No abstract

No abstract

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease with unknown etiology. CCN1, an extracellular matrix-associated protein, is associated with carcinoma, inflammation, liver fibrosis, and even autoimmune diseases. However, the role that CCN1 plays in AIH has remained undetermined. In this study, expression of CCN1 in liver was detected by real-time PCR, western blot and immunohistochemistry (IHC). CCN1 level in serum was detected by ELISA. Diagnostic value of CCN1 was determined by receiver operating characteristic (ROC) curve analysis. CCN1 conditional knockout (CCN1fl/flCre+) mice were generated by mating CCN1fl/fl C57BL/6J and CAG-Cre-ERT C57BL/6J mice. Autoimmune hepatitis mice model was induced by concanavalin A (ConA). IKKα/β, IκBα, NF-κB p65 and Akt phosphorylation were determined by western blot. NF-κB p65 nuclear translocation was examined by immunofluorescence. Here, we found that CCN1 was over-expressed in hepatocytes of AIH patients. CCN1 level also increased in serum of AIH patients compared to healthy controls (HC). ROC curve analysis results showed that serum CCN1 was able to distinguish AIH patients from HD. In ConA induced hepatitis mice model, CCN1 conditional knockout (CCN1fl/flCre+) attenuated inflammation by reducing ALT/AST level and IL-6 expression. In vitro, CCN1 treatment dramatically induced IL-6 production in LO2 cells. Moreover, the production of IL-6 was attenuated by CCN1 knockdown. Furthermore, we showed that CCN1 could activate IL-6 production via the PI3K/Akt/NF-κB signaling pathway by binding to α6β1 receptor. In summary, our results reveal a novel role of CCN1 in promoting inflammation by upregulation of IL-6 production in AIH. Our study also suggests that targeting of CCN1 may represent a novel strategy in AIH treatment.

Aim Gut microbiota play an important role in rheumatoid arthritis (RA). Biological therapies targeting tumor necrosis factor‐α (TNF‐α) have been used for treatment in RA patients. However, whether TNF‐α antagonist has some influence on gut microbiota is still unknown. This study aims to investigate the distribution of gut microbiota in collagen‐induced arthritis (CIA) mice treated with the TNF‐α antagonist etanercept. Methods Collagen‐induced arthritis mice were induced by type II collagen. Cytokine expression was detected by real‐time polymerase chain reaction. 16S ribosomal RNA sequencing was performed to characterize the gut microbiota in CIA mice treated with vehicle or etanercept. Sequencing reads were processed by Microbial Ecology software program. Results Compared with vehicle‐treated mice, we showed that CIA mice treated with etanercept led to attenuation of inflammation and reduced expression of TNF‐α, interferon (IFN)‐γ, interleukin (IL)‐6 and IL‐21. Meanwhile, results showed operational taxonomic units, richness estimators and the diversity indices of gut microbiota in etanercept‐treated mice were lower than that in vehicle‐treated mice. Moreover, bacterial abundance analyses showed that genus Escherichia/Shigella was more abundant in etanercept‐treated mice, and Lactobacillus, Clostridium XlVa, Tannerella were less abundant. The altered bacterial genus was correlated with TNF‐α, IFN‐γ, IL‐6, IL‐21 and IL‐10. Conclusion Our results revealed that TNF‐α antagonist treatment can reduce the abundance and diversity of gut microbiota in CIA mice. Targeted gut microbiota may be a new therapeutic strategy for the treatment of RA.

ObjectiveEarly and correct diagnosis would be beneficial for outcomes of rheumatoid arthritis (RA), but there are some limitations in current diagnostic tools. In this study, we aimed to evaluate the diagnostic value of circulating miR-22-3p and let-7a-5p in RA. MethodsSeventy-six RA patients, 30 systemic lupus erythematosus patients, 32 Sjögren's syndrome patients and 36 healthy donors recruited at the First Affiliated Hospital of Fujian Medical University (China) were included in this study. in plasma were measured using reverse transcriptase quantitative PCR and serum cytokines were detected by cytometric bead array. The participants' clinical materials were also collected. Receiver operating characteristic curve analysis and correlation analysis were performed to assess the potential value of circulating miRNAs in RA. Results Circulating miR-22-3p and let-7a-5p are significantly increased in RA patients and able to distinguish RA patients from other populations. Circulating let-7a-5p has been shown to improve the diagnostic ability of current laboratory indicators anti-cyclic citrullinated peptide antibodies and rheumatoid factor. Moreover, the discriminatory capacityof both circulating miRNAs contribute to complement the diagnosis for seronegative RA. Meanwhile, correlation analysis reveals that circulating miR-22-3p positively correlates with haemoglobin, serum bilirubin, albumin and IL-17 but negatively correlates with mean platelet volume as well as let-7a-5p. ConclusionThe increased circulating miR-22-3p and let-7a-5p levels in RA patients, especially in seronegative RA patients, may provide potential promising diagnostic biomarkers for RA in clinical practice.

ObjectiveThe aim of the study was to investigate the role of N6‐Methyladenosine (m6A) modification in the progression of rheumatoid arthritis (RA).MethodsPeripheral blood mononuclear cells (PBMCs) from RA patients and healthy controls were collected. The expression of m6A‐modification related proteins and m6A levels were detected using PCR, western blot and m6A ELISA. The roles of methyltransferase‐like 14 (METTL14) in the regulation of inflammation in RA was explored using MeRIP‐sequencing and RNA immunoprecipitation assays. Collagen antibody‐induced arthritis (CAIA) mice were used as an in vivo model to study the role of METTL14 in the inflammation progression of RA.ResultsWe found that m6A writer METTL14 and m6A levels were decreased in PBMCs of active RA patients, and correlated negatively with the disease activity score using 28 joint counts (DAS28). Knockdown of METTL14 down‐regulated m6A, and promoted the secretion of inflammatory cytokines IL‐6 and IL‐17 in PBMCs of RA patients. Consistently, METTL14 knockdown promoted joint inflammation accompanied by upregulation of IL‐6 and IL‐17 in CAIA mice. MeRIP‐sequencing and functional studies confirmed that tumor necrosis factor alpha induced protein 3 (TNFAIP3), a key suppressor of NF‐κB inflammatory pathway, was involved in m6A‐regulated PBMCs. Mechanistic investigations revealed that m6A affected TNFAIP3 expression by regulation of mRNA stability and translocation in TNFAIP3 protein‐coding regions (CDS).ConclusionsOur study highlights the critical roles of m6A on regulation of inflammation in RA progression. Treatment strategies targeting m6A modification may represent a new option for management of RA.This article is protected by copyright. All rights reserved.image

Objective The diagnosis of seronegative rheumatoid arthritis (SNRA) is often difficult due to the unavailability of reliable laboratory markers. The aim of this study was to identify differentially expressed proteins in sera of SNRA, seropositive RA (SPRA), and healthy donors (HD). Methods A total of 32 seropositive RA patients, 32 SNRA patients, and 35 HD were enrolled in our study. Differentially expressed proteins between 3 groups were identified via isobaric tags for relative and absolute quantitation (iTRAQ)‐based proteomic analysis, and an ELISA test was used for the validation test. Correlation analysis was conducted by GraphPad Prism. Results Using iTRAQ quantitative proteomics, we identified 14 proteins were significantly different between SPRA and SNRA, including 4 upregulated proteins and 10 downregulated proteins. Four differentially expressed proteins were validated by ELISA test, and the results showed that SAA1 protein was significantly higher in SPRA and SNRA patients compared with HD, and PSME1 was elevated in SPRA patients. What's more, SAA1 was increased in the anti‐CCP or RF high‐level group in RA patients, and PSME1 was increased in the RF high‐level group. Alternatively, SAA1 was positively correlated with inflammation indicators in RA patients, while PSME1 showed no correlation with inflammation indicators. Conclusions iTRAQ proteomic approaches revealed variations in serum protein composition among SPRA patients, SNRA patients, and HD and provided new idea for advanced diagnostic methods and precision treatment of RA.

The aim of this study was to systematically evaluate the efficacy and safety of gefitinib and cetuximab-based therapies in patients with advanced non-small-cell lung cancer (NSCLC). The studies to be used for the comparisons were selected from the available literature on gefitinib and cetuximab-based therapies compared to conventional chemotherapy in patients with advanced NSCLC. The meta-analysis was performed with RevMan 5.0 software and the Bucher approach was applied to conduct the indirect comparisons. A total of 4 studies, including 935 patients, on gefitinib therapy vs. conventional chemotherapy and 4 studies, including 1,015 patients, on cetuximab-based therapy vs. conventional chemotherapy, were used for indirect comparisons. As regards efficacy, the risk ratio (RR) of objective response rate and 1-year survival rate between gefitinib and cetuximab-based therapies in patients with advanced NSCLC were 0.99 [95% confidence interval (CI): 0.75-1.32; P=0.9584] and 0.85 (95% CI: 0.71-1.01; P=0.0696), respectively, and the mean difference of progression-free survival and overall survival (OS) were -0.15 (95% CI: -0.90 to 0.60; P=0.6946) and -1.84 (95% CI: -3.53 to -0.15; P=0.0331), respectively. As regards safety, the RR of grade 3/4 adverse events (AEs) was 0.29 (95% CI: 0.19-0.44; P=0.0001). The results demonstrated that cetuximab-based therapy was superior to gefitinib therapy in terms of OS and inferior to gefitinib therapy in terms of AEs, whereas there were no significant differences in terms of efficacy and safety between the two therapies on other endpoints adopted for advanced NSCLC. However, further well-designed randomized controlled trials and continuous studies are required to confirm our findings.