Publications by authors named "Chang-Deok Kim"

138 Publications

Quercitrin Stimulates Hair Growth with Enhanced Expression of Growth Factors via Activation of MAPK/CREB Signaling Pathway.

Molecules 2020 Sep 2;25(17). Epub 2020 Sep 2.

LG Household & Health Care (LG H&H) R&D Center, 70, Magokjoongang 10-ro, Gangseo-gu, Seoul 07795, Korea.

The present study aimed to investigate the molecular mechanism of quercitrin, a major constituent of extract, for its hair growth stimulating activities in cultured human dermal papilla cells (hDPCs). Quercitrin enhanced the cell viability and cellular energy metabolism in cultured hDPCs by stimulating the production of NAD(P)H and mitochondrial membrane potential (ΔΨ). The expression of Bcl2, an essential marker for anagen hair follicle and cell survival, was increased by quercitrin treatment. Quercitrin also increased the cell proliferation marker Ki67. The expression of growth factors-such as bFGF, KGF, PDGF-AA, and VEGF-were increased by quercitrin both in mRNA and protein levels. In addition, quercitrin was found to increase the phosphorylation of Akt, Erk, and CREB in cultured hDPCs, while inhibitors of MAPKs reversed the effects of quercitrin. Finally, quercitrin stimulated hair shaft growth in cultured human hair follicles. Our data obtained from present study are in line with those previously reported and demonstrate that quercitrin is (one of) the active compound(s) of extract which showed hair growth promoting effects. It is strongly suggested that the hair growth stimulating activity of quercitrin was exerted by enhancing the cellular energy metabolism, increasing the production of growth factors via activation of MAPK/CREB signaling pathway.
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http://dx.doi.org/10.3390/molecules25174004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504764PMC
September 2020

Autophagy Suppresses Toll-Like Receptor 3-Mediated Inflammatory Reaction in Human Epidermal Keratinocytes.

Biomed Res Int 2020 1;2020:4584626. Epub 2020 May 1.

Department of Medicine, Soonchunhyang University College of Medicine, 22, Soonchunhyang-ro, Sinchang-myeon, Asan 31538, Republic of Korea.

Autophagy, one mechanism of programmed cell death, is fundamental to cellular homeostasis. Previous studies have identified autophagy as a novel mechanism by which cytokines control the immune response. However, its precise role in immune-related inflammatory skin diseases such as psoriasis remains unclear. Thus, this study explored the functional role of autophagy in psoriatic inflammation of epidermal keratinocytes. Strong light chain 3 immunoreactivity was observed in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model, and it was readily induced by polycytidylic acid (poly (I:C)), which stimulates Toll-like receptor 3 (TLR3), in human epidermal keratinocytes in vitro. Rapamycin-induced activation of autophagy significantly reduced poly (I:C)-induced inflammatory reaction, whereas, inhibition of autophagy by 3-methyladeine increased that. Our results indicate that the induction of autophagy may attenuate TLR3-mediated immune responses in human epidermal keratinocytes, thus providing novel insights into the mechanisms underlying the development of inflammatory skin diseases including psoriasis.
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http://dx.doi.org/10.1155/2020/4584626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222544PMC
May 2020

Sorafenib induces pigmentation via the regulation of β-catenin signalling pathway in melanoma cells.

Exp Dermatol 2020 May 11. Epub 2020 May 11.

Department of Dermatology and Institute of Health Sciences, School of Medicine, Gyeongsang National University & Hospital, Jinju, Korea.

We conducted large-scale screening test on drugs that were already approved for other diseases to find pigmentation-modulating agents. Among drugs with potential for pigmentation control, we selected sorafenib and further investigated the effect on pigmentation using HM3KO melanoma cells. As a result of treating melanoma cells with sorafenib, pigmentation was promoted in terms of melanin content and tyrosinase activity. Sorafenib increased mRNA and protein levels of pigmentation-related genes such as MITF, tyrosinase and TRP1. To uncover the action mechanism, we investigated the effect of sorafenib on the intracellular signalling pathways. Sorafenib reduced phosphorylation of AKT and ERK, suggesting that sorafenib induces pigmentation through inhibition of the AKT and ERK pathways. In addition, sorafenib significantly increased the level of active β-catenin, together with activation of β-catenin signalling. Mechanistic study revealed that sorafenib decreased phosphorylation of serine 9 (S9) of GSK3β, while it increased phosphorylation of tyrosine 216 (Y216) of GSK3β. These results suggest that sorafenib activates the β-catenin signalling through the regulation of GSK3β phosphorylation, thereby affecting the pigmentation process.
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http://dx.doi.org/10.1111/exd.14112DOI Listing
May 2020

Deficiency of Crif1 in hair follicle stem cells retards hair growth cycle in adult mice.

PLoS One 2020 24;15(4):e0232206. Epub 2020 Apr 24.

Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea.

Hair growth is the cyclically regulated process that is characterized by growing phase (anagen), regression phase (catagen) and resting phase (telogen). Hair follicle stem cells (HFSCs) play pivotal role in the control of hair growth cycle. It has been notified that stem cells have the distinguished metabolic signature compared to differentiated cells, such as the preference to glycolysis rather than mitochondrial respiration. Crif1 is a mitochondrial protein that regulates the synthesis and insertion of oxidative phosphorylation (OXPHOS) polypeptides to inner membrane of mitochondria. Several studies demonstrate that tissue-specific knockout of Crif1 leads to mitochondrial dysfunction. In this study, we investigated the effect of mitochondrial dysfunction in terms of Crif1 deficiency on the hair growth cycle of adult mice. We created two kinds of inducible conditional knockout (icKO) mice. In epidermal specific icKO mice (Crif1 K14icKO), hair growth cycle was significantly retarded compared to wild type mice. Similarly, HFSC specific icKO mice (Crif1 K15icKO) showed significant retardation of hair growth cycle in depilation-induced anagen model. Interestingly, flow cytometry revealed that HFSC populations were maintained in Crif1 K15icKO mice. These results suggest that mitochondrial function in HFSCs is important for the progression of hair growth cycle, but not for maintenance of HFSCs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232206PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182249PMC
July 2020

Putative therapeutic mechanisms of simvastatin in the treatment of alopecia areata.

J Am Acad Dermatol 2021 Mar 9;84(3):782-784. Epub 2020 Apr 9.

Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea; Department of Dermatology, Rutgers Robert Wood Johnson Medical School, Somerset, New Jersey. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.03.102DOI Listing
March 2021

Tumor Suppressive Function of NQO1 in Cutaneous Squamous Cell Carcinoma (SCC) Cells.

Biomed Res Int 2019 22;2019:2076579. Epub 2019 Nov 22.

Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea.

Cutaneous squamous cell carcinoma (SCC) is a common cancer that significantly decreases the quality of life. It is known that external stimulus such as ultraviolet (UV) radiation induces cutaneous SCC via provoking oxidative stress. NAD(P)H dehydrogenase 1 (NQO1) is a ubiquitous flavoenzyme that functions as a guardian against oxidative stress. However, the effect of NQO1 on cutaneous SCC is not clearly elucidated. In this study, we investigated the effect of NQO1 on cutaneous SCC cells using the recombinant adenoviruses that can upregulate and/or downregulate NQO1 expression. Overexpression of NQO1 resulted in significant decrease of cell proliferation and colony forming activity of SCC lines (SCC12 and SCC13 cells). By contrast, knockdown of NQO1 increased the cell proliferation and colony forming activity. Accordingly, the levels of proliferation-related regulators, such as Cyclin D1, Cyclin E, PCNA, SOX2, and p63, were decreased by the overexpression of NQO1, while those were increased by knockdown of NQO1. In addition, NQO1 affected the invasion and migration of SCC cells in a very similar way, with the regulation of epithelial-mesenchymal transition- (EMT-) related molecules, including E-cadherin, N-cadherin, Vimentin, Snail, and Slug. Finally, the overexpression of NQO1 decreased the level of phosphorylated AKT, JNK, and p38 MAPK, while the knockdown of NQO1 increased the level of phosphorylated signaling molecules. Based on these data, NQO1 has tumor suppressive function in cutaneous SCC cells.
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http://dx.doi.org/10.1155/2019/2076579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893255PMC
May 2020

KLF4 suppresses the tumor activity of cutaneous squamous cell carcinoma (SCC) cells via the regulation of SMAD signaling and SOX2 expression.

Biochem Biophys Res Commun 2019 09 6;516(4):1110-1115. Epub 2019 Jul 6.

Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, South Korea. Electronic address:

Kruppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays a role in terminal differentiation of epidermal keratinocytes. There are conflicting reports regarding the role of KLF4 in tumor development, with both the tumor suppressive and/or oncogenic properties depending on different conditions and cell types. In this study, we investigated the functional importance of KLF4 in cutaneous squamous cell carcinoma (SCC). Immunohistochemistry showed that KLF4 expression was relatively low in SCC lesion compared to normal epidermis. To examine the effects of KFL4, we transduced SCC lines (SCC12 and SCC13 cells) with the KLF4-expressing recombinant adenovirus. Overexpression of KLF4 significantly decreased cell proliferation and colony forming activity. In addition, overexpression of KLF4 markedly reduced invasive potential, along with the downregulation of epithelial-mesenchymal transition (EMT)-related molecules. In a mechanistic study, KLF4 inhibited SOX2, of which expression is critical for tumor initiation and growth of SCC. Further investigations indicated that SOX2 expression is induced by TGF-β/SMAD signaling, and that overexpression of KLF4 inhibited SMAD signaling via upregulation of SMAD7, an important inhibitory SMAD molecule. Based on these data, KLF4 plays a tumor suppressive role in cutaneous SCC cells.
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http://dx.doi.org/10.1016/j.bbrc.2019.07.011DOI Listing
September 2019

Antitumor Effect of Albendazole on Cutaneous Squamous Cell Carcinoma (SCC) Cells.

Biomed Res Int 2019 9;2019:3689517. Epub 2019 Jun 9.

Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea.

Drug repurposing and/or repositioning is an alternative method to develop new treatment for certain diseases. Albendazole was originally developed as an anthelmintic medication, and it has been used to treat a variety of parasitic infestations. In this study, we investigated the antitumor effect of albendazole and putative action mechanism. Results showed that albendazole dramatically decreased the cell viability of SCC cell lines (SCC12 and SCC13 cells). Albendazole increased apoptosis-related signals, including cleaved caspase-3 and PARP-1 in a dose-dependent fashion. The mechanistic study showed that albendazole induced endoplasmic reticulum (ER) stress, evidenced by increase of CHOP, ATF-4, caspase-4, and caspase-12. Pretreatment with ER stress inhibitor 4-PBA attenuated albendazole-induced apoptosis of SCC cells. In addition, albendazole decreased the colony-forming ability of SCC cells, together with inhibition of Wnt/-catenin signaling. These results indicate that albendazole shows an antitumor effect via regulation of ER stress and cancer stemness, suggesting that albendazole could be repositioned for cutaneous SCC treatment.
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http://dx.doi.org/10.1155/2019/3689517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590486PMC
December 2019

Tropomyosin-receptor kinase fused gene (TFG) regulates lipid production in human sebocytes.

Sci Rep 2019 04 29;9(1):6587. Epub 2019 Apr 29.

Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, Korea.

The endoplasmic reticulum (ER) is an organelle in which important cellular events such as protein synthesis and lipid production occur. Although many lipid molecules are produced in the ER, the effect of ER-organizing proteins on lipid synthesis in sebocytes has not been completely elucidated. Tropomyosin-receptor kinase fused gene (TFG) is located in ER exit sites and participates in COPII-coated vesicle formation along with many scaffold proteins, such as Sec. 13 and Sec. 16. In this study, we investigated the putative role of TFG in lipid production in sebocytes using an immortalized human sebocyte line. During IGF-1-induced lipogenesis, the level of the TFG protein was increased in a time- and dose-dependent manner. When TFG was over-expressed using recombinant adenovirus, lipid production in sebocytes was increased along with an up-regulation of the expression of lipogenic regulators, such as PPAR-γ, SREBP-1 and SCD. Conversely, down-regulation of TFG using a microRNA (miR) decreased lipid production and the expression of lipogenic regulators. Based on these data, TFG is a novel regulator of lipid synthesis in sebocytes.
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http://dx.doi.org/10.1038/s41598-019-43209-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488642PMC
April 2019

Adiponectin Enhances Human Keratinocyte Lipid Synthesis via SIRT1 and Nuclear Hormone Receptor Signaling.

J Invest Dermatol 2019 03 28;139(3):573-582. Epub 2018 Oct 28.

Department of Dermatology, Chung-Ang University Hospital, Seoul, Korea.

Adiponectin is known to have beneficial effects on lipid and insulin metabolism, wound healing, and cellular senescence, but its effect on skin barrier formation remains unknown. We investigated the effects of adiponectin on keratinocyte lipid synthesis with respect to skin barrier function. Lipid staining revealed an adiponectin-mediated increase in keratinocyte intracellular and reconstructed epidermal lipid content. Moreover, significant increases in the levels of ceramide and its downstream metabolites (sphingosine and sphingosine-1-phosphate) following adiponectin stimulation were detected using liquid chromatography-mass spectrometry. Expression levels of keratinocyte differentiation markers were also increased. Adiponectin also increased expression of lipid biosynthesis enzymes (fatty acid synthase, HMG-CoA reductase, and serine palmitoyltransferase), nuclear hormone receptors (peroxisome proliferator-activated receptors and liver X receptors), and the adiponectin signal molecule SIRT1. Suppression of SIRT1, liver X receptor-α, or peroxisome proliferator-activated receptor-α downregulated the expression of lipid synthetic enzymes, decreasing lipid content. Inhibition of adiponectin receptors decreased expression of nuclear hormone receptors, SIRT1, lipid-synthesizing enzymes, and sphingolipids. Thus, activation of adiponectin signaling increases the expression of transcription factors, including SIRT1, liver X receptor-α, and peroxisome proliferator-activated receptor-α, enhancing lipid synthesis and keratinocyte cell differentiation and possibly aiding in the maintenance of skin barrier homeostasis.
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http://dx.doi.org/10.1016/j.jid.2018.08.032DOI Listing
March 2019

Induction of alopecia areata in C3H/HeJ mice using polyinosinic-polycytidylic acid (poly[I:C]) and interferon-gamma.

Sci Rep 2018 08 21;8(1):12518. Epub 2018 Aug 21.

Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea.

Alopecia areata (AA) is a chronic, relapsing hair-loss disorder that is considered to be a T-cell-mediated autoimmune disease. Several animal models for AA have been created to investigate the pathophysiology and screen for effective therapeutic targets. As C3H/HeJ mice develop AA spontaneously in a low frequency, a novel animal model is needed to establish an AA-like condition faster and more conveniently. In this study, we present a novel non-invasive AA rodent model that avoids skin or lymph-node cell transfer. We simply injected C3H/HeJ mice subcutaneously with interferon-gamma (IFNγ) along with polyinosinic:polycytidylic acid (poly[I:C]), a synthetic dsRNA, to initiate innate immunity via inflammasome activation. Approximately 80% of the IFNγ and poly(I:C) co-injected mice showed patchy AA lesions after 8 weeks. None of the mice displayed hair loss in the IFNγ or poly(I:C) solely injection group. Immunohistochemical staining of the AA lesions revealed increased infiltration of CD4 and CD8 cells infiltration around the hair follicles. IFNγ and poly(I:C) increased the expression of NLRP3, IL-1β, CXCL9, CXCL10, and CXCL11 in mouse skin. Taken together, these findings indicate a shorter and more convenient means of AA animal model induction and demonstrate that inflammasome-activated innate immunity is important in AA pathogenesis.
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http://dx.doi.org/10.1038/s41598-018-30997-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104095PMC
August 2018

Possible Role of Single Stranded DNA Binding Protein 3 on Skin Hydration by Regulating Epidermal Differentiation.

Ann Dermatol 2018 Aug 28;30(4):432-440. Epub 2018 Jun 28.

Department of Dermatology, College of Medicine, Chungnam National University, Daejeon, Korea.

Background: Skin hydration is a common problem both in elderly and young people as dry skin may cause irritation, dermatological disorders, and wrinkles. While both genetic and environmental factors seem to influence skin hydration, thorough genetic studies on skin hydration have not yet been conducted.

Objective: We used a genome-wide association study (GWAS) to explore the genetic elements underlying skin hydration by regulating epidermal differentiation and skin barrier function.

Methods: A GWAS was conducted to investigate the genetic factors influencing skin hydration in 100 Korean females along with molecular studies of genes in human epidermal keratinocytes for functional study in vitro.

Results: Among several single nucleotide polymorphisms identified in GWAS, we focused on Single Stranded DNA Binding Protein 3 (SSBP3) which is associated with DNA replication and DNA damage repair. To better understand the role of SSBP3 in skin cells, we introduced a calcium-induced differentiation keratinocyte culture system model and found that SSBP3 was upregulated in keratinocytes in a differentiation dependent manner. When SSBP3 was overexpressed using a recombinant adenovirus, the expression of differentiation-related genes such as loricrin and involucrin was markedly increased.

Conclusion: Taken together, our results suggest that genetic variants in the intronic region of could be determinants in skin hydration of Korean females. represents a new candidate gene to evaluate the molecular basis of the hydration ability in individuals.
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http://dx.doi.org/10.5021/ad.2018.30.4.432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029969PMC
August 2018

Three Streams for the Mechanism of Hair Graying.

Ann Dermatol 2018 Aug 28;30(4):397-401. Epub 2018 Jun 28.

Department of Anatomy, Chungnam National University College of Medicine, Daejeon, Korea.

Hair graying is an obvious sign of human aging. Although graying has been investigated extensively, the mechanism remains unclear. Here, we reviewed previous studies on the mechanism of graying and seek to offer some new insights. The traditional view is that hair graying is caused by exhaustion of the pigmentary potential of the melanocytes of hair bulbs. Melanocyte dysfunction may be attributable to the effects of toxic reactive oxygen species on melanocyte nuclei and mitochondria. A recent study suggests that bulge melanocyte stem cells (MSCs) are the key cells in play. Graying may be caused by defective MSC self-maintenance, not by any deficiency in bulbar melanocytes. Our previous study suggested that graying may be principally attributable to active hair growth. Active hair growth may produce oxidative or genotoxic stress in hair bulge. These internal stress may cause eventually depletion of MSC in the hair follicles. Taken together, hair graying may be caused by MSC depletion by genotoxic stress in the hair bulge. Hair graying may also be sometimes caused by dysfunction of the melanocytes by oxidative stress in the hair bulb. In addition, hair graying may be attributable to MSC depletion by active hair growth.
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http://dx.doi.org/10.5021/ad.2018.30.4.397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029974PMC
August 2018

Induction of pigmentation by a small molecule tyrosine kinase inhibitor nilotinib.

Biochem Biophys Res Commun 2018 09 28;503(4):2271-2276. Epub 2018 Jun 28.

Department of Dermatology and Institute of Health Sciences, School of Medicine, Gyeongsang National University & Hospital, Jinju, South Korea. Electronic address:

Skin color is determined by the melanin pigments that are produced in melanocytes then transferred to surrounding keratinocytes. Despite the growing number of commercial products claiming the pigmentation-regulatory effects, there is still a demand for the development of new materials that are safe and more efficacious. We tried to screen the pigmentation-regulatory materials using a commercially available drugs, and found that nilotinib could induce pigmentation in melanoma cells. When HM3KO melanoma cells were treated with nilotinib, melanin content was increased together with increase of tyrosinase activity. Nilotinib increased the expression of pigmentation-related genes such as MITF, tyrosinase and TRP1. Consistent with these results, the protein level for MITF, tyrosinase, and TRP1 was significantly increased by nilotinib. To delineate the action mechanism of nilotinib, we investigated the effects of nilotinib on intracellular signaling. As a result, nilotinib decreased the phosphorylation of AKT, while increased the phosphorylation of CREB. The pretreatment of PKA inhibitor H89 markedly blocked the nilotinib-induced phosphorylation of CREB. In accordance with, pretreatment of H89 significantly inhibited the nilotinib-induced pigmentation, indicating that nilotinib induces pigmentation via the activation of PKA signaling. Together, our data suggest that nilotinib can be developed for the treatment of hypopigmentary disorder such as vitiligo.
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http://dx.doi.org/10.1016/j.bbrc.2018.06.148DOI Listing
September 2018

Isoginkgetin Inhibits Insulin-Like Growth Factor-1-Induced Sebum Production in Cultured Human Sebocytes.

Ann Dermatol 2018 Jun 23;30(3):394-396. Epub 2018 Apr 23.

Department of Dermatology, Chungnam National University School of Medicine, Daejeon, Korea.

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http://dx.doi.org/10.5021/ad.2018.30.3.394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929972PMC
June 2018

β-Catenin Regulates the Expression of cAMP Response Element-Binding Protein 1 in Squamous Cell Carcinoma Cells.

Ann Dermatol 2018 Feb 26;30(1):119-122. Epub 2017 Dec 26.

Department of Dermatology, Chungnam National University School of Medicine, Daejeon, Korea.

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http://dx.doi.org/10.5021/ad.2018.30.1.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762468PMC
February 2018

Corrigendum: The Effect of Micro-Spicule Containing Epidermal Growth Factor on Periocular Wrinkles.

Ann Dermatol 2017 Dec 30;29(6):828. Epub 2017 Oct 30.

Department of Dermatology, Chungnam National University School of Medicine, Daejeon, Korea.

[This corrects the article on p. 187 in vol. 29, PMID: 28392646.].
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http://dx.doi.org/10.5021/ad.2017.29.6.828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705381PMC
December 2017

The Effect of FK 506 on the Reepithelialization of Superficial Skin Wound.

Ann Dermatol 2017 Oct 25;29(5):635-637. Epub 2017 Aug 25.

Department of Dermatology, Chungnam National University School of Medicine, Daejeon, Korea.

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http://dx.doi.org/10.5021/ad.2017.29.5.635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597662PMC
October 2017

Possible role of tropomyosin-receptor kinase fused gene on skin collagen remodeling.

J Dermatol Sci 2017 Dec 24;88(3):375-377. Epub 2017 Aug 24.

Department of Dermatology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea; Department of Biochemistry and Molecular Biology, School of Medicine, KyungHee University, Seoul, Republic of Korea; LG Household and Healthcare, Daejeon, Republic of Korea; Department of Dermatology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jdermsci.2017.08.010DOI Listing
December 2017

Establishment and evaluation of immortalized human epidermal keratinocytes for an alternative skin irritation test.

J Pharmacol Toxicol Methods 2017 Nov - Dec;88(Pt 2):130-139. Epub 2017 Aug 19.

Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea; Institute of Life Science and Bio-Engineering, TheraCell Bio & Science, Cheongju, Chungbuk, Republic of Korea. Electronic address:

Human skin is located at the outermost part of the body, and various cosmetics and chemicals that may come in contact with human skin need to be evaluated for their potential to cause irritation. Until recently, the Draize test was considered the standard method for skin irritation; however, this technique has disadvantages such as the need to sacrifice many rabbits and subjective scoring. Thus, to contribute to the development of an animal-free alternative skin irritation test, we investigated the cytotoxicity and inflammatory response to standard skin irritants in SV40 large T antigen-transformed human epidermal keratinocyte 2 cells (SV-HEK2 cells). In this study, we established an SV-HEK2 cell line immortalized by SV40 large T antigen (SV40 T) and characterized the inherent morphological and cytological properties. We next used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) or neutral red uptake (NRU) assays of cell viability to investigate the optimal experimental conditions for determining SV-HEK2 cell viability after exposure to sodium dodecyl sulfate at 6.25×10% to 1×10% as a standard skin irritant. We then examined the viability of SV-HEK2 cells in response to five skin irritants (benzalkonium chloride, isopropanol, sodium dodecyl sulfate, Triton X-100 and Tween20) at 5×10% to 1×10% by MTT or NRU assay. Finally, we estimated the level of cytokines secretion in response to stimulation by skin irritants in SV-HEK2 cells. The results revealed that SV-HEK2 cells responded well to skin irritants in a concentration-dependent manner and that there was good correlation between irritant concentration and cytotoxicity (or cytokine secretion) when cells were exposed to skin irritants for 10min at room temperature (RT) using an MTT assay. Overall, these findings suggest that SV-HEK2 cells could be a good alternative in vitro model for skin irritation tests.
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http://dx.doi.org/10.1016/j.vascn.2017.08.005DOI Listing
July 2018

Inhibitory effect of 5-iodotubercidin on pigmentation.

Biochem Biophys Res Commun 2017 09 4;490(4):1282-1286. Epub 2017 Jul 4.

Department of Dermatology and Institute of Health Sciences, School of Medicine, Gyeongsang National University & Hospital, Jinju, Republic of Korea. Electronic address:

Melanin pigments are the primary contributors for the skin color. They are produced in melanocytes and then transferred to keratinocytes, eventually giving various colors on skin surface. Although many depigmenting and/or skin-lightening agents have been developed, there is still a growing demand on materials for reducing pigmentation. We attempted to find materials for depigmentation and/or skin-lightening using the small molecule compounds commercially available, and found that 5-iodotubercidin had inhibitory potential on pigmentation. When HM3KO melanoma cells were treated with 5-iodotubercidin, pigmentation was dramatically reduced. The 5-iodotubercidin decreased the protein level for pigmentation-related molecules such as MITF, tyrosinase, and TRP1. In addition, 5-iodotubercidin decreased the phosphorylation of CREB, while increased the phosphorylation of AKT and ERK. These data suggest that 5-iodotubercidin inhibits melanogenesis via the regulation of intracellular signaling related with pigmentation. Finally, 5-iodotubercidin markedly inhibited the melanogenesis of zebrafish embryos, an in vivo evaluation model for pigmentation. Together, these data suggest that 5-iodotubercidin can be developed as a depigmenting and/or skin-lightening agent.
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http://dx.doi.org/10.1016/j.bbrc.2017.07.008DOI Listing
September 2017

Effects of Brn2 overexpression on eccrine sweat gland development in the mouse paw.

Biochem Biophys Res Commun 2017 08 23;490(3):901-905. Epub 2017 Jun 23.

Department of Anatomy, College of Medicine, Chungnam National University, Daejeon, South Korea. Electronic address:

Eccrine sweat glands regulate body temperature by secreting water and electrolytes. In humans, eccrine sweat glands are ubiquitous in the skin, except in the lips and external genitalia. In mice, eccrine sweat glands are present only in the paw pad. Brn2 is a protein belonging to a large family of transcription factors. A few studies have examined Brn2 in melanoma cells and epidermal keratinocytes. This study investigated changes in the skin in the K5-Brn2 transgenic mouse, which overexpresses Brn2 and contains the keratin 5 promotor. Interestingly, the volume of eccrine sweat glands was reduced markedly in the K5-Brn2 transgenic mouse compared with the wild-type, while the expression of aquaporin 5, important molecule in sweat secretion, was increased in each sweat gland cell, probably to compensate for the reduction in gland development. However, sweating response to a pilocarpine injection in the hind paw was significantly decreased in the K5-Brn2 transgenic mouse compared with the wild-type. The paw epidermis was thicker in the K5-Brn2 transgenic mouse compared with the wild-type. Taken together, eccrine sweat gland development and sweat secretion were suppressed markedly in the K5-Brn2 transgenic mouse. These results may be associated with dominant development of the epidermis by Brn2 overexpression in the paw skin.
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http://dx.doi.org/10.1016/j.bbrc.2017.06.138DOI Listing
August 2017

Low-Dose Systemic Methotrexate Therapy for Recalcitrant Alopecia Areata.

Ann Dermatol 2017 Jun 11;29(3):263-267. Epub 2017 May 11.

Department of Dermatology, Chungnam National University School of Medicine, Daejeon, Korea.

Background: Alopecia areata (AA) is an autoimmune skin disease difficult to manage and treat. The pathogenesis of AA features a T-cell-associated autoimmune process, and systemic immunosuppressive therapy is prescribed widely for AA.

Objective: To evaluate the efficacy and tolerance of systemic low-dose methotrexate (LD-MTX) therapy in treatment of recalcitrant AA multiplex.

Methods: In a retrospective, non-controlled study, we evaluated 29 patients with recalcitrant AA treated with LD-MTX and assessed the therapeutic response according to severity of disease, disease duration, cumulative dose of MTX, and drug safety.

Results: MTX was administered twice weekly, and the mean maximum weekly dose was 14.48 mg. The response was A5 (regrowth=100.0%) in 14 (48.3%) patients and A4 (regrowth of 75%~90%) in 12 (41.4%) patients. Three patients had poor response to LD-MTX treatment (A2: n=2 [6.9%], A1: n=1 [3.4%]). All three of the patients showing a poor response had disease durations exceeding 24 months. Relapse was observed in 31% of patients with more than 75% regrowth. Common side-effects were elevated liver enzyme levels and gastrointestinal discomfort.

Conclusion: LD-MTX appears to be an effective and well-tolerated treatment for recalcitrant AA multiplex.
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http://dx.doi.org/10.5021/ad.2017.29.3.263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438930PMC
June 2017

The Effect of Micro-Spicule Containing Epidermal Growth Factor on Periocular Wrinkles.

Ann Dermatol 2017 Apr 24;29(2):187-193. Epub 2017 Mar 24.

Department of Dermatology, Chungnam National University School of Medicine, Daejeon, Korea.

Background: Micro-needle patches have been recently used to increase skin permeability, which improves drug delivery, and for cosmetic purposes. However, these patches may often have limited efficacy due to insufficient skin penetration and reduced compliance caused by discomfort.

Objective: We evaluated the efficacy and the safety of soluble micro-spicule containing epidermal growth factor (MS-EGF) for the treatment of periocular wrinkles.

Methods: Twenty healthy volunteers aged 33 to 54 years were enrolled in a randomized, controlled, split-face study. For 4 weeks, a periocular wrinkle was treated daily with either a soluble MS-EGF cream or a cream containing EGF alone. All subjects underwent 8 weeks of follow-up. Efficacy was assessed using an ultrasonic measurement of dermal depth and density, digital skin image analysis, 5-point photonumeric scale for periocular wrinkles and subjective satisfaction.

Results: MS-EGF group showed statistically significant increase of dermal depth and density compared to EGF alone group after 4 and 8 weeks. In addition, there was a marked improvement shown in clinical and 3-dimensional skin image in MS-EGF group. The treatments were well-tolerated; no significant side-effect was noted.

Conclusion: The MS-EGF formulation may represent an effective and biocompatible advance in the treatment of periocular wrinkles.
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http://dx.doi.org/10.5021/ad.2017.29.2.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383744PMC
April 2017

Targeted deletion of Crif1 in mouse epidermis impairs skin homeostasis and hair morphogenesis.

Sci Rep 2017 03 20;7:44828. Epub 2017 Mar 20.

Departmentof Dermatology, Chungnam National University School of Medicine, Daejeon, Korea.

The epidermis, which consists mainly of keratinocytes, acts as a physical barrier to infections by regulating keratinocyte proliferation and differentiation. Hair follicles undergo continuous cycling to produce new one. Therefore, optimum supply of energy from the mitochondria is essential for maintaining skin homeostasis and hair growth. CRIF1 is a mitochondrial protein that regulates mitoribosome-mediated synthesis and insertion of mitochondrial oxidative phosphorylation polypeptides into the mitochondrial membrane in mammals. Recent studies reveal that conditional knockout (cKO) of Crif1 in specific tissues of mice induced mitochondrial dysfunction. To determine whether the mitochondrial function of keratinocytes affects skin homeostasis and hair morphogenesis, we generated epidermis-specific Crif1 cKO mice. Deletion of Crif1 in epidermis resulted in impaired mitochondrial function and Crif1 cKO mice died within a week. Keratinocyte proliferation and differentiation were markedly inhibited in Crif1 cKO mice. Furthermore, hair follicle morphogenesis of Crif1 cKO mice was disrupted by down-regulation of Wnt/β-catenin signaling. These results demonstrate that mitochondrial function in keratinocytes is essential for maintaining epidermal homeostasis and hair follicle morphogenesis.
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http://dx.doi.org/10.1038/srep44828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357846PMC
March 2017

Double-stranded RNA induces inflammation via the NF-κB pathway and inflammasome activation in the outer root sheath cells of hair follicles.

Sci Rep 2017 03 7;7:44127. Epub 2017 Mar 7.

Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea.

Alopecia areata (AA), a chronic, relapsing, hair-loss disorder, is considered to be a T cell-mediated autoimmune disease. It affects approximately 1.7% of the population, but its precise pathogenesis remains to be elucidated. Despite the recent attention focused on the roles of inflammasomes in the pathogenesis of autoinflammatory diseases, little is known about inflammasome activation in AA. Thus, in this study, we investigated the pattern of NLRP3 inflammasome activation in the outer root sheath (ORS) cells of hair follicles. We found that interleukin (IL)-1β and caspase-1 expression was increased in hair follicle remnants and inflammatory cells of AA tissue specimens. After stimulation of ORS cells with the double-stranded (ds)RNA mimic polyinosinic:polycytidylic acid (poly[I:C]), the activation of caspase-1 and secretion of IL-1β were enhanced. Moreover, NLRP3 knockdown decreased this poly(I:C)-induced IL-1β production. Finally, we found that high-mobility group box 1 (HMGB1) translocated from the nucleus to the cytosol and was secreted into the extracellular space by inflammasome activation. Taken together, these findings suggest that ORS cells are important immunocompetent cells that induce NLRP3 inflammasomes. In addition, dsRNA-induced IL-1β and HMGB1 secretion from ORS cells may contribute to clarifying the pathogenesis and therapeutic targets of AA.
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http://dx.doi.org/10.1038/srep44127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339809PMC
March 2017

Hyaluronic Acid Decreases Lipid Synthesis in Sebaceous Glands.

J Invest Dermatol 2017 06 3;137(6):1215-1222. Epub 2017 Feb 3.

Department of Dermatology, College of Medicine, Chungnam National University, Daejeon, Korea. Electronic address:

Hyaluronic acid (HA) is the major glycosaminoglycan in the extracellular matrix and has been implicated in several functions in skin cells. However, evidence is lacking regarding the HA signaling in sebaceous glands, and its potential role needs to be clarified. We investigated the role of HA in lipid production in sebaceous glands in an experimental study of human sebocytes followed by a clinical study. We first examined the effects of HA on sebaceous glands in hamsters and intradermal injection of HA into hamster auricles decreased both the size of sebaceous glands and the level of lipid production. We demonstrated that human skin sebaceous glands in vivo and sebocytes in vitro express CD44 (HA binding receptor) and that HA downregulates lipid synthesis in a dose-dependent manner. To evaluate the clinical relevance of HA in human skin, 20 oily participants were included in a double-blind, placebo-controlled, split-face study, and the HA-treated side showed a significant decrease in sebum production. The results of this study indicate that HA plays a functional role in human sebaceous gland biology and HA signaling is an effective candidate in the management of disorders in which sebum production is increased.
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http://dx.doi.org/10.1016/j.jid.2017.01.017DOI Listing
June 2017