High bacterial colonization and lipase activity in microcomedones.

BACKGROUND: Although acne vulgaris has a multifactorial aetiology, comedogenesis and bacteria colonization of the pilosebaceous unit are known to play a major role in the onset of inflammatory acne lesions. However, many aspects remain poorly understood such as where and when is the early stage of the Propionibacterium acnes colonization in follicular unit? Our research aimed at providing a precise analysis of microcomedone's structure to better understand the interplay between Propionibacterium acnes and follicular units, and therefore, the role of its interplay in the formation of acne lesions. METHODS: Microcomedones were sampled using cyanoacrylate skin surface stripping (CSSS). Their morphology was investigated with multiphoton imaging and their ultrastructure with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Bacterial lipase activity in the microcomedones was quantified using a dedicated enzymatic test as well as a Fourier Transform Infra-Red (FTIR) analysis. The porphyrin produced by bacteria was analysed with HPTLC and fluorescence spectroscopy. RESULTS: The imaging analysis showed that microcomedones' structure resembles a pouch, whose interior is mostly composed of lipids with clusters of bacteria and whose outer shell is made up of corneocyte layers. The extensive bacteria colonization is clearly visible using TEM. Even after sampling, clear lipase activity was still seen in the microcomedone. A high correlation, r = .85, was observed between porphyrin content measured with HPTLC and with fluorescence spectroscopy. These observations show that microcomedones, which are generally barely visible clinically, already contain a bacterial colonization.

Strategic Targets in Acne: The Comedone Switch in Question.

The sequence of events and mechanisms leading to the development of the primary acne lesion, the comedone, is revisited. Recent knowledge obtained both from lineage tracing experiments in the mouse and the pilosebaceous response to xenobiotics in humans provides robust models for further understanding key biological events at the cellular roots of comedogenesis. The focus is set on the LRIG1+ sebaceous stem cells in the isthmus of the pilosebaceous duct. The master switch that transforms a normally functioning sebaceous gland into a microcomedone and the hierarchy of factors involved in this process are reviewed. The key strategic target in acne care appears to be the naïve pilosebaceous follicle that is not involved yet in the acne cycle. The prevention of the comedone switch implies that the key switching factors are adequately controlled in the long term.

Aryl Hydrocarbon Receptor Activation in Acne Vulgaris Skin: A Case Series from the Region of Naples, Italy.

BACKGROUND: Dioxins are persistent organic pollutants present in the environment. They exert their biological effects by binding to an intracellular receptor, the aryl hydrocarbon receptor (AhR). Activation of AhR leads to the induction of cytochrome p450 1A1 (CYP1A1). Expression of CYP1A1 in human skin is a key marker for AhR activation, and it may induce comedogenesis resulting in acne-like lesions known as chloracne/metabolising acquired dioxin-induced skin hamartomas (MADISH). The contribution of this pathway in patients seen in a busy acne clinic is unknown. MATERIALS AND METHODS: We explored the expression of CYP1A1 by immunohistochemistry in the acne lesions of 16 patients living in the region of Naples, Italy, where epidemiological studies have suggested a possibly increased exposure to environmental dioxins. A composite score to outline potential components of the chloracne/MADISH histological pattern was used. RESULTS: CYP1A1 expression was observed in 11 lesions (69%) and was distributed in sebaceous glands, follicular epithelium, cystic wall and endothelial cells. The histological score for chloracne/MADISH was 'likely' in 3 cases and 'possible' in 11 cases. Compared to current data on CYP1A1 expression in the skin of 67 patients with proven exposure to AhR agonists, these data indicate a high incidence of AhR activation in this series. CONCLUSION: This is the first study analysing AhR activation in skin in a series of patients from a hospital-based acne clinic. It provides information for future controlled prospective studies. The significance of CYP1A1 expression in terms of AhR ligand exposure is discussed.

Topical retinoids in skin ageing: a focused update with reference to sun-induced epidermal vitamin A deficiency.

Vitamin A is an important constituent of the epidermis, where it plays a crucial role in epidermal turnover. A deficiency of epidermal vitamin A may be the consequence of nutritional vitamin A deficiency, exposure to sunlight or any UV source, oxidative stress or chronological ageing. As a consequence, any treatment aiming at increasing epidermal vitamin A would exert a protective effect against these deleterious conditions. Retinoids may counteract some deleterious actions of UV radiation by physical and biological mechanisms. Topical natural retinoic acid precursors such as retinaldehyde or retinol are less irritant than acidic retinoids and may prevent epidermal vitamin A deficiency due to nutritional deficiency, exposure to sunlight or any condition leading to free radical production. Retinoids may be combined with other compounds with complementary actions against ageing, nutritional deficiency and cancer, such as antioxidants, to potentiate their beneficial effects in the skin.

Hyalurosome gene regulation and dose-dependent restoration of skin atrophy by retinaldehyde and defined-size hyaluronate fragments in dermatoporosis.

BACKGROUND: Dermatoporosis is an emerging clinical condition caused by chronological skin aging, long-term sun exposure and chronic use of corticosteroids; however, genomic expression in dermatoporosis and the efficacy of different therapeutic approaches to prevent and treat dermatoporosis have not been investigated so far. OBJECTIVE: We examined the possible effect of topical retinaldehyde (RAL) and defined-size hyaluronate fragments (HAFi) on the expression of hyalurosome genes potentially involved in the pathogenesis of dermatoporosis. We also explored the effect of different concentrations of HAFi on skin thickness. METHODS: 13 persons were separated into a young control group (n = 8) and a dermatoporosis group (n = 5). Topical treatment of both groups with a combination of 0.05% RAL and 1 or 0.2% HAFi was applied on the forearm twice daily for 30 days. Forearm skin biopsies of both groups were performed before and after application. Hyalurosome genes CD44, heparin-binding epidermal growth factor (HB-EGF), ErbB1, hyaluronate synthase 3 (HAS3) and Hyal2 were chosen as potential markers of dermatoporosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for quantification of mRNA expression of the target hyalurosome genes. Measurement of forearm skin thickness before and after treatment was performed by ultrasonography. Analysis of the results was done by Student's t test. A p value <0.05 was considered statistically significant. RESULTS: In qRT-PCR analysis the relative expression of hyalurosome (CD44, HAS3, HB-EGF) genes was found to be reduced in patients prior to topical treatment and to be notably increased following treatment. The reduced expression of CD44 and HAS3 in patients was specifically restored in dermatoporotic patients after treatment. No difference in skin thickness was observed in controls after treatment. The treatment caused a significant increase in skin thickness in dermatoporotic patients. This increase was more significant with 1% HAFi when compared to 0.2% HAFi. RAL and HAFi also caused a significant reduction in purpuric lesions in patients with dermatoporosis. CONCLUSION: Our results indicate that topically applied RAL and HAFi regulate hyalurosome gene expression in dermatoporosis and that they show a dose-dependent effect on the correction of skin atrophy in dermatoporotic patients.

Development of skin diseases following systemic exposure: example of dioxins.

Most skin manifestations of exposure to toxic compounds are a consequence of a direct contact with the toxicants. However, some toxicants may reach the skin following systemic exposure, and promote skin diseases. Good examples of such chemicals are dioxin-like compounds. This family of lipophilic molecules comprises polychlorinated (dibenzodioxins, dibenzofurans and biphenyls). The most potent member of this family is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Following oral ingestion of as little as a few mg TCDD, skin lesions appear in a couple of weeks, starting from the face and diffuse then on the trunk and limbs. This syndrome was historically called "chloracne" and the skin lesions have now been shown to be skin hamartoma induced by TCDD. Sweat glands release their lipid content on the surface of the skin by a holocrine secretion, and so any lost sebocyte should be transmitted to progenitor cells to differentiate and migrate to the sebaceous gland to replace the lost sebocyte. TCDD acts by inducing a switch in this signal and skin hamartoma develop in place of new sebocytes.

Corrigendum: Development of skin diseases following systemic exposure: example of dioxins.

[This corrects the article DOI: 10.3389/ftox.2023.1243192.].

Senotherapeutic Effect of Retinaldehyde and Hyaluronate Fragments in Dermatoporosis.

Cellular senescence is one of the important mechanisms of skin aging. In a recent study, we have shown that in patients with dermatoporosis, an extreme senescence condition of the skin, cells positive for p16Ink4a, a biomarker of senescence, were significantly increased in the epidermis. Senescent cells can develop a senescence-associated secretory phenotype (SASP) comprising pro-inflammatory cytokines, chemokines, and other soluble factors, leading to chronic inflammation and tissue dysfunction. These senescent cells and SASP pathways represent therapeutic targets for the development of senotherapeutics either by inducing selective cell death of senescent cells called senolytics, or suppressing markers of the SASP, called senomorphics. In this study where we conducted a retrospective immunohistochemical analysis of p16Ink4a expression in the skin samples of dermatoporosis patients included in a previous clinical study, we describe the senotherapeutic effect of retinaldehyde (RAL) and intermediate-size hyaluronate fragments (HAFi). Topical application of RAL and HAFi significantly reduced the number of p16Ink4a-positive cells in the epidermis and dermis in dermatoporosis patients which also showed a significant clinical improvement.

Tolerability and effectiveness of a dermocosmetic product containing Silybum marianum fruit extract in adolescents and young adults with acne-prone skin: An international, phase IV, longitudinal study.

BACKGROUND: Dermocosmetic products are often used to maintain or enhance the tolerance and effectiveness of medical anti-acne therapies. Recent discoveries about the pathophysiology of acne-prone skin indicate that skincare products may help maintain homeostasis around the sebaceous gland progenitor cells, thereby preventing microcomedone formation. AIMS: To evaluate the tolerance and effectiveness of a dermocosmetic product containing Silybum marianum fruit extract (SMFE) in adolescents and young adults with acne-prone skin. PATIENTS/METHODS: This real-life, international, observational, multicenter study was conducted in patients aged 12-25 years with mild-to-moderate acne. Patients (N = 4230) used the product twice daily for 8-12 weeks, either alone before ("initial group") or after an anti-acne therapy ("maintenance group"), or in association with their usual prescribed anti-acne therapies ("association group"). The tolerance, effectiveness, and cosmetic properties of the product were assessed. Patient quality of life (QoL) was also evaluated. RESULTS: Dermatologists rated the tolerance of the product as "good" or "very good" in about 95% of the patients and the effectiveness of the product as "effective" or "highly effective" in about 80% of the patients, with a significant reduction in the mean global evaluation of acne (GEA) grade (-36% ± 39%, p < 0.0001) at study end. The QoL of most patients (80%) improved by the end of the study, and the majority (79% to 94%) appreciated the cosmetic properties of the product. Overall, the product was a clinical success in >84% of patients. CONCLUSIONS: This dermocosmetic product can be used by adolescents and young adults with acne-prone skin to limit the initial or chronic use of medical anti-acne therapies.

Ebselen is a new skin depigmenting agent that inhibits melanin biosynthesis and melanosomal transfer.

We assessed the ability of ebselen, a glutathione peroxidase mimic, to reduce pigmentation in various models. In murine B16 melanocytes, 25 µm ebselen inhibited melanogenesis and induced a depolymerisation of actin filaments. In co-cultures of B16 melanocytes with BDVII keratinocytes, a pretreatment of melanocytes with ebselen resulted in a strong inhibition of melanosome transfer to keratinocytes, as shown under optical and electron microscopy. In reconstructed epidermis, topical 0.5% ebselen led to a twofold decrease of melanin without affecting the density of active melanocytes. A similar result was obtained with topical 0.5% ebselen in black guinea pig ears. Ebselen induced a decrease of epidermal melanin parallel to a localisation of melanin and melanosomes in the basal layer. Ebselen appears as a new depigmenting compound that inhibits melanin synthesis and melanosome transfer to keratinocytes.

Evaluation of scientific programs at a large-scale academic congress: lessons from the 22nd World Congress of Dermatology.

BACKGROUND: The organization of a scientific program and the arrangement of the speakers require a considerable amount of time and effort. However, little is known about how to reinforce the participants' satisfaction with scientific programs at a large-scale academic congress with multiple parallel sessions. OBJECTIVES: This study had three main purposes: (1) to create a reference for future congresses, (2) to determine session popularity and participation rate, and (3) to identify which characteristics of sessions can affect the perception of the audience. METHODS: A total of 216 scientific sessions during the 22nd World Congress of Dermatology were evaluated using printed evaluation surveys. RESULTS: The average scores for all sessions and speakers were relatively high. There were significant differences in the numbers of total session scores, collected surveys and speakers for each session category. The number of speakers at each session was not related to the session results. It was found that among the three different session grades (excellent, fair and poor), the proportion of speakers of each grade especially contributed to the perceived quality of the poor-grade sessions. CONCLUSIONS: This survey will help to organize scientific sessions and improve the quality of academic congresses.

Long-Term Use of Silybum marianum fruit extract Contributes to Homeostasis in Acne-Prone Skin-A 12-Month Follow-Up International "Real Life" Cohort Study.

BACKGROUND: Homeostasis in the differentiation programme of sebaceous stem cells has been identified as a key step in comedogenesis and should be a target for acne-prone skin care. OBJECTIVE: To report on a multicentre, year-long/real-life use study of a patented natural product containing S. marianum fruit extract proven to modulate molecular actors in the initial steps of comedogenesis. METHODS: An open-label multicentric international study, with a 12 month follow-up, included 54 teenage and young adult subjects with mild to moderate facial acne. The study was aimed at reproducing a real-life use context. RESULTS: Total lesion count mean was 88.3 at inclusion. There was a sustained, highly significant decrease over the months of clinical lesion counts (45.6% improvement after 6 months and 59.6% at 12 months) and on other efficacy markers, associated with a significant decrease in global microcomedone quantity on cyanoacrylate superficial skin surface biopsies. Importantly, the study protocol allowed the dermatologist to prescribe, if needed as in real life, any of the acne drugs registered in the acne guidelines. The exposure to these acne drugs during the whole year was calculated as a percentage of S. marianum fruit extract/352 days of use and happened to be very limited at less than 4%, which indicates a marginal contribution to the sustained clinical improvement. (Oral and local acne treatments: Lymecycline 1.46%; Doxycycline 0.24%; Adapalene 0.16% or gel association with Benzoyl peroxide 1.17%; Clindamycin 0.04%; Benzoyl peroxide 1.5%; Erythromycin 0.75%). The tolerance with daily S. marianum fruit extract long-term use was good. LIMITATIONS: The association with routine prescription acne drugs when needed, even if limited, does not allow a full evaluation of the intrinsic quantitative efficacy of S. marianum fruit extract in lesion reduction. CONCLUSION: This open, real-life, year-long multicentre study confirms a previous 48-week proof of concept study and qualifies the use of S. marianum fruit extract as a "field-dermo cosmetic" contributing to homeostasis of acne-prone skin in association with acne drugs.

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells.

Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo[3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-gamma, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4(+) T cells. The specific AHR-inhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4(+) T cells to produce IL-22 without IL-17 and IFN-gamma. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161(+) Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4(+) T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage.

A new spectrophotometric method for simple quantification of melanosomal transfer from melanocytes to keratinocytes.

Three major difficulties must be overcome to establish a quantitative method for melanosomal transfer analysis: (i) establishing a three-dimensional co-culture reassuring direct melanocyte to keratinocyte transfer, (ii) separation of melanocytes and keratinocytes following co-culture and (iii) melanosome quantification in each cell population. Melanocytes and keratinocytes are cultured on the opposite sides of the porous membrane of hanging cell inserts (1µm pores, 2×10(6) pores/cm(2) ). Cell separation is performed after 3days of co-culture by simple trypsinisation. Melanosome quantification in separated cell populations was accomplished by an ELISA-like method using gp-100 as the antigen. Melanocytes and keratinocytes come into 'direct' contact through the pores, and melanosomal transfer is accomplished without cell passage through the membrane. Cell separation by simple trypsinisation results in pure melanocyte and keratinocyte populations. Melanosome quantification by the ELISA-like method proved to be sensitive and specific to distinguish the known inhibitors and inducers of melanosomal transfer.

Lipid Droplet Proteins in Acne Skin: A Sound Target for the Maintenance of Low Comedogenic Sebum and Acne-Prone Skin Health.

In adipocytes and sebocytes, lipid droplet proteins control the storage of lipids in organized droplets and their release on demand. The contribution of lipid droplet proteins to the pathogenesis of acne is plausible because they control the levels of comedogenic free fatty acids. The expression of two lipid droplet proteins, CIDEA and PLIN2, was analyzed in the skin of patients with acne by immunohistochemistry and western blotting. The design of clinical protocols allowed correlating the expression of CIDEA and PLIN2 with both comedogenesis and the release of free fatty acids. Both proteins were detected by immunohistochemistry in the sebaceous glands of patients with acne, with a disturbed expression pattern of PLIN2 compared with that in the controls. Higher levels of PLIN2 and CIDEA, as detected by western blotting in the infundibulum, significantly correlated with lower ongoing comedogenesis over 48 weeks of Silybum marianum fruit extract application. Accordingly, free fatty acid release from sebum triglycerides was significantly decreased, as shown with two distinct methods. The data are consistent with the expected role of PLIN2 and CIDEA in the prevention of comedogenic free fatty acid release. Modulation of PLIN2 and CIDEA expression appears as a sound target for the maintenance of low comedogenic sebum and acne-prone skin health.

Skin and nail responses after 1 year of infliximab therapy in patients with moderate-to-severe psoriasis: a retrospective analysis of the EXPRESS Trial.

BACKGROUND: The EXPRESS study demonstrated the initial efficacy of infliximab in psoriasis affecting the skin and nails. OBJECTIVE: To further assess how patients with a positive initial response to infliximab respond to 1 year of continuous infliximab treatment. METHODS: A retrospective analysis of patients with moderate-to-severe plaque and nail psoriasis who initiated and continued infliximab treatment up to week 46 was conducted. RESULTS: Among all nail psoriasis patients receiving 1 year of infliximab (n = 186), 74.6 and 54.1% achieved at least 75 or 90% improvement in the Psoriasis Area and Severity Index (PASI) at week 50. These PASI-75 (n = 138) and PASI-90 (n = 100) responders had respective mean improvements from baseline to week 50 of 93.6 and 97.3% for the PASI, 90.6 and 94.1% for the Dermatology Life Quality Index (DLQI) and 78.2 and 80.3% for the Nail Psoriasis Severity Index (NAPSI). CONCLUSIONS: Infliximab treatment for 1 year produced sustained improvement in PASI, DLQI and NAPSI scores.

High prevalence of potential drug-drug interactions for psoriasis patients prescribed methotrexate or cyclosporine for psoriasis: associated clinical and economic outcomes in real-world practice.

BACKGROUND: Methotrexate (MTX) and cyclosporine (CYC) may adversely interact with common medications in patients with psoriasis. OBJECTIVE: Our purpose was to investigate the prevalence and outcomes of MTX/CYC polypharmacy. METHODS: We evaluated rates of events that may be associated with drug-related toxicity, health care resource utilization and costs for patients with psoriasis in the Ingenix(R) Impact National Managed Care Database (1999-2007) who were exposed or not exposed to potential drug-drug interactions. RESULTS: Among 4,583 (57.6%) exposed and 3,372 (42.4%) nonexposed patients, nonsteroidal anti-inflammatory drugs and antibiotics were the most common drugs with potential interactions. The exposed patients had significantly greater risks of developing renal [adjusted odds ratio (OR): 2.58; p = 0.0145], gastrointestinal (OR: 1.36; p = 0.0197) and pulmonary events (OR: 1.20; p = 0.0470), and significantly greater health care resource utilization (e.g. OR for inpatient and emergency department visits: 1.47; p < 0.0001) and costs (adjusted incremental cost: USD 1,722; p < 0.0001). CONCLUSIONS: MTX/CYC polypharmacy is prevalent in patients with psoriasis and associated with significant risks.