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Combining anti-inflammatory and unfolding protein responses to fight stroke

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neural Regeneration Research 2019年第3期14卷 450-451页

作者： Berta Anuncibay-Soto Enrique Font-belmonte Arsenio Fernández-López área de Biología Celular Instituto de Biomedicina Universidad de León neural therapies SL Edificio Institutos de Investigación Campus de Vegazana

this perspective shows an attempt to obtain synergy effects to fight ischemic stroke by combining agents acting on two different homeostatic mechanisms:inflammation and unfolded protein response (Anuncibay-Soto et al.,2018).Different pharmacological approaches have been assayed to alleviate cerebrovascular accident (stroke), which represents one of the most devastating diseases in the elderly.

关键词： Combining anti-inflammatory

Single-cell profiling reveals a potent role of quercetin in promoting hair regeneration

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Protein & Cell 2023年第6期14卷 398-415页

作者： Qian Zhao Yandong Zheng Dongxin Zhao Liyun Zhao Lingling Geng Shuai ma Yusheng Cai Chengyu Liu Yupeng Yan Juan Carlos Izpisua belmonte Si Wang Weiqi Zhang Guang-Hui Liu Jing Qu Advanced Innovation Center for Human Brain Protection and national Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China Aging translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuan Wu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciencesand China National Center for BioinformationBeijing 100101China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China the Fifth People's Hospital of Chongqing Chongqing 400062China Shanghai Institute of materia Medica Chinese Academy of SciencesShanghai 201203China Altos Labs Inc.San DiegoCA 94022USA

Hair loss affects millions of people at some time in their life,and safe and efficient treatments for hair loss are a significant unmet medical *** report that topical delivery of quercetin(Que)stimulates resting hair follicles to grow with rapid follicular keratinocyte proliferation and replenishes perifollicular microvasculature in *** construct dynamic single-cell transcriptome landscape over the course of hair regrowth and find that Que treatment stimulates the differentiation trajectory in the hair follicles and induces an angiogenic signature in dermal endothelial cells by activating HIF-1αin endothelial *** administration of a HIF-1αagonist partially recapitulates the pro-angiogenesis and hair-growing effects of ***,these findings provide a molecular understanding for the efficacy of Que in hair regrowth,which underscores the translational potential of targeting the hair follicle niche as a strategy for regenerative medicine,and suggest a route of pharmacological intervention that may promote hair regrowth.

关键词： single-cell RnA-sequencing Que hair follicle regeneration endothelial cells HIF-1α

A single-cell transcriptomic atlas of primate pancreatic islet aging

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national Science Review 2021年第2期8卷 17-31页

作者： Jingyi Li Yuxuan Zheng Pengze Yan Moshi Song Si Wang Liang Sun Zunpeng Liu Shuai ma Juan Carlos Izpisua belmonte Piu Chan Qi Zhou Weiqi Zhang Guang-Hui Liu Fuchou tang Jing Qu State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of Sciences national Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of Sciences Beijing Institute for Brain Disorders Advanced Innovation Center for Human Brain ProtectionNational Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical University University of Chinese Academy of Sciences Beijing Advanced Innovation Center for Genomics Biomedical Pioneering Innovation CenterCollege of Life SciencesPeking University Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Peking-tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking University Institute for Stem Cell and Regeneration Chinese Academy of Sciences the MOH Key Laboratory of Geriatrics Beijing HospitalNational Center of Gerontology State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of Sciences Gene Expression Laboratory Salk Institute for Biological Studies CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences China national Center for Bioinformation

Aging-related degeneration of pancreatic islet cells contributes to impaired glucose tolerance and *** cells age heterogeneously, complicating the efforts to unravel the molecular drivers underlying endocrine aging. to overcome these obstacles, we undertook single-cell RnA sequencing of pancreatic islet cells obtained from young and aged non-diabetic cynomolgus monkeys. Despite sex differences and increased transcriptional variations, aged β-cells showed increased unfolded protein response(UPR) along with the accumulation of protein aggregates. We observed transcriptomic dysregulation of UPR components linked to canonical AtF6 and IRE1 signaling pathways, comprising adaptive UPR during pancreatic aging. notably, we found aging-related β-cell-specific upregulation of HSP90 B1, an endoplasmic reticulum-located chaperone, impeded high glucose-induced insulin secretion. Our work decodes aging-associated transcriptomic changes that underlie pancreatic islet functional decay at single-cell resolution and indicates that targeting UPR components may prevent loss of proteostasis,suggesting an avenue to delaying β-cell aging and preventing aging-related diabetes.

关键词： islet β-cell aging single-cell RnA sequencing primate

necroptosis in global cerebral ischemia: a role for endoplasmic reticulum stress

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neural Regeneration Research 2020年第3期15卷 455-456页

作者： Enrique Font-belmonte Paloma González-Rodríguez Arsenio Fernández-López Area de Biologia Celular Instituto de BiomedicinaUniversidad de LeonLeonSpain neural therapies SL Edificio Institutos de InvestigacionCampus de VegazanaLeonSpain

necroptosis has been reported in the last years as a type of regulated cell death that can be ignited by a number of specific death receptors,such as FAS,tumor necrosis factor receptor 1(tnFR1),or pathogen recognition *** cell death subroutine is involved in the response to stress and in homeostatic functions,such as the maintenance of adult t-cell balance(Galluzzi et al.,2018).Dead receptor activation leads to the recruitment of protein complexes that act as nodes of signaling that can elicit different pathways driving to death or survival,depending on the cell conditions.

关键词： death cerebral ischemia

Resilience to structural and molecular changes in excitatory synapses in the hippocampus contributes to cognitive function recovery in tg2576 mice

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neural Regeneration Research 2024年第9期19卷 2068-2074页

作者： Carolina Aguado Sara Badesso Joséma.tínez-Hernández a.eja.dro ma.tín-belmonte Rocío Alfaro-Ruiz Miriam Fernández Ana Esther Moreno-ma.tínez mar Cuadrado-tejedor Ana García-Osta Rafael Luján Synaptic Structure Laboratory Instituto de Investigación en Discapacidades Neurológicas(IDINE)Department of Medical SciencesFacultad de MedicinaUniversidad de Castilla-La ManchaCampus BiosanitarioAlbaceteSpain Gene therapy for neurological Disease Program Center for Applied Medical Research(CIMA)University of NavarraInstituto de Investigación Sanitaria de Navarra(IdiSNA)PamplonaSpain Pharmacology Unit Department of Pathology and Experimental TherapeuticsFaculty of Medicine and Health SciencesInstitute of NeurosciencesUniversity of BarcelonaBarcelonaSpain neuropharmacology and Pain Group Neuroscience ProgramInstitut d’InvestigacióBiomèdica de BellvitgeIDIBELLL’Hospitalet de LlobregatSpain Department of Pathology Anatomy and PhysiologySchool of MedicineUniversity of NavarraPamplonaSpain UniversitéGrenoble Alpes Grenoble Institut des NeurosciencesGrenobleFrance

Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive *** the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic *** hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels,which may underlie healthy cognitive performance in aged AD *** the Morris Water maze test,we selected resilient(asymptomatic)and cognitively impaired aged tg2576 *** the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups,western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant *** further investigate the density of synapses in the hippocampus of 16-18 month-old tg2576 mice,we employed stereological and electron microscopic *** findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired tg2576 mice compared with age-matched resilient tg2576 and non-transgenic ***,through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient tg2576 transgenic AD mice,we uncovered differences in the subcellular localization of glutamate ***,the density of GluA1,GluA2/3,and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired tg2576 mice was significantly reduced compared with age-matched resilient tg2576 and non-transgenic ***,the density of GluA2/3 in resilient tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired tg2576 and non-transgenic *** subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play cr

关键词： aging Alzheimer´s disease cognitive hippocampus immunoelectron microscopy resilience synapse

A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

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Protein & Cell 2024年第2期15卷 98-120页

作者： Shanshan Yang Chengyu Liu Mengmeng Jiang Xiaoqian Liu Lingling Geng Yiyuan Zhang Shuhui Sun Kang Wang jian Yin Shuai ma Si Wang Juan Carlos Izpisua belmonte Weiqi Zhang Jing Qu Guang-Hui Liu Advanced Innovation Center for Human Brain Protection and national Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Membrane 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 Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China Xuanwu Hospital Capital Medical University Beijing 100053China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Aging Biomarker Consortium Beijing 100101China Altos Labs Inc.San DiegoCA 94022USA

Aging increases the risk ofliver diseases and systemic susceptibility to aging-related ***,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely ***,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche *** in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during *** particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular *** study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

关键词： single-nucleus RnA sequencing liver hepatocytes aging senescence SREBP2

First progeria monkey model generated using base editor

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Protein & Cell 2020年第12期11卷 862-865页

作者： Pradeep Reddy Yanjiao Shao Reyna Hernandez-Benitez Estrella nunez Delicado Juan Carlos Izpisua belmonte Gene Expression Laboratory Salk Institute for Biological Studies10010 North Torrey Pines RoadLa JollaCA 92037USA Universidad Catolica San Antonio de Murcia(UCAM) Campus de los JerdnimosN°13512Guadalupe 30107Spain

In this issue,Wang et *** on the generation of a nonhuman primate model of Hutchinson-Gilford progeria syndrome(HGPS)using a base *** editing is an emerging novel genome editing technique for modifying a single base pair at specific sites in the *** editors(BEs)have two prin cipal comp orients,a catalytically in active or single strand cleaving Cas-variant,which binds to the guide RnA and a nucleobase deaminase domain to convert specific base pairs at the target loci(Komor et al.,2016;nishida et al.,2016;Gaudelli et al.,2017).Cytosine base editor(CBE)and adenine base editor(ABE)are two baseeditors,which con vert Cytosi ne-Gua nine(C-G)to thymine-Adenine(t-A)and A-t to G-C,respectively.

关键词： base convert editor

Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

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Protein & Cell 2019年第4期10卷 249-271页

作者： Chen Ling Zunpeng Liu Moshi Song Weiqi Zhang Si Wang Xiaoqian Liu Shuai ma Shuhui Sun Lina Fu Qun Chu Juan Carlos Izpisua belmonte Zhaoxia Wang Jing Qu Yun Yuan Guang-Hui Liu Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China Beijing Institute for Brain Disorders Capital Medical UniversityBeijing 100069China Department of neurology Peking University First HospitalBeijing 100034China national Laboratory of Biomacromolecules CAS Center for Excellenee in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Gene Expression Laboratory Salk Institute for Biological Studies10010 North Torrey Pines RoadLa JollaCA 92037USA Institute for Stem cell and Regeneration CASBeijing 100101China Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative MedicineJinan UniversityGuangzhou 510632China

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is a rare hereditary cerebrovascular disease caused by a nOtCH3 ***,the underlying cellular and molecular mechanisms remain ***,we generated non-integrative induced pluripotent stem cells(iPSCs)from fibroblasts of a CADASIL patient harboring a heterozygous nOtCH3 mutation(c.3226C>t,p.R1076C).Vascular smooth muscle cells(VSMCs)differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes,including activation of the nOtCH and nF-kB signaling pathway,cytoskeleton disorganization,and excessive cell *** comparison,these abnormalities were not observed in vascular endothelial cells(VECs)derived from the patients ***,the abnormal upregulation of nF-kB target genes in CADASIL VSMCs was diminished by a nOtCH pathway inhibitor,providing a potential therapeutic strategy for ***,using this iPSCbased disease model,our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.

关键词： CADASIL iPSC nOtCH nF-kB vascular smooth muscle

transcriptome landscape of the early Brassica napus seed

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Journal of Integrative Plant Biology 2019年第5期61卷 639-650页

作者： Dylan J.Ziegler Deirdre Khan Jenna L.Kalichuk Michael G.Becker mark F.belmonte University of manitoba

Brassica napus L.(canola) is one of the world’s most economically important oilseeds. Despite our growing knowledge of Brassica genetics, we still know little about the genes and gene regulatory networks underlying early seed development. In this work, we use laser microdissection coupled with RnA sequencing to profile gene activity of both the maternal and filial subregions of the globular seed. We find subregions of the chalazal end including the chalazal endosperm, chalazal proliferating tissue, and chalazal seed coat, have unique transcriptome profiles associated with hormone biosynthesis and polysaccharide metabolism. We confirm that the chalazal seed coat is uniquely enriched for sucrose biosynthesis and transport, and that the chalazal endosperm may function as an important regulator of the maternal region through brassinosteroid synthesis. the chalazal proliferating tissue,a poorly understood subregion, was specifically enriched in transcripts associated with megasporogenesis and trehalose biosynthesis, suggesting this ephemeral structure plays an important role in both sporophytic development and carbon nutrient balance, respectively. Finally, compartmentalization of transcription factors and their regulatory circuits has uncovered previously unknown roles for the chalazal pole in early seed development.

关键词： Brassica napus L.(canola) understood subregion