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Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies

Signal Transduction and Targeted Therapy 2024年第1期9卷 173-210页

作者： Md Entaz Bahar Hyun Joon Kim Deok Ryong Kim department of Biochemistry and Convergence medical sciences and Institute of medical Science Gyeongsang National UniversityCollege of MedicineJinjuSouth Korea department of Anatomy and Convergence medical sciences and Institute of medical Science Gyeongsang National UniversityCollege of MedicineJinjuSouth Korea

Metastatic dissemination of solid tumors,a leading cause of cancer-related mortality,underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis,chemoresistance,and the mechanistic backgrounds of individuals whose cancers are prone to *** most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase(MAPK)pathway,encompassing the RAS–RAF–MAPK kinase(MEK)–extracellular signal-related kinase(ERK)*** kinase is a primary mediator of the MAPK pathway,responsible for the sequential activation of downstream targets,such as MEK and the transcription factor ERK,which control numerous cellular and physiological processes,including organism development,cell cycle control,cell proliferation and differentiation,cell survival,and *** in this signaling cascade are associated with diseases such as *** inhibitors(RAFi)combined with MEK blockers represent an FDAapproved therapeutic strategy for numerous RAF-mutant cancers,including melanoma,non-small cell lung carcinoma,and thyroid ***,the development of therapy resistance by cancer cells remains an important ***,an intracellular lysosome-dependent catabolic recycling process,plays a critical role in the development of RAFi resistance in ***,targeting RAF and autophagy could be novel treatment strategies for RAF-mutant *** this review,we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and ***,we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic ***,this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.

关键词： RAF insight mechanism

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Perspectives on the role of Pannexin 1 in neural precursor cell biology

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Neural Regeneration Research 2016年第10期11卷 1540-1544页

作者： Juan C.Sanchez-Arias Leigh E.Wicki-Stordeur Leigh Anne Swayne Division of medical sciences University of Victoria island medical program and department of cellular and physiological sciences University of British Columbia

We recently reported that targeted deletion of Pannexin 1 in neural precursor cells of the ventricular zone impairs the maintenance of these cells in healthy and stroke-injured brain. Here we frame this exciting new finding in the context of our previous studies on Pannexin 1 in neural precursors as well as the close rela- tionship between Pannexin 1 and purinergic receptors established by other groups. Moreover, we identify important gaps in our understanding of Pannexin 1 in neural precursor cell biology in terms of the under- lying molecular mechanisms and functional/behavioural outcomes.

关键词： neural precursor ventricular zone pannexin ATP cytoskeleton proliferation phagoptosis

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CircPTEN-MT from PTEN regulates mitochondrial energy metabolism

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Journal of Genetics and Genomics 2024年第5期51卷 531-542页

作者： Danhui Ruan Jiancheng Xu Yang Liu Juan Luo Xuyang Zhao Yuhua Li Guangxi Wang Jiawen Feng Hui Liang Yue Yin Jianyuan Luo Yuxin Yin Institute of Systems Biomedicine Department of PathologySchool of Basic Medical SciencesBeijing Key Laboratory of Tumor Systems BiologyPeking University International Cancer InstitutePeking-Tsinghua Center of Life SciencesPeking University Health Science CenterBeijing 100191China Institute of Precision Medicine Peking University Shenzhen HospitalShenzhenGuangdong 518036China department of Pharmacology School of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China department of medical Genetics Center for Medical GeneticsSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Soochow University Cancer Institute SuzhouJiangsu 215127China

Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological *** RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or ***,PTEN-related circRNAs are largely ***,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy ***-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in *** down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate *** data demonstrate that circPTEN-MT is an important regulator of cellular energy *** study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.

关键词： Circular RNA LRPPRC Mitochondrial energy metabolism mtDNA post-transcriptional regulation

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TGF-βsignaling in health,disease,and therapeutics

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1466-1505页

作者： Ziqin Deng Tao Fan Chu Xiao He Tian Yujia Zheng Chunxiang Li Jie He department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

ransforming growth factor(TGF)-βis a multifunctional cytokine expressed by almost every tissue and cell *** signal transduction of TGF-βcan stimulate diverse cellular responses and is particularly critical to embryonic development,wound healing,tissue homeostasis,and immune homeostasis in *** dysfunction of TGF-βcan play key roles in many diseases,and numerous targeted therapies have been developed to rectify its pathogenic *** the past decades,a large number of studies on TGF-βsignaling have been carried out,covering a broad spectrum of topics in health,disease,and ***,a comprehensive overview of TGF-βsignaling is required for a general picture of the studies in this *** this review,we retrace the research history of TGF-βand introduce the molecular mechanisms regarding its biosynthesis,activation,and signal *** also provide deep insights into the functions of TGF-βsignaling in physiological conditions as well as in pathological ***-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are *** the summary of previous knowledge and recent updates,this review aims to provide a systematic understanding of TGF-βsignaling and to attract more attention and interest to this research area.

关键词： homeostasis healing wound

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Extracellular vesicles as tools and targets in therapy for diseases

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Signal Transduction and Targeted Therapy 2024年第3期9卷 872-912页

作者： Mudasir A.Kumar Sadaf K.Baba Hana Q.Sadida Sara Al.Marzooqi Jayakumar Jerobin Faisal H.Altemani Naseh Algehainy Mohammad A.Alanazi Abdul-Badi Abou-Samra Rakesh Kumar Ammira S.Al-Shabeeb Akil Muzafar A.Macha Rashid Mir Ajaz A.Bhat Watson-Crick Centre for Molecular Medicine Islamic University of Science and TechnologyAwantiporaKashmir 192122India department of Human Genetics-Precision Medicine in Diabetes Obesity and Cancer ProgramSidra MedicineDohaQatar Qatar Metabolic Institute Academic Health SystemHamad Medical CorporationDohaQatar department of medical Laboratory Technology Prince Fahad Bin Sultan Chair for Biomedical ResearchFaculty of Applied Medical SciencesUniversity of TabukTabukSaudi Arabia School of Biotechnology Shri Mata Vaishno Devi UniversityKatraIndia

Extracellular vesicles(EVs)are nano-sized,membranous structures secreted into the extracellular *** exhibit diverse sizes,contents,and surface markers and are ubiquitously released from cells under normal and pathological *** serum is a rich source of these EVs,though their isolation from serum proteins and non-EV lipid particles poses *** vesicles transport various cellular components such as proteins,mRNAs,miRNAs,DNA,and lipids across distances,influencing numerous physiological and pathological events,including those within the tumor microenvironment(TME).Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents,drug delivery systems,and disease *** in cancer diagnostics,EV detection can pave the way for early identification and offers potential as diagnostic ***,various EV subtypes are emerging as targeted drug delivery tools,highlighting their potential clinical *** need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains *** into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the *** this review,we discuss in detail the roles of EVs across various conditions,including cancers(encompassing head and neck,lung,gastric,breast,and hepatocellular carcinoma),neurodegenerative disorders,diabetes,viral infections,autoimmune and renal diseases,emphasizing the potential advancements in molecular diagnostics and drug delivery.

关键词： diseases sized sizes

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Three-dimensional bioprinting biphasic multicellular living scaffold facilitates osteochondral defect regeneration

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Interdisciplinary Materials 2024年第5期3卷 738-756页

作者： Xingge Yu Mazaher Gholipourmalekabadi Xudong Wang Changyong Yuan Kaili Lin department of Oral and Cranio-Maxillofacial Science Shanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina College of Stomatology Shanghai Jiao Tong UniversityShanghaiChina National Center for Stomatology ShanghaiChina National Clinical Research Center for Oral Diseases ShanghaiChina Shanghai Key Laboratory of Stomatology ShanghaiChina Research Unit of Oral and Maxillofacial Regenerative Medicine Chinese Academy of Medical SciencesShanghaiChina cellular and Molecular Research Center Iran University of Medical SciencesTehranIran department of medical Biotechnology Faculty of Allied MedicineIran University of Medical SciencesTehranIran Affiliated Stomatological Hospital of Xuzhou medical University XuzhouJiangsuChina School of Stomatology Xuzhou Medical UniversityXuzhouJiangsuChina

Due to tissue lineage variances and the anisotropic physiological character-istics,regenerating complex osteochondral tissues(cartilage and subchondral bone)remains a great challenge,which is primarily due to the distinct requirements for cartilage and subchondral bone *** cartilage regeneration,a significant amount of newly generated chondrocytes is required while maintaining their ***,bone regeneration necessitates inducing stem cells to differentiate into ***,the construction of the osteochondral interface is *** this study,we fabricated a biphasic multicellular bioprinted scaffold mimicking natural osteochondral tissue employing three-dimensional(3D)bioprinting ***,gelatin-methacryloyl(GelMA)loaded with articular chondrocytes and bone marrow mesenchymal stem cells(ACs/BMSCs),serving as the cartilage layer,preserved the phenotype of ACs and promoted the differentia-tion of BMSCs into chondrocytes through the interaction between ACs and BMSCs,thereby facilitating cartilage ***/strontium-substituted xonotlite(Sr-CSH)loaded with BMSCs,serving as the subchondral bone layer,regulated the differentiation of BMSCs into osteoblasts and enhanced the secretion of cartilage matrix by ACs in the cartilage layer through the slow release of bioactive ions from ***,GelMA,serving as the matrix material,contributed to the reconstruction of the osteochondral ***,this biphasic multicellular bioprinted scaffold demonstrated satisfactory simultaneous regeneration of osteochondral *** this study,a promising strategy for the application of 3D bioprinting technology in complex tissue regeneration was proposed.

关键词： 3D bioprinting biphasic scaffolds interface reconstruction multicellularity osteochondral defects

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Developing a fluorescence substrate for HRP-based diagnostic assays with superiorities over the commercial ADHP

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Chinese Chemical Letters 2024年第6期35卷 439-444页

作者： Zhichao Zhou Fuqian Chen Xiaotong Xia Dong Ye Rong Zhou Lei Li Tao Deng Zhenhua Ding Fang Liu department of Radiation Medicine Guangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhou 510515China School of Pharmaceutical sciences Guangzhou University of Chinese MedicineGuangzhou 510006China Artemisinin Research Center Guangzhou University of Chinese MedicineGuangzhou 510006China State Key Laboratory of Respiratory Disease the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhou 510120China Guangzhou Laboratory Bio-IslandGuangzhou 510030China Nanshan Pharmaceutical Innovation Research Institute of Guangdong Province Foshan 528225China

The combination of horseradish peroxidase(HRP)and a fluorescence substrate has been attracting great interests in developing sensitive biochemical analysis and immunoassays.10-Acetyl-3,7-dihydroxyphenoxazine(ADHP or Amplex red)is the most sensitive fluorogenic substrate known for HRP in current market,however,it suffers from some drawbacks,such as non-specific reactivity to carboxylesterase and limited fluorescence *** the present study,a novel HRP substrate10-cyclopropylcarbonyl-dichloro-dihydroxyphenoxazine(AR-2),has been prepared,which exhibited improved sensitivity than ADHP in sensing ***,the fluorescence of AR-2/HRP demonstrated improved tolerance to physiological relevant p H fluctuation as compared to ADHP/*** detection of uric acid/urate oxidase reaction indicated excellent application prospect of AR-2/HRP for monitoring H_(2)O_(2)-generating biochemical *** interestingly,an enzyme-linked immunosorbent assay(ELISA)using AR-2 as the fluorescence reporter has been successfully used in detecting IgG against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)from human serum ***,AR-2 exhibits improved performances over the commercial ADHP,which will be an ideal alternative to ADHP in HRP-based fluorescence biochemical analysis and immunoassays.

关键词： Fluorescence immunoassay HRP fluorescence substrate Hydroresorufin Amplex red/ADHP SARS-CoV-2

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TSPO deficiency exacerbates acute lung injury via NLRP3 inflammasome-mediated pyroptosis

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Chinese medical Journal 2024年第13期137卷 1592-1602页

作者： Jingyi Han Xue Zhang Menghua Cai Feng Tian Yi Xu Hui Chen Wei He Jianmin Zhang Hui Tian department of Thoracic Surgery Qilu Hospital of Shandong UniversityJinanShandong 250012China CAMS Key Laboratory of T Cell and Immunotherapy Department of ImmunologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and School of Basic MedicinePeking Union Medical CollegeState Key Laboratory of Medical Molecular BiologyBeijing 100005China Changzhou Xitaihu Institute for Frontier Technology of Cell Therapy ChangzhouJiangsu 213000China Haihe Laboratory of Cell Ecosystem Chinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China

Background:Acute respiratory distress syndrome(ARDS)is a common cause of respiratory failure in many critically ill *** inflammasome activation plays an important role in the induction of acute lung injury(ALI)and ARDS,the regulatory mechanism of this process is still *** cells are stimulated by inflammation,the integrity and physiological function of mitochondria play a crucial part in ***,the underlying mechanisms and function of mitochondrial proteins in the process of pyroptosis are largely not yet ***,we identified the 18-kDa translocator protein(TSPO),a mitochondrial outer membrane protein,as an important mediator regulating nucleotide-binding domain,leucine-rich repeat,and pyrin domain-containing protein 3(NLRP3)inflammasome activation in macrophages during ***:TSPO gene knockout(KO)and lipopolysaccharide(LPS)-induced ALI/ARDS mouse models were employed to investigate the biological role of TSPO in the pathogenesis of *** macrophages were used to further characterize the effect of TSPO on the NLRP3 inflammasome *** of NLRP3 inflammasome was preformed through LPS+adenosine triphosphate(ATP)co-stimulation,followed by detection of mitochondrial membrane potential,reactive oxygen species(ROS)production,and cell death to evaluate the potential biological function of *** between two groups were performed with a two-sided unpaired ***:TSPO-KO mice exhibited more severe pulmonary inflammation in response to LPS-induced *** deficiency resulted in enhanced activation of the NLRP3 inflammasome pathway,promoting more proinflammatory cytokine production of macrophages in LPS-injured lung tissue,including interleukin(IL)-1β,IL-18,and macrophage inflammatory protein(MIP)-*** in TSPO-KO macrophages tended to depolarize in response to cellular *** increased production of mitochondrial damage-associated molecular pattern led to enhanced mitochondrial membr

关键词： Acute respiratory distress syndrome Acute lung injury 18-kDa translocator protein Macrophage NLRP3 inflammasome Inflammation

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Skeletal stem cells in bone development,homeostasis,and disease

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Protein & Cell 2024年第8期15卷 559-574页

作者： Guixin Yuan Xixi Lin Ying Liu Matthew B.Greenblatt Ren Xu The First Affliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell State Key Laboratory of Cellular Stress BiologySchool of MedicineFaculty of Medicine and Life SciencesXiamen UniversityXiamen 361005China Xiamen Key Laboratory of Regeneration Medicine Fujian Provincial Key Laboratory of Organ and Tissue RegenerationOrgan Transplantation InstituteSchool of MedicineXiamen UniversityXiamen 361102China department of Pathology and Laboratory Medicine Weill Cormell Medical CollegeNew YorkNY 10065USA Research Division Hospital for Special SurgeryNew YorkNY10065USA

Tissue-resident stem cells are essential for development and repair,and in the skeleton,this function is fulfilled by recently identified skeletal stem cells(SSCs).However,recent work has identified that SSCs are not monolithic,with long bones,craniofacial sites,and the spine being formed by distinct stem *** studies have utilized techniques such as fluorescence-activated cell sorting,lineage tracing,and single-cell sequencing to investigate the involvement of ssCs in bone development,homeostasis,and *** investigations have allowed researchers to map the lineage commitment trajectory of ssCs in different parts of the body and at different time ***,recent studies have shed light on the characteristics of ssCs in both physiological and pathological *** review focuses on discussing the spatiotemporal distribution of ssCs and enhancing our understanding of the diversity and plasticity of ssCs by summarizing recent discoveries.

关键词： skeletal stem cells bone development endochondral ossification intramembranous ossification lineage tracing

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cellular and Transcriptional Dynamics during Brown Adipose Tissue Regeneration under Acute Injury

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Research 2024年第3期2023卷 345-357页

作者： Wenjing You Ziye Xu Wentao Chen Xin Yang Shiqi Liu Liyi Wang Yuang Tu Yanbing Zhou Teresa G.Valencak Yizhen Wang Shihuan Kuang Tizhong Shan College of Animal sciences Zhejiang UniversityHangzhouChina The Key Laboratory of Molecular Animal Nutrition Ministry of EducationHangzhouChina Zhejiang Provincial Laboratory of Feed and Animal Nutrition HangzhouChina department of Laboratory Medicine the First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina department of Animal sciences Purdue UniversityWest LafayetteINUSA.

Brown adipose tissue(BAT)is the major site of non-shivering thermogenesis and crucial for systemic *** chronic cold exposures and high-fat diet challenges,BAT undergoes robust remodeling to adapt to physiological ***,whether and how BAT regenerates after acute injuries are poorly ***,we established a novel BAT injury and regeneration model(BAT-IR)in mice and performed single-cell RNA sequencing(scRNA-seq)and bulk RNA-seq to determine cellular and transcriptomic dynamics during *** further defined distinct fibro-adipogenic and myeloid progenitor populations contributing to BAT *** trajectory and gene expression analyses uncovered the involvement of MAPK,Wnt,and Hedgehog(Hh)signaling pathways in BAT *** confirmed the role of Hh signaling in BAT development through Myf5Cre-mediated conditional knockout(cKO)of the Sufu gene to activate Hh signaling in BAT and muscle *** BAT-IR model therefore provides a paradigm to identify conserved cellular and molecular mechanisms underlying BAT development and remodeling.

关键词： injuries involvement acute

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