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Disorders of keratinization and other genodermatoses
Published in Rashmi Sarkar, Anupam Das, Sumit Sethi, Concise Dermatology, 2021
Profilaggrin is a precursor of the protein filaggrin, which is important for aggregation of keratin filaments and retention of water in the keratinocytes. Filaggrin is a component of the keratohyaline granules. Mutations in the profilaggrin gene lead to decreased synthesis of profilaggrin with a resultant decrease or absence of filaggrin in the keratinocytes. Histopathology shows mild hyperkeratosis with a diminished or absent granular layer. The keratohyalin granules are absent or are abnormal in shape and small, as shown by electron microscopy.
Comparative Anatomy, Physiology, and Biochemistry of Mammalian Skin
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
The stratum corneum layer contains a fibrous substance similar to that found in basal cells, along with dark-staining tonofilaments that are 5 nm in diameter. Modification of the plasmalemma takes place and the intercellular space disappears in the stratum corneum. The plasmalemma is thicker (150 A) than in the basal layer (70 A) and is coated with the substance released from the membrane-coating granules.65,67 The final product of the epidermal differentiation and keratinization process is a stratum corneum which consists of thick, plasma membrane-limited, protein-rich cells containing fibrous keratin and keratohyalin, surrounded by the extracellular lipid matrix. This forms the so-called “brick and mortar” structure which is the morphological basis for the heterogeneous, two-compartment stratum corneum model proposed by Elias.68
The skin
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
This upper epidermal layer is made up of up to three layers of flattened keratinocytes and derives its name from the basophilic staining cytoplasmic keratohyalin granules. These granules are largely made up of profilaggrin, a precursor of filaggrin which promotes aggregation of keratin filaments in the cornified layer. Additionally present are much smaller lamellar granules, secretion of whose contents into the intercellular space produces a lipid membrane which acts as a barrier to water loss and also aid in the desquamation process.
The role of kallikreins in inflammatory skin disorders and their potential as therapeutic targets
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Caitlin T. Di Paolo, Eleftherios P. Diamandis, Ioannis Prassas
A number of proteases in the skin are responsible for the retention of hydration in the SC. Natural moisturizing factor (NMF) is made up of amino acids or their derivatives, and hygroscopic, low-molecular weight compounds that are formed from the proteolysis of FLG [44]. The complete catabolism of FLG is responsible for more than 70% of the FFAs and their metabolites are observed in the SC [45]. Its precursor, profilaggrin (proFLG) is a large protein (approximately 435 kDa) transcribed from the epidermal differentiation complex that is located on chromosome 1q21 [46]. Mature proFLG is phosphorylated and stored in keratohyalin granules. Interestingly, many proteases have been shown to cleave this protein in vitro, resulting in trimers and dimers, including matriptase, elastase-2, calpain-1, furin, and profilaggrin endoproteinase 1 [47–50]. Once processed into monomers and released from its association with keratin fibers, FLG can be further processed into FFAs by calpain-1 and caspase-14 [51]. The final catabolic products of FLG are pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA). These hygroscopic NMF components absorb the atmospheric water and act as efficient humectants, allowing the SC to remain hydrated. KLK5 was found to be capable of cleaving the proFLG linker domain both in biochemical assays and in cultured keratinocytes (Figure 2(A)) [52]. Additionally, KLK5 colocalized with proFLG in the vicinity of keratohyalin granules in granular cells, further supporting the involvement of KLK5 in the biochemical processing of proFLG in the epidermis.
In vitro skin irritation assessment using EpiDerm™: applicability for updating toxicity information of oxybenzone and N,N-diethyl-m-toluamide
Published in Drug and Chemical Toxicology, 2020
Ji-Seok Han, Yong-Bum Kim, Heejin Park, Wan-Jung Im, Woo-Jin Kim, Younhee Kim, Joo-Yun Won, Hwa-Young Son, Byoung-Seok Lee
In determining the correlation between cell viability and tissue morphology, most viability results reflected the corresponding tissue morphology. The histological features of the DPBS and oxybenzone were similar to those seen in the normal human epidermis. They were characterized by sufficient epidermal thickness (six to eight viable layers), a well-differentiated corneal layer, straightforward arrangement of basal cells, and keratinocytes with normal cytoplasm and nuclei. However, one tissue sample in the sequential administration group with cell viability of 84% showed diffuse incomplete keratinization of the stratum corneum, an indistinct granular layer, and cellular necrosis in parts of the stratum spinosum. This discrepancy implies that cell viability does not fully reflect the tissue morphology. For tissues with cell viability ≤50%, the changes commonly included some incomplete keratinization such as parakeratosis, indistinct granular layers with faint keratohyalin granules, cytoplasmic eosinophilia, and pyknosis, karyorrhexis, or karyolysis of the nuclei of the stratum spinosum or basal layers. Especially, the lack of dense and distinct keratinization in the deep corneal or supra-granular layer is considered critical criteria for the morphological evaluation of irritancy with cellular necrosis.
The emerging role of skin microbiome in atopic dermatitis and its clinical implication
Published in Journal of Dermatological Treatment, 2019
Jean-François Stalder, Joachim W. Fluhr, Tim Foster, Martin Glatz, Ehrhardt Proksch
In the past 10 years, the role of the structural protein filaggrin in the development of AD has become apparent. In healthy skin, profilaggrin, filaggrin’s precursor protein, is a major component of the keratohyalin granules in epidermal granular cells (18). When profilaggrin is cleaved to filaggrin, the monomeric protein binds to and condenses the keratin cytoskeleton, playing a critical role in the cell compaction process necessary for squame biogenesis (18). In addition, the breakdown products of filaggrin (urocanic acid and pyrrolidone carboxylic acid) are key components of the natural moisturizing factor (NMF), which are essential for stratum corneum hydration, and maintenance of skin pH (18,19).