Editorial

3 pages, 170 KiB

Open AccessEditorial

Synopsis of Barrier Function of Skin and Oral Mucosa—Volume 1

by Philip W. Wertz

Int. J. Mol. Sci. 2021, 22(17), 9383; https://doi.org/10.3390/ijms22179383 - 30 Aug 2021

Cited by 3 | Viewed by 1527

This is an attempt to make readers of the second edition of International Journal of Molecular Sciences Special Issue on the Barrier Function of Skin and Oral Mucosa aware of the content of the first edition on this same topic [...] Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

Research

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16 pages, 5759 KiB

Open AccessArticle

Drug Delivery through the Psoriatic Epidermal Barrier—A “Skin-On-A-Chip” Permeability Study and Ex Vivo Optical Imaging

by Dorottya Kocsis, Szabina Horváth, Ágnes Kemény, Zsófia Varga-Medveczky, Csaba Pongor, Rózsa Molnár, Anna Mihály, Dániel Farkas, Bese Márton Naszlady, András Fülöp, András Horváth, Balázs Rózsa, Erika Pintér, Rolland Gyulai and Franciska Erdő

Int. J. Mol. Sci. 2022, 23(8), 4237; https://doi.org/10.3390/ijms23084237 - 11 Apr 2022

Cited by 8 | Viewed by 2778

Abstract

Psoriasis is a chronic inflammatory disease with unmet medical needs. To clarify potential therapeutic targets, different animal models have been developed. In the current study, imiquimod-induced psoriasiform dermatitis was used for monitoring the changes in skin thickness, transepidermal water loss, body weight, blood [...] Read more.

Psoriasis is a chronic inflammatory disease with unmet medical needs. To clarify potential therapeutic targets, different animal models have been developed. In the current study, imiquimod-induced psoriasiform dermatitis was used for monitoring the changes in skin thickness, transepidermal water loss, body weight, blood perfusion and drug permeability for a topical cream formulation of caffeine, both in wild type and in knock out mice. Morphological characterization of control and diseased tissues was performed by scanning electron microscopy and two-photon microscopy. The chemically induced psoriatic group showed increased skin permeability for the model drug during disease progression. In wild type and TRPA1 KO mice, however, enhanced skin thickness and hyperkeratosis blocked further increase of drug penetration at the late phase (96 h). These results indicate that topical drug therapy can be more effective in early phases of plaque development, when skin thickness is lower. Although paracellular connections (tight junctions) are looser in the advanced phase, hyperkeratosis blocks drug delivery through the transappendageal routes. Novel drug formulations may have the potency for effective drug delivery across the epidermal barrier even in the advanced phase. For development of more effective topical drugs, further research is proposed to explore drug penetration both in healthy and diseased conditions. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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21 pages, 4006 KiB

Open AccessArticle

HPV Lesions and Other Issues in the Oral Cavity Treatment and Removal without Pain

by Salima El Moussaoui, Mireia Mallandrich, Núria Garrós, Ana Cristina Calpena, Maria José Rodríguez Lagunas and Francisco Fernández-Campos

Int. J. Mol. Sci. 2021, 22(20), 11158; https://doi.org/10.3390/ijms222011158 - 16 Oct 2021

Cited by 4 | Viewed by 2690

Abstract

Due to different oral and dental conditions, oral mucosa lesions such as those caused by the human papilloma virus and temporomandibular joint pathologies often have to be treated by surgical, ablative or extractive procedures. The treatment and control of pain and inflammation during [...] Read more.

Due to different oral and dental conditions, oral mucosa lesions such as those caused by the human papilloma virus and temporomandibular joint pathologies often have to be treated by surgical, ablative or extractive procedures. The treatment and control of pain and inflammation during these procedures is essential to guarantee the patient’s well-being. For the foregoing reason, a hydrogel based on sodium alginate and hyaluronic acid containing 2% of ketorolac tromethamine has been developed. We characterized it physically, mechanically and morphologically. The rheological results suggest that the formulation can be easily and gently applied. Ex vivo permeation studies show that Ketorolac Tromethamine is able to penetrate through the buccal and sublingual mucosae, in addition to being retained in the mucosae’s structure. Through an in vitro test, we were able to evaluate the role that saliva plays in the bioavailability of the drug, observing that more than half of the applied dose is eliminated in an hour. The histological and cytotoxic studies performed on pigs in vivo showed the excellent safety profile of the formulation, as well as its high tolerability. In parallel, a biomimetic artificial membrane (PermeaPad^®) was evaluated, and it showed a high degree of correlation with the oral and sublingual mucosa. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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Graphical abstract

15 pages, 1122 KiB

Open AccessArticle

Electron Spin Resonance Evaluation of Buccal Membrane Fluidity Alterations by Sodium Caprylate and L-Menthol

by Laxmi Shanthi Chede, Brett A. Wagner, Garry R. Buettner and Maureen D. Donovan

Int. J. Mol. Sci. 2021, 22(19), 10708; https://doi.org/10.3390/ijms221910708 - 02 Oct 2021

Cited by 6 | Viewed by 1656

Abstract

The ability of sodium caprylate and l-menthol to fluidize phospholipid bilayers composed of lipids simulating the buccal epithelium was investigated using electron spin resonance (ESR) to evaluate the action of these agents as permeation enhancers. 5-Doxyl stearic acid (5-DSA) and 16-doxyl stearic acid [...] Read more.

The ability of sodium caprylate and l-menthol to fluidize phospholipid bilayers composed of lipids simulating the buccal epithelium was investigated using electron spin resonance (ESR) to evaluate the action of these agents as permeation enhancers. 5-Doxyl stearic acid (5-DSA) and 16-doxyl stearic acid (16-DSA) were used as spin labels to identify alterations in membrane fluidity near the polar head groups or inner acyl regions of the lipid bilayer, respectively. The molecular motion of both 5-DSA and 16-DSA showed increased disorder near the polar and inner hydrophobic regions of the bilayer in the presence of sodium caprylate suggesting fluidization in both the regions, which contributes to its permeation enhancing effects. L-menthol decreased the order parameter for 16-DSA, showing membrane fluidization only in the inner acyl regions of the bilayer, which also corresponded to its weaker permeation enhancing effects. The rapid evaluation of changes in fluidity of the bilayer in the presence of potential permeation enhancers using ESR enables improved selection of effective permeation enhancers and enhancer combinations based on their effect on membrane fluidization. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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12 pages, 4835 KiB

Open AccessArticle

Trop2 Expression in Extramammary Paget’s Disease and Normal Skin

by Takamichi Ito, Keiko Tanegashima, Yuka Tanaka, Hiroki Hashimoto, Maho Murata, Yoshinao Oda and Yumiko Kaku-Ito

Int. J. Mol. Sci. 2021, 22(14), 7706; https://doi.org/10.3390/ijms22147706 - 19 Jul 2021

Cited by 11 | Viewed by 2645

Abstract

Extramammary Paget’s disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas. Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies. Trophoblast cell surface antigen 2 (Trop2), a [...] Read more.

Extramammary Paget’s disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas. Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies. Trophoblast cell surface antigen 2 (Trop2), a surface glycoprotein, has drawn attention as a potential therapeutic target for solid tumors. Sacituzumab govitecan, an antibody–drug conjugate of Trop2, has recently entered clinical use for the treatment of various solid cancers. However, little is known about the role of Trop2 in EMPD. In this study, we immunohistochemically examined Trop2 expression in 116 EMPD tissue samples and 10 normal skin tissues. In normal skin, Trop2 was expressed in the epidermal keratinocytes, inner root sheaths, and infundibulum/isthmus epithelium of hair follicles, eccrine/apocrine glands, and sebaceous glands. Most EMPD tissues exhibited homogeneous and strong Trop2 expression, and high Trop2 expression was significantly associated with worse disease-free survival (p = 0.0343). These results suggest the potential use of Trop2-targeted therapy for EMPD and improve our understanding of the skin-related adverse effects of current Trop2-targeted therapies such as sacituzumab govitecan. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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14 pages, 2865 KiB

Open AccessArticle

Effects of (R)- and (S)-α-Hydroxylation of Acyl Chains in Sphingosine, Dihydrosphingosine, and Phytosphingosine Ceramides on Phase Behavior and Permeability of Skin Lipid Models

by Andrej Kováčik, Petra Pullmannová, Lukáš Opálka, Michaela Šilarová, Jaroslav Maixner and Kateřina Vávrová

Int. J. Mol. Sci. 2021, 22(14), 7468; https://doi.org/10.3390/ijms22147468 - 12 Jul 2021

Cited by 11 | Viewed by 2692

Abstract

Ceramides (Cers) with α-hydroxylated acyl chains comprise about a third of all extractable skin Cers and are required for permeability barrier homeostasis. We have probed here the effects of Cer hydroxylation on their behavior in lipid models comprising the major SC lipids, Cer/free [...] Read more.

Ceramides (Cers) with α-hydroxylated acyl chains comprise about a third of all extractable skin Cers and are required for permeability barrier homeostasis. We have probed here the effects of Cer hydroxylation on their behavior in lipid models comprising the major SC lipids, Cer/free fatty acids (C ₁₆-C ₂₄)/cholesterol, and a minor component, cholesteryl sulfate. Namely, Cers with (R)-α-hydroxy lignoceroyl chains attached to sphingosine (Cer AS), dihydrosphingosine (Cer AdS), and phytosphingosine (Cer AP) were compared to their unnatural (S)-diastereomers and to Cers with non-hydroxylated lignoceroyl chains attached to sphingosine (Cer NS), dihydrosphingosine (Cer NdS), and phytosphingosine (Cer NP). By comparing several biophysical parameters (lamellar organization by X-ray diffraction, chain order, lateral packing, phase transitions, and lipid mixing by infrared spectroscopy using deuterated lipids) and the permeabilities of these models (water loss and two permeability markers), we conclude that there is no general or common consequence of Cer α-hydroxylation. Instead, we found a rich mix of effects, highly dependent on the sphingoid base chain, configuration at the α-carbon, and permeability marker used. We found that the model membranes with unnatural Cer (S)-AS have fewer orthorhombically packed lipid chains than those based on the (R)-diastereomer. In addition, physiological (R)-configuration decreases the permeability of membranes, with Cer (R)-AdS to theophylline, and increases the lipid chain order in model systems with natural Cer (R)-AP. Thus, each Cer subclass makes a distinct contribution to the structural organization and function of the skin lipid barrier. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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16 pages, 9925 KiB

Open AccessArticle

Can Human Oral Mucosa Stem Cells Differentiate to Corneal Epithelia?

by Sonia López, Lía Hoz, Eda Patricia Tenorio, Beatriz Buentello, Fátima Sofía Magaña, Ana Wintergerst, Alejandro Navas, Yonathan Garfias and Higinio Arzate

Int. J. Mol. Sci. 2021, 22(11), 5976; https://doi.org/10.3390/ijms22115976 - 01 Jun 2021

Cited by 10 | Viewed by 3070

Abstract

Human oral mucosa stem cells (hOMSCs) arise from the neural crest, they can self-renew, proliferate, and differentiate to several cell lines and could represent a good source for application in tissue engineering. Because of their anatomical location, hOMSCs are easy to isolate, have [...] Read more.

Human oral mucosa stem cells (hOMSCs) arise from the neural crest, they can self-renew, proliferate, and differentiate to several cell lines and could represent a good source for application in tissue engineering. Because of their anatomical location, hOMSCs are easy to isolate, have multilineage differentiation capacity and express embryonic stem cells markers such as—Sox2, Oct3/4 and Nanog. We have used SHEM (supplemented hormonal epithelial medium) media and cultured hOMSCs over human amniotic membrane and determined the cell’s capacity to differentiate to an epithelial-like phenotype and to express corneal specific epithelial markers—CK3, CK12, CK19, Pan-cadherin and E-cadherin. Our results showed that hOMSCs possess the capacity to attach to the amniotic membrane and express CK3, CK19, Pan-Cadherin and E-Cadherin without induction with SHEM media and expressed CK12 or changed the expression pattern of E-Cadherin to a punctual-like feature when treated with SHEM media. The results observed in this study show that hOMSCs possess the potential to differentiate toward epithelial cells. In conclusion, our results revealed that hOMSCs readily express markers for corneal determination and could provide the ophthalmology field with a therapeutic alternative for tissue engineering to achieve corneal replacement when compared with other techniques. Nevertheless, further studies are needed to develop a predictable therapeutic alternative for cornea replacement. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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16 pages, 1569 KiB

Open AccessArticle

Multitargeted Approach for the Optimization of Morphogenesis and Barrier Formation in Human Skin Equivalents

by Arnout Mieremet, Richard W. J. Helder, Andreea Nadaban, Walter A. Boiten, Gert S. Gooris, Abdoelwaheb El Ghalbzouri and Joke A. Bouwstra

Int. J. Mol. Sci. 2021, 22(11), 5790; https://doi.org/10.3390/ijms22115790 - 28 May 2021

Cited by 5 | Viewed by 2279

Abstract

In vitro skin tissue engineering is challenging due to the manifold differences between the in vivo and in vitro conditions. Yet, three-dimensional (3D) human skin equivalents (HSEs) are able to mimic native human skin in many fundamental aspects. However, the epidermal lipid barrier [...] Read more.

In vitro skin tissue engineering is challenging due to the manifold differences between the in vivo and in vitro conditions. Yet, three-dimensional (3D) human skin equivalents (HSEs) are able to mimic native human skin in many fundamental aspects. However, the epidermal lipid barrier formation, which is essential for the functionality of the skin barrier, remains compromised. Recently, HSEs with an improved lipid barrier formation were generated by (i) incorporating chitosan in the dermal collagen matrix, (ii) reducing the external oxygen level to 3%, and (iii) inhibiting the liver X receptor (LXR). In this study, we aimed to determine the synergic effects in full-thickness models (FTMs) with combinations of these factors as single-, double-, and triple-targeted optimization approaches. The collagen–chitosan FTM supplemented with the LXR inhibitor showed improved epidermal morphogenesis, an enhanced lipid composition, and a better lipid organization. Importantly, barrier functionality was improved in the corresponding approach. In conclusion, our leading optimization approach substantially improved the epidermal morphogenesis, barrier formation, and functionality in the FTM, which therefore better resembled native human skin. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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14 pages, 2187 KiB

Open AccessArticle

Increased Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 Contributes to Epidermal Permeability Barrier Dysfunction in Aged Skin

by Beom Jun Kim, Noo Ri Lee, Chung Hyeok Lee, Young Bin Lee, Sung Jay Choe, Solam Lee, Hyun Jee Hwang, Eunjung Kim, Gareth G. Lavery, Kyong-Oh Shin, Kyungho Park and Eung Ho Choi

Int. J. Mol. Sci. 2021, 22(11), 5750; https://doi.org/10.3390/ijms22115750 - 27 May 2021

Cited by 10 | Viewed by 2975

Abstract

Inactive cortisone is converted into active cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Excessive levels of active glucocorticoids could deteriorate skin barrier function; barrier impairment is also observed in aged skin. In this study, we aimed to determine whether permeability barrier impairment in [...] Read more.

Inactive cortisone is converted into active cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Excessive levels of active glucocorticoids could deteriorate skin barrier function; barrier impairment is also observed in aged skin. In this study, we aimed to determine whether permeability barrier impairment in the aged skin could be related to increased 11β-HSD1 expression. Aged humans (n = 10) showed increased cortisol in the stratum corneum (SC) and oral epithelium, compared to young subjects (n = 10). 11β-HSD1 expression (as assessed via immunohistochemical staining) was higher in the aged murine skin. Aged hairless mice (56-week-old, n = 5) manifested greater transepidermal water loss, lower SC hydration, and higher levels of serum inflammatory cytokines than the young mice (8-week-old, n = 5). Aged 11β-HSD1 knockout mice (n = 11), 11β-HSD1 inhibitor (INHI)-treated aged wild type (WT) mice (n = 5) and young WT mice (n = 10) exhibited reduced SC corticosterone level. Corneodesmosome density was low in WT aged mice (n = 5), but high in aged 11β-HSD1 knockout and aged INHI-treated WT mice. Aged mice exhibited lower SC lipid levels; this effect was reversed by INHI treatment. Therefore, upregulation of 11β-HSD1 in the aged skin increases the active-glucocorticoid levels; this suppresses SC lipid biosynthesis, leading to impaired epidermal permeability barrier. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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12 pages, 3550 KiB

Open AccessArticle

Molecule-Resolved Visualization of Particulate Matter on Human Skin Using Multimodal Nonlinear Optical Imaging

by Eun-Soo Lee, Suho Kim, Sang-Won Lee, Jinsang Jung, Sung Hoon Lee, Hye-Won Na, Hyoung-June Kim, Yong Deog Hong, Won Seok Park, Tae Geol Lee, Dong-Gyu Jo and Se-Hwa Kim

Int. J. Mol. Sci. 2021, 22(10), 5199; https://doi.org/10.3390/ijms22105199 - 14 May 2021

Cited by 6 | Viewed by 2373

Abstract

Precise measurement of particulate matter (PM) on skin is important for managing and preventing PM-related skin diseases. This study aims to directly visualize the deposition and penetration of PM into human skin using a multimodal nonlinear optical (MNLO) imaging system. We successfully obtained [...] Read more.

Precise measurement of particulate matter (PM) on skin is important for managing and preventing PM-related skin diseases. This study aims to directly visualize the deposition and penetration of PM into human skin using a multimodal nonlinear optical (MNLO) imaging system. We successfully obtained PM particle signals by merging two different sources, C–C vibrational frequency and autofluorescence, while simultaneously visualizing the anatomical features of the skin via keratin, collagen, and elastin. As a result, we found morphologically dependent PM deposition, as well as increased deposition following disruption of the skin barrier via tape-stripping. Furthermore, PM penetrated more and deeper into the skin with an increase in the number of tape-strippings, causing a significant increase in the secretion of pro-inflammatory cytokines. Our results suggest that MNLO imaging could be a useful technique for visualizing and quantifying the spatial distribution of PM in ex vivo human skin tissues. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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14 pages, 2943 KiB

Open AccessArticle

The Importance of Free Fatty Chain Length on the Lipid Organization in the Long Periodicity Phase

by Charlotte M. Beddoes, Denise E. Rensen, Gert S. Gooris, Marc Malfois and Joke A. Bouwstra

Int. J. Mol. Sci. 2021, 22(7), 3679; https://doi.org/10.3390/ijms22073679 - 01 Apr 2021

Cited by 10 | Viewed by 2372

Abstract

The skin’s barrier ability is an essential function for terrestrial survival, which is controlled by intercellular lipids within the stratum corneum (SC) layer. In this barrier, free fatty acids (FFAs) are an important lipid class. As seen in inflammatory skin diseases, when the [...] Read more.

The skin’s barrier ability is an essential function for terrestrial survival, which is controlled by intercellular lipids within the stratum corneum (SC) layer. In this barrier, free fatty acids (FFAs) are an important lipid class. As seen in inflammatory skin diseases, when the lipid chain length is reduced, a reduction in the barrier’s performance is observed. In this study, we have investigated the contributing effects of various FFA chain lengths on the lamellar phase, lateral packing. The repeat distance of the lamellar phase increased with FFA chain length (C20–C28), while shorter FFAs (C16 to C18) had the opposite behaviour. While the lateral packing was affected, the orthorhombic to hexagonal to fluid phase transitions were not affected by the FFA chain length. Porcine SC lipid composition mimicking model was then used to investigate the proportional effect of shorter FFA C16, up to 50% content of the total FFA mixture. At this level, no difference in the overall lamellar phases and lateral packing was observed, while a significant increase in the water permeability was detected. Our results demonstrate a FFA C16 threshold that must be exceeded before the structure and barrier function of the long periodicity phase (LPP) is affected. These results are important to understand the lipid behaviour in this unique LPP structure as well as for the understanding, treatment, and development of inflammatory skin conditions. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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25 pages, 6995 KiB

Open AccessArticle

Nanostructured Non-Ionic Surfactant Carrier-Based Gel for Topical Delivery of Desoximetasone

by Parinbhai Shah, Benjamin Goodyear, Nirali Dholaria, Vinam Puri and Bozena Michniak-Kohn

Int. J. Mol. Sci. 2021, 22(4), 1535; https://doi.org/10.3390/ijms22041535 - 03 Feb 2021

Cited by 12 | Viewed by 4219

Abstract

Psoriasis is a chronic autoimmune skin disease impacting the population globally. Pharmaceutical products developed to combat this condition commonly used in clinical settings are IV bolus or oral drug delivery routes. There are some major challenges for effectively developing new dosage forms for [...] Read more.

Psoriasis is a chronic autoimmune skin disease impacting the population globally. Pharmaceutical products developed to combat this condition commonly used in clinical settings are IV bolus or oral drug delivery routes. There are some major challenges for effectively developing new dosage forms for topical use: API physicochemical nature, the severity of the disease state, and low bioavailability present challenges for pharmaceutical product developers. For non-severe cases of psoriasis, topical drug delivery systems may be preferred or used in conjunction with oral or parenteral therapy to address local symptoms. Elastic vesicular systems, termed “niosomes”, are promising drug delivery vehicles developed to achieve improved drug delivery into biological membranes. This study aimed to effectively incorporate a corticosteroid into the niosomes for improving the drug bioavailability of desoximetasone, used to treat skin conditions via topical delivery. Niosomes characterization measurements were drug content, pH, spreadability, specific gravity, content uniformity, rheology, and physicochemical properties. Formulations used a topical gelling agent, Carbomer 980 to test for in vitro skin permeation testing (IVPT) and accelerated stability studies. The developed niosomal test gel provided approximately 93.03 ± 0.23% to 101.84 ± 0.11% drug content with yield stresses ranging from 16.12 to 225.54 Pa. The permeated amount of desoximetasone from the niosomal gel after 24 h was 9.75 ± 0.44 µg/cm² compared to 24.22 ± 4.29 µg/cm² released from the reference gel tested. Furthermore, a drug retention study compared the test gel to a reference gel, demonstrating that the skin retained 30.88 ng/mg of desoximetasone while the reference product retained 26.01 ng/mg. A controlled drug release profile was obtained with a niosomal formulation containing desoximetasone for use in a topical gel formulation showing promise for potential use to treat skin diseases like psoriasis. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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8 pages, 1138 KiB

Open AccessArticle

Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model

by Jihyun Lee, Yujin Jung, Seo won Jeong, Ga Hee Jeong, Gue Tae Moon and Miri Kim

Int. J. Mol. Sci. 2021, 22(2), 931; https://doi.org/10.3390/ijms22020931 - 19 Jan 2021

Cited by 9 | Viewed by 2472

Abstract

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study [...] Read more.

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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Review

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31 pages, 66020 KiB

Open AccessReview

Targeted Delivery of Zinc Pyrithione to Skin Epithelia

by Sean E. Mangion, Amy M. Holmes and Michael S. Roberts

Int. J. Mol. Sci. 2021, 22(18), 9730; https://doi.org/10.3390/ijms22189730 - 08 Sep 2021

Cited by 13 | Viewed by 10578

Abstract

Zinc pyrithione (ZnPT) is an anti-fungal drug delivered as a microparticle to skin epithelia. It is one of the most widely used ingredients worldwide in medicated shampoo for treating dandruff and seborrheic dermatitis (SD), a disorder with symptoms that include skin flaking, erythema [...] Read more.

Zinc pyrithione (ZnPT) is an anti-fungal drug delivered as a microparticle to skin epithelia. It is one of the most widely used ingredients worldwide in medicated shampoo for treating dandruff and seborrheic dermatitis (SD), a disorder with symptoms that include skin flaking, erythema and pruritus. SD is a multi-factorial disease driven by microbiol dysbiosis, primarily involving Malassezia yeast. Anti-fungal activity of ZnPT depends on the cutaneous availability of bioactive monomeric molecular species, occurring upon particle dissolution. The success of ZnPT as a topical therapeutic is underscored by the way it balances treatment efficacy with formulation safety. This review demonstrates how ZnPT achieves this balance, by integrating the current understanding of SD pathogenesis with an up-to-date analysis of ZnPT pharmacology, therapeutics and toxicology. ZnPT has anti-fungal activity with an average in vitro minimum inhibitory concentration of 10–15 ppm against the most abundant scalp skin Malassezia species (Malassezia globosa and Malassezia restrica). Efficacy is dependent on the targeted delivery of ZnPT to the skin sites where these yeasts reside, including the scalp surface and hair follicle infundibulum. Imaging and quantitative analysis tools have been fundamental for critically evaluating the therapeutic performance and safety of topical ZnPT formulations. Toxicologic investigations have focused on understanding the risk of local and systemic adverse effects following exposure from percutaneous penetration. Future research is expected to yield further advances in ZnPT formulations for SD and also include re-purposing towards a range of other dermatologic applications, which is likely to have significant clinical impact. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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16 pages, 3021 KiB

Open AccessReview

Lipid-Based Nanosystems as a Tool to Overcome Skin Barrier

by Maddalena Sguizzato, Elisabetta Esposito and Rita Cortesi

Int. J. Mol. Sci. 2021, 22(15), 8319; https://doi.org/10.3390/ijms22158319 - 02 Aug 2021

Cited by 53 | Viewed by 4494

Abstract

Skin may be affected by many disorders that can be treated by topical applications of drugs on the action site. With the advent of nanotechnologies, new efficient delivery systems have been developed. Particularly, lipid-based nanosystems such as liposomes, ethosomes, transferosomes, solid lipid nanoparticles, [...] Read more.

Skin may be affected by many disorders that can be treated by topical applications of drugs on the action site. With the advent of nanotechnologies, new efficient delivery systems have been developed. Particularly, lipid-based nanosystems such as liposomes, ethosomes, transferosomes, solid lipid nanoparticles, nanostructured lipid carriers, cubosomes, and monoolein aqueous dispersions have been proposed for cutaneous application, reaching in some cases the market or clinical trials. This review aims to provide an overview of the different lipid-based nanosystems, focusing on their use for topical application. Particularly, biocompatible nanosystems able to dissolve lipophilic compounds and to control the release of carried drug, possibly reducing side effects, are described. Notably, the rationale to topically administer antioxidant molecules by lipid nanocarriers is described. Indeed, the structural similarity between the nanosystem lipid matrix and the skin lipids allows the achievement of a transdermal effect. Surely, more research is required to better understand the mechanism of interaction between lipid-based nanosystems and skin. However, this attempt to summarize and highlight the possibilities offered by lipid-based nanosystems could help the scientific community to take advantage of the benefits derived from this kind of nanosystem. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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15 pages, 680 KiB

Open AccessReview

Potential Therapeutic Approaches through Modulating the Autophagy Process for Skin Barrier Dysfunction

by Min Sik Choi, Yoon-Jee Chae, Ji Woong Choi and Ji-Eun Chang

Int. J. Mol. Sci. 2021, 22(15), 7869; https://doi.org/10.3390/ijms22157869 - 23 Jul 2021

Cited by 11 | Viewed by 2951

Abstract

Autophagy is an attractive process to researchers who are seeking novel potential treatments for various diseases. Autophagy plays a critical role in degrading damaged cellular organelles, supporting normal cell development, and maintaining cellular homeostasis. Because of the various effects of autophagy, recent human [...] Read more.

Autophagy is an attractive process to researchers who are seeking novel potential treatments for various diseases. Autophagy plays a critical role in degrading damaged cellular organelles, supporting normal cell development, and maintaining cellular homeostasis. Because of the various effects of autophagy, recent human genome research has focused on evaluating the relationship between autophagy and a wide variety of diseases, such as autoimmune diseases, cancers, and inflammatory diseases. The skin is the largest organ in the body and provides the first line of defense against environmental hazards, including UV damage, chemical toxins, injuries, oxidative stress, and microorganisms. Autophagy takes part in endogenous defense mechanisms by controlling skin homeostasis. In this manner, regulating autophagy might contribute to the treatment of skin barrier dysfunctions. Various studies are ongoing to elucidate the association between autophagy and skin-related diseases in order to find potential therapeutic approaches. However, little evidence has been gathered about the relationship between autophagy and the skin. In this review, we highlight the previous findings of autophagy and skin barrier disorders and suggest potential therapeutic strategies. The recent research regarding autophagy in acne and skin aging is also discussed. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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15 pages, 1778 KiB

Open AccessReview

An Overview of Physical, Microbiological and Immune Barriers of Oral Mucosa

by Sevda Şenel

Int. J. Mol. Sci. 2021, 22(15), 7821; https://doi.org/10.3390/ijms22157821 - 22 Jul 2021

Cited by 45 | Viewed by 10991

Abstract

The oral mucosa, which is the lining tissue of the oral cavity, is a gateway to the body and it offers first-line protection against potential pathogens, exogenous chemicals, airborne allergens, etc. by means of its physical and microbiological-immune barrier functions. For this reason, [...] Read more.

The oral mucosa, which is the lining tissue of the oral cavity, is a gateway to the body and it offers first-line protection against potential pathogens, exogenous chemicals, airborne allergens, etc. by means of its physical and microbiological-immune barrier functions. For this reason, oral mucosa is considered as a mirror to the health of the individual as well as a guard or early warning system. It is organized in two main components: a physical barrier, which consists of stratified epithelial cells and cell–cell junctions, and a microbiological-immune barrier that keeps the internal environment in a condition of homeostasis. Different factors, including microorganism, saliva, proteins and immune components, have been considered to play a critical role in disruption of oral epithelial barrier. Altered mucosal structure and barrier functions results in oral pathologies as well as systemic diseases. About 700 kinds of microorganisms exist in the human mouth, constituting the oral microbiota, which plays a significant role on the induction, training and function of the host immune system. The immune system maintains the symbiotic relationship of the host with this microbiota. Crosstalk between the oral microbiota and immune system includes various interactions in homeostasis and disease. In this review, after reviewing briefly the physical barriers of oral mucosa, the fundamentals of oral microbiome and oral mucosal immunity in regard to their barrier properties will be addressed. Furthermore, their importance in development of new diagnostic, prophylactic and therapeutic strategies for certain diseases as well as in the application for personalized medicine will be discussed. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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18 pages, 1727 KiB

Open AccessReview

The Impact of the Circadian Clock on Skin Physiology and Cancer Development

by Janet E. Lubov, William Cvammen and Michael G. Kemp

Int. J. Mol. Sci. 2021, 22(11), 6112; https://doi.org/10.3390/ijms22116112 - 06 Jun 2021

Cited by 19 | Viewed by 5943

Abstract

Skin cancers are growing in incidence worldwide and are primarily caused by exposures to ultraviolet (UV) wavelengths of sunlight. UV radiation induces the formation of photoproducts and other lesions in DNA that if not removed by DNA repair may lead to mutagenesis and [...] Read more.

Skin cancers are growing in incidence worldwide and are primarily caused by exposures to ultraviolet (UV) wavelengths of sunlight. UV radiation induces the formation of photoproducts and other lesions in DNA that if not removed by DNA repair may lead to mutagenesis and carcinogenesis. Though the factors that cause skin carcinogenesis are reasonably well understood, studies over the past 10–15 years have linked the timing of UV exposure to DNA repair and skin carcinogenesis and implicate a role for the body’s circadian clock in UV response and disease risk. Here we review what is known about the skin circadian clock, how it affects various aspects of skin physiology, and the factors that affect circadian rhythms in the skin. Furthermore, the molecular understanding of the circadian clock has led to the development of small molecules that target clock proteins; thus, we discuss the potential use of such compounds for manipulating circadian clock-controlled processes in the skin to modulate responses to UV radiation and mitigate cancer risk. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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14 pages, 11529 KiB

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Strategies to Develop a Suitable Formulation for Inflammatory Skin Disease Treatment

by Jiun-Wen Guo and Shiou-Hwa Jee

Int. J. Mol. Sci. 2021, 22(11), 6078; https://doi.org/10.3390/ijms22116078 - 04 Jun 2021

Cited by 11 | Viewed by 3525

Abstract

Skin barrier functions, environmental insults, and genetic backgrounds are intricately linked and form the basis of common inflammatory skin disorders, such as atopic dermatitis, psoriasis, and seborrheic dermatitis, which may seriously affect one’s quality of life. Topical therapy is usually the first line [...] Read more.

Skin barrier functions, environmental insults, and genetic backgrounds are intricately linked and form the basis of common inflammatory skin disorders, such as atopic dermatitis, psoriasis, and seborrheic dermatitis, which may seriously affect one’s quality of life. Topical therapy is usually the first line of management. It is believed that successful topical treatment requires pharmaceutical formulation from a sufficient dosage to exert therapeutic effects by penetrating the stratum corneum and then diffusing to the target area. However, many factors can affect this process including the physicochemical properties of the active compound, the composition of the formulation base, and the limitations and conditions of the skin barrier, especially in inflammatory skin. This article briefly reviews the available data on these issues and provides opinions on strategies to develop a suitable formulation for inflammatory skin disease treatment. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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15 pages, 1055 KiB

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Roles of Lipids in the Permeability Barriers of Skin and Oral Mucosa

by Philip W. Wertz

Int. J. Mol. Sci. 2021, 22(10), 5229; https://doi.org/10.3390/ijms22105229 - 15 May 2021

Cited by 34 | Viewed by 4220

Abstract

PubMed searches reveal much literature regarding lipids in barrier function of skin and less literature on lipids in barrier function of the oral mucosa. In terrestrial mammals, birds, and reptiles, the skin’s permeability barrier is provided by ceramides, fatty acids, and cholesterol in [...] Read more.

PubMed searches reveal much literature regarding lipids in barrier function of skin and less literature on lipids in barrier function of the oral mucosa. In terrestrial mammals, birds, and reptiles, the skin’s permeability barrier is provided by ceramides, fatty acids, and cholesterol in the outermost layers of the epidermis, the stratum corneum. This layer consists of about 10–20 layers of cornified cells embedded in a lipid matrix. It effectively prevents loss of water and electrolytes from the underlying tissue, and it limits the penetration of potentially harmful substances from the environment. In the oral cavity, the regions of the gingiva and hard palate are covered by keratinized epithelia that much resemble the epidermis. The oral stratum corneum contains a lipid mixture similar to that in the epidermal stratum corneum but in lower amounts and is accordingly more permeable. The superficial regions of the nonkeratinized oral epithelia also provide a permeability barrier. These epithelial regions do contain ceramides, cholesterol, and free fatty acids, which may underlie barrier function. The oral epithelial permeability barriers primarily protect the underlying tissue by preventing the penetration of potentially toxic substances, including microbial products. Transdermal drug delivery, buccal absorption, and lipid-related disease are discussed. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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16 pages, 478 KiB

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Daily Lifestyle and Cutaneous Malignancies

by Yu Sawada and Motonobu Nakamura

Int. J. Mol. Sci. 2021, 22(10), 5227; https://doi.org/10.3390/ijms22105227 - 14 May 2021

Cited by 12 | Viewed by 2673

Abstract

Daily lifestyle is a fundamental part of human life and its influence accumulates daily in the human body. We observe that a good daily lifestyle has a beneficial impact on our health; however, the actual effects of individual daily lifestyle factors on human [...] Read more.

Daily lifestyle is a fundamental part of human life and its influence accumulates daily in the human body. We observe that a good daily lifestyle has a beneficial impact on our health; however, the actual effects of individual daily lifestyle factors on human skin diseases, especially skin cancers, have not been summarized. In this review, we focused on the influence of daily lifestyle on the development of skin cancer and described the detailed molecular mechanisms of the development or regulation of cutaneous malignancies. Several daily lifestyle factors, such as circadian rhythm disruption, smoking, alcohol, fatty acids, dietary fiber, obesity, and ultraviolet light, are known to be associated with the risk of cutaneous malignancies, malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and Merkel cell carcinoma. Although the influence of some daily lifestyles on the risk of skin cancers is controversial, this review provides us a better understanding of the relationship between daily lifestyle factors and skin cancers. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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18 pages, 1135 KiB

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Effect of Different Wavelengths of Laser Irradiation on the Skin Cells

by Aleksandra Cios, Martyna Ciepielak, Łukasz Szymański, Aneta Lewicka, Szczepan Cierniak, Wanda Stankiewicz, Mariola Mendrycka and Sławomir Lewicki

Int. J. Mol. Sci. 2021, 22(5), 2437; https://doi.org/10.3390/ijms22052437 - 28 Feb 2021

Cited by 44 | Viewed by 12628

Abstract

The invention of systems enabling the emission of waves of a certain length and intensity has revolutionized many areas of life, including medicine. Currently, the use of devices emitting laser light is not only an indispensable but also a necessary element of many [...] Read more.

The invention of systems enabling the emission of waves of a certain length and intensity has revolutionized many areas of life, including medicine. Currently, the use of devices emitting laser light is not only an indispensable but also a necessary element of many diagnostic procedures. It also contributed to the development of new techniques for the treatment of diseases that are difficult to heal. The use of lasers in industry and medicine may be associated with a higher incidence of excessive radiation exposure, which can lead to injury to the body. The most exposed to laser irradiation is the skin tissue. The low dose laser irradiation is currently used for the treatment of various skin diseases. Therefore appropriate knowledge of the effects of lasers irradiation on the dermal cells’ metabolism is necessary. Here we present current knowledge on the clinical and molecular effects of irradiation of different wavelengths of light (ultraviolet (UV), blue, green, red, and infrared (IR) on the dermal cells. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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12 pages, 729 KiB

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Pathophysiology and Treatment of Pruritus in Elderly

by Bo Young Chung, Ji Young Um, Jin Cheol Kim, Seok Young Kang, Chun Wook Park and Hye One Kim

Int. J. Mol. Sci. 2021, 22(1), 174; https://doi.org/10.3390/ijms22010174 - 26 Dec 2020

Cited by 24 | Viewed by 9448

Abstract

Pruritus is a relatively common symptom that anyone can experience at any point in their life and is more common in the elderly. Pruritus in elderly can be defined as chronic pruritus in a person over 65 years old. The pathophysiology of pruritus [...] Read more.

Pruritus is a relatively common symptom that anyone can experience at any point in their life and is more common in the elderly. Pruritus in elderly can be defined as chronic pruritus in a person over 65 years old. The pathophysiology of pruritus in elderly is still unclear, and the quality of life is reduced. Generally, itch can be clinically classified into six types: Itch caused by systemic diseases, itch caused by skin diseases, neuropathic pruritus, psychogenic pruritus, pruritus with multiple factors, and from unknown causes. Senile pruritus can be defined as a chronic pruritus of unknown origin in elderly people. Various neuronal mediators, signaling mechanisms at neuronal terminals, central and peripheral neurotransmission pathways, and neuronal sensitizations are included in the processes causing itch. A variety of therapies are used and several novel drugs are being developed to relieve itch, including systemic and topical treatments. Full article

(This article belongs to the Special Issue Barrier Function of Skin and Oral Mucosa)

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