PHYTOMEDICINE
·
2023
·
IF 7.9
Baohong Li,Zichao Chen,Zhenyong Zhang,Hui Liu,Dongli Han,Haolin Yang,Zhen Zhang
Background: Breast cancer bone metastasis is closely associated with the bone microenvironment. Zuogui Pill (ZGP), a clinically approved formulation in China, effectively regulates the bone microenvironment for the prevention and treatment of osteoporosis. Purpose: Few reports have utilized the ZGP for bone metastasis models. This study investigated the intervention and bone-protective properties of ZGP against breast cancer bone metastasis, explored the potential mechanism, and screened for its active compositions by molecules fishing. Methods: To investigate the intervention efficacy of ZGP and its protein-level mechanism of action, the mouse bone metastasis model and in vitro cell co-culture model were constructed. Affinity ultrafiltration, molecular docking, cellular thermal shift assay and physical scale detection were used to investigate the affinity components of the RANKL protein in ZGP. Results: The administration of ZGP combined with zoledronic acid inhibited the development of tumors and secondary lung metastasis in mice. This translated to a prolonged survival period and enhanced quality of life. ZGP could disrupt the malignant cycle by modulating the Piezo1-Notch-1-GPX4 signaling pathway in the "bone-cancer" communication in the cell co-culture model. Furthermore, 25 chemical components of ZGP were identified, with 10 active compounds exhibiting significant affinity for the RANKL protein. Conclusion: The findings of this work highlighted ZGP's potential for intervening in the progression of breast cancer bone metastasis. Thus, this investigation served as an experimental foundation for expanding the application scope of ZGP and for advancing drug development efforts in bone metastasis treatment.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Kamarulzaman Karim,Nelli Giribabu,Naguib Salleh
Background M. pumilum has been claimed to protect the bone against the adverse effect of estrogen deficiency . Additionally, it also exhibits anti-diabetic activity. In view of these, this study aims to identify the mechanisms underlying the bone protective effect of M. pumilum in the presence of both estrogen deficiency and diabetes mellitus (DM). Methods Ovariectomized, diabetic female rats were given M. pumilum leave aqueous extract (MPLA) (50 and 100 mg/kg/day), estrogen, glibenclamide and estrogen plus glibenclamide for 28 consecutive days. At the end of the treatment , fasting blood glucose (FBG), serum insulin , Ca 2+ , PO 4 3− and bone alkaline phosphatase (BALP) levels were measured. Rats were sacrificed and femur bones were harvested for determination of expression level and distribution of RANK , RANKL , OPG and oxidative stress and inflammatory proteins by molecular biological techniques. Results 100 mg/kg/day MPLA treatment decreased the FBG and BALP levels but increased the serum insulin, Ca 2+ and PO 4 3− levels in estrogen deficient, diabetic rats. Expression and distribution of RANKL, NF-κB p65, IKKβ, IL-6, IL-1β and Keap-1 decreased however expression and distribution of RANK, OPG, BMP-2, Type-1 collagen, Runx2, TRAF6 , Nrf2, NQO-1, HO-1, SOD and CAT increased in the bone of estrogen deficient, diabetic rats which received 100 mg/kg/day MPLA with greater effects than estrogen-only, glibenclamide-only and estrogen plus glibenclamide treatments. Conclusion MPLA helps to overcome the adverse effect of estrogen deficiency and DM on the bone and thus this herb could potentially be used for the treatment and prevention of osteoporosis in postmenopausal women with diabetes.
研究领域:
药理学
·
内分泌学
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糖尿病研究
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骨生物学
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炎症研究
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氧化应激
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DOI
PubMed
高影响因子
FASEB JOURNAL
·
2018
·Vol. 32
·期 6
·3398-3410
·
IF 5.595
Yugai Jia,Yumeng Miao,Mengfan Yue,Mei Shu,Zhifeng Wei,Yue Dai
Tetrandrine, a bisbenzylisoquinoline alkaloid, was previously demonstrated to attenuate inflammation and cartilage destruction in the ankles of mice with collagen-induced arthritis (CIA). Here, we explored the underlying mechanism by which tetrandrine prevented arthritis-induced bone erosion by focusing on the differentiation and function of osteoclasts. We found that daily administration of tetrandrine (30 mg/kg) markedly reduced the bone damage and decreased the number of osteoclasts in CIA rats. In vitro , tetrandrine inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis at the early stage and reduced the expressions of osteoclast-related marker genes. In bone marrow-derived macrophages and RAW264.7 cells, tetrandrine inhibited RANKL-induced translocation of NF-κB-p65 and nuclear factor of activated T cell 1 (NFATc1) through suppressing spleen tyrosine kinase (Syk)-Bruton's tyrosine kinase-PLCγ2-Ca 2+ signaling. Of interest, tetrandrine did not affect the phosphorylation of immunoreceptor tyrosine-based activation motifs, the conventional upstream of Syk, but it inhibited the activity of Syk by enhancing its ubiquitination and degradation. The anti–osteoclastogenesis effect of tetrandrine nearly disappeared when it was used in combination with the Syk inhibitor piceatannol or in constitutively activated Syk-overexpressing cells. Taken together, tetrandrine attenuated CIA-induced bone destruction by inhibiting osteoclastogenesis through hindering the translocation of NF-κB-p65 and NFATc1 via reducing the activation of Syk.—Jia Y., Miao, Y., Yue, M., Shu, M., Wei, Z., Dai Y. Tetrandrine attenuates the bone erosion in collagen-induced arthritis rats by inhibiting osteoclastogenesis via spleen tyrosine kinase. FASEB J. 32, 3398–3410 (2018). www.fasebj.org
研究领域:
药理学
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免疫学
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风湿病学
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产品关联
DOI
PubMed
高影响因子
MATERIALS & DESIGN
·
2023
·
IF 8.4
Guichun Wang,Chengjun Peng,Maomao Tang,Yuxiao Wang,Jiaxin Li,Hairong Chen,Xiangwei Chang,Zixuan Shu,Ning He,Jian Guo,Shuangying Gui
Currently, the antibiotics-loaded hydrogels have not shown an over standard of clinical effects on periodontitis treatment. Abnormal crosstalk between macrophages and periodontal ligament stem cells (PDLSCs) is a key factor for unexpected clinical efficacy. Here, we reported a therapeutic strategy for the programmed intervention of macrophages and PDLSCs based on folic acid-modified liposome hydrogel composites loaded with genistein (FA-GEN-Lip@Gel). FA-GEN-Lip@Gel exhibited excellent thermos-sensitivity and injectability, could sustained-release genistein for more than 120 h. Flow cytometry showed that FA-GEN-Lip@Gel shifted macrophages from the M1 to M2 phenotype. We further confirmed the anti-inflammatory mechanisms that FA-GEN-Lip@Gel regulate TLR4/MyD88/NF-κB axis in macrophages. In addition, FA-GEN-Lip@Gel could promote osteogenic differentiation of PDLSCs via remodeling of cytokine secretion of IL-6, IL-17, TNF-α and IL-10 in macrophages, as verified by conditioned culture system. Therefore, FA-GEN-Lip@Gel significantly reduced periodontal inflammation in vivo according to ELISA, H&E and immunofluorescence staining. Meanwhile, FA-GEN-Lip@Gel promoted alveolar bone regeneration by remodeling RANKL/OPG balance and increasing osteogenic markers of ALP, BMP2 and RUNX2. Altogether, this study develops a novel liposome-hydrogel composites that can be efficiently simultaneously boost inflammation resolution and osteogenic differentiation in periodontitis via modulating the crosstalk between macrophages and PDLSCs.
研究领域:
牙科学
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药学
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生物医学工程
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免疫学
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产品关联
DOI
高影响因子
Small
·
2023
·
IF 13.3
Yongzhi Cui,Bin Lv,Zhongying Li,Chunming Ma,Zhengwei Gui,Yongtao Geng,Guohui Liu,Linchao Sang,Chen Xu,Qi Min,Li Kong,Zhiping Zhang,Yang Liu,Xiangbei Qi,Dehao Fu
Insufficient bone formation and excessive bone resorption caused by estrogen deficiency are the major factors resulting in the incidence of postmenopausal osteoporosis (PMOP). The existing drugs usually fail to re-establish the osteoblast/osteoclast balance from both sides and generate side-effects owing to the lack of bone-targeting ability. Here, engineered cell-membrane-coated nanogels PNG@mR&C capable of scavenging receptor activator of nuclear factor-κB ligand (RANKL) and responsively releasing therapeutic PTH 1–34 in the bone microenvironment are prepared from RANK and CXCR4 overexpressed bone mesenchymal stem cell (BMSC) membrane-coated chitosan biopolymers. The CXCR4 on the coated-membranes confer bone-targeting ability, and abundant RANK effectively absorb RANKL to inhibit osteoclastogenesis. Meanwhile, the release of PTH 1–34 triggered by osteoclast-mediated acid microenvironment promote osteogenesis. In addition, the dose and frequency are greatly reduced due to the smart release property, prolonged circulation time, and bone-specific accumulation. Thus, PNG@mR&C exhibits satisfactory therapeutic effects in the ovariectomized (OVX) mouse model. This study provides a new paradigm re-establishing the bone metabolic homeostasis from multitargets and shows great promise for the treatment of PMOP.
研究领域:
生物医学工程
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药学
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组织工程
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骨生物学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Ziying Sun,Faheem Muhammad,Chenfeng Qiao,Wenli Gong,Zheng Wang,Yuan Liu,Xin Yu,Jian Dong,Jie Lv,Xi Cheng,Zhihao Lu,Chenguang Lin,Zhongyang Lv,Wenshuang Sun,Tao Yuan,Jia Meng,Rui Wu,Dongquan Shi,Hui Wei,Nirong Bao
Wear particulate debris-induced osteoclast over-activation is a major causative factor in periprosthetic osteolysis and aseptic loosening, resulting in the non-infectious failure of total joint arthroplasty. To mitigate such pathological bone loss, various therapeutic targets have been identified. Oxidative stress is one of the main contributing factors in the promotion of osteoclastogenesis. Herein, using a template-assisted approach, hollow ruthenium oxide (RuO 2 ) nanospheres are synthesized as an effective antioxidant for the treatment of CoCrMo alloy particles-induced osteolysis. Hollow RuO 2 significantly suppressed receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis, bone resorption, and the expression of specific markers (including NFATc1, c-Fos, MMP9, CTSK, and DC-STAMP) of bone marrow-derived macrophages via inhibition of the nuclear factor kappa-B (NF-κB) and tumor necrosis factor (TNF)-α pathways. In mouse calvaria, hollow RuO 2 nanozymes demonstrate an appreciable attenuation in osteoclast differentiation, bone loss, and soft tissue malformations induced by CoCrMo alloy particles. This study envisions that the antioxidant nanozymes may be further applied as a therapeutic entity in the prevention and treatment of other inflammatory and oxidative stress-related ailments.
研究领域:
材料科学
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纳米技术
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骨科
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生物化学
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药理学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Lan Zeng,Kang Ma,Ying Huang,Bingqing Liao,Luyao Zhong,Yue Zhao,Yongling Lu,Kai Xu,Shi Wang,Ning Mu,Yaning Shi,Chuanyan Yang,Xianyong Fu,Rong Hu,Hua Feng,Qiang Zhang,Xiaoming Wang,Tunan Chen
Long-segment peripheral nerve injury (PNI) represents a significant global health challenge, often leading to sensory and motor deficits, neuropathic pain, and secondary complications. Early reconnection of injured nerves is essential for preserving function and minimizing sequelae. In this study, we present a novel Silk Fibroin-MXene (SF-MXene) pIGF1 GelMA Hydrogel Nerve Conduit as an effective solution to optimize the bio-electrical and cellular microenvironment, thereby accelerating nerve regeneration. Unlike standalone plasmid Insulin-like Growth Factor-1 (pIGF1) releasing conduits, which disrupt growth direction and attract non-neuronal repair cells that obstruct nerve elongation, this advanced conduit enhances directional nerve growth and myelination while facilitating efficient electrical signal transmission in PNI rats. In this multifunctional NGC, pIGF1 optimizes the cellular microenvironment by promoting Schwann cell proliferation and migration, while the conductive SF-MXene NGC supports spatially ordered distribution and accelerates nerve elongation. Additionally, the conduit sustains long-term RANKL upregulation, activating NF-κB signaling to drive Schwann cell differentiation into myelinating subtypes, thereby promoting efficient and durable myelination of regenerated nerves and facilitating effective electrical signal transmission. These findings underscore the potential of the Silk-MXene+pIGF1 Nerve Conduit as a promising strategy for long-segment nerve injury repair, with strong implications for future clinical applications.
研究领域:
生物医学工程
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神经组织工程
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再生医学
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生物材料
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神经科学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Ting Li,Yangge Du,Hantao Yao,Boxuan Zhao,Zijun Wang,Rourong Chen,Yaoting Ji,Minquan Du
As bone-resorbing cells rich in mitochondria, osteoclasts require high iron uptake to promote mitochondrial biogenesis and maintain a high-energy metabolic state for active bone resorption. Given that abnormal osteoclast formation and activation leads to imbalanced bone remodeling and osteolytic bone loss, osteoclasts may be crucial targets for treating osteolytic diseases such as periodontitis. Isobavachin (IBA), a natural flavonoid compound, has been confirmed to be an inhibitor of receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation from bone marrow-derived macrophages (BMMs). However, its effects on periodontitis-induced bone loss and the potential mechanism of its anti-osteoclastogenesis effect remain unclear. Our study demonstrated that IBA suppressed RANKL-induced osteoclastogenesis in BMMs and RAW264.7 cells and inhibited osteoclast-mediated bone resorption in vitro. Transcriptomic analysis indicated that iron homeostasis and reactive oxygen species (ROS) metabolic process were enriched among the differentially expressed genes following IBA treatment. IBA exerted its anti-osteoclastogenesis effect by inhibiting iron accumulation in osteoclasts. Mechanistically, IBA attenuated iron accumulation in RANKL-induced osteoclasts by inhibiting the mitogen-activated protein kinase (MAPK) pathway to upregulate ferroportin1 (Fpn1) expression and promote Fpn1-mediated intracellular iron efflux. We also found that IBA inhibited mitochondrial biogenesis and function, and reduced RANKL-induced ROS generation in osteoclasts. Furthermore, IBA attenuated periodontitis-induced bone loss by reducing osteoclastogenesis in vivo. Overall, these results suggest that IBA may serve as a promising therapeutic strategy for bone diseases characterized by osteoclastic bone resorption.
研究领域:
药理学
·
牙科
·
细胞生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Anwei Zhang,Zhiwei Liu,Ling Zou,Lu Yang,Yonghui Wu,Xinxing Wang,Daigui Cao,Junli Liu,Xiaochao Yang,Shengli Zhang
Osteoporosis induced by the long-term administration of glucocorticoids is a common clinical problem. Current anti-osteoporosis therapies mainly focus on bone resorption inhibition or bone formation promotion unilaterally. However, the imbalance between bone formation and resorption often leads to suboptimal therapeutic outcomes. This study confirms the pathways through which dexamethasone (DEX), a typical glucocorticoid, triggers GIO, and explores both the therapeutic potential and underlying mechanisms of ceria nanoparticles (CNPs) in mitigating GIO. Our results demonstrate that DEX-induced bone homeostasis imbalance is the primary mechanism underlying GIO development in mice. Specifically, DEX inhibits pre-osteoblast proliferation and differentiation by inducing apoptosis and ferroptosis. Concurrently, DEX promotes osteoclast precursor proliferation and differentiation, significantly accelerating bone resorption. Administration of CNPs significantly mitigates DEX-induced disruption of bone homeostasis by ameliorating intracellular reactive oxygen species (ROS) accumulation via regulation of the Keap1/Nrf2 signaling pathway. Regarding osteogenesis, CNPs are capable of alleviating DEX-induced pre-osteoblast apoptosis and ferroptosis through the regulation of GPX4/ACSL4 signaling pathway. In terms of bone resorption, CNPs inhibit the RANKL-dependent osteoclast formation pathway. These findings validate the potential application of inorganic nanoparticles in GIO prevention.
研究领域:
纳米医学
·
骨骼生物学
·
药理学
·
分子生物学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Zuoxing Wu,Chen Li,Yu Chen,Qian Liu,Na Li,Xuemei He,Weibin Li,Rong Shen,Li Li,Chenming Wei,Siyuan Shao,Fangsheng Fu,Jiaxin Ding,Xiaochen Sun,Dairong Wang,Guixin Yuan,Yiji Su,Jinmin Zhao,Jiake Xu,Ren Xu,Xin Xu,Feng Xu
Bone homeostasis only exists when the physical function of osteoblast and osteoclast stays in the balance between bone formation and resorption. Bone resorption occurs when the two processes are uncoupled, shifting the balance in favour of bone resorption. Excessive activation of osteoclasts leads to a range of osteolytic bone diseases including osteoporosis, aseptic prosthesis loosening, rheumatoid arthritis, and osteoarthritis. Receptor activator of nuclear factor kappa-B ligand (RANKL) and its downstream signaling pathways are recognized as key mediators that drive the formation and activation of osteoclastic function. Hence, osteoclast formation and/or its function remain as dominant targets for research and development of agents reaching the treatment towards osteolytic diseases. Chrysin (CHR) is a flavonoid with a wide range of anti-inflammatory and anti-tumor effects. However, its effect on osteoclasts remains unknown. In this study, we found the effects of CHR on inhibiting osteoclast differentiation which were assessed in terms of the number and size of TRAcP positive multinucleated osteoclasts (OCs). Further, the inhibitory effects of CHR on bone resorption and osteoclast fusion of pre-OC were assessed by hydroxyapatite resorption pit assay and F-actin belts staining; respectively. Western blotting analysis of RANKL-induced signaling pathways and immunofluorescence analysis for p65 nuclear translocation in response to RANKL-induced osteoclasts were used to analyze the mechanism of action of CHR affecting osteoclasts. Lastly, the murine calvarial osteolysis model revealed that CHR could protect against particle-induced bone destruction in vivo . Collectively, our data strongly suggested that CHR with its promising anti-tumor effects would also be a potential therapeutic agent for osteolytic diseases.
研究领域:
药理学
·
骨科
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2022
·Vol. 10
·期 42
·8719-8732
·
IF 7.571
Mengen Zhao,Guo Chen,Shixiong Zhang,Bin Chen,Zhaoying Wu,Chao Zhang
Due to the lower regeneration capacity of the osteoporotic bone, the treatment of osteoporotic defects is extremely challenging in clinics. In this study, strontium-doped bioactive glass nanoparticles loaded with sodium alendronate (ALN), namely A-SrBG, were incorporated into the poly(ether-ether-ketone) matrix to fabricate a bioactive composite scaffold (ASP), which was expected to both inhibit bone resorption and promote bone regeneration. The results showed that such a composite scaffold with interconnected macropores (200–400 μm) could release Ca2+, Sr2+, and ALN in vitro. The proliferation, alkaline phosphatase (ALP) activity, expression of osteogenesis-related genes, and formation of calcified nodules of rat bone marrow stromal cells (rBMSCs) were clearly evidenced, and the reduction in the proliferation, tartrate-resistant acid phosphatase (TRAP) activity, cell fusion, and expression of osteoclastogenesis-related genes of osteoclasts was observed as well. In the presence of the ASP scaffold, enhanced osteogenesis along with inhibiting osteoclastogenesis was observed by modulating the osteoprotegerin (OPG)/receptor activator for nuclear factor κB ligand (RANKL) ratio. The efficacy of the composite scaffold in the regeneration of osteoporotic critical-sized cranial defect in a rat model was evaluated. Therefore, the bioactive composite scaffold with excellent biocompatibility and osteogenic potential could be a promising material for the repair of osteoporotic bone defects.
研究领域:
生物材料
·
组织工程
·
骨科
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2021
·
IF 4.315
Jinpeng Zhuang,Hua Ning,Maoqing Wang,Wei Zhao,Yongbin Jing,Xiaoqi Liu,Jianing Zu,Pengyu Kong,Xiaoyan Wang,Changhao Sun,Jinglong Yan
During osteoporosis, fat mass and obesity-associated protein (FTO) promotes the shift of bone marrow mesenchymal stem cells to adipocytes and represses osteoblast activity. However, the role and mechanisms of FTO on osteoclast formation and bone resorption remain unknown. In this study, we investigated the effect of FTO on RAW264.7 cells and bone marrow monocytes (BMMs)-derived osteoclasts in vitro and observed the influence of FTO on ovariectomized (OVX) mice model to mimic postmenopausal osteoporosis in vivo. Results found that FTO was up-regulated in BMMs from OVX mice. Double immunofluorescence assay showed co-localization of FTO with tartrate-resistant acid phosphatase (TRAP) in femurs of OVX mice. FTO overexpression enhanced TRAP-positive osteoclasts and F-actin ring formation in RAW264.7 cells upon RANKL stimulation. The expression of osteoclast differentiation-related genes, including nuclear factor of activated T cells c1 (NFATc1) and c-FOS, was upregulated in BMMs and RAW264.7 cells after FTO overexpression. FTO overexpression induced the phosphorylation and nuclear translocation of factor-kappa B (NF-κB) p65 in BMMs and RAW264.7 cells exposed to RANKL. ChIP and dual-luciferase assays revealed that FTO overexpression contributed to RANKL-induced binding of NF-κB to NFATc1 promoter. Rescue experiments suggested that FTO overexpression-mediated osteoclast differentiation was suppressed after intervention with a NF-κB inhibitor pyrrolidine dithiocarbamate . Further in vivo evidence revealed that FTO knockdown increased bone trabecula and bone mineral density, inhibited bone resorption and osteoclastogenesis in osteoporotic mice. Collectively, our research demonstrates that downregulated FTO inhibits bone resorption and osteoclastogenesis through NF-κB inactivation, which provides a novel reference for osteoporosis treatment.
研究领域:
骨骼生物学
·
分子生物学
·
细胞生物学
·
内分泌学
✓ 已验证
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）