The skin, which serves as the first barrier of the human body, is particularly susceptible to exogenous injuries. Skin wounds, including acute burns and chronic non-healing ulcers, are commonly ...observed in clinics. Healing of skin wounds is a complex process, consisting of infiltration of inflammatory cells, cellular proliferation, and tissue remodeling phases, which restore the integrity and functions of the skin. Epithelialization is involved in wound healing through re-establishing an intact keratinocyte layer. Epidermal stem cells are indispensable for epithelialization, and they are regulated by multiple proinflammatory cytokines or growth factors. In this review, we summarize recent advances in the effect of these cytokines on migration, proliferation, and differentiation processes of epidermal stem cells. We also introduce promising therapeutic strategies targeting epidermal stem cells or related proinflammatory cytokines for patients with skin wounds.
Viaminate, a vitamin A acid drug developed in China, has been clinically used in acne treatment to regulate epithelial cell differentiation and proliferation, inhibit keratinization, reduce sebum ...secretion, and control immunological and anti-inflammatory actions; however, the exact method by which it works is unknown.
In the present study, acne was induced in the ears of rats using
acnes combined with sebum application.
After 30 days of treatment with viaminate, the symptoms of epidermal thickening and keratin overproduction in the ears of rats were significantly improved. Transcriptomic analysis of rat skin tissues suggested that viaminate significantly regulated the biological pathways of cellular keratinization. Gene differential analysis revealed that the S100A8 and S100A9 genes were significantly downregulated after viaminate treatment. The results of qPCR and Western blotting confirmed that viaminate inhibited the expression of S100A8 and S100A9 genes and proteins in rat and HaCat cell acne models, while its downstream pathway MAPK (MAPK p38/JNK/ERK1/2) protein expression levels were suppressed. Additional administration of the S100A8 and S100A9 complex protein significantly reversed the inhibitory effect of viaminate on abnormal proliferation and keratinization levels in acne cell models.
In summary, viaminate can improve acne by modulating S100A8 and S100A9 to inhibit MAPK pathway activation and inhibit keratinocyte proliferation and keratinization levels.
Cutaneous malignant melanoma (CMM) ranks the most lethal skin cancer worldwide. However, other risk factors have been hardly explored, aside from ultraviolet radiation (UVR). Polychlorinated ...biphenyls (PCBs) were implied to be potential risk factors for CMM, although all the evidence was obtained from the western countries. This study examined the relationships between plasma levels of PCBs and CMM risk adjusting for sun sensitivity and sun exposure in a Chinese population, using a case-control study, including 450 CMM cases and 500 healthy controls. Plasma levels of a total of 33 PCB congeners were assayed in both cases and controls. Our results showed that there was a significant association between total summed PCB level and CMM risk, with a 1.44-fold increased risk for those in the highest quartile compared to those in the lowest quartile (OR = 1.44, 95% CI: 1.02–2.03, P for trend = 0.031). Significantly increased ORs were also observed for individual PCB congeners (PCB52, PCB170 and PCB180). These associations persisted after control for sun sensitivity and sun exposure. Our study represents the first evidence conducted in Asians, and does support the hypothesis that PCB exposure increases CMM risk.
•Significant associations were detected between plasma levels of PCBs and risk of cutaneous malignant melanoma.•This study is the largest study to examine the relationships between plasma levels of PCBs and CMM risk.•Our study represented the first evidence conducted in Asians.
Tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) participates in multiple biological activities via binding to its sole receptor—fibroblast growth factor-inducible 14 (Fn14). The ...TWEAK/Fn14 signaling pathway is activated in skin inflammation and modulates the inflammatory responses of keratinocytes by activating nuclear factor-κB signals and enhancing the production of several cytokines, including interleukins, monocyte chemotactic protein-1, RANTES (regulated on activation, normal T cell expressed and secreted), and interferon gamma-induced protein 10. Mild or transient TWEAK/Fn14 activation contributes to tissular repair and regeneration while excessive or persistent TWEAK/Fn14 signals may lead to severe inflammatory infiltration and tissue damage. TWEAK also regulates cell fate of keratinocytes, involving the function of Fn14-TNF receptor-associated factor-TNF receptor axis. By recruiting inflammatory cells, promoting cytokine production, and regulating cell fate, TWEAK/Fn14 activation plays a pivotal role in the pathogenesis of various skin disorders, such as psoriasis, atopic dermatitis, cutaneous vasculitis, human papillomavirus infection and related skin tumors, and cutaneous autoimmune diseases. Therefore, the TWEAK/Fn14 pathway may be a potential target for the development of novel therapeutics for skin inflammatory diseases.
The skin is a complex organ that faces the external environment and participates in the innate immune system. Skin immune homeostasis is necessary to defend against external microorganisms and to ...recover from stress to the skin. This homeostasis depends on interactions among a variety of cells, cytokines, and the complement system. Collectins belong to the lectin pathway of the complement system, and have various roles in innate immune responses. Mannose-binding lectin (MBL), collectin kidney 1, and liver (CL-K1, CL-L1) activate the lectin pathway, while all have multiple functions, including recognition of pathogens, opsonization of phagocytosis, and modulation of cytokine-mediated inflammatory responses. Certain collectins are localized in the skin, and their expressions change during skin diseases. In this review, we summarize important advances in our understanding of how MBL, surfactant proteins A and D, CL-L1, and CL-K1 function in skin immune homeostasis. Based on the potential roles of collectins in skin diseases, we suggest therapeutic strategies for skin diseases through the targeting of collectins and relevant regulators.
Tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) engages its sole receptor, fibroblast growth factor-inducible 14 (Fn14), which participates in various inflammatory and ...immunologic processes. TWEAK/Fn14 interaction induces different cell fates depending on the local microenvironment, which correlates with certain expression profiles of TNF receptors (TNFR). The predominant expression of TNFR1 or TNFR2 facilitates cell death or proliferation, respectively, on TWEAK/Fn14 activation. TNFR-associated factors (TRAF) interact with Fn14, cellular inhibitor of apoptosis protein (cIAP)-1, and TNFR, consequently transducing signals from TWEAK to downstream cytokines and cell cycle mediators. An Fn14-TRAF2-TNFR axis has been suggested in the function of TWEAK/Fn14 signaling, which may serve as a target in the development of novel therapeutic strategies for many diseases that have Fn14-overexpressing cells in affected tissues. The aims of this review are: 1) to present the main results on TWEAK/Fn14 regulation of cell fates, 2) to analyze the mechanism of the Fn14-TRAF2-TNFR axis, and 3) to summarize the potential strategies in the pharmacologic targeting of this axis.
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.
Background: Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant skin disease. The mutation of the ADAR1 gene is the pathogenesis of this disorder. Aims: This study aimed to ...identify the mutations of the ADAR1 gene in two Chinese families with DSH. Methods and Materials: Eight patients from two Chinese families were diagnosed with DSH clinically. Blood samples were collected from the patients and unaffected individuals. Sanger sequencing for all polymerase chain reaction products of the whole coding regions of the ADAR1 gene was performed to identify the mutations. Mutation Taster software was used to predict the impact of the variant on the resultant protein. Results: The c.3358-3359insT (p.L1053fs-1092X) mutation in exon 12 was found in affected members of the pedigree1. In pedigree2, the c.3820-3821insG (p.G1207fs-1213X) mutation in exon 15 was found. These two mutations were not found in 100 unrelated healthy people. In this study, both mutations were damaged by the Mutation Taster software. Conclusions: We identified two novel frameshift mutations in the ADAR1 gene. Our study expands the database of ADAR1 gene mutations in DSH.
Mal de Meleda is an autosomal recessive palmoplantar keratoderma, with SLURP1 identified as the pathogenic gene responsible. Although over 20 mutations in SLURP1 have been reported, only the mutation ...c.256G > A (p.G87R) has been detected in Chinese patients. Here, we report a novel heterozygous SLURP1 mutation in a Chinese family.
We assessed the clinical manifestations of two Chinese patients with Mal de Meleda and collected specimens from the patients and other family members for whole-exome and Sanger sequencing. We used algorithms (MutationTaster, SIFT, PolyPhen-2, PROVEAN, PANTHER, FATHMM, mCSM, SDM and DUET) to predict the pathogenetic potential of the mutation detected. We also employed AlphaFold2 and PyMOL for protein structure analysis.
Both patients displayed the typical manifestation of palmoplantar keratoderma. In Proband 1, we detected a novel compound heterozygous mutation (c.243C > A and c.256G > A) in exon 3 of SLURP1. Proband 2 was an adult female born to a consanguineous family and carried a homozygous mutation (c.211C > T). Algorithms indicated both mutations to be probably disease causing. We used AlphaFold2 to predict the protein structure of these mutations and found that they cause instability, as shown by PyMOL.
Our study identified a novel compound heterozygous mutation (c.243C > A and c.256G > A) in a Chinese patient with Mal de Meleda that has the potential to cause instability in protein structure. Moreover, this study expands on the existing knowledge of SLURP1 mutations and contributes to knowledge of Mal de Meleda.
BP180, also known as collagen XVII, is a hemidesmosomal component and plays a key role in maintaining skin dermal/epidermal adhesion. Dysfunction of BP180, either through genetic mutations in ...junctional epidermolysis bullosa (JEB) or autoantibody insult in bullous pemphigoid (BP), leads to subepidermal blistering accompanied by skin inflammation. However, whether BP180 is involved in skin inflammation remains unknown. To address this question, we generated a BP180-dysfunctional mouse strain and found that mice lacking functional BP180 (termed ΔNC16A) developed spontaneous skin inflammatory disease, characterized by severe itch, defective skin barrier, infiltrating immune cells, elevated serum IgE levels, and increased expression of thymic stromal lymphopoietin (TSLP). Severe itch is independent of adaptive immunity and histamine, but dependent on increased expression of TSLP by keratinocytes. In addition, a high TSLP expression is detected in BP patients. Our data provide direct evidence showing that BP180 regulates skin inflammation independently of adaptive immunity, and BP180 dysfunction leads to a TSLP-mediated itch. The newly developed mouse strain could be a model for elucidation of disease mechanisms and development of novel therapeutic strategies for skin inflammation and BP180-related skin conditions.
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