Skin Research: Cellular Mechanism and Therapeutic Potentials

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Tissues and Organs".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 17917

Special Issue Editor


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Guest Editor
1. Department of Dermatology, University Hospital of Brest, 29200 Brest, France
2. Laboratory of Neurosciences, University of Western Brittany, 29238 Brest, France
Interests: itch; pain; neurodermatology; psychodermatology; autoimmune diseases
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Special Issue Information

Dear Colleagues,

Skin research has extremely varied aspects, as the skin is a complex organ and in close connection with other systems, such as immunity, the nervous system, or the vascular network. In the skin itself, the study of healthy skin can concern these interactions, as well as the different components of the epidermis, dermis, or hypodermis. As for dermatology, it is probably the medical specialty with the greatest number of diseases. This Special Issue edition is open to all aspects of skin research, from basic and translational to clinical and therapeutic research.

Prof. Dr. Laurent Misery
Guest Editor

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Keywords

  • skin
  • dermatology
  • immunology
  • biology
  • neuron
  • clinical trial
  • epidermis
  • dermis
  • hypodermis

Published Papers (8 papers)

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Research

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24 pages, 4071 KiB  
Article
A Thia-Analogous Indirubin N-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells
by Franziska Wendt, Felix Wittig, Anne Rupprecht, Robert Ramer, Peter Langer, Steffen Emmert, Marcus Frank and Burkhard Hinz
Cells 2023, 12(19), 2409; https://doi.org/10.3390/cells12192409 - 5 Oct 2023
Viewed by 1268
Abstract
Skin cancer is the most common malignant disease worldwide and, therefore, also poses a challenge from a pharmacotherapeutic perspective. Derivatives of indirubin are an interesting option in this context. In the present study, the effects of 3-[3′-oxo-benzo[b]thiophen-2′-(Z)-ylidene]-1-(β-d-glucopyranosyl)-oxindole [...] Read more.
Skin cancer is the most common malignant disease worldwide and, therefore, also poses a challenge from a pharmacotherapeutic perspective. Derivatives of indirubin are an interesting option in this context. In the present study, the effects of 3-[3′-oxo-benzo[b]thiophen-2′-(Z)-ylidene]-1-(β-d-glucopyranosyl)-oxindole (KD87), a thia-analogous indirubin N-glycoside, on the viability and mitochondrial properties of melanoma (A375) and squamous cell carcinoma cells (A431) of the skin were investigated. In both cell lines, KD87 caused decreased viability, the activation of caspases-3 and -7, and the inhibition of colony formation. At the mitochondrial level, a concentration-dependent decrease in both the basal and ATP-linked oxygen consumption rate and in the reserve capacity of oxidative respiration were registered in the presence of KD87. These changes were accompanied by morphological alterations in the mitochondria, a release of mitochondrial cytochrome c into the cytosol and significant reductions in succinate dehydrogenase complex subunit B (SDHB, subunit of complex II) in A375 and A431 cells and NADH:ubiquinone oxidoreductase subunit B8 (NDUFB8, subunit of complex I) in A375 cells. The effect of KD87 was accompanied by a significant upregulation of the enzyme heme oxygenase-1, whose inhibition led to a partial but significant reduction in the metabolic-activity-reducing effect of KD87. In summary, our data show a mitochondria-targeting effect of KD87 as part of the cytotoxic effect of this compound on skin cancer cells, which should be considered in future studies with this class of compounds. Full article
(This article belongs to the Special Issue Skin Research: Cellular Mechanism and Therapeutic Potentials)
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30 pages, 4648 KiB  
Article
Human Keratinocytes and Fibroblasts Co-Cultured on Silk Fibroin Scaffolds Exosomally Overrelease Angiogenic and Growth Factors
by Peng Hu, Ubaldo Armato, Giuliano Freddi, Anna Chiarini and Ilaria Dal Prà
Cells 2023, 12(14), 1827; https://doi.org/10.3390/cells12141827 - 11 Jul 2023
Cited by 2 | Viewed by 1998
Abstract
Objectives: The optimal healing of skin wounds, deep burns, and chronic ulcers is an important clinical problem. Attempts to solve it have been driving the search for skin equivalents based on synthetic or natural polymers. Methods: Consistent with this endeavor, we used regenerated [...] Read more.
Objectives: The optimal healing of skin wounds, deep burns, and chronic ulcers is an important clinical problem. Attempts to solve it have been driving the search for skin equivalents based on synthetic or natural polymers. Methods: Consistent with this endeavor, we used regenerated silk fibroin (SF) from Bombyx mori to produce a novel compound scaffold by welding a 3D carded/hydroentangled SF-microfiber-based nonwoven layer (C/H-3D-SFnw; to support dermis engineering) to an electrospun 2D SF nanofiber layer (ESFN; a basal lamina surrogate). Next, we assessed—via scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimetry, mono- and co-cultures of HaCaT keratinocytes and adult human dermal fibroblasts (HDFs), dsDNA assays, exosome isolation, double-antibody arrays, and angiogenesis assays—whether the C/H-3D-SFnws/ESFNs would allow the reconstitution of a functional human skin analog in vitro. Results: Physical analyses proved that the C/H-3D-SFnws/ESFNs met the requirements for human soft-tissue-like implants. dsDNA assays revealed that co-cultures of HaCaTs (on the 2D ESFN surface) and HDFs (inside the 3D C/H-3D-SFnws) grew more intensely than did the respective monocultures. Double-antibody arrays showed that the CD9+/CD81+ exosomes isolated from the 14-day pooled growth media of HDF and/or HaCaT mono- or co-cultures conveyed 35 distinct angiogenic/growth factors (AGFs). However, versus monocultures’ exosomes, HaCaT/HDF co-cultures’ exosomes (i) transported larger amounts of 15 AGFs, i.e., PIGF, ANGPT-1, bFGF, Tie-2, Angiogenin, VEGF-A, VEGF-D, TIMP-1/-2, GRO-α/-β/-γ, IL-1β, IL-6, IL-8, MMP-9, and MCP-1, and (ii) significantly more strongly stimulated human dermal microvascular endothelial cells to migrate and assemble tubes/nodes in vitro. Conclusions: Our results showed that both cell–cell and cell–SF interactions boosted the exosomal release of AGFs from HaCaTs/HDFs co-cultured on C/H-3D-SFnws/ESFNs. Hence, such exosomes are an asset for prospective clinical applications as they advance cell growth and neoangiogenesis and consequently graft take and skin healing. Moreover, this new integument analog could be instrumental in preclinical and translational studies on human skin pathophysiology and regeneration. Full article
(This article belongs to the Special Issue Skin Research: Cellular Mechanism and Therapeutic Potentials)
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14 pages, 6680 KiB  
Article
Anti-Melanogenic Effects of Fractioned Cynanchum atratum by Regulation of cAMP/MITF Pathway in a UVB-Stimulated Mice Model
by Jing-Hua Wang, Seung-Ju Hwang, Sam-Keun Lee, Yujin Choi, Chang Kyu Byun and Chang-Gue Son
Cells 2023, 12(10), 1390; https://doi.org/10.3390/cells12101390 - 14 May 2023
Viewed by 1765
Abstract
Based on traditional pharmacological applications and partial in vitro data, Cynanchum atratum (CA) is proposed to act on skin whitening. However, its functional evaluation and underlying mechanisms have yet to be identified. This study aimed to examine the anti-melanogenesis activity of CA fraction [...] Read more.
Based on traditional pharmacological applications and partial in vitro data, Cynanchum atratum (CA) is proposed to act on skin whitening. However, its functional evaluation and underlying mechanisms have yet to be identified. This study aimed to examine the anti-melanogenesis activity of CA fraction B (CAFB) on UVB-induced skin hyperpigmentation. Forty C57BL/6j mice were exposed to UVB (100 mJ/cm2, five times/week) for eight weeks. After irradiation, CAFB was applied to the left ear once a day for 8 weeks (the right ear served as an internal control). The results showed that CAFB significantly reduced melanin production in the ear skin, as indicated by the gray value and Mexameter melanin index. In addition, CAFB treatment notably decreased melanin production in α-MSH-stimulated B16F10 melanocytes, along with a significant reduction in tyrosinase activity. Cellular cAMP (cyclic adenosine monophosphate), MITF (microphthalmia-associated transcription factor), and tyrosinase-related protein 1 (TRP1) were also noticeably downregulated by CAFB. In conclusion, CAFB is a promising ingredient for treating skin disorders caused by the overproduction of melanin and its underlying mechanisms involving the modulation of tyrosinase, mainly mediated by the regulation of the cAMP cascade and MITF pathway. Full article
(This article belongs to the Special Issue Skin Research: Cellular Mechanism and Therapeutic Potentials)
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21 pages, 4274 KiB  
Article
Short-Term Treatment with Rho-Associated Kinase Inhibitor Preserves Keratinocyte Stem Cell Characteristics In Vitro
by Vignesh Jayarajan, George T. Hall, Theodoros Xenakis, Neil Bulstrode, Dale Moulding, Sergi Castellano and Wei-Li Di
Cells 2023, 12(3), 346; https://doi.org/10.3390/cells12030346 - 17 Jan 2023
Cited by 2 | Viewed by 2403
Abstract
Primary keratinocytes including keratinocyte stem cells (KSCs) can be cultured as epidermal sheets in vitro and are attractive for cell and gene therapies for genetic skin disorders. However, the initial slow growth of freshly isolated keratinocytes hinders clinical applications. Rho-associated kinase inhibitor (ROCKi) [...] Read more.
Primary keratinocytes including keratinocyte stem cells (KSCs) can be cultured as epidermal sheets in vitro and are attractive for cell and gene therapies for genetic skin disorders. However, the initial slow growth of freshly isolated keratinocytes hinders clinical applications. Rho-associated kinase inhibitor (ROCKi) has been used to overcome this obstacle, but its influence on the characteristics of KSC and its safety for clinical application remains unknown. In this study, primary keratinocytes were treated with ROCKi Y-27632 for six days (short-term). Significant increases in colony formation and cell proliferation during the six-day ROCKi treatment were observed and confirmed by related protein markers and single-cell transcriptomic analysis. In addition, short-term ROCKi-treated cells maintained their differentiation ability as examined by 3D-organotypic culture. However, these changes could be reversed and became indistinguishable between treated and untreated cells once ROCKi treatment was withdrawn. Further, the short-term ROCKi treatment did not reduce the number of KSCs. In addition, AKT and ERK pathways were rapidly activated upon ROCKi treatment. In conclusion, short-term ROCKi treatment can transiently and reversibly accelerate initial primary keratinocyte expansion while preserving the holoclone-forming cell population (KSCs), providing a safe avenue for clinical applications. Full article
(This article belongs to the Special Issue Skin Research: Cellular Mechanism and Therapeutic Potentials)
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22 pages, 19077 KiB  
Article
Dexamethasone and OLT1177 Cooperate in the Reduction of Melanoma Growth by Inhibiting STAT3 Functions
by Alberto Dinarello, Taylor S. Mills, Isak W. Tengesdal, Nicholas E. Powers, Tania Azam and Charles A. Dinarello
Cells 2023, 12(2), 294; https://doi.org/10.3390/cells12020294 - 12 Jan 2023
Cited by 2 | Viewed by 2639
Abstract
The NLRP3 inflammasome is a multimolecular complex that processes inactive IL-1β and IL-18 into proinflammatory cytokines. OLT1177 is an orally active small compound that specifically inhibits NLRP3. Here, B16F10 melanoma were implanted in mice and treated with OLT1177 as well as combined with [...] Read more.
The NLRP3 inflammasome is a multimolecular complex that processes inactive IL-1β and IL-18 into proinflammatory cytokines. OLT1177 is an orally active small compound that specifically inhibits NLRP3. Here, B16F10 melanoma were implanted in mice and treated with OLT1177 as well as combined with the glucocorticoid dexamethasone. At sacrifice, OLT1177 treated mice had significantly smaller tumors compared to tumor-bearing mice treated with vehicle. However, the combined treatment of OLT1177 plus dexamethasone revealed a greater suppression of tumor growth. This reduction was accompanied by a downregulation of nuclear and mitochondrial STAT3-dependent gene transcription and by a significant reduction of STAT3 Y705 and S727 phosphorylations in the tumors. In vitro, the human melanoma cell line 1205Lu, stimulated with IL-1α, exhibited significantly lower levels of STAT3 Y705 phosphorylation by the combination treatment, thus affecting the nuclear functions of STAT3. In the same cells, STAT3 serine 727 phosphorylation was also lower, affecting the mitochondrial functions of STAT3. In addition, metabolic analyses revealed a marked reduction of ATP production rate and glycolytic reserve in cells treated with the combination of OLT1177 plus dexamethasone. These findings demonstrate that the combination of OLT1177 and dexamethasone reduces tumor growth by targeting nuclear as well as mitochondrial functions of STAT3. Full article
(This article belongs to the Special Issue Skin Research: Cellular Mechanism and Therapeutic Potentials)
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16 pages, 2664 KiB  
Article
Evaluation of Hormonal Factors in Acne Vulgaris and the Course of Acne Vulgaris Treatment with Contraceptive-Based Therapies in Young Adult Women
by Dominika Borzyszkowska, Mirela Niedzielska, Mateusz Kozłowski, Agnieszka Brodowska, Adam Przepiera, Kinga Malczyk-Matysiak, Aneta Cymbaluk-Płoska and Elżbieta Sowińska-Przepiera
Cells 2022, 11(24), 4078; https://doi.org/10.3390/cells11244078 - 16 Dec 2022
Cited by 5 | Viewed by 2624
Abstract
Acne vulgaris is a common chronic inflammatory skin disease, which is considered one of the diseases of civilization due to the significant influence of environmental factors on the severity and frequency of these lesions. The aim of this study was to evaluate the [...] Read more.
Acne vulgaris is a common chronic inflammatory skin disease, which is considered one of the diseases of civilization due to the significant influence of environmental factors on the severity and frequency of these lesions. The aim of this study was to evaluate the hormonal profile of patients before treatment and to assess selected hormonal parameters after treatment. Our first objective was to examine the correlation between the selected hormonal parameters and the severity of acne before treatment. Our second objective was to evaluate the impact of treatment with three therapies, as measured by the selected hormonal parameters and acne severity. Statistical calculations were performed using the R v.4.1.1 statistical calculation environment (IDE RStudio v. 1.4.1717) with a significance level for the statistical tests set at α = 0.05. The results showed that the women in the pre-treatment (T1) and control (C) groups had significant differences in testosterone, androstendione, FAI, SHBG, prolactin, ACTH, and cortisol concentrations. After treatment, there were still significant differences in testosterone, androstendione, FAI, and SHBG concentrations between the post-treatment (T2) and control groups. We concluded that testosterone, androstendione, and cortisol concentrations correlate with acne severity. Acne in adult women may be an important clinical marker of androgen excess syndrome and cannot be considered a transient symptom of puberty. The mainstay of acne treatment is contraceptive therapy (ethonylestradiol and drospirenone). In this study, we confirmed the effectiveness of three contraceptive-based treatments using hormonal parameters and acne severity. Full article
(This article belongs to the Special Issue Skin Research: Cellular Mechanism and Therapeutic Potentials)
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Review

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18 pages, 1160 KiB  
Review
“Mens Sana in Cute Sana”—A State of the Art of Mutual Etiopathogenetic Influence and Relevant Pathophysiological Pathways between Skin and Mental Disorders: An Integrated Approach to Contemporary Psychopathological Scenarios
by Vincenzo Papa, Federica Li Pomi, Francesco Borgia, Sara Genovese, Giovanni Pioggia and Sebastiano Gangemi
Cells 2023, 12(14), 1828; https://doi.org/10.3390/cells12141828 - 12 Jul 2023
Cited by 4 | Viewed by 1439
Abstract
The negative socioeconomic impact of mental health disorders and skin diseases has increased in part due to the conflict between Russia and Ukraine, which has been a fertile ground for the emergence of psychopathologies. It is firmly established that there is a direct [...] Read more.
The negative socioeconomic impact of mental health disorders and skin diseases has increased in part due to the conflict between Russia and Ukraine, which has been a fertile ground for the emergence of psychopathologies. It is firmly established that there is a direct thread of etiopathogenetic communication between skin diseases and neuropsychiatric disorders, and the literature has tried to reveal the pathophysiological mechanisms governing such bidirectionality. This paper discusses this complex network of molecular pathways that are targeted by conventional and biological pharmacological agents that appear to impact two pathological spheres that previously seemed to have little connection. This molecular discussion is supplemented with a literature review, from a clinical viewpoint, regarding skin–brain etiopathogenetic bidirectionality. We focus on post-traumatic stress disorder (PTSD), which can be considered for all intents and purposes a systemic inflammatory disease that also affects the skin. A brief overview is also provided on the diagnostic–therapeutic and follow-up potential of oxidative and inflammatory markers potentially involved in the pathophysiological mechanisms treated. The aim is to clarify how these mechanisms may be useful in defining different stress-coping strategies and thus individual phenotypes of stress sensitivity/resistance in order to promote personalized medicine in the field of psychodermatology. Full article
(This article belongs to the Special Issue Skin Research: Cellular Mechanism and Therapeutic Potentials)
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18 pages, 5912 KiB  
Review
Novel Approaches in Non-Melanoma Skin Cancers—A Focus on Hedgehog Pathway in Basal Cell Carcinoma (BCC)
by Paulina Chmiel, Martyna Kłosińska, Alicja Forma, Zuzanna Pelc, Katarzyna Gęca and Magdalena Skórzewska
Cells 2022, 11(20), 3210; https://doi.org/10.3390/cells11203210 - 13 Oct 2022
Cited by 8 | Viewed by 2997
Abstract
Basal cell carcinoma (BCC) is one of the most common neoplasms in the population. A good prognosis and mainly non-aggressive development have made it underdiagnosed and excluded from the statistics. Due to the availability of efficient surgical therapy, BCC is sometimes overlooked in [...] Read more.
Basal cell carcinoma (BCC) is one of the most common neoplasms in the population. A good prognosis and mainly non-aggressive development have made it underdiagnosed and excluded from the statistics. Due to the availability of efficient surgical therapy, BCC is sometimes overlooked in the search for novel therapies. Most clinicians are unaware of its complicated pathogenesis or the availability of effective targeted therapy based on Hedgehog inhibitors (HHI) used in advanced or metastatic cases. Nevertheless, the concomitance and esthetic burden of this neoplasm are severe. As with other cancers, its pathogenesis is multifactorial and complicated with a network of dependencies. Although the tumour microenvironment (TME), genetic aberrations, and risk factors seem crucial in all skin cancers, in BCC they all have become accessible as therapeutic or prevention targets. The results of this review indicate that a central role in the development of BCC is played by the Hedgehog (Hh) signalling pathway. Two signalling molecules have been identified as the main culprits, namely Patched homologue 1 (PTCH1) and, less often, Smoothened homologue (SMO). Considering effective immunotherapy for other neoplastic growths being introduced, implementing immunotherapy in advanced BCC is pivotal and beneficial. Up to now, the US Food and Drug Administration (FDA) has approved two inhibitors of SMO for the treatment of advanced BCC. Sonidegib and vismodegib are registered based on their efficacy in clinical trials. However, despite this success, limitations might occur during the therapy, as some patients show resistance to these molecules. This review aims to summarize novel options of targeted therapies in BCC and debate the mechanisms and clinical implications of tumor resistance. Full article
(This article belongs to the Special Issue Skin Research: Cellular Mechanism and Therapeutic Potentials)
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