Osteoporosis is a common disorder of bone remodeling, marked by excessive osteoclast formation. Recent studies indicated that berberine (BBR) is a potential natural drug for the treatment of various bone diseases. However, it still needs to be further studied for the treatment of osteoporosis. The current study investigated the inhibitory effects of BBR on receptor activator of nuclear factor-[Formula: see text]B ligand (RANKL)-induced osteoclast differentiation in vitro and in vivo. Cell-based assays were performed using osteoclasts generated in cultures of murine bone marrow-derived macrophages (BMMs) treated with RANKL and M-CSF. The effects of BBR on in vivo lipopolysaccharide (LPS)-mediated bone loss were evaluated using ICR mice. BBR significantly inhibited TRAP-positive osteoclast formation induced by RANKL. BBR also inhibited RANKL-induced Akt, p38 and ERK phosphorylation and I[Formula: see text]B degradation, and suppressed RANKL-induced expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which is a key transcription factors for osteoclast formation. BBR reduced the mRNA levels of osteoclast markers, including TRAP, osteoclast-associated receptor (OSCAR), cathepsin K, and ATPase H[Formula: see text] transporting V0 subunit d2 (ATP6v0d2). Moreover, BBR prevented LPS-mediated bone loss in vivo. We suggest BBR as a natural compound that can be a potential therapeutic agent for osteoclast-related bone diseases.
Osteoporosis results from imbalance between new bone formation and bone resorption leading to bone loss and is especially troublesome for postmenopausal women who suffer from estrogen deficiency. The ability of new therapeutic agents to treat this bone disease with minimal side effects has been extensively reported on and is continuously being sought out by researchers in this field. Thus, the purpose of this study was to investigate a natural herb that was already being used as a new treatment for osteoporosis. Here we found that water extract of Glycyrrhizae radix (GR) inhibits receptor activator of nuclear factor-[Formula: see text]B ligand (RANKL)-induced osteoclast differentiation in a dose-dependent manner without causing cytotoxicity. The mRNA expression of c-Fos, nuclear factor of activated T cells cytoplasmic 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), and osteoclast-associated receptor (OSCAR) was considerably inhibited by GR treatment. GR inhibited RANKL-mediated c-Fos and NFATc1 expression in a dose-dependent manner. GR inhibited the degradation of I-[Formula: see text]B in RANKL-stimulated BMMs. However, GR-mediated inhibition of osteoclast differentiation and osteoclast-specific gene expression, including NFATc1, was reversed by ectopic expression of c-Fos. Also, GR significantly inhibited osteoclast formation in mouse calvariae in the presence of IL-1 and prostaglandin E2 (PGE2). Taken together, these results suggest that GR inhibited osteoclast differentiation, raising the possibility that GR may serve as a useful drug for osteoporosis.
Poligoni Multiflori Radix (PMR) is a traditional Korean medicinal herb that is known to have various pharmacological effects, including antihyperlipidemic, anticancer, and anti-inflammatory effects. However, the effects of PMR on bone metabolism have not been elucidated to date. The present study aimed to investigate the in vitro and in vivo effect of PMR water extract on the regulation of osteoblast and osteoclast activity. Effects of PMR water extract on receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclast differentiation and survival of mouse bone marrow macrophages (BMMs) obtained from femurs were investigated by tartrate-acid resistant acid phosphatase (TRAP)-positive cells and XTT assay. Expression of osteoclast-related genes was assayed by western blot analysis and reverse transcription-quantitative polymerase chain reaction. Additionally, the effects of PMR water extract on osteoblastic proliferation and differentiation were investigated by alkaline phosphatase (ALP) activity assay, alizarin red staining, and levels of mRNA encoding known osteoblast markers. Furthermore, the effects of PMR water extract on lipopolysaccharide (LPS)-induced bone loss were examined in a mouse model. PMR inhibited RANKL-induced osteoclast differentiation of BMMs in a dose-dependent manner without significant cytotoxicity, and suppressed expression of the main osteoclast differentiation markers Fos proto-oncogene and nuclear factor of activated T-cell. In addition, PMR decreased the mRNA expression levels of NFATc1 target genes, including TRAP, osteoclast-associated receptor, ATPase H+ transporting, lysosomal 38 kDa V0 subunit d2, and Cathepsin K. These inhibitory effects were mediated by the p38 and extracellular signal-regulated kinase/nuclear factor-κB pathway. Simultaneously, PMR enhanced the differentiation of primary osteoblasts, and increased the mRNA expression of runt-related transcription factor 2, ALP, osterix, and osteocalcin. Notably, PMR improved LPS-induced trabecular bone loss in mice. Collectively, the present findings demonstrated that PMR may regulate bone remodeling by reducing osteoclast differentiation and stimulating osteoblast formation. These results suggest that PMR may be used for the treatment of bone diseases, such as osteoporosis and rheumatoid arthritis.
Objectives : Aconiti Lateralis Preparata Radix (Aconitum Carmichaeli, AC) and Cinnamomi Cortex (Cinnamomi Cortex, CC) have been treated to elderly for kidney yang enhancement in Korean traditional medicine. In this study, the effects of water extract of AC and CC on RANKL (Receptor Activator for Nuclear Factor κ B Ligand)-induced osteoclast differentiation were evaluated in culture system. Methods : MTT assay was used to evaluate the potential cytotoxicity of AC and CC extracts in bone macrophage marrows (BMMs) stimulated with M-CSF. TRAP (tartrate-resistant acid phosphatase) staining and TRAP activity were performed to know the inhibitory effect on osteoclast differentiation. The protein expression levels of nuclear factors such as activated T cell(NFAT)c1, c-Fos, MAPKs and β -actin in cell lysates treated with AC and CC extracts were analysed by western blotting. Results : AC, CC extracts and their co-administration inhibited significantly RANKL-induced osteoclast differentiation in BMMs in a dose dependent manner without toxicity. Each AC and CC extracts inhibited the phosphorylation of p38. Also, AC and CC extracts, respectively, inhibited the protein expression of c-Fos and NFATc1 more than Co-administration of AC and CC even if all treatments did. It was observed that RANKL-induced degradation of I-κ B is significantly suppressed by all treatments. Conclusions : Taken together, It was concluded that AC and CC have beneficial effect on osteoporosis by inhibition of osteoclast differentiation. Thus, Atractylodis AC and CC could be a treatment option for osteoporosis.
Yukmijihwang-tang (YJ) has been used to treat diabetes mellitus, renal disorders, and cognitive impairment in traditional medicine. This study aimed to evaluate the anti-osteoporotic effect of YJ on ovariectomy (OVX)-induced bone loss in a rat and receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclast differentiation in bone marrow macrophages (BMMs). YJ reduced the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) in an osteoclast/osteoblast co-culture system by regulating the ratio of RANKL/osteoprotegerin (OPG) by osteoblasts. Overall, YJ reduced TRAP-positive cell formation and TRAP activity and F-actin ring formation. Analysis of the underlying mechanisms indicated that YJ inhibited the activation of the nuclear factor of activated T cell cytoplasmic 1 (NFATc1) and c-Fos, resulting in the suppression of osteoclast differentiation-related genes such as TRAP, ATPase, H+ transporting, lysosomal 38 kDa, V0 subunit d2, osteoclast-associated receptor, osteoclast-stimulatory transmembrane protein, dendritic cell-specific transmembrane protein, matrix metalloproteinase-9, cathepsin K, and calcitonin receptor. YJ also inhibited the nuclear translocation of NFATc1. Additionally, YJ markedly inhibited RANKL-induced phosphorylation of signaling pathways activated in the early stages of osteoclast differentiation including the p38, JNK, ERK, and NF-κB. Consistent with these in vitro results, the YJ-administered group showed considerably attenuated bone loss in the OVX-mediated rat model. These results provide promising evidence for the potential novel therapeutic application of YJ for bone diseases such as osteoporosis.
Objectives : This study was conducted to investigate the management status of extramural herbal dispensary facility, which could serve as a foundation for further research and policy establishment.Method : According to herbal dispensary data collected by Ministry of Health and Welfare, 78 sites were confirmed among 1,160 sites which checked extramural herbal dispensary facility. We carried out a survey on them. The survey consisted of 42 questions including general provisions, personnel management, spaces and facilities, equipment and utensils, procedure requirement for production and/or processing.Results : From their responses, hygiene was regarded generally admittable. In personnel management, some answers that herbal medicines were prepared not by Korean medicine doctor or pharmacist, but by general worker.On preparation method, dosage frequency and volume were different among preparation facilities. Regarding facility management, prescription inspection was substantially carried out in many extramural preparation facilities, however, some of them was not.
The aim of this study was to evaluate the effects of root bark of Eleutherococcus sessiliflorus (ES) on osteoclast differentiation and function in vitro and in vivo. In vitro, we found that ES significantly inhibited the RANKL-induced formation of TRAP-positive multinucleated osteoclasts and osteoclastic bone resorption without cytotoxic effects. ES markedly downregulated the expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1); c-Fos; and osteoclast-related marker genes, such as TRAP, osteoclast-associated receptor (OSCAR), matrix metalloproteinase-9 (MMP-9), calcitonin receptor, cathepsin K, the 38 kDa d2 subunit of the vacuolar H+-transporting lysosomal ATPase (Atp6v0d2), dendritic cell-specific transmembrane protein (DC-STAMP), and osteoclast-stimulatory transmembrane protein (OC-STAMP). These effects were achieved by inhibiting the RANKL-mediated activation of MAPK signaling pathway proteins, including p38, ERK, and JNK. In vivo, ES attenuated OVX-induced decrease in bone volume to tissue volume ratio (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and bone mineral density, but increased trabecular separation (Tb.Sp) in the femur. Collectively, our findings showed that ES inhibited RANKL-activated osteoclast differentiation in bone marrow macrophages and prevented OVX-mediated bone loss in rats. These findings suggest that ES has the potential to be used as a therapeutic agent for bone-related diseases, such as osteoporosis.
intervention followed by 3 to 7 days of washout period. Acupuncture in all groups was implemented at left LI10 with manipulation after insertion, 5 min, 10 min after insertion followed by needle removal. Microcirculation by laser Doppler perfusion imaging (LDPI) was measured 5 minutes before acupuncture till 10 minutes after removal of acupuncture. A repeated measures ANOVA was used for statistical analysis.Results: In each group, microperfusion increased by needle insertion was maintained till after needle removal, and different needle size induced different blood perfusion changes, with the increase in ST group significantly higher than SP, DT and DP groups (repeated measures ANOVA, P < 0.0001), but there was no significant difference by needling depth.Conclusion: ST intervention induced the greatest blood perfusion changes compared with other interventions, but the impact of different needling depths was not clear with blood perfusion changes. Studies investigating other physiological changes than blood perfusion by different acupuncture needle sizes and needling depths are needed.Contact: Xiuyu Zhang, Purpose: Indirubin-3'-monoxime (I3O), an active ingredient of Danggui Longhui Wan, exhibit antithrombotic activity through antiplatelet activity. Hence, we investigated the antiplatelet activity of I3O and the underlying mechanisms, focusing on the possible involvement of phospholipase C␥2 (PLC␥2) and extracellular signal-regulated kinase (ERK) 1/2. Methods: To identify the antithrombotic activity of I3O, we investigated using FeCl3-induced thrombus formation model, and platelet aggregation and coagulation ex vivo. In addition, the mechanism by which I3O is mediated the antithrombotic activity was assessed by determining platelet aggregation, immunoblotting, adenylyl cyclase activity, arachidonic acid (AA) liberation, and AA-metabolites conversion.Results: In a rat carotid artery injury model, oral administration (20 mg/kg/day) of I3O for 3 days significantly prolonged occlusion time, and ADP-and collagen-induced platelet aggregation, comparable with aspirin. In washed platelets in vitro, I3O potently inhibited collagen-induced platelet aggregation by suppression of PLC␥2 phosphorylation, consistent with the blockade of diacylglycerol (DAG) and AA formation, P-selectin secretion and the production of thromboxane B2 (TXB2). As expected, platelet aggregation induced by phorbol-12myristate 13-acetate (PMA), a protein kinase C (PKC) activator, was inhibited by I3O. Both I3O and U0126 markedly reduced collagen-induced phosphorylation of ERK1/2 and p47. Besides, I3O generally suppressed phosphorylation of JNK, p38, GSK-3, and AKT. Hence, we investigated to identify the effect of I3O in collagen receptor level; as a result, I3O concentrationdependently showed the inhibition pattern in immunofluorescence assay of glycoprotein VI (GPVI), as a collagen receptor. Moreover, I3O not only inhibited the phosphorylation of the tyrosine kinase Syk of GPVI but also suppressed the phosphorylation of PLC␥2 and ERK1/2 stimulated by...
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