Food & Function
·
2022
·Vol. 13
·期 11
·6419-6432
·
IF 6.317
Furong Wang,Pengze Rong,Juan Wang,Xiao Yu,Na Wang,Shengyu Wang,Zikai Xue,Junnan Chen,Wenlong Meng,Xin Peng
Osteoporosis (OP) is characterized by the flaccidity of bones or bone bi-disease caused by kidney deficiency. Lindera aggregate has been used to strengthen kidney function in China for thousands of years. It has been approved by Chinese Pharmacopoeia that the root of Lindera aggregata (RLA) can replenish and tonify the kidney, which is thought to be an effective way to alleviate OP. In this study, a network pharmacology approach was applied to explore the active components and potential mechanisms of RLA in osteoporosis treatment. Then, the ethanolic extract of the root of L. aggregata (EERL) was prepared and these predicted results were validated by prednisone-induced zebrafish embryos model. Moreover, the candidate compounds were identified by UPLC-ESI-MS/MS. The anti-OP results showed that EERL could significantly reverse the bone loss of zebrafish induced by prednisone. The mRNA expressions results showed that EERL decreased osteoclast bone resorption by regulating the RANK/RANKL/OPG system. Also, it increased bone formation by regulating the gene expressions of spp1, mmp2, mmp9, runx2b, alp, and entpd5a. Our results demonstrated the reliability of the network pharmacology method, and also revealed the anti-OP effect and potential mechanism of RLA.
研究领域:
药理学
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分子生物学
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中医药学
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斑马鱼研究
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Ningning Jiang,Hui Jin,Kun Yang,Zhongyuan Zhang,Wenshu Xu,Xiaoxue Chen,Zhenhua Zhang,Hui Xu
The present study evaluated the in vitro effect of metformin (Met) and total flavonoids of Rhizoma Drynariae (TFRD) on osteoclasts, osteocytes, and osteoblasts at different stages. We also assessed the effect and mechanism of treatment with Met combined with TFRD on ovariectomy (OVX)-induced osteoporosis in rats. The results showed that Met combined with TFRD significantly promoted the migration of osteoprogenitor cells and stimulated the differentiation and maturation of osteoblast precursor cells. Furthermore, Met combined with TFRD treatment significantly inhibited the osteogenic inhibitor sclerostin (SOST)/dickkopf 1 (DKK1) protein expression and the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio in osteocytes. In the in vivo study, Met combined with TFRD effectively reduced bone resorption markers levels, including type-I collagen carboxy-terminal peptide (CTX-1) and tartrate-resistant acid phosphatase (TRAP), and remarkably increased the bone formation marker propeptide of type I procollagen (PINP) level in the serum of rats with osteoporosis. Met combined with TFRD treatment improved bone mineral density (BMD), trabecular microstructure, and mechanical properties of osteoporotic rats. Mechanistically, Met combined with TFRD downregulated SOST and DKK1 levels, and upregulated Wnt10b, β-catenin, runt-related transcription factor 2 (Runx2) et al. Meanwhile, Met combined with TFRD treatment reduced the RANKL/OPG ratio, and reduced the receptor activator of nuclear factor-κB (RANK), nuclear factor of activated T cells c1 (NFATC1), and TRAP levels. In conclusion, Met combined with TFRD ameliorated bone mass in osteoporotic rats through regulating Wnt/β-catenin signaling pathway and OPG/RANKL/RANK axis.
研究领域:
药理学
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骨科
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内分泌学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2026
·
IF 5.2
Zhongyan Bao,Juan Du,Yu Gao,Sinian Liu,Nanhai Xiao,Hang Wang,Luoyuan Zhao,Ming Chen,Fengqin Feng,Wei Qu,Qianqian Wang
This study was designed to comprehensively analyze the benefit effect and underlying mechanism of egg yolk-derived peptide VPF (Val-Pro-Phe) in bone development by integrating network pharmacology, molecular docking/dynamics simulation, and zebrafish in vivo experiments. Results demonstrated that VPF exhibited dose-dependent intervention effects within the concentration range of 0.2–10 μg/mL in normal and bone dysplasia zebrafish. Specifically, 0.2 μg/mL of VPF exhibited significant enhancements in total length (TL), mineralization, and swimming distance by 4.01%, 14.00% (P < 0.05), and 7.31% in normal zebrafish model, whereas 1 μg/mL of VPF led to significant increases in the aforementioned indexes by 6.30%, 45.26%, and 51.05% (P < 0.05) in bone dysplasia zebrafish model. Then, network pharmacology revealed that the highest correlation between VPF in improving bone development and osteoclast differentiation pathway, with osteoprotegerin (OPG) being the core node in this pathway. Molecular docking results showed that VPF exhibited the highest binding affinity for OPG, and this interaction was further validated by 200 ns molecular dynamics simulations, which demonstrated the stability of the VPF-OPG complex. Furthermore, VPF upregulated the gene expression of OPG, and downregulated the gene expression of the receptor activator of the NF-κB ligand (RANKL) and TNF receptor-associated factor 6 Gene (TRAF6), and downregulated the RANKL/OPG ratio in zebrafish. These data indicate that VPF alleviates skeletal dysplasia primarily by OPG-mediated suppression of osteoclast differentiation within the OPG/RANKL/RANK axis, thereby supporting its potential value as a functional food ingredient for promoting bone development.
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DOI
PubMed
高影响因子
Quantitative Imaging in Medicine and Surgery
·
2023
·
IF 2.8
Fenfang Liu,Fen Chen,Le Yang,Fucheng Qiu,Guangen Zhong,Shan Gao,Weizhe Xi,Meilian Lai,Qiting He,Ying Chen,Weiming Chen,Jiping Zhang,Lu Yang
Background Rheumatoid arthritis (RA) is an autoimmune disease leading to chronic joint inflammation. Bone erosion is the most serious pathological condition of RA and the main cause of joint deformities and disability. Melittin acupoint injection (MAI) is an effective traditional Chinese medicine (TCM) method for RA treatment. This study aimed to investigate the effect of MAI on RA bone erosion and to elucidate the underlying mechanism. Methods A collagen-induced arthritis (CIA) mouse model was established as the experimental subject. MAI was administrated once every other day for 28 days to mice with CIA. The effects of MAI on joint diseases were assessed by body weight, arthritis index (AI) score, swollen joint count (SJC) score, and hind paw thickness. Ankle radiological changes were captured by micro-computed tomography (micro-CT) and histological changes were observed by pathological staining. Organ histological changes, spleen index, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine (Crea) levels of serum were tested to evaluate the toxicity of MAI. Cytokine expression levels were confirmed by enzyme-linked immunosorbent assay (ELISA) to evaluate the immunity of CIA mice. Results MAI administration markedly improved the clinical signs of CIA in mice, including hind paw thickness, AI, and the number of swollen paw joints (most of them P<0.05 or even <0.01). According to histopathological analysis, MAI ameliorated inflammatory cell infiltration, synovial hyperplasia, pannus formation, and bone erosion (all P<0.01). Micro-CT and tartrate-resistant acid phosphatase (TRAP) staining (P<0.01) also revealed that MAI could relieve bone erosion via reducing the formation of osteoclasts. Not only could MAI relieve the immunological boost [P<0.05 for the high-dose MAI (HM) group], but also it had no liver or kidney side effects (P>0.05). In addition, it decreased the serum levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) and increased the serum levels of IL-4 and IL-10 (the majority of P<0.05 or even <0.01). Transcriptome sequencing results indicated that MAI affected the expression of osteoclast differentiation pathway genes, which was connected with the receptor activator of the nuclear factor κB ligand/nuclear factor kappa B (RANKL/NF-κB) pathway. Conclusions Based on our findings, MAI could suppress joint inflammation and inhibit RANKL/NF-κB-mediated osteoclast differentiation to rescue bone erosion in CIA mice, suggesting that MAI can be a potentially therapeutic substance for RA.
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产品关联
DOI
PubMed
高影响因子
CELL PROLIFERATION
·
2020
·Vol. 54
·期 1
·e12955
·
IF 5.753
Jun Ma,Lei Zhu,Zhibin Zhou,Tengfei Song,Lei Yang,Xu Yan,Aimin chen,Tian Wen Ye
Objectives Calcium ion signals are important for osteoclast differentiation. Transient receptor potential vanilloid 6 (TRPV6) is a regulator of bone homeostasis. However, it was unclear whether TRPV6 was involved in osteoclast formation. Therefore, the aim of this study was to evaluate the role of TPRV6 in bone metabolism and to clarify its regulatory role in osteoclasts at the cellular level. Materials and methods Bone structure and histological changes in Trpv6 knockout mice were examined using micro-computed tomography and histological analyses. To investigate the effects of Trpv6 on osteoclast function, we silenced or overexpressed Trpv6 in osteoclasts via lentivirus transfection, respectively. Osteoclast differentiation and bone resorption viability were measured by tartrate-resistant acid phosphatase (TRAP) staining and pit formation assays. The expression of osteoclast marker genes, including cathepsin k, DC-STAMP, Atp6v0d2 and TRAP, was measured by qRT-PCR. Cell immunofluorescence and Western blotting were applied to explore the mechanisms by which the IGF-PI3K-AKT pathway was involved in the regulation of osteoclast formation and bone resorption by Trpv6. Results We found that knockout of Trpv6 induced osteoporosis and enhanced bone resorption in mice, but did not affect bone formation. Further studies showed that Trpv6, which was distributed on the cell membrane of osteoclasts, acted as a negative regulator for osteoclast differentiation and function. Mechanistically, Trpv6 suppressed osteoclastogenesis by decreasing the ratios of phosphoprotein/total protein in the IGF–PI3K–AKT signalling pathway. Blocking of the IGF–PI3K–AKT pathway significantly alleviated the inhibitory effect of Trpv6 on osteoclasts formation. Conclusions Our study confirmed the important role of Trpv6 in bone metabolism and clarified its regulatory role in osteoclasts at the cellular level. Taken together, this study may inspire a new strategy for the treatment of osteoporosis.
研究领域:
骨骼生物学
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细胞信号传导
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Bioactive Materials
·
2021
·
IF 14.593
Yongzhi Cui,Yuanyuan Guo,Li Kong,Jingyu Shi,Ping Liu,Rui Li,Yongtao Geng,Weihang Gao,Zhiping Zhang,Dehao Fu
The complex pathogenesis of osteoporosis includes excessive bone resorption, insufficient bone formation and inadequate vascularization, a combination which is difficult to completely address with conventional therapies. Engineered exosomes carrying curative molecules show promise as alternative osteoporosis therapies, but depend on specifically-functionalized vesicles and appropriate engineering strategies. Here, we developed an exosome delivery system based on exosomes secreted by mesenchymal stem cells (MSCs) derived from human induced pluripotent stem cells (iPSCs). The engineered exosomes BT-Exo-si Shn3 , took advantage of the intrinsic anti-osteoporosis function of these special MSC-derived exosomes and collaborated with the loaded siRNA of the Shn3 gene to enhance the therapeutic effects. Modification of a bone-targeting peptide endowed the BT-Exo-si Shn3 an ability to deliver siRNA to osteoblasts specifically. Silencing of the osteoblastic Shn3 gene enhanced osteogenic differentiation, decreased autologous RANKL expression and thereby inhibited osteoclast formation. Furthermore, Shn3 gene silencing increased production of SLIT3 and consequently facilitated vascularization, especially formation of type H vessels. Our study demonstrated that BT-Exo-si Shn3 could serve as a promising therapy to kill three birds with one stone and implement comprehensive anti-osteoporosis effects.
研究领域:
生物技术
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药学
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干细胞研究
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分子生物学
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再生医学
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2023
·Vol. 18
·期 2
·e0281845
·
IF 3.7
Hao Tang,Shida Zhu,Kai Chen,Shujie Yuan,Junzu Hu,Hongkai Wang
Bone is a frequent target of tumor metastasis, with high incidence rate and poor prognosis. Osteoclasts play a key role in the process of tumor bone metastasis. Interleukin-17A (IL-17A) is an inflammatory cytokine, highly expressed in a variety of tumor cells, that can alter the autophagic activity of other cells, thereby causing corresponding lesions. Previous studies have shown that low concentration IL-17A can promote osteoclastogenesis. The aim of this study was to clarify the mechanism of low concentration IL-17A promoting osteoclastogenesis by regulating autophagic activity. The results of our study showed that IL-17A could promote the differentiation of osteoclast precursors (OCPs) into osteoclasts in the presence of RANKL, and increase the mRNA levels of osteoclast-specific genes. Moreover, IL-17A increased the expression of Beclin1 by inhibiting the phosphorylation of ERK and mTOR, leading to enhanced autophagy of OCPs, accompanied by decreased OCP apoptosis. Furthermore, knockdown of Beclin1 and suppression of autophagy by 3-methyladenine (3-MA) significantly attenuated the enhanced osteoclastogenesis induced by IL-17A. In summary, these results indicate that low concentration IL-17A enhances the autophagic activity of OCPs through the ERK/mTOR/Beclin1 pathway during osteoclastogenesis, and further promotes osteoclast differentiation, suggesting that IL-17A may serve as a potential therapeutic target for cancer-related bone resorption in cancer patients.
研究领域:
肿瘤学
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免疫学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2023
·Vol. 29
·期 2
·1-11
·
IF 3.4
Xiaoqian Guo,Guangwei Qiao,Jingjiao Wang,Changyi Yang,Min Zhao,Qian Zhang,Yingbiao Wan
Diabetic periodontitis (DP) refers to destruction of periodontal tissue and absorption of bone tissue in diabetic patients. Tumor necrosis factor receptor‑associated factor (TRAF)‑interacting protein with forkhead‑associated domain (TIFA) as a crucial regulator of inflammation activates the NF‑κB signaling pathway to regulate cell biological behavior. However, the function and mechanism of TIFA on DP suffer from a lack of research. In the present study, TIFA was upregulated in the periodontal tissue of a DP mouse model. In addition, the expression of TIFA in RAW264.7 cells was induced by high glucose (HG) culture and increased by lipopolysaccharide (LPS) from Porphyromonas gingivalis treatment in a time‑dependent manner. Knockdown of TIFA significantly reduced the levels of inflammatory cytokines, including TNF‑α, IL‑6, IL‑1β and monocyte chemoattractant protein‑1, in HG and LPS‑induced RAW264.7 cells. The nuclear translocation of NF‑κB p65 was induced by HG and LPS and was clearly suppressed by absence of TIFA. The expression of downstream factors Nod‑like receptor family pyrin domain‑containing 3 and apoptosis‑associated speck‑like protein was inhibited by silencing TIFA. Moreover, TIFA was increased by receptor activator of NF‑κB (RANK) ligand (RANKL) in a concentration dependent manner. The expression of cathepsin K, MMP9 and nuclear factor of activated T cells cytoplasmic 1 was downregulated by depletion of TIFA. RANKL‑induced osteoclast differentiation was inhibited by silencing of TIFA. Meanwhile, the decrease of TIFA blocked activation of the NF‑κB pathway in RANKL‑treated RAW264.7 cells. In conclusion, TIFA as a promoter regulates the inflammation and osteoclast differentiation via activating the NF‑κB signaling pathway.
研究领域:
牙科
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2016
·
IF 2.618
Xiaonan Zhang,Kang Chen,Bo Wei,Xingwang Liu,Zeming Lei,Xizhuang Bai
Glucocorticoid-induced osteoporosis (GIOP) is the primary cause of secondary osteoporosis and the existing therapeutic strategies are limited. The aim of this study is to evaluate the effects of ginsenosides (GS) Rg3 on dexamethasone (DEX)-induced osteoporosis in vivo and in vitro. GIOP rat was established by DEX injection for 5 weeks and treated by GS Rg3 10 or 20 mg/kg. Body weight and bone mineral density (BMD) of rats were measured at the beginning and the end of the experiment. Histological changes of femurs were observed using HE staining. The in vitro model was established on primary osteoblasts induced by DEX. CCK-8 assay was used to test the cell viability. Bone metabolism markers in serum or primary osteoblasts were detected using biochemical kits. Real time PCR and western blot were used to measure nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG), bone morphogenic protein-2 (BMP-2), BMP receptor 1A (BMPR1A) and Runx2 expression. The results demonstrated that GS Rg3 prevented DEX-induced body weight and BMD reduction, enhanced secretion of bone formation markers and decreased bone resorption markers. In addition, GS Rg3 was found to prevent the suppression of BMP-2/BMPR1A/Runx2 signals induced by DEX both in GIOP rats and primary osteoblasts. Inhibition of BMP-2 by noggin completely blocked the bone-alkaline phosphatase-secretion-promoted effect of GS Rg3 in vitro. These data suggest that GS Rg3 attenuates GIOP through regulating BMP-2 signaling pathway. This study provides a potential drug candidate for GIOP therapy.
研究领域:
药理学
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骨科
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ORAL DISEASES
·
2023
·
IF 3.8
Shiqun Sun,Tongtong Yan,Nan Yang,Jian Wu,Zhihui Liu
Objectives The aim of this study was to explore the potential role of zinc-finger homeodomain transcription factor (TCF8) in osteoclastogenesis and inflammation during periodontitis. Materials and Methods Rats with periodontitis were induced via Porphyromonas gingivalis -lipopolysaccharide (Pg-LPS) injection. The recombinant lentivirus delivering short hairpin RNA (shRNA) against TCF8 was used to downregulate TCF8 in vivo. Alveolar bone loss in rats was determined by micro-computed tomography (Micro-CT). Typical pathological changes, periodontal tissue inflammation, and osteoclastogenesis were evaluated via histological analyses. The RAW264.7-derived osteoclasts were induced by RANKL stimulation. TCF8 downregulation in vitro was achieved by lentivirus infection. The osteoclast differentiation and inflammatory signaling in RANKL-induced cells were measured via immunofluorescence methods and molecular biology approaches. Results Porphyromonas gingivalis -lipopolysaccharide induced rats exhibited overexpressed TCF8 in their periodontal tissues, while TCF8 knockdown attenuated the bone loss, tissue inflammation, and osteoclastogenesis in LPS-induced rats. Besides, TCF8 silencing inhibited RANKL-induced osteoclast differentiation in RAW264.7 cells, as evidenced by the reduced numbers of TRAP-positive osteoclasts, less formation of F-actin rings, and downregulated expressions of osteoclast-specific markers. It also exerted an inhibitory effect on the NF-κB signaling in RANKL-induced cells via blocking NF-κB p65 phosphorylation and nuclear translocation. Conclusions TCF8 silencing inhibited alveolar bone loss, osteoclast differentiation, and inflammation in periodontitis.
研究领域:
牙科学
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分子生物学
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炎症
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转录因子
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骨骼生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2022
·
IF 18.027
Yimin Niu,Hongbin Yang,Zhenyan Yu,Cuicui Gao,Shuaishuai Ji,Jie Yan,Lei Han,Qiang Huo,Ming Xu,Yang Liu
Bone metastasis is a common metastasis site such as lung cancer, prostate cancer, and other malignant tumors. The occurrence of bone metastases of lung cancer is often accompanied by bone loss, fracture, and other skeletal-related events (SREs) caused by tumor proliferation and osteoclast activation. Furthermore, along with the differentiation and maturation of osteoclasts in the bone microenvironment, it will further promote the occurrence and development of bone metastasis. Protein drugs are one of the most promising therapeutic pharmaceuticals, but in vivo delivery of protein therapeutics still confronts great challenges. In order to more effectively conquer bone metastases and alleviate SREs, herein, we constructed biomineralized metal–organic framework (MOF) nanoparticles carrying protein toxins with both bone-seeking and CD44-receptor-targeting abilities. More importantly, through combination with Receptor Activator of Nuclear Factor-κ B Ligand (RANKL) antibody, in vivo results demonstrated that these two protein agents not only enhanced the detraction effects of protein toxin agents as ribosome-inactivating protein (RIP) on bone metastatic tumor cells but also exhibited synergistic intervention of the crosstalk between bone cells and tumor cells and reduced SREs such as bone loss. Collectively, we expect that this strategy can provide an effective and safe option in regulating bone-tumor microenvironments to overcome bone metastasis and SREs.
研究领域:
肿瘤学
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药学
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生物材料
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产品关联
DOI
PubMed
高影响因子
POULTRY SCIENCE
·
2025
·
IF 4.2
Yawen Sun,Guangxiao Zhang,Bowen Zhao,Chenxue Fu,Bin Li,Fang Wang,Ming Tian,Minghui Wang,Hai Lin,Haifang Li
Laying hens are prolific egg producers, and the nutrient composition of breeder eggs critically influences the growth and development of offspring chicks. This study investigated the long-term effects of in ovo vitamin D3 injection (IOI-VD3) on bone development in chicks hatched from eggs laid during the late laying stage (68 weeks old, termed eggs-late). Compared to eggs from the peak laying period (44 weeks old, eggs-peak), eggs-late exhibited significantly lower phosphorus (↓7%, P =0.077) and vitamin D3 (↓26.9%, P <0.001). Consequently, chicks from eggs-late demonstrated inferior bone development at both 1 day (lower leg bone weight by 18%, P <0.05) and 4 weeks (reduced bone mineral content by 10%; P <0.05) of age relative to eggs-peak chicks. Notably, IOI-VD3 efficiently improved embryonic and long-term bone growth in late-egg-derived chicks, increasing bone mass by 14% and accelerating growth rate by 10% ( P <0.05). Further in vivo and in vitro analyses revealed that vitamin D3 promoted bone development by activating osteogenesis-related genes ( P <0.05) and suppressing osteoclastogenic markers ( P <0.05), with the vitamin D receptor (VDR) mediating these effects. Chromatin immunoprecipitation (ChIP) assays confirmed that 1,25-(OH)2D3 strengthened VDR binding to promoter regions of RANKL ( P =0.016) and RUNX2 ( P =0.031). In conclusion, this study highlights the disparity in egg quality between late and peak laying periods and its impact on chick bone development. IOI-VD3 ameliorated bone deficits in eggs-late chicks via VDR-dependent mechanisms.
研究领域:
动物科学
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家禽科学
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营养学
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发育生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）