Adipose tissue-derived exosomes alleviate particulate matter-induced inflammatory response and skin barrier damage in atopic dermatitis-like triple-cell model.

Recently, particulate matter (PM) has been shown to exacerbate atopic dermatitis (AD) by inducing an inflammatory response. Meanwhile, several studies revealed that exosomes derived from adipose tissue-derived mesenchymal stem cells promote wound healing and alleviate inflammation via their regenerative and immunomodulatory capacities. Our study aimed to investigate the effects of human adipose tissue-derived mesenchymal stem cell-derived (ASC)-exosomes in PM-induced AD. An AD-like triple-cell model was established by treating human keratinocytes, dermal fibroblasts, and mast cells with polyinosinic:polycytidylic acid (Poly I:C) and interleukin 1 alpha (IL-1α). The effects of PM and ASC-exosomes on the expression of pro-inflammatory cytokines and skin barrier proteins were examined using quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. PM increased pro-inflammatory cytokines (IL-6, IL-1ß, and IL-1α) and decreased the anti-inflammatory cytokine IL-10, while the mRNA expression of skin barrier proteins (loricrin and filaggrin) decreased. However, when the cells were treated with ASC-exosomes, the PM-induced effects on pro-inflammatory cytokines and skin barrier proteins were reversed. Our results confirmed that PM-induced inflammation and skin barrier damage were alleviated by ASC-exosomes in our AD-like triple-cell model. These data suggest that ASC-exosomes can serve as a therapeutic agent for PM-exacerbated AD.

Adipose-derived stem cell exosomes for treatment of dupilumab-related facial redness in patients with atopic dermatitis.

BACKGROUND: Dupilumab facial redness (DFR) is a side effect of dupilumab treatment that has only been recently reported. We previously reported on two patients with DFR who were successfully treated with a topical formulation containing human adipose tissue-derived mesenchymal stem cell-derived exosomes (ASCEs). OBJECTIVES: The study aimed to evaluate the efficacy and safety of ASCEs in DFR. PARTICIPANTS AND METHODS: We performed 12-week prospective study at single center. Twenty adult atopic dermatitis patients diagnosed with DFR were enrolled. They were treated with a topical application of the exosome formulation every week for five consecutive weeks. RESULTS: After exosome treatment, both the average investigator global assessment score and clinical erythema assessment scale scores decreased. 19 patients (95%) were satisfied with the treatment. Compared to baseline, erythema index at week 4 were decreased by 31, 27, 13, and 25 units on the forehead, chin, right and left cheek respectively. The analysis of stratum corneum samples revealed the expression of IL-1α and human thymic stromal lymphopoietin was suppressed after exosome treatment, whereas filaggrin and vascular endothelial growth factor expression increased. CONCLUSIONS: This study suggests topical formulation containing ASCEs can alleviate DFR by downregulating local inflammation and restoring skin barrier function.

Roles of Virtual Memory T Cells in Diseases.

Memory T cells that mediate fast and effective protection against reinfections are usually generated upon recognition on foreign Ags. However, a "memory-like" T-cell population, termed virtual memory T (TVM) cells that acquire a memory phenotype in the absence of foreign Ag, has been reported. Although, like innate cells, TVM cells reportedly play a role in first-line defense to bacterial or viral infections, their protective or pathological roles in immune-related diseases are largely unknown. In this review, we discuss the current understanding of TVM cells, focusing on their distinct characteristics, immunological properties, and roles in various immune-related diseases, such as infections and cancers.

Combination of Non-Ablative Fractional Laser with Q-Switched Laser for the Treatment of Becker's Nevus: Efficacy and Limitations.

Becker's nevus (BN) is a benign hamartoma that may present as a distressing cosmetic problem. The treatment of BN poses a significant challenge as current therapeutic modalities are suboptimal and have an increased risk of adverse effects, such as scarring and dyspigmentation. We present the use of non-ablative fractional laser therapy combined with Q-switched Nd:YAG laser as a possible therapeutic option for BN treatment and review relevant literature to discuss its efficacy and limitations.

Treatment of facial pigmented disorders with a 785-nm picosecond Ti:sapphire laser in Asians: A report of three cases.

Since the advent of the theory of selective photothermolysis, the importance of targeting the chromophore and minimizing the surrounding damage has been extensively discussed. Picosecond-domain laser (ps-laser) treatment with a wide range of wavelengths is an emerging option for various pigmented lesions; however, no definitive treatment choice has been confirmed. The authors aimed to investigate the efficacy and safety of a ps-laser with a 785-nm wavelength for the treatment of facial pigmented lesions in Asians. Three Korean patients with facial pigmented lesions were recruited for the study. A 785-nm ps-laser with a fractionated and an unfractionated handpiece was utilized to administer the treatment. The clinical outcome was evaluated by a clinician by comparing pre- and post-treatment photographs. All patients exhibited a significant improvement in pigmented lesions including freckles, lentigines, and melasma, after three to four sessions of treatment. No adverse events, including post-inflammatory hyperpigmentation or hypopigmentation were observed. In conclusion, this novel 785-nm Ti:sapphire ps-laser may be an effective and safe modality for treating pigmented lesions in skin of color.

Screening of Plant-Derived Natural Extracts to Identify a Candidate Extract Capable of Enhancing Lipid Synthesis in Keratinocytes.

BACKGROUND: Reduced lipid content in the stratum corneum is a major cause of skin-barrier dysfunction in various pathological conditions. Promoting lipid production is a potential strategy to improve skin-barrier function. Recent evidence supports the beneficial effects of adiponectin on lipid metabolism and senescence in keratinocytes. OBJECTIVE: This study aimed to investigate whether plant extracts can enhance skin-barrier function. METHODS: We screened fruit and herb extracts that enhance the lipid synthesis of keratinocytes via AMP-activated protein kinase (AMPK) activation and SIRT1 signaling in the adiponectin pathway. The levels of major lipid synthesis enzymes and transcription factors as well as epidermal barrier lipids involved in adiponectin-associated epidermal barrier formation were evaluated in the herbal extracts- or adiponectin-treated human epidermal keratinocyte and equivalent models. The mRNA expression of major lipid synthesis enzymes increased following treatment with Lycii Fructus , Prunus tomentosa , and Melia toosendan extracts. RESULTS: The expression of transcription factors SIRT1, liver X receptor α, peroxisome proliferator-activated receptors (PPARs), and sterol regulatory element-binding proteins (SREBPs) were upregulated. Levels of free fatty acids, cholesterol, and ceramides were elevated. The expression of keratinocyte differentiation markers increased. In particular, among fruit extracts with a detectable effect, Melia toosendan induced the highest expression of lipid synthase. CONCLUSION: These results indicate that Melia toosendan is a promising candidate for improving skin-barrier function.

Particulate matter increases Cutibacterium acnes-induced inflammation in human epidermal keratinocytes via the TLR4/NF-κB pathway.

Recent studies have demonstrated that particulate matter (PM) can induce oxidative stress and inflammatory responses that are related to the development or exacerbation of several inflammatory dermatoses. However, the effect of PM on acne vulgaris has yet to be determined. In this study, we induced acne-like inflammation in HEKn cells with several concentrations of Cutibacterium acnes (C. acnes) and Staphylococcus aureus peptidoglycan (PGN) to investigate whether PM exposure exacerbates acne-like inflammation and elucidate the underlying mechanisms. To confirm whether PM increases the messenger ribonucleic acid (mRNA) and protein levels of proinflammatory cytokines (IL-1α, IL-1ß, IL-6, IL-8, and TNF-α) and cyclooxygenase (COX)-2 expression in C. acnes- or PGN-treated HEKn cells, we used quantitative real-time polymerase chain reactions, enzyme-linked immunosorbent assays, and western blot assays. The results demonstrated that C. acnes, PGN, and PM induced the expression of proinflammatory cytokines in a time- and dose-dependent manner at the mRNA and protein levels, respectively. Moreover, PM further increased the expression of proinflammatory cytokines, COX2, TLR4, and the phosphorylation of NF-κB in C. acnes- and PGN-treated HEKn cells. In conclusion, our results suggest that PM may exacerbate acne symptoms by increasing the inflammatory response.

Rheological properties and preclinical data of novel hyaluronic acid filler containing epidermal growth factor.

Recently, a novel hyaluronic acid (HA) filler containing the epidermal growth factor (EGF) was developed. The objective of this study was to evaluate the rheological properties, preclinical efficacy and biocompatibility of the EGF-containing HA filler (HA-EGF filler) using a photoaged mouse model. The rheological properties of the new HA-EGF filler were assessed. Twenty-four female hairless mice (SKH1) underwent photoaging induction with 8 weeks of ultraviolet-B irradiation. The mice were randomly divided into four groups and intradermally injected 100 µl of phosphate-buffered saline, HA-EGF filler, HA filler or polynucleotide (PN) into the dorsal region. We examined the effect of fillers on photoaged skin by dermoscopic examination. Furthermore, histological evaluation with immunohistochemical staining was performed to determine the biocompatibility and collagen formation at the 10th week. A real-time quantitative polymerase chain reaction analysis and western blot test assessed the expression of collagen I/III, matrix metalloproteinases (MMPs) and transforming growth factor. The viscosity and elasticity of the HA-EGF filler were lower than those of the HA filler. Histological evaluation revealed no significant differences in the collagen synthesis between the HA-EGF, HA and PN filler groups. No inflammation was observed during the experimental period. The HA-EGF filler induced type I/III collagen production and downregulated the expression of MMP-1, 3 and 9. Our results suggest that the novel HA-EGF filler may be an additional therapeutic option for photoaged skin, which works by inducing collagen synthesis. Based on these preclinical results, further well-controlled clinical studies are required.

Innovative Use of Negative Air Ions As an Alternative Therapy for Acne Vulgaris: A Report of Three Cases.

Acne vulgaris is a universal skin disease with multifactorial pathogenesis. Although an extensive range of treatment options exist for acne, a substantial number of patients are still struggling for an optimal treatment option due to the side effects or contraindications to the conventional acne treatment. Negative air ions (NAIs) are electrically charged molecules that naturally exist in the atmosphere. Since they are natural component of air, there are no known side effects and contraindications to their application. Furthermore, among the identified benefits of NAIs, certain mechanisms are related to acne pathogenesis, allowing them to be attractive candidates for acne treatment. Here, we describe three patients with acne who showed considerable clinical improvement after NAI therapy. All of the patients had failed to tolerate traditional acne treatment options. In all three cases, considerable improvement was observed in acne severity and the number of total lesions. Based on the three cases and a review of literature underlying the effects of NAIs, we suggest that NAIs may be a safe and effective alternative therapeutic option for acne vulgaris.

Quantitative Evaluation of Volume Augmentation and Durational Changes in the Anteromedial Cheek with Hyaluronic Acid Fillers Using Three-Dimensional Measurement: 2-Year Results from a Comparative Split-Face Study.

SUMMARY: Hyaluronic acid fillers are widely used for the augmentation of facial soft tissues. Hyaluronic acid fillers can be monophasic or biphasic and have different characteristics, especially regarding volumetric effects and maintenance potential. However, there is paucity of long-term quantitative and objective data on clinical outcomes following hyaluronic acid injection. In this study, the authors evaluated volumetric changes over 2 years and the maintenance potentials of both types of fillers on the anteromedial cheek using objective three-dimensional measurements. This comparative split-face study enrolled participants aged 30 to 50 years who received a midfacial injection of the test filler (Belotero Volume) on one side and a random control filler (Juvéderm, Restylane SubQ, or Yvoire Contour) on the contralateral side. The authors conducted three-dimensional scanning assessments at baseline and after 30 minutes; 3 days; 2, 4, 12, and 24 weeks; and 2 years. The volume augmentation effects for the anteromedial cheek of two monophasic fillers (Belotero Volume and Juvéderm Voluma) were maintained for at least 2 years (81 percent and 66 percent, respectively, compared to the volume at 4 weeks). Two biphasic fillers (Yvoire Contour and Restylane SubQ) maintained over 50 percent volume compared to the volume 4 weeks after injection. Monophasic fillers showed better outcomes than biphasic fillers; however, both types of hyaluronic acid fillers demonstrated superior efficacy, safety, and durability for volumetric augmentation in the anteromedial cheek. Objective data obtained using three-dimensional imaging analysis will enable dermatologists to better demonstrate the results of the procedure to patients, through the provision of visual aids. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Dupilumab Provides Acceptable Safety and Sustained Efficacy for up to 4 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) often requires long-term management with systemic therapies. OBJECTIVE: Our objective was to report the safety and efficacy of dupilumab treatment up to 4 years in adults with moderate-to-severe AD and efficacy in a subgroup of patients who transitioned from dupilumab once-weekly (qw) to administration every other week (q2w). METHODS: This interim analysis of the open-label extension study (NCT01949311) evaluated dupilumab 300 mg qw or q2w in adults previously enrolled in dupilumab trials for moderate-to-severe AD. Patients switched from qw to q2w following protocol amendment. The primary outcome was safety; efficacy was also assessed. RESULTS: Of 2677 patients enrolled and treated, 352 (13.1%) completed week 204 (end of efficacy assessments) and 202 (7.5%) completed safety follow-up through week 244. Self-reported compliance was 98.1%. Dupilumab's safety profile was consistent with previous reports. Common treatment-emergent adverse events (≥5%) included nasopharyngitis, AD, upper respiratory tract infection, oral herpes, conjunctivitis, injection-site reaction, and headache. At week 204, mean ± standard deviation (SD) Eczema Area and Severity Index was 2.46 ± 3.98, and mean percent change from parent study baseline (PSBL) was -91.07%; mean ± SD Pruritus Numerical Rating Scale score was 2.10 ± 1.83, and mean percent change from PSBL was -68.74%. Efficacy was maintained in patients (n = 226) who transitioned from qw to q2w dosing. Limitations of this study included its open-label design, the lack of control arm, and smaller subsets of patients at later timepoints and receiving the approved q2w regimen. CONCLUSION: These results support dupilumab as continuous long-term treatment for adults with moderate-to-severe AD; efficacy was sustained following transition from qw to q2w dosing. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01949311.

Atopic dermatitis is a chronic skin disease associated with inflamed skin and intense itching. People with moderate-to-severe atopic dermatitis often need long-term treatment, but many available treatments do not have demonstrated long-term safety data. In multiple clinical trials, dupilumab treatment resulted in significant improvements in signs and symptoms of atopic dermatitis. This study examined the safety and efficacy of up to 4 years of dupilumab treatment in adults with moderate-to-severe atopic dermatitis, and whether dupilumab continued to be effective in patients who switched from receiving treatment each week to treatment every other week. To address these questions, we collected data from adults who received 300 milligrams of dupilumab every week or every other week. In this study, safety findings were consistent with the known dupilumab safety profile. Patients' signs and symptoms were evaluated before and during treatment with evaluation tools including the Eczema Area and Severity Index (EASI), which indicates the extent and severity of disease, and the Pruritus Numerical Rating Scale (NRS), which indicates the intensity of itching. Reductions of 91% in EASI scores and 69% in Pruritus NRS scores showed that the improvement in signs and symptoms persisted for 204 weeks (almost 4 years) of treatment, and these effects were sustained following the switch from weekly treatment to the approved every other week treatment with dupilumab. The safety and efficacy data presented here support the use of dupilumab as a continuous, long-term treatment for up to 4 years for adults with moderate-to-severe atopic dermatitis. Video abstract: What is the long-term safety and efficacy profile of dupilumab in adults with moderate-to-severeatopic dermatitis for up to 4 years? (MP4 102515 KB).

Development of In Vitro Co-Culture Model to Mimic the Cell to Cell Communication in Response to Urban PM2.5.

Background: Airborne particulate matter (PM), a widespread air contaminant, is a complex mixture of solids and aerosols composed of particles suspended in the air. PM is associated with inflammatory responses and may worsen inflammatory skin diseases. However, the mechanisms through which PM affects atopic dermatitis (AD) remain unclear. Objective: To establish an in vitro model that more accurately mimics AD using human keratinocyte (HaCaT), dermal fibroblast (HDF), and mast cell (HMC-1) and using this model to investigate the mechanism through which PMs affect AD. Methods: An AD-like in vitro model was established by seeding HaCaT, HDF, and HMC-1 cells with recombinant human interleukin (IL)-1α and polyinosinic:polycytidylic acid. We confirmed the effect of PM on the inflammatory cytokine expression of a triple-cell culture model. SRM 1649b Urban Dust, which is mainly composed of polycyclic aromatic hydrocarbons, was used as the reference PM. The effects of PM on the expression levels of proinflammatory cytokines and skin barrier markers were assessed using quantitative real-time polymerase chain reaction and western blotting. Inflammatory cytokine levels were measured using an enzyme-linked immunosorbent assay. Results: Interactions between various skin cell types were evaluated using a co-culture system. PM treatment increased mRNA and protein levels of the inflammatory cytokines IL-6, IL-1α, tumor necrosis factor-α, IL-4, and IL-1ß and decreased the expression of the skin barrier markers filaggrin and loricrin. Conclusion: Our results suggest that an in vitro triple-cell culture model using HaCaT, HDF, and HMC-1 cells may be reliable for obtaining more physiological, functional, and reproducible data on AD and skin barriers.

Comparative Analysis of Cutaneous Fungi in Atopic Dermatitis Patients and Healthy Individuals.

Background: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease triggered by diverse factors. Microbes are one of the crucial risk factors for AD development or exacerbation. However, the effect of a fungal burden on AD has been overlooked compared to bacteria. Objective: This study aimed to comparatively analyze cutaneous fungal distribution between AD patients and healthy individuals by polymerase chain reaction (PCR)-based analysis. Methods: Skin samples of AD outpatients and healthy individuals collected at the Chung-Ang University were analyzed. Representative AD-associated fungal genera, Candida, dermatophytes, and Malassezia , were analyzed using specific primer and amplification methods. Amplicons were sequenced, and the fungal distribution of both groups were compared. Results: Totally, 211 patients and 23 healthy individuals were studied. Of the 211 patients, 10.90% (23/211) had Candida species, whereas 0% (0/23) healthy individuals showed its presence. The most frequently detected species in patients was Candida albicans (5.21%) followed by Candida parapsilosis (3.79%). For dermatophytes, 1.42% (3/211) of patients showed positive results, whereas 0% (0/23) healthy individuals showed positive results. Malassezia species were identified in 20.85% (44/211) and 8.70% (2/23) in patients and healthy individuals, respectively. Malassezia restricta was the most frequently identified species in the AD patient group, and the only species found in the healthy control group. Conclusion: The distribution of Candida spp., dermatophytes, and Malassezia spp. are altered with AD development.

Evaluation of the efficacy and safety of the 1064 nm picosecond Nd:YAG laser with a topically applied gold and diamond suspension for facial skin rejuvenation: A pilot study.

To investigate the efficacy and safety of combined treatment with a serum comprising a micro-diamond suspension and micro-gold cage with a 1064 nm picosecond neodymium-doped yttrium aluminum garnet (Nd:YAG) laser for facial skin rejuvenation. Topical serum was applied to the entire face and allowed to penetrate the skin and hair follicles for 20 min. Each participant was then treated with a 1064 nm picosecond Nd:YAG laser on the face. Photographs of each participant were taken at baseline, immediately after treatment, and 2 weeks after treatment using an imaging tool (Mark-Vu®; PSI PLUS, Suwon, Republic of Korea). Global improvement scores by two blinded investigators and participants' satisfaction scores were also assessed. The melanin index (MI), transepidermal water loss (TEWL), and skin hydration were evaluated using a device. Parameters associated with skin rejuvenation were assessed using Mark-Vu®. Adverse events were observed and reported by participants and physicians during the treatment and follow-up visit. At week 2, 40% (4/10) of the participants showed more than moderate clinical improvement in the investigator's global improvement assessment. No significant differences were observed in the MI, TEWL, skin hydration level, or skin parameters of Mark-Vu®. At week 2, 40% of the participants reported a high satisfaction score and minimal side effects. The novel topical facial serum comprising micro-diamond suspension and micro-gold cage is safe and effective when combined with laser treatment for facial rejuvenation.

The Role of Collagen VI α6 Chain Gene in Atopic Dermatitis.

BACKGROUND: In a previous study, we carried out whole-exome sequencing to identify genetic variants associated with early onset atopic dermatitis (AD) in Koreans and found that collagen VI α6 chain (COL6A6) gene polymorphisms are associated. COL6A6 is one of the chains that makes up the triple helix of collagen VI, and little is known about its role in AD. OBJECTIVE: To identify how COL6A6 changes in AD and clarify its role. METHODS: Immunohistochemical staining for COL6A6 was performed on tissues of AD, other skin diseases, and healthy controls. Human keratinocytes and fibroblasts were exposed to inflammatory cytokines and cultured to evaluate changes in COL6A6 expression. COL6A6 small interfering RNA (siRNA) was transfected into cells to identify the role of COL6A6. RESULTS: Total COL6A6 mRNA was higher in AD than in controls. In AD tissues, COL6A6 mRNA decreased significantly in the epidermis compared to controls, whereas COL6A6 protein was increased in the dermis. In the cultured cells, COL6A6 mRNA was suppressed in the epidermis by interleukin (IL)-4 and IL-13, whereas COL6A6 protein was induced in the dermis. In the COL6A6 siRNA-transfected keratinocyte, mRNA of FLG, LOR, and CASP14 decreased compared to controls; in contrast, mRNA of MMP1 increased. CONCLUSION: The reduction of epidermal COL6A6 due to the genetic mutation can cause skin barrier damage and it can contributes to the early onset of AD. COL6A6 is induced by IL-4 and IL-13, and it may play a role in fibrotic remodeling and inflammatory processes, which are major features of AD.

Utilization of Ultrasonography in Dermatology: Two Case Reports of Calcinosis Cutis.

Development of newer generation of cost-effective ultrasonic devices in recent years has increased the use of ultrasonography in dermatology. Several lesions can be diagnosed and managed using ultrasonography. Calcinosis cutis involves the deposition of insoluble calcium salts in the cutaneous and subcutaneous tissues. On ultrasonography, it specifically presents as hyperechoic deposits with a posterior acoustic shadowing artifact due to the acoustic properties of calcium. A 62-year-old female patient presented with a solitary, skin-colored, palpable nodule on the inner side of the right lower leg. The lesion was beneath the intact skin and detectable only on palpation. However, ultrasonography demonstrated a clear delineation of the lesion, showing hyperechoic deposits with a posterior acoustic shadow (15 MHz, linear probe). Skin biopsy and curettage were performed, revealing histological features consistent with calcinosis cutis. Four weeks after the procedure, ultrasonography performed to evaluate the outcome of treatment, showed recurrence. Another 18-year-old female patient presented with a skin-colored deep-seated nodule on the left temple. On ultrasonography, linear hyperechoic deposits with a posterior acoustic shadow were visible. Skin biopsy was performed, and histopathologic features showed calcified material in the subcutaneous tissue. These two cases of calcinosis cutis highlight the diagnostic value of ultrasonography in dermatology.