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ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT

Acta Pharmaceutica Sinica B 2024年第7期14卷 3027-3048页

作者： Mengdie Dong Yunjia Zhang Minghong Chen Yongkang Tan Jiao Min Xian He Fuhao Liu Jiaming Gu Hong Jiang Longbin Zheng Jiajing Chen Quanwen Yin Xuesong Li Xiang Chen Yongfeng Shao Yong Ji Hongshan Chen Department of Cardiovascular Surgery the First Affiliated Hospital of Nanjing Medical Universityand Key Laboratory of Cardiovascular and Cerebrovascular MedicineSchool of PharmacyNational Vaccine Innovation PlatformNanjing Medical UniversityNanjing 211166China Key laboratory of Cardiovascular and Cerebrovascular Medicine School of PharmacyNanjing Medical UniversityNanjing 211166China Department of Clinical Medicine Nanjing Medical University TIANYUAN Honors SchoolNanjing Medical UniversityNanjing 211166China Department of Anesthesiology Sir Run Run HospitalNanjing Medical UniversityNanjing 211166China Department of Cardiovascular Surgery the First Affiliated Hospital of Nanjing Medical UniversityNanjing 211166China Key laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted Intervention of Cardiovascular DiseaseCollaborative Innovation Center for Cardiovascular Disease Translational MedicineState Key Laboratory of Reproductive MedicineSchool of Pharmacythe Affiliated Suzhou Hospital of Nanjing Medical UniversityGusu SchoolNanjing Medical UniversityNanjing 211166China National Key laboratory of Frigid Zone Cardiovascular Diseases(NKLFZCD) Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China)College of PharmacyKey Laboratory of Cardiovascular Medicine Research and Key Laboratory of Myocardial IschemiaChinese Ministry of EducationNHC Key Laboratory of Cell Transplantationthe Central Laboratory of the First Affiliated HospitalHarbin Medical UniversityHarbin 150081China Key laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational MedicineNanjing Medical UniversityNanjing 211166China Department of Cardiology Huai’an First People’s Hospital Affiliated with Nanjing Medical UniversityHuai’an 223399China

Endothelial-to-mesenchymal transition(EndMT)is a key driver of *** glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate *** lactylation,mediated by lactate,can regulate gene expression and participate in disease ***,whether histone lactylation is involved in atherosclerosis remains ***,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactatedependent histone H3 lysine 18 lactylation(H3K18la)in vitro and in vivo,as well as in atherosclerotic patients’***,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K18la at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting *** found that deletion of ASF1A inhibited EndMT and improved endothelial *** analysis based on Apoe^(KO)Asf1a^(ECKO) mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endotheliumspecific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis *** of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la,SNAI1 transcription,and EndMT-induced *** study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.

关键词： Histone lactylation Atherosclerosis Endothelial-tomesenchymal transition ASF1A SNAI1 Endothelial dysfunction Lactate Epigenetic

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Super-resolution imaging for in situ monitoring sub-cellular micro-dynamics of small molecule drug

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1864-1877页

作者： Huimin Chen Guiqian Fang Youxiao Ren Weiwei Zou Kang Ying Zhiwei Yang Qixin Chen School of Pharmaceutical Sciences&Institute of Materia Medica Medical Science and Technology Innovation CenterShandong First Medical University&Shandong Academy of Medical SciencesJinan 250062China MOE Key laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter School of PhysicsXi'an Jiaotong UniversityXi'an 710049China reproductive Medicine Center Department of Obstetrics and Gynecologythe First Affiliated Hospital of Anhui Medical UniversityHefei 230022China

Small molecule drugs play a pivotal role in the arsenal of anticancer pharmacological agents. Nonetheless, their small size poses a challenge when directly visualizing their localization, distribution, mechanism of action (MOA), and target engagement at the subcellular level in real time. We propose a strategy for developing triple-functioning drug beacons that seamlessly integrate therapeutically relevant bioactivity, precise subcellular localization, and direct visualization capabilities within a single molecular entity. As a proof of concept, we have meticulously designed and constructed a boronic acid fluorescence drug beacon using coumarin–hemicyanine (CHB). Our CHB design includes three pivotal features: a boronic acid moiety that binds both adenosine triphosphate (ATP) and adenosine diphosphate (ADP), thus depleting their levels and disrupting the energy supply within mitochondria;a positively charged component that targets the drug beacon to mitochondria;and a sizeable conjugated luminophore that emits fluorescence, facilitating the application of structured illumination microscopy (SIM). Our study indicates the exceptional responsiveness of our proof-of-concept drug beacon to ADP and ATP, its efficacy in inhibiting tumor growth, and its ability to facilitate the tracking of ADP and ATP distribution around the mitochondrial cristae. Furthermore, our investigation reveals that the micro-dynamics of CHB induce mitochondrial dysfunction by causing damage to the mitochondrial cristae and mitochondrial DNA. Altogether, our findings highlight the potential of SIM in conjunction with visual drug design as a potent tool for monitoring the in situ MOA of small molecule anticancer compounds. This approach represents a crucial advancement in addressing a current challenge within the field of small molecule drug discovery and validation.

关键词： Mitochondrial Drug beacon Sub-cellular Small molecule Energy supply Anti-tumor

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Integrative analysis of tumor stemness and immune microenvironment deciphers novel molecular subtypes in hepatocellular carcinoma

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Genes & Diseases 2024年第5期11卷 81-84页

作者： Zhiyi Wang Shuang Chen Dongxiao Li Hui Xu Siyuan Weng Yuyuan Zhang Yuqing Ren Chunguang Guo Xiuling Li Zaoqu Liu Xinwei Han Department of Interventional Radiology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Department of Gastroenterology Henan Provincial People’s HospitalZhengzhou University People’s HospitalZhengzhouHenan 450004China Center of reproductive Medicine The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Department of Respiratory and Critical Care Medicine The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Department of Endovascular Surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China State Key laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China State Key laboratory of Medical molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical SciencesDepartment of PathophysiologyPeking Union Medical CollegeBeijing 100730China

Hepatocellular carcinoma(HCC)is a highly heterogeneous tumor,with dynamic equilibrium and complex interplay between its intricate tumor nature and ambient tumor immune microenvironment(TIME).1 Elegant research has indicated that cancer stem cells,a small subset of neoplastic cells confined within dedicated niches,display stem cell-like properties and interact with cells in TIME,thereby imparting an indelible impact on stemness regulation,tumor heterogeneity,and cancer cell plasticity.2 Previous taxonomies solely from the perspective of stemness or TIME may introduce some degree of bias in the comprehension of HCC carcinogenesis,3,4 and thus it is of paramount importance to systematically consider tumor stemness and TIME as a whole to truly portray the biological landscape of HCC.

关键词： thereby landscape stem

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Central cell: the key to determine persistent pollen tube attraction or termination

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Science China Life Sciences 2024年第9期67卷 2030-2032页

作者： Jiang-Guo Meng Shi-Zhen Li Hong-Ju Li Center for Developmental Biology Institute of Genetics and Developmental Biology Chinese Academy of Sciences Chongqing Key laboratory of Plant Resource Conservation and Germplasm Innovation Integrative Science Center of Germplasm Creation Western China (Chongqing) Science City School of Life SciencesSouthwest University Key laboratory of Seed Innovation Institute of Genetics and Developmental Biology Chinese Academy of Sciences Center for molecular Agrobiology Institute of Genetics and Developmental Biology Chinese Academy of Sciences

Most eukaryotic species depend on sexual reproduction, characterized by fertilization, to produce a new individual. This process requires the transfer of sperm(male gamete), containing half of the genetic information, from the male to the egg cell(female gamete), which holds half of the maternal genome, within the female reproductive organs. Various strategies have been evolved to ensure fertilization success in plants.

关键词： GUIDANCE FUSION BLOCK

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Duphaston as a suitable medication for women taking intracytoplasmic sperm injection to treat infertility

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reproductive and Developmental Medicine 2024年第2期8卷 89-92页

作者： Leila Naserpour Katayon Berjis Sanaz Soleymani Moud Rahil Jannatifar Department of reproductive Biology Academic Center for EducationCultureand Research(ACECR)Qom BranchQomIran Infertility Treatment Center Academic Center for EducationCultureand Research(ACECR)Qom BranchQomIran Cellular and molecular Research Center Qom University of Medical SciencesQomIran Midwifery Ward Infertility Treatment CenterAcademic Center for EducationCultureand Research(ACECR)Qom BranchQomIran

Objective:Duphaston is used as an alternative to gonadotropin-releasing hormone(GnRH)antagonists for suppressing premature luteinizing hormone(LH)*** study aimed to compare the efficacy of Duphaston protocols with that of Cetrotide in suppressing the LH ***:In this retrospective cross-sectional study,669 infertile women(aged 25-40 years)were administered recombinant follicle-stimulating hormone(rFSH)from the third day of their menstrual *** the follicular diameter reached 13 to 14 mm,Cetrotide was prescribed orally to the control subjects,also case subjects took Duphaston *** retrieved oocytes were fertilized by an intracytoplasmic sperm injection(ICSI).Results:The levels of FSH,LH,and estradiol did not differ significantly between the groups(P>0.05).However,the findings indicated that Duphaston led to greater oocyte retrieval than Cetrotide(P=0.006).However,the number of mature oocytes and viable embryos in the case subjects did not reach a significant difference compared to that in the control subjects(P>0.05).The number of good-quality embryos(stage 1)was significantly higher in the case subjects(P=0.04).In addition,there is no significant difference in the chemical,clinical pregnancy,implantation rate,and miscarriage rate between both groups(P>0.05).Conclusion:Duphaston could be utilized as a suitable medication rather than a GnRH antagonist in women subjected to controlled ovarian hyperstimulation.

关键词： Duphaston Cetrotide Progesterone protocol Ovarian hyperstimulation GnRH antagonist

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Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

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Journal of Pharmaceutical Analysis 2024年第1期14卷 100-114页

作者： Sze Wan Hung Massimiliano Gaetani Yiran Li Zhouyurong Tan Xu Zheng Ruizhe Zhang Yang Ding Gene Chi Wai Man Tao Zhang Yi Song Yao Wang Jacqueline Pui Wah Chung Tak Hang Chan Roman A.Zubarev Chi Chiu Wang Department of Obstetrics&Gynaecology The Chinese University of Hong KongHong KongChina Division of Physiological Chemistry I Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSE 17177Sweden Chemical Proteomics Core Facility Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSE 17177Sweden Unit of Chemical Proteomics Science for Life Laboratory(SciLifeLab)StockholmSE 17177Sweden Center for reproductive Medicine Henan Key Laboratory of Reproduction and GeneticsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450003China Department of Chemistry McGill UniversityMontrealH3A2K6Canada Department of Pharmacological&Technological Chemistry I.M.Sechenov First Moscow State Medical UniversityMoscow119146Russia Reproduction and Development Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong KongChina School of Biomedical Sciences The Chinese University of Hong KongHong KongChina Chinese University of Hong Kong-Sichuan University Joint laboratory in reproductive Medicine The Chinese University of Hong KongHong KongChina

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the *** is a major pathophysiology in *** previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain *** this study,we demonstrated that oral ProEGCG can be effective in preventing and treating ***,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,*** simulation and BioLayer interferometry were used to confirm their binding *** results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)*** vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling ***,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

关键词： molecular targets ProEGCG EGCG Angiogenesis Treatment Endometriosis

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Role of fatty acids and calcium in male reproduction

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reproductive and Developmental Medicine 2022年第1期6卷 57-64页

作者： Taniya Naz Srinjoy Chakraborty Sudipta Saha molecular reproductive physiology laboratory Amity Institute of Physiology and Allied SciencesAmity University Uttar PradeshNoida 201313India

Both fatty acids (FAs) and calcium ions play important roles in contraceptive cyclesvia several systems. Polyunsaturated FAs (PUFAs) act as precursors for prostaglandin production and can alter the expression of numerous crucial catalysts that are involved in prostaglandin and steroid digestion. Lipids are essential components of cell membranes. A diet rich in PUFAs enhances sperm motility and viability. It also improves testis development and spermatogenesis in several domesticated animal species. Increased PUFA content in spermatozoa increases plasma membrane fluidity, which is important for fertilization. However, the major drawback of high dietary PUFA intake is that it increases the levels of reactive oxygen species in the body. An increase in reactive oxygen species levels markedly affects fertility. Calcium is an important component that acts as an intra-cellular secondary messenger and plays an important role in some of the physiological processes that occur in male gametes. Some of these processes include spermatogenesis, sperm motility, capacitation, acrosome response, and fusion of gametes. These processes are associated with calcium influx through ion protein channels. Dietary fat intake is associated with increased intestinal calcium absorption. In this review, we discuss the impact of lipids, particularly PUFAs and monounsaturated FAs, and calcium ions on male reproduction, along with their effects on each other.

关键词： Infertility treatment Male infertility Motility regulation Polyunsaturated fatty acids Sperm motility

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RAD51B-AS1 promotes the malignant biological behavior of ovarian cancer through upregulation of RAD51B

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第7期25卷 581-593页

作者： Xinyi WEI Conghui WANG Sangsang TANG Qian YANG Zhangjin SHEN Jiawei ZHU Xiaodong CHENG Xinyu WANG Xing XIE Junfen XU Weiguo LU Women's reproductive Health laboratory of Zhejiang Province Women�s HospitalZhejiang University School of MedicineHangzhou 310006China Department of Gynecologic Oncology Women�s HospitalZhejiang University School of MedicineHangzhou 310006China Cancer Center Zhejiang UniversityHangzhou 310058China Department of Obstetrics and Gynecology the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology Hangzhou 310006China

Long non-coding RNAs(lncRNAs)play an indispensable role in the occurrence and development of ovarian cancer(OC).However,the potential involvement of lncRNAs in the progression of OC is largely *** investigate the detailed roles and mechanisms of RAD51 homolog B-antisense 1(RAD51B-AS1),a novel lncRNA in OC,reverse transcription-quantitative polymerase chain reaction(RT-qPCR)was performed to verify the expression of *** proliferation,metastasis,and apoptosis were detected using the cell counting kit-8(CCK-8),colony-formation,transwell,and flow cytometry *** xenograft models were established for the detection of *** results revealed that RAD51B-AS1 was significantly upregulated in a highly metastatic human OC cell line and OC ***51B-AS1 significantly increased the proliferation and metastasis of OC cells and enhanced their resistance to *** prediction analysis revealed that the only target gene of RAD51B-AS1 was *** gene function experiments revealed that RAD51B exerts the same biological effects as *** experiments demonstrated that the malignant biological behaviors promoted by RAD51B-AS1 overexpression were partially or completely reversed by RAD51B silencing in vitro and in ***,RAD51B-AS1 promotes the malignant biological behaviors of OC and activates the protein kinase B(Akt)/B cell lymphoma protein-2(Bcl-2)signaling pathway,and these effects may be associated with the positive regulation of RAD51B ***51B-AS1 is expected to serve as a novel molecular biomarker for the diagnosis and prediction of poor prognosis in OC,and as a potential therapeutic target for disease management.

关键词： Ovarian cancer(OC) Long non-coding RNA(LncRNA) Metastasis Anoikis

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Toeless and reversible DNA strand displacement based on Hoogsteen-bond triplex

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Chinese Chemical Letters 2024年第5期35卷 330-337页

作者： Yang Qin Jiangtian Li Xuehao Zhang Kaixuan Wan Heao Zhang Feiyang Huang Limei Wang Hongxun Wang Longjie Li Xianjin Xiao Institute of reproductive Health Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Pancreatic Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Wuhan Polytechnic University Wuhan 430023China

Strand displacement reaction is a crucial component in the assembly of diverse DNA-based nanodevices,with the toehold-mediated strand displacement reaction representing the prevailing ***,the single-stranded Watson-Crick sticky region that serves as the trigger for strand displacement can also cause leakage reactions by introducing crosstalk in complex DNA ***,we proposed the toeless and reversible DNA strand displacement reaction based on the Hoogsteen-bond triplex,which is compatible with most of the existing DNA *** demonstrated that our proposed reaction can occur at pH 5 and can be reversed at pH *** also observed an approximately linear relationship between the degree of reaction and pH within the range of pH 5-6,providing the potential for precise regulation of the ***,by altering the sequence orientation,we have demonstrated that our proposed reaction can be initiated or regulated through the same toeless mechanism without the requirement for protonation in low pH *** on the proposed reaction principle,we further constructed a variety of DNA nanodevices,including two types of DNA logic gates that rely on pH 5/pH 9 changes for initiating and reversing:the AND gate and the OR *** also successfully constructed a DNA Walker based on our proposed reaction modes,which can move along a given track after the introduction of a programmable DNA sequence and complete a cycle after 4 *** findings suggest that this innovative approach will have broad utility in the development of DNA circuits,molecular sensors,and other complex biological systems.

关键词： DNA strand displacement Toeless Triplex DNA strands Reversible DNA circuit DNA walker

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High-yield and rapid isolation of extracellular vesicles by flocculation via orbital acoustic trapping:FLOAT

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Microsystems & Nanoengineering 2024年第1期10卷 313-323页

作者： Joseph Rufo Peiran Zhang Zeyu Wang Yuyang Gu Kaichun Yang Joseph Rich Chuyi Chen Ruoyu Zhong Ke Jin Ye He Jianping Xia Ke Li Jiarong Wu Yingshi Ouyang Yoel Sadovsky Luke P.Lee Tony Jun Huang Department of Mechanical Engineering and Materials Science Duke UniversityDurhamNCUSA Department of Biomedical Engineering Duke UniversityDurhamNCUSA Department of Obstetrics Gynecologyand Reproductive SciencesMagee-Womens Research InstituteUniversity of PittsburghPittsburghPAUSA Department of Microbiology and molecular Genetics School of MedicineUniversity of PittsburghPittsburghPAUSA Renal Division and Division of Engineering in Medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical SchoolBostonMAUSA Department of Bioengineering Department of Electrical Engineering and Computer ScienceUniversity of CaliforniaBerkeleyBerkeleyCAUSA Department of Biophysics Institute of Quantum BiophysicsSungkyunkwan UniversitySuwonKorea

Extracellular vesicles(EVs)have been identified as promising biomarkers for the noninvasive diagnosis of various ***,challenges in separating EVs from soluble proteins have resulted in variable EV recovery rates and low ***,we report a high-yield(>90%)and rapid(<10 min)EV isolation method called FLocculation via Orbital Acoustic Trapping(FLOAT).The FLOAT approach utilizes an acoustofluidic droplet centrifuge to rotate and controllably heat liquid *** adding a thermoresponsive polymer flocculant,nanoparticles as small as 20 nm can be rapidly and selectively concentrated at the center of the *** demonstrate the ability of FLOAT to separate urinary EVs from the highly abundant Tamm-Horsfall protein,addressing a significant obstacle in the development of EV-based liquid *** to its high-yield nature,FLOAT reduces biofluid starting volume requirements by a factor of 100(from 20 mL to 200µL),demonstrating its promising potential in point-of-care diagnostics.

关键词： trapping utilize separating

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