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A pancreatic player in dementia:pathological role for islet amyloid polypeptide accumulation in the brain

Neural Regeneration Research 2023年第10期18卷 2141-2146页

作者： Angelina S.Bortoletto Ronald J.Parchem center for cell and Gene Therapy Stem Cell and Regenerative Medicine CenterDepartment of NeuroscienceDepartment of Molecular and Cellular BiologyTranslational Biology and Molecular Medicine ProgramMedical Scientist Training ProgramBaylor College of MedicineHoustonTXUSA

Type 2 diabetes mellitus patients have a markedly higher risk of developing *** multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes *** amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are *** this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of *** discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced *** are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at ***,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating *** such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.

关键词： Alzheimer’s disease amylin amyloid dementia diabetes human islet amyloid polypeptide islet amyloid polypeptide protofibrils type 2 diabetes mellitus vascular dementia

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Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

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Bone Research 2018年第2期6卷 167-176页

作者： Babita Madan Mitchell J.McDonald Gabrielle E.Foxa Cassandra R.Diegel Bart O.Williams David M.Virshup Program in Cancer and stem cell biology Duke-NUS Medical School center for Cancer and cell biology and Program for Skeletal Disease and Tumor Microenvironment Van Andel Research Institute department of Pediatrics Duke University

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine（PORCN） that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159（ETC-159） had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably,simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family,mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN *** of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

关键词： Wnt ETC Bone loss Wnt inhibition mitigated concurrent alendronate therapy

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Emerging strategies for nerve repair and regeneration in ischemic stroke:neural stem cell therapy

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Neural Regeneration Research 2024年第11期19卷 2430-2443页

作者： Siji Wang Qianyan He Yang Qu Wenjing Yin Ruoyu Zhao Xuyutian Wang Yi Yang Zhen-Ni Guo Stroke center Department of Neurologythe First Hospital of Jilin UniversityChangchunJilin ProvinceChina Neuroscience Research center Department of Neurologythe First Hospital of Jilin UniversityChangchunJilin ProvinceChina department of Breast Surgery General Surgery Centerthe First Hospital of Jilin UniversityChangchunJilin ProvinceChina

Ischemic stroke is a major cause of mortality and disability worldwide,with limited treatment options available in clinical *** emergence of stem cell therapy has provided new hope to the field of stroke treatment via the restoration of brain neuron *** neural stem cells are beneficial not only in cell replacement but also through the bystander *** stem cells regulate multiple physiological responses,including nerve repair,endogenous regeneration,immune function,and blood-brain barrier permeability,through the secretion of bioactive substances,including extracellular vesicles/***,due to the complex microenvironment of ischemic cerebrovascular events and the low survival rate of neural stem cells following transplantation,limitations in the treatment effect remain *** this paper,we provide a detailed summary of the potential mechanisms of neural stem cell therapy for the treatment of ischemic stroke,review current neural stem cell therapeutic strategies and clinical trial results,and summarize the latest advancements in neural stem cell engineering to improve the survival rate of neural stem *** hope that this review could help provide insight into the therapeutic potential of neural stem cells and guide future scientific endeavors on neural stem cells.

关键词： bystander effect cell replacement extracellular vesicles ischemic stroke neural stem cells neural stem cell engineering

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Insights into female germ cell biology： from in vivo development to in vitro derivations

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Asian Journal of Andrology 2015年第3期17卷 415-420页

作者： Dajung Jung Kehkooi Kee department of Basic Medical Sciences Center for Stem Cell Biology and Regenerative Medicine School of Medicine Tsinghua University Beijing 100084 China

Understanding the mechanisms of human germ cell biology is important for developing infertility treatments. However, little is known about the mechanisms that regulate human gametogenesis due to the difficulties in collecting samples, especially germ cells during fetal development. In contrast to the mitotic arrest of spermatogonia stem cells in the fetal testis, female germ cells proceed into meiosis and began folliculogenesis in fetal ovaries. Regulations of these developmental events, including the initiation of meiosis and the endowment of primordial follicles, remain an enigma. Studying the molecular mechanisms of female germ cell biology in the human ovary has been mostly limited to spatiotemporal characterizations of genes or proteins. Recent efforts in utilizing in vitro differentiation system of stem cells to derive germ cells have allowed researchers to begin studying molecular mechanisms during human germ cell development. Meanwhile, the possibility of isolating female germline stem cells in adult ovaries also excites researchers and generates many debates. This review will mainly focus on presenting and discussing recent in vivo and in vitro studies on female germ cell biology in human. The topics will highlight the progress made in understanding the three main stages of germ cell developments： namely, primordial germ cell formation, meiotic initiation, and folliculogenesis.

关键词： embryonic stem cell female germline stem cell folliculogenesis in vitro derivations meiotic initiation primordial germ cell

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Helicase-assisted continuous editing for programmable mutagenesis of endogenous genomes

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四川生理科学杂志 2024年第10期46卷 2326-2326页

作者： Xi Dawn Chen Gene Regulation Observatory Broad Institute of MIT and Harvard Cambridge MA 02142 USA. department of stem cell and Regenerative biology Harvard University Cambridge MA 02138 USA. Systems Synthetic and Quantitative Biology PhD Program Harvard University Cambridge MA 02138 USA. department of Cancer biology Dana-Farber Cancer Institute Boston MA 02215 USA. department of cell biology and Pathology Harvard Medical School Boston MA 02115 USA. department of Chemistry and Chemical biology Harvard University Cambridge MA 02138 USA. Cancer Program Broad Institute of MIT and Harvard Cambridge MA 02142 USA. Cecil H. and Ida Green center for Reproductive biology Sciences University of Texas Southwestern Medical Center Dallas TX 75390 USA. department of Obstetrics and Gynecology University of Texas Southwestern Medical Center Dallas TX 75390 USA. The Novo Nordisk Foundation center for Genomic Mechanisms of Disease Broad Institute of MIT and Harvard Cambridge MA 02142 USA.

Deciphering the context-specific relationship between sequence and function is a major challenge in *** tools for inducing locus-specific hypermutation and evolution in the native genome context are *** we present a programmable platform for long-range,locus-specific hypermutation called helicase-assisted continuous editing(HACE).HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs mutations across large(>1000-base pair)genomic *** applied HACE to identify mutations in mitogen-activated protein kinase kinase 1(MEK1)that confer kinase inhibitor resistance,to dissect the impact of individual variants in splicing factor 3B subunit 1(SF3B1)-dependent missplicing,and to evaluate noncoding variants in a stimulation-dependent immune enhancer of *** provides a powerful tool for investigating coding and noncoding variants,uncovering combinatorial sequence-to-function relationships,and evolving new biological functions.

关键词： endogenous stimulation continuous

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Hippo-YAP/TAZ signaling in breast cancer:Reciprocal regulation of microRNAs and implications in precision medicine

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Genes & Diseases 2024年第2期11卷 760-771页

作者： Farzad Sadri Seyede fatemeh Hosseini Zohreh Rezaei Mohammad Fereidouni Student Research Committee Birjand University of Medical SciencesBirjand ***Iran Tabas School of Nursing Birjand University of Medical SciencesBirjand ***Iran department of biology University of Sistan and BaluchestanZahedan ***Iran cellular and Molecular Research center Birjand University of Medical SciencesBirjand ***Iran

Breast cancer is a molecularly heterogeneous disease and the most common female *** recent years,therapy approaches have evolved to accommodate molecular diversity,with a focus on more biologically based therapies to minimize negative *** regulate cell fate in human breast cells,the Hippo signaling pathway has been associated with the alpha subtype of estrogen *** pathway regulates tissue size,regeneration,and healing,as well as the survival of tissue-specific stem cells,proliferation,and apoptosis in a variety of organs,allowing for cell *** signaling is mediated by the kinases MST1,MST2,LATS1,and LATS2,as well as the adaptor proteins SAV1 and *** kinases phosphorylate the downstream effectors of the Hippo pathway,yes-associated protein(YAP),and transcriptional coactivator with PDZ-binding motif(TAZ),suppressing the expression of their downstream target *** Hippo signaling pathway kinase cascade plays a significant role in all *** the principles of this kinase cascade would prevent the occurrence of breast *** recent years,small noncoding RNAs,or microRNAs,have been implicated in the development of several malignancies,including breast *** interconnections between miRNAs and Hippo signaling pathway core proteins in the breast,on the other hand,remain poorly *** this review,we focused on highlighting the Hippo signaling system,its key parts,its importance in breast cancer,and its regulation by miRNAs and other related pathways.

关键词： Breast cancer Hippo signaling Large tumor suppressor kinase 1 microRNAs PDZ-binding motif Yes-associated protein

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Recent advances in the application of MXenes for neural tissue engineering and regeneration

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Neural Regeneration Research 2024年第2期19卷 258-263页

作者： Menghui Liao Qingyue Cui Yangnan Hu Jiayue Xing Danqi Wu Shasha Zheng Yu Zhao Yafeng Yu Jingwu Sun Renjie Chai State Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck SurgeryZhongda HospitalSchool of Life Sciences and TechnologyAdvanced Institute for Life and HealthJiangsu Province High-Tech Key Laboratory for Bio-Medical ResearchSoutheast UniversityNanjingJiangsu ProvinceChina Co-Innovation center of Neuroregeneration Nantong UniversityNantongJiangsu ProvinceChina department of Oto-Rhino-Laryngology West China HospitalSichuan UniversityChengduSichuan ProvinceChina First Affiliated Hospital of Soochow University SuzhouJiangsu ProvinceChina department of Otolaryngology-Head and Neck Surgery The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui ProvinceChina department of Otolaryngology Head and Neck Surgery Sichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan ProvinceChina Institute for stem cell and Regeneration Chinese Academy of SciencesBeijingChina Beijing Key Laboratory of Neural Regeneration and Repair Capital Medical UniversityBeijingChina

Transition metal carbides and nitrides(MXenes)are crystal nanomaterials with a number of surface functional groups such as fluorine,hydroxyl,and oxygen,which can be used as carriers for proteins and *** have excellent biocompatibility,electrical conductivity,surface hydrophilicity,mechanical properties and easy surface ***,at present,the stability of most MXenes needs to be improved,and more synthesis methods need to be *** are good substrates for nerve cell regeneration and nerve reconstruction,which have broad application prospects in the repair of nervous system *** the application of MXenes in neuroscience,mainly at the cellular level,the long-term in vivo biosafety and effects also need to be further *** review focuses on the progress of using MXenes in nerve regeneration over the last few years;discussing preparation of MXenes and their biocompatibility with different cells as well as the regulation by MXenes of nerve cell regeneration in two-dimensional and three-dimensional environments in *** have great potential in regulating the proliferation,differentiation,and maturation of nerve cells and in promoting regeneration and recovery after nerve *** addition,this review also presents the main challenges during optimization processes,such as the preparation of stable MXenes and long-term in vivo biosafety,and further discusses future directions in neural tissue engineering.

关键词： hydrogels MXenes nerve regeneration neural cells neural stem cells organoids spiral ganglion neurons

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Hepatic differentiation from embryonic stem cells in vitro

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Chinese Medical Journal 2003年第12期116卷 1893-1897页

作者：胡安斌蔡继业郑启昌何晓青潘运龙李凌松 department of General Surgery College Huaqiao Hospital stem cell Research center

OBJECTIVE: To investigate an method for hepatic differentiation from embryonic stem cells (ES cells) in vitro and the resulting differentiation ratio, in order to develop a procedure for producing a new type of hepatocyte for hepatocyte replacement therapy in the treatment of liver failure. METHODS: ES cells from Balb/C mice were cultured and maintained in an undifferentiated state in gelatin-coated dishes using Dulbecco's modified Eagle's medium (DMEM) containing 1000 U/ml leukemia inhibitory factor (LIF). Then, LIF was withdrawn from the DMEM to allow the ES cells to develop into embryonic bodies (EBs). EBs were plated onto tissue culture dishes, and growth factors such as acidicfibroblast growth factor (aFGF) and hepatocyte growth factor (HGF) were added to the medium to promote directional differentiation. The course of development and differentiation was observed dynamically using an inversion microscope. The expression of hepatic proteins, such as alpha-fetoprotein (AFP), albumin (ALB), cytokeratin 8 (CK8), cytokeratin 18 (CK18), in cytoplasm was analyzed by immunocytochemistry (ICC). The concentration of ALB in the medium was determined dynamically by radioimmunoassay (RIA). RESULTS: ES cells replicated as clones, without differentiating, in DMEM containing LIF. They developed into EBs in medium without LIF. Our ICC assay showed that differentiating cells did not express hepatic proteins, such as AFP, ALB, CK8, and CK18 until day 7, day 9, day 11, and day 11, respectively (up to 2 days later when growth factors are not present). The concentration of AFP in the medium was first detected on day 8, at a concentration of 3.4 ng/ml, and increased to 22.8 ng/ml by day 15. The concentration of ALB in the medium was 0.2 micro g/ml on day 11, and increased to 2.2 micro g/ml by day 15. ALB-positive cells under ICC manifest morphological structures were consistent with normal mouse hepatocytes. The differentiation ratio of hepatocytes in the ES cell differentiation syst

关键词： Animals cell Differentiation cells, Cultured Embryo Hepatocytes Liver Mice Mice, Inbred BALB C Research Support, Non-U.S. Gov't stem cells

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Single-cell Analysis of CAR-T cell Activation Reveals A Mixed T_H1/T_H2 Response Independent of Differentiation

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Genomics, Proteomics & Bioinformatics 2019年第2期17卷 129-139页

作者： Iva Xhangolli Burak Dura GeeHee Lee Dongjoo Kim Yang Xiao Rong Fan department of Biomedical Engineering Yale University New Haven CT 06520 USA yale Cancer center Yale School of Medicine New Haven CT 06520 USA yale stem cell center Yale School of Medicine New Haven CT 06520

The activation mechanism of chimeric antigen receptor (CAR)-engineered T cells may differ substantially from T cells carrying native T cell receptor,but this difference remains poorly understood. We present the first comprehensive portrait of single-cell level transcriptional and cyto-kine signatures of anti-CD19/4-1BB/CD28/CD3ζ CAR-T cells upon antigen-specific stimulation. Both CD4+helper T (TH) cells and CD8+cytotoxic CAR-T cells are equally effective in directly killing target tumor cells and their cytotoxic activity is associated with the elevation of a range of TH1 and TH2 signature cytokines,e.g.,interferon γ,tumor necrotic factor α,interleukin 5 (IL5),and IL13,as confirmed by the expression of master transcription factor genes TBX21 and GATA3. However,rather than conforming to stringent TH1 or TH2 subtypes,single-cell analysis reveals that the predominant response is a highly mixed TH1/TH2 function in the same cell. The reg-ulatory T cell activity,although observed in a small fraction of activated cells,emerges from this hybrid TH1/TH2 population. Granulocyte-macrophage colony stimulating factor (GM-CSF) is pro-duced from the majority of cells regardless of the polarization states,further contrasting CAR-T to classic T cells. Surprisingly,the cytokine response is minimally associated with differentiation status,although all major differentiation subsets such as na?ve,central memory,effector memory,and effector are detected. All these suggest that the activation of CAR-engineered T cells is a canon-ical process that leads to a highly mixed response combining both type 1 and type 2 cytokines together with GM-CSF,supporting the notion that polyfunctional CAR-T cells correlate with objective response of patients in clinical trials. This work provides new insights into the mechanism of CAR activation and implies the necessity for cellular function assays to characterize the quality of CAR-T infusion products and monitor therapeutic responses in patients.

关键词： Single-cell transcriptomics Single-cell proteomics CAR-T T cell activation

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Sorafenib inhibits ossification of the posterior longitudinal ligament by blocking LOXL2-mediated vascularization

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Bone Research 2024年第2期12卷 372-389页

作者： Longqing Wang Wenhao Jiang Siyuan Zhao Dong Xie Qing Chen Qi Zhao Hao Wu Jian Luo Lili Yang Spine center Department of OrthopaedicsShanghai Changzheng HospitalSecond Affiliated Hospital of Naval Medical UniversityShanghai 200003PR China Yangzhi Rehabilitation Hospital(Shanghai Sunshine Rehabilitation center) Tongji University School of MedicineShanghaiPR China Shanghai Key Laboratory of Regulatory biology Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghaiPR China department of Orthopaedics No.905 Hospital of PLA NavyShanghaiPR China

Ossification of the Posterior Longitudinal Ligament(OPLL)is a degenerative hyperostosis disease characterized by the transformation of the soft and elastic vertebral ligament into bone,resulting in limited spinal mobility and nerve *** both bulk and single-cell RNA sequencing,we elucidate the molecular characteristics,cellular components,and their evolution during the OPLL process at a single-cell resolution,and validate these findings in clinical *** study also uncovers the capability of ligament stem cells to exhibit endothelial cell-like phenotypes in vitro and in ***,our study identifies LOXL2 as a key regulator in this *** gain-and loss-of-function studies,we elucidate the role of LOXL2 in the endothelial-like differentiation of ligament *** acts via the HIF1A pathway,promoting the secretion of downstream VEGFA and *** function is not related to the enzymatic activity of ***,we identify sorafenib,a broad-spectrum tyrosine kinase inhibitor,as an effective suppressor of LOXL2-mediated vascular *** disrupting the coupling between vascularization and osteogenesis,sorafenib demonstrates significant inhibition of OPLL progression in both BMP-induced and enpp1 deficiency-induced animal models while having no discernible effect on normal bone *** findings underscore the potential of sorafenib as a therapeutic intervention for OPLL.

关键词： LOXL2 ligament finding

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