The causal relationship between blood metabolites and rosacea: A Mendelian randomization.

BACKGROUND: An increasing amount of research demonstrates that metabolic disorders are related to rosacea. However, the correlations and causal relationships among them remain unknown. METHODS: We conducted not only forward 2-sample MR (Mendelian randomization) analyses but also reverse MR analyses which showed positive results in the forward MR analysis. In the forward MR analyses, inverse-variance weighted (IVW) and MR-Egger were performed as MR analyses. Cochran's Q test and the MR-Egger Intercept were used for sensitivity analyses. Concerning reverse MR analyses, IVW, MR-Egger, weighted median, simple mode, and weighted mode were applied. Cochran's Q test, MR-Egger Intercept, and MR pleiotropy residual sum and outlier (MR-PRESSO) outlier test were applied as sensitivity analyses. RESULTS: A total of 24 metabolites and 1 metabolite ratio were shown to have a causal effect on rosacea. N-lactoyl phenylalanine (N-Lac-Phe) was estimated as statistically significant by Bonferroni correction. Interestingly, we found three metabolites that were negatively associated with rosacea, especially caffeine, which are in line with the results of a large cohort study of females. For reverse MR analysis, we revealed that rosacea could potentially decrease the generation of two metabolites: octadecenedioate (C18:1-DC) and methyl vanillate sulfate. CONCLUSION: This study identified blood metabolites that may be associated with the development of rosacea. However, the exact mechanism by which these positive metabolites influence rosacea remains uncertain due to the paucity of experimental investigations. The combination of genetics and metabolomics offers novel viewpoints on the research of underlying mechanisms of rosacea and has significant value in screening and prevention of rosacea.

Dissecting hair breakage in alopecia areata: the central role of dysregulated cysteine homeostasis.

In the initial stages of Alopecia Areata (AA), the predominance of hair breakage or exclamation mark hairs serves as vital indicators of disease activity. These signs are non-invasive and are commonly employed in dermatoscopic examinations. Despite their clinical salience, the underlying etiology precipitating this hair breakage remains largely uncharted territory. Our exhaustive review of the existing literature points to a pivotal role for cysteine-a key amino acid central to hair growth-in these mechanisms. This review will probe and deliberate upon the implications of aberrant cysteine metabolism in the pathogenesis of AA. It will examine the potential intersections of cysteine metabolism with autophagy, ferroptosis, immunity, and psychiatric manifestations associated with AA. Such exploration could illuminate new facets of the disease's pathophysiology, potentially paving the way for innovative therapeutic strategies.

Efficacy and safety of botulinum toxin A in the treatment of female pattern hair loss.

BACKGROUND: Female pattern hair loss (FPHL) is the most prevalent type of alopecia among adult women. Presently, topical minoxidil stands as the sole treatment endorsed by the FDA. Addressing cases of FPHL in individuals who develop contact dermatitis in response to minoxidil can pose a challenge for dermatologists. OBJECTIVE: To assess the efficacy and safety of subcutaneous injections of Botulinum Toxin Type A (BTA) in treating FPHL. METHODS: Enrolled outpatients with FPHL who exhibited an allergic reaction to minoxidil solution. Diagnosis of FPHL was established through clinical examination and trichoscopy. Inclusion criteria involved patients with no prior treatment within the last year and without any comorbidities. BTA, specifically 100 units, was mixed with 2 mL of 0.9% normal saline. Twenty injection target sites, spaced 2-3 cm apart, were symmetrically marked on the hairless area of the scalp. A dosage of five units was intradermally injected at each target site. Representative photographs and dermoscopic images of the scalp were captured before and after 3 months of treatment. RESULTS: A total of 10 FPHL, aged between 26 and 40 years, were included. The average age was 30.3 ± 4.64 years, and all patients had a positive family history of Androgenetic Alopecia. The average duration of the disease was 3.70 ± 1.42 years. According to patients' self-assessment, after 1 month of treatment, 10 FPHL patients reported experiencing moderate to marked improvement in symptoms related to scalp oil secretion. Three months later, dermatological assessments showed that three had mild improvement, six had no change, and one had a worsening condition. No adverse effects were observed. CONCLUSIONS: Our study suggests that the effectiveness of BTA for FPHL is limited to 3 months. However, it can be considered for tentative use after effective communication with patients. The long-term efficacy and safety of BTA in treating FPHL require further observation and study.

Definition of refractory melasma and its treatment: a review.

Although patients with refractory melasma have been treated using various methods, there is still no precise definition or summary of the therapies. To define refractory melasma and conduct a review of the treatments, we searched for relevant publications in PubMed, Web of Science, and the Cochrane Library, and a total of 35 references were obtained. Refractory melasma can be roughly defined as an ineffective treatment for melasma, including topical bleaching agents, chemical peels, laser therapy, microdermabrasion for more than six months, or chemical peels treated more than six times. Meanwhile, physicians should be careful when treating patients with darker skin and dermal or mixed types of melasma since these individuals do not respond well to treatment. Lasers combined with other methods, especially different types of lasers or topical agents, are considered more effective than monotherapy. Oral tranexamic acid (TXA) is a prospective cure for refractory melasma. Other methods include a combination of chemical peels, microneedling, or injections with additional therapies. In conclusion, we were able to provide a rough definition of refractory melasma and list the available therapies. According to the literature, the most prevalent treatment is laser combination therapy. However, laser treatment should be considered only after topical agents and chemical peeling have failed. Considering its side effects, efficacy, and safety, oral TXA may be a better option, but more research is needed to make a firm conclusion. Moreover, maintenance therapy is required after treatment.

Identification of SLC40A1, LCN2, CREB5, and SLC7A11 as ferroptosis-related biomarkers in alopecia areata through machine learning.

Alopecia areata (AA) is a common non-scarring hair loss condition driven by the collapse of immune privilege and oxidative stress. The role of ferroptosis, a type of cell death linked to oxidative stress, in AA is yet to be explored, even though it's implicated in various diseases. Using transcriptome data from AA patients and controls from datasets GSE68801 and GSE80342, we aimed to identify AA diagnostic marker genes linked to ferroptosis. We employed Single-sample gene set enrichment analysis (ssGSEA) for immune cell infiltration evaluation. Correlations between ferroptosis-related differentially expressed genes (FRDEGs) and immune cells/functions were identified using Spearman analysis. Feature selection was done through Support vector machine-recursive feature elimination (SVM-RFE) and LASSO regression models. Validation was performed using the GSE80342 dataset, followed by hierarchical internal validation. We also constructed a nomogram to assess the predictive ability of FRDEGs in AA. Furthermore, the expression and distribution of these molecules were confirmed through immunofluorescence. Four genes, namely SLC40A1, LCN2, CREB5, and SLC7A11, were identified as markers for AA. A prediction model based on these genes showed high accuracy (AUC = 0.9052). Immunofluorescence revealed reduced expression of these molecules in AA patients compared to normal controls (NC), with SLC40A1 and CREB5 showing significant differences. Notably, they were primarily localized to the outer root sheath and in proximity to the sebaceous glands. Our study identified several ferroptosis-related genes associated with AA. These findings, emerging from the integration of immune cell infiltration analysis and machine learning, contribute to the evolving understanding of diagnostic and therapeutic strategies in AA. Importantly, this research lays a solid foundation for subsequent studies exploring the intricate relationship between AA and ferroptosis.

New Target for Minoxidil in the Treatment of Androgenetic Alopecia.

Objective: To investigate the mechanism of minoxidil in treating androgenetic alopecia (AGA). Methods: The mechanism of action of minoxidil on AGA was first systematically investigated from the viewpoint of network pharmacology, including minoxidil-AGA target prediction, protein-protein interaction (PPI) network analysis, molecular docking and enrichment analysis of targets related to minoxidil and AGA, and dermal papilla cell assays to confirm the viability of prediction. Results: The combined analysis revealed that minoxidil treatment of AGA not only acts on androgenic receptors (AR) but also on 2 new targets, steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) and aromatase (CYP19A1). The biological processes linked to these targets were concentrated on several pathways, including enzymes and hormones. Further experiments have revealed that minoxidil suppresses the expression of AR and CYP17A1, boosts the activity of CYP19A1, decreases the formation and binding of dihydrotestosterone, and enhances the production of estradiol. Through these changes, minoxidil acts as a treatment for AGA. Conclusion: Minoxidil may act by altering hormonal and enzymatic pathways. Our study finds two new targets (CYP17A1, CYP19A1) of minoxidil and demonstrates that minoxidil inhibits AR. These targets may provide new ideas for drug research.

Reflectance Confocal Microscopy of Adult Periorificial Dermatitis: A Case Report.

Periorificial dermatitis (PD) is an inflammatory disorder of the facial skin that mainly occurs around the mouth and manifests as erythema, papules, pustules, scales and other lesions. Special attention is needed in the clinical diagnosis of PD to distinguish it from acne, seborrheic dermatitis (SD), granulomatous rosacea (GR), sarcoidosis and childhood granulomatous periorificial dermatitis (CGPD). We used reflectance confocal microscopy (RCM) images of a patient with PD to assist in the diagnosis of PD. RCM of PD showed slight oedema of the spinous layer. Numerous dendritic cells, scattered hair follicular keratotic plugging and hair follicle dilatation were observed. The dilation and congestion of superficial dermis blood vessels, an increasing vascular density and accelerated blood flow, and a greater abundance of infiltrated inflammatory cells were also detected.

Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia.

Transient receptor potential vanilloid 1 (TRPV1) ion channel is a classic analgesic target, but antagonists of TRPV1 failed in clinical trials due to their side effects like hyperthermia. Here we rationally engineer a peptide s-RhTx as a positive allosteric modulator (PAM) of TRPV1. Patch-clamp recordings demonstrate s-RhTx selectively potentiated TRPV1 activation. s-RhTx also slows down capsaicin-induced desensitization of TRPV1 in the presence of calcium to cause more calcium influx in TRPV1-expressing cells. In addition, our thermodynamic mutant cycle analysis shows that E652 in TRPV1 outer pore specifically interacts with R12 and K22 in s-RhTx. Furthermore, we demonstrate in vivo that s-RhTx exhibits long-lasting analgesic effects in noxious heat hyperalgesia and CFA-induced chronic inflammatory pain by promoting the reversible degeneration of intra-epidermal nerve fiber (IENF) expressing TRPV1 channels in mice, while their body temperature remains unaffected. Our results suggest s-RhTx is an analgesic agent as a PAM of TRPV1.

The Efficacy of Fractional Carbon Dioxide Laser in Surgical Scars Treatment: A system Review and Meta-analysis.

BACKGROUND: Surgical scars seriously affect a patient's quality of life, and they have a strong impact on individuals. Many studies have reported the results of using fractional carbon dioxide (CO2) laser to treat surgical scars and have generally found it to be effective. OBJECTIVES: We conducted a meta-analysis with the objective of evaluating and proving the efficacy of fractional CO2 laser therapy for surgical scars. METHODS: We performed a search of databases including PubMed, Web of Science, Embase and the Cochrane Library. The outcomes of the meta-analysis were overall scores on the Vancouver Scar Scale (VSS) and its four dimensions (pigmentation, vascularity, pliability and height). Statistical analysis was performed using RevMan 5.4 software. RESULTS: A total of ten studies were included in this meta-analysis, including six randomized controlled trials (RCTs) and four nonrandomized controlled trials (N-RCTs). In the meta-analysis of RCTs and N-RCTs, similar results were obtained, and fractional CO2 laser irradiation significantly decreased VSS scores (P < 0.00001). In addition, fractional CO2 laser irradiation also had a significant effect on scores on the pigmentation (P = 0.08), vascularity (P = 0.001), flexibility (P = 0.005) and height (P = 0.008) dimensions. Except for mild pain during treatment and temporary erythema after treatment, most patients had no obvious adverse reactions. CONCLUSION: Our study found that fractional CO2 laser exhibits excellent efficacy and safety in terms of surgical scar treatment. Thus, we hope it becomes more widely available to patients with surgical scars. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .

Single and combined 1064 nm Q-switched Nd: YAG laser therapy in melasma: A meta-analysis.

PURPOSE: This article attempted to describe the efficacy and safety of 1064QNYL in combination with other treatments for refractory melasma. METHODS: Two researchers independently retrieved randomized controlled trials (RCTs) according to inclusion and exclusion criteria. Primary outcome was evaluated with MASI and mMASI scores in control group and experiment group. The secondary outcome was evaluated with MI scores. We calculated 95% CI of standardized mean difference (SMD) and heterogeneity of the included literature by Higgins I2 test, and assessed publication bias by Funnel plots, Egger's, and Begg's tests. RESULTS: A total of 12 articles including 322 subjects were analyzed. Experiment group was treated with 1064QNYL combined with single treatment (e.g., PDL, IPL, RF, and TA). Control group was treated with 1064QNYL alone. A greater reduction of Melasma Area and Severity Index (MASI)/modified Melasma Area and Severity Index (mMASI) scores were shown in experiment group than that in control group at the end of the treatment (SMD, -0.37; 95% CI -0.70 to -0.04, p = 0.03, I2  = 33%). The SMD of MI scores further supported this conclusion by -0.32 (95% CI -0.63 to -0.02, p = 0.04, I2  = 27%). As for adverse events (AEs), combined treatment gave rise to more mild burning, stinging, and erythema that resolved spontaneously. Several studies reported focal purpura, punctate leukoderma, hyperpigmentation, hypopigmentation, and so on. CONCLUSION: Combined 1064QNYL treatment was better than single laser treatment, with the highest short-term benefit and long-term follow-up to maintain the effect in favor of combined treatment.

Efficacy of photodynamic therapy for warts induced by human papilloma virus infection: A systematic review and meta-analysis.

BACKGROUND: The incidence of warts caused by human papilloma virus (HPV) infection is very high in the population. Photodynamic therapy (PDT), as an emerging method for wart treatment, has been demonstrated to be effective and safe by an increasing number of studies. This meta-analysis of previous literature aimed to investigate the potential of PDT as a first-line treatment for warts. METHODS: To acquire proper and accurate information from relevant literature, the four databases PubMed, Embase, Web of Science and the Cochrane Library were searched. The wart clearance rate and patient cure rate were analysed as the primary outcomes. The recurrence rate, patient satisfaction and adverse reactions were also recorded. RESULTS: A total of 19 randomized controlled trials (RCTs) were included based on our search strategy. In the hand and foot wart group, PDT showed a statistically significant improvement in the wart clearance rate compared with placebo (P = 0.02), other lasers (P < 0.0001), and cryotherapy (P < 0.009). PDT use in the condyloma acuminatum group was not superior in terms of the wart clearance rate, with a value lower than that of the carbon dioxide (CO2) laser (P = 0.003) and electrosurgical generator (P < 0.00001). However, all studies mentioned a significant decrease in the recurrence rate after PDT. In the plane wart group, PDT demonstrated its superiority over placebo (P = 0.003) and cryotherapy (P = 0.007) in terms of the cure rate. CONCLUSION: Our study demonstrated that PDT provided several benefits, including but not limited to positive clinical outcomes, low recurrence rates and minor adverse reactions. The use of PDT as first-line therapy can be recommended.

The impaired unfolded protein-premelanosome protein and transient receptor potential channels-autophagy axes in apoptotic melanocytes in vitiligo.

Vitiligo is an autoimmune skin disease, characterized by depigmentation and epidermal melanocytes loss. The specific mechanisms underlying vitiligo have not been fully understood. As a result, treating vitiligo is a dermatological challenge. Recently, much attention has been paid to the dysfunction and interaction of organelles under environmental stress. The impaired organelles could generate misfolded proteins, particularly accumulated toxic premelanosome protein (PMEL) amyloid oligomers, activating the autoimmune system and cause melanocyte damage. Unfolded protein response (UPR) dysfunction accelerates toxic PMEL accumulation. Herein, we presented a narrative review on UPR's role in vitiligo, the misfolded PMEL-induced attack of the autoimmune system under autophagy dysfunction caused by abnormal activation of transient receptor potential (TRP) channels and the background of UPR system defects in melanocytes. All of these mechanisms were integrated to form UPR/PMEL-TRP channels/autophagy axis, providing a new understanding of vitiligo pathogenesis.

Tape stripping and lipidomics reveal skin surface lipid abnormity in female melasma.

The skin barrier of melasma is involved in the pathogenesis of melasma. Previous studies have shown that there are differences in the expression of epidermal lipid genes in melasma, but little is known about the epidermis lipid composition of melasma. Compared with the non-lesional skin, the content of total lipids, phosphatidic acid, phosphatidylserine, and ceramide (Cer) increased significantly in the lesional skin. Multivariate data analysis indicated that 40 individual Cer lipid species were responsible for the discrimination. In terms of acyl chain length in Cer, the expressions of very long chain (VLC) (C20-C26) and ultra-long chain (ULC) (>C26) increased significantly in the lesional skin. However, Cer[AH] had negative correlations with the activation of melanocytes in the lesional skin. Some lipid species had lower expression in lesional skin with high activation of melanocytes, as well as the high darkness. The epidermal thickness of lesional skin was higher compared with the non-lesional skin. These results suggest that Cer increased significantly in the lesional skin of melasma, possibly as a compensatory mechanism to maintain skin barrier function. Between different groups of darkness and activation of melanocytes, the change of ceramides might have correlation with the pigmentation progress of melasma.

The multi-targets mechanism of hydroxychloroquine in the treatment of systemic lupus erythematosus based on network pharmacology.

BACKGROUND: Network pharmacology is used with bioinformatic tools to broaden the understanding of drugs' potential targets and the intersections with key genes of particular disease. Here we applied network pharmacology to collect testable hypotheses about the multi-targets mechanism of hydroxychloroquine (HCQ) against systemic lupus erythematosus (SLE). METHODS: Firstly, we predicted the potential targets of HCQ. Secondly, we got the related genes of SLE returned from databases. Thirdly, the intersections of the potential targets (HCQ) and related genes (SLE) were analyzed with gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, we validated our predictions of the potential targets by performing docking studies with HCQ. RESULTS: The results suggest that the efficacy of HCQ against SLE is mainly associated with the targets of cyclin-dependent kinase 2 (CDK2), estrogen receptor alpha (ESR1) and CDK1, which regulate PI3K/Akt/GSK3ß as well as interferon (IFN) signaling pathway. Biological process of the network associated with the three targets is concentrated in the inhibition of immune response, negative regulation of gene expression and regulation of immune system process. Molecular docking analysis proves that hydrogen bonding and π-π stacking are the main forms of interaction. CONCLUSIONS: Our research provides protein targets affected by HCQ in the treatment of SLE. Three key targets (CDK2, ESR1 and CDK1) involving 1766 proteins become the multi-targets mechanism of HCQ in the treatment of SLE. As well, the research also provides a new idea for introducing network pharmacology into the evaluation of the drugs with multi-targets in dermatology.

Melanocyte activation and skin barrier disruption induced in melasma patients after 1064 nm Nd:YAG laser treatment.

Melasma is a frequently acquired hyperpigmentary skin disorder, for which several therapies are available. Among them, 1064 nm QS Nd:YAG laser therapy is an effective method, but the recurrence rate of laser treatment is still high. The aim of the present study was to elucidate the mechanism of the high relapse rate of melasma after 1064 nm Nd:YAG laser treatment. Twenty-five female melasma patients were treated with 1064 nm Nd:YAG laser for 10 times. The lesional skin and non-lesional skin were evaluated by means of a reflectance confocal laser scanning microscope before and after laser treatment. Melanin content and transepidermal water loss (TEWL) were measured by an MPA9 skin multifunction tester accordingly. The melanin index value was significantly decreased in the lesional skin after laser treatment, while the non-lesional skin had no difference. The dendritic cells were observed at the level of the dermal-epidermal junction (DEJ) in the lesions of 8 patients before laser treatment, while after laser treatment, the dendritic cells were observed in all 25 subjects. Moreover, there was significant difference between the TEWL value of the lesions before and after laser treatment. Furthermore, the TEWL value was higher in lesions of the 8 subjects which had dendritic cells compared with other 17 subjects which had no dendritic cells, no matter before or after laser treatment. The relapse patients of melasma had higher TEWL value compared with the non-relapse patients. Melanocyte activation and skin barrier disruption may be related to the high relapse rate of melasma after laser treatment.

Analysis of debrided and non-debrided invasive squamous cell carcinoma skin lesions by in vivo reflectance confocal microscopy before and after therapy.

Hyperkeratosis hinders the application of reflectance confocal microscopy (RCM) to image squamous cell carcinoma (SCC). Not all lesions with SCC show hyperkeratosis, and these lesions can be directly imaged. However, lesions with hyperkeratosis can be treated by debriding the hyperkeratotic surface for further imaging. RCM was used to investigate patients with suspected SCC. Lesions without obvious keratosis underwent direct RCM examinations. Lesions with obvious keratosis were treated by debriding the hyperkeratotic surface. The following main RCM criteria were used to diagnose invasive SCC: atypical keratinocytes arranged in nests, islands, and disarrangement patterns; an atypical honeycomb pattern; the absence of a cobblestone pattern; and non-edged dermal papillae. Other characteristics of invasive SCC observed by confocal microscopy included keratin pearl structures, hyperkeratosis, and inflammatory cell infiltration. During the follow-up period after treatment, both the cobblestone pattern and edged dermal papillae were as important as the typical honeycomb pattern in suggesting a normal skin structure. Our findings indicate RCM is a valuable tool to noninvasively examine the histology of invasive SCC before and after therapy.

Real-time in vivo confocal laser scanning microscopy of melanin-containing cells: A promising diagnostic intervention.

The use of noninvasive imaging techniques to evaluate different types of skin lesions is increasing popular. In vivo confocal laser scanning microscopy (CLSM) is a new method for high resolution non-invasive imaging of intact skin in situ and in vivo. Although many studies have investigated melanin-containing cells in lesions by in vivo CLSM, few studies have systematically characterized melanin-containing cells based on their morphology, size, arrangement, density, borders, and brightness. In this study, the characteristics of melanin-containing cells were further investigated by in vivo CLSM. A total of 130 lesions, including common nevi, giant congenital pigmented nevi, vitiligo, melasma, melanoma, and chronic eczema, were imaged by in vivo CLSM. This research helps dermatologists understand the characteristics of melanin-containing cells and facilitate the clinical application of melanin-containing cells in the investigation of dermatological disease. In summary, melanin-containing cells include keratinocytes, melanocytes, macrophages, and melanocytic skin tumor cells. Our study presents the CLSM characteristics of melanin-containing cells to potentially facilitate in vivo diagnosis based on shape, size, arrangement, density, borders, and brightness.