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Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent

Acta Pharmaceutica Sinica B 2024年第2期14卷 729-750页

作者： Xin Chen Xianggang Mu Lele Ding Xi Wang fei mao Jinlian Wei Qian Liu Yixiang Xu Shuaishuai Ni Lijun Jia Jian Li State Key Laboratory of Bioreactor Engineering Shanghai Frontiers Science Center of Optogenetic Techniques for Cell MetabolismFrontiers Science Center for Materiobiology and Dynamic ChemistryShanghai Key Laboratory of New Drug DesignSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China Cancer Institute Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China College of Pharmacy Jinan UniversityGuangzhou 510632China

Chemotherapy-induced complications,particularly lethal cardiovascular diseases,pose significant challenges for cancer survivors.The intertwined adverse effects,brought by cancer and its complication,further complicate anticancer therapy and lead to diminished clinical outcomes.Simple supplementation of cardioprotective agents falls short in addressing these challenges.Developing bifunctional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously.Drug repurposing was naturally endowed with co-therapeutic potential of two indications,implying a unique chance in the development of bi-functional agents.Herein,we further proposed a novel“trilogy of drug repurposing”strategy that comprises function-based,targetfocused,and scaffold-driven repurposing approaches,aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent.Through function-based repurposing,a cardioprotective agent,carvedilol(CAR),was identified as a potential neddylation inhibitor to suppress lung cancer growth.Employing target-focused SAR studies and scaffold-driven drug design,we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection.Remarkably,optimal derivative 43 displayed promising bi-functional effects,especially in various self-established heart failure mice models with and without tumor-bearing.Collectively,the present study validated the practicability of the“trilogy of drug repurposing”strategy in the development of bi-functional cotherapy agents.

关键词： Anticancer Heartfailure Complication Drug repurposing Bi-functional drug

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THE TRUNCATED EM METHOD FOR JUMP-DIFFUSION SDDES WITH SUPER-LINEARLY GROWING DIFFUSION AND JUMP COEFFICIENTS

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Journal of Computational Mathematics 2024年第1期42卷 178-216页

作者： Shounian Deng Chen fei Weiyin fei Xuerong mao Key Laboratory of Advanced Perception and Intelligent Control of High-end Equipment Ministry of Educationand School of Mathematics-Physics and FinanceAnhui Polytechnic UniversityWuhu 241000China Business School University of Shanghai for Science and TechnologyShanghai 200093China Department of Mathematics and Statistics University of StrathclydeGlasgow G11XHUK

This work is concerned with the convergence and stability of the truncated EulerMaruyama(EM)method for super-linear stochastic differential delay equations(SDDEs)with time-variable delay and Poisson jumps.By constructing appropriate truncated functions to control the super-linear growth of the original coefficients,we present two types of the truncated EM method for such jump-diffusion SDDEs with time-variable delay,which is proposed to be approximated by the value taken at the nearest grid points on the left of the delayed argument.The first type is proved to have a strong convergence order which is arbitrarily close to 1/2 in mean-square sense,under the Khasminskii-type,global monotonicity with U function and polynomial growth conditions.The second type is convergent in q-th(q<2)moment under the local Lipschitz plus generalized Khasminskii-type conditions.In addition,we show that the partially truncated EM method preserves the mean-square and H∞stabilities of the true solutions.Lastly,we carry out some numerical experiments to support the theoretical results.

关键词： SDDEs Truncated EM method Time-variable delay Poisson jumps

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Engineered extracellular vesicles: A new approach for targeted therapy of tumors and overcoming drug resistance

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Cancer Communications 2024年第2期44卷 205-225页

作者： Chen Ming-Kun Chen Zi-Xian Cai mao-Ping Chen Hong Chen Zhuang-fei Zhao Shan-Chao Department of Urology The Third Affiliated Hospital of Southern Medical UniversityGuangzhouGuangdongP.R.China The Third Clinical College Southern Medical UniversityGuangzhouGuangdongP.R.China Luoyang Key Laboratory of Organic Functional Molecules College of Food and DrugLuoyang Normal UniversityLuoyangHenanP.R.China Department of Urology Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP.R.China

Targeted delivery of anti-tumor drugs and overcoming drug resistance in malig-nant tumor cells remain significant clinical challenges.However,there are only few effective methods to address these issues.Extracellular vesicles(EVs),actively secreted by cells,play a crucial role in intercellular information transmis-sion and cargo transportation.Recent studies have demonstrated that engineered EVs can serve as drug delivery carriers and showed promising application prospects.Nevertheless,there is an urgent need for further improvements in the isolation and purification of EVs,surface modification techniques,drug assem-bly processes,and precise recognition of tumor cells for targeted drug delivery purposes.In this review,we summarize the applications of engineered EVs in cancer treatment and overcoming drug resistance,and current challenges asso-ciated with engineered EVs are also discussed.This review aims to provide new insights and potential directions for utilizing engineered EVs as targeted delivery systems for anti-tumor drugs and overcoming drug resistance in the near future.

关键词： drug delivery drug resistance extracellular vesicles nanoparticles

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Nanocavity enriched CuPd alloy with high selectivity for CO2 electroreduction toward C2H4

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Rare Metals 2024年第4期43卷 1513-1523页

作者： Ze-Yu Zhang Hai-Bin Wang fei-fei Zhang Jing-Wei Li Xin-Zhuo Hu Si-Wei Yan Yi-Ming Bai Xun Zhang Gu-Rong Shen Peng-fei Yin Jing Yang Cun-Ku Dong Jing mao Hui Liu Xi-Wen Du Institute of New-Energy Materials School of Materials Science and EngineeringTianjin University

Electrocatalysis of CO2reduction reaction is an effective way to convert CO2into high value-added products,but the selectivity of Cu-based catalysts for C2+products needs to be improved due to the high energy barrier of C-C coupling.Therefore,a viable catalyst design strategy to decrease energy barrier of C-C coupling should be put forward.Here,a nanocavity-enriched CuPd single atom alloy（CuPd SAA） catalyst is designed to promote CC coupling process.The faradaic efficiency of CuPd SAA for ethylene and C2+reaches 75.6% and 85.7% at-0.7 V versus reversible hydrogen electrode（RHE）,respectively.Based on the results given by in situ characterization,the porous hollow structure dramatically increases the ratio of the linear-bond*CO,thus enhancing the faradaic efficiency for ethylene.Density functional theory（DFT） calculation reveals that the Pd doping can regulate the electronic structure of neighboring Cu atoms to decrease the energy barrier of C-C coupling,further improving the faradaic efficiency.This work provides a new idea for designing catalyst with high selectivity for ethylene.

关键词： Adsorption configuration C–C coupling CO 2 electrocatalysis Ethylene Single atom alloy

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Postoperative encapsulated hemoperitoneum in a patient with gastric stromal tumor treated by exposed endoscopic full-thickness resection: A case report

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World Journal of Gastrointestinal Surgery 2024年第2期16卷 601-608页

作者： Hui-fei Lu Jing-Jing Li De-Bin Zhu Li-Qi mao Li-Fen Xu Jing Yu Lin-Hua Yao Department of Gastroenterology the First People’s Hospital of HuzhouHuzhou 313000Zhejiang ProvinceChina

BACKGROUND Gastric stromal tumors,originating from mesenchymal tissues,are one of the most common tumors of the digestive tract.For stromal tumors originating from the muscularis propria,compared with conventional endoscopic submucosal dissection(ESD),endoscopic full-thickness resection(EFTR)can remove deep lesions and digestive tract wall tumors completely.However,this technique has major limitations such as perforation,postoperative bleeding,and post-polypectomy syndrome.Herein,we report a case of postoperative serous surface bleeding which formed an encapsulated hemoperitoneum in a patient with gastric stromal tumor that was treated with exposed EFTR.Feasible treatment options to address this complication are described.CASE SUMMARY A 47-year-old male patient had a hemispherical protrusion found during gastric endoscopic ultrasonography,located at the upper gastric curvature adjacent to the stomach fundus,with a smooth surface mucosa and poor mobility.The lesion was 19.3 mm×16.1 mm in size and originated from the fourth ultrasound layer.Computed tomography(CT)revealed no significant evidence of lymph node enlargement or distant metastasis.Using conventional ESD technology for mucosal pre-resection,exposed EFTR was performed to resect the intact tumor in order to achieve a definitive histopathological diagnosis.Based on its morphology and immunohistochemical expression of CD117 and DOG-1,the lesion was proven to be consistent with a gastric stromal tumor.Six days after exposed EFTR,CT showed a large amount of encapsulated fluid and gas accumulation around the stomach.In addition,gastroscopy suggested intracavitary bleeding and abdominal puncture drainage indicated serosal bleeding.Based on these findings,the patient was diagnosed with serosal bleeding resulting in encapsulated abdominal hemorrhage after exposed EFTR for a gastric stromal tumor.The patient received combined treatments,such as hemostasis under gastroscopy,gastrointestinal decompression,and abdominal drainage.All examinations were normal within six

关键词： Exposed endoscopic full-thickness resection Gastric stromal tumors Hemoperitoneum Abdominal infection Complication Postoperative bleeding Case report

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Nanoindentation behavior and creep-induced cracking of long-term crept austenitic steel at 650℃

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Journal of Iron and Steel Research(International) 2024年第2期31卷 464-474页

作者： Zhen Zhang Yu-hang Duan Shuai Wang Jin-shan Chen An-zhe Wang Xiang-yang mao Yuan-ji Shi Jie Zhang Ming Liu Zheng-fei Hu School of Materials Science and Engineering Nanjing Institute of TechnologyNanjing211167JiangsuChina Jiangsu Key Laboratory of Advanced Structural Materials and Application Technology Nanjing211167JiangsuChina Jiangsu Wind Power Engineering Technology Center Nanjing210023JiangsuChina Nanjing Vocational University of Industry Technology Nanjing210023JiangsuChina Baoshan Iron&Steel Co. Ltd.Shanghai201900China Fujian Provincial Key Laboratory of Terahertz Functional Devices and Intelligent Sensing School of Mechanical Engineering and AutomationFuzhou UniversityFuzhou350116FujianChina School of Materials Science and Engineering Tongji UniversityShanghai201804China

The grain boundary(GB)damage of long-term crept HR3C(25Cr–20Ni–Nb–N)austenitic steel with solid solution state was investigated by nanoindentation test accompanied with in-situ electron back-scattered diffraction.The corresponding microstructure was characterized by scanning electron microscopy and transmission electron microscopy.Results show that the increase in nanoindentation hardness at the GBs and triple grain junctions may be related to the dislocation accumulation and carbide growth during the creep.Coarsened M23C6 and dislocations piling-up at the GB accelerate the nucleation and coalescence of creep cavity along the GB.The nanoindentation hardness in grains varies with orientation of the stress axis.The orientation difference of neighbor grains may induce local high geometrically necessary dislocation densities and strain gradients near the GB,consequently causing stress concentration and subsequent crack growth at specific GBs.

关键词： Austenitic steel Creep Nanoindentation Grain orientation Creep-induced cracking

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Comparison of hepatic gene expression profiles between three mouse models of Nonalcoholic Fatty Liver Disease

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Genes & Diseases 2022年第1期9卷 201-215页

作者： Liping Xiang Yang Jiao Yiling Qian Yao Li fei mao Yan Lu Department of Endocrinology and Metabolism Zhongshan HospitalFudan UniversityShanghai 200032PR China Department of Endocrinology and Metabolism Minhang BranchZhongshan HospitalCentral Hospital of Minhang DistrictShanghai Minhang HospitalFudan UniversityShanghai 200032PR China Department of Laboratory Animal Science Shanghai Jiao Tong University School of MedicineShanghai 200025PR China

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder worldwide. Murine models of NAFLD have been widely used to explore its pathogenesis. In this study, we performed a systematic evaluation of hepatic genome-wide mRNA expression by RNA-Sequencing using three mouse models of NAFLD: leptin receptor deficient db/db mice, high-fat high-sugar diet (HSHF)-induced obese mice, and dexamethasone (DEX)-induced NAFLD mice. As a result, we found both distinct and common pathways in the regulation of lipid metabolism from transcriptomes of three mouse models. Moreover, only a total of 12 differentially expressed genes (DEGs) were commonly detected among all three mouse groups, indicating very little overlap among all three models. Therefore, our results suggest that NAFLD is a heterogeneous disease with highly variable molecular mechanisms.

关键词： DEGs Murine models NAFLD Pathway analysis Transcriptome

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Comparison of corrosion mechanisms of 510L low alloy steel treated by ACS and EPS techniques under various service environments

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Journal of Iron and Steel Research(International) 2024年第2期31卷 501-518页

作者： Bao-sheng Liu Peng-fei Xu Shao-hua Zhang Yan-rui Li Li-ming Mou Jia-li Li Yue-zhong Zhang Pei-mao Fu Fa-cai Shi College of Materials Science and Engineering Taiyuan University of Science and TechnologyTaiyuan030024ShanxiChina College of Chemical and Biological Engineering Taiyuan University of Science and TechnologyTaiyuan030024ShanxiChina Technical Center Taiyuan Iron and Steel(Group)Co.Ltd.Taiyuan030003ShanxiChina

The corrosion mechanism of 510L low alloy steel treated by acid-cleaned surface(ACS)and eco-pickled surface(EPS)techniques in three simulated solutions(S0:atmospheric environment;S1:soil environment;S2:industrial environment)and the influence of interaction between different corrosive anions on corrosion were investigated.The results show that the total corrosion rates of samples in three simulated solutions were in order of S2>S0>S1,which is simultaneously correlated with initial corrosion dissolution processes as well as after the formation of corrosion products.HCO3−will inhibit the initial corrosion owing to the formation of films,whereas HSO3−will accelerate the dissolutions of the matrix based on the synergistic action of HSO3−and Cl−.On the other hand,there is no significant difference in corrosion rates between the samples treated by ACS and EPS techniques.The EPS technique that is safe,reusable and environmentally friendly can be further widely used in future work.

关键词： Corrosion mechanism Low alloy steel Simulated solution Surface technique Immersion time

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Role of mitochondrial dysfunction in kidney disease: Insights from the cGAS-STING signaling pathway

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中华医学杂志(英文版) 2024年第9期137卷 2024 Mar 6页

作者： Li Lu Liu fei Feng Chunyue Chen Zhenjie Zhang Nan mao Jianhua Department of Nephrology Children’s Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China Department of Pediatric Intensive Care Unit Children’s Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China

Over the past decade, mitochondrial dysfunction has been investigated as a key contributor to acute and chronic kidney disease. However, the precise molecular mechanisms linking mitochondrial damage to kidney disease remain elusive. The recent insights into the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthetase (cGAS)-stimulator of interferon gene (STING) signaling pathway have revealed its involvement in many renal diseases. One of these findings is that mitochondrial DNA (mtDNA) induces inflammatory responses via the cGAS-STING pathway. Herein, we provide an overview of the mechanisms underlying mtDNA release following mitochondrial damage, focusing specifically on the association between mtDNA release-activated cGAS-STING signaling and the development of kidney diseases. Furthermore, we summarize the latest findings of cGAS-STING signaling pathway in cell, with a particular emphasis on its downstream signaling related to kidney diseases. This review intends to enhance our understanding of the intricate relationship among the cGAS-STING pathway, kidney diseases, and mitochondrial dysfunction.

关键词： Mitochondrial dysfunction Mitochondrial DNA cGAS-STING pathway Kidney diseases Chronic kidney disease

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Systematic identification of wheat spike developmental regulators by integrated multiomics, transcriptional network, GWAS, and genetic analyses

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Molecular Plant 2024年第3期17卷 438-459页

作者： Xuelei Lin Yongxin Xu Dongzhi Wang Yiman Yang Xiaoyu Zhang Xiaomin Bie Lixuan Gui Zhongxu Chen Yiliang Ding Long mao Xueyong Zhang fei Lu Xiansheng Zhang Cristobal Uauyo Xiangdong Fu Jun Xiao Key Laboratory of Plant Cell and Chromosome Engineering Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Nanjing Agricultural University NanjingJiangsu 210095China Key Laboratory of Crop Biology College of Life SciencesShandong Agricultural UniversityTaianShandong 271018China Department of Life Science Tcuni Inc.ChengduSichuan 610000China John Innes Centre Norwich Research ParkNorwich NR47UHUK Institute of Crop Sciences Chinese Academy of Agricultural SciencesBeijing 100081China CAS-JIC Centre of Excellence for Plant and Microbial Science(CEPAMS) Institute of Genetics and Developmental BiologyCASBeijing 100101China

The spike architecture of wheat plays a crucial role in determining grain number,making it a key trait for optimization in wheat breeding programs.In this study,we used a multi-omic approach to analyze the transcriptome and epigenome profiles of the young spike at eight developmental stages,revealing co-ordinated changes in chromatin accessibility and H3K27me3 abundance during the flowering transition.We constructed a core transcriptional regulatory network(TRN)that drives wheat spike formation and experimentally validated a multi-layer regulatorymodule involving TaSPL15,TaAGLG1,and TaFUL2.By integrating the TRN with genome-wide association studies,we identified 227 transcription factors,including 42 with known functions and 185 with unknown functions.Further investigation of 61 novel transcription factors using multiple homozygous mutant lines revealed 36 transcription factors that regulate spike architecture or flowering time,such as TaMYC2-A1,TaMYB30-A1,and TaWRKY37-A1.Of particular interest,TaMYB30-A1,downstream of and repressed by WFzP,was found to regulate fertile spikelet number.Notably,the excellent haplotype of TaMYB30-A1,which contains a C allele at the WFzP binding site,was enriched during wheat breeding improvement in China,leading to improved agronomic traits.Finally,we constructed a free and open access Wheat Spike Multi-Omic Database(http://39.***.48.156:8800/#/).Our study identifies novel and high-confidence regulators and offers an effective strategy for dissecting the genetic basis of wheat spike development,with practical value forwheat breeding.

关键词： wheat spike development epigenome TRN TaMYB30-A1 breeding selection

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