Delta opioid receptor expression correlates to skin ageing and melanin expression in Asian women.

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.

Navigating the evolving landscape of atopic dermatitis: Challenges and future opportunities: The 4th Davos declaration.

The 4th Davos Declaration was developed during the Global Allergy Forum in Davos which aimed to elevate the care of patients with atopic dermatitis (AD) by uniting experts and stakeholders. The forum addressed the high prevalence of AD, with a strategic focus on advancing research, treatment, and management to meet the evolving challenges in the field. This multidisciplinary forum brought together top leaders from research, clinical practice, policy, and patient advocacy to discuss the critical aspects of AD, including neuroimmunology, environmental factors, comorbidities, and breakthroughs in prevention, diagnosis, and treatment. The discussions were geared towards fostering a collaborative approach to integrate these advancements into practical, patient-centric care. The forum underlined the mounting burden of AD, attributing it to significant environmental and lifestyle changes. It acknowledged the progress in understanding AD and in developing targeted therapies but recognized a gap in translating these innovations into clinical practice. Emphasis was placed on the need for enhanced awareness, education, and stakeholder engagement to address this gap effectively and to consider environmental and lifestyle factors in a comprehensive disease management strategy. The 4th Davos Declaration marks a significant milestone in the journey to improve care for people with AD. By promoting a holistic approach that combines research, education, and clinical application, the Forum sets a roadmap for stakeholders to collaborate to improve patient outcomes in AD, reflecting a commitment to adapt and respond to the dynamic challenges of AD in a changing world.

Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization.

BACKGROUND: There is limited data on the mechanisms of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema (NIUA). OBJECTIVES: We sought to characterize the transcriptomic and metabolomic profiles of patients with NIUA undergoing aspirin desensitization. METHODS: PBMCs and plasma were separated from the blood of patients with NIUA undergoing aspirin desensitization for coronary artery disease and NSAID-tolerant controls. RNA was isolated from PBMCs and subjected to messenger RNA (mRNA)- and long noncoding RNA (lncRNA)-sequencing. Plasma samples were analyzed using LC-MS/MS for metabolite shifts using a semitargeted metabolomics panel. RESULTS: Eleven patients with NIUA and 10 healthy controls were recruited. The mRNA gene profiles of predesensitization versus postdesensitization and healthy control versus postdesensitization did not differ significantly. However, we identified 739 mRNAs and 888 lncRNAs as differentially expressed from preaspirin desensitization patients and controls. A 12-mRNA gene signature was trained using a machine learning algorithm to distinguish between controls, postdose, and predose samples. Ingenuity Pathway Analysis identified 5 canonical pathways that were significantly enriched in preaspirin desensitization samples. IL-22 was the most upregulated pathway. To investigate the potential regulatory roles of the differentially expressed lncRNA on the mRNAs, 9 lncRNAs and 12 mRNAs showed significantly correlated expression patterns in the IL-22 pathway. To validate the transcriptomics data, IL-22 was measured in the plasma samples of the subjects using ELISA. IL-22 was significantly higher in preaspirin desensitization patients compared with controls. In parallel, metabolomic analysis revealed stark differences in plasma profiles of preaspirin desensitization patients and healthy controls. In particular, 2-hydroxybenzoic acid (salicylic acid) was significantly lower in preaspirin desensitization patients compared with healthy controls. CONCLUSIONS: This is the first study to combine both transcriptomic and metabolomic approaches in patients with NIUA, which contributes to a deeper understanding about the pathogenesis of NIUA and may potentially pave the way toward a molecular diagnosis of NSAID hypersensitivity.

Investigations on detoxification mechanisms of novel para-phenylenediamine analogues through N-acetyltransferase 1 (NAT-1).

Para-phenylenediamine (PPD) is one of the most used chemicals in oxidative hair dyes. However, its use has been associated with adverse effects on health, including contact dermatitis and other systemic toxicities. Novel PPD derivatives have been proposed as a safer replacement for PPD. This can be achieved if these molecules minimally permeate the skin and/or are easily metabolised by enzymes in the skin (e.g., N-acetyltransferase-1 (NAT-1)) into innocuous compounds before gaining systemic entry. This study investigated the detoxification pathway mediated by NAT-1 enzymes on 6 synthesized PPD analogues (namely, P1-P6) with different chemical properties, to study the role of functional groups on detoxification mechanisms in HaCaT skin cells. These compounds were carefully designed with different chemical properties (whereby the ortho position of PPD was substituted by nucleophile and electrophile groups to promote N-acetylation reactions, metabolism and clearance). Compounds P2-P4 N-acetylated at 54-49 nmol/mg/min, which is 1.6 times higher than N-acetylation of PPD, upregulated NAT-1 activity from 8-7% at 50 µM to 22-11% at 100 µM and showed 4 times higher rate of elimination (k equal to 0.141 ± 0.016-0.124 ± 0.01 h-1) and 3 times faster rate of clearance (0.172 ± 0.007-0.158 ± 0.005 h-1mgprotein-1) than PPD (0.0316 ± 0.0019 h-1, 0.0576 ± 0.003 h-1mg protein-1, respectively). The data suggest that nucleophile substituted compounds detoxify at a faster rate than PPD. Our metabolic and detoxification mechanistic studies revealed significantly higher rates of N-acetylation, NAT-1 activity and higher detoxification of P2-P4 in keratinocytes, suggesting the importance of nucleophilic groups at the ortho position in PPD to reduce toxicity of aniline-based dyes on human skin cells.

Functionally expressed bitter taste receptor TAS2R14 in human epidermal keratinocytes serves as a chemosensory receptor.

Traditionally, it is theorized that skin sensation is initiated when cutaneous sensory afferents and Merkel cells receive sensory stimuli, while epidermal keratinocytes were deemed to have no role. However, mounting evidence has shown that keratinocytes can initiate skin sensation by receiving sensory stimuli and transmitting sensory information to sensory afferents. Knowledge regarding the mechanisms by which keratinocytes receive exogenous stimuli is limited, with TRP channels and olfactory receptors having been proposed to serve as receptors for exogenous stimuli in keratinocytes. Recently, expression analyses have demonstrated the expression of multiple TAS2R genes in human skin. TAS2Rs are chemosensory GPCRs employed by taste cells to detect bitter-tasting substances. However, only subtypes TAS2R1 and TAS2R38 have been characterized in epidermal keratinocytes. We present evidence suggesting that subtype TAS2R14 is functionally expressed in epidermal keratinocytes. TAS2R14 transcripts and protein were detected in primary and N/TERT-1 keratinocytes. Additionally, keratinocytes responded to α-thujone, a TAS2R14 ligand, with an increase in intracellular free Ca2+ concentration. The tastant-evoked Ca2+ signals were found to be mediated by wild-type TAS2R14 and heterotrimeric G proteins. We conclude that TAS2R14 serves as a chemosensory receptor in epidermal keratinocytes and hypothesize that it enables the cells to recognize potentially harmful chemical substances.

Controversies in drug allergy: Testing for delayed reactions.

Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell-mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches.

The Roles of Opioid Receptors in Cutaneous Wound Healing.

The process of recovery from skin wounding can be protracted and painful, and scarring may lead to weakness of the tissue, unpleasant sensations such as pain or itch, and unfavorable cosmetic outcomes. Moreover, some wounds simply fail to heal and become a chronic burden for the sufferer. Understanding the mechanisms underlying wound healing and the concomitant sensory disorders and how they might be manipulated for therapeutic benefit has attracted much interest in recent years, and here we discuss the latest developments in the field, focusing on the emergent roles of the peripheral opioid receptor (OPr) system.

An Asian Perspective on Povidone Iodine in Wound Healing.

Antiseptics, with a broader spectrum of antimicrobial efficacy, lower risk of antibiotic resistance development, and minimal collateral damage to host tissues, are important alternatives to control the bioburden in wounds. Povidone iodine (PVP-I), in use for several decades, has the broadest spectrum of activity, a persistent antimicrobial effect, an ability to penetrate biofilms, and a lack of acquired or cross-resistance. It demonstrates good skin tolerance and low cytotoxicity. However, some reports on PVP-I have raised concerns over allergy, ineffective penetration, and toxic effects on host cells. The majority of these concerns are based on in vitro or rodent wound studies with diverse study designs and outcomes; these results may not be directly applicable in the clinical reality in humans. In this paper, we discuss the efficacy and safety of PVP-I and outline its place in wound healing in Asia, based on an appraisal of recent literature and clinical practice across the region.

Selective susceptibility of human skin antigen presenting cells to productive dengue virus infection.

Dengue is a growing global concern with 390 million people infected each year. Dengue virus (DENV) is transmitted by mosquitoes, thus host cells in the skin are the first point of contact with the virus. Human skin contains several populations of antigen-presenting cells which could drive the immune response to DENV in vivo: epidermal Langerhans cells (LCs), three populations of dermal dendritic cells (DCs), and macrophages. Using samples of normal human skin we detected productive infection of CD14(+) and CD1c(+) DCs, LCs and dermal macrophages, which was independent of DC-SIGN expression. LCs produced the highest viral titers and were less sensitive to IFN-ß. Nanostring gene expression data showed significant up-regulation of IFN-ß, STAT-1 and CCL5 upon viral exposure in susceptible DC populations. In mice infected intra-dermally with DENV we detected parallel populations of infected DCs originating from the dermis and migrating to the skin-draining lymph nodes. Therefore dermal DCs may simultaneously facilitate systemic spread of DENV and initiate the adaptive anti-viral immune response.

Opioids and skin homeostasis, regeneration and ageing - What's the evidence?

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 ß-endorphin, produced in the pituitary gland and a variety of skin cells, promotes wound healing via regulation of cytokeratin 16 and TGF-ß 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.

Wheat-dependent exercise-induced anaphylaxis: a retrospective case review from a tertiary hospital.

BACKGROUND: Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a specific form of wheat allergy caused by the combination of wheat ingestion and physical exercise and has been reported in other parts of Asia. At present, there are no published reports of WDEIA in Singapore. The objective of this study is to characterise the common local clinical and laboratory manifestations of WDEIA. METHODS: This was a retrospective descriptive study of all WDEIA who presented to a tertiary Singaporean Hospital over a 5-year-period from 1 January 2009 to 30 June 2013. RESULTS: Eight patients aged 9-41 years old were characterised. Six were males and the majority (5) was of Chinese ethnicity. An atopic history was found in four patients. The symptoms of anaphylaxis included cutaneous manifestations such as urticaria (n=7), angioedema (n=6), respiratory symptoms of dyspnoea and wheezing (n=5) and hypotension (n=5). The symptoms occurred 20-75 min after consumption of wheat-based products, often upon cessation of exercise [running (n=3), walking (n=4) and swimming (n=1)]. The WDEIA was recurrent in seven patients. The skin prick tests were positive to wheat in seven patients, and ω-5 gliadin test to wheat was positive in five patients. CONCLUSIONS: With the emergence of wheat allergy in East Asian countries, WDEIA has become an important condition for physicians and Singapore is no exception. Under-recognition combined with life-threatening symptoms warrants better public awareness measures. In addition, further studies are necessary to identify possible unique genetic and environmental exposures that could explain the inter-regional differences of WDEIA.

Demonstration of Convolutional Neural Networks to Determine Patch Test Reactivity.

Background: 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. Objective: 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. Methods: 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. Results: 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%. Conclusions: 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.

The Diagnostic Value of Delayed-Type Reactions to Perennial Aeroallergens for Atopic Disease.

Background: Delayed-type reactions to aeroallergens have been observed, however, their clinical significance continues to be debated. Objective: We assessed the prevalence and significance of delayed-type reactions to aeroallergens in atopic patients. Methods: 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 (Dermatophagoides farinae, Dermatophagoides pteronyssinus) and perennial molds (Aspergillus fumigatus, Penicillium notatum). 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. Results: 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. Conclusion: 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.

The Opioid Receptor Influences Circadian Rhythms in Human Keratinocytes through the ß-Arrestin Pathway.

The recent emphasis on circadian rhythmicity in critical skin cell functions related to homeostasis, regeneration and aging has shed light on the importance of the PER2 circadian clock gene as a vital antitumor gene. Furthermore, delta-opioid receptors (DOPrs) have been identified as playing a crucial role in skin differentiation, proliferation and migration, which are not only essential for wound healing but also contribute to cancer development. In this study, we propose a significant association between cutaneous opioid receptor (OPr) activity and circadian rhythmicity. To investigate this link, we conducted a 48 h circadian rhythm experiment, during which RNA samples were collected every 5 h. We discovered that the activation of DOPr by its endogenous agonist Met-Enkephalin in N/TERT-1 keratinocytes, synchronized by dexamethasone, resulted in a statistically significant 5.6 h delay in the expression of the core clock gene PER2. Confocal microscopy further confirmed the simultaneous nuclear localization of the DOPr-ß-arrestin-1 complex. Additionally, DOPr activation not only enhanced but also induced a phase shift in the rhythmic binding of ß-arrestin-1 to the PER2 promoter. Furthermore, we observed that ß-arrestin-1 regulates the transcription of its target genes, including PER2, by facilitating histone-4 acetylation. Through the ChIP assay, we determined that Met-Enkephalin enhances ß-arrestin-1 binding to acetylated H4 in the PER2 promoter. In summary, our findings suggest that DOPr activation leads to a phase shift in PER2 expression via ß-arrestin-1-facilitated chromatin remodeling. Consequently, these results indicate that DOPr, much like its role in wound healing, may also play a part in cancer development by influencing PER2.

Honey flower dermatitis: Contact allergy to ellagic acid in Melianthuscomosus.

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.

[Chronic hand eczema, conventional and new treatments]. / Eczcma chronique des mains: traitements conventionnels et nouveautés.

Chronic hand eczema is a frequent cause of consultation. In Europe and Switzerland, it's one of the main reasons for patients to interrupt their profession. The etiology is pluri-factorial. Atopic patients are more likely predisposed. Pruritus, associated to pain and bleeding, is intense. Psychosocial consequences are huge, making this illness to an important public health problem. Topical treatment and UV-light are the main therapeutical strategy but the results are often disappointing. Recently, alitretinoine (9-cis retinoic acid) became the treatment of second choice with good response, allowing patients to preserve a good quality of life and their job.

Substance P-induced skin inflammation is not modulated by a single dose of sitagliptin in human volunteers.

Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.