Based on network pharmacology and bioinformatics to analyze the mechanism of action of Astragalus membranaceus in the treatment of vitiligo and COVID-19.

Coronavirus disease 2019 (COVID-19) is spreading rapidly around the world. However, the treatment of vitiligo combined with COVID-19 has not been reported. Astragalus membranaceus (AM) has a therapeutic effect on patients with vitiligo and COVID-19. This study aims to discover its possible therapeutic mechanisms and provide potential drug targets. Using the Chinese Medicine System Pharmacological Database (TCMSP), GEO database and Genecards websites and other databases, AM target, vitiligo disease target, and COVID-19 related gene set were established. Then find the crossover genes by taking the intersection. Then use GO, KEGG enrichment analysis, and PPI network to discover its underlying mechanism. Finally, by importing drugs, active ingredients, crossover genes, and enriched signal pathways into Cytoscape software, a "drug-active ingredient-target signal pathway-" network is constructed. TCMSP screened and obtained 33 active ingredients including baicalein (MOL002714), NEOBAICALEIN (MOL002934), Skullcapflavone II (MOL002927), and wogonin (MOL000173), which acted on 448 potential targets. 1166 differentially expressed genes for vitiligo were screened by GEO. CIVID-19 related genes were screened by Genecards. Then by taking the intersection, a total of 10 crossover genes (PTGS2, CDK1, STAT1, BCL2L1, SCARB1, HIF1A, NAE1, PLA2G4A, HSP90AA1, and HSP90B1) were obtained. KEGG analysis found that it was mainly enriched in signaling pathways such as IL-17 signaling pathway, Th17 cell differentiation, Necroptosis, NOD-like receptor signaling pathway. Five core targets (PTGS2, STAT1, BCL2L1, HIF1A, and HSP90AA1) were obtained by analyzing the PPI network. The network of "active ingredients-crossover genes" was constructed by Cytoscape, and the 5 main active ingredients acting on the 5 core crossover genes acacetin, wogonin, baicalein, bis2S)-2-ethylhexyl) benzene-1,2-dicarboxylate and 5,2'-Dihydroxy-6,7,8-trimethoxyflavone. The core crossover genes obtained by PPI and the core crossover genes obtained by the "active ingredient-crossover gene" network are intersected to obtain the three most important core genes (PTGS2, STAT1, HSP90AA1). AM may act on PTGS2, STAT1, HSP90AA1, etc. through active components such as acacetin, wogonin, baicalein, bis2S)-2-ethylhexyl) benzene-1,2-dicarboxylate and 5,2'-Dihydroxy-6,7,8-trimethoxyflavone to activate IL-17 signaling pathway, Th17 cell differentiation, Necroptosis, NOD-like receptor signaling pathway, Kaposi sarcoma-associated herpesvirus infection, and VEGF signaling pathway and other signaling pathways to achieve the effect of treating vitiligo and COVID-19.

Altered levels of lymphocyte enhancer-binding factor-1 modulates the pigmentation in acral and non-acral lesions of non-segmental vitiligo patients: a follow-up-based study in North India.

BACKGROUND: Lymphocyte enhancer-binding factor-1 (LEF1) is responsible for melanocyte proliferation, migration and differentiation and its downregulation may result in depigmentation in vitiligo. Narrowband UVB (NB-UVB) phototherapy is known to enhance melanocyte migration from hair follicles to lesional epidermis; hence, it may have a role in the upregulation of LEF1. OBJECTIVES: We intended to assess the expression of LEF1 both before and after NB-UVB therapy and correlate it with the extent of re-pigmentation. MATERIALS AND METHODS: In this prospective cohort study, 30 patients of unstable non-segmental vitiligo were administered NB-UVB phototherapy for 24 weeks. Skin biopsies were obtained from acral and non-acral sites in all patients, both prior to initiation and after completion of phototherapy and LEF1 expression was measured. RESULTS: Amongst the 16 patients who completed the study, at 24 weeks, all patients achieved > 50% re-pigmentation. However, > 75% re-pigmentation was achieved in only 11.1% of acral patches, whereas it was achieved in a significantly higher number of non-acral patches (66.6%) (p = 0.05). A significant increase was observed in the mean fluorescent intensity of the LEF1 gene in both acral as well as non-acral areas at 24 weeks as compared to baseline (p = 0.0078), However, no difference was observed between acral and non-acral lesions in the LEF1 expression at 24 weeks or the change in LEF1 expression from baseline. CONCLUSION: LEF1 expression modulates the re-pigmentation of vitiligo lesions after treatment with NBUVB phototherapy.

Contributions of NR1H3 genetic polymorphisms to susceptibility and effects of narrowband UVB phototherapy to nonsegmental vitiligo.

Vitiligo is the most common depigmenting disorder to which both genetic and environmental factors contribute. The aim of the current work was to evaluate the relationship between polymorphisms of the gene nuclear receptor subfamily 1 Group H member 3 (NR1H3) and the risk of vitiligo and phototherapy effects in the Chinese Han population. Two independent samples were enrolled to form the discovery set (comprised of 1668 nonsegmental vitiligo [NSV] patients and 2542 controls) and the validation set (comprised of 745 NSV patients and 1492 controls). A total of 13 tag single nucleotide polymorphisms (SNPs) were genotyped in the samples from the discovery stage. SNPs that achieved nominal significance were validated in another independent sample set. The serum level of NR1H3 protein was assayed using enzyme-linked immunosorbent assay kits in the validation set. Genetic association analysis was carried out at allelic and genotypic levels. The therapeutic effects of significant SNPs were examined in the validation set. The SNP rs3758672 was significantly associated with NSV. The A allele was correlated with NSV risk and poorer therapeutic effects. The A allele was strongly correlated with the increased level of serum NR1H3 in both controls and patients. In summary, SNP rs3758672 in NR1H3 was significantly associated with both disease susceptibility and individualized therapeutic effects of NSV in study participants with Han Chinese ancestry.

Evaluation of vitamin D receptor gene polymorphisms (ApaI and TaqI) as risk factors of vitiligo and predictors of response to narrowband UVB phototherapy.

Vitiligo is acquired depigmentation due to multiple factors. Vitamin D in skin, through its receptors (VDR), regulates cell growth, differentiation, immune response and exerts both stimulatory and protective effects on melanocytes. The gene sequence encoding VDR has polymorphic forms such as ApaI and TaqI that may affect vitamin D actions. Narrowband ultraviolet B (NB-UVB) phototherapy became the mainstay of vitiligo treatment because of its efficacy and little side effects. The current work aimed at evaluating the possible association between VDR gene polymorphisms (TaqI and ApaI) and susceptibility of vitiligo and if they could be predictors of response to NB-UVB phototherapy in Egyptian vitiligo patients. 100 vitiligo patients indicated for NB-UVB phototherapy and 100 healthy age and sex matched controls were included. All participants were subjected to history taking, general and dermatological examinations, and VDR ApaI and TaqI gene polymorphisms analysis by PCR-RFLP. The patients received NB-UVB 3times per week for 6 months then revaluated. There was significant increase in Aa genotype of ApaI polymorphism in patients associated with significant increase in vitiligo activity. 66% of patient showed variable degrees of response to NB-UVB. The responders significantly had AA genotype of ApaI polymorphism. TaqI polymorphism showed nonsignificant effects on vitiligo susceptibility and response to NB-UVB. A allele of ApaI was significant independent predictor of NB-UVB phototherapy responders. VDR gene polymorphism (ApaI) may share in vitiligo pathogenesis and response to NB-UVB. Knowing the genetic background of the patient helps individualization of treatment to get better results.

Molecular mechanism of vitiligo treatment by bailing tablet based on network pharmacology and molecular docking.

BACKGROUND: Bailing tablet, a patent Chinese medicine, is widely used to treat vitiligo in China. However, the underlying mechanism of this combined drug in treating vitiligo still remains unclear. OBJECTIVE: This study aimed to investigate the pharmacological mechanism of bailing tablet in the prevention and treatment of vitiligo using network pharmacology and molecular docking. METHODS: Genetic data of vitiligo and normal people were obtained by gene expression omnibus (GEO) DataSets database and GEO difference analysis was conducted to obtain differential genes. The main active compounds and corresponding target genes of bailing tablet were collected from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Combined with the results of GEO difference analysis, the main compounds and corresponding target genes of bailing tablet in the treatment of vitiligo were screened. The network diagram of "traditional Chinese medicine compound target" was constructed by Cytoscape software. According to the differential genes, the core targets with potential therapeutic effect were searched, the protein-protein interaction network was constructed, and the key proteins were explored by topological analysis (CytoNCA). Meanwhile, the core targets were analyzed by biological process (gene ontology) and signal pathway (Kyoto encyclopedia of genes and genomes) function enrichment. Molecular docking technology was adopted to verify the combination of main components and core targets. RESULTS: A total of 170 active compounds and 1777 prediction targets were screened from 11 traditional Chinese medicines of bailing tablet, of which 65 active components and 68 related prediction targets were closely related to vitiligo. A total of 320 key proteins were obtained by analyzing the topological characteristics of the protein-protein interaction network, mainly including neurotrophic receptor tyrosine kinase 1, tumor protein P53, cullin 3, estrogen receptor 1, etc. The main biological processes involve oxidative stress response, cell response to reactive oxygen species, and reactive oxygen species metabolism. Bailing tablet treats vitiligo mainly by regulating immune inflammation, apoptosis, and autophagy, which involves phosphatidylinositol-4,5-bisphosphate 3-kinase Akt signal pathway, mitogen-activated protein kinase signal pathway, Janus kinase signal transducer and activator of transcription signal pathway, melanin production, and helper T cell (Th)1, Th2, and Th17 differentiation pathway, etc. Molecular docking results showed that the main components could bind to the target protein well. CONCLUSIONS: Based on network pharmacology and molecular docking, the mechanism of bailing tablet in the treatment of vitiligo through multicomponent, multitarget, and multichannel was deeply explored.

Current Debates on Etiopathogenesis and Treatment Strategies for Vitiligo.

Vitiligo is an acquired, chronic, and progressive depigmentation or hypopigmentation characterized by the destruction of melanocytes and the occurrence of white patches or macules in the skin, mucosal surface of eyes, and ears. Melanocytes are the melanin pigment-producing cells of the skin which are destroyed in pathological conditions called vitiligo. Approximately 0.5 - 2.0% of the population is suffering from vitiligo, and a higher prevalence rate of up to 8.8% has been reported in India. It is caused by various pathogenic factors like genetic predisposition, hyperimmune activation, increased oxidative stress, and alteration in neuropeptides level. Genetic research has revealed a multi- genetic inheritance that exhibits an overlap with other autoimmune disorders. However, melanocytes specific genes are also affected (such as DDR1, XBP1, NLRP1, PTPN22, COMT, FOXP3, ACE, APE, GSTP1, TLR, SOD, and CTLA-4). A number of therapeutic options are employed for the treatment of vitiligo. The topical corticosteroids and immunomodulators are currently in practice for the management of vitiligo. Phototherapies alone and in combinations with other approaches are used in those patients who do not respond to the topical treatment. The main focus of this review is on the etiopathological factors, pharmacological management (phototherapy, topical, systemic, and surgical therapy), and herbal drugs used to treat vitiligo.

The multi-target mechanism of Cyclosporin A in the treatment of vitiligo based on network pharmacology.

Network pharmacology is an emerging discipline that designs drugs based on systems biology theory and biological system network analysis. Here, we applied network pharmacology to analyze the multi-target mechanism of Cyclosporin A in the treatment of vitiligo First, we predicted the targets of Cyclosporin A. Second, we obtained the genes related to vitiligo from the database. Third, we constructed the PPI network of the mutual genes between Cyclosporin A and vitiligo and used gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to analyze. Finally, we verified the prediction of potential targets through a docking study with Cyclosporin A. We found that there were 15 shared target genes between Cyclosporin A and vitiligo. We analyzed these 15 genes by Cytoscape and obtained a network diagram of 885 nodes. Through screening and molecular docking, PRKDC, CUL7, CUL1, HSPA8, HSPA4, and SIRT7 were the most likely multi-target mechanism of Cyclosporin A in the treatment of vitiligo. In our study, Cyclosporin A might not only affect the repair of DNA strands by targeting PRKDC, but also affected the innate and adaptive immune function of vitiligo patients by the targets of CUL1, CUL7, and HSP70. In addition, Cyclosporin A might promote the repigmentation of vitiligo by adjusting the expression of SIRT7.

DEFB1 gene polymorphisms modify vitiligo extent and response to NB-UVB phototherapy.

Human beta defensin-1(hBD-1); an antimicrobial peptide, has immune regulatory effects which may be involved in autoimmunity. The aims were to evaluate the association between defensin beta 1 (DEFB1) (-44 C/G) and (-20 G/A) gene polymorphisms with the risk of vitiligo development, the extent of the disease and the response to NB-UVB treatment in a sample of Egyptian population. 178 active nonsegmental vitiligo patients and 182 control subjects were included in this prospective case control study. Vitiligo extent was evaluated using vitiligo area scoring index (VASI). Gene polymorphisms in all participants were studied by RFLP PCR technique. Patients were treated by three narrowband UVB (NB-UVB) treatment sessions per week. After 12 weeks, the patients were reevaluated clinically to assess the extent of the disease using VASI scoring again and to evaluate the type of repigmentation, if any. AA genotype of DEFB1 (-20G/A) has a protective role against vitiligo development, while (DEFB1 -44 C/G) GG genotype and G allele increase the risk of vitiligo development about two folds. Patients carrying polymorphism in DEFB1 (-20G/A) only showed the lowest VASI scores (14.23 ± 2.77) and the highest percentage of improvement (66.12 ± 18.01%), while patients carrying polymorphism in DEFB1(-44 C/G) only showed the highest baseline VASI scores (38.87 ± 6.7) and the lowest therapeutic response (23.79 ± 19.42%) among all patients groups. Different DEFB1 gene polymorphisms may modify the risk of vitiligo development, the disease extent and the response to NB-UVB phototherapy.

Evaluation of the effect of narrow band-ultraviolet B on the expression of tyrosinase, TYRP-1, and TYRP-2 mRNA in vitiligo skin and their correlations with clinical improvement: A retrospective study.

Narrowband-ultraviolet B (NB-UVB) is considered one of the main therapeutic tools in vitiligo, which is able to induce repigmentation and halt depigmentation. However, little remains known about the effect of NB-UVB on TYR gene family, the main pigmentary genes, in vitiligo patients. To assess the effect of NB-UVB on expression of some genes related to the pigmentary problem of vitiligo; tyrosinase (TYR), tyrosinase related protein 1 (TYRP1) and tyrosinase related protein 2 (TYRP2), mRNA levels of those genes were quantitatively evaluated by Real-Time quantitative Polymerase Chain Reaction (RT-qPCR) in skin biopsies obtained from 30 patients with nonsegmental vitiligo and five healthy controls. Vitiligo patients were classified into two groups; group 1, involving 12 untreated vitiligo patients and group 2, including 18 vitiligo patients treated by NB-UVB. The levels of TYR, TYRP-1, and TYRP-2 mRNAs in untreated group were significantly lower than in control subjects (P < .001). In NB-UVB treated group, the three genes were significantly higher than in group 1 (P < .001), however, they were still significantly lower than in the control subjects (P < .001). A significant positive correlation was detected between TYR and TYRP-2 genes in group 2 (P = .03). This study demonstrated that mRNA level of TYR, TYRP-1, and TYRP-2, which decreased in vitiligo, was significantly increased upon treatment with NB-UVB. Accordingly, the mechanism of depigmentation in vitiligo disease and repigmentation by NB-UVB treatment may be related to the changes in the expression of these genes.

Cytokines: the yin and yang of vitiligo pathogenesis.

INTRODUCTION: Dysregulation of melanocyte function is associated with vitiligo, an idiopathic autoimmune hypopigmentary skin disorder, caused by the selective destruction of melanocytes. Cytokines, the key mediators of immune response, which are pivotal in maintaining immune homeostasis, are crucial in vitiligo pathogenesis. Several studies indicate that there is an imbalance between pro- and anti-inflammatory cytokines in the skin and serum of vitiligo patients. Areas covered: In this comprehensive review, we have summarized the correlation of cytokine imbalance and vitiligo pathogenesis, its role in melanocyte biology, and its impact on vitiligo treatment. We have integrated various published reports on the levels of major cytokines from skin and serum samples of vitiligo patients. We have also discussed the role of endoplasmic reticulum and oxidative stress on cytokine imbalance and vice versa leading to destruction of melanocytes. Expert commentary: The review reflects that dysregulation of cytokines is multifactorial, ranging from genetic predisposition to altered protein expression relevant to vitiligo pathogenesis. We emphasize that cytokine imbalance in systemic and skin microenvironment plays a crucial role in vitiligo pathogenesis and has promising potential as therapeutic targets for vitiligo.

Evaluation of skin expression profiles of patients with vitiligo treated with narrow-band UVB therapy by targeted RNA-seq

Abstract: Background: Vitiligo is characterized by a lack of pigmentation in the skin. To date, there are no studies that analyze the changes in gene expression in the skin of vitiligo patients in response to narrow-band ultraviolet B (nb-UVB) phototherapy treatment. Objective: Explore the usefulness of new generation RNA sequencing in the identification of gene expression changes in the skin of vitiligo patients treated with nb-UVB phototherapy. Methods: Four skin biopsies (4mm in diameter) were collected from 45 Mexican vitiligo vulgaris patients, 2 specimens before and 2 after treatment with nb-UVB phototherapy, obtained from pigmented and non-pigmented tissue. RNA extracted from the biopsies was analyzed using the Illumina TruSeq Targeted RNA Expression protocol to study the expression of genes that participate in pathways of skin homeostasis. The 2 groups were compared using Student's t-test and the Mann-Whitney U-test. Results: The expression analysis identified differences in 12 genes included in this study after comparing the samples obtained before and after treatment: 5 genes involved in skin pigmentation, 2 genes involved in apoptosis, 2 genes involved in cell survival, 2 genes involved in oxidative stress responses and 1 gene involved in signal transduction mechanisms (p<0.05). Study limitations: The small size of skin biopsies limits the amount of RNA obtained, the number of genes to be analyzed and the use of conventional techniques such as RT-qPCR. Conclusion: We demonstrated usefulness of new generation RNA sequencing in the identification of gene expression changes, in addition to identifying new targets in the study of vitiligo.

Evaluation of skin expression profiles of patients with vitiligo treated with narrow-band UVB therapy by targeted RNA-seq.

BACKGROUND: Vitiligo is characterized by a lack of pigmentation in the skin. To date, there are no studies that analyze the changes in gene expression in the skin of vitiligo patients in response to narrow-band ultraviolet B (nb-UVB) phototherapy treatment. OBJECTIVE: Explore the usefulness of new generation RNA sequencing in the identification of gene expression changes in the skin of vitiligo patients treated with nb-UVB phototherapy. METHODS: Four skin biopsies (4mm in diameter) were collected from 45 Mexican vitiligo vulgaris patients, 2 specimens before and 2 after treatment with nb-UVB phototherapy, obtained from pigmented and non-pigmented tissue. RNA extracted from the biopsies was analyzed using the Illumina TruSeq Targeted RNA Expression protocol to study the expression of genes that participate in pathways of skin homeostasis. The 2 groups were compared using Student's t-test and the Mann-Whitney U-test. RESULTS: The expression analysis identified differences in 12 genes included in this study after comparing the samples obtained before and after treatment: 5 genes involved in skin pigmentation, 2 genes involved in apoptosis, 2 genes involved in cell survival, 2 genes involved in oxidative stress responses and 1 gene involved in signal transduction mechanisms (p<0.05). STUDY LIMITATIONS: The small size of skin biopsies limits the amount of RNA obtained, the number of genes to be analyzed and the use of conventional techniques such as RT-qPCR. CONCLUSION: We demonstrated usefulness of new generation RNA sequencing in the identification of gene expression changes, in addition to identifying new targets in the study of vitiligo.

Baicalein protects human vitiligo melanocytes from oxidative stress through activation of NF-E2-related factor2 (Nrf2) signaling pathway.

Vitiligo is a complex disorder characterized by patchy loss of skin pigmentation due to abnormal melanocyte function. Overwhelming evidences have suggested that oxidative stress plays a major role in the loss of melanocytes thereby mediating the onset and progression of vitiligo. The nuclear factor erythroid 2-like factor 2 (Nrf2) is a master regulator of cellular redox homeostasis and the activation of Nrf2 signaling pathway is impaired in the vitiligo melanocytes. Baicalein, as flavonoid extracted from the Scutellaria baicalensis, has been proved to possess the ability to activate Nrf2 signaling pathway in other cell types and mouse model. Our previous data found that baicalein exerts a cytoprotective role in H2O2-induced apoptosis in human melanocytes cell line (PIG1). Based on these founding, we hypothesized that baicalein activates Nrf2 signaling pathway, alleviates H2O2-induced mitochondrial dysfunction and cellular damage, thereby protecting human vitiligo melanocytes from oxidative stress. In the present study, we found that baicalein effectively inhibited H2O2-induced cytotoxicity and apoptosis in human vitiligo melanocytes (PIG3V). Further results demonstrated that baicalein promoted Nrf2 nucleus translocation as well as up-regulated the expression of Nrf2 and its target gene, heme oxygenase-1 (HO-1). Moreover, the protective effects of baicalein against H2O2-induced cellular damage and apoptosis as well as mitochondrial dysfunction were abolished by Nrf2 knockdown. Additionally, we observed that Nrf2 knockdown suppressed proliferation and increased the sensitivity of PIG3V cells to H2O2 treatment. Finally, we explored the mechanism of baicalein associated with Nrf2 activation and found that the phosphorylation of Nrf2 as well as ERK1/2and PI3K/AKT signaling were not involved in the baicalein-induced activation of Nrf2. Taken together, these data clearly suggest that baicalein enhances cellular antioxidant defense capacity of human vitiligo melanocytes through the activation of the Nrf2 signaling pathway, providing beneficial evidence for the application of baicalein in the vitiligo treatment.

The role of systemic steroids and phototherapy in the treatment of stable vitiligo: a randomized controlled trial.

Pathogenesis of vitiligo is believed to be multifactorial disease with a wide variety of therapeutic modalities. The aim of this work is to assess the efficacy of oral mini-pulse steroids (OMP) plus Nb-U.V.B in comparison to OMP alone and Nb-U.V.B alone in treating stable vitiligo. A prospective randomized controlled study including 45 patients categorized into three groups receiving therapy for 3 months; Group A received Nb-U.V.B plus OMP, Group B received OMP alone while Group C received Nb-U.V.B alone. Clinical assessment and PCR evaluation of bFGF, ICAM1, and ELISA for AMA were done. Patients receiving Nb-U.V.B plus OMP and using Nb-U.V.B alone gave statistically significant clinical response than those treated with OMP alone. Statistically significant rise of BFGF was noticed after treatment with Nb-U.V.B plus OMP and with Nb-U.V.B alone. Patients treated with OMP alone and with Nb-U.V.B alone showed statistically significant drop of ICAM-1 after therapy. NB-U.V.B plus OMP and Nb-U.V.B alone were found to be clinically superior over OMP alone in treating stable vitiligo patients, hence suggesting that adding OMP to Nb-U.V.B can maintain clinical and laboratory success for a longer period of time and with less relapse.

Evaluation of the correlation between serum levels of vitamin D and vitamin D receptor gene polymorphisms in an Egyptian population.

BACKGROUND: Vitiligo is an autoimmune depigmentation disorder. Polymorphisms in the vitamin D receptor (VDR) have been found to be associated with vitiligo. OBJECTIVES: To evaluate the potential association between VDR gene polymorphisms (ApaI, TaqI, and FokI) and vitiligo susceptibility, and to detect if there is correlation between serum 25-hydroxyvitamin D [25(OH)D] levels and vitiligo and between VDR gene polymorphisms and 25(OH)D levels in vitiligo. MATERIALS AND METHODS: Seventy-five patients with vitiligo and 75 age and sex-matched controls were subjected to detailed history taking and dermatological examination to determine the extent and clinical type of vitiligo. A blood sample (5 ml) was retrieved to investigate VDR gene polymorphisms and serum 25(OH)D level. RESULTS: Our results showed that the serum level of vitamin D is statistically significantly lower in patients than controls. The frequency of the ApaI variant a allele, the variant genotype (aa), and the variant genotype (tt) were significantly higher among the vitiligo cases than among controls. Our study also showed that the serum 25(OH)D levels were not significantly different among the different ApaI, TaqI, and FokI genotypes. CONCLUSION: The present study showed that serum level of 25(OH)D is statistically significantly lower in patients than controls, so screening for vitamin D deficiency seems of value in patients with vitiligo for the possibility of vitamin D supplementation. We also report that VDR gene polymorphisms may be a risk for the development of vitiligo in an Egyptian population.

Understanding autoimmunity of vitiligo and alopecia areata.

PURPOSE OF REVIEW: Vitiligo and alopecia areata are common, disfiguring skin diseases. Treatment options are limited and include nontargeted approaches, such as corticosteroids, topical calcineurin inhibitors, narrow band ultraviolet B phototherapy, and other immune-modifying agents. The purpose of this article is to review shared, novel mechanisms between vitiligo and alopecia areata, as well as discuss how they inform the development of future targeted treatments. RECENT FINDINGS: Vitiligo and alopecia areata are both autoimmune diseases, and striking similarities in pathogenesis have been identified at the level of both the innate and adaptive immune system. Increased reactive oxygen species and high cellular stress level have been suggested as the initiating trigger of the innate immune system in both diseases, and genome-wide association studies have implicated risk alleles that influence both innate and adaptive immunity. Most importantly, mechanistic studies in mouse models of vitiligo and alopecia areata have specifically implicated an interferon (IFN)γ-driven immune response, including IFNγ, IFNγ-induced chemokines, and cytotoxic CD8 T cells as the main drivers of disease pathogenesis. These recent discoveries may reveal an effective strategy to develop new treatments, and several proof-of-concept clinical studies support this hypothesis. SUMMARY: The identification of IFNγ-driven immune signaling pathways has enabled discoveries of potential new treatments for vitiligo and alopecia areata, and supports initiation of larger clinical trials.

The role of IL-17 in vitiligo: A review.

IL-17 is involved in the pathogenesis of several autoimmune diseases; however its role in vitiligo has not been well defined. Emerging human and mouse studies have demonstrated that systemic, tissue, and cellular levels of IL-17 are elevated in vitiligo. Many studies have also shown significant positive correlations between these levels and disease activity, extent, and severity. Treatments that improve vitiligo, such as ultraviolet B phototherapy, also modulate IL-17 levels. This review synthesizes our current understanding of how IL-17 may influence the pathogenesis of autoimmune vitiligo at the molecular level. This has implications for defining new vitiligo biomarkers and treatments.

A functional single-nucleotide polymorphism in the ERCC1 gene alters the efficacy of narrowband ultraviolet B therapy in patients with active vitiligo in a Chinese population.

BACKGROUND: T lymphocytes have been shown to cause the destruction of melanocytes in vitiligo pathogenesis. Narrowband ultraviolet B (NB-UVB), as an effective therapeutic strategy in vitiligo, can lead to the formation of DNA photoproducts such as cyclobutane pyrimidine dimers (CPDs) in perilesional lymphocytes and thus induce skin immunosuppression. The repair of DNA photoproducts is performed mainly through the nucleotide excision repair (NER) pathway. We hypothesized that single-nucleotide polymorphisms (SNPs) in NER genes might influence the repair capacity of CPDs and thus contribute to variations in phototherapy efficiency. OBJECTIVES: To detect genetic polymorphisms in NER genes and their relationship with the efficacy of NB-UVB therapy in patients with active vitiligo. METHODS: We investigated the association of NER SNPs (XPA A23G, XPC Ci11A, XPC C2919A and ERCC1 C118T) with phototherapy efficacy in 86 patients with vitiligo who received NB-UVB treatment. Furthermore, we examined the impact of ERCC1 C118T on the apoptosis of T lymphocytes and CPD accumulation after NB-UVB irradiation. RESULTS: We found that patients with vitiligo with the ERCC1 codon 118 CC genotype showed better efficacy after NB-UVB irradiation than those with the ERCC1 118 TT and CT genotypes, whereas no such association was documented among the genotypes of XPA A23G, XPC Ci11A or XPC C2919A. Additionally, the apoptosis rates and CPD levels of lymphocytes after NB-UVB irradiation in patients with the ERCC1 118 CC genotype were significantly higher than those in patients with the ERCC1 118 TT and CT genotypes. CONCLUSIONS: The ERCC1 118 CC genotype confers better efficacy of NB-UVB therapy in patients with active vitiligo.

Repair efficiency and PUVA therapeutic response variation in patients with vitiligo.

Vitiligo is an acquired depigmentation disorder affecting 0.1% to >8.8% in Indian population. Psoralen and ultraviolet A radiation (PUVA) is a gold standard treatment for vitiligo, however, response is still empirical. In order to investigate whether drug response variation is influenced by the repair ability of PUVA treated vitiligo subjects, single cell gel electrophoresis (SCGE) for genotoxicity and serum malonaldehyde (MDA) for cytotoxicity were performed on 107 subjects (77 cases and 30 healthy controls) in South Indian population. In vitro repair ability was assessed by considering the residual damage. A significant difference was observed between the patients and controls with regard to their mean values of DNA damage and MDA levels (p<0.05). On categorization to fast and slow responders based on the time of response, patients exhibited a significant deviation in residual DNA damage, suggestive of variation with respect to DNA repair efficiency (p<0.05). This is the first study to our knowledge with respect to PUVA drug response variation in vitiligo in relation to DNA repair. Large systematic studies on DNA repair may help in a better understanding of the mechanisms involved in the PUVA drug response variation.

Low-energy helium-neon laser induces melanocyte proliferation via interaction with type IV collagen: visible light as a therapeutic option for vitiligo.

BACKGROUND: The treatment of vitiligo remains a challenge for clinical dermatologists. We have previously shown that the helium-neon laser (He-Ne laser, 632.8 nm) is a therapeutic option for treatment of this depigmentary disorder. OBJECTIVES: Addressing the intricate interactions between melanocytes, the most important cellular component in the repigmentation scheme of vitiligo, and their innate extracellular matrix collagen type IV, the current study aimed to elucidate the effects of the He-Ne laser on melanocytes. METHODS: Cultured melanocytes were irradiated with the He-Ne laser. Relevant biological parameters including cell attachment, locomotion and growth were evaluated. In addition, the potentially involved molecular pathways were also determined. RESULTS: Our results show that in addition to suppressing mobility but increasing attachment to type IV collagen, the He-Ne laser stimulates melanocyte proliferation through enhanced alpha2beta1 integrin expression. The expression of phosphorylated cyclic-AMP response element binding protein (CREB), an important regulator of melanocyte growth, was also upregulated by He-Ne laser treatment. Using a specific mitochondrial uncoupling agent [carbonyl cyanide m-chlorophenyl-hydrazone (CCCP)], the proliferative effect of the He-Ne laser on melanocytes was abolished and suppression of melanocyte growth was noted. CONCLUSIONS: In summary, we have demonstrated that the He-Ne laser imparts a growth stimulatory effect on functional melanocytes via mitochondria-related pathways and proposed that other minor pathways including DNA damage may also be inflicted by laser treatment on irradiated cells. More importantly, we have completed the repigmentation scheme of vitiligo brought about by He-Ne laser light in vitro and provided a solid theoretical basis regarding how the He-Ne laser induces recovery of vitiligo in vivo.