also in this issue - department of dermatology...2 fall 2016 dermatology foundation expert faculty...

Focus on ResearchBotanical Antioxidants—A Multifunctional Approach to Preventing and Treating Skin Damage and DiseaseHasan Mukhtar, PhD Director and Vice Chair for Research, Department of Dermatology, University of Wisconsin Medical Sciences Center

Dr. Mukhtar’s interest is in identifying

novel strategies to pro-tect and treat the skin.His concerns are thedamaging impact ofexposure to ultravioletB (UVB) radiation—photoaging and photo-carcinogenesis—andthe chronic inflammatory disease psoriasis.The criteria potential candidates must meetgo beyond excellent efficacy in preventingdamage or reversing pathology. They mustbe easily affordable once they come to mar-ket, and benign in terms of side effects profile.

The pool from which Mukhtar selectspotential candidates is the extensive worldof polyphenols—the compounds that pro-vide our fruits and vegetables with their colors (see box on page 10). Polyphenolsare abundant micronutrients in our diet,“and one of the interesting things aboutthem,” Mukhtar says, “is that they are allantioxidants. Thus they are all equipped totrap the free radicals that are notoriouslyharmful for our skin.” Many of these plant-

xtrinsic skin aging—which produces coarse wrinkles, irregular pigment spots,

and elastosis—is clearly distinguishable fromintrinsic skin aging at clinical, histological,and molecular levels. It is commonly—andinaccurately, it now turns out— referred to asphotoaging. Although long regarded as dueexclusively to the interaction between skinand ultraviolet radiation (UVR), recent epi-demiologic and mechanistic research hasnow established that extrinsic aging resultsfrom other common environmental stressorsas well—stressors that lack a visually obviousconnection to skin aging but are no less

damaging to exposed human skin. They arethe particulate matter (PM) and noxiousgases in air pollution.

These studies—directed by Jean Krut-mann, MD (see box on page 6), ScientificDirector of the IUF-Leibniz Research Institute for Environmental Medicine andProfessor of Dermatology and Environmen-tal Medicine at Düsseldorf University in Germany—have mapped and begun to char-acterize this important new landscape. Andin doing so, he and his colleagues have alsoadvanced our knowledge of skin biology.They found the molecular mechanism re-

sponsible for air pollu-tion-induced skin aging tobe the aryl hydrocarbonreceptor (AHR), a little-known ligand-activatedtranscription factor (seebox on page 8) that turnsout to be an importantregulatory and protectivecomponent of skin cellsand melanocytes.

The clinical implica-tions of Dr. Krutmann’s re-search are significant, as airpollution is a serious prob-lem worldwide. Across theglobe, about 90% of thepopulation living in cities is exposed to traffic-relatedPM in concentrations ex-ceeding WHO air qualityguidelines. In some areas,cooking with unclean fuelsor inefficient technologies

Extrinsic Skin Aging:UVR Just Part of the Story

(Continued on page 10)

E

DERMATOLOGYFOCUS

DERMATOLOGYFOCUS™

VOL. 35 NO. 3 FALL 2016

A DERMATOLOGY FOUNDATION PUBLICATIONSPONSORED BY VALEANT PHARMACEUTICALS NORTH AMERICA LLC

Also In This Issue

JAAD Highlights Research From DF-Supported Investigators

Dr. Johann Gudjonsson Leads Medical & Scientific Committee

DF Welcomes 139 Leaders Society Members

UV Radiation Air Pollution

macromolecular damage & AHR activation

EIL

macromolecular damage

> release of soluble factors

macromolecular damage & AHR activation

> inhibition of apoptosis > sustained release of soluble factors

Environment-Induced Lentigines

maturation, proliferation& activation

Fibroblasts Melanocytes Keratinocytes

Environment-induced lentigines (EIL). Caused by chronic exposure toUVR and/or the particulate matter (PM) in air pollution, especially via the prolific PAHs (polyaromatic hydrocarbons) attached to these nanoparticles andabsorbed into the skin. Induced soluble factors and AHR activation (aryl hydro-carbon receptor) disorder cross-talk between fibroblasts, keratinocytes, andmelanocytes, reprogramming melanocytes to form EILs. Solar-induced lentigines(SIL) are one subtype. (Reprinted with permission from M. Nakamura et al. Exp Dermatol. 2015;407–11.) (Continued on page 3)

2 Fall 2016 Dermatology Foundation

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Jean L. Bolognia, MD Yale School of Medicine

Jeremy S. Bordeaux, MD, MPH Case Western Reserve University

Janet A. Fairley, MDUniversity of Iowa

Lindy P. Fox, MD University of California, San Francisco

Kenneth Fox, MDKaiser Permanente San Francisco

Philip E. LeBoit, MDUniversity of California, San Francisco

Moise L. Levy, MD Dell Children’s Medical Center of Central Texas

Henry W. Lim, MD Henry Ford Health System

Erin F.D. Mathes, MD University of California, San Francisco

Michael D. Rosenblum, MD, PhDUniversity of California, San Francisco

Anthony M. Rossi, MDMemorial Sloan Kettering Cancer Center

Jordan W. Tappero, MD, MPH Centers for Disease Control and Prevention;Center for Global Health

Bruce U. Wintroub, MD University of California, San Francisco

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SPECTRUM OF PRACTICE-RELEVANT MINI-SYMPOSIA Monitoring for MalignancyPediatric DermatologyCPCInflammatory DiseasesCare Delivery, Practice Improvement, and PoliticsSkin Cancer Infectious Disease What’s New: Therapeutic Updates

The Dermatology Foundation’s Clinical Symposia program provides 17.5AMA PRA Category 1 Credits™ throughaccreditation by The Yale School of Medicine. This activity has been planned and implemented in accordance withthe Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) throughthe joint sponsorship of The Yale School of Medicine and the Dermatology Foundation. The Yale School of Medicine is accredited by the ACCME to provide continuing medical education to physicians. This program is also recognized by the American Academy of Dermatology for 17.5 AAD Recognized Credits and may be used toward the American Academy of Dermatology’s Continuing Medical Education Award.

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pollutes the air indoors. Recognizing the sig-nificant aging impact of air pollution on skinenables the institution of protective efforts.And understanding how the underlying signalpathways are initiated provides a meaningfulmolecular target for the development of preventive and therapeutic agents.

Focusing the IUF on AgingThe IUF-Leibniz Research Institute for

Environmental Medicine—a joint govern-ment and academic venture—was estab-lished in 2001 specifically to addressenvironmentally induced disorders, and doso via molecular medical research aimed atthe biological effects of air pollution (PM,nonionizing radiation—which includes in-frared and near ultraviolet, and chemicals).The IUF was responding to a critical globalneed, as air pollution—both ambient (out-door) and indoor—has become responsiblefor significant mortality and morbidityworldwide, and the numberscontinue to rise. The WHO’smost recent report calls airpollution “the largest singleenvironmental health risk,”which caused an estimated6.5 million deaths in 2012—11.6% of all global deaths thatyear, the latest for which fig-ures are available. “Fine par-ticulate matter has the greatesteffect on human health,” theWHO states. “And most fineparticulate matter comes fromfuel combustion.”

Aging and the environment, however,was not yet part of the newly establishedIUF’s research agenda when Krutmann hadbeen invited to become Scientific Director.He was concerned about the surginggrowth of the world’s aging population andthe pressing need to learn a great deal moreabout aging and health, and was convincedthat this critical need had not been recog-nized. Here was an exceptional opportu-nity—thus Krutmann ensured that mappingand understanding the aging impact ofchronic air pollution exposure became the IUF’s focus.

Thus the IUF is dedicated to exploringthe ways in which air pollution ages thehuman cardiovascular system, skin, andlungs, and impairs the immune system andbrain function. Their investigators repre-sent scientific expertise in toxicology, im-munology, molecular aging research, andepidemiology. And the allied goals are improving healthcare and developing preventive strategies.

Krutmann personally looked forwardto exploring the environment’s impact on

skin aging. “The aging of our skin has med-ical, psychological, and social conse-quences because it is the most visible of allour organs and directly impacts an individ-ual’s self-esteem,” he underlines, “and agingfrom extrinsic factors is far more amenableto intervention than intrinsic aging.” In addition, the skin is “a great model for understanding aging in other organs. So understanding skin aging will enable us todraw many conclusions about the aging of other organs,” Krutmann points out.

The First Observations—Airborne Particle ExposureAges Skin

Many millions of humans worldwideare exposed to rising levels of ambient PM,which have long been shown to increasethe risk for cancer and for pulmonary andcardiovascular diseases. More recent evi-dence has indicated that human skin can

be directly affected by ambi-ent PM, as particles in thenanosize range—which areamong the most harmfulcomponents of ambient PM,and include those from traf-fic sources—can penetrateskin transepidermally andthrough hair follicles. Krut-mann and his colleagueswere the first to assess the effects of long-term ambientPM exposure on human skin,hypothesizing that it mightlead to extrinsic skin aging

either through oxidative stress generated directly by the particles themselves, or bypolycyclic aromatic hydrocarbons (PAHs)that are adsorbed on the surface of parti-cles suspended in the air.

During 2008–2009, they assessed theimpact of these nanoparticles in a cohortof 400 Caucasian women 70–80 years oldwho were participating in a long-termstudy of pulmonary aging. These womenwere almost equally distributed betweenthe urban Ruhr region and the villages andfarms of rural Borken. Skin aging was assessed with the clinically validatedSCINEXA (SCore of INtrinsic and EXtrinsicskin Aging), an instrument Krutmann haddeveloped that differentiates between ex-trinsic and intrinsic skin aging. Exposure totraffic-related particle emissions in general,to soot in particular, and to backgroundparticle concentration was determined ateach subject’s place of residence withstate-of-the-art technology, and the studydesign took the necessary measures to en-sure that sun exposure could not confoundresults.

Krutmann et al. not only found signifi-cant association between extrinsic skinaging signs and exposures to traffic-pro-duced air pollution and soot—most stronglyfor lentigines, less so for rhytides (the upperlip and nasolabial fold)—but the skin response appeared to be dose-related. Afterdividing the range of absorbance values forthese nanoparticles into quartiles, each in-crease from one quartile of soot absorbanceto the next, for example, was associatedwith an additional 22% increase in the num-ber of forehead lentigines and 20% on thecheeks. The composite of traffic-producednanoparticles produced 16% more lentig-ines on the forehead and 17% more on thecheeks with each interquartile increase inabsorbance. And looking at the impact of

Sponsored byValeant Pharmaceuticals North America LLCEditors-in-ChiefLindy Fox, MDAssociate Professor of DermatologyUniversity of California, San FranciscoMary M. Tomayko, MD, PhDAssistant Professor of DermatologyYale School of Medicine, New Haven, CTHeidi A. Waldorf, MDDirector, Laser and Cosmetic DermatologyThe Mount Sinai Medical Center, New York, NYExecutive DirectorSandra Rahn BenzDeputy Executive DirectorChristine M. BorisPlease address correspondence to:Editors-in-ChiefDermatology Focusc/o The Dermatology Foundation1560 Sherman AvenueEvanston, Illinois 60201Tel: 847-328-2256 Fax: 847-328-0509e-mail: [email protected] for the Dermatology Foundation byRobert B. GoetzDesigner, ProductionSheila Sperber Haas, PhDManaging Editor, Writer

This issue of Dermatology Focus is distributed without charge through an educational grant from Valeant Pharmaceuticals North America LLC.The opinions expressed in this publication do not necessarily reflect those of the Dermatology Foundation or Valeant Pharmaceuticals North America LLC.©Copyright 2016 by the Dermatology Foundation

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Jean Krutmann, MD

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traffic-produced particles for women wholived within 100 meters from a busy road,each interquartile increase in absorbanceproduced allied increases in lentigines of35% on the forehead and 15% on the cheeks.

Because lentigines had always beenconsidered exclusive to chronic UV radia-tion exposure, Krutmann was highly intriguedthat they showed the strongest associationwith air pollution’s skin-aging impact, and thestrongest of all when only soot was involved.He gathered together other observations in-dicating that lentigines can occur in the ab-sence of UV radiation. “They are the leading

extrinsic skin aging symptom in Asians who,in contrast to Caucasians, avoid sun expo-sure and thus should have fewer rather thanmore lentigines,” he pointed out at the time.And “of particular interest,” Krutmann says,“we had recently shown that AHR ligands,such as dioxin and PAHs, could inducemelanocyte proliferation, and thereby skintanning, in mice.” PAHs constitute a group ofmore than 100 different organic compoundsreleased from burning organic matter, in-cluding fuels, tobacco, trash, wood, andmeat. They frequently bind to the surface ofthese combustion-derived nanoparticles,

with soot carrying an especially high PAHconcentration. “And the strongest effectamong these women was seen for soot,”Krutmann underlines.

Extending the Outdoor EvidenceWhen Krutmann and his colleagues de-

cided to expand their focus and see if chronicexposure to nitrogen dioxide (NO2)—a gaseouscomponent of traffic-related air pollution—induces skin aging, it was the first time that itseffects on human skin had been investigated.Krutmann’s research at the IUF had stronglysuggested that “environmentally induced lung


Committee members are carefully chosen for their valuable research acumenand ability to identify applicants who holdthe strongest potential to advance the future of the specialty. Collectively their expertise and experience reflect thebreadth of medical and surgical dermatol-ogy. The highly defined evaluation processis based on the NIH grant review proce-dure and ensures the thorough, equitable,and science-based assessment of all applications.

This process has been refined over the DF’s many years of experience to assess both scientific merit and the applicant’s potential, ensuring the wise selection of individuals who have the potential to make major contributions to the specialty. A survey of past Career Development Award recipients confirms that most of them (80%) remain in academics.

The DF proudly presents the 2017 Medical & Scientific Committee, and extends deep appreciation to each member for the substantial time, effort, and expertise they are devoting to thisyear’s Research Awards program.

Committee ChairJohann E. Gudjonsson,

MD, PhDUniversity of Michigan

Committee MembersRobert P. Dellavalle, MD,

PhD, MSPHUniversity of Colorado, Denver John E. Harris, MD, PhDUniversity of Massachusetts Valerie Horsley, PhD

Yale University

Lu Q. Le, MD, PhDUT Southwestern Medical Center Delphine J. Lee, MD, PhDHarbor-UCLA Medical CenterLloyd S. Miller, MD, PhD

Johns Hopkins Medical Institutions

Abrar A. Qureshi, MD, MPHBrown University

Michael D. Rosenblum, MD, PhD

University of California, San Francisco

Panel Chair Désirée Ratner, MDIcahn School of Medicine,

Mount Sinai

Panel MembersJeremy S. Bordeaux, MD, MPHCase Western Reserve University

Jerry D. Brewer, MDMayo Clinic

Anna L. Bruckner, MDUniversity of Colorado, Denver

Pedram Gerami, MDNorthwestern University

Robert S. Kirsner, MD, PhDUniversity of Miami

Misha A. Rosenbach, MDUniversity of PennsylvaniaJulie V. Schaffer, MDHackensack University

Medical CenterJanis Marie Taube, MD, MSc

Johns Hopkins Medical Institutions

2017 Medical & Scientific Committee

Clinical/Medical/Surgical/Dermatopathology Panel

2017 Medical & Scientific Committee:Critical to DF’s Record of Success

The Foundation’s Medical & Scientific Committee is the key group of volunteer expertscharged with maintaining the outstanding record of supporting research by new investigatorswho become the driving force behind advances in patient care. This year the Committee and its Panel will evaluate applications in a broad offering of 12 award categories.

and skin aging appear to be closely related,” hesays, and NO2 exposure is known to be associ-ated both with low lung function and with lungcancer. To assess the link between chronic ex-posure to NO2 and lentigo development, Krut-mann and his group evaluated women fromtwo geographic areas: an expanded Caucasiancohort (806 subjects) and 1,072 Han women>50 years old from a larger Chinese study.Lentigines were visually evaluated by trainedpersonnel. The results recapitulated what hadbeen found with PM. Exposure to NO2 was significantly associated with more lentigineson the cheeks in both cohorts.

This was the largest epidemiologic studyto demonstrate the link between traffic-re-lated air pollution and lentigo formation. Andit showed the association not only in Cau-casians but in Asians, a population in whichlentigo formation is a hallmark of skin aging.

Environment-induced Lentigines—and the AHR

Solar lentigines have been consideredthe exclusive hallmark of skin exposed tocumulative doses of UVR, the clinical iconof photoaged skin. Photoaging and extrinsicaging have been interchangeable terms.

But in light of such powerful evidence thatwidespread lentigo formation also occursindependently of UVR, Krutmann has recently reformulated the concept and terminology. He proposes the term environ-ment-induced lentigo—or EIL—to replace the “solar” lentigo misnomer.

“We define EILs as acquired pigmentspots (PS) of human skin that result fromchronic exposure to a variety of environmen-tal noxae,” Krutmann explains (see illustra-tion on front cover). (Noxae are agentscapable of exerting a harmful effect on thebody.) In addition to UVR, these stressors


This native of Iceland received three DF research awards early in his career that were essential to his becoming an independent investigator. “They were critical because theycovered the period right after I finished my der-matology residency training at the University ofMichigan, during those difficult early years as ajunior investigator” when there wereno other sources of support available.

Dr. Gudjonsson was drawn to der-matology out of curiosity about psoria-sis, which affected some of his familymembers. A two- to three-month re-search project on psoriasis that he hadbegun at the University of Iceland Med-ical School “extended into summer andthen into full PhD training.” It also ledultimately to the University of Michigan,where the Department of Dermatologywas engaged in groundbreaking research delin-eating the immune system’s active role in psoria-sis, and documenting that it is treatable withimmunosuppressive drugs. Dr. Gudjonsson is now an Assistant Professor there. His primary research focus has been basic immunologic andgenetic research on psoriasis, with projects directed at improving the diagnosis and treatmentof this inflammatory disease. He also sees patientsand directs the inpatient consultation service.

The new direction that his research hasbegun to take involves learning why so manymore women than men develop autoimmune diseases. Naturally, he has started out by lookingat genomic differences, and a paper reporting his initial findings will be in Nature Immunologyby the end of the year.

Dr. Gudjonsson, an experiencedgrant reviewer, has been a memberof the Medical & Scientific Commit-tee for the past three years. He profoundly enjoys the great group ofpeople and the collegial discussions,and “I am quite honored to lead itthis year.” His goal as Chair is to“move the best science and peopleforward so we can keep growing thefield.” Dr. Gudjonsson stresses thatdermatology continues to lose too

many talented new investigators because of re-search funding concerns. “We desperately needmore individuals who are dedicated to the intellectual excitement of exploration, discov-ery, and advancing the state of knowledge.”

Johann E. Gudjonsson, MD, PhD

Dr. Gudjonsson received three Dermatology Foundationresearch awards to advance his work in psoriasis:

2005: Research Fellowship, 2008: Research Grant, and2010: Physician Scientist Career Development Award.

2017 Committee Chair: Early DF Research Award Essential to Career as Independent Investigator

Johann Gudjonsson, MD, PhD, Chair of the Dermatology Foundation’s 2017 Medical &Scientific Committee, says he knows just how much a DF research award can mean to ayoung investigator. “I am actually the poster child for what these grants are capable of.”

include particulate and gaseous constituentsof ambient air pollution. It is clear that cumu-lative UV irradiation is a major contributor, inpart because UVR is the most important physi-ological trigger for skin pigmentation in general, and in part because, in Caucasians,EILs preferentially occur on chronically sun-exposed areas of skin. But the fact that Asianwomen typically avoid sun exposure, yet develop PS substantially sooner than do age-matched sun-exposed Caucasians, highlightsthat there is more than sun exposure at work.

Krutmann places the AHR (see box onpage 8) front and center. He points to mech-anistic studies strongly indicating that lentig-ines form in human skin as a consequenceof disturbed crosstalk between melanocyteson the one hand and keratinocytes and fibroblasts on the other. Krutmann’s earlierresearch had already shown that the AHR

is expressed in both mouse and human skin cells andmelanocytes, and that it reg-ulates melanocyte prolifera-tion and melanin synthesis,and thus is central to the tan-ning response. This alteredcommunication occurs be-cause the keratinocytes andfibroblasts have been stimu-lated to overproduce pig-mentation-relevant solublefactors directly affectingmelanocyte behavior andfunction. These soluble fac-tors are induced by signalingpathways that can be acti-vated by both UVR and airpollution (see illustration at left). “So the common denominator—explaining the fact that these diverse environmental insults are causing similar clinical con-sequences,” Krutmann ex-plains, “is activation of AHRsignaling in these skin cells.”

Because of its role in tan-ning, the AHR connection is obvious for UVR-induced lentigines. PAHs—the major harmfulcomponents of soot and other PM from ambient and indoor pollution, which arelipophilic and thus easily penetrate the skin—are also AHR ligands. And in addition, AHRactivation would explain the wrinkling that occurs with both UVR and chronic airpollution exposure. Krutmann’s research hasshown that the AHR can also play a role incollagen breakdown (as well as in photocar-cinogenesis and in skin inflammation).

Indoor Air Pollution Also AgesSkin—But Differently

In China, indoor air pollution from theuse of solid fuels (such as coal) for cookingis a known risk for significant pulmonaryproblems—serious respiratory infections,COPD, and lung cancer. Krutmann wanted

to see whether it also increases the risk ofskin aging in Chinese women. The evalua-tion used independent study populationsliving in two geographically different areas.Each was a large cross-sectional group in-volving women from 30–90 years old, with405 women from Pingding in northernChina and 857 from Taizhou in the south.The SCINEXA was used to assess their skin.

Krutmann’s group found that, inde-pendently of age and other influences onskin aging, cooking with solid fuels is signif-icantly associated with a 5–8% increase insevere wrinkling on the face, and a 75%greater risk of having fine wrinkles on theback of the hands. Possible mechanistic ex-planations for this association come from invitro studies that have examined the effectsof exposing cultured human fibroblasts totobacco smoke extract, which is a complexmixture of pollutants similar to air pollution.Tobacco smoke induces skin aging—mainlythe development of wrinkles—apparently byshifting the balance from collagen produc-tion to collagen degradation. And here againthe AHR is at work. The PAHs included in to-bacco smoke can trigger the AHR signalingpathway, and the result in this case induces fibroblasts to produce the matrix metallo-proteinases that break down collagen. ThePAHs that attach to the fine particles pro-duced by indoor solid cooking fuels also activate the AHR signaling pathway.

Treatment AttemptsPycnogenolO. Krutmann carried out

a small trial of the nutritional supplement Py-cnogenolO, an extract from the bark of theFrench maritime pine that is standardized tocontain a variety of bioactive molecules pro-tective against oxidative stress. It had exertedbeneficial effects on skin cells in vitro and inanimal studies. Claims had been made forclinical benefit in ameliorating extrinsicaging in human subjects. Krutmann knewthat PycnogenolO has a high physical affin-ity for extracellular matrix proteins that arerich in hydroxyprolines, such as collagen


A Prime Mover in ImmunodermatologyDr. Jean Krutmann helped lay the groundwork in immunodermatology in the 1980s and 1990s. Although he was

first attracted to the field of dermatology during medical school at the University of Münster in Germany becauseit offered the ability to balance patient care and research, Krutmann credits his mentor there—Egon Macher, MD,a leader in the emerging field of immunodermatology—with his choice of focus. Macher had been the first to recognize the skin as an immune organ, and Krutmann found his excitement contagious. During a several-yearpost-doc in photoimmunology and immunodermatology in the U.S. at Case Western Reserve University, Krutmannwas in the group generating foundational knowledge in immunodermatology. Once he established his own lab at Freiburg University in 1989, he joined the race to identify and characterize the elements of the skin’s immunesystem. In 2001, Krutmann was appointed founding Scientific Director of the newly established IUF-Leibniz Research Institute for Environmental Medicine, and began his pioneering exploration of extrinsic skin aging.

Pollution-induced skin damage. With intact skin, ozone acts super-ficially on the SC but the organic compounds sticking to nanoparticle PMpenetrate skin and affect keratinocytes, melanocytes, and fibroblasts→altered signal pathways→pigmentation and rhytides, plus oxidativestress→skin inflammation. Barrier-deficient skin exacerbates the impact. AHR (aryl hydrocarbon receptor); MITF (microphthalmia-associated transcription factor); O3 (ozone); PAHs (polyaromatic hydrocarbons); POMC (pro-opiome-lanocortin); PM (particulate matter); ROS (reative oxygen species); VOC (volatile organic compounds). (Reprinted with permission from Japanese Society for Investigative Dermatology; J. Krutmann et al. See “Suggested Readings” for citation.)


and elastin, “both critically involved in skinaging,” he notes. An earlier clinical trialelsewhere with a multinutrient productcontaining PycnogenolO as the leading ac-tive ingredient improved visible signs ofskin aging as well as skin elasticity andsmoothness after 6 weeks. This appears toaddress at least some of the changes in-duced or exacerbated by environmentalstressors. But in general, molecular evi-dence substantiating clinical observationsof skin benefit is scarce, and there was nonefor PycnogenolO. Krutmann used a pure PycnogenolO product in a 12-week trial, andif he observed similar clinical benefit, heplanned to look for evidence of concomi-tant changes at the molecular level.

His subjects were 20 healthy post-menopausal women who received a daily PycnogenolO supplement for 12 weeks. Thecondition of their skin was assessed both bynoninvasive biophysical methods and viabiopsies used for gene expression analyses re-lated to extracellular matrix homeostasis. Thesupplement, which was well tolerated by allvolunteers, significantly improved skin elas-ticity (top graphs) and hydration. This im-proved skin physiology was accompanied bya significant increase in the mRNA expressionof hyaluronic acid synthase-1 (an enzyme crit-ically involved in the synthesis of hyaluronicacid) (left-hand graph below), and an in-crease in gene expression involved in de novocollagen synthesis (right-hand graph below).This could counteract the collagen degradingeffect of chronic exposure to air pollution and

The Journal of the American Academy of Dermatology (JAAD) has published seven articles this year in its new “From the Dermatol-ogy Foundation” section created in partnershipwith the DF. Announced in the May issue of theJAAD, it features clinically relevant articles byresearchers whose work was supported by DF Career Development Awards.

The articles are available online to all JAAD subscribers and also through the DF’sFacebook page. “From the Dermatology Foundation” is a great way to see how DF award recipients are working to further the science of the specialty for the benefit of all dermatologists and the patients intheir care.

Be sure to read the most recent articles:

JAAD Highlights Research by DF-Supported Investigators

October, 2016“Persistence of atopic dermatitis (AD): A systematicreview and meta-analysis.” Jooho P. Kim, Lucy X.Chao, Eric L. Simpson**, and Jonathan I. Silverberg*November, 2016“Impact of pruritus on quality of life: A systematic review.” Robert Kantor, Prarthana Dalal, David Cella,and Jonathan I. Silverberg*“Direct-to-Consumer Teledermatology Services forPediatric Patients: Room for Improvement.”Alexander L. Fogel, Joyce Teng**, and Kavita Y. Sarin*December, 2016“Association of atopic dermatitis with smoking: A systematic review and meta-analysis.” Robert Kantor, Ashley Kim, Jacob P. Thyssen, andJonathan I. Silverberg**Recent DF Award Recipient ** Former DF Award Recipient

Cut

omet

er R

2 (A

U)

0.5

0.6

0.7

– Pycnogenol + Pycnogenol

p=0.011

p=0.006 p=0.772C

utom

eter

R7

(AU

)

0.3

0.4 p=0.02

p=0.002 p=0.418

Day 8 Day 49 Day 91 Day 8 Day 49 Day 91

Skin elasticity: Improves significantly from baseline (Day 8) through 6 weeks (Day 49) and 12 weeks (Day 91)of PycnogenolO supplementation in 20 healthy postmenopausal women. Mean ±SE of the most important elasticity parameters—R2 (left) and R7 (right)—are presented. The closer to 1 (ie, 100%), the more elastic theskin. (Reprinted with permission from S. Karger; A. Marini et al. Skin Pharmacol Physiol.;2012;86-92.)

– Pycnogenol + Pycnogenol

HA

S-1/

18S

rRN

A

0

1

2

p<0.001

Gen

e Ex

pres

ssio

n/18

S rR

NA

0

1

2 p=0.645p=0.777

COL1A1 COL1A2Day 9 Day 92 Day 9 Day 92 Day 9 Day 92

Hydration and collagen expression: Both improve from baseline (Day 9) through 12 weeks (Day 92) of PycnogenolO supplementation. Biopsy samples were from buttock skin. The mean values ±SE for assessinggene expression are presented. The increase for hyaluronic acid synthase (HAS, left) achieved significance,but not the increases for collagen 1A1 and 1A2. (Reprinted with permission from S. Karger. A. Marini et al. Skin Pharmacol Physiol.;2012;86-92.)


AHR: The Ligand-Activated Aryl Hydrocarbon ReceptorPoorly understood and thus marginalized until now, the AHR is highly expressed and active in all skin cells and in

melanocytes. It is essential for normal cell function and pigmentation as well as for protecting the skin against environ-mental threats, including UVR. This molecular lynch pin can bind with a variety of activating ligands, both endogenousand exogenous, and it is the particular situation-specific ligand that determines the molecular and clinical outcome.The AHR had first come to Krutmann’s notice once he began working hands-on at the IUF. “Toxicologists here

had been studying dioxin—its effects on liver cells, its effects in mouse models, its ability to impair T-cell devel-opment. And they had found all of these effects to be mediated by this almost unknown ligand-activated tran-scription factor. Then not long after I had begun working here,” he continues, “other roles for these ligand-activatedreceptors were discovered.” They were found to be important in the embryo for tissue and organ development. Anda particularly big breakthrough was finding a significant functional role in the immune system. Treg cells expressit, and it is extremely important for their immunosuppressive function. “But no one had systematically looked at whether, where, and why the AHR is expressed in skin cells,” Krut-

mann recalls, “so I asked our AHR experts to take a look.” And they hit paydirt. They showed that epidermal keratinocytes express functionally active AHR, that they can be activated by UVB radiation (mediating both skintanning and immunosuppression), by PM in air pollution, and by the PAHs that attach themselves to thesenanoparticles. At this point, Krutmann knows the AHR plays substantial roles in the adaptive responses to envi-ronmental challenges (such as UVB exposure and topical chemicals, including those in polluted air and in tobacco smoke), in maintaining skin cell homeostasis, in regulating melanogenesis (by controlling melanocyteproliferation and melanin synthesis), and in skin immunity.

improve any damage that may have occurredto the skin barrier. Krutmann finds furtherstudies warranted to evaluate these benefitsmore closely.

Infrared A (IRA) Protection. IRA—part of the spectrum of nonionizing radia-tion—is also an environmental stressor that accelerates aging, in part by upregulating theexpression of collagen-degrading matrix metalloproteinase-1 (MMP-1) in dermal fibro-blasts. Krutmann and his colleagues createdan enriched sunscreen and assessed its pro-tective capability against IRA exposure. Theirhope was to protect human skin against the upregulation of MMP-1 that exposure induces. They compared a standard SPF30sunscreen to the identical sunscreen supple-mented with an antioxidant cocktail contain-ing grape seed extract, vitamin E, ubiquinone,and vitamin C. The antioxidant-enriched for-mulation was successful. As expected, expo-sure to IRA radiation significantly upregulatedMMP-1 expression compared to nonirradiatedskin. Use of the unmodified SPF30 sunscreendid not offer adequate protection against theincreased presence of MMP-1, but the anti-oxidant-amplified product reduced this in-creased expression significantly. Krutmannand his coworkers concluded that the topicalapplication of specific antioxidants effectivelyprotects human skin against IRA radiation,and that regular sunscreens need to be supplemented with this antioxidant cocktailto be effective.

AHR Antagonist. And finally, Krut-mann’s group has developed an AHR antag-onist—called BDDI—that transiently preventsAHR activation during UVB exposure. Theunligated, inactive AHR is trapped in a cy-

tosolic multiprotein complex that rapidly dis-sociates upon ligand binding, allowing theactivated AHR to shuttle into the cell nucleuswhere it binds to elements in the promoterregion of target genes. This initiates tran-scription of these genes, in turn unleashingthe signal pathways that result in much of thedamage from UVB exposure. In cultures ofnormal human epidermal keratinocytes,BDDI temporarily prevented AHR activation.Then a placebo-controlled study was donewith 10 healthy volunteers who applied a top-ical agent containing BDDI to defined skinareas once daily for 4 days. After applicationon day 4, volunteers were irradiated (orsham-irradiated) with 1.5 MED. Skin biopsiestaken 24 hours later clearly showed typicalAHR activation in response to placebo-mediated UVB irradiation. But the BDDI-containing cream prevented AHR from acti-vating any of its target genes, thus eliminat-ing the AHR-dependent signal pathways.Krutmann adds that “our in vitro data also in-dicate that BDDI may protect against the ad-verse effects of PAHs typically found onairborne particulate matter, and that poten-tially makes this AHR antagonist relevant aswell for protection against the skin aging effects of air pollution indoors and out.”

ConclusionsA great deal of research remains to be

done to arrive at a full understanding of theaging impact that air pollution componentshave on human skin, and to develop themost effective preventive and therapeuticagents. One of Krutmann’s additional con-cerns is the role of sensitive skin. The patho-physiology of sensitive skin, although not yet

fully understood, is thought to be associatedwith disturbed barrier function and in-creased stratum corneum permeability. Con-sidering that individuals with sensitive skinhave a barrier defect, they may represent asubgroup within the population that is par-ticularly sensitive to pollution-induced skinproblems. This is an additional question re-quiring further study, which Krutman hasbegun to pursue by exploring the involve-ment of the AHR in skin barrier function.

Suggested ReadingsVierkötter A, Schikowski T, Ranft U,

Sugiri D, et al. “Airborne particle exposureand extrinsic aging.” J Invest Dermatol.2010;130:2719–26.

Li M, Vierkötter A, Schikowski T, Hüls A,et al. “Epidemiological evidence that indoorair pollution from cooking with solid fuelsaccelerates skin aging in Chinese women.”J Dermatol Sci. 2015;79:148–54.

Vierkötter A, Krutmann J. “Environ-mental influences on skin aging and ethnic-specific manifestations.” Dermatoendocrinol.2012;4:227–31.

Krutmann J, Liu W, Li L, Pan X, et al.“Pollution and skin: From epidemiologicaland mechanistic studies to clinical implica-tions.” J Dermatol Sci. 2014;76:163–8.

Haas K, Weighardt H, Deenen R, KöhrerK, et al. “Aryl hydrocarbon receptor in ker-atinocytes is essential for murine skin barrierintegrity.” J Invest Dermatol. 2016;136;2260–9.

Haarman-Stemmann T, Esser C, KrutmannJ. “The Janus-faced role of aryl hydrocarbon re-ceptor signaling in the skin: Consequences forprevention and treatment of skin disorders.” J Invest Dermatol.2015;135:2572–6. �


ALABAMAHolly N. Burford, MDGrant E. Eudy, MDAnna Gray, MDJulie C. Harper, MDKeith Harrigill, MDLauren C. Hughey, MDHolly L. McIntire, MDMelinda Birchmore Musick, MDPatricia Wilson, MD

ARIZONAMatthew Beal, MDNancy Kim, MDBrenda C. LaTowsky, MDAaron R. Mangold, MDAnthony A. Nuara, MD, PhDJesse Olmedo, MDKristine A. Romine, MD

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CALIFORNIAIris Z. Ahronowitz, MDKatrina E. Abuabara, MDTina Bhutani, MDAnne Lynn S. Chang, MDNoel T. Chiu, MDGary W. Cole, MDJonathan A. Cotliar, MDEileen Crowley, MD, PhDMarlys S. Fassett, MD, PhDDavid C. Gorsulowsky, MDNina Hansra, MDLaura B. Pincus, MDAmanda K. Raymond, MDAman Samrao, MDMeiling Fang Yuen, MDAnonymous

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As of November 28, 2016

derived antioxidants are absorbed throughthe skin, which ensures reaching their targettissue. Determining the absorption capabil-ity for any given polyphenol is very straight-forward. Apply it to the skin, and if itbecomes detectable in the blood, then ithas been absorbed and metabolized.

Reaching Out to Botanicals forTreating the Skin

Having grown up in India, Mukhtar hadalways been personally aware that manyplants have medicinal value. India’s traditional health care system—Ayurvedicmedicine—includes a sophisticated experi-ence-based understanding and applicationof regional plant compounds. With a PhD inbiochemistry and drawn to drug metabo-lism, Mukhtar came to the U.S. in the mid-1970s as a postdoctoral fellow, then movedto a pharmacology/toxicology lab at the Na-tional Institute of Environmental Sciencesto study the cytochrome P450 system ofmetabolic enzymes. He began some re-search involving natural products, amongothers, but not involving their medicinal activity.

Mukhtar’s work there brought him to abasic realization about the skin’s nature andfunction, and that ultimately led him to thedermatology department at Case WesternReserve. Back at that time the skin was stillregarded as simply an inert mechanical barrier, but Mukhtar began to see clear evidence that it is a great deal more. Instudying the P450 system, he saw that someagents applied to the skin were ultimatelymetabolized for excretion by one of theseliver enzymes—and this clearly could notoccur unless they had first been absorbed

through and processed by the skin. Thismeant that the skin is clearly an active meta-bolic organ, and Mukhtar wanted to showthis. “So I began some work to demonstratethe skin’s true nature,” he recalls, “and thatgot me so interested in skin that I chose it tobe my life’s work.” Once at Case Western Reserve and learning about cutaneousdamage and diseases, Mukhtar suddenly re-alized the value in a partnership betweenthe antioxidant power of botanical polyphe-nols and caring for the skin.

Green Tea—First on the MenuMukhtar began to focus on skin can-

cers. The first botanical he chose to study inthis context was green tea, which Mukhtarand his group eventually put on the map asa dietary constituent with dramatic chemo-preventive properties for the skin, amongother organs. Green tea is one of the world’smost ancient and popular beverages(grown in about 30 countries) and con-sumed by the Chinese as a medicine because of its pharmacologic and physio-logical effects. But no one at that point un-derstood why green tea appeared to haveimportant health benefits, nor had the bio-logical foundation for these benefits beenassessed with the tools and techniques ofcontemporary science. “It was natural forme to see if it has any activity against skincancer,” Mukhtar says. He and his col-leagues concentrated on green tea’spolyphenols, ie, its antioxidant compounds.He parsed them down to the molecules thatprovide their primary chemopreventivepower—the epicatechin familiarly referredto as EGCG (epigallocatechin gallate)—andhe established the compelling data that put

green tea on the therapeutic map. Now Mukhtar is working intensely with

three additional botanical agents (see boxon page 12). He has been studying the juiceand fruit of the pomegranate (a fruit with acomplex of potent antioxidants) for sometime, and more recently has added the in-dividual polyphenols delphinidin andfisetin. He is addressing photodamagedskin, skin cancers (including melanoma),and psoriasis.

Photochemoprevention—One Goal, Multiple Benefits

“Exposure of the skin to UV radiationfrom the sun—particularly its UVB compo-nent, which is in the 280- to 320-nm range—results in erythema, edema, hyperplasia,hyperpigmentation, sunburn cells, im-munosuppression, photoaging, and skincancer,” Mukhtar notes. “And within thisspectrum of impact, skin cancer and pho-toaging are of great concern. In fact, solarUV radiation is the most prominent andubiquitous physical carcinogen in our nat-ural environment,” Mukhtar points out.Changes in lifestyle have led to a signifi-cant increase in the amount of UVB radia-tion that people receive, creating acontinuing surge in the incidence of bothskin cancer and photoaging. “Thus the ad-verse effects of UVB have become a majorhuman health concern,” Mukhtar states.“And this makes it highly desirable to de-velop novel strategies to reduce the occur-rence of skin cancer and delay the processof photoaging.”

One way to do this is through pho-tochemoprevention—the use of agents ca-pable of ameliorating the adverse effects ofUVB on the skin. Using botanical antioxi-dants that are present in the typical humandiet “has gained considerable attention,”Mukhtar points out, and he lists green tea,pomegranate, resveratrol, and genistein asthe more commonly encountered options.Accumulating laboratory data indicate thatmany botanical agents with antioxidantproperties exert anti-inflammatory, cancerpreventive, and anti-photoaging effects inthe skin (see illustration on page 11). “Be-cause UVB radiation plays such an impor-tant role in cutaneous damage, agents thatcan protect against it would simultaneouslybe photochemoprotective against photoag-ing and skin cancer. The use of skin careproducts with sunscreen and supplemented


Focus on ResearchBotanical Antioxidants—A Multifunctional Approach to

Preventing and Treating Skin Damage and Disease(Continued from cover)

PolyphenolsThese common antioxidants are present in many foods and bever-

ages of plant origin. Their chemical structure involves one or more phe-nolic groups, which are capable of reducing reactive oxygen species andvarious organic substrates and minerals. These prominent redox proper-ties explain the considerable interest in their potential for preventing ortreating major chronic diseases associated with oxidative stress, especiallycardiovascular diseases, cancers, type 2 diabetes, neuro-degenerative diseases, and osteoporosis. Polyphenols come in a great variety, and over500 different molecules have been identified in foods. A handful of themore well-known ones are the flavonoids and flavonols, ellagic acid, tannic acid, resorcinol, the anthocyanidins, catechins, and epicatechin.

with several effective agents that workthrough different pathways may be an idealway to reduce UVB-generated ROS-medi-ated photoaging and skin cancer in hu-mans.”

To this end, Mukhtar has been puttingpomegranate through its paces to preventboth photoaging and skin cancer. He is alsostudying delphinidin—an important con-stituent of pomegranate as well as other red-and blue-colored fruits and vegetables—forcancer prevention, and has done a handfulof studies now with fisetin specifically in thecontext of melanoma. He has been provid-ing the strong mechanistic foundation thatis laying the ground for further preclinicalwork and clinical trials.

Emphasis: Preventing Photoaging

Mukhtar has assessed the photo-chemopreventive capabilities of pome-granate extracts in two different settings todetermine whether it has the potential toprotect against the damage that underliesphotoaging. His first set of studies used


The need for Dermatology Foundation research support has heightened as the New Yearapproaches. In an era of economic and political uncertainty, the specialty’s most promising researchers will be looking to the DF to provide the early funding they need to begin innovativework that will expand the opportunities for greaterknowledge and improved therapies.

As you plan your charitable contributions forthe year, give extra consideration to the member-ship options offered by the Foundation to ensurethe future of the specialty. One of them is right for you.

Your commitment today will have a direct impact on the funds available to tomorrow’s researchers, whose work will advance the scienceof dermatology and ultimately enhance patient care.

Help fill the urgent need for research dollars.Now—before the year is over—join or increaseyour membership contribution! Visit dermatologyfoundation.org or call 847-328-2256.

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Skin

Sunscreen (1st line) Antioxidant (2nd line) Redox regulation ofsignal transductionpathway (3rd line)Radical scavenger

Reduces oxidative stressReduces DNA damage

Suppresses Inflammation

Suppresses Proliferation

Transformationspecific apoptosis in

transformed cells

p53

DNA excision repair Gene inactivation

Prevention Correction

Prevention ofDamage

Botanical Antioxidants Act As

UVB

Multifunctional botanical antioxidants. Three simultaneous photochemoprotective modes of actionprevent (the changes → photodamage and/or skin cancer), repair (existing changes), and suppress (inflammation and consequent damage). (Reprinted with permission from Blackwell Munksgaard. F. Afaq et al. 2006;Exp. Dermatol. See “Suggested Readings” for citation.)

HaCaT cells, which belong to an immortal-ized line of keratinocytes widely used forstudies of skin biology and cell differentia-tion. He pretreated some of his cell cultureswith a pomegranate fruit extract (PFE) be-fore exposing them, and untreated controlcultures, to UVB radiation. Mukhtar foundthat pretreating cell cultures with PFE re-duced oxidative stress and photoaging. It inhibited UVB’s ability to diminish cell viability, to decrease intracellular glu-tathione, and to increase lipid peroxidation.Using immunoblotting to detect protein

synthesis, Mukhtar showed that PFE also in-hibited several elements responsible for col-lagen breakdown. It prevented activation ofthe MAPK (mitogen-activated protein ki-nase) pathway, which is largely responsiblefor stimulating the transcription factor AP-1,which in turn stimulates the transcription of matrix metalloproteins (MMPs) that degrade the extracellular matrix—MMP-1,MMP-2, and MMP-9. Not only did theseMMP’s not increase, but PFE also main-tained the collagen-friendly expression of TIMP-1.

Next, Mukhtar and his coworkerslooked at several pomegranate extracts—PFE, juice, and oil—to treat a reconstitutedskin model 1 hour before exposing this skinto UVB. After exposure, assessing proteinoxidation along with markers of DNA dam-age and photoaging confirmed the protec-tive profile. Pretreatment with each producthad inhibited a variety of UVB-induced alterations and DNA and protein damage.Pretreatment had also minimized cancer-promoting changes in the proto-oncogenesc-Fos and c-Jun.

Mukhtar found these studies to providea strong basis “for more in-depth investiga-tions to assess the effectiveness of pomegran-ate fruit and its derived products in preventingUVB-mediated damage and photoaging.”

Skin Cancer StatisticsSkin cancer represents a substantial

health care burden in the U.S.—and roughly90% of cases are associated with exposureto UV radiation from the sun. The Skin Can-cer Foundation notes that over the pastthree decades, more people have had skincancer than all other cancers combined.Each year in the U.S., more than 40 millioncases of basal cell carcinoma and morethan one million cases of squamous cell car-cinoma are diagnosed. The annual cost oftreating these skin cancers is estimated at$8.1 million. Melanoma rates doubled be-tween 1982 and 2011, and they are still rising.Although melanoma accounts for less than1% of all skin cancer cases, it is responsiblefor the vast majority of skin cancer deaths.An estimated 10,130 people will have diedof melanoma in 2016. The new cases of skincancer identified in the U.S. each year in-volve considerable morbidity. Mortality becomes a significant concern with moreaggressive cancers. Effective photochemo-prevention would dramatically improve thislandscape.

Prevention: Nonmelanoma Skin Cancers

UV-induced responses result in inflam-mation, oxidative stress, dysregulation ofapoptosis (allowing abnormal proliferationof keratinocytes containing DNA damage),acquisition of p53 mutations, alterations in signal transduction pathways, and im-munosuppression. All of these changes con-tribute to the onset of skin cancers. Inaddition, UV radiation from the sun is acomplete carcinogen, which is what makesit particularly dangerous. It causes the DNAdamage initiating the carcinogenic process,and later it is equally effective at promotingtumorigenesis by generating clonal expan-


(Continued on page 15)

Under the Microscope—Mukhtar’s Polyphenol Menu

Mukhtar is currently concentrating on three botanical polyphenols.The fact that their antioxidant qualities affect a variety of cell pathwaysmakes each of them relevant to multiple arenas—a highly appealingadded benefit of these plant-based extracts.

Pomegranate. Pomegranates, Punica granatum, are a hot-climatefruit that has been used medicinally for thousands of years. It is so ex-ceptionally rich in antioxidant compounds that a screening in 2002 forthe total antioxidant content of dietary plants found pomegranate to beamong the eight most richly endowed plant families. Eastern countriesmake use of every part of the plant. The West uses the fruit plus juice ex-tracted from the seeds. Consumption of pomegranate juice has beenfound to benefit patients with carotid artery stenosis, hypertension, hyperlipidemia, coronary heart disease, and mild-to-moderate erectiledysfunction. The juice has been shown in vitro to suppress inflamma-tory cell signaling, and inhibit prostate tumor growth, aromatase activity, endogenous estrogen biosynthesis, and breast cancer cell pro-liferation. Pomegranate fruit extracts have shown promise in cancer, car-diovascular disease, and osteoarthritis, and in slowing the progress of Alzheimer’s disease. The polyphenol punicalagin, an ellagitannin, accounts for >50% of this fruit’s antioxidant activity.

Delphinidin. Delphinidin is the most abundant of the six antho-cyanidins present in pomegranate fruit extract. It is also the most abun-dant in the many other pigmented fruits and vegetables in which it isfound, including berries, dark grapes, eggplant, tomatoes, carrots, pur-ple sweet potatoes, red cabbage, and red onion. It has been shown topossess antimicrobial, anti-inflammatory, antioxidant, and antiprolifer-ative activity—and even more significantly, anticarcinogenic activity—when assessed in diverse cell culture and animal model systems.Because of the evidence showing its ability to inhibit the mTOR cell-growth pathway (which plays a significant role in many cancers, amongother diseases), an effect first observed with the drug rapamycin, del-phinidin is considered to be a rapalog—one of the first generation of rapamycin analogs.

Fisetin. This flavonol—a class of flavonoid—is present in fruits andvegetables such as strawberries, apples, cucumber, persimmon, grapes,and onion. As with delphinidin, it has been shown to possess antimi-crobial, anti-inflammatory, antioxidant, and antiproliferative activity—and especially anticarcinogenic activity—when it has been assessed in diverse cell culture and animal model systems.

®/TMs are trademarks of Valeant Pharmaceuticals International, Inc. or its affiliates. All other product or brand names are trademarks of their respective owners. ©2016 Valeant Pharmaceuticals North America LLC. JUB.0058.USA.16 Printed in US

*For the treatment of onychomycosis of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes.

AT THE SITE OF INFECTION1

STEALING THE SHOW?

FIGHT IT

*

JUBLIA allows some patients to have clearer toenails grow back. Individual results may vary.

INDICATIONJUBLIA (efinaconazole) topical solution, 10% is indicated for the topical treatment of onychomycosis (tinea unguium) of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes.

IMPORTANT SAFETY INFORMATION• JUBLIA is for topical use only and is not for oral, ophthalmic, or intravaginal use.

• Patients should be instructed to contact their health care professional if a reaction suggesting sensitivity or severe irritation occurs.

• The most common adverse reactions (incidence >1%) were (vs vehicle): ingrown toenail (2.3% vs 0.7%), application-site dermatitis (2.2% vs 0.2%), application-site vesicles (1.6% vs 0%), and application-site pain (1.1% vs 0.2%).

• JUBLIA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, and should be used with caution in nursing women. The safety and effectiveness in pediatric patients have not been established.

Please see Brief Summary of full Prescribing Information on the adjacent page.Reference: 1. JUBLIA [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2015.

Find out more by visiting www.JubliaRx.com.

8 mLLARGER

Rx OnlyAVAILABLE

size

Trim: 8.5"x11" File Format: PDF Carling Communications 4/19/2016 B

BRIEF SUMMARY OF PRESCRIBING INFORMATION

This Brief Summary does not include all the information needed to use JUBLIA safely and effectively. See full prescribing information for JUBLIA.

JUBLIA® (e�naconazole) topical solution, 10%

For topical useInitial U.S. Approval: 2014

INDICATIONS AND USAGEJUBLIA (e�naconazole) topical solution, 10% is an azole antifungal indicated for the topical treatment of onychomycosis of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes.

DOSAGE AND ADMINISTRATIONApply JUBLIA to affected toenails once daily for 48 weeks, using the integrated �ow-through brush applicator. When applying JUBLIA, ensure the toenail, the toenail folds, toenail bed, hyponychium, and the undersurface of the toenail plate, are completely covered.

JUBLIA is for topical use only and not for oral, ophthalmic, or intravaginal use.

CONTRAINDICATIONSNone.

ADVERSE REACTIONSClinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not re�ect the rates observed in practice.

In two clinical trials, 1227 subjects were treated with JUBLIA, 1161 for at least 24 weeks and 780 for 48 weeks. Adverse reactions reported within 48 weeks of treatment and in at least 1% of subjects treated with JUBLIA and those reported in subjects treated with the vehicle are presented in Table 1.

Table 1: Adverse Reactions Reported by at Least 1% of Subjects Treated for up to 48 Weeks

Adverse Event, n (%)JUBLIA

N = 1227Vehicle N = 413

Ingrown toenail 28 (2.3%) 3 (0.7%)

Application site dermatitis 27 (2.2%) 1 (0.2%)

Application site vesicles 20 (1.6%) 0 (0.0%)

Application site pain 13 (1.1%) 1 (0.2%)

DRUG INTERACTIONSIn vitro studies have shown that JUBLIA, at therapeutic concentrations, neither inhibits nor induces cytochrome P450 (CYP450) enzymes.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies with JUBLIA in pregnant women. JUBLIA should be used during pregnancy only if the potential bene�t justi�es the potential risk to the fetus.

Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 2, 10 and 50 mg/kg/day e�naconazole were administered during the period of organogenesis (gestational days 6-16) to pregnant female rats. In the presence of maternal toxicity, embryofetal toxicity (increased embryofetal deaths, decreased number of live fetuses, and placental effects) was noted at 50 mg/kg/day [559 times the Maximum Recommended Human Dose (MRHD) based on Area Under the Curve (AUC) comparisons]. No embryofetal toxicity was noted at 10 mg/kg/day (112 times the MRHD based on AUC comparisons). No malformations were observed at 50 mg/kg/day (559 times the MRHD based on AUC comparisons).

Subcutaneous doses of 1, 5, and 10 mg/kg/day e�naconazole were administered during the period of organogenesis (gestational days 6-19) to pregnant female rabbits. In the presence of maternal toxicity, there was no embryofetal toxicity or malformations at 10 mg/kg/day (154 times the MRHD based on AUC comparisons).

In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day e�naconazole were administered from the beginning of organogenesis (gestation day 6) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal toxicity (increased prenatal pup mortality, reduced live litter sizes and increased postnatal pup mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted at 5 mg/kg/day (17 times the MRHD based on AUC comparisons). No effects on postnatal development were noted at 25 mg/kg/day (89 times the MRHD based on AUC comparisons).

Nursing MothersIt is not known whether e�naconazole is excreted in human milk. After repeated subcutaneous administration, e�naconazole was detected in milk of nursing rats. Because many drugs are excreted in human milk, caution should be exercised when JUBLIA is administered to nursing women.

Pediatric UseSafety and effectiveness of JUBLIA in pediatric subjects have not been established.

Geriatric UseOf the total number of subjects in clinical trials of JUBLIA, 11.3% were 65 and over, while none were 75 and over. No overall differences in safety and effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identi�ed differences in responses between the elderly and the younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityA 2-year dermal carcinogenicity study in mice was conducted with daily topical administration of 3%, 10% and 30% e�naconazole solution. Severe irritation was noted at the treatment site in all dose groups, which was attributed to the vehicle and confounded the interpretation of skin effects by e�naconazole. The high dose group was terminated at week 34 due to severe skin reactions. No drug-related neoplasms were noted at doses up to 10% e�naconazole solution (248 times the MRHD based on AUC comparisons).

E�naconazole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung cell chromosome aberration assay) and one in vivo genotoxicity test (mouse peripheral reticulocyte micronucleus assay).

No effects on fertility were observed in male and female rats that were administered subcutaneous doses up to 25 mg/kg/day e�naconazole (279 times the MRHD based on AUC comparisons) prior to and during early pregnancy. E�naconazole delayed the estrous cycle in females at 25 mg/kg/day but not at 5 mg/kg/day (56 times MRHD based on AUC comparisons).

PATIENT COUNSELING INFORMATIONSee FDA-Approved Patient Labeling (Patient Information).

Manufactured for:Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807 USA

Manufactured by: Kaken Pharmaceutical Co. Ltd, Shizuoka, Japan

Product of Japan

U.S. Patents 8,039,494; 7,214,506

Based on 9391902 DM/JUB/15/0076 Issued: 02/2015

Trim: 8.5"x11" File Format: PDF Carling Communications 4/19/2016 B

sion of these damaged cells. At the heart ofthis process is the fact that UV exposure in-creases the generation of reactive oxygenspecies to a degree that overwhelms theskin’s antioxidant defense mechanisms, adisequilibrium termed oxidative stress.Mukhtar chose two items to assess for theirability to prevent this oxidative stress. Onewas pomegranate, well known by then forits antioxidant strengths. The other—basedon his earlier assessment—was delphinidin.

When Mukhtar and his coworkers stud-ied delphinidin’s ability to protect againstthe early changes leading to UVB-inducedskin cancer, they looked first at humanHaCaT keratinocytes, and then at hairlessmice. With HaCaT cell cultures, 24 hours ofdelphinidin before a 24-hour period of UVBexposure substantially improved the out-

come. Delphinidin protected cell viabilityand survival, reduced lipid peroxidationand DNA damage, maintained the protec-tive presence of proliferating cell nuclearantigen (PCNA), minimized the appear-ance of important biomarkers of DNA dam-age, and significantly limited a variety ofUVB-induced changes that create an envi-ronment favoring the creation and preser-vation of DNA-damaged cells. Applyingdelphinidin to the skin of hairless mice bothbefore and after UVB exposure demon-strated its strong antioxidant activity, andshowed substantially reduced DNA damageand consequent apoptosis in keratinocytes.The observed benefits translated to a potentphotochemopreventive effect.

Mukhtar et al. also looked at the pre-ventive strengths of pomegranate. First they

assessed the effect of PFE on early biomark-ers of photocarcinogenesis. After mixing itin drinking water and feeding it to hairlessmice for 14 days before a single UVB expo-sure, the treated mice showed only verymodest increases in skin edema, hyperpla-sia, leukocyte infiltration, lipid peroxide andhydrogen peroxide generation (see graphon page 16), among a variety of early mark-ers. PFE pretreatment also increased the el-evation of tumor suppressor p53 and itspartner, cyclin kinase inhibitor p21. This wasconvincing evidence that oral feeding ofPFE to mice affords them substantial protec-tion from the adverse effects of UVB radiation, intervening right at the start andminimizing the early biomarkers of photo-carcinogenesis.

A more recent study involving oral


The Dermatology Foundation warmly welcome its newest Annenberg Circle (AC) members. Theyjoin more than 600 colleagues who have pledged $25,000 over five years to provide funding for newresearch by tomorrow’s leaders dedicated to strengthening the specialty and enhancing patient care.

The DF gratefully acknowledges the following members who completed their Annenberg Circlecommitment and have chosen to continue their generous support by becoming AC Sustainingmembers. Each has pledged to provide an annual contribution of $5,000 to support research thatwill advance the future of dermatology. Listed below are each member’s cumulative Annenberg Circle and Sustaining contributions and pledges.

Linda J. Banta, MDM. Kari Connolly, MDJeri Beth Foshee, MDLinda K. Franks, MD

Christine J. Ko, MDPaul Nghiem, MD, PhD

Tri Van Nguyen, MDJulia R. Nunley, MDRyan S. Owsley, MD

Stephen M. Purcell, DOJoel Stephen Shavin, MD

Anjali H. Singh, MDMartha E. Stewart, MD

DF is Pleased to Welcome New AnnenbergCircle and AC Sustaining Members

$50,000

$30,000

$125,000

$75,000


Andrew S. Calciano, MDRoger I. Ceilley, MD

Ronald E. Grimwood, MD*Sharon A. Glick, MDJon M. Hanifin, MD

Scott B. Karlene, MDDavid N. Kingsley, MDAva T. Shamban, MD

Kanade Shinkai, MD, PhDPayam Tristani-Firouzi, MD

Clay J. Cockerell, MD* James J. Leyden, MDScott L. Zahner, MD*

From the PublicGlenn A. Oclassen

Donald J. Miech, MD*D. Scott Miller, MD*

Melanie L. Zahner, MD*From the Public

Mitchell S. Wortzman, PhD*

*New multi-year pledge


feeding of PFE to hairless mice repeated the pretreatment PFE regimen and daily UVdose, but increased this from a single expo-sure to a total of 7 given on alternating days.This time, Mukhtar et al. looked at PFE’sability to normalize the activity of signalpathways critical to carcinogenesis. Onewas the MAPK pathway, which is importantin tumorigenesis as well as photoaging. It normally links extracellular signals to the intracellular machinery that controlsfundamental existential cellular processes. Tumorigenesis requires deregulation of atleast 6 of these cellular processes to enable acquisition of the abilities to proliferate in-dependently, evade apoptosis, ignore anti-growth signals, replicate without limitation,invade and metastasize, stimulate angio-genesis, acquire drug resistance, and avoidinduced senescence—and abnormalities inMAPK signaling facilitate most, if not all, ofthese processes. MAPK abnormalities areactivated by UVB exposure. Mukhtar alsomonitored the inflammatory NF-�B path-way that becomes involved in cell growthand proliferation. “Taken together, our datashow that PFE consmption affords protec-tion to mouse skin against the adverse ef-fects of UVB radiation by modulating thesesignaling pathways,” Mukhtar explains.“And thus it points to PFE’s potential effi-cacy as a photochemopreventive agent for skin cancer.”

Prevention: Melanoma Skin Cancers

Although the new immunotherapiesnow helping some patients with advancedor unresectable disease are the first signifi-cant improvement in many years, the out-look remains bleak for the large majority.And for those who do respond to these newdrugs, side effects can be damaging and thecost for these drugs is monumental.

Mukhtar is approaching melanomawith fisetin, a common and potentflavonoid already being investigated for itsgrowth inhibitory properties in other cancer

models. He and his coworkers initiallyfound that fisetin inhibits melanoma cellproliferation both in vitro and in vivo. Thenthey used a 3-D full-thickness melanomaskin model to study the effect of fisetin onmelanoma progression. Days 12 and 16showed a dramatic decrease in melanomacells versus untreated control skin. Un-treated skin contained nests of tumor cellsand many invading disseminated cells. (Seegraph above.) By day 16, melanocytic le-sions were barely detectable in fisetin-treated skin tissue, contrasting significantlywith untreated controls. Further studies inmelanoma cultures and mouse xenograftsshowed that fisetin-mediated growth inhibi-tion was associated with deactivating sev-eral essential proteins, including mTOR.

Mukhtar’s studies characterized, for thefirst time, the distinctive interactions of abotanical agent with kinases specifically in-volved in melanoma growth. They demon-strated that fisetin binds directly to mTORand p70/S6K to achieve inhibition of thesecritical melanoma pathways, but achievesinhibition of Akt indirectly by targeting path-ways that then turn Akt off. Additional studymade it clear that fisetin induces cytotoxic-ity in cultured metastatic human melanomacells. Looking for the molecular basis of thisimpact, they discovered that the primarymechanism through which fisetin inhibitsmelanoma cell growth is apoptosis, and thatthis impact integrates activation of both extrinsic and intrinsic pathways.

Treating PsoriasisThe ideal treatment of psoriasis re-

mains elusive. Although patients are nowbenefiting from dramatic progress in treat-ment capability stemming from funda-mental advances in understanding theunderlying immunopathology, the targetedbiologic drugs now used are extremelycostly and come with significant side ef-fects. Most concerning is the more general

As you make your plans to travel to Orlando, Florida this next March, please be sure to add the

Foundation’s events to your schedule. Join your colleagues at the Annual Meeting of Membership to come up to speed on DF activities, and to recognize this year’s honorary awardees and the recipients of DF research awards.

2017 DF Annual Meeting Events:Mark Your Calendar

Friday, March 3 – Sunday, March 5DF Exhibit Booth #3310

Orange County Convention Center

� � � �

Saturday, March 4DF Annual Meeting of Membership & Awards

PresentationsHyatt Regency Orlando,

Plaza Ballroom G5:30 – 6:30 pm

Sunday, March 5Annual Leadership Gala

Orchid Garden at Church Street Station7:30 – 9:00 pm

Pre-Gala Young Leaders Reception 6:45 – 7:30 pmCo-sponsored by:

Amgen Inc.Celgene Corporation

Valeant Pharmaceuticals North America LLC

(By invitation only—tickets required)

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PFE: Feeding pomegranate fruit extract (PFE) to 8SKH-1 hairless mice for 14 days inhibits early biomark-ers of UVBR-induced carcinogenesis, including hydro-gen peroxide (H2O2), after a single UVB exposure. The number of H2O2-positive cells are represented aspercent of those in the control group. (#P <0.001 vscontrol; *P <0.001 vs UVB) (Reprinted with permissionfrom Elsevier. F. Afaq et al, 2010; Photochem Photobiol.See “Suggested Readings” for citation.)

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Fisetin: In 3-D melanoma skin equivalents, fisetin decreased the number of tumor nests while those inuntreated control skin continued to climb. (*P <0.05;**P <0.001) (Reprinted with permission from DN Syed et al, 2014;Biochem Pharmacol. See “SuggestedReadings” for citation.)

immunosuppression imposed on patientsthat is currently the price to pay for inhibit-ing the immune hyperactivity responsiblefor psoriatic lesions. The goal of finding away to restrain the signaling abnormalitiesunderlying psoriasis without creating otherhealth vulnerabilities motivated Mukhtar to explore a botanical option.

He had noticed that the PI3K/Akt/mTOR pathway—frequently deregulated inmany malignancies—is also clinically rele-vant in psoriasis. So he decided to use del-phinidin, a polyphenol from pigmentedfruits and vegetables that had already showngood activity against this pathway in a skincancer setting, and see what it might possi-bly do in psoriasis. His first attempt used anexperimental system that closely mimics invivo human skin—and the results were ex-cellent. Treating reconstituted human skinwith this extract “increased the expressionof caspase-14, which is involved in corni-fication,” Mukhtar explains. “And it also increases the expression of epidermal dif-ferentiation marker proteins.” These obser-vations meant that delphinidin could be auseful agent for dermatoses associated withepidermal barrier defects, including theaberrant keratinization, hyperproliferation,and inflammation that occur in skin diseaseslike psoriasis and ichthyoses.

Next they used delphinidin in a full-thick-ness 3-D reconstitution of psoriatic skin aswell as in a normal skin equivalent. Applyingdelphinidin daily for 2–5 days producedhighly encouraging changes. It induced dif-ferentiation, thickened the stratum corneum(see graph on page 18) and epidermis, andinhibited proliferation. And it minimized theexpression of endogenous antimicrobials—such as psoriasin and koebnerisin—that arestrongly increased in inflamed psoriatic skin(see photos at right).


The DF Board of Directors offers its profound gratitude to those listed below, who each welcomed at least three (3) new members to the Leaders Society this year. Each of the volun-teers recognized here devoted exceptional time and effort to ensure that tomorrow’s leadershave the early DF support they need to conduct the innovative research vital to strengthening the specialty for years to come.


A Special Thank You to 2016 Leaders Society Volunteers

Misty D. Caudell, MDYvonne E. Chiu, MD

Robert P. Dellavalle, MD, PhDRebecca L. Euwer, MDEric S. Fromer, MD

Sherri K. Kaplan, MDCarrie L. Kovarik, MDJohn C. Maize, Jr., MDAaron Mangold, MD

Elizabeth I. McBurney, MD

John M. Pelachyk, MDJack S. Resneck, Jr, MDVera Y. Soong, MD

Kathleen S. Stokes, MDRuth A. Yates, MD

Delphinidin minimized the characteristic features of human psoriasis seen in imiquimod-treated mice. 3 groups—control (black), 5% imiquimod cream (red), imiquimod + topical delphinidin (green)—were evaluated regularly. Thickened ear skin, inflammatory erythema, and scales were dramatically minimizedwith delphinidin. (**P ≤0.01; ***P ≤0.0001) (Reprinted with permission from Mary Ann Liebert. JC Chamcheu et al. 2016;Antioxidants Redox Sig. See “Suggested Readings” for citation.)

Delphinidin suppresses inflammation in psoriatic skin. This shows the substantial reduction in expression of the proinflammatory alarmins psoriasin (S100A7) and koebnerisin (S100A15) in dose-relatedfashion. (Reprinted with permission from Karger. JC Chamcheu et al. 2015;Skin Pharmacol Physiol. See “Suggested Readings” for citation.)

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The need for DF re-search funding continuesto intensify. With increas-ingly heated competitionfor limited research funds,every contribution tothe Dermatology Foundation is vital to ensure the future of improved patient care in dermatology.

A mutually beneficial way to contribute to the vital work of the DF is now permanent underlaw. If you are age 70-1/2 years or older, a

charitable contribution of up to $100,000 fromyour IRA can be moveddirectly to the DF as yourchosen charity and not included in your taxable

income. The distribution must come from a qualified IRA, and your transaction must be initiated by your IRA administrator.

Contact your tax or financial advisor now totake advantage of this tax-friendly opportunitybefore the year is over.

Then Mukhtar et al. moved to the flakyskin mouse, a murine model of psoriasis, tosee if topically applied delphinidin can mini-mize pathologic markers of psoriasiform le-sions. And it did. Five-week-old mice weredivided into 3 groups. Groups 2 and 3 weretreated topically with delphinidin 5 times aweek until 14 weeks of age. Control mice weretreated with vehicle. Treatment “reduced pso-riasiform lesion pathogenesis,” Mukhtar says.And he adds that it inhibited keratinocyte pro-liferation, spurred keratinocyte differentiation,and improved the expression of epidermaltight junction proteins. Delphinidin treatmentalso inhibited proinflammatory cytokines, infiltration of macrophages and neutrophils,and increased the expression of AP-1 pro-teins,” he adds. Benefits equaled thoseachieved by vitamin D agents, and were

superior to the performance of retinoic acid.

Most recently, Mukhtar andhis team studied topically ap-plied delphinidin in a psoriasismouse model created by im-iquimod application. They werehighly encouraged to find inhi-bition of key kinases involved inpsoriasis pathogenesis—a num-ber of which are involved in the PI3K/Akt/mTOR pathway—and alleviation of the psoriasis-like disease in these mice (seegraphs on page 17). Mukhtarconcluded that “a novel PI3K/Akt/mTOR pathway modulatorto treat psoriasis can be devel-oped from delphinidin.”

Reviewing these consistently positiveresults, Mukhtar says that “these promisingbiological effects, coupled with the rela-tively low cost and toxicity of natural agents,combine to make delphinidin a highlypromising agent for treating psoriasis andother hyperproliferative skin disorders.”

ConclusionsMukhtar’s in vitro and preclinical stud-

ies with these plant-derived antioxidants forphotochemoprevention and the treatmentof psoriasis have produced results thatclearly support the progression to clinicaltrials. He welcomes the opportunity to part-ner with interested colleagues.

Suggested ReadingsAfaq F, Mukhtar H. “Botanical antioxi-

dants in the prevention of photocarcino-

genesis and photoaging.” Exp Dermatol.2006;15:678–84.

Afaq F, Zaid MA, Khan N, Dreher M, et al. “Protective effect of pomegranate-derived products on UB-mediated damagein human reconstituted skin.” Exp Dermatol.2009;18:553–61.

Afaq F, Khan N, Sued DN, Mikhtar H.“Oral feeding of pomegranate fruit extractinhibits early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairlessmouse epidermis.” Photochem Photobiol.2010;86:1318–26.

Syed DN, Adhami VM, Khan N, KhanMI, et al. “Exploring the molecular targets ofdietary flavonoid fisetin in cancer.” SeminCancer Biol. 2016;40-41:130–40.

Syed DN, Chamcheu JC, Khan MI,Sechi M, et al. “Fisetin inhibits humanmelanoma cell growth through direct bind-ing to p70S6K and mTOR: Findings from 3-Dmelanoma skin equivalents and computa-tional modeling.” Biochem Pharmacol.2014;89:349–60.

Chamcheu JC, Pal HC, Siddiqui IA, Adhami VM, et al. “Prodifferentiation, anti-inflammatory and antiproliferative effects of delphinidin, a dietary anthocyanidin, in afull-thickness three-dimensional reconsti-tuted human skin model of psoriasis.” SkinPharmacol Physiol. 2015;28:177–88.

Chamcheu JC, Adhami VM, Esnault S,Sechi M, et al. “Dual inhibition of PI3K/Aktand mTOR by the dietary antioxidant, del-phinidin, ameliorates psoriatic features in vitro and in an imiquimod-induced psoriasis-like disease in mice.” Antiox RedoxSig. 2016 (Oct 4);Epub ahead of print. �


Gift to the DF Also Reaps Tax BenefitThe IRA Charitable Rollover is Here to Stay

Control RA Vit-D310 μM Del.

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In a 3-D full-thickness reconstituted human skin model of psoriasis, delphinidin significantly enhances stratum corneum cornification indose-related fashion, comparable to vitamin D3 (Vit-D3) and significantlymore effective than retinoic acid (RA). (**P <0.01;*** P <0.0001).(Reprinted with permission from Karger. JC Chamcheu et al. 2015;Skin Pharmacol Physiol. See “Suggested Readings” for citation.)

For further information on getting started, please contact the DF office at 847.328.2256 or email [email protected].


2015 Corporate Honor SocietyPartners in Shaping Dermatology’s Future

The Dermatology Foundation is grateful to the following corporations for their generouscontributions last year. Their support furthers the DF’s mission to develop and retain tomorrow’s leaders in the specialty, enabling advancements in patient care.

Cornerstone Benefactor ($500,000 or more)

Platinum Benefactor ($200,000 or more)

Gold Benefactor ($100,000 or more)

DUSA Pharmaceuticals

Silver Benefactor ($50,000 or more)

Amgen Inc.Sun Pharmaceuticals

ADDRESS SERVICE REQUESTED

Dermatology Focusc/o Dermatology Foundation1560 Sherman Avenue Evanston, Illinois 60201-4808

Non-ProfitU.S. Postage

PAIDPermit No. 236 Melrose Park, IL

VOL. 35 NO. 3 FALL 2016

A DERMATOLOGY FOUNDATION PUBLICATIONSPONSORED BY VALEANT PHARMACEUTICALS NORTH AMERICA LLC

Dr. Mangold was so grateful for the researchaward he received from the Dermatology Founda-tion when he was a resident at the Mayo Clinic inPhoenix, that he joined the Leaders Society just as soon as he could “I wanted to pay it forward,”says Dr. Mangold, Assistant Professor at theDepartment of Dermatology at MayoClinic in Arizona. “It’s the minimum I can contribute, given the currenteconomic environment we have for research. It is really critical thatwe have an organization like theDermatology Foundation.” Soonafter joining the Leaders Society in2016, he volunteered to add his energyand enthusiasm to the national cam-paign and invite his Arizona colleaguesto join him in leadership giving.

Dr. Mangold received a DF MedicalDermatology Career Development Award in 2015for research on the prognostic value of inositolpolyphosphate 5-phosphatase in cutaneous squamous cell carcinoma. In addition to his ongoing

research, he maintains a busy clinical schedule. A main driver of dermatology’s appeal for him is theunique aspect “that we not only diagnose both com-mon and very rare diseases, we also manage them.”In addition to his DF volunteer role, Dr. Mangold isalready actively involved in his state and regional

dermatology societies. He feelsstrongly that new dermatologists needto contribute to the leadership of theirlocal, state and national communitiesto further the specialty at every level.

Given limited improvement ex-pected in tight federal research fund-ing, Dr. Mangold sees the DF’s workremaining essential to new investiga-tors and becoming even more impor-tant to the future of the specialty. “It’s in a league of its own.” As both a volunteer and Leaders Society

member, he shares that “the most importantthing we can do is encourage young people to get involved—to make a commitment to theirfield. We need this organization.”

Giving Back—Profile of a DF Volunteer“The DF is in a league of its own”

The DF is exceptionally grateful to its many volunteers who give so generously of their time to keep dermatology at the forefront of medicine.

Aaron R. Mangold, MD

also in this issue - department of dermatology...2 fall 2016 dermatology foundation expert faculty...

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