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Acta Pharmaceutica Sinica B 2024年第4期14卷 1592-1604页

作者： Yuanjin Zhang Junze Huang Shengbo Huang Jie Liu Luyao Deng Chenmeizi Liang Yuanqing Guo Bingyi Yao Xin Wang Changning Maternity and Infant Health Hospital and School of Life Sciences Shanghai Key Laboratory of Regulatory BiologyEast China Normal UniversityShanghai 200241China

Organic anion-transporting polypeptides IB1(OATPIB1)plays a crucial role in the transport of ***,there are too few animal models related to OATPIB1,especially humanized animal *** this study,the human SLCOIB1 cDNA was inserted into the second exon of the rat Slcolb2 gene using CRISPR/Cas9 *** characteristics of statins were conducted in wild-type(WT),humanized OATPIB1(hOATPIB1),and OATPIB2 knockout(OATPIB2 KO)rats,*** results showed that human OATPIB1 was successfully expressed in rat liver and exhibited transport ***,the pharmacokinetic results revealed that OATPIB1 exhibited varying uptake levels of pivastatin,rosuvastatin,and fluvastatin,leading to different levels of exposure within the *** results were consistent with those obtained from in vitro experiments using overexpressed cell *** conclusion,we established a novel humanized SLCOIBI transgenic rat model to assess the role of human OATPIB1 in the uptake of different *** different uptake mediated by OATPIB1 may be an important reason for the different efficacy of *** hOATPIB1 rat is a promising model for improving the prediction of human drug transport.

关键词： CRISPR/Cas9 Drug transport Drug disposition Geneediting Humanized rat model OATP1B1 SLCO1B1 Statins

Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A_(2)receptors

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Science China(Life Sciences) 2024年第5期67卷 986-995页

作者： Yuan Weng Xinyu Yang Qiansen Zhang Ying Chen Yueming Xu Chenyu Zhu Qiong Xie Yonghui Wang Huaiyu Yang Mingyao Liu Weiqiang Lu Gaojie Song shanghai key laboratory of regulatory biology Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China Department of Medicinal Chemistry School of PharmacyFudan UniversityShanghai 201203China

The adenosine subfamily G protein-coupled receptors A_(2A)R and A_(2B)R have been identified as promising cancer immunotherapy *** of the A_(2A)R/A_(2B)R dual antagonists,AB928,has progressed to a phaseⅡclinical trial to treat rectal ***,the precise mechanism underlying its dual-antagonistic properties remains ***,we report crystal structures of the A_(2A)R complexed with AB928 and a selective A_(2A)R antagonist *** structures revealed a common binding mode on A_(2A)R,wherein the ligands established extensive interactions with residues from the orthosteric and secondary *** contrast,the cAMP assay and A_(2A)R and A_(2B)R molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A_(2B)*** analysis of their chemical structures suggested that AB928 readily adapted to the A_(2B)R pocket,while 2-118 did not due to intrinsic *** disparity potentially accounted for the difference in inhibitory efficacy between A_(2B)R and A_(2A)*** study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A_(2A)R/A_(2B)R for cancer therapy.

关键词： adenosine receptor A2AR A2BR inhibitor dual-antagonism drug discovery

Pyruvate kinase M in germ cells is essential for sperm motility and male fertility but not spermatogenesis

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Asian Journal of Andrology 2024年第2期26卷 212-219页

作者： Gao-Qing Qian Xiao-Chen Wang Xi Zhang Bin Shen Qiang Liu State key laboratory of Reproductive Medicine and Offspring Health Nanjing Medical UniversityNanjing 211166China shanghai key laboratory of Reproductive Medicine Department of HistoembryologyGenetics and Developmental BiologyShanghai Jiao Tong University School of MedicineShanghai 200025China State key laboratory of Molecular biology Shanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 200031China

Male germ cells employ specific metabolic pathways throughout their developmental *** a previous study,we discovered heightened expression of pyruvate kinase M(PKM),a pivotal glycolytic enzyme,in spermatogonia and *** gain deeper insights into PKM's roles in spermatogenesis,sperm function,and male fertility,we engineered a conditional-knockout mouse model(Pkm-vkO mice)to selectively disrupt the Pkm gene within germ *** maintaining regular testicular histology and sperm morphology,the male Pkm-vko mice were infertility,characterized by significant impairments in sperm motility and adenosine triphosphate(ATP)*** addition,Pkm-null spermatozoa exhibited similar deficits in protein tyrosine phosphorylation linked to capacitation,as well as compromised performance in in vitro fertilization *** conclude,PKM's presence is not obligatory for the entirety of spermatogenesis in male germ cells;however,it emerges as a critical factor influencing sperm motility and overall male fertility.

关键词： glycolysis male fertility pyruvate kinase M sperm motility spermatogenesis

Multistep continuous flow synthesis of Erlotinib

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Chinese Chemical Letters 2024年第4期35卷 371-375页

作者： Hui Jin Qin Cai Peiwen Liu Yan Chen Derong Wang Weiping Zhu Yufang Xu Xuhong Qian State key laboratory of Bioreactor Engineering Shanghai Key Laboratory of Chemical BiologySchool of PharmacyEast China University of Science and TechnologyShanghai 200237China

Erlotinib is an orally administered, highly effective, specific epidermal growth factor receptor tyrosine kinase inhibitor, used to treat non-small cell lung cancer and pancreatic cancer. The traditional synthetic methods for Erlotinib exhibit long reaction time and safety concern. Herein, we describe a novel five-step route for the synthesis of Erlotinib in flow. These five steps comprise etherification, nitration, reduction,addition and cyclization reactions. All steps were optimized and converted to continuous flow process,which drastically reduces the reaction time and considerably improves the process safety as well as the total yield. Enabled by five continuous flow units, Erlotinib is efficiently afforded with an E-factor of 38,an overall yield of 83%, and a total residence time of 25.1 min. Majority steps in this process have been optimized for quantitative conversion, which offers the possibility of telescoping the entire process.

关键词： Erlotinib Continuous flow synthesis Microchannel flow reactor Process optimization Continuous nitration Continuous hydrogenation

Remodeling the immune microenvironment for gastric cancer therapy through antagonism of prostaglandin E2 receptor 4

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Genes & Diseases 2024年第4期11卷 411-425页

作者： Mengmeng Guo Pan Hu Jiayi Xie Kefu Tang Shixiu Hu Jialiang Sun Yundong He Jing Li Weiqiang Lu Huirong Liu Mingyao Liu Zhengfang Yi Shihong Peng shanghai key laboratory of regulatory biology School of Life SciencesEast China Normal UniversityShanghai 200241China Prenatal Diagnosis Center Department of Clinical LaboratoryChangning Maternity and Infant Health HospitalEast China Normal UniversityShanghai 200051China key laboratory of Acupuncture and Immunological Effects Shanghai University of Traditional Chinese MedicineShanghai 201203China Fengxian Hospital Affiliated to Southern Medical University Shanghai 201400China shanghai Yuyao Biotech Co. Ltd.Shanghai 200241China

Gastric cancer is highly prevalent among digestive tract *** to the intri-cate nature of the gastric cancer immune microenvironment,there is currently no effective treatment available for advanced gastric ***,there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4(EP4)in gastric *** our previous study,we identified a novel small molecule EP4 receptor antagonist called *** with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse ***,adminis-tration of YYo01 stimulated a robust immune response within the tumor microenvironment,characterized by increased infiltration of antigen-presenting cells,T cells,and M1 ***,our research revealed that YYo01 exhibited remarkable synergistic ef-fects when combined with the PD-1 antibody and the clinically targeted drug apatinib,rather than *** findings suggest that YYo01 holds great promise as a potential therapeutic strategy for gastric cancer,whether used as a standalone treatment or in combination with other drugs.

关键词： EP4 Immunomodulation Synergy Tumor microenvironment YY001

Copper-catalyzed enantioselective desymmetrizing C(sp^(2))-H functionalization of azide-ynamides via α-imino copper carbenes

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Science China Chemistry 2024年第9期67卷 2982-2988页

作者： En-He Huang Li-Gao Liu You-Wei Yin Hao-Xuan Dong Ji-Jia Zhou Xin Lu Bo Zhou Long-Wu Ye key laboratory for Chemical biology of Fujian Province and State key laboratory of Physical Chemistry of Solid Surfaces College of Chemistry and Chemical EngineeringXiamen UniversityXiamen 361005China State key laboratory of Organometallic Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China

α-Imino metal carbenes are versatile intermediates in organic synthesis,and have broad applications in the assembly of divergent ***,the catalytic enantioselective desymmetrization based onα-imino metal carbenes has not been developed to ***,we disclose an enantioselective desymmetrizing C(sp^(2))-H functionalization of azide-ynamides viaα-imino copper carbenes,leading to the efficient assembly of divergent chiral indoloazepines in generally moderate to excellent yields with high ***,this reaction represents the first enantioselective desymmetrization based onα-imino metal *** synthetic transformations and biological tests show the potential utility of this ***,computational studies are employed to elucidate the reaction mechanism and the origin of enantioselectivity.

关键词： enantioselective desymmetrization metal carbenes copper catalysis nitrene transfer alkynes

Establishment and transcriptome analysis of single blastomerederived cell lines from zebrafish

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Journal of Genetics and Genomics 2024年第9期51卷 957-969页

作者： Jia Xu Siqi Liu Yirui Ai Yunbin Zhang Shifeng Li Yiping Li key laboratory of Multi-Cell Systems Shanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China

Maintaining chromosome euploidy in zebrafish embryonic cells is challenging because of the degradation of genomic integrity during cell *** this study,we report the derivation of zebrafish cell lines from single *** cell lines have a stable chromosome status attributed to BMP4 and exhibit continuous proliferation in *** zebrafish cell lines are successfully established from single ***-cell transcriptome sequencing analysis confirms the fidelity of gene expression profiles throughout long-term culturing of at least 45 *** long-term cultured cells are specialized into epithelial cells,exhibiting similar expression patterns validated by integrative transcriptomic ***,this work provides a protocol for establishing zebrafish cell lines from single blastomeres,which can serve as valuable tools for in vitro investigations of epithelial cell dynamics in terms of lifeedeath balance and cell fate determination during normal homeostasis.

关键词： Zebrafish Single embryo Cell lines Sngle-cell RNA sequencing(scRNA-Seq) Embryonic epidermis Epithelium

Recent Advances in Pd-Catalyzed Reactions Involving the “On-Water” Mechanism

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Chinese Journal of Chemistry 2024年第5期42卷 533-542页

作者： Dong Wei Guo-Qiang Lin State key laboratory of Systems Medicine for Cancer Shanghai Cancer InstituteShanghai Key Laboratory of Systems Regulation and Clinical Translation for CancerRen Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200127 China State key laboratory of Chemical biology Shanghai Institute of Organic ChemistryUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200032 China

As the chemical industry grapples with the need for more eco-friendly practices,the use of water as a reaction medium is gaining attraction in organic *** mini-review delves into Pd-catalyzed reactions that utilize the "on-water" mechanism,spanning from 2019 to late *** reactions are neatly categorized into several types: (A) Catalytic C—H activations,(B) Mizoroki- Heck-type reactions,(C) Suzuki-Miyaura reactions,and (D) Cyclization *** showcasing the potential of water as a sustainable reaction medium for organic transformations,these reactions leave no doubt about the importance of embracing eco-friendly practices in the chemical *** Scientists In 1980,a seminal work by Breslow et *** an acceleration of reaction rate in the Diels-Alder *** and co-workers noted a significant increase in the rate of the [2σ+2σ+2π] cycloaddition of quadricyclane and dimethyl azodicarboxylate (DMAD) when the reaction was conducted in water,as opposed to when it was carried out in organic *** term "on-water" was then coined to describe this *** strategy was further expanded to transition-metal catalyzed transformations by Ackermann in ***,Varma and Leazer disclosed a Pd-catalyzed Mizoroki-Heck type arylation of alkenes with diaryliodonium salts “on-water”.The enantioselective version of "on-water" process was not realized until 2014 by the Zhou *** on,the Schaub group described a Pd-catalyzed Suzuki–Miyaura coupling reaction of electron-poor aryl chlorides with water,using only 50 ppm of catalyst *** recently,Liu and Lin extended the "on-water" strategy to Pd-catalyzed double Mizoroki-Heck *** mini-review has focused on Pd-catalyzed reactions involving the “on-water” mechanism.

关键词： Pd-catalyzed “On-water” Green chemistry Aqueous reactions Mechanism Methodology and reactions Mizoroki-Heck reaction Cross-coupling

Coiled-coil domain-containing 38 is required for acrosome biogenesis and fibrous sheath assembly in mice

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Journal of Genetics and Genomics 2024年第4期51卷 407-418页

作者： Yaling Wang Xueying Huang Guoying Sun Jingwen Chen Bangguo Wu Jiahui Luo Shuyan Tang Peng Dai Feng Zhang Jinsong Li Lingbo Wang shanghai key laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Institute of Reproduction and Development Obstetrics and Gynecology HospitalFudan UniversityShanghai 200011China shanghai key laboratory of Maternal and Fetal Medicine Clinical and Translational Research Center of Shanghai First Maternity and Infant HospitalFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China State key laboratory of Cell biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China

During spermiogenesis,haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes,which are required for successful *** deformities in flagella cause a male infertility syndrome,multiple morphological abnormalities of the flagella(MMAF),while acrosomal hypoplasia in some cases leads to sub-optimal embryonic developmental ***,evidence regarding the occurrence of acrosomal hypoplasia in MMAF is ***,we report the generation of base-edited mice knocked out for coiled-coil domain-containing 38(Ccdc38)via inducing a nonsense mutation and find that the males are *** Ccdc38-KO sperm display acrosomal hypoplasia and typical MMAF *** find that the acrosomal membrane is loosely anchored to the nucleus and fibrous sheaths are disorganized in Ccdc38-KO *** analyses reveal that Ccdc38 knockout causes a decreased level of TEKT3,a protein associated with acrosome biogenesis,in testes and an aberrant distribution of TEKT3 in *** finally show that intracytoplasmic sperm injection overcomes Ccdc38-related *** study thus reveals a previously unknown role for CCDC38 in acrosome biogenesis and provides additional evidence for the occurrence of acrosomal hypoplasia in MMAF.

关键词： Acrosomal hypoplasia Multiple morphological abnormalities of the flagella(MMAF) Infertility Sperm motility Asthenoteratozoospermia Disease modeling

Tal6b/AvrXa27A,a hidden TALE targeting the susceptibility gene OsSWEET11a and the resistance gene Xa27 in rice

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Plant Communications 2024年第2期5卷 122-134页

作者： Zhengyin Xu Xiameng Xu Ying Li Linlin Liu Qi Wang Yijie Wang Yong Wang Jiali Yan Guanyun Cheng Lifang Zou Bo Zhu Gongyou Chen shanghai Collaborative Innovation Center of Agri-Seeds School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai 200240China State key laboratory of Microbial Metabolism Shanghai Jiao Tong UniversityShanghai 200240China

Xanthomonas oryzae ***(Xoo)secretes transcription activator-like effectors(TALEs)to activate rice susceptibility(S)genes,causing bacterial blight(BB),as well as resistance(R)genes,leading to de-fense against *** activation follows a gene-for-gene paradigm that results in an arms race between the TALE of the pathogen and effector-binding elements(EBEs)in the promoters of host *** this study,we characterized a novel TALE,designated Tal6b/AvrXa27A,that activates the rice S gene OsSWEET11a and the rice R gene ***6b/AvrXa27A is a member of the AvrXa27/TalAO class and contains 16 repeat variable diresidues(RVDs);one RVD is altered and one is deleted in Tal6b/AvrXa27A compared with AvrXa27,a known avirulence(avr)effector of ***6b/AvrXa27A can transcriptionally activate the expression of Xa27 and OsSWEET11a via EBEs in their corresponding promoters,leading to effector-triggered immunity and susceptibility,*** 16 RVDs in Tal6b/AvrXa27A have no obvious similarity to the 24 RVDs in the effector PthXo1,but EBETal6b and EBEPthXo1 are overlapped in the OsSWEET11a ***6b/AvrXa27A is prevalent among Asian Xoo isolates,but PthXo1 has only been reported in the Philippine strain *** editing of EBETal6b in the OsSWEET11a pro-moter further confirmed the requirement for OsSWEET11a expression in Tal6b/AvrXa27A-dependent susceptibility to ***,Tal6b/AvrXa27A resulted in higher transcription of Xa27 than of OsSWEET11a,which led to a strong,rapid resistance response that blocked disease *** suggest that Tal6b/AvrXa27A has a dual function:triggering resistance by activating Xa27 gene expression as an avirulence factor and inducing transcription of the S gene OsSWEET11a,resulting in ***,Tal6b/AvrXa27A,but not AvrXa27,can bind to the promoter of *** underlying recognition mechanism for this binding remains unclear but appears to deviate from the currently accepted TALE code.

关键词： Xanthomonas oryzae pv.oryzae TALE AvrXa27 tal6b Xa27 OsSWEET11a