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Decoding the intracellular trafficking rule for circular RNAs

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science China Life sciences 2024年

作者： Jiao Li Xiaojuan Yang Yong Peng center for molecular Oncology Frontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University

Circular RNAs (circRNAs) are endogenous single-stranded RNAs with a covalently closed loop generated from‘backsplicing’of precursor mRNA (pre-mRNA)in the *** evidence emphasizes their significance in cellular homeostasis by serving as miRNA sponges,scaffolds for biomolecules,or templates for *** dysregulation has been implicated in human diseases,and clinical trials of circRNAs as potential biomarkers or therapeutic agents are ongoing.

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PEG400-mediated nanocarriers improve the delivery and therapeutic efficiency of mRNA tumor vaccines

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Chinese Chemical Letters 2024年第5期35卷 314-319页

作者： Wen Xiao Fazhan Wang Yangzhuo Gu Xi He Na Fan Qian Zheng Shugang Qin Zhongshan He Yuquan Wei Xiangrong Song Department of Critical Care Medicine Frontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Medical Research center The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450000China

Dendritic cell(DC)-targeted delivery of mRNA is a prominent method to boost the efficacy of mRNA tumor *** targeting ligands are often modified on nanocarriers by polyethylene glycol(PEG)linker in mRNA delivery *** the PEG linker length influences the targeting delivery efficiency of mRNA nanocarrier in vivo remains ***,we designed and constructed DC-targeted mRNA delivery systems modified by mannose via different PEG linker lengths(100/400/1000/2000)(MPn-LPX).The top candidate MP_(400)-LPX(the linker was PEG400)showed the optimal mRNA expression and antigen presentation owing to the highly efficient uptake by ***,MP_(400)-LPX could better inhibited tumor growth and extended survival in the E.G7-OVA lymphoma and TC-1 cervical tumor mouse ***,these results demonstrated that PEG400 was the optimal linker for the PEGylated DC-targeted mRNA *** findings provided a new platform for the rational design of targeted mRNA nanovaccines with shorter-length PEG.

关键词： Cancer immunotherapy mRNA vaccines DC-targeted delivery PEGylated liposomes Cellular uptake

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A novel structural variant of RET causes familial Hirschsprung's disease via nonsense-mediated mRNA decay

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Genes & diseases 2024年第1期11卷 7-10页

作者： Qi Wang Siyu Pu Bo Xiang Jing Chen Department of Pediatric Surgery and Laboratory of Pediatric Surgery Rare Diseases CenterInstitute of Immunology and InflammationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduSichuan 610041China

Hirschsprung's disease(HsCR)is the most common type of developmental gastrointestinal malformation causing intestinal obstruction in children,with an incidence of 1/5000 in live births.1 it is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the distal gastrointestinal tract,leading to the dysregulation of smooth muscle contraction/relaxation and resulting in intestinal *** on the length of the aganglionic intestine,HSCR can be categorized into short-segmental HSCR(S-HSCR),which affects up to the sigmoid colon from the anus,and long-segmental HSCR(LHSCR),which affects beyond the sigmoid colon.1 In some rare conditions,aganglionic lesions can affect the full length of the colon or even the whole intestine.

关键词： intestine colon relaxation

A novel deep generative model for mRNA vaccine development: Designing 5′ UTRs with N1-methyl-pseudouridine modification

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1814-1826页

作者： Xiaoshan Tang Miaozhe Huo Yuting Chen Hai Huang Shugang Qin Jiaqi Luo Zeyi Qin Xin Jiang Yongmei Liu Xing Duan Ruohan Wang Lingxi Chen Hao Li Na Fan Zhongshan He Xi He Bairong Shen Shuai Cheng Li Xiangrong Song Institute of Systems Genetics Department of Critical Care MedicineFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610000China Department of Computer science City University of Hong KongHong Kong 99907China Department of Biology Brandeis UniversityBostonMA 02453USA

Efficient translation mediated by the 5'untranslated region(5'UTR)is essential for the robust efficacy of mRNA ***,the N1-methyl-pseudouridine(m1)modification of mRNA can impact the translation efficiency of the 5'*** discovered that the optimal 5'UTR for m1y-modified mRNA(m1y-5'UTR)differs significantly from its unmodified counterpart,high-lighting the need for a specialized tool for designing mly-5'UTRs rather than directly utilizing high-expression endogenous gene 5'*** response,we developed a novel machine learning-based tool,Smart5UTR,which employs a deep generative model to identify superior m1y-5'UTRs in *** tailored loss function and network architecture enable Smart5UTR to overcome limitations inherent in existing *** a result,Smart5UTR can successfully design superior 5'UTRs,greatly benefiting mRNA vaccine ***,Smart5UTR-designed superior 5'UTRs significantly enhanced antibody titers induced by COVID-19 mRNA vaccines against the Delta and Omicron variants of SARS-CoV-2,surpassing the performance of vaccines using high-expression endogenous gene 5'UTRs.

关键词： mRNA vaccine Machine learning 5'UTR mRNA design Sequence design N1-Methyl-pseudouridine COVID-19 SARS-CoV-2

A nonenzymatic electrochemical sensor for the detection of hydrogen peroxide in vitro and in vivo fibrosis models

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Chinese Chemical Letters 2024年第3期35卷 394-398页

作者： Hongyao Liu Yan Yu Taixiong Xue Cailing Gan Yuting Xie Doudou Wang Peilin Li Zhiyong Qian Tinghong Ye Department of Gastroenterology and Hepatology Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer and Frontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Fibrosis occurs due to the excessive deposition of extracellular matrix caused by cell *** various types of tissue injury,the dysregulation of the internal response can eventually lead to the destruction of organ structure and *** is increasing evidence that oxidative stress,which is characterized by excessive production of hydrogen peroxide(H_(2)O_(2)),is an important cause of ***,we synthesized a biosensitive and efficient electrochemical H_(2)O_(2)sensor based on PtNi nanoparticle-doped N-reduced graphene oxide(PtNi-N-rGO)to detect H_(2)O_(2)released from transforming growth factorβ1(TGFβ1)-induced *** addition,the sensor could easily detect changes in H_(2)O_(2)in the lung and bronchoalveolar lavage fluid(BALF)of mice with pulmonary ***,the sensor could also detect H_(2)O_(2)in activated hepatic stellate cells and the liver of carbon tetrachloride(CCl_(4))-induced liver ***,the alterations in H_(2)O_(2)detected by the sensor were consistent with nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)protein expression and the staining results of pathological *** together,these results highlight the use of H_(2)O_(2)sensors for the rapid detection of fibrosis and facilitate the rapid evaluation of antifibrotic drug candidates.

关键词： Fibrosis H_(2)O_(2) Electrochemical sensor NOX4 Nintedanib

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Dendritic nanomedicine enhances chemoimmunotherapy by disturbing metabolism of cancer-associated fibroblasts for deep penetration and activating function of immune cells

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3680-3696页

作者： Yunkun Li Xiaoding Shen Haitao Ding Yuxin Zhang Dayi Pan Liping Su Yahui Wu Zaixiang Fang Jie Zhoua Qiyong Gong Kui Luo Department of Radiology Huaxi MR Research Center(HMRRC)Frontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Functional and molecular Imaging key Laboratory of Sichuan Province and Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu 610041China Department of Radiology West China Xiamen Hospital of Sichuan UniversityXiamen 361021China

Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune ***,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)*** cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen ***,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating *** a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.

关键词： Dendritic prodrug Enhanced penetration Metabolic intervention Cancer-associated fibroblasts Immunogenic cell death Chemotherapy Immunotherapy Immune microenvironment reconstitution

Expanding the horizons of targeted protein degradation:A non-small molecule perspective

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2402-2427页

作者： Xiaowei Huang Fengbo Wu Jing Ye Lian Wang Xiaoyun Wang Xiang Li Gu He Department of Pharmacy and Department of Dermatology&Venerology West China HospitalSichuan UniversityChengdu 610041China Department of Urology West China HospitalSichuan UniversityChengdu 610041China Laboratory of Dermatology Clinical Institute of Inflammation and ImmunologyFrontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Targeted protein degradation(TPD)represented by proteolysis targeting chimeras(PROTACs)marks a significant stride in drug discovery.A plethora of innovative technologies inspired by PROTAC have not only revolutionized the landscape of TPD but have the potential to unlock functionalities beyond ***-small-molecule-based approaches play an irreplaceable role in this field.A wide variety of agents spanning a broad chemical spectrum,including peptides,nucleic acids,antibodies,and even vaccines,which not only prove instrumental in overcoming the constraints of conventional small molecule entities but also provided rapidly renewing *** we summarize the burgeoning non-small molecule technological platforms inspired by PROTACs,including three major trajectories,to provide insights for the design strategies based on novel paradigms.

关键词： Targeted protein degradation Proteolysis targeting chimera Endocytosis Autophagy Proximity-inducing modality Post-translational modification

Deep simulated annealing for the discovery of novel dental anesthetics with local anesthesia and anti-inflammatory properties

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3086-3109页

作者： Yihang Hao Haofan Wang Xianggen Liu Wenrui Gai Shilong Hu Wencheng Liu Zhuang Miao Yu Gan Xianghua Yu Rongjia Shi Yongzhen Tan Ting Kang Ao Hai Yi Zhao Yihang Fu Yaling Tang Ling Ye Jin Liu Xinhua Liang Bowen Ke State key Laboratory of Oral diseases and National Clinical Research center for Oral diseases West China Hospital of StomatologySichuan UniversityChengdu 610041China College of Computer science Sichuan UniversityChengdu 610065China Department of Anesthesiology Laboratory of Anesthesia and Critical Care MedicineNational-Local Joint Engineering Research Centre of Translational Medicine of AnesthesiologyFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengdu 610041China

Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic *** primary challenge is to integrate diverse pharmacophores within a single-molecule *** address this,we introduced DeepSA,a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine,a wellknown local *** integrates deep neural networks into metaheuristics,effectively constraining molecular space during compound *** framework employs a sophisticated objective function that accounts for scaffold preservation,anti-inflammatory properties,and covalent *** a sequence of local editing to navigate the molecular space,DeepSA successfully identified AT-17,a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal *** insights into AT-17 revealed its dual mode of action:selective inhibition of NaV1.7 and 1.8 channels,contributing to its prolonged local anesthetic effects,and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome *** findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery,particularly within stringent chemical constraints.

关键词： Multifunctional drugs Deep simulated annealing Molecule generation Articaine derivatives AI-enhanced drug discovery

Intracellular redox potential-driven live-cell synthesis of CdSe quantum dots in Staphylococcus aureus

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science China Chemistry 2024年第3期67卷 990-999页

作者： Cai-Qin Wu An-An Liu Xu Li Jia-Wei Tu Juan Kong Ling-Ling Yang Jian-Hong Jia Chuan Wang Bin Hu Zhi-Xiong Xie Dai-Wen Pang The Institute for Advanced Studies College of Chemistry and Molecular SciencesCollege of Life SciencesHubei Key Laboratory of Cell HomeostasisWuhan UniversityWuhan 430072China Research center for Analytical sciences College of ChemistryState Key Laboratory of Medicinal Chemical BiologyTianjin Key Laboratory of Biosensing and Molecular RecognitionFrontiers Science Center for New Organic MatterFrontiers Science Center for Cell Responsesand Haihe Laboratory of Sustainable Chemical TransformationsNankai UniversityTianjin 300071China

Biosynthesized semiconductor quantum dots(QDs) have bright fluorescence,adjustable particle sizes,and environmental friendliness,endowing them with convenience and potential for biological *** to the unclear mechanism of the cellular environment on the live-cell synthesis of QDs,it is still difficult to regulate their optical ***,the critical role of the intracellular redox environment in regulating the fluorescence properties of biosynthesized CdSe QDs in Staphylococcus aureus(***) has been *** glutathione peroxidase(GPx) activity directly affects the intracellular H_(2)O_(2) produced in the SeO_(3)^(2-) reduction,which further manipulates the glutathione redox cycle to determine the content of low-valence *** a result,the fluorescence intensity of the synthesized CdSe QDs increases by 60% in the GPx overexpressed *** cellular redox potential that is controlled by the GSH redox cycle provides the driving force for the reduction of SeO_(3)^(2-),facilitating the synthesis of CdSe QDs in *** *** proposed mechanism of the cellular redox state provides a new perspective for regulating the synthesis of semiconductor nanomaterials in live cells.

关键词： redox H_(2)O_(2) peroxidase quantum dot Staphylococcus aureus

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