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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 June 2025 | Viewed by 16742

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Special Issue Editor

Dr. Alessandro Terrinoni

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Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
Interests: keratinocyte; skin differentiation; genodermatosis; psoriasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The skin is a tissue at the interface between the host and the environment. It is the first line of defense against chemicals and physical insults and pathogens. This barrier function is of critical importance, which became evident after injury, in several different types of dermatitis, and in ichthyoses diseases.

Human skin is the largest immune organ that, in addition to providing a strong barrier against external insults, is fundamental in a wide variety of inflammatory processes, including immunity against infections, tumor immunity, autoimmunity, and allergy, continuously exposed to pathogens and external stress. This because, once the barrier is impaired, the rapid but nonspecific innate immune response is recruited in defense, a process that relies on detection of both self and foreign “danger signals” as the initial alarm. Next, the slower, but specific adaptive immune response may be required for definitive clearance of a pathogen.

The number of genetic skin disorders with known genetic defects has increased during the last decade. Advances in molecular biology provide new insights into immune and genetic aspects of skin diseases.

In this Special Issue of IJMS, we will publish cutting-edge information regarding recent advances in the research of skin diseases from molecular viewpoints. We warmly welcome research and review articles concerning a variety of factors relating to skin diseases, including their genetic/epigenetic regulation, therapy, and prevention. In this Special Issue, we aim to present molecular advances in all fields of skin diseases, whether inflammatory, neoplastic, or infectious.

Dr. Alessandro Terrinoni
Guest Editor

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Keywords

skin diseases
immunology
genetics

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Published Papers (8 papers)

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Research

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13 pages, 2365 KiB

Open AccessArticle

Irisin and Metastatic Melanoma: Selective Anti-Invasiveness Activity in BRAF Wild-Type Cells

by Simona Serratì, Roberta Zerlotin, Michele Manganelli, Roberta Di Fonte, Manuela Dicarlo, Angela Oranger, Graziana Colaianni, Letizia Porcelli, Amalia Azzariti, Stefania Guida, Maria Grano, Silvia Concetta Colucci and Gabriella Guida

Int. J. Mol. Sci. 2025, 26(2), 652; https://doi.org/10.3390/ijms26020652 - 14 Jan 2025

Viewed by 975

Abstract

Irisin is a newly discovered 12 kDa messenger protein involved in energy metabolism. Irisin affects signaling pathways in several types of cancer; however, the role of irisin in metastatic melanoma (MM) has not been described yet. We explored the biological effects of irisin in in vitro models of MM cells (HBL^wt/wt, LND1^wt/wt, Hmel1^V600K/wt and M3^V600E/V600E) capable of the oncogenic activation of BRAF. We treated MM cells with different concentrations of r-irisin (10 nM, 25 nM, 50 nM, 100 nM) for 24 h–48 h. An MTT assay highlighted that r-irisin did not affect the proliferation of MM cells. We subsequently treated MM cells with 10 nM r-irisin, corresponding to the dose exhibiting biological activity in vitro. Irisin reduced the invasive ability of only LND1^wt/wt (p < 0.05), which highly expressed αv gene levels, but did not affect the invasion of BRAF^mut cells. Gelatin zymography analysis showed a reduction in the enzymatic activity of MMP-2 and MMP-9 in BRAF^wt/wt cells treated with 10 nM r-irisin. Moreover, gene expression analysis (qPCR) of MMP-2 and MMP-9 and of the fibrinolytic system (uPAR, uPA and PAI-1) highlighted a crucial role of 10 nM r-irisin treatment in the inhibition of pro-invasive systems in BRAF^wt/wt. In conclusion, our results may suggest a possible differential role of irisin in melanoma cells. Full article

(This article belongs to the Special Issue Skin Diseases: From Molecular Mechanisms to Pathology)

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12 pages, 803 KiB

Open AccessArticle

Exploring the Impact of IL-33 Gene Polymorphism (rs1929992) on Susceptibility to Chronic Spontaneous Urticaria and Its Association with Serum Interleukin-33 Levels

by Carmen-Teodora Dobrican-Băruța, Diana Mihaela Deleanu, Mihaela Iancu, Ioana Adriana Muntean, Irena Nedelea, Radu-Gheorghe Bălan, Lucia Maria Procopciuc and Gabriela Adriana Filip

Int. J. Mol. Sci. 2024, 25(24), 13709; https://doi.org/10.3390/ijms252413709 - 22 Dec 2024

Viewed by 854

Abstract

Urticaria is a debilitating skin condition affecting up to 20% of the global population, characterized by erythematous, maculopapular lesions and significant quality of life impairment. This study focused on the role of interleukin 33 (IL-33) and its polymorphisms, particularly SNP rs1929992, in chronic spontaneous urticaria (CSU). Using demographic, clinical, and laboratory data from CSU patients and controls, we estimated allele and genotype frequencies, Hardy–Weinberg equilibrium condition, and serum IL-33 levels, using unconditional binomial logistic regression for association analysis. Results revealed that CSU patients had significantly higher frequencies of the minor allele of IL-33 rs1929992 compared to controls (31.25% vs. 17.35%, p = 0.024), and carriers of the GA genotype exhibited increased odds of CSU (adjusted OR = 2.208, p ≤ 0.001). Additionally, serum IL-33 levels were markedly elevated in CSU patients, particularly those with the GA genotype. The findings suggest that the IL-33 SNP is associated with an increased susceptibility to CSU, emphasizing its potential as a diagnostic and therapeutic biomarker. This study underscores the genetic and immunological underpinnings of CSU, paving the way for personalized treatment approaches. Full article

(This article belongs to the Special Issue Skin Diseases: From Molecular Mechanisms to Pathology)

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10 pages, 2960 KiB

Open AccessArticle

Characterising a Novel Therapeutic Target for Psoriasis, TYK2, Using Functional Genomics

by Shraddha S. Rane, Sarah Elyoussfi, Elan Shellard, Steve Eyre and Richard B. Warren

Int. J. Mol. Sci. 2024, 25(23), 13229; https://doi.org/10.3390/ijms252313229 - 9 Dec 2024

Viewed by 1954

Abstract

Psoriasis (Ps) is a debilitating immune-mediated chronic skin condition. It affects about 1–3% of the world population, with an 8–11% prevalence in Northern European populations. Tyrosine kinase 2 (TYK2) is a newly identified target for Ps. An independent non-coding genetic association with Ps has been identified ~400 kb upstream of TYK2. The variants making up the credible Ps Single-Nucleotide Polymorphism (SNP) set were identified in their genomic context with the potential to influence TYK2 expression by interacting with regulatory elements involved in gene regulation. Previous evidence from our laboratory has suggested that credible SNP sets in intronic regions can be distal regulators of the genes of interest through long-range chromatin interactions. We hypothesise that SNPs at ILF3 are distal regulators of TYK2 expression via long-range chromatin interactions and Ps risk. The dysregulation of the TYK2 pathway in Ps may be mediated by a combination of GWAS risk SNPs at ILF3 and TYK2 and downstream genes. We investigated this by employing functional genomics and molecular biology methods. We developed a CD4 T cell model system with Jurkat-dCAS9-VP64 and Jurkat-dCAS9-KRAB cells using CRISPR activation and CRISPR inhibition of the risk variants rs892086 and rs7248205, selected from the latest Ps GWAS SNP set for their long-range interaction and light Linkage Disequilibrium (R² > 0.8), respectively. Using CRISPR activation, we demonstrate here that these risk SNPs, although distal to TYK2, do indeed regulate the TYK2 gene. Investigations into annotating the TYK2 pathway using RNA-seq analysis revealed differentially regulated genes, including VEGFA, C1R, ADORA1, GLUD2, NDUFB8, and FCGR2C, which are thought to be implicated in Ps. These genes were observed to be associated with conditions such as psoriatic arthritis, atopic dermatitis, and systemic sclerosis when compared using published databases, which confirms their relevance and importance in inflammatory conditions. With the developed cell model systems using CRISPR technology and differential gene regulation, we demonstrate here that these genes have the potential to define the TYK2/Ps pathway and our understanding of the disease biology. Full article

(This article belongs to the Special Issue Skin Diseases: From Molecular Mechanisms to Pathology)

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31 pages, 3927 KiB

Open AccessArticle

Exploring the Biological Activity of Phytocannabinoid Formulations for Skin Health Care: A Special Focus on Molecular Pathways

by Guilherme Trigo, Mariana Coelho, Carolina Borges Ferreira, Matteo Melosini, Inês Sousa Lehmann, Catarina P. Reis, Maria Manuela Gaspar and Susana Santos

Int. J. Mol. Sci. 2024, 25(23), 13142; https://doi.org/10.3390/ijms252313142 - 6 Dec 2024

Viewed by 1634

Abstract

Recent advancements have highlighted the potential of cannabis and its phytocannabinoids (pCBs) in skin health applications. These compounds, through their interaction with the endocannabinoid system (ECS), show promise for skin health products. Their ability to regulate inflammation, oxidative stress and cell proliferation makes them useful in addressing skin problems such as inflammation, scarring, healing, acne and aging, positioning them as valuable tools for innovative skincare solutions. In the present work, the cellular and molecular effects of proprietary pCB-based formulations on ECS modulation, inflammation and skin regeneration were investigated. Using human dermal fibroblasts (HDF) and keratinocytes (HaCaT), the effect of formulations in both pre-treatment and treatment scenarios following exposure to stress-inducing agents was assessed. Key molecular markers were analyzed to tackle their efficacy in mitigating inflammation and promoting structural integrity and regeneration. In vitro results showed that these formulations significantly reduced inflammation, promoted skin regeneration and improved structural functions. In vivo studies confirmed that the formulations were well-tolerated and led to noticeable improvements in skin health, including enhanced barrier function. This study demonstrates the safety and efficacy of pCB-based formulations for cosmeceutical applications. By combining molecular analysis with in vivo testing, this research provides new insights into the therapeutic potential of pCBs for managing various skin conditions. Full article

(This article belongs to the Special Issue Skin Diseases: From Molecular Mechanisms to Pathology)

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14 pages, 2461 KiB

Open AccessArticle

Heterogeneous IL-9 Production by Circulating Skin-Tropic and Extracutaneous Memory T Cells in Atopic Dermatitis Patients

by Irene García-Jiménez, Lídia Sans-de San Nicolás, Laia Curto-Barredo, Marta Bertolín-Colilla, Eloi Sensada-López, Ignasi Figueras-Nart, Montserrat Bonfill-Ortí, Antonio Guilabert-Vidal, Anna Ryzhkova, Marta Ferran, Giovanni Damiani, Tali Czarnowicki, Ramon M. Pujol and Luis F. Santamaria-Babí

Int. J. Mol. Sci. 2024, 25(16), 8569; https://doi.org/10.3390/ijms25168569 - 6 Aug 2024

Cited by 4 | Viewed by 1562

Abstract

Interleukin (IL)-9 is present in atopic dermatitis (AD) lesions and is considered to be mainly produced by skin-homing T cells expressing the cutaneous lymphocyte-associated antigen (CLA). However, its induction by AD-associated triggers remains unexplored. Circulating skin-tropic CLA⁺ and extracutaneous/systemic CLA⁻ memory T cells cocultured with autologous lesional epidermal cells from AD patients were activated with house dust mite (HDM) and staphylococcal enterotoxin B (SEB). Levels of AD-related mediators in response to both stimuli were measured in supernatants, and the cytokine response was associated with different clinical characteristics. Both HDM and SEB triggered heterogeneous IL-9 production by CLA⁺ and CLA⁻ T cells in a clinically homogenous group of AD patients, which enabled patient stratification into IL-9 producers and non-producers, with the former group exhibiting heightened HDM-specific and total IgE levels. Upon allergen exposure, IL-9 production depended on the contribution of epidermal cells and class II-mediated presentation; it was the greatest cytokine produced and correlated with HDM-specific IgE levels, whereas SEB mildly induced its release. This study demonstrates that both skin-tropic and extracutaneous memory T cells produce IL-9 and suggests that the degree of allergen sensitization reflects the varied IL-9 responses in vitro, which may allow for patient stratification in a clinically homogenous population. Full article

(This article belongs to the Special Issue Skin Diseases: From Molecular Mechanisms to Pathology)

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17 pages, 8443 KiB

Open AccessArticle

Phenylalanine Butyramide: A Butyrate Derivative as a Novel Inhibitor of Tyrosinase

by Ritamaria Di Lorenzo, Vincenzo Di Lorenzo, Teresa Di Serio, Adua Marzocchi, Lucia Ricci, Eleonora Vardaro, Giovanni Greco, Maria Maisto, Lucia Grumetto, Vincenzo Piccolo, Elena Morelli and Sonia Laneri

Int. J. Mol. Sci. 2024, 25(13), 7310; https://doi.org/10.3390/ijms25137310 - 3 Jul 2024

Cited by 2 | Viewed by 1637

Abstract

Metabolites resulting from the bacterial fermentation of dietary fibers, such as short-chain fatty acids, especially butyrate, play important roles in maintaining gut health and regulating various biological effects in the skin. However, butyrate is underutilized due to its unpleasant odor. To circumvent this organoleptic unfavorable property, phenylalanine butyramide (PBA), a butyrate precursor, has been synthesized and is currently available on the market. We evaluated the inhibition of mushroom tyrosinase by butyrate and PBA through in vitro assays, finding IC₅₀ values of 34.7 mM and 120.3 mM, respectively. Docking calculations using a homology model of human tyrosinase identified a putative binding mode of PBA into the catalytic site. The anti-aging and anti-spot efficacy of topical PBA was evaluated in a randomized, double-blind, parallel-arm, placebo-controlled clinical trial involving 43 women affected by photo-damage. The results of this study showed that PBA significantly improved skin conditions compared to the placebo and was well tolerated. Specifically, PBA demonstrated strong skin depigmenting activity on both UV and brown spots (UV: −12.7% and −9.9%, Bs: −20.8% and −17.7% after 15 and 30 days, respectively, p < 0.001). Moreover, PBA brightened and lightened the skin (ITA°: +12% and 13% after 15 and 30 days, respectively, p < 0.001). Finally, PBA significantly improved skin elasticity (Ua/Uf: +12.4% and +32.3% after 15 and 30 days, respectively, p < 0.001) and firmness (Uf: −3.2% and −14.9% after 15 and 30 days, respectively, p < 0.01). Full article

(This article belongs to the Special Issue Skin Diseases: From Molecular Mechanisms to Pathology)

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Review

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18 pages, 1583 KiB

Open AccessReview

Combining Phototherapy and Gold-Based Nanomaterials: A Breakthrough in Basal Cell Carcinoma Treatment

by Karolyne Silva Baioco, Raquel Pereira, Tânia Ferreira-Gonçalves, João M. P. Coelho, Maria Manuela Gaspar and Catarina Pinto Reis

Int. J. Mol. Sci. 2024, 25(21), 11494; https://doi.org/10.3390/ijms252111494 - 26 Oct 2024

Cited by 2 | Viewed by 1724

Abstract

Basal cell carcinoma (BCC) is the most common type of skin carcinoma worldwide. BCC development is the result of a complex interaction between environmental, phenotypic, and genetic factors. While conventional treatments such as surgery and topical therapies have demonstrated variable efficacy (some of them with limited efficacy), they are not free of adverse side effects, most of them debilitating. Thus, there is a notable gap in the literature regarding alternative and non-invasive therapeutic options. This review aims to address this gap, exploring the potential of photothermal therapy (PTT) combined with metallic nanoparticles, namely gold nanoparticles (AuNPs), as a minimally invasive treatment approach. Through a comprehensive review of the literature in the period from 2014 to 2024, using experimental investigations, this review seeks to elucidate the intricate interplay between genetic factors, environmental influences, and the tumor microenvironment in BCC disease progression, with PTT as a potential therapeutic strategy. Those studies confirmed an enhanced targeting of cancer cells and selective ablation of tumor tissue, using emerging technologies like PTT. A significant tumor reduction, often exceeding 50%, was observed, with some studies reporting complete elimination of the tumor. The main adverse effects noted were localized skin irritation and transient hyperpigmentation, but these were generally minimal and manageable, highlighting the promise of PTT as an effective treatment. Thus, by leveraging the unique properties of AuNPs to enhance the effectiveness of PTT, the targeting of cancer cells can more precisely occur, reducing collateral damage to healthy tissues. This approach not only aims to achieve better clinical results, but also contributes to the broader knowledge base in the field of BCC research. Continued research and clinical trials will be crucial in refining those techniques and validating their efficacy, ultimately paving the way for more effective and less invasive treatments for BCC. Full article

(This article belongs to the Special Issue Skin Diseases: From Molecular Mechanisms to Pathology)

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24 pages, 2240 KiB

Open AccessReview

Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology

by Simona N. Shirley, Abigail E. Watson and Nabiha Yusuf

Int. J. Mol. Sci. 2024, 25(18), 10152; https://doi.org/10.3390/ijms251810152 - 21 Sep 2024

Cited by 5 | Viewed by 5194

Abstract

Many skin diseases begin with inflammatory changes on a molecular level. To develop a more thorough understanding of skin pathology and to identify new targets for therapeutic advancements, molecular mechanisms of inflammation in the context of skin disease should be studied. Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and crosstalk between immune and neuronal processes (neuro-immune crosstalk). This review seeks to summarize recent developments in our understanding of inflammatory processes in skin disease and to highlight opportunities for therapeutic advancements. With a focus on publications within the past 5 years (2019–2024), the databases PubMed and EBSCOhost were used to search for peer-reviewed papers regarding inflammatory molecular mechanisms and skin disease. Several themes of research interest regarding inflammatory processes in skin disease were determined through extensive review and were included based on their relative representation in current research and their focus on therapeutic potential. Several skin diseases such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and scleroderma were described in the paper to demonstrate the widespread influence of inflammation in skin disease. Full article

(This article belongs to the Special Issue Skin Diseases: From Molecular Mechanisms to Pathology)

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