The Role of Notch Signaling in Genetic Reticular Pigmentary Disorders

Notch signaling is an essential conserved mechanism through local cell interactions.It regulates cell differentiation,proliferation,and apoptotic,influencing organ formation and morphogenesis.Notch signaling plays a vital role in both development of melanocyte during embryogenesis and maintenance of melanocyte stem cells.POFUT1,POGLUT1,ADAM10,presenilin enhancer-2,and nicastrin genes are pathogenic genes of genetic reticular pigmentation diseases Dowling-Degos disease,reticulate acropigmentation of Kitamura,and acne inversa with pigment abnormalities separately.And they are all vital genes in Notch signaling pathway.This group of pigmentary diseases have similarities and overlaps in clinical manifestations and pathological characteristics.We review the essential role of Notch signaling in genetic reticular pigmentary disorders,and discuss the underlying mechanisms behind dysfunction of melanocyte induced by gene mutations in Notch signaling.

NCSTN Gene Silencing Inhibits the Retinoic Acid Signaling Pathway in Human Immortalized Keratinocytes

Objective:Acne inversa is a multifactorial chronic debilitating disease.Genetic factors are involved in 40%of patients,especially the nicastrin(NCSTN)gene.However,the role of the mutated NCSTN gene in the pathogenesis of acne inversa remains unclear.Retinoic acid is recommends to treat moderate to severe acne inversa,therefor we conduct this in vitro research to study the association between NCSTN gene mutation and the retinoic acid signaling pathway in human immortalized skin keratinocyte(HaCaT)cells.Methods:HaCaT cells were infected with a lentivirus-mediated short hairpin RNA(shRNA)expression plasmid specifically targeting the NCSTN gene.Real-time polymerase chain reaction(PCR)and Western blotting were used to detect the interference efficiency of NCSTN.RNA sequencing was used to detect differential genes in the NSCTN-deficient HaCaT cells.Based on bioinformatics analysis and clinical treatment data,the retinoic acid signal pathway was selected for screening.Quantitative PCR was used to verify the changes in the expressions of retinoic acid signaling pathway-related receptors and molecules in the HaCaT cell line after NCSTN silencing.The Student t test and one-way analysis of variance were used to evaluate intergroup differences.Results:Sequencing showed that the NCSTN-shRNA lentiviral recombinant expression plasmid was successfully constructed.After lentivirus infection of HaCaT cells,real-time PCR results showed significantly reduced NCSTN mRNA expression in the interference group compared with the negative control group,and the interference efficiency was 75.0%.Western blotting showed that the inhibition rate of NCSTN protein expression in the shRNA group was 71.7%.RNA sequencing revealed significant differential expression of some genes,and changes in signaling pathways.Compared with the control group,the group with the silenced NCSTN showed significantly decreased expression of retinoic acid receptors(RARα:F=23.482,RARβ:F=603.241,RXRα:F=69.689,and RARRES1:F=167.482,and all P<0.001),and peroxisome proliferator-activated receptorγ(F=8.138,P<0.01).Conclusion:Defective function of the NCSTN gene leads to an impaired retinoic acid signaling pathway in HaCaT cells,which suggests that the retinoic acid signaling pathway may play a role on the onset of acne inversa caused by NCSTN gene mutation.

Targeted treatments of psoriasis vulgaris recommended by guidelines

Introduction Psoriasis is a common chronic recurrent inflammatory skin disease with most common clinical form of chronic plaque type (90%).For moderate-to-severe psoriasis vulgaris patients,who were inadequately responding to other synthetic therapies,targeting therapeutic drugs may have unexpected effects.And with the deepening understanding of pathogenesis,the targeted therapy for psoriasis is increasingly diverse and accurate.Biologic agents can block T cell activation,antagonise T cell secretion of tumor necrosis factor alpha (TNF-α),interleukin (IL)-17,IL-23,and other cytokines,and then effectively block the immune inflammatory response.

Dowling-Degos disease:current research progress

Introduction Dowling-Degos disease (DDD) was first described as a benign form of acanthosis nigricans by Dowling and Freudenthal in 1938, then referred to as'dermatose reticulée des plis'by Degos and Ossipowski in 1954, and was first named DDD by Wilson-Jones and Grice in 1978(1)The disease has been reported worldwide and affects both genders equally. As an autosomal dominant pigment disorder, it usually occurs in post-pubertal individuals, and is seldom seen in children(2)However, a Chinese newborn with DDD was reported in 2008(3)In this review, we summarize features of DDD, emphasizing advances in genetics research and looking to the future for further understanding of its etiology and the development of therapeutic methods.

Papular acantholytic dyskeratosis of the anogenital area with novel ATP2C1 gene mutations

To the Editor:Focal acantholytic dyskeratosis(FAD)is used to describe a group of diseases with diverse clinical manifestations but characteristic histological structures.In 1984,the first case of“papular acantholytic dyskeratosis(PAD)of the vulvocrural area”was reported in a 23-year-old female with pathological manifestations of FAD and the researchers believed that it might be a new independent disease.[1]Recently,the relationship between PAD and Hailey-Hailey disease(HHD)as well as Darier disease(DD)is receiving increasing attention from scholars.We performed gene mutation screening in two patients with sporadic PAD and explored the nature of PAD.

Zebrafish Model of Hereditary Pigmentary Disorders

Introduction Pigmentary disorders are a heterogeneous group of hereditary or acquired disorders characterized by varying degrees of hyperpigmentation and/or hypopigmentation.Pigmentary disorders originate from abnormalities in melanocyte development,defects in melanin synthesis,or changes in melanosome transfer.1-2 Several skin pigmentation disorders and diseases are heritable,including dyschromatosis universalis hereditaria(DUH),Dowling-Degos disease(DDD),and albinism.To elucidate the pathogenesis of these heritable pigmentary disorders,a cross-species approach has been widely applied and has resulted in a detailed understanding of melanocyte physiology and pathophysiology.

Disseminated pyoderma gangrenosum with oral involvement:successful treatment with systemic steroids and cyclosporine

Introduction Pyoderma gangrenosum (PG) is a chronic skin disease characterized by progressive lesions that present as painful suppurative ulcers and tend to recur. The pathogenesis of the disease is incompletely under-stood;however, 50%to 70%of affected persons have an associated concomitant systemic disease such as inflammatory bowel disease (IBD) (1)Any site of the body can be affected;however, involvement of the oropharynx is rare. Here, we present a patient with disseminated PG with oropharyngeal involvement.