Publications by authors named "Kyu Han Kim"

133 Publications

Importance of extracutaneous organ involvement in determining the clinical severity and prognosis of incontinentia pigmenti caused by mutations in the IKBKG gene.

Exp Dermatol 2021 Mar 2. Epub 2021 Mar 2.

Department of Pediatrics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Incontinentia pigmenti (IP) is a rare X-linked skin disease caused by mutations in the IKBKG gene, which is required for activation of the nuclear factor-kappa B signalling pathway. Multiple systems can be affected with highly variable phenotypic expressivity. We aimed to clarify the clinical characteristics observed in molecularly confirmed Korean IP patients. The medical records of 25 females confirmed as IP by molecular genetic analysis were retrospectively reviewed. The phenotypic score of extracutaneous manifestations was calculated to assess the disease severity. The IKBKG gene partial deletion or intragenic mutations were investigated using long-range PCR, multiplex ligation-dependent probe amplification and direct sequencing methods. Among the 25 individuals, 18 (72%) were sporadic cases. All patients showed typical skin manifestations at birth or during the neonatal period. Extracutaneous findings were noted in 17 (68%) patients; ocular manifestations (28%), neurological abnormalities (28%), hair abnormalities (20%), dental anomalies (12%), nail dystrophy (8%). The common exon 4-10 IKBKG deletion was observed in 20 (80%) patients. In addition, five intragenic sequence variants were identified, including three novel variants. The phenotype scores were highly variable, ranging from abnormal skin pigmentation only to one or more extracutaneous features, although no significant difference was observed for each clinical characteristic between the group with sequence variants and that with common large deletion. Our cohort with IP showed heterogeneity of extracutaneous manifestations and high incidence of sporadic cases. Long-term monitoring with multidisciplinary management is essential for evaluating the clinical status, providing adequate genetic counselling and understanding the genotype-phenotype correlation in IP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.14313DOI Listing
March 2021

"Two-Cell Assemblage" Assay: A Simple Method for Screening Hair Growth-Promoting Compounds.

Front Cell Dev Biol 2020 24;8:581528. Epub 2020 Nov 24.

Laboratory of Cutaneous Aging and Hair Research, Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea.

Alopecia arises due to inadequate hair follicle (HF) stem cell activation or proliferation, resulting in prolongation of the telogen phase of the hair cycle. Increasing therapeutic and cosmetic demand for alleviating alopecia has driven research toward the discovery or synthesis of novel compounds that can promote hair growth by inducing HF stem cell activation or proliferation and initiating the anagen phase. Although several methods for evaluating the hair growth-promoting effects of candidate compounds are being used, most of these methods are difficult to use for large scale simultaneous screening of various compounds. Herein, we introduce a simple and reliable assay for the simultaneous screening of the hair growth-promoting effects of candidate compounds on a large scale. In this study, we first established a 3D co-culture system of human dermal papilla (hDP) cells and human outer root sheath (hORS) cells in an ultra-low attachment 96-well plate, where the two cell types constituted a polar elongated structure, named "two-cell assemblage (TCA)." We observed that the long axis length of the TCA gradually increased for 5 days, maintaining biological functional integrity as reflected by the increased expression levels of hair growth-associated genes after treatment with hair growth-promoting molecules. Interestingly, the elongation of the TCA was more prominent following treatment with the hair growth-promoting molecules (which occurred in a dose-dependent manner), compared to the control group ( < 0.05). Accordingly, we set the long axis length of the TCA as an endpoint of this assay, using a micro confocal high-content imaging system to measure the length, which can provide reproducible and reliable results in an adequate timescale. The advantages of this assay are: (i) it is physiologically and practically advantageous as it uses 3D cultured two-type human cells which are easily available; (ii) it is simple as it uses length as the only endpoint; and (iii) it is a high throughput system, which screens various compounds simultaneously. In conclusion, the "TCA" assay could serve as an easy and reliable method to validate the hair growth-promoting effect of a large volume of library molecules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2020.581528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732514PMC
November 2020

Treatment of pediatric periorificial dermatitis with topical calcineurin inhibitor and topical/oral metronidazole.

J Dermatol 2021 Mar 4;48(3):405-407. Epub 2020 Dec 4.

Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.

Pediatric periorificial dermatitis is a papulopustular eruption found around the facial orifices in children. Although the treatment of the disease has been largely anecdotal and experience-based, studies have shown that topical calcineurin inhibitors, as well as other topical and oral antibiotics, such as metronidazole, can be effective treatment options. However, most of the studies with a sizable number of patients have been based on the Caucasian population. Herein, we evaluated the clinical efficacy of topical calcineurin inhibitors and topical/oral metronidazole in 24 Korean patients with pediatric periorificial dermatitis. The majority of the patients showed a complete response to treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15695DOI Listing
March 2021

Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis- and psoriasis-associated genes.

J Allergy Clin Immunol 2020 Oct 16. Epub 2020 Oct 16.

Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Background: Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear.

Objective: We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate.

Methods: We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies.

Results: We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis.

Conclusions: Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2020.09.035DOI Listing
October 2020

Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation.

Int J Mol Sci 2020 Sep 28;21(19). Epub 2020 Sep 28.

Department of Life Science, Sogang University, Seoul 04107, Korea.

Caffeic acid (CA) is produced from a variety of plants and has diverse biological functions, including anti-inflammation activity. It has been recently demonstrated that caffeoyl-prolyl-histidine amide (CA-PH), which is CA conjugated with proline-histidine dipeptide, relieves atopic dermatitis (AD)-like phenotypes in mouse. In this study, we investigated the molecular mechanism underlying CA-PH-mediated alleviation of AD-like phenotypes using cell line and AD mouse models. We confirmed that CA-PH suppresses AD-like phenotypes, such as increased epidermal thickening, infiltration of mast cells, and dysregulated gene expression of cytokines. CA-PH suppressed up-regulation of cytokine expression through inhibition of nuclear translocation of NF-κB. Using a CA-PH affinity pull-down assay, we found that CA-PH binds to Fyn. In silico molecular docking and enzyme kinetic studies revealed that CA-PH binds to the ATP binding site and inhibits Fyn competitively with ATP. CA-PH further suppressed spleen tyrosine kinase (SYK)/inhibitor of nuclear factor kappa B kinase (IKK)/inhibitor of nuclear factor kappa B (IκB) signaling, which is required for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. In addition, chronic application of CA-PH, in contrast with that of glucocorticoids, did not induce up-regulation of regulated in development and DNA damage response 1 (REDD1), reduction of mammalian target of rapamycin (mTOR) signaling, or skin atrophy. Thus, our study suggests that CA-PH treatment may help to reduce skin inflammation via down-regulation of NF-κB activation, and Fyn may be a new therapeutic target of inflammatory skin diseases, such as AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21197160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582254PMC
September 2020

Infection, antibiotic exposure and development of atopic dermatitis: A nationwide case-control study.

J Dermatol 2020 Jul 22;47(7):707-713. Epub 2020 May 22.

Laboratory of Cutaneous Aging and Hair Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.

Previous studies suggest an association between atopic dermatitis (AD) and exposure to microorganisms and antibiotics. However, these studies have limitations, and the sole influence on the development of AD was elusive. We performed a nationwide population-based case-control study in a Korean population to investigate the association between AD and early-life infection or antibiotic exposure. A total of 244 805 children with AD from the 2 283 601 children born between January 2010 and December 2014 and an equal number of sex- and age-matched healthy children were enrolled. A conditional logistic regression analysis showed that the episode of infection and antibiotic exposure were associated with an increased risk of AD (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.58-1.63 for infection; and OR, 1.11; 95% CI, 1.09-1.13 for antibiotic exposure). A dose-dependent relationship was observed between risk for AD, the number of infection episodes and antibiotic cycles and the duration of antibiotic exposure. On further analysis using a conditional logistic model, the risk of AD was less when the antibiotics were used during the infection episode than that without the use of antibiotics, especially if the duration of the infection was short. Although our study could not consider the effect of cause or severity of infection, class of antibiotics and genetic or environmental factors of enrolled subjects, our results suggested that infection and antibiotic exposure were associated with an increased risk of AD. In addition, the results also implied that the use of antibiotics during an infection episode can decrease the risk of AD induced by the infection and that appropriate management of infections can minimize the risk of AD induced by infection or antibiotics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15387DOI Listing
July 2020

Caffeoyl-Pro-His amide relieve DNCB-Induced Atopic Dermatitis-Like phenotypes in BALB/c mice.

Sci Rep 2020 05 21;10(1):8417. Epub 2020 May 21.

Laboratory of Cutaneous Aging and Hair Research, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.

The main factors involved in the pathogenesis of atopic dermatitis (AD) are skin barrier abnormality, allergy/immunology, and pruritus. Considering how oxidative stress influences these factors, antioxidant agents may be effective candidates in the treatment of AD. To evaluate the effect of Caffeoyl-Pro-His amide (CA-PH), an antioxidant agent, on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like phenotypes in BALB/c mice. Topical sensitization and challenge by DNCB were performed on the dorsal skin of BALB/c mice to induce AD-like cutaneous lesions, phenotypes, and immunologic response. CA-PH was applied topically for 2 weeks to assess its effects on DNCB-induced AD-like phenotypes. As a result, CA-PH relieved DNCB-induced AD-like phenotypes quantified by dermatitis severity score, scratching duration, and trans-epidermal water loss. Histopathological analysis showed that CA-PH decreased epidermal thickening, the number of mast cells, and eosinophil infiltration in dermis. Immunohistochemical staining revealed that CA-PH recovered skin barrier-related proteins: filaggrin, involucrin, and loricrin. As for the immunologic aspects, CA-PH treatment lowered mRNA or protein levels of interleukin (IL)-4, IL-6, IL-17a, IL-1b, IL-31, and IL-33 levels and thymic stromal lymphopoietin (TSLP) levels in cutaneous tissue, reducing the DNCB-induced serum IgE level elevation. In conclusion, topical CA-PH may be a therapeutic option for the treatment of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-65502-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242424PMC
May 2020

110-year history of dermatology at the Seoul National University Hospital: prosperity through international cooperation.

Int J Dermatol 2020 Apr 20;59(4):e112-e114. Epub 2020 Jan 20.

Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ijd.14784DOI Listing
April 2020

Association of frequent intake of fast foods, energy drinks, or convenience food with atopic dermatitis in adolescents.

Eur J Nutr 2020 Oct 10;59(7):3171-3182. Epub 2019 Dec 10.

Department of Dermatology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Purpose: Specific food consumption, besides food allergy, may aggravate atopic dermatitis (AD). However, previous reports on the association between AD and food intake in adolescents are scarce. The aim of this study was to determine the relationship between AD and specific food consumption frequency in adolescents.

Methods: A cross-sectional analysis using data from the Korea Youth Risk Behavior Web-based Survey 2017 was performed. The frequency of food consumption in the recent-diagnosed AD group (AD diagnosed within 12 months) compared to those in the previous-diagnosed AD (AD diagnosed more than 12 months ago) or control group were investigated.

Results: A total of 53,373 participants were eligible for this study. The weighted prevalence of the recent-diagnosed AD and the previous-diagnosed AD was 7.39% and 18.00%, respectively. When compared with subjects with the previous-diagnosed AD, those with the recent-diagnosed AD were significantly more likely to frequently consume fast foods (odds ratio OR 1.405; 95% CI 1.150-1.717), energy drinks (OR 1.457; 95% CI 1.175-1.807), or convenience food (OR 1.304; 95% CI 1.138-1.495). Patients of the recent-diagnosed AD were significantly more likely to frequently consume fast foods (OR 1.374; 95% CI 1.155-1.634) than the control group. The differences in the frequency of specific food consumption among groups were more pronounced in high school students than in middle school students.

Conclusions: Frequent intake of fast foods, energy drinks, and convenience food was related to the recent-diagnosed AD in adolescents. Prospective cohort and interventional studies are needed to identify causal relationships.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00394-019-02157-4DOI Listing
October 2020

Penta-O-galloyl-β-D-glucose from Paeonia lactiflora Pall. root extract enhances the expression of skin barrier genes via EGR3.

J Ethnopharmacol 2020 Feb 23;248:112337. Epub 2019 Oct 23.

Basic Research & Innovation Division, R&D Unit, AmorePacific Corporation, Yongin-si, Gyeonggi-do, 446-729, South Korea.

Ethnopharmacoligical Relevance: Paeonia lactiflora Pall. has long been used to treat inflammatory skin diseases, such as psoriasis.

Aim Of The Study: The skin acts as a barrier and provides protection against various stresses by expressing skin barrier genes during keratinocyte differentiation. However, the effect of Paeonia lactiflora Pall. root extract on the expression of skin barrier genes has not been investigated. Here, we aimed to show that treatment of keratinocytes with Paeonia lactiflora Pall. root can upregulate genes related to keratinocyte differentiation.

Materials And Methods: To determine the effect Paeonia lactiflora Pall. root extract, RNA-Seq, gene ontology, and gene set enrichment analysis were performed. Reverse transcriptase quantitative polymerase chain reaction analysis was performed to confirm the increased expression of skin barrier genes.

Results: Treatment with Paeonia lactiflora Pall. root enhanced the expression of skin barrier genes, including the filaggrin, loricrin, and involucrin. Moreover, we found that penta-O-galloyl-β-D-glucose (PGG), one of the ingredients in Paeonia lactiflora Pall. root, enhanced the expression of skin barrier genes, by upregulating the expression of the transcription factor EGR3.

Conclusions: PGG and Paeonia lactiflora Pall. root extract have therapeutic potential for the treatment of diseases related to skin barrier disruption and can be used in cosmetics to enhance skin barrier function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jep.2019.112337DOI Listing
February 2020

IL-17A-Producing Innate Lymphoid Cells Promote Skin Inflammation by Inducing IL-33-Driven Type 2 Immune Responses.

J Invest Dermatol 2020 04 16;140(4):827-837.e9. Epub 2019 Oct 16.

Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea. Electronic address:

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease characterized by type 2 cytokines secreted by T helper type 2 cells and group 2 innate lymphoid cells. Despite a high degree of heterogeneity, AD is still explained by type 2 immunity, and the role of IL-17A, which is increased in acute, pediatric, or Asian patients with AD, remains poorly understood. Here, we aimed to investigate the role of IL-17A-producing group 3 innate lymphoid cells (ILC3s), which are unexplored immune cells, in the pathogenesis of AD. We found that the numbers of ILC3s in the skin of AD-induced mice were increased, and that neutralizing IL-17A delayed development of AD. Moreover, adoptive transfer of ILC3s accelerated the symptoms of AD. Mechanically, ILC3s induced IL-33 production by nonimmune skin cells, keratinocytes, and fibroblasts, which promoted type 2 immune responses. Because AD has a complex pathophysiology and a broad spectrum of clinical phenotypes, the presence of ILC3s in the skin and their interaction with nonimmune skin cells could explain the pathogenesis of cutaneous AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2019.08.447DOI Listing
April 2020

Priming mobilization of hair follicle stem cells triggers permanent loss of regeneration after alkylating chemotherapy.

Nat Commun 2019 08 27;10(1):3694. Epub 2019 Aug 27.

Department of Dermatology, Seoul National University College of Medicine, Seoul, 03080, Korea.

The maintenance of genetic integrity is critical for stem cells to ensure homeostasis and regeneration. Little is known about how adult stem cells respond to irreversible DNA damage, resulting in loss of regeneration in humans. Here, we establish a permanent regeneration loss model using cycling human hair follicles treated with alkylating agents: busulfan followed by cyclophosphamide. We uncover the underlying mechanisms by which hair follicle stem cells (HFSCs) lose their pool. In contrast to immediate destructive changes in rapidly proliferating hair matrix cells, quiescent HFSCs show unexpected massive proliferation after busulfan and then undergo large-scale apoptosis following cyclophosphamide. HFSC proliferation is activated through PI3K/Akt pathway, and depletion is driven by p53/p38-induced cell death. RNA-seq analysis shows that HFSCs experience mitotic catastrophe with G2/M checkpoint activation. Our findings indicate that priming mobilization causes stem cells to lose their resistance to DNA damage, resulting in permanent loss of regeneration after alkylating chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11665-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711970PMC
August 2019

Evaluating hair growth promoting effects of candidate substance: A review of research methods.

J Dermatol Sci 2019 Mar 12;93(3):144-149. Epub 2019 Mar 12.

Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea; Laboratory of Cutaneous Aging and Hair Research, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Androgenetic alopecia (AGA) is the most common form of hair loss disorder. As the prevalence of AGA rises, the demand for AGA treatments is rising accordingly, prompting research to identify therapeutic candidates to treat AGA. Because AGA is caused by crosstalk among multiple hair follicle (HF) cell components, understanding the effects of candidate molecules on HF cells is essential to determining therapeutic candidates for treatment. To date, research has centered on HF dermal papilla and outer root sheath cells and has indicated that the hair growth effects of candidate substances may be mediated via alterations in several signaling pathways and signature genes in these HF cells. In more integrative evaluations, the HF unit is used as an ex vivo organ culture model to verify the effects of therapeutic candidates. Animal models have also been used to evaluate the effects of candidate substances. The main outcomes used to evaluate the effects of candidate substances are 1) changes in HF growth rates in vitro, 2) anagen induction capabilities, and 3) the effects of androgen modulation. This article reviews a series of methods used to evaluate the hair growth-promoting effects of candidate substances, providing an overview of cell assays, organs, and animal models used in AGA research in order to facilitate AGA research moving forward.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jdermsci.2019.02.004DOI Listing
March 2019

Skin equivalent assay: An optimized method for testing for hair growth reconstitution capacity of epidermal and dermal cells.

Exp Dermatol 2019 04 13;28(4):367-373. Epub 2019 Mar 13.

Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.

Hair follicle reconstitution requires highly organized epithelial-mesenchymal interactions. Skin equivalents containing the epidermal and dermal cells with hair reconstitution capacity can reproduce these processes, but have not been established. This study was conducted to develop a hair follicle-producing three-dimensional (3D) skin equivalent assay using neonate mouse epidermal and dermal cells. A skin equivalent comprised of mouse dermal cells (MDCs) embedded in type I collagen and overlaid with mouse epidermal cells (MECs) was used. MDCs were mixed with type I collagen and cultured for 7 days. One day after adding MECs on top, the composites were grafted onto nude mice. MDCs cultured on a two-dimensional (2D) plate for 7 days and mixed with MECs as a negative control, and freshly isolated MDCs and MECs mixture (chamber assay) as a positive control were also grafted. Six weeks after grafting, regenerated hair follicles were analysed. Our 3D skin equivalent culture assay reproducibly regenerated hair follicles, while MDCs precultured in the 2D model with MECs did not. Compared to the chamber assay, which produced randomly oriented hair follicles, nearly all regenerated hair follicles in our assay extruded through the skin and numerous regenerated hair follicles were higher than those in the chamber assay. Several representative genes associated with hair induction showed higher expression in our assay than in the 2D model. When Wnt3a was added, the number of regenerated hairs increased. Organized hair follicle regeneration was accomplished using our assay. This approach can be applied to assess a test agent with hair growth-promoting effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.13897DOI Listing
April 2019

UVB-induced depletion of donor-derived dendritic cells prevents allograft rejection of immune-privileged hair follicles in humanized mice.

Am J Transplant 2019 05 28;19(5):1344-1355. Epub 2018 Dec 28.

Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.

Dendritic cells (DCs) are key targets for immunity and tolerance induction; they present donor antigens to recipient T cells by donor- and recipient-derived pathways. Donor-derived DCs, which are critical during the acute posttransplant period, can be depleted in graft tissue by forced migration via ultraviolet B light (UVB) irradiation. Here, we investigated the tolerogenic potential of donor-derived DC depletion through in vivo and ex vivo UVB preirradiation (UV) combined with the injection of anti-CD154 antibody (Ab) into recipients in an MHC-mismatched hair follicle (HF) allograft model in humanized mice. Surprisingly, human HF allografts achieved long-term survival with newly growing pigmented hair shafts in both Ab-treated groups (Ab-only and UV plus Ab) and in the UV-only group, whereas the control mice rejected all HF allografts with no hair regrowth. Perifollicular human CD3 T cell and MHC class II cell infiltration was significantly diminished in the presence of UV and/or Ab treatment. HF allografts in the UV-only group showed stable maintenance of the immune privilege in the HF epithelium without evidence of antigen-specific T cell tolerance, which is likely promoted by normal HFs in vivo. This immunomodulatory strategy targeting the donor tissue exhibited novel biological relevance for clinical allogeneic transplantation without generalized immunosuppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.15207DOI Listing
May 2019

EGR3 Is a Late Epidermal Differentiation Regulator that Establishes the Skin-Specific Gene Network.

J Invest Dermatol 2019 03 18;139(3):615-625. Epub 2018 Oct 18.

Basic Research and Innovation Division, Research and Development Unit, AmorePacific Corporation, Yongin-si, Gyeonggi-do, Korea. Electronic address:

Late epidermal differentiation is a key step of skin barrier formation; however, the specific genetic factors that distinguish late differentiation from early differentiation remain unknown. Here, we demonstrated that EGR3 is highly expressed in the stratum granulosum, and that it contributes to late epidermal differentiation. However, its expression is lost under poorly differentiated conditions, such as parakeratosis-lesional skin. EGR3 mediated the regulation of genes located in the epidermal differentiation complex through activation of enhancers and induction of enhancer RNAs. We further identified 20 targets of EGR3 specific for late differentiation. Additionally, we discovered that EGR3- and EGR3-related genes exhibited high tissue specificity on the skin. Through weighted gene co-expression analysis, EGR3 was found to be related to the keratinocyte differentiation-related module as an important part of the skin-specific genetic network. These findings shed light on the transcriptional regulation of late epidermal differentiation, highlighting candidate targets for diseases related to disrupted differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2018.09.019DOI Listing
March 2019

Pyruvate Protects against Cellular Senescence through the Control of Mitochondrial and Lysosomal Function in Dermal Fibroblasts.

J Invest Dermatol 2018 12 28;138(12):2522-2530. Epub 2018 Jun 28.

Basic Research & Innovation Division, Amorepacific Corporation R&D Center, Yongin-si, Gyeonggi-do, Republic of Korea. Electronic address:

Mitochondrial dysfunction can drive cellular senescence, which is accompanied by changes in metabolism and increases in senescence-associated secretory phenotypes. Although pyruvate, a key metabolite for numerous aspects of metabolism, has been used as general supplement in synthetic media, the physiological function of pyruvate underlying its protective role against cellular senescence under normal conditions has remained unknown. Here, we show that extracellular pyruvate prevents senescence in normal human dermal fibroblasts through increasing the generation of oxidized nicotinamide adenine dinucleotide (NAD) during the conversion to lactate. Acetylated peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), vacuolar-type H-ATPaseV0A1 (v-ATPaseV0A1), NF-κB p65 subunit (RelA), and histone H3 accumulate under pyruvate deprivation conditions, resulting in the onset of senescence in normal human dermal fibroblasts through the accumulation of abnormal mitochondria generated by lysosomal inactivation-induced mitophagy defects, and through an increase in senescence-associated secretory phenotypes. Furthermore, pyruvate showed a protective effect against aging phenotypes in skin equivalents, which consist of a dermis and epidermis that act similarly to in vivo skin tissues. Our findings reveal a connection between pyruvate and mitochondrial dysfunction in the progression of senescence that is, to our knowledge, previously unreported. These results suggest that the pyruvate deprivation-induced senescence model can be used to study the connection between metabolism and senescence under normal conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2018.05.033DOI Listing
December 2018

Morgellons Disease: a Manifestation of Psychiatric Disorder.

Ann Dermatol 2018 Jun 23;30(3):362-363. Epub 2018 Apr 23.

Department of Dermatology, Seoul National University College of Medicine, Institute of Human-Environment Interface Biology, Seoul National University Medical Research Center, Laboratory of Cutaneous Aging and Hair Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5021/ad.2018.30.3.362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929959PMC
June 2018

TNFSF14 inhibits melanogenesis via NF-kB signaling in melanocytes.

Cytokine 2018 10 3;110:126-130. Epub 2018 May 3.

Basic Research & Innovation Division, R&D Unit, AmorePacific Corporation, Yongin-si, Gyeonggi-do 446-729, Republic of Korea. Electronic address:

Melanin synthesis in melanocytes is affected by various cytokines. Here, we reported for the first time that tumor necrosis factor superfamily member 14 (TNFSF14) inhibits melanogenesis in the primary culture of human epidermal melanocytes. TNFSF14 is known to bind to its receptors herpes virus entry mediator (HVEM) and lymphotoxin β receptor (LTβR) for signal transduction, but TNFSF14-induced hypopigmentation was independent of HVEM and LTβR in melanocytes. To explore signaling in melanocytes treated with TNFSF14, we performed RNA-seq and found that nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling is activated by TNFSF14. Further, we observed that inhibition of NF-kB effectively blocks the hypopigmentation induced by TNFSF14. We conclude that TNFSF14 inhibits melanogenesis in melanocytes via NF-κB signaling and could be applied in the treatment of cutaneous pigment disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cyto.2018.04.034DOI Listing
October 2018

The effect of cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, on human hair growth with the dual promoting mechanisms.

J Dermatol Sci 2018 Jul 11;91(1):60-68. Epub 2018 Apr 11.

Laboratory of Cutaneous Aging and Hair Research, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Institute of Human Environment Interface Biology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: Cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, increases the intracellular level of cyclic adenosine monophosphate to cause vasodilation. Topical application of cilostazol is reported to improve local blood flow and enhance wound healing; however, its effect on human hair follicles is unknown.

Objective: The purpose of this study was to determine the effect of cilostazol on hair growth.

Methods: We investigated the expression of PDE3 in human dermal papilla cells (DPCs), outer root sheath cells (ORSCs), and hair follicles. The effects of cilostazol on DPC and ORSC proliferation were evaluated using BrdU and WST-1 assays. The expression of various growth factors in DPCs was investigated by growth factor antibody array. Additionally, hair shaft elongation was measured using ex vivo hair follicle organ cultures, and anagen induction was evaluated in C57BL/6 mice. Finally, the effects of cilostazol on vessel formation and activation of the mitogen-activated protein kinase pathway were evaluated.

Results: We confirmed high mRNA and protein expression of PDE3 in human DPCs. Cilostazol not only enhanced the proliferation of human DPCs but also regulated the secretion of several growth factors responsible for hair growth. Furthermore, it promoted hair shaft elongation ex vivo, with increased proliferation of matrix keratinocytes. Cilostazol also accelerated anagen induction by stimulating vessel formation and upregulating the levels of phosphorylated extracellular signal-regulated kinase, c-Jun N-terminal kinase, and P38 after its topical application in C57BL/6 mice.

Conclusion: Our results show that cilostazol promotes hair growth and may serve as a therapeutic agent for the treatment of alopecia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jdermsci.2018.04.005DOI Listing
July 2018

The Prevalence and Risk Factors of Atopic Dermatitis and Clinical Characteristics according to Disease Onset in 19-Year-Old Korean Male Subjects.

Ann Dermatol 2018 Feb 26;30(1):20-28. Epub 2017 Dec 26.

Department of Dermatology, Seoul National University College of Medicine and Institute of Human-Environment Interface Biology, Seoul National University Medical Research Center, Laboratory of Cutaneous Aging and Hair Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.

Background: The natural course of atopic dermatitis (AD) in infancy, childhood, and adolescence is not yet completely known.

Objective: To investigate the prevalence and risk factors of atopic dermatits among 19-year-old Korean male subjects.

Methods: All 19-year-old Korean males must undergo medical examination for conscription. We precisely evaluated the prevalence of AD in three Korean provinces using the information from this physical checkup. AD was diagnosed by experienced dermatologists according to the Hanifin and Rajka criteria. The disease severity was assessed by the scoring of atopic dermatitis (SCORAD) index. In order to investigate the risk factors for AD, a questionnaire was administered to all subjects regarding parental atopic history, geographical characteristics of past habitation, past economic status, number of siblings, parental occupation, etc.

Results: The point prevalence in the Korean provinces ranged from 1.15% to 1.44%. In multivariable analysis, a parental history of AD was a significant risk factor in all 3 disease-onset groups (infancy, childhood, and adolescent onset). In the infancy-onset group, low economic status was also a significant risk factor for AD. The SCORAD index was significantly higher in AD subjects with early onset and those living in small-sized habitations. Moreover, erythema, edema, lichenification, dryness of skin, and sleep loss appeared to be more severe in early-onset cases.

Conclusion: The younger the age of disease onset, the more severe the clinical outcomes in 19-year-old male subjects. In addition, active AD treatment at younger ages might affect the prevalence and the severity of AD in adulthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5021/ad.2018.30.1.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762472PMC
February 2018

Hydrogen peroxide (HO) suppresses hair growth through downregulation of β-catenin.

J Dermatol Sci 2018 Jan 27;89(1):91-94. Epub 2017 Sep 27.

Department of Dermatology, College of Medicine, Seoul National University, Seoul, Republic of Korea, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea; Laboratory of Cutaneous Aging and Hair Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jdermsci.2017.09.003DOI Listing
January 2018

Epidermal long non-coding RNAs are regulated by ultraviolet irradiation.

Gene 2017 Dec 21;637:196-202. Epub 2017 Sep 21.

Basic Research & Innovation Division, R&D Unit, AmorePacific Corporation, Yongin-si, Gyeonggi-do 446-729, Republic of Korea. Electronic address:

Ultraviolet (UV) radiation causes the harmful effects on skin by the photochemical reaction and gene expression regulation. Recent evidences have shown that long non-coding RNAs (lncRNAs) play critical roles in a diverse range of biological functions. However, research on the effects of UV irradiation on lncRNA expression in epidermal cells is limited. The aim of this study was to identify changes in the expression profile of lncRNAs after UVB irradiation. To accomplish this, we performed a microarray analysis of both mRNA and lncRNA expression levels in irradiated skin cells. Gene ontology (GO) analysis of differentially expressed mRNAs showed that the expression of immune response- and cell membrane-related genes was up-regulated, while cell-cell adhesion-associated genes were down-regulated by UVB irradiation. Moreover, we found that lncRNAs up-regulated by UVB irradiation were associated with the regulation of gene transcription, while lncRNAs down-regulated by UVB irradiation were associated with tumorigenesis. Finally, we compiled a list of the lncRNAs that showed the strongest association with the development of non-melanoma skin cancers caused by UV exposure. These findings lay a foundation for future investigations into the expression patterns of lncRNAs with roles in the response to UV irradiation and in non-melanoma skin cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2017.09.043DOI Listing
December 2017

The Basic Mechanism of Hair Growth Stimulation by Adipose-derived Stem Cells and Their Secretory Factors.

Curr Stem Cell Res Ther 2017 ;12(7):535-543

Department of Dermatology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744. Korea.

Background: Adipose-derived stem cells (ADSCs) are mesenchymal stem cells (MSCs) within the stromal vascular fraction of subcutaneous adipose tissue. ADSCs secrete growth factors and other proteins, and have been used to regenerate skin with satisfactory results.

Objective: This review focuses on the effect of ADSCs and their secretory factors on the stimulation of hair growth in vitro, ex vivo and in vivo.

Results: The conditioned media of ADSCs (ADSC-CM) increases the proliferation rate of human follicular cells. ADSCs-derived proteins improve hair growth and protect human dermal papilla cells against cytotoxic injury caused by androgen and reactive oxygen species. Moreover, ADSC-CM induces the anagen phase and promotes hair growth in mice, and enhances the elongation of hair shafts in ex vivo human hair organ cultures.

Conclusion: ADSC-CM promotes hair growth in vitro, ex vivo, and in vivo. Given that ADSCs are one of the most accessible sources of MSCs, ADSC-derived proteins may be feasible clinical therapeutic agents for the treatment of hair loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1574888X12666170829161058DOI Listing
September 2018

SH3BP4, a novel pigmentation gene, is inversely regulated by miR-125b and MITF.

Exp Mol Med 2017 08 18;49(8):e367. Epub 2017 Aug 18.

Basic Research &Innovation Division, R&D Unit, AmorePacific Corporation, Gyeonggi-do, Korea.

Our previous work has identified miR-125b as a negative regulator of melanogenesis. However, the specific melanogenesis-related genes targeted by this miRNA had not been identified. In this study, we established a screening strategy involving three consecutive analytical approaches-analysis of target genes of miR-125b, expression correlation analysis between each target gene and representative pigmentary genes, and functional analysis of candidate genes related to melanogenesis-to discover melanogenesis-related genes targeted by miR-125b. Through these analyses, we identified SRC homology 3 domain-binding protein 4 (SH3BP4) as a novel pigmentation gene. In addition, by combining bioinformatics analysis and experimental validation, we demonstrated that SH3BP4 is a direct target of miR-125b. Finally, we found that SH3BP4 is transcriptionally regulated by microphthalmia-associated transcription factor as its direct target. These findings provide important insights into the roles of miRNAs and their targets in melanogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/emm.2017.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579509PMC
August 2017

Comparison of Efficacy and Safety Between Propranolol and Steroid for Infantile Hemangioma: A Randomized Clinical Trial.

JAMA Dermatol 2017 06;153(6):529-536

Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea.

Importance: There are limited data from randomized clinical trials comparing propranolol and steroid medication for treatment of infantile hemangioma (IH).

Objective: To determine the efficacy and safety of propranolol compared with steroid as a first-line treatment for IH.

Design, Setting, And Participants: This randomized clinical noninferiority trial tested the efficacy and safety of propranolol vs steroid treatment for IH at a single academic hospital. All participants were diagnosed with IH between June 2013 and October 2014, had normal heart function, and had not been previously treated for IH.

Interventions: The participants were randomly assigned to either the propranolol group or the steroid group. In the propranolol group, the patients were admitted, observed for adverse effects for 3 days after treatment initiation, and then released and treated as outpatients for 16 weeks (2 mg/kg/d). In the steroid group, the patients were seen as outpatients from the beginning and were also treated for 16 weeks (2 mg/kg/d).

Main Outcomes And Measures: The primary efficacy variable was the response to treatment at 16 weeks, which was evaluated by the hemangioma volume using magnetic resonance imaging before and at 16 weeks after treatment initiation. While comparing the effect of medication between the groups, we monitored the adverse effects of both drugs.

Results: A total of 34 patients (15 boys, 19 girls; mean age, 3.3 months; range, 0.3-8.2 months) were randomized to receive either propranolol or steroid treatment (17 in each treatment group). Guardians for 2 patients in the steroid group withdrew their consent, and 1 patient in the propranolol group did not complete the efficacy test. The intention-to-treat analysis, applying multiple imputations, found the treatment response rate in the propranolol group to be 95.65%, and that of the steroid group was 91.94%. Because the difference in response rate between the groups was 3.71%, propranolol was considered noninferior. We found that there was no difference between the groups in safety outcomes.

Conclusions And Relevance: Our trial demonstrated that propranolol was not inferior to steroid with respect to therapeutic effects in IH.

Trial Registration: clinicaltrials.gov Identifier: NCT01908972.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamadermatol.2017.0250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817616PMC
June 2017

Morgellons Disease.

Ann Dermatol 2017 Apr 24;29(2):223-225. Epub 2017 Mar 24.

Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.

Morgellons disease is a rare disease with unknown etiology. Herein, we report the first case of Morgellons disease in Korea. A 30-year-old woman presented with a 2-month history of pruritic erythematous patches and erosions on the arms, hands, and chin. She insisted that she had fiber-like materials under her skin, which she had observed through a magnifying device. We performed skin biopsy, and observed a fiber extruding from the dermal side of the specimen. Histopathological examination showed only mild lymphocytic infiltration, and failed to reveal evidence of any microorganism. The polymerase chain reaction for was negative in her serum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5021/ad.2017.29.2.223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383751PMC
April 2017

Dermoscopy of giant juvenile xanthogranuloma.

J Am Acad Dermatol 2017 Feb;76(2S1):S76-S78

Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2016.09.011DOI Listing
February 2017

Galanin contributes to ultraviolet irradiation-induced inflammation in human skin.

Exp Dermatol 2017 08 23;26(8):744-747. Epub 2017 Mar 23.

Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.

Exposure of the skin to ultraviolet (UV) irradiation causes various consequences such as inflammation and photoageing. Galanin is an active neuropeptide expressed widely in the central nervous system and peripheral tissues including the skin. Galanin promotes or inhibits inflammation in a context-dependent manner, but its role in UV irradiation-induced responses in human skin was still unknown. UV irradiation induced a substantial expression of galanin in primary epidermal keratinocytes in vitro and in human epidermis in vivo. Galanin knock-down by siRNA transfection markedly inhibited UV irradiation-induced expression of matrix metalloproteinase (MMP)-1, interleukin (IL)-1β, IL-6 and cyclooxygenase (COX)-2. Moreover, siRNA-mediated knock-down of GAL , a principal galanin receptor in the skin, led to a considerable decrease in these mediators in keratinocytes. Collectively, our findings suggest that galanin is an important messenger between the neuroendocrine system and UV irradiation-damaged skin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.13268DOI Listing
August 2017

Acute Stress-Induced Changes in Follicular Dermal Papilla Cells and Mobilization of Mast Cells: Implications for Hair Growth.

Ann Dermatol 2016 Oct 30;28(5):600-606. Epub 2016 Sep 30.

Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.; Laboratory of Cutaneous Aging and Hair Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.

Background: Stress is a known cause of hair loss in many species.

Objective: In this study, we investigated the role of acute stress on hair growth using a rat model.

Methods: Rats were immobilized for 24 hours and blood samples, and skin biopsies were taken. The effect of stress-serum on the proliferation of rat and human dermal papilla cells (hDPCs), as well as serum cortisol and corticotropin-releasing hormone levels, were measured. Mast cell staining was performed on the biopsied tissue. In addition, Western blot and quantitative real time polymerase chain reaction were used to assess mast cell tryptase and cytokine expression, respectively in rat skin biopsies.

Results: Stress-serum treatment reduced significantly the number of viable hDPCs and arrested the cell cycle in the G1 phase, compared to serum from unrestrained rats (<0.05, respectively). Moreover, restrained rats had significantly higher levels of cortisol in serum than unrestrained rats (<0.01). Acute stress serum increased mast cell numbers and mast cell tryptase expression, as well as inducing interleukin (IL)-6 and IL-1β up-regulation.

Conclusion: These results suggest that acute stress also has an inhibitory effect on hair growth via cortisol release in addition to substance P-mast cell pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5021/ad.2016.28.5.600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064190PMC
October 2016