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Argatroban promotes recovery of spinal cord injury by inhibiting the PAR1/JAK2/STAT3 signaling pathway

Neural Regeneration research 2024年第2期19卷 434-439页

作者： Chenxi Zhao Tiangang Zhou Ming Li Jie Liu Xiaoqing Zhao Yilin Pang Xinjie Liu Jiawei Zhang Lei Ma Wenxiang Li Xue Yao Shiqing Feng Department of orthopedics Tianjin Medical University General HospitalTianjinChina International science and Technology Cooperation base of Spinal Cord Injury Tianjin Key Laboratory of Spine and Spinal Cord InjuryDepartment of OrthopedicsTianjin Medical University General HospitalTianjinChina Orthopedic research Center of Shandong University Cheeloo College of MedicineDepartment of OrthopedicsQilu Hospital of Shandong UniversityJinanShandong ProvinceChina

Argatroban is a synthetic thrombin inhibitor approved by *** and Drug Administration for the treatment of ***,whether it plays a role in the repair of spinal cord injury is *** this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive *** results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal *** sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar *** blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal *** also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal *** together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.

关键词： argatroban astrogliosis JAK/STAT signaling pathway protease-activated receptor-1 spinal cord injury thrombin vimentin

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Biophysical-driven piezoelectric and aligned nanofibrous scaffold promotes bone regeneration by re-establishing physiological electrical microenvironment

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Nano research 2024年第8期17卷 7376-7393页

作者： Aoao Wang Xinbo Ma Yafeng Yang Guoliang Shi Liwei Han Xiantong Hu Rui Shi Jun Yan Quanyi Guo Yantao Zhao Senior Department of orthopedics the Fourth Medical Center of PLA General HospitalBeijing 100048China Department of Chemistry Capital Normal UniversityBeijing 100048China National Center for Orthopaedics Beijing Research Institute of Traumatology and OrthopaedicsBeijing Jishuitan HospitalCapital Medical UniversityBeijing 100035China Xijing 986 Hospital Department The Fourth Military Medical UniversityXi'an 710032China Institute of orthopedics Chinese PLA General HospitalBeijing Key Laboratory of Regenerative Medicine in OrthopedicsKey Laboratory of Musculoskeletal Trauma&War Injuries PLABeijing 100853China

The initial healing stages of bone fracture is a complex physiological process involving a series of spatially and temporally overlapping events,including pathogen clearance,immunological modulation,and *** this study,we have developed a piezoelectric and aligned nanofibrous scaffold composed of ZnO@PCL/PVDF with multiple antibacterial,immunomodulatory,and osteogenic effects using electrospinning *** scaffold’s piezoelectric signal output under ultrasound(US)control can be similar to the physiological electrical signals of healthy bone tissue,creating a truly biomimetic electrical microenvironment in the bone *** vitro studies have shown that ZnO@PCL/PVDF scaffold significantly enhances the proliferation,migration,and osteogenic differentiation of MC3T3-E1 cells under piezoelectric drive provided by ***,the scaffold exhibits inhibitory effects on the growth of *** and ***,as well as the ability to induce M2 macrophage polarization,indicating potent antibacterial and immunomodulatory *** vivo experiments demonstrated that the ZnO@PCL/PVDF scaffold can accelerate the repair of mandibular defects in rats,effectively inhibit bacterial colonization,and reduce inflammatory ***,this study confirms that the newly developed ZnO@PCL/PVDF scaffold effectively promotes bone repair by truly mimicking the endogenous electrical microenvironment and precisely regulating the temporospatial disorders of initial bone healing,thus providing a simple and effective solution for bone defects.

关键词： piezoelectricity bone defect bacterial infection ZnO nanoparticles immunomodulation osteogenesis

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BMP9 induces osteogenic differentiation through up-regulating LGR4 via the mTORC1/ Stat3 pathway in mesenchymal stem cells

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Genes & Diseases 2024年第3期11卷 468-483页

作者： Jie Zhang Jinhai Jiang Hang Liu Shiyu Wang Kaixin Ke Siyuan Liu Yue Jiang Lu Liu Xiang Gao Baicheng He Yuxi Su Department of Pharmacology School of PharmacyChongqing Medical UniversityChongqing 400016China Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing Chongqing Medical UniversityChongqing 400016China Department of orthopedics Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China orthopedics Department Children's Hospital of Chongqing Medical UniversityChongqing 400014China China International science and Technology Cooperation base of Child Development and Critical Disorders Jiangxi Hospital Affiliated Children's Hospital of Chongqing Medical UniversityJiangxi 330000China National Clinical research Center for Child Health and Disorders China

Bone defects and non-union are prevalent in clinical orthopedy,and the outcomes of current treatments are often *** tissue engineering offers a promising approach to treating these conditions *** morphogenetic protein 9(BMP9)can commit mesenchymal stem cells to osteogenic lineage,and a knowledge of the underlying mechanisms may help advance the field of bone tissue ***-rich repeats con-taining G protein-coupled receptor 4(LGR4),a member of G protein-coupled receptors,is essential for modulating bone *** study is aimed at investigating the impact of LGR4 on BMP9-induced osteogenesis in mesenchymal stem cells as well as the underlying *** marrow stromal cells from BMp9-knockout mice exhibited diminished LGR4 expression,and exogenous LGR4 clearly restored the impaired osteogenic potency of the bone marrow stromal ***,LGR4 expression was increased by BMP9 in C3H10T1/2 ***4 augmented the benefits of BMP9-induced osteogenic markers and bone formation,whereas LGR4 inhibition restricted these ***,the BMP9-induced li-pogenic markers were increased by LGR4 *** protein levels of Raptor and p-Stat3 were elevated by *** knockdown or p-Stat3 suppression attenuated the osteoblastic markers and LGR4 expression brought on by ***4 significantly reversed the blocking ef-fect of Raptor knockdown or p-Stat3 suppression on the BMP9-induced osteoblastic *** interacts with p-Stat3,and p-Stat3 activates the LGR4 promoter *** conclusion,LGR4 boosts BMP9 osteoblastic potency in mesenchymal stem cells,and BMP9 may up-regulate LGR4 via the mTORC1/Stat3 signal activation.

关键词： BMP9 LGR4 mTORC1 Osteogenic differentiation Stat3

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Maternal High-Fat Diet Impairs Offspring Glucose Metabolism and Programs Hepatic DNA Methylation Linked to NK Cell-Mediated Cytotoxicity Signaling Pathway at Weaning

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Food science and Human Wellness 2024年

作者： Sheng Zheng Ling Zhang Shixuan Zhang Guanyu Hu Yikai Li Jia Zheng Department of Traditional Chinese orthopedics and traumatology， Center for Orthopedic Surgery， The Third Affiliated Hospital of Southern Medical University Department of Endocrinology， Peking University First Hospital

Maternal consumption of a high-fat diet has been linked to increased risks of obesity and impaired glucose metabolism in offspring. However， the precise epigenetic mechanisms governing these intergenerational effects， particularly during the early stages of offspring development， remain poorly understood. In this study， female C57BL/6J mice were randomly assigned to either a high-fat diet or normal chow diet throughout gestation and lactation. Methylated DNA immunoprecipitation (MeDIP) coupled with microarray analysis was employed to identify differentially methylated genes in the livers of offspring at weaning age. We found that maternal high-fat diet feeding predisposes offspring to obesity and impaired glucose metabolism as early as the weaning period. DNA methylation profile analysis unveiled a significant enrichment of differentially methylated genes within the natural killer (NK) cell-mediated cytotoxicity pathway. MeDIP-PCR validated reduced methylation levels of specific genes within this pathway， including TNFα， PI3K， and SHC1. Consistently， the expressions of TNFα， PI3K， and SHC1 were significantly upregulated， accompanied by elevated serum TNFα and IL-6 levels in offspring from dams fed with high-fat diet. Moreover， we assessed the expressions of genes associated with NK cell activities， uncovering a notable rise in hepatic granzyme B levels and a trend towards increased CD107a expression in offspring from dams fed a high-fat diet. In addition， methylation levels of TNFα， PI3K， and SHC1 promoters were inversely correlated with glucose response during glucose tolerance testing. In conclusion， our findings underscore the critical role of the NK cell-mediated cytotoxicity signaling pathway in mediating DNA methylation patterns， thereby contributing to the programming effects of maternal high-fat diet consumption on offspring glucose metabolism as early as the weaning period.

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Dual-directional regulation of spinal cord injury and the gut microbiota

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Neural Regeneration research 2024年第3期19卷 548-556页

作者： Yinjie Cui Jingyi Liu Xiao Lei Shuwen Liu Haixia Chen Zhijian Wei Hongru Li Yuan Yang Chenguang Zheng Zhongzheng Li Academy of Medical Engineering and Translational Medicine Tianjin UniversityTianjinChina School of Medical Technology Tianjin University of Traditional Chinese MedicineTianjinChina research Center of Experimental Acupuncture science Tianjin University of Traditional Chinese MedicineTianjinChina International Cooperation and Exchange Office Chengdu University of Traditional Chinese MedicineChengduSichuan ProvinceChina International Cooperation base of Spinal Cord Injury Tianjin Key Laboratory of Spine and Spinal Cord InjuryDepartment of OrthopedicsTianjin Medical University General HospitalTianjinChina Department of orthopedics Qilu Hospital of Shandong UniversityJinanShandong ProvinceChina

There is increasing evidence that the gut microbiota affects the incidence and progression of central nervous system diseases via the brain-gut *** spinal cord is a vital important part of the central nervous system;however,the underlying association between spinal cord injury and gut interactions remains *** studies suggest that patients with spinal cord injury frequently experience intestinal dysfunction and gut *** in the gut microbiota can cause disruption in the intestinal barrier and trigger neurogenic inflammatory responses which may impede recovery after spinal cord *** review summarizes existing clinical and basic research on the relationship between the gut microbiota and spinal cord *** research identified three key ***,the gut microbiota in patients with spinal cord injury presents a key characteristic and gut dysbiosis may profoundly influence multiple organs and systems in patients with spinal cord ***,following spinal cord injury,weakened intestinal peristalsis,prolonged intestinal transport time,and immune dysfunction of the intestine caused by abnormal autonomic nerve function,as well as frequent antibiotic treatment,may induce gut ***,the gut microbiota and associated metabolites may act on central neurons and affect recovery after spinal cord injury;cytokines and the Toll-like receptor ligand pathways have been identified as crucial mechanisms in the communication between the gut microbiota and central nervous *** microbiota transplantation,probiotics,dietary interventions,and other therapies have been shown to serve a neuroprotective role in spinal cord injury by modulating the gut *** targeting the gut microbiota or associated metabolites are a promising approach to promote functional recovery and improve the complications of spinal cord injury.

关键词： chemokines cytokines gut microbiota NLRP3 spinal cord injury Toll-like receptor ligand tryptophan

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A Dielectric Ink Combining Acrylate and Cyanate Moieties for Inkjet 3D Printing with Good Thermal Stability

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Chinese Journal of Polymer science 2024年第6期42卷 766-774页

作者： Yi-Xuan Li Liang-Ying Wu Yan Yang Yao-Zhong Lu Zhong-Ying Ji Yu-Xiong Guo Xiao-Long Wang Qiao-Sheng Pu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical EngineeringLanzhou UniversityLanzhou730000China State Key Laboratory of Solid Lubrication Lanzhou Institute of Chemical PhysicsLanzhou730000China Lanzhou Traditional Chinese Medicine Hospital of orthopedics and traumatology Lanzhou730000China Shandong Laboratory of Advanced Materials and Green Manufacturing at Yantai Yantai Zhongke Research Institute of Advanced Materials and Green Chemical EngineeringYantai264006China

Inkjet 3D printing has potential in the additive manufacturing of electronic circuits and ***,inks that can be used for printing layers with T5%>300℃ or hardness>200 MPa have been rarely *** ester(CE)polymers have excellent thermal stability,high strength,and low shrinkage compared to other common dielectric inks for inkjet 3D printing,but cannot be quickly shaped by ultraviolet(UV)irradiation or thermal *** CEs with UV-curable monomers may be a possible way to accelerate crosslinking,but there are challenges from the adverse effects of the dilution of both *** this study,dielectric inks with acrylate and cyanate moieties were *** low viscosity and surface tension of the CE precursor(Bisphenol E cyanate ester)were combined with photocurable acrylate diluent monomers and cross-linker to realize an ink suitable for inkjet 3D *** internal dual three-dimensional cross-linked network structure resin was prepared by a combination of photocuring and thermal curing with T5%up to 326.69℃,hardness up to 431.84 MPa,dielectric constant of 2.70 at 8 GHz,and shrinkage of 1.64%.The developed dielectric inks can be applied to the 3D printing of printed circuit boards and other electronic devices that require dielectric properties.

关键词： Inkjet printing Cyanate ester resin 3D doubly cross-linked network Good thermal stability

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Mapk7 deletion in chondrocytes causes vertebral defects by reducing MEF2C/PTEN/AKT signaling

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Genes & Diseases 2024年第2期11卷 964-977页

作者： Chengzhi Wu Hengyu Liu Dongmei Zhong Xiaoming Yang Zhiheng Liao Yuyu Chen Shun Zhang Deying Su Baolin Zhang Chuan Li Liru Tian Caixia Xu Peiqiang Su Guangdong Provincial Key Laboratory of orthopedics and traumatology Department of Spine SurgeryThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510080China research Center for Translational Medicine The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510080China Precision Medicine Institute The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510080China Department of orthopedics Renmin Hospital of Wuhan UniversityWuhanHubei 430060China Guangdong Provincial Key Laboratory of Proteomics and State Key Laboratory of Organ Failure research School of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong 510515China

Mutation of the MAPK7 gene was related to human ***7 regulated the development of limb bones and skulls in ***,the role of MAPK7 in vertebral development is still *** this study,we constructed Col2a1-cre;Mapk7 f/f transgenic mouse model to delete Mapk7 in cartilage,which displayed kyphosis and ***,Mapk7 loss decreased MEF2C expression and thus activated PTEN to oppose PI3K/AKT signaling in vertebral growth plate chondrocytes,which impaired chondrocyte hypertrophy and attenuated vertebral *** vivo,systemic pharmacological activation of AKT rescued impaired chondrocyte hypertrophy and alleviated mouse vertebral defects caused by Mapk7 *** study firstly clarified the mechanism by which MAPK7 was involved in vertebral development,which might contribute to understanding the pathology of spinal deformity and provide a basis for the treatment of developmental disorders of the spine.

关键词： Chondrocyte hypertrophy Growth plate Kyphosis MAPK7 MEF2C Osteopenia PI3K/AKT PTEN

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Antioxidant and anti-inflammatory injectable hydrogel microspheres for in situ treatment of tendinopathy

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Regenerative Biomaterials 2024年第3期3卷 92-104页

作者： Qibin Han Lang Bai Yinhua Qian Xiaoyu Zhang Juan Wang Jing Zhou Wenguo Cui Yuefeng Hao Xing Yang Department of orthopedics The Affliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Municipal HospitalGusu SchoolNanjing Medical University Suzhou215008P.R.China Department of orthopedics Kunshan Hospital of Traditional Chinese MedicineSuzhou 215300P.R.China Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025P.R.China

Tendinopathy is a common disorder that causes local dysfunction and reduces quality of *** research has indicated that alterations in the inflammatory microenvironment play a vital role in the pathogenesis of ***,injectable methacrylate gelatin(GelMA)microspheres(GM)were fabricated and loaded with heparin-dopamine conjugate(HDC)and hepatocyte growth factor(HGF).GM@HDC@HGF were designed to balance the inflammatory microenvironment by inhibiting oxidative stress and inflammation,thereby regulating extracellular matrix(ECM)metabolism and halting tendon *** growth factors with heparin was expected to improve the encaption,the catechol groups on dopamine have adhesion and antioxidant properties,allowing potential attachment at the injured site,and better function synergized with ***@HDC@HGF injected in situ in rat Achilles tendinopathy(AT)models significantly downregulated oxidative stress and inflammation,and ameliorated ECM *** conclusion,the multifunctional platform developed presents a promising alternative for the treatment of tendinopathy.

关键词： tendinopathy oxidative stress inflammation microspheres

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Human umbilical cord mesenchymal stem cell-derived exosomes loaded into a composite conduit promote functional recovery after peripheral nerve injury in rats

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Neural Regeneration research 2024年第4期19卷 900-907页

作者： Haoshuai Tang Junjin Li Hongda Wang Jie Ren Han Ding Jun Shang Min Wang Zhijian Wei Shiqing Feng Department of Othopaedics Tianjin Medical University General Hospital International science and Technology Cooperation base of Spinal Cord Injury Tianjin Key Laboratory of Spine and Spinal Cord InjuryDepartment of OrthopedicsTianjin Medical University General Hospital Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment Tianjin Lung Cancer InstituteTianjin Medical University General Hospital Department of Othopaedics Qilu Hospital of Shandong UniversityShandong University Centre for OthopedicsAdvanced Medical Research InstituteShandong University Orthopedic research Center of Shandong University&Advanced Medical research Institute Cheeloo College of MedicineShandong University

Complete transverse injury of peripheral nerves is challenging to *** secreted by human umbilical cord mesenchymal stem cells are considered to play an important role in intercellular communication and regulate tissue *** previous studies,a collagen/hyaluronic acid sponge was shown to provide a suitable regeneration environment for Schwann cell proliferation and to promote axonal *** three-dimensional(3D)composite conduit contains a collagen/hyaluronic acid inner sponge enclosed in an electrospun hollow poly(lactic-co-glycolic acid)***,whether there is a synergy between the 3D composite conduit and exosomes in the repair of peripheral nerve injury remains *** this study,we tested a comprehensive strategy for repairing long-gap(10 mm)peripheral nerve injury that combined the 3D composite conduit with human umbilical cord mesenchymal stem cell-derived *** effectiveness was evaluated by sciatic functional index,sciatic nerve compound muscle action potential recording,recovery of muscle mass,measuring the cross-sectional area of the muscle fiber,Masson trichrome staining,and transmission electron microscopy of the regenerated nerve in *** results showed that transplantation of the 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes promoted peripheral nerve regeneration and restoration of motor function,similar to autograft *** CD31-positive endothelial cells were observed in the regenerated nerve after transplantation of the loaded conduit than after transplantation of the conduit without exosomes,which may have contributed to the observed increase in axon regeneration and distal nerve ***,the use of a 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes represents a promising cell-free therapeutic option for the treatment of peripheral nerve injury.

关键词： axon growth collagen exosome human umbilical cord mesenchymal stem cells hyaluronic acid muscular atrophy nerve guidance conduits peripheral nerve regeneration

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Mutual regulation of microglia and astrocytes after Gas6 inhibits spinal cord injury

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Neural Regeneration research 2025年第2期20卷 557-573页

作者： Jiewen Chen Xiaolin Zeng Le Wang Wenwu Zhang Gang Li Xing Cheng Peiqiang Su Yong Wan Xiang Li Department of Spine Surgery The First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong ProvinceChina Guangdong Province Key Laboratory of orthopedics and traumatology GuangzhouGuangdong ProvinceChina

Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord *** and astrocytes play key roles in the spinal cord injury micro-environment and share a close ***,the mechanisms involved remain *** this study,we found that after spinal cord injury,resting microglia(M0)were polarized into pro-inflammatory phenotypes(MG1 and MG3),while resting astrocytes were polarized into reactive and scar-forming *** expression of growth arrest-specific 6(Gas6)and its receptor Axl were significantly down-regulated in microglia and astrocytes after spinal cord *** vitro experiments showed that Gas6 had negative effects on the polarization of reactive astrocytes and pro-inflammatory microglia,and even inhibited the cross-regulation between *** further demonstrated that Gas6 can inhibit the polarization of reactive astrocytes by suppressing the activation of the Yes-associated protein signaling ***,in turn,inhibited the polarization of pro-inflammatory microglia by suppressing the activation of the nuclear factor-κB/p65 and Janus kinase/signal transducer and activator of transcription signaling *** vivo experiments showed that Gas6 inhibited the polarization of pro-inflammatory microglia and reactive astrocytes in the injured spinal cord,thereby promoting tissue repair and motor function ***,Gas6 may play a role in the treatment of spinal cord *** can inhibit the inflammatory pathway of microglia and polarization of astrocytes,attenuate the interaction between microglia and astrocytes in the inflammatory microenvironment,and thereby alleviate local inflammation and reduce scar formation in the spinal cord.

关键词： astrocytes Axl cell polarization Gas6 Hippo signal inflammatory micro-environment intercellular interaction microglia single-cell sequencing spinal cord injury

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