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Strategies that regulate LSD1 for novel therapeutics

Acta Pharmaceutica Sinica B 2024年第4期14卷 1494-1507页

作者： Meng Li Mengge Dai Bing Cheng Shaotong Li Enhui Guo Junwei Fu Ting Ma Bin Yu School of Pharmaceutical sciences&Key laboratory of advanced Drug Preparation Technologies Ministry of EducationZhengzhou UniversityZhengzhou 450001China College of Chemistry Zhengzhou UniversityZhengzhou 450001China tianjian laboratory of advanced biomedical sciences Institute of Advanced Biomedical SciencesZhengzhou UniversityZhengzhou 450000China Pingyuan laboratory State Key Laboratory of Antiviral DrugsHenan Normal UniversityXinxiang 453007China State Key laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Histone methylation plays crucial roles in regulating chromatin structure and gene transcrip-tion in epigenetic modifications.Lysine-specific demethylase 1(LSD1),the first identified histone de-methylase,is universally overexpressed in various diseases.LSD1 dysregulation is closely associated with cancer,viral infections,and neurodegenerative diseases,etc.,making it a promising therapeutic target.Several LSD1 inhibitors and two small-molecule degraders(UM171 and BEA-17)have entered the clinical stage.LSD1 can remove methyl groups from histone 3 at lysine 4 or lysine 9(H3K4 or H3K9),resulting in either transcription repression or activation.While the roles of LSD1 in transcrip-tional regulation are well-established,studies have revealed that LSDl can also be dynamically regulated by other factors.For example,the expression or activity of LSD1 can be regulated by many proteins that form transcriptional corepressor complexes with LSD1.Moreover,some post-transcriptional modifica-tions and cellular metabolites can also regulate LSD1 expression or its demethylase activity.Therefore,in this review,we will systematically summarize how proteins involved in the transcriptional corepressor complex,various post-translational modifications,and metabolites act as regulatory factors for LSD1 ac-tivity.

关键词： LSD1 regulation Transcription repression Transcription activation the Corepressor complex Post-transcriptional modifications Metabolites

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Increased long-distance and homo-trans interactions related to H3K27me3 in Arabidopsis hybrids

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Journal of Integrative Plant Biology 2024年第2期66卷 208-227页

作者： Zhaoxu Gao Yanning Su Le Chang Guanzhong Jiao Yang Ou Mei Yang Chao Xu Pengtao Liu Zejia Wang Zewen Qi Wenwen Liu Linhua Sun Guangming He Xing Wang Deng Hang He School of advanced Agriculture sciences and School of Life sciences State Key Laboratory of Protein and Plant Gene ResearchPeking UniversityBeijing 100871China College of Grassland Science Beijing Forestry UniversityBeijing 100083China Peking University Institute of advanced Agricultural sciences Shandong Laboratory of Advanced Agricultural Sciences in WeifangWeifang 261325China

In plants,the genome structure of hybrids changes compared with their parents,but the effects of these changes in hybrids remain elusive.Comparing reciprocal crosses between Col×C24 and C24×Col in Arabidopsis using high-throughput chromosome conformation capture assay(Hi-C)analysis,we found that hybrid three-dimensional(3D)chromatin organization had more long-distance interactions relative to parents,and this was mainly located in promoter regions and enriched in genes with heterosis-related pathways.The interactions between euchromatin and heterochromatin were increased,and the compartment strength decreased in hybrids.In compartment domain(CD)boundaries,the distal interactions were more in hybrids than their parents.In the hybrids of CURLY LEAF(clf)mutants clfCol×clfC24and clfC24×clfCol,the heterosis phenotype was damaged,and the long-distance interactions in hybrids were fewer than in their parents with lower H3K27me3.ChIP-seq data revealed higher levels of H3K27me3 in the region adjacent to the CD boundary and the same interactional homo-trans sites in the wild-type(WT)hybrids,which may have led to more long-distance interactions.In addition,the differentially expressed genes(DEGs)located in the boundaries of CDs and loop regions changed obviously in WT,and the functional enrichment for DEGs was different between WT and clf in the longdistance interactions and loop regions.Our findings may therefore propose a new epigenetic explanation of heterosis in the Arabidopsis hybrids and provide new insights into crop breeding and yield increase.

关键词： 3D chromatin organization H3K27me3 homo-trans hybrids long-distanceinteractions

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Rab18 maintains homeostasis of subcutaneous adipose tissue to prevent obesity-induced metabolic disorders

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Science China(Life sciences) 2024年第6期67卷 1170-1182页

作者： Jiaming Liu Liangkui Li Dijin Xu Yuqi Li Tao Chen Yeyang Liu Yuqian Bao Yan Wang Longyan Yang Peng Li Li Xu State Key laboratory of Membrane Biology and Tsinghua-Peking Center for Life sciences Beijing Advanced Innovation Center for Structural BiologySchool of Life SciencesTsinghua UniversityBeijing 100084China Shanghai Qi Zhi Institute Shanghai 200232China Shanghai Key laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China tianjian laboratory of advanced biomedical sciences Zhengzhou UniversityZhengzhou 450001China Department of Physiology School of Basic Medical SciencesGannan Medical UniversityGanzhou 341000China Department of Endocrinology and Metabolism Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s HospitalShanghai 200025China Center for Endocrine Metabolism and Immune Diseases Beijing Luhe HospitalCapital Medical UniversityBeijing 101149China Beijing Key laboratory of Diabetes Research and Care Beijing 101149China

Metabolically healthy obesity refers to obese individuals who do not develop metabolic disorders.These people store fat in subcutaneous adipose tissue(SAT)rather than in visceral adipose tissue(VAT).However,the molecules participating in this specific scenario remain elusive.Rab18,a lipid droplet(LD)-associated protein,mediates the contact between the endoplasmic reticulum(ER)and LDs to facilitate LD growth and maturation.In the present study,we show that the protein level of Rab18 is specifically upregulated in the SAT of obese people and mice.Rab18 adipocyte-specific knockout(Rab18 AKO)mice had a decreased volume ratio of SAT to VAT compared with wildtype mice.When subjected to high-fat diet(HFD),Rab18 AKO mice had increased ER stress and inflammation,reduced adiponectin,and decreased triacylglycerol(TAG)accumulation in SAT.In contrast,TAG accumulation in VAT,brown adipose tissue(BAT)or liver of Rab18AKO mice had a moderate increase without ER stress stimulation.Rab18 AKO mice developed insulin resistance and systematic inflammation.Rab18 AKO mice maintained body temperature in response to acute and chronic cold induction with a thermogenic SAT,similar to the counterpart mice.Furthermore,Rab18-deficient 3T3-L1 adipocytes were more prone to palmitate-induced ER stress,indicating the involvement of Rab18 in alleviating lipid toxicity.Rab18 AKO mice provide a good animal model to investigate metabolic disorders such as impaired SAT.In conclusion,our studies reveal that Rab18 is a key and specific regulator that maintains the proper functions of SAT by alleviating lipid-induced ER stress.

关键词： Rab18 subcutaneous adipose tissue(SAT) metabolically healthy obesity(MHO) lipotoxicity ER stress ectopic lipid storage LD-ER contact

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Tumor microenvironment-activatable neuropeptide-drug conjugates enhanced tumor penetration and inhibition via multiple delivery pathways and calcium deposition

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Chinese Chemical Letters 2024年第4期35卷 292-297页

作者： Yi Cao Xiaojiao Ge Yuanyuan Wei Lulu He Aiguo Wu Juan Li Ningbo Key laboratory of biomedical Imaging Probe Materials and Technology Zhejiang International Cooperation Base of Biomedical Materials Technology and ApplicationChinese Academy of Sciences(CAS)Key Laboratory of Magnetic Materials and DevicesNingbo Cixi Institute of Biomedical EngineeringZhejiang Engineering Research Center for Biomedical MaterialsNingbo Institute of Materials Technology and EngineeringChinese Academy of SciencesNingbo 315201China University of Chinese Academy of sciences Beijing 100049China advanced Energy Science and Technology Guangdong laboratory Huizhou 516000China

Peptide-drug conjugates have achieved considerable development and application as a novel strategy for targeted delivery of anticancer drugs. Bioactive peptides induced calcium deposition can irreversibly assist inhibition of tumors. However, active regulation of calcium level through signal transduction of bioactive substances has not been reported yet. In this study, novel neuropeptide-doxorubicin conjugates(NP-DOX) with lysosome-specific acid response were described for neuropeptide Y_1 receptor(Y_1R)-overexpressed triple-negative breast cancer. The delivery mechanism of NP-DOX was clarified that diverse pathways were involved, including intracellular and intercellular transport. Importantly, up-regulation of Y_1 R-mediated intracellular calcium level via second messenger inositol triphosphate was presented in NP-DOX treated MDA-MB-231 cells. In vivo antitumor efficacy demonstrated that NP-DOX showed less organ toxicity and enhanced tumor inhibition benefited from its controlled release and Y_1R-mediated calcium deposition, compared with free DOX. This bioconjugate is a proof-of-concept confirming that neuropeptide-mediated control of signaling responses in neuropeptide-drug conjugates enables great potential for further applications in tumor chemotherapy.

关键词： Neuropeptide-drug conjugate Tumor penetration Calcium deposition Tumor inhibition Triple-negative breast cancer

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Stable graphene oxide-based lyotropic liquid crystals for interfacial lubrication

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Friction 2024年第5期12卷 954-967页

作者： Yumei GUO Hanglin LI Jiusheng LI Xiangqiong ZENG laboratory for advanced Lubricating Materials Shanghai Advanced Research InstituteChinese Academy of SciencesShanghai201210China University of Chinese Academy of sciences Beijing100049China

Lyotropic liquid crystals have lubricating properties due to their ordered assembly and fluidity,whose mesogens are often characterized by amphiphilic properties.Despite the attention that graphene oxide(GO)has been studied as a novel amphiphilic lyotropic mesogen this decade,and GO applied as a lubrication additive has been demonstrated in both oil and water-based systems,little research reveals the interfacial lubrication of GO liquid crystals yet.This work reports that GO aqueous dispersion can form lyotropic liquid crystals above a specific critical concentration of 5.00 mg/mL,providing a form of stable water-based lubricant,which can keep stable for several months and can reduce friction by 37.3%and wear by 25.24%.The liquid crystal phase was verified by polarizing microscope and synchrotron radiation small-angle X-ray scattering,and its rheological properties and viscoelasticity were studied by interfacial rheometer.The formation of lyotropic liquid crystals can enhance the stability of GO aqueous dispersions at high density,simultaneously ensuring friction decrease and anti-wear effect.It is attributed to the stable nematic network by the ordered GO sheets.The ordered assembly structure bears vertical shear force,therefore,reducing the wear.It is also assumed that the wide lateral size of graphene oxide promotes the nematic phase thus smoothes the graphene oxide film composed spontaneously under the coincidence of lamellar liquid crystal and 2D layered material.Through this work,the interlayer lubrication of GO was optimized,and the problem of GO dispersion sedimentation was solved by self-assembly.The range of interfacial lubrication of GO aqueous dispersion has been expanded and the synergistic effect is conducive to the environmentally friendly lubricants.

关键词： lyotropic liquid crystal graphene oxide aqueous lubrication tribological behavior

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Protein translation:biological processes and therapeutic strategies for human diseases

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1048-1064页

作者： Xuechao Jia Xinyu He Chuntian Huang Jian Li Zigang Dong Kangdong Liu Department of Pathophysiology School of Basic Medical SciencesAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan 450000China China-US(Henan)Hormel Cancer Institute ZhengzhouHenan 450000China Department of Pathology and Pathophysiology Henan University of Chinese MedicineZhengzhouHenan 450000China tianjian laboratory of advanced biomedical sciences ZhengzhouHenan 450052China Research Center for Basic Medicine sciences Academy of Medical SciencesZhengzhou UniversityZhengzhou 450052 HenanChina Provincial Cooperative Innovation Center for Cancer Chemoprevention Zhengzhou UniversityZhengzhouHenan 450000China State Key laboratory of Esophageal Cancer Prevention and Treatment Zhengzhou UniversityZhengzhouHenan 450000China The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention ZhengzhouHenan 450000China

Protein translation is a tightly regulated cellular process that is essential for gene expression and protein synthesis.The deregulation of this process is increasingly recognized as a critical factor in the pathogenesis of various human diseases.In this review,we discuss how deregulated translation can lead to aberrant protein synthesis,altered cellular functions,and disease progression.We explore the key mechanisms contributing to the deregulation of protein translation,including functional alterations in translation factors,tRNA,mRNA,and ribosome function.Deregulated translation leads to abnormal protein expression,disrupted cellular signaling,and perturbed cellular functions-all of which contribute to disease pathogenesis.The development of ribosome profiling techniques along with mass spectrometry-based proteomics,mRNA sequencing and single-cell approaches have opened new avenues for detecting diseases related to translation errors.Importantly,we highlight recent advances in therapies targeting translation-related disorders and their potential applications in neurodegenerative diseases,cancer,infectious diseases,and cardiovascular diseases.Moreover,the growing interest lies in targeted therapies aimed at restoring precise control over translation in diseased cells is discussed.In conclusion,this comprehensive review underscores the critical role of protein translation in disease and its potential as a therapeutic target.Advancements in understanding the molecular mechanisms of protein translation deregulation,coupled with the development of targeted therapies,offer promising avenues for improving disease outcomes in various human diseases.Additionally,it will unlock doors to the possibility of precision medicine by offering personalized therapies and a deeper understanding of the molecular underpinnings of diseases in the future.

关键词： translation offering precise

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Ultrafast micro/nano-manufacturing of metastable materials for energy

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National Science Review 2024年第4期11卷 283-298页

作者： Xiaoya Cui Yanchang Liu Yanan Chen School of Materials Science and Engineering Key Laboratory of Advanced Ceramics and Machining Technology(Ministry of Education) and Tianjin Key Laboratory of Composite and Functional MaterialsTianjin University Ministry of Education Key laboratory of Protein sciences School of Life SciencesTsinghua University

The structural engineering of metastable nanomaterials with abundant defects has attracted much attention in energy-related fields. The high-temperature shock(HTS) technique, as a rapidly developing and advanced synthesis strategy, offers significant potential for the rational design and fabrication of high-quality nanocatalysts in an ultrafast, scalable, controllable and eco-friendly way. In this review, we provide an overview of various metastable micro-and nanomaterials synthesized via HTS, including single metallic and bimetallic nanostructures, high entropy alloys, metal compounds(e.g. metal oxides) and carbon nanomaterials. Note that HTS provides a new research dimension for nanostructures, i.e. kinetic modulation. Furthermore, we summarize the application of HTS—as supporting films for transmission electron microscopy grids—in the structural engineering of 2D materials, which is vital for the direct imaging of metastable materials. Finally, we discuss the potential future applications of high-throughput and liquid-phase HTS strategies for non-equilibrium micro/nano-manufacturing beyond energy-related fields.It is believed that this emerging research field will bring new opportunities to the development of nanoscience and nanotechnology in both fundamental and practical aspects.

关键词： high-temperature shock technique defect engineering metastable phase kinetic modulation non-equilibrium micro/nano-manufacturing

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The dynamic surface evolution of halide perovskites induced by external energy stimulation

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National Science Review 2024年第4期11卷 185-194页

作者： Feiyu Cheng Pengdong Wang Chenzhe Xu Qingliang Liao Suicai Zhang Haochun Sun Wenqiang Fan Guodong Liu Zhiyun Li Yaping Kong Li Wang Fangsen Li Zhuo Kang Yue Zhang Academy for advanced Interdisciplinary Science and Technology State Key Laboratory for Advanced Metals and Materials University of Science and Technology Beijing Beijing Key laboratory for advanced Energy Materials and Technologies Key Laboratory of Advanced Materials and Devices for Post-Moore ChipsMinistry of EducationBeijing Advanced Innovation Center for Materials Genome Engineering School of Materials Science and EngineeringUniversity of Science and Technology Beijing Vacuum Interconnected Nanotech Workstation(Nano-X) Suzhou Institute of Nano-Tech and Nano-BionicsChinese Academy of Sciences Beijing National laboratory for Condensed Matter Physics Institute of Physics Chinese Academy of Sciences

Tracking the dynamic surface evolution of metal halide perovskite is crucial for understanding the corresponding fundamental principles of photoelectric properties and intrinsic instability. However, due to the volatility elements and soft lattice nature of perovskites, several important dynamic behaviors remain unclear. Here, an ultra-high vacuum（UHV） interconnection system integrated by surface-sensitive probing techniques has been developed to investigate the freshly cleaved surface of CH3NH3PbBr3in situ under given energy stimulation. On this basis, the detailed three-step chemical decomposition pathway of perovskites has been clarified. Meanwhile, the evolution of crystal structure from cubic phase to tetragonal phase on the perovskite surface has been revealed under energy stimulation. Accompanied by chemical composition and crystal structure evolution, electronic structure changes including energy level position,hole effective mass, and Rashba splitting have also been accurately determined. These findings provide a clear perspective on the physical origin of optoelectronic properties and the decomposition mechanism of perovskites.

关键词： metal halide perovskite external energy stimulation surface dynamic evolution surface electronic structure ultra-high vacuum interconnection system

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Amino acids in piglet diarrhea: Effects, mechanisms and insights

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Animal Nutrition 2024年第1期16卷 267-274页

作者： Xihong Zhou Jing Liang Xia Xiong Yulong Yin Key laboratory of Agro-ecological Processes in Subtropical Region Institute of Subtropical Agriculture The Chinese Academy of Sciences College of advanced Agricultural sciences University of Chinese Academy of Sciences

Piglet diarrhea is among one of the most serious health problems faced by the pig industry, resulting in significant economic losses. Diarrheal disease in piglets has a multifactorial etiology that is affected by physiology, environment, and management strategy. Diarrhea is the most apparent symptom of intestinal dysfunction. As a key class of essential nutrients in the piglet diet, amino acids confer a variety of beneficial effects on piglets in addition to being used as a substrate for protein synthesis, including maintaining appropriate intestinal integrity, permeability and epithelial renewal, and alleviating morphological damage and inflammatory and oxidative stress. Thus, provision of appropriate levels of amino acids could alleviate piglet diarrhea. Most amino acid effects are mediated by metabolites, gut microbes, and related signaling pathways. In this review, we summarize the current understanding of dietary amino acid effects on gut health and diarrhea incidence in piglets, and reveal the mechanisms involved. We also provide ideas for using amino acid blends and emphasize the importance of amino acid balance in the diet to prevent diarrhea in piglets.

关键词： Piglet Amino acid Diarrhea Gut microbe Immune

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Recent advances in small-scale hydrogel-based robots for adaptive biomedical applications

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Nano Research 2024年第2期17卷 649-662页

作者： Mingzhe Nie Qilong Zhao Xuemin Du Institute of biomedical&Health Engineering Shenzhen Institute of Advanced Technology(SIAT)Chinese Academy of Sciences(CAS)Shenzhen 518055China

Small-scale robots,ranging in size from micrometers to centimeters,have gained significant attention in the biomedical field.However,conventional small-scale robots made of rigid materials encounter challenges in adapting themselves to the soft tissues and complicated environments of human body.Compared to the rigid counterpart,small-scale hydrogel-based robots hold great promises due to their tissue-like low modulus,outstanding biocompatibility and accessible stimuli-responsive capabilities.These attributes offer small-scale hydrogel-based robots with multimodal locomotion and reinforced functions,further enhancing the adaptability in manipulation and tasks execution for various biomedical applications.In this review,we present recent advances in small-scale hydrogel-based robots.We first summarize the design principles of small-scale hydrogel-based robots including materials,fabrication techniques and manipulation strategies,then highlighting their upgraded functions and adaptive biomedical applications.Finally,we discuss existing challenges and future perspectives for small-scale hydrogel-based robots.

关键词： small-scale robot hydrogel locomotion multi-function adaptability

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