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Drug repurposing: A novel strategy to target cancer stem cells and therapeutic resistance

Genes & Diseases 2024年第1期11卷 148-175页

作者： Divya Ajmeera Rajanna Ajumeera cell biology Department ICMR-National Institute of Nutrition(NIN)HyderabadTelangana 500007India

Chemotherapy is an effortless and frequently used approach in cancer therapy.However,in most cases,it can only prolong life expectancy and does not guarantee a complete cure.Furthermore,chemotherapy is associated with severe adverse effects,one of the major complications of effective cancer therapy.In addition,newly published research outputs show that cancer stem cells are involved in cancer disease progression,drug resistance,metastasis,and recurrence and that they are functional in the trans-differentiation capacity of cancer stem cells to cancer cells in response to treatments.Novel strategies are therefore required for better management of cancer therapy.The prime approach would be to synthesize and develop novel drugs that need extensive resources,time,and endurance to be brought into therapeutic use.The subsequent approach would be to screen the anti-cancer activity of avail-able non-cancerous drugs.This concept of repurposing non-cancer drugs as an alternative to current cancer therapy has become popular in recent years because using existing anticancer drugs has several adverse effects.Micronutrients have also been investigated for cancer ther-apy due to their significant anti-cancer effects with negligible or no side effects and availabil-ity in food sources.In this paper,we discuss an ideal hypothesis for screening available non-cancerous drugs with anticancer activity,with a focus on cancer stem cells and their clinical application for cancer treatment.Further,drug repurposing and the combination of micronu-trients that can target both cancers and cancer stem cells may result in a better therapeutic approach leading to maximum tumor growth control.

关键词： Cancerstem cells Chemotherapy Combination therapy micronutrients Non-cancer drugs Novel strategies

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Physical exercise and traumatic brain injury: is it question of time?

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Neural Regeneration Research 2024年第3期19卷 475-476页

作者： Valentina Mastrorilli Stefano Farioli Vecchioli institute of Biochemistry and cell biology Institute of Biochemistry and Cell BiologyNational Research Council(IBBC/CNR)MonterotondoRomeItaly Plaisant S.R.L. RomeItaly

Is it better to be safe than sorry?This Hamletic dilemma has always stimulated medical-scientific debates in numerous fields of biomedicine.And among these,the preventive-therapeutic approach to the treatment of brain trauma is one of the most striking examples.Traumatic brain injury(TBI)is a leading cause of brain damage among young and elderly populations with a very high hospitalization and death rate.TBI is characterized by two pathologically distinct but strictly consequential phases:a first characterized by an immediate and highly variable mechanical dysfunction of the brain tissue,which involves widespread cell death and tissue degeneration,followed by a second phase which can last from days to even years depending on the severity of the TBI and the patient’s pre-existing health status.Secondary processes,including inflammatory phenomena,oxidative stress associated with metabolic,vascular,and neuro-modulatory deficits,are very often responsible for neuro-motor and psychological deficits leading to long-term disabilities(Kaur and Sharma,2018).

关键词： injury striking modulator

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Angiogenesis in diseases:A half-century excursion from the initial therapeutic concept to current clinical benefits

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Chinese Medical Journal 2024年第6期137卷 636-637页

作者： Yihai Cao Department of Microbiology Tumor and Cell BiologyKarolinska InstituteStockholm 17177Sweden

Except a few tissues such as the cornea and cartilage that are avascular,blood vessels constitute a significant proportion of tissue masses in virtually all organs.Under physiological conditions,the adult vasculature remains quiescent to retain tissue and organ homeostatic functions.Too few or too many blood vessels are associated with the onset and progression of many diseases.In response to injuries,most tissues undergo repair by switching on angiogenesis,a key process of new blood vessel formation.^([1])Similarly,angiogenesis is often active in pathological tissues,including tumors and ischemic tissues to aggravate disease progression.

关键词： injuries organs diseases

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The evolving views of hematopoiesis:from embryo to adulthood and from in vivo to in vitro

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Journal of Genetics and Genomics 2024年第1期51卷 3-15页

作者： Yifan Zhang Feng Liu Shandong Provincial Key Laboratory of Animal cell and Developmental biology School of Life SciencesShandong UniversityQingdaoShandong 266237China State Key Laboratory of Membrane biology Institute of ZoologyInstitute for Stem Cell and RegenerationUniversity of Chinese Academy of SciencesChinese Academy of SciencesBeijing 100101China

The hematopoietic system composed of hematopoietic stem and progenitor cells(HSPCs)and their differentiated lineages serves as an ideal model to uncover generic principles of cell fate transitions.From gastrulation onwards,there successively emerge primitive hematopoiesis(that produces specialized he-matopoietic cells),pro-definitive hematopoiesis(that produces lineage-restricted progenitor cells),and definitive hematopoiesis(that produces multipotent HSPCs).These nascent lineages develop in several transient hematopoietic sites and finally colonize into lifelong hematopoietic sites.The development and maintenance of hematopoietic lineages are orchestrated by cell-intrinsic gene regulatory networks and cell-extrinsic microenvironmental cues.Owing to the progressive methodology(e.g.,high-throughput lineage tracing and single-cell functional and omics analyses),our understanding of the developmental origin of hematopoietic lineages and functional properties of certain hematopoietic organs has been updated;meanwhile,new paradigms to characterize rare cell types,cell heterogeneity and its causes,and comprehensive regulatory landscapes have been provided.Here,we review the evolving views of HSPC biology during developmental and postnatal hematopoiesis.Moreover,we discuss recent advances in the in vitro induction and expansion of HSPCs,with a focus on the implications for clinical applications.

关键词： Hematopoietic stem and progenitor cell Developmental hematopoiesis Postnatal hematopoiesis In vitro hematopoiesis

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Programmable synthetic receptors:the next-generation of cell and gene therapies

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Signal Transduction and Targeted Therapy 2024年第2期9卷 376-400页

作者： Fei Teng Tongtong Cui Li Zhou Qingqin Gao Qi Zhou Wei Li University of Chinese Academy of Sciences Beijing 101408China State Key Laboratory of Stem cell and Regenerative biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China institute for Stem cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing institute for Stem cell and Regenerative Medicine Beijing 100101China

cell and gene therapies hold tremendous promise for treating a range of difficult-to-treat diseases.However,concerns over the safety and efficacy require to be further addressed in order to realize their full potential.Synthetic receptors,a synthetic biology tool that can precisely control the function of therapeutic cells and genetic modules,have been rapidly developed and applied as a powerful solution.Delicately designed and engineered,they can be applied to finetune the therapeutic activities,i.e.,to regulate production of dosed,bioactive payloads by sensing and processing user-defined signals or biomarkers.This review provides an overview of diverse synthetic receptor systems being used to reprogram therapeutic cells and their wide applications in biomedical research.With a special focus on four synthetic receptor systems at the forefront,including chimeric antigen receptors(CARs)and synthetic Notch(synNotch)receptors,we address the generalized strategies to design,construct and improve synthetic receptors.Meanwhile,we also highlight the expanding landscape of therapeutic applications of the synthetic receptor systems as well as current challenges in their clinical translation.

关键词： synthetic landscape payload

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AtVQ25 promotes salicylic acid-related leaf senescence by fine-tuning the self-repression of AtWRKY53

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Journal of Integrative Plant biology 2024年第6期66卷 1126-1147页

作者： Qi Tan Mingming Zhao Jingwei Gao Ke Li Mengwei Zhang Yunjia Li Zeting Liu Yujia Song Xiaoyue Lu Zhengge Zhu Rongcheng Lin Pengcheng Yin Chunjiang Zhou Geng Wang Ministry of Education Key Laboratory of Molecular and cellular biology Hebei Research Center of the Basic Discipline of Cell BiologyHebei Collaboration Innovation Center for Cell Signaling and Environmental Adaptation Hebei Key Laboratory of Molecular and Cellular Biology College of Life Sciences Hebei Normal University College of Chemical Engineering Shijiazhuang University institute of Botany Chinese Academy of Sciences

Most mechanistic details of chronologically ordered regulation of leaf senescence are unknown.Regulatory networks centered on AtWRKY53 are crucial for orchestrating and integrating various senescence-related signals. Notably, AtWRKY53binds to its own promoter and represses transcription of AtWRKY53, but the biological significance and mechanism underlying this selfrepression remain unclear. In this study, we identified the VQ motif-containing protein AtVQ25as a cooperator of AtWRKY53. The expression level of AtVQ25 peaked at mature stage and was specifically repressed after the onset of leaf senescence. AtVQ25-overexpressing plants and atvq25 mutants displayed precocious and delayed leaf senescence, respectively. Importantly, we identified AtWRKY53 as an interacting partner of AtVQ25. We determined that interaction between AtVQ25 and AtWRKY53 prevented AtWRKY53from binding to W-box elements on the AtWRKY53promoter and thus counteracted the selfrepression of AtWRKY53. In addition, our RNA-sequencing data revealed that the AtVQ25-AtWRKY53 module is related to the salicylic acid(SA) pathway. Precocious leaf senescence and SA-induced leaf senescence in AtVQ25-overexpressing lines were inhibited by an SA pathway mutant, atsid2, and Nah G transgenic plants; AtVQ25-overexpressing/atwrky53 plants were also insensitive to SA-induced leaf senescence. Collectively, we demonstrated that AtVQ25 directly attenuates the self-repression of AtWRKY53 during the onset of leaf senescence,which is substantially helpful for understanding the timing of leaf senescence onset modulated by AtWRKY53.

关键词： AtWRKY53 leaf senescence salicylic acid transcriptional regulation VQ motif-containing proteins

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Opto-fluidically multiplexed assembly and micro-robotics

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Light(Science & Applications) 2024年第3期13卷 544-554页

作者： Elena Erben Weida Liao Antonio Minopoli Nicola Maghelli Eric Lauga Moritz Kreysing Max Planck institute of Molecular cell biology and Genetics Dresden 01307Germany Center for Systems biology Dresden 01307Germany institute of Biological and Chemical Systems–Biological Information Processing.Karlsruhe institute of Technology(KIT) Eggenstein-Leopoldshafen 76344Germany Department of Applied Mathematics and Theoretical Physics University of CambridgeCambridge CB30WAUK

Techniques for high-definition micromanipulations,such as optical tweezers,hold substantial interest across a wide range of disciplines.However,their applicability remains constrained by material properties and laser exposure.And while microfluidic manipulations have been suggested as an alternative,their inherent capabilities are limited and further hindered by practical challenges of implementation and control.Here we show that the iterative application of laser-induced,localized flow fields can be used for the relative positioning of multiple micro-particles,irrespectively of their material properties.Compared to the standing theoretical proposal,our method keeps particles mobile,and we show that their precision manipulation is non-linearly accelerated via the multiplexing of temperature stimuli below the heat diffusion limit.The resulting flow fields are topologically rich and mathematically predictable.They represent unprecedented microfluidic control capabilities that are illustrated by the actuation of humanoid micro-robots with up to 30 degrees of freedom,whose motions are sufficiently well-defined to reliably communicate personal characteristics such as gender,happiness and nervousness.Our results constitute high-definition micro-fluidic manipulations with transformative potential for assembly,micro-manufacturing,the life sciences,robotics and optohydraulically actuated micro-factories.

关键词： manipulation fluid assembly

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One-step cell biomanufacturing platform:porous gelatin microcarrier beads promote human embryonic stem cell-derived midbrain dopaminergic progenitor cell differentiation in vitro and survival after transplantation in vivo

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Neural Regeneration Research 2024年第2期19卷 458-464页

作者： Lin Feng Da Li Yao Tian Chengshun Zhao Yun Sun Xiaolong Kou Jun Wu Liu Wang Qi Gu Wei Li Jie Hao Baoyang Hu Yukai Wang State Key Laboratory of Stem cell and Reproductive biology Institute of ZoologyChinese Academy of SciencesBeijingChina institute for Stem cell and Regenerative Medicine Chinese Academy of SciencesBeijingChina National Stem cell Resource Center Chinese Academy of SciencesBeijingChina Savaid Medical School University of Chinese Academy of SciencesBeijingChina Beijing institute for Stem cell and Regenerative Medicine BeijingChina State Key Laboratory of Membrane biology Institute of ZoologyChinese Academy of SciencesBeijingChina

Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a promising treatment for Parkinson’s disease.However,transplanted cells can be injured by mechanical damage during handling and by changes in the transplantation niche.Here,we developed a one-step biomanufacturing platform that uses small-aperture gelatin microcarriers to produce beads carrying midbrain dopaminergic progenitor cells.These beads allow midbrain dopaminergic progenitor cell differentiation and cryopreservation without digestion,effectively maintaining axonal integrity in vitro.Importantly,midbrain dopaminergic progenitor cell bead grafts showed increased survival and only mild immunoreactivity in vivo compared with suspended midbrain dopaminergic progenitor cell grafts.Overall,our findings show that these midbrain dopaminergic progenitor cell beads enhance the effectiveness of neuronal cell transplantation.

关键词： axonal integrity cell cryopreservation cellular environment cellular niche cell replacement therapy dopaminergic progenitors human pluripotent stem cell mechanical damage neuronal cell delivery Parkinson’s disease small-aperture gelatin microcarriers

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Exploring noncoding variants in genetic diseases:from detection to functional insights

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Journal of Genetics and Genomics 2024年第2期51卷 111-132页

作者： Ke Wu Fengxiao Bu Yang Wu Gen Zhang Xin Wang Shunmin He Mo-Fang Liu Runsheng Chen Huijun Yuan institute of Rare Diseases West China Hospital of Sichuan UniversityChengduSichuan 610041China Key Laboratory of Systems Health Science of Zhejiang Province School of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhouZhejiang 310024China Key Laboratory of RNA biology Center for Big Data Research in HealthInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Molecular biology State Key Laboratory of Cell BiologyShanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai 200031China

Previous studies on genetic diseases predominantly focused on protein-coding variations, overlooking the vast noncoding regions in the human genome. The development of high-throughput sequencing technologies and functional genomics tools has enabled the systematic identification of functional noncoding variants. These variants can impact gene expression, regulation, and chromatin conformation, thereby contributing to disease pathogenesis. Understanding the mechanisms that underlie the impact of noncoding variants on genetic diseases is indispensable for the development of precisely targeted therapies and the implementation of personalized medicine strategies. The intricacies of noncoding regions introduce a multitude of challenges and research opportunities. In this review, we introduce a spectrum of noncoding variants involved in genetic diseases, along with research strategies and advanced technologies for their precise identification and in-depth understanding of the complexity of the noncoding genome. We will delve into the research challenges and propose potential solutions for unraveling the genetic basis of rare and complex diseases.

关键词： Noncoding variation Genetic disease Research approach Challenge

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Recent progress in hair follicle stem cell markers and their regulatory roles

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World Journal of Stem cells 2024年第2期16卷 126-136页

作者： Yi-Zhan Xing Hai-Ying Guo Fei Xiang Yu-Hong Li Department of cell biology Army Medical UniversityChongqing 400038China institute of Burn Research Southwest HospitalArmy Medical UniversityChongqing 400038China

Hair follicle stem cells(HFSCs)in the bulge are a multipotent adult stem cell population.They can periodically give rise to new HFs and even regenerate the epidermis and sebaceous glands during wound healing.An increasing number of biomarkers have been used to isolate,label,and trace HFSCs in recent years.Considering more detailed data from single-cell transcriptomics technology,we mainly focus on the important HFSC molecular markers and their regulatory roles in this review.

关键词： Hair follicle stem cells Bulge Secondary hair germ Marker Single-cell RNA-sequencing

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