International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Skin Epidermis and Barrier Function

by Kyung-Min Lim

Int. J. Mol. Sci. 2021, 22(6), 3035; https://doi.org/10.3390/ijms22063035 - 16 Mar 2021

Cited by 20 | Viewed by 7076

Abstract

The skin epidermis is the outermost epithelial tissue that protects the body from the external environment [...] Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

Research

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16 pages, 4884 KiB

Open AccessArticle

hiPSC-Derived Epidermal Keratinocytes from Ichthyosis Patients Show Altered Expression of Cornification Markers

by Dulce Lima Cunha, Amanda Oram, Robert Gruber, Roswitha Plank, Arno Lingenhel, Manoj K. Gupta, Janine Altmüller, Peter Nürnberg, Matthias Schmuth, Johannes Zschocke, Tomo Šarić, Katja M. Eckl and Hans C. Hennies

Int. J. Mol. Sci. 2021, 22(4), 1785; https://doi.org/10.3390/ijms22041785 - 11 Feb 2021

Cited by 4 | Viewed by 3035

Abstract

Inherited ichthyoses represent a large heterogeneous group of skin disorders characterised by impaired epidermal barrier function and disturbed cornification. Current knowledge about disease mechanisms has been uncovered mainly through the use of mouse models or human skin organotypic models. However, most mouse lines [...] Read more.

Inherited ichthyoses represent a large heterogeneous group of skin disorders characterised by impaired epidermal barrier function and disturbed cornification. Current knowledge about disease mechanisms has been uncovered mainly through the use of mouse models or human skin organotypic models. However, most mouse lines suffer from severe epidermal barrier defects causing neonatal death and human keratinocytes have very limited proliferation ability in vitro. Therefore, the development of disease models based on patient derived human induced pluripotent stem cells (hiPSCs) is highly relevant. For this purpose, we have generated hiPSCs from patients with congenital ichthyosis, either non-syndromic autosomal recessive congenital ichthyosis (ARCI) or the ichthyosis syndrome trichothiodystrophy (TTD). hiPSCs were successfully differentiated into basal keratinocyte-like cells (hiPSC-bKs), with high expression of epidermal keratins. In the presence of higher calcium concentrations, terminal differentiation of hiPSC-bKs was induced and markers KRT1 and IVL expressed. TTD1 hiPSC-bKs showed reduced expression of FLG, SPRR2B and lipoxygenase genes. ARCI hiPSC-bKs showed more severe defects, with downregulation of several cornification genes. The application of hiPSC technology to TTD1 and ARCI demonstrates the successful generation of in vitro models mimicking the disease phenotypes, proving a valuable system both for further molecular investigations and drug development for ichthyosis patients. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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16 pages, 5798 KiB

Open AccessArticle

Ex Vivo Live Full-Thickness Porcine Skin Model as a Versatile In Vitro Testing Method for Skin Barrier Research

by Jee-hyun Hwang, Haengdueng Jeong, Nahyun Lee, Sumin Hur, Nakyum Lee, Jeong Jun Han, Hye Won Jang, Wang Keun Choi, Ki Taek Nam and Kyung-Min Lim

Int. J. Mol. Sci. 2021, 22(2), 657; https://doi.org/10.3390/ijms22020657 - 11 Jan 2021

Cited by 32 | Viewed by 7301

Abstract

Since the European Union (EU) announced their animal testing ban in 2013, all animal experiments related to cosmetics have been prohibited, creating a demand for alternatives to animal experiments for skin studies. Here, we investigated whether an ex vivo live porcine skin model [...] Read more.

Since the European Union (EU) announced their animal testing ban in 2013, all animal experiments related to cosmetics have been prohibited, creating a demand for alternatives to animal experiments for skin studies. Here, we investigated whether an ex vivo live porcine skin model can be employed to study the safety and skin barrier-improving effects of hydroxyacids widely used in cosmetics for keratolytic peels. Glycolic acid (1–10%), salicylic acid (0.2–2%), and lactobionic acid (1.2–12%) were used as representative substances for α-hydroxyacid (AHA), β-hydroxyacid (BHA), and polyhydroxyacid (PHA), respectively. When hydroxyacids were applied at high concentrations on the porcine skin every other day for 6 days, tissue viability was reduced to 50–80%, suggesting that the toxicity of cosmetic ingredients can be evaluated with this model. Based on tissue viability, the treatment scheme was changed to a single exposure for 20 min. The protective effects of a single exposure of hydroxyacids on skin barrier function were evaluated by examining rhodamine permeability and epidermal structural components of barrier function using immunohistochemistry (IHC) and immunofluorescence (IF) staining. Lactobionic acid (PHAs) improved skin barrier function most compared to other AHAs and BHAs. Most importantly, trans-epidermal water loss (TEWL), an important functional marker of skin barrier function, could be measured with this model, which confirmed the significant skin barrier-protective effects of PHAs. Collectively, we demonstrated that the ex vivo live full-thickness porcine skin model can be an excellent alternative to animal experiments for skin studies on the safety and efficacy of cosmetic ingredients. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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16 pages, 4028 KiB

Open AccessArticle

miR-155 Contributes to Normal Keratinocyte Differentiation and Is Upregulated in the Epidermis of Psoriatic Skin Lesions

by Lucian Beer, Polina Kalinina, Martin Köcher, Maria Laggner, Markus Jeitler, Salman Abbas Zadeh, Dragan Copic, Erwin Tschachler and Michael Mildner

Int. J. Mol. Sci. 2020, 21(23), 9288; https://doi.org/10.3390/ijms21239288 - 5 Dec 2020

Cited by 16 | Viewed by 2539

Abstract

The role of microRNAs (miRNAs) during keratinocyte (KC) differentiation and in skin diseases with epidermal phenotypes has attracted strong interest over the past few years. However, combined mRNA and miRNA expression analyses to elucidate the intricate mRNA–miRNA networks of KCs at different stages [...] Read more.

The role of microRNAs (miRNAs) during keratinocyte (KC) differentiation and in skin diseases with epidermal phenotypes has attracted strong interest over the past few years. However, combined mRNA and miRNA expression analyses to elucidate the intricate mRNA–miRNA networks of KCs at different stages of differentiation have not been performed yet. In the present study, we investigated the dynamics of miRNA and mRNA expression during KC differentiation in vitro and in normal and psoriatic epidermis. While we identified comparable numbers of up- and downregulated mRNAs (49% and 51%, respectively), miRNAs were predominantly upregulated (76% vs 24%) during KC differentiation. Further bioinformatics analyses suggested an important inhibitory role for miR-155 in KC differentiation, as it was repressed during KC differentiation in normal skin but strongly upregulated in the epidermis of psoriatic skin lesions. Mimicking the inflammatory milieu of psoriatic skin in vitro, we could show that the pro-inflammatory cytokines IL17, IL1β and INFγ synergistically upregulated miR-155 expression in KCs. Forced over-expression of miR-155 in human in vitro skin models specifically reduced the expression of loricrin (LOR) in KCs, indicating that miR-155 interferes with the establishment of a normal epidermal barrier. Together, our data indicate that downregulation of miR-155 during KC differentiation is a crucial step for epidermal barrier formation. Furthermore, its strong upregulation in psoriatic lesions suggests a contributing role of miR-155 in the altered keratinocyte differentiation observed in psoriasis. Therefore, miR-155 represents as a potential target for treating psoriatic skin lesions. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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17 pages, 2152 KiB

Open AccessArticle

Effects of Tenascin C on the Integrity of Extracellular Matrix and Skin Aging

by Young Eun Choi, Min Ji Song, Mari Hara, Kyoko Imanaka-Yoshida, Dong Hun Lee, Jin Ho Chung and Seung-Taek Lee

Int. J. Mol. Sci. 2020, 21(22), 8693; https://doi.org/10.3390/ijms21228693 - 18 Nov 2020

Cited by 39 | Viewed by 5757

Abstract

Tenascin C (TNC) is an element of the extracellular matrix (ECM) of various tissues, including the skin, and is involved in modulating ECM integrity and cell physiology. Although skin aging is apparently associated with changes in the ECM, little is known about the [...] Read more.

Tenascin C (TNC) is an element of the extracellular matrix (ECM) of various tissues, including the skin, and is involved in modulating ECM integrity and cell physiology. Although skin aging is apparently associated with changes in the ECM, little is known about the role of TNC in skin aging. In this study, we found that the Tnc mRNA level was significantly reduced in the skin tissues of aged mice compared with young mice, consistent with reduced TNC protein expression in aged human skin. TNC-large (TNC-L; 330-kDa) and -small (TNC-S; 240-kDa) polypeptides were observed in conditional media from primary dermal fibroblasts. Both recombinant TNC polypeptides, corresponding to TNC-L and TNC-S, increased the expression of type I collagen and reduced the expression of matrix metalloproteinase-1 in fibroblasts. Treatment of fibroblasts with a recombinant TNC polypeptide, corresponding to TNC-L, induced phosphorylation of SMAD2 and SMAD3. TNC increased the level of transforming growth factor-β1 (TGF-β1) mRNA and upregulated the expression of type I collagen by activating the TGF-β signaling pathway. In addition, TNC also promoted the expression of type I collagen in fibroblasts embedded in a three-dimensional collagen matrix. Our findings suggest that TNC contributes to the integrity of ECM in young skin and to prevention of skin aging. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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18 pages, 2728 KiB

Open AccessArticle

Weak Ultraviolet B Enhances the Mislocalization of Claudin-1 Mediated by Nitric Oxide and Peroxynitrite Production in Human Keratinocyte-Derived HaCaT Cells

by Mao Kobayashi, Shokoku Shu, Kana Marunaka, Toshiyuki Matsunaga and Akira Ikari

Int. J. Mol. Sci. 2020, 21(19), 7138; https://doi.org/10.3390/ijms21197138 - 27 Sep 2020

Cited by 11 | Viewed by 3803

Abstract

A tight junction (TJ) makes a physical barrier in the epidermal cells of skin. Ultraviolet (UV) light may disrupt the TJ barrier, but the mechanism has not been well clarified. Weak UVB (5 mJ/cm²) caused mislocalization of claudin-1 (CLDN1), a component [...] Read more.

A tight junction (TJ) makes a physical barrier in the epidermal cells of skin. Ultraviolet (UV) light may disrupt the TJ barrier, but the mechanism has not been well clarified. Weak UVB (5 mJ/cm²) caused mislocalization of claudin-1 (CLDN1), a component of the TJ strand, and disruption of TJ barrier in human keratinocyte-derived HaCaT cells. The UVB-induced mislocalization of CLDN1 was inhibited by monodansylcadaverine (MDC), a clathrin-dependent endocytosis inhibitor, suggesting that UVB enhances the internalization of CLDN1. Transepidermal electrical resistance and paracellular flux of lucifer yellow, a fluorescent hydrophilic marker, were rescued by MDC. UVB changed neither the total nor phosphorylation levels of CLDN1, but it increased both mono-ubiquitination and tyrosine nitration levels of CLDN1. Fluorescence measurements revealed that UVB increased intracellular free Ca²⁺, nitric oxide (NO), and peroxynitrite contents, which were inhibited by Opsin2 (OPN2) siRNA, suggesting that OPN2 functions as a UVB sensor. The effects of UVB were inhibited by an antagonist of transient receptor potential type vanilloid 1 (TRPV1) and Ca²⁺ chelator. Both NO donor and peroxynitrite donor induced the mislocalization of CLDN1 and disruption of TJ barrier, which were rescued by a NO synthase (NOS) inhibitor and a peroxynitrite scavenger. Weak UVB irradiation induced the disruption of TJ barrier mediated by mislocalization of CLDN1 in HaCaT cells. The OPN2/TRPV1/NOS signaling pathway may be a novel target for preventing destruction of the TJ barrier by UVB irradiation. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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Graphical abstract

12 pages, 2789 KiB

Open AccessArticle

Synthetic Retinoid Seletinoid G Improves Skin Barrier Function through Wound Healing and Collagen Realignment in Human Skin Equivalents

by Eun-Soo Lee, Yujin Ahn, Il-Hong Bae, Daejin Min, Nok Hyun Park, Woonggyu Jung, Se-Hwa Kim, Yong Deog Hong, Won Seok Park and Chang Seok Lee

Int. J. Mol. Sci. 2020, 21(9), 3198; https://doi.org/10.3390/ijms21093198 - 30 Apr 2020

Cited by 18 | Viewed by 5553

Abstract

The outer epidermal skin is a primary barrier that protects the body from extrinsic factors, such as ultraviolet (UV) radiation, chemicals and pollutants. The complete epithelialization of a wound by keratinocytes is essential for restoring the barrier function of the skin. However, age-related [...] Read more.

The outer epidermal skin is a primary barrier that protects the body from extrinsic factors, such as ultraviolet (UV) radiation, chemicals and pollutants. The complete epithelialization of a wound by keratinocytes is essential for restoring the barrier function of the skin. However, age-related alterations predispose the elderly to impaired wound healing. Therefore, wound-healing efficacy could be also considered as a potent function of an anti-aging reagent. Here, we examine the epidermal wound-healing efficacy of the fourth-generation retinoid, seletinoid G, using HaCaT keratinocytes and skin tissues. We found that seletinoid G promoted the proliferation and migration of keratinocytes in scratch assays and time-lapse imaging. It also increased the gene expression levels of several keratinocyte proliferation-regulating factors. In human skin equivalents, seletinoid G accelerated epidermal wound closure, as assessed using optical coherence tomography (OCT) imaging. Moreover, second harmonic generation (SHG) imaging revealed that seletinoid G recovered the reduced dermal collagen deposition seen in ultraviolet B (UVB)-irradiated human skin equivalents. Taken together, these results indicate that seletinoid G protects the skin barrier by accelerating wound healing in the epidermis and by repairing collagen deficiency in the dermis. Thus, seletinoid G could be a potent anti-aging agent for protecting the skin barrier. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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14 pages, 3513 KiB

Open AccessArticle

Altered Levels of Sphingosine, Sphinganine and Their Ceramides in Atopic Dermatitis Are Related to Skin Barrier Function, Disease Severity and Local Cytokine Milieu

by Ruzica Jurakic Toncic, Ivone Jakasa, Suzana Ljubojevic Hadzavdic, Susan MI Goorden, Karen JM Ghauharali-van der Vlugt, Femke S Stet, Anamaria Balic, Mikela Petkovic, Borna Pavicic, Kristina Zuzul, Branka Marinovic and Sanja Kezic

Int. J. Mol. Sci. 2020, 21(6), 1958; https://doi.org/10.3390/ijms21061958 - 13 Mar 2020

Cited by 47 | Viewed by 5950

Abstract

Dysfunctional skin barrier plays a key role in the pathophysiology of atopic dermatitis (AD), a common inflammatory skin disease. Altered composition of ceramides is regarded as a major cause of skin barrier dysfunction, however it is not clear whether these changes are intrinsic [...] Read more.

Dysfunctional skin barrier plays a key role in the pathophysiology of atopic dermatitis (AD), a common inflammatory skin disease. Altered composition of ceramides is regarded as a major cause of skin barrier dysfunction, however it is not clear whether these changes are intrinsic or initiated by inflammation and aberrant immune response in AD. This study investigated the levels of free sphingoid bases (SBs) sphingosine and sphinganine and their ceramides and glucosylceramide in the stratum corneum (SC) and related them to skin barrier function, disease severity and local cytokine milieu. Ceramides were measured in healthy skin, and lesional and non-lesional skin of AD patients by a novel method based on deacylation of ceramides which were subsequently determined as corresponding sphingoid bases by using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The cytokine levels were determined by multiplex immunoassay. Atopic skin showed increased levels of most investigated markers, predominantly in lesional skin. The largest difference in respect to healthy skin was found for glucosylceramide with respective median values of 0.23 (IQR 0.18–0.61), 0.56 (IQR 0.32–0.76) and 19.32 (IQR 7.86–27.62) pmol/g protein for healthy, non-lesional and lesional skin. The levels of investigated ceramide markers were correlated with disease severity (scoring atopic dermatitis, SCORAD) and skin barrier function (trans-epidermal water loss, TEWL) and furthermore with cytokines involved in innate, Th-1, and Th-2 immune response. Interestingly, the strongest association with SCORAD was found for sphinganine/sphingosine ratio (r = −0.69, p < 0.001; non-lesional skin), emphasizing the importance of SBs in AD. The highest correlation with TEWL was found for glucosylceramide (r² = 0.60, p < 0.001), which was investigated for the first time in AD. Findings that the changes in SBs and ceramide levels were predominant in lesional skin and their association with disease severity and cytokine levels suggest an immune-system driven effect. a novel analysis method demonstrates a robust and simple approach that might facilitate wider use of lipid biomarkers in the clinics e.g., to monitor (immune) therapy or dissect disease endotypes. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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Review

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23 pages, 2043 KiB

Open AccessReview

The Role of MicroRNAs in Epidermal Barrier

by Ai-Young Lee

Int. J. Mol. Sci. 2020, 21(16), 5781; https://doi.org/10.3390/ijms21165781 - 12 Aug 2020

Cited by 17 | Viewed by 3759

Abstract

MicroRNAs (miRNAs), which mostly cause target gene silencing via transcriptional repression and degradation of target mRNAs, regulate a plethora of cellular activities, such as cell growth, differentiation, development, and apoptosis. In the case of skin keratinocytes, the role of miRNA in epidermal barrier [...] Read more.

MicroRNAs (miRNAs), which mostly cause target gene silencing via transcriptional repression and degradation of target mRNAs, regulate a plethora of cellular activities, such as cell growth, differentiation, development, and apoptosis. In the case of skin keratinocytes, the role of miRNA in epidermal barrier integrity has been identified. Based on the impact of key genetic and environmental factors on the integrity and maintenance of skin barrier, the association of miRNAs within epidermal cell differentiation and proliferation, cell–cell adhesion, and skin lipids is reviewed. The critical role of miRNAs in the epidermal barrier extends the use of miRNAs for control of relevant skin diseases such as atopic dermatitis, ichthyoses, and psoriasis via miRNA-based technologies. Most of the relevant miRNAs have been associated with keratinocyte differentiation and proliferation. Few studies have investigated the association of miRNAs with structural proteins of corneocytes and cornified envelopes, cell–cell adhesion, and skin lipids. Further studies investigating the association between regulatory and structural components of epidermal barrier and miRNAs are needed to elucidate the role of miRNAs in epidermal barrier integrity and their clinical implications. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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14 pages, 1530 KiB

Open AccessReview

Skin Barrier Abnormalities and Immune Dysfunction in Atopic Dermatitis

by Gabsik Yang, Jin Kyung Seok, Han Chang Kang, Yong-Yeon Cho, Hye Suk Lee and Joo Young Lee

Int. J. Mol. Sci. 2020, 21(8), 2867; https://doi.org/10.3390/ijms21082867 - 20 Apr 2020

Cited by 219 | Viewed by 26961

Abstract

Atopic dermatitis (AD) is a common and relapsing skin disease that is characterized by skin barrier dysfunction, inflammation, and chronic pruritus. While AD was previously thought to occur primarily in children, increasing evidence suggests that AD is more common in adults than previously [...] Read more.

Atopic dermatitis (AD) is a common and relapsing skin disease that is characterized by skin barrier dysfunction, inflammation, and chronic pruritus. While AD was previously thought to occur primarily in children, increasing evidence suggests that AD is more common in adults than previously assumed. Accumulating evidence from experimental, genetic, and clinical studies indicates that AD expression is a precondition for the later development of other atopic diseases, such as asthma, food allergies, and allergic rhinitis. Although the exact mechanisms of the disease pathogenesis remain unclear, it is evident that both cutaneous barrier dysfunction and immune dysregulation are critical etiologies of AD pathology. This review explores recent findings on AD and the possible underlying mechanisms involved in its pathogenesis, which is characterized by dysregulation of immunological and skin barrier integrity and function, supporting the idea that AD is a systemic disease. These findings provide further insights for therapeutic developments aiming to repair the skin barrier and decrease inflammation. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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11 pages, 1358 KiB

Open AccessReview

Anti-Aging Effects of GDF11 on Skin

by Luc Rochette, Loubna Mazini, Alexandre Meloux, Marianne Zeller, Yves Cottin, Catherine Vergely and Gabriel Malka

Int. J. Mol. Sci. 2020, 21(7), 2598; https://doi.org/10.3390/ijms21072598 - 9 Apr 2020

Cited by 33 | Viewed by 8749

Abstract

Human skin is composed of three layers: the epidermis, the dermis, and the hypodermis. The epidermis has four major cell layers made up of keratinocytes in varying stages of progressive differentiation. Skin aging is a multi-factorial process that affects every phase of its [...] Read more.

Human skin is composed of three layers: the epidermis, the dermis, and the hypodermis. The epidermis has four major cell layers made up of keratinocytes in varying stages of progressive differentiation. Skin aging is a multi-factorial process that affects every phase of its biology and function. The expression profiles of inflammation-related genes analyzed in resident immune cells demonstrated that these cells have a strong ability to regenerate adult skin stem cells and to produce endogenous substances such as growth differentiation factor 11 (GDF11). GDF11 appears to be the key to progenitor proliferation and/or differentiation. The preservation of youthful phenotypes has been tied to the presence of GDF11 in different human tissues, and, in the skin, this factor inhibits inflammatory responses. The protective role of GDF11 depends on a multi-factorial process implicating various types of skin cells such as keratinocytes, fibroblasts and inflammatory cells. GDF11 should be further studied for the purpose of developing novel therapies for the treatment of skin diseases. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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28 pages, 3759 KiB

Open AccessReview

Loricrin: Past, Present, and Future

by Yosuke Ishitsuka and Dennis R. Roop

Int. J. Mol. Sci. 2020, 21(7), 2271; https://doi.org/10.3390/ijms21072271 - 25 Mar 2020

Cited by 36 | Viewed by 10858

Abstract

The terminal differentiation of the epidermis is a complex physiological process. During the past few decades, medical genetics has shown that defects in the stratum corneum (SC) permeability barrier cause a myriad of pathological conditions, ranging from common dry skin to lethal ichthyoses. [...] Read more.

The terminal differentiation of the epidermis is a complex physiological process. During the past few decades, medical genetics has shown that defects in the stratum corneum (SC) permeability barrier cause a myriad of pathological conditions, ranging from common dry skin to lethal ichthyoses. Contrarily, molecular phylogenetics has revealed that amniotes have acquired a specialized form of cytoprotection cornification that provides mechanical resilience to the SC. This superior biochemical property, along with desiccation tolerance, is attributable to the proper formation of the macromolecular protein-lipid complex termed cornified cell envelopes (CE). Cornification largely depends on the peculiar biochemical and biophysical properties of loricrin, which is a major CE component. Despite its quantitative significance, loricrin knockout (LKO) mice have revealed it to be dispensable for the SC permeability barrier. Nevertheless, LKO mice have brought us valuable lessons. It is also becoming evident that absent loricrin affects skin homeostasis more profoundly in many more aspects than previously expected. Through an extensive review of aggregate evidence, we discuss herein the functional significance of the thiol-rich protein loricrin from a biochemical, genetic, pathological, metabolic, or immunological aspect with some theoretical and speculative perspectives. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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17 pages, 1986 KiB

Open AccessReview

Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities

by Ai-Young Lee

Int. J. Mol. Sci. 2020, 21(4), 1194; https://doi.org/10.3390/ijms21041194 - 11 Feb 2020

Cited by 48 | Viewed by 6810

Abstract

Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell–cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions through vicious [...] Read more.

Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell–cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions through vicious cycles make the mechanism complicated in connection with other mechanisms, particularly immunologic responses. In this article, the molecular mechanisms concerning epidermal barrier abnormalities are reviewed in terms of the following categories: epidermal calcium gradients, filaggrin, cornified envelopes, desquamation, and skin lipids. Mechanisms linked to ichthyoses, atopic dermatitis without exacerbation or lesion, and early time of experimental irritation were included. On the other hand, the mechanism associated with epidermal barrier abnormalities resulting from preceding skin disorders was excluded. The molecular mechanism involved in epidermal barrier dysfunction has been mostly episodic. Some mechanisms have been identified in cultured cells or animal models. Nonetheless, research into the relationship between the causative molecules has been gradually increasing. Further evidence-based systematic data of target molecules and their interactions would probably be helpful for a better understanding of the molecular mechanism underlying the dysfunction of the epidermal barrier. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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17 pages, 1226 KiB

Open AccessReview

Trends in Atopic Dermatitis—From Standard Pharmacotherapy to Novel Drug Delivery Systems

by Eliana B. Souto, João Dias-Ferreira, Jéssica Oliveira, Elena Sanchez-Lopez, Ana Lopez-Machado, Marta Espina, Maria L. Garcia, Selma B. Souto, Carlos Martins-Gomes and Amélia M. Silva

Int. J. Mol. Sci. 2019, 20(22), 5659; https://doi.org/10.3390/ijms20225659 - 12 Nov 2019

Cited by 53 | Viewed by 6478

Abstract

Atopic dermatitis (AD) is a predominant and deteriorating chronic inflammation of the skin, categorized by robust burning and eczematous lacerations in diverse portions of the body. AD affects about 20% of both offspring and adults worldwide. The pathophysiology of AD combines environmental, hereditary, [...] Read more.

Atopic dermatitis (AD) is a predominant and deteriorating chronic inflammation of the skin, categorized by robust burning and eczematous lacerations in diverse portions of the body. AD affects about 20% of both offspring and adults worldwide. The pathophysiology of AD combines environmental, hereditary, and immunological aspects, together with skin barrier dysfunction. The procedures used to prevent the disease are the everyday usage of creams to support the restoration of the epidermal barrier. The classical treatments include the use of topical corticosteroids as a first-line therapy, but also calcineurin inhibitors, antihistamines, antibiotics, phototherapy, and also immunosuppressant drugs in severe cases of AD. Topical drug delivery to deeper skin layers is a difficult task due to the skin anatomic barrier, which limits deeper penetration of drugs. Groundbreaking drug delivery systems, based on nanoparticles (NPs), have received much attention due to their ability to improve solubility, bioavailability, diffusion, targeting to specific types of cells, and limiting the secondary effects of the drugs employed in the treatment of AD. Even so, additional studies are still required to recognize the toxicological characteristics and long-term safety of NPs. This review discusses the current classical pharmacotherapy of AD against new nanoparticle skin delivery systems and their toxicologic risks. Full article

(This article belongs to the Special Issue Skin Epidermis and Barrier Function)

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