Yaling Zeng’s research while affiliated with Macau University of Science and Technology and other places

Rheumatoid arthritis (RA) is an autoimmune inflammation disease characterized by imbalance of immune homeostasis. p53 mutants are commonly described as the guardian of cancer cells by conferring them drug-resistance and immune evasion. Importantly, p53 mutations have also been identified in RA patients, and this prompts the investigation of its role in RA pathogenesis. The cytotoxicity of disease-modifying anti-rheumatic drugs (DMARDs) against p53 wild-type (WT)/mutant-transfected RA fibroblast-like synoviocytes (RAFLSs) was evaluated by MTT assay. Adeno-associated virus (AAV) was employed to establish p53 WT/R211* adjuvant-induced arthritis (AIA) rat model. The arthritic condition of rats was assessed by various parameters such as micro-CT analysis. Knee joint samples were isolated for total RNA sequencing analysis. The expressions of cytokines and immune-related genes were examined by qPCR, ELISA assay and immunofluorescence. The mechanistic pathway was determined by immunoprecipitation and Western blotting in vitro and in vivo. Among p53 mutants, p53R213* exhibited remarkable DMARD-resistance in RAFLSs. However, AAV-induced p53R211* overexpression ameliorated inflammatory arthritis in AIA rats without Methotrexate (MTX)-resistance, and our results discovered the immunomodulatory effect of p53R211* via suppression of T-cell activation and T helper 17 cell (Th17) infiltration in rat joint, and finally downregulated expressions of pro-inflammatory cytokines. Total RNA sequencing analysis identified the correlation of p53R211* with immune-related pathways. Further mechanistic studies revealed that p53R213*/R211* instead of wild-type p53 interacted with TANK-binding kinase 1 (TBK1) and suppressed the innate immune TBK1–Interferon regulatory factor 3 (IRF3)–Stimulator of interferon genes (STING) cascade. This study unravels the role of p53R213* mutant in RA pathogenesis, and identifies TBK1 as a potential anti-inflammatory target.

Epalrestat, an aldose reductase inhibitor (ARI), has been clinically adopted in treating diabetic neuropathy in China and Japan. Apart from the involvement in diabetic complications, AR has been implicated in inflammation. Here, we seek to investigate the feasibility of clinically approved ARI, epalrestat, for the treatment of rheumatoid arthritis (RA). The mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression. Epalrestat significantly suppressed lipopolysaccharide (LPS) induced TNF-α, IL-1β, and IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly, epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Interestingly, the combined treatment of epalrestat with N-Acetylcysteine (NAC), an anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory cytokines, and significantly improved the arthritic condition. Taken together, the anti-arthritic effect of epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of epalrestat, suggesting that the combined therapy of epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need epalrestat for the treatment of diabetic complications.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder which is associated with the dysregulation of autoimmune response. In recent years, early diagnosis, aggressive treatment and alternative therapeutic options of disease-modifying anti-rheumatic drugs (DMARDs) markedly improve both the management and long-term prognosis of RA. Since the discovery of non-coding RNA (ncRNA) including microRNA (miRNA), long non-coding RNA (lncRNA) and others, their altered expressions have been unraveled to be deregulated in various diseases including RA. Several lines of evidence are emerging that ncRNA may contribute to the pathogenesis, disease progression and treatment of RA. For example, SNP rs2850711 within lnc00305 was indicated to associate with RA development susceptibility, whereas a higher level of miR-10a represented a good response to methotrexate (MTX) treatment in RA patients. In the aspect of refractory RA, ncRNA also plays an important role by affecting or regulating drug sensitivity in RA patients. Of note, lower expression of miR-20a in rheumatoid arthritis synovial fibroblast (RASFs) was demonstrated to activate the Janus Kinase (JAK)- signal transducer and activator of transcription 3(STAT3)-mediated inflammation, thereby promoting cell proliferation and apoptosis-resistant. In this review, we have illustrated the changes of ncRNAs and their underlying mechanisms in the whole developing period of RA pathogenesis and disease progression, as well as highlighted the novel therapeutic targets/strategies and bio-markers for RA therapy.

Ageing is an unavoidable process in humans and a major factor for the increasing risk of various diseases. In the United States, more than 50% of rheumatoid arthritis patients are middle-aged or elderly, but the risk factors and mechanisms by which ageing increases the incidence of rheumatoid arthritis are not known. It has been suggested that the accumulation of DNA fragments increases the risk of autoimmune diseases, such as systemic lupus erythematosus. DNA fragments are a common nucleic acid metabolite in ageing organisms as well as in the serum of humans and animals with rheumatoid arthritis; therefore, we hypothesize that DNA fragments are one of the factors contributing to the development of rheumatoid arthritis due to ageing. First, we analysed two in vitro DNA damage response models by using a gene silencing approach and determined that the DNA fragment clearance gene TREX1 can regulate inflammatory factor release in normal cells. Second, after TREX1 expression was knocked down locally or systemically in rats via the Cre-LoxP system and compared with that in AIA(adjuvant-induced arthritis) model rats treated with AAV-TREX1, it was determined that DNA fragments can result in manifestations of arthritis and abnormal activation of the immune system in rats. These results, including the low expression of the TREX1 gene in clinical patient and AIA model samples and the results of immunohistochemical, Western blot, and transcriptome analyses, revealed that the TREX1 gene can regulate cellular senescence-associated secretory phenotype (SASP)-related manifestations and showed that dysregulation of c-Jun and c-Fos, components of the TREX1 transcription factor AP-1, is associated with SASP induction. Finally, it was confirmed in vitro that different causes of decreased c-Fos expression can inhibit TREX1 expression. These DNA fragments are potent producers of inflammation-releasing mediators, and TREX1 is an effective degrader of DNA fragments; it is also a key gene that regulates cellular immunity and ageing. Therefore, effectively clearing excess DNA fragments from the body and ensuring the health of senescent cells may be a potential prevention strategy for RA.