Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses and matrix-degrading enzymes
Graphical abstract
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by changes in synovial inflammation, hyperplasia, erosion, and destruction of cartilage (Nam et al., 2013). The pathogenesis of RA is complex and includes the infiltration of many cell types on articular joints, such as T cells, B cells, macrophages, and synovial fibroblasts (Muller-Ladner et al., 2005). Rheumatoid synovial fibroblasts play a critical role by producing inflammatory cytokines and chemokines that induce the production of matrix metalloproteinases (MMPs) contributing to cartilage and bone destruction (Bartok and Firestein, 2010). Further, T cells initiate the autoimmune process and mediate chronic synovitis, leading to joint destruction (Lubberts, 2014). Thus, RA treatment is directed primarily from minimizing the infiltration of inflammatory cells and preventing joint damage.
Type II collagen-induced arthritis (CIA) mice develop a chronic form of RA and this model closely resembles human RA (Cho et al., 2007). Current approaches to drug therapy for RA include anti-tumor necrosis factors (TNF), interleukin (IL)-1 antagonist drugs, non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) (Asquith et al., 2009, Bevaart et al., 2010). However, the side effects of anti-inflammatory drugs and DMARDs induce significant tissue damage and variety of toxicity.
Recent studies demonstrated that natural products have been used to determine the safe and potential efficacious treatment for RA. Vigna angularis (adzuki bean) is one of the most important crops in Asia and has been widely cultivated in Korea, China, Japan, and Taiwan. V. angularis has a variety of biological actions, including infection, edema, and inflammation of the appendix, kidney, and bladder (Itoh et al., 2005). In addition, oral administration of ethanol extract of V. angularis showed a therapeutic effect on CIA mice (Oh et al., 2014). Oleanolic acid acetate (OAA), a compound isolated from V. angularis, possesses pharmacological activities, such as anti-inflammation and anti-allergy (Oh et al., 2014). We previously reported that oral administration of OAA derived from V. angularis inhibited atopic dermatitis and allergic contact dermatitis in mice (Choi et al., 2013). OAA also inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis through the PLCγ2–Ca2+–NFATc1 pathway, and suppressed inflammatory bone erosion in mice (Kim et al., 2014). However, the effect of OAA on RA has not been studied yet. The objective of this study was to elucidate the therapeutic efficacy of OAA using a CIA mouse model and identify the underlying mechanisms of action.
Section snippets
Purification of OAA from V. angularis
OAA was purified from V. angularis as previously described (Oh et al., 2014). The air-dried and pulverized V. angularis (20 kg) was extracted twice with 95% EtOH at 70 °C. The residue (100 L) was filtered, and then evaporated in a rotary evaporator to yield 95% EtOH extract (2.2 kg). All extract was suspended with distilled water, and sequentially fractionated with EtOAc, n-BuOH, and distilled water. For the isolation of compound, the EtOAc extract was further chromatographed on a silica gel column
OAA suppressed the development of CIA
To evaluate the anti-arthritic effects of OAA, we used CIA mice models treated with an oral administration of OAA (2, 10 or 50 mg/kg) from 28 to 53 days after the initial immunization. The experimental schedules of CIA are shown in Supplementary Fig. S1. The onset of arthritis was monitored until day 56. The known drugs for RA, dexamethasone and ketoprofen, were used as positive controls for treating arthritis pain and inflammation. The paws were appraised for clinical symptoms of arthritis. OAA
Discussion
Oleanolic acid (OA) is a triterpenoid with many beneficial effects. Triterpenoid compounds such as oleanolic acid (OA), ursolic acid, and rosmarinic acid improve inflammation and ulcers in arthritis (Baek et al., 2014, Kapil and Sharma, 1995, Youn et al., 2003). OAA, a derivative of OA and a triterpenoid compound, is known to have therapeutic effects, including atopic dermatitis, allergic contact dermatitis, and inflammatory bone loss in vivo (Choi et al., 2013, Dai et al., 1989, Giner-Larza et
Conflict of interest
The authors have declared no conflict of interest.
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Acknowledgments
This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (2014R1A5A2009242 and 2012M3A9B6055416), KRIBB Research Initiative Program, and by High Value-added Food Technology Development Program, Ministry of Agriculture, Food and Rural Affairs.
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2021, Bioorganic ChemistryCitation Excerpt :Once they are activated via phosphorylation in LPS-stimulated BV2 cells, they will activate AP-1 and NF-κB to enhance the transcription of pro-inflammatory mediators [49]. Some studies have reported that OA relieved inflammatory response through suppressing PI3K/Akt and MAPK signaling pathways [12,20,22,48]. Therefore, to further elucidate the underlying mechanism of the anti-inflammatory effects of compounds 8 and 9, we determined the effects of compounds 8 and 9 on the activation of PI3K/Akt and MAPK signaling pathways in LPS-stimulated BV2 cells by Western blot.
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These authors contributed equally to this work.