scholarly journals Keratinocyte differentiation and proteolytic pathways in skin (patho)physiology

2021 ◽  
Author(s):  
Eleni Zingkou ◽  
Georgios Pampalakis ◽  
Georgia Sotiropoulou
Keyword(s):  
Skin Diseases ◽  
Seborrheic Dermatitis ◽  
Epidermal Differentiation ◽  
Keratinocyte Differentiation ◽  
Altered Expression ◽  
Netherton Syndrome ◽  
Skin Biopsies ◽  
And Control ◽  
Histology And Immunohistochemistry ◽  
Desmosomal Protein

Epidermis is a stratified epithelium that forms the barrier between the organism and its environment. It is mainly composed of keratinocytes at different stages of differentiation. Stratum corneum is the outermost layer of the epidermis and is formed of multiple layers of anucleated keratinocytes called corneocytes. We aim to highlight the roles of epidermal differentiation and proteolysis in skin diseases. Skin biopsies isolated from Spink5-/- mice, the established model of Netherton syndrome (NS), and from patients with NS, seborrheic dermatitis (SD) and psoriasis, as well as healthy controls, were analyzed by histology and immunohistochemistry. Our results showed that NS, SD, and psoriasis are all characterized by abnormal epidermal differentiation, manifested by hyperplasia, hyperkeratosis, and parakeratosis. At the molecular level, abnormal differentiation is accompanied by increased expression of involucrin and decreased expression of loricrin in NS and psoriasis. Increased epidermal proteolysis associated with increased kallikrein-related peptidases (KLK) expression is also observed in both NS and psoriatic epidermis. Further, reduced expression of desmosomal proteins is observed in NS but increased in psoriasis. Since desmosomal protein are proteolytic substrates and control keratinocyte differentiation, their altered expression directly links epidermal proteolysis to differentiation. In conclusion, abnormal cellular differentiation and proteolysis are interconnected and underlie the pathology of NS, SD and psoriasis.

scholarly journals ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phospholipase C γ1 and protein kinase C pathways

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Cristina Wolf ◽  
Yawen Qian ◽  
Matthew A. Brooke ◽  
David P. Kelsell ◽  
Claus-Werner Franzke
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Skin Diseases ◽  
Skin Barrier ◽  
Epidermal Differentiation ◽  
Keratinocyte Differentiation ◽  
Inflammatory Skin Diseases ◽  
Cholesterol Sulfate ◽  
Kinase C ◽  
Barrier Formation

Abstract The vitally important skin barrier is formed by extensive cross-linking activity of transglutaminases (TGs) during terminal epidermal differentiation. We have previously shown that epidermal deficiency of a disintegrin and metalloproteinase 17 (ADAM17), the principal EGFR ligand sheddase, results in postnatal skin barrier defects in mice due to impeded TG activity. However, the mechanism by which ADAM17/EGFR signalling maintains TG activity during epidermal differentiation remains elusive. Here we demonstrate that ADAM17-dependent EGFR signalling promotes TG activity in keratinocytes committed to terminal differentiation by direct induction of TG1 expression. Restored TG1 expression of EGF-stimulated differentiated Adam17 −/− keratinocytes was strongly repressed by inhibitors for PLCγ1 or protein kinase C (PKC) pathways, while treatment with the PKC stimulator 12-O-tetradecanoylphorbol-13-acetate restored TG activity in the epidermis of keratinocyte-specific Adam17 −/− (AD17 ΔKC ) mice. Further investigations emphasized the expression of PKCη, a mediator of TGM1 transcription, to be sensitive to EGFR activation. In agreement, topical skin application of cholesterol sulfate, an activator of PKCη, significantly improved TG activity in epidermis of AD17 ΔKC mice. Our results suggest ADAM17/EGFR-driven PLCγ1 and PKC pathways as important promoters of TG1 expression during terminal keratinocyte differentiation. These findings may help to identify new therapeutic targets for inflammatory skin diseases related to epidermal barrier defects.

scholarly journals EGFR regulation of epidermal barrier function

2012 ◽  
Vol 44 (8) ◽  
pp. 455-469 ◽  
Author(s):  
Quynh T. Tran ◽  
Lawrence H. Kennedy ◽  
Sandra Leon Carrion ◽  
Sridevi Bodreddigari ◽  
Shirlean B. Goodwin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Barrier Function ◽  
Skin Diseases ◽  
Transepidermal Water Loss ◽  
Epidermal Differentiation ◽  
Keratinocyte Differentiation ◽  
Disease Genes ◽  
Epidermal Barrier ◽  
Epidermal Growth

Keratinocyte terminal differentiation is the process that ultimately forms the epidermal barrier that is essential for mammalian survival. This process is controlled, in part, by signal transduction and gene expression mechanisms, and the epidermal growth factor receptor (EGFR) is known to be an important regulator of multiple epidermal functions. Using microarray analysis of a confluent cell density-induced model of keratinocyte differentiation, we identified 2,676 genes that are regulated by epidermal growth factor (EGF), a ligand of the EGFR. We further discovered, and separately confirmed by functional assays, that EGFR activation abrogates all of the known essential processes of keratinocyte differentiation by 1) decreasing the expression of lipid matrix biosynthetic enzymes, 2) regulating numerous genes forming the cornified envelope, and 3) suppressing the expression of tight junction proteins. In organotypic cultures of skin, EGF acted to impair epidermal barrier integrity, as shown by increased transepidermal water loss. As defective epidermal differentiation and disruption of barrier function are primary features of many human skin diseases, we used bioinformatic analyses to identify genes that are known to be associated with skin diseases. Compared with non-EGF-regulated genes, EGF-regulated genes were significantly enriched for skin disease genes. These results provide a systems-level understanding of the actions of EGFR signaling to inhibit keratinocyte differentiation, providing new insight into the role of EGFR imbalance in skin pathogenesis.

scholarly journals Proteomic Identification of Altered Cerebral Proteins in the Complex Regional Pain Syndrome Animal Model

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Francis Sahngun Nahm ◽  
Zee-Yong Park ◽  
Sang-Soep Nahm ◽  
Yong Chul Kim ◽  
Pyung Bok Lee
Keyword(s):  
Animal Model ◽  
Complex Regional Pain Syndrome ◽  
Proteomic Analysis ◽  
Protein Identification ◽  
Pain Syndrome ◽  
Differentially Expressed ◽  
Control Groups ◽  
Altered Expression ◽  
Rat Cerebrum ◽  
And Control

Background. Complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder. Although the exact pathophysiology of CRPS is not fully understood, central and peripheral mechanisms might be involved in the development of this disorder. To reveal the central mechanism of CRPS, we conducted a proteomic analysis of rat cerebrum using the chronic postischemia pain (CPIP) model, a novel experimental model of CRPS.Materials and Methods. After generating the CPIP animal model, we performed a proteomic analysis of the rat cerebrum using a multidimensional protein identification technology, and screened the proteins differentially expressed between the CPIP and control groups.Results. A total of 155 proteins were differentially expressed between the CPIP and control groups: 125 increased and 30 decreased; expressions of proteins related to cell signaling, synaptic plasticity, regulation of cell proliferation, and cytoskeletal formation were increased in the CPIP group. However, proenkephalin A, cereblon, and neuroserpin were decreased in CPIP group.Conclusion. Altered expression of cerebral proteins in the CPIP model indicates cerebral involvement in the pathogenesis of CRPS. Further study is required to elucidate the roles of these proteins in the development and maintenance of CRPS.

scholarly journals EAAT2 Expression in the Hippocampus, Subiculum, Entorhinal Cortex and Superior Temporal Gyrus in Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Jason H. Y. Yeung ◽  
Thulani H. Palpagama ◽  
Oliver W. G. Wood ◽  
Clinton Turner ◽  
Henry J. Waldvogel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Entorhinal Cortex ◽  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Expression Patterns ◽  
Superior Temporal Gyrus ◽  
Altered Expression ◽  
And Control ◽  
Transporter Expression

Alzheimer’s disease (AD) is a neuropathological disorder characterized by the presence and accumulation of amyloid-beta plaques and neurofibrillary tangles. Glutamate dysregulation and the concept of glutamatergic excitotoxicity have been frequently described in the pathogenesis of a variety of neurodegenerative disorders and are postulated to play a major role in the progression of AD. In particular, alterations in homeostatic mechanisms, such as glutamate uptake, have been implicated in AD. An association with excitatory amino acid transporter 2 (EAAT2), the main glutamate uptake transporter, dysfunction has also been described. Several animal and few human studies examined EAAT2 expression in multiple brain regions in AD but studies of the hippocampus, the most severely affected brain region, are scarce. Therefore, this study aims to assess alterations in the expression of EAAT2 qualitatively and quantitatively through DAB immunohistochemistry (IHC) and immunofluorescence within the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus (STG) regions, between human AD and control cases. Although no significant EAAT2 density changes were observed between control and AD cases, there appeared to be increased transporter expression most likely localized to fine astrocytic branches in the neuropil as seen on both DAB IHC and immunofluorescence. Therefore, individual astrocytes are not outlined by EAAT2 staining and are not easily recognizable in the CA1–3 and dentate gyrus regions of AD cases, but the altered expression patterns observed between AD and control hippocampal cases could indicate alterations in glutamate recycling and potentially disturbed glutamatergic homeostasis. In conclusion, no significant EAAT2 density changes were found between control and AD cases, but the observed spatial differences in transporter expression and their functional significance will have to be further explored.

scholarly journals The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation

2020 ◽  
Author(s):  
Emma Carley ◽  
Rachel K. Stewart ◽  
Abigail Zieman ◽  
Iman Jalilian ◽  
Diane. E. King ◽  
...  
Keyword(s):  
Cell Fate ◽  
Control Cell ◽  
Nuclear Lamina ◽  
Epidermal Differentiation ◽  
Keratinocyte Differentiation ◽  
Linc Complex ◽  
Force Transmission ◽  
Cell Fate Decisions

AbstractWhile the mechanisms by which chemical signals control cell fate have been well studied, how mechanical inputs impact cell fate decisions are not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells, and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate.

scholarly journals Pedagogical conditions for the formation of counteraction to stressful phenomena in educational institutions

2021 ◽  
pp. 69-77
Author(s):  
Г.А. Арсаханова
Keyword(s):  
Skin Diseases ◽  
First Graders ◽  
Behavioral Disorder ◽  
Educational Institutions ◽  
Daily Routine ◽  
The Social ◽  
The Status ◽  
The Individual ◽  
And Control ◽  
Psychosomatic Diseases

Жизнедеятельность школьника полна проблем, решение которых приводит к стрессовым ситуациям. Прежде всего, это изменение социального статуса и изменение дошкольной деятельности ребенка на учебную. Статус школьника требует больше обязанностей, ответственности, дисциплинированности, структурированности режима дня, контроля собственных поступков. Даже в самом продуманном и хорошо налаженному жизни случаются ситуации, которые негативно влияют на детей и приводят к стрессу. Первоклассники не всегда готовы к таким изменениям, что вызывает ряд психофизиологических и поведенческих проявлений. В состоянии стресса поведение ребенка дезорганизовывается, наблюдаются неконтролируемые движения, определенные речевые отклонения, появляются эмоции, не соответствующие культуре взаимоотношений. Стресс – это сильное проявление эмоций вызывает комплексную физиологическую реакцию, это состояние душевного и поведенческого расстройства, связанного с неспособностью личности целесообразно действовать в соответствующих ситуациях. Из-за недостаточной сформированности эмоциональной сферы в школьном возрасте при частых стрессовых ситуациях у ребенка исчезает аппетит, наступает депрессия, снижается интерес к учебе, общению, наступает апатия. Стрессовые ситуации негативно сказываются на здоровье школьника, у ребенка появляется целый «букет» опасных психосоматических заболеваний: мигрень, гипертония, астма, артрит, аллергия, диабет, кожные болезни и тому подобное. The student's life is full of problems, the solution of which leads to stressful situations. First of all, this is a change in the social status and a change in the preschool activity of the child to the educational one. The status of a student requires more responsibilities, responsibility, discipline, structured daily routine, and control of one's own actions. Even in the most thoughtful and well-established life, there are situations that negatively affect children and lead to stress. First-graders are not always ready for such changes, which causes a number of psychophysiological and behavioral manifestations. In a state of stress, the child's behavior is disorganized, uncontrolled movements are observed, certain speech deviations appear, emotions that do not correspond to the culture of relationships. Stress-this strong manifestation of emotions causes a complex physiological reaction, this is a state of mental and behavioral disorder associated with the inability of the individual to act appropriately in appropriate situations. Due to the lack of formation of the emotional sphere at school age, with frequent stressful situations, the child's appetite disappears, depression sets in, interest in learning, communication decreases, and apathy sets in. Stressful situations negatively affect the health of the student, the child has a whole "bouquet" of dangerous psychosomatic diseases: migraine, hypertension, asthma, arthritis, allergies, diabetes, skin diseases, and the like.

scholarly journals Equine Hoof Canker: Bovine Papillomavirus Infection Is Not Associated With Impaired Keratinocyte Differentiation

2020 ◽  
Vol 57 (4) ◽  
pp. 525-534
Author(s):  
Veronika Apprich ◽  
Theresia Licka ◽  
Sabrina Freiler ◽  
Cordula Gabriel
Keyword(s):  
Adhesion Molecules ◽  
Intermediate Filaments ◽  
Expression Patterns ◽  
Keratinocyte Differentiation ◽  
Bovine Papillomavirus ◽  
Tissue Samples ◽  
Altered Expression ◽  
Morphological Alterations ◽  
Papillomavirus Infection ◽  
Equine Hoof

Impaired keratinocyte differentiation has recently been suggested as a key event in equine hoof canker development. Koilocytotic appearance of keratinocytes, one of the most characteristic morphological alterations in hoof canker tissue, is also a common marker for papillomavirus (PV) infection, and bovine PV-1 and/or -2 (BPV-1/2) has previously been detected in equine canker patients. Therefore, the present study aimed to correlate the frequency and severity of koilocytotic keratinocytes with BPV detection in hoof canker samples. Hoof tissue of 5/18 canker-affected horses and 2/6 control horses tested positive for BPV-1/2 DNA using polymerase chain reaction. Thus, no association between the presence of BPV-1/2 papillomaviral DNA and koilocytotic appearance was found. Proteins associated with but not specific for PV infection were also investigated. Using immunohistochemistry, specific adhesion molecules (E-cadherin and β-catenin) and intermediate filaments (keratins 6 and 14) important for intact epidermal barrier function and keratinocyte differentiation were documented in control samples ( n = 6) and in hoof canker tissue samples ( n = 19). Altered expression patterns of intermediate filaments and adhesion molecules were demonstrated in canker tissue, confirming the importance of incomplete keratinocyte differentiation, as well as the crucial role of keratinocyte differentiation in hoof canker.

scholarly journals The Effect of Single CpG Demethylation on the Pattern of DNA-Protein Binding

2019 ◽  
Vol 20 (4) ◽  
pp. 914 ◽  
Author(s):  
Barbara Sobiak ◽  
Wiesława Leśniak
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Epidermal Differentiation ◽  
Keratinocyte Differentiation ◽  
Splicing Factors ◽  
Targeted Next Generation Sequencing ◽  
Factors Analysis ◽  
Epidermal Differentiation Complex ◽  
Complex Process ◽  
Next Generation Sequencing Ngs

Epidermal differentiation is a complex process and its regulation may involve epigenetic factors. Analysis of DNA methylation in 20 selected regions within the epidermal differentiation complex (EDC) gene cluster by targeted next-generation sequencing (NGS) detected no or only minor changes in methylation, mostly slight demethylation, occurring during the course of keratinocyte differentiation. However, a single CpG pair within the exon of the PGLYRP3 gene underwent a pronounced demethylation concomitant with an increase in PGLYRP3 expression. We have employed a DNA-affinity precipitation assay (DAPA) and mass spectrometry to examine changes in the composition of proteins that bind to DNA containing either methylated or unmethylated CpG. We found that the unmethylated probe attracted mostly RNA binding proteins, including splicing factors, which suggests that demethylation of this particular CpG may facilitate PGLYRP3 transcription and/or pre-mRNA splicing.

Altered expression of selected genes in kidney of rats with lithium-induced NDI

2005 ◽  
Vol 288 (6) ◽  
pp. F1276-F1289 ◽  
Author(s):  
Aleksandra Rojek ◽  
Jakob Nielsen ◽  
Heddwen L. Brooks ◽  
Hong Gong ◽  
Young-Hee Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Cellular Proliferation ◽  
Collecting Duct ◽  
Lithium Treatment ◽  
Altered Expression ◽  
Ezrin Expression ◽  
Microarray Screening ◽  
And Control ◽  
Thin Limb

Lithium treatment is associated with development of nephrogenic diabetes insipidus, caused in part by downregulation of collecting duct aquaporin-2 (AQP2) and AQP3 expression. In the present study, we carried out cDNA microarray screening of gene expression in the inner medulla (IM) of lithium-treated and control rats, and selected genes were then investigated at the protein level by immunoblotting and/or immunohistochemistry. The following genes exhibited significantly altered transcription and mRNA expression levels, and these were compatible with the changes in protein expression. 11β-Hydroxysteroid dehydrogenase type 2 protein expression in the IM was markedly increased (198 ± 25% of controls, n = 6), and immunocytochemistry demonstrated an increased labeling of IM collecting duct (IMCD) principal cells. This indicated altered renal mineralocorticoid/glucocorticoid responses in lithium-treated rats. The inhibitor of cyclin-dependent kinases p27 (KIP) protein expression was significantly decreased or undetectable in the IMCD cells, pointing to increased cellular proliferation and remodeling. Heat shock protein 27 protein expression was decreased in the IM (64 ± 6% of controls, n = 6), likely to be associated with the decreased medullary osmolality in lithium-treated rats. Consistent with this, lens aldose reductase protein expression was markedly decreased in the IM (16 ± 2% of controls, n = 6), and immunocytochemistry revealed decreased expression in the thin limb cells in the middle and terminal parts of the IM. Ezrin protein expression was upregulated in the IM (158 ± 16% of controls, n = 6), where it was predominantly expressed in the apical and cytoplasmic domain of the IMCD cells. Increased ezrin expression indicated remodeling of the actin cytoskeleton and/or altered regulation of IMCD transporters. In conclusion, the present study demonstrates changes in gene expression not only in the collecting duct but also in the thin limb of the loop of Henle in the IM, and several of these genes are linked to altered sodium and water reabsorption, cell cycling, and changes in interstitial osmolality.

scholarly journals Human epidermal stem cell differentiation is modulated by specific lipid subspecies

2020 ◽  
Vol 117 (36) ◽  
pp. 22173-22182
Author(s):  
Matteo Vietri Rudan ◽  
Ajay Mishra ◽  
Christian Klose ◽  
Ulrike S. Eggert ◽  
Fiona M. Watt
Keyword(s):  
Stem Cell ◽  
Stem Cell Differentiation ◽  
Human Keratinocytes ◽  
Epidermal Differentiation ◽  
Keratinocyte Differentiation ◽  
Fatty Acid Transport ◽  
Epidermal Stem Cell ◽  
Primary Human Keratinocytes ◽  
Induced Differentiation ◽  
Lipid Species

While the lipids of the outer layers of mammalian epidermis and their contribution to barrier formation have been extensively described, the role of individual lipid species in the onset of keratinocyte differentiation remains unknown. A lipidomic analysis of primary human keratinocytes revealed accumulation of numerous lipid species during suspension-induced differentiation. A small interfering RNA screen of 258 lipid-modifying enzymes identified two genes that on knockdown induced epidermal differentiation:ELOVL1, encoding elongation of very long-chain fatty acids protein 1, andSLC27A1, encoding fatty acid transport protein 1. By intersecting lipidomic datasets from suspension-induced differentiation and knockdown keratinocytes, we pinpointed candidate bioactive lipid subspecies as differentiation regulators. Several of these—ceramides and glucosylceramides—induced differentiation when added to primary keratinocytes in culture. Our results reveal the potential of lipid subspecies to regulate exit from the epidermal stem cell compartment.

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