Cell Metabolism
·
2022
·
IF 31.373
Ke Lu,Tian-Shu Shi,Si-Yu Shen,Yong Shi,Hong-Liang Gao,Jing Wu,Xiang Lu,Xiang Gao,Huang-xian Ju,Wei Wang,Yi Cao,Di Chen,Chao-Jun Li,Bin Xue,Qing Jiang
Summary Hepatic osteodystrophy (HOD) is a metabolic bone disease that is often associated with chronic liver disease and is marked by bone loss. Here, we demonstrate that hepatic expression of the phosphatase PP2Acα is upregulated during HOD, leading to the downregulation of expression of the hepatokine lecithin-cholesterol acyltransferase (LCAT). Loss of LCAT function markedly exacerbates the bone loss phenotype of HOD in mice. In addition, we found that alterations in cholesterol levels are involved in the regulation of osteoblast and osteoclast activities. We also found that LCAT improves liver function and relieves liver fibrosis in the mouse HOD model by promoting reversal of cholesterol transport from the bone to the liver. In summary, defects in a liver-bone axis occur during HOD that can be targeted to ameliorate disease progression.
研究领域:
肝病学
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内分泌学
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代谢性疾病
·
骨生物学
✓ 已验证
DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2025
·
IF 6.2
Bin Zhang,Yanlong Zhong,Peng Luo,Xiaolong Yu,Shaorong Huang,Xiaoyong Zhang,Xiaowei Yang
Osteoporosis is a metabolic bone disorder characterized by a reduction in bone mass and strength, which in turn leads to an increased likelihood of fracture. Although natural compounds show promising potential for osteoporosis treatment, their performance has been largely restricted by their poor water dispersibility and lack of bone-targeting ability. In this study, curcumin (Cur) was phosphorylated by a facile one-step nucleophilic substitution reaction to create phosphorylated Cur (p-Cur), in which the phenolic hydroxyl groups of Cur were converted to phosphate moieties through reaction with POCl 3 , enabling spontaneous self-assembly of p-Cur into carrier-free nanoparticles (p-Cur NPs) with excellent colloidal stability and bone-targeting ability in aqueous solution. In vitro results revealed p-Cur NPs effectively inhibited osteoclastogenesis in a dose-dependent manner, likely by scavenging reactive oxygen species. Using an ovariectomized murine model, p-Cur NPs demonstrated superior therapeutic outcomes compared to unmodified Cur, particularly in mitigating trabecular bone loss and maintaining skeletal microarchitecture. This phosphorylation-mediated nanonization approach combines simple synthesis with high biosafety, offering a promising paradigm for repurposing hydrophobic natural products into targeted therapeutics for metabolic bone diseases.
研究领域:
药学
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纳米医学
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骨代谢
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天然产物化学
✓ 已验证
产品关联
DOI
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Binhua Zou,Zushuang Xiong,Yanzi Yu,Sujiang Shi,Xiaoling Li,Tianfeng Chen
Osteoclast hyperactivation stands as a significant pathological factor contributing to the emergence of bone disorders driven by heightened oxidative stress levels. The modulation of the redox balance to scavenge reactive oxygen species emerges as a viable approach to addressing this concern. Selenoproteins, characterized by selenocysteine (SeCys 2 ) as the active center, are crucial for selenium-based antioxidative stress therapy for inflammatory diseases. This study reveals that surface-active elemental selenium (Se) nanoparticles, particularly lentinan-Se (LNT-Se), exhibit enhanced cellular accumulation and accelerated metabolism to SeCys 2 , the primary active Se form in biological systems. Consequently, LNT-Se demonstrates significant inhibition of osteoclastogenesis. Furthermore, in vivo studies underscore the superior therapeutic efficacy of LNT-Se over SeCys 2 , potentially attributable to the enhanced stability and safety profile of LNT-Se. Specifically, LNT-Se effectively modulates the expression of the selenoprotein GPx1, thereby exerting regulatory control over osteoclastogenesis inhibition, and the prevention of osteolysis. In summary, these results suggest that the prompt activation of selenoproteins by Se nanoparticles serves to suppress osteoclastogenesis and pathological bone loss by upregulating GPx1. Moreover, the utilization of bioactive Se species presents a promising avenue for effectively managing bone disorders.
研究领域:
生物材料
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生物医学工程
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药理学
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骨骼生物学
✓ 已验证
DOI
高影响因子
Neural Regeneration Research
·
2022
·Vol. 18
·期 8
·1809
·
IF 6.058
Xu Ai-Hua,Yang Yang,Shao Yang,Jiang Man-Yu,Sun Yong-Xin
Poly(ADP-ribose)polymerase family member 14 ( PARP14 ), which is an intracellular mono(ADP-ribosyl) transferase, has been reported to promote post-stroke functional recovery, but its role in spinal cord injury (SCI) remains unclear. To investigate this, a T10 spinal cord contusion model was established in C57BL/6 mice, and immediately after the injury PARP14 shRNA-carrying lentivirus was injected 1 mm from the injury site to silence PARP14 expression. We found that PARP14 was up-regulated in the injured spinal cord and that lentivirus-mediated downregulation of PARP14 aggravated functional impairment after injury, accompanied by obvious neuronal apoptosis , severe neuroinflammation , and slight bone loss. Furthermore, PARP14 levels were elevated in microglia after SCI, PARP14 knockdown activated microglia in the spinal cord and promoted a shift from M2-polarized microglia (anti-inflammatory phenotype) to M1-polarized microglia (pro-inflammatory phenotype) that may have been mediated by the signal transducers and activators of transcription (STAT) 1/6 pathway. Next, microglia M1 and M2 polarization were induced in vitro using lipopolysaccharide/interferon-γ and interleukin-4, respectively. The results showed that PARP14 knockdown promoted microglia M1 polarization , accompanied by activation of the STAT1 pathway . In addition, PARP14 overexpression made microglia more prone to M2 polarization and further activated the STAT6 pathway . In conclusion, these findings suggest that PARP14 may improve functional recovery after SCI by regulating the phenotypic transformation of microglia via the STAT1/6 pathway.
研究领域:
神经科学
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分子生物学
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细胞生物学
✓ 已验证
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ORAL DISEASES
·
2024
·
IF 2.9
Huiwen Chen,Yining Zhou,Yingli Liu,Wei Zhou,Lina Xu,Dihua Shang,Jing Ni,Zhongchen Song
Objectives The purpose of this study was to determine whether indoxyl sulfate (IS) is involved in alveolar bone deterioration and to elucidate the mechanism underlying alveolar bone loss in chronic kidney disease (CKD) patients. Materials and Methods Mice were divided into the control group, CP group (ligature-induced periodontitis), CKD group (5/6 nephrectomy), and CKD + CP group. The concentration of IS in the gingival crevicular fluid (GCF) was determined by HPLC. The bone microarchitecture was evaluated by micro-CT. MC3T3-E1 cells were stimulated with IS, and changes in mitochondrial morphology and ferroptosis-related factors were detected. RT-PCR, western blotting, alkaline phosphatase activity assays, and alizarin red S staining were utilized to assess how IS affects osteogenic differentiation. Results Compared with that in the other groups, alveolar bone destruction in the CKD + CP group was more severe. IS accumulated in the GCF of mice with CKD. IS activated the aryl hydrocarbon receptor (AhR) in vitro, inhibited MC3T3-E1 cell osteogenic differentiation, caused changes in mitochondrial morphology, and activated the SLC7A11/GPX4 signaling pathway. An AhR inhibitor attenuated the aforementioned changes induced by IS. Conclusions IS activated the AhR/SLC7A11/GPX4 signaling pathway, inhibited osteogenesis in MC3T3-E1 cells, and participated in alveolar bone resorption in CKD model mice through ferroptosis.
研究领域:
牙科学
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肾病学
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细胞生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Fiber Materials
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2025
·
IF 21.3
Zhao Qing,Li Yuping,Zhang Jinzheng,Lei Xiaoyu,Tang Jiajing,Chen Jieqiong,Li Jidong,Guo Weihua,Zuo Yi,Li Yubao
The rejuvenation of bone tissue remains a formidable challenge for osteoporosis (OP) patients who suffer severe bone degeneration or structural deterioration. To reverse the bone loss associated with OP, a dual-enzyme cascade system (PCF@EA) was engineered as a biomimetic engine to regulate bone metabolism imbalance. The bienzyme-driven system was constructed by integrating functionalized polymeric composite fibers with two mineralization-promoting hydrolases: recombinant human ectonucleotide pyrophosphatase/phosphodiesterase 1 (rhENPP1) and recombinant human alkaline phosphatase (rhALP). The bienzyme-driven engine efficaciously navigates mitochondria-activated mineralization through an autophagic process, thereby promoting osteogenic differentiation, increasing intracellular inorganic phosphate (Pi), and facilitating calcium influx. Concurrently, metabolic regulation mediated by the bienzyme-driven engine involves the PI3K–Akt pathway, tricarboxylic acid (TCA) cycle and glycerophosphate metabolism, significantly down-regulating the mineralization inhibitor pyrophosphate (PPi) while accelerating the formation of phosphate-related metabolites. Moreover, the enzyme-loaded substrates inhibited bone resorption by reducing expression of osteoclast activity markers, including Trap and Cath-K. This bienzymatic cascade strategy has demonstrated efficacy in restoring bone homeostasis in osteoporotic rats, significantly improving defect maturation and catalyzing the recovery of bone mineral density from severe loss back to baseline levels. The unique features of the bienzyme-driven engine provide a promising approach for the therapeutic treatment of degenerative skeletal diseases.
研究领域:
生物医学工程
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分子生物学
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生物化学
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再生医学
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药理学
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR MEDICINE
·
2024
·Vol. 30
·期 1
·1-16
·
IF 6
Zhang Yanbin,Bai Jing,Xiao Bin,Li Chunyan
Osteoporosis is characterized by reduced bone mass due to imbalanced bone metabolism. Exosomes derived from bone mesenchymal stem cells (BMSCs) have been shown to play roles in various diseases. This study aimed to clarify the regulatory function and molecular mechanism of BMSCs-derived exosomes in osteogenic differentiation and their potential therapeutic effects on osteoporosis. Exosomes were extracted from BMSCs. Bone marrow-derived macrophages (BMDMs) were cultured and internalized with BMSCs-derived exosomes. Real-time quantitative PCR was used to detect the expression of macrophage surface markers and tripartite motif (TRIM) family genes. BMDMs were co-cultured with human osteoblasts to assess osteogenic differentiation. Western blot was performed to analyze the ubiquitination of triggering receptor expressed on myeloid cell 1 (TREM1) mediated by TRIM25. An ovariectomized mice model was established to evaluate the role of TRIM25 and exosomes in osteoporosis. Exosomes were successfully isolated from BMSCs. BMSCs-derived exosomes upregulated TRIM25 expression, promoting M2 macrophage polarization and osteogenic differentiation. TRIM25 facilitated the ubiquitination and degradation of TREM1. Overexpression of TREM1 reversed the enhanced M2 macrophage polarization and osteogenic differentiation caused by TRIM25 overexpression. TRIM25 enhanced the protective effect of BMSCs-derived exosomes against bone loss in mice. These findings suggested that BMSCs-derived exosomes promoted osteogenic differentiation by regulating M2 macrophage polarization through TRIM25-mediated ubiquitination and degradation of TREM1. This mechanism might provide a novel approach for treating osteoporosis.
研究领域:
细胞生物学
·
骨代谢
·
干细胞研究
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巨噬细胞生物学
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疾病分子机制
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-18
·
IF 10.6
Gao Weihang,Li Jiao Jiao,Shi Jingyu,Lan Hongbing,Guo Yuanyuan,Fu Dehao
Osteoporosis is a highly prevalent metabolic disease characterized by low systemic bone mass and deterioration of bone microarchitecture, resulting in reduced bone strength and increased fracture risk. Current treatment options for osteoporosis are limited by factors such as efficacy, cost, availability, side effects, and acceptability to patients. Gold nanoparticles show promise as an emerging osteoporosis therapy due to their osteogenic effects and ability to allow therapeutic delivery but have inherent constraints, such as low specificity and the potential for heavy metal accumulation in the body. This study reports the synthesis of ultrasmall gold particles almost reaching the Ångstrom (Ång) dimension. The antioxidant alpha-lipoic acid (LA) is used as a dispersant and stabilizer to coat Ångstrom-scale gold particles (AuÅPs). Alendronate (AL), an amino-bisphosphonate commonly used in drug therapy for osteoporosis, is conjugated through LA to the surface of AuÅPs, allowing targeted delivery to bone and enhancing antiresorptive therapeutic effects. In this study, alendronate-loaded Ångstrom-scale gold particles (AuÅPs-AL) were used for the first time to promote osteogenesis and alleviate bone loss through regulation of the WNT signaling pathway, as shown through in vitro tests. The in vivo therapeutic effects of AuÅPs-AL were demonstrated in an established osteoporosis mouse model. The results of Micro-computed Tomography, histology, and tartrate-resistant acid phosphatase staining indicated that AuÅPs-AL significantly improved bone density and prevented bone loss, with no evidence of nanoparticle-associated toxicity. These findings suggest the possible future application of AuÅPs-AL in osteoporosis therapy and point to the potential of developing new approaches for treating metabolic bone diseases using Ångstrom-scale gold particles.
研究领域:
纳米技术
·
药学
·
生物医学工程
·
骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2020
·Vol. 34
·期 6
·8402-8415
·
IF 4.966
Xingquan Xu,Rongliang Wang,Rui Wu,Wenjin Yan,Tianshu Shi,Qing Jiang,Dongquan Shi
Bone loss is a severe complication of primary biliary cirrhosis (PBC). Trehalose was intermittently administered in bile duct-ligated (BDL) male rats, a PBC-related osteoporosis model, for 4 weeks to reduce osteoporosis. Femoral bones were assessed ex vivo by micro computed tomography (CT) and histomorphometry. The potential mechanisms related to the reduction of osteoporosis were explored by evaluating the effect of trehalose on osteoblast autophagy, osteogenesis, osteoclastogenesis, and ERK phosphorylation. The results demonstrated that trehalose reduced osteoporosis of BDL rats and decreased osteoblast-mediated osteoclast differentiation by enhancing osteoblast autophagy to regulate osteoprotegerin (OPG) secretion. Hydroxychloroquine (HCQ) increased the expression of OPG and OPG /receptor activator genes for nuclear factor-κB ligand (RANKL) ratio, and reduced osteoblast-mediated osteoclastogenesis by inhibiting autophagy flux and inducing autophagosome formation. Furthermore, trehalose increased the phosphorylation of ERK1/2 in MC3T3-E1 cells, and the ERK inhibitor PD98059 reversed the upregulation of OPG gene and reduction of trehalose-induced osteoclastogeneis. The treatment with HCQ markedly increased the ERK phosphorylation. The correlation between autophagosome formation and ERK phosphorylation was confirmed in autophagy proteins (ATG) 4B or ATG5-deficient cells. Thus, trehalose could decrease osteoblast-mediated osteoclastogenesis and reduce PBC-related bone loss by regulating ERK phosphorylation via autophagosome formation.
研究领域:
药理学
·
病理学
·
分子生物学
·
骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2022
·Vol. 10
·期 19
·5583-5595
·
IF 7.59
Han Li,Jiming Xu,Jun-Feng Hu,Qing-Yun Hu,Xiaolin Fang,Zhi-Jun Sun,Zhigang Xu,Lu Zhang
Periodontitis is a prevalent chronic inflammatory disease that destroys the periodontal supporting tissues, impinges on oral health, and is correlated with an increased risk of systemic disease. Currently, the main drug treatment is antibiotic therapy; however, systemic antibiotic therapy still has various drawbacks such as bacterial resistance, low bioavailability and burst release. It is noteworthy that the local use of non-antibiotic drugs with sustained release characteristics can effectively overcome these problems. It has been documented that chlorogenic acid (CGA) has good anti-inflammatory and antioxidant properties. To achieve the sustained release of CGA, we synthesized CGA–PLGA@PVP nanomicelles by loading CGA onto poly(D,L-lactide-co-glycolide) (PLGA) and modified them with polyvinylpyrrolidone (PVP) for better dispersion. The results demonstrated that CGA–PLGA@PVP nanomicelles could prolong the release time of CGA, and could not only effectively remove reactive oxygen species (ROS) but also downregulate the overexpression of proinflammatory cytokines in lipopolysaccharide (LPS)-treated RAW264.7 cells. Moreover, CGA–PLGA@PVP nanomicelles could remain in gingival tissue for more than 24 hours after local injection, inhibit alveolar bone resorption and prevent the progression of periodontitis in a mouse model, showing good biocompatibility. Therefore, CGA–PLGA@PVP nanomicelles have great properties and are expected to be a novel therapeutic strategy for periodontitis.
研究领域:
药剂学
·
牙科学
·
材料科学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2023
·
IF 3.8
Bing Liang,Xiongbin Chen,Min Li,Lingling Zhang,Xia Yang,Liangqin Shi,Yanju Gong,Yuanyuan Gong,Huan Xu,Xiao Wu,Zhong Jin,Yanru Wang,Luwei Liu,Xiaohong Yi,Lushuang Xie,Hua Zhong,Chongyang Shen,Yong Wang,Lan Yang
Context Liuwei Dihuang pill (LWDH) has been used to treat postmenopausal osteoporosis (PMOP).Objective To explore the effects and mechanisms of action of LWDH in PMOP.Materials and methods Forty-eight female Sprague-Dawley rats were divided into four groups: sham-operated (SHAM), ovariectomized (OVX), LWDH high dose (LWDH-H, 1.6 g/kg/d) and LWDH low dose (LWDH-L, 0.8 g/kg/d); the doses were administered after ovariectomy via gavage for eight weeks. After eight weeks, the bone microarchitecture was evaluated. The effect of LWDH on the differentiation of bone marrow mesenchymal stem cells (BMSCs) was assessed via osteogenesis- and lipogenesis-induced BMSC differentiation. The senescence-related biological indices were also detected using senescence staining, cell cycle analysis, quantitative real-time polymerase chain reaction and western blotting. Finally, the expression levels of autophagy-related proteins and Yes-associated protein (YAP) were evaluated.Results LWDH-L and LWDH-H significantly modified OVX-induced bone loss. LWDH promoted osteogenesis and inhibited adipogenesis in OVX-BMSCs. Additionally, LWDH decreased the positive ratio of senescence OVX-BMSCs and improved cell viability, cell cycle, and the mRNA and protein levels of p53 and p21. LWDH upregulated the expression of autophagy-related proteins, LC3, Beclin1 and YAP, in OVX-BMSCs and downregulated the expression of p62.Discussion and conclusions LWDH improves osteoporosis by delaying the BMSC senescence through the YAP-autophagy axis.
研究领域:
药理学
·
骨科
·
干细胞生物学
·
老年医学
✓ 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）