Large language multimodal models for new-onset type 2 diabetes prediction using five-year cohort electronic health records.

Type 2 diabetes mellitus (T2DM) is a prevalent health challenge faced by countries worldwide. In this study, we propose a novel large language multimodal models (LLMMs) framework incorporating multimodal data from clinical notes and laboratory results for diabetes risk prediction. We collected five years of electronic health records (EHRs) dating from 2017 to 2021 from a Taiwan hospital database. This dataset included 1,420,596 clinical notes, 387,392 laboratory results, and more than 1505 laboratory test items. Our method combined a text embedding encoder and multi-head attention layer to learn laboratory values, and utilized a deep neural network (DNN) module to merge blood features with chronic disease semantics into a latent space. In our experiments, we observed that integrating clinical notes with predictions based on textual laboratory values significantly enhanced the predictive capability of the unimodal model in the early detection of T2DM. Moreover, we achieved an area greater than 0.70 under the receiver operating characteristic curve (AUC) for new-onset T2DM prediction, demonstrating the effectiveness of leveraging textual laboratory data for training and inference in LLMs and improving the accuracy of new-onset diabetes prediction.

3D-hUMSCs Exosomes Ameliorate Vitiligo by Simultaneously Potentiating Treg Cells-Mediated Immunosuppression and Suppressing Oxidative Stress-Induced Melanocyte Damage.

Vitiligo is an autoimmune disease characterized by epidermal melanocyte destruction, with abnormal autoimmune responses and excessive oxidative stress as two cardinal mechanisms. Human umbilical mesenchymal stem cells-derived exosomes (hUMSCs-Exos) are regarded as promising therapeutic choice for autoimmune diseases due to potent immunosuppressive and anti-oxidative properties, which can be potentiated under 3D cell culture condition. Nevertheless, whether exosomes derived from 3D spheroids of hUMSCs (3D-Exos) exhibit considerable therapeutic effect on vitiligo and the underlying mechanism remain elusive. In this study, systemic administration of 3D-Exos showed a remarkable effect in treating mice with vitiligo, as revealed by ameliorated skin depigmentation, less CD8+T cells infiltration, and expanded Treg cells in skin, and 3D-Exos exerted a better effect than 2D-Exos. Mechanistically, 3D-Exos can prominently facilitate the expansion of Treg cells in vitiligo lesion and suppress H2O2-induced melanocytes apoptosis. Forward miRNA profile analysis and molecular experiments have demonstrated that miR-132-3p and miR-125b-5p enriched in 3D-Exos greatly contributed to these biological effects by targeting Sirt1 and Bak1 respectively. In aggregate, 3D-Exos can efficiently ameliorate vitiligo by simultaneously potentiating Treg cells-mediated immunosuppression and suppressing oxidative stress-induced melanocyte damage via the delivery of miR-132-3p and miR-125b-5p. The employment of 3D-Exos will be a promising treament for vitiligo.

Bioinspired polydopamine nanoparticles as efficient antioxidative and anti-inflammatory enhancers against UV-induced skin damage.

Excessive and prolonged ultraviolet radiation (UVR) exposure causes photodamage, photoaging, and photocarcinogenesis in human skin. Therefore, safe and effective sun protection is one of the most fundamental requirements. Living organisms tend to evolve various natural photoprotective mechanisms to avoid photodamage. Among them, melanin is the main functional component of the photoprotective system of human skin. Polydopamine (PDA) is synthesized as a mimic of natural melanin, however, its photoprotective efficiency and mechanism in protecting against skin damage and photoaging remain unclear. In this study, the novel sunscreen products based on melanin-inspired PDA nanoparticles (NPs) are rationally designed and prepared. We validate that PDA NPs sunscreen exhibits superior effects on photoprotection, which is achieved by the obstruction of epidermal hyperplasia, protection of the skin barrier, and resolution of inflammation. In addition, we find that PDA NPs are efficiently intake by keratinocytes, exhibiting robust ROS scavenging and DNA protection ability with minimal cytotoxicity. Intriguingly, PDA sunscreen has an influence on maintaining homeostasis of the dermis, displaying an anti-photoaging property. Taken together, the biocompatibility and full photoprotective properties of PDA sunscreen display superior performance to those of commercial sunscreen. This work provides new insights into the development of a melanin-mimicking material for sunscreens.

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.

A population-based cohort study for presence of ulceration among cutaneous malignant melanoma subgroups of patients.

Background: Observational studies suggest that ulceration is considered to be a negative prognostic factor for cutaneous melanoma. However, the impact of ulceration over different subgroups (e.g. AJCC Stage, thickness level) are controversial and its true causal effect on survival is lack of studies in the view of treating ulceration as an exposure. Objective: To explore the true causal effect of ulceration on melanoma's survival by adopting a combination of methods to discover proper adjustment set and confirming its correctness through a variety of means. Methods: A minimal sufficient adjustment set (MSAS) was found using directed acyclic graphs (DAG) to adjust the effect of causality. Sensitivity analysis was conducted to diagnose potential confounders in addition to MSAS. Cox models were built to analyze the causality in-depth and the model was validated using a novel method. Lastly, stratified effects of ulceration were examined to illustrate its impact within subgroups. Results: Hazard ratio (HR) of ulceration after adjustment by MSAS variables was 1.99 (95% CI=1.88-2.09). The sensitivity analysis of propensity score matching and E-value both demonstrated that variables other than MSAS do not have great influence on ulceration and MSS relationship. The HR of ulceration in AJCC Stage, thickness level, invasion level and tumor extension were all monotonically decreased from 5.76 to 1.57, 4.03 to 1.78, 2.75 to 1.78 and 2.65 to 1.71 respectively. Conclusion: Ulceration in all subgroups were shown to have a significantly negative impact on MSS and its magnitude of effect was monotonically decreased as the disease progressed. The true effect of ulceration can be adjusted by MSAS and its correctness was validated through a variety of approaches.

Treatment of Cutaneous Balamuthia mandrillaris Infection With Diminazene Aceturate: A Report of 4 Cases.

Four cases of cutaneous Balamuthia mandrillaris infection were treated with diminazene aceturate. One patient was cured with mainly monotherapy, 2 patients were cured with diminazene aceturate and excision, and 1 patient died of drug-induced liver damage. This is the first report of B. mandrillaris infection treated with diminazene aceturate.

NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation induced skin injury.

Oxidative stress and lipid peroxidation are major causes of skin injury induced by ultraviolet (UV) irradiation. Ferroptosis is a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids and contributes to kinds of tissue injuries. However, it remains unclear whether the accumulation of lipid peroxides in UV irradiation-induced skin injury could lead to ferroptosis. We generated UV irradiation-induced skin injury mice model to examine the accumulation of the lipid peroxides and iron. Lipid peroxides 4-HNE, the oxidative enzyme COX2, the oxidative DNA damage biomarker 8-OHdG, and the iron level were increased in UV irradiation-induced skin. The accumulation of iron and lipid peroxidation was also observed in UVB-irradiated epidermal keratinocytes without actual ongoing ferroptotic cell death. Ferroptosis was triggered in UV-irradiated keratinocytes stimulated with ferric ammonium citrate (FAC) to mimic the iron overload. Although GPX4 protected UVB-injured keratinocytes against ferroptotic cell death resulted from dysregulation of iron metabolism and the subsequent increase of lipid ROS, keratinocytes enduring constant UVB treatment were markedly sensitized to ferroptosis. Nicotinamide mononucleotide (NMN) which is a direct and potent NAD+ precursor supplement, rescued the imbalanced NAD+/NADH ratio, recruited the production of GSH and promoted resistance to lipid peroxidation in a GPX4-dependent manner. Taken together, our data suggest that NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation-induced skin injury and inhibits oxidative skin damage. NMN or ferroptosis inhibitor might become promising therapeutic approaches for treating oxidative stress-induced skin diseases or disorders.

Artificial intelligence modelling in differentiating core biopsies of fibroadenoma from phyllodes tumor.

Breast fibroepithelial lesions (FEL) are biphasic tumors which consist of benign fibroadenomas (FAs) and the rarer phyllodes tumors (PTs). FAs and PTs have overlapping features, but have different clinical management, which makes correct core biopsy diagnosis important. This study used whole-slide images (WSIs) of 187 FA and 100 PT core biopsies, to investigate the potential role of artificial intelligence (AI) in FEL diagnosis. A total of 9228 FA patches and 6443 PT patches was generated from WSIs of the training subset, with each patch being 224 × 224 pixel in size. Our model employed a two-stage architecture comprising a convolutional neural network (CNN) component for feature extraction from the patches, and a recurrent neural network (RNN) component for whole-slide classification using activation values from the global average pooling layer in the CNN model. It achieved an overall slide-level accuracy of 87.5%, with accuracies of 80% and 95% for FA and PT slides respectively. This affirms the potential role of AI in diagnostic discrimination between FA and PT on core biopsies which may be further refined for use in routine practice.

HSF1-Dependent Autophagy Activation Contributes to the Survival of Melanocytes Under Oxidative Stress in Vitiligo.

Autophagy plays a protective role in oxidative stress‒induced melanocyte death. Dysregulated autophagy increases the sensitivity of melanocytes in response to oxidative damage and promotes melanocyte degeneration in vitiligo. However, the molecular mechanism underlying this process is not fully understood. In this study, using RNA-sequencing technology, we compared the transcriptome change between normal and vitiligo melanocytes with or without treatment of oxidative stress. We found that ATG5 and ATG12, the critical components for autophagosome formation, were significantly reduced in vitiligo melanocytes under oxidative stress. Mechanistically, HSF1 is the prime transcription factor for both ATG5 and ATG12, accounting for the reduced level of ATG5 and ATG12 in vitiligo melanocytes. Deficiency of HSF1 led to accumulation of intracellular ROS, imbalance of mitochondrion membrane potential, and apoptosis in melanocytes exposure to oxidative stress. Furthermore, overexpression of HSF1 could ameliorate oxidative stress‒induced melanocytes death through the activation of autophagy by upregulating ATG5 and ATG12. These findings suggested that targeting HSF1-ATG5/12 axis could prevent oxidative stress‒induced melanocyte death and may be used as a therapeutic strategy for vitiligo treatment.

The Formation of Melanocyte Apoptotic Bodies in Vitiligo and the Relocation of Vitiligo Autoantigens under Oxidative Stress.

BACKGROUND: Oxidative stress has a vital role in the early stages of vitiligo. Autoantigens released from apoptotic melanocytes (MC) under oxidative stress are involved in the presentation and recognition of antigens. However, the transport of autoantigens to the cell surface and their release to the extracellular environment are still unclear. Apoptotic bodies (ABs) have always been considered as a key source of immunomodulators and autoantigens. Yet, the role of ABs in the immune mechanism of vitiligo is still unknown. PURPOSE: To explore whether MC's autoantigens translocate into ABs during oxidative stress-induced apoptosis and study the molecular mechanisms underlying autoantigen migration and AB formation. METHODS: PIG3V (an immortalized human vitiligo melanocyte cell line) were treated with H2O2, and ABs were separated. Transmission electron microscopy, flow cytometry, Western blot, mass spectrometry, and other methods were used to determine the relocation of specific antigens in PIG3V cells to ABs. After pretreatment with specific inhibitors (Rho kinase (Y-27632), myosin light chain kinase (MLCK, ML-9), pan-caspase (zVAD-FMK), and JNK (SP600125)), the pathway of autoantigen translocation into ABs and the formation of apoptotic bodies were determined. RESULTS: When treated with 0.8 mM H2O2, ABs were released from these cells. Autoantigens such as tyrosinase-related protein 1 (TYRP-1) and cleavage nuclear membrane antigen Lamin A/C (Asp230) were concentrated in ABs. The expression of autoantigens and the formation of ABs increased in a time- and dose-dependent manner after treatment with H2O2, while the application of specific inhibitors inhibited the formation of apoptotic bodies, i.e., the expression of antigens. CONCLUSION: Vitiligo autoantigens translocate into ABs in the process of apoptosis induced by oxidative stress. The cytoskeletal protein activation pathway and the JNK-related apoptosis pathway are involved in the transport of autoantigens and the formation of ABs. ABs may be the key bridge between MC cell apoptosis and cellular immunity.

A randomized, split-face controlled trial on the safety and effects of microneedle fractional radiofrequency and fractional erbium-doped glass 1,565-nm laser therapies for baggy lower eyelids.

The non-ablative fractional erbium-doped glass 1,565-nm laser (NAFL) and the microneedle fractional radiofrequency (MFR) procedures are effective treatments that enable periorbital skin rejuvenation. To compare the clinical effectiveness and side effects of MFR and the NAFL for baggy lower eyelids (BLEs) in the Chinese population. Fifteen Chinese subjects with BLEs received three split-face treatments on a monthly basis randomly. Objective and subjective assessments were performed at baseline, as well as 1 month and 3 months after the third treatment. The results were evaluated using Antera-3D and CineScan systems. Blinded investigator assessments were performed by two plastic surgeons using a 0 to 4 score in six anatomic categories of BLEs. The patients also reported their level of satisfaction based on a four-point score. Most of the patients reported a greater than 47% satisfaction rate with both treatments. The cumulative contribution scores of prolapse of orbital fat, hollow tear trough, and skin laxity for each category variable declined with time. Using Antera 3D, the volume of elevation (mm3) decreased from 0.6 ± 0.4 to 0.4 ± 0.3 and from 0.6 ± 0.3 to 0.3 ± 0.3, the elevation area (mm2) decreased from 17.0 ± 8.4 to 13.0 ± 7.1 and from 17.0 ± 7.8 to 10.0 ± 5.6, and the maximum peak height (mm) also decreased from 0.10 ± 0.04 to 0.06 ± 0.04 and from 0.10 ± 0.03 to 0.06 ± 0.02 in the MFR and NAFL groups, respectively. Using CineScan, the depth of middle orbital fat (mm) decreased significantly from 10.2 ± 2.2 to 8.0 ± 0.7 and from 9.8 ± 1.1 to 8.0 ± 0.9 and the length of orbital fat significantly decreased from 9.2 ± 1.2 to 7.7 ± 0.7 and from 9.7 ± 1.4 to 7.8 ± 0.6 in the MFR and NAFL groups, respectively. MFR and NAFL therapies were effective for the treatment of BLEs, especially in BLE patients with skin elasticity in addition to tear trough deformity and orbital fat prolapse. TRIAL REGISTRATION NUMBER: NCT04237324. TRIAL REGISTER: ClinicalTrials.gov. LEVEL OF EVIDENCE: Level I, therapeutic study.

Fractional microneedle radiofrequency device and fractional erbium-doped glass 1,565-nm device treatment of human facial photoaging: a prospective, split-face, random clinical trial.

Microneedle fractional radiofrequency (MFR) and non-ablative 1565 nm fractional laser (NAFL) have recently been introduced as new techniques to address the growing concern of facial photoaging. In this prospective randomized split-face study, we wanted to compare the safety and efficacy of MFR with that of NAFL for the treatment of facial photoaging in Asian patients. Fifteen healthy Chinese patients were enrolled for this randomized split-face study. Each patient underwent three sessions of treatment with MFR and NAFL on opposite sides of their face, one month apart. A blinded outcome assessment of the photoaging severity was performed by two independent plastic surgeons on a 5-point visual analogue scale (VAS, 0-4). Patient satisfaction was also scored based on a 5-point VAS (0 = dissatisfaction, 4 = extremely satisfied). Sagging of the nasolabial groove was evaluated using the Antera 3D camera, facial wrinkles and pores using the VISIA skin analysis system. Any adverse events that occurred during the study were also evaluated. Based on the VAS scores and results from the Antera 3D and VISIA, it was noted that there was a significant improvement in facial skin laxity, wrinkles, and pores, and lesser sagging of the nasolabial groove on both the MFR and NAFL sides of the face, compared with that of the baseline. Most patients were satisfied with the treatment and reported tolerable pain and crusting. Although no significant differences were observed between the MFR and NAFL treatments, the NAFL treatment resulted in a shorter downtime(4.56 ± 2.72d) than the MFR treatment(6.96 ± 3.27d). This study confirms the efficacy of MFR and NAFL treatments for facial skin rejuvenation in Asian patients. Furthermore, the therapies were found to be safe and well-tolerated. Our findings suggest that NAFL may be a more convenient treatment modality for facial photoaging because of its shorter downtime. However, sagging of the nasolabial groove was more improved by the MFR treatment than by the NAFL treatment.

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.

Balamuthia mandrillaris infection in China: a retrospective report of 28 cases.

Balamuthia mandrillaris infection is a rare and fatal disease. We have recorded 28 cases of Balamuthia mandrillaris infection during the past 20 years. Eighteen patients (64%) were male and 10 (36%) were female. Patient age ranged from 3 to 74 (mean, 27) years. Patient locations were distributed among 12 Provinces in China. Twenty-seven (96%) patients lived in rural areas, and 17 (61%) patients reported a history of trauma before the appearance of skin lesions. All cases presented with skin lesions as the primary symptom, and 16 (57%) cases developed encephalitis. Histopathology of skin lesions revealed granulomatous changes with histiocytes, lymphocytes, and plasma cells infiltration. Amebas were identified in all cases with immunohistochemical staining. Follow-up information was available in 27 (96%) cases. Fifteen (56%) patients died due to encephalitis and 12 (44%) were free of disease after treatment. Our results show that the clinical characteristics of Balamuthia mandrillaris infection in China are very different from those in the US. Infection of traumatized skin may play an important role in the pathogenesis of the disease in China. Encephalitis usually develops 3-4 years after skin lesions in Chinese cases. Patients with only skin lesions have a higher cure rate than patients with encephalitis.

MSC-derived exosomes protect against oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system.

Oxidative stress is a major cause of skin injury induced by damaging stimuli such as UV radiation. Currently, owing to their immunomodulatory properties, mesenchymal stem cell-derived exosomes (MSC-Exo), as a nanotherapeutic agent, have attracted considerable attention. Here, we investigated the therapeutic effects of MSC-Exo on oxidative injury in H2O2-stimulated epidermal keratinocytes and UV-irradiated wild type and nuclear factor-erythroid 2-related factor-2 (Nrf2) knocked down cell and animal models. Our findings showed that MSC-Exo treatment reduced reactive oxygen species generation, DNA damage, aberrant calcium signaling, and mitochondrial changes in H2O2-stimulated keratinocytes or UV-irradiated mice skin. Exosome therapy also improved antioxidant capacities shown by increased ferric ion reducing antioxidant power and glutathione peroxidase or superoxide dismutase activities in oxidative stress-induced cell and skin injury. In addition, it alleviated cellular and histological responses to inflammation and oxidation in cell or animal models. Furthermore, the NRF2 signaling pathway was involved in the antioxidation activity of MSC-Exo, while Nrf2 knockdown attenuated the antioxidant capacities of MSC-Exo in vitro and in vivo, suggesting that these effects are partially mediated by the NRF2 signaling pathway. These results indicate that MSC-Exo can repair oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system. Thus, MSC-Exo may be used as a potential dermatological nanotherapeutic agent for treating oxidative stress-induced skin diseases or disorders.

Tranilast Directly Targets NLRP3 to Protect Melanocytes From Keratinocyte-Derived IL-1ß Under Oxidative Stress.

The activation of NLRP3 inflammasome-IL-1ß pathway in keratinocytes contributes to the melanocyte death via autoimmunity-dependent manner in vitiligo. As a safe small-compound drug employed frequently in clinic, tranilast (TR) is newly reported to block the activation of NLRP3 inflammasome in macrophage. Nevertheless, whether keratinocyte-derived IL-1ß damages melanocytes in an autoimmunity-independent way and whether TR could ameliorate the melanocyte damage via inhibiting the NLRP3-IL-1ß pathway in keratinocyte still are not clear. In the present study, we initially found that TR could impede the secretion of IL-1ß from keratinocytes by interfering the NLRP3 oligomerization. More importantly, we illustrated that TR could decrease the melanocyte apoptosis, improve the melanogenesis, and have the capacity to optimize the melanosome translocation by abolishing the keratinocyte-derived IL-1ß. Additionally, TR could mitigate the secretion of inflammatory cytokines such as IL-6, IL-8, TNF-α, and IL-18 in keratinocytes under oxidative stress. In short, our data indicate that IL-1ß plays detrimental roles in the melanocyte survival, melanogenesis, melanosome translocation and the secretion of inflammatory cytokines, and TR could be a promising therapeutic strategy in vitiligo by attenuating the keratinocyte-derived IL-1ß under oxidative stress.

Intracellular virus sensor MDA5 exacerbates vitiligo by inducing the secretion of chemokines in keratinocytes under virus invasion.

Vitiligo is a disfiguring disease featuring chemokines-mediated cutaneous infiltration of autoreactive CD8+ T cells that kill melanocytes. Copious studies have indicated that virus invasion participates in the pathogenesis of vitiligo. IFIH1, encoding MDA5 which is an intracellular virus sensor, has been identified as a vitiligo susceptibility gene. However, the specific role of MDA5 in melanocyte death under virus invasion is not clear. In this study, we first showed that the expression of anti-CMV IgM and MDA5 was higher in vitiligo patients than healthy controls. Then, by using Poly(I:C) to imitate virus invasion, we clarified that virus invasion significantly activated MDA5 and further potentiated the keratinocyte-derived CXCL10 and CXCL16 which are the two vital chemokines for the cutaneous infiltration of CD8+ T cells in vitiligo. More importantly, IFN-ß mediated by the MDA5-MAVS-NF-κB/IRF3 signaling pathway orchestrated the secretion of CXCL10 via the JAK1-STAT1 pathway and MDA5-meidiated IRF3 transcriptionally induced the production of CXCL16 in keratinocytes under virus invasion. In summary, our results demonstrate that MDA5 signaling orchestrates the aberrant skin immunity engaging in melanocyte death via mediating CXCL10 and CXCL16 secretion, which supports MDA5 as a potential therapeutic target for vitiligo under virus invasion.

Homocysteine induces melanocytes apoptosis via PERK-eIF2α-CHOP pathway in vitiligo.

Vitiligo is a depigmentation disorder that develops as a result of the progressive disappearance of epidermal melanocytes. The elevated level of amino acid metabolite homocysteine (Hcy) has been identified as circulating marker of oxidative stress and known as a risk factor for vitiligo. However, the mechanism underlying Hcy-regulated melanocytic destruction is currently unknown. The present study aims to elucidate the effect of Hcy on melanocytic destruction and its involvement in the pathogenesis of vitiligo. Our results showed that Hcy level was significantly elevated in the serum of progressive vitiligo patients. Notably, Hcy induced cell apoptosis in melanocytes via activating reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress protein kinase RNA-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. More importantly, folic acid, functioning in the transformation of Hcy, could lower the intracellular Hcy level and further reverse the apoptotic effect of Hcy on melanocytes. Additionally, Hcy disrupted melanogenesis whereas folic acid supplementation could reverse the melanogenesis defect induced by Hcy in melanocytes. Taken together, Hcy is highly increased in vitiligo patients at progressive stage, and our in vitro studies revealed that folic acid could protect melanocytes from Hcy-induced apoptosis and melanin synthesis inhibition, indicating folic acid as a potential benefit agent for patients with progressive vitiligo.

Activated NLR family pyrin domain containing 3 (NLRP3) inflammasome in keratinocytes promotes cutaneous T-cell response in patients with vitiligo.

BACKGROUND: Keratinocytes can function as innate immune cells under oxidative stress and aggravate the cutaneous T-cell response that undermines melanocytes in the setting of vitiligo. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a regulator of innate immunity that exists in keratinocytes. However, the role of the NLRP3 inflammasome in the pathogenesis of vitiligo has not been investigated. OBJECTIVE: We sought to explicate the contribution of the activated NLRP3 inflammasome in keratinocytes to the autoimmune response in patients with vitiligo. METHODS: Perilesional and serum samples from patients with vitiligo were collected to examine the status of the NLRP3 inflammasome in the setting of vitiligo. Cultured keratinocytes were treated with H2O2 to investigate the mechanism for NLRP3 inflammasome activation under oxidative stress. Peripheral blood T cells were extracted from patients with vitiligo to explore the influence of the NLRP3 inflammasome on the T-cell response in patients with vitiligo. RESULTS: Expressions of NLRP3 and downstream cytokine IL-1ß were consistently increased in perilesional keratinocytes of patients with vitiligo. Notably, serum IL-1ß levels were increased in patients with vitiligo, correlated with disease activity and severity, and decreased after effective therapy. Furthermore, oxidative stress promoted NLRP3 inflammasome activation in keratinocytes through transient receptor potential cation channel subfamily M member 2 (TRPM2), a redox-sensitive cation channel, which was dependent on TRPM2-mediated calcium influx. More importantly, blocking TRPM2-induced NLRP3 inflammasome activation in keratinocytes impaired chemotaxis for CD8+ T cells and inhibited the production of cytokines in T cells in patients with vitiligo. CONCLUSION: Oxidative stress-induced NLRP3 inflammasome activation in keratinocytes promotes the cutaneous T-cell response, which could be targeted for the treatment of vitiligo.