Peptides play decisive roles in the skin, ranging from host defense responses to various forms of neuroendocrine regulation of cell and organelle function. Synthetic peptides conjugated to ...radionuclides or photosensitizers may serve to identify and treat skin tumors and their metastatic forms in other organs of the body. In the introductory part of this review, the role and interplay of the different peptides in the skin are briefly summarized, including their potential application for the management of frequently occurring skin cancers. Special emphasis is given to different targeting options for the treatment of melanoma and melanotic lesions. Radionuclide Targeting: α-Melanocyte-stimulating hormone (α-MSH) is the most prominent peptide for targeting of melanoma tumors via the G protein-coupled melanocortin-1 receptor that is (over-)expressed by melanoma cells and melanocytes. More than 100 different linear and cyclic analogs of α-MSH containing chelators for 111In, 67/68Ga, 64Cu, 90Y, 212Pb, 99mTc, 188Re were synthesized and examined with experimental animals and in a few clinical studies. Linear Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys-NH2 (NAP-amide) and Re-cyclized Cys- Cys-Glu-His-D-Phe-Arg-Trp-Cys-Arg-Pro-Val-NH2 (ReArg11CCMSH) containing different chelators at the N- or C-terminus served as lead compounds for peptide drugs with further optimized characteristics. Alternatively, melanoma may be targeted with radiopeptides that bind to melanin granules occurring extracellularly in these tumors. Photosensitizer targeting: A more recent approach is the application of photosensitizers attached to the MSH molecule for targeted photodynamic therapy using LED or coherent laser light that specifically activates the photosensitizer. Experimental studies have demonstrated the feasibility of this approach as a more gentle and convenient alternative compared to radionuclides.
Convolutional neural networks (CNNs) have the potential to assist allergists and dermatologists in the analysis of patch tests. Such models can help reduce interprovider variability and improve ...consistency of patch test interpretations.
Our aim is to evaluate the performance of a CNN model as a proof of concept in discriminating between patch tests with reactions and patch tests without reactions.
We performed a retrospective analysis of patch test images from March 2020 to March 2021. The CNN model was trained as a binary classifier to discriminate between reaction and nonreaction patches. Performance of the model was determined using summary statistics and receiver operator characteristics (ROC) curves.
In total, 13,622 images from 125 patients were recorded for analysis. The majority of patients in the cohort were female (81.6%) with Fitzpatrick skin types I-II (88.0%). The area under curve was 0.940, indicating a high discriminative performance of the model for this data set. This resulted in a total accuracy of 90.1%, sensitivity of 86.0%, and specificity of 90.2%.
CNNs have the capacity to determine the presence of delayed-type reactions in patch tests. Future prospective studies are required to assess the generalizability of such models.
While the evidence for the implication of opioid receptors (OPr) in ageing is growing, there is, to our knowledge, no study focusing directly on changes in vivo cutaneous OPr expression with ...increasing age. We thus investigated OPr expression in 30 healthy female Asian volunteers in Southern China whose ages range from the early 20s to the early 60s. Excisional biopsies were taken from the sun‐exposed extensor area of the lower arm and the photo‐protected area of the upper inner arm. The thickness of the epidermal layers, melanin content, as well as expression of mu‐opioid receptors (MOPr) and delta‐opioid receptors (DOPr) were compared between different age ranges and photo‐exposure status. Significant increased epidermal hypertrophy on the extensor surface was observed. There was significant reduction of DOPr in the epidermis with increasing age, independent of photo‐ageing. The increase of melanin was significantly correlated with epidermal DOPr expression, not with MOPr expression. DOPr expression could thus serve as a marker for real biological ageing unaffected by chronic photo‐exposure. Additionally, DOPr expression was inversely correlated with the deposition of melanin. Based on these results, we hypothesise that regulation of DOPr expression could be used to improve aged skin, including hyperpigmentation.
A case study is reported whereby a patient with no prior allergies developed a strong and spreading delayed-type hypersensitivity reaction to Melianthus plants, nectar and synthetic pigment derived ...from it after frequent handling of these substances. The lesions improved after treatment with topical steroids and allergen avoidance within 1–2 weeks. Subsequent patch testing with the plants, nectar and synthetic ingredients identified ellagic acid (EA) as the sensitizing agent. This is the first proven case of allergic contact dermatitis to EA, a phenolic substance present in numerous plants, fruits, and nuts regularly consumed by humans. Melianthus use is growing worldwide as an ornamental plant. Moreover, it is used in traditional South African medicine for its anti-inflammatory effects. In recent years, these extracts and EA have been added to natural, plant-based topical formulations for the treatment of inflammatory skin disorders. Our observation that the EA found in Melianthus can induce severe contact allergy should caution for the possible dangers of specific allergic sensitizations to these increasingly used additives in natural medicines.
•The first case of allergic contact dermatitis to Melianthus and ellagic acid (EA).•Melianthus is used increasingly worldwide as an ornamental plant.•EA is included in natural topical medications to treat inflammatory skin diseases.•We observed that the EA found in Melianthus can induce severe contact allergy.•Cautions for the possible dangers of allergic sensitization to EA in products.
What has the opioid receptor system, known for beneficial as well as disastrous effects in the central nervous system, to do with skin? The question is appropriate considering the fact that the ...nervous system and the skin both derive from the ectoderm. As part of the skin neuroendocrine system, the opioid receptor system exemplifies the closeness between the nervous system and the skin. Overexpression of the δ‐opioid receptor in keratinocytes yields dysregulation of involucrin, loricrin, and filaggrin, proteins essential to the integrity of the skin barrier. The μ‐opioid receptor ligand β‐endorphin, produced in the pituitary gland and a variety of skin cells, promotes wound healing via regulation of cytokeratin 16 and TGF‐β type II receptor expression in keratinocytes. These and other published results discussed in this viewpoint are evidence for the fundamental role of the skin opioid receptor system in skin homeostasis, regeneration and ageing. While considerable progress in understanding the opioid receptors’ function on the cellular level has been made, there is a need to link these results to physiological observations for the development of local skin therapies.
Opioids in skin function during stress response, regeneration, ageing and, particularly in regulating sensation. In chronic pruritus, topical treatment with Naltrexone changes μ-opioid receptor ...(μ-OR) localization to relieve itch. The molecular mechanisms behind the effects of Naltrexone on μ-OR function in reduction of itching behavior has not been studied. There is an immediate need to understand the endogenous complexity of μ-OR dynamics in normal and pathological skin conditions. Here we evaluate real-time behavior of μ-OR-Endomorphine complexes in the presence of agonist and antagonists. The μ-OR ligand Endomorphine-1 (EM) was conjugated to the fluorescent dye Tetramethylrhodamine (TAMRA) to investigate the effects of agonist and antagonists in N/TERT-1 keratinocytes. The cellular localization of the EM-TAMRA was followed through time resolved confocal microscopy and population analysis was performed by flow cytometry. The in vitro analyses demonstrate fast internalization and trafficking of the endogenous EM-TAMRA-μ-OR interactions in a qualitative manner. Competition with Endomorphine-1, Naltrexone and CTOP show both canonical and non-canonical effects in basal and differentiated keratinocytes. Acute and chronic treatment with Naltrexone and Endomorphine-1 increases EM-TAMRA binding to skin cells. Although Naltrexone is clinically effective in relieving itch, the mechanisms behind re-distribution of μ-ORs during clinical treatments are not known. Our study has given insight into cellular mechanisms of μ-OR ligand-receptor interactions after opioid agonist and antagonist treatments in vitro. These findings potentially offer opportunities in using novel treatment strategies for skin and peripheral sensory disorders.
Delayed-type reactions to aeroallergens have been observed, however, their clinical significance continues to be debated.
We assessed the prevalence and significance of delayed-type reactions to ...aeroallergens in atopic patients.
Retrospective study including 266 patients with history or evidence of atopic disease (atopic dermatitis AD, allergic rhinitis, and/or allergic asthma) and tested via either the intradermal skin test (IDT) or atopy patch test for common aeroallergens, specifically house dust mites (
,
) and perennial molds (
,
). All patients were tested via IDT with both immediate (15 minute) and delayed (2 and 4 days) readings. Delayed reading was considered positive if the IDT injection site demonstrated at least 5 mm induration 48 hours after inoculation.
In total, 195 (73.3%) patients demonstrated an immediate-type reaction, whereas 118 (44.4%) had a delayed-type reaction. In total, 75 (28.2%) patients experienced both immediate- and delayed-type reactions, 43 (16.2%) reacted delayed-type only, and 85.3% of delayed-type reactions to individual aeroallergens were associated with eczematous lesions predominantly in air-exposed areas.
Delayed-type reactions to aeroallergens are prevalent and clinically significant as a component of extrinsic AD and atopic diseases. The data support delayed reading of the IDT to guide diagnosis and management in these patients.
Opioids and the skin - where do we stand? Bigliardi, Paul L.; Tobin, Desmond J.; Gaveriaux-Ruff, Claire ...
Experimental dermatology,
20/May , Letnik:
18, Številka:
5
Journal Article
Recenzirano
: The common ectodermal origin of the skin and nervous systems can be expected to predict likely interactions in the adult. Over the last couple of decades much progress has been made to elucidate ...the nature of these interactions, which provide multidirectional controls between the centrally located brain and the peripherally located skin and immune system. The opioid system is an excellent example of such an interaction and there is growing evidence that opioid receptors (OR) and their endogenous opioid agonists are functional in different skin structures, including peripheral nerve fibres, keratinocytes, melanocytes, hair follicles and immune cells. Greater knowledge of these skin‐associated opioid interactions will be important for the treatment of chronic and acute pain and pruritus. Topical treatment of the skin with opioid ligands is particularly attractive as they are active with few side effects, especially if they cannot cross the blood–brain barrier. Moreover, cutaneous activation of the opioid system (e.g. by peripheral nerves, cutaneous and immune cells, especially in inflamed and damaged skin) can influence cell differentiation and apoptosis, and thus may be important for the repair of damaged skin. While many of the pieces of this intriguing puzzle remain to be found, we attempt in this review to weave a thread around available data to discuss how the peripheral opioid system may impact on different key players in skin physiology and pathology.
Neuropeptides and their receptors are present in human skin, and their importance for cutaneous homeostasis and during wound healing is increasingly appreciated. However, there is currently a lack of ...understanding of the molecular mechanisms by which their signaling modulates keratinocyte function. Here, we show that δ-opioid receptor (DOPr) activation inhibits proliferation of human keratinocytes, resulting in decreased epidermal thickness in an organotypic skin model. DOPr signaling markedly delayed induction of keratin intermediate filament (KRT10) during in vitro differentiation and abolished its induction in the organotypic skin model. This was accompanied by deregulation of involucrin (IVL), loricrin, and filaggrin. Analysis of the transcription factor POU2F3, which is involved in regulation of KRT10, IVL, and profilaggrin expression, revealed a DOPr-mediated extracellular signal-regulated kinase (ERK)-dependent downregulation of this factor. We propose that DOPr signaling specifically activates the ERK 1/2 mitogen-activated protein kinase pathway to regulate keratinocyte functions. Complementing our earlier studies in DOPr-deficient mice, these data suggest that DOPr activation in human keratinocytes profoundly influences epidermal morphogenesis and homeostasis.
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