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Natural products targeting the p53-MDM2 pathway and mutant p53: Recent advances and implications in cancer medicine

Genes & Diseases 2018年第3期5卷 204-219页

作者： jiang-jiang qin Xin Li Courtney Hunt Wei Wang Hui Wang Ruiwen Zhang Department of Pharmacological and Pharmaceutical Sciences College of PharmacyUniversity of HoustonHoustonTX77204USA Center for Drug Discovery University of HoustonHoustonTX77204USA School of Public Health Shanghai Jiao Tong University School of MedicineShanghai200025China

The p53 tumor suppressor plays a major role in controlling the initiation and development of cancer by regulating cell cycle arrest,apoptosis,senescence,and DNA *** MDM2 oncogene is a major negative regulator of p53 that inhibits the activity of p53 and reduces its protein ***2,p53,and the p53-MDM2 pathway represent welldocumented targets for preventing and/or treating *** products,especially those from medicinal and food plants,are a rich source for the discovery and development of novel therapeutic and preventive agents against human *** natural product-derived MDM2 inhibitors have shown potent efficacy against various human *** contrast to synthetic small-molecule MDM2 inhibitors,the majority of which have been designed to inhibit MDM2-p53 binding and activate p53,many natural product inhibitors directly decrease MDM2 expression and/or MDM2 stability,exerting their anticancer activity in both p53-dependent and p53-independent *** recently,several natural products have been reported to target mutant p53 in ***,identification of natural products targeting MDM2,mutant p53,and the p53-MDM2 pathway can provide a promising strategy for the development of novel cancer chemopreventive and chemotherapeutic *** this review,we focus our discussion on the recent advances in the discovery and development of anticancer natural products that target the p53-MDM2 pathway,emphasizing several emerging issues,such as the efficacy,mechanism of action,and specificity of these natural products.

关键词： MDM2 Natural products Oncogene p53 Tumor suppressor

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Identification of lineariifolianoid A as a novel dual NFAT1 and MDM2 inhibitor for human cancer therapy

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The Journal of Biomedical Research 2016年第4期30卷 322-333页

作者： jiang-jiang qin Sushanta Sarkar Sukesh Voruganti Rajesh Agarwal Wei Wang Ruiwen Zhang Department of Pharmaceutical Sciences Texas Tech University Health Sciences CenterAmarilloTX 79106USA Cancer Biology Center School of PharmacyTexas Tech University Health Sciences CenterAmarilloTX 79106USA Department of Pharmaceutical Sciences Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Cancer Center University of Colorado DenverAuroraCO 80045USA

There is an increasing interest in development of novel anticancer agents that target oncogenes. We have recently discovered that nuclear factor of activated T cells 1 （NFAT1） is a novel regulator of the Mouse Double Minute 2 （MDM2） oncogene and the NFAT1-MDM2 pathway has been implicated in human cancer development and pro- gression, justifying that targeting the NFAT1-MDM2 pathway could be a novel strategy for discovery and develop- ment of novel cancer therapeutics. The present study was designed to examine the anticancer activity and underlying mechanisms of action of lineariifolianoid A （LinA）, a novel natural product inhibitor of the NFAT 1-MDM2 pathway. The cytotoxicity of LinA was first tested in various human cancer cell lines in comparison with normal cell lines. The results showed that the breast cancer cells were highly sensitive to LinA treatment. We next demonstrated the effects of LinA on cell proliferation, colony formation, cell cycle progression, and apoptosis in breast cancer MCF7 and MDA-MB-231 cells, in dose-dependent and p53-independent manners. LinA also inhibited the migration and invasion of these cancer cells. Our mechanistic studies further indicated that its anticancer activities were attributed to its inhibitory effects on the NFAT 1-MDM2 pathway and modulatory effects on the expression of key proteins involved in cell cycle progression, apoptosis, and DNA damage. In summary, LinA is a novel NFAT 1-MDM2 inhib- itor and may be developed as a preventive and therapeutic agent against human cancer.

关键词： lineariifolianoid A NFAT1 MDM2 breast cancer p53 apoptosis

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C-CORE:Clustering by Code Representation to Prioritize Test Cases in Compiler Testing

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Computer Modeling in Engineering & Sciences 2024年第5期139卷 2069-2093页

作者： Wei Zhou Xincong jiang Chuan qin School of Electronic Information and Electrical Engineering Shanghai Jiao Tong UniversityShanghai200240China Hikvision Research Institute Hangzhou Hikvision Digital Technology Co.Ltd.Hangzhou310051China

Edge devices,due to their limited computational and storage resources,often require the use of compilers for program ***,ensuring the security and reliability of these compilers is of paramount importance in the emerging field of edge *** widely used testing method for this purpose is fuzz testing,which detects bugs by inputting random test cases into the target ***,this process consumes significant time and *** improve the efficiency of compiler fuzz testing,it is common practice to utilize test case prioritization *** researchers use machine learning to predict the code coverage of test cases,aiming to maximize the test capability for the target compiler by increasing the overall predicted coverage of the test ***,these methods can only forecast the code coverage of the compiler at a specific optimization level,potentially missing many optimization-related *** this paper,we introduce C-CORE(short for Clustering by Code Representation),the first framework to prioritize test cases according to their code representations,which are derived directly from the source *** approach avoids being limited to specific compiler states and extends to a broader range of compiler ***,we first train a scaled pre-trained programming language model to capture as many common features as possible from the test cases generated by a *** this pre-trained model,we then train two downstream models:one for predicting the likelihood of triggering a bug and another for identifying code representations associated with ***,we cluster the test cases according to their code representations and select the highest-scoring test case from each cluster as the high-quality test *** reduction in redundant testing cases leads to time *** evaluation results reveal that code representations are better at distinguishing test capabilities,and C-CORE significantly enhanc

关键词： Compiler testing test case prioritization code representation

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Associative Tasks Computing Offloading Scheme in Internet of Medical Things with Deep Reinforcement Learning

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China Communications 2024年第4期21卷 38-52页

作者： jiang Fan qin Junwei Liu Lei Tian Hui School of Communications and Information Engineering Xi’an University of Posts and TelecommunicationsXi’an 710121China State Key Laboratory of Networking and Switching Technology Beijing University of Posts and TelecommunicationsBeijing 100876China

The Internet of Medical Things(Io MT) is regarded as a critical technology for intelligent healthcare in the foreseeable 6G era. Nevertheless, due to the limited computing power capability of edge devices and task-related coupling relationships, Io MT faces unprecedented challenges. Considering the associative connections among tasks, this paper proposes a computing offloading policy for multiple-user devices(UDs) considering device-to-device(D2D) communication and a multi-access edge computing(MEC)technique under the scenario of Io MT. Specifically,to minimize the total delay and energy consumption concerning the requirement of Io MT, we first analyze and model the detailed local execution, MEC execution, D2D execution, and associated tasks offloading exchange model. Consequently, the associated tasks’ offloading scheme of multi-UDs is formulated as a mixed-integer nonconvex optimization problem. Considering the advantages of deep reinforcement learning(DRL) in processing tasks related to coupling relationships, a Double DQN based associative tasks computing offloading(DDATO) algorithm is then proposed to obtain the optimal solution, which can make the best offloading decision under the condition that tasks of UDs are associative. Furthermore, to reduce the complexity of the DDATO algorithm, the cacheaided procedure is intentionally introduced before the data training process. This avoids redundant offloading and computing procedures concerning tasks that previously have already been cached by other UDs. In addition, we use a dynamic ε-greedy strategy in the action selection section of the algorithm, thus preventing the algorithm from falling into a locally optimal solution. Simulation results demonstrate that compared with other existing methods for associative task models concerning different structures in the Io MT network, the proposed algorithm can lower the total cost more effectively and efficiently while also providing a tradeoff between delay and energy co

关键词： associative tasks cache-aided procedure double deep Q-network Internet of Medical Things(IoMT) multi-access edge computing(MEC)

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A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance

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Genes & Diseases 2019年第4期6卷 419-430页

作者： Wei Wang Bo Hu jiang-jiang qin Jian-Wen Cheng Xin Li Mehrdad Rajaei Jia Fan Xin-Rong Yang Ruiwen Zhang Department of Pharmacological and Pharmaceutical Sciences College of PharmacyUniversity of HoustonHoustonTX77204USA Drug Discovery Institute University of HoustonHoustonTX77204USA Department of Liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghai200032China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Fudan UniversityShanghai200032China

Overexpression of the MDM2 oncogene and mutations in the p53 tumor suppressor commonly occur in hepatocellular carcinoma(HCC)and are associated with increased mortality due to this *** MDM2 has been demonstrated to be a valid approach for the treatment of ***,most of the MDM2 inhibitors evaluated to date have been designed to block the MDM2 and p53 binding,and have limited efficacy against tumors with mutant or deficient *** the present study,we developed a novel MDM2 inhibitor(termed SP141)that has direct effects on MDM2 and exerts anti-HCC activity independent of the p53 status of the cancer *** demonstrate that SP141 inhibits cell growth and prevents cell migration and invasion,independent of ***,SP141 directly binds the MDM2 protein and promotes MDM2 *** inhibition of MDM2 by SP141 also increases the sensitivity of HCC cells to *** addition,in orthotopic and patient-derived xenograft models,SP141 inhibits MDM2 expression and suppresses tumor growth and metastasis,without any host ***,the inhibition of MDM2 by SP141 is essential for its anti-HCC *** results provide support for the further development of SP141 as a lead candidate for the treatment of HCC.

关键词： CRISPR/Cas9 Hepatocellular carcinoma MDM2 p53-independent Patient-derived xenograft

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Thick Electrodes of a Self-Assembled MXene Hydrogel Composite for High-Rate Energy Storage

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Energy & Environmental Materials 2024年第4期7卷 255-261页

作者： Leiqiang qin Jianxia jiang Lintao Hou Fengling Zhang Johanna Rosen Department of Physics Chemistry and Biology (IFM) Link?ping University Flexible Electronics Innovation Institute (FEII) Jiangxi Key Laboratory of Flexible Electronics Jiangxi Science and Technology Normal University Guangzhou Key Laboratory of Vacuum Coating Technologies and New Energy Materials Physics Department Jinan University

Supercapacitors based on two-dimensional MXene （Ti3C2Tz） have shown extraordinary performance in ultrathin electrodes with low mass loading,but usually there is a significant reduction in high-rate performance as the thickness increases,caused by increasing ion diffusion *** limitations include restacking of the nanosheets,which makes it challenging to realize the full potential of these electrode materials.

关键词： energy storage high-rate hydrogel MXene self-assemble

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Defect Engineering and Carbon Supporting to Achieve Ni‑Doped CoP_(3) with High Catalytic Activities for Overall Water Splitting

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Nano-Micro Letters 2024年第11期16卷 569-584页

作者： Daowei Zha Ruoxing Wang Shijun Tian Zhong‑Jie jiang Zejun Xu Chu qin Xiaoning Tian Zhongqing jiang Department of Physics Zhejiang Sci-Tech UniversityHangzhou 310018People’s Republic of China Department of Materials and Chemical Engineering Ningbo University of TechnologyNingbo 315211People’s Republic of China Guangzhou Key Laboratory for Surface Chemistry of Energy Materials Guangdong Engineering and Technology Research Center for Surface Chemistry of Energy MaterialsCollege of Environment and EnergySouth China University of TechnologyGuangzhou 510006People’s Republic of China

This work reports the use of defect engineering and carbon supporting to achieve metal-doped phosphides with high activities and stabilities for the hydrogen evolution reaction(HER)and the oxygen evolution reaction(OER)in alkaline ***,the nitrogen-doped carbon nanofiber-supported Ni-doped CoP_(3) with rich P defects(Pv·)on the carbon cloth(p-NiCoP/NCFs@CC)is synthesized through a plasma-assisted phosphorization *** p-NiCoP/NCFs@CC is an efficient and stable catalyst for the HER and the *** only needs overpotentials of 107 and 306 mV to drive 100 mA cm^(-2) for the HER and the OER,*** catalytic activities are higher than those of other catalysts reported *** high activities of the p-NiCoP/NCFs@CC mainly arise from its peculiar structural *** density functional theory calculation indicates that the Pv·richness,the Ni doping,and the carbon supporting can optimize the adsorption of the H atoms at the catalyst surface and promote the strong electronic couplings between the carbon nanofiber-supported p-NiCoP with the surface oxide layer formed during the OER *** gives the p-NiCoP/NCFs@CC with the high activities for the HER and the *** used in alkaline water electrolyzers,the p-NiCoP/NCFs@CC shows the superior activity and excellent stability for overall water splitting.

关键词： Plasma Electrocatalysis Hydrogen evolution reaction Oxygen evolution reaction Water splitting

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The CBL-interacting protein kinase OsCIPK1 phosphorylated by SAPK10 positively regulates responses to ABA and osmotic stress in rice

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The Crop Journal 2024年第2期12卷 364-374页

作者： Caihua qin Xing Fan Qianqian Fang Lan Ni Mingyi jiang College of Life Sciences State Key Laboratory of Crop Genetics&Germplasm Enhancement and UtilizationKey Laboratory of Crop Physiology Ecology and Production ManagementMinistry of AgricultureNanjing Agricultural UniversityNanjing 210095JiangsuChina

SubclassⅢsucrose nonfermenting1-related protein kinase 2s(SnRK2s)function in ABA and abiotic stress responses by unknown *** found that osmotic stress/ABA-activated protein kinase 10(SAPK10),a member of rice SnRK2s,physically interacted with CBL-interacting protein kinase 1(OsCIPK1).OsCIPK1 expression was up-regulated by ABA and PEG treatment,and overexpression increased the ABA sensitivity of seed germination and root growth and plant osmotic stress *** stress or ABA-induced activation of OsCIPK1 is dependent on ***10 phosphorylates Thr-24 of OsCIPK1 in vitro,and this phosphorylation increases the activity of OsCIPK1 and positively regulates the function of OsCIPK1 in ABA responses and plant osmotic stress *** study suggests that OsCIPK1 is a direct phosphorylated substrate of SAPK10,and SAPK10-mediated phosphorylation of OsCIPK1 functions in ABA signaling and increases rice osmotic stress tolerance.

关键词： Rice ABA Osmotic stress OsCIPK1 SAPK10

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Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3966-3982页

作者： Yancheng Tang Liming Wang Tao Yi Jun Xu Jigang Wang jiang-jiang qin Qilei Chen Ka-Man Yip Yihang Pan Peng Hong Yingying Lu Han-Ming Shen Hu-Biao Chen School of Chinese Medicine Hong Kong Baptist UniversityHong Kong SAR 999077China School of Biomedical Sciences Hunan UniversityChangsha 410082China Department of Physiology Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117597Singapore Artemisinin Research Center China Academy of Chinese Medical SciencesBeijing 100700China The First Affiliated Hospital of Southern University of Science and Technology the Second Clinical Medical College of Jinan UniversityShenzhen People’s HospitalShenzhen 518020China The Cancer Hospital of the University of Chinese Academy of Sciences(Zhejiang Cancer Hospital) Institute of Basic Medicine and Cancer(IBMC)Chinese Academy of SciencesHangzhou 310022China epartment of Medical Research Seventh Affiliated HospitalSun Yat-sen UniversityShenzhen 518107China Department of Biomedical Science City University of Hong KongHong Kong SAR 999077China Faculty of Health Sciences University of MacaoMacao SAR 999078China

Mitochondria as a signaling platform play crucial roles in deciding cell *** classic anticancer agents are known to trigger cell death through induction of mitochondrial ***,one selective autophagy,is the key mitochondrial quality control that effectively removes damaged ***,the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely ***,we examined the functional implication of mitophagy in the anticancer properties of magnolol,a natural product isolated from herbal Magnolia ***,we found that magnolol induces mitochondrial depolarization,causes excessive mitochondrial fragmentation,and increases mitochondrial reactive oxygen species(mtROS).Second,magnolol induces PTEN-induced putative kinase protein 1(PINK1)-Parkin-mediated mitophagy through regulating two positive feedforward amplification ***,magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis ***,magnolol prolongs the survival time of tumor-bearing ***,inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy,both in vitro and in ***,our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis,whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol,suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.

关键词： PINK1-Parkin-mediated mitophagy Magnolol Combination therapy Apoptosis Tumor suppression

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Large eddy simulation of boundary layer combustion of hydrogen and hydrocarbon fuel films in a modeled scramjet combustor

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Chinese Journal of Aeronautics 2024年第7期37卷 109-133页

作者： Jianfei WEI Silong ZHANG Jingying ZUO Xin LI jiang qin Wen BAO School of Energy Science and Engineering Harbin Institute of TechnologyHarbin 150001China

Supersonic fuel film cooling is a promising way to simultaneously reduce the severe wall heat and friction load of the internal passage in a scramjet engine when operating at hypersonic *** eddy simulations were performed to investigate the cooling and wall friction characteristics of hydrogen and hydrocarbon films under inert and reactive *** results show that the essential difference of the turbulent state in the mixing layer contributes to the totally different behaviors of the cooling and wall friction reduction performances of the two fuel *** turbulent transport processes between the hydrogen film and the mainstream are much weaker as compared to the case of hydrocarbon film,making inert hydrogen rather superior in cooling and friction reduction ***,the increase of wall temperature for hydrogen film under the inert case is mainly driven by the loss of hydrogen with high heat capacity instead of by direct heat ***,the film cooling performance severely deteriorates when the hydrogen film burns due to presence of severe heat release sources near the *** the other hand,combustion of hydrocarbon film in the boundary layer can remarkably improve its originally barely-satisfactory cooling and friction reduction performance to the level comparable to that of hydrogen film,due to the suppression of turbulent transport processes in the mixing layer and presence of heat absorption sources near the ***,the hydrogen film is more advantageous in friction reduction,while the hydrocarbon film is more suitable for cooling.

关键词： Supersonic film cooling Hydrogen Hydrocarbon Boundary layer combustion Large eddy simulation

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