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lysyl oxidase inhibition enhances browning of white adipose tissue and adaptive thermogenesis

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Genes & Diseases 2022年第1期9卷 140-150页

作者： Chun Xing Duo Jiang Yang Liu Qiqun Tang Haiyan Huang Key Laboratory of Metabolism and Molecular Medicine The Ministry of EducationDepartment of Biochemistry and Molecular BiologyFudan University School of Basic Medical SciencesShanghai 200032PR China

Accumulating evidence from both animal and human studies suggests that activation of beige fat increases cellular energy expenditure,ultimately reducing ***,we report the central role of adipocyte-derived lysyl oxidase(Lox)in the formation of thermogenic beige *** exposed to cold or aβ3 agonist showed drastically lower Lox expression in thermogenically activated beige ***,inhibition of Lox activity with BAPN stimulated biogenesis of beige fat in inguinal white adipose tissue(iWAT)under housing conditions and potentiated cold-induced adaptive thermogenesis and beiging in both iWAT and epididymal white adipose tissue(eWAT).Notably,white adipocytes with Lox repression undergo transdifferentiation into beige adipocytes which can be suppressed by tumor necrosis factor-α(TNFα)via ERK *** work provides new insight into the molecular control to expand beige fat by Lox inhibition and suggest the potential for utilizing inhibitor of Lox to treat the emerging epidemics of obesity and diabetes.

关键词： Adaptive thermogenesis BAT Beige fat lysyl oxidase TNFa

Critical involvement of lysyl oxidase in seizure-induced neuronal damage through ERK-Alox5-dependent ferroptosis and its therapeutic implications

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3513-3528页

作者： Xiaoyuan Mao Xuan Wang Mingzhu Jin Qin Li Jining Jia Menghuan Li Honghao Zhou Zhaoqian Liu Weilin Jin Yanli Zhao Zhong Luo Department of Clinical Pharmacology Xiangya HospitalCentral South UniversityChangsha 410008China Institute of Clinical Pharmacology Central South UniversityHunan Key Laboratory of PharmacogeneticsChangsha 410078China Engineering Research Center of Applied Technology of Pharmacogenomics Ministry of EducationChangsha 410078China National Clinical Research Center for Geriatric Disorders Changsha 410008China School of Life Science Chongqing UniversityChongqing 400044China Department of Gynecology and Obstetrics Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China Institute of Cancer Neuroscience Medical Frontier Innovation Research Centerthe First Hospital of Lanzhou Universitythe First Clinical Medical College of Lanzhou UniversityLanzhou 730000China Division of Chemistry and Biological Chemistry School of Physical and Mathematical SciencesNanyang Technological UniversitySingapore 637371Singapore

Recent insights collectively suggest the important roles of lysyl oxidase(LysOX)in the pathological processes of several acute and chronic neurological diseases,but the molecular regulatory mechanisms remain ***,we explore the regulatory role of LysOX in the seizure-induced ferroptotic cell death of ***,LysOX promotes ferroptosis-associated lipid peroxidation in neurons via activating extracellular regulated protein kinase(ERK)-dependent 5-lipoxygenase(Alox5)*** addition,overexpression of LysOX via adeno-associated viral vector(AAV)-based gene transfer enhances ferroptosis sensitivity and aggravates seizure-induced hippocampal *** studies show that pharmacological inhibition of LysOX withβ-aminopropionitrile(BAPN)significantly blocks seizure-induced ferroptosis and thereby alleviates neuronal damage,while the BAPN-associated cardiotoxicity and neurotoxicity could further be reduced through encapsulation with bioresponsive amorphous calcium carbonate-based *** findings unveil a previously unrecognized LysOX-ERK-Alox5 pathway for ferroptosis regulation during seizure-induced neuronal *** this pathway may yield therapeutic implications for restoring seizure-induced neuronal injury.

关键词： Drug delivery Ferroptosis lysyl oxidase Neuronal damage Seizure

Mechanistic insight into lysyl oxidase in vascular remodeling and angiogenesis

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Genes & Diseases 2023年第3期10卷 771-785页

作者： Zhao-Jun Wang Qi-Wen Guan Hong-Hao Zhou Xiao-Yuan Mao Fang-Hui Chen Department of Clinical Pharmacology Xiangya HospitalCentral South UniversityChangshaHunan 410008China Institute of Clinical Pharmacology Central South UniversityHunan Key Laboratory of PharmacogeneticsChangshaHunan 410078China Engineering Research Center of Applied Technology of Pharmacogenomics Ministry of EducationChangshaHunan 410078China National Clinical Research Center for Geriatric Disorders ChangshaHunan 410008China Department of Pharmacy The First Affliated Hospital of Gannan Medical UniversityGanzhouJiangxi 341000China

Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provides the mechanical foundation for vascular walls. lysyl oxidase (LOX), the key matrix-modifying enzyme, has been demonstrated to significantly affect structural abnormality and dysfunction in the blood vessels. The role of LOX in vascular remodeling and angiogenesis has always been the subject in the current medical research. Therefore, we presently make a summarization of the biosynthesis of LOX and the mechanisms involved in vascular remodeling and angiogenesis, as well as the role of LOX in diseases associated with vascular abnormalities and the therapeutic potential via targeting LOX. In particular, we give a proposal that LOX likely reshapes matrisome-associated genes expressions in the regulation of vascular remodeling and angiogenesis, which serves as a mechanistic insight into the critical role of LOX in these two aspects. Additionally, LOX has also dual effects on the vascular dysfunction, namely, inhibition of LOX for improving hypertension, restenosis and malignant tumor while activation of LOX for curing arterial aneurysm and dissection. LOX-targeted therapy may provide a promising therapeutic strategy for the treatment of various vascular pathologies associated with vascular remodeling and angiogenesis.

关键词： Angiogenesis Disease pathology lysyl oxidase Therapeutic target Vascular homeostasis Vascular remodeling

LOX upregulates FAK phosphorylation to promote metastasis in osteosarcoma

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Genes & Diseases 2023年第1期10卷 254-266页

作者： Xiang Chen Margaret Clement MJohn Hicks Poonam Sarkar MWaleed Gaber Tsz-Kwong Man Department of Pediatrics Baylor College of MedicineOne Baylor PlazaHoustonTX 77030USA Department of Pathology Baylor College of MedicineOne Baylor PlazaHoustonTX 77030USA Dan L.Duncan Comprehensive Cancer Center 7200 Cambridge StreetHoustonTX 77054USA Texas Children's Cancer and Hematology Centers 1102 Bates StHoustonTX 77030USA

Osteosarcoma is a malignant bone tumor that commonly occurs in the pediatric *** the use of chemotherapy and surgery,metastasis remains to be the leading cause of death in patients with *** have previously reported that cytoplasmic mislocalization of p27 is associated with a poor outcome in *** this study,we further show that lysyl oxidase(LOx)expression was associated with p27 *** is an enigmatic molecule that acts as a tumor suppressor or a metastatic promoter;however,its role in osteosarcoma is still ***,we performed both in vitro and in vivo analyses to dissect the role of Lox in *** result of our survival analysis indicated that Lox expression significantly correlated with a poor outcome in osteosarcoma with or without controlling for the initial metastasis status(P<0.05).Functionally,we found that higher LoX expression promoted osteosarcoma cell proliferation,migration,and invasiveness in vitro and produced a higher number of mice with pulmonary metastases in an orthotopic xenograft mouse ***,phospho-FAK was increased in osteosarcoma cells with high LOX *** results further showed that FAK inhibition significantly reduced tumor cell proliferation and migration in vitro as well as LoX-mediated metastasis in ***,our findings suggest that there is a novel link between p27 mislocalization and LOX *** plays a pivotal role in osteosarcoma metastasis by upregulating FAK *** inhibition may constitute a promising therapeutic strategy to reduce the development of metastasis in osteosarcoma with Lox overexpression.

关键词： Focal adhesion kinase lysyl oxidase Metastasis Osteosarcoma

A multifunctional scaffold that promotes the scaffold-tissue interface integration and rescues the ROS microenvironment for repair of annulus fibrosus defects

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Bioactive Materials 2024年第11期41卷 257-270页

作者： Runze Zhao Feng Han Qifan Yu Zhuang Zhu Zhengdong Tu Tingting Xia Bin Li Medical 3D Printing Center Orthopedic InstituteDepartment of Orthopedic SurgeryThe First Affiliated HospitalMOE Key Laboratory of Geriatric Diseases and ImmunologySchool of Biology and Basic Medical SciencesSuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China Center of Translational Medicine and Clinical Laboratory The Fourth Affiliated Hospital to Soochow UniversitySuzhou215028China Division of Spine Surgery Department of Orthopedic SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing210000China Second Department of Orthopaedics Suzhou Kowloon HospitalShanghai Jiaotong University Medical SchoolSuzhou215127China Institute of Clinical Medicine Research Suzhou HospitalAffiliated Hospital of Medical SchoolNanjing UniversitySuzhou215153China Collaborative Innovation Center of Hematology Soochow UniversitySuzhouJiangsu215000China

Due to the limited self-repair ability of the annulus fibrosus (AF), current tissue engineering strategies tend to use structurally biomimetic scaffolds for AF defect repair. However, the poor integration between implanted scaffolds and tissue severely affects their therapeutic effects. To solve this issue, we prepared a multifunctional scaffold containing loaded lysyl oxidase (LOX) plasmid DNA exosomes and manganese dioxide nanoparticles (MnO2 NPs). LOX facilitates extracellular matrix (ECM) cross-linking, while MnO2 NPs inhibit excessive reactive oxygen species (ROS)-induced ECM degradation at the injury site, enhancing the crosslinking effect of LOX. Our results revealed that this multifunctional scaffold significantly facilitated the integration between the scaffold and AF tissue. Cells were able to migrate into the scaffold, indicating that the scaffold was not encapsulated as a foreign body by fibrous tissue. The functional scaffold was closely integrated with the tissue, effectively enhancing the mechanical properties, and preventing vascular invasion, which emphasized the importance of scaffold-tissue integration in AF repair.

关键词： Annulus fibrosus Scaffold-tissue integration lysyl oxidase Reactive oxygen species regulation Manganese dioxide nanoparticles

Three-dimensional decellularized tumor extracellular matrices with different stiffness as bioengineered tumor scaffolds

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Bioactive Materials 2021年第9期6卷 2767-2782页

作者： Yonggang Lv Hongjun Wang Gui Li Boyuan Zhao Mechanobiology and Regenerative Medicine Laboratory Bioengineering CollegeChongqing UniversityChongqing400044PR China Key Laboratory of Biorheological Science and Technology Chongqing UniversityMinistry of EducationBioengineering CollegeChongqing UniversityChongqing400044PR China

In the three-dimensional(3D)tumor microenvironment,matrix stiffness is associated with the regulation of tumor cells *** vitro tumor models with appropriate matrix stiffness are urgently ***,we prepare 3D decellularized extracellular matrix(DECM)scaffolds with different stiffness to mimic the microenvironment of human breast tumor tissue,especially the matrix stiffness,components and structure of ***,the effects of matrix stiffness on the drug resistance of human breast cancer cells are explored with these developed scaffolds as case *** results confirm that DECM scaffolds with diverse stiffness can be generated by tumor cells with different lysyl oxidase(LOX)expression levels,while the barely intact structure and major components of the ECM are maintained without *** versatile 3D tumor model with suitable stiffness can be used as a bioengineered tumor scaffold to investigate the role of the microenvironment in tumor progression and to screen drugs prior to clinical use to a certain extent.

关键词： Breast tumor cell Decellularized scaffold lysyl oxidase Extracellular matrix Matrix stiffness Drug resistance

Progression and Regression of Abdominal Aortic Aneurysms in Mice

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Current Medical Science 2021年第5期41卷 901-908页

作者： Yu-chao DING Xian-jing ZHANG Ji-xiu ZHANG Zi-yi ZHAI Mei-xia ZHANG Bao-hong JIANG Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China The College of Basic Medical Science China Medical UniversityShenyang 110122China

Objective:Abdominal aortic aneurysm(AAA)is a significant medical problem with a high mortality ***,the underlying mechanism for the progression and regression of AAA is ***:Experimental model of AAA was first created by porcine pancreatic elastase incubation around the infrarenal aorta of C57BL/6 ***,AAA progression and regression were evaluated based on the diameter and volume of *** aortas were harvested for hematoxylin-eosin staining(HE),orcein staining,sirius red staining,immunofluorescence analysis and peris’prussian blue staining at the indicated time ***,P-aminopropionitrile monofumarate(BAPN)was used to explore the underlying mechanism of the regression of ***:When we extended the observation period to 100 days,we not only observed an increase in the AAA diameter and volume in the early stage,but also a decrease in the late *** with AAA diameter and volume,the aortic thickness showed the same tendency based on HE *** elastin and collagen content first degraded and then regenerated,which corresponds to the early deterioration and late regression of ***,endogenous up-regulation of lysyl oxidase(LOX)was detected,accompanying the regression of AAA,as detected by an immunofluorescent *** and LOX inhibitor considerably inhibited the regression of AAA,paralleling the degradation of elastin lamella and ***:Taken together,we tentatively conclude that endogenous re-generation of LOX played an influential role in the regression of ***,regulatory factors on the generation of LOX exhibit promising therapeutic potential against AAA.

关键词： abdominal aortic aneurysm disease progression disease regression elastogenesis lysyl oxidase