Venetoclax(Vene),a BCL-2 inhibitor,is widely used as a chemotherapeutic drug in acute myeloid leukemia(AML).However,its treatment specificity for leukemia cells is limited,often leading to side effects and treatment r...Venetoclax(Vene),a BCL-2 inhibitor,is widely used as a chemotherapeutic drug in acute myeloid leukemia(AML).However,its treatment specificity for leukemia cells is limited,often leading to side effects and treatment resistance.In this study,we utilized L-phenylalanine as an efficient nanocarrier to enhance the delivery of Vene,forming the complex Vene@8P6.This complex was then applied to AML mouse models and human AML cell lines.The in vitro analysis showed that THP-1 and HL60 cells rapidly absorbed the Vene@8P6 nanoparticles.This absorption resulted in severe DNA damage,increased reactive oxygen species(ROS)production,elevated apoptosis rates,and decreased cell proliferation compared to the administration of Vene alone.In vivo studies demonstrated that Vene@8P6 more efficiently targeted leukemia cells than normal hematopoietic cells within the bone marrow and other major organs in AML mice,as evidenced by bioluminescence imaging and flow cytometry analysis.Furthermore,Vene@8P6 treatment resulted in reduced drug side effects and improved therapeutic efficacy in AML mice.Overall,Vene@8P6 represents a novel and efficient therapeutic agent for AML,offering enhanced leukemia target specificity,reduced side effects,and improved treatment outcomes.展开更多
In multicellular organisms,developmental history of cell divisions and functional annotation of terminal cells can be organized into a cell lineage tree(CLT).The reconstruction of the CLT has long been a major goal in...In multicellular organisms,developmental history of cell divisions and functional annotation of terminal cells can be organized into a cell lineage tree(CLT).The reconstruction of the CLT has long been a major goal in developmental biology and other related fields.Recent technological advancements,especially those in editable genomic barcodes and single-cell high-throughput sequencing,have sparked a new wave of experimental methods for reconstructing CLTs.Here we review the existing experimental approaches to the reconstruction of CLT,which are broadly categorized as either image-based or DNA barcode-based methods.In addition,we present a summary of the related literature based on the biological insight pro-vided by the obtained CLTs.Moreover,we discuss the challenges that will arise as more and better CLT data become available in the near future.Genomic barcoding-based CLT reconstructions and analyses,due to their wide applicability and high scalability,offer the potential for novel biological discoveries,especially those related to general and systemic properties of the developmental process.展开更多
The vertebrate limb development serves as an excellent model in morphology,developmental biology,and evolutionary studies owing to its remarkable morphological and functional diversity.Forelimbs and hindlimbs originat...The vertebrate limb development serves as an excellent model in morphology,developmental biology,and evolutionary studies owing to its remarkable morphological and functional diversity.Forelimbs and hindlimbs originate from the lateral plate mesoderm(LPM),located along the embryo’s flank,with the initiation of differential expression of the transcription factors TBX5 for the forelimb and TBX4 and PITX1 for the hindlimb.Initially,limbs emerge as small buds comprising an undifferentiated mesodermal core covered by a layer of ectoderm[1].展开更多
Cardiac fibrosis is a pathological response characterized by excessive deposition of fibrous connective tissue within the heart.It typically occurs following cardiac injuries or diseases.However,the lack of suitable m...Cardiac fibrosis is a pathological response characterized by excessive deposition of fibrous connective tissue within the heart.It typically occurs following cardiac injuries or diseases.However,the lack of suitable models for disease modeling and high-throughput drug discovery has hindered the establishment of an effective treatments for cardiac fibrosis.The emergence and rapid progress of stem-cell and lineage reprogramming technology offer an unprecedented opportunity to develop an improved humanized and patient-specific model for studying cardiac fibrosis,providing a platform for screening potential drugs and synchronously elucidating the underlying molecular mechanisms.Furthermore,reprogramming cardiac fibroblasts into cardiomyocyte-like cells to reduce scar volume and induce myocardial tissue regeneration is a promising approach in treating cardiac fibrosis.In this review,we summarize the current advancements in stem cell technologies applied to study cardiac fibrosis and provide insights for future investigations into its mechanisms,drug discovery as well as therapy method.展开更多
Oncolytic viruses(OVs),a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact,are emerging as promising living anticancer agents.Unlike traditiona...Oncolytic viruses(OVs),a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact,are emerging as promising living anticancer agents.Unlike traditional drugs composed of non-replicating compounds or biomolecules,the replicative nature of viruses confer unique pharmacokinetic properties that require further studies.Despite some pharmacokinetics studies of OVs,mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague.Here,we characterized the pharmacokinetic profile of oncolytic virus M1(OVM)in immunocompetent mouse tumor models and identified the JAK-STAT pathway as a key modulator of OVM pharmacokinetics.By suppressing the JAK-STAT pathway,early OVM pharmacokinetics are ameliorated,leading to enhanced tumor-specific viral accumulation,increased AUC and Cmax,and improved antitumor efficacy.Rather than compromising antitumor immunity after JAK-STAT inhibition,the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment,providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade,such as anti-PD-L1.Taken together,this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.展开更多
Clostridioides difficile is a leading cause of healthcare-associated infections,causing billions of economic losses every year.Its symptoms range from mild diarrhea to life-threatening damage to the colon.Transmission...Clostridioides difficile is a leading cause of healthcare-associated infections,causing billions of economic losses every year.Its symptoms range from mild diarrhea to life-threatening damage to the colon.Transmission and recurrence of c.difficile infection(CDl)are mediated by the metabolically dormant spores,while the virulence of C.difficile is mainly due to the two large clostridial toxins,TcdA and TcdB.Producing toxins or forming spores are two different strategies for C.difficile to cope with harsh environmental conditions.It is of great significance to understand the molecular mechanisms for C.difficile to skew to either of the cellular processes.Here,we summarize the current understanding of the regulation and connections between toxin production and sporulation in C.difficile and further discuss the potential solutions for yet-to-be-answered questions.展开更多
Cell fate transition is a fascinating process involving complex dynamics of three-dimensional(3D)chromatin organization and phase separation,which play an essential role in cell fate decision by regulating gene expres...Cell fate transition is a fascinating process involving complex dynamics of three-dimensional(3D)chromatin organization and phase separation,which play an essential role in cell fate decision by regulating gene expression.Phase separation is increasingly being considered a driving force of chromatin folding.In this review,we have summarized the dynamic features of 3D chromatin and phase separation during physiological and pathological cell fate transitions and systematically analyzed recent evidence of phase separation facilitating the chromatin structure.In addition,we discuss current advances in understanding how phase separation contributes to physical and functional enhancerpromoter contacts.We highlight the functional roles of 3D chromatin organization and phase separation in cell fate transitions,and more explorations are required to study the regulatory relationship between 3D chromatin organization and phase separation.展开更多
Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum...Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.展开更多
基金the National Natural Science Foundation of China(No.52173150 to J.Wu)the National Natural Science Foundation of China(No.82370164 to C.Chen)+5 种基金Guangzhou Science and Technology Program City-University Joint Funding Project(No.2023A03J0001 to J.Wu)the Affiliated Qingyuan Hospital of Guangzhou Medical University Open Project Fund(No.202301–211 to J.Wu)Sanming Project of Medicine in Shenzhen(No.SZSM201911004 to D.Lin and M.Zhao)National Natural Science Foundation of China(No.92268205 to D.Lin)Doctoral Scientific Research Foundation of Changzhi Medical College,China(to Z.Zhao)Post-doctoral Science Foundation(No.2022M723670 to L.Wang)。
文摘Venetoclax(Vene),a BCL-2 inhibitor,is widely used as a chemotherapeutic drug in acute myeloid leukemia(AML).However,its treatment specificity for leukemia cells is limited,often leading to side effects and treatment resistance.In this study,we utilized L-phenylalanine as an efficient nanocarrier to enhance the delivery of Vene,forming the complex Vene@8P6.This complex was then applied to AML mouse models and human AML cell lines.The in vitro analysis showed that THP-1 and HL60 cells rapidly absorbed the Vene@8P6 nanoparticles.This absorption resulted in severe DNA damage,increased reactive oxygen species(ROS)production,elevated apoptosis rates,and decreased cell proliferation compared to the administration of Vene alone.In vivo studies demonstrated that Vene@8P6 more efficiently targeted leukemia cells than normal hematopoietic cells within the bone marrow and other major organs in AML mice,as evidenced by bioluminescence imaging and flow cytometry analysis.Furthermore,Vene@8P6 treatment resulted in reduced drug side effects and improved therapeutic efficacy in AML mice.Overall,Vene@8P6 represents a novel and efficient therapeutic agent for AML,offering enhanced leukemia target specificity,reduced side effects,and improved treatment outcomes.
基金supported by the National Key Research and Development Program of China(2021YFF1200904,2021YFA1302500 to J.-R.Y.)the National Natural Science Foundation of China(32122022,31871320 to J.-R.Y.)by Science and Technology Planning Project of Guangdong Province,China(2014A030304053 to X.Z.).
文摘In multicellular organisms,developmental history of cell divisions and functional annotation of terminal cells can be organized into a cell lineage tree(CLT).The reconstruction of the CLT has long been a major goal in developmental biology and other related fields.Recent technological advancements,especially those in editable genomic barcodes and single-cell high-throughput sequencing,have sparked a new wave of experimental methods for reconstructing CLTs.Here we review the existing experimental approaches to the reconstruction of CLT,which are broadly categorized as either image-based or DNA barcode-based methods.In addition,we present a summary of the related literature based on the biological insight pro-vided by the obtained CLTs.Moreover,we discuss the challenges that will arise as more and better CLT data become available in the near future.Genomic barcoding-based CLT reconstructions and analyses,due to their wide applicability and high scalability,offer the potential for novel biological discoveries,especially those related to general and systemic properties of the developmental process.
基金supported by the National Key Research and Development Program(2022YFA1104900 and 2019YFA0801703)the National Natural Science Foundation of China(31871370)。
文摘The vertebrate limb development serves as an excellent model in morphology,developmental biology,and evolutionary studies owing to its remarkable morphological and functional diversity.Forelimbs and hindlimbs originate from the lateral plate mesoderm(LPM),located along the embryo’s flank,with the initiation of differential expression of the transcription factors TBX5 for the forelimb and TBX4 and PITX1 for the hindlimb.Initially,limbs emerge as small buds comprising an undifferentiated mesodermal core covered by a layer of ectoderm[1].
基金supported by the National Natural Science Foundation of China(92057113 and 32122027)the Natural Science Foundation of Guangdong Province(2021A1515012489 and 2022A1515011819)+1 种基金the National Natural Science Foundation of China(82200280)the China Postdoctoral Science Foundation(2022M713573).
文摘Cardiac fibrosis is a pathological response characterized by excessive deposition of fibrous connective tissue within the heart.It typically occurs following cardiac injuries or diseases.However,the lack of suitable models for disease modeling and high-throughput drug discovery has hindered the establishment of an effective treatments for cardiac fibrosis.The emergence and rapid progress of stem-cell and lineage reprogramming technology offer an unprecedented opportunity to develop an improved humanized and patient-specific model for studying cardiac fibrosis,providing a platform for screening potential drugs and synchronously elucidating the underlying molecular mechanisms.Furthermore,reprogramming cardiac fibroblasts into cardiomyocyte-like cells to reduce scar volume and induce myocardial tissue regeneration is a promising approach in treating cardiac fibrosis.In this review,we summarize the current advancements in stem cell technologies applied to study cardiac fibrosis and provide insights for future investigations into its mechanisms,drug discovery as well as therapy method.
基金supported by National Key R&D Program of China(No.2021YFA0909800,China)Guangdong Basic and Applied Basic Research Foundation(Nos.2022B1515020056,2021A1515011881,2023A1515010737,China)+3 种基金Leading team for entrepreneurship in Guangzhou,Guangdong Province(No.201809020004,China)Fundamental Research Funds for the Central Universities(No.22ykqb12,China)Pioneering talents project of Guangzhou Development Zone,Guangdong Province(2020-L036,China)Natural Science Foundation of Guangdong Province(No.2022A1515011056,China).
文摘Oncolytic viruses(OVs),a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact,are emerging as promising living anticancer agents.Unlike traditional drugs composed of non-replicating compounds or biomolecules,the replicative nature of viruses confer unique pharmacokinetic properties that require further studies.Despite some pharmacokinetics studies of OVs,mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague.Here,we characterized the pharmacokinetic profile of oncolytic virus M1(OVM)in immunocompetent mouse tumor models and identified the JAK-STAT pathway as a key modulator of OVM pharmacokinetics.By suppressing the JAK-STAT pathway,early OVM pharmacokinetics are ameliorated,leading to enhanced tumor-specific viral accumulation,increased AUC and Cmax,and improved antitumor efficacy.Rather than compromising antitumor immunity after JAK-STAT inhibition,the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment,providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade,such as anti-PD-L1.Taken together,this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.
文摘Clostridioides difficile is a leading cause of healthcare-associated infections,causing billions of economic losses every year.Its symptoms range from mild diarrhea to life-threatening damage to the colon.Transmission and recurrence of c.difficile infection(CDl)are mediated by the metabolically dormant spores,while the virulence of C.difficile is mainly due to the two large clostridial toxins,TcdA and TcdB.Producing toxins or forming spores are two different strategies for C.difficile to cope with harsh environmental conditions.It is of great significance to understand the molecular mechanisms for C.difficile to skew to either of the cellular processes.Here,we summarize the current understanding of the regulation and connections between toxin production and sporulation in C.difficile and further discuss the potential solutions for yet-to-be-answered questions.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.31970811,31771639 and 32170798)the Guangdong Regenerative Medicine and Health of Guangdong Laboratory Frontier Exploration Project(2018GZR110105007)+6 种基金the Guangdong Innovative and Entrepreneurial Research Team Program(2016ZT06S029)Guangdong Basic and Applied Basic Research Foundation(2011B1515120063)to J.D.the Fundamental Research Funds for the Central Universities of Jinan University(Natural Science)(2162004)China Postdoctoral Science Foundation(2021M701441)China Postdoctoral Special Grant Foundation(2022T150269)Guangdong Basic and Applied Basic Research Foundation(2021A1515)Guangzhou Basic and Applied Basic Research Foundation(202201010961)to L.F..
文摘Cell fate transition is a fascinating process involving complex dynamics of three-dimensional(3D)chromatin organization and phase separation,which play an essential role in cell fate decision by regulating gene expression.Phase separation is increasingly being considered a driving force of chromatin folding.In this review,we have summarized the dynamic features of 3D chromatin and phase separation during physiological and pathological cell fate transitions and systematically analyzed recent evidence of phase separation facilitating the chromatin structure.In addition,we discuss current advances in understanding how phase separation contributes to physical and functional enhancerpromoter contacts.We highlight the functional roles of 3D chromatin organization and phase separation in cell fate transitions,and more explorations are required to study the regulatory relationship between 3D chromatin organization and phase separation.
基金supported by the National Natural Science Foundation of China(31730036,31871380,31871382,31930055,31930058,32000500,32022034,32030033,32070730,32130046,3217050247,32150005,32200595,32222024,81730019,81730022,81830014,81921006,81925005,81970426,81971301,81971312,82030041,82061160495,82070805,82071595,82090020,82100841,82120108009,82122024,82125002,82125011,82125012,82130045,82171284,82173061,82173398,82225007,82225015,82225017,82225018,82230047,82230088,82271600,91949106,91949201,92049116,92049302,92049304,92149303,92149306,92157202,92168201,92169102,92249301,92268201)the National Key Research and Development Program of China(2018YFA0800700,2018YFC2000100,2018YFC2000102,2018YFC2002003,2019YFA0110900,2019YFA0801703,2019YFA0801903,2019YFA0802202,2019YFA0904800,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002900,2020YFC2008000,2020YFE0202200,2021YFA0804900,2021YFA1100103,2021YFA1100900,2021YFE0114200,2021ZD0202400,2022YFA0806001,2022YFA0806002,2022YFA0806600,2022YFA1103200,2022YFA1103601,2022YFA1103701,2022YFA1103800,2022YFA1103801,2022YFA1104100,2022YFA1104904,2022YFA1303000,2022YFC2009900,2022YFC2502401,2022YFC3602400,2022YFE0118000,2022ZD0213200)+14 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030302,XDB39000000,XDB39030600)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2020085,2021080)CAS Project for Young Scientists in Basic Research(YSBR-076)the Program of the Beijing Natural Science Foundation(JQ20031)Clinical Research Operating Fund of Central High level hospitals(2022-PUMCHE-001)CAMS Innovation Fund for Medical Sciences(CIFMS)(2022-I2M1-004)Talent Program of the Chinese Academy of Medical Science(2022RC310-10)Research Funds from Health@Inno HK Program launched by Innovation Technology Commission of the Hong Kong Special Administrative Region,Guangdong Basic and Applied Basic Research Foundation(2020B1515020044)Guangzhou Planned Project of Science and Technology(202002020039)the Major Technology Innovation of Hubei Province(2019ACA141)the Science and Technology Major Project of Hunan Provincial Science and Technology Department(2021SK1010)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Natural Science Foundation of Sichuan Province(2023NSFSC0003)Yunnan Fundamental Research Project(202201AS070080)the State Key Laboratory of Membrane Biology。
文摘Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.
