Cell Reports
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2021
·
IF 9.423
Ke Li,Hongguang Wu,Ao Wang,Jean Charron,Yuji Mishina,Samy L. Habib,Huijuan Liu,Baojie Li
Summary mTOR, the sensor of nutrients and growth factors, has important roles in tissue homeostasis and tumorigenesis. However, how mTOR controls gastric epithelial cell turnover and gastric cancer development, a leading malignancy, remains poorly understood. Here, we provide genetic evidence that mTOR activation promotes proliferation and inhibits differentiation of Lgr5 + gastric epithelial progenitors (GEPs) in gastric homeostasis and tumorigenesis. mTOR signaling increases MEK1 and Smad1 expression and enhances activation of MEK1-ERKs and BMP-Smad1 pathways, respectively, in GEPs and gastric tumors. Mek1 deletion or inhibition rescues hyperproliferation, whereas Bmpr1a ablation or inhibition rescues differentiation defects of Tsc1 −/− GEPs. Tsc1 deficiency in Lgr5 + GEPs accelerates gastric tumor initiation and development, which require MEK1-ERKs for hyperplasia and BMP-Smad1 for differentiation suppression. These findings reveal how mTOR signaling controls Lgr5 + GEP homeostasis and cancerization and suggest that ERKs and Smad1 signaling can be safely targeted to substitute mTOR inhibitors in gastric cancer therapy.
研究领域:
癌症生物学
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细胞信号传导
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胃肠病学
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DOI
PubMed
高影响因子
RSC Advances
·
2018
·Vol. 8
·期 48
·27191-27200
·
IF 2.936
Qinli Xu,Ye Li,Yuhang Zhu,Kunchi Zhao,Rui Gu,Qingsan Zhu
Poly(lactic-co-glycolic acid) (PLGA) and hydroxyapatite (HA) are considered potential osteoinductive materials because of their biodegradability and mineralization features. However, the hydrophobicity of scaffold surfaces is less supportive of cell attachment and proliferation because of poor wettability. The mode of binding of growth factors to the scaffold also affects cell differentiation into osteoblasts. The half-life of a growth factor in vivo can be increased by binding the factor to the scaffold surface. In this work, we prepared a porous PLGA/HA scaffold grafted with recombinant human bone morphogenic protein-7 (rhBMP-7) attached via polydopamine (pDA) for bone repair. The pDA coated PLGA/HA (pDA-PLGA/HA) scaffolds were characterized by energy dispersive X-ray analysis and Fourier-transform infrared spectroscopy. The microstructure and porosity of PLGA/HA scaffolds were analyzed by scanning electron microscopy and micro-computed tomography. The release profile of rhBMP-7 grafted onto the pDA-PLGA/HA (pDA-PLGA/HA/BMP-7) scaffolds was examined for 21 days. The attachment efficiency, cell proliferation rate, alkaline phosphatase activity, calcium deposition, and osteoblast-related gene expression of bone marrow-derived stem cells to PLGA/HA, pDA-PLGA/HA, and pDA-PLGA/HA/BMP-7 scaffolds were evaluated. To assess the ability of bone repair in vivo, scaffolds were implanted into critical-sized calvarial defects created in mice, and the in vivo tissue-engineered bone was monitored by micro-computed tomography and histology. In vivo experiments revealed rapid healing of the defects treated with the pDA-PLGA/HA/BMP-7 scaffolds compared with pDA-PLGA/HA and PLGA/HA scaffolds at week 8 post-surgery. These results collectively demonstrate that the rhBMP-7-immobilized PLGA/HA scaffold via pDA is a promising candidate for calvarial repair.
研究领域:
生物医学工程
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组织工程
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材料科学
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骨科
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产品关联
DOI
PubMed
高影响因子
Materials Today Advances
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2023
·
IF 10
Weiye Cai,Xiaoping Xu,Yingcun Jiang,Kang Cheng,Fei Liu,Chao Song,Daru Guo,Zhenming Hu,Zhihong Liu,Zongchao Liu
Bone tissue repair is influenced by the synergistic interaction between acute immune microenvironment and osteogenesis. In this study will be independently by film dispersion method and static loading shell polymers and resveratrol liposome preparation CS - Res @ Lipo (CRL) and microfluidic technology preparation of HAMA@HepMA hydrogel microspheres (MS) by condensation reaction of chemical grafting, and then the non-covalent binding site of the MS microsphere was used to skillfully bind BMP-2, construct procedural release of hydrogel microspheres (CRL @ BMP - 2 @ MS). CRL@BMP-2@MS inhibit the acute immune peak by rapidly releasing Res, in addition, the sustained liberation of BMP-2 synchronizes osteoimmunity and osteogenesis, thereby accelerating bone repair. The results showed that Res was released with an increased cumulative rate of 72.4 ± 3.6% in the first 24 h, TNF-α and IL-1β levels were significantly decreased by 4.27 times and 3.65 times as compared to the control group, respectively. Furthermore, continuous release of approximately 40.26 ± 6.8% of BMP-2 occurred within the first 72 h, CRL@BMP-2@MS microspheres significantly increased osteogenic activity compared with the control group by 2.98 and 2.82 times, respectively. In conclusion, the programmed CRL@BMP-2@MS constructed in this study can realize the programmed synergistic linkage of immunity and osteogenesis, dynamically regulate bone repair, and the treatment of clinical bone repair will be based on a new strategy for diagnosis and treatment.
研究领域:
生物医学工程
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组织工程
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免疫学
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药剂学
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DOI
高影响因子
Frontiers of Materials Science
·
2015
·Vol. 9
·期 1
·38-50
·
IF 1
Du Ya-Wei,Zhang Li-Nan,Ye Xin,Nie He-Min,Hou Zeng-Tao,Zeng Teng-Hui,Yan Guo-Ping,Shang Peng
Polyetheretherketone (PEEK) is regarded as one of the most potential candidates of biomaterials in spinal implant applications. However, as a bioinert material, PEEK plays a limited role in osteoconduction and osseointegration. In this study, recombinant human bone morphogenetic protein-2 (rhBMP-2) was immobilized onto the surface of collagen-coated PEEK in order to prepare a multi-functional material. After adsorbed onto the PEEK surface by hydrophobic interaction, collagen was cross-linked with N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS). EDC/NHS system also contributed to the immobilization of rhBMP-2. Water contact angle tests, XPS and SEM clearly demonstrated the surface changes. ELISA tests quantified the amount of rhBMP-2 immobilized and the release over a period of 30 d. In vitro evaluation proved that the osteogenesis differentiation rate was higher when cells were cultured on modified PEEK discs than on regular ones. In vivo tests were conducted and positive changes of major parameters were presented. This report demonstrates that the rhBMP-2 immobilized method for PEEK modification increase bioactivity in vitro and in vivo , suggesting its practicability in orthopedic and spinal clinical applications.
研究领域:
生物医学工程
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骨科
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材料科学
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DOI
高影响因子
Oxidative Medicine and Cellular Longevity
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2019
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IF 4.868
Yang Zhao,Yan Cai,Li-Yan Cui,Wen Tang,Bo Liu,Jia-Jia Zheng,Wen-Zhe Si,Xian Wang,Ming-Jiang Xu
Aims. Vascular calcification (VC) is a primary risk factor for cardiovascular mortality in chronic renal failure (CRF) patients; thus, effective therapeutic targets are urgently needed to be explored. Here, we identified the role of intestinal bacterial translocation in CRF-related VC. Methods and Results. Antibiotic supplementation by oral gavage significantly suppressed intestinal bacterial translocation, CRF-related VC, and aortic osteogenic gene and Toll-like receptor (TLR) gene expression in CRF rats. Furthermore, TLR4 and TLR9 activation in vascular smooth muscle cells (VSMCs) aggravated inorganic phosphate- (Pi-) induced calcification. TLR9 inhibition, but not TLR4 inhibition, by both a pharmacological inhibitor and genetic methods could significantly reduce CRF rats’ serum or CRF-induced VC. Interestingly, bone morphogenic protein-2 (BMP-2) levels were increased in the aorta and sera from CRF rats. Increased BMP-2 levels were also observed in VSMCs treated with TLR9 agonist, which was blocked by NF-κB inhibition. Both siRNA knockdown of BMP-2 and NF-κB inhibitor significantly blocked TLR9 agonist-induced VSMC calcification. Conclusions. Gut bacterial translocation inhibited by oral antibiotic significantly reduces CRF-related VC through inhibition of TLR9/NF-κB/BMP-2 signaling.
研究领域:
心血管疾病
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肾脏生理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
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2017
·Vol. 5
·期 44
·8770-8779
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IF 4.543
Jiachen Sun,Yanxia Zhang,Bin Li,Yong Gu,Liang Chen
Stimulating the adhesion and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is crucial for the scaffold materials used in bone tissue engineering. In this study, a silk fibroin (SF)/nano-hydroxyapatite (nHAp) scaffold was prepared, embedded with SF microspheres containing bone morphogenetic protein-2 (BMP-2) and surface-modified through chemical conjugation with the type I collagen-mimetic peptide GFOGER. Surface-bound GFOGER and sustained BMP-2 release promoted the adhesion and osteogenic differentiation, respectively, of BMSCs. Our results indicated that this system released low doses of BMP-2 in a sustained manner, thereby avoiding cost and safety problems. The biological responses to this scaffold were investigated both in vitro and in vivo. Our results indicated that the synergistic effect of GFOGER and BMP-2 promoted the adhesion and osteogenic differentiation of BMSCs, thus leading to complete bone bridging of rat cranial defects after 12 weeks of implantation. This system might provide a powerful platform for treating bone defects and for bone tissue engineering.
研究领域:
组织工程
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生物医用材料
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再生医学
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
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2021
·
IF 4.749
Han Sun,Jian Dong,Yangyufan Wang,Siyu Shen,Yong Shi,Lei Zhang,Jie Zhao,Xiaoliang Sun,Qing Jiang
The periosteum plays an important role in vascularization and ossification during bone repair. However, in most studies, an artificial periosteum cannot restore both functions of the periosteum concurrently. In this study, a novel nanofiber that can sustain the release of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) was fabricated to enhance the durability of angiogenesis and osteogenesis during bone regeneration. A cell-free tissue engineered periosteum based on an electrospinning poly-l-lactic acid (PLLA) nanofiber was fabricated, on which VEGF and BMP-2 were immobilized through a polydopamine (PDA) coating conveniently and safely (BVP@PLLA membrane). The results indicated a significantly improved loading rate as well as a slow and sustained release of VEGF and BMP-2 with the help of the PDA coating. BMP-2 immobilized on nanofibers successfully induced the osteogenic differentiation of human bone marrow mesenchymal stem cells (BMSCs) in vitro with high expression of runt-related transcription factor 2 (Runx2), osteopontin (OPN), and alkaline phosphatase (ALP). Similarly, angiogenic differentiation of BMSCs with the expression of fetal liver kinase-1 (Flk-1) and vascular endothelial cadherin (VE-cadherin) was observed under the environment of VEGF sustained release. Moreover, an in vivo study revealed that the BVP@PLLA membrane could enhance vascular formation and new bone formation, which accelerates bone regeneration in rat femoral defects along with a massive periosteum defect. Therefore, our study suggests that the novel artificial periosteum with dual growth factor controlled release is a promising system to improve bone regeneration in bone defects along with a massive periosteum defect.
研究领域:
组织工程
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生物材料
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再生医学
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骨修复
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产品关联
DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
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2022
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IF 4.831
Qi Liu,Yatong Liu,Zhiyong Xing,Yuntong Huang,Li Ling,Xinglin Mo
In this study, a novel dual-function probe BMP based on benzothiazole was easily synthesized and characterized through common optical technique. In the system consisting of DMF/H 2 O (v/v, 2/3), probe BMP showed azure and blue-green to Al 3+ and Ga 3+ , respectively. Besides, the binding ratios of BMP to Al 3+ and Ga 3+ were determined as 1:1, which confirmed by Job’s plot. Furthermore, for Al 3+ and Ga 3+ , the limit of detection (LOD) was determined to be 1.51 × 10 -6 M and 4.28 × 10 -6 M, respectively. Moreover, it was worth noting that BMP showed good performances in paper colorimetry, cell phone colorimetric identification and cell imaging.
研究领域:
分析化学
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材料科学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
·
2026
·Vol. 21
·期 1
·101
·
IF 3.8
Li Gui,Song Qianbo,Song Ye,Liao Wenxing,Zhao Dong,Hong Binqing,Cao Guangru
Background To meet the needs of local treatment for spinal tuberculosis, this study developed a thermosensitive gel microsphere composite with both anti-tuberculosis and osteogenesis-promoting functions for efficient drug sustained release. The composite consists of anti-tuberculosis drugs (Pretomanid, Pa-824; Moxifloxacin, M; Pyrazinamide, Z) and bone morphogenetic protein-2 (BMP-2) to optimize drug release kinetics and enhance local therapeutic effects. Methods PaMZ/BMP-2 microspheres were prepared using microfluidics and characterized by SEM, particle size analysis, and XRD. LC–MS and ELISA measured drug and BMP-2 release. The thermosensitive gel (P407/P188) ratio was optimized to ensure it remained liquid at room temperature and formed a gel at 37 °C for sustained release. Results Microspheres were spherical with an average size of 203.92 ± 27.76 μm. Encapsulation rates were 112.69%, 24.15%, and 15.18% for Pa, M, and Z, respectively. In vitro release showed Pa and M sustained release for over 17 days, with the gel prolonging drug release. Conclusion This study successfully prepared PaMZ/BMP-2 microspheres with good morphology and drug loading capacity, achieving controlled sustained release through thermosensitive gel. This offers a potential formulation approach for future localized therapy of spinal tuberculosis and lays the foundation for subsequent in vivo experiments and clinical translation.
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DOI
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 5
·2027
·
IF 4.9
Shuangliu Chen,Jiřimutu Xiao,Shijie Zhou,Taxi Wumiti,Zitong Zhao,Ruihua Zhao,Yalan Pan,Qing Wang,Yong Ma,Lan Wu,Yang Guo
Dysregulated iron metabolism-induced ferroptosis is considered a key pathological mechanism in the development of osteoporosis (OP). G protein-coupled receptor 30 (GPR30, also known as Gper1) is an estrogen-binding receptor that has shown therapeutic benefits in patients with certain degenerative diseases. Moreover, several studies have demonstrated the anti-ferroptotic effects of estrogen receptor activation. However, its role in the prevention and treatment of OP remains unclear, and there are currently no reports on the anti-ferroptotic function of GPR30 in OP. Therefore, this study aimed to investigate the ferroptosis-related effects and mechanisms of GPR30 in the context of OP. In vivo and in vitro experiments were conducted using wild-type (WT)C57BL/6female mice and GPR30-knockout (GPR30-KO)C57BL/6Jfemale mice. The microarchitecture of the distal femur was assessed using micro-computed tomography (micro-CT), and histomorphological changes were analyzed via hematoxylin and eosin (H&E) staining. Bone marrow mesenchymal stem cells (BMSCs) were isolated and cultured to establish an iron overload model using ferric ammonium citrate (FAC). Interventions included GPR30 overexpression via transfection and BMP-6 inhibition using LDN-214117. Cell viability was evaluated with the CCK-8 assay, while osteogenic differentiation and mineralization levels were assessed using ALP and Alizarin Red S (ARS) staining. Iron accumulation was detected via Prussian blue staining, oxidative stress levels were evaluated using ROS staining, and mitochondrial membrane potential changes were analyzed using JC-1 staining. Transmission electron microscopy (TEM) was employed to observe mitochondrial ultrastructural changes. Additionally, key gene and protein expression levels were measured using immunofluorescence and Western blotting. The micro-CT analysis revealed significant bone microarchitecture deterioration and bone loss in the GPR30-KO mouse model. At the cellular level, GPR30 overexpression markedly reduced iron accumulation and oxidative stress in BMSCs, restored the mitochondrial membrane potential, and improved the mitochondrial ultrastructure. Furthermore, GPR30 enhanced osteogenic differentiation in BMSCs by promoting the activation of the BMP-6/HEP/FPN signaling pathway, leading to increased expression of osteogenic markers. The protective effects of GPR30 were reversed by the BMP-6 inhibitor LDN-214117, indicating that BMP-6 is a critical mediator in GPR30-regulated iron metabolism and ferroptosis inhibition. GPR30 inhibits ferroptosis in BMSCs and enhances osteogenic differentiation by activating the BMP-6/HEP/FPN signaling pathway. This provides new insights and potential therapeutic targets for the treatment of osteoporosis OP.
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2026
·
IF 5.9
Wei Ma,Xinyue Zhang,Jiajia Cen,Qin Chen,Kai Chen,Cunao Feng,Hongyu Zhang,Dekun Zhang
Efficient bone regeneration requires scaffolds that combine mechanical strength with controlled osteoinductive factor delivery. Here, we present a porous Ti6Al4V scaffold (PXTC4) functionalized with polydopamine and integrated with dual-level BMP2–PLA–Alg core–shell microspheres (BMP2-HPLA-Alg) for sustained BMP2 release. The PXTC4 scaffold exhibited high porosity (∼75%) and an elastic modulus (∼6.5 GPa) compatible with cortical bone, while the microspheres ensured heparin-mediated BMP2 adsorption, tunable degradation, and reduced initial burst release by 53.5% compared to the single-level BMP2-Alg microspheres. In vitro studies demonstrated enhanced MC3T3-E1 adhesion, proliferation, cytoskeletal organization, early osteogenic differentiation, and late-stage matrix mineralization. These results indicate that BMP2 synergizes with scaffold topography to create a favorable osteogenic microenvironment. This BMP2-HPLA-Alg microsphere-functionalized porous Ti6Al4V scaffold provides a robust platform with mechanical stability and sustained pro-osteogenic activity, offering a promising strategy for bone regeneration that warrants further in vivo investigation.
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DOI
PubMed
高影响因子
American Journal of Translational Research
·
2019
·
IF 3.266
Zhao Wang,Hong-Wei Bao
Our aim was to study the osteogenic effect of cnidium lactone for bone marrow mesenchymal stem cells (BMSCs) and its potential mechanism. BMSCs were isolated and identified by flow cytometry and multidirectional differentiation capacity. Cell Counting Kit-8 (CCK-8) was used to identify the optimal concentration of cnidium lactone. Alkaline Phosphatase (ALP) and Alizarin Red S (ARS) was performed to identify whether cnidium lactone has effect on osteogenesis at early and late phase respectively. Moreover, we used estrogen receptor antagonist, ICI182780, to identify the receptor of cnidium lactone. The expression of Runt-related transcription factor 2 (RUNX2), Osterix (OSX), osteopontin (OPN), estrogen receptor (ER), Smad4, p-Smad1, Smad1 and bone morphogenetic protein 2 (BMP-2) protein were measured by PCR and western blot. Cnidium lactone (2 μM) demonstrated increased osteogenesis after osteogenic inducible medium (OIM) induction, as evidenced by more ALP activity and mineralization. When blocked with ICI182780, osteogenesis capacity was decreased. Moreover, the polymerase chain reaction (PCR) and western blotting results indicated that cnidium lactone enhanced ER, BMP2, Smad1, Smad4, RUNX2, OSX, and OPN expression and Smad1 phosphorylation. Cnidium lactone can effectively stimulates osteogenic differentiation of BMSCs via BMP-2/Smad-Signaling cascades mediated by ER.
研究领域:
药理学
·
干细胞生物学
·
骨骼再生
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）