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Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis

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Bone Research 2022年第3期10卷 509-523页

作者： Yiqi Yang Yixuan Lin Minqi Wang Kai Yuan Qishan Wang Pei Mu Jingke Du Zhifeng Yu Shengbing Yang Kai Huang Yugang Wang Hanjun Li Tingting Tang Shanghai Key laboratory of Orthopaedic Implants Department of Orthopaedic SurgeryShanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina department of Bone and Joint surgery Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina department of Orthopaedics Shanghai Jiangong HospitalShanghaiChina department of Trauma surgery Department of OrthopedicsRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Clinical stem cell Research Center Renji HospitalShanghai Jiao Tong University School of MedicineShanghaiChin

Diabetic osteoporosis(DOP) is the leading complication continuously threatening the bone health of patients with diabetes. A key pathogenic factor in DOP is loss of osteocyte viability. However, the mechanism of osteocyte death remains unclear. Here, we identified ferroptosis, which is iron-dependent programmed cell death, as a critical mechanism of osteocyte death in murine models of DOP. The diabetic microenvironment significantly enhanced osteocyte ferroptosis in vitro, as shown by the substantial lipid peroxidation, iron overload, and aberrant activation of the ferroptosis pathway. RNA sequencing showed that heme oxygenase-1(HO-1) expression was notably upregulated in ferroptotic osteocytes. Further findings revealed that HO-1 was essential for osteocyte ferroptosis in DOP and that its promoter activity was controlled by the interaction between the upstream NRF2 and c-JUN transcription factors. Targeting ferroptosis or HO-1 efficiently rescued osteocyte death in DOP by disrupting the vicious cycle between lipid peroxidation and HO-1 activation, eventually ameliorating trabecular deterioration. Our study provides insight into DOP pathogenesis, and our results provide a mechanism-based strategy for clinical DOP treatment.

关键词： peroxidation osteoporosis diabetic

CRISPR,CAR-T,and NK:Current applications and future perspectives

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Genes & Diseases 2024年第4期11卷 246-257页

作者： Mohadeseh Khoshandam Hossein Soltaninejad Amir Ali Hamidieh Saman Hosseinkhani department of Reproductive biology Academic Center for EducationCultureand Research(ACECR)Qom branch***Iran National Institute of Genetic Engineering and Biotechnology(NIGEB) Tehran 14965/161Iran department of stem cells technology and Tissue Regeneration Faculty of Interdisciplinary Science and TechnologiesTarbiat Modares UniversityTehran 15614Iran pediatric cell Therapy and Gene Therapy Research Center GeneCell&Tissue Research InstituteTehran University of Medical SciencesTehran ***Iran department of Biochemistry Faculty of Biological SciencesTarbiat Modares UniversityTehran 15614Iran

Chimeric antigen receptor T(CAR-T)cell therapy represents a breakthrough in personalized cancer *** this regard,synthetic receptors comprised of antigen recognition domains,signaling,and stimulatory domains are used to reprogram T-cells to target tum or cells and destroy *** the success of this approach in refractory B-cell malignancies,the optimal potency of CAR T-cell therapy for many other cancers,particularly solid tumors,has not been *** killer cells are powerful cytotoxic lymphocytes specialized in recognizing and dispensing the tumor cells in coordination with other anti-tumor immunity *** on these studies,many investigations are focused on the accurate designing of CAR T-cells with clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)system or other novel gene editing tools that can induce hereditary changes with or without the presence of a double-stranded break into the *** methodologies can be specifically focused on negative controllers of T-cells,induce modifications to a particular gene,and produce reproducible,safe,and powerful allogeneic CAR T-cells for on-demand cancer *** improvement of the CRISPR/Cas9 innovation offers an adaptable and proficient gene-editing capability in activating different pathways to help natural killer cells interact with novel CARs to particularly target tumor *** achievements and future challenges of combining next-generation CRISPR-Cas9 gene editing tools to optimize CAR T-cell and natural killer cell treatment for future clinical trials toward the foundation of modern cancer treatments have been assessed inthis review.

关键词： Cancer CAR T-cell CRISPR Gene editing Immunotherapy NK cell

Bis(2-butoxyethyl) Phthalate Delays Puberty Onset by Increasing Oxidative Stress and Apoptosis in Leydig cells in Rats

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Biomedical and Environmental Sciences 2023年第1期36卷 60-75页

作者： LIU Miao Qing CHEN Hai Qiong DAI Hai Peng LI Jing Jing TIAN Fu Hong WANG Yi Yan CHEN Cong De LI Xiao Heng LI Jun Wei LI Zhong Rong GE Ren Shan department of pediatric surgery the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou 325027ZhejiangChina Key laboratory of Structural Malformations in Children of Zhejiang Province Wenzhou 325000ZhejiangChina

Objective This study investigated the effects of bis(2-butoxyethyl) phthalate(BBOP) on the onset of male puberty by affecting Leydig cell development in *** Thirty 35-day-old male Sprague-Dawley rats were randomly allocated to five groups mg/kg bw per day that were gavaged for 21 days with BBOP at 0, 10, 100, 250, or 500 mg/kg bw per day. The hormone profiles;Leydig cell morphological metrics;mRNA and protein levels;oxidative stress;and AKT,mTOR, ERK1/2, and GSK3β pathways were *** BBOP at 250 and/or 500 mg/kg bw per day decreased serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels mg/kg bw per day(P cell number mg/kg bw per day and downregulated Cyp11a1, Insl3, Hsd11b1,and Dhh in the testes, and Lhb and Fshb mRNAs in the pituitary gland(P cells after 24 h of treatment in vitro(P cells in *** graphical abstract is available on the website ***.

关键词： Bis(2-butoxyethyl)phthalate Leydig cells Testosterone Oxidative stress Gonadotropin

Drugging SUMOylation for neuroprotection and oncotherapy

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Neural Regeneration Research 2018年第3期13卷 415-416页

作者： Joshua D. Bernstock Daniel G. Ye Yang-ja Lee Florian Gessler Gregory K. Friedman Wei Zheng John M. Hallenbeck Stroke Branch National Institute of Neurological Disorders and Stroke National institutes of Health (NINDS/NIH) Bethesda MD USA department of Clinical Neurosciences - Division of stem cell Neurobiology Wellcome Trust-Medical Research Council Stem Cell Institute and NIHR Biomedical Research Centre University of Cambridge UK department of pediatrics Division of Pediatric Hematology and Oncology University of Alabama at Birmingham Birmingham AL USA National Center for Advancing Translational Sciences National Institutes of Health (NCATS/NIH) Bethesda MD USA

Recently there have been exciting research advances in neuroprotective therapies for ischemic stroke. In the past, the search for neu- roprotective agents has been fraught with failure at the clinical trials stage due to numerous factors, including subject heterogeneity and improper therapeutic windows （Tymianski, 2017）. Moreover, it is becoming clearer that the complex and evolving pathobiology of stroke requires multimodal therapeutic approaches capable of modulating the numerous axes that contribute to ischemia/reperfusion damage, rather than targeting a single axis （Bernstock et al., 2018a）. With the success of recent endovascular thrombectomy （EVT） trials, it has been suggested that clinical trials of EVT with adjunct neuroprotection can overcome past difficulties and maximize the effect size by using imaging to reduce patient heterogeneity （i. e., selecting those with large vessel occlusions, small ischemic cores, and good collateral circulation）, restoring perfusion using better EVT devices, and enrolling patients in the correct therapeutic window （i.e., when they still have salvageable brain tissue）（Tymianski, 2017）. Considering the opportunity that this represents for new, better clinical trials of neuroprotective agents, the search is on for high-potential compounds that may be investigated in these future studies.

关键词： Drugging SUMOylation for neuroprotection and oncotherapy OGD

Comparison of Effects of Mechanical Stretching on Osteogenic Potential of ASCs and BMSCs

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Bone Research 2013年第3期1卷 282-290页

作者： Brian E. Grottkau Xingmei Yang Liang Zhang Ling Ye Yunfeng Lin department of Orthopaedic surgery MassGeneral Hospital for Children and the Pediatric Orthopaedic Laboratory for Tissue Engineering and Regenerative Medicine Harvard Medical SchoolBoston Massachusetts USA State Key laboratory of Oral Diseases West China Hospital of Stomatology Sichuan University

Mechanical forces play critical roles in the development and remodeling processes of bone. As an alternative cell source for bone engineering, adipose-derived stem cells （ASCs） should be fully investigated for their responses to mechanical stress. Similarly, the osteogenic potential, stimulated by mechanical stress, should be compared with bone marrow stromal cells （BMSCs）, which have been clinically used for bone tissue engineering. In this study, ASCs and BMSCs were osteogenic-induced for 48 hours, and then subjected to uniaxial mechanical stretching for 2 or 6 hours. cell orientation, osteogenic regulatory genes, osteogenic genes and ALP activities were measured and compared between ASCs and BMSCs. ASCs could align in a perpendicular way to the direction of stretching stress, while BMSCs did not present a specific alignment. Both 2 and 6 hours mechanical stretching could enhance the mRNA expression of Osx and Runx2 in BMSCs and ASCs, while OCN mRNA only increased in ASCs after 6 hours mechanical loading. Mechanical stretching enhanced the BMP-2 mRNA expression in ASCs, while only after 6 hours of mechanical loading significantly increased the BMP-2 gene expression in BMSCs. Significant differences only exist between ASCs and BMSCs loaded at 2 hours of mechanical stretching. It is concluded that ASCs are more rapid responders to mechanical stress, and have greater potential than BMSCs in osteogenesis when stimulated by mechanical stretching, indicating their usefulness for bone study in a rat model.

关键词： mechanotransduction stem cells osteoblasts adipocytes

A self-fused hydrogel for the treatment of glottic insufficiency through outstanding durability,extracellular matrix-inducing bioactivity and function preservation

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Bioactive Materials 2023年第6期24卷 54-68页

作者： Chen-Yu Zou Juan-Juan Hu Dan Lu Qian-Jin Li Yan-Lin Jiang Rui Wang Hai-Yang Wang Xiong-Xin Lei Jesse Li-Ling Hui Yang Hui-Qi Xie laboratory of stem cell and Tissue Engineering Orthopedic Research InstituteMed-X Center for MaterialsState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduSichuan610041PR China department of Otolaryngology Head and Neck SurgeryWest China HospitalSichuan UniversityChengduSichuan610041PR China department of Medical Genetics West China Second HospitalSichuan UniversityChengduSichuan610041PR China

Injection laryngoplasty with biomaterials is an effective technique to treat glottic ***,the inadequate durability,deficient pro-secretion of extracellular matrix(ECM)and poor functional preservation of current biomaterials have yielded an unsatisfactory therapeutic ***,a self-fusing bioactive hydrogel comprising modified carboxymethyl chitosan and sodium alginate is developed through a dual-crosslinking mechanism(photo-triggered and dynamic covalent bonds).Owing to its characteristic networks,the synergistic effect of the hydrogel for vocal folds(VFs)vibration and phonation is adequately ***,owing to its inherent bioactivity of polysaccharides,the hydrogel could significantly enhance the secretion of major components(type I/III collagen and elastin)in the lamina propria of the VFs both in vivo and in *** a rabbit model for glottic insufficiency,the optimized hydrogel(C1A1)has demonstrated a durability far superior to that of the commercially made hyaluronic acid(HA)*** importantly,owing to the ECM-inducing bioactivity,the physiological functions of the VFs treated with the C1A1 hydrogel also outperformed that of the HA Gel,and were similar to those of the normal *** together,through a simple-yet-effective strategy,the novel hydrogel has demonstrated outstanding durability,ECM-inducing bioactivity and physiological function preservation,therefore has an appealing clinical value for treating glottic insufficiency.

关键词： Glottic insufficiency Self-fusion Hydrogel Extracellular matrix Physiological function

BMP-IHH-mediated interplay between mesenchymal stem cells and osteoclasts supports calvarial bone homeostasis and repair

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Bone Research 2018年第4期6卷 355-367页

作者： Yuxing Guo Yuan Yuan Ling Wu Thach-Vu Ho Junjun Jing Hideki Sugii Jingyuan Li Xia Han Jifan Feng Chuanbin Guo Yang Chai Center for Craniofacial Molecular biology University of Southern California department of Oral and Maxillofacial surgery Peking University School and Hospital of Stomatology In Vitro cell Research LLC State Key laboratory of Oral Diseases West China Hospital of Stomatology Sichuan University Division of Endodontology Kyushu University Hospital Kyushu University

Calvarial bones are connected by fibrous sutures. These sutures provide a niche environment that includes mesenchymal stem cells(MSCs), osteoblasts, and osteoclasts, which help maintain calvarial bone homeostasis and repair. Abnormal function of osteogenic cells or diminished MSCs within the cranial suture can lead to skull defects, such as craniosynostosis. Despite the important function of each of these cell types within the cranial suture, we have limited knowledge about the role that crosstalk between them may play in regulating calvarial bone homeostasis and injury repair. Here we show that suture MSCs give rise to osteoprogenitors that show active bone morphogenetic protein(BMP) signalling and depend on BMP-mediated Indian hedgehog(IHH) signalling to balance osteogenesis and osteoclastogenesis activity. IHH signalling and receptor activator of nuclear factor kappa-Β ligand(RANKL) may function synergistically to promote the differentiation and resorption activity of osteoclasts. Loss of Bmpr1a in MSCs leads to downregulation of hedgehog(Hh) signalling and diminished cranial sutures. Significantly, activation of Hh signalling partially restores suture morphology in Bmpr1a mutant mice, suggesting the functional importance of BMP-mediated Hh signalling in regulating suture tissue homeostasis. Furthermore, there is an increased number of CD200+ cells in Bmpr1a mutant mice, which may also contribute to the inhibited osteoclast activity in the sutures of mutant mice. Finally, suture MSCs require BMPmediated Hh signalling during the repair of calvarial bone defects after injury. Collectively, our studies reveal the molecular and cellular mechanisms governing cell–cell interactions within the cranial suture that regulate calvarial bone homeostasis and repair.

关键词： BMP-IHH-mediated interplay between mesenchymal stem cells and osteoclasts supports calvarial bone homeostasis and repair RANKL

Modification of polycarbonateurethane surface with poly （ethylene glycol） monoacrylate and phosphorylcholine glyceraldehyde for anti-platelet adhesion

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Frontiers of Chemical Science and Engineering 2014年第2期8卷 188-196页

作者： Jing YANG Juan LV Bin GAO Li ZHANG Dazhi YANG Changcan SHI Jintang GUO Wenzhong LI Yakai FENG School of Chemical Engineering and Technology Tianjin University Tianjin 300072 China Tianjin University-Helmholtz-Zentrum Geesthacht Joint Laboratory for Biomaterials and Regenerative Medicine Tianjin 300072 China Key laboratory of Systems Bioengineering Ministry of Education Tianjin University Tianjin 300072 China University of Rostock Department of Cardiac Surgery Reference & Translation Center for Cardiac Stem Cell Therapy Schillingallee 69 D-18057 Rostock Germany

Poly（ethylene glycol） monoacrylate （PEGMA） is grafted onto polycarbonateurethane （PCU） surface via ultraviolet initiated photopolymerization. The hydroxyl groups of poly（PEGMA） on the surface react with one NCO group of isophorone diisocyanate （IPD1） and another NCO group of IPDI is then hydrolyzed to form amino terminal group, which is further grafted with phosphorylcholine glyceraldehyde to establish a biocompatible hydrophilic structure on the surface. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy confirm the successful grafting of both PEG and phosphorylcholine functional groups on the surface. The decrease of the water contact angle for the modified film is caused by synergic effect of PEG and phosphorylcholine, which both have the high hydrophilicity. Furthermore, the number of platelets adhered is relative low on the synergetically modified PCU film compared with the PCU film modified only by poly（PEGMA）. Our synergic modification method using both PEG and phosphorylcho- line may be applied in surface modification of bloodcontacting biomaterials and some relevant devices.

关键词： poly(ethylene glycol) monoacrylate phos-phorylcholine polycarbonateurethane surface modifica-tion anti-platelet adhesion biomaterials

Retroperitoneal teratoma resection assisted by 3-dimensional visualization and virtual reality:A case report

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World Journal of Clinical Cases 2021年第4期9卷 935-942页

作者： Tao Liu Kun Chen Rong-Mu Xia Wen-Gang Li department of Hepatobiliary surgery Xiang’an HospitalXiamen UniversityXiamen 361102Fujian ProvinceChina Institute of stem cell and Regenerative Medicine School of MedicineXiamen UniversityXiamen 361102Fujian ProvinceChina department of Hepatobiliary surgery Xiang’an HospitalSchool of MedicineXiamen UniversityXiamen 361102Fujian ProvinceChina

BACKGROUND Primary retroperitoneal tumor is a rare type of tumor with insidious onset,large tumor size at the time of diagnosis,and often extensive involvement of surrounding tissues and blood vessels in the *** for primary retroperitoneal tumors is technically *** imaging evaluation is critical for the selection of the optimal surgical approach and can influence complete resection and recurrence ***-dimensional model reconstruction combined with virtual reality is useful for preoperative *** SUMMARY A 17-year-old female patient was admitted for abdominal pain lasting for half a year that had been worsening for half a *** enhanced helical computed tomography revealed a retroperitoneal space-occupying lesion about 11.3 cm×9.1 cm in size,with well-defined borders in the upper left quadrant of the *** lesion compressed the left renal artery and vein resulting in vascular displacement and deformation.A multidisciplinary team decided on the optimal treatment *** three-dimensional visualization and virtual reality technology were used to assess and simulate the surgical ***,retroperitoneal tumor resection along with renal artery reconstruction was decided as the *** resection of the retroperitoneal tumor was *** blood flow was established after renal artery *** tumor was diagnosed as mature cystic teratoma(retroperitoneal tumor)by postoperative pathologic *** patient,who recovered well,was discharged after 2 wk and maintains regular *** A combination of three-dimensional reconstruction and virtual reality technology before surgery improves the rate of complete resection of retroperitoneal teratoma.

关键词： Three-dimensional reconstruction Virtual reality Renal artery reconstruction Retroperitoneal teratoma surgery Case report