Pigmented contact dermatitis and hair dyes: A retrospective case-control multicentre study in Korea.

BACKGROUND: Pigmented contact dermatitis (PCD), a rare variant of non-eczematous contact dermatitis, is clinically characterized by sudden-onset brown or grey pigmentation on the face and neck. It is hypothesized to be caused by repeated contact with low levels of allergens. OBJECTIVES: This study evaluated the risk of using hair dyes in patients with PCD in Korea. METHODS: A total of 1033 PCD patients and 1366 controls from 31 university hospitals were retrospectively recruited. We collected and analysed the data from the patient group, diagnosed through typical clinical findings of PCD and the control group, which comprised age/sex-matched patients who visited the participating hospitals with pre-existing skin diseases other than current allergic disease or PCD. RESULTS: Melasma and photosensitivity were significantly more common in the control group, and a history of contact dermatitis was more common in the PCD group. There were significantly more Fitzpatrick skin type V participants in the PCD group than in the control group. There was no significant difference in sunscreen use between the groups. Using dermatologic medical history, Fitzpatrick skin type and sunscreen use as covariates, we showed that hair dye use carried a higher PCD risk (odds ratio [OR] before adjustment: 2.06, confidence interval [CI]: 1.60-2.65; OR after adjustment: 2.74, CI: 1.88-4.00). Moreover, henna users had a higher risk of PCD (OR before adjustment: 5.51, CI: 4.07-7.47; OR after adjustment: 7.02, CI: 4.59-10.74), indicating a significant increase in the risk of PCD with henna dye use. Contact dermatitis history was more prevalent in henna users than in those using other hair dyes in the PCD group (17.23% vs. 11.55%). CONCLUSION: Hair dye use is a risk factor for PCD. The risk significantly increased when henna hair dye was used by those with a history of contact dermatitis.

Pitavastatin Induces Apoptosis of Cutaneous Squamous Cell Carcinoma Cells through Geranylgeranyl Pyrophosphate-Dependent c-Jun N-Terminal Kinase Activation.

BACKGROUND: Pitavastatin is a cholesterol-lowering drug and is widely used clinically. In addition to this effect, pitavastatin has shown the potential to induce apoptosis in cutaneous squamous cell carcinoma (SCC) cells. OBJECTIVE: The purpose of this study is to investigate the effects and possible action mechanisms of pitavastatin. METHODS: SCC cells (SCC12 and SCC13 cells) were treated with pitavastatin, and induction of apoptosis was confirmed by Western blot. To examine whether pitavastatin-induced apoptosis is related to a decrease in the amount of intermediate mediators in the cholesterol synthesis pathway, the changes in pitavastatin-induced apoptosis after supplementation with mevalonate, squalene, geranylgeranyl pyrophosphate (GGPP) and dolichol were investigated. RESULTS: Pitavastatin dose-dependently induced apoptosis of cutaneous SCC cells, but the viability of normal keratinocytes was not affected by pitavastatin at the same concentrations. In supplementation experiments, pitavastatin-induced apoptosis was inhibited by the addition of mevalonate or downstream metabolite GGPP. As a result of examining the effect on intracellular signaling, pitavastatin decreased Yes1 associated transcriptional regulator and Ras homolog family member A and increased Rac family small GTPase 1 and c-Jun N-terminal kinase (JNK) activity. All these effects of pitavastatin on signaling molecules were restored when supplemented with either mevalonate or GGPP. Furthermore, pitavastatin-induced apoptosis of cutaneous SCC cells was inhibited by a JNK inhibitor. CONCLUSION: These results suggest that pitavastatin induces apoptosis of cutaneous SCC cells through GGPP-dependent JNK activation.

Adults' Perception of Children's Vowel Production.

The study examined the link between Korean-speaking children's vowel production and its perception by inexperienced adults and also observed whether ongoing vowel changes in mid-back vowels affect adults' perceptions when the vowels are produced by children. This study analyzed vowels in monosyllabic words produced by 20 children, ranging from 2 to 6 years old, with a focus on gender distinction, and used them as perceptual stimuli for word perception by 20 inexperienced adult listeners. Acoustic analyses indicated that F0 was not a reliable cue for distinguishing gender, but the first two formants served as reliable cues for gender distinction. The results confirmed that the spacing of the two low formants is linguistically and para-linguistically important in identifying vowel types and gender. However, a pair of non-low back vowels caused difficulties in correct vowel identification. Proximal distance between the vowels could be interpreted to result in the highest mismatch between children's production and adults' perception of the two non-low back vowels in the Korean language. We attribute the source of the highest mismatch of the two non-low back vowels to the ongoing sound change observed in high and mid-back vowels in adult speech. The ongoing vowel change is also observed in the children's vowel space, which may well be shaped after the caregivers whose non-low back vowels are close to each other.

Inhibitory Effect of Mitoxantrone on Collagen Synthesis in Dermal Fibroblasts.

Background: Fibroblasts produce collagen molecules that support the structure of the skin. The decrease and hypersynthesis of collagen causes skin problems such as skin atrophy, wrinkles and scars. Objective: The purpose of this study is to investigate the mechanism of mitoxantrone on collagen synthesis in fibroblasts. Methods: Cultured fibroblasts were treated with mitoxantrone, and then collagen synthesis was confirmed by reverse transcription-polymerase chain reaction and Western blot. Results: Mitoxantrone inhibited the expression of type I collagen in fibroblasts at both the mRNA and protein levels. In the collagen gel contraction assay, mitoxantrone significantly inhibited gel contraction compared to the control group. Mitoxantrone inhibited transforming growth factor (TGF)-ß-induced phosphorylation of SMAD3. Finally, mitoxantrone inhibited the expression of LARP6, an RNA-binding protein that regulates collagen mRNA stability. Conclusion: These results suggest that mitoxantrone reduces collagen synthesis by inhibiting TGF-ß/SMAD signaling and LARP6 expression in fibroblasts, which can be developed as a therapeutic agent for diseases caused by collagen hypersynthesis.

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

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 ß-catenin, together with activation of ß-catenin signalling. Mechanistic study revealed that sorafenib decreased phosphorylation of serine 9 (S9) of GSK3ß, while it increased phosphorylation of tyrosine 216 (Y216) of GSK3ß. These results suggest that sorafenib activates the ß-catenin signalling through the regulation of GSK3ß phosphorylation, thereby affecting the pigmentation process.

Development of Pigmentation-Regulating Agents by Drug Repositioning.

Skin color is determined by the processes of melanin synthesis and distribution. Problems in various molecules or signaling pathways involved in melanin synthesis contribute to skin pigmentation defects. Several trials have been conducted on the production of pigmentation-regulating agents, and drug repositioning has emerged as a modern technique to identify new uses for existing drugs. Our research team has researched substances or drugs associated with pigmentation control and, as a result, nilotinib, sorafenib, and ICG-001 have been found to promote pigmentation, while 5-iodotubercidin inhibits pigmentation. Therefore, these substances or medications were suggested as potential therapeutics for pigmentation disorders by drug repositioning.

Palisaded Neutrophilic and Granulomatous Dermatitis in a Patient with Behçet's Disease: A Case Report.

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is an uncommon skin eruption and characterized histopathologically by the presence of granulomatous inflammation with or without leukocytoclastic vasculitis. PNGD is known to be associated with various immune-mediated connective tissue diseases such as rheumatoid arthritis and lupus erythematosus. However, to our knowledge, a case of PNGD in a patient with Behçet's disease is extremely rare and only one case has been reported in foreign literature to date. Herein, we report an unusual case of a 60-year-old female with Behçet's disease who presented multiple erythematous to flesh-colored papules on the extremities, buttocks, and ear lobes and was diagnosed with PNGD. After the treatment of systemic corticosteroids, colchicine and azathioprine, the skin lesions and oral ulcers improved. The patient is under observation without recurrence of skin lesions for 6 months.

Performance of the BIG Score in Predicting Mortality in Normotensive Children With Trauma.

OBJECTIVES: Children have a larger reserve for traumatic hemorrhagic shock, requiring a score that uses physiologic variables other than hypotension. Recently, the BIG score comprising admission base deficit, international normalized ratio, and the Glasgow Coma Scale has been reported to predict traumatic mortality. We aimed to validate the performance of the BIG score in mortality prediction of normotensive children with trauma. METHODS: We reviewed 1046 injured children (<18 years) who visited a Korean academic hospital from 2010 to 2018, excluding those with age-adjusted hypotension. In-hospital mortality, the BIG score and its predicted mortality, Revised Trauma Score, and Pediatric Trauma Score were calculated. We compared areas under the curve (AUCs) for in-hospital mortality of the 3 scores and did in-hospital and BIG-predicted mortalities. RESULTS: Of the 1046 children, 554 were enrolled with a 4.9% in-hospital mortality rate. The median BIG score was higher in the nonsurvivors (6.4 [interquartile range, 4.4-9.2] vs 20.1 [16.5-24.8]; P < 0.001). The AUC of the BIG score was 0.94 (95% confidence interval [CI], 0.92-0.96), which was higher than that of Pediatric Trauma Score (0.87 [95% CI, 0.84-0.90]; P < 0.001). The AUC of the BIG score tended to be higher than that of Revised Trauma Score without statistical significance (0.90 [95% CI, 0.87-0.92]; P = 0.130). We noted a parallel between in-hospital and BIG-predicted mortalities. The hemorrhage-related nonsurvivors showed higher median base deficit and BIG score than did the isolated traumatic brain injury-related ones. CONCLUSIONS: The BIG score can predict mortality with excellent accuracy in normotensive children with trauma.

Nicotinamide N­methyltransferase induces the proliferation and invasion of squamous cell carcinoma cells.

Cutaneous squamous cell carcinoma (cSCC) is a common malignancy initiated by keratinocytes of the epidermis, which are able to invade the dermis and its periphery. Although most patients with cSCC present with curable localized tumors, recurrence, metastasis and mortality occasionally occur. In the present study, nicotinamide N­methyltransferase (NNMT) was identified as an upregulated protein in the SCC12 cell line, which has high invasive potential compared with the SCC13 cell line. The effects of NNMT knockdown on proliferation, migration and invasion were investigated using SCC cells. shRNA­mediated downregulation of NNMT expression levels inhibited the proliferation and density­dependent growth of SCC12 cells. In addition, the results of a cell motility assay showed that the migration and invasion of SCC cells were markedly decreased in NNMT­knockdown cells. The assessment of epithelial­mesenchymal transition (EMT)­associated gene expression using PCR array analysis revealed that high NNMT expression levels were accompanied by high expression levels of EMT­associated genes, and that NNMT knockdown effectively suppressed the expression of matrix metalloproteinase 9, osteopontin, versican core protein and zinc finger protein SNAI2 in SCC12 cells. These results revealed that the upregulation of NNMT induced cellular invasion via EMT­related gene expression in SCC cells.

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

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/ß-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.

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

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.

Prevention of total thyroidectomy in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) based on combined interpretation of ultrasonographic and cytopathologic results.

OBJECTIVE: To explore the potential preoperative ultrasonography (US) and cytopathological features to avoid total thyroidectomy in NIFTP. CONTEXT: Recently, it has been proposed that that noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) be classified as tumours, rather than cancer. PATIENTS: A total of 142 surgically proven follicular variant papillary thyroid carcinomas (FVPTCs; 45 NIFTP, 97 non-NIFTP; mean size: 20.4±11.0 mm, range: 10.0-65.0 mm) from 142 patients were included in this study. MEASUREMENTS: Three preoperative features of thyroid nodules (each US finding, US and Bethesda category) were compared in NIFTP and non-NIFTP groups. The preoperative decision-making process to avoid total thyroidectomy in NIFTP was evaluated based on combination of those features. RESULTS: In each US finding, there was only significantly less macrocalcification in the NIFTP group than in the non-NIFTP group (8.8% [4/45] vs 32.0% [31/97], P = .006). In US category, all of the NIFTP nodules were a low or intermediate suspicion (100% [45/45]). In Bethesda category, 26.7% [12/45] of the NIFTP was diagnosed as either suspicious malignancy or malignant, which increased the risk of a total thyroidectomy. In our study, a total thyroidectomy might be avoided in all of the NIFTP cases if lobectomy was selected for the nodules classified as a low or intermediate suspicion in US, despite being classified as a suspicious malignancy or malignant by cytopathology. CONCLUSIONS: Combining the US and cytopathological results could sensitively reduce total thyroidectomy in cases of NIFTP.

Procyanidins from Vitis vinifera seeds induce apoptotic and autophagic cell death via generation of reactive oxygen species in squamous cell carcinoma cells.

Procyanidins can inhibit cell proliferation and tumorigenesis and induce apoptosis in human skin, breast and prostate carcinoma cell lines. Squamous cell carcinoma (SCC) of the skin is a common form of keratinocytic or non-melanoma skin cancer and is a deadly disease with a poor prognosis due to the ineffectiveness of therapy. The present study aimed to determine whether grape seed proanthocyanidin (GSP) may regulate different modes of cell death in the human SCC12 cell line. The present study found that the treatment of SCC12 cells with GSP inhibited proliferation in a dose-dependent manner and reduced the motility and invasiveness of SCC12 cells through suppression of matrix metalloproteinase-2/9 expression. GSP treatment also resulted in induction of apoptosis and autophagy via generation of reactive oxygen species. The inhibition of autophagy by 3-methyladenine decreased GSP-induced cell death, which suggested that GSP-induced autophagy can promote cell death. The results of the present study suggested that autophagy functions as a death mechanism in SCC and provided a rationale for the use of GSP in combination with autophagy activators for treating cancers such as SCC.

Inhibitory effect of 5-iodotubercidin on pigmentation.

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.

Inhibition of collagen synthesis by IWR-1 in normal and keloid-derived skin fibroblasts.

AIMS: Keloid is a benign tumor that is characterized by the hyperproliferation of dermal fibroblasts and excessive deposition of extracellular matrix (ECM) especially the collagen. Aberrant activation of Wnt/ß-catenin signaling is implicated in the pathogenesis of keloid. In this study, we investigated the effects of IWR-1, a small molecule inhibitor for Wnt/ß-catenin signaling via the inhibition of tankyrase, on production of collagen and matrix metalloproteinase (MMP) in dermal fibroblasts. MAIN METHODS: We cultured human normal skin- and keloid-derived fibroblasts, then treated with IWR-1. The effects of IWR-1 on collagen and MMP production were determined by Western blot, ELISA and zymography. KEY FINDINGS: IWR-1 significantly suppressed the proliferation and migration of both the normal and keloid fibroblasts. IWR-1 also inhibited the production and secretion of type I collagen from the fibroblasts. In addition, IWR-1 significantly increased the expression of MMPs, such as MMP-1, MMP-3 and MMP-13, along with the increase of gelatinase activity. These results suggest that inhibitory effect of IWR-1 on collagen production may be related with the increased MMP activity. SIGNIFICANCE: This study provides the possible action mechanism of IWR-1 on regulation of collagen expression, on which to base further investigation for preventing skin fibrotic diseases such as keloid.

Wnt/ß-catenin signaling inhibitor ICG-001 enhances pigmentation of cultured melanoma cells.

BACKGROUND: Wnt/ß-catenin signaling is important in development and differentiation of melanocytes. OBJECTIVE: The object of this study was to evaluate the effects of several Wnt/ß-catenin signaling inhibitors on pigmentation using melanoma cells. METHODS: Melanoma cells were treated with Wnt/ß-catenin signaling inhibitors, and then melanin content and tyrosinase activity were checked. RESULTS: Although some inhibitors showed slight inhibition of pigmentation, we failed to observe potential inhibitory effect of those chemicals on pigmentation of HM3KO melanoma cells. Rather, one of powerful Wnt/ß-catenin signaling inhibitors, ICG-001, increased the pigmentation of HM3KO melanoma cells. Pigmentation-enhancing effect of ICG-001 was reproducible in other melanoma cell line MNT-1. Consistent with these results. ICG-001 increased the expression of pigmentation-related genes, such as MITF, tyrosinase and TRP1. When ICG-001 was treated, the phosphorylation of CREB was significantly increased. In addition, ICG-001 treatment led to quick increase of intracellular cAMP level, suggesting that ICG-001 activated PKA signaling. The blockage of PKA signaling with pharmaceutical inhibitor H89 inhibited the ICG-001-induced pigmentation significantly. CONCLUSIONS: These results suggest that PKA signaling is pivotal in pigmentation process itself, while the importance of Wnt/ß-catenin signaling should be emphasized in the context of development and differentiation.

The inhibitory effect of A20 on the inflammatory reaction of epidermal keratinocytes.

A20 is a negative regulator of nuclear factor κ-light­chain-enhancer of activated B cells (NF-κB) signaling, and has been implicated in the pathogenesis of psoriasis through genome-wide association study (GWAS). In the present study, we investigated the putative role of A20 in epidermal keratinocytes. Immunohistochemical analysis showed that A20 was expressed in all layers of the epidermis, with an increasing pattern in the upper layers. In our model of calcium-induced keratinocyte differentiation, A20 expression was increased in a time-dependent manner. To investigate whether A20 affected keratinocyte differentiation, we overexpressed A20 in cultured keratinocytes. As a result, we noted that A20 overexpression did not affect keratinocyte differentiation, suggesting that A20 is not a direct modulator of keratinocyte differentiation. Interestingly, we found that A20 levels were decreased in psoriatic lesional skin compared to non-lesional areas. To investigate whether A20 played a role in the innate immune response of keratinocytes, we overexpressed A20 and then examined poly(I:C)-induced cytokine expression. We noted that A20 significantly inhibited poly(I:C)-induced cytokine production, and this effect was related to the inhibition of NF-κB signaling. These results suggest that the downregulation of A20 increased the susceptibility of keratinocytes to external stimuli, thus contributing to the development of psoriasis.

Identification of a possible susceptibility locus for UVB-induced skin tanning phenotype in Korean females using genomewide association study.

A two-stage genomewide association (GWA) analysis was conducted to investigate the genetic factors influencing ultraviolet (UV)-induced skin pigmentation in Korean females after UV exposure. Previously, a GWA study evaluating ~500 000 single nucleotide polymorphisms (SNPs) in 99 Korean females identified eight SNPs that were highly associated with tanning ability. To confirm these associations, we genotyped the SNPs in an independent replication study (112 Korean females). We found that a novel SNP in the intron of the WW domain-containing oxidoreductase (WWOX) gene yielded significant replicated associations with skin tanning ability (P-value = 1.16 × 10(-4) ). To understand the functional consequences of this locus located in the non-coding region, we investigated the role of WWOX in human melanocytes using a recombinant adenovirus expressing a microRNA specific for WWOX. Inhibition of WWOX expression significantly increased the expression and activity of tyrosinase in human melanocytes. Taken together, our results suggest that genetic variants in the intronic region of WWOX could be determinants in the UV-induced tanning ability of Korean females. WWOX represents a new candidate gene to evaluate the molecular basis of the UV-induced tanning ability in individuals.

Inhibitory effect of cucurbitacin B on imiquimod-induced skin inflammation.

Psoriasis is a common skin disease, of which pathogenesis involves the increase of inflammatory reaction in epidermal cells. In an attempt to find therapeutics for psoriasis, we found that cucurbitacin B has an inhibitory potential on imiquimod-induced inflammation of keratinocytes. Cucurbitacin B significantly inhibited imiquimod-induced expression of crucial psoriatic cytokines, such as IL-8 and CCL20, via down-regulation of NF-κB and STAT3 signaling pathway in human keratinocytes. In addition, keratinocyte proliferation was markedly inhibited by cucurbitacin B. The potential beneficial effect of cucurbitacin B on psoriasis was further validated in imiquimod-induced psoriasiform dermatitis of experimental animal. Topical application of cucurbitacin B resulted in significant reduction of epidermal hyperplasia and inflammatory cytokines production, and ameliorated the psoriatic symptom. Taken together, these results suggest that cucurbitacin B may be a potential candidate for the treatment of psoriasis.