Angiogenesis is a critical factor for rheumatoid arthritis (RA). Although anti-TNF biologics work effectively on some RA patients, concerns have been raised about the possible increased development of malignancies alongside such treatments. Arsenic trioxide (As2O3) has attracted worldwide attention and has been reported to treat some cancers. However, the effects of As2O3 on angiogenesis in the RA synovium remain unclear. Here, we report a systematic increased expression of TSP-1, TGF-β1, CTGF and VEGF in supernatants of a RA fibroblast-like synoviocytes (RA-FLS) and human dermal microvascular endothelial cells (HDMECs) co-culture compared with those from a normal human fibroblast-like synoviocytes (NH-FLS) and HDMECs co-culture. This increased expression may up-regulate endothelial tube formation and transwell migration, as well as microvessel sprouting in ex vivo aortic ring assay. These networked angiogenic factors mainly form a functional module regulating angiogenesis in the RA synovium. We show that As2O3 inhibits angiogenesis in the collagen-induced arthritis (CIA) synovium and consequently arthritis severity via significant suppression of TSP-1, TGF-β1, CTGF and VEGF expression in the CIA synovium, plus in the RA-FLS and HDMECs co-culture as well as NH-FLS and HDMECs co-culture system along with the presence or absence of TNF-α treatment. Thus As2O3 has a significant anti-angiogenesis effect on the RA-FLS and CIA synovium via its inhibition of the RA angiogenic functional module of TSP-1, TGF-β1, CTGF and VEGF and may have a potential for treating RA beyond cancer therapy.

Objective: NLRP3 inflammasome may play a key role in OA pathogenesis. Stromal cell-derived factor-1 (SDF-1) is a homeostatic CXC chemokine. Since the role of SDF-1 in OA has not been explored, this study aimed to examine the effect of SDF-1 on NLRP3 inflammasome and pyroptosis in synoviocytes from OA joints. Materials and methods: Human synovium was obtained from OA patients for isolation of primary synoviocytes and a murine model of collagenase-induced OA was established for testing intra-articular injections of SDF-1. Immunoblotting assays were used to examine the effects and underlying mechanism of action of SDF-1 on NLRP3 inflammasome and synoviocyte pyroptosis in synoviocytes. Inhibitors of AMPK and PI3K–mTOR were utilized to investigate the key signaling pathways involved in SDF-1-mediated OA inflammasome formation and pyroptosis. Results: Synoviocytes from OA joints exhibited significantly higher expression of NLRP3 inflammasome and biomarkers of synoviocyte pyroptosis relative to healthy individuals. This was confirmed in the collagenase-induced OA model, where OA synoviocytes had a significantly lower SDF-1 expression than healthy ones. SDF-1 treatment in synoviocytes of OA patients and collagenase-induced OA led to significant downregulation in the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers. Inhibition of the AMPK signaling pathway significantly suppressed the inhibitory effect of SDF-1 on NLRP3 inflammasome expression of OA synoviocytes. However, blocking the SDF-1-activated PI3K–mTOR signaling pathway could still suppress the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers. Conclusions: SDF-1 ameliorates NLRP3 inflammasome and pyroptosis in OA synoviocytes through activation of the AMPK signaling pathway. Therefore, SDF-1 may be a novel therapeutic target for OA.

Hepatitis B virus (HBV) infection is responsible for 50% of liver cancer cases globally; this disease is one of the leading causes of cancer-associated mortality. One reported mechanism underlying the development of liver cancer is the mutation of tumor suppressor genes induced by the overexpression of apolipoprotein B mRNA-editing enzyme catalytic subunit 2 (APOBEC2) in hepatocytes. In addition, it has been observed that HBV inhibited microRNA (miR)-122 expression in hepatocytes; however, the molecular mechanisms involved in liver cancer development remain unknown and further investigations are required. In the present study, the mechanistic roles of HBV infection in modulating the expression of miR-122 and APOBEC2, and the development of liver cancer, were investigated. Reverse transcription-quantitative PCR and western blot analyses revealed that APOBEC2 expression was markedly upregulated following HBV infection. Of note, the expression profile of APOBEC2 in the Huh7 and HepG2 liver cancer cell lines opposed that of miR-122; this miR is the most abundant miRNA in the liver and has been associated with hepatocarcinogenesis. Mechanistically, it was demonstrated via a dual-luciferase assay that miR-122 could specifically bind to the 3 '-untranslated region (3 ' UTR) of APOBEC2 mRNA, inhibiting its expression. Collectively, the findings of the present study may provide insight into the mechanistic role of HBV infection in modulating the expression of miR-122, which targets the 3 ' UTR of APOBEC2 mRNA, subsequently inducing liver carcinogenesis.