The aim of the present study was to determine the effects of curcumin on the osteoclastogenic potential of peripheral blood mononuclear cells (PBMCs) obtained from patients with rheumatoid arthritis (RA), and to investigate the underlying molecular mechanisms. PBMCs from patients with RA (n=12) and healthy controls (n=10) were cultured to assess osteoclastogenic potential. The number of tartrate-resistant acid phosphatase-positive osteoclasts differentiated from PBMCs isolated from patients with RA was significantly increased compared with that of the healthy controls. In addition, the osteoclast number in patients with RA was correlated with the clinical indicators, Sharp score (r=0.810; P=0.001) and lumbar T-score (r=−0.685; P=0.014). Furthermore, the resorption area was increased in the RA group compared with the healthy controls. The mRNA and protein expression levels in PBMC-derived osteoclasts treated with curcumin were measured by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Curcumin inhibited the osteoclastogenic potential of PBMCs, potentially by suppressing activation of extracellular signal-regulated kinases 1 and 2, p38 and c-Jun N-terminal kinase, and inhibiting receptor activator of nuclear factor κB (RANK), c-Fos and nuclear factor of activated T cells (NFATc1) expression. The results of the present study demonstrated that curcumin may inhibit the osteoclastogenic potential of PBMCs from patients with RA through the suppression of the mitogen-activated protein kinase/RANK/c-Fos/NFATc1 signaling pathways, and that curcumin may be a potential novel therapeutic agent for the treatment of bone deterioration in inflammatory diseases such as RA.

Abstract. Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator. The present study aimed to investigate the effect of FGF21 on cholesterol efflux and the expression of ATP binding cassette (ABC) A1 and G1 in human THP-1 macrophage-derived foam cells. Furthermore, the present study aimed to investigate the role of the liver X receptor (LXR) α in this process. A model of oxidized low-density lipoprotein-induced foam cells from human THP-1 cells was established. The effect of FGF21 on cholesterol efflux was analyzed using a liquid scintillation counter. The expression of ABCA1 and ABCG1 was determined using quantitative polymerase chain reaction and western blot analyses. FGF21 was found to enhance apolipoprotein A1-and high-density lipoprotein-mediated cholesterol efflux. FGF21 was also observed to increase the mRNA and protein expression of ABCA1 and ABCG1. Furthermore, LXRα-short interfering RNA attenuated the stimulatory effects induced by FGF21. These findings suggest that FGF21 may have a protective effect against atherosclerosis by enhancing cholesterol efflux through the induction of LXRα-dependent ABCA1 and ABCG1 expression. IntroductionAtherosclerosis, one of the leading causes of morbidity and mortality worldwide, is a chronic inflammatory disease and a disorder of lipid metabolism (1). The accumulation of excess cholesterol has been recognized as a crucial event in the development of atherosclerosis (2); therefore, preventing or reversing cholesterol accumulation may be effective protective strategies against atherosclerosis. A growing body of evidence suggests that high density lipoprotein (HDL) has an important role in the removal of cholesterol from atherosclerotic plaques and the transport of the excess cholesterol back to the liver for its subsequent elimination as bile acids and neutral steroids. This process is termed reverse cholesterol transport (RCT) and is one of the major protective mechanisms against the development of atherosclerosis (3-5).Cholesterol efflux from macrophage-derived foam cells is an initial and key step in RCT (6), and serves as an integrated measure of HDL quantity and quality (7). This cholesterol efflux involves numerous genes, including ATP-binding cassette (ABC) A1 and G1 (8). ABCA1 is a member of the ABC superfamily and is the defective gene in Tangier disease. ABCA1 has been reported to have an important role in the prevention of atherosclerosis through facilitating cholesterol efflux from macrophages to lipid-poor apolipoproteinA-Ⅰ (apoA-Ⅰ), and decreasing cholesterol accumulation in macrophages (9). Similar to ABCA1, ABCG1 is capable of promoting cholesterol efflux from macrophages to mature HDL particles, but not to apoA-Ⅰ (10).Liver X receptor (LXR) α, a member of the nuclear hormone receptor superfamily, has a crucial role in cholesterol metabolism (11). Upon activation, LXRα induces numerous genes, which are involved in cholesterol efflux, absorption, transport and excretion. ABCA1 and ABCG1 have been identified as direct targets of LXRα (12).Fibro...

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by synovial inflammation and joint bone and cartilage destruction. Curcumin can improve joint inflammation in rats with arthritis and inhibit synovial revascularization and abnormal proliferation of fibroblasts. However, it is unclear whether curcumin affects the RA progression. The TNF-α-stimulated primary RA fibroblast-like synoviocytes (RA-FLS) and SV-40 transformed MH7A cells were used as the in vitro model of RA. A mouse model of collagen-induced arthritis (CIA) was used as the in vivo model. The effects of curcumin on cell proliferation, apoptosis, migration, invasion, and inflammatory response were assessed by colony formation, flow cytometry, wound scratch, Transwell assays, and western blotting analysis. Arthritis index scores and degree of paw swelling in mice were assessed to evaluate RA. Curcumin inhibited the TNF-α-induced proliferation, migration, invasion of MH7A and RA-FLS cells and promoted cell apoptosis. Administration with curcumin reversed the CIA-induced increase in arthritis scores, hind paw edema, and loss of appetite, while these effects were rescued by insulin-like growth factor 1, the upstream cytokine of PI3K/AKT. Moreover, curcumin suppressed the inflammatory response by reducing TNF-α, IL-6, and IL-17 secretion in CIA-stimulated mice. Curcumin has an excellent anti-RA effect in vivo and in vitro , which is exerted by inhibiting the expression of pro-inflammatory factors TNF-a, IL-6 and IL-17 and inhibiting the activation of PI3K/AKT signaling pathway. Thus, curcumin may be a promising candidate for anti-RA treatment.

Introduction: Atherosclerosis is one of the major causes of cardiovascular diseases. Lipid uptake and accumulation in macrophages play a major role in atherosclerotic plaque formation from its initiation to advanced atheroma formation. The dipeptidyl peptidase-4 (DPP-4) inhibitor Linagliptin is commonly used to lower blood glucose in type 2 diabetes patients. Recent studies report that Linagliptin has cardiovascular protective and anti-inflammatory effects. Methods: THP-1 macrophage cells were treated with 100 nM PMA for 72 hour to induce foam cell formation. The differentiated cells were exposed to 100 μg/mL ox-LDL in the presence or absence of the DPP-4 inhibitor Linagliptin. The expression levels of DPP-4 and inflammatory cytokines were detected by RT-PCR, ELISA, and Western blot experiments. The cellular ROS level was measured by staining the cells with the fluorescent probe DCFH-DA. The separation of lipoprotein fractions was achieved by high-performance liquid chromatography (HPLC). The cells were labeled with fluorescent-labeled cholesterol to measure cholesterol efflux, and lipid droplets were revealed by Nile red staining. Results: The presence of Linagliptin significantly reduced ox-LDL-induced cytokine production (IL-1β and IL-6) and ROS production. Linagliptin ameliorated ox-LDL-induced lipid accumulation and impaired cholesterol efflux in macrophages. Mechanistically, this study showed that Linagliptin mitigated ox-LDL-induced expression of the scavenger receptors CD36 and LOX-1, but not SRA. Furthermore, Linagliptin increased the expression of the cholesterol transporter ABCG1, but not ABCA1. Conclusion: Linagliptin possesses a potent inhibitory effect on THP-1 macrophage-derived foam cell formation in response to ox-LDL. This effect could be mediated through a decrease in the expression of CD36 and LOX-1 on macrophages and an increase in the expression of the cholesterol transporter ABCG1. This study indicates that the DPP-4 inhibitor Linagliptin plays a critical role in preventing foam cell formation in vitro. However, future research using an atherosclerotic animal model is necessary to determine its effectiveness and to prove its potential implication in the prevention and treatment of atherosclerosis.