Gradiently Foaming Ultrasoft Hydrogel with Stop Holes for Highly Deformable, Crack-Resistant and Sensitive Conformal Human-Machine Interfaces.

Hydrogels are considered as promising materials for human-machine interfaces (HMIs) owing to their merits of tailorable mechanical and electrical properties; nevertheless, it remains challenging to simultaneously achieve ultrasoftness, good mechanical robustness and high sensitivity, which are the pre-requisite requirements for wearable sensing applications. Herein, for the first time, this work proposes a universal phase-transition-induced bubbling strategy to fabricate ultrasoft gradient foam-shaped hydrogels (FSHs) with stop holes for high deformability, crack-resistance and sensitive conformal HMIs. As a typical system, the FSH based on polyacrylamide/sodium alginate system shows an ultralow Young's modulus (1.68 kPa), increased sustainable strain (1411%), enhanced fracture toughness (915.6 J m-2), improved tensile sensitivity (21.77), and compressive sensitivity (65.23 kPa-1). The FSHs are used for precisely acquiring and identifying gesture commands of the operator to remotely control a surgical robot for endoscopy and an electric ship in a first-person perspective for cruising, feeding crabs and monitoring the environmental change in real-time.

The gut-joint axis: Genetic evidence for a causal association between gut microbiota and seropositive rheumatoid arthritis and seronegative rheumatoid arthritis.

This study aimed to assess the causal relationship between GM and RA (seropositive RA and seronegative RA). A two-sample Mendelian randomization (MR) analysis was performed to assess the causality of GM on seropositive RA and seronegative RA. GM's genome-wide association study (GWAS) was used as the exposure, whereas the GWAS datasets of seropositive RA and seronegative RA were the outcomes. The primary analysis approach was used as inverse-variance weighted (IVW), followed by 3 additional MR methods (MR-Egger, weighted median, and weighted mode). Cochran's Q test was used to identify heterogeneity. The MR-Egger intercept test and leave-one-out analyses were used to assess horizontal pleiotropy. All statistical analyses were performed in R software. We discovered that Alloprevotella (IVW OR 0.84, 95% CI 0.71-0.99, P = .04) and Christensenellaceae R 7 group (IVW OR 0.71, 95% CI 0.52-0.99, P = .04) were negatively correlated with seropositive RA, Ruminococcaceae UCG002 (IVW OR 1.30, 95% CI 1.10-1.54, P = .002) was positively associated with seropositive RA. Actinomyces (IVW OR 0.73, 95% CI 0.54-0.99, P = .04), Christensenellaceae R 7 group (IVW OR 0.62, 95% CI 0.39-0.97, P = .04), Terrisporobacter (IVW OR 0.64, 95% CI 0.44-0.93, P = .02), Lactobacillales (IVW OR 0.65, 95% CI 0.47-0.90, P = .01) were negatively correlated with seronegative RA. The present MR analysis showed a protective effect of Alloprevotella and Christensenellaceae R 7 group and a potentially anti-protective effect of Ruminococcaceae UCG002 on seropositive RA; and a protective effect of Actinomyces, Christensenellaceae R 7 group, Terrisporobacter, and Lactobacillales on seronegative RA. Further experimental studies and randomized controlled trials are needed to validate these findings.

Case report: Whole exome sequencing and genome-wide methylation profiling of Czech dysplasia in a Chinese pedigree.

Background: Czech dysplasia is a rare skeletal disorder with symptomatology including platyspondyly, brachydactyly of the third and fourth toes, and early-onset progressive pseudorheumatoid arthritis. The disorder segregates in an autosomal dominant fashion. A specific missense mutation (R275C, c.823C > T) in exon 13 of the COL2A1 gene has been identified in German and Japanese families. Case summary: We present the case of a Chinese woman diagnosed with Czech dysplasia (proband) who carried a variant in the COL2A1 gene. Whole-exome sequencing (WES) identified the COL2A1 missense mutation (R275C, c.823C > T) in close relatives of the proband who also exhibited the same disorder. Conclusion: This study is a thorough clinical and physiological description of Czech dysplasia in a Chinese patient.

Circulating DNA methylation level of CXCR5 correlates with inflammation in patients with rheumatoid arthritis.

OBJECTIVES: To assess the differences in circulating DNA methylation levels of CXCR5 between rheumatoid arthritis (RA) and osteoarthritis (OA) and healthy controls (HC), and the correlation of methylation changes with clinical characteristics of RA patients. METHODS: Peripheral blood samples were collected from 239 RA patients, 30 patients with OA, and 29 HC. Target region methylation sequencing to the promoter region of CXCR5 was achieved using MethylTarget. The methylation level of cg04537602 and methylation haplotype were compared among the three groups, and the correlation between methylation levels and clinical characteristics of RA patients was performed by Spearman's rank correlation analysis. RESULTS: The methylation level of cg04537602 was significantly higher in the peripheral blood of RA patients compared with OA patients (p = 1.3 × 10-3 ) and in the HC group (p = 5.5 × 10- 4 ). The sensitivity was enhanced when CXCR5 methylation level combined with rheumatoid factor and anti-cyclic citrullinated peptide with area under curve (AUC) of 0.982 (95% confidence interval 0.970-0.995). The methylation level of cg04537602 in RA was positively correlated with C-reactive protein (CRP) (r = .16, p = .01), and in RA patients aged 60 years and above, cg04537602 methylation levels were positively correlated with CRP (r = .31, p = 4.7 × 10- 4 ), tender joint count (r = .21, p = .02), visual analog scales score (r = .21, p = .02), Disease Activity Score in 28 joints (DAS28) using the CRP level DAS28-CRP (r = .27, p = 2.1 × 10- 3 ), and DAS28-ESR (r = .22, p = .01). We also observed significant differences of DNA methylation haplotypes in RA patients compared with OA patients and HC, which was consistent with single-loci-based CpG methylation measurement. CONCLUSION: The methylation level of CXCR5 was significantly higher in RA patients than in OA and HC, and correlated with the level of inflammation in RA patients, our study establishes a link between CXCR5 DNA methylation and clinical features that may help in the diagnosis and disease management of RA patients.

[Traditional Chinese medicine therapy for rheumatoid arthritis: a review].

Rheumatoid arthritis(RA) is an autoimmune disease that seriously affects the physical and mental health of patients, but its pathogenesis is still unclear. At present, clinical treatment drugs include conventional synthetic disease modifing anti-rheumatic drugs(csDMARDs), nonsteroid anti-inflammtory drugs(NSAIDs), hormones, small molecule targeted drugs, biological agents, etc. These drugs can relieve the clinical symptoms of most patients with RA to a certain extent, but there are still many limitations, such as drug adverse reactions and individual differences in drug efficacy. Therefore, the research on drug treatment targets and the development of low-toxicity drugs helps further improve the precise prevention, diagnosis, and treatment of RA. There is an urgent need for efficient and low-toxic treatments to delay the clinical progress of RA. As a treasure of Chinese culture, traditional Chinese medicine(TCM) is widely used as an alternative therapy in the treatment of various diseases, and has a significant clinical efficacy. TCM therapy(including monomer traditional Chinese medicine, classical compounds, and non-drug therapies) has a significant curative effect on RA. Based on the literature research in recent years, this paper reviewed the clinical and mechanism research of TCM therapy in the treatment of RA, and provided more in-depth thinking for the wide application of TCM therapy in clinical practice.

Circulating Level of Blood Iron and Copper Associated with Inflammation and Disease Activity of Rheumatoid Arthritis.

This study aims to compare the concentrations of circulating levels of iron, zinc, and copper in blood samples of rheumatoid arthritis (RA) patients which determine the correlations with inflammation and disease activity. A total of 102 RA patients and 66 healthy controls were enrolled. Circulation of iron, zinc, and copper levels in whole blood were assessed. Hemoglobin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anticyclic citrullinated peptide antibody (anti-CCP) levels were collected. A meta-analysis was performed to validate our findings. Single and multiple variate generalized linear regression were applied to identify the correlation between trace elements and clinical characteristics. Blood copper level was significantly higher in RA patients (P < 0.001), while iron and zinc levels were decreased (P < 0.001 and P = 0.02, respectively). Meta-analysis confirmed our findings for zinc (SMD = - 1.17, P < 0.001) and copper (SMD = 1.24, P < 0.001). Copper level was positively correlated with DAS28-CRP (r = 0.35, P < 0.01), CRP (r = 0.45, P < 0.01) and ESR (r = 0.58, P < 0.01). Iron level was negatively correlated with DAS28-CRP (r = - 0.37, P < 0.01), CRP (r = - 0.46, P < 0.01) and ESR (r = - 0.55, P < 0.01). Circulating blood copper was significantly higher and positively correlated with DAS28-CRP and inflammatory markers, while circulating blood iron was decreased and negatively correlated with DAS28-CRP and inflammatory markers in RA patients.

Identification of DNA methylation-regulated differentially expressed genes in RA by integrated analysis of DNA methylation and RNA-Seq data.

OBJECTIVE: To identify novel DNA methylation-regulated differentially expressed genes (MeDEGs) in RA by integrated analysis of DNA methylation and RNA-Seq data. METHODS: The transcription and DNA methylation profiles of 9 RA and 15 OA synovial tissue were generated by RNA-Seq and Illumina 850K DNA methylation BeadChip. Gene set enrichment analysis (GSEA) and Weighted gene co-expression network analysis (WGCNA) were used to analyze methylation-regulated expressed genes by R software. The differentially expressed genes (DEGs), differentially methylated probes (DMPs), differentially methylated genes (DMGs) were analyzed by DESeq and ChAMP R package. The functional correlation of MeDEGs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein-protein interaction (PPI) network of MeDEGs was constructed by STRING and Reactome FI Cytoscape Plugin. Correlation analysis between methylation level and mRNA expression was conducted with R software. RESULTS: A total of 17,736 genes, 25,578 methylated genes and 755,852 methylation probes were detected. A total of 16,421 methylation-regulated expressed genes were obtained. The GSEA showed that these genes are associated with activation of immune response, adaptive immune response, Inflammatory response in C5 (ontology gene sets). For KEGG analysis, these genes are associated with rheumatoid arthritis, NF-kappa B signaling pathway, T cell receptor signaling pathway. The WGCNA showed that the turquoise module exhibited the strongest correlation with RA (R = 0.78, P = 1.27 × 10- 05), 660 genes were screened in the turquoise module. A total of 707 MeDEGs were obtained. GO analysis showed that MeDEGs were enriched in signal transduction, cell adhesion for BP, enriched in plasma membrane, integral component of membrane for CC, and enriched in identical protein binding, calcium ion binding for MF. The KEGG pathway analysis showed that the MeDEGs were enriched in calcium signaling pathway, T cell receptor signaling pathway, NF-kappa B signaling pathway, Rheumatoid arthritis. The PPI network containing 706 nodes and 882 edges, and the enrichment p value < 1.0 × 10- 16. With Cytoscape, based on the range of more than 10 genes, a total of 8 modules were screened out. Spearman correlation analysis showed RGS1(cg10718027), RGS1(cg02586212), RGS1(cg10861751) were significantly correlated with RA. CONCLUSIONS: RGS1 can be used as novel methylated biomarkers for RA.

Metabolomics in rheumatoid arthritis: Advances and review.

Rheumatoid arthritis (RA) is an autoimmune disease accompanied by metabolic alterations. The metabolic profiles of patients with RA can be determined using targeted and non-targeted metabolomics technology. Metabolic changes in glucose, lipid, and amino acid levels are involved in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, the arachidonic acid metabolic pathway, and amino acid metabolism. These alterations in metabolic pathways and metabolites can fulfill bio-energetic requirements, promote cell proliferation, drive inflammatory mediator secretion, mediate leukocyte infiltration, induce joint destruction and muscle atrophy, and regulate cell proliferation, which may reflect the etiologies of RA. Differential metabolites can be used as biomarkers for the diagnosis, prognosis, and risk prediction, improving the specificity and accuracy of diagnostics and prognosis prediction. Additionally, metabolic changes associated with therapeutic responses can improve the understanding of drug mechanism. Metabolic homeostasis and regulation are new therapeutic strategies for RA. In this review, we provide a comprehensive overview of advances in metabolomics for RA.

SFRP1 Negatively Modulates Pyroptosis of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis: A Review.

Secreted frizzled-related protein 1 (SFRP1) is a member of secretory glycoprotein SFRP family. As a primitive gene regulating cell growth, development and transformation, SFRP1 is widely expressed in human cells, including various cancer cells and fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA). Deletion or silencing of SFRP1 involves epigenetic and other mechanisms, and participates in biological behaviors such as cell proliferation, migration and cell pyroptosis, which leads to disease progression and poor prognosis. In this review, we discuss the role of SFRP1 in the pathogenesis of RA-FLS and summarize different experimental platforms and recent research results. These are helpful for understanding the biological characteristics of SFRP1 in RA, especially the mechanism by which SFRP1 regulates RA-FLS pyroptosis through Wnt/ß-catenin and Notch signaling pathways. In addition, the epigenetic regulation of SFRP1 in RA-FLS is emphasized, which may be considered as a promising biomarker and therapeutic target of RA.

RNA-seq and Network Analysis Reveal Unique Chemokine Activity Signatures in the Synovial Tissue of Patients With Rheumatoid Arthritis.

Purpose: This study aimed to provide a comprehensive understanding of the genome-wide expression patterns in the synovial tissue samples of patients with rheumatoid arthritis (RA) to investigate the potential mechanisms regulating RA occurrence and development. Methods: Transcription profiles of the synovial tissue samples from nine patients with RA and 15 patients with osteoarthritis (OA) (control) from the East Asian population were generated using RNA sequencing (RNA-seq). Gene set enrichment analysis (GSEA) was used to analyze all the detected genes and the differentially expressed genes (DEGs) were identified using DESeq. To further analyze the DEGs, the Gene Ontology (GO) functional enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. The protein-protein interaction (PPI) network of the DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and the hub genes were identified by topology clustering with the Molecular Complex Detection (MCODE)-Cytoscape. The most important hub genes were validated using quantitative real-time PCR (qRT-PCR). Results: Of the 17,736 genes detected, 851 genes were identified as the DEGs (474 upregulated and 377 downregulated genes) using the false discovery rate (FDR) approach. GSEA revealed that the significantly enriched gene sets that positively correlated with RA were CD40 signaling overactivation, Th1 cytotoxic module, overactivation of the immune response, adaptive immune response, effective vs. memory CD8+ T cells (upregulated), and naïve vs. effective CD8+ T cells (downregulated). Biological process enrichment analysis showed that the DEGs were significantly enriched for signal transduction (P = 3.01 × 10-6), immune response (P = 1.65 × 10-24), and inflammatory response (P = 5.76 × 10-10). Molecule function enrichment analysis revealed that the DEGs were enriched in calcium ion binding (P = 1.26 × 10-5), receptor binding (P = 1.26 × 10-5), and cytokine activity (P = 2.01 × 10-3). Cellular component enrichment analysis revealed that the DEGs were significantly enriched in the plasma membrane (P = 1.91 × 10-31), an integral component of the membrane (P = 7.39 × 10-13), and extracellular region (P = 7.63 × 10-11). The KEGG pathway analysis showed that the DEGs were enriched in the cytokine-cytokine receptor interaction (P = 3.05 × 10-17), chemokine signaling (P = 3.50 × 10-7), T-cell receptor signaling (P = 5.17 × 10-4), and RA (P = 5.17 × 10-4) pathways. We confirmed that RA was correlated with the upregulation of the PPI network hub genes, such as CXCL13, CXCL6, CCR5, CXCR5, CCR2, CXCL3, and CXCL10, and the downregulation of the PPI network hub gene such as SSTR1. Conclusion: This study identified and validated the DEGs in the synovial tissue samples of patients with RA, which highlighted the activity of a subset of chemokine genes, thereby providing novel insights into the molecular mechanisms of RA pathogenesis and identifying potential diagnostic and therapeutic targets for RA.

Biomarkers to Predict DMARDs Efficacy and Adverse Effect in Rheumatoid Arthritis.

Rheumatoid arthritis (RA), one of the most common immune system diseases, mainly affects middle-aged and elderly individuals and has a serious impact on the quality of life of patients. Pain and disability caused by RA are significant symptoms negatively affecting patients, and they are especially seen when inappropriate treatment is administered. Effective therapeutic strategies have evolved over the past few decades, with many new disease-modifying antirheumatic drugs (DMARDs) being used in the clinic. Owing to the breakthrough in the treatment of RA, the symptoms of patients who could not be treated effectively in the past few years have been relieved. However, some patients complain about symptoms that have not been reported, implying that there are still some limitations in the RA treatment and evaluation system. In recent years, biomarkers, an effective means of diagnosing and evaluating the condition of patients with RA, have gradually been used in clinical practice to evaluate the therapeutic effect of RA, which is constantly being improved for accurate application of treatment in patients with RA. In this article, we summarize a series of biomarkers that may be helpful in evaluating the therapeutic effect and improving the efficiency of clinical treatment for RA. These efforts may also encourage researchers to devote more time and resources to the study and application of biomarkers, resulting in a new evaluation system that will reduce the inappropriate use of DMARDs, as well as patients' physical pain and financial burden.

MicroRNA-Mediated Epigenetic Regulation of Rheumatoid Arthritis Susceptibility and Pathogenesis.

MicroRNAs (miRNAs) play crucial roles in regulating the transcriptome and development of rheumatoid arthritis (RA). Currently, a comprehensive map illustrating how miRNAs regulate transcripts, pathways, immune system differentiation, and their interactions with terminal cells such as fibroblast-like synoviocytes (FLS), immune-cells, osteoblasts, and osteoclasts are still laking. In this review, we summarize the roles of miRNAs in the susceptibility, pathogenesis, diagnosis, therapeutic intervention, and prognosis of RA. Numerous miRNAs are abnormally expressed in cells involved in RA and regulate target genes and pathways, including NF-κB, Fas-FasL, JAK-STAT, and mTOR pathways. We outline how functional genetic variants of miR-499 and miR-146a partly explain susceptibility to RA. By regulating gene expression, miRNAs affect T cell differentiation into diverse cell types, including Th17 and Treg cells, thus constituting promising gene therapy targets to modulate the immune system in RA. We summarize the diagnostic and prognostic potential of blood-circulating and cell-free miRNAs, highlighting the opportunity to combine these miRNAs with antibodies to cyclic citrullinated peptide (ACCP) to allow accurate diagnosis and prognosis, particularly for seronegative patients. Furthermore, we review the evidence implicating miRNAs as promising biomarkers of efficiency and response of, and resistance to, disease-modifying anti-rheumatic drugs and immunotherapy. Finally, we discuss the autotherapeutic effect of miRNA intervention as a step toward the development of miRNA-based anti-RA drugs. Collectively, the current evidence supports miRNAs as interesting targets to better understand the pathogenetic mechanisms of RA and design more efficient therapeutic interventions.

Enhanced antibacterial efficacy and mechanism of octyl gallate/beta-cyclodextrins against Pseudomonas fluorescens and Vibrio parahaemolyticus and incorporated electrospun nanofibers for Chinese giant salamander fillets preservation.

A series of alkyl gallates were evaluated for the antibacterial activity against two common Gram-negative foodborne bacteria (Pseudomonas fluorescens and Vibrio parahaemolyticus) associated with seafood. The length of the alkyl chain plays a pivotal role in eliciting their antibacterial activities and octyl gallate (OG) exerted an excellent inhibitory efficacy. To extend the aqueous solubility, stability, and bactericidal properties of octyl gallate (OG), an inclusion complex between OG and ß-cyclodextrin (ßCD), OG/ßCD, was prepared and identified with various methods including X-ray diffraction (XRD), differential scanning calorimeter (DSC) and Fourier transform infrared spectroscopy (FTIR). Furthermore, the enhanced inhibitory effect and potential antibacterial mechanism of OG/ßCD against two Gram-negative and Gram-positive foodborne bacteria were comprehensively investigated. The results show that OG/ßCD could function against bacteria through effectively damaging the membrane, permeating into cells, and then disturbing the activity of the respiratory electron transport chain to cause the production of high-level intracellular hydroxyl radicals. Moreover, the reinforced OG/ßCD-incorporated polylactic acid (PLA) nanofibers were fabricated using the electrospinning technique as food packaging to extend the Chinese giant salamander fillet's shelf life at 4 °C. This research highlights the antibacterial effectiveness of OG/ßCD in aqueous media, which can be used as a safe multi-functionalized food additive combined with the benefits of electrospun nanofibers to extend the Chinese giant salamander fillets shelf life by 15 d at 4 °C.

DNA methylation change of HIPK3 in Chinese rheumatoid arthritis and its effect on inflammation.

Introduction: Homeodomain-interacting protein kinase 3 (HIPK3) plays an important role in cell proliferation, apoptosis, and inflammation. Over-expression of HIPK3 in immune cells in rheumatoid arthritis (RA) has been reported. In this study, we investigated blood methylation levels and clinical characteristics of RA in a Chinese population. Methods: A total of 235 patients with RA, 30 with osteoarthritis (OA), and 30 matched healthy controls were recruited. The methylation status of seven CpGs in the differentially methylated region of HIPK3 (cg05501357) was measured using targeted methylation-sequencing technology. The association between methylation haplotypes and the overall methylation status of HIPK3 with clinical characteristics was assessed using generalized linear regression. Results: All seven CpGs showed hypomethylation status in RA blood compared with OA and normal individuals (overall p= 1.143×10-8 and FDR= 2.799×10-7), which is consistent with the previously reported high expression of HIPK3 in RA immune cells. Among all seven CpGs, 33286785 showed the highest predictive power with an area under the curve (AUC) of 0.829; we received a higher AUC=0.864 when we combined HIPK3 with anti-citrullinated protein antibodies (ACPA -) and rheumatoid factor (RF +) in the prediction model, indicating that when a patient's ACPA is negative, HIPK3 can assist RF as a new clinical index for the diagnosis of RA. We also found that HIPK3 methylation levels were negatively correlated with C-reactive protein (CRP; r= -0.16, p= 0.01). Methylation haplotypes were analyzed, and the full methylation haplotype (FMH; r= 0.16, p= 0.01) and full non-methylation haplotype (FNH; r= 0.18, p= 0.0061) were negatively correlated with CRP. Conclusion: Circulating blood methylation levels in the protein region of HIPK3 can be utilized as a supportive diagnostic biomarker and CRP level indicator for RA.

MicroRNA Variants and HLA-miRNA Interactions are Novel Rheumatoid Arthritis Susceptibility Factors.

Genome-wide association studies have identified >100 genetic risk factors for rheumatoid arthritis. However, the reported genetic variants could only explain less than 40% heritability of rheumatoid arthritis. The majority of the heritability is still missing and needs to be identified with more studies with different approaches and populations. In order to identify novel function SNPs to explain missing heritability and reveal novel mechanism pathogenesis of rheumatoid arthritis, 4 HLA SNPs (HLA-DRB1, HLA-DRB9, HLA-DQB1, and TNFAIP3) and 225 common SNPs located in miRNA, which might influence the miRNA target binding or pre-miRNA stability, were genotyped in 1,607 rheumatoid arthritis and 1,580 matched normal individuals. We identified 2 novel SNPs as significantly associated with rheumatoid arthritis including rs1414273 (miR-548ac, OR = 0.84, p = 8.26 × 10-4) and rs2620381 (miR-627, OR = 0.77, p = 2.55 × 10-3). We also identified that rs5997893 (miR-3928) showed significant epistasis effect with rs4947332 (HLA-DRB1, OR = 4.23, p = 0.04) and rs2967897 (miR-5695) with rs7752903 (TNFAIP3, OR = 4.43, p = 0.03). In addition, we found that individuals who carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, p < 1.0 × 10-6) times more risk of being affected by RA. Finally, we demonstrated that the targets of the significant miRNAs showed enrichment in immune related genes (p = 2.0 × 10-5) and FDA approved drug target genes (p = 0.014). Overall, 6 novel miRNA SNPs including rs1414273 (miR-548ac, p = 8.26 × 10-4), rs2620381 (miR-627, p = 2.55 × 10-3), rs4285314 (miR-3135b, p = 1.10 × 10-13), rs28477407 (miR-4308, p = 3.44 × 10-5), rs5997893 (miR-3928, p = 5.9 × 10-3) and rs45596840 (miR-4482, p = 6.6 × 10-3) were confirmed to be significantly associated with RA in a Chinese population. Our study suggests that miRNAs might be interesting targets to accelerate understanding of the pathogenesis and drug development for rheumatoid arthritis.

Identification of differential key biomarkers in the synovial tissue between rheumatoid arthritis and osteoarthritis using bioinformatics analysis.

INTRODUCTION/OBJECTIVES: Rheumatoid arthritis (RA) and osteoarthritis (OA) are two common joint diseases with similar clinical manifestations. Our study aimed to identify differential gene biomarkers in the synovial tissue between RA and OA using bioinformatics analysis and validation. METHOD: GSE36700, GSE1919, GSE12021, GSE55235, GSE55584, and GSE55457 datasets were downloaded from the Gene Expression Omnibus database. A total of 57 RA samples and 46 OA samples were included. The differentially expressed genes (DEGs) were identified. The Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also performed. Protein-protein interaction (PPI) network of DEGs and the hub genes were constructed and visualized via Search Tool for the Retrieval of Interacting Genes/Proteins, Cytoscape, and R. Selected hub genes were validated via reverse transcription-polymerase chain reaction. RESULTS: A total of 41 DEGs were identified. GO functional enrichment analysis showed that DEGs were enriched in immune response, signal transduction, regulation of immune response for biological process, in plasma membrane and extracellular region for cell component, and antigen binding and serine-type endopeptidase activity for molecular function. KEGG pathway analysis showed that DEGs were enriched in cytokine-cytokine receptor interaction and chemokine signaling pathway. PPI network analysis established 70 nodes and 120 edges and 15 hub genes were identified. The expression of CXCL13, CXCL10, and ADIPOQ was statistically different between RA and OA synovial tissue. CONCLUSION: Differential expression of CXCL13, CXCL10, and ADIPOQ between RA and OA synovial tissue may provide new insights for understanding the RA development and difference between RA and OA. Key Points • Bioinformatics analysis was used to identify the differentially expressed genes in the synovial tissue between rheumatoid arthritis and osteoarthritis. • CXCL13, CXCL10, and ADIPOQ might provide new insight for understanding the differences between RA and OA.

On the mechanism behind enhanced antibacterial activity of alkyl gallate esters against foodborne pathogens and its application in Chinese icefish preservation.

The objective of this study was to investigate antibacterial activities and action mode of alkyl gallates against three food-related bacteria. Results show that the length of the alkyl chain plays a critical role in eliciting their antibacterial activities and octyl gallate (GAC8) exhibited an outstanding bactericidal effect against these strains. A possible bactericidal mechanism of GAC8 against E. coli was fully elucidated by analyzing associated changes in cellular functions of E. coli, including assessments of membrane modification and intracellular oxidation state. Our data strongly suggested that GAC8 functions outside and inside the bacterial membrane and causes increased intracellular reactive oxygen species (hydroxyl radicals) and subsequent oxidative damage. We demonstrated that the hydroxyl radical formation induced by GAC8 is the end product of an oxidative damage cellular death pathway involving a transient depletion of NADH, the tricarboxylic acid cycle, intrinsic redox cycling activities, and stimulation of the Fenton reaction. Also, chitosan-based edible films containing GAC8 have unique superiorities for icefish preservation at 4 °C. This research highlights the effectiveness of GAC8 as an attractive antibacterial, which possesses both antioxidant and antibacterial activities and can be used as a multifunctional food additive combined with the benefit of active packaging for food preservations.

Therapeutic Effects of (5R)-5-Hydroxytriptolide on Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via lncRNA WAKMAR2/miR-4478/E2F1/p53 Axis.

Rheumatoid arthritis (RA) is an autoimmune disease. Fibroblast-like synoviocytes (FLS) serve a major role in synovial hyperplasia and inflammation in RA. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, shows promising therapeutic effects for RA and is now in phase II clinical trials in China. However, the underlying mechanism of LLDT-8 is still not fully understood. Here, we found that LLDT-8 inhibited proliferation and invasion of RA FLS, as well as the production of cytokines. Microarray data demonstrated that LLDT-8 upregulated the expression of long non-coding RNA (lncRNA) WAKMAR2, which was negatively associated with proliferation and invasion of RA FLS, as well as the production of pro-inflammatory cytokines. Knockdown of WAKMAR2 abolished the inhibitory effects of LLDT-8 on RA FLS. Mechanistically, WAKMAR2 sponged miR-4478, which targeted E2F1 and downstreamed p53 signaling. Rescue experiments indicated that the inhibitory effects of LLDT-8 on RA FLS were dependent on WAKMAR2/miR-4478/E2F1/p53 axis.

Antimicrobial effect and mechanism of non-antibiotic alkyl gallates against Pseudomonas fluorescens on the surface of Russian sturgeon (Acipenser gueldenstaedti).

Since Pseudomonas fluorescens is the main microorganism causing severe spoilage in refrigerated aquatic products, the searching for non-antibiotic antibacterial agents effective against it continues to receive increasing interest. This study aimed to investigate the antibacterial effects and mechanisms of alkyl gallic esters against P. fluorescens isolated from the Russian sturgeon (Acipenser gueldenstaedti), as well as the effectiveness in combination with chitosan films on the preservation of sturgeon meats at 4 °C. Our data shows that the alkyl chain length plays a significant role in eliciting their antibacterial activities and octyl gallate (GAC8) exhibited an outstanding inhibitory efficacy. GAC8 can rapidly enter into the membrane lipid bilayer portion to disorder the membrane, and further inhibit the growth of the P. fluorescens through interfering both tricarboxylic acid cycle related to energy supply and amino acid metabolism associated with cell membranes, suppressing oxygen consumption and disturbing the respiration chain. Moreover, the alteration in membrane fatty acids indicated that GAC8 could disrupt the composition of cell membrane fatty acids, rendering the bacteria more sensitive to the antibacterial. The SEM results also substantiate the damage of the structure of the bacterial membrane caused by GAC8. Additionally, the edible chitosan-based films incorporated with GAC8 showed the enhanced antibacterial efficacy to remarkably extend the shelf life of Russian sturgeon. Overall, our findings not only provide new insight into the mode of action of GAC8 against P. fluorescens but also demonstrate composite films containing GAC8, as a kind of safe and antibacterial material, have a great promise for application in food preservations.

Antimicrobial mechanism of alkyl gallates against Escherichia coli and Staphylococcus aureus and its combined effect with electrospun nanofibers on Chinese Taihu icefish preservation.

The objective of this study was to investigate the antibacterial activity and potential mechanism of alkyl gallates against Escherichia coli and Staphylococcus aureus. Results show that the length of the alkyl chain plays a pivotal role in eliciting the activity and octyl gallate (OG) exerted excellent bactericidal activity through a multiple bactericidal mechanism. OG functions against both bacteria through damaging bacterial cell wall integrity, permeating into cells and then interacting with DNA, as well as disturbing the activity of the respiratory electron transport chain to induce a high-level toxic ROS (hydroxyl radicals) generation and up-regulation of the ROS genes. Also, electrospun nanofibers with OG have unique superiorities for maintaining the freshness of the icefish (4 °C). This research not only provides a more in-depth understanding of the interaction between OG and microorganisms but also highlights the great promise of using OG as a safe multi-functionalized food additive for food preservations.