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Computer-aided molecular design and optimization of potent inhibitors disrupting APC-Asef interaction

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2631-2645页

作者： Xuefei Wang Zeqian Du Yuegui Guo jie Zhong Kun song Junyuan Wang jianqiang Yu Xiuyan Yang Chen-ying liu Ting Shi jian Zhang Department of Pathophysiology Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China Key Laboratory of Protection Development and Utilization of Medicinal Resources in Liupanshan AreaMinistry of EducationPeptide&Protein Drug Research CenterSchool of PharmacyNingxia Medical UniversityYinchuan 750004China State Key Laboratory of Microbial Metabolism Joint International Research Laboratory of Metabolic and Developmental SciencesSchool of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China Department of Colorectal and Anal Surgery Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Basic Science Research Center Base(Pharmaceutical Science) Yantai UniversityYantai 264005China Medicinal Chemistry and Bioinformatics Center Shanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Colorectal cancer(CRC)is the second leading cause of cancer mortality *** initial diagnosis,approximately 20%of patients are diagnosed with metastatic CRC(mCRC).Although the APC-Asef interaction is a well-established target for mCRC therapy,the discovery and development of effective and safe drugs for mCRC patients remains an urgent and challenging *** this study,we identified a novel structural scaffold based on MAI inhibitors,the first-in-class APC-Asef inhibitors we reported *** model-driven optimizations of the N-terminal cap and experimental evaluations of inhibitory activity were performed,and 24-fold greater potency was obtained with the best inhibitor compared to the parental *** addition,the cocrystal structure validated that the two-layerπ-πstacking interactions were essential for inhibitor stabilization in the bound ***,in vitro and in vivo studies have demonstrated that novel inhibitors suppressed lung metastasis in CRC by disrupting the APC-Asef *** results provide an intrinsic structural basis to further explore drug-like molecules for APC-Asef-mediated CRC therapy.

关键词： APC-Asef Peptidomimetic Computer-aided molecular design ONIOM model π-πstacking Metastatic colorectal cancer

Transcriptomic analysis identifies the neuropeptide cortistatin (CORT) as an inhibitor of temozolomide (TMZ) resistance by suppressing the NF-kB-MGMT signaling axis in human glioma

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Genes & Diseases 2024年第3期11卷 385-399页

作者： Zongze He Bo Peng Qi Wang jie Tian Ping liu jie Feng Yiwei liao Longyi Chen Ping Jia jian Tang Department of Neurosurgery Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan 610072China Department of Rehabilitation Medicine Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan 610072China Department of Neurosurgery Xiangya HospitalCentral South UniversityChangshaHunan 410008China

Glioma is a common tumor originating in the brain that has a high mortality ***(TMZ)is the first-line treatment for high-grade ***,a large pro-portion of gliomas are resistant to TMZ,posing a great challenge to their *** the study,the specific functions and mechanism(s)by which cortistatin(CORT)regulates TMZ resis-tance and glioma progression were *** decreased expression of CoRT was detected in glioma tissues,and highly expressed CORT was associated with a better survival rate in pa-tients with *** overexpression notably decreased the capacity of glioma cells to pro-liferate and migrate in vitro and to form tumors in *** overexpression also markedly suppressed the viability and enhanced the apoptosis of TMZ-resistant U251 cells by regulating MGMT,p21,and Puma ***,CORT overexpression reduced the resistance of gliomas to TMZ in *** expression Was negatively correlated with MGMT expression in both glioma tissues and cells,and it was found that CORT inhibited NF-kB pathway activation in glioma cells,thereby inhibiting MGMT *** conclusion,CORT regulates glioma cell growth,migration,apoptosis,and TMZ resistance by weakening the activity of NF-kB/p65 and thereby regulating MGMT *** CORT/NF-kB/MGMT axis might be regarded as a molecular mechanism contributing to the resistance of glioma to *** data also suggest that CORT regulates the viability and metastatic potential of glioma cells,independent of its effects on TMZ resistance,providing evidence of novel therapeutic targets for glioma that should be evaluated infurther studies.

关键词： Cortistatin Glioma MGMT NF-kB pathway Temozolomide

Mesenchymal stem cells-extracellular vesicles alleviate pulmonary fibrosis by regulating immunomodulators

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World Journal of Stem Cells 2024年第6期16卷 670-689页

作者： ying Gao Mei-Fang liu Yang Li Xi liu Yu-jie Cao Qian-Fa Long Jun Yu jian-ying Li Department of Respiratory and Critical Care Medicine Shaanxi Provincial Rehabilitation HospitalXi’an 710000Shaanxi ProvinceChina Department of Respiratory and Critical Care Medicine Second Affiliated Hospital of Ningxia Medical University(The First People’s Hospital of Yinchuan)Yinchuan 750001Ningxia Hui Autonomous RegionChina School of Clinical Medicine Xi’an Medical UniversityXi’an 710021Shaanxi ProvinceChina Department of Respiratory and Critical Care Medicine Xi’an Central HospitalXi’an 710000Shaanxi ProvinceChina Department of Neurosurgery Xi’an Central HospitalXi’an 710000Shaanxi ProvinceChina Department of Emergency Xi’an Central HospitalXi’an 710000Shaanxi ProvinceChina

BACKGROUND Pulmonary fibrosis(PF)is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation,causing structural damage and lung *** cell therapy and mesenchymal stem cells-extracellular vesicles(MSC-EVs)offer new hope for PF *** To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis,oxidative stress,and immune inflammation in A549 cells and bleomycin(BLM)-induced mouse *** The effect of MSC-EVs on A549 cells was assessed by fibrosis markers[collagen I andα-smooth muscle actin(α-SMA),oxidative stress regulators[nuclear factor E2-related factor 2(Nrf2)and heme oxygenase-1(HO-1),and inflammatory regu-lators[nuclear factor-kappaB(NF-κB)p65,interleukin(IL)-1β,and IL-2].Similarly,they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV ***-EVs ion PF mice were detected by pathological staining and western ***-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in *** Transforming growth factor(TGF)-β1 enhanced fibrosis in A549 cells,significantly increasing collagen I andα-SMA ***,treatment with MSC-EVs demonstrated a remarkable alleviation of these ***,the expression of oxidative stress regulators,such as Nrf2 and HO-1,along with inflammatory regulators,including NF-κB p65 and IL-1β,were mitigated by MSC-EV ***,in a parallel manner,MSC-EVs exhibited a downregulatory impact on collagen deposition,oxidative stress injuries,and inflammatory-related cytokines in the lungs of mice with ***,the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory *** findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes,oxidative stres

关键词： Mesenchymal stem cells Extracellular vesicles Pulmonary fibrosis Oxidative stress response Epithelial-mesenchymal transition

A weak allele of TGW5 enables greater seed propagation and efficient size-based seed sorting for hybrid rice production

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Plant Communications 2024年第4期5卷 137-140页

作者： jiezheng ying Yaobing Qin Fengyong Zhang liu Duan Peng Cheng Man Yin Yifeng Wang Xiaohong Tong jie Huang Zhiyong Li Xianjun song jian Zhang State Key Lab of Rice Biology and Breeding China National Rice Research InstituteHangzhou 311400China State Key Laboratory of Biocatalysis and Enzyme Engineering School of Life SciencesHubei UniversityWuhan 430062China Key Laboratory of Plant Molecular Physiology Institute of Botanythe Chinese Academy of SciencesBeijing 100093China These authors contributed equally to this article

Dear Editors,Heterosis utilization is an effective way to improve crop *** rice typically out-yield inbred rice varieties by 10%and show better stress resistance,and they have been widely adopted in Asian countries since the 1980s(Cheng et al.,2007).To produce rice F1 hybrid seeds(HSDs),male sterile lines(MSLs)are grown side by side with restorer lines(RLs)in order to receive the RL *** seed production system faces challenges in maintaining the seed purity of the HSDs owing to the physical proximity of MSL and RL plants in the ***,MSLs and RLs are planted in alternate rows to enable physical separation of seeds during harvesting.

关键词： planted sterile enable

Association of acute glycemic parameters at admission with cardiovascular mortality in the oldest old with acute myocardial infarction

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Journal of Geriatric Cardiology 2024年第3期21卷 349-358页

作者： Hui-Hui liu Meng ZHANG Yuan-lin GUO Cheng-Gang ZHU Na-Qiong WU ying GAO Rui-Xia XU jie QIAN Ke-Fei DOU jian-Jun LI Cardiometabolic Center State Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesNational Clinical Research Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

OBJECTIVES Stress-related glycemic indicators,including admission blood glucose(ABG),stress-hyperglycemia ratio(SHR),and glycemic gap(GG),have been associated with worse outcomes after acute myocardial infarction(AMI).However,data regarding their prognostic value in the oldest old with AMI are ***,this study aimed to investigate the association of stress-related glycemic indicators with short-and long-term cardiovascular mortality(CVM)in the oldest old(≥80 years)with *** In this prospective study,a total of 933 consecutive old patients with AMI admitted to FuWai hospital(Beijing,China)were *** admission,ABG,SHR,and GG were assessed and all participants were classified according to their ***-Meier,restricted cubic splines(RCS),and multivariate Cox regression analyses were performed to evaluate the association between these glycemic indicators and CVM within 30 days and long-term *** During an average of 1954 patient-years of follow-up,a total of 250 cardiovascular deaths were ***-Meier analyses showed the lowest CVM in quartile 1 of ABG and in quartile 2 of SHR and *** adjusting for potential covariates,patients in quartile 4 of ABG,SHR,and GG had a respective 1.67-fold(95%CI:1.03-2.69;P=0.036),1.80-fold(95%CI:1.16-2.79;P=0.009),and 1.78-fold(95%CI:1.14-2.79;P=0.011)higher risk of long-term CVM risk compared to those in the reference groups(quartile 1 of ABG and quartile 2 of SHR and GG).Furthermore,RCS suggested a J-shaped relationship of ABG and a Ushaped association of SHR and GG with long-term ***,we observed similar associations of these acute glycemic parameters with 30-day *** Our data first indicated that SHR and GG consistently had a U-shaped association with both 30-day and longterm CVM among the oldest old with AMI,suggesting that they may be useful for risk stratification in this special population.

关键词： admitted infarction shaped

Anti-epileptic and Neuroprotective Effects of Ultra-low Dose NADPH Oxidase Inhibitor Dextromethorphan on Kainic Acid-induced Chronic Temporal Lobe Epilepsy in Rats

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Neuroscience Bulletin 2024年第5期40卷 577-593页

作者： Jing-Jing Yang ying-Xin liu Yan-Fang Wang Bi-ying Ge ying Wang Qing-Shan Wang Sheng Li jian-jie Zhang ling-ling Jin Jau-Shyong Hong Sheng-Ming Yin jie Zhao College of Basic Medical Sciences Dalian Medical UniversityDalian116044China Department of Neurology The First Affiliated Hospital of Dalian Medical UniversityDalian116011China National and Local Joint Engineering Research Center for Drug Research and Development of Neurodegenerative Diseases Dalian116044China School of Public Health Dalian Medical UniversityDalian116044China Neurobiology Laboratory National Institute of Environmental Health SciencesNational Institutes of HealthResearch Triangle ParkDurhamNC27709USA

Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy(TLE).We postulated that kainic acid(KA)-Induced status epilepticus triggers microglia-dependent inflammation,leading to neuronal damage,a lowered seizure threshold,and the emergence of spontaneous recurrent seizures(SRS).Extensive evidence from our laboratory suggests that dextromethorphan(DM),even in ultra-low doses,has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative *** results showed that administration of DM(10 ng/kg per day;subcutaneously via osmotic minipump for 4 weeks)significantly mitigated the residual effects of KA,including the frequency of SRS and seizure *** addition,DM-treated rats showed improved cognitive function and reduced hippocampal neuronal *** found suppressed microglial activation-mediated neuroinflammation and decreased expression of hippocampal gp91^(phox) and p47^(phox) proteins in KA-induced chronic TLE ***,even after discontinuation of DM treatment,ultra-low doses of DM continued to confer long-term anti-seizure and neuroprotective effects,which were attributed to the inhibition of microglial NADPH oxidase 2 as revealed by mechanistic studies.

关键词： Temporal lobe epilepsy Dextromethorphan NADPH oxidase Ultra-low dose

In-flight Energy Calibration of the GECAM Gamma-ray Detectors

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Research in Astronomy and Astrophysics 2024年第10期24卷 48-57页

作者： Rui Qiao Dong-Ya Guo Wen-Xi Peng Yan-Qiu Zhang Shuo Xiao Shao-lin Xiong Chao zheng Chao-Yang Li Jia-Cong liu Wang-Chen Xue jian-jian He zheng-Hua An Da-Li Zhang Xin-Qiao Li Li-Ming song Shi-jie zheng Ke Gong Ya-Qing liu Xin-ying song Xiao-Yun Zhao Xiang-Yang Wen Yan-Bing Xu Xiang Ma Xiao-Bo Li Ping Wang Yue Huang Ce Cai Qi-Bin Yi Yi Zhao Chen-Wei Wang Institute of High Energy Physics Chinese Academy of SciencesBeijing 100049China University of Chinese Academy of Sciences Beijing 100049China China West Normal University Nanchong 637002China Xiangtan University Xiangtan 411105China Beijing Normal University Beijing 100875China

The Gravitational wave high-energy Electromagnetic Counterpart All-sky Monitor(GECAM)mission is designed to monitor the Gamma-Ray Bursts(GRBs)associated with gravitational waves and other high-energy transient *** mission consists of two microsatellites which are planned to operate at the opposite sides of the *** GECAM satellite could detect and localize GRBs in about 8 keV-5 MeV with its 25 Gamma-Ray Detectors(GRDs).In this work,we report the in-flight energy calibration of GRDs using the characteristic gamma-ray lines in the background spectra,and show their performance evolution during the commissioning ***,a preliminary cross-calibration of energy response with Fermi GBM data is also presented,validating the energy response of GRDs.

关键词： (stars:)gamma-ray burst:general instrumentation:detectors methods:data analysis

Enhancing layered perovskite ferrites with ultra-high-density nanoparticles via cobalt doping for ceramic fuel cell anode

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Journal of Energy Chemistry 2024年第9期96卷 39-48页

作者： Shuo Zhai Rubao Zhao Hailong liao ling Fu Senran Hao Junyu Cai Yifan Wu jian Wang Yunhong jiang jie Xiao Tao liu Heping Xie State Key Laboratory of Intelligent Construction and Healthy Operation and Maintenance of Deep Underground Engineering Shenzhen University&Sichuan UniversityShenzhen 518060GuangdongChina National and Local Joint Engineering Research Center for Lithium-ion Batteries and Materials Preparation Technology Key Laboratory of Advanced Battery Materials of Yunnan ProvinceFaculty of Metallurgical and Energy EngineeringKunming University of Science and TechnologyKunming 650093YunnanChina School of Energy and Environment City University of Hong KongKowloon 999077Hong KongChina

Nanoparticles anchored on the perovskite surface have gained considerable attention for their wide-ranging applications in heterogeneous catalysis and energy conversion due to their robust and integrated structural ***,we employ controlled Co doping to effectively enhance the nanoparticle exsolution process in layered perovskite ferrites *** alloy nanoparticles with ultra-high-density are exsolved on the(PrBa)_(0.95)(Fe_(0.8)Co_(0.1)Nb_(0.1))2O_(5+δ)(PBFCN_(0.1))surface under reducing atmosphere,providing significant amounts of reaction sites and good durability for hydrocarbon *** a reducing atmosphere,cobalt facilitates the reduction of iron cations within PBFCN_(0.1),leading to the formation of CoFe alloy *** formation is accompanied by a cation exchange process,wherein,with the increase in temperature,partial cobalt ions are substituted by ***,Co doping significantly enhance the electrical conductivity due to the stronger covalency of the Cosingle bondO bond compared with Fesingle bondO bond.A single cell with the configuration of PBFCN_(0.1)-Sm_(0.2)Ce_(0.8)O_(1.9)(SDC)|SDC|Ba_(0.5)Sr_(0.5)Co_(0.8)Fe_(0.2)O_(3−δ)(BSCF)-SDC achieves an extremely low polarization resistance of 0.0163Ωcm^(2)and a high peak power density of 740 mW cm^(−2)at 800℃.The cell also shows stable operation for 120 h in H_(2)with a constant current density of 285 mA cm^(−2).Furthermore,employing wet C_(2)H_(6)as fuel,the cell demonstrates remarkable performance,achieving peak power densities of 455 mW cm^(−2)at 800℃and 320 mW cm^(−2)at 750℃,marking improvements of 36%and 70%over the cell with(PrBa)_(0.95)(Fe_(0.9)Nb_(0.1))_(2)O_(5+δ)(PBFN)-SDC at these respective *** discovery emphasizes how temperature influences alloy nanoparticles exsolution within doped layered perovskite ferrites materials,paving the way for the development of high-performance ceramic fuel cell anodes.

关键词： Solid oxide fuel cell Anode Ethane fuel Nanoparticle Exsolution Layered perovskite Ferrites

Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) via dephosphorylation of the EGFR signaling pathway

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Journal of Biomedical Research 2024年第4期38卷 382-396页

作者： Muhammad Zubair Hafiz jie Pan Zhiwei Gao ying Huo Haobin Wang Wei liu jian Yang Department of Pharmacology Nanjing Medical UniversityNanjingJiangsu 211166China

The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer *** in vivo experiments were conducted on nude and ICR *** a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver *** the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ *** in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)*** with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 ***,other CAR target genes also showed a significant increase in the *** up-regulation of murine CAR was observed in the liver tissues of both nude and ICR *** findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator *** of the ERK1/2 signaling pathway was also observed in ***,T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and *** the nude mice,T-AⅢ also inhibited EGFR *** results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.

关键词： timosaponin AⅢ CAR metabolism enzyme ERK1/2 signaling pathway EGFR signaling pathway