STEM CELLS vol 26 no 9 pp 2266ndash22742008

[129] A Dupuy J Valton S Leduc J Armier R Galetto and AGouble ldquoTargeted gene therapy of xeroderma pigmentosumcells using meganuclease and TALENrdquo PLoS ONE vol 8 no11 Article ID e78678 2013

[130] E Warrick M Garcia and C Chagnoleau ldquopreclinical correc-tive gene transfer in xeroderma pigmentosum human skin stemcellsrdquoMolecular Therapy vol 20 no 4 pp 798ndash807 2012

[131] J M Wood and K U Schallreuter ldquoA plaidoyer for cutaneousenzymology our view of some important unanswered ques-tions on the contributions of selected key enzymes to epidermalhomeostasisrdquo Experimental Dermatology vol 17 no 7 pp 569ndash578 2008

[132] J Kenyon and S L Gerson ldquoThe role of DNA damage repair inaging of adult stem cellsrdquoNucleic Acids Research vol 35 no 22pp 7557ndash7565 2007

[133] R Mouzannar J McCafferty G Benedetto and C Richard-son ldquoTranscriptional and phospho-proteomic screens revealstem cell activation of insulin-resistance and transformationpathways following a single minimally toxic episode of RosrdquoInternational Journal of Genomics and Proteomics vol 2 no 1pp 34ndash49 2011

[134] U Wolfle G Seelinger G Bauer M C Meinke J Lade-mann and C M Schempp ldquoReactive molecule species andantioxidative mechanisms in normal skin and skin agingrdquo SkinPharmacology and Physiology vol 27 no 6 pp 316ndash332 2014

[135] S R Pinnell ldquoCutaneous photodamage oxidative stressand topical antioxidant protectionrdquo Journal of the AmericanAcademy of Dermatology vol 48 no 1 pp 1ndash22 2003

[136] RKohen ldquoSkin antioxidants their role in aging and in oxidativestressmdashnew approaches for their evaluationrdquo Biomedicine ampPharmacotherapy vol 53 no 4 pp 181ndash192 1999

[137] H-L Hu R J Forsey T J Blades M E J Barratt P Parmarand J R Powell ldquoAntioxidants may contribute in the fightagainst ageing an in vitro modelrdquo Mechanisms of Ageing andDevelopment vol 121 no 1ndash3 pp 217ndash230 2001

[138] V I Perez A Bokov H Van Remmen et al ldquoIs the oxidativestress theory of aging deadrdquo Biochimica et Biophysica ActamdashGeneral Subjects vol 1790 no 10 pp 1005ndash1014 2009

[139] S K George Y Jiao C E Bishop and B Lu ldquoMitochon-drial peptidase IMMP2L mutation causes early onset of age-associated disorders and impairs adult stem cell self-renewalrdquoAging Cell vol 10 no 4 pp 584ndash594 2011

[140] Y H Edrey and A B Salmon ldquoRevisiting an age-old questionregarding oxidative stressrdquo Free Radical BiologyampMedicine vol71 pp 368ndash378 2014

[141] L B Boyette and R S Tuan ldquoAdult stem cells and diseases ofagingrdquo Journal of ClinicalMedicine vol 3 no 1 pp 88ndash134 2014

[142] K Wang T Zhang Q Dong E C Nice C Huang and Y WeildquoRedox homeostasis the linchpin in stem cell self-renewal anddifferentiationrdquo Cell Death amp Disease vol 4 article e537 2013

[143] L O Klotz C Sanchez-Ramos I Prieto-Arroyo P UrbanekH Steinbrenner and M Monsalve ldquoRedox regulation of FoxOtranscription factorsrdquo Redox Biology vol 6 pp 51ndash72 2015

[144] Z Tothova and D G Gilliland ldquoFoxO transcription factors andstem cell homeostasis insights from the hematopoietic systemrdquoCell Stem Cell vol 1 no 2 pp 140ndash152 2007

[145] S Yalcin X Zhang J P Luciano et al ldquoFoxo3 is essential for theregulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cellsrdquoThe Journalof Biological Chemistry vol 283 no 37 pp 25692ndash25705 2008

[146] E V Knatko S H Ibbotson Y Zhang et al ldquoNrf2 activationprotects against solar-simulated ultraviolet radiation in miceand humansrdquoCancer Prevention Research vol 8 no 6 pp 475ndash486 2015

[147] L Marrot C Jones P Perez and J-R Meunier ldquoThe signif-icance of Nrf2 pathway in (photo)-oxidative stress responsein melanocytes and keratinocytes of the human epidermisrdquoPigment Cell and Melanoma Research vol 21 no 1 pp 79ndash882008


[148] M Schafer and S Werner ldquoNrf2mdashA regulator of keratinocyteredox signalingrdquo Free Radical Biology and Medicine vol 88 pp243ndash252 2015

[149] F Gruber H Mayer B Lengauer et al ldquoNF-E2-related factor 2regulates the stress response to UVA-1-oxidized phospholipidsin skin cellsrdquoThe FASEB Journal vol 24 no 1 pp 39ndash48 2010

[150] J L Zhong G P Edwards C Raval H Li and R M TyrrellldquoThe role of Nrf2 in ultraviolet A mediated heme oxygenase 1induction in human skin fibroblastsrdquo Photochemical amp Photobi-ological Sciences vol 9 no 1 pp 18ndash24 2010

[151] A L Benedict E V Knatko and A T Dinkova-Kostova ldquoTheindirect antioxidant sulforaphane protects against thiopurine-mediated photooxidative stressrdquo Carcinogenesis vol 33 no 12pp 2457ndash2466 2012

[152] Y-C Hseu C-W Chou K J Senthil Kumar et al ldquoEllagicacid protects human keratinocyte (HaCaT) cells against UVA-induced oxidative stress and apoptosis through the upregu-lation of the HO-1 and Nrf-2 antioxidant genesrdquo Food andChemical Toxicology vol 50 no 5 pp 1245ndash1255 2012

[153] S Braun C Hanselmann M G Gassmann et al ldquoNrf2transcription factor a novel target of keratinocyte growth factoractionwhich regulates gene expression and inflammation in thehealing skin woundrdquoMolecular and Cellular Biology vol 22 no15 pp 5492ndash5505 2002

[154] M Schafer S Dutsch U auf dem Keller et al ldquoNrf2 establishesa glutathione-mediated gradient of UVB cytoprotection in theepidermisrdquoGenes ampDevelopment vol 24 no 10 pp 1045ndash10582010

[155] W Stahl and H Sies ldquo120573-carotene and other carotenoids inprotection from sunlightrdquo The American Journal of ClinicalNutrition vol 96 no 5 pp 1179Sndash1184S 2012

[156] F Lieder F Reisen T Geppert et al ldquoIdentification of UV-protective activators of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) by combining a chemical library screenwith computer-based virtual screeningrdquo Journal of BiologicalChemistry vol 287 no 39 pp 33001ndash33013 2012

[157] S Tao R Justiniano D D Zhang and G T Wondrak ldquoTheNrf2-inducers tanshinone I and dihydrotanshinone protecthuman skin cells and reconstructed human skin against solarsimulated UVrdquo Redox Biology vol 1 no 1 pp 532ndash541 2013

[158] K J Rodriguez H-K Wong T Oddos M Southall B Freiand S Kaur ldquoA purified feverfew extract protects from oxidativedamage by inducing DNA repair in skin cells via a PI3-kinase-dependent Nrf2ARE pathwayrdquo Journal of Dermatological Sci-ence vol 72 no 3 pp 304ndash310 2013

[159] J Jang B-R Ye S-J Heo et al ldquoPhoto-oxidative stress byultraviolet-B radiation and antioxidative defense of eckstolonolin human keratinocytesrdquo Environmental Toxicology and Phar-macology vol 34 no 3 pp 926ndash934 2012

[160] S-Z Kong H-M Chen X-T Yu et al ldquoThe protective effectof 18120573-Glycyrrhetinic acid against UV irradiation inducedphotoaging inmicerdquo Experimental Gerontology vol 61 pp 147ndash155 2015

[161] E Rodrıguez-Yanes J Cuevas S Gonzalez and J MallolldquoOral administration of Polypodium leucotomos delays skintumor development and increases epidermal p53 expressionand the anti-oxidant status of UV-irradiated hairless micerdquoExperimental Dermatology vol 23 no 7 pp 526ndash528 2014

[162] J-E Park H-B Pyun S WWoo J-H Jeong and J-K HwangldquoThe protective effect of kaempferia parviflora extract on UVB-induced skin photoaging in hairless micerdquo Photodermatology

Photoimmunology and Photomedicine vol 30 no 5 pp 237ndash245 2014

[163] W Thangboonjit S Limsaeng-u-rai T Pluemsamran and UPanich ldquoComparative evaluation of antityrosinase and antiox-idant activities of dietary phenolics and their activities inmelanoma cells exposed to UVArdquo Siriraj Medicine Journal vol66 no 1 pp 5ndash10 2014

[164] T Pluemsamran T Onkoksoong and U Panich ldquoCaffeic acidand ferulic acid inhibit UVA-induced matrix metalloprote-inase-1 through regulation of antioxidant defense system inkeratinocyte HaCaT cellsrdquo Photochemistry and Photobiologyvol 88 no 4 pp 961ndash968 2012

[165] U Panich T Onkoksoong S Limsaengurai P Akarasereenontand A Wongkajornsilp ldquoUVA-induced melanogenesis andmodulation of glutathione redox system in different melanomacell lines the protective effect of gallic acidrdquo Journal of Photo-chemistry and Photobiology B Biology vol 108 pp 16ndash22 2012

[166] A Chaiprasongsuk T Onkoksoong T Pluemsamran S Lim-saengurai and U Panich ldquoPhotoprotection by dietary phe-nolics against melanogenesis induced by UVA through Nrf2-dependent antioxidant responsesrdquoRedox Biology vol 8 pp 79ndash90 2016

[167] H-R Choi Y-A Kang J-W Shin J-I Na C-H Huh andK-C Park ldquoRedox status is critical for stemness in skinequivalentsrdquo Oxidative Medicine and Cellular Longevity vol2012 Article ID 819623 7 pages 2012

[168] H-R Choi J-W Shin J-I Na K-M Nam H-S Lee andK-C Park ldquoNovel antioxidant tripeptide lsquoACQrsquo can preventUV-induced cell death and preserve the number of epidermalstem cellsrdquoOxidativeMedicine and Cellular Longevity vol 2015Article ID 359740 11 pages 2015

[169] W-S Kim B-S Park and J-H Sung ldquoThe wound-healingand antioxidant effects of adipose-derived stem cellsrdquo ExpertOpinion on Biological Therapy vol 9 no 7 pp 879ndash887 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


fibroblasts (a component of blood vessels that provide nutri-ents to skin) subcutaneous adipocytes and immune cells inthe skin

Dermal fibroblasts are the main mesenchymal cell typein dermis Substructurally they were shown to be derivedfrom the upper dermis and lower dermisThefibroblasts fromthe former contribute to hair follicle formation while thefibroblasts from the later produce fibril extracellular matrix(ECM) ECM from dermal fibroblasts plays a crucial role instructural integrity and repair of the skin and wound healing[9]

Skin is also populated by specialized cells includingmelanocytes and sensory nerve endings of the skin that arederived from neural crest cells Overall approximately 20different cell types reside within the skin [8 10]

ESCs are defined by their ability to self-renew and differ-entiate into different cell lineages belonging to the skin [11]ESCs are capable of differentiating into the entire set of cellsthat comprise the skin Thus the epidermis is used for skingraft to replace damaged or missing skin [12] ESCs wereshown to be able to develop into three distinct layers of epi-dermis spinous layer granular layer and cornified layer (orstratum corneum composed of dead flattened and anucle-ated cells) ESCswere also shown to be capable of differentiat-ing intomultiple skin cell lineages includingmature and spe-cialized keratinocytes sebocytes or pigmented melanocytes[13 14]

In addition to the interfollicular stem cell ESCs includestem cells in hair follicles the hair follicle stem cells (HFSCs)that reconstitute hair follicles and play role in wound healing[15] Another type of stem cells in the epidermis ismelanocytestem cells (MSCs) which are intermingled withHFSCs in thehair bulge MSCs generate mature melanocytes that producemelanin which absorbs ultraviolet (UV) light to preventDNA damage and gives skin and hair their distinctive colors[16]

Microenvironment within skin is important for mainte-nance of stem cells The microenvironment provided fromthe complex structure of ECM and basement membraneform integral stem cell niches for the ESCs [17] Adult ESCsresiding within the niches remain there for self-renewalwhereas their progeny committed to differentiation leave thebasal call layer and migrate towards the epidermal surface[13] This made it relatively useful to track each lineage alongthe steps of differentiation Thus skin has served as oneof the ideal models for studying stem cell differentiationand the interaction between stem cells and their respectivemicroenvironments [18]

Because of their exposure to DNA damaging conditionsskin stem cells are innately highly resistant to the agingprocess andDNAdamage and carry highly activeDNA repairmechanisms [19ndash21] Nevertheless ESCs can be impaired inadvanced age [22] and are vulnerable to repetitive exposure toUVR [23ndash25] If not repaired properly damaged DNA mayresult in mutation or chromosomal rearrangements whichnegatively influences self-renewal and potency of stem cellsand promotes skin aging andor cancer formation [26]

To prevent photoaging and skin cancers reduced expo-sure to DNA damaging agent (UVR) and well-controlled

DNA repair mechanisms in ESCs are required to preventphotoaging and DNA damage-associated skin diseases suchas cutaneous basal cell and squamous cell carcinoma (BCCsand SCCs) [27]

While the role of UVR-induced DNA damage and oxida-tive stress in the skin aging involving ESC changes will be thefocus of this review it should also be noted that other factorsmay also contribute to this process Skin in the area notnormally exposed to UVR also can exhibit aging phenotypeFactors such as chronological shortening of skin cell telomere[28] increased inflammatory responses and accumulation ofsenescent cells could contribute to skin aging by impairingstem cell function and homeostasis [29]

2 UV-Induced DNA Damage in Skin Cells

Repetitive exposure to solar UVR is among the principalenvironmental factors that can hasten the aging process of theskin accompanied by progressive impairment of epidermalstem cell function [30] UVR is a natural component ofsunlight and is invisible to human eye Three types of UVare categorized according to their wavelength UV-A (315ndash400 nm) UV-B (280ndash315 nm) and UV-C (100ndash280 nm) UV-C is completely filtered out by the ozone layer of the Earthrsquosstratosphere Only UV-A and UV-B can reach the earthsurface However climate change and depletion of the ozonelayer may lead to increases in UV radiation at ground-levelUVR is known to be a mutagen long-term overexposureto sunlight is associated with photoaging and formation ofskin cancers [31] Interestingly both photoaging and cancer-inducing effects of UVR are mediated through UVRrsquos directand indirect toxicity to the DNA [32]

The direct effect of UV irradiation occurs when DNAabsorbs photons from UV-B This results in structural rear-rangement of nucleotides that then leads to defects in theDNA strand Cyclobutane pyrimidine dimers (CPD) andpyrimidine (6-4) pyrimidone (6-4 photoproducts 6-4 PPs)are the major products of UV-B-induced DNA damage [32]Direct absorption of UV-B photons induces cycloadditionbetweenC5-C6 of two adjacent pyrimidine bases and changesthem into CPD Meanwhile covalent bond formation ofC6-C4 of two adjacent pyrimidine bases generates 6-4 PPsphotoproduct which further converts to its Dewar valenceisomer upon UV excitation at 314 nm The hotspot withinthese UV-induced DNA lesions is where tandem pyrimidineresidues form (TT TC CT and CC) [33] At this pointcells will respond by promptly halting cell division to preventfurther DNA damage and allow the DNA repair mechanismto start In lower species photolyase enzyme is employedto repair DNA by removal of UV-induced DNA lesionsin a specific manner The enzyme binds CPD or 6-4 PPsat lesion sites and splits the dimers back to undamagedbases However human and othermammalian cells no longerpossess this enzyme The main UV-induced DNA damageresponse in humans is the nucleotide excision repair (NER)pathway There are 9 major proteins that function as NERin mammalian cells RAD23s RPA ERCC1 proteins andothers also participate in nucleotide excision repair [34 35]





























UVR

DNA damage




Damage ofdermal





ESC depletion

Skin aging

ROS

fibroblasts

DDR contact

UV-A UV-B











2



2O2)



















2








Photoaging

ROS

UVR














Competing Interests


Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





























UVR

DNA damage




Damage ofdermal





ESC depletion

Skin aging

ROS

fibroblasts

DDR contact

UV-A UV-B











2



2O2)



















2








Photoaging

ROS

UVR














Competing Interests


Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology














UVR

DNA damage




Damage ofdermal





ESC depletion

Skin aging

ROS

fibroblasts

DDR contact

UV-A UV-B











2



2O2)



















2








Photoaging

ROS

UVR














Competing Interests


Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


UVR

DNA damage




Damage ofdermal





ESC depletion

Skin aging

ROS

fibroblasts

DDR contact

UV-A UV-B











2



2O2)



















2








Photoaging

ROS

UVR














Competing Interests


Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology







2



2O2)



















2








Photoaging

ROS

UVR














Competing Interests


Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology












2








Photoaging

ROS

UVR














Competing Interests


Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Photoaging

ROS

UVR














Competing Interests


Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





Competing Interests


Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology










































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Documents

Review Article Ultraviolet Radiation-Induced Skin …downloads.hindawi.com/journals/sci/2016/7370642.pdfDNA damage and gives skin and hair their distinctive colors []. Microenvironment