Epidermal turnover and iron metabolism in senile lentigo.

Senile lentigo (SL) is a pigmentary disorder associated with disrupted epidermal turnover. Trace minerals in the skin are known to regulate keratinocyte proliferation and differentiation. To clarify the role of iron in SL, we compared the expression of molecules related to iron metabolism between SL lesion (lesion) and the surrounding normal skin (nonlesion). Our results revealed that proteins involved in iron uptake and utilization such as transferrin receptor 1, iron regulatory protein 1, mitoferrin 1, and divalent metal transporter 1 were expressed in the lower epidermis in the nonlesion, while expression of them was also observed in the upper epidermis in the lesion. Ferroportin (FPN), involved in iron export, was expressed in the upper epidermis in the nonlesion, but was only scarcely expressed in the upper epidermis in the lesion. Hepcidin, which promotes FPN degradation, was expressed in the lower epidermis in the nonlesion; however, its expression was also observed in the upper epidermis in the lesion. These changes in the expression of molecules involved in iron uptake/export/utilization might reflect the altered iron utilization state in SL, resulting in disruption of keratinocyte differentiation and disturbing epidermal turnover. Our results suggest that the metabolism of iron in keratinocytes in SL differs from that in the normal epidermis, and these changes could be associated with the abnormal epidermal turnover and decreased melanin excretion in SL.

[Translated article] Fixed Sunlight Eruption: A Series of 13 Cases in Bogotá, Colombia.

Few reports describing an association between UV radiation and fixed skin eruptions have been published since 1975. These reactions have received various names, including fixed sunlight eruption, fixed exanthema due to UV radiation, and broad-spectrum abnormal localized photosensitivity syndrome. We present a series of 13 patients (4 men [30.8%] and 9 women [69.2%]) aged between 28 and 56 years who were evaluated for fixed eruptions induced by UV radiation at a dermatology referral hospital in Bogotá, Colombia. The lesions were located on the inner thighs, buttocks, popliteal region, anterior and posterior axilla, and dorsum of the feet. Photoprovocation reproduced lesions in all the affected areas, and histopathology showed changes similar to those seen in fixed drug eruptions. While these UV-provoked reactions may be a type of fixed skin eruption, we cannot rule out that they may also be a distinct condition that simply shares a pathogenic mechanism with fixed eruptions.

Photosensitivity is an important cause of refractory facial erythema in atopic dermatitis: A retrospective study of 82 Chinese patients.

BACKGROUND: Ultraviolet radiation can aggravate facial erythema in atopic dermatitis (AD) patients. OBJECTIVE: To investigate the photobiological testing results of Chinese AD patients with refractory facial erythema. METHODS: We conducted a retrospective analysis of 82 AD patients with refractory facial erythema who visited our department during 2004-2021. All of them completed phototesting and photopatch testing. RESULTS: 82 patients were enrolled in the study, and 53 (64.6%) were between 18 and 30 years old. 51.2% (42/82) had positive phototesting results and were considered photosensitive AD (PhAD) patients. One-third of them were both allergic to ultraviolet A and ultraviolet B. 65.9% (54/82) suffered from photoallergic contact dermatitis. Chlorpromazine (50.7%), potassium dichromate (13.2%), and thimerosal (11.8%) were the top three common photoallergens. Overall, 86.3% of AD patients with refractory facial erythema had direct photoallergy or photocontact allergy. PhAD patients had fewer allergic comorbidities than the other group (p = .007). More non-PhAD patients (55.0%) suffered from AD at 2-14 years old (p = .015). CONCLUSIONS: Photosensitivity contributes a lot to the facial lesions of AD patients, especially in their 20s. 86.3% of these patients had direct photoallergy or photocontact allergy. Therefore, AD patients with facial erythema should undergo phototesting and photopatch testing routinely.

A postulated model for photoimmunopathogenesis of chronic actinic dermatitis around adaptive immunity, including Th17 cells, Tregs, TRMs, cytotoxic T cells, and/or common-γ chain receptor+ cells.

BACKGROUND/PURPOSE: The pathogenesis of chronic actinic dermatitis (CAD) is more complicated than other photodermatoses. However, the relationship between the clinical severity of CAD and the offending photocontact or contact allergens or both, and the correlations of CAD immunopathogenesis with the immunoregulatory molecules involved in adaptive immunity are yet to be investigated. METHODS: We performed phototesting with broad-spectrum ultraviolet (UV) B, UVA, and visible light to establish the presence of photosensitivity in 121 patients with CAD, together with photopatch and contact patch testing. Nine patients with CAD were selected according to their clinical severity score for CAD (CSS-CAD), and triple direct immunofluorescence analysis was performed with paraffin-embedded skin biopsy samples. RESULTS: As CSS-CAD was closely correlated with the multiplicity of photo(contact) allergens, particularly photoallergens, three or more photoallergens were detected in the severe CAD group (52.5%); less in the moderate group (32.8%); and only one in the mild group (14.8%; P = .025). In the groups showing greater severity of disease, the absolute numbers of IFN-γ+ , IL-17+ , CD4+, CD8+, common-γ chain receptor (common-γCR)+ , and CD69+ tissue-resident memory cells increased on average; there was also an increase in the CD4+/CD8+ cell ratio, with the more severely affected groups. However, the levels of TNF-α+ and FoxP3+ regulatory T (Treg) cells and the mean IL-17/IFN-γ cell ratio decreased in the more severely affected CSS-CAD subgroups. CONCLUSIONS: Based on the clinical analysis and immunopathogenic results, avoidance of excessive sun exposure, and topical and systemic blocking agents for photo(contact) allergens are recommended. Additionally, conventional immunomodulators and emerging agents including JAK-STAT inhibitors may be administered for CAD treatment in the future.

Association of polymorphous light eruption with NOD-2 and TLR-5 gene polymorphisms.

BACKGROUND: Polymorphous light eruption (PLE) is a common, immunologically mediated, photosensitive skin disease. After ultraviolet-B (UV-B) irradiation, patients with PLE show reduced Langerhans cell (LC) depletion in the epidermis, which results in a non-suppressive microenvironment in the skin. Interestingly, severe acute graft-versus-host disease (aGvHD) occurred in stem cell transplanted patients that showed no or incomplete depletion of LCs after UVB irradiation. Genetic variation in nucleotide-binding oligomerization domain 2 (NOD-2) and toll-like receptor 5 (TLR-5) genes also confers susceptibility to aGvHD. OBJECTIVES: We hypothesized that PLE is associated with genetic variation in the NOD-2 and TLR-5 genes. METHODS: We investigated single-nucleotid polymorphisms (SNPs) of NOD-2 (R702W, G908R, 3020Cins) and TLR-5 (A592S, P616L, N392STOP) in skin biopsies of patients with PLE (n = 143) and in healthy controls (n = 104) using restriction fragment length polymorphism analysis. RESULTS: The frequency of NOD-2 alleles with the SNP R702W was significantly higher in PLE than in controls (31.8% vs. 6.3%; P < 0.0001), and homozygous carriers of this mutation were more common in PLE (27.9% vs. 0%; P < 0.0001). For SNP 3020Cins, the allele frequency (7.3% vs. 0.7%; P = 0.0025) and the number of heterozygotes (14.7% vs. 1.3%; P = 0.0019) were higher in PLE. The frequency of alleles with the N392STOP SNP of the TLR5 gene, which is associated with a truncated, non-functional receptor, was significantly higher in PLE (21% vs. 5%; 7% vs. 1% homozygotes, 28% vs. 8% heterozygotes; P < 0.0001). The other SNPs did not differ significantly. CONCLUSIONS: This study yielded a high frequency of functional SNPs in the NOD-2 and TLR-5 genes in PLE. The same SNPs are associated with aGvHD and there are similarities in the reaction of LCs after UVB irradiation between aGvHD and PLE. This leads to the hypothesis that patients with PLE may be more susceptible to developing GvHD after stem cell transplantation, an assumption that needs to be investigated further.

First report of the c.1676G>A homozygous variant in a family with Kindler syndrome.

Kindler syndrome (KS) was first described by Theresa Kindler in 1954, and since then > 60 pathogenic variants have been identified in the FERMT1 gene for KS. Most FERMT1 variants associated with KS are null variants. We present the case of a child with poikilodermic changes on the forehead and cheeks, who was found to have a homozygous c.1676G>A mutation. To our knowledge, this is the first report of this mutation in a family with KS.

A Retrospective Study of 105 Patients with Elastolytic Giant Cell Granuloma and a Proposal for a New Clinical Classification.

Elastolytic giant cell granuloma, an idiopathic granulomatous dermatosis, is characterized by annular plaques on sun-exposed areas, and has been termed actinic granuloma or annular elastolytic giant cell granuloma. Many atypical clinical manifestations and lesions involving sun-protected areas have been reported. The aims of this retrospective study of 105 patients were to summarize the clinical and histological features of patients with this condition; to provide evidence for the viewpoint that elastolytic giant cell granuloma is a better term to include all clinical morphological types presenting with elastolysis, elastophagocytosis, and an infiltrate of multinucleated giant cells histologically; and to establish a new clinical classification. The varying clinical manifestations were further categorized into annular, papular, giant, mixed and generalized forms. The pathological manifestations were classified into giant cell, necrobiotic, histiocytic, sarcoidal and mixed patterns. Diabetes mellitus or impaired glucose tolerance were the most commonly identified comorbidities. Oral low-dose corticosteroid may be an effective treatment.

Mechanisms of Photosensitivity in Autoimmunity.

Aberrant responses to UV light frequently lead to the formation of skin lesions and the activation of systemic inflammation in some autoimmune diseases, especially systemic lupus erythematosus. Whereas the effects of UV light on the skin have been studied for decades, only recently have some of the mechanisms that contribute to abnormal responses to UV light in patients with autoimmune diseases been uncovered. This review will discuss the biology of UV in the epidermis and discuss the abnormal epidermal and inflammatory mechanisms that contribute to photosensitivity. Further research is required to fully understand how to normalize UV-mediated inflammation in patients with autoimmune diseases.

Violet-blue light exposure of the skin: is there need for protection?

Advocates of skin protection against blue light express concern about exposure to indoor lighting and electronic screens as well as natural outdoor exposure. However, the nature of adverse effects in skin is unclear and the doses to induce effects are unknown. We aimed to reveal whether there is a scientific basis for promoting skin protection against violet-blue light (400-500 nm, VBL). Based on published literature, we determined the time to reach a threshold dose that induced a biological response in human skin. In the absence of an action spectrum for effects on skin, we used a hand held probe with a defined spectral response and measurements of the unweighted exposure between 400 and 500 nm to estimate the exposure by a selection of artificial light sources and solar light. For comparison, an outdoor threshold erythemally weighted UV dose was set to 1 SED (standard erythema dose). Outdoor, weighted irradiances were obtained using a radiative transfer model. Induction of pigmentation in human skin tissue was the only consistently reported endpoint after VBL exposure of about 65 Jcm-2. This threshold dose was reached in 0.5 to 20 months of exposure to indoor lighting sources. In comparison, specialised medical sources reached this dose in 0.5 min to 45 h. The time outdoors to reach 1 SED was shorter than the time to reach a VBL threshold dose throughout all seasons. Skin protection against VBL is superfluous for exposures to domestic lighting sources or screens and for solar radiation; however, it may be advantageous for patients suffering from photosensitive diseases or taking photosensitising medication.

Protective effects of liquiritin on UVB-induced skin damage in SD rats.

Overexposure to ultraviolet B (UVB) rays can cause damage to the skin. Liquiritin has a variety of pharmacological effects, such as anti-inflammatory and antioxidant. In the present study, the effect of liquiritin on UVB irradiated rat skin was investigated. Results showed that UVB irradiation caused erythema and wrinkles on the skin surface, as well as thickening and loss of elasticity of the epidermis and a significant increase in the level of ROS in the skin tissue. At the same time, western blot detected an increase in nuclear factor kappa-B (NF-κB) and matrix metalloproteinases (MMPs) and Elisa also detected an increase in pro-inflammatory factors. Therefore, we hypothesized that UVB irradiation-induced damage is associated with inflammation. Interestingly, application of liquiritin to exposed skin of rats reduced the increase in ROS, pro-inflammatory factors, and MMPs caused by UVB irradiation and increased the levels of Sirtuin3 (SIRT3) and Collagen α1. In addition, after intraperitoneal injection of the SIRT3 inhibitor 3-TYP in rats, the protective effect of liquiritin against UVB damage was found to be diminished. These results suggested that promotion of SIRT3 with liquiritin inhibits UVB-induced production of pro-inflammatory mediators, possibly acting through the SIRT3/ROS/NF-κB pathway. In conclusion, this study suggests that liquiritin is an effective drug candidate for the prevention of UVB damage.

In vitro assessment of the photo(geno)toxicity associated with Lapatinib, a Tyrosine Kinase inhibitor.

The epidermal growth factor receptors EGFR and HER2 are the main targets for tyrosine kinase inhibitors (TKIs). The quinazoline derivative lapatinib (LAP) is used since 2007 as dual TKI in the treatment of metastatic breast cancer and currently, it is used as an oral anticancer drug for the treatment of solid tumors such as breast and lung cancer. Although hepatotoxicity is its main side effect, it makes sense to investigate the ability of LAP to induce photosensitivity reactions bearing in mind that BRAF (serine/threonine-protein kinase B-Raf) inhibitors display a considerable phototoxic potential and that afloqualone, a quinazoline-marketed drug, causes photodermatosis. Metabolic bioactivation of LAP by CYP3A4 and CYP3A5 leads to chemically reactive N-dealkylated (N-LAP) and O-dealkylated (O-LAP) derivatives. In this context, the aim of the present work is to explore whether LAP and its N- and O-dealkylated metabolites can induce photosensitivity disorders by evaluating their photo(geno)toxicity through in vitro studies, including cell viability as well as photosensitized protein and DNA damage. As a matter of fact, our work has demonstrated that not only LAP, but also its metabolite N-LAP have a clear photosensitizing potential. They are both phototoxic and photogenotoxic to cells, as revealed by the 3T3 NRU assay and the comet assay, respectively. By contrast, the O-LAP does not display relevant photobiological properties. Remarkably, the parent drug LAP shows the highest activity in membrane phototoxicity and protein oxidation, whereas N-LAP is associated with the highest photogenotoxicity, through oxidation of purine bases, as revealed by detection of 8-Oxo-dG.

Inhibition of α2-adrenoceptor is renoprotective in 5/6 nephrectomy-induced chronic kidney injury rats.

In the present study, we investigated the renoprotective effects of long-term treatment with yohimbine, an α2-adrenoceptor inhibitor, in a 5/6 nephrectomy-induced chronic kidney disease (CKD) rat model. Male Sprague-Dawley rats were randomly allocated into the following groups: sham-operated, 5/6-nephrectomized (5/6 Nx), 5/6 Nx + low or high dose of yohimbine (0.3 or 3.0 mg/L in drinking water, respectively), and 5/6 Nx + hydralazine (250 mg/L in drinking water). The 5/6 Nx group presented with renal dysfunction, hypertension, noradrenaline overproduction, and histopathological injuries. Blood pressure decreased in both the yohimbine- and hydralazine-treated groups. Treatment with high dose of yohimbine, but not hydralazine, apparently attenuated urinary protein excretion and noradrenaline concentration of renal venous plasma. Renal fibrosis and upregulated fibrosis-related gene expression were suppressed by high dose of yohimbine. Furthermore, yohimbine, but not hydralazine, treatment ameliorated the urinary concentration ability. These findings suggest that long-term yohimbine treatment can be a useful therapeutic option to prevent the progression of CKD.

Actinic prurigo in a dermatological reference center in Colombia: 108 cases / Prurigo actínico en un centro dermatológico de referencia en Colombia: 108 casos.

Introduction: Actinic prurigo is a chronic photodermatosis. It affects the Latin American population more frequently, predominantly women, and involves the sun-exposed areas of the skin, conjunctiva, and lips. Objective: To update the information on the clinical-epidemiological characteristics and treatment of patients with actinic prurigo in Colombia. Materials and methods: We conducted a cross-sectional study including the medical records of patients with actinic prurigo treated in the Photodermatology Service of Hospital Universitario Centro Dermatológico Federico Lleras Acosta between 2011 and 2016. We described the demographic, clinical, histopathological, and treatment characteristics of the patients. Results: We included 108 patients, 77 (71.3%) were women and 31 (28.7%) men, mainly with phototypes III-IV (70%). The disease had begun during the first decade of life in 66.4% of the cases and 25% of the patients had a family history with the condition. The lesions predominated on the face (93.5%), forearms (79.6%), and back of the hands (70.4%). Ocular (87.9%) and lip (88.8%) involvement was also documented. A photo-provocation test with UVA was performed in 25% of the cases and skin biopsies in 19.4%. Physical and chemical photoprotection was indicated in all patients. Mild to moderate cases were treated with topical corticosteroids (91.7%) and calcineurin inhibitors (65.7%) while severe cases received thalidomide (33.3%) and pentoxifylline (14.8%). Conclusion: The characteristics of actinic prurigo patients in Colombia are similar to those reported in other Latin American countries: early onset of the disease, predominance in women, frequent involvement of conjunctiva and lips, and adequate response to topical and systemic treatment.

Introducción. El prurigo actínico es una fotodermatosis crónica. Afecta con mayor frecuencia a la población latinoamericana, predomina en mujeres y compromete la piel expuesta al sol, las conjuntivas y los labios. Objetivo. Actualizar la información sobre las características clínico-epidemiológicas y el tratamiento de pacientes con prurigo actínico en Colombia. Materiales y métodos. Se hizo un estudio de corte transversal que incluyó los registros clínicos de pacientes con prurigo actínico atendidos en el Servicio de Fotodermatología del Hospital Universitario Centro Dermatológico Federico Lleras Acosta entre el 2011 y el 2016, y se describieron sus características demográficas, clínicas e histopatológicas, así como su tratamiento. Resultados. Se incluyeron 108 pacientes, el 71,3 % de ellos mujeres y el 28,7% hombres, con predominio de los fototipos III-IV (70 %). La enfermedad se había iniciado durante la primera década de vida en el 66,4% de los casos y el 25 % de los pacientes tenía antecedentes familiares de la enfermedad. Las lesiones predominaban en el rostro (93,5 %), los antebrazos (79,6 %) y el dorso de las manos (70,4 %). También, se documentó compromiso ocular (87,9 %) y de los labios (88,8 %). Se hizo la prueba de fotoprovocación con radiación ultravioleta A en el 25 % de los casos y biopsia cutánea en el 19,4 %. Todos los pacientes se trataron con protección solar química y física. En los casos leves a moderados, se formularon corticoides tópicos (91,7 %) e inhibidores de la calcineurina (65,7 %), y en los graves, talidomida (33,3 %) y pentoxifilina (14,8 %). Conclusión. Las características de los pacientes colombianos con prurigo actínico son similares a las reportadas en otros países latinoamericanos: inicio temprano de la enfermedad, predominio en mujeres, compromiso frecuente de conjuntivas y labios, y adecuada respuesta al tratamiento tópico y sistémico.

Superficial dermal melanocytosis of the elderly: An exceptional occurrence?

The development of flat pigmented lesions on chronically sun-damaged (CSD) skin of the face may represent the clinical manifestation of a wide variety of hyperplastic/neoplastic melanocytic proliferations. We report the exceptional case of an acquired pigmented patch occurring on CSD skin, histopathologically characterized by diffuse hyperplasia of dendritic/spindled melanocytes in the superficial dermis within a widened band of actinic elastosis. This lesion was associated with a small focus of early invasive lentigo maligna melanoma (LMM). We show the melanocytic nature of the population of dermal pigmented cells by means of single and double immunohistochemical staining for melanocytic and histiocytic markers. The biologic significance of the focus of LMM within the hyperpigmented lesion (whether random collision phenomenon or causally related occurrence), as well as the pathogenesis of the whole dermal lesion are difficult to elucidate. Our case emphasizes the need for a better understanding of the pathophysiology of so-called dermal melanocytes.