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Oncogenic β-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis

Chinese Medical Journal 2024年第2期137卷 181-189页

作者： Fangming Liu Yuting Wu Baohui Zhang Shuhui Yang Kezhuo Shang Jie Li Pengju Zhang Weiwei Deng Linlin Chen Liang Zheng Xiaochen Gai Hongbing Zhang Department of Physiology State Key Laboratory of Common Mechanism Research for Major DiseasesHaihe Laboratory of Cell EcosystemInstitute of Basic Medical Sciences and School of Basic MedicineChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China Department of Physiology Institute of Basic Medical Sciences and School of Basic MedicineGraduate School of Peking Union Medical CollegeChinese Academy of Medical SciencesBeijing100005China Department of Physiology School of Life ScienceChina Medical UniversityShenyangLiaoning 110122China School of life sciences Westlake UniversityHangzhouZhejiang 310024China Key Laboratory of Pediatric Hematology and Oncology Ministry of HealthInstitute of Pediatric Translational MedicineShanghai Children’s Medical CenterShanghai Jiao Tong School of MedicineShanghai 200127China

Background:Liver cancer is largely resistant to chemotherapy.This study aimed to identify the effective chemotherapeutics forβ-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1(CTNNB1),the most frequently altered proto-oncogene in hepatic neoplasms.Methods:Constitutiveβ-catenin-activated mouse embryonic fibroblasts(MEFs)were established by deleting exon 3(β-catenin^(Δ(ex3)/+)),the most common mutation site in CTNNB1 gene.A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibitedβ-catenin^(Δ(ex3)/+)but not for wild-type MEFs.Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis.The efficacy and selectivity of methotrexate(MTX)onβ-catenin-activated human liver cancer cells were determined in vitro.Immuno-deficient nude mice subcutaneously inoculated withβ-catenin wild-type or mutant liver cancer cells and hepatitis B virus(HBV);β-catenin^(lox(ex3)/+)mice were used,respectively,to evaluate the efficacy of MTX in the treatment ofβ-catenin mutant liver cancer.Results:MTX was identified and validated as a preferential agent against the proliferation and tumor formation ofβ-catenin-activated cells.Boosted nucleotide synthesis was the major metabolic aberration inβ-catenin-active cells,and this alteration was also the target of MTX.Moreover,MTX abrogated hepatocarcinogenesis of HBV;β-catenin^(lox(ex3)/+)mice,which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer.Conclusion:MTX is a promising chemotherapeutic agent forβ-catenin hyperactive liver cancer.Since repurposing MTX has the advantages of lower risk,shorter timelines,and less investment in drug discovery and development,a clinical trial is warranted to test its efficacy in the treatment ofβ-catenin mutant liver cancer.

关键词： Liver cancer β-catenin Methotrexate Nucleotide synthesis Chemotherapy

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

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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 migration.The 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)pathway.RAF 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 death.Defects in this signaling cascade are associated with diseases such as cancer.RAF 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 cancer.However,the development of therapy resistance by cancer cells remains an important barrier.Autophagy,an intracellular lysosome-dependent catabolic recycling process,plays a critical role in the development of RAFi resistance in cancer.Thus,targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers.In this review,we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance.Furthermore,we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles.Additionally,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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Immune checkpoint inhibitors:breakthroughs in cancer treatment

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Cancer Biology & medicine 2024年第6期21卷 451-472页

作者： Xueqing Kong Jinyi Zhang Shuwei Chen Xianyang Wang Qing Xi Han Shen Rongxin Zhang Laboratory of Immunology and Inflammation School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University Department of Biology School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University

Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade(ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies(mAbs) are currently available as immune checkpoint inhibitors(ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4(CTLA-4) and programmed cell death protein 1(PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response.Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1(anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains(TIGIT), mucin domain containing-3(TIM-3), lymphocyte activation gene-3(LAG-3), V-domain immunoglobulin suppressor of T cell activation(VISTA), B and T lymphocyte attenuator(BTLA), and signal-regulatory protein α(SIRPα). Functional m Abs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in m Abs targeting these immune checkpoint molecules and their potential applications.

关键词： CTLA-4 ICIs Immunotherapy PD-1 cancer

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Comparative and Phylogenetic Analysis of the Complete Chloroplast Genomes of 19 Species in Rosaceae Family

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Phyton-International Journal of Experimental Botany 2024年第6期93卷 1203-1219页

作者： Riwa Mahai Rongpeng Liu Xiaolang Du Zejing Mu Xiaoyun Wang Jun Yuan Research Center for Traditional Chinese medicine Resources and Ethnic Minority medicine Jiangxi University of Chinese MedicineNanchang330004China college of life sciences Jiangxi University of Chinese MedicineNanchang330004China

Rosaceae represents a vast and complex group of species,with its classiﬁcation being intricate and contentious.The taxonomic placement of many species within this family has been a subject of ongoing debate.The study utilized the Illumina platform to sequence 19 plant species from 10 genera in the Rosaceae.The cp genomes,vary-ing in size from 153,366 to 159,895 bp,followed the typical quadripartite organization consisting of a large single-copy(LSC)region(84,545 to 87,883 bp),a small single-copy(SSC)region(18,174 to 19,259 bp),and a pair of inverted repeat(IR)regions(25,310 to 26,396 bp).These genomes contained 132–138 annotated genes,including 87 to 93 protein-coding genes(PCGs),37 tRNA genes,and 8 rRNA genes using MISA software,52 to 121 simple sequence repeat(SSR)loci were identiﬁed.D.arbuscular contained the least of SSRs and did not have hexanotides,A.lineata contained the richest SSRs.Long terminal repeats(LTRs)were primarily composed of palindromic and forward repeat sequences,meanwhile,The richest LTRs were found in Argentina lineata.Except for Argentina lineata,Fragariastrum eriocarpum,and Prunus trichostoma,which varied in gene type and position on both sides of the boundary,the remaining species were found to be mostly conserved according to IR boundary analysis.The examination of the Ka/Ks ratio revealed that only the infA gene had a value greater than 1,indicating that this gene was primarily subjected to positive selection during evolution.Additionally,9 hotspots of variation were identiﬁed in the LSC and SSC regions.Phylogenetic analysis conﬁrmed the scientiﬁc validity of the genus Prunus L.sensu lato(s.l.)within the Rosaceae family.The separation of the three genera Argentina Hill,Fragariastrum Heist.ex Fabr.and Dasiphora Raf.from Potentilla L.may be a more scientiﬁc classiﬁcation.These results offer fresh perspectives on the taxonomy of the Rosaceae.

关键词： Rosaceae chloroplast genomes comparative genomes phylogeny

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Density functional theory study of B- and Si-doped carbons and their adsorption interactions with sulfur compounds

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Carbon Energy 2024年第2期6卷 195-208页

作者： Peng Guo Hong Zhang Shuliang Dong Libao An college of Mechanical Engineering North China University of Science and TechnologyTangshanHebeiChina college of life sciences North China University of Science and TechnologyTangshanHebeiChina

Understanding the adsorption interactions between carbon materials and sulfur compounds has far-reaching impacts,in addition to their well-known important role in energy storage and conversion,such as lithium-ion batteries.In this paper,properties of intrinsic B or Si single-atom doped,and B-Si codoped graphene(GR)and graphdiyne(GDY)were investigated by using density functional theory-based calculations,in which the optimal doping configurations were explored for potential applications in adsorbing sulfur compounds.Results showed that both B or Si single-atom doping and B-Si codoping could substantially enhance the electron transport properties of GR and GDY,improving their surface activity.Notably,B and Si atoms displayed synergistic effects for the codoped configurations,where B-Si codoped GR/GDY exhibited much better performance in the adsorption of sulfurcontaining chemicals than single-atom doped systems.In addition,results demonstrated that,after B-Si codoping,the adsorption energy and charge transfer amounts of GDY with sulfur compounds were much larger than those of GR,indicating that B-Si codoped GDY might be a favorable material for more effectively interacting with sulfur reagents.

关键词： adsorption density functional theory doping graphdiyne graphene sulfur compounds

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C1QTNF5 is a novel attachment factor that facilitates the entry of influenza A virus

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Virologica Sinica 2024年第2期39卷 277-289页

作者： Lei Yu Xinjin Liu Xiaoqin Wei Junrui Ren Xueyun Wang Shuwen Wu Ke Lan State Key Laboratory of Virology Medical Research InstituteCollege of Life SciencesWuhan UniversityWuhan430072China Frontier Science Center for Immunology and Metabolism Wuhan UniversityWuhan430072China Taikang Center for life and Medical sciences Wuhan UniversityWuhan430072China

Influenza A virus(IAV)binds sialic acid receptors on the cell surface to enter the host cells,which is the key step in initiating infection,transmission and pathogenesis.Understanding the factors that contribute to the highly efficient entry of IAV into human cells will help elucidate the mechanism of viral entry and pathogenicity,and provide new targets for intervention.In the present study,we reported a novel membrane protein,C1QTNF5,which binds to the hemagglutinin protein of IAV and promotes IAV infection in vitro and in vivo.We found that the HA1 region of IAV hemagglutinin is critical for the interaction with C1QTNF5 protein,and C1QTNF5 interacts with hemagglutinin mainly through its N-terminus(1–103 aa).In addition,we further demonstrated that overexpression of C1QTNF5 promotes IAV entry,while blocking the interaction between C1QTNF5 and IAV hemagglutinin greatly inhibits viral entry.However,C1QTNF5 does not function as a receptor to mediate IAV infection in sialic acid-deficient CHO-Lec2 cells,but promotes IAV to attach to these cells,suggesting that C1QTNF5 is an important attachment factor for IAV.This work reveals C1QTNF5 as a novel IAV attachment factor and provides a new perspective for antiviral strategies.

关键词： C1QTNF5 Influenza A virus Viral entry Hemagglutinin Attachment factor

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miR319-TCPs-TGA9/TGA10/ROXY2 regulatory module controls cell fate specification in early anther development in Arabidopsis

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Science China(life sciences) 2024年第4期67卷 839-842页

作者： Jinyuan Tao Zijie Pan Wenwen Kong Beixin Mo Xuemei Chen Yu Yu Guangdong Provincial Key Laboratory for Plant Epigenetics Longhua Bioindustry and Innovation Research InstituteCollege of Life Sciences and OceanographyShenzhen UniversityShenzhen 518060China Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province College of Optoelectronic EngineeringShenzhen UniversityShenzhen 518060China School of life sciences Peking-Tsinghua Joint Center for Life SciencesPeking UniversityBeijing 100871China

Dear Editor,The process of anther development is generally conserved across plant species(Ma,2005).Many protein-coding genes and noncoding RNAs have been identified to participate in early anther development in Arabidopsis(Walbot and Egger,2016).mi R319 is one of the most ancient and conserved mi RNA families in land plants(Chávez Montes et al.,2014).

关键词： Arabidopsis miR319 ancient

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Sleep-based neuronal oscillations as a physiological biomarker for Alzheimer's disease:is night time the right time?

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Neural Regeneration Research 2024年第7期19卷 1417-1418页

作者： Jonathan Witton Erica S.Brady Michael T.Craig Department of Clinical and Biomedical sciences Faculty of Health and Life SciencesUniversity of ExeterExeterEnglandUK Gladstone Institute for Neurological Disease San FranciscoCAUSA School of Psychology and Neuroscience College of MedicalVeterinary and Life SciencesUniversity of GlasgowGlasgowScotlandUK

Dementia is a devastating syndrome characterized by memory problems,confusion,and behavior changes that prevent people from performing everyday activities.It is the leading cause of dependency and disability amongst older people,resulting in a global economic cost of ~$1.3 trillion.Around 58 million people are currently afflicted by dementia worldwide,with Alzheimer s disease(AD) causing most(60-70%) of these cases.

关键词： Alzheimer everyday performing

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How incubation temperature affects hatchling performance in reptiles: an integrative insight based on plasticity in metabolic enzyme

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Current Zoology 2024年第2期70卷 195-203页

作者： Dan-Yang Wu Xing-Zhi Han Teng Li Bao-Jun Sun Xiao-Yan Qin college of life and Environment sciences Minzu University of ChinaBeijing 100081China Key Laboratory of Animal Ecology and Conservational Biology Institute of ZoologyChinese Academy of SciencesBeijing 10011China college of Wildlife and Protected Area Northeast Forestry UniversityHarbin 150040China college of Resources and Environmental sciences Nanjing Agricultural UniversityNanjing 210095China

Evaluating the effects of temperature variations on animals plays an important role in understanding the threat of climate warming.The effects of developmental temperature on offspring performance are critical in evaluating the effects of warming temperatures on the fitness of ovipa-rous species,but the physiological and biochemical basis of this developmental plasticity is largely unknown.In this study,we incubated eggs of the turtle Pelodiscus sinensis at low(24℃),medium(28℃),and high(32℃)temperatures,and evaluated the effects of developmental temperature on offspring fitness,and metabolic enzymes in the neck and limb muscles of hatchlings.The hatchlings from eggs incubated at the medium temperature showed better fitness-related performance(righting response and swimming capacity)and higher activities of metabolic enzymes(hexokinase,HK;lactate dehydrogenase,LDH)than hatchlings from the eggs incubated at high or low temperatures.In addition,the swimming speed and righting response were significantly correlated with the HK activities in limb(swimming speed)and neck(righting response)muscles,suggesting that the developmental plasticity of energy metabolic pathway might play a role in determining the way incubation temperature affects offspring phenotypes.Integrating the fitness-related performance and the activities of metabolic enzymes,we predict that the P sinensis from high latitude would not face the detrimental effects of climate warming until the average nest temperatures reach 32℃.

关键词： developmental plasticity energetic metabolism enzyme activity hatchling turtle.

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RNA modifications in cellular metabolism:implications for metabolism-targeted therapy and immunotherapy

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1565-1594页

作者： Wei-Wei Liu Si-Qing Zheng Tian Li Yun-Fei Fei Chen Wang Shuang Zhang Fei Wang Guan-Min Jiang Hao Wang Department of Laboratory medicine The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina School of Clinical medicine Shandong UniversityJinanChina Core Unit of National Clinical Research Center for Laboratory medicine HefeiChina Neurosurgical Department The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina Department of Clinical Laboratory The Fifth Affiliated HospitalSun Yat-sen UniversityZhuhaiChina

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells.Relevant studies have been constantly making inroads in our understanding of pathophysiology,and inspiring development of therapeutics.As a crucial component of epigenetics at post-transcription level,RNA modification significantly determines RNA fates,further affecting various biological processes and cellular phenotypes.To be noted,immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts.In this review,we characterize the distribution features,modifying mechanisms and biological functions of 8 RNA modifications,including N6-methyladenosine(m6A),N6,2'-O-dimethyladenosine(m6Am),N1-methyladenosine(m1A),5-methylcytosine(m5C),N4-acetylcytosine(ac4C),N7-methylguanosine(m7G),Pseudouridine(V),adenosine-to-inosine(A-to-l)editing,which are relatively the most studied types.Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described,categorized as glucose,lipid,amino acid,and mitochondrial metabolism.And we highlight the regulation of RNA modifications on immunometabolism,further influencing immune responses.Above all,we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy,progression of RNA modification-targeted agents,and its potential in RNAtargeted therapeutics.Eventually,we give legitimate perspectives for future researches in this field from methodological requirements,mechanistic insights,to therapeutic applications.

关键词： metabolism targeted alterations

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