Serum cytokine profiles predict response to systemic glucocorticoid in active vitiligo.

Introduction: Vitiligo is an immune-related skin disease. Cytokines regulate immune response and inflammation and are involved in the pathogenesis of vitiligo. Aim: To assess the serum levels of pro-inflammatory cytokines pre- and post- systemic glucocorticoid treatment in patients with active vitiligo. Material and methods: We measured serum cytokine levels using the enzyme-linked immunosorbent assay in 31 patients with active vitiligo before and after treatment. All patients received systemic glucocorticoid (compound betamethasone injection) in combination with topical halometasone cream and tacrolimus ointment for 3 months. Twenty healthy controls were also examined. The cytokines measured included TNF-α, IL-1ß, IL-6, IFN-γ, IL-2, IL-17, IL-10, IL-8, and CXCL10. Results: The serum levels of TNF-α, IL-1ß, IL-6, IFN-γ, IL-2, IL-17, IL-8, and CXCL10 were significantly higher, and levels of IL-10 were lower in vitiligo patients compared to controls. Additionally, serum IFN-γ (r = 0.378; p = 0.036), IL-17 (r = 0.426; p = 0.017), and CXCL10 (r = 0.514; p = 0.003) showed a positive correlation with affected body surface area in vitiligo patients. After 3 months of systemic glucocorticoid treatment, the levels of IL-1ß, IFN-γ, IL-2, IL-17, and CXCL10 in responders were significantly decreased and nearly restored to normal levels. The IL-10 level was also increased in response to treatment. In contrast, the non-responder group had persistently high IL-6, IL-17, IL-8, and CXCL10 levels, and negligible changes in TNF-α, IL-1ß, IFN-γ, IL-2, and IL-10. Conclusions: Our study indicated that the levels of inflammatory cytokines were significantly ameliorated in the glucocorticoid responder group. Altered cell-mediated immunity may contribute to the resistance in vitiligo. The cytokines such as TNF-α, IL-1ß, IFN-γ and IL-2 could serve as therapeutic targets for managing glucocorticoid-resistant vitiligo.

Optimizing vitiligo diagnosis with ResNet and Swin transformer deep learning models: a study on performance and interpretability.

Vitiligo is a hypopigmented skin disease characterized by the loss of melanin. The progressive nature and widespread incidence of vitiligo necessitate timely and accurate detection. Usually, a single diagnostic test often falls short of providing definitive confirmation of the condition, necessitating the assessment by dermatologists who specialize in vitiligo. However, the current scarcity of such specialized medical professionals presents a significant challenge. To mitigate this issue and enhance diagnostic accuracy, it is essential to build deep learning models that can support and expedite the detection process. This study endeavors to establish a deep learning framework to enhance the diagnostic accuracy of vitiligo. To this end, a comparative analysis of five models including ResNet (ResNet34, ResNet50, and ResNet101 models) and Swin Transformer series (Swin Transformer Base, and Swin Transformer Large models), were conducted under the uniform condition to identify the model with superior classification capabilities. Moreover, the study sought to augment the interpretability of these models by selecting one that not only provides accurate diagnostic outcomes but also offers visual cues highlighting the regions pertinent to vitiligo. The empirical findings reveal that the Swin Transformer Large model achieved the best performance in classification, whose AUC, accuracy, sensitivity, and specificity are 0.94, 93.82%, 94.02%, and 93.5%, respectively. In terms of interpretability, the highlighted regions in the class activation map correspond to the lesion regions of the vitiligo images, which shows that it effectively indicates the specific category regions associated with the decision-making of dermatological diagnosis. Additionally, the visualization of feature maps generated in the middle layer of the deep learning model provides insights into the internal mechanisms of the model, which is valuable for improving the interpretability of the model, tuning performance, and enhancing clinical applicability. The outcomes of this study underscore the significant potential of deep learning models to revolutionize medical diagnosis by improving diagnostic accuracy and operational efficiency. The research highlights the necessity for ongoing exploration in this domain to fully leverage the capabilities of deep learning technologies in medical diagnostics.

TRPM2-dependent autophagy inhibition exacerbates oxidative stress-induced CXCL16 secretion by keratinocytes in vitiligo.

Vitiligo is a depigmented skin disease due to the destruction of melanocytes. Under oxidative stress, keratinocyte-derived chemokine C-X-C motif ligand 16 (CXCL16) plays a critical role in recruiting CD8+ T cells, which kill melanocytes. Autophagy serves as a protective cell survival mechanism and impairment of autophagy has been linked to increased secretion of the proinflammatory cytokines. However, the role of autophagy in the secretion of CXCL16 under oxidative stress has not been investigated. Herein, we initially found that autophagy was suppressed in both keratinocytes of vitiligo lesions and keratinocytes exposed to oxidative stress in vitro. Autophagy inhibition also promoted CXCL16 secretion. Furthermore, upregulated transient receptor potential cation channel subfamily M member 2 (TRPM2) functioned as an upstream oxidative stress sensor to inhibit autophagy. Moreover, TRPM2-mediated Ca2+ influx activated calpain to shear autophagy related 5 (Atg5) and Atg12-Atg5 conjugate formation was blocked to inhibit autophagy under oxidative stress. More importantly, Atg5 downregulation enhanced the binding of interferon regulatory factor 3 (IRF3) to the CXCL16 promoter region by activating Tank-binding kinase 1 (TBK1), thus promoting CXCL16 secretion. These findings suggested that TRPM2-restrained autophagy promotes CXCL16 secretion via the Atg5-TBK1-IRF3 signaling pathway under oxidative stress. Inhibition of TRPM2 may serve as a potential target for the treatment of vitiligo. © 2024 The Pathological Society of Great Britain and Ireland.

Establishment of a multicomponent quality control method and the transfer characteristics of five markers from Qidongning Formula to rat tissues by HPLC-QQQ-MS/MS.

Introduction: Traditional Chinese medicine compound preparations have become an increasingly utilized strategy for tumour treatment. Qidongning Formula (QDN) is a kind of antitumour compound preparation used in hospitals, and it can inhibit the growth of lung cancer cells. However, due to the complexity of botanical drugs, the quality evaluation of QDN is inconsistent, affecting clinical efficacy and posing potential safety risks for clinical application. Additionally, tissue distribution is an integral part of the drug development process. Methods: To study the distribution characteristics of markers in compound preparations and rat tissues, a novel HPLC-QQQ-MS/MS quantitative analytical method was established to determine five markers in QDN simultaneously, and the method was verified. Results and discussion: The analytical results showed that the contents of salidroside (51.6 ± 5.75 µg/g), calycosin-7-O-ß-D-glucoside (94.2 ± 15.4 µg/g), specnuezhenide (371 ± 72.5 µg/g), formononetin (23.8 ± 5.39 µg/g), and polyphyllin I (87.7 ± 10.6 µg/g) were stable in different batches of QDN. After intragastric administration (13.5 g/kg) in rats for 1 h, four markers in the QDN, except polyphyllin I, were distributed in most tissues. QDN was distributed chiefly in the stomach and small intestine, followed by the liver or kidney. The study also found that specnuezhenide had the highest concentration in both QDN and rat tissues (102 ± 22.1 µg/g in the stomach), while formononetin had the highest transfer rate (0.351%) from QDN to rat intestines. The above research lays a quality research foundation for the antitumour application of QDN and provides a scientific reference for the quality control of Chinese medicine compound preparations.

Advanced Glycation End Products-Induced Activation of Keratinocytes: A Mechanism Underlying Cutaneous Immune Response in Psoriasis.

Psoriasis is a common inflammatory skin disease, in which epidermal keratinocytes play a vital role in its pathogenesis by acting both as the responder and as the accelerator to the cutaneous psoriatic immune response. Advanced glycation end products (AGEs) are a class of proinflammatory metabolites that are commonly accumulating in cardiometabolic disorders. Recent studies have also observed the increased level of AGEs in the serum and skin of psoriasis patients, but the role of AGEs in psoriatic inflammation has not been well investigated. In the present study, we initially detected abnormal accumulation of AGEs in epidermal keratinocytes of psoriatic lesions collected from psoriasis patients. Furthermore, AGEs promoted the proliferation of keratinocytes via upregulated Keratin 17 (K17)-mediated p27KIP1 inhibition followed by accelerated cell cycle progression. More importantly, AGEs facilitated the production of interleukin-36 alpha (IL-36α) in keratinocytes, which could enhance T helper 17 (Th17) immune response. In addition, the induction of both K17 and IL-36α by AGEs in keratinocytes was dependent on the activation of signal transducer and activator of transcription 1/3 (STAT1/3) signaling pathways. At last, the effects of AGEs on keratinocytes were mediated by the receptor for AGEs (RAGE). Taken together, these findings support that AGEs potentiate the innate immune function of keratinocytes, which contributes to the formation of psoriatic inflammation. Our study implicates AGEs as a potential pathogenic link between psoriasis and cardiometabolic comorbidities.

Influences of vitiligo-associated characteristics on the occurrence of diabetes mellitus: Interactive analysis of a cross-sectional study.

The risk of diabetes mellitus (DM) in vitiligo patients is higher than that in non-vitiligo population. Our goal was to explore the influencing factors for DM in vitiligo patients. A matched-pair design of 107 cases with DM and 428 controls without DM was conducted among vitiligo patients in Xijing hospital from January 2010 to October 2021. The baseline characteristics of patients were analysed based on standard descriptive statistics. The vitiligo-associated characteristics were analysed by logistic regression to identify influencing factors of DM. Interaction analysis was performed to explore the additive interactions between vitiligo-associated characteristics and baseline characteristics. After adjustment for the baseline characteristics, the severity of vitiligo [odds ratio (OR) = 2.47, 95% confidence interval (CI): 1.47-4.14] and onset age of vitiligo (OR = 0.98, 95% CI: 0.97-0.99) had a significant correlation with occurrence of DM. The severity of vitiligo had additive interaction with family history of diabetes [relative excess risk due to interaction (RERI) = 132.51 (95% CI: 5.51-1100.20), attributable proportion (AP) = 0.91 (95% CI: 0.17-0.95), synergy index (S) = 11.53 (95% CI: 1.32-100.5)] and with smoking history [RERI = 6.54 (95% CI: 0.67-19.83), AP = 0.64 (95% CI: 0.04-0.80), S = 3.48 (95% CI: 1.17-10.36)]. Earlier onset age of vitiligo and greater BSA involvement might be two independent risk factors for DM in vitiligo patients. Interaction assessment identified the severity of vitiligo as additive interaction factors with diabetes family history and with smoking history for the DM occurrence.

Type-II Bi2O2Se/MoTe2 van der Waals Heterostructure Photodetectors with High Gate-Modulation Photovoltaic Performance.

In recent years, two-dimensional (2D) nonlayered Bi2O2Se-based electronics and optoelectronics have drawn enormous attention owing to their high electron mobility, facile synthetic process, stability to the atmosphere, and moderate narrow band gaps. However, 2D Bi2O2Se-based photodetectors typically present large dark current, relatively slow response speed, and persistent photoconductivity effect, limiting further improvement in fast-response imaging sensors and low-consumption broadband detection. Herein, a Bi2O2Se/2H-MoTe2 van der Waals (vdWs) heterostructure obtained from the chemical vapor deposition (CVD) approach and vertical stacking is reported. The proposed type-II staggered band alignment desirable for suppression of dark current and separation of photoinduced carriers is confirmed by density functional theory (DFT) calculations, accompanied by strong interlayer coupling and efficient built-in potential at the junction. Consequently, a stable visible (405 nm) to near-infrared (1310 nm) response capability, a self-driven prominent responsivity (R) of 1.24 A·W-1, and a high specific detectivity (D*) of 3.73 × 1011 Jones under 405 nm are achieved. In particular, R, D*, fill factor, and photoelectrical conversion efficiency (PCE) can be enhanced to 4.96 A·W-1, 3.84 × 1012 Jones, 0.52, and 7.21% at Vg = -60 V through a large band offset originated from the n+-p junction. It is suggested that the present vdWs heterostructure is a promising candidate for logical integrated circuits, image sensors, and low-power consumption detection.

SIRT7 orchestrates melanoma progression by simultaneously promoting cell survival and immune evasion via UPR activation.

Melanoma is the most lethal type of skin cancer, originating from the malignant transformation of melanocyte. While the development of targeted therapy and immunotherapy has gained revolutionary advances in potentiating the therapeutic effect, the prognosis of patients with melanoma is still suboptimal. During tumor progression, melanoma frequently encounters stress from both endogenous and exogenous sources in tumor microenvironment. SIRT7 is a nuclear-localized deacetylase of which the activity is highly dependent on intracellular nicotinamide adenine dinucleotide (NAD+), with versatile biological functions in maintaining cell homeostasis. Nevertheless, whether SIRT7 regulates tumor cell biology and tumor immunology in melanoma under stressful tumor microenvironment remains elusive. Herein, we reported that SIRT7 orchestrates melanoma progression by simultaneously promoting tumor cell survival and immune evasion via the activation of unfolded protein response. We first identified that SIRT7 expression was the most significantly increased one in sirtuins family upon stress. Then, we proved that the deficiency of SIRT7 potentiated tumor cell death under stress in vitro and suppressed melanoma growth in vivo. Mechanistically, SIRT7 selectively activated the IRE1α-XBP1 axis to potentiate the pro-survival ERK signal pathway and the secretion of tumor-promoting cytokines. SIRT7 directly de-acetylated SMAD4 to antagonize the TGF-ß-SMAD4 signal, which relieved the transcriptional repression on IRE1α and induced the activation of the IRE1α-XBP1 axis. Moreover, SIRT7 up-regulation eradicated anti-tumor immunity by promoting PD-L1 expression via the IRE1α-XBP1 axis. Additionally, the synergized therapeutic effect of SIRT7 suppression and anti-PD-1 immune checkpoint blockade was also investigated. Taken together, SIRT7 can be employed as a promising target to restrain tumor growth and increase the effect of melanoma immunotherapy.

MIF inhibition alleviates vitiligo progression by suppressing CD8+ T cell activation and proliferation.

In vitiligo, autoreactive CD8+ T cells have been established as the main culprit considering its pathogenic role in mediating epidermal melanocyte-specific destruction. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule that plays a central role in various immune processes including the activation and proliferation of T cells; but whether MIF is intertwined in vitiligo development and progression and its involvement in aberrantly activated CD8+ T cells remains ill-defined. In this study, we found that MIF was overabundant in vitiligo patients and a mouse model for human vitiligo. Additionally, inhibiting MIF ameliorated the disease progression in vitiligo mice, which manifested as less infiltration of CD8+ T cells and more retention of epidermal melanocytes in the tail skin. More importantly, in vitro experiments indicated that MIF-inhibition suppressed the activation and proliferation of CD8+ T cells from the lymph nodes of vitiligo mice, and the effect extended to CD8+ T cells in peripheral blood mononuclear cells of vitiligo patients. Finally, CD8+ T cells derived from MIF-inhibited vitiligo mice also exhibited an impaired capacity for activation and proliferation. Taken together, our results show that MIF might be clinically targetable in vitiligo treatment, and its inhibition might ameliorate vitiligo progression by suppressing autoreactive CD8+ T cell activation and proliferation. © 2023 The Pathological Society of Great Britain and Ireland.

Management of the refractory vitiligo patient: current therapeutic strategies and future options.

Vitiligo is an autoimmune disease that leads to disfiguring depigmented lesions of skin and mucosa. Although effective treatments are available for vitiligo, there are still some patients with poor responses to conventional treatment. Refractory vitiligo lesions are mostly located on exposed sites such as acral sites and lips, leading to significant life stress. Understanding the causes of refractory vitiligo and developing targeted treatments are essential to enhance vitiligo outcomes. In this review, we summarized recent treatment approaches and some potential methods for refractory vitiligo. Janus kinase inhibitors have shown efficacy in refractory vitiligo. A variety of surgical interventions and fractional carbon dioxide laser have been widely applied to combination therapies. Furthermore, melanocyte regeneration and activation therapies are potentially effective strategies. Patients with refractory vitiligo should be referred to psychological monitoring and interventions to reduce the potential pathogenic effects of chronic stress. Finally, methods for depigmentation and camouflage may be beneficial in achieving uniform skin color and improved quality of life. Our ultimate focus is to provide alternative options for refractory vitiligo and to bring inspiration to future research.

Effects of visual landscape on subjective environmental evaluations in the open spaces of a severe cold city.

The environmental quality and subjective environmental evaluations in urban open spaces are essential. In this study, the effects of building, green, and water landscapes, which are typical visual landscapes, on the subjective environmental evaluations (including thermal sensation and comfort, and overall comfort) in different seasons were analyzed by conducting questionnaire surveys and field measurements in a severely cold city. It was found that the visual landscapes significantly affected subjective environmental evaluations in winter and summer, but there were no effects in the transitional season. In summer, compared with the building and green landscape, the thermal sensation vote in the water landscape was the lowest at 0.4, and the differences were 0.3∼1.0. However, the thermal comfort vote in the water landscape was found to be 0.6 times higher. In winter, the thermal sensation and comfort votes in the water landscape were the lowest, the average evaluation under different UTCI was -2.2, and the results were similar for the overall comfort evaluation. In addition, the subjects believed that green and water landscapes improved thermal comfort and had more significant effects on improving the environmental temperature in the three seasons. Additionally, visual landscape evaluations significantly affect subjective environmental evaluations in summer than in the winter and transitional season; the higher the visual landscape evaluation, the better the thermal and overall comfort.

Identification and validation of ferroptosis-related lncRNA signature as a prognostic model for skin cutaneous melanoma.

Background: Melanoma is a type of skin cancer, which originates from the malignant transformation of epidermal melanocytes, with extremely high lethality. Ferroptosis has been documented to be highly related to cancer pathogenesis and the effect of immunotherapy. In addition, the dysregulation of lncRNAs is greatly implicated in melanoma progression and ferroptosis regulation. However, the significance of ferroptosis-related lncRNA in melanoma treatment and the prognosis of melanoma patients remains elusive. Methods: Via Least Absolute Shrinkage Selection Operator (LASSO) regression analysis in the TCGA SKCM database, a cutaneous melanoma risk model was established based on differentially-expressed ferroptosis-related lncRNAs (DEfrlncRNAs). The nomogram, receiver operating characteristic (ROC) curves, and calibration plots were conducted to examine the predictive performance of this model. Sequentially, we continued to analyze the differences between the high- and low-risk groups, in terms of clinical characteristics, immune cell infiltration, immune-related functions, and chemotherapy drug sensitivity. Moreover, the expressions of DEfrlncRNAs, PD-L1, and CD8 were also examined by qRT-PCR and immunohistochemical staining in melanoma tissues to further confirm the potential clinical implication of DEfrlncRNAs in melanoma immunotherapy. Results: 16 DEfrlncRNAs were identified, and a representative risk score for patient survival was constructed based on these 16 genes. The risk score was found to be an independent prognostic factor for the survival of melanoma patients. In addition, the low-risk group of patients had higher immune cell infiltration in the melanoma lesions, higher sensitivity to chemotherapeutic agents, and a better survival prognosis. Besides, the high expression of the identified 5 DEfrlncRNA in the low-risk group might suggest a higher possibility to benefit from immune checkpoint blockade therapy in the treatment of melanoma. Conclusion: The DEfrlncRNA risk prediction model related to ferroptosis genes can independently predict the prognosis of patients with melanoma and provide a basis for evaluating the response of clinical treatment in melanoma.

Th1-like Treg in vitiligo: An incompetent regulator in immune tolerance.

Vitiligo is an autoimmune skin disease resulting from epidermal melanocyte destruction mediated by CD8+T cells that breach the self-tolerance. Regulatory T cells (Tregs) are critical for keeping the CD8+T cells in check, but the deficiency of Tregs leading to the immune disequilibrium in vitiligo remains undefined. In the present study, we used RNA-sequencing (RNA-seq) to acquire the transcriptome data of Tregs from vitiligo patients and healthy controls, respectively. Further flow cytometry analysis and immunofluorescence assays substantiated the phenotype of Th1-like Tregs in vitiligo. CD8+T cell-/vitiligo serum-Treg co-culture assays and chemotaxis assays were used to functionally examine this subset of Tregs. As a result, RNA-seq, flow cytometry, and immunofluorescence all indicated the transition of bona fide Treg to the Th1-like T-bet+IFN-γ+Treg in vitiligo patients. Besides, these Th1-like Tregs exhibited significantly dampened suppression on the proliferation and activation of CD8+T cells and a markedly higher tendency to be chemoattracted by CXCL10 and CXCL16. More interestingly, vitiligo serum could even elicit bona fide Tregs of healthy controls to adopt the Th1-like phenotype and manifest impaired suppression. To conclude, Tregs from vitiligo patients are functionally disturbed and the Th1-skewed inflammatory microenvironment in the serum of vitiligo patients is responsible for the generation of Th1-like Tregs. We provide a clinical exploitable strategy that in addition to simply replenishing the bona fide Treg or promoting the homing of Treg to the skin, the normalization of the Th1-skewed inflammatory environment in vitiligo patients and targeting the incompetent Th1-like Tregs might be critical in the future treatment of vitiligo.

Nanoparticle delivery of miR-21-3p sensitizes melanoma to anti-PD-1 immunotherapy by promoting ferroptosis.

BACKGROUND: Although anti-programmed cell death protein 1 (PD-1) immunotherapy is greatly effective in melanoma treatment, low response rate and treatment resistance significantly hinder its efficacy. Tumor cell ferroptosis triggered by interferon (IFN)-γ that is derived from tumor-infiltrating CD8+ T cells greatly contributes to the effect of immunotherapy. However, the molecular mechanism underlying IFN-γ-mediated ferroptosis and related potentially promising therapeutic strategy warrant further clarification. MicroRNAs (miRNAs) participate in ferroptosis execution and can be delivered systemically by multiple carriers, which have manifested obvious therapeutic effects on cancer. METHODS: MiRNAs expression profile in IFN-γ-driven ferroptosis was obtained by RNA sequencing. Biochemical assays were used to clarify the role of miR-21-3p in IFN-γ-driven ferroptosis and the underlying mechanism. MiR-21-3p-loaded gold nanoparticles were constructed and systemically applied to analyze the role of miR-21-3p in anti-PD-1 immunotherapy in preclinical transplanted tumor model. RESULTS: MiRNAs expression profile of melanoma cells in IFN-γ-driven ferroptosis was first obtained. Then, upregulated miR-21-3p was proved to facilitate IFN-γ-mediated ferroptosis by potentiating lipid peroxidation. miR-21-3p increased the ferroptosis sensitivity by directly targeting thioredoxin reductase 1 (TXNRD1) to enhance lipid reactive oxygen species (ROS) generation. Furthermore, miR-21-3p overexpression in tumor synergized with anti-PD-1 antibody by promoting tumor cell ferroptosis. More importantly, miR-21-3p-loaded gold nanoparticles were constructed, and the systemic delivery of them increased the efficacy of anti-PD-1 antibody without prominent side effects in preclinical mice model. Ultimately, ATF3 was found to promote miR-21-3p transcription in IFN-γ-driven ferroptosis. CONCLUSIONS: MiR-21-3 p upregulation contributes to IFN-γ-driven ferroptosis and synergizes with anti-PD-1 antibody. Nanoparticle delivery of miR-21-3 p is a promising therapeutic approach to increase immunotherapy efficacy without obvious systemic side effects.

Integrative Genomic Profiling Uncovers Therapeutic Targets of Acral Melanoma in Asian Populations.

PURPOSE: Acral melanoma is the major subtype of melanoma seen in Asian patients with melanoma and is featured by its insidious onset and poor prognosis. The genomic study that elucidates driving mutational events is fundamental to the development of gene-targeted therapy. However, research on genomic profiles of acral melanoma in Asian patients is still sparse. EXPERIMENTAL DESIGN: We carried out whole-exome sequencing (WES) on 60 acral melanoma lesions (with 55 primary samples involved), targeted deep sequencing in a validation cohort of 48 cases, RNA sequencing in 37 acral melanoma samples (all from the 60 undergoing WES), and FISH in 233 acral melanoma specimens (54 of the 60 undergoing WES included). All the specimens were derived from Asian populations. RESULTS: BRAF, NRAS, and KIT were discerned as significantly mutated genes (SMG) in acral melanoma. The detected COSMIC signature 3 related to DNA damage repair, along with the high genomic instability score, implied corresponding pathogenesis of acral melanoma. Moreover, the copy number gains of EP300 were associated with the response of acral melanoma to targeted therapy of A485 (a p300 inhibitor) and immune checkpoint blockade treatment. In addition, the temporal order in mutational processes of the samples was reconstructed, and copy-number alterations were identified as early mutational events. CONCLUSIONS: Our study provided a detailed view of genomic instability, potential therapeutic targets, and intratumoral heterogeneity of acral melanoma, which might fuel the development of personalized strategies for treating acral melanoma in Asian populations.

Oxeiptosis: a novel pathway of melanocytes death in response to oxidative stress in vitiligo.

Vitiligo is a cutaneous depigmenting autoimmune disease caused by the extensive destruction of epidermal melanocytes. Convincing data has defined a critical role for oxidative stress in the pathogenesis of vitiligo. Oxeiptosis is a caspase-independent cell death modality that was reportedly triggered by oxidative stress and operative in pathogen clearance. However, whether oxeiptosis exists in oxidative stress-induced melanocytes demise in vitiligo remains undetermined. In the present study, we initially found that other cell death modalities might exist in addition to the well-recognized apoptosis and necroptosis in H2O2-treated melanocytes. Furthermore, AIFM1 was found to be dephosphorylated at Ser116 in oxidative stress-induced melanocytes death, which was specific to oxeiptosis. Moreover, KEAP1 and PGAM5, upstream of the AIFM1 in oxeiptosis, were found to operate in melanocytic death. Subsequently, the KEAP1-PGAM5-AIFM1 signaling pathway was proved to be involved in oxidative stress-triggered melanocytes demise through the depletion of KEAP1 and PGAM5. Altogether, our study indicated that oxeiptosis might occur in melanocytes death under oxidative stress and contribute to the pathogenesis of vitiligo.

Metabolomics Signature and Potential Application of Serum Polyunsaturated Fatty Acids Metabolism in Patients With Vitiligo.

Vitiligo is a depigmented skin disorder caused by a variety of factors, including autoimmune, metabolic disturbance or their combined effect, etc. Non-targeted metabolomic analyses have denoted that dysregulated fatty acids metabolic pathways are involved in the pathogenesis of vitiligo. However, the exact category of fatty acids that participate in vitiligo development and how they functionally affect CD8+ T cells remain undefined. We aimed to determine the difference in specific fatty acids among vitiligo patients and healthy individuals and to investigate their association with clinical features in patients with vitiligo. Serum levels of fatty acids in 48 vitiligo patients and 28 healthy individuals were quantified by performing ultra-performance liquid chromatography-tandem mass spectrometry. Univariate and multivariate analyses were carried out to evaluate the significance of differences. Moreover, flow cytometry was used to explore the effect of indicated fatty acids on the function of CD8+ T cells derived from patients with vitiligo. We demonstrated that serological level of alpha-linolenic acid (ALA) was markedly upregulated, while that of arachidonic acid (ARA), arachidic acid (AA) and behenic acid were significantly downregulated in patients with vitiligo. Moreover, ALA levels were positively associated with vitiligo area scoring index (VASI) and ARA was a probable biomarker for vitiligo. We also revealed that supplementation with ARA or nordihydroguaiaretic acid (NDGA) could suppress the function of CD8+ T cells. Our results showed that vitiligo serum has disorder-specific phenotype profiles of fatty acids described by dysregulated metabolism of polyunsaturated fatty acids. Supplementation with ARA or NDGA might promote vitiligo treatment. These findings provide novel insights into vitiligo pathogenesis that might add to therapeutic options.

Mechanisms of melanocyte death in vitiligo.

Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction. The destruction of melanocyte is thought to be of multifactorial causation. Genome-wide associated studies have identified single-nucleotide polymorphisms in a panel of susceptible loci as risk factors in melanocyte death. But vitiligo onset can't be solely attributed to a susceptive genetic background. Oxidative stress triggered by elevated levels of reactive oxygen species accounts for melanocytic molecular and organelle dysfunction, a minority of melanocyte demise, and melanocyte-specific antigens exposure. Of note, the self-responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo. The aberrantly heightened innate immunity, type-1-skewed T helper, and incompetent regulatory T cells tip the balance toward autoreaction and CD8+ cytotoxic T lymphocytes finally execute the killing of melanocytes, possibly alarmed by resident memory T cells. In addition to the well-established apoptosis and necrosis, we discuss several death modalities like oxeiptosis, ferroptosis, and necroptosis that are probably employed in melanocyte destruction. This review focuses on the various mechanisms of melanocytic death in vitiligo pathogenesis to demonstrate a panorama of that. We hope to provide new insights into vitiligo pathogenesis and treatment strategies by the review.

Gut Microbial Dysbiosis and Plasma Metabolic Profile in Individuals With Vitiligo.

Autoimmune diseases are increasingly linked to aberrant gut microbiome and relevant metabolites. However, the association between vitiligo and the gut microbiome remains to be elucidated. Thus, we conducted a case-control study through 16S rRNA sequencing and serum untargeted-metabolomic profiling based on 30 vitiligo patients and 30 matched healthy controls. In vitiligo patients, the microbial composition was distinct from that of healthy controls according to the analysis on α- and ß-diversity (P < 0.05), with a characteristic decreased Bacteroidetes: Firmicutes ratio. Meanwhile, the levels of 23 serum metabolites (including taurochenodeoxycholate and L-NG-monomethyl-arginine) in the vitiligo patients were different from those in the healthy individuals and showed significant correlations with some microbial markers. We found that Corynebacterium 1, Ruminococcus 2, Jeotgalibaca and Psychrobacter were correlated significantly with disease duration and serum IL-1ß level in vitiligo patients. And Psychrobacter was identified as the most predictive features for vitiligo by machine learning analysis ("importance" = 0.0236). Finally, combining multi-omics data and joint prediction models with accuracies up to 0.929 were established with dominant contribution of Corynebacterium 1 and Psychrobacter. Our findings replenished the previously unknown relationship between gut dysbiosis and vitiligo circulating metabolome and enrolled the gut-skin axis into the understanding of vitiligo pathogenesis.