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Boosting ferroptosis and microtubule inhibition for antitumor therapy via a carrier-free supermolecule nanoreactor

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Journal of Pharmaceutical Analysis 2023年第1期13卷 99-109页

作者： Min Mu Xiaoyan Liang Na Zhao Di Chuan Bo Chen Shasha Zhao Guoqing Wang Rangrang Fan Bingwen Zou Bo Han Gang Guo State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityChengdu610041China Key Laboratory of Xinjiang Phytomedicine Resource and Utilization Ministry of EducationSchool of PharmacyShihezi UniversityShiheziXinjiang832002China Department of Neurosurgery West China HospitalSichuan UniversityChengdu610041China Department of Radiation Oncology Cancer CenterWest China HospitalSichuan UniversityChengdu610041China

Traditional microtubule inhibitors fail to significantly enhance+e effect of colorectal cancer;hence,new and efficient strategies are necessary.In+is study,a supramolecular nanoreactor(DOC@TA-Fe^(3+))based on tannic acid(TA),iron ion(Fe^(3+)),and docetaxel(DOC)wi+microtubule inhibition,reactive oxygen species(ROS)generation,and gluta+ione peroxidase 4(GPX4)inhibition,is prepared for ferroptosis/apoptosis treatment.After internalization by CT26 cells,+e DOC@TA-Fe^(3+)nanoreactor escapes from+e lysosomes to release payloads.+e subsequent Fe^(3+)/Fe^(2+)conversion mediated by TA reducibility can trigger+e Fenton reaction to enhance+e ROS concentration.Additionally,Fe^(3+)can consume gluta+ione to repress+e activity of GPX4 to induce ferroptosis.Meanwhile,+e released DOC controls microtubule dynamics to activate+e apoptosis pa+way.+e superior in vivo antitumor efficacy of DOC@TA-Fe^(3+)nanoreactor in terms of tumor grow+inhibition and improved survival is verified in CT26 tumor-bearing mouse model.+erefore,+e nanoreactor can act as an effective apoptosis and ferroptosis inducer for application in colorectal cancer+erapy.

关键词： Carrier-free nanoreactor Ferroptosis microtubule Colorectal cancer

MDP25 mediates the fine-tuning of microtubule organization in response to salt stress

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Journal of Integrative Plant Biology 2022年第6期64卷 1181-1195页

作者： Peizhi Yang Jingwei Jin Jingru Zhang Dan Wang Xuechun Bai Wenfei Xie Tianming Hu Xuan Zhao Tonglin Mao Tao Qin College of Grassland Agriculture Northwest A&F UniversityYangling 712100China Research Center of Chinese Jujube Hebei Agricultural UniversityBaoding 071001China College of Horticulture Hebei Agricultural UniversityBaoding 071001China State Key Laboratory of Plant Physiology and Biochemistry Department of Plant SciencesCollege of Biological SciencesChina Agricultural UniversityBeijing 100193China

microtubules are dynamic cytoskeleton structures playing fundamental roles in plant responses to salt stress.The precise mechanisms by which microtubule organization is regulated under salt stress are largely unknown.Here,we report that Arabidopsis thaliana microtubule-DESTABILIZING PROTEIN 25(MDP25;also known as PLASMA MEMBRANEASSOCIATED CATION-BINDING PROTEIN 1(PCaP1))helps regulate microtubule organization.Under salt treatment,elevated cytosolic Ca^(2+) concentration caused MDP25 to partially dissociate from the plasma membrane,promoting microtubule depolymerization.When Ca^(2+) signaling was blocked by BAPTA-AM or LaCl_(3),microtubule depolymerization in wild-type and MDP25-overexpressing cells was slower,while there was no obvious change in mdp25 cells.Knockout of MDP25 improved microtubule reassembly and was conducive to microtubule integrity under long-term salt treatment and microtubule recovery after salt stress.Moreover,mdp25 seedlings exhibited a higher survival rate under salt stress.The presence microtubule-disrupting reagent oryzalin or microtubule-stabilizing reagent paclitaxel differentially affected the survival rates of different genotypes under salt stress.MDP25 promoted microtubule instability by affecting the catastrophe and rescue frequencies,shrinkage rate and time in pause phase at the microtubule plus-end and the depolymerization rate at the microtubule minus-end.These findings reveal a role for MDP25 in regulating microtubule organization under salt treatment by affecting microtubule dynamics.

关键词： calcium MDP25 microtubule salt stress

Recent clinical trials and optical control as a potential strategy to develop microtubule-targeting drugs in colorectal cancer management

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World Journal of Gastroenterology 2024年第13期30卷 1780-1790页

作者： Katsuhiro Kita Allen Burdowski Department of Biology St.Francis CollegeBrooklynNY 11201United States

Colorectal cancer(CRC)has remained the second and the third leading cause of cancer-related death worldwide and in the United States,respectively.Although significant improvement in overall survival has been achieved,death in adult populations under the age of 55 appears to have increased in the past decades.Although new classes of therapeutic strategies such as immunotherapy have emerged,their application is very limited in CRC so far.microtubule(MT)inhibitors such as taxanes,are not generally successful in CRC.There may be some way to make MT inhibitors work effectively in CRC.One potential advantage that we can take to treat CRC may be the combination of optical techniques coupled to an endoscope or other fiber optics-based devices.A combination of optical devices and photo-activatable drugs may allow us to locally target advanced CRC cells with highly potent MT-targeting drugs.In this Editorial review,we would like to discuss the potential of optogenetic approaches in CRC management.

关键词： Colorectal cancer Chemotherapy microtubule Combretastatin Photopharmacology

CDK11 negatively regulates Wnt/β-catenin signaling in the endosomal compartment by affecting microtubule stability

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Cancer Biology & Medicine 2020年第2期17卷 328-342页

作者： Danmin Ou Lin Chen Jiang He Zhuoxian Rong Jie Gao Liyu Liu Feiyu Tang Jiang Li Yuezhen Deng Lunquan Sun Department of Oncology Center for Molecular MedicineXiangya HospitalCentral South UniversityChangsha 410008China international Cooperation Base of Cancer Precision Therapy Department of Science and Technology of Hunan ProvinceChangsha 410008China Key Laboratory of Molecular Radiation Oncology of Hunan Province Changsha 410008China National Clinical Research Center for Geriatric Disorders Changsha 410008China

Objectives:Improper activation of Wnt/β-catenin signaling has been implicated in human diseases.Beyond the well-studied glycogen synthase kinase 3p(GSK3p)and casein kinase 1(CK1),other kinases affecting Wnt/β-catenin signaling remain to be defined.Methods:To identify the kinases that modulate Wnt/β-catenin signaling,we applied a kinase small interfering RNA(siRNA)library screen approach.Luciferase assays,immunoblotting,and real-time polymerase chain reaction(PCR)were performed to confirm the regulation o f the Wnt/β-catenin signaling pathway by cyclin-dependent kinase 11(CDK11)and to investigate the underlying mechanism.Confocal immunofluorescence,coimmunoprecipitation(co-IP),and scratch wound assays were used to demonstrate colocalization,detect protein interactions,and explore the function of CDK11.Results:CDK11 was found to be a significant candidate kinase participating in the negative control of Wnt/P-catenin signaling.Down-regulation of CDK11 led to the accumulation of Wnt/β-catenin signaling receptor complexes,in a manner dependent on intact adenomatosis polyposis coli(APC)protein.Further analysis showed that CDK11 modulation of Wnt/P-catenin signaling engaged the endolysosomal machinery,and CDK11 knockdown enhanced the colocalization of Wnt/β-catenin signaling receptor complexes with early endosomes and decreased colocalization with lysosomes.Mechanistically,CDK11 was found to function in Wnt/β-catenin signaling by regulating microtubule stability.Depletion of CDK11 down-regulated acetyl-a-tubulin.Moreover,co-IP assays demonstrated that CDK11 interacts with the a-tubulin deacetylase SIRT2,whereas SIRT2 down-regulation in CDK11-depleted cells reversed the accumulation of Wnt/(3-catenin signaling receptor complexes.CDK11 was found to suppress cell migration through altered W nt/β-catenin signaling.Conclusions:CDK11 is a negative modulator of Wnt/β-catenin signaling that stabilizes microtubules,thus resulting in the dysregulation of receptor complex trafficking from early endosomes to lysosomes.

关键词： Wnt/β-catenin signaling CDK11 endosome microtubule SIRT2

The molecular chaperone Hsp90 maintains Golgi organization and vesicular trafficking by regulating microtubule stability

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Journal of Molecular Cell Biology 2020年第6期12卷 448-461页

作者： Yuan Wu Yubo Ding Xiudan Zheng Kan Liao Key Laboratory of Systems Biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 200031China

Hsp90 is an abundant and special molecular chaperone considered to be the regulator of many transcription factors and signaling kinases. Its high abundance is indicative of its involvement in some more fundamental processes. In this study, we provide evidence that Hsp90 is required for microtubule stabilization, Golgi organization, and vesicular trafficking. We showed that Hsp90 is bound to microtubule-associated protein 4 (MAP4), which is essential for maintaining microtubule acetylation and stabilization. Hsp90 depletion led to the decrease in MAP4, causing microtubule deacetylation and destabilization. Furthermore, in Hsp90-depleted cells, the Golgi apparatus was fragmented and anterograde vesicle trafficking was impaired, with phenotypes similar to those induced by silencing MAP4. These disruptive effects of Hsp90 depletion could be rescued by the expression of exogenous MAP4 or the treatment of trichostatin A that increases microtubule acetylation as well as stability. Thus, microtubule stability is an essential cellular event regulated by Hsp90.

关键词： Hsp90 microtubule Golgi fragmentation vesicular trafficking MAP4

Mid1ip1b modulates apical reorientation of non-centrosomal microtubule organizing center in epithelial cells

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Journal of Genetics and Genomics 2018年第8期45卷 433-442页

作者： Xin Zhou Chun Xiao Yu Li Yanna Shang Dongqin Yin Siying Li Bo Xiang Ran Lu Yi Ji Yang Wu Wentong Meng Hongyan Zhu Jin Liu Huozhen Hu Xianming Mo Hong Xu Department of Pediatric Surgery and Laboratory of Stem Cell Biology State Key Laboratory of Biotherapy West China Hospital Sichuan University and Collaborative Innovation Center for Biotherapy National Clinical Research Center of Geriatrics West China Hospital Sichuan University

In most kinds of animal cells, the centrosome serves as the main microtubule organizing center （MTOC） that nucleates microtubule arrays throughout the cytoplasm to maintain cell structure, cell division and intracellular transport. Whereas in epithelial cells, non-centrosomal MTOCs are established in the apical domain for generating asymmetric microtubule fibers and cilia in epithelial cells for the organ morphogenesis during embryonic development. However, the mechanism by which MTOCs localize to the apical domain in epithelial cells remains largely unknown. Here, we show that Mid liplb has a close interaction with γ-tubulin protein, the central component of MTOC, and modulates lumen opening of the neural tube, gut, intestine, and kidney of zebrafish. Knockdown or dominant negative effect of Mid 1ip 1 b resulted in failure of lumen formation of the organs as aforementioned. Moreover, the non-centrosomal MTOCs were unable to orientate to the apical domain in Midliplb knockdown epithelial cells, and the centrosomal MTOCs were inaccurately placed in the apical domain, resulting in defective formation of asymmetric microtubules and misplacement of cilia in the apical domain. These data uncover a molecule that controls the proper localization of MTOCs in the apical domain in epithelial cells for organ morphogenesis during embryonic development.

关键词： Mid1ip1b microtubule organizing center Non-centrosomal MTOC microtubule Epithelial cell

Towards a better recording of microtubule cytoskeletal spatial organization and dynamics in plant cells

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Journal of Integrative Plant Biology 2019年第4期61卷 388-393页

作者： Weiwei Liu Chaofeng Wang Guangda Wang Yinping Ma Juan Tian Yanjun Yu Li Dong Zhaosheng Kong State Key Laboratory of Plant Genomics Institute of Microbiology the Chinese Academy of Sciences The University of Chinese Academy of Sciences

Numerous fluorescent marker lines are currently available to visualize microtubule(MT)architecture and dynamics in living plant cells, such as markers expressing p35S::GFP-MBD or p35S::GFP-TUB6.However, these MT marker lines display obvious defects that affect plant growth or produce unstable fluorescent signals. Here, a series of new marker lines were developed, including the pTUB6::VisGreen-TUB6-expressing line in which TUB6 is under the control of its endogenous regulatory elements and e GFP is replaced with VisGreen, a brighter fluorescent protein. Moreover, two different markers were combined into one expression vector and developed two dual-marker lines.These marker lines produce bright, stable fluorescent signals in various tissues, and greatly shorten the screening process for generating dual-marker lines.These new marker lines provide a novel resource for MT research.

关键词： microtubule cytoskeletal plant cells^FA

Fractional soliton dynamics of electrical microtubule transmission line model with local M-derivative

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Communications in Theoretical Physics 2021年第9期73卷 17-25页

作者： Nauman Raza Saima Arshed Kashif Ali Khan Mustafa Inc Department of Mathematics University of the PunjabQuaid-e-Azam CampusLahorePakistan Department of Mathematics University of Engineering and TechnologyLahorePakistan Department of Computer Engineering Biruni UniversityIstanbulTurkey Department of Mathematics Science FacultyFirat UniversityElazigTurkey Department of Medical Research Medical University HospitalChina Medical UniversityTaichungTaiwanChina

In this paper,two integrating strategies namely exp[-Ф(Х)]and (G'/G^(2))-expansion methods together with the attributes of local-M derivatives have been acknowledged on the electrical microtubule(MT)model to retrieve soliton solutions.The said model performs a significant role in illustrating the waves propagation in nonlinear systems.MTs are also highly productive in signaling,cell motility,and intracellular transport.The proposed algorithms yielded solutions of bright,dark,singular,and combo fractional soliton type.The significance of the fractional parameters of the fetched results is explained and presented vividly.

关键词： solitons solution microtubule nonlinear transmission line (G'/G^(2))-expansion method

A biomass carbon material with microtubule bundling and natural O-doping derived from goldenberry calyx and its electrochemical performance in supercapacitor

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Chinese Chemical Letters 2020年第3期31卷 805-808页

作者： Yang Liu Mengyi Zhang Liqiu Wang Yajuan Hou Chenxiao Guo Haiying Xin Shuang Xu College of Environmental and Chemical Engineering Yanshan UniversityQinhuangdao 066004China College of Pharmacy State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjin 300350China Key Laboratory of Advanced Energy Materials Chemistry(Ministry of Education) College of ChemistryNankai UniversityTianjin 300071China

A promising biomass carbon material,manufactured by the carbonation of Physalis peruviana L.calyx at 700℃,is presented in this wo rk.Morphology characterization shows that the carbon material possesses long microtubule bundling and above 30%natural O-atom component on the surface.After KOH chemical etching,the materials maintain the oxygen content but exhibit more micropores and higher specific surface area up to 1732.6 m^2/g.Using as an electrode material for supercapacitor,the active carbon material exhibits high specific capacitance up to 339.7 F/g at 0.5 A/g in 3 mol/L KOH aqueous solution through three-electrode system.The active carbon material also exhibits excellent cycling stability(97%retention)by 10,000 cycles at 10 A/g.The outstanding electrochemical performances are attributing to the unique long microtubule bundling with much more pores and the abundant Oelement on the surface.This biomass carbon material with excellent electrochemical properties could be a useful material for multiple applications.

关键词： Biomass carbon material Physalis peruviana L.calyx Carbon microtubule bundling High O-doping Supercapacitor