Peripheral blood mononuclear cell- transcriptome signatures of atopic dermatitis and prediction for the efficacy of dupilumab.

BACKGROUND: Few studies have explored transcriptome of the peripheral blood mononuclear cells (PBMCs) of atopic dermatitis (AD). Parameters for prediction of the efficacy of dupilumab in AD remain obscure. OBJECTIVE: To explore transcriptome signature of the PBMCs from Chinese AD patients and the usage in predication for the efficacy of dupilumab. METHODS: A total of 56 moderate-to-severe adult AD patients were enrolled and followed up for 16 week-dupilumab treatment. PBMCs samples were collected at baseline and 16 weeks after dupilumab treatment. Thirty-five patients were subjected to RNA-sequencing. Weighted gene co-expression network analysis (WGCNA) was used to find genes for prediction of dupilumab efficacy, which was validated in the rest 21 AD patients. Another 30 healthy individuals were enrolled and subjected to RNA-sequencing as healthy controls. RESULTS: Upregulation of the T helper (Th) 2/Th22 pathway, Th17 antimicrobial genes, and natural T-regulatory cell abundance in the PBMCs of AD cases was observed, whereas TGF-ß signaling and NK-cell signaling were decreased. Dupilumab treatment reversed the increase in the expression of Th2 cytokine receptors. WGCNA identified two immune-related modules that were correlated significantly with the efficacy of dupilumab. Hub gene MAP2K3 and UBE2L3 of these two modules demonstrated potential predictive ability for efficacy in the RNA-sequencing group by Spearman correlation, ROC analysis, and regression analysis, which was further validated in additional 21 AD cases. CONCLUSION: We firstly revealed the molecular phenotype of PBMCs in Chinese patients with AD, and uncovered two molecules that might be useful for prediction of the efficacy of dupilumab.

Serum biomarker-based endotypes of atopic dermatitis in China and prediction for efficacy of dupilumab.

BACKGROUND: Atopic dermatitis (AD) is a highly heterogeneous disease clinically and biologically. Serum biomarkers have been utilized for endotype identification and have the potential to be predictors for treatment. OBJECTIVES: To explore the serum biomarker-based endotypes of Chinese patients with AD and to identify biomarkers for prediction of the efficacy of dupilumab. METHODS: Sera from 125 patients with moderate-to-severe AD and 60 normal controls (NC) were analysed for 24 cytokines/chemokines using the magnetic Luminex assay. After the patients received 16 weeks of dupilumab treatment, the efficacy was evaluated, and blood eosinophils, serum immunoglobulin (Ig) E and biomarkers were measured. RESULTS: Chinese patients with moderate-to-severe AD were characterized by T-helper (Th)2-dominant serum biomarkers that were mixed with differentially increased Th1-, Th17- and Th22-type cytokines/chemokines, and it was mainly Th2-type serum biomarkers that were positively correlated with disease severity and eosinophil counts. Adult (but not adolescent or elderly) patients with AD showed a consistent and more significant increase of biomarkers across different types of inflammation. The patients were grouped into two clusters by unsupervised k-means analysis, which were differentially associated with inflammation. Treatment with dupilumab decreased the levels of most cytokines/chemokines analysed. While there was no difference between the two clusters in the efficacy of dupilumab, baseline levels of CD25/soluble interleukin (sIL)-2Rα, IL-31 and IL-36ß were identified as predictive factors associated with the efficacy. CONCLUSIONS: Our study revealed two inflammation-related endotypes of Chinese patients with AD based on serum biomarkers. High levels of CD25/sIL-2Rα, IL-31 and IL-36ß might predict good efficacy of dupilumab treatment.

Dysregulated lipidome of sebum in patients with atopic dermatitis.

BACKGROUND: Lipids are the major components of skin barrier, mainly produced by keratinocytes and sebaceous glands. Previous studies on barrier dysfunction of atopic dermatitis (AD) mainly focus on the lipids from keratinocytes, whereas the role of sebaceous gland-derived lipids in AD has long been underrecognized. METHODS: The sebum secreted on the skin surface of AD patients was measured using the Delfin Sebum Scale. Sebum was collected using Sebutape patches and subjected for liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis. Multivariate data analysis was applied to explore the relationship among the lipidome, clinical features, and sebaceous gland-related molecules. RESULTS: The amount of sebum secreted from sebaceous glands was decreased in AD patients and was negatively correlated with the barrier function and disease severity. LC-MS/MS revealed the lipidome of sebum, which clustered distinctly between AD patients and healthy individuals. Among the differential lipid subclasses, triglycerides (TG) were exclusively decreased in AD patients and correlated with disease severity. The first principal component scores of AD patients, which represented the main signature of the lipidome, were positively correlated with the SCORAD scores and were significantly different across the patient groups with differential clinical symptoms such as skin dryness and pruritus. Further analysis on the previously published transcriptome data revealed aberrant expression of lipid metabolism-related genes in non-lesional skin of AD patients, which was associated with skin inflammation and barrier dysfunction and mainly derived from inner root sheath keratinocytes and sebaceous gland cells. CONCLUSION: Atopic dermatitis patients demonstrated a deviated lipidome of sebum and aberrant lipid metabolism in sebaceous glands, indicating a possible role of lipids from sebaceous glands in the pathogenesis of AD.

A dysregulated sebum-microbial metabolite-IL-33 axis initiates skin inflammation in atopic dermatitis.

Microbial dysbiosis in the skin has been implicated in the pathogenesis of atopic dermatitis (AD); however, whether and how changes in the skin microbiome initiate skin inflammation, or vice versa, remains poorly understood. Here, we report that the levels of sebum and its microbial metabolite, propionate, were lower on the skin surface of AD patients compared with those of healthy individuals. Topical propionate application attenuated skin inflammation in mice with MC903-induced AD-like dermatitis by inhibiting IL-33 production in keratinocytes, an effect that was mediated through inhibition of HDAC and regulation of the AhR signaling pathway. Mice lacking sebum spontaneously developed AD-like dermatitis, which was improved by topical propionate application. A proof-of-concept clinical study further demonstrated the beneficial therapeutic effects of topical propionate application in AD patients. In summary, we have uncovered that the dysregulated sebum-microbial metabolite-IL-33 axis might play an initiating role in AD-related skin inflammation, thereby highlighting novel therapeutic strategies for the treatment of AD.

Identification of Molecular Signatures in Mild Intrinsic Atopic Dermatitis by Bioinformatics Analysis.

BACKGROUND: Atopic dermatitis (AD) is recognized as a common inflammatory skin disease and frequently occurred in Asian and Black individuals. OBJECTIVE: Since the limitation of dataset associated with human severe AD, this study aimed to screen potential novel biomarkers involved in mild AD. METHODS: Expression profile data (GSE75890) were obtained from the database of Gene Expression Omnibus. Using limma package, the differentially expressed genes (DEGs) between samples from AD and healthy control were selected. Furthermore, function analysis was conducted. Meanwhile, the protein-protein interaction (PPI) network and transcription factor (TF)-miRNA-target regulatory network were constructed. And quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the expressions patterns of key genes. RESULTS: In total, 285 DEGs including 214 upregulated and 71 downregulated genes were identified between samples from two groups. The upregulated DEGs were mainly involved in nine pathways, such as hematopoietic cell lineage, pertussis, p53 signaling pathway, staphylococcus aureus infection, and cell cycle, while tight junction was the only pathway enriched by the downregulated DEGs. Cyclin B (CCNB)1, CCNB2, cyclin A (CCNA)2, C-X-C motif chemokine ligand (CXCL)10, and CXCL9 were key nodes in PPI network. The TF-miRNA-target gene regulatory network focused on miRNAs such as miR-106b, miR-106a, and miR-17, TFs such as nuclear factor kappa B subunit 1, RELA proto-oncogene, Sp1 transcription factor, and genes such as matrix metallopeptidase 9, peroxisome proliferator activated receptor gamma , and serpin family E member 1. Moreover, the upregulation of these genes, including CCNB1, CCNB2, CCNA2, CXCL10, and CXCL9 were confirmed by qRT-PCR. CONCLUSION: CCNB1, CCNB2, CCNA2, and CXCL9 might be novel markers of mild AD. miR-106b and miR-17 may involve in regulation of immune response in AD patients.

Visualization data on concentrating apple juice with a trinitarian crystallization suspension freeze concentrator.

This article contains visualization data on concentrating apple juice with a trinitarian suspension crystallization freeze concentrator, which integrates scraped-surface heat exchanger, suspension crystallizer and wash-column into one piece of equipment. The visualization data on ice accumulation, ice bed development and consolidation in the crystallizer/wash-column of the freeze concentrator are presented in a set of photographs in chronological order and videos attached as appendix materials. These data refer to the related research article entitled "Concentration of Apple Juice with an Intelligent Freeze Concentrator" Ding et al., 2019.

Synthesis of Humin-Phenol-Formaldehyde Adhesive.

Humins are low-value-added byproducts from the biomass acid hydrolysis process. In the present work, humins were first employed as a phenol replacement for synthesis of modified phenol-formaldehyde adhesives through a two-step process. In this process, humins were first utilized to obtain alkaline soluble products, mainly consisting of phenolics, through a hydrothermal process. The obtained alkaline soluble products then reacted with phenol and formaldehyde to produce humin-phenol-formaldehyde adhesive (HPFA). The physicochemical properties of HPFA, including viscosity, bonding strength, pH, free formaldehyde level, free phenol level and solid content, met the requirements of the GB/T 14732-2006 Chinese National Standard.

Baicalin protects human skin fibroblasts from ultraviolet A radiation-induced oxidative damage and apoptosis.

Reactive oxygen species (ROS) are an important factor in the development of skin photodamage after ultraviolet A (UVA) radiation. A flavonoid antioxidant, baicalin, can selectively neutralize super-oxide anion (O(2)(-)) while having no significant effect on (•)OH. Fibroblasts are a key component of skin dermis. In the present study, we investigated the protective effects of baicalin on human skin fibroblasts (HSFs) under UVA induced oxidative stress. Fluorescence microscopy and flow cytometry were used to assay the intracellular O(2)(-), NO, ROS concentrations and the mitochondrial membrane potential. Cell viability was determined using the Cell Counting Kit-8 (CCK-8). The concentrations of cellular MDA, SOD, GSH, T-AOC, and 8-oxo-dG were also measured. Cellular apoptosis was measured by flow cytometry and caspase-3 detection. The results revealed that UVA radiation could cause oxidative stress and apoptosis in HSFs. Interestingly, the use of baicalin after UVA radiation significantly reduced the level of intracellular O(2)(-), NO, and ROS, stabilized the mitochondrial membrane potential, and attenuated production of MDA and 8-oxo-dG. These efficiently enhanced the antioxidative defense system and protected the HSFs from subsequent oxidative stress damage and apoptosis. In other words, baicalin decreased the excessive generation of intracellular ROS and NO, and elevated the cellular antioxidative defense, which eventually mitigate the UVA-induced apoptosis. Based on our results, baicalin may have applications in the treatment of skin photodamage caused by UVA irradiation.

[Th17 in the immunity against parasitic infection].

Th17 lymphocytes have been recently identified as a novel subset of CD4+ cells. It has been defined that IL-17, the main product of Th17, plays an important role in immunity against parasitic infection. There is a two-way influence between Th17 and cytokine network: on one hand Th17 consummate cytokine network, on the other hand many cytokines regulate Th17's activity in parasitic infection. In the anti-parasitic infection process, Th17 cells protect host or promote inflammation, even cause immune pathogenesis in different cases, which comprise host's immune state, the burden of parasitic infection, as well as the treatment.