Abstract
Anemone flaccida Fr. Schmidt (Ranunculaceae) (Di Wu in Chinese) is used to treat punch injuries and rheumatoid arthritis (RA). Our previous report has shown that crude triterpenoid saponins from Anemone flaccida exhibited anti-arthritic effects on type II collagen-induced arthritis in rats. Furthermore, anhuienoside C (AC), a saponin compound isolated from A. flaccida, was observed to suppress the nitric oxide production in lipopolysaccharide (LPS)-treated macrophage RAW 264.7 cells. In this study, we examined the effects of AC on the prevention and treatment of collagen-induced arthritis in a mouse model and evaluated the potential mechanisms involved. We observed that oral administration of AC significantly suppressed the paw swelling and arthritic score, decreased the body weight loss, and decreased the spleen index. Improvement in the disease severity was accompanied by the reduction of cluster of differentiation 68 (CD68)-positive cells in the ankle joint and inhibition of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) in the synovium of the joint. Mechanistic studies indicated that AC exerted its anti-inflammatory activity by inhibiting the mRNA expression levels of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, interleukin (IL)-1β, and IL-6 and by suppressing the production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in LPS-treated RAW 264.7 cells. AC also blocked the LPS-induced activation of the extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase pathways. Additionally, the LPS-induced activation of nuclear factor kappa-B (NF-κB) was significantly suppressed by AC treatment, as indicated by down-regulation of TLR4 and inhibition of the nuclear translocation of NF-κB p65 and by activation and degradation of the inhibitor of kappa B. These findings indicated that AC has a great potential to be developed as a therapeutic agent for human RA.
Highlights
Rheumatoid arthritis is an autoimmune disease marked by chronic inflammation and synovial proliferation, leading to the cartilage damage and joint destruction (Vincent et al, 2012)
We have previously reported that crude triterpenoid saponins from A. flaccida (Di Wu) showed antiarthritic effects on type II collagen-induced arthritis (CIA) in rats
Administration of anhuienoside C (AC) (20, 30, and 40 mg/kg/day) significantly blocked the progression of arthritis development, and according to the mean arthritis scores, the severity of CIA was significantly attenuated by AC (Figure 2A)
Summary
Rheumatoid arthritis is an autoimmune disease marked by chronic inflammation and synovial proliferation, leading to the cartilage damage and joint destruction (Vincent et al, 2012). The exact etiology and pathogenesis of RA are unclear, the disease is characterized, in particular, by the involvement of numerous activated macrophages and FLSs in the inflammation of the synovial membrane and cartilage-pannus junction (GarciaCarbonell et al, 2016; Tang et al, 2016). These dysregulated immune cell interactions can induce the overproduction of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α. Biologics, including TNF-α inhibitors (infliximab and adalimumab), IL-1β inhibitors (anakinra), and IL-6 inhibitors (tocilizumab and atlizumab), represent a prominent group of drugs used in the treatment of RA, but their administration may cause side effects and can interfere with the immune defense responses. In the present study, we examined the anti-rheumatic effects of AC in a mouse model and evaluated the potential mechanisms involved
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