Nuclear receptors for epidermal lipid barrier: Advances in mechanisms and applications.

The skin plays an essential role in preventing the entry of external environmental threats and the loss of internal substances, depending on the epidermal permeability barrier. Nuclear receptors (NRs), present in various tissues and organs including full-thickness skin, have been demonstrated to exert significant effects on the epidermal lipid barrier. Formation of the lipid lamellar membrane and the normal proliferation and differentiation of keratinocytes (KCs) are crucial for the development of the epidermal permeability barrier and is regulated by specific NRs such as PPAR, LXR, VDR, RAR/RXR, AHR, PXR and FXR. These receptors play a key role in regulating KC differentiation and the entire process of epidermal lipid synthesis, processing and secretion. Lipids derived from sebaceous glands are influenced by NRs as well and participate in regulation of the epidermal lipid barrier. Furthermore, intricate interplay exists between these receptors. Disturbance of barrier function leads to a range of diseases, including psoriasis, atopic dermatitis and acne. Targeting these NRs with agonists or antagonists modulate pathways involved in lipid synthesis and cell differentiation, suggesting potential therapeutic approaches for dermatosis associated with barrier damage. This review focuses on the regulatory role of NRs in the maintenance and processing of the epidermal lipid barrier through their effects on skin lipid synthesis and KC differentiation, providing novel insights for drug targets to facilitate precision medicine strategies.

YAP1/Piezo1 involve in the dynamic changes of lymphatic vessels in UVR-induced photoaging progress to squamous cell carcinoma.

BACKGROUND: UV-induced cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers. The constant alterations of the lymphatic-centered immune microenvironment are essential in transforming from photoaging to cSCC. Studying the mechanism will be beneficial for new targets exploration to the early prediction of cSCC. AIMS: To investigate the dynamic changes and mechanism of the lymphatic-centered immune microenvironment in transforming from photoaging to cSCC induced by ultraviolet irradiation (UVR). METHODS: TIMER2.0 was used to analyze whether YAP1/VEGFC signaling pathway is involved in lymphangiogenesis in head and neck squamous cell carcinoma (HNSCC). Meanwhile, lymphatic-centered immune microenvironments alterations and the related cumulative survival time were also analyzed. With the accumulated UVR, skin photoaging developed and gradually progressed into actinic keratosis and cSCC on SKH-1 hairless mice. The skin lymphatic-centered immune microenvironment was evaluated at the 0th, 8th, 12th, 16-18th, and 20-24th week of UVR. Skin phenotype was assessed using optical coherence tomography (OCT) and skin image. H&E and Masson's trichrome staining evaluated epidermis and dermis. The structure of lymphatic vessels (LVs), blood vessels, and different types of T cells were evaluated by immunohistochemistry staining. The expression of Piezo1 whose deletion in adult lymphatics led to substantial valve degeneration, VE-cadherin that maintained the permeability of LVs, and YAP1 were evaluated by immunohistochemistry staining as well. Besides, the drainage function of LVs was assessed by Evans Blue assay in vivo. RESULTS: The lymphatic function and immune cell infiltration underwent adaptive changes under continuous UVR. TIMER2.0 analysis indicated that VEGFC genes high expressed in HNSCC. YAP1 gene expression was positive correlated with VEGFC in HNSCC. LV density increased in human cSCC. More LVs in HNSCC were beneficial to prolong the survival time. VEGFC gene overexpression was positive correlated to CD8+T cell infiltration. More CD8A+T cells and CD8B+T cell infiltration in HNSCC extended survival time. When YAP1 gene overexpression and high infiltration of endothelial cells took place simultaneously might prolong the survival time of HNSCC patients. And high infiltration of CD8+T cells prolonged the survival time as well. In animal studies, UVR-induced eight weeks (photoaging) and 16-18 weeks (precancerous) were two turning points. The density of LVs in UV-8w was the least. When photoaged skin developed into AK lesions (UV-16-18w), LV slightly exceeded healthy skin and proliferated sharply in cSCC (UV-20-24w). YAP1 expression was almost consistent with LV but rose after the photoaging stage. The drainage of cSCC mice induced by UVR was better than that of photoaged skin and worse than that of health skin. The dynamic alterations of LVs number, Piezo1 expression, and collagen might be reasons for it. The expression of Piezo1 was in the highest point after 8 weeks of UVR, then gradually descended to the platform. The total T cells increased slowly, but the infiltration of CD4+T cells increased, and CD8+T cells decreased after eight weeks of UVR. The CD8+T cells and CD4+T cells increased sharply in UV-16-18w and UV-20-24w groups. CONCLUSION: The lymphatic-centered immune microenvironment underwent adaptive changes under continuous UVR via regulating YAP1/VEGFC and Piezo1. During the formation of cSCC, there are two turning points, eight weeks (photoaging) and 16-18 weeks (precancerous). YAP1, Piezo1, LVs, and immune cells constantly changed with the skin state induced by UVR. According to these changes the process of cSCC can be identified in advance and intervene timely.

Dermoscopy combined with reflectance confocal microscopy as a noninvasive involvement for monitoring Cutaneous Rosai-Dorfman: A case report.

Cutaneous Rosai-Dorfman disease(CRDD) is an extremely rare entity and features histiocytic proliferation in the skin. Dermoscopy and reflectance confocal microscopy(RCM) reports on CRDD are rare. We reported a case of CRDD and summarized the dermoscopy(FotoFinder Medicare 800HD, FotoFinder-Systems GmbH, Birbach Germany) and RCM(VivaScope® 1500, V Caliber Imaging and Diagnostics) features of CRDD. The dermoscopic features of CRDD showed red-orange background with pale yellowish roundish areas similar to millet, surrounded by branched blood vessels. Sometimes the white structureless materials of CRDD could be observed by dermoscopy, which may be a hint of spontaneous regression. The RCM features of CRDD revealed dense highly refractile roundish or ovoid structures(inflammatory cells), and multiple larger structures with central low refraction and moderately refractive peripheral semicircle or circle(engulfed inflammatory cells), together with low refractive branched structures(blood vessels). Dermoscopic and RCM features of CRDD can help the dermatologists recognize and follow-up the disease in real time.

Modified painless photodynamic therapy for facial multiple actinic keratosis in China: A prospective split-face control study.

BACKGROUND: Aminolevulinic acid photodynamic therapy (ALA-PDT) is an effective treatment for multiple actinic keratosis (AK). However, PDT-induced pain often discontinues the therapy to reduce its efficacy, limiting its application. If modified painless PDT schedule with shorter photosensitizer dressing and higher dose illumination could achieve good efficacy in AK, it is still unknown. OBJECTIVES: To explore the efficacy and pain tolerance of the modified painless PDT (M-PDT) in facial multiple AK. METHODS: A split-face controlled clinical study including 14 patients with facial multiple AK was conducted. The patients received conventional PDT (C-PDT) on the left and M-PDT in the contralateral area. The left area (C-PDT) was illuminated by a red light-emitting diode light (144 J/cm2 ) after applying the 10% ALA cream for 3 h; the other had illumination for a total light dose of 288 J/cm2 after applying the 10% ALA cream for 0.5 h. The primary endpoint was the lesion clearance rate at 1-month postthree sessions of PDT. Secondary endpoints included pain scores, the incidence of adverse events during treatment, and cosmetic outcomes. RESULTS: At 1 month following three treatments, the total lesion clearance rate was comparable between M-PDT and C-PDT (91.6% vs. 89.0%). While the lesion clearance rate of M-PDT was higher than that of C-PDT in the Grade III lesions (86.5% vs. 72.0%, respectively) (p < 0.05). M-PDT achieved a 100% lesion clearance rate for Grade I lesions earlier than C-PDT, with M-PDT treated twice and C-PDT treated thrice. Moreover, the pain score during illumination was significantly lower for M-PDT than for C-PDT (p < 0.01). Regarding photoaging, the Global Subjective Skin Aging Assessment score showed that the total and atrophy scores of C-PDT and M-PDT were significantly improved, and M-PDT also reduced discoloration. There was no significant difference in adverse reactions between C-PDT and M-PDT. CONCLUSIONS: M-PDT is comparable to C-PDT's efficacy for treating facial multiple AK, resulting in much lower pain scores.

A dose-dependent protective effect of n-3 PUFAs in photoaging by promoting collagen production through MAPK pathway in SKH-1 mouse model.

BACKGROUND: Dietary supplementation of n-3 polyunsaturated fatty acids (n-3 PUFAs) can inhibit inflammation and oxidation of photoaging, but the effect and mechanism on regulation of dermis collagen remains poorly elucidated. The destruction of dermal collagen plays a crucial role in the process of long-term ultraviolet radiation (UVR) induced-photoaging, especially leading to deterioration of skin appearance and function. METHODS: In this study, we explored the protective effect of n-3 PUFAs on the regulation of collagen through the MAPK pathway using the SKH-1 photoaging mouse model. RESULTS: The results showed that n-3 PUFAs promoted collagen synthesis and reduced collagen degradation in a dose-dependent manner, which was mediated by the down-regulation of the MAPK pathway. In addition, n-3 PUFAs supplementation inhibited the production of MMP-1 and the UV-induced abnormal proliferation of keratinocytes. All these effects resulted in the remodeling of extracellular matrix (ECM) and finally made a significant improvement in the appearance of skin. CONCLUSION: Overall, the present study suggested that dietary supplementation of n-3 PUFAs has the potential clinical prospect to prevent UV-induced skin damage and photoaging.

Comparison of red light and blue light therapies for mild-to-moderate acne vulgaris: A randomized controlled clinical study.

BACKGROUND: Red and blue light therapies are safe and effective treatments for mild-to-moderate acne vulgaris. However, very few previous studies have directly compared the characteristics of these two methods. OBJECTIVE: To compare the efficacy and side effects of red light (RL) and blue light (BL) for acne vulgaris and to assess these two therapies in different types of lesions. MATERIALS AND METHODS: A total of 28 subjects with mild-to-moderate acne vulgaris were randomized into the RL group or the BL group. Subjects in each group received different light treatments, and they were followed up regularly until 2 weeks after the last treatment. The improvement rates of different types of acne lesions were compared between the 2 groups, as well as the incidence of adverse reactions. RESULTS: At the 2-week follow-up, the average improvement rate of total acne lesions was 36.2% in the RL group and 30.7% in the BL group (p > .05). The average improvement rate of inflammatory and non-inflammatory lesions was 51.5% and 17.3% in the RL group, compared with 26.4% and 10.0% in the BL group (all p > .05). Treatment-related adverse reactions were observed distinctly in the BL group. CONCLUSIONS: Red light and BL therapies have similar efficacy in mild-to-moderate acne vulgaris, especially for inflammatory lesions. RL had advantages with fewer adverse reactions compared with BL.