W026B is a new compound that has a protective effect on cerebral ischemia reperfusion(I-R)injury in mice,while its specific mechanism is still unknown.In this study,proteomics was used to observe the effect of W026B o...W026B is a new compound that has a protective effect on cerebral ischemia reperfusion(I-R)injury in mice,while its specific mechanism is still unknown.In this study,proteomics was used to observe the effect of W026B on protein expression in brain I-R tissue,and to reveal its potential target.A total of 42 significantly altered proteins were identified in both brain I-R model and W026B treatment from 4852 proteins detected by proteomics,and most of these proteins were related to immunity and inflammation,metabolism,neuroprotection as well as cell proliferation and cell structure.Western blotting analysis showed that three out of five selected proteins showed consistent alteration with the proteomics.Regulator of G protein signaling 17(RGS17)was selected for further study,and its knockdown by siRNA RGS17 aggravated brain injury and abolished the protective effect of W026B.W026B could bind with RGS17(KD:6.04×10–6 mol/L).The knockdown of RGS17 aggravated Neuro-2 a cell damage induced by group I metabotropic glutamate receptors(mGluRs)agonist,and abolished the protective effect of W026B.In conclusion,W026B protected brain against I-R injury by affecting diverse proteins.RGS17 might be one of its targets and a potential therapeutic target of brain I-R injury.The upstream receptor of G protein,which was regulated by RGS17 and affected by W026B,might be group I m GluRs.This study provided useful evidence for the further R&D and the potential clinical application of W026B.展开更多
Target discovery,involving target identification and validation,is the prerequisite for drug discovery and screening.Novel methodologies and technologies for the precise discovery and confirmation of drug targets are ...Target discovery,involving target identification and validation,is the prerequisite for drug discovery and screening.Novel methodologies and technologies for the precise discovery and confirmation of drug targets are powerful tools in understanding the disease,looking for a drug and elucidating the mechanism of drug treatment.Among the common target identification and confirmation methods,the modified method is time-consuming and laborious,which may reduce or change the activity of natural products.The unmodified methods developed in recent years without chemical modification have gradually become an important means of studying drug targets.A wide range of unmodified approaches have been reported,introducing and analyzing the recent emerging methodologies and technologies.This review highlights the advantages and limitations of these methods for the application of drug target discovery and presents an overview of their contributions to the target discovery of small molecule drugs.The application and future development trends of methodologies in target discovery are also prospected to provide a reference for drug target research.展开更多
The modernization and internationalization of traditional Chinese medicine(TCM)have long been constrained by the"black box"problem of its complex compositional system and unclear mechanisms of action.Target ...The modernization and internationalization of traditional Chinese medicine(TCM)have long been constrained by the"black box"problem of its complex compositional system and unclear mechanisms of action.Target discovery,as a core step in revealing drug action principles,is key to promoting TCM's transition from"empirical medicine"to"precision medicine".In recent years,the rapid development of chemical biology technologies has provided powerful tools to address this challenge.This article focuses on the latest progress in applying chemical biology strategies,such as molecular probes,click chemistry,fluorescent labeling,and photo-crosslinking microarrays,in TCM target identification research.Combined with typical case studies like Sapanone A and Eupalinolide B,it elaborates on how these cutting-edge technologies can precisely identify the direct targets of active TCM components,thereby achieving comprehensive mechanism analysis from cells and animals to clinical samples.Furthermore,this article prospectively discusses novel"supramolecular drugs"formed by the self-assembly of TCM components at the nanoscale and their unique biological effects.It also preliminarily constructs a modern scientific interpretation framework for TCM theories like"property-flavor-channel tropism"and"processing theory",centered around target distribution and regulation.Finally,this article proposes that"chemical biology of TCM,"as a key driver to discover original drug targets derived from TCM theory,is posited to offer a novel paradigm for innovative drug discovery and to contribute significantly to the modernization and scientific elucidation of TCM theory.展开更多
Traditional medicines serve not only as an integral part of medical treatments prescribed by healthcare providers but also as a fundamental reservoir for novel molecular scaffolds. However, gaps remain in our understa...Traditional medicines serve not only as an integral part of medical treatments prescribed by healthcare providers but also as a fundamental reservoir for novel molecular scaffolds. However, gaps remain in our understanding of the mechanisms underlying their activity. A superfamily of membraneproteins, G protein-coupled receptors (GPCRs), have been demonstrated tobe potential targets for several compounds isolated from traditional medicines. Given that GPCRs serve as targets for approximately one-third of allmarketed drugs, they may be compelling targets for repurposing traditionalmedicines. Despite this potential, research investigating their activity or potential ligands across GPCRome, the library of human GPCRs, is scarce.Drawing on the functional and structural knowledge presently available,this review contemplates prospective trends in GPCR drug discovery, proposes innovative strategies for investigating traditional medicines, andhighlights ligand screening approaches for identifying novel drug-like molecules. To discover bioactive molecules from traditional medicines thateither directly bind to GPCRs or indirectly modify their function, a genomewide pan-GPCR drug discovery platform was designed for the identificationof bioactive components and targets, and the evaluation of their pharmacological profiles. This platform aims to aid the exploration of all-sided relations between traditional medicines and GPCRome using advanced highthroughput screening techniques. We present various approaches used bymany, including ourselves, to illuminate the previously unexplored aspectsof traditional medicines and GPCRs.展开更多
This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving aca...This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.展开更多
In the post-genomic era, biological studies are characterized by the rapid development and wide application of a series of "omics" technologies, including genomics, proteomics, metabolomics, transcriptomics,...In the post-genomic era, biological studies are characterized by the rapid development and wide application of a series of "omics" technologies, including genomics, proteomics, metabolomics, transcriptomics, lipidomics, cytomics, metallomics, ionomics, interactomics, and phenomics. These "omics" are often based on global analyses of biological samples using high through-put analytical approaches and bioinformatics and may provide new insights into biological phenomena. In this paper, the development and advances in these omics made in the past decades are reviewed, especially genomics, transcriptomics, proteomics and metabolomics; the applications of omics technologies in pharmaceutical research are then summarized in the fields of drug target discovery, toxicity evaluation, personalized medicine, and traditional Chinese medicine; and finally, the limitations of omics are discussed, along with the future challenges associated with the multi-omics data processing, dynamics omics analysis, and analytical approaches, as well as amenable solutions and future prospects.展开更多
Drug discovery and development affects various aspects of human health and dramatically impacts the pharmaceutical market.However,investments in a new drug often go unrewarded due to the long and complex process of dr...Drug discovery and development affects various aspects of human health and dramatically impacts the pharmaceutical market.However,investments in a new drug often go unrewarded due to the long and complex process of drug research and development(R&D).With the advancement of experimental technology and computer hardware,artificial intelligence(AI)has recently emerged as a leading tool in analyzing abundant and high-dimensional data.Explosive growth in the size of biomedical data provides advantages in applying AI in all stages of drug R&D.Driven by big data in biomedicine,AI has led to a revolution in drug R&D,due to its ability to discover new drugs more efficiently and at lower cost.This review begins with a brief overview of common AI models in the field of drug discovery;then,it summarizes and discusses in depth their specific applications in various stages of drug R&D,such as target discovery,drug discovery and design,preclinical research,automated drug synthesis,and influences in the pharmaceutical market.Finally,the major limitations of AI in drug R&D are fully discussed and possible solutions are proposed.展开更多
BACKGROUND Colorectal cancer(CRC)is the third most frequent and the second most fatal cancer.The search for more effective drugs to treat this disease is ongoing.A better understanding of the mechanisms of CRC develop...BACKGROUND Colorectal cancer(CRC)is the third most frequent and the second most fatal cancer.The search for more effective drugs to treat this disease is ongoing.A better understanding of the mechanisms of CRC development and progression may reveal new therapeutic strategies.Ubiquitin-specific peptidases(USPs),the largest group of the deubiquitinase protein family,have long been implicated in various cancers.There have been numerous studies on the role of USPs in CRC;however,a comprehensive view of this role is lacking.AIM To provide a systematic review of the studies investigating the roles and functions of USPs in CRC.METHODS We systematically queried the MEDLINE(via PubMed),Scopus,and Web of Science databases.RESULTS Our study highlights the pivotal role of various USPs in several processes implicated in CRC:Regulation of the cell cycle,apoptosis,cancer stemness,epithelial–mesenchymal transition,metastasis,DNA repair,and drug resistance.The findings of this study suggest that USPs have great potential as drug targets and noninvasive biomarkers in CRC.The dysregulation of USPs in CRC contributes to drug resistance through multiple mechanisms.CONCLUSION Targeting specific USPs involved in drug resistance pathways could provide a novel therapeutic strategy for overcoming resistance to current treatment regimens in CRC.展开更多
Colorectal cancer is a leading cause of cancer deaths.Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies.Here,we used patient-derived colorectal cancer organoi...Colorectal cancer is a leading cause of cancer deaths.Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies.Here,we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment.Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression.CRISPR/Cas9 silencing of fibroblast growth factor receptor 1(FGFR1)and oxytocin receptor(OXTR)helped overcome oxaliplatin resistance.Similarly,treatment with oxaliplatin in combination with an FGFR1 inhibitor(PD166866)or an antagonist of OXTR(L-368,899)suppressed chemoresistant organoids.However,oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid,suggesting that chromatin accessibility changes are patient-specific.The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer.展开更多
Metastasis is the leading cause of death from cutaneous melanoma.Identifying metastasisrelated targets and developing corresponding therapeutic strategies are major areas of focus.While functional genomics strategies ...Metastasis is the leading cause of death from cutaneous melanoma.Identifying metastasisrelated targets and developing corresponding therapeutic strategies are major areas of focus.While functional genomics strategies provide powerful tools for target discovery,investigations at the protein level can directly decode the bioactive epitopes on functional proteins.Aptamers present a promising avenue as they can explore membrane proteomes and have the potential to interfere with cell function.Herein,we developed a target and epitope discovery platform,termed functional aptamer evolution-enabled target identification(FAETI),by integrating affinity aptamer acquisition with phenotype screening and target protein identification.Utilizing the aptamer XH3C,which was screened for its migration-inhibitory function,we identified the Chondroitin Sulfate Proteoglycan 4(CSPG4),as a potential target involved in melanoma migration.Further evidence demonstrated that XH3C induces cytoskeletal rearrangement by blocking the interaction between the bioactive epitope of CSPG4 and integrin a4.Taken together,our study demonstrates the robustness of aptamer-based molecular tools for target and epitope discovery.Additionally,XH3C is an affinity and functional molecule that selectively binds to a unique epitope on CSPG4,enabling the development of innovative therapeutic strategies.展开更多
Pathogenic xenobiotics are ubiquitous in the environment.Environmental carcinogens induce mutations leading to tumors;pathogens relying on environmental media transmission cause infections;exposure to chemical or biol...Pathogenic xenobiotics are ubiquitous in the environment.Environmental carcinogens induce mutations leading to tumors;pathogens relying on environmental media transmission cause infections;exposure to chemical or biological pollutants triggers toxicant poisoning.The mechanisms of xenobiotics work by abnormal expression of genes.Since their inception,genome-wide CRISPR/Cas9 knockout libraries have been rapidly applied in vitro to dissect the mechanism of diseases.Genome-wide screening of CRISPR/Cas9 knockout libraries has helped to identify genes essential for tumor survival,combinations of genes for synthetic lethal effects,and genes associated with drug resistance or susceptibility.In addition,key host factors and complex toxicological mechanisms of viral infection have been elucidated,contributing to the development of antidotes and the reduction of the incidence of adverse effects.CRISPR/Cas9 library screening can be combined with single-cell sequencing and organoid technologies to identify novel gene interactions and more reliable preclinical data.Future trends in such screening aim to identify more potential molecular targets for more exogenous pathogenic factors,combine screening with other emerging technologies to expand its use in in vitro models,and develop more accurate,accessible,and cost-effective genome editing tools.展开更多
High throughput screening(HTS)is a widely used effective approach in genome-wide association and large scale protein expression studies,drug discovery,and biomedical imaging research.How to accurately identify candid...High throughput screening(HTS)is a widely used effective approach in genome-wide association and large scale protein expression studies,drug discovery,and biomedical imaging research.How to accurately identify candidate‘targets’or biologically meaningful features with a high degree of confidence has led to extensive statistical research in an effort to minimize both false-positive and false-negative rates.A large body of literature on this topic with in-depth statistical contents is available.We examine currently available statistical methods on HTS and aim to summarize some selected methods into a concise,easy-tofollow introduction for experimental biologists.展开更多
Chinese medicine(CM) is usually prescribed as CM formula to treat disease. The lack of effective research approach makes it difficult to elucidate the molecular mechanisms of CM formula owing to its complicated chemic...Chinese medicine(CM) is usually prescribed as CM formula to treat disease. The lack of effective research approach makes it difficult to elucidate the molecular mechanisms of CM formula owing to its complicated chemical compounds. Network pharmacology is increasingly applied in CM formula research in recent years, which is identified suitable for the study of CM formula. In this review, we summarized the methodology of network pharmacology, including network construction, network analysis and network verification. The aim of constructing a network is to achieve the interaction between the bioactive compounds and targets and the interaction between various targets, and then find out and validate the key nodes via network analysis and network verification. Besides, we reviewed the application in CM formula research, mainly including targets discovery, bioactive compounds screening, toxicity evaluation, mechanism research and quality control research. Finally, we proposed prospective in the future and limitations of network pharmacology, expecting to provide new strategy and thinking on study for CM formula.展开更多
基金National Natural Science Foundation of China(Grant No.81503060,81573333)
文摘W026B is a new compound that has a protective effect on cerebral ischemia reperfusion(I-R)injury in mice,while its specific mechanism is still unknown.In this study,proteomics was used to observe the effect of W026B on protein expression in brain I-R tissue,and to reveal its potential target.A total of 42 significantly altered proteins were identified in both brain I-R model and W026B treatment from 4852 proteins detected by proteomics,and most of these proteins were related to immunity and inflammation,metabolism,neuroprotection as well as cell proliferation and cell structure.Western blotting analysis showed that three out of five selected proteins showed consistent alteration with the proteomics.Regulator of G protein signaling 17(RGS17)was selected for further study,and its knockdown by siRNA RGS17 aggravated brain injury and abolished the protective effect of W026B.W026B could bind with RGS17(KD:6.04×10–6 mol/L).The knockdown of RGS17 aggravated Neuro-2 a cell damage induced by group I metabotropic glutamate receptors(mGluRs)agonist,and abolished the protective effect of W026B.In conclusion,W026B protected brain against I-R injury by affecting diverse proteins.RGS17 might be one of its targets and a potential therapeutic target of brain I-R injury.The upstream receptor of G protein,which was regulated by RGS17 and affected by W026B,might be group I m GluRs.This study provided useful evidence for the further R&D and the potential clinical application of W026B.
基金supported by grants from the National Natural Science Foundation of China(No.31870946)the Funding of Double First-rate discipline construction(No.CPU2018GF07)+1 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutionsthe Open Project Program of MOE Key Laboratory of Drug Quality Control and Pharmacovigilance(No.DQCP20/21MS01).
文摘Target discovery,involving target identification and validation,is the prerequisite for drug discovery and screening.Novel methodologies and technologies for the precise discovery and confirmation of drug targets are powerful tools in understanding the disease,looking for a drug and elucidating the mechanism of drug treatment.Among the common target identification and confirmation methods,the modified method is time-consuming and laborious,which may reduce or change the activity of natural products.The unmodified methods developed in recent years without chemical modification have gradually become an important means of studying drug targets.A wide range of unmodified approaches have been reported,introducing and analyzing the recent emerging methodologies and technologies.This review highlights the advantages and limitations of these methods for the application of drug target discovery and presents an overview of their contributions to the target discovery of small molecule drugs.The application and future development trends of methodologies in target discovery are also prospected to provide a reference for drug target research.
基金supported by the Natural Science Foundation of Shandong Province(No.ZR2023ZD25)the Taishan Scholars Project in Shandong Province(Nos.tstp20230633 and tsqn202408246).
文摘The modernization and internationalization of traditional Chinese medicine(TCM)have long been constrained by the"black box"problem of its complex compositional system and unclear mechanisms of action.Target discovery,as a core step in revealing drug action principles,is key to promoting TCM's transition from"empirical medicine"to"precision medicine".In recent years,the rapid development of chemical biology technologies has provided powerful tools to address this challenge.This article focuses on the latest progress in applying chemical biology strategies,such as molecular probes,click chemistry,fluorescent labeling,and photo-crosslinking microarrays,in TCM target identification research.Combined with typical case studies like Sapanone A and Eupalinolide B,it elaborates on how these cutting-edge technologies can precisely identify the direct targets of active TCM components,thereby achieving comprehensive mechanism analysis from cells and animals to clinical samples.Furthermore,this article prospectively discusses novel"supramolecular drugs"formed by the self-assembly of TCM components at the nanoscale and their unique biological effects.It also preliminarily constructs a modern scientific interpretation framework for TCM theories like"property-flavor-channel tropism"and"processing theory",centered around target distribution and regulation.Finally,this article proposes that"chemical biology of TCM,"as a key driver to discover original drug targets derived from TCM theory,is posited to offer a novel paradigm for innovative drug discovery and to contribute significantly to the modernization and scientific elucidation of TCM theory.
基金funded by introducing the talented person scientific research starts funds subsidization project of Chengdu University of Traditional Chinese Medicine(030040043,030040017).
文摘Traditional medicines serve not only as an integral part of medical treatments prescribed by healthcare providers but also as a fundamental reservoir for novel molecular scaffolds. However, gaps remain in our understanding of the mechanisms underlying their activity. A superfamily of membraneproteins, G protein-coupled receptors (GPCRs), have been demonstrated tobe potential targets for several compounds isolated from traditional medicines. Given that GPCRs serve as targets for approximately one-third of allmarketed drugs, they may be compelling targets for repurposing traditionalmedicines. Despite this potential, research investigating their activity or potential ligands across GPCRome, the library of human GPCRs, is scarce.Drawing on the functional and structural knowledge presently available,this review contemplates prospective trends in GPCR drug discovery, proposes innovative strategies for investigating traditional medicines, andhighlights ligand screening approaches for identifying novel drug-like molecules. To discover bioactive molecules from traditional medicines thateither directly bind to GPCRs or indirectly modify their function, a genomewide pan-GPCR drug discovery platform was designed for the identificationof bioactive components and targets, and the evaluation of their pharmacological profiles. This platform aims to aid the exploration of all-sided relations between traditional medicines and GPCRome using advanced highthroughput screening techniques. We present various approaches used bymany, including ourselves, to illuminate the previously unexplored aspectsof traditional medicines and GPCRs.
文摘This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.
基金supported by Professor of Chang Jiang Scholars Program,NSFC(No.81230090)Shanghai Leading Academic Discipline Project(B906)+3 种基金Key laboratory of drug research for special environments,PLA,Shanghai Engineering Research Center for the Preparation of Bioactive Natural Products(No.10DZ2251300)the Scientific Foundation of Shanghai,China(Nos.12401900801,13401900 101)National Major Project of China(No.2011ZX09307-002-03)the National Key Technology R&D Program of China(No.2012BAI29B06)
文摘In the post-genomic era, biological studies are characterized by the rapid development and wide application of a series of "omics" technologies, including genomics, proteomics, metabolomics, transcriptomics, lipidomics, cytomics, metallomics, ionomics, interactomics, and phenomics. These "omics" are often based on global analyses of biological samples using high through-put analytical approaches and bioinformatics and may provide new insights into biological phenomena. In this paper, the development and advances in these omics made in the past decades are reviewed, especially genomics, transcriptomics, proteomics and metabolomics; the applications of omics technologies in pharmaceutical research are then summarized in the fields of drug target discovery, toxicity evaluation, personalized medicine, and traditional Chinese medicine; and finally, the limitations of omics are discussed, along with the future challenges associated with the multi-omics data processing, dynamics omics analysis, and analytical approaches, as well as amenable solutions and future prospects.
基金funded by the Natural Science Foundation of Zhejiang Province(LR21H300001)National Key R&D Program of China(2022YFC3400501)+4 种基金National Natural Science Foundation of China(22220102001,U1909208,81872798,and 81825020)Leading Talent of the“Ten Thousand Plan”-National High-Level Talents Special Support Plan of ChinaFundamental Research Fund of Central University(2018QNA7023)Key R&D Program of Zhejiang Province(2020C03010)“Double Top-Class”University(181201*194232101)。
文摘Drug discovery and development affects various aspects of human health and dramatically impacts the pharmaceutical market.However,investments in a new drug often go unrewarded due to the long and complex process of drug research and development(R&D).With the advancement of experimental technology and computer hardware,artificial intelligence(AI)has recently emerged as a leading tool in analyzing abundant and high-dimensional data.Explosive growth in the size of biomedical data provides advantages in applying AI in all stages of drug R&D.Driven by big data in biomedicine,AI has led to a revolution in drug R&D,due to its ability to discover new drugs more efficiently and at lower cost.This review begins with a brief overview of common AI models in the field of drug discovery;then,it summarizes and discusses in depth their specific applications in various stages of drug R&D,such as target discovery,drug discovery and design,preclinical research,automated drug synthesis,and influences in the pharmaceutical market.Finally,the major limitations of AI in drug R&D are fully discussed and possible solutions are proposed.
文摘BACKGROUND Colorectal cancer(CRC)is the third most frequent and the second most fatal cancer.The search for more effective drugs to treat this disease is ongoing.A better understanding of the mechanisms of CRC development and progression may reveal new therapeutic strategies.Ubiquitin-specific peptidases(USPs),the largest group of the deubiquitinase protein family,have long been implicated in various cancers.There have been numerous studies on the role of USPs in CRC;however,a comprehensive view of this role is lacking.AIM To provide a systematic review of the studies investigating the roles and functions of USPs in CRC.METHODS We systematically queried the MEDLINE(via PubMed),Scopus,and Web of Science databases.RESULTS Our study highlights the pivotal role of various USPs in several processes implicated in CRC:Regulation of the cell cycle,apoptosis,cancer stemness,epithelial–mesenchymal transition,metastasis,DNA repair,and drug resistance.The findings of this study suggest that USPs have great potential as drug targets and noninvasive biomarkers in CRC.The dysregulation of USPs in CRC contributes to drug resistance through multiple mechanisms.CONCLUSION Targeting specific USPs involved in drug resistance pathways could provide a novel therapeutic strategy for overcoming resistance to current treatment regimens in CRC.
基金WethankDukeCenterforGenomicandComputational Biology sequencingcorefacilityforresearchsupport.This work wassupportedbyNIHNCIU01CA217514andU01 CA214300.
文摘Colorectal cancer is a leading cause of cancer deaths.Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies.Here,we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment.Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression.CRISPR/Cas9 silencing of fibroblast growth factor receptor 1(FGFR1)and oxytocin receptor(OXTR)helped overcome oxaliplatin resistance.Similarly,treatment with oxaliplatin in combination with an FGFR1 inhibitor(PD166866)or an antagonist of OXTR(L-368,899)suppressed chemoresistant organoids.However,oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid,suggesting that chromatin accessibility changes are patient-specific.The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer.
基金financially supported by the National Key Research&Development Program of China(Grant No.2022YFA1304500)the National Natural Science Foundation of China(Grant No.22227805,22374004)+2 种基金Excellent Young Scientists Fund Program(Overseas)Clinical Medicine Plus X-Young Scholars Project of Peking Universitythe Fundamental Research Funds for the Central Universities(No.PKU2024LCXQ026,China).
文摘Metastasis is the leading cause of death from cutaneous melanoma.Identifying metastasisrelated targets and developing corresponding therapeutic strategies are major areas of focus.While functional genomics strategies provide powerful tools for target discovery,investigations at the protein level can directly decode the bioactive epitopes on functional proteins.Aptamers present a promising avenue as they can explore membrane proteomes and have the potential to interfere with cell function.Herein,we developed a target and epitope discovery platform,termed functional aptamer evolution-enabled target identification(FAETI),by integrating affinity aptamer acquisition with phenotype screening and target protein identification.Utilizing the aptamer XH3C,which was screened for its migration-inhibitory function,we identified the Chondroitin Sulfate Proteoglycan 4(CSPG4),as a potential target involved in melanoma migration.Further evidence demonstrated that XH3C induces cytoskeletal rearrangement by blocking the interaction between the bioactive epitope of CSPG4 and integrin a4.Taken together,our study demonstrates the robustness of aptamer-based molecular tools for target and epitope discovery.Additionally,XH3C is an affinity and functional molecule that selectively binds to a unique epitope on CSPG4,enabling the development of innovative therapeutic strategies.
基金supported by the National Natural Science Foundation of China(Grant Nos.82273665,82401550).
文摘Pathogenic xenobiotics are ubiquitous in the environment.Environmental carcinogens induce mutations leading to tumors;pathogens relying on environmental media transmission cause infections;exposure to chemical or biological pollutants triggers toxicant poisoning.The mechanisms of xenobiotics work by abnormal expression of genes.Since their inception,genome-wide CRISPR/Cas9 knockout libraries have been rapidly applied in vitro to dissect the mechanism of diseases.Genome-wide screening of CRISPR/Cas9 knockout libraries has helped to identify genes essential for tumor survival,combinations of genes for synthetic lethal effects,and genes associated with drug resistance or susceptibility.In addition,key host factors and complex toxicological mechanisms of viral infection have been elucidated,contributing to the development of antidotes and the reduction of the incidence of adverse effects.CRISPR/Cas9 library screening can be combined with single-cell sequencing and organoid technologies to identify novel gene interactions and more reliable preclinical data.Future trends in such screening aim to identify more potential molecular targets for more exogenous pathogenic factors,combine screening with other emerging technologies to expand its use in in vitro models,and develop more accurate,accessible,and cost-effective genome editing tools.
基金This work is supported in part by NIH P50-CA70907,NIH U24CA126608,and NASA NNJ05HD36G.
文摘High throughput screening(HTS)is a widely used effective approach in genome-wide association and large scale protein expression studies,drug discovery,and biomedical imaging research.How to accurately identify candidate‘targets’or biologically meaningful features with a high degree of confidence has led to extensive statistical research in an effort to minimize both false-positive and false-negative rates.A large body of literature on this topic with in-depth statistical contents is available.We examine currently available statistical methods on HTS and aim to summarize some selected methods into a concise,easy-tofollow introduction for experimental biologists.
基金Supported by the National Natural Science Foundation of China(No.81530102)Guangdong Provincial Science and Technology Agency Special Funds(No.2017B050504005)Guangzhou City Science and Technology Agency Special Funds(No.201803010069)
文摘Chinese medicine(CM) is usually prescribed as CM formula to treat disease. The lack of effective research approach makes it difficult to elucidate the molecular mechanisms of CM formula owing to its complicated chemical compounds. Network pharmacology is increasingly applied in CM formula research in recent years, which is identified suitable for the study of CM formula. In this review, we summarized the methodology of network pharmacology, including network construction, network analysis and network verification. The aim of constructing a network is to achieve the interaction between the bioactive compounds and targets and the interaction between various targets, and then find out and validate the key nodes via network analysis and network verification. Besides, we reviewed the application in CM formula research, mainly including targets discovery, bioactive compounds screening, toxicity evaluation, mechanism research and quality control research. Finally, we proposed prospective in the future and limitations of network pharmacology, expecting to provide new strategy and thinking on study for CM formula.
