Alamandine, a new member of the renin-angiotensin system (RAS), attenuates collagen-induced arthritis in mice via inhibiting cytokine secretion in synovial fibroblasts.

Alamandine is a novel component of the renin-angiotensin system (RAS) as well as an important biologically active peptide. It has predominantly been studied in cardiovascular context. However, its role in rheumatoid arthritis (RA) remains unknown. Here we illustrated its effects on inflammatory cytokines production by synovial fibroblasts from RA and pathological changes in collagen-induced arthritis (CIA) mice. Alamandine (0.1, 1 and 10 µg/ml) did not affect the survival of the synovial fibroblasts, but decreased the migration and proinflammatory cytokines expression in TNF-α (10 ng/ml) stimulated cells in vitro. Additionally, alamandine selectively decreased phosphorylated-JNK expression induced by TNF-a stimulation in RA FLS. DBA/1 J mice were induced arthritis by a primary injection with an emulsion of bovine type II collagen (CII) and complete Freund's adjuvant (day 0) and a booster injection of CII in incomplete Freund's adjuvant (day 21). Mice were then given alamandine intraperitoneally in saline (50 µg/kg/day) from days 21-42. Histology and multiplex immunobead assay showed that alamandine treatment inhibited the development of arthritis and reduced the joint damage. This effect was accompanied by the reduced inflammatory cytokines (IL-6, IL-23, IFN-γ) mRNA expression in local joints, the decreased TNF-α, IL-6, IL-17 and the increased IL-10 levels in the serum from alamandine administrated CIA mice. In conclusion, alamandine attenuates the development of arthritis by suppressing inflammatory cytokines expression in RA synovial fibroblasts via MAPK signaling pathway, suggesting a potential therapeutic role for RA.

Prognostic and immunological role of Ras-related protein Rap1b in pan-cancer.

Ras-related Protein Rap1b, a GTP-binding protein belonging to the proximal RAS, which affects tumor progression through regulating tumor cell proliferation, invasion and participates in the functions of various immune cells. However, the potential roles and mechanisms of Rap1b in tumor progression and immunology remains unclear. In this study, we systematically analyzed the pan-cancer expression and prognostic correlation of Rap1b based on GTEX, CCLE, Oncomine, PrognoScan, Kaplan-Meier plotters and TCGA databases. The potential correlations of Rap1b with immune infiltration were revealed via TIMER and TCGA database. SangerBox database was used to analyzed the correlations between Rap1b expression and immune checkpoint (ICP), tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repairs (MMRs) and DNA methylation. The results indicated that the expression level of Rap1b varies in different tumors. Meanwhile, the expression level of Rap1b strongly correlated with prognosis in patients with tumors, higher expression of Rap1b usually was linked to poor prognosis in different datasets. Rap1b was correlated closely with tumor immunity and interacted with various immune cells in different types of cancers. In addition, there were significant positive correlations between Rap1b expression and ICP, TMB, MSI, MMRs and DNA methylation. In conclusion, the results of pan-cancer analysis showed that the abnormal Rap1b expression was related to poor prognosis and tumor immune infiltration in different cancers. Furthermore, Rap1b gene may be used as a potential biomarker of clinical tumor prognosis.

CFP is a prognostic biomarker and correlated with immune infiltrates in Gastric Cancer and Lung Cancer.

Complement factor properdin (CFP), encodes plasma glycoprotein, is a critical gene that regulates the complement pathway of the innate immune system. However, correlations of CFP in cancers remain unclear. In this study, the expression pattern and prognostic value of CFP in pan-cancer were analyzed via the Oncomine, PrognoScan, GEPIA and Kaplan-Meier plotters. In addition, we used immunohistochemical staining to validate CFP expression in clinical tissue samples. Finally, we evaluated the correlations between CFP and cancer immune infiltrates particularly in stomach adenocarcinoma (STAD) and lung adenocarcinoma (LUAD) by using GEPIA and TIMER databases. The results of database analysis and immunohistochemistry showed that the expression level of CFP in STAD and LUAD was lower than that in normal tissues. Low expression level of CFP was associated with poorer overall survival (OS), first progression (FP), post progression survival (PPS) and was detrimental to the prognosis of STAD and LUAD, specifically in stage 3, stage T3, stage N2 and N3 of STAD (P<0.05). Moreover, expression of CFP had significant positive correlations with the infiltration levels of CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells (DCs) in STAD and LUAD. Furthermore, gene markers of infiltrating immune cells exhibited different CFP-related immune infiltration patterns such as tumor-associated-macrophages (TAMs). These results suggest that CFP can serve as a prognostic biomarker for determining prognosis and immune infiltration in STAD and LUAD.

Identifying a marked inflammation mediated cardiac dysfunction during the development of arthritis in collagen-induced arthritis mice.

OBJECTIVES: Systemic inflammation is very closely linked to the increased risk of cardiovascular diseases (CVD) in rheumatoid arthritis (RA). We investigated the cardiac changes during the development of arthritis in collagen-induced arthritis (CIA) mice to explore the potential role of inflammation on cardiac dysfunction in RA. METHODS: Arthritis severity was evaluated using clinical indices, micro-computed tomography and histopathology. Cardiac function was determined by transthoracic echocardiography at weeks 5, 7, 9 and 11 after immunisation in mice. At week 7 (day 50), mice joints and hearts were removed for pathological study, and cardiomyocytes and cardiac fibroblasts were isolated using Langendorff perfusion method ex vivo to measure the expression of inflammatory and cardiac-related genes by real time PCR. The expression of key molecule in cardiac dysfunction (ß-MHC) was also tested in H9c2 cardiomyocyte treated with sera derived from CIA mice or RA patients. RESULTS: At day 50 after immunisation, cardiac function in CIA mice was prominently reduced as evidenced by decreased ejection fraction (EF) and fractional shortening (FS), increased left ventricular end-systolic volume (LVESV) and internal systolic diameter (LVIDs). Accordingly, enhanced inflammatory cell infiltration and fibrosis were identified in ventricular tissues pathologically, and increased inflammatory gene expression including TNF-α, IL-6, IL-17 and MMP3 was detected in isolated ventricular cardiomyocytes and cardiac fibroblasts from CIA mice. Furthermore, H9c2 cells treated with sera from CIA mice or RA patients exhibited high levels of ß-MHC. CONCLUSIONS: Joint inflammation is associated with an obvious cardiac dysfunction and enhanced inflammation infiltration and inflammatory cytokine production in cardiomyocytes and cardiac fibroblasts during CIA development. Our data provide the direct evidence that inflammation contributes to the development of cardiac diseases in RA patients.