Publications by authors named "Zhe Jian"

47 Publications

Treatment of cutaneous Balamuthia mandrillaris infection with diminazene aceturate: a report of 4 cases.

Clin Infect Dis 2022 May 6. Epub 2022 May 6.

Department of Dermatology, Xijing Hospital, the Fourth Military Medical University, No. 127 of Changlexi Road, Xian 710032, China.

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 Balamuthia mandrillaris infection treated with diminazene aceturate.
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http://dx.doi.org/10.1093/cid/ciac356DOI Listing
May 2022

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.

J Cosmet Laser Ther 2021 Aug 27;23(5-6):142-148. Epub 2022 Jan 27.

Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.

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.
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http://dx.doi.org/10.1080/14764172.2022.2033783DOI Listing
August 2021

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.

J Cosmet Laser Ther 2021 Aug 23;23(5-6):105-112. Epub 2021 Nov 23.

Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, SN, China.

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 (mm) 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 (mm) 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.
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http://dx.doi.org/10.1080/14764172.2021.2001532DOI Listing
August 2021

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

J Invest Dermatol 2022 Jun 13;142(6):1659-1669.e4. Epub 2021 Nov 13.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jid.2021.11.007DOI Listing
June 2022

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

Oxid Med Cell Longev 2021 28;2021:7617839. Epub 2021 Oct 28.

Department of Dermatology, Air Force Medical Center, PLA, Beijing, China 100142.

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 HO, 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 HO, 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 HO, 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.
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http://dx.doi.org/10.1155/2021/7617839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568525PMC
February 2022

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

Biochim Biophys Acta Mol Basis Dis 2022 01 6;1868(1):166287. Epub 2021 Oct 6.

National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bbadis.2021.166287DOI Listing
January 2022

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

Front Microbiol 2020 14;11:592248. Epub 2020 Dec 14.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

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 β-diversity ( < 0.05), with a characteristic decreased 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 , , and were correlated significantly with disease duration and serum IL-1β level in vitiligo patients. And 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 and . 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.
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http://dx.doi.org/10.3389/fmicb.2020.592248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768019PMC
December 2020

infection in China: a retrospective report of 28 cases.

Emerg Microbes Infect 2020 Dec;9(1):2348-2357

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xian, People's Republic of China.

infection is a rare and fatal disease. We have recorded 28 cases of 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 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.
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http://dx.doi.org/10.1080/22221751.2020.1835447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599003PMC
December 2020

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

Biomaterials 2020 10 28;257:120264. Epub 2020 Jul 28.

Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, PR China. Electronic address:

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 HO-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 HO-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.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120264DOI Listing
October 2020

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

Front Cell Dev Biol 2020 10;8:588. Epub 2020 Jul 10.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

The activation of NLRP3 inflammasome-IL-1β 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-1β damages melanocytes in an autoimmunity-independent way and whether TR could ameliorate the melanocyte damage via inhibiting the NLRP3-IL-1β pathway in keratinocyte still are not clear. In the present study, we initially found that TR could impede the secretion of IL-1β 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-1β. 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-1β 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-1β under oxidative stress.
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http://dx.doi.org/10.3389/fcell.2020.00588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365842PMC
July 2020

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

Cell Death Dis 2020 06 12;11(6):453. Epub 2020 Jun 12.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, No 127 of West Changle Road, Xi'an, Shaanxi, 710032, China.

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-β 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.
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http://dx.doi.org/10.1038/s41419-020-2665-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293308PMC
June 2020

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

Clin Sci (Lond) 2020 05;134(10):1127-1141

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, No. 127 of West Changle Road, Xi'an 710032, Shaanxi, China.

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.
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http://dx.doi.org/10.1042/CS20200218DOI Listing
May 2020

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

J Allergy Clin Immunol 2020 02 19;145(2):632-645. Epub 2019 Nov 19.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address:

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 HO 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-1β were consistently increased in perilesional keratinocytes of patients with vitiligo. Notably, serum IL-1β 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.
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http://dx.doi.org/10.1016/j.jaci.2019.10.036DOI Listing
February 2020

Role of the aryl hydrocarbon receptor signaling pathway in promoting mitochondrial biogenesis against oxidative damage in human melanocytes.

J Dermatol Sci 2019 Oct 6;96(1):33-41. Epub 2019 Sep 6.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, Shaanxi 710032, China. Electronic address:

Background: Reactive oxygen species (ROS)-induced mitochondrial damage aggravates oxidative stress and activates mitochondrial apoptosis pathway to mediate melanocyte death. However, the repair mechanisms underlying damaged mitochondria of melanocytes remain unclear. Accumulative evidence has revealed that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a vital role in maintaining mitochondrial homeostasis.

Objective: To investigate whether the AHR signaling pathway could protect human melanocytes from oxidative damage through controlling mitochondrial quality.

Methods: We constructed an oxidative stress model of melanocytes with hydrogen peroxide (HO) in the human normal melanocyte PIG1 cell line, and detected ROS level, apoptosis, mitochondrial ROS level, mitochondrial membrane potential, ATP production, mitochondrial DNA and mitochondrial modulators after co-treatment with AHR ligand or antagonist and HO in the PIG1 cells.

Results: In the present study, we found that HO-induced oxidative stress directly activated the AHR signaling pathway in melanocytes, whereas abnormal activation of AHR signaling pathway enhanced oxidative damage to mitochondria and melanocytes. Further studies showed that the AHR signaling pathway promoted mitochondrial DNA synthesis and ATP production probably by regulating the expression of nuclear respiratory factor 1 (NRF1) and its downstream targets.

Conclusion: Our findings reveal that the AHR signaling pathway might have a major role in protecting melanocytes against oxidative damage via inducing mitochondrial biogenesis, while impaired AHR activation could cause defective repair of mitochondria and exacerbate oxidative damage-induced apoptosis in melanocytes. Our data suggest that the AHR signaling pathway might be a novel mechanism of mitochondrial biogenesis involved in protecting melanocytes from oxidative stress.
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http://dx.doi.org/10.1016/j.jdermsci.2019.09.001DOI Listing
October 2019

Ginkgo biloba extract protects human melanocytes from H O -induced oxidative stress by activating Nrf2.

J Cell Mol Med 2019 08 31;23(8):5193-5199. Epub 2019 May 31.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Vitiligo is a common skin depigmenting disorder characterized by the loss of functional melanocytes. Its pathogenesis is complicated and oxidative stress plays a critical role in the development of vitiligo. Thus, antioxidant therapy is a promising therapeutic strategy to prevent or even reverse the progression of depigmentation. Ginkgo biloba extract EGb761 has been confirmed to have protective effects on neurons against oxidative stress. Notably, several clinical trials have shown that patients with stable vitiligo achieved repigmentation after taking EGb761. However, the exact mechanism underlying the protective effects of EGb761 on melanocytes against oxidative stress has not been fully elucidated. In the present study, we found that EGb761 effectively protected melanocytes against oxidative stress-induced apoptosis and alleviated the excessive accumulation of reactive oxygen species (ROS) and lipid peroxidation by enhancing the activity of antioxidative enzymes. Furthermore, the antioxidative effect of EGb761 was achieved by activating Nrf2 and its downstream antioxidative genes. In addition, interfering Nrf2 with siRNA abolished the protective effects of EGb761 on melanocytes against oxidative damage. In conclusion, our study proves that EGb761 could protect melanocytes from H O -induced oxidative stress by activating Nrf2. Therefore, EGb761 is supposed to be a potential therapeutic agent for vitiligo.
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http://dx.doi.org/10.1111/jcmm.14393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653340PMC
August 2019

Development of a Consumer Health Vocabulary by Mining Health Forum Texts Based on Word Embedding: Semiautomatic Approach.

JMIR Med Inform 2019 May 23;7(2):e12704. Epub 2019 May 23.

Center for Medical Informatics, Peking University, Beijing, China.

Background: The vocabulary gap between consumers and professionals in the medical domain hinders information seeking and communication. Consumer health vocabularies have been developed to aid such informatics applications. This purpose is best served if the vocabulary evolves with consumers' language.

Objective: Our objective is to develop a method for identifying and adding new terms to consumer health vocabularies, so that it can keep up with the constantly evolving medical knowledge and language use.

Methods: In this paper, we propose a consumer health term-finding framework based on a distributed word vector space model. We first learned word vectors from a large-scale text corpus and then adopted a supervised method with existing consumer health vocabularies for learning vector representation of words, which can provide additional supervised fine tuning after unsupervised word embedding learning. With a fine-tuned word vector space, we identified pairs of professional terms and their consumer variants by their semantic distance in the vector space. A subsequent manual review of the extracted and labeled pairs of entities was conducted to validate the results generated by the proposed approach. The results were evaluated using mean reciprocal rank (MRR).

Results: Manual evaluation showed that it is feasible to identify alternative medical concepts by using professional or consumer concepts as queries in the word vector space without fine tuning, but the results are more promising in the final fine-tuned word vector space. The MRR values indicated that on an average, a professional or consumer concept is about 14th closest to its counterpart in the word vector space without fine tuning, and the MRR in the final fine-tuned word vector space is 8. Furthermore, the results demonstrate that our method can collect abbreviations and common typos frequently used by consumers.

Conclusions: By integrating a large amount of text information and existing consumer health vocabularies, our method outperformed several baseline ranking methods and is effective for generating a list of candidate terms for human review during consumer health vocabulary development.
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http://dx.doi.org/10.2196/12704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552449PMC
May 2019

Oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to CD8 T cells activation via JAK-STAT pathway in vitiligo.

Free Radic Biol Med 2019 08 10;139:80-91. Epub 2019 May 10.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address:

Oxidative stress and effector memory CD8 T cells have been greatly implicated in vitiligo pathogenesis. However, the crosstalk between these two crucial pathogenic factors has been merely investigated. IL-15 has been regarded as an important cytokine exerting its facilitative effect on memory CD8 T cells function in various autoimmune diseases. In the present study, we initially discovered that the IL-15 expression was significantly increased in vitiligo epidermis and highly associated with epidermal HO content. In addition, epidermal IL-15 expression was mainly derived from keratinocytes. Then, we showed that oxidative stress promoted IL-15 and IL-15Rα expression as well as IL-15 trans-presentation by activating NF-κB signaling in keratinocytes. What's more, the trans-presented IL-15, rather than the secreted one, was accounted for the potentiation of CD8 T activation. We further investigated the mechanism underlying trans-presented IL-15 in potentiating CD8 T activation and found that the blockage of IL-15-JAK-STAT signaling could be a potent therapeutic approach. Taken together, our results demonstrate that oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to the activation of CD8 T, providing a novel mechanism by which oxidative stress initiates autoimmunity in vitiligo.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.05.011DOI Listing
August 2019

SIRT3-Dependent Mitochondrial Dynamics Remodeling Contributes to Oxidative Stress-Induced Melanocyte Degeneration in Vitiligo.

Theranostics 2019 28;9(6):1614-1633. Epub 2019 Feb 28.

Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi'an, Shannxi, China.

Mitochondrial dysregulation has been implicated in oxidative stress-induced melanocyte destruction in vitiligo. However, the molecular mechanism underlying this process is merely investigated. Given the prominent role of nicotinamide adenine dinucleotide (NAD)-dependent deacetylase Sirtuin3 (SIRT3) in sustaining mitochondrial dynamics and homeostasis and that SIRT3 expression and activity can be influenced by oxidative stress-related signaling, we wondered whether SIRT3 could play an important role in vitiligo melanocyte degeneration by regulating mitochondrial dynamics. We initially testified SIRT3 expression and activity in normal and vitiligo melanocytes via PCR, immunoblotting and immunofluorescence assays. Then, cell apoptosis, mitochondrial function and mitochondrial dynamics after SIRT3 intervention were analyzed by flow cytometry, immunoblotting, confocal laser microscopy, transmission electron microscopy and oxphos activity assays. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), immunoblotting and immunofluorescence assays were performed to clarify the upstream regulatory mechanism of SIRT3. Finally, the effect of honokiol on protecting melanocytes and the underlying mechanism were investigated via flow cytometry and immunoblotting analysis. We first found that the expression and the activity of SIRT3 were significantly impaired in vitiligo melanocytes both and . Then, SIRT3 deficiency led to more melanocyte apoptosis by inducing severe mitochondrial dysfunction and cytochrome c release to cytoplasm, with Optic atrophy 1 (OPA1)-mediated mitochondrial dynamics remodeling involved in. Moreover, potentiated carbonylation and dampened peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) activation accounted for SIRT3 dysregulation in vitiligo melanocytes. Finally, we proved that honokiol could prevent melanocyte apoptosis under oxidative stress by activating SIRT3-OPA1 axis. Overall, we demonstrate that SIRT3-dependent mitochondrial dynamics remodeling contributes to oxidative stress-induced melanocyte degeneration in vitiligo, and honokiol is promising in preventing oxidative stress-induced vitiligo melanocyte apoptosis.
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http://dx.doi.org/10.7150/thno.30398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485185PMC
March 2020

Oxidative Stress-Induced HMGB1 Release from Melanocytes: A Paracrine Mechanism Underlying the Cutaneous Inflammation in Vitiligo.

J Invest Dermatol 2019 10 15;139(10):2174-2184.e4. Epub 2019 Apr 15.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address:

Vitiligo is a cutaneous depigmentation disorder caused by the destruction of epidermal melanocytes. The generation and the skin infiltration of autoreactive CD8 cytotoxic T cells triggered by oxidative stress play a critical role in vitiligo. High-mobility group protein B1 (HMGB1) is a classic damage-associated molecular pattern molecule with strong proinflammatory effects in inflammatory reactions. A previous study reported an enhanced expression of HMGB1 in vitiligo lesions, but the role of HMGB1 in cutaneous inflammation of vitiligo is still unknown. In the present study, we initially found that HMGB1 was released from the nucleus of melanocytes in vitiligo perilesional skin. Furthermore, cultured normal human melanocytes could release HMGB1 under treatment with hydrogen peroxide. Moreover, HMGB1 facilitated the secretion of CXCL16 and IL-8 from keratinocytes by binding to the receptor for advanced glycation end products and activating NF-κB and extracellular signal-regulated kinase signaling pathways. Subsequently, HMGB1 led to the formation of chemotaxis for the migration of CD8 T cells from patients with vitiligo by increasing the release of CXCL16 from keratinocytes. Additionally, HMGB1 promoted the maturation of dendritic cells from patients with vitiligo. Altogether, our study demonstrates that HMGB1 released from melanocytes contributes to the formation of oxidative stress-induced autoimmunity in vitiligo.
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http://dx.doi.org/10.1016/j.jid.2019.03.1148DOI Listing
October 2019

Berberine protects immortalized line of human melanocytes from HO-induced oxidative stress via activation of Nrf2 and Mitf signaling pathway.

J Dermatol Sci 2019 Apr 2;94(1):236-243. Epub 2019 Apr 2.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address:

Background: Oxidative stress plays important roles in the pathogenesis of vitiligo. The removal of hydrogen peroxided (HO) has been established to be beneficial to vitiligo patients. Berberine (BBR), a natural isoquinoline alkaloid, has antioxidant activity, however, whether BBR can defend human melanocytes against oxidative injury remains to be elucidated.

Objective: In the present study, we investigated the potential protective effect of BBR against oxidative stress on an immortalized normal human melanocyte cell line PIG1.

Methods: Generally, PIG1 cells were pretreated with various concentrations of BBR for 1 h followed by exposure to 1.0 mM HO for 24 h. Cell apoptosis, intracellular reactive oxygen species (ROS) levels were assessed through flow cytometry. Cell apoptosis, melanogenesis and the activation of Nrf2-ARE and Mitf signaling pathway were assayed.

Results: Our results showed that cell viability rose and intracellular ROS generation, cell apoptosis of melanocytes decreased significantly in response to HO through pretreatment with BBR. Furthermore, We found that BBR can dramatically induce Nrf2 nuclear translocation, increase total Nrf2 levels and enhance ARE activity. Besides, Nrf2-siRNA transfection can abrogate the protection of BBR in melanocytes against oxidative injury. At last, we verified that BBR could facilitate melanogenesis function via modulation of Mitf and its target proteins.

Conclusion: The results above suggest that BBR can protect melanocytes against oxidative stress via its anti-oxidative activity. Also, we found HO-induced activation of NFκB was inhibited by BBR. Therefore, it is worthy of investigation BBR as a potential drug for treatment of vitiligo.
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http://dx.doi.org/10.1016/j.jdermsci.2019.03.007DOI Listing
April 2019

Transcellular traversal of the blood-brain barrier by the pathogenic Propionibacterium acnes.

J Cell Biochem 2018 Nov 28. Epub 2018 Nov 28.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.

Background: Propionibacterium acnes (P. acnes) is an anaerobe commonly stay in the body as part of the commensal microbiota, and a dominant bacterium of the human skin and hair follicles. It has been found that this bacterium could participate in brain inflammation that causes Alzheimer's disease (AD) and Parkinson's disease (PD). But how P. acnes invade the brain remains elusive.

Methods: We established the in vitro blood-brain barrier (BBB) model by culturing the HBMEC/D3 cell line on collagen-coated PFTE membrane. The BBB model was verified by the transepithelial electrical resistance (TEER) and horseradish peroxidase (HRP) permeability rate, and observed by the scanning electron microscope (SEM), transmission electron microscope (TEM), as well as confocal microscope. The P. acnes was then cocultured with the in vitro BBB model and the permeability of P. acnes was measured by counting the bacteria clones collected from the lower chamber of the model.

Results: High local concentration of P. acnes invaded the in vitro BBB model through the transcellular traversal pathway. The permeability for P. acnes was increased by the treatment of lipopolysaccharide (LPS), but not mannitol. P. acnes invasion elevated the expression of cell adhesion molecules E-selectin, ICAM-1, and VCAM-1 in HBMEC cells.

Conclusion: P. acnes has the ability to penetrate the brain though transcellular invasion of the blood-brain barrier.
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http://dx.doi.org/10.1002/jcb.28132DOI Listing
November 2018

Smad7 Ameliorates TGF-β-Mediated Skin Inflammation and Associated Wound Healing Defects but Not Susceptibility to Experimental Skin Carcinogenesis.

J Invest Dermatol 2019 04 10;139(4):940-950. Epub 2018 Nov 10.

Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA; Allander Biotechnologies, LLC, Aurora, Colorado, USA. Electronic address:

We assessed the roles of Smad7 in skin inflammation and wound healing using genetic and pharmacological approaches. In K5.TGFβ1/K5.Smad7 bigenic (double transgenic) mice, Smad7 transgene expression reversed transforming growth factor (TGF)-β1 transgene-induced inflammation, fibrosis, and subsequent epidermal hyperplasia and molecularly abolished TGF-β and NF-κB activation. Next, we produced recombinant human Smad7 protein with a Tat-tag (Tat-Smad7) that rapidly enters cells. Subcutaneous injection of Tat-Smad7 attenuated infiltration of F4/80 and CD11b leukocytes and α-smooth muscle actin fibroblasts before attenuating epidermal hyperplasia in K5.TGFβ1 skin. Furthermore, topically applied Tat-Smad7 on K5.TGFβ1 skin wounds accelerated wound closure, with improved re-epithelialization and reductions in inflammation and fibrotic response. A short treatment with Tat-Smad7 was also sufficient to reduce TGF-β and NF-κB signaling in K5.TGFβ1 skin and wounds. Relevant to the clinic, we found that human diabetic wounds had elevated TGF-β and NF-κB signaling compared with normal skin. To assess the oncogenic risk of a potential Smad7-based therapy, we exposed K5.Smad7 skin to chemical carcinogenesis and found reduced myeloid leukocyte infiltration in tumors but not accelerated carcinogenesis compared with wild-type littermates. Our study suggests the feasibility of using exogenous Smad7 below an oncogenic level to alleviate skin inflammation and wound healing defects associated with excessive activation of TGF-β and NF-κB.
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http://dx.doi.org/10.1016/j.jid.2018.10.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457120PMC
April 2019

Baicalein protects human vitiligo melanocytes from oxidative stress through activation of NF-E2-related factor2 (Nrf2) signaling pathway.

Free Radic Biol Med 2018 12 18;129:492-503. Epub 2018 Oct 18.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, No. 127 Changlexi Road, Xi'an 710032, Shaanxi, China. Electronic address:

Vitiligo is a complex disorder characterized by patchy loss of skin pigmentation due to abnormal melanocyte function. Overwhelming evidences have suggested that oxidative stress plays a major role in the loss of melanocytes thereby mediating the onset and progression of vitiligo. The nuclear factor erythroid 2-like factor 2 (Nrf2) is a master regulator of cellular redox homeostasis and the activation of Nrf2 signaling pathway is impaired in the vitiligo melanocytes. Baicalein, as flavonoid extracted from the Scutellaria baicalensis, has been proved to possess the ability to activate Nrf2 signaling pathway in other cell types and mouse model. Our previous data found that baicalein exerts a cytoprotective role in HO-induced apoptosis in human melanocytes cell line (PIG1). Based on these founding, we hypothesized that baicalein activates Nrf2 signaling pathway, alleviates HO-induced mitochondrial dysfunction and cellular damage, thereby protecting human vitiligo melanocytes from oxidative stress. In the present study, we found that baicalein effectively inhibited HO-induced cytotoxicity and apoptosis in human vitiligo melanocytes (PIG3V). Further results demonstrated that baicalein promoted Nrf2 nucleus translocation as well as up-regulated the expression of Nrf2 and its target gene, heme oxygenase-1 (HO-1). Moreover, the protective effects of baicalein against HO-induced cellular damage and apoptosis as well as mitochondrial dysfunction were abolished by Nrf2 knockdown. Additionally, we observed that Nrf2 knockdown suppressed proliferation and increased the sensitivity of PIG3V cells to HO treatment. Finally, we explored the mechanism of baicalein associated with Nrf2 activation and found that the phosphorylation of Nrf2 as well as ERK1/2and PI3K/AKT signaling were not involved in the baicalein-induced activation of Nrf2. Taken together, these data clearly suggest that baicalein enhances cellular antioxidant defense capacity of human vitiligo melanocytes through the activation of the Nrf2 signaling pathway, providing beneficial evidence for the application of baicalein in the vitiligo treatment.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.10.421DOI Listing
December 2018

Identification of the Risk HLA-A Alleles and Autoantigen in Han Chinese Vitiligo Patients and the Association of CD8+T Cell Reactivity with Disease Characteristics.

Med Sci Monit 2018 Sep 16;24:6489-6497. Epub 2018 Sep 16.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China (mainland).

BACKGROUND Multiple studies have implicated a role for CD8+T cell-mediated immune response to autoantigens in vitiligo. However, the antigen-specific T lymphocyte reactivity against the peptide epitopes is diverse among different world populations. This study aimed to identify the risk HLA-A allele in vitiligo and study CD8+ T cell reactivity to 5 autoantigenic peptides in Han Chinese populations, and to analyze the association of CD8+ T cell reactivity with disease characteristics. MATERIAL AND METHODS The risk HLA-A allele was analyzed by case-control study. Enzyme linked immunospot (ELISPOT) assay was used to compare T cell reactivity to the 5 autoantigenic peptides between vitiligo patients and healthy controls, then we analyzed the association of CD8+ T cell reactivity to 2 positive peptides with disease activity and area of skin lesions. RESULTS The results indicated that the most frequent allele in the Han Chinese vitiligo patients was the HLA-A*02: 01 allele with a significantly higher frequency compared to controls (20.20% versus 13.79%, P=6.64×10-5). The most frequently encountered epitopes were 2 gp100 modified peptides, IMDQVPFSV and YLEPGPVTV, whereas a weak T cell reactivity against tyrosinase and Melan-A/MART-1 were evaluated. Moreover, we demonstrated that T cell reactivity against the 2 positive peptides was significantly associated with disease characteristics including disease activity and area of skin lesions. CONCLUSIONS Our findings showed that the HLA-A*02: 01 allele was the major risk HLA-A allele, and 2 gp100 modified peptides were identified as autoantigens and were found to be closely related to disease characteristics which might play a critical role in Han Chinese vitiligo patients.
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http://dx.doi.org/10.12659/MSM.910515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154310PMC
September 2018

Topical Application of Tat-Rac1 Promotes Cutaneous Wound Healing in Normal and Diabetic Mice.

Int J Biol Sci 2018 23;14(10):1163-1174. Epub 2018 Jun 23.

Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA.

The endogenous small GTPase, Rac1, plays a critical role during normal skin wound healing. It remains to be determined whether endogenous Rac1 can be appropriately activated in chronic wounds; if not, whether exogenous Rac1 has therapeutic effects on wound healing. Here we show that Rac1 protein levels were lower in wounds of db/db diabetic mice than wounds in wild type mice during the healing process. To assess the therapeutic potential of exogenous Rac1 in wound healing, we produced a Tat-Rac1 fusion protein that enters into cells through protein transduction. Tat-Rac1 increased proliferation and migration of keratinocytes and dermal fibroblasts . Topical application of Tat-Rac1 accelerated cutaneous wound closure in db/db mice as well as wild type mice. Further analyses revealed that Tat-Rac1 had faster re-epithelialization, higher keratinocyte proliferation and migration without an earlier onset of myofibroblast activation than vehicle treated wounds. Tat-Rac1 also reduced inflammation in wounds. Our findings revealed the failure of diabetic wounds to elevate Rac1 expression and suggested a therapeutic strategy utilizing a Rac1-based biologic to compensate for this defect thereby promoting wound healing.
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http://dx.doi.org/10.7150/ijbs.25920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097474PMC
August 2019

HO-1 regulates the function of Treg: Association with the immune intolerance in vitiligo.

J Cell Mol Med 2018 09 5;22(9):4335-4343. Epub 2018 Jul 5.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

In vitiligo, cutaneous depigmentation is accompanied by increased T cell cytolytic activity targeting melanocytes, indicating that autoimmune tolerance is disrupted. The inhibited amount and function of Tregs have been indicated to be involved in the autoimmune intolerance in vitiligo, however, with the conclusion still controversial and the involved mechanism unknown. In this study, we explored the molecular and cellular alterations accounting for the impaired Treg response in vitiligo. Our results showed that the amount of Tregs was drastically reduced in peripheral blood of active vitiligo patients. Furthermore, the immunoregulatory function of Tregs was attenuated, with lower expression of CTLA4, IL-10 and TGF-β. Moreover, the expression of HO-1, a functional modulator of Tregs, was decreased in vitiligo Tregs, and the concentrations of HO-1 metabolites, including bilirubin, CoHb and iron, were correspondingly decreased in serum of vitiligo patients. In addition, we treated the Tregs from vitiligo patients with Hemin, an agonist of HO-1, and found that enhanced HO-1 expression restored the function of Tregs by up-regulating IL-10 expression. Our study demonstrates the essential role of HO-1 in the impaired Treg response in vitiligo and indicates the potential of HO-1 as a therapeutic target in vitiligo management.
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http://dx.doi.org/10.1111/jcmm.13723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111856PMC
September 2018

Downregulated TRPV1 Expression Contributes to Melanoma Growth via the Calcineurin-ATF3-p53 Pathway.

J Invest Dermatol 2018 10 23;138(10):2205-2215. Epub 2018 Mar 23.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address:

Melanoma is the most lethal form of skin cancer with increasing incidence over the years. Because of its rapid proliferative and drastic metastatic capacity, the prognosis of melanoma remains dismal, although the targeted therapy and immunotherapy have gained revolutionary progress recently. Therefore, it is of necessity to further clarify the mechanism of melanoma pathogenesis for developing an alternative treatment strategy. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective Ca channel greatly involved in regulating cell apoptosis, proliferation, metabolism, and cancer development, but its role in melanoma remains unknown. Herein, we first found that TRPV1 expression was significantly decreased in melanoma tissues and cell lines, compared with nevus tissues and normal melanocytes, respectively. We then proved that TRPV1 overexpression or its agonist capsaicin treatment inhibited melanoma growth by activating p53 and inducing cell apoptosis. A subsequent mechanistic study revealed that TRPV1 induced Ca influx to regulate p53 activation via calcineurin-ATF3 transcriptional cascade. Finally, the effect of TRPV1 on melanoma growth was proved in vivo. Altogether, our study demonstrates that TRPV1 is a potential tumor suppressor in melanoma.
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http://dx.doi.org/10.1016/j.jid.2018.03.1510DOI Listing
October 2018

Up-regulated deubiquitinase USP4 plays an oncogenic role in melanoma.

J Cell Mol Med 2018 05 14;22(5):2944-2954. Epub 2018 Mar 14.

Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.

Melanoma is the most malignant skin cancer with increasing incidence worldwide. Although innovative therapies such as BRAF inhibitor and immune checkpoint inhibitor have gained remarkable advances, metastatic melanoma remains an incurable disease for its notorious aggressiveness. Therefore, further clarification of the underlying mechanism of melanoma pathogenesis is critical for the improvement of melanoma therapy. Ubiquitination is an important regulatory event for cancer hallmarks and melanoma development, and the deubiquitinating enzymes including ubiquitin-specific peptidase (USP) families are greatly implicated in modulating cancer biology. Herein, we first found that the expression of the deubiquitinase USP4 was significantly up-regulated in melanoma tissues and cell lines. Furthermore, although USP4 knockdown had little impact on melanoma cell proliferation, it could increase the sensitivity to DNA damage agent cisplatin. We subsequently showed that USP4 regulated cisplatin-induced cell apoptosis via p53 signalling. More importantly, USP4 could accentuate the invasive and migratory capacity of melanoma cells by promoting epithelial-mesenchymal transition. Altogether, our results demonstrate that the up-regulated USP4 plays an oncogenic role in melanoma by simultaneously suppressing stress-induced cell apoptosis and facilitating tumour metastasis.
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http://dx.doi.org/10.1111/jcmm.13603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908120PMC
May 2018

Multiple pro-tumorigenic functions of the human minor Histocompatibility Antigen-1 (HA-1) in melanoma progression.

J Dermatol Sci 2017 Nov 8;88(2):216-224. Epub 2017 Jul 8.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, No. 127 Changlexi Road, Xi'an 710032, Shaanxi, China. Electronic address:

Background: Remodeling of cytoskeleton plays an important role in development of multiple cancers, including melanoma. As a group of F-actin regulators, the Ras homology (Rho) GTPase-activating proteins (ARHGAPs) were reported by accumulating studies as a set of significant mediators in cell morphology, proliferation, migration and invasion.

Objective: To investigate the function of HMHA1 and its encode protein HA-1 in melanoma.

Methods: The mRNA microarray was performed to screen the expression of ARHGAP family genes between melanoma tissues and nevi tissues. QRT-PCR and Western Blot were used to detect the expression of mRNA of HMHA1 and its relevant protein HA-1 respectively. Small interfering RNA was used to knock down the expression of HMHA1. Cell-count kit 8 assays and colony formation assays were used to evaluate the cell proliferative viability of melanoma cells. Flow cytometry was employed to analyze cell apoptosis. Transwell assay and the observation of cell morphology were used to evaluate the invasive and migrating activity of melanoma cells.

Results: In previous study, we first found that both the mRNA level of HMHA1and the expression of HA-1 were up-regulated in melanoma tissues and cell lines compared with nevi tissues and normal human melanocytes respectively. Blocking HMHA1 expression in melanoma cell lines WM35 and A375 suppressed their proliferation and function of colony forming. Moreover, silencing HMHA1 not only significantly increased cell apoptosis but also suppressed cell migration and invasion.

Conclusion: Our results demonstrate that HMHA1 significantly promotes melanoma cells proliferation, invasion and migration, and prevents cell apoptosis. Additionally, it can be considered as a new diagnostic marker and drug target of melanoma.
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http://dx.doi.org/10.1016/j.jdermsci.2017.07.004DOI Listing
November 2017

SOX4 Promotes Proliferative Signals by Regulating Glycolysis through AKT Activation in Melanoma Cells.

J Invest Dermatol 2017 11 29;137(11):2407-2416. Epub 2017 Jul 29.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address:

The sex-determining region Y-related high-mobility group box transcription factor 4 (SOX4) plays a fundamental role during embryogenesis and controls cell fate and differentiation. Recently, increased SOX4 expression has been reported in various cancer types, contributing to the progression and survival of cancer cells. However, the distinct functions and downstream targets of SOX4 remain to be fully elucidated. In this study, we initially found elevated SOX4 expression in melanoma. SOX4 regulates apoptosis and cell cycle arrest, affects glucose consumption and lactate production, and consequently, promotes melanoma cell proliferation. Moreover, we found that SOX4 rewires glucose metabolism by regulating the expression of glucose transporter type 1, hexokinase 2, and lactate dehydrogenase A at the transcriptional level. Mechanistically, SOX4 knockdown reduced activation of acutely transforming retrovirus AKT8 in rodent T-cell lymphoma and mTORC1, leading to an attenuated malignant phenotype. We also identified p70 ribosomal S6 kinase and eukaryotic initiation factor 4E-binding protein 1 as key substrates involved in the regulation of mTORC1 in melanoma cells. In conclusion, our study demonstrates the essential role of SOX4 in melanoma glycolytic metabolism through the acutely transforming retrovirus AKT8 in rodent T-cell lymphoma signaling pathway and highlights its potential as a therapeutic target in melanoma management.
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http://dx.doi.org/10.1016/j.jid.2017.06.026DOI Listing
November 2017
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