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Rongxin Zhang,1,2 Zhao Hou,2 Kexin Liao,2 Chao Yu,2 Rongrong Jing,1,2 Caixia Tu1,2 1Institute of Integrative Medicine, Dalian Medical University, Dalian, 116044, People’s Republic of China; 2Department of Dermatology, The Second Hospital of Dalian Medical University, Dalian, 116027, People’s Republic of ChinaCorrespondence: Caixia Tu, Department of Dermatology, The Second Hospital of Dalian Medical University, No. 467 Zhongshan Road, Dalian, 116027, People’s Republic of China, Tel +8617709872288, Fax +86 411 84672130, Email tucx2010@sina.comPurpose: Circular RNAs (circRNAs) are abundant, stable, and evolutionarily conserved noncoding RNAs with impacts on cell proliferation, differentiation, invasion, apoptosis, and immunity by acting as an miRNA sponge. This study aimed to investigate the expression of circRNAs in vitiligo and analyze the differentially expressed circRNAs (DEcircRNAs) bioinformatically.Patients and Methods: Biopsies of five lesional and five nonlesional skins of patients with vitiligo and five healthy skins (control) were harvested in this study. The expression profiles of circRNAs and DEcircRNAs were determined by microarray analysis and qRT-PCR. Bioinformatics analysis was used to predict target genes of DEcircRNAs binding to miRNAs and their underlying functions. Meanwhile, a competing endogenous RNA (ceRNA) network was constructed using Cytoscape.Results: A total of 817 and 508 DEcircRNAs were identified in lesional and nonlesional skins of patients with vitiligo, respectively. The results of hsa_circRNA_000957 and hsa_circRNA_101798 validation were consistent with our microarray analysis. Furthermore, 32 miRNA response elements (MREs) and related target genes of DEcircRNAs were identified, whose main functions were involved in the pathogenesis of vitiligo. Hsa_circRNA_000957 and hsa_circRNA_101798 might be candidate biomarkers for vitiligo.Conclusion: This study provides scientific clues for understanding the mechanism of vitiligo.Keywords: vitiligo, circular RNAs, microRNAs, miRNA response element, ceRNA

BACKGROUND Treatment of vitiligo has several challenges. Phototherapy and topical calcipotriol have been reported to be effective in combination with other therapies, but there is no consensus on the combination use. OBJECTIVE To perform a systematic review and meta-analysis that elucidates the efficacy of the combination of phototherapy and topical calcipotriol. METHODS This systematic review was performed by searching PubMed, EMBASE, Web of Science, Cochrane Library databases, Chinese National Knowledge Infrastructure (CNKI), WanFang and VIP databases for relevant publications till February 28, 2021. Relative risk (RR) and its 95% confidence interval (CI) were used to evaluate the data. Bias assessment, heterogeneity and sensitivity analysis were conducted in this meta-analysis. RESULTS After screening, nine studies with 700 participants were included. The meta-analysis indicated that the combination of phototherapy and topical calcipotriol showed significantly higher effective rate (RR 1.11, 95% CI 1.02-1.22; p

Vitiligo is a chronic, autoimmune destruction of melanocytes, resulting in progressively expanding depigmented skin patches. Severity of the disorder, which affects approximately 1% of humans, may be mitigated using topical corticosteroids combined with phototherapy; along with other clinical strategies; however, no definitive cures are currently available. Here, the capacity of apigenin, a plant-derived aglycone, to inhibit oxidative stress–mediated melanocyte depletion in vitro using a PIG3V vitiligo perilesional melanocyte cell model is evaluated. PIG3V cells, treated with selected doses of apigenin, were challenged with H(2)O(2), then assessed for viability and the oxidative stress–related parameters: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) by enzyme-linked immunoabsorbent assay (ELISA). Additionally, expression of nuclear factor erythroid 2p45 (NF-E2)–related factor 2 (Nrf2) and downstream targets was detected using Western blotting. Outcomes demonstrated that compared with negative control cultures, apigenin-treated cells exhibited enhanced viability. Likewise, apigenin enhanced expression of the cellular anti-oxidants SOD, CAT, and GSH-Px, but inhibited production of MDA, an oxidative stress biomarker. Interestingly, the expression and nuclear localization of the Nrf2 transcription factor, an important regulator oxidative stress and its downstream target genes, was significantly increased by apigenin treatment. Apigenin influence on Nrf2 was further validated by experiments demonstrating that Nrf2 knockdown cells failed to exhibit significant apigenin-mediated effects on cell viability and oxidative stress. Apigenin’s non-toxicity and ability to affect multiple oxidative stress–related parameters through its effects on Nrf2 signaling in melanocytes suggests that it may prove to be a valuable therapeutic tool in long-term management of vitiligo.

Background The PD-L1/PD-1 pathway blockade-mediated immune therapy has shown promising efficacy in the treatment of multiple cancers including melanoma. The present study investigated the effects of the flavonoid apigenin on the PD-L1 expression and the tumorigenesis of melanoma. Methods The influence of flavonoids on melanoma cell growth and apoptosis was investigated using cell proliferation and flow cytometric analyses. The differential IFN-γ-induced PD-L1 expression and STAT1 activation were examined in curcumin and apigenin-treated melanoma cells using immunoblotting or immunofluorescence assays. The effects of flavonoid treatment on melanoma sensitivity towards T cells were investigated using Jurkat cell killing, cytotoxicity, cell viability, and IL-2 secretion assays. Melanoma xenograft mouse model was used to assess the impact of flavonoids on tumorigenesis in vivo. Human peripheral blood mononuclear cells were used to examine the influence of flavonoids on PD-L1 expression in dendritic cells and cytotoxicity of cocultured cytokine-induced killer cells by cell killing assays. Results Curcumin and apigenin showed growth-suppressive and pro-apoptotic effects on melanoma cells. The IFN-γ-induced PD-L1 upregulation was significantly inhibited by flavonoids, especially apigenin, with correlated reductions in STAT1 phosphorylation. Apigenin-treated A375 cells exhibited increased sensitivity towards T cell-mediated killing. Apigenin also strongly inhibited A375 melanoma xenograft growth in vivo, with enhanced T cell infiltration into tumor tissues. PD-L1 expression in dendritic cells was reduced by apigenin, which potentiated the cytotoxicity of cocultured cytokine-induced killer cells against melanoma cells. Conclusions Apigenin restricted melanoma growth through multiple mechanisms, among which its suppression of PD-L1 expression exerted a dual effect via regulating both tumor and antigen presenting cells. Our findings provide novel insights into the anticancer effects of apigenin and might have potential clinical implications.

Mutations in sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) underlie Darier disease (DD), a dominantly inherited skin disorder characterized by loss of keratinocyte adhesion (acantholysis) and abnormal keratinization (dyskeratosis) resulting in characteristic mucocutaneous abnormalities. However, the molecular pathogenic mechanism by which these changes influence keratinocyte adhesion and viability remains unknown. We show here that SERCA2 protein is extremely sensitive to endoplasmic reticulum (ER) stress, which typically results in aggregation and insolubility of the protein. Depletion of ER calcium stores is not necessary for the aggregation but accelerates the progression. Systematic analysis of diverse mutants identical to those found in DD patients demonstrated that the ER stress initiator is the SERCA2 mutant protein itself. These SERCA2 proteins were found to be less soluble, to aggregate and to be more polyubiquitinylated. After transduction into primary human epidermal keratinocytes, mutant SERCA2 aggregates elicited ER stress, caused increased numbers of cells to round up and detach from the culture plate, and induced apoptosis. These mutant induced events were exaggerated by increased ER stress. Furthermore, knockdown SERCA2 in keratinocytes rendered the cells resistant to apoptosis induction. These features of SERCA2 and its mutants establish a mechanistic base to further elucidate the molecular pathogenesis underlying acantholysis and dyskeratosis in DD.

In order to study the possible role of neuropeptide-Y (NPY) in the pathogenesis of vitiligo, the authors measured the levels of NPY in the plasma from 47 patients with vitiligo compared with 25 healthy volunteers, and the tissue fluids of skin lesions and uninvolved skin from 32 patients, employing a NPY 125I RIA Kit. The results showed that the levels of NPY in the patients with vitiligo of all of the generalized, local and segmental types were significantly higher than the normal controls. In both local and segmental type, the levels in progressive stage were significantly higher than those in stable stage, while in generalized type, there was no significant difference between those in progressive stage and stable stage. The levels of NPY in the tissue fluids from skin lesions were significantly higher than those from uninvolved skin in both the local type and segmental type, while in the generalized type, there was no significant difference between the NPY level in the tissue fluid from skin lesion and that from uninvolved skin. It is speculated that NPY may play certain roles in the pathogenesis of vitiligo, via neuro-immunity mechanism or neuronal affection on the melanocytes.