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Modulating the function of ABCB1: in vitro and in vivo characterization of sitravatinib, a tyrosine kinase inhibitor

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Cancer Communications 2020年第7期40卷 285-300页

作者： Yuqi Yang ning Ji Chao-Yun Cai Jing-Quan Wang zi-ning lei Qiu-Xu Teng Zhuo-Xun Wu Qingbin Cui Yihang Pan Zhe-Sheng Chen Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNew York 11439USA State Key Laboratory of Experimental Hematology Chinese Academy of Medical Science and Peking Union Medical CollegeInstitute of Hematology and Blood Diseases HospitalTianjin 300020P.R.China School of Public Health Guangzhou Medical UniversityGuangzhouGuangdong 511436P.R.China Tomas Lindahl Nobel Laureate Laboratory the Seventh Affiliated Hospital of Sun Yat-sen UniversityShenzhenGuangdong 518107P.R.China

Background:Overexpression of ATP-binding cassette(ABC)transporter is a major contributor to multidrug resistance(MDR),in which cancer cells acquire resistance to a wide spectrum of chemotherapeutic *** this work,we evaluated the sensitizing effect of sitravatinib,a broad-spectrum tyrosine kinase inhibitor(TKI),on ATP-binding cassette subfamily B member 1(ABCB1)-and ATP-binding cassette subfamily C member 10(ABCC10)-mediated ***:MTT assay was conducted to examine cytotoxicity and evaluate the sensitizing effect of sitravatinib at non-toxic ***-labeled paclitaxel transportation,Western blotting,immunofluorescence analysis,and ATPase assay were carried out to elucidate the mechanism of sitravatinib-induced *** in vitro findings were translated into preclinical evaluation with the establishment of xenograft ***:Sitravatinib considerably reversed MDR mediated by ABCB1 and partially antagonized ABCC10-mediated *** in silico docking simulation analysis indicated that sitravatinib strongly and stably bound to the transmembrane domain of ABCB1 human-mouse chimeric ***,sitravatinib inhibited hydrolysis of ATP and synchronously decreased the efflux function of ***,sitravatinib could considerably enhance the intracellular concentration of anticancer ***,no significant alterations of both expression level and localization of ABCB1 were *** importantly,sitravatinib could remarkably restore the antitumor activity of vincristine in ABCB1-mediated xenograft model without observable toxic ***:The findings in this study suggest that the combination of sitrvatinib and substrate antineoplastic drugs of ABCB1 could attenuate the MDR mediated by the overexpression of ABCB1.

关键词： Sitravatinib

Signaling pathways and therapeutic interventions in gastric cancer

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Signal Transduction and Targeted Therapy 2022年第11期7卷 4118-4155页

作者： zi-ning lei Qiu-Xu Teng Qin Tian Wei Chen Yuhao Xie Kaiming Wu Qianlin Zeng Leli Zeng Yihang Pan Zhe-Sheng Chen Yulong He Guangdong Provincial Key Laboratory of Digestive Cancer Research Digestive Diseases CenterScientific Research CenterThe Seventh Affiliated Hospital of Sun Yat-Sen University518107ShenzhenGuangdongChina Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY11439USA Institute for Biotechnology St.John’s UniversityQueensNY11439USA

Gastric cancer(GC)ranks fifth in global cancer diagnosis and fourth in cancer-related *** tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival,the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages,which leads to unsatisfactory prognosis and high recurrence *** the recent advances in genome analysis,biomarkers have been identified that have clinical importance for GC diagnosis,treatment,and *** molecular classifications have uncovered the vital roles that signaling pathways,including EGFR/HER2,p53,PI3K,immune checkpoint pathways,and cell adhesion signaling molecules,play in GC tumorigenesis,progression,metastasis,and therapeutic *** biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC ***,the relative significance,temporal activation,interaction with GC risk factors,and crosstalk between these signaling pathways in GC are not well ***,we review the regulatory roles of signaling pathways in GC potential biomarkers,and therapeutic targets with an emphasis on recent *** therapies,including signaling-based and immunotherapies exploited in the past decade,and the development of treatment for GC,particularly the challenges in developing precision medications,are *** advances provide a direction for the integration of clinical,molecular,and genomic profiles to improve GC diagnosis and treatments.

关键词： diagnosis therapeutic precise

Repurposing FDA-approved drugs for SARS- CoV-2 through an ELISA-based screening for the inhibition of RBD/ACE2 interaction

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Protein & Cell 2021年第7期12卷 586-591页

作者： Wenyu Fu Yujianan Chen Kaidi Wang Aubryanna Hettinghouse Wenhuo Hu Jing-Quan Wang zi-ning lei Zhe-Sheng Chen Kenneth A.Stapleford Chuan-ju Liu Department of Orthopaedic Surgery New York University Medical Center301 East 17th StreetNew YorkNY 10003USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Department of Pharmaceutical Science College of Pharmacy and Health SciencesSt.John’s UniversityNew YorkNY 11439USA Department of Microbiology New York University School of MedicineNew YorkNY 10016USA Department of Cell Biology New York University School of MedicineNew YorkNY 10016USA

Dear Editor,The ongoing coronavirus disease 2019(COVID-19)global pandemic is caused by a novel coronavirus,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which instigates severe and often fatal *** of September 4th,2020,more than 26 million cases of COVID-19 and almost 900,000 deaths have been reported to *** on Kissler and colleagues’modeled projections of future viral transmission scenarios,a resurgence in SARS-CoV-2 could occur over the next five years(Kissler et al.,2020).

关键词： ACE2 drugs acute

Establishment and characterization of arsenic trioxide resistant KB/ATO cells

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Acta Pharmaceutica Sinica B 2017年第5期7卷 564-570页

作者： Yun-Kai Zhang Chunling Dai Chun-gang Yuan Hsiang-Chun Wu Zhijie Xiao zi-ning lei Dong-Hua Yang X. Chris Le Liwu Fu Zhe-Sheng Chen Department of Pharmaceutical Sciences College of Pharmacy and Health Sciences St. John's University Department of Medical Oncology Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer Medicine Department of Laboratory Medicine and Pathology University of Alberta School of Environmental Science & Engineering North China Electric Power University

Arsenic trioxide(ATO) is used as a chemotherapeutic agent for the treatment of acute promyelocytic leukemia. However, increasing drug resistance is reducing its efficacy. Therefore, a better understanding of ATO resistance mechanism is required. In this study, we established an ATO-resistant human epidermoid carcinoma cell line, KB/ATO, from its parental KB-3-1 cells. In addition to ATO, KB/ATO cells also exhibited cross-resistance to other anticancer drugs such as cisplatin, antimony potassium tartrate, and 6-mercaptopurine. The arsenic accumulation in KB/ATO cells was significantly lower than that in KB-3-1 cells. Further analysis indicated that neither application of P-glycoprotein inhibitor, breast cancer resistant protein(BCRP) inhibitor, or multidrug resistance protein 1(MRP1) inhibitor could eliminate ATO resistance. We found that the expression level of ABCB6 was increased in KB/ATO *** conclusion, ABCB6 could be an important factor for ATO resistance in KB/ATO cells. The ABCB6 level may serve as a predictive biomarker for the effectiveness of ATO therapy.

关键词： Arsenic trioxide KB/ATO cells Multidrug resistance ABCB6 KB-3-1 cells Biomarker

Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent,specific and orally active P-glycoprotein(P-gp)inhibitor

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3263-3280页

作者： Sai-Qi Wang Qiu-Xu Teng Shuai Wang zi-ning lei Hui-Hui Hu Hui-Fang Lv Bei-Bei Chen Jian-Zheng Wang Xiao-Jing Shi Wei-Feng Xu Hong-Min Liu Xiao-Bing Chen Zhe-Sheng Chen Bin Yu Department of Oncology the Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalHenan Cancer InstituteZhengzhou 450008China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China State Key Laboratory of Esophageal Cancer Prevention&Treatment Zhengzhou UniversityZhengzhou 450052China College of Pharmacy and Health Sciences St.John’s UniversityQueensNY 11439USA Laboratory Animal Center Academy of Medical ScienceZhengzhou UniversityZhengzhou 450052China

Multidrug resistance(MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein(P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp,WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel(PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4(CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft(PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.

关键词： Multidrug resistance(MDR) ATP-Binding cassette P-gp inhibitors Triazolo[1,5-a]pyrimidine Drug combination Preclinical studies Cancer therapy

Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases

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Neural Regeneration Research 2025年第1期20卷 6-20页

作者： Xiu-Yun Zhao De-En Xu Ming-lei Wu Ji-Chuan Liu zi-Ling Shi Quan-Hong Ma Department of Neurology and Clinical Research Center of Neurological Disease the Second Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina Institute of Neuroscience&Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases Soochow UniversitySuzhouJiangsu ProvinceChina Department of Neurology Jiangnan University Medical CenterWuxiJiangsu ProvinceChina

The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular *** reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and *** this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular *** also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative *** summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve *** review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.

关键词： autophagy endoplasmic reticulum endoplasmic reticulum autophagy endoplasmic reticulum quality control system endoplasmic reticulum receptors endoplasmic reticulum-associated degradation neurodegeneration neurodegenerative disease selective autophagy unfolded protein response

Alternative Expression of XRCC1 Gene in Target Organs of Rats Exposed Subchronically to Cadmium

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Alternative Expression of XRCC1 Gene in Target Organs of Rat...

Attention Eraser and Quantitative Measures for Automated Bone Age Assessment

2012年环境污染与大众健康学术会议

作者： Chao Shao, Yi-xiong lei , Qian Lu, Chao-cai He, zi-ning lei School of Public Health, Guangzhou Medical University, Guangzhou 510182, China. Yi-xiong lei, School of Public Health, Guangzhou Medical University, 195 Dongfeng Rd. W. Guangzhou 510182, P.R. China

The research is to investigate the alternative expression of XRCC1 gene in target organs of rats exposed subchronically to cadmium （Cd）, to understand the toxic effects of certain DNA repair genes in vivo. Based on our pre-established animal model of subchronic cadmium exposure, the abnormal expressions of XRCC1 gene in the liver, kidney, heart and lung of rats treated with CdCl 2 at different concentration were detected by fluorescent quantitative polymerase chain reaction （FQ-PCR）. The levels of XRCC1 protein were further confirmed by western blotting analysis. Compared to the corresponding controls, under the inner standard of TBP, the expression levels of XRCC1 mRNA were significantly decreased in all the measured liver and kidney in all Cd exposed rats with dose-dependent manner （P＜0.01）. Among low-dose, mid-dose and high-dose groups of the rats exposed to Cd, FQ-PCR assay showed that the XRCC1 mRNA expressions were respectively 45%, 32%, 13% of controls in the liver;68%, 31%, 16% of controls in the kidney;42%, 30%, 15% of controls in the heart;and 47%, 28%, 19% of controls in the lung. The western blotting analysis further displayed that the tendency of XRCC1 protein level was consistent with XRCC1 mRNA expression, indicating the subchronic Cd exposure can obviously regulate down the expression of XRCC1 gene in main inner organs of rats. The alternative expression of XRCC1 gene in rat’s liver, kidney, heart and lung might be an important biomarker for toxic effects during long-term low level exposure to Cd in vivo.

关键词： Cadmium (Cd) Rats XRCC1 gene FQ-PCR Western blotting

来源： cnki会议评论

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Computers, Materials & Continua 2025年第1期82卷 627-644页

作者： Liuqiang Shu lei Yu College of Computer and Information Science Chongqing Normal UniversityChongqing401331China

Bone age assessment(BAA)aims to determine whether a child’s growth and development are normal concerning their chronological *** predict bone age more accurately based on radiographs,and for the left-hand X-ray images of different races model can have better adaptability,we propose a neural network in parallel with the quantitative features from the left-hand bone measurements for *** this study,a lightweight feature extractor(LFE)is designed to obtain the featuremaps fromradiographs,and amodule called attention erasermodule(AEM)is proposed to capture the fine-grained ***,the dimensional information of the metacarpal parts in the radiographs is measured to enhance the model’s generalization capability across images fromdifferent *** is trained and validated on the RSNA,RHPE,and digital hand atlas datasets,which include images from various racial *** model achieves a mean absolute error(MAE)of 4.42 months on the RSNA dataset and 15.98 months on the RHPE *** to ResNet50,InceptionV3,and several state-of-the-art methods,our proposed method shows statistically significant improvements(p<0.05),with a reduction in MAE by 0.2±0.02 years across different racial ***,t-tests on the features also confirm the statistical significance of our approach(p<0.05).

关键词： Bone age assessment attention eraser quantitative feature metacarpal bones

Boosting Photocatalytic Performance of Cu-Mn Co-doped CeO_(2) Nanoparticles for Tetracycline Degradation

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Journal of Wuhan University of Technology(Materials Science) 2025年第1期40卷 42-48页

作者： XU Rongqi MI Jianxin WANG Shulin XU Man ZHU Li BAI lei TANG Dandan lei Yu Engineering Research Center of Environmental Materials and Membrane Technology of Hubei Province School of Materials Science and EngineeringWuhan Institute of TechnologyWuhan 430205China Shaanxi Coal Chemical Industry Technology Research Institute Co. Ltd.Xi’an 710100China

Cu-Mn co-doped CeO_(2) photocatalyst was successfully synthesized by the sol-gel method to assess its capability in degrading *** and TEM results showed that Cu and Mn were successfully co-doped into CeO_(2) without forming heterostructure,XPS and photoelectrochemical results revealed that Mn ions doping amplified the generation of photo-induced charge carriers,while Cu ions doping significantly facilitated the interfacial charge transfer ***,the optimized Cu3Mn2CeO_(2) nanoparticles exhibited the highest TC removal efficiency,achieved a rate of 78.18%and maintained a stable cycling performance.

关键词： photocatalyst co-doped charge separation water treatment