SOCS1 and SOCS3 as key checkpoint molecules in the immune responses associated to skin inflammation and malignant transformation.

SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo.

Causal relationship between inflammatory skin diseases and breast cancer: A bidirectional Mendelian randomization study.

INTRODUCTION: Prior research has explored the relationship between inflammatory skin disorders and breast cancer (BC), yet the causality of this association remains uncertain. METHODS: Utilizing a bidirectional two-sample Mendelian randomization (MR) approach, this study aimed to elucidate the causal dynamics between various inflammatory skin conditions-namely acne, atopic dermatitis, psoriasis vulgaris, urticaria, and rosacea-and BC. Genetic variants implicated in these disorders were sourced from comprehensive genome-wide association studies representative of European ancestry. In the forward MR, BC was posited as the exposure, while the reverse MR treated each inflammatory skin disease as the exposure. A suite of analytical methodologies, including random effects inverse variance weighted (IVW), weighted median (WME), and MR-Egger, were employed to probe the causative links between inflammatory skin diseases and BC. Sensitivity analyses, alongside evaluations for heterogeneity and pleiotropy, were conducted to substantiate the findings. RESULTS: The MR analysis revealed an increased risk of acne associated with BC (IVW: OR = 1.063, 95% CI = 1.011-1.117, p = 0.016), while noting a decreased risk of atopic dermatitis (AD) in BC patients (IVW: OR = 0.941, 95% CI = 0.886-0.999, p = 0.047). No significant associations were observed between BC and psoriasis vulgaris, urticaria, or rosacea. Conversely, reverse MR analyses detected no effect of BC on the incidence of inflammatory skin diseases. The absence of pleiotropy and the consistency of these outcomes strengthen the study's conclusions. CONCLUSION: Findings indicate an elevated incidence of acne and a reduced incidence of AD in individuals with BC within the European population.

Cold atmospheric plasma in combination with laser therapy provides a window for the treatment of hyperproliferative skin disease.

Modern medical understanding suggests that hyperproliferative skin diseases (HSDs) are complex syndromes characterized by localized hypertrophy or hyperplasia and infiltration of inflammatory cells. Various treatments, including systemic and topical pharmacotherapy, laser interventions, photodynamic therapy, and surgery, have been proposed for managing HSDs. However, challenges such as wound healing and recurrence after laser treatment have hindered the effectiveness of laser therapy. To overcome these challenges, we conducted a study combining laser therapy with cold atmospheric plasma (CAP) for the treatment of HSDs. Seven patients with different forms of HSDs, who had not responded well to conventional treatments, were enrolled in the study. These HSDs included cases of erythroplasia of Queyrat, pyoderma gangrenosum, keloids and hypertrophic scars, cellulitis, cutaneous lichen planus, and verruca vulgaris. Laser therapy was performed to remove the hyperplastic skin lesions, followed immediately by daily CAP treatment. The results were promising, with all patients successfully treated and no recurrence observed during the follow-up periods. The combined application of CAP and laser therapy proved to be an effective and complementary strategy for managing HSDs. This innovative approach provide evidence for addressing the limitation of laser therapy by utilizing CAP to promote wound healing and mitigate inflammatory responses. Chinese Clinical Trial Registry (ChiCTR2300069993).

Matrikines in the skin: Origin, effects, and therapeutic potential.

The extracellular matrix (ECM) represents a complex multi-component environment that has a decisive influence on the biomechanical properties of tissues and organs. Depending on the tissue, ECM components are subject to a homeostasis of synthesis and degradation, a subtle interplay that is influenced by external factors and the intrinsic aging process and is often disturbed in pathologies. Upon proteolytic cleavage of ECM proteins, small bioactive peptides termed matrikines can be formed. These bioactive peptides play a crucial role in cell signaling and contribute to the dynamic regulation of both physiological and pathological processes such as tissue remodeling and repair as well as inflammatory responses. In the skin, matrikines exert an influence for instance on cell adhesion, migration, and proliferation as well as vasodilation, angiogenesis and protein expression. Due to their manifold functions, matrikines represent promising leads for developing new therapeutic options for the treatment of skin diseases. This review article gives a comprehensive overview on matrikines in the skin, including their origin in the dermal ECM, their biological effects and therapeutic potential for the treatment of skin pathologies such as melanoma, chronic wounds and inflammatory skin diseases or for their use in anti-aging cosmeceuticals.

Breast cancer-related lymphedema results in impaired epidermal differentiation and tight junction dysfunction.

Breast cancer-related lymphedema (BCRL) is characterized by skin changes, swelling, fibrosis, and recurrent skin infections. Clinical studies have suggested that lymphedema results in skin barrier defects; however, the underlying cellular mechanisms and the effects of bacterial contamination on skin barrier function remain unknown. In matched biopsies from patients with unilateral BCRL, we observed decreased expression of filaggrin and the tight junction protein zona occludens-1 (ZO-1) in skin affected by moderate lymphedema, or by subclinical lymphedema in which dermal backflow of lymph was identified by indocyanine green lymphography, relative to controls (areas without backflow and from the unaffected arm). In vitro stimulation of keratinocytes with lymph fluid obtained from patients undergoing lymphedema surgery led to the same changes, as well as increased expression of keratin 14, a marker of immature keratinocytes. Finally, using mouse models of lymphedema, we showed that like the clinical scenario, the expression of skin barrier proteins was decreased relative to normal skin and that colonization with S. epidermidis bacteria amplified this effect, as well as lymphedema severity. Taken together, our findings suggest that lymphatic fluid stasis contributes to skin barrier dysfunction in lymphedema.

SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-type Palmoplantar Keratoderma.

Nagashima-type palmoplantar keratoderma (NPPK) is an autosomal recessive genodermatosis caused by loss-of-function variants in SERPINB7 and is the most prevalent form of inherited palmoplantar keratodermas among Asians. However, there is currently no effective therapy for NPPK because its pathogenesis remains unclear. In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment. The skin of these Serpinb7-/- mice showed weakened cytoskeletal proteins. Additionally, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a three-dimensional human epidermal model. We also demonstrated that SERPINB7 was an inhibitory serpin that mainly inhibited the protease legumain. SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo. Furthermore, we found that SERPINB7 inhibited legumain in a 'protease-substrate' manner and identified the cleavage sites of SERPINB7 as Asn71 and Asn343. Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor, and identified legumain as a key target protease of SERPINB7. Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in NPPK. These findings may lead to the development of therapeutic strategies for NPPK.

Revolutionizing dermatology: harnessing mesenchymal stem/stromal cells and exosomes in 3D platform for skin regeneration.

Contemporary trends reveal an escalating interest in regenerative medicine-based interventions for addressing refractory skin defects. Conventional wound healing treatments, characterized by high costs and limited efficacy, necessitate a more efficient therapeutic paradigm to alleviate the economic and psychological burdens associated with chronic wounds. Mesenchymal stem/stromal cells (MSCs) constitute cell-based therapies, whereas cell-free approaches predominantly involve the utilization of MSC-derived extracellular vesicles or exosomes, both purportedly safe and effective. Exploiting the impact of MSCs by paracrine signaling, exosomes have emerged as a novel avenue capable of positively impacting wound healing and skin regeneration. MSC-exosomes confer several advantages, including the facilitation of angiogenesis, augmentation of cell proliferation, elevation of collagen production, and enhancement of tissue regenerative capacity. Despite these merits, challenges persist in clinical applications due to issues such as poor targeting and facile removal of MSC-derived exosomes from skin wounds. Addressing these concerns, a three-dimensional (3D) platform has been implemented to emend exosomes, allowing for elevated levels, and constructing more stable granules possessing distinct therapeutic capabilities. Incorporating biomaterials to encapsulate MSC-exosomes emerges as a favorable approach, concentrating doses, achieving intended therapeutic effectiveness, and ensuring continual release. While the therapeutic potential of MSC-exosomes in skin repair is broadly recognized, their application with 3D biomaterial scenarios remains underexplored. This review synthesizes the therapeutic purposes of MSCs and exosomes in 3D for the skin restoration, underscoring their promising role in diverse dermatological conditions. Further research may establish MSCs and their exosomes in 3D as a viable therapeutic option for various skin conditions.

Air pollution and skin diseases: A comprehensive evaluation of the associated mechanism.

Air pollutants deteriorate the survival environment and endanger human health around the world. A large number of studies have confirmed that air pollution jeopardizes multiple organs, such as the cardiovascular, respiratory, and central nervous systems. Skin is the largest organ and the first barrier that protects us from the outside world. Air pollutants such as particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs) will affect the structure and function of the skin and bring about the development of inflammatory skin diseases (atopic dermatitis (AD), psoriasis), skin accessory diseases (acne, alopecia), auto-immune skin diseases (cutaneous lupus erythematosus(CLE) scleroderma), and even skin tumors (melanoma, basal cell carcinoma (BCC), squamous-cell carcinoma (SCC)). Oxidative stress, skin barrier damage, microbiome dysbiosis, and skin inflammation are the pathogenesis of air pollution stimulation. In this review, we summarize the current evidence on the effects of air pollution on skin diseases and possible mechanisms to provide strategies for future research.

Macrophage Functions in Psoriasis: Lessons from Mouse Models.

Psoriasis is a systemic autoimmune/autoinflammatory disease that can be well studied in established mouse models. Skin-resident macrophages are classified into epidermal Langerhans cells and dermal macrophages and are involved in innate immunity, orchestration of adaptive immunity, and maintenance of tissue homeostasis due to their ability to constantly shift their phenotype and adapt to the current microenvironment. Consequently, both macrophage populations play dual roles in psoriasis. In some circumstances, pro-inflammatory activated macrophages and Langerhans cells trigger psoriatic inflammation, while in other cases their anti-inflammatory stimulation results in amelioration of the disease. These features make macrophages interesting candidates for modern therapeutic strategies. Owing to the significant progress in knowledge, our review article summarizes current achievements and indicates future research directions to better understand the function of macrophages in psoriasis.

Multiplicative Effects of Essential Oils and Other Active Components on Skin Tissue and Skin Cancers.

Naturally derived essential oils and their active components are known to possess various properties, ranging from anti-oxidant, anti-inflammatory, anti-bacterial, anti-fungal, and anti-cancer activities. Numerous types of essential oils and active components have been discovered, and their permissive roles have been addressed in various fields. In this comprehensive review, we focused on the roles of essential oils and active components in skin diseases and cancers as discovered over the past three decades. In particular, we opted to highlight the effectiveness of essential oils and their active components in developing strategies against various skin diseases and skin cancers and to describe the effects of the identified essential-oil-derived major components from physiological and pathological perspectives. Overall, this review provides a basis for the development of novel therapies for skin diseases and cancers, especially melanoma.

Síndrome de Wells: presentación con un gran polimorfismo clínico

El síndrome de Wells es una afección dérmica que presenta un gran polimorfismo clínico. Es una patología autolimitada, recurrente y su origen es incierto. Reportamos el caso de una paciente de 29 años, procedente del área Central de Paraguay, comerciante, sin patología de base que consultó por edema de manos y piel. El tratamiento indicado fue corticoide vía oral y desparasitación con buena evolución y sin recidivas.

Wells syndrome is a dermal condition with a high clinical polymorphism. It is a self-limited, recurrent pathology and its origin is uncertain. We report the case of a 29-year-old female patient from the central area of Paraguay, a shopkeeper, with no underlying pathology, who consulted for hand and skin edema. The indicated treatment was oral corticosteroid and deworming with good evolution and no recurrences.

Punica granatum L. (Pomegranate) Extracts and Their Effects on Healthy and Diseased Skin.

The aim of this review is to provide a summary of the botany, phytochemistry and dermatological effects of Punica granatum (PG), with special emphasis on therapeutic mechanisms in various skin conditions. PG peel contains the highest levels of chemical compounds. Due to the high abundance of polyphenolic compounds, including phenolic acids, anthocyanins and flavonoids, exhibiting strong antioxidant properties, PG peel possesses significant health-promoting effects. Up until now, different parts of PG in the form of various extracts, fixed seed oil or individual active compounds have been investigated for various effects on skin conditions in in vitro and in vivo studies, such as antioxidant, anti-inflammatory, antimicrobial, chemoprotective and antiaging effects, as well as positive effects on striae distensae, skin repair mechanisms, erythema, pigmentation and psoriasis. Therefore, formulations containing PG active compounds have been used for skincare of diseased and healthy skin. Only a few effects have been confirmed on human subjects. Based on encouraging results obtained in in vitro and animal studies about the numerous substantial dermatological effects of PG active compounds, future perspectives should incorporate more in vivo investigations in human volunteers. This approach can aid in identifying the optimal concentrations and formulations that would be most efficacious in addressing specific skin conditions.

Zinc, Copper, and Iron in Selected Skin Diseases.

Trace elements are essential for maintaining the body's homeostasis, and their special role has been demonstrated in skin physiology. Among the most important trace elements are zinc, copper, and iron. A deficiency or excess of trace elements can be associated with an increased risk of skin diseases, so increasing their supplementation or limiting intake can be helpful in dermatological treatment. In addition, determinations of their levels in various types of biological material can be useful as additional tests in dermatological treatment. This paper describes the role of these elements in skin physiology and summarizes data on zinc, copper, and iron in the course of selected, following skin diseases: psoriasis, pemphigus vulgaris, atopic dermatitis, acne vulgaris and seborrheic dermatitis. In addition, this work identifies the potential of trace elements as auxiliary tests in dermatology. According to preliminary studies, abnormal levels of zinc, copper, and iron are observed in many skin diseases and their determinations in serum or hair can be used as auxiliary and prognostic tests in the course of various dermatoses. However, since data for some conditions are conflicting, clearly defining the potential of trace elements as auxiliary tests or elements requiring restriction/supplement requires further research.

A Retrospective Study: Clinical Characteristics and Lifestyle Analysis of Chinese Senile Gluteal Dermatosis Patients.

Purpose: To summarize the clinical, histopathological and therapeutic features of senile gluteal dermatosis. Patients and Methods: Retrospective analysis of 230 cases who visited the outpatient clinic of Hangzhou No. 3 People's Hospital for skin lesions on the buttocks and hips from 2018.8-2023.8 were included in the study, basic clinical information was collected, and they were subjected to physical examination of the buttocks and hips, and 36 cases were senile gluteal dermatosis, of which 7 underwent histopathological biopsy. Results: A total of 230 patients were included, of which 36 were diagnosed with geriatric buttock dermatosis, with a mean age of (84.2±12.6) years, mean body mass index of (21.7±3.8) kg/m2, and a male to female ratio of 2:1. There was a significant correlation between the occurrence of the disease and age, gender, body mass index, sedentary time, type of chair used, and hypertension (P<0.05). The severity of the lesions may be associated with longer sitting time and prolonged use of bamboo chairs (P<0.05). Histopathologic changes were not specific. The skin lesions could subside after general treatment such as improvement of lifestyle, use of pressure-reducing air mattresses, salicylic acid cream, and moisturizing creams. Conclusion: Senile gluteal dermatosis is a common senile physical dermatosis, mainly manifested as brownish scaly plaques, erythema and crusted ulcers, which can often be cured under reasonable treatment.

Cutaneous toxicities of mitogen-activated protein kinase inhibitors in children and young adults with neurofibromatosis-1.

PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. However, cutaneous adverse events (CAEs) are common and may hinder patients' abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS: We reviewed institutional medical records of patients under 30 years with a diagnosis of "NF1," "NF2," or "other neurofibromatoses" on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS: Our cohort consisted of 40 patients with NF1 (median age, 14 years). Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi. There was no significant association between CAE presence and tumor response (p = 0.39). CONCLUSIONS: Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

Extracorporeal Photopheresis in Dermatological Diseases.

Extracorporeal photopheresis (ECP) is an apheresis procedure that is conventionally used as a first-line treatment for cutaneous and leukemic subtypes of T-cell lymphoma, such as Sezary's syndrome and mycosis fungoides. Over the past three decades, its immunotherapeutic properties have been tested on a variety of autoimmune conditions, including many dermatologic diseases. There is ample evidence of ECP's ability to modify leukocytes and alter cytokine production for certain dermatologic diseases that have been refractory to first-line treatments, such as atopic dermatitis. However, the evidence on the efficacy of ECP for the treatment of these dermatologic diseases is unclear and/or lacks sufficient evidence. The purpose of this paper is to review the literature on the utilization and clinical efficacy of ECP in the treatment of several [autoimmune] dermatologic diseases and discuss its applications, guidelines, recommendations, and future implementation for dermatologic diseases.

Therapeutic Potential of Fungal Terpenes and Terpenoids: Application in Skin Diseases.

Terpenes and their derivatives comprise a diverse group of natural compounds with versatile medicinal properties. This article elucidates the general characteristics of fungal terpenes and terpenoids, encompassing their structure and biogenesis. The focal point of this work involves a comprehensive overview of these compounds, highlighting their therapeutic properties, mechanisms of action, and potential applications in treating specific skin conditions. Numerous isolated terpenes and terpenoids have demonstrated noteworthy anti-inflammatory and anti-microbial effects, rivalling or surpassing the efficacy of currently employed treatments for inflammation or skin infections. Due to their well-documented antioxidant and anti-cancer attributes, these compounds exhibit promise in both preventing and treating skin cancer. Terpenes and terpenoids sourced from fungi display the capability to inhibit tyrosinase, suggesting potential applications in addressing skin pigmentation disorders and cancers linked to melanogenesis dysfunctions. This paper further disseminates the findings of clinical and in vivo research on fungal terpenes and terpenoids conducted thus far.

Immunological aspects of probiotics for improving skin diseases: Influence on the Gut-Brain-Skin Axis.

The interplay between gut microbiota and human health, both mental and physical, is well-documented. This connection extends to the gut-brain-skin axis, linking gut microbiota to skin health. Recent studies have underscored the potential of probiotics and prebiotics to modulate gut microbiota, supported by in vivo and clinical investigations. In this comprehensive review, we explore the immunological implications of probiotics in influencing the gut-skin axis for the treatment and prevention of skin conditions, including psoriasis, acne, diabetic ulcers, atopic dermatitis, and skin cancer. Our analysis reveals that probiotics exert their effects by modulating cytokine production, whether administered orally or topically. Probiotics bolster skin defenses through the production of antimicrobial peptides and the induction of keratinocyte differentiation and regeneration. Yet, many questions surrounding probiotics remain unanswered, necessitating further exploration of their mechanisms of action in the context of skin diseases.

Exploring the polarization of M1 and M2 macrophages in the context of skin diseases.

Macrophages are critical components of the immune system and play vital roles in pathogen defense, immune regulation, and tissue repair. These cells exhibit different polarization states depending on environmental signals, and the M1/M2 paradigm is a useful tool for comprehending these states. This review article comprehensively presents the underlying mechanisms of M1 and M2 macrophage polarization and examines their polarization in various skin diseases. Additionally, this paper discusses therapeutic strategies that target M1 and M2 macrophage polarization in skin diseases. A more profound understanding of macrophage polarization in skin diseases could provide valuable insights for the development of innovative therapeutic strategies.