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Objective Xanthohumol (XAN), a natural isoflavone from Humulus lupulus L. possesses biological activities on relieving oxidative stress and osteoporosis (OP). This study aimed to evaluate the antioxidative and osteoprotective effect of XAN on Aβ-injured osteoblasts, and explore its underlying mechanism. Methods Osteoblasts were pretreated with XAN followed by stimulation with Aβ1–42. Cell proliferation, ALP activity, bone mineralization and bone formation index were measured. Apoptosis and reactive oxygen species (ROS) were analysed with flow cytometer. PI3K inhibitor LY294002 or siRNA-Nrf2 was added and transfected in osteoblasts, to further confirm whether the pathway participated in the regulation of XAN-induced cytoprotection. Key findings XAN markedly improved the proliferation, differentiation and mineralization of Aβ-injured osteoblasts. Additionally, XAN reduced cell apoptosis rate and ROS level, and increased the expression of p-AKT, Nrf2, NQO1, HO-1 and SOD-2. More importantly, LY294002 or siNrf2 abolished the beneficial effect of XAN on osteoblasts activity and decreased the PI3K expression and inhibited its downstream proteins, indicating XAN activated PI3K/AKT/Nrf2 pathway in Aβ-injured osteoblasts. Conclusion It was the first time to reveal the antioxidative and osteoprotective effect of XAN through regulating PI3K/AKT/Nrf2 pathway in Aβ - injured osteoblasts, which provides reference for the clinical application of XAN in the prevention and treatment of OP. [ABSTRACT FROM AUTHOR]

Litsea cubeba (Lour.) Pers. has been traditionally used as a folk prescription for treating rheumatic diseases in China. This study aimed to investigate the effects and underlying mechanism of LCA, a new type of dibenzyl butane lignin compound extracted from L. cubeba , on macrophage colony stimulating factor (M-CSF) plus receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation in mouse-derived bone marrow macrophages (BMMs). TRAP staining, TRAP enzyme activity assay and actin ring staining were applied to identify the effects of LCA on osteoclast differentiation. Protein expression of NFATc1, c-Fos and MMP-9, and phosphorylation of p65, Akt, JNK, ERK and p38 in RANKL-induced osteoclasts was determined using western blotting to investigate the underlying mechanism. LCA significantly suppressed RANKL-induced osteoclast differentiation by inhibiting TRAP activity, decreasing the number of TRAP+ multinuclear osteoclasts and reducing the formation of F-actin ring without obvious cytotoxicity in BMMs. Moreover, LCA treatment strongly reduced protein expression of NFATc1, c-Fos and MMP-9, and attenuated the phosphorylation of p65, Akt, JNK, ERK and p38 in RANKL-stimulated BMMs. LCA ameliorated RANKL-induced osteoclast differentiation via inhibition of Akt and MAPK signalings in BMMs, and may serve as a potential pro-drug for bone destruction prevention. • The anti-osteoclastogenic effect of LCA and the underlying mechanism of action were investigated for the first time. • LCA, a new type of dibenzyl butane lignin compound extracted from L. cubeba, has a rather different structure from the available anti-RA drugs. • LCA inhibits osteoclast differentiation by regulating Akt and MAPK signalings. • LCA may be a potential prodrug to prevent bone destruction. [ABSTRACT FROM AUTHOR]