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Reactive Oxygen Species (ROS) is a key factor in the pathogenesis of osteoporosis (OP) primarily characterized by excessive osteoclast activity. Active fraction of Polyrhachis vicina Rogers (AFPR) exerts antioxidant effects and possesses extensive promising therapeutic effects in various conditions, however, its function in osteoclastogenesis and OP is unknown. The aim of this study is to elucidate the cellular and molecular mechanisms of AFPR in OP. CCK8 assay was used to evaluate the cell viability under AFPR treatment. TRAcP staining, podosome belts staining and bone resorption were used to test the effect of AFPR on osteoclastogenesis. Immunofluorescence staining was used to observe the effect of AFPR on ROS production. si-RNA transfection, coimmunoprecipitation and Western-blot were used to clarify the underlying mechanisms. Further, an ovariectomy (OVX) -induced OP mice model was used to identify the effect of AFPR on bone loss using Micro-CT scanning and histological examination. In the present study, AFPR inhibited osteoclast differentiation and bone resorption induced by nuclear factor-κB receptor activator (NF-κB) ligand (RANKL) in dose-/ time-dependent with no cytotoxicity. Meanwhile, AFPR decreased RANKL-mediated ROS levels and enhanced ROS scavenging enzymes. Mechanistically, AFPR promoted proteasomal degradation of TRAF6 by significantly upregulating its K48-linked ubiquitination, subsequently inhibiting NFATc1 activity. We further observed that tripartite motif protein 38 (TRIM38) could mediate the ubiquitination of TRAF6 in response to RANKL. Moreover, TRIM38 could negatively regulate the RANKL pathway by binding to TRAF6 and promoting K48-linked polyubiquitination. In addition, TRIM38 deficiency rescued the inhibition of AFPR on ROS and NFATc1 activity and osteoclastogenesis. In line with these results, AFPR reduced OP caused by OVX through ameliorating osteoclastogenesis. AFPR alleviates ovariectomized-induced bone loss via suppressing ROS and NFATc1 by targeting Trim38 mediated proteasomal degradation of TRAF6. The research offers innovative perspectives on AFPR's suppressive impact in vivo OVX mouse model and in vitro , and clarifies the fundamental mechanism. Polyrhachis vicina is a species of ant insects (also called black ant) (Wei et al., 2023 ; Zhang et al., 2022). AFPR is the components of active fraction of Polyrchachis vicina Rogers. As shown in the figure, AFPR alleviates ovariectomized-induced bone loss via suppressing ROS and NFATc1 by targeting Trim38 mediated proteasomal degradation of TRAF6. AFPR reduced RANKL-mediated ROS level by down-regulating TRAF6/NOX1 signaling cascade and enhancing Nrf2-mediated ROS scavenging enzymes (HO-1, Nqo1), followed by inhibiting NF-κB and MAPK pathways, leading to the suppression of NFATc1 activity and the expression of osteoclast-related genes, such as Ctsk and Atp6v0d2. [Display omitted] [ABSTRACT FROM AUTHOR]

Osteoclast plays an important role in maintaining the balance between bone anabolism and bone catabolism. The abnormality of osteoclast is closely related to osteolytic bone diseases such as osteoporosis, rheumatoid arthritis and tumor bone metastasis. We aim to search for natural compound that may suppress osteoclast formation and function. In this study, we assessed the impact of Dauricine (Dau) on the formation and function of osteoclasts in vitro , as well as its potential in preventing bone loss in an ovariectomy mouse model in vivo. Multiple in vitro experiments were carried out, including osteoclastogenesis, podosomal belt formation, bone resorption assay, RNA-sequencing, real-time quantitative PCR, ROS level detection, surface plasmon resonance assay, luciferase assay and western blot. To verify the effect in vivo , an ovariectomized mouse model (OVX model) was constructed, and bone parameters were measured using micro-CT and histology. Furthermore, metabolomics analysis was performed on blood serum samples from the OVX model. In vitro experiments demonstrated that Dau inhibits RANKL-induced osteoclastogenesis, podosomal belt formation, and bone resorption function. RNA-sequencing results revealed that Dau significantly suppresses genes related to osteoclast. Functional enrichment analysis indicated that Dau's inhibition of osteoclasts may be associated with NF-κB signaling pathway and reactive oxygen metabolism pathway. Molecular docking, surface plasmon resonance assay and western blot analysis further confirm ed that Dau inhibits RANKL-induced osteoclastogenesis by modulating the ROS/NF-κB/NFATc1 pathway. Moreover, administration of Dau to OVX-induced mice validated its efficacy in treating bone loss disease. Dau prevents OVX-induced bone loss by inhibiting osteoclast activity and bone resorption, potentially offering a new approach for preventing and treating metabolic bone diseases such as osteoporosis. This study provides innovative insights into the inhibitory effects of Dau in an in vivo OVX model and elucidates the underlying mechanism. Dau primarily inhibits osteoclast differentiation and bone resorption, thus preventing ovariectomy-induced bone loss. The mechanism underlying this inhibition involves Dau binding to NF-κB and preventing P65 from entering the nucleus, thereby reducing NFATc1 transcription. Additionally, Dau reduced the production of reactive oxygen species (ROS) induced by RANKL. Our study results indicate that Dau effectively suppresses osteoclast formation and bone resorption by attenuating NF-κB signaling pathway and intracellular ROS level. [Display omitted] [ABSTRACT FROM AUTHOR]

Three kinds of Prussian blue analogues (Ni-Fe PBA, Co-Fe PBA, Co/Ni-Fe PBA) with similar cubic nanostructures have been synthesized simply by one-step solution-precipitation method. By utilizing simultaneous oxidative decomposition and crystal growth, iron-group metal oxides (NiO/Fe 3 O 4 , Co 3 O 4 /Fe 3 O 4 , NiO/Co 3 O 4 /Fe 3 O 4 ) with porous nanocubic structures have been converted successfully in situ from precursors of PBAs. When evaluated as anode materials for supercapacitors, the mixed metal oxides with a porous cubic structure manifest high specific capacity. The specific capacitance of ternary metal oxides (NiO/Co 3 O 4 /Fe 3 O 4 ) is 2.3 times that of NiO/Fe 3 O 4 and 3.7 times that of Co 3 O 4 /Fe 3 O 4 . Besides, the ternary metal oxides exhibit high rate stability (retention up to 72% even at 20 A g −1 ) and long cycle performance. The improved electrochemical performance may owe to the synergistic effect of mixed-metal-oxide porous nanostructures, which accelerates electron transport and ion diffusion. [ABSTRACT FROM AUTHOR]

Reactive oxidative species (ROS) generation triggers pyroptosis and induces development of inflammatory osteolysis. Hecogenin (HG) has anti-inflammatory and antioxidative property, but its effects on inflammatory osteolysis remains unclear. In our study, we investigated the mechanism of HG on pyroptosis and its effect on inflammatory osteolysis in vitro and in vivo. The impact of HG on osteoclastogenesis was evaluated using cytotoxicity, TRAcP staining and bone resorption assays. The RNA-sequencing was employed to identify potential signaling pathways, and then RT-qPCR, western blot, immunofluorescence, and ELISA were used to verify. To determine the protective effect of HG in vivo , Lipopolysaccharide (LPS)-induced animal models were utilized, along with micro-CT and histological examination. HG suppressed RANKL-induced osteoclast differentiation, bone resorption, NFATc1 activity and downstream factors. RNA-sequencing results showed that HG inhibited osteoclastogenesis by modulating the inflammatory response and macrophage polarization. Furthermore, HG inhibited the NF-κB pathway, and deactivated the NLRP3 inflammasome. HG activated the expression of nuclear factor E2-related factor 2 (Nrf2) to eliminate ROS generation. Importantly, the inhibitory effect of HG on NLRP3 inflammasome could be reversed by treatment with the Nrf2 inhibitor ML385. In viv o, HG prevented the mice against LPS-induced osteolysis by suppressing osteoclastogenesis and inflammatory factors. In conclusion, HG could activate Nrf2 to eliminate ROS generation, inactivate NLRP3 inflammasome and inhibit pyroptosis, thereby suppressing osteoclastogenesis in vitro and alleviating inflammatory osteolysis in vivo, which indicating that HG might be a promising candidate to treat inflammatory osteolysis. [Display omitted] • HG suppressed osteoclast formation and resorption function. • HG modulated the inflammatory response and macrophage polarization. • HG restrained pyroptosis by inactivating NLRP3 inflammasome. • HG suppressed NLRP3 inflammasome involved Nrf2 activation • HG exhibited protective effects against LPS-induced osteolysis in vivo. [ABSTRACT FROM AUTHOR]

[Display omitted] Reactive Oxygen Species (ROS) play an essential role in the pathogenesis of osteoporosis mainly characterized by excessive osteoclasts (OCs) activity. OCs are rich in mitochondria for energy support, which is a major source of total ROS. Tussilagone (TSG), a natural Sesquiterpenes from the flower of Tussilago farfara , has plentiful beneficial pharmacological characteristics with anti-inflammatory and anti-oxidative activity, but its effects and mechanism in osteopathology are still unclear. In our study, we investigated the regulation of ROS generated from the mitochondria in OCs. We found that TSG inhibited OCs differentiation and bone resorption without any cytotoxicity. Mechanistically, TSG reduced RANKL-mediated total ROS level by down-regulating intracellular ROS production and mitochondrial function, leading to the suppression of NFATc1 transcription. We also found that nuclear factor erythroid 2-related factor 2 (Nrf2) could enhance ROS scavenging enzymes in response to RANKL-induced oxidative stress. Furthermore, TSG up-regulated the expression of Nrf2 by inhibiting its proteosomal degradation. Interestingly, Nrf2 deficiency reversed the suppressive effect of TSG on mitochondrial activity and ROS signaling in OCs. Consistent with this finding, TSG attenuated post-ovariectomy (OVX)- and lipopolysaccharide (LPS) induced bone loss by ameliorating osteoclastogenesis. Taken together, TSG has an anti-bone resorptive effect by modulating mitochondrial function and ROS production involved Nrf2 activation. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Osteoporosis is a chronic bone lytic disease, because of inadequate bone ossification and/or excessive bone resorption. Even though drugs are currently available for the treatment of osteoporosis, there remains an unmet need for the development of more specific novel agents with less adverse effects. Dehydrocostus lactone (DHC), a natural sesquiterpene lactone, was previously found to affect the differentiation of inflammatory cells by inhibiting NF-κB pathways, and garnered much interest for its anti-cancer properties via SOCS-mediated cell cycle arrest and apoptosis. As NF-κB pathway plays an essential role in osteoclast differentiation, we sought to discover the biological effects of DHC on osteoclast differentiation and resorptive activity, as well as the underlying mechanisms on these effects. Our research found that DHC inhibited RANKL-induced osteoclast differentiation, bone resorption and osteoclast specific genes expression via suppression of NF-κB and NFAT signaling pathways in vitro. We further demonstrated that DHC protected against ovariectomy (OVX)-induced bone loss in mice and the protective effect was mediated at least in part through the attenuation of NF-κB signaling pathway. Thus, this study provides insight that DHC might be used as a potential pharmacological treatment for osteoporosis. [ABSTRACT FROM AUTHOR]

Bone metastasis causes bone pain and pathological bone fracture in breast cancer patients with a serious complication. Previous studies have demonstrated that a novel phosphatidyl inositol 3-kinase (PI3K)-mTOR inhibitor PKI-402 suppressed the growth of breast cancer cells. However, the role of PKI-402 involved in osteolysis induced by breast cancer remains unclear. In this study, we showed that treatment of PKI-402 led to significant decreases in RANKL-induced osteoclastogenesis and osteoclast-specific gene expression in mouse bone marrow-derived macrophages and reduced proliferation, migration and invasion of MDA-MB-231 breast cancer cells by blocking the PI3K-AKT-mTOR signaling pathway. Importantly, as evidenced by the observation that the administration of PKI-402 inhibited MDA-MB-231-induced osteolysis in vivo, PKI-402 exerted an inhibitory effect on osteoclast formation and bone resorption, critical for cancer cells-induced bone destruction. These results strongly suggest that PKI-402 might have a therapeutic potential to inhibit breast cancer induced osteolysis. [ABSTRACT FROM AUTHOR]

[Display omitted] • ROS-responsive nanocomposite nanofibers were fabricated by using PCL, PEGDA-EDT and rGO, as stimuli-responsive drug delivery system. • The ROS-responsive nanocomposite nanofibers enabled high loading of puerarin, and facilitate efficient controlled release based on ROS condition in the OA microenvironment. • The PPE@rGO-Pue nanofibers exhibited favourable anti-inflammatory and antioxidative properties for chonro-protection. • The PPE@rGO-Pue nanofibers enable to downregulating the expression of IL-1β and MMP13, therefore limiting the cartilage degradation in OA model. Reactive Oxygen Species (ROS) plays an important role in osteoarthritis (OA) development and progression. Here, a ROS-responsive nanocomposite scaffold called PPE@rGO-Pue was fabricated by electrospinning, wherein PCL served as the backbone, PEGDA-EDT as the ROS responsive motif, and rGO as puerarin (Pue) carrier. The electrospun nanofibers composed of PEGDA-EDT and rGO exhibits accelerated Pue release behavior in the response to H 2 O 2 through dose-dependent manner in 2 weeks. The interactions of PEGDA-EDT and Pue dramatically inhibits ROS production and activates antioxidant enzymes such as CAT, GSS, SOD, and GSH. Furthermore, the expression of inflammatory factor IL-1β had decrease significantly. Subsequently, PPE@rGO-Pue had shown chondro-protective effect for OA, which was evidenced by the suppression of MMPs, resulting in matrix degradation and the increase of Col2a1 and GAG that attenuated the cartilage erosion. In summary, this ROS-responsive electrospun nanofibers with sustained release of Pue exhibited antioxidative, anti-inflammatory, and chondro-protective potentials, suggesting that it could be an excellent drug carrier for OA therapy. This work may shed light on the design of antioxidative biomaterials for OA. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent joint inflammation leading to bone and cartilage damage and even disability. However, the pathogenesis of RA is multi-factorial and to a large degree, remains unknown. Danggui Sini decoction (DSD), a traditional Chinese medicine (TCM) formula, has been widely used as a remedy for rheumatoid arthritis (RA) in recent years. In our study, 1 H-nuclear magnetic resonance ( 1 H NMR) based metabolomics analysis of 7 potential biomarkers, including taurine ( 1 ), urea ( 2 ), betaine ( 3 ), pyruvate ( 4 ), hippurate ( 5 ), succinate ( 6 ) and acetone ( 7 ) was performed to investigate the progression of RA and assess the efficacy of DSD in collagen-induced arthritis (CIA) rats. According to pathway analysis using identified metabolites and correlation construction, taurine and hypotaurine metabolism, gut microbiota metabolism, pyruvate metabolism, glycolysis/gluconeogenesis, the citrate cycle (TCA cycle) and lipid metabolism were recognized as being the most influenced metabolic pathways associated with RA. As a result, deviations of metabolites 1, 3, 4, 5, 6 and 7 in CIA rats were improved by DSD, which suggested that DSD mediated the abnormal metabolic pathways synergistically. In summary, the efficacy and its underlying therapeutic mechanisms of DSD on RA were systematically investigated and expect to provide a new insight in relevant studies of other TCM formulas. [ABSTRACT FROM AUTHOR]

Osteoclasts play an important role in maintaining the relative stability of bone mass. Abnormal number and function of osteoclasts are closely related to osteoporosis and osteolytic diseases. Thiaplakortone B (TPB), a natural compound derived from the Great Barrier Reef sponge Plakortis lita , has been reported to inhibit the growth of the malaria parasite, Plasmodium falciparum , but its effect on osteoclastogenesis has not been previously investigated. In our study, we found that TPB suppresses the receptor activator of nuclear factor‐κB (NF-κB) ligand (RANKL)-induced osteoclast formation and resorption activity by tartrate‐resistant acid phosphatase (TRAcP) staining, immunofluorescence staining of F-actin belts and hydroxyapatite resorption assay. Furthermore, using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting analysis, we discovered that TPB inhibits osteoclast-specific genes and proteins expression. Mechanistically, TPB blocks multiple upstream pathways including calcium oscillation, NF‐κB, mitogen-activated protein kinase (MAPK) and nuclear factor of activated T cells 1(NFATc1) signaling pathways. In vivo , TPB could dampen bone loss in an ovariectomy (OVX) mouse model by micro-CT assessment and histological staining. Therefore, TPB may serve as a potential therapeutic candidate for the treatment of osteoporosis and osteolysis. [Display omitted] • Thiaplakortone B inhibits RANKL-induced osteoclast differentiation in vitro. • Thiaplakortone B hampers osteoclastogenesis via calcium oscillation, NF-κB and MAPK signaling pathways. • Thiaplakortone B attenuates bone loss of Ovariectomised mice in vivo. [ABSTRACT FROM AUTHOR]

[Display omitted] Excessive bone erosion by osteoclasts is associated with osteoporosis, rheumatoid arthritis, and periprosthetic osteolysis. Targeting osteoclasts may serve as an effective treatment for osteolytic diseases. Although drugs are currently available for the treatment of these diseases, exploring potential anti-osteoclast natural compounds with safe and effective treatment remains needed. Oroxylin A (OA), a natural flavonoid isolated from the root of Scutellaria baicalensis Georgi , has numerous beneficial pharmacological characteristics, including anti-inflammatory and antioxidant activity. However, its effects and mechanisms on osteoclast formation and bone resorption have not yet been clarified. Our research showed that OA attenuated the formation and function of osteoclast induced by RANKL in a time- and concentration-dependent manner without any cytotoxicity. Mechanistically, OA suppressed intracellular reactive oxygen species (ROS) levels through the Nrf2-mediated antioxidant response. Moreover, OA inhibited the activity of NFATc1, the master transcriptional regulator of RANKL-induced osteoclastogenesis. OA exhibited protective effects in mouse models of post-ovariectomy (OVX)- and lipopolysaccharide (LPS)‐induced bone loss, in accordance with its in vitro anti-osteoclastogenic effect. Collectively, our findings highlight the potential of OA as a pharmacological agent for the prevention of osteoclast-mediated osteolytic diseases. [ABSTRACT FROM AUTHOR]

Postmenopausal osteoporosis and other osteolytic bone diseases are often caused by the elevation in osteoclastogenesis and/or increased osteoclastic bone resorption, leading to excessive bone loss. Hederagenin (Hed) is a pentacyclic triterpenoid saponin extracted from various natural medicinal plants and exhibits numerous biological activities and may offer benefits against bone-related conditions. We evaluated the effects of Hed on osteoclast formation and bone resorption in vitro and the in vivo therapeutic benefits in the mouse model of ovariectomy (OVX)-induced bone loss. In vitro, osteoclast formation were determined by TRAcp staining; bone resorption were examined using Hydroxyapatite resorption assay and Podosomal actin belt formation assay; Related molecular mechanisms were determined by western blot assay. Construction of OVX mice by bilateral oophorectomy to simulate bone loss in vivo. In vitro cellular assays showed that Hed inhibited RANKL-induced osteoclast formation and osteoclast bone (hydroxyapatite) resorption as well as marker gene expression from BMM culture. Mechanistically, Hed attenuated RANKL-induced intracellular reactive oxygen species (ROS) production, and MAPK signaling pathway (ERK and p38) activation which curbed the downstream induction of c-Fos and NFATc1. Consistent with the in vitro findings, Hed administration effectively protected OVX mice from bone loss by reducing osteoclast number and activity on bone surface. Our data provided promising evidence for the potential use of Hederagenin in the treatment of osteoclast-mediated osteolytic bone diseases such as postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]