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Cationic polymeric nanoformulation: Recent advances in material design for CRISPR/Cas9 gene therapy

Progress in Natural Science:Materials International 2019年第6期29卷 617-627页

作者： Kaifeng Chen Shan Jiang Yun Hong Zibiao Li Yunlong Wu Caisheng Wu fujian provincial key laboratory of innovative drug target research State Key Laboratory of Cellular Stress Biology School of Pharmaceutical Sciences Xiamen University Institute of Materials research and Engineering Agency for Science Technology and Research

CRISPR/Cas9(clustered regularly interspaced short palindromic repeat/clustered regularly interspaced short palindromic repeat associated proteins 9) gene editing platform is a promising therapeutic tool for genetic disorders, due to its ability to manipulate the pathogenic gene in genomic level and to easily target specific gene by manipulating single-guide RNA. However, its successful delivery remains a challenge. Up to now, great efforts have been made to explore an effective strategy for CRISPR/Cas9 delivery. But among those delivery methods,physical methods are mainly operated on cultured cells thus limited to laboratorial use; viral vectors are hindered by fetal immunogenic and carcinogenic effects thus dubious in clinical application. Therefore, cationic polymeric vectors, with the ability to interact with CRISPR/Cas9 system to form a nanoformulation as a nonviral approach, are attracting increasing attentions, due to advantages such as well protection of cargos, less limitation in payload size, low immunogenicity or carcinogenicity, potential modifications for further functions,and ease in mass production. In this review, the recent discoveries on polymeric vectors utilized in delivery of CRISPR/Cas9 system will be summarized. With emphasis on advanced features of those polymeric vectors or their nanoformulations to meet the demands of different CRISPR/Cas9 delivery forms(plasmid, m RNA or protein), the detailed illustrations on their disease treatment applications, such as cancer, diabetes or antibioticresistant infections, will also be reviewed.

关键词： CRISPR/Cas9 Polymeric vectors Gene therapy Gene delivery Cancer therapy

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The synthesis of PROTAC molecule and new target KAT6A identification of CDK9 inhibitor i CDK9

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Chinese Chemical Letters 2023年第4期34卷 216-221页

作者： Mingtao Ao Jun Wu Yin Cao Yaohui He Yuxiang Zhang Xiang Gao Yuhua Xue Meijuan Fang Zhen Wu Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology School of Pharmaceutical SciencesXiamen UniversityXiamen 361102China School of Pharmacy Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei ProvinceHubei University of Science and TechnologyXianning 437100China

Cyclin-dependent kinases(CDKs) have become potential targets for treating various diseases, especially cancer. Compound i CDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential toxicity and poor understanding of the underlying mechanism. The PROTAC(proteolysis targeting chimera) degraders of bioactive molecules can significantly induce in vitro and in vivo degradation of their target protein with high selectivity and effectively reduce the dose-limiting toxicity of small molecule drugs. Therefore, we designed and synthesized the bifunctional PROTAC molecules of i CDK9, being used for identifying its previously unknown target and revealing the underlying pharmacological mechanism.The PROTAC bifunctional molecule CD-5 could selectively and significantly degrade CDK9 with low cell toxicity. Therefore, we selected CD-5 as a chemical prober in the SILAC quantitative proteomic analysis, which disclosed that CD-5 could enormously lessen the lysine acetyltransferase KAT6A. Furthermore,KAT6A degradation induced by CD-5 repressed the levels of H3K14Ac and H3K23Ac. Lastly, the streptavidin immunoprecipitation(IP) assay confirmed a direct interaction between KAT6A and i CDK9. Collectively, our results uncover that KAT6A is a potential non-kinase target of i CDK9. Notably, this study also demonstrates that the PROTAC-SILAC strategy is an alternative approach for cellular target identification of bioactive molecules.

关键词： PROTAC SILAC iCDK9 KAT6A target identification

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Recent advances in non-toxic quantum dots and their biomedical applications

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Progress in Natural Science:Materials International 2019年第6期29卷 628-640页

作者： Chunyan Zhu Zhao Chen Shuai Gao Ban Leng Goh Ismail Bin Samsudin Kai Wen Lwe Yunlong Wu Caisheng Wu Xiaodi Su Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology School of Pharmaceutical Sciences Xiamen University Department of Chemistry National University of Singapore Institute of Materials research and Engineering Agency for Science Technology and Research

Quantum dots(QDs) with unique quantum confinement effect and electro-optical properties are attractive for biomedical applications. Toxic effects of traditional semiconductor QDs made of heavy metal ions have serious safety concerns for their undesired environmental or healthy impact. Recent reports on core-shell structure modification of QDs by using biocompatible ligands or polymers is one way to be effectively minimizing toxicity effects of traditional QDs. Furthermore, designs of heave metal-free and metal-free QDs formulations are more promising alternatives, due to the non-toxic and eco-friendly nature of the starting materials. In article, we will review the recent designs of non-toxic or less toxic QDs, including carbon-based, biomolecules-based, siliconbased, and ternary I-III-VI QDs, and their biological applications(bio-imaging, drug delivery, gene therapy and immunoassay).

关键词： Quantum dots Non-toxic Bio-imaging Core-shell Metal-free

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DDB1 prepares brown adipocytes for cold-induced thermogenesis

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Life Metabolism 2022年第1期1卷 39-53页

作者： Xu Wang Shen-Ying Liu Guo-Sheng Hu Hao-Yan Wang Guo-Liang Zhang Xiang Cen Si-Ting Xiang Wen Liu Peng Li Haobin Ye Tong-Jin Zhao state key laboratory of Genetic Engineering Shanghai Key Laboratory of Metabolic Remodeling and HealthInstitute of Metabolism and Integrative BiologyZhongshan HospitalFudan UniversityShanghaiChina Shanghai Qi Zhi Institute ShanghaiChina School of Pharmaceutical Sciences Fujian Provincial Key Laboratory of Innovative Drug Target ResearchXiamen UniversityXiamenFujianChina state key laboratory of cellular stress biology School of Life SciencesXiamen UniversityXiamenFujianChina state key laboratory of Membrane biology and Tsinghua-Peking Center for Life Sciences School of Life SciencesTsinghua UniversityBeijingChina

Brown adipose tissue(BAT)plays a key role in thermogenesis during acute cold exposure.However,it remains unclear how BAT is prepared to rapidly turn on thermogenic genes.Here,we show that damage-specific DNA binding protein 1(DDB1)mediates the rapid transcription of thermogenic genes upon acute cold exposure.Adipose-or BAT-specific Ddb1 knockout mice show severely whitened BAT and significantly decreased expression of thermogenic genes.These mice develop hypothermia when subjected to acute cold exposure at 4℃ and partial lipodystrophy on a high-fat diet due to deficiency in fatty acid oxidation.Mechanistically,DDB1 binds the promoters of Ucp1 and Ppargc1a and recruits positive transcriptional elongation factor b(P-TEFb)to release promoter-proximally paused RNA polymerase II(Pol II),thereby enabling rapid and synchronized transcription of thermogenic genes upon acute cold exposure.Our findings have thus provided a regulatory mechanism of how BAT is prepared to respond to acute cold challenge.

关键词： brown adipose tissue thermogenesis DDB1 RNA polymerase II promoter-proximal pausing UCP1 PGC1α

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The role of tyrosine phosphatase Shp2 in spermatogonial differentiation and spermatocyte meiosis

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Asian Journal of Andrology 2020年第1期22卷 79-87页

作者： Yang Li Wen-Sheng Liu Jia Yi Shuang-Bo Kong Jian-Cheng Ding Yi-Nan Zhao Ying-Pu Tian Gen-Sheng Feng Chao-Jun Li Wen Liu Hai-Bin Wang Zhong-Xian Lu School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress BiologyXiamen UniversityXiamen 361005China fujian provincial key laboratory of Reproductive Health research Medical College of Xiamen UniversityXiamen 361005China fujian provincial key laboratory of innovative drug target research School of Pharmaceutical SciencesXiamen 361005China Department of Pathology Division of Biological SciencesUniversity of California at San DiegoLa JollaCA 92093USA Ministry of Education key laboratory of Model Animals for Disease Study Model Animal Research Center and Medical School of Nanjing UniversityNational Resource Center for Mutant MiceNanjing 210061China

The transition from spermatogonia to spermatocytes and the initiation of meiosis are key steps in spermatogenesis and are precisely regulated by a plethora of proteins.However,the underlying molecular mechanism remains largely unknown.Here,we report that Src homology domain tyrosine phosphatase 2(Shp2;encoded by the protein tyrosine phosphatase,nonreceptor type 11[Ptpn11]gene)is abundant in spermatogonia but markedly decreases in meiotic spermatocytes.Conditional knockout of Shp2 in spermatogonia in mice using stimulated by retinoic acid gene 8(Stra8)-cre enhanced spermatogonial differentiation and disturbed the meiotic process.Depletion of Shp2 in spermatogonia caused many meiotic spermatocytes to die;moreover,the surviving spermatocytes reached the leptotene stage early at postnatal day 9(PN9)and the pachytene stage at PN11-13.In preleptotene spermatocytes,Shp2 deletion disrupted the expression of meiotic genes,such as disrupted meiotic cDNA 1(Dmc1),DNA repair recombinase rad51(Rad51),and structural maintenance of chromosome 3(Smc3),and these deficiencies interrupted spermatocyte meiosis.In GC-1 cells cultured in vitro,Shp2 knockdown suppressed the retinoic acid(RA)-induced phosphorylation of extracellular-regulated protein kinase(Erk)and protein kinase B(Akt/PKB)and the expression of target genes such as synaptonemal complex protein 3(Sycp3)and Dmc1.Together,these data suggest that Shp2 plays a crucial role in spermatogenesis by governing the transition from spermatogonia to spermatocytes and by mediating meiotic progression through regulating gene transcription,thus providing a potential treatment target for male infertility.

关键词： cell differentiation gene expression spermatogenesis transgenic mouse

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Poly（ADP-ribosylation） of P-TEFb disrupts phase separation to inhibit global transcription upon genotoxic stress

Poly（ADP-ribosylation） of P-TEFb disrupts phase separation...

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2021年全国生物相分离和相变学术研讨会

作者： Huanyi Fu Rongdiao Liu Ran Li Zixuan Jia Feifeng Zhu Wenxuan Zhu Yangqing Shao Yiyang Jin Yuhua Xue Kunxin Luo Xiang Gao Huasong Lu Qiang Zhou Life Sciences Institute Zhejiang University state key laboratory of cellular stress biology and fujian provincial key laboratory of innovative drug target research School of Pharmaceutical SciencesXiamen University Department of Molecular and Cell biology University of California

DNA damage is known to trigger a genome-wide transcriptional shutdown to prevent transcriptional mutagenesis and to initiate repair signaling,but the mechanism to stall elongating RNA polymerase（Pol） Ⅱ,especially by the less bulky DNA lesions,is not fully understood.At the center of the DNA damage response（DDR）,a complex network of pathways for maintaining genomic integrity,lies the Poly（ADP-ribose）（PAR） polymerase 1（PARP1） that initiates DNA repair by translocating to the lesions,where it catalyzes covalent attachment of the PAR polymers to its substrates.Here,we report the identification of an essential function of PARP1 in inhibiting Pol Ⅱelongation through inactivating the key transcription elongation factor P-TEFb,a heterodimer of CDK9 and cyclin T1（CycT1）.Upon sensing DNA damage,which produces global transcriptional changes resembling those caused by direct CDK9 inhibition,the activated PARP1 binds to transcriptionally engaged P-TEFb and modifies CycT1 at multiple positions,including histidines that are rarely used as an acceptor site,in and around the histidine-rich domain（HRD）.This prevents CycT1 from undergoing liquid-liquid phase separation that is required for CDK9 to hyperphosphorylate Pol Ⅱ and stimulate transcriptional elongation.Functionally,the PARP1 modification of CycT1 is shown to promote DNA repair and cell survival.Thus,the PARP1-P-TEFb axis plays a protective role in transcription quality control and maintenance of genomic stability in response to genotoxic stress.

关键词： Phase separation DNA damage Transcription elongation ADP-ribosylation

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Deep proteome profiling promotes whole proteome characterization and drug discovery for esophageal squamous cell carcinoma

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Cancer biology & Medicine 2022年第3期19卷 273-277页

作者： Wei Liu Yongping Cui Wen Liu Zhihua Liu Liyan Xu Enmin Li College of Science Heilongjiang Institute of TechnologyHarbin 150050China Guangdong provincial key laboratory of Infectious Diseases and Molecular Immunopathology the Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantou 515041China Department of Pathology Key Laboratory of Cellular Physiology(Shanxi Medical University)Ministry of EducationTaiyuan 030001China fujian provincial key laboratory of innovative drug target research School of Pharmaceutical SciencesXiamen UniversityXiamen 361005China state key Lab of Molecular Oncology National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Proteins are key players in various cellular processes.As the ultimate executors of cellular processes,they play essential roles in linking genotypes to phenotypes.Abnormalities in protein expression and post-translational modifications(PTMs)are closely associated with the initiation and development of cancer,and they carry biological information inaccessible to genomics and transcriptomics1.Proteomics complements genomic and transcriptomic data,thus enabling comprehensive analysis of cancer pathogenesis and accelerating biomedical research2.

关键词： esophageal linking carry

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Identifying potential anti-COVID-19 pharmacological components of traditional Chinese medicine Lianhuaqingwen capsule based on human exposure and ACE2 biochromatography screening

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Acta Pharmaceutica Sinica B 2021年第1期11卷 222-236页

作者： Xiaofei Chen Yunlong Wu Chun Chen Yanqiu Gu Chunyan Zhu Suping Wang Jiayun Chen Lei Zhang Lei Lv Guoqing Zhang Yongfang Yuan Yifeng Chai Mingshe Zhu Caisheng Wu School of Pharmacy Naval Medical UniversityShanghai 200433China Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology School of Pharmaceutical SciencesXiamen UniversityXiamen 361102China Department of Pharmacy Shanghai Ninth People’s HospitalShanghai Jiao Tong UniversityShanghai 201999China Department of Pharmacy Shanghai Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghai 200438China MassDefect Technologies PrincetonNJ 08540USA

Lianhuaqingwen(LHQW)capsule,a herb medicine product,has been clinically proved to be effective in coronavirus disease 2019(COVID-19)pneumonia treatment.However,human exposure to LHQW components and their pharmacological effects remain largely unknown.Hence,this study aimed to determine human exposure to LHQW components and their anti-COVID-19 pharmacological activities.Analysis of LHQW component profiles in human plasma and urine after repeated therapeutic dosing was conducted using a combination of HRMS and an untargeted data-mining approach,leading to detection of 132 LHQW prototype and metabolite components,which were absorbed via the gastrointestinal tract and formed via biotransformation in human,respectively.Together with data from screening by comprehensive 2 D angiotensin-converting enzyme 2(ACE2)biochromatography,8 components in LHQW that were exposed to human and had potential ACE2 targeting ability were identified for further pharmacodynamic evaluation.Results show that rhein,forsythoside A,forsythoside I,neochlorogenic acid and its isomers exhibited high inhibitory effect on ACE2.For the first time,this study provides chemical and biochemical evidence for exploring molecular mechanisms of therapeutic effects of LHQW capsule for the treatment of COVID-19 patients based on the components exposed to human.It also demonstrates the utility of the human exposure-based approach to identify pharmaceutically active components in Chinese herb medicines.

关键词： Lianhuaqingwen capsule PATBS COVID-19 ACE2 Biochromatography Comprehensive 2D analysis In vivo exposure Surface plasma response Molecular docking

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Effectiveness of an ocular adhesive polyhedral oligomeric silsesquioxane hybrid thermo-responsive FK506 hydrogel in a murine model of dry eye

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Bioactive Materials 2022年第3期7卷 77-91页

作者： Yi Han Lu Jiang Huihui Shi Chenfang Xu Minting Liu Qingjian Li Lan Zheng Hong Chi Mingyue Wang Zuguo Liu Mingliang You Xian Jun Loh Yun-Long Wu Zibiao Li Cheng Li fujian provincial key laboratory of Ophthalmology and Visual Science&Ocular Surface and Corneal Diseases Eye Institute&Affiliated Xiamen Eye CenterSchool of MedicineXiamen UniversityXiamen361102China Institute of Materials research and Engineering A*STAR(Agency for ScienceTechnology and Research)Singapore138634Singapore School of Chemical Sciences University of Chinese Academy of ScienceBeijing100049China key laboratory of Marine Materials and Related Technologies Zhejiang Key Laboratory of Marine Materials and Protective TechnologiesNingbo Institute of Material Technology and EngineeringChinese Academy of ScienceNingbo315201China Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology School of Pharmaceutical SciencesXiamen UniversityXiamen361102China Hangzhou Cancer Institute Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang ProvinceAffiliated Hangzhou Cancer HospitalZhejiang University School of MedicineHangzhou310002China Shandong provincial key laboratory of Molecular Engineering School of Chemistry and Pharmaceutical EngineeringQilu University of Technology(Shandong Academy of Sciences)Jinan250353China Department of Materials Science and Engineering National University of SingaporeSingapore117575Singapore

Dry eye is a common ocular disease that results in discomfort and impaired vision,impacting an individual’s quality of life.A great number of drugs administered in eye drops to treat dry eye are poorly soluble in water and are rapidly eliminated from the ocular surface,which limits their therapeutic effects.Therefore,it is imperative to design a novel drug delivery system that not only improves the water solubility of the drug but also prolongs its retention time on the ocular surface.Herein,we develop a copolymer from mono-functional POSS,PEG,and PPG(MPOSS-PEG-PPG,MPEP)that exhibits temperature-sensitive sol-gel transition behavior.This thermo-responsive hydrogel improves the water solubility of FK506 and simultaneously provides a mucoadhesive,long-acting ocular delivery system.In addition,the FK506-loaded POSS hydrogel possesses good biocompatibility and significantly improves adhesion to the ocular surface.In comparison with other FK506 formulations and the PEG-PPG-FK506(F127-FK506)hydrogel,this novel MPOSS-PEG-PPG-FK506(MPEP-FK506)hydrogel is a more effective treatment of dry eye in the murine dry eye model.Therefore,delivery of FK506 in this POSS hydrogel has the potential to prolong drug retention time on the ocular surface,which will improve its therapeutic efficacy in the management of dry eye.

关键词： Ocular adhesive Polyhedral oligomeric silsesquioxane FK506 Dry eye

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A SARS-CoV-2-specific CAR-T-cell model identifies felodipine,fasudil,imatinib,and caspofungin as potential treatments for lethal COVID-19

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cellular & Molecular Immunology 2023年第4期20卷 351-364页

作者： in Xia Lun-zhi Yuan Ya-hong Hu Jun-yi Liu Guo-sheng Hu Ruo-yao Qi Tian-ying Zhang Hua-long Xiong Zao-zao Zheng Hong-wei Lin Jia-mo Zhang Chao Yu Ming Zhou Jian Ma Tong Cheng Ri-rong Chen Yi Guan Ning-shao Xia Wen Liu state key laboratory of cellular stress biology School of Pharmaceutical SciencesXiamen UniversityXiang’an South RoadXiamenFujian 361102China fujian provincial key laboratory of innovative drug target research School of Pharmaceutical SciencesXiamen UniversityXiang’an South RoadXiamenFujian 361102China state key laboratory of Molecular Vaccinology and Molecular Diagnostics National Institute of Diagnostics and Vaccine Development in Infectious DiseasesSchool of Life SciencesSchool of Public HealthXiamen UniversityXiang’an South RoadXiamenFujian 361102China state key laboratory of Emerging Infectious Diseases School of Public HealthLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina.

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019(COVID-19)severity and lethality.However,drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed.Here,we constructed a SARS-CoV-2 spike protein-specific CAR,and human T cells infected with this CAR(SARS-CoV-2-S CAR-T)and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients,causing cytokine storm and displaying a distinct memory,exhausted,and regulatory T-cell phenotype.THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture.Based on this"two-cell"(CAR-T and THP1 cells)model,we screened an FDA-approved drug library and found that felodipine,fasudil,imatinib,and caspofungin were effective in suppressing the release of cytokines,which was likely due to their ability to suppress the NF-kB pathway in vitro.Felodipine,fasudi,imatinib,and caspofungin were further demonstrated,although to different extents,to attenuate lethal inflammation,ameliorate severe pneumonia,and prevent mortality in a SARS-CoV-2-infected Syrian hamster model,which were also linked to their suppressive role in inflammation.In summary,we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner.The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe,inexpensive,and easily accessible for immediateuseinmostcountries.

关键词： COVID-19 SARS-CoV-2 CAR-T anti-inflammation NF-kB pathway

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