International Journal of Molecular Sciences

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Editorial: Special Issue, “Molecular Advances in Skin Diseases 2.0”

by Naoko Kanda

Int. J. Mol. Sci. 2024, 25(11), 5928; https://doi.org/10.3390/ijms25115928 - 29 May 2024

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Abstract

Recently, the pathomechanisms of various skin diseases have been progressively elucidated [...] Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

Research

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12 pages, 1876 KiB

Open AccessArticle

Differential Photosensitivity of Fibroblasts Obtained from Normal Skin and Hypertrophic Scar Tissues

by Junya Kusumoto, Masaya Akashi, Hiroto Terashi and Shunsuke Sakakibara

Int. J. Mol. Sci. 2024, 25(4), 2126; https://doi.org/10.3390/ijms25042126 - 9 Feb 2024

Cited by 1 | Viewed by 1328

Abstract

It is unclear whether normal human skin tissue or abnormal scarring are photoreceptive. Therefore, this study investigated photosensitivity in normal skin tissue and hypertrophic scars. The expression of opsins, which are photoreceptor proteins, in normal dermal fibroblasts (NDFs) and hypertrophic scar fibroblasts (HSFs) [...] Read more.

It is unclear whether normal human skin tissue or abnormal scarring are photoreceptive. Therefore, this study investigated photosensitivity in normal skin tissue and hypertrophic scars. The expression of opsins, which are photoreceptor proteins, in normal dermal fibroblasts (NDFs) and hypertrophic scar fibroblasts (HSFs) was examined. After exposure to blue light (BL), changes in the expression levels of αSMA and clock-related genes, specifically PER2 and BMAL1, were examined in both fibroblast types. Opsins were expressed in both fibroblast types, with OPN3 exhibiting the highest expression levels. After peripheral circadian rhythm disruption, BL induced rhythm formation in NDFs. In contrast, although HSFs showed changes in clock-related gene expression levels, no distinct rhythm formation was observed. The expression level of αSMA was significantly higher in HSFs and decreased to the same level as that in NDFs upon BL exposure. When OPN3 knocked-down HSFs were exposed to BL, the reduction in αSMA expression was inhibited. This study showed that BL exposure directly triggers peripheral circadian synchronization in NDFs but not in HSFs. OPN3-mediated BL exposure inhibited HSFs. Although the current results did not elucidate the relationship between peripheral circadian rhythms and hypertrophic scars, they show that BL can be applied for the prevention and treatment of hypertrophic scars and keloids. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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21 pages, 3971 KiB

Open AccessArticle

Study on the Antioxidant Effect of Shikonin-Loaded β-Cyclodextrin Forming Host–Guest Complexes That Prevent Skin from Photoaging

by Yan Yue, Yuqing Fang, Ruoyang Jia, Keang Cao, Xue Chen, Hongmei Xia and Zhiqing Cheng

Int. J. Mol. Sci. 2023, 24(20), 15177; https://doi.org/10.3390/ijms242015177 - 14 Oct 2023

Cited by 4 | Viewed by 1512

Abstract

When the skin is overexposed to ultraviolet rays, free radicals will accumulate in the skin, causing lipid damage and even inducing photoaging of the skin. Combination therapy with antioxidant drugs is a good choice for topical treatment of skin photoaging due to its [...] Read more.

When the skin is overexposed to ultraviolet rays, free radicals will accumulate in the skin, causing lipid damage and even inducing photoaging of the skin. Combination therapy with antioxidant drugs is a good choice for topical treatment of skin photoaging due to its special physiological structure. In this paper, shikonin was encapsulated in β-cyclodextrin (SH-β-CD) by the precipitation crystallization method, which delayed the release of the drug and increased drug solubility. The average diameter of SH-β-CD was 203.0 ± 21.27 nm with a zeta potential of −14.4 ± 0.5 mV. The encapsulation efficiency (EE%) was 65.9 ± 7.13%. The results of the in vitro permeation across the dialysis membrane and ex vivo transdermal release rates were 52.98 ± 1.21% and 88.25 ± 3.26%, respectively. In vitro antioxidant and antilipid peroxidation model assay revealed the antioxidant potential of SH and SH-β-CD. In the mice model of skin photoaging, SH and SH-β-CD had a recovery effect on the skin damage of mice, which could significantly increase the superoxide dismutase (SOD) activity in the skin. Briefly, SH-β-CD had an obvious therapeutic effect on the skin photoaging of mice caused by UV, and it is promising in skin disease treatment and skin care. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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23 pages, 4827 KiB

Open AccessArticle

Efficacy and Microbiota Modulation Induced by LimpiAL 2.5%, a New Medical Device for the Inverse Psoriasis Treatment

by Laura Pietrangelo, Annunziata Dattola, Irene Magnifico, Giulio Petronio Petronio, Marco Alfio Cutuli, Noemi Venditti, Antonio Guarnieri, Andreas Wollenberg, Giovanni Pellacani and Roberto Di Marco

Int. J. Mol. Sci. 2023, 24(7), 6339; https://doi.org/10.3390/ijms24076339 - 28 Mar 2023

Cited by 4 | Viewed by 2084

Abstract

(1) Inverse psoriasis (IP), also known as intertriginous, typically affects the groin, armpits, navel, intergluteal fissure, and external genitalia. Skin lesions are erythematous plaques of inflammatory nature, smooth, well-delimited, non-scaly, and non-infiltrated. Lesions may be accompanied by itching, pain, or burning sensation. The [...] Read more.

(1) Inverse psoriasis (IP), also known as intertriginous, typically affects the groin, armpits, navel, intergluteal fissure, and external genitalia. Skin lesions are erythematous plaques of inflammatory nature, smooth, well-delimited, non-scaly, and non-infiltrated. Lesions may be accompanied by itching, pain, or burning sensation. The aim of this study is both to investigate the modulation of the skin microbiota induced by IP and, on the other hand, to test the effectiveness of the new biotechnological product LimpiAL 2.5%. (2) Patients affected by IP were recruited in a private practice and treated for 4 weeks with LimpiAL 2.5% exclusively. The clinical effects on the lesion skin were evaluated, and the skin microbiotas before and after treatment were compared. (3) The clinical outcomes reveled a significant beneficial effect of the tested product. At the same time, LimpiAL increased the biological diversity of the skin microbiota and exerted a significant decrease of some Corynebacterium species, and the increase of some Staphylococcus species. (4) Together, the clinical outcomes and the microbiota analysis suggest that LimpiAL treatment improves the skin condition of affected patients, basically restoring the eubiosis conditions of the affected sites and modulating the bacterial composition of the resident microbiota. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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20 pages, 6735 KiB

Open AccessArticle

Amniotic Membrane Restores Chronic Wound Features to Normal in a Keratinocyte TGF-β-Chronified Cell Model

by Sergio Liarte, Ángel Bernabé-García, Mónica Rodríguez-Valiente, José M. Moraleda, Gregorio Castellanos and Francisco J. Nicolás

Int. J. Mol. Sci. 2023, 24(7), 6210; https://doi.org/10.3390/ijms24076210 - 25 Mar 2023

Cited by 6 | Viewed by 2017

Abstract

Unsuccessful wound closure in chronic wounds can be linked to altered keratinocyte activation and their inability to re-epithelize. Suggested mechanisms driving this impairment involve unbalanced cytokine signaling. However, the molecular events leading to these aberrant responses are poorly understood. Among cytokines affecting keratinocyte [...] Read more.

Unsuccessful wound closure in chronic wounds can be linked to altered keratinocyte activation and their inability to re-epithelize. Suggested mechanisms driving this impairment involve unbalanced cytokine signaling. However, the molecular events leading to these aberrant responses are poorly understood. Among cytokines affecting keratinocyte responses, Transforming Growth Factor-β (TFG-β) is thought to have a great impact. In this study, we have used a previously characterized skin epidermal in vitro model, HaCaT cells continuously exposed to TGF-β1, to study the wound recovery capabilities of chronified/senescent keratinocytes. In this setting, chronified keratinocytes show decreased migration and reduced activation in response to injury. Amniotic membrane (AM) has been used successfully to manage unresponsive complicated wounds. In our in vitro setting, AM treatment of chronified keratinocytes re-enabled migration in the early stages of wound healing, also promoting proliferation at later stages. Interestingly, when checking the gene expression of markers known to be altered in TGF-β chronified cells and involved in cell cycle regulation, early migratory responses, senescence, and chronic inflammation, we discovered that AM treatment seemed to reset back to keratinocyte status. The analysis of the evolution of both the levels of keratinocyte activation marker cytokeratin 17 and the spatial-temporal expression pattern of the proliferation marker Ki-67 in human in vivo biopsy samples suggests that responses to AM recorded in TGF-β chronified HaCaT cells would be homologous to those of resident keratinocytes in chronic wounds. All these results provide further evidence that sustained TGF-β might play a key role in wound chronification and postulate the validity of our TGF-β chronified HaCaT in vitro model for the study of chronic wound physiology. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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12 pages, 3424 KiB

Open AccessArticle

The Interplay of Type 1, Type 2, and Type 3 Lymphocytes and Cytokines in Atopic Dermatitis

by Keiichi Yamanaka, Yui Kono, Shohei Iida, Takehisa Nakanishi, Mai Nishimura, Yoshiaki Matsushima, Makoto Kondo, Koji Habe and Yasutomo Imai

Int. J. Mol. Sci. 2023, 24(4), 3310; https://doi.org/10.3390/ijms24043310 - 7 Feb 2023

Cited by 4 | Viewed by 2622

Abstract

Atopic dermatitis (AD) is classified as a type 2 disease owing to the majority of type 2 lymphocytes that constitute the skin-infiltrating leukocytes. However, all of the type 1–3 lymphocytes intermingle in inflamed skin lesions. Here, using an AD mouse model where caspase-1 [...] Read more.

Atopic dermatitis (AD) is classified as a type 2 disease owing to the majority of type 2 lymphocytes that constitute the skin-infiltrating leukocytes. However, all of the type 1–3 lymphocytes intermingle in inflamed skin lesions. Here, using an AD mouse model where caspase-1 was specifically amplified under keratin-14 induction, we analyzed the sequential changes in type 1–3 inflammatory cytokines in lymphocytes purified from the cervical lymph nodes. Cells were cultured and stained for CD4, CD8, and γδTCR, followed by intracellular cytokines. Cytokine production in innate lymphocyte cells (ILCs) and the protein expression of type 2 cytokine IL-17E (IL-25) were investigated. We observed that, as inflammation progresses, the cytokine-producing T cells increased and abundant IL-13 but low levels of IL-4 are produced in CD4-positive T cells and ILCs. TNF-α and IFN-γ levels increased continuously. The total number of T cells and ILCs peaked at 4 months and decreased in the chronic phase. In addition, IL-25 may be simultaneously produced by IL-17F-producing cells. IL-25-producing cells increased in a time-dependent manner during the chronic phase and may work specifically for the prolongation of type 2 inflammation. Altogether, these findings suggest that inhibition of IL-25 may be a potential target in the treatment of inflammation. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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Review

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14 pages, 1752 KiB

Open AccessReview

CD147/Basigin Is Involved in the Development of Malignant Tumors and T-Cell-Mediated Immunological Disorders via Regulation of Glycolysis

by Takuro Kanekura

Int. J. Mol. Sci. 2023, 24(24), 17344; https://doi.org/10.3390/ijms242417344 - 11 Dec 2023

Cited by 3 | Viewed by 2229

Abstract

CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is a multifunctional molecule with various binding partners. CD147 binds to monocarboxylate transporters (MCTs) and supports their expression on plasma membranes. MTC-1 and MCT-4 export the lactic acid that is converted from pyruvate in [...] Read more.

CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is a multifunctional molecule with various binding partners. CD147 binds to monocarboxylate transporters (MCTs) and supports their expression on plasma membranes. MTC-1 and MCT-4 export the lactic acid that is converted from pyruvate in glycolysis to maintain the intracellular pH level and a stable metabolic state. Under physiological conditions, cellular energy production is induced by mitochondrial oxidative phosphorylation. Glycolysis usually occurs under anaerobic conditions, whereas cancer cells depend on glycolysis under aerobic conditions. T cells also require glycolysis for differentiation, proliferation, and activation. Human malignant melanoma cells expressed higher levels of MCT-1 and MCT-4, co-localized with CD147 on the plasma membrane, and showed an increased glycolysis rate compared to normal human melanocytes. CD147 silencing by siRNA abrogated MCT-1 and MCT-4 membrane expression and disrupted glycolysis, inhibiting cancer cell activity. Furthermore, CD147 is involved in psoriasis. MCT-1 was absent on CD4⁺ T cells in CD147-deficient mice. The naïve CD4⁺ T cells from CD147-deficient mice exhibited a low capacity to differentiate into Th17 cells. Imiquimod-induced skin inflammation was significantly milder in the CD147-deficient mice than in the wild-type mice. Overall, CD147/Basigin is involved in the development of malignant tumors and T-cell-mediated immunological disorders via glycolysis regulation. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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15 pages, 1922 KiB

Open AccessReview

The Pressurized Skin: A Review on the Pathological Effect of Mechanical Pressure on the Skin from the Cellular Perspective

by Wei-Chen Chien and Tsen-Fang Tsai

Int. J. Mol. Sci. 2023, 24(20), 15207; https://doi.org/10.3390/ijms242015207 - 15 Oct 2023

Cited by 3 | Viewed by 3019

Abstract

Since human skin is the primary interface responding to external mechanical stimuli, extrinsic forces can disrupt its balanced microenvironment and lead to cutaneous lesions. We performed this review to delve into the pathological effects of mechanical pressure on skin from the cellular perspective. [...] Read more.

Since human skin is the primary interface responding to external mechanical stimuli, extrinsic forces can disrupt its balanced microenvironment and lead to cutaneous lesions. We performed this review to delve into the pathological effects of mechanical pressure on skin from the cellular perspective. Fibroblasts of different subsets act as heterogeneous responders to mechanical load and express diverse functionalities. Keratinocytes relay mechanical signals through mechanosensitive receptors and the ensuing neurochemical cascades to work collaboratively with other cells and molecules in response to pressure. Mast cells release cytokines and neuropeptides, promoting inflammation and facilitating interaction with sensory neurons, while melanocytes can be regulated by pressure through cellular and molecular crosstalk. Adipocytes and stem cells sense pressure to fine-tune their regulations of mechanical homeostasis and cell differentiation. Applying mechanical pressure to the skin can induce various changes in its microenvironment that potentially lead to pathological alterations, such as ischemia, chronic inflammation, proliferation, regeneration, degeneration, necrosis, and impaired differentiation. The heterogeneity of each cellular lineage and subset from different individuals with various underlying skin conditions must be taken into consideration when discussing the pathological effects of pressure on the skin. Thus, elucidating the mechanotransduction and mechanoresponsive pathways from the cellular viewpoint is crucial in diagnosing and managing relevant dermatological disorders. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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11 pages, 487 KiB

Open AccessReview

Inflammaging and Immunosenescence as Part of Skin Aging—A Narrative Review

by Justyna Pająk, Danuta Nowicka and Jacek C. Szepietowski

Int. J. Mol. Sci. 2023, 24(9), 7784; https://doi.org/10.3390/ijms24097784 - 24 Apr 2023

Cited by 24 | Viewed by 4611

Abstract

Inflammaging and immunosenescence are associated with aging of the human body, but there are key differences between them. Immunosenescence aims to adapt the body systems to aging, while inflammaging is considered a consequence of immunosenescence. There has been much research in the area [...] Read more.

Inflammaging and immunosenescence are associated with aging of the human body, but there are key differences between them. Immunosenescence aims to adapt the body systems to aging, while inflammaging is considered a consequence of immunosenescence. There has been much research in the area of immunosenescence and inflammaging recently, yet our understanding of aging and the ability to develop interventions to decrease the harmful effect of aging on the human body is insufficient. This review is focused on immunosenescence and inflammaging processes in the skin. We aimed to identify factors that influence inflammaging, skin aging, and their mechanisms. We discussed the role of triggering factors (e.g., UV radiations, changes in bioavailability of nitric oxide, senescence-associated secretory phenotype factors, and reactive oxygen species) and inhibiting factors that can potentially be used as anti-aging treatments, as well as the idea of geroprotectors and senotherapeutics. We concluded that while knowledge on external factors can help people to improve their health conditions, knowledge on biochemical factors can help researchers to understand inflammaging process and develop interventions to minimize the impact of aging on the human body. Further research is needed to better understand the role of factors that can slow down or accelerate inflammaging. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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14 pages, 698 KiB

Open AccessReview

Changes in the Immune Cell Repertoire for the Treatment of Malignant Melanoma

by Kenta Nakamura and Ryuhei Okuyama

Int. J. Mol. Sci. 2022, 23(21), 12991; https://doi.org/10.3390/ijms232112991 - 27 Oct 2022

Cited by 5 | Viewed by 1678

Abstract

Immune checkpoint inhibitors (ICIs) have been used for the treatment of various types of cancers, including malignant melanoma. Mechanistic exploration of tumor immune responses is essential to improve the therapeutic efficacy of ICIs. Since tumor immune responses are based on antigen-specific immune responses, [...] Read more.

Immune checkpoint inhibitors (ICIs) have been used for the treatment of various types of cancers, including malignant melanoma. Mechanistic exploration of tumor immune responses is essential to improve the therapeutic efficacy of ICIs. Since tumor immune responses are based on antigen-specific immune responses, investigators have focused on T cell receptors (TCRs) and have analyzed changes in the TCR repertoire. The proliferation of T cell clones against tumor antigens is detected in patients who respond to treatment with ICIs. The proliferation of these T cell clones is observed within tumors as well as in the peripheral blood. Clonal proliferation has been detected not only in CD8-positive T cells but also in CD4-positive T cells, resident memory T cells, and B cells. Moreover, changes in the repertoire at an early stage of treatment seem to be useful for predicting the therapeutic efficacy of ICIs. Further analyses of the repertoire of immune cells are desirable to improve and predict the therapeutic efficacy of ICIs. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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15 pages, 2343 KiB

Open AccessReview

Inflammation Causes Exacerbation of COVID-19: How about Skin Inflammation?

by Mayumi Komine, Tuba Mussarat Ansary, Md Razib Hossain, Koji Kamiya and Mamitaro Ohtsuki

Int. J. Mol. Sci. 2022, 23(20), 12260; https://doi.org/10.3390/ijms232012260 - 14 Oct 2022

Cited by 3 | Viewed by 2624

Abstract

COVID-19 is a recently emerged viral infection worldwide. SARS-CoV-2, the causative virus, is believed to have emerged from bat coronaviruses, probably through host conversion. The bat coronavirus which has the highest gene homology to SARS-CoV-2 specifically infects deep forest bats in China whose [...] Read more.

COVID-19 is a recently emerged viral infection worldwide. SARS-CoV-2, the causative virus, is believed to have emerged from bat coronaviruses, probably through host conversion. The bat coronavirus which has the highest gene homology to SARS-CoV-2 specifically infects deep forest bats in China whose habitat extends through the Middle East to Southern Europe. Host conversion might have occurred due to the deforestation by humans exposing wild bats to the environment they had never encountered before. SARS-CoV-2 infects cells through two mechanisms: through its receptor ACE2 with the help of enzyme TMPRSS and through membrane fusion with the help of elastases in the inflammatory condition. Obesity, hypertension, diabetes mellitus, and pulmonary diseases cause poor prognosis of COVID-19. Aging is another factor promoting poor prognosis. These diseases and aging cause low-level and persistent inflammation in humans, which can promote poor prognosis of COVID-19. Psoriasis and atopic dermatitis are the major inflammatory skin diseases. These inflammatory skin conditions, however, do not seem to cause poor prognosis for COVID-19 based on the epidemiological data accumulated so far. These mechanisms need to be elucidated. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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21 pages, 3632 KiB

Open AccessReview

Molecular Mechanisms and Targeted Therapies of Advanced Basal Cell Carcinoma

by Toshihiko Hoashi, Naoko Kanda and Hidehisa Saeki

Int. J. Mol. Sci. 2022, 23(19), 11968; https://doi.org/10.3390/ijms231911968 - 8 Oct 2022

Cited by 10 | Viewed by 3919

Abstract

Among human cutaneous malignancies, basal cell carcinoma is the most common. Solid advances in unveiling the molecular mechanisms of basal cell carcinoma have emerged in recent years. In Gorlin syndrome, which shows basal cell carcinoma predisposition, identification of the patched 1 gene (PTCH1) [...] Read more.

Among human cutaneous malignancies, basal cell carcinoma is the most common. Solid advances in unveiling the molecular mechanisms of basal cell carcinoma have emerged in recent years. In Gorlin syndrome, which shows basal cell carcinoma predisposition, identification of the patched 1 gene (PTCH1) mutation was a dramatic breakthrough in understanding the carcinogenesis of basal cell carcinoma. PTCH1 plays a role in the hedgehog pathway, and dysregulations of this pathway are known to be crucial for the carcinogenesis of many types of cancers including sporadic as well as hereditary basal cell carcinoma. In this review, we summarize the clinical features, pathological features and hedgehog pathway as applied in basal cell carcinoma. Other crucial molecules, such as p53 and melanocortin-1 receptor are also discussed. Due to recent advances, therapeutic strategies based on the precise molecular mechanisms of basal cell carcinoma are emerging. Target therapies and biomarkers are also discussed. Full article

(This article belongs to the Special Issue Molecular Advances in Skin Diseases 2.0)

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