Identification of dietary factors that impact the gut microbiota associated with vitiligo: A Mendelian randomization study and meta-analysis.

Previous observational studies have suggested that gut microbiota might be associated with vitiligo. However, owing to the limitations in observational studies of reverse causality and confounders, it remains unclear that whether and how the causal relationships exist. The results suggested that pylum.Bacteroidetes, family.BacteroidalesS24.7, genus.LachnospiraceaeND3007, genus.Marvinbryantia are protective factors for vitiligo. Conversely, family.Lachnospiraceae, order.Burkholderiales, genus.Adlercreutzia, genus.Catenibacterium and genus.Lachnospira are risk factors for vitiligo. In addition, the causative connection between dietary factors and the gut microbiota associated with vitiligo was also investigated. The results revealed that 'alcohol intake versus 10 years pervious' results in a reduction in the abundance of genus.Lachnospiraceae ND3007 and family.BacteroidalesS24.7, bread intake leads to a reduction of genus.Marvinbryantia, 'average weekly red wine intake' is linked to a decrease in the abundance of order.Burkholderiales, tea intake is associated with an augmentation in the abundance of genus.Catenibacterium, salad/raw vegetable intake elevates the abundance of order.Burkholderiales. In summary, this Mendelian randomization study substantiates potential causal effects of gut microbiota on vitiligo. Modulating the gut microbiota through regulating dietary composition may be a novel strategy for preventing vitiligo.

Efficacy of Photodynamic Therapy in the Treatment of Actinic Keratosis: A Network Meta-Analysis.

BACKGROUND: Photodynamic therapy (PDT) is an effective treatment for actinic keratosis (AK) and uses different light sources as well as photosensitizers. In addition, PDT is often combined with other physical therapies or drugs. OBJECTIVES: This study was aimed to compare the efficacy of different PDTs against AK lesions based on Complete Response (CR) by conducting a network meta-analysis (NMA). METHODS: Randomized controlled trials (RCTs) using PDT for AK were screened and a Bayesian model was developed to perform an NMA of CR at 3 months after the first treatment. RESULTS: Twenty-six trials involving 2285 patients and 14 treatments were included. The treatments were broadly divided into mono-PDT and combination therapy. The photodynamic monotherapies included methyl 5-aminolevulinic acid (MAL)-daylight (DL)-PDT, MAL-light-emitting diode (LED)-PDT, 5-aminolevulinic acid (ALA)-LED-PDT, etc. Combination therapies included ablative fractional laser (AFL)-assisted MAL-LED-PDT, calcipotriol (CAL)-assisted MAL-LED-PDT, and 5-fluorouracil (5-Fu)-assisted MAL-DL-PDT. The results of the NMA showed that there is a high probability that AFL-MAL-LED-PDT is the most effective treatment option, followed by CAL-MAL-LED-PDT and ALA-LED-PDT. The subgroup analysis showed that MAL-based PDT had better efficacy when using LED versus other light sources, while LED-based PDT was likely to have better efficacy when using ALA versus other photosensitizers. CONCLUSIONS: The results of this NMA suggest that AFL-MAL-LED-PDT may be the superior choice for achieving complete clearance of AK lesions. PDT using LED as the light source and ALA as the photosensitizer may be more effective for the treatment of AK. However, more RCTs are needed to verify the results of this analysis.

The amino acid transporter SLC16A10 promotes melanogenesis by facilitating the transportation of phenylalanine.

Phenylalanine is a crucial amino acid in the process of melanogenesis. However, the exact mechanism by which it is transported into melanocytes has not been disclosed. The aim of this study was to identify and examine the key transporters that are responsible for phenylalanine transportation and evaluate their significance in melanogenesis. The amino acid transporter SLC16A10 was found to be up-regulated in both melasma (GSE72140) and sun-exposed skin (GSE67098). The protein levels of SLC16A10 were proportional to the melanin content in melanocytic nevi, indicating that SLC16A10 was related to melanogenesis. After SLC16A10 overexpression, melanin increased significantly in MNT1 cells. Meanwhile, the expression of melanogenesis-related proteins such as TYR and TYRP1 increased, while their RNA levels did not change. Transcriptomics data indicated that SLC16A10 can enhance the function of ribosome. Furthermore, targeted metabolomics data and ELISA results demonstrated SLC16A10 mainly affected the transport of phenylalanine into the cells. Then, phenylalanine was added to the cell culture medium after SLC16A10 overexpression, melanin synthesis in cells furtherly increased, which verified that SLC16A10 enhances melanogenesis by promoting the uptake of phenylalanine. Finally, we found that SLC16A10 expression increased after UVB irradiation. Knockdown SLC16A10 reduced UVB-induced melanin production and phenylalanine uptake by cells. In summary, SLC16A10 enhances melanogenesis by promoting the uptake of phenylalanine, and upregulation SLC16A10 is likely responsible for the UVB-induced hyperpigmentation as well.

Polycyclic aromatic hydrocarbons exposure associated with increased risk of psoriasis.

Psoriasis is considered to be multifactorial, with both genetic and environmental factors contributing to its development. Polycyclic aromatic hydrocarbons (PAHs) are widespread in the environment, originating from sources such as cigarette smoke, exhaust emissions, grilled foods, smoked foods and urban air. Researchs have established a link between PAHs exposure and autoimmune disorders; however, specific effects of PAHs on psoriasis remain underexplored. This study aims to evaluate the correlation between PAHs exposure and susceptibility to psoriasis. We analysed eight monohydroxy PAHs (1-Hydroxynaphthalene (1-NAP), 2-Hydroxynaphthalene (2-NAP), 3-Hydroxyfluorene (3-FLU), 2-Hydroxyfluorene (2-FLU), 1-Hydroxyphenanthrene (1-PHE), 1-Hydroxypyrene (1-PYR), 2-Hydroxyphenanthrene (2-PHE) and 3-Hydroxyphenanthrene (3-PHE)) in 5996 participants from the National Health and Nutrition Examination Survey (NHANES). We employed multivariate logistic regression, trend analysis, weighted quantile sum (WQS) regression and restricted cubic spline (RCS) analysis to investigate the relationship between PAHs exposure and psoriasis risk. Multivariate logistic regression and trend analysis revealed that monohydroxy PAHs, including 2-NAP, 3-FLU, 2-FLU and the mixture of 2-PHE and 3-PHE, are associated with an increased risk of psoriasis. Additionally, WQS regression showed a significant positive correlation between combined exposure to monohydroxy PAHs and psoriasis risk, with the mixture of 2-PHE and 3-PHE (47.3%) being the most influential factor. RCS regression further corroborated these findings. Specifically, 2-FLU can increase the expression of psoriasis-related inflammatory factors in HaCaT cells. In conclusion, PAHs exposure increases the risk of developing psoriasis. Efforts to reduce PAHs levels in the environment and minimise exposure are crucial for public health strategies aimed at preventing psoriasis.

UVB-induced TRPS1 regulates MITF transcription activity to promote skin pigmentation.

Hyperpigmented dermatoses are characterized by increased skin pigmentation caused by genetic, environmental factors and inflammation, which lasts a long time and is difficult to treat. Ultraviolet (UV), especially ultraviolet B (UVB), is the primary external factor inducing skin pigmentation. However, the specific regulatory mechanisms are not fully understood. Through analysis of GEO datasets from four UV-exposed skin cell/tissue samples, we found that TRPS1 is the only gene differentially expressed in multiple datasets (GSE22083, GSE67098 and GSE70280) and highly positively correlated with the expression of key melanogenesis genes. Consistently, we observed that TRPS1 is highly expressed in sun-exposed skin tissues compared to non-exposed skin. Additionally, the expression of TRPS1 was also significantly upregulated after UVB irradiation in isolated skin tissues and melanocytes, while knockdown of TRPS1 expression inhibited the UVB-induced melanogenesis. Further research revealed that overexpression of TRPS1 increased melanin content and tyrosinase activity in MNT1 cells, as well as upregulated the expression levels of key melanogenesis genes (MITF, TYR, TYRP1, DCT). In contrast, inhibition of TRPS1 expression showed the opposite effect. Moreover, we found that TRPS1 can bind to the promoter region of MITF, inhibiting the expression of MITF can antagonize the melanogenesis induced by TRPS1. In conclusion, UVB-induced TRPS1 promotes melanogenesis by activating the transcriptional activity of MITF.

Reflectance confocal microscopy for the early diagnosis of herpes zoster.

For herpes zoster (HZ) infection, early diagnosis and treatment are important in order to shorten the course of the disease and reduce sequelae, however, there is a lack of non-invasive diagnostic methods. Reflectance confocal microscopy (RCM) is a non-invasive technique often used to diagnose dyspigmented dermatosis, skin tumours, human papillomavirus infectious dermatosis, etc. To evaluate the clinical value of RCM for the early diagnosis of HZ. We collected RCM images from 30 HZ patients with typical vesicles in order to analyse their features. We then utilized RCM to analyse early lesions of another 12 HZ patients, who presented with localized erythema or papules, but not typical vesicles. In addition, we recruited one patient with HZ and observed the lesions over 14 days also using RCM. RCM images showed that the typical lesions of HZ mainly involved oedema of the spinous layer, intraepidermal blister formation, ballooning multinucleated giant (BMG) cells, and dermal papillary oedema. Among them, BMG cells were of specific diagnostic value. Early lesions of HZ patients without typical vesicles showed BMG cells under RCM. A few BMG cells were observed during the early stage of HZ. However, the number of BMG cells increased significantly as typical clustered blisters gradually appeared in the lesions. With the regression of the lesions, the number of BMG cells decreased gradually. RCM, with the advantages of being non-invasive, rapid, and convenient, has an important role in monitoring the evolution of HZ.

Macrophage migration inhibitory factor mediates skin aging via CD74: Insights from single-cell and bulk RNA sequencing data.

Cell-cell communication is crucial for regulating signaling and cellular function. However, the precise cellular and molecular changes remain poorly understood in skin aging. Based on single-cell and bulk RNA data, we explored the role of cell-cell ligand-receptor interaction in skin aging. We found that the macrophage migration inhibitory factor (MIF)/CD74 ligand-receptor complex was significantly upregulatedin aged skin, showing the predominant paracrine effect of keratinocytes on fibroblasts. Enrichment analysis and in vitro experiment revealed a close association of the activation of the MIF/CD74 with inflammatory pathways and immune response. Mechanistically, MIF/CD74 could significantly inhibit PPARγ protein, which thus significantly increased the degree of fibroblast senescence, and significantly up-regulated the expression of senescence-associated secretory phenotype (SASP) factors and FOS gene. Therefore, our study reveals that MIF/CD74 inhibits the activation of the PPAR signaling pathway, subsequently inducing the production of SASP factors and the upregulation of FOS expression, ultimately accelerating fibroblast senescence.

Decreased oxidative stress response and oxidant detoxification of skin during aging.

Oxidative stress plays an important role in the skin aging process; however, the mechanisms are not fully elucidated. Especially the changes in various types of skin cells with aging and the key oxidative stress-related genes that play a regulatory role are not clear. In this study, single-cell RNA sequencing data and microarray transcriptome data were used to explore the changes in oxidative stress response and oxidant detoxification capacity of skin cells during aging and oxidative stress-related genes potentially involved in regulating skin aging were searched. The oxidative stress response and oxidant detoxification ability were weakened in the elderly compared with those of the young. Among the different types of skin cells, keratinocytes, melanocytes, vascular endothelial cells, fibroblasts, and lymphatic endothelial cells exhibited a stronger oxidative stress response and oxidant detoxification ability, while immune cells exhibited a weaker oxidative stress response and detoxification capacity. During aging, the oxidative stress response and oxidant detoxification capacity of keratinocytes, fibroblasts, macrophages, and vascular endothelial cells were significantly weakened. Annexin A1 (ANXA1) and Apolipoprotein E (APOE) may be key oxidative stress-related genes affecting skin aging.

Disease Awareness and Treatment Preferences in Vitiligo: A Cross-sectional Study in China.

In China, there is a lack of data regarding the awareness and treatment preferences among patients with vitiligo and their families. To address this gap, a cross-sectional questionnaire-based study was conducted to investigate disease awareness and treatment preferences in Chinese patients with vitiligo. The study also evaluated willingness to pay, using 2 standardized items, and assessed quality of life, using the Dermatology Life Quality Index (DLQI) score. Data from 307 patients with vitiligo (59.3% women, mean age 28.98 years, range 2-73 years) were analysed. Of these patients, 44.7% had insufficient knowledge of vitiligo, particularly those from rural areas or with low levels of education. Mean DLQI total score was 4.86 (5.24 for women and 4.30 for men). Among the most accepted treatments were topical drugs, phototherapy, and systemic therapy. Patients were relatively conservative about the duration and cost of treatment, with only 27.7% willing to pay more than 10,000 Chinese yuan renminbi (CNY) for complete disease remission. High level of education, high income, skin lesions in specific areas, and skin transplantation therapy predicted higher willingness to pay. Insufficient knowledge was associated with a higher burden of disease. In order to reduce the disease burden and improve treatment adherence it is crucial to enhance disease awareness and take into account patient preferences.

Fraxin inhibits melanogenesis by suppressing the ERK/MAPK pathway and antagonizes oxidative stress by activating the NRF2 pathway.

Hyperpigmentation disorders, such as melasma and freckles, are highly prevalent and draw increasing attention. Patients thus tend to seek effective and safe cosmetic whitening agents. Fraxin, a bioactive substance extracted from Cortex Fraxini, possesses anti-inflammation and antioxidant properties. In this study, we further explored the anti-melanogenic activities of fraxin were explored in vitro and in vivo. We found that pretreatment with fraxin decreased the melanin content of MNT1 cells and zebrafishes. In MNT1 cells, melanogenesis-related proteins, such as MITF, TYR, TYRP1, and DCT were down-regulated and tyrosinase activity was reduced under fraxin treatment. Further exploration of the mechanism revealed that fraxin could inhibit the phosphorylation of ERK, which is closely related to melanogenesis. Besides, fraxin also protected MNT1 cells from H2O2-induced apoptosis via scavenging reactive oxygen species (ROS) in cells. Further experimentation revealed that fraxin could activate NRF2 and upregulate antioxidase CAT and HO-1. In conclusion, fraxin could be an effective agent with anti-melanogenesis and antioxidant properties for hyperpigmentation disorders.

Dynamic panoramic presentation of skin function after fractional CO2 laser treatment.

Fractional CO2 laser, as a typical ablative laser, has been used to assist in the treatment of many skin diseases, such as photoaging, atrophic scar, hypertrophic scar, superficial pigmentation, vitiligo, and so on. However, the dynamic changes in skin function after fractional CO2 laser treatment are still unclear. This study explored the changes in local skin function and possible regulatory mechanisms after fractional CO2 laser treatment for 1, 3, 5, and 7 days through transcriptome high-throughput sequencing. The results showed that fractional CO2 laser tended to transform the "lesions" into "normal skin", regulate the skin barrier, coordinate the rearrangement of collagen, enhance the local microvascular circulation, activate the immune system to secrete a large number of cytokines, and act as an auxiliary tool to assist drug transport. In conclusion, according to the basic principle of destruction before reconstruction, fractional CO2 laser plays a key role of balancer in skin reconstruction.

UVB promotes melanogenesis by regulating METTL3.

Ultraviolet (UV) radiation is the primary exogenous inducer of skin pigmentation, although the mechanism has not been fully elucidated. N6-methyladenosine (m6 A) modification is one of the key epigenetic form of gene regulation that affects multiple biological processes. The aim of this study was to explore the role and underlying mechanisms of m6 A modification in UVB-induced melanogenesis. Low-dose UVB increased global m6 A modification in melanocytes (MCs) and MNT1 melanoma cell line. The GEPIA database predicted that methyltransferase METTL3 is positively correlated with the melanogenic transcription factor MITF in the sun-exposed skin tissues. After METTL3 respectively overexpressed and knocked down in the MNT1, the melanin content and melanogenesis-related genes were significantly upregulated after overexpression of METTL3, especially with UVB irradiation, and downregulated after METTL3 knockdown. METTL3 levels were also higher in melanocytic nevi with high melanin content. METTL3 overexpression and knockdown also altered the protein level of YAP1. SRAMP analysis predicted four high-potential m6 A modification sites on YAP1 mRNA, of which three were confirmed by methylated RNA immunoprecipitation. Inhibition of YAP1 expression can partially reverse melanogenesis induced by overexpression of METTL3. In conclusion, UVB irradiation promotes global m6 A modification in MCs and upregulates METTL3, which increases the expression level of YAP1 through m6 A modification, thereby activating the co-transcription factor TEAD1 and promoting melanogenesis.

Heat promotes melanogenesis by increasing the paracrine effects in keratinocytes via the TRPV3/Ca2+/Hh signaling pathway.

Global warming and rising temperature significantly increase the incidence of heat stress, which is known to affect the process of inflammation and aging. However, the effect of heat stress on skin melanogenesis is not fully known. We found that healthy foreskin tissues underwent significant pigmentation when exposed to 41°C. Furthermore, heat stress promoted melanogenesis in pigment cells by increasing the paracrine effects of keratinocytes. High-throughput RNA sequencing showed that heat stress activates the Hedgehog (Hh) signaling pathway in keratinocytes. The agonists of Hh signaling promote the paracrine effect of keratinocytes on melanogenesis. In addition, transient receptor potential vanilloid (TRPV) 3 agonists activate the Hh signaling in keratinocytes and augment its paracrine effect on melanogenesis. The heat-induced activation of Hh signaling is dependent on TRPV3-mediated Ca2+ influx. Heat exposure promotes melanogenesis by increasing the paracrine effects in keratinocytes via the TRPV3/Ca2+/Hh signaling pathway. Our findings provide insights into the mechanisms of heat-induced skin pigmentation.

LncRNA UCA1 promotes keratinocyte-driven inflammation via suppressing METTL14 and activating the HIF-1α/NF-κB axis in psoriasis.

Keratinocytes are closely associated with innate immunity and inflammatory responses, and are dysregulated during the development of psoriasis, but the underlying mechanisms are not yet fully understood. This work aims to reveal the effects of long non-coding RNA (lncRNA) UCA1 in psoriatic keratinocytes. UCA1 was identified as a psoriasis-related lncRNA that highly expressed in psoriatic lesions. The transcriptome and proteome data of keratinocyte cell line HaCaT showed that UCA1 could positively regulate inflammatory functions, such as response to cytokine. Furthermore, UCA1 silencing decreased inflammatory cytokine secretion and innate immunity gene expression in HaCaT, its culture supernatant also decreased the migration and tube formation ability of vascular endothelial cells (HUVECs). Mechanistically, UCA1 activated the NF-κB signaling pathway, which is regulated by HIF-1α and STAT3. We also observed a direct interaction between UCA1 and N6-methyladenosine (m6A) methyltransferase METTL14. Knocking down METTL14 counteracted the effects of UCA1 silencing, indicating that it can suppress inflammation. In addition, the levels of m6A-modified HIF-1α were decreased in psoriatic lesions, indicating that HIF-1α is a potential target of METTL14. Taken together, this work indicates that UCA1 positively regulates keratinocyte-driven inflammation and psoriasis development by binding to METTL14, and activating HIF-1α and NF-κB signaling pathway. Our findings provide new insights into the molecular mechanisms of keratinocyte-driven inflammation in psoriasis.

Crosstalk between G-quadruplex and ROS.

The excessive production of reactive oxygen species (ROS) can lead to single nucleic acid base damage, DNA strand breakage, inter- and intra-strand cross-linking of nucleic acids, and protein-DNA cross-linking involved in the pathogenesis of cancer, neurodegenerative diseases, and aging. G-quadruplex (G4) is a stacked nucleic acid structure that is ubiquitous across regulatory regions of multiple genes. Abnormal formation and destruction of G4s due to multiple factors, including cations, helicases, transcription factors (TFs), G4-binding proteins, and epigenetic modifications, affect gene replication, transcription, translation, and epigenetic regulation. Due to the lower redox potential of G-rich sequences and unique structural characteristics, G4s are highly susceptible to oxidative damage. Additionally, the formation, stability, and biological regulatory role of G4s are affected by ROS. G4s are involved in regulating gene transcription, translation, and telomere length maintenance, and are therefore key players in age-related degeneration. Furthermore, G4s also mediate the antioxidant process by forming stress granules and activating Nrf2, which is suggestive of their involvement in developing ROS-related diseases. In this review, we have summarized the crosstalk between ROS and G4s, and the possible regulatory mechanisms through which G4s play roles in aging and age-related diseases.

Melatonin reduces melanogenesis by inhibiting the paracrine effects of keratinocytes.

Keratinocytes regulate melanogenesis in a paracrine manner. Previous studies have shown that melatonin can directly inhibit melanin production in the melanocytes. However, it is unclear whether melatonin can also indirectly regulate melanogenesis through the keratinocytes. In this study, we explored the role of melatonin in regulating keratinocyte-mediated melanogenesis using reconstructed human epidermis (RHE). Melatonin showed an inhibitory effect on melanin synthesis in this model. Furthermore, the conditioned media from melatonin-treated HaCaT cells downregulated melanogenesis-related genes, including MITF, TYR, TYRP1, DCT and RAB27A in the pigment MNT1 cells, and decreased levels of phosphorylated ERK, JNK and p38. RNA sequencing further showed that mitochondrial functions and oxidative stress pathway in the MNT1 cells were inhibited by the conditioned medium from melatonin-treated HaCaT cells. Furthermore, melatonin reduced the secretion of ET-1 and PTGS2 from HaCaT cells by inhibiting the JAK2/STAT3 signalling pathway. In conclusion, melatonin downregulates the paracrine factors ET-1 and PTGS2 in the keratinocytes by inhibiting the JAK2/STAT3 pathway, which reduces melanin production in pigment cells. Thus, melatonin has a potential therapeutic effect on skin pigmentation disorders.

Characteristics and pathogenesis of Koebner phenomenon.

The Koebner phenomenon, also known as isomorphic reaction, refers to the development of secondary lesions with the same clinical manifestations and histopathological characteristics as the primary lesions in normal skin after trauma or other stimuli. The triggering factors of Koebner phenomenon include physical trauma, chemical stimulation, mechanical stress, iatrogenic stimulation and pathogenic infection. Vitiligo, psoriasis and lichen planus are considered true Koebner phenomenon. Recent studies have shown that immunological disorders, oxidative stress, defective melanocyte adhesion and growth factor deficiency are the main pathological mechanisms of vitiligo Koebner phenomenon. In psoriasis, triggers may drive skin inflammation to induce a psoriatic phenotype through multiple signalling pathways and thereby cause Koebner phenomenon in susceptible individuals. Significantly, keratinocytes mediate the occurrence of Koebner phenomenon in psoriasis through mechano-induced signalling pathways after sensing mechanical signals and explains the high frequency of psoriasis lesions on the extensor side of the elbow and knee joints. On the contrary, TRPA1-driven mechano-transduction, autoimmunity and actinic damage are the underlying mechanisms of Koebner phenomenon in lichen planus. In this review, we have summarized the current understanding of the characteristics and pathogenesis of Koebner phenomenon.

Establishment and validation of evaluation models for post-inflammatory pigmentation abnormalities.

Post-inflammatory skin hyper- or hypo-pigmentation is a common occurrence with unclear etiology. There is currently no reliable method to predict skin pigmentation outcomes after inflammation. In this study, we analyzed the 5 GEO datasets to screen for inflammatory-related genes involved in melanogenesis, and used candidate cytokines to establish different machine learning (LASSO regression, logistic regression and Random Forest) models to predict the pigmentation outcomes of post-inflammatory skin. Further, to further validate those models, we evaluated the role of these candidate cytokines in pigment cells. We found that IL-37, CXCL13, CXCL1, CXCL2 and IL-19 showed high predictive value in predictive models. All models accurately classified skin samples with different melanogenesis-related gene scores in the training and testing sets (AUC>0.7). Meanwhile, we mainly evaluated the effects of IL-37 in pigment cells, and found that it increased the melanin content and expression of melanogenesis-related genes (MITF, TYR, TYRP1 and DCT), also enhanced tyrosinase activity. In addition, CXCL13, CXCL1, CXCL2 and IL-19 could down-regulate the expression of several melanogenesis-related genes. In conclusion, evaluation models basing on machine learning may be valuable in predicting outcomes of post-inflammatory pigmentation abnormalities. IL-37, CXCL1, CXCL2, CXCL13 and IL-19 are involved in regulating post-inflammatory pigmentation abnormalities.