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Dynamic transcriptional programs define distinct mammalian cortical lineages

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Neural Regeneration Research 2024年第2期19卷 387-389页

作者： Tanzila Mukhtar Verdon Taylor department of biomedicine University of BaselBaselSwitzerland Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of CaliforniaSan FranciscoCAUSA

The cerebral cortex is composed of billions of neurons and glia that are generated sequentially during corticogenesis.These cells are generated in an organized fashion during development.At early stages of brain devel... 详细信息

关键词： cortex cerebral development

New pharmacological tools:the use of diterpenes to promote adult hippocampal neurogenesis

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Neural Regeneration Research 2024年第8期19卷 1629-1630页

作者： Ricardo Gomez-Oliva Pedro Nunez-Abades Carmen Castro department of biomedicine Biotechnology and Public HealthDivision of PhysiologyUniversity of CadizCadizSpain Biomedical Research and Innovation Institute of Cadiz(INiBICA) CadizSpain department of Physiology University of SevilleSevilleSpain

Tissue regeneration maintains homeostasis and preserves the functional features of each tissue.However,not all tissues show a strong repairing capacity.This is the case of the central nervous system.It is now well established that the generation of new functional neurons from stem cells in the adult brain occurs in specific regions of the brain of different species such as rodents,birds,primates,and humans(Eriksson et al.,1998).

关键词： capacity maintain preserve

Bone marrow-derived microglia confer neuroprotection to a mouse model of amyotrophic lateral sclerosis

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Neural Regeneration Research 2024年第12期19卷 2586-2587页

作者： Beka Solomon department of Molecular Microbiology and Biotechnology The Shmunis School of Biomedicine and Cancer Researchthe George S.Wise Faculty of Life Sciences Tel-Aviv UniversityRamat AvivIsrael

Amyotrophic lateral sclerosis(ALS) is a neurodegenerative disease that causes the progressive loss of both upper and lower motor neurons in the brain,brainstem,and spinal cord.The exact mechanisms of ALS are still unclear,but genetic and molecular studies have revealed some key factors that may contribute to motor neuron death.Besides motor neurons,other cell types in the nervous system,such as reactive astrocytes and activated microglia,also show pathological changes and secrete harmful substances and inflammatory cytokines(Appel et al.,2011).

关键词： sclerosis brainstem

Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer

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National Science Review 2024年第1期11卷 107-119页

作者： Shuren Zhang Dongfan Song Wenhao Yu Ji Li Xiaoyu Wang Yachao Li Zihan Zhao Qi Xue Jing Zhao Jie P.Li Zijian Guo State Key Laboratory of Coordination Chemistry School of Chemistry and Chemical EngineeringChemistry and Biomedicine Innovation Center (ChemBIC) Nanjing University department of Urology Afflliated Drum Tower HospitalMedical SchoolNanjing University Nanchuang (Jiangsu)Institute of Chemistry and Health

Mounting evidence suggests that strategies combining DNA-damaging agents and stimulator of interferon genes(STING) agonists are promising cancer therapeutic regimens because they can amplify STING activation and remodel the immunosuppressive tumor microenvironment. However, a single molecular entity comprising both agents has not yet been developed. Herein, we designed two PtIV-MSA-2 conjugates(Ⅰand Ⅱ) containing the DNA-damaging chemotherapeutic drug cisplatin and the innate immuneactivating STING agonist MSA-2; these conjugates showed great potential as multispecific small-molecule drugs against pancreatic cancer. Mechanistic studies revealed that conjugate Ⅰ upregulated the expression of transcripts associated with innate immunity and metabolism in cancer cells, significantly differing from cisplatin and MSA-2. An analysis of the tumor microenvironment demonstrated that conjugate I could enhance the infiltration of natural killer(NK) cells into tumors and promote the activation of T cells, NK cells and dendritic cells in tumor tissues. These findings indicated that conjugate I, which was created by incorporating a Pt chemotherapeutic drug and STING agonist into one molecule, is a promising and potent anticancer drug candidate, opening new avenues for small-molecule-based cancer metalloimmunotherapy.

关键词： platinum drug STING agonist single-molecule multitarget metalloimmunology

RNA m6A dynamic modification mediated by nucleuslocalized FTO is involved in follicular reserve

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Zoological Research 2024年第2期45卷 415-428页

作者： Jiao-Na Zhang Rui-Ting Wang Francesca-Gioia Klinger Shun-Feng Cheng Wei Shen Xiao-Feng Sun College of Life Sciences Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of ShandongQingdao Agricultural UniversityQingdaoShandong 266109China department of biomedicine and Prevention University of Rome Tor VergataRome 00133Italy

In eukaryotic organisms,the most common internal modification of messenger RNA(m RNA)is N6-methyladenosine(m6A).This modification can be dynamically and reversibly controlled by specific enzymes known as m6A writers and erasers.The fat-mass and obesity-associated protein(FTO)catalyzes RNA demethylation and plays a critical role in various physiological and pathological processes.Our research identified dynamic alterations in both m6A and FTO during the assembly of primordial follicles,with an inverse relationship observed for m6A levels and nuclear-localized FTO expression.Application of Fto small interfering RNA(si RNA)altered the expression of genes related to cell proliferation,hormone regulation,and cell chemotaxis,and affected RNA alternative splicing.Overexpression of the full-length Fto gene led to changes in m6A levels,alternative splicing of Cdk5,cell proliferation,cell cycle progression,and proportion of primordial follicles.Conversely,overexpression of Fto lacking a nuclear localization signal(NLS)did not significantly alter m6A levels or primordial follicle assembly.These findings suggest that FTO,localized in the nucleus but not in the cytoplasm,regulates RNA m6A demethylation and plays a role in cell proliferation,cell cycle progression,and primordial follicle assembly.These results highlight the potential of m6A and its eraser FTO as possible biomarkers and therapeutic targets.

关键词： m6A FTO Ovary Primordial follicle assembly Alternative splicing

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m^(6)A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation

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Frontiers of Medicine 2024年第3期18卷 499-515页

作者： Han Wu Weitao Jiang Ping Pang Wei Si Xue Kong Xinyue Zhang Yuting Xiong Chunlei Wang Feng Zhang Jinglun Song Yang Yang Linghua Zeng Kuiwu Liu Yingqiong Jia Zhuo Wang Jiaming Ju Hongtao Diao Yu Bian Baofeng Yang department of Pharmacology(National Key Laboratory of Frigid Zone Cardiovascular Diseases the State-Province Key Laboratories of Biomedicine-Pharmaceutics of ChinaKey Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbin150081China

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction(MI)can lead to heart failure.RNA N6-methyladenosine(m^(6)A)methylation has been shown to play a pivotal role in the occurrence and development of many illnesses.In investigating the biological function of the m^(6)A reader YTHDF1 in cardiac fibrosis,adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts,and MI surgery in vivo and transforming growth factor-β(TGF-β)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models.Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis,whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development.Mechanistically,zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter.YTHDF1 augmented AXL translation and activated the TGF-β-Smad2/3 signaling pathway,thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis.Consistently,our data indicated that YTHDF1 was involved in activation,proliferation,and migration to participate in cardiac fibrosis in vitro.Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

关键词： cardiac fibrosis YTHDF1 AXL ZBED6 heart failure

Intracellular zinc signaling via Kruppel-like transcription factor 6 promotes HuD expression in pancreaticβcell

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Genes & Diseases 2024年第4期11卷 24-27页

作者： Seongho Cha Chongtae Kim Myeongwoo Jung Seungyeon Ryu Sukyoung Han Wook Kim Eun Kyung Lee department of Biochemistry Department of Biomedicine&Health SciencesCollege of MedicineThe Catholic University of KoreaSeoul 06591South Korea Catholic Institute for Visual Science College of MedicineThe Catholic University of KoreaSeoul 06591South Korea department of Molecular Science&Technology Ajou UniversitySuwon 16499South Korea

Dysfunction of pancreaticβcells caused by zinc deficiency is related to the pathogenesis of diabetes.1 Impaired zinc homeostasis in diabetes is associated with reduced zinc transporters.2 Down-regulation of HuD,an es... 详细信息

关键词： βcell homeostasis zinc

Osteoarthritis versus psoriasis arthritis: Physiopathology, cellular signaling, and therapeutic strategies

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Genes & Diseases 2024年第3期11卷 232-247页

作者： Salma Nassor Juma Junguang Liao Yuping Huang Rexhina Vlashi Qingwan Wang Bocong Wu Dan Wang Mengrui Wu Guiqian Chen College of Life Science and Medicine Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and BiomedicineZhejiang Sci-Tech UniversityHangzhouZhejiang 310018China department of Cell and Developmental Biology College of Life SciencesZhejiang UniversityHangzhouZhejiang 310058China

Osteoarthritis and psoriasis arthritis are two degenerative forms of arthritis that share similar yet also different manifestations at the histological,cellular,and clinical levels.Rheumatologists have marked them as two entirely distinct arthropathies.Given recent dis-coveries in disease initiation and progression,potential mechanisms,cellular signaling path-ways,and ongoing clinical therapeutics,there are now more opportunities for discovering osteoarthritis drugs.This review summarized the osteoarthritis and psoriasis arthritis signaling pathways,crosstalk between BMP,WNT,TGF-β,VEGF,TLR,and FGF signaling pathways,bio-markers,and anatomical pathologies.Through bench research,we demonstrated that regen-erative medicine is a promising alternative for treating osteoarthritis by highlighting significant scientific discoveries on entheses,multiple signaling blockers,and novel molecules such as immunoglobulin new antigen receptors targeted for potential drug evaluation.Furthermore,we offered valuable therapeutic approaches with a multidisciplinary strategy to treat patients with osteoarthritis or psoriasis arthritis in the coming future in the clinic.

关键词： Newantigen receptor Osteoarthritis Physiopathology Psoriasisarthritis Signaling pathway

Integration of multiple flexible electrodes for realtime detection of barrier formation with spatial resolution in a gut-on-chip system

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Microsystems & Nanoengineering 2024年第1期10卷 105-114页

作者： Mara Lucchetti Gabriel Werr Sofia Johansson Laurent Barbe Léa Grandmougin Paul Wilmes Maria Tenje Luxembourg Centre for Systems biomedicine(LCSB) University of LuxembourgEsch-sur-Alzette L-4362Luxembourg Division of Biomedical Engineering Department of Materials Science and EngineeringScience for Life LaboratoryUppsala University75121 UppsalaSweden department of Life Sciences and Medicine Faculty of ScienceTechnology and MedicineUniversity of LuxembourgEsch-sur-Alzette L-4362Luxembourg

In healthy individuals,the intestinal epithelium forms a tight barrier to prevent gut bacteria from reaching blood circulation.To study the effect of probiotics,dietary compounds and drugs on gut barrier formation and disruption,human gut epithelial and bacterial cells can be cocultured in an in vitro model called the human microbial crosstalk(HuMiX)gut-on-a-chip system.Here,we present the design,fabrication and integration of thin-film electrodes into the HuMiX platform to measure transepithelial electrical resistance(TEER)as a direct readout on barrier tightness in realtime.As various aspects of the HuMiX platform have already been set in their design,such as multiple compressible layers,uneven surfaces and nontransparent materials,a novel fabrication method was developed whereby thin-film metal electrodes were first deposited on flexible substrates and sequentially integrated with the HuMiX system via a transfer-tape approach.Moreover,to measure localized TEER along the cell culture chamber,we integrated multiple electrodes that were connected to an impedance analyzer via a multiplexer.We further developed a dynamic normalization method because the active measurement area depends on the measured TEER levels.The fabrication process and system setup can be applicable to other barrier-on-chip systems.As a proof-of-concept,we measured the barrier formation of a cancerous Caco-2 cell line in real-time,which was mapped at four spatially separated positions along the HuMiX culture area.

关键词： barrier system multiple