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Both atopic dermatitis (AD) and psoriasis are characterized by complex inflammatory circuits that may be regulated through “feed-forward” mechanisms in the epidermis that amplify cellular immune responses through production of keratinocyte-derived cytokines and inflammatory mediators. IL-17C is a unique cytokine that is produced by keratinocytes and that is involved in such synergistic loops that may be responsible for amplifying the inflammation in both diseases. This may ultimately lead to induction of S100As and other molecules that accompany epidermal hyperplasia.
Mann et al. (2018) use recombinant human tyrosinase to screen for novel inhibitors of pigmentation. They develop thiamidol, a new thiazolyl-resorcinol derivative, that is a submicromolar tyrosinase inhibitor and effective for treating solar lentigines. Thiamidol and established inhibitors of pigmentation exhibit substantially different activities on human and mushroom tyrosinase, supporting use of the human enzyme in high-throughput screens.
Web-based surveys, or e-surveys, are surveys designed and delivered using the internet. The use of these survey tools is becoming increasingly common in medical research. Their advantages are appealing to surveyors because they allow for rapid development and administration of surveys, fast data collection and analysis, low cost, and fewer errors due to manual data entry than telephone or mailed questionnaires. Internet surveys may be used in clinical and academic research settings with improved speed and efficacy of data collection compared with paper or verbal survey modalities.
Mitochondrial dysfunction can drive cellular senescence, which is accompanied by changes in metabolism and increases in senescence-associated secretory phenotypes (SASP). Although pyruvate, a key metabolite for numerous aspects of metabolism, has been used as general supplement in synthetic media, the physiological function of pyruvate underlying its protective role against cellular senescence under normal conditions has remained unknown. Here, we show that extracellular pyruvate prevents senescence in normal human dermal fibroblasts (NHDFs) through increasing the generation of NAD+ during the conversion to lactate.
Variants in IRF6 can lead to Van der Woude Syndrome and Popliteal Pterygium syndrome. Furthermore, genes upstream and downstream of IRF6, including GRHL3 and TP63, are also associated with orofacial clefting. Additionally, a variant in an enhancer (MCS9.7) that regulates IRF6 is associated with risk for isolated orofacial clefting. This variant (rs642961) abrogates AP2A protein binding at MCS9.7. Here, we found that AP2A protein regulates MCS9.7 enhancer activity in vivo and IRF6 protein expression in epidermal development.
Overexpression of hexokinase 2 (HK2), and its binding to VDAC1 on the outer mitochondrial membrane of cancer cells, is key to their metabolic reprogramming to aerobic glycolysis, which enables them to proliferate. We describe Comp-1, an allosteric small molecule that selectively detaches HK2 from the mitochondria. Detachment of HK2 reduces glycolysis and triggers apoptosis in cancer cells, without affecting HK1 expressing normal cells. The anti-cancer activity of Comp-1 was demonstrated in the UVB-damaged skin model in SKH-1 mice.
Wound healing is a dynamic process involving gene-expression changes that drive re-epithelialization. Here, we describe an essential role for polyamine regulator, AMD1 in driving cell migration at the wound edge. The polyamines, putrescine, spermidine and spermine are small cationic molecules that play essential roles in many cellular processes. We demonstrate that AMD1, is rapidly upregulated following wounding in human skin biopsies. Knockdown of AMD1 with shRNAs causes a delay in cell migration that is rescued by the addition of spermine.
Skin homeostasis relies on fine tuning of epidermis/dermis interactions and is affected by aging. While extracellular matrix (ECM) proteins, such as integrins, are involved in aging, the molecular basis of the skin changes need to be further investigated. Here, we showed that integrin co-receptor, SLC3A2, required for cell proliferation, is expressed at the surface of resting dermal fibroblasts (DF) in young patients, and drastically reduced with aging. In vivo SLC3A2 DF deletion induced major skin phenotypes resembling premature aging.
It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n=1,035) and the UK (n=1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses.
Destruction of epidermal barrier function associated with atopic dermatitis or Darier's disease often causes severe secondary skin infections. Patients with skin barrier disorders often repeatedly acquire Kaposi varicelliform eruption, which is caused by herpes simplex virus, but the underlying mechanisms and effective preventive methods have yet to be found. Viral infection through an impaired epidermal barrier can be prevented by enhancing innate immunity and/or inhibiting viral entry. In this study, we established a three-dimensional skin barrier dysfunction model by silencing ATP2A2, which is mutated in some Darier's disease patients.
Psoriasis is a chronic inflammatory skin disease dependent on the IL-23/IL-17 axis, a potent inflammatory pathway involved in pathogen clearance and autoimmunity. Several triggers have been proposed as initiators for psoriasis, including alarmins such as ATP. However, the role of alarmins in psoriasis pathogenesis and cutaneous inflammation has not been well addressed. Herein studies demonstrate that signaling through the P2X7 receptor (P2X7R) pathway underlies the development of psoriasiform inflammation.