Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.

Hypertrophic Lichenoid Eruption in a Child Successfully Treated Using Acitretin and Surgery: A Case Report and Literature Review.

A 9-year-old boy presented with a history of keratotic violaceous plaques on the limbs and face for 8 years that had gradually progressed to erosive nodules on the extremities for 2 years. Several biopsies revealed hyperkeratosis, liquefactive degeneration of the basal layer, and a bandlike predominantly lymphocytic infiltrate. Based on the clinical and histologic findings, the patient was diagnosed with keratosis lichenoides chronica, a rare chronic dermatosis that is particularly uncommon in childhood. There are fewer than 20 reported cases of pediatric-onset keratosis lichenoides chronica in the current literature, with occurrence of pseudoepitheliomatous hyperplasia of primary keratosis lichenoides chronica lesions being even rarer. Here we present a unique pediatric-onset case accompanied by pseudoepitheliomatous hyperplasia that posed a significant treatment challenge to dermatologists. Significant improvement in the pseudoepitheliomatous skin lesions was achieved after treatment with oral acitretin capsules and surgical excision with skin grafting.

Aloe-emodin-mediated antimicrobial photodynamic therapy against dermatophytosis caused by Trichophyton rubrum.

Trichophyton rubrum is responsible for the majority of dermatophytosis. Current systemic and topical antifungals against dermatophytosis are often tedious and sometimes unsatisfactory. Antimicrobial photodynamic therapy (aPDT) is a non-invasive alternative suitable for the treatment of superficial fungal infections. This work investigated the photodynamic inactivation efficacy and effects of aloe-emodin (AE), a natural photosensitizer (PS) against T. rubrum microconidia in vitro, and evaluated the treatment effects of AE-mediated aPDT for T. rubrum-caused tinea corporis in vivo and tinea unguium ex vivo. The photodynamic antimicrobial efficacy of AE on T. rubrum microconidia was evaluated by MTT assay. The inhibition effect of AE-mediated aPDT on growth of T. rubrum was studied. Intracellular location of AE, damage induced by AE-mediated aPDT on cellular structure and surface of microconidia and generation of intracellular ROS were investigated by microscopy and flow cytometry. The therapeutic effects of AE-mediated aPDT against dermatophytosis were assessed in T. rubrum-caused tinea corporis guinea pig model and tinea unguium ex vivo model. AE-mediated aPDT effectively inactivated T. rubrum microconidia in a light energy dose-dependent manner and exhibited strong inhibitory effect on growth of T. rubrum. Microscope images indicated that AE is mainly targeted to the organelles and caused damage to the cytoplasm of microconidia after irradiation through generation of abundant intracellular ROS. AE-mediated aPDT demonstrated effective therapeutic effects for T. rubrum-caused tinea corporis on guinea pig model and tinea unguium in ex vivo model. The results obtained suggest that AE is a potential PS for the photodynamic treatment of dermatophytosis caused by T. rubrum, but its permeability in skin and nails needs to be improved.

Antifungal Effect of Antimicrobial Photodynamic Therapy Mediated by Haematoporphyrin Monomethyl Ether and Aloe Emodin on Malassezia furfur.

Infectious dermatological diseases caused by Malassezia furfur are often chronic, recurrent, and recalcitrant. Current therapeutic options are usually tedious, repetitive, and associated with adverse effects. Alternatives that broaden the treatment options and reduce side effects for patients are needed. Antimicrobial photodynamic therapy (aPDT) is an emerging approach that is quite suitable for superficial infections. The aim of this study is to investigate the antimicrobial efficacy and effect of aPDT mediated by haematoporphyrin monomethyl ether (HMME) and aloe emodin (AE) on clinical isolates of M. furfur in vitro. The photodynamic antimicrobial efficacy of HMME and AE against M. furfur was assessed by colony forming unit (CFU) assay. The uptake of HMME and AE by M. furfur cells was investigated by fluorescence microscopy. Reactive oxygen species (ROS) probe and flow cytometry were employed to evaluate the intracellular ROS level. The effect of HMME and AE-mediated aPDT on secreted protease and lipase activity of M. furfur was also investigated. The results showed that HMME and AE in the presence of light effectively inactivated M. furfur cells in a photosensitizer (PS) concentration and light energy dose-dependent manner. AE exhibited higher antimicrobial efficacy against M. furfur than HMME under the same irradiation condition. HMME and AE-mediated aPDT disturbed the fungal cell envelop, significantly increased the intracellular ROS level, and effectively inhibited the activity of secreted protease and lipase of M. furfur cells. The results suggest that HMME and AE have potential to serve as PSs in the photodynamic treatment of dermatological diseases caused by M. furfur, but further ex vivo or in vivo experiments are needed to verify that they can meet the requirements for clinical practice.

Short-Term Efficacy and Safety of IL-17, IL-12/23, and IL-23 Inhibitors Brodalumab, Secukinumab, Ixekizumab, Ustekinumab, Guselkumab, Tildrakizumab, and Risankizumab for the Treatment of Moderate to Severe Plaque Psoriasis: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The role of interleukin-12 (IL-12), interleukin-23 (IL-23), and interleukin-17 (IL-17) has been recognized in psoriasis pathogenesis, and new drugs targeting this axis have already been developed which may provide a new therapeutic approach for patients with moderate to severe psoriasis. OBJECTIVE: To compare the direct and indirect evidences of the efficacy and safety of brodalumab, secukinumab, ixekizumab, ustekinumab, guselkumab, tildrakizumab, and risankizumab in the short-term treatment of moderate to severe plaque psoriasis using network meta-analysis (NMA). METHODS: A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for the available relevant studies. NMA was conducted by Stata 15.0 software using relative risks (RR) with 95% confidence interval to assess the clinical effectiveness and safety. Ranked the efficacy and safety for each drug accordance with the surface under the cumulative ranking curve (SUCRA). RESULTS: This meta-analysis included 28 studies. All the interventions performed better than placebo in short-term achievement. Based on the result of SUCRA, ixekizumab 80 mg every 2 weeks ranked the highest in short-term achievement of PASI 75 (SUCRA = 93.0%). Brodalumab 210 mg ranked the highest in short-term achievement of PASI 100 (SUCRA = 85.0%). Secukinumab 300 mg ranked the highest in short-term achievement of sPGA 0/1 or IGA 0/1 or PGA 0/1 (SUCRA = 98.1%). In terms of having a risk of adverse events, the rates were higher in brodalumab, secukinumab, ixekizumab, and ustekinumab 45 mg compared with placebo. Ixekizumab 80 mg every 4 weeks ranked the highest in the risk of adverse events during short-term treatment (SUCRA = 4.5%). Guselkumab 50 mg ranked the highest in the risk of serious adverse events during short-term treatment (SUCRA = 25.9%). Ixekizumab 80 mg every 4 weeks ranked the highest in the risk of discontinuations due to adverse events during short-ter treatment (SUCRA = 10.7%). CONCLUSIONS: IL-17, IL-12/23, and IL-23 inhibitors had high efficacy in the achievement of PASI 75, PASI 100, and sPGA 0/1 or IGA 0/1 or PGA 0/1 in moderate to severe plaque psoriasis after 12 or 16 weeks of treatment. IL-17 inhibitors showed superior efficacy. However, its clinical safety was poor. Risankizumab appeared to have relatively high efficacy and low risk. The clinical tolerance of other biological agents needs to be further observed.

Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.

AIMS: To identify potential causative gene mutations in a large Han Chinese pedigree with diffuse nonepidermolytic palmoplantar keratoderma (NEPPK). METHODS: We enrolled 11 patients and 8 healthy individuals from a pedigree with NEPPK and 100 randomly selected healthy controls. Biopsy samples were obtained from the proband. Genomic DNA was extracted from a peripheral blood sample from each participant. Mutation detection via polymerase chain reaction and Sanger sequencing of relevant potential causative genes, including KRT1, KRT6C, KRT10, KRT16, AQP5, and SERPINB7, was performed. Comparisons were made between sequencing outcomes and currently available reference genome databases, including HGMD Pro, Pubmed, 1000 Genomics, and dbSNP. RESULTS: Histological findings, clinical features, and medical history were in accordance with the diagnosis of diffuse NEPPK. We identified a novel splice-site mutation c.1255-1G > C in intron 6 of KRT1 in all individuals with NEPPK in the pedigree. CONCLUSIONS: Diffuse NEPPK is a relatively rare subtype of palmoplantar keratoderma. The results of this study expand the spectrum of KRT1 mutations in diffuse NEPPK and provide insights into the understanding of its underlying pathological mechanisms and phenotype-genotype correlations.

Retinoic acid ameliorates photoaged skin through RAR­mediated pathway in mice.

Retinoic acid (RA), the bioactive metabolite of vitamin A, has demonstrated efficacy in the treatment of photoaged skin; however, the mechanism of action of RA remains unclear. The aim of the present study was to examine whether the therapeutic effects of RA on photoaged skin are mediated by retinoic acid receptor (RAR) and/or retinoid X receptor (RXR) in mice, and to investigate the underlying mechanism. Photoaged skin in Imprinting Control Region mice was induced by repeated exposure to ultraviolet (UV) irradiation. Mice were randomly divided into nine groups: Normal; UV control; all­trans retinoic acid (ATRA); ATRA + RAR antagonist; ATRA + RXR antagonist; RAR agonist; RAR agonist + RAR antagonist; RXR agonist; and RXR agonist + RXR antagonist. Masson's trichrome staining was used to examine skin collagen fibers. Hydroxyproline assays were used to determine collagen content. The protein expression of matrix metalloproteinase (MMP)­3, MMP­13, type I procollagen, c­Jun and c­Fos was detected using western blot analysis. The results demonstrated that ATRA and RAR agonist ameliorated the UV­induced damage to skin collagen fibers, and increased the collagen content in photoaged skin through RAR. Furthermore, ATRA and RAR agonist stimulated type I procollagen protein expression, and inhibited MMP­3, MMP­13 and c­Jun protein expression through RAR in photoaged skin. However, ATRA and RAR agonist exhibited no significant effect on the protein expression of c­Fos in photoaged skin. These findings suggest that RA ameliorates photoaged skin through a RAR­mediated signaling pathway in mice.

[Effects of bFGF and alpha-MSH on adhesion and migration of human melanocytes in vitro].

OBJECTIVE: To observe the effect of basic fibroblast growth factor (bFGF) and alpha-melanocyte stimulating hormone (alpha-MSH) on adhesion and migration of melanocytes in vitro. METHODS: Human melanocytes were obtained from normal human foreskins. Culture dishes covered with fibronectin were used to perform melanocytes adhesion assay, and cell motility was assessed using the Transwell micropore filter method. RESULT: bFGF and alpha-MSH increased melanocytes adhesion on culture dishes covered with fibronectin. bFGF stimulated melanocytes migration through micropore filter while alpha-MSH had no significant effects. CONCLUSION: bFGF and alpha-MSH could promote the adhesion and migration of melanocytes, which suggests that two agents may play a role in the repigmentation of vitiligo.

[Mechanism of receptor for retinoids inducing apoptosis of human melanoma cell line A375].

OBJECTIVE: To investigate the mechanism of receptors for retinoids inducing apoptosis of human melanoma cell line A375. METHODS: The effects of 3 kinds of retinoids (9-cis-RA, at-RA and 13-cis-RA), of TTNPB (RAR agonist) and of Methoprene acid (Ma, RXR agonist) on apoptosis of A375 cells were studied by detecting the expression of Bcl-2/Bax and by using. Annexin V/PI staining analysis, TUNEL detection and active Caspase-3 analysis. RESULTS: Retinoids and TTNPB could up-regulate the expression of Bax and down-regulate the expression of Bcl-2. The results of TUNEL and Annexin V/PI staining analysis showed that all of retinoids and TTNPB could induce apoptosis of A375 cells, compared with control group (P < 0.05); the effect of TTNPB was significantly greater than that of others (P < 0.05), but Ma was similar to the control (P > 0.05). Active Caspase-3 analysis showed that TTNPB and all of retinoids could up-regulate the expression of Caspase-3, and the effect of TTNPB was significantly greater than that of others (P < 0.05). CONCLUSION: Caspase-3 pathway is involved in the process for retinoids inducing apoptosis of A375 cells. The activation of RAR may have relation with retinoids inducing apoptosis of A375 cells, but may have no longer relation with RXR.

Meta-Analysis of the Association between Vitiligo and Human Leukocyte Antigen-A.

Objective. The objective of this study was to systematically evaluate the association between vitiligo and human leukocyte antigen- (HLA-) A. Methods. PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, and reference lists were searched for relevant original articles. Results. Nineteen case-control studies comprising 3042 patients and 5614 controls were included, in which 33 HLA-A alleles were reported. Overall, three alleles (HLA-A⁎02, A⁎33, and Aw⁎31) were significantly associated with increased risk of vitiligo, two (HLA-A⁎09 and Aw⁎19) were associated with decreased risk, and the remaining 28 were unassociated. Twelve alleles, seven alleles, and 19 alleles were common to three ethnicities, both types of vitiligo, and both typing methods, respectively. In the subgroup analysis by ethnicity and typing methods, the association of six alleles and five alleles was inconsistent in three populations and both typing methods, respectively. In the subgroup analysis by clinical type, the association of all seven alleles was consistent in both types of vitiligo. Conclusion. The meta-analysis suggests that HLA-A⁎02, A⁎33, and Aw⁎31 are associated with increased risk of vitiligo, while HLA-A⁎09 and Aw⁎19 are associated with decreased risk of vitiligo. The association of some alleles varies in terms of ethnicity and typing methods.

Effects of single herbal drugs on adhesion and migration of melanocytes.

OBJECTIVE: To find herbs with effects on adhesion and migration of melanocytes in vitro. MATERIALS AND METHODS: Ethanol extracts from 14 herbs were tested. Normal human melanocytes were obtained from neonatal foreskin, and the 48-well culture dish covered with fibronectin was used for the melanocyte adhesion assay. Motility was assessed by using the micropore filter method. RESULTS: The extracts of Danshen (Radix Salviae Miltiorrhizae), Tusizi (Semen Cuscutae) and Honghua (Flos Carthami) could enhance melanocyte adhesion to fibronectin, while Cijili (Fructus Tribuli) and Huangqi (Radix Astragali) promote melanocyte migration in vitro. Buguzhi (Fructus Psoraleae), Nü Zhen Zi (Fructus Ligustri Lucidi) and Baizhi (Radix Angelicae Dahuricae) could promote both adhesion and migration of melanocytes. CONCLUSION: The above herbs may play a role through promoting adhesion and/or migration of melanocytes in the treatment of vitiligo.

[Receptor-related mechanism of proliferation inhibilion and apoptosis induetion of human tongue squamous cell line Tca8113 by retinoids].

OBJECTIVE: To investigate the receptor-related mechanism of retinoids inhibiting proliferation and inducing apoptosis of human oral squamous cell carcinoma cell line Tca8113. METHODS: The effects of 3 retinoids (namely 9-cis-RA, at-RA and 13-cis-RA), TTNPB (RAR agonist) and methoprene acid (Ma, RXR agonist) on proliferation and cell cycle of Tca8113 cells were analyzed by MTT assay and flow cytometry. The roles of these agents in inducing apoptosis of Tca8113 cells were also evaluated by detecting the expression of Bcl-2/Bax, TUNEL and active caspase-3 analysis. RESULTS: Both retinoids and TTNPB could inhibit the proliferation of Tca8113 cells, and the effect of TTNPB was the most powerful in all the reagents, but MA had no such effect. At the concentration of 1 x 10(-5) mol/L, all the agents except for Ma could increase the percentage of G(1)/G(0)-stage cells after incubation of the cells for 24 h and 48 h. Retinoids and TTNPB could up-regulate the expression of Bax and down-regulate Bcl-2 expression. The results of TUNEL demonstrated that retinoids and TTNPB, but not Ma, could induce apoptosis of Tca8113 cells as compared with the control group (P<0.05). Except for Ma, all the agents up-regulated caspase-3 expression, and the effect of TTNPB was the strongest (P<0.05). CONCLUSIONS: Retinoids can suppress the proliferation of and induce apoptosis of Tca8113 cells, the effect of which involves activation of RAR but not RXR. caspase-3 pathway is involved in apoptosis-inducing effects of retinoids.

Dermatofibrosarcoma protuberans with pit-like lesions: A case report and literature review.

The present study describes a case of pit-like dermatofibrosarcoma protuberans (DFSP) with the clinical manifestations, histopathological features and criteria for diagnosis. The study also reviews the relevant literature in order to raise awareness among dermatologists with regard to the specific behavior of DFSP. A 27-year-old female presented with subcutaneous nodules on the left side of the neck that had been apparent for 5 years and which had gradually begun caving in during the last year. Histopathological examination revealed that the tumor was composed of a large number of spindle cells arranged in a whirlpool-like pattern. Immunohistochemical studies revealed positive staining for cluster of differentiation 34, vimentin and lysozyme, which could be used as diagnostic markers of DFSP. The patient was finally diagnosed with DFSP by pathological and immunohistochemical analyses. The DFSP was treated with an extended resection followed by adjacent skin repair. The patient responded well and no relapse occurred during the 8-month clinical follow-up. Thus, the current study describes a unique pit-like clinical manifestation of DFSP with typical immunohistochemical and pathological features. In addition, histopathological examination revealed a downward depression in the epidermis. Therefore, histopathological examination should be considered as an essential diagnostic tool for DFSP.

Acitretin exerted a greater influence on T-helper (Th)1 and Th17 than on Th2 cells in treatment of psoriasis vulgaris.

T-helper (Th) cells, including Th1, Th2 and Th17 cells, may play an important role in the pathogenesis of psoriasis vulgaris (PV). Acitretin is an effective treatment for PV; however, its influence on Th cells during the treatment of PV is unclear. This study aimed to investigate the influence of acitretin on Th1, Th2 and Th17 cells in PV patients. PV patients (n = 30) received acitretin p.o. (20 mg/day) for 8 weeks. Sera and skin biopsies were obtained before and after treatment. Double-labeled immunofluorescence was used to analyze T, Th1, Th2 and Th17 cells in skin lesions. Enzyme-linked immunosorbent assay and western blot were used to analyze the expressions of interferon (IFN)-γ, interleukin (IL)-4 and IL-17 in sera and skin lesions. The expressions of IFN-γ mRNA, IL-4 mRNA and IL-17 mRNA in skin lesions were detected by in situ hybridization. Acitretin decreased the quantity of T, Th1 and Th17 cells in PV lesions, but had no significant influence on Th2 cells. Acitretin also decreased the expression of IFN-γ and IL-17 in serum and lesions. The expressions of IFN-γ mRNA and IL-17 mRNA decreased significantly after 8 weeks of therapy. However, acitretin had no significant influence on the expression of IL-4 protein and mRNA. Acitretin can reverse Th1 and Th17 preponderance in PV patients to some degree. This may be due to the mechanism of acitretin on PV; however, Th2 cells were not affected by acitretin treatment.

Epidemiologic study of the predisposing factors in erythema toxicum neonatorum.

BACKGROUND: Erythema toxicum neonatorum (ETN) is a very common disease, but its predisposing factors are still unknown. OBJECTIVE: To determine the predisposing factors of ETN. METHODS: Seven hundred and eighty-three neonates born in the same hospital during the same period were investigated, and the factors predisposing to ETN were evaluated in a case-control study. RESULTS: (1) The incidence of ETN is about 43.68%, and it is significantly higher in males than in females (p < 0.001). (2) Term birth (p < 0.05), first-pregnancy birth (p < 0.001), the birth season (summer and autumn, p < 0.005), being fed with milk powder substitute or a mixed diet (p < 0.001) and vaginal delivery (p < 0.001) are the predisposing factors of ETN. (3) The severity of ETN in neonates born by vaginal delivery is significantly correlated with the total length of labor (p < 0.001). CONCLUSION: Our findings suggest that environmental factors play an important role in the onset of ETN.