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Human ESC-derived vascular cells promote vascular regeneration in a HIF-1α dependent manner

Protein & Cell 2024年第1期15卷 36-51页

作者： Jinghui Lei Xiaoyu Jiang Daoyuan Huang Ying Jing Shanshan Yang Lingling geng Yupeng Yan Fangshuo zheng Fang Cheng Weiqi zhang juan carlos Izpisua Belmonte guang-Hui Liu Si Wang Jing Qu Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational medicine Center Intermational Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Beijing Institute for Stem Cell and Regenerative medicine Beijing 100101China National Laboratory of Biomacromolecules CAs Center for Excellence in BiomacromoleculesInstitute of BiophysicsBeijing 100101China CAS Key Laboratory of genomic and Precision medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Beijing 100101China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Sino-Danish Center for Education and Research Beijing 101408China Aging Biomarker Consortium China Altos Labs San DiegoCA 92121United State

Hypoxia-inducible factor(HIF-1α),a core transcription factor responding to changes in cellular oxygen levels,is closely associated with a wide range of physiological and pathological ***,its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely ***,we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-ia-deficient human vascular cells including vascular endothelial cells,vascular smooth muscle cells,and mesenchymal stem cells(msCs),as a platform for discovering cell type-specific hypox-ia-induced response *** comparative molecular profiling across cell types under normoxic and hypoxic conditions,we provide insight into the indispensable role of HIF-1αin the promotion of ischemic vascular *** found human mSCs to be the vascular cell type most susceptible to HIF-1a deficiency,and that transcriptional inactivation of ANKzF1,an effector of HIF-1a,impaired pro-angiogenic ***,our findings deepen the understanding of HIF-ia in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

关键词： HIF-1 human ESC vascular cell regeneration

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Dietary(poly)phenol intake is associated with cardiometabolic health parameters in adolescents

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Food Science and Human Wellness 2024年

作者： Emily P.Laveriano-Santos Sara Castro-Barquero Camila Arancibia-Riveros Ana maría Ruiz-León Rosa Casas Ramón Estruch Patricia Bodega mercedes de miguel Amaya de Cos-gandoy Jesús martínez-góm.z gloria Santos-Beneit juan m.Fernández-Alvira Rodrigo Fernández-Jiménez Rosa m.Lamuela-Raventós Anna Tresserra-Rimbau The zena and michael A.Wiener Cardiovascular Institute， Icahn School of medicine at mount Sinai Department de Nutrició， Ciències de l'Alimentació I gastronomia， XIA， Facultat de Farmàcia i Ciències de l'alimentació， Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB)， Universitat de Barcelona Department of Internal medicine， Hospital Clínic， Institutd'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS)， University of Barcelona Consorcio CIBER， m.P.Fisiopatología de la Obesidad y Nutrición (CIBERObn)， Instituto de Salud carlos III (ISCIII) mediterranean Diet Foundation 5. Foundation for Science， Health and Education (SHE) 6. Centro Nacional de Investigaciones Cardiovasculares (CNIC) CIBER de Enfermedades Cardiovasculares (CIBERCV) 9. Hospital Universitario Clínico San carlos

Background: The protective role of (poly)phenols against metabolic disorders has been extensively studied in adults but not in ***: To assess associations of dietary (poly)phenols and their subclasses with cardiometabolic health parameters in adolescents. methods: A cross-sectional study was conducted in 944 individuals aged 11 to 14 years enrolled in the SI! Program for Secondary Schools trial (NCT03504059). (Poly)phenol intake was assessed using semi-quantitative food frequency questionnaires and the Phenol-Explorer database. The measured cardiometabolic parameters were waist circumference (WC) age-sex z-score， blood pressure (BP) age-sex z-score， blood glucose (Bg)， triglycerides (Tg)， and high-density lipoprotein cholesterol (HDL-c). multilevel mixed-effect linear regression models were applied to examine the association between (poly)phenol quintiles and cardiometabolic health ***: Compared to the lowest quintile， adolescents in the highest quintile of total (poly)phenol intake had lower WC z-scores (β=-0.09， 95%CI=-0.09;-0.08， P-for trend=0.002)， mean arterial pressure z-scores (β =-0.11， 95%CI=-0.12;-0.09， P-for trend=0.206)， and HDL-c (β=-1.52， 95%CI=-2.90;-0.14， P-for trend=0.108)， after multivariable adjustment. The WC z-scores (β=-0.11， 95%CI=-0.19;-0.03， P-for trend=0.013) and HDL-c (β=-2.16， 95%CI=-3.78;-0.53， P-for trend=0.046) were lower in the highest quintile of flavonoid intake compared to the lowest quintile. The highest quintile of phenolic acid intake was associated with a lower WC z-score (β=-0.14， 95%CI=-0.26;-0.02， P-for trend=0.011) and Tg levels (β=-8.83， 95%CI=-12.37;-5.30， P-for trend ghest quintile of stilbene intake with lower Bg (β=-1.83， 95%CI= -3.103;-0.64， P-for trend g (β=-3.22， 95%CI= -4.95;-1.49， P-for trend=0.034)， and with higher HDL-c (β=2.328， 95%CI= 1.40;3.17， P-for trend=0.466) compared to the lowest quintile. Conclusion: A higher intake of (poly)phenols， espe

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Arabidopsis SWC4 Binds DNA and Recruits the SWR1 Complex to modulate Histone H2A.z Deposition at Key Regulatory genes

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molecular Plant 2018年第6期11卷 815-832页

作者： Angeles gom.z-zambrano Pedro Crevillen Jose m. Franco-zorrilla juan A. Lopez Jordi moreno-Romero Pawel Roszak juan Santos-gonzalez Silvia Jurado Jesus Vazquez Claudia Kohler Roberto Solano manuel Pineiro Jose A. Jarillo Centro de Biotecnologia y genomica de Plantas Universidad Politecnica de Madrid (UPM) - Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria (INIA) Campus Montegancedo UPM Pozuelo de Alarcon 28223 Madrid Spain Plant molecular genetics Department and genomics Unit Centro Nacional de Biotecnologia Consejo Superior de Investigaciones Cientfficas 28049 Madrid Spain Proteomics Unit Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) 28029 Madrid Spain Department of Plant Biology Uppsala BioCenter Swedish University of Agricultural Sciences and Linnean Center for Plant Biology Uppsala 75652 Sweden Laboratory of Cardiovascular Proteomics Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) 28029 Madrid Spain Instituto de Bioquimica Vegetal y Fotosintesis Consejo Superior de Investigaciones Cientfficas and Universidad de Sevilla 41092 Sevilla Spain Centre for Research in Agricultural genomics (CRAg) CSIC-IRTA-UAB-UB Campus UAB Bellaterra Barcelona Spain The Sainsbury Laboratory Cambridge CB2 1LR UK

Deposition of the H2A.z histone variant by the SWR1 complex （SWRI-C） in regulatory regions of specific loci modulates transcription. Characterization of mutations in Arabidopsis thaliana homologs of yeast SWRI-C has revealed a role for H2A.z exchange in a variety of developmental processes. Nevertheless, the exact composition of plant SWRI-C and how it is recruited to target genes remains to be established. Here we show that SWC4, the Arabidopsis homolog of yeast SANT domain protein Swc4/Eaf2, is a DNA-binding protein that interacts with SWR1-C subunits. We demonstrate that the swc4-1 knockout mutant is embryo- lethal, while SWC4 RNAi knockdown lines display pleiotropic phenotypic alterations in vegetative and repro- ductive traits, including acceleration of flowering time, indicating that SWC4 controls post-embryonic processes. Transcriptomic analyses and genome-wide profiling of H2A.z indicate that SWC4 represses tran- scription of a number of genes, including the floral integrator FT and key transcription factors, mainly by modulating H2A.z deposition. Interestingly, SWC4 silencing does not affect H2A.z deposition at the FLC locus nor expression of this gene, a master regulator of flowering previously shown to be controlled by SWR1-C. Importantly, we find that SWC4 recognizes specific AT-rich DNA elements in the chromatin regions of target genes and that SWC4 silencing impairs SWRI-C binding at FT. Collectively, our data suggest that SWC4 regulates plant growth and development by aiding SWR1-C recruitment and modulating H2A.z deposition.

关键词： Arabidopsis SWC4 chromatin SWR1 complex H2A.z deposition flowering time

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Beta-blocker therapy in elderly patients with renal dysfunction and heart failure

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Journal of geriatric Cardiology 2021年第1期18卷 20-29页

作者： juan martínez-milla marcelino Cortés garcía Julia Anna Palfy mikel Taibo Urquía marta López Castillo Ana Devesa Arbiol Ana Lucía Rivero monteagudo maría Luisa martín mariscal Inés Jiménez-Varas Sem Briongos Figuero juan Antonio Franco-Pelaéz JoséTuñón Department of Cardiology Hospital Universitario Fundación Jiménez Díaz-Quirónsalud Centro Nacional de Investigaciones Cardiovasculares MadridSpain Department of Cardiology Hospital Central de Asturias Department of Cardiology Hospital Universitario Ruber-Quirónsalud Department of Cardiology Hospital Universitario Infanta Leonor Department of Endocrinology Hospital Clínico San Carlos Universidad Autónoma de madrid CIBERCV MadridSpain

OBJECTIVE To assess the role of beta-blockers(BB)in patients with chronic kidney disease(CKD)aged≥75 *** AND RESULTS From January 2008 to July 2014,we included 390 consecutive patients≥75 years of age with ejection fraction≤35%and glomerular filtration rate(gFR)≤60 m L/min per 1.73 m^*** analyzed the relationship between treatment with BB and mortality or cardiovascular *** mean age of our population was 82.6±4.1 *** ejection fraction was 27.9%±6.5%.gFR was 60-45 m L/min per 1.73 m^2 in 50.3%of patients,45-30 m L/min per 1.73 m^2 in 37.4%,andm L/min per 1.73 m^2 in 12.3%.At the conclusion of follow-up,67.4%of patients were receiving *** median follow-up was28.04(IR:19.41-36.67)*** the study period,211 patients(54.1%)died and 257(65.9%)had a major cardiovascular event(death or hospitalization for heart failure).BB use was significantly associated with a reduced risk of death(HR=0.51,95%CI:0.35-0.74;Pg BB consistently showed a reduced risk of death across the different stages of CKD:stage IIIa(gFR=30-45 m L/min per 1.73 m^2;HR=0.47,95%CI:0.26-0.86,Pge IIIb(gFR 30-45 m L/min per 1.73 m^2;HR=0.55,95%CI:0.26-1.06,P=0.007),and stages IV and V(gFRm L/min per 1.73 m~2;HR=0.29,95%CI:0.11-0.76;P=0.047).CONCLUSIONS The use of BB in elderly patients with HFr EF and renal impairment was associated with a better *** of BB should be encouraged when possible.

关键词： CKD gFR Beta-blocker therapy in elderly patients with renal dysfunction and heart failure

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mutations in foregut SOX2^+ cells induce efficient proliferation via CXCR2 pathway

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Protein & Cell 2019年第7期10卷 485-495页

作者： Tomoaki Hishida Eric Vazquez-Ferrer Yuriko Hishida-Nozaki Ignacio Sancho-martinez Yuta Takahashi Fumiyuki Hatanaka Jun Wu Alejandro Ocampo Pradeep Reddy min-zu Wu Laurie gerken Reuben J. Shaw Concepcion Rodriguez Esteban Christopher Benner Hiroshi Nakagawa Pedro guillen garcia Estrella Nunez Delicado Antoni Castells Josep m. Campistol guang-Hui Liu juan carlos Izpisua Belmonte gene Expression Laboratory Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Advaneed Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical University Beijing 100053 China National Laboratory of Biomacromolecules CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China University of the Chinese Academy of Sciences Beijing 100049 China Insitute for Stem Cell and Regeneration Chinese Academy of Sciences Beijing 100101 China Beijing Institute for Brain Disorder Beijing 100069 China Universidad Catolica San Antonio de Murcia Campus de los Jeronimos 135 Guadalupe 30107 Spain molecular and Cell Biology Laboratory Dulbecco Center for Cancer Research Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Howard Hughes medical Institute Dulbecco Center for Cancer Research Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Integrative genomics Core Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Division of gastroenterology Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA Abramson Cancer Center University of Pennsylvania Philadelphia PA 19104 USA Department of Traumatology and Research Unit Clinica CEMTRO Av. Ventisquero de la Condesa 42 Madrid 28035 Spain gastroenterology Department Hospital Clinic University of Barcelona IDIBAPS CIBEREHD Barcelona 08036 Spain

Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2^+ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as Kras^g12D and p53 deletion. gFP-based lineage-tracing experiments indicate that SOX2^+ cells are the cells-of-origin of esophagus and stomach hyperplasia. Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion. p53 hom.zygous deletion is required for the acquisition of an invasive potential, and Kras^g12D expression, but not p53 deletion, suffices for tumor formation. global gene expression analysis reveals secreting factors upregulated in the hyperplasia induced by oncogenic KRAS and highlights a crucial role for the CXCR2 pathway in driving hyperplasia. Collectively, the array of genetic models presented here demonstrate that stratified epithelial cells are susceptible to oncogenic insults, which may lead to a better understanding of tumor initiation and aid in the design of new cancer therapeutics.

关键词： Sox2 tumor CXCR2 stratified epithelia

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CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs

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Protein & Cell 2017年第5期8卷 365-378页

作者： Lixia Wang Fei Yi Lina Fu Jiping Yang Si Wang zhaoxia Wang Keiichiro Suzuki Liang Sun Xiuling Xu Yang Yu Jie Qiao juan carlos Izpisua Belmonte ze Yang Yun Yuan Jing Qu guang-Hui Liu National Laboratory of Biomacromolecules CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100049 China Department of molecular and Cellular Physiology Stanford University School of Medicine Stanford CA 94305 USA Department of Neurology Peking University First Hospital Beijing 100034 China gene Expression Laboratory Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Universidad Catolica San Antonio de murcia (UCAm) Campus de los Jeronimos N 135 Guadalupe 30107 Murcia Spain Department of gynecology and Obstetrics Peking University Third Hospital Beijing 100191 China Beijing Hospital of the ministry of Health Beijing 100730 China Key Laboratory of Regenerative medicine of ministry of Education Institute of Aging and Regenerative Medicine Jinan University Guangzhou 510632 China Beijing Institute for Brain Disorders Capital Medical University Beijing 100069 China

Amyotrophic lateral sclerosis （ALS） is a complex neu- rodegenerative disease with cellular and molecular mechanisms yet to be fully described. mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells （iPSCs） from fibroblasts of familial ALS patients bearing SOD1＋1A27~c and FUS＋/gISe6A mutations, respectively. We further gener- ated gene corrected ALS iPSCs using CRISPR/Cas9 system. genome-wide RNA sequencing （RNA-seq） analysis of motor neurons derived from SOD1＋~A272c and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.

关键词： ALS CRISPR/Cas9 gene correction,iPSC disease modeling

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A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis

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Protein & Cell 2023年第12期14卷 888-907页

作者： Daoyuan Huang Yuesheng zuo Chen zhang guoqiang Sun Ying Jing Jinghui Lei Shuai ma Shuhui Sun Huifen Lu Yusheng Cai Weiqi zhang Fei gao Andy Peng Xiang juan carlos Izpisua Belmonte guang-Hui Liu Jing Qu Si Wang Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative medicine Beijing 100101China CAS Key Laboratory of genomic and Precision medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Institute for Stemcell and Regeneration CAsBeijing100101China China National Center for Bioinformation Beijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China 11Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Sino-Danish Center for Education and Research Beijing 101408China Center for Stem Cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue EngineeringMinistry of EducationSun Yat-sen UniversityGuangzhou510000China Department of Biochemistry Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510000China Altos Labs Inc.San DiegoCA 92121USA and Aging Biomarker Consortium China

The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with ***,the regulatory mechanism underlying primate testicular aging remains largely ***,we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic ***-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir,disturbed meiosis and impaired spermiogenesis along the sequential ***,Sertoli cell was identified as the cell type most susceptible to aging,given its deeply perturbed age-associated transcriptional ***,downregulation of the transcription factor Wilms'Tumor 1(WTi),essential for Sertoli cell homeostasis,was associated with accelerated cellular senescence,disrupted tight junctions,and a compromised cell identity signature,which altogether may help create a hostile microenvironment for ***,our study depicts in-depth transcriptomic traits of non-human primate(NHP)testicular aging at single-cell resolution,providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.

关键词： single-nucleus RNA sequencing primate testis aging WT1

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Exosomes from antler stem cells alleviate mesenchymal stem cell senescence and osteoarthritis

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Protein & Cell 2022年第3期13卷 220-226页

作者： Jinghui Lei Xiaoyu Jiang Wei Li Jie Ren Datao Wang zhejun Ji zeming Wu Fang Cheng Yusheng Cai zheng-Rong Yu juan carlos Izpisua Belmonte Chunyi Li guang-Hui Liu Weiqi zhang Jing Qu Si Wang Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational medicine Center Xuanwu HospitalCapital Medical UniversityBeijing 100053China CAS Key Laboratory of genomic and Precision medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Institute of Antler Science and Product Technology Changchun Sci-Tech UniversityChangchun 130000China University of Chinese Academy of Sciences Beijing 100049China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China China National Center for Bioinformation Beijing 100101China Beijing Institute for Stem Cell and Regenerative medicine Beijing 100101China Department of Orthopaedics Peking University First HospitalBeijing 100034China gene Expression Laboratory Salk Institute for Biological StudiesLa JollaCAUSA

Dear Editor,Stem cell therapy holds enormous and revolutionary promise to treat various age-related diseases,such as diabetes,heart failure,and Parkinson’s ***,low retention and survival rate of delivered stem cells,partially due to immunological rejection,constitute major hurdles for the clinical implementation of stem cell therapy(Lei et al.,2021a).Since mounting evidence showed that several types of stem cells mainly exert their therapeutic effects through the secretion of paracrine effects,exosomes,which are released by stem cells and execute most paracrine functions,have begun to draw attention in the field(Tran and Damaser,2015).Exosomes are membrane-enclosed vesicles with an average diameter of∼100 nanometers secreted by the cells,containing cytokines.

关键词： Exosomes holds mount

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modeling xeroderma pigmentosum associated neurological pathologies with patients-derived iPSCs

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Protein & Cell 2016年第3期7卷 210-221页

作者： Lina Fu Xiuling Xu Ruotong Ren Jun Wu Weiqi zhang Jiping Yang Xiaoqing Ren Si Wang Yang zhao Liang Sun Yang Yu zhaoxia Wang ze Yang Yun Yuan Jie Qiao juan carlos Izpisua Belmonte Jing Qu guang-Hui Liu National Laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China FSU-CAS Innovation Institute Foshan University Foshan 528000 China State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 China gene Expression Laboratory Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Universidad Cato1ica San Antonio de murcia (UCAIVI) Campus de los Jer6nimos N° 135 Guadalupe 30107 Murcia Spain Beijing Hospital of the ministry of Health Beijing 100730 China Department of gynecology and Obstetrics Peking University Third Hospital Beijing 100191 China Department of Neurology Peking University First Hospital Beijing 100034 China Beijing Institute for Brain Disorders Capital Medical University Beijing 100069 China University of Chinese Academy of Sciences Beijing 100049 China

Xeroderma pigmentosum （XP） is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patientspecific induced pluripotent stem cells （iPSCs） harboring mutations in five different XP genes including XPA, XPB, XPC, XPg, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. mutation of XPA in either neural stem cells （NSCs） or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clari the molecular mechanisms of neurological abnormalities in the XP patients.

关键词： xeroderma pigmentosum iPSC disease model neural stem cell. neuron

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Effect of <i>Carica papaya</i>Leaf Extract on Serum Lipids and Liver metabolic Parameters of Rats Fed a High Cholesterol Diet

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Health 2015年第9期7卷 1196-1205页

作者： Alma m. zetina-Esquivel carlos A. Tovilla-zárate Crystell guzmán-garcia Arturo Rodríguez-Hernández Andrés E. Castell-Rodríguez Jorge L. Ble-Castillo Angela Avila-Fernandez Isela E. Juárez-Rojop juan C. Díaz-zagoya Centro de Investigación División Académica de Ciencias de la Salud Universidad Juárez Autónoma de Tabasco Villahermosa México División Académica multidisciplinaria de Comalcalco Universidad Juárez Autónoma de Tabasco Comalcalco México Unidad de medicina Familiar 10 Instituto Mexicano del Seguro Social Xalapa México División de Investigación Facultad de Medicina Universidad Nacional Autónoma de México México D. F. México

Hyperlipidemia plays an important role in the development of atherosclerosis, the main cause of death in the world. In this study, the lipid-lowering effect of Carica papaya leaf in rats fed with a high cholesterol diet was evaluated. Daily doses of C. papaya extract 0, 31, 62 or 125 mg/kg body weight were orally administered in 300 μl polyethylene glycol to hypercholesterolemic rats;it was also administered 62 mg/kg body weight of the extract to rats with normal diet. After a 20-day treatment, the animals were sacrificed;blood and liver were analyzed. Hypercholesterolemic rats showed an increased serum and liver cholesterol, triacylglycerols, and atherogenic index. The C. papaya extract produced a significant decrease of serum and liver cholesterol concentrations in hypercholesterolemic rats, but did not modify serum or liver triacylglycerols;however, the extract reduced the atherogenic index in a dose-dependent manner. C. papaya treatment decreased LDL-C and increased HDL-C in serum significantly. When the oxygen consumption was evaluated in phosphorylating and resting states, the respiratory control in hypercholesterolemic rats mitochondria was lower than in normal diet rats. However, a higher respiratory control in hypercholesterolemic rats mitochondria was observed after C papaya treatment. The liver morphological data are in accordance with serum and liver biochemical values. Our data support that C. papaya has a significant hypocholesterolemic action and HDL-C raising effect on rats fed with a cholesterol-rich diet, however, the precise metabolites responsible of this effect remain unknown.

关键词： Serum Lipids Carica papaya Cholesterol mitochondria

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