Asian Journal of Pharmaceutical Sciences
·
2025
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IF 11.9
Yasi Deng,Bin Li,Hao Zheng,Ling Liang,Yupei Yang,Shiqi Liu,Mengyun Wang,Caiyun Peng,Bin Liu,Wei Wang,Huanghe Yu
Abnormal activation of macrophages and osteoclasts (OCs) contributes significantly to rheumatoid arthritis (RA) development by secretion of numerous inflammatory factors. Notably, these cells exhibit significant upregulation of folate receptor proteins on their surfaces. Unfortunately, there is a current lack of safe and effective therapeutic drugs for RA. Xuetongsu (XTS), a triterpenoid compound extracted from Kadsura heteroclita Roxb Craib, has demonstrated the ability to significantly inhibit the proliferation of RA fibroblast-like synoviocytes (RAFLS). However, its clinical application is hampered by poor targeting and short half-life. To address these drawbacks, we previously developed a nano-drug system named HRPS nanoparticles (NPs), which effectively targets RAFLS and inhibits synovial hyperplasia. However, this system overlooked the essential role of OCs in RA-related bone destruction. Therefore, we designed a novel folate-modified biomimetic Prussian blue (PB)-XTS NP (FMPX NP) for the selective delivery of XTS into inflammatory macrophages and OCs. The NP exhibits an excellent photothermal effect when assisted by laser irradiation, facilitating targeted release of XTS within inflammatory macrophages and OCs. The synergistic anti-inflammatory and reactive oxygen species scavenging effects of PB NPs and XTS are mediated by the inhibition of the NF-κB signaling pathway in inflammatory macrophages and RANK/RANKL/NFATc1 signaling pathway in OCs. In vivo experiments showed that FMPX NPs extended the half-life of XTS by 2.32 times, decreased hind foot swelling from 12.10 ± 0.49 to 8.24 ± 0.09 mm in the model group, and prevented bone damage. In conclusion, this study introduces a novel dual-targeted nano-based therapy for RA joints and highlights its potential for biochemical photothermal triple therapy for RA. FMPX NPs inhibit arthritis-related inflammation and bone destruction through a dual-target strategy, providing new insights for targeted drug therapies in clinical RA treatment.
研究领域:
药理学
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纳米医学
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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
BIOCHEMICAL PHARMACOLOGY
·
2016
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IF 5.091
Shan Liu,Lingxin Zhu,Jie Zhang,Jingjing Yu,Xue Cheng,Bin Peng
Previous studies, including those from our laboratory, have demonstrated that the natural flavonoid isoliquiritigenin (ISL) is a promising agent for bone destructive diseases. However, the mechanisms underlying its anti-osteoclastogenic effects are still far from clear. Here, we evaluated the potential alterations of autophagy and nuclear factor-κB (NF-κB) during anti-osteoclastogenic effects by ISL in vitro and in vivo . We observed that ISL inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and suppressed autophagic microtubule-associated protein light chain 3 (LC3)-II and Beclin 1 accumulation. ISL treatment resulted in the interruption of several specific features for autophagy in osteoclast precursors, including acidic vesicular organelle formation, LC3-II accumulation, and appearance of autophagic vacuoles. The RANKL-stimulated expression levels of autophagy-related genes and proteins also diminished in ISL-treated osteoclast precursors. The reactivation of autophagy by rapamycin almost reversed the ISL-elicited anti-osteoclastogenic effects. Interestingly, ISL inhibited the RANKL-stimulated NF-κB expression and nuclear translocation, whereas the NF-κB inhibitor Bay 11-7082 markedly suppressed the RANKL-induced autophagic activation. Consistent with the in vitro results, the administration of ISL could attenuate osteoclastogenic cathepsin K , autophagic LC3, and NF-κB expression to protect against inflammatory calvarial bone erosion in vivo . Our findings highlight the inhibition of NF-κB-dependent autophagy as an important mechanism of ISL-mediated anti-osteoclastogenic activity.
研究领域:
药理学
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免疫学
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骨骼生物学
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DOI
PubMed
高影响因子
JOURNAL OF ARTHROPLASTY
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2024
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IF 3.4
Junqi Niu,Fanggang Bi,Qing Tian,Ke Tian
Background Aseptic loosening around the prosthesis is a common cause of failure in total joint arthroplasty. Polyethylene wear particles trigger the release of inflammatory factors by macrophages. Key mediators involved in osteoclastogenesis include interleukin-6, tumor necrosis factor-α, receptor activator of nuclear factor kappa B (RANK), RANK ligand (RANKL), and bone protection hormone (Osteoprotegerin [OPG]). The purpose of our experiment was to see whether melittin can slow down the release of inflammatory mediators through the NF-kB pathway, regulate the RANKL/OPG ratio, reduce osteoclast formation, and delay the onset of arthritis in rats. Methods A total of 20 male Sprague-Dawley rats (10 months, Specific Pathogen Free, 350 g ± 20 g) were randomly divided into 5 groups: sham group, model group, melittin concentration 1 group (0.2 mg/kg), concentration 2 group (0.4 mg/kg), and concentration 3 group (0.6 mg/kg). All rats were implanted with TA2 high-purity titanium rods. A drill was used to create a bone canal along the long axis of the femur in the intercondylar notch. The model group and experimental groups were exposed to polyethylene particles, while the sham group did not receive any particles. Results The melittin group exhibited significantly increased serum levels of serum P, calcium-phosphorus product, OPG, PINP, PINP/CTX-I, and OPG/RANKKL ( P < .05). In the experimental group, micro computed tomography scanning results revealed a decrease in the amount of bone defect around the prosthesis. Immunofluorescence analysis demonstrated a decrease in the expression of IKKα and P65, while the expression of OPG showed an upward trend. Both Hematoxylin-Eosin and Tartrate-Resistant Acid Phosphatase staining revealed less osteoclast and inflammatory cell infiltration in bone resorption pits. Conclusions Our study demonstrates that melittin has the ability to inhibit the NF-kB pathway in a rat model, and reduce the impact of RANKL/OPG, thereby delaying osteoclast activity and alleviating periprosthetic osteolysis.
研究领域:
骨科
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免疫学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2024
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IF 4
Lv ZhaoHui,Chen Xiao C.
Postmenopausal osteoporosis (PMOP) is a common chronic disease, and the loss of bone density and bone strength after menopause is its main symptom. Effective treatments for PMOP are still uncertain, but Chinese medicine has some advantages in slowing down bone loss. Shengu granules are often used clinically to treat PMOP. It has been shown to be an effective prescription for the treatment of PMOP, and there is evidence that gut flora may play an important role.However, whether Shengu granules attenuate PMOP by modulating gut flora and related mechanisms remains unclear. In this study. We examined the bone strength of the femur, the structure of the intestinal microbiota and SCFAs in the feces, the level of FOXP3 cells in the colon, the condition of the mucosa, and the level of cytokines in the serum, the protein expression of OPG and RANKL in femur, the protein expression of ZO-1 and Occludin in colon. Our research has found that Shengu granules restored a significant amount of intestinal flora. Improvement of intestinal flora disorders, elevation of its metabolite SCFAs and elevation of the proportion of FOXP3 cells decreased the expression of serum IL-17 and TNF-α and increased the expression of serum IL-10 and TGF-β. On the one hand, it reduced intestinal inflammation and repaired the intestinal barrier; on the other hand, it regulated the OPG/RANKL signaling axis, thus thereby ameliorating bone loss.
研究领域:
药理学
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免疫学
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内分泌学
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胃肠病学
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骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
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IF 6.6
Lixin Xie,Lihua Feng,Xiaomin Tang,Yunping Xu,Hengyi Xu,Yang Liu
Purpose To evaluate the therapeutic effect of oral administration of Lactiplantibacillus plantarum P101 (P101) on skeletal injury in young rats exposed to titanium dioxide nanoparticles (TiO2 NPs), and explore the potential mechanism.Methods Four-week-old male rats were orally administration to TiO2 NPs and supplemented with P101 2 hours later for 4 weeks. The growth and development, food intake, bone metabolism and serum inflammatory markers of the rats were evaluated. Their tibias were observed and evaluated using microcomputed tomography (micro-CT), tartrate-resistant acid phosphatase (TRAP) staining, immunohistochemistry (IHC) and real-time quantitative PCR (RT-qPCR). We observed the tibia growth plate using safranin and fast green staining. 16S rDNA sequence analysis of fecal samples was performed to observe changes in the gut microbiota.Results Our results showed that TiO2 NPs can lead to bone growth inhibition and osteoporosis, induce intestinal flora imbalance, and induce inflammation in young rats. Further mechanistic studies suggested that TiO2 NPs disrupts intestinal flora and increases serum IL-1β levels, which increased the expression of RANKL in bone, thereby enhancing osteoclast differentiation and function, leading to bone loss. Through a P101 supplementation experiment, we found that P101 ameliorated the inflammation and osteoporosis on bone caused by TiO2 NPs.Conclusion This study showed that the mechanism by which P101 alleviates bone damage caused by TiO2 NPs may be through restoring intestinal microbial homeostasis and inhibiting inflammatory response.
研究领域:
微生物学
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免疫学
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骨骼生物学
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纳米技术
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药理学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2022
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IF 7.419
Hui Jin,Ningning Jiang,Wenshu Xu,Zhongyuan Zhang,Yang Yang,Jingmin Zhang,Hui Xu
In this experimental study, we evaluated the protective effects and the safety of main flavanones derived from Rhizoma Drynariae (Gusuibu) in vitro and in vivo. The MTT assay showed that compared with vehicle treatment, treatment with such flavanones as neoeriocitrin, naringin, and naringenin significantly promoted the viability of osteocyte-like cells. Quantitative real-time PCR showed that neoeriocitrin and naringin significantly attenuated mRNA expressions of RANKL and SOST in osteocyte-like cells. In rats with retinoic acid-induced osteoporosis, total flavonoid of Rhizoma Drynariae (TFRD) , naringin, and naringenin significantly increased the number of trabeculae and improved trabecular bone structure compared with no treatment, without affecting liver and renal function. In addition, naringenin and naringin administration significantly increased bone mineral density of femur neck and femur shaft compared with the osteoporotic model rats. Western blot analysis showed that naringenin and naringin significantly attenuated protein expressions of bone resorption-related factors (TRAP, RANKL and RANK), and inhibited sclerostin expression compared with the osteoporotic model rats. On the other hand, naringin markedly increased protein expressions of ALP and PTH1R, and TFRD and naringenin also promoted PTH1R expression compared with the model rats. In conclusion, such flavanones as naringenin and naringin exhibited antiresorptive properties, and naringin particularly showed potential benefits for osteoporosis treatment.
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
JOURNAL OF NON-CRYSTALLINE SOLIDS
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2023
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IF 3.5
Mengen Zhao,Chao Zhang,Chenyu Gao,Zhaoying Wu
Bioactive glass (BG) has emerged as a promising material for bone regeneration. In this study, strontium-doped bioactive glass nanoparticles loaded with alendronate (A-SrBG) were fabricated and characterized to evaluate their potential for bone regeneration in osteoporosis. A-SrBG nanoparticles have excellent bioactivity, inducing apatite mineralization and achieving sustained release of bioactive ions in vitro . Moreover, A-SrBG nanoparticles could promote the differentiation of osteoblasts while inhibiting the differentiation of osteoclasts by preventing RANKL-induced activation of the NF-κB and mevalonate pathways. A-SrBG nanoparticles could be phagocytosed into the cells and present in the cytoplasm, which could enhance the efficiency of ALN. When implanted in vivo , A-SrBG discs promoted the regeneration of new bone. The results demonstrated that the ability of A-SrBG to dually regulate both osteogenesis and osteoclastogenesis makes it a promising candidate for the reconstruction of bone defects in osteoporosis.
研究领域:
材料科学
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生物医学工程
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骨骼生物学
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药学
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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2024
·Vol. 25
·期 12
·6754
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IF 4.9
Danyang Zhang,Xiaoyu Wang,Kezhuo Sun,Jianli Guo,Jia Zhao,Yuesheng Dong,Yongming Bao
Osteoporosis, a prevalent chronic health issue among the elderly, is a global bone metabolic disease. Flavonoids, natural active compounds widely present in vegetables, fruits, beans, and cereals, have been reported for their anti-osteoporotic properties. Onion is a commonly consumed vegetable rich in flavonoids with diverse pharmacological activities. In this study, the trabecular structure was enhanced and bone mineral density (BMD) exhibited a twofold increase following oral administration of onion flavonoid extract (OFE). The levels of estradiol (E2), calcium (Ca), and phosphorus (P) in serum were significantly increased in ovariectomized (OVX) rats, with effects equal to alendronate sodium (ALN). Alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) levels in rat serum were reduced by 35.7% and 36.9%, respectively, compared to the OVX group. In addition, the effects of OFE on bone health were assessed using human osteoblast-like cells MG-63 and osteoclast precursor RAW 264.7 cells in vitro as well. Proliferation and mineralization of MG-63 cells were promoted by OFE treatment, along with increased ALP activity and mRNA expression of osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB ligand (RANKL). Additionally, RANKL-induced osteoclastogenesis and osteoclast activity were inhibited by OFE treatment through decreased TRAP activity and down-regulation of mRNA expression-related enzymes in RAW 264.7 cells. Overall findings suggest that OFE holds promise as a natural functional component for alleviating osteoporosis.
研究领域:
药理学
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骨代谢
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细胞生物学
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功能性食品
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产品关联
DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
·
2022
·Vol. 8
·期 2
·e10414
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IF 10.684
Peng Luo,Jiarui Fang,Dazhi Yang,Lan Yu,Houqing Chen,Changging Jiang,Rui Guo,Tao Zhu,Shuo Tang
Bone injury caused changes to surrounding tissues, leading to a large number of osteoclasts appeared to clear the damaged bone tissue before bone regeneration. However, overactive osteoclasts will inhibit bone formation. In this study, we prepared methacrylylated gelatin (GelMA)-based hydrogel to co-crosslink with OP3-4 peptide, a receptor activator of NF-κB ligand (RANKL) binding agent, to achieve the slow release of OP3-4 peptide to inhibit the activation of osteoclasts, thus preventing the long-term existence of osteoclasts from affecting bone regeneration, and promoting osteogenic differentiation. Moreover, CXCL9 secreted by osteoblasts will bind to endogenous VEGF and inhibit vascularization, finally hinder bone formation. Thus, anti-CXCL9 antibodies (A-CXCL9) were also loaded in the hydrogel to neutralize excess CXCL9. The hydrogel slow released of OP3-4 cyclic peptide and A-CXCL9 to simultaneously inhibiting osteoclast activation and promoting vascularization, thereby accelerating the healing of femur defect. Further analysis of osteogenic protein expression and signal pathways showed that the hydrogel may be through activating the AKT-RUNX2-ALP pathway and ultimately promote osteogenic differentiation. This dual-acting hydrogel can effectively prevent nonunion caused by low vascularization and provide long-term support for the treatment of bone injury.
研究领域:
生物医学工程
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骨科
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再生医学
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药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
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IF 8
Wenshu Cheng,Xinyue Xu,Yuanyuan Lang,Zugen Cheng,Mohammad Rizwan,Xiaomin Tang,Lixin Xie,Yanling Liu,Hengyi Xu,Yang Liu
Purpose To evaluate the effects of anatase and rutile TiO2 nanoparticles (NPs) on the growth and development of bones in young rats and explore their possible mechanisms.Methods Three-week-old male rats were orally administered anatase TiO2 NPs and rutile TiO2 NPs for 28 days. The indicators of rat growth and development, liver function, bone metabolism, and insulin-like growth factor-1 (IGF-1) levels were evaluated. Micro-computed tomography (micro-CT) and immunohistochemistry were used to evaluate the tibia.Results No significant differences were observed among growth and development indicators in young rats. Significant differences were found in IGF-1 levels, phosphorus levels, and liver function. Micro-CT revealed osteoporosis in the bones. The micro-CT data supported the same result. Bone immunohistochemistry results showed that the expression of osteoprotegerin (OPG) was decreased and the expression of receptor activator of nuclear factor-κB ligand (RANKL) and cathepsin K (CTSK) was increased.Conclusion This study demonstrated that TiO2 NPs can damage bones via the IGF-1/OPG/RANKL/CTSK pathway in young rats. Furthermore, rutile TiO2 NPs damaged the bones more seriously than anatase TiO2 NPs.
研究领域:
纳米技术
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生物材料
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骨骼生物学
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毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aging-US
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2024
·
IF 3.9
Yaming Yang,Zheng Yan,Qi Xie,Yong Wang,Zhiying Liu,Min Lei
Background: The purpose of this study is to observe LP45 ( Lactobacillus plantarum 45) to investigate the mechanism by which LP45 attenuates oxidative stress-induced damage and regulates the osteoblast-osteoclast balance. Materials and Methods: The oxidative stress level and osteoblast- and osteoclast-related proteins were detected by immunofluorescence staining, Western blotting, ROS fluorescent probe and ELISA. Osteoblast cell proliferation capacity was determined by the CCK-8 assay. X-ray observation and HE staining were used to detect the effect of LP45 on osteoporosis. Results: The expression level of SHP2 and Src was significantly increased, and the expression levels of NOX4, P22, P47, IL-1β, NLRP3, IRF3, RANK, β-catenin and INF-β were inhibited in LP45 group and LPS + LP45 group as compared to those in LPS group. Compared with that in LPS group, the concentration of SOD was increased and the concentration of MDA was decreased in LPS + LP45 group. The protein expressions of OPG, RANKL, RUNX3, RANK and β-catenin in LP45 group and LPS + LP45 group increased. The protein expressions of NF-κB, CREB and AP-1 in LP45 group and LPS + LP45 group decreased significantly. The results were also confirmed by immunofluorescence staining and ROS fluorescent probe. X-ray observation and HE staining showed that LP45 could inhibit the progression of osteoporosis. Conclusion: LP45 can exert its antioxidant effect by inhibiting the production of oxidative stress to activate the SHP2 signaling pathway, thus promoting osteoblast differentiation and repressing osteoclast formation to maintain bone homeostasis and improve bone metabolism.
研究领域:
微生物学
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骨骼生物学
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药理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
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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
✓ 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）