Abstract
Gout is regarded as a painful inflammatory arthritis induced by the deposition of monosodium urate crystals in joints and soft tissues. Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated IL-1β production plays a crucial role in the pathological process of gout. Cyclocarya paliurus (CP) tea was found to have an effect on reducing the blood uric acid level of people with hyperuricemia and gout. However, its medicinal ingredients and mechanism for the treatment of gout are still unclear. Thus, this study was designed to investigate the effects of the active triterpenoids isolated from C. paliurus on gout and explore the underlying mechanism. The results showed that compound 2 (3β,23-dihydroxy-12-ene-28-ursolic acid) from C. paliurus significantly decreased the protein expression of IL-1β, caspase-1, pro-IL-1β, pro-caspase-1, and NLRP3. Furthermore, the production of ROS in the intracellular was reduced after compound 2 treatment. However, ROS agonist rotenone remarkably reversed the inhibitory effect of compound 2 on the protein expression of NLRP3 inflammasome. Additionally, the expression level of LC3 and the ratio of LC3II/LC3I were increased, but the expression level of p62 was suppressed by compound 2 whereas an autophagy inhibitor 3-methyladenine (3-MA) significantly abolished the inhibitory effects of compound 2 on the generation of ROS and the protein expression of NLRP3 inflammasome. Moreover, compound 2 could ameliorate the expression ratio of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR. Interestingly, mTOR activator MHY-1485 could block the promotion effect of compound 2 on autophagy regulation and inhibitory effect of compound 2 on induction of ROS and IL-1β. In conclusion, these findings suggested that compound 2 may effectively improve NLRP3 inflammasome-mediated gout via PI3K-AKT-mTOR-dependent autophagy and could be further investigated as a potential agent against gout.
Highlights
Gout is regarded as an inflammatory arthritis because of the formation and deposition of monosodium urate (MSU) crystals in the joints and soft tissues [1,2,3]
Our previous studies found that the triterpenoid-enriched fraction from Cyclocarya paliurus (CP) (CPT) was the main active ingredient with good antiinflammatory effects [26]. The pentacyclic triterpenoid such as asiatic acid was reported to improve oxidative stress to inhibit NLRP3 inflammasome activation and the phosphatidylinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway to activate autophagy [30, 31]. erefore, we speculate that CPT may be the effective substances to suppress NLRP3 inflammasome activation via PI3K-AKT-mTOR-dependent autophagy to ameliorate gout. us, this study aimed to investigate the efficacy of CPT and their triterpenoids on gout and their potential mechanisms
Primary antibodies against GAPDH, pro-IL-1β, pro-caspase-1, IL-1β, caspase-1, NLRP3, LC3, p62, p-PI3K, p-AKT, p-mTOR, PI3K, AKT, and mTOR were purchased from Cell Signaling Technology (Danvers, USA)
Summary
Gout is regarded as an inflammatory arthritis because of the formation and deposition of monosodium urate (MSU) crystals in the joints and soft tissues [1,2,3]. Gout induces damage and Evidence-Based Complementary and Alternative Medicine degeneration of the joints of the patient, and causes deformity and disability [5]. It is an independent risk factor for many diseases such as metabolic syndrome and cardiovascular diseases [6,7,8,9]. The release of IL-1β can induce pro-inflammatory cytokine and chemokine production through interaction with IL-1 receptor (IL-1R), leading to neutrophil infiltration at the site of inflammation accompanied by substantial pain and swelling [13]. erefore, the inhibition of NLRP3 inflammasome-mediated IL-1β production process is a new and beneficial strategy for the treatment of gout
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