Pharmacodynamics material basis and effective mechanisms are the two main issues to decipher the mechnisms of action of Traditional Chinese medicines(TCMs)for the treatment of diseases.TCMs,in“multi-component,multi-t...Pharmacodynamics material basis and effective mechanisms are the two main issues to decipher the mechnisms of action of Traditional Chinese medicines(TCMs)for the treatment of diseases.TCMs,in“multi-component,multi-target,multi-pathway”paradigm,show satisfactory clinical results in complex diseases.New ideas and methods are urgently needed to explain the complex interactions between TCMs and diseases.Network pharmacology(NP)provides a novel paradigm to uncover and visualize the underlying interaction networks of TCMs against multifactorial diseases.The development and application of NP has promoted the safety,efficacy,and mechanism investigations of TCMs,which then reinforces the credibility and popularity of TCMs.The current organcentricity of medicine and the“one disease-one target-one drug”dogma obstruct the understanding of complex diseases and the development of effective drugs.Therefore,more attentions should be paid to shift from“phenotype and symptom”to“endotype and cause”in understanding and redefining current diseases.In the past two decades,with the advent of advanced and intelligent technologies(such as metabolomics,proteomics,transcriptomics,single-cell omics,and artificial intelligence),NP has been improved and deeply implemented,and presented its great value and potential as the next drug-discovery paradigm.NP is developed to cure causal mechanisms instead of treating symptoms.This review briefly summarizes the recent research progress on NP application in TCMs for efficacy research,mechanism elucidation,target prediction,safety evaluation,drug repurposing,and drug design.展开更多
Cells within tissues are subject to various mechanical forces,including hydrostatic pressure,shear stress,compression,and tension.These mechanical stimuli can be converted into biochemical signals through mechanorecep...Cells within tissues are subject to various mechanical forces,including hydrostatic pressure,shear stress,compression,and tension.These mechanical stimuli can be converted into biochemical signals through mechanoreceptors or cytoskeleton-dependent response processes,shaping the microenvironment and maintaining cellular physiological balance.Several studies have demonstrated the roles of Yes-associated protein(YAP)and its homolog transcriptional coactivator with PDZ-binding motif(TAZ)as mechanotransducers,exerting dynamic influence on cellular phenotypes including differentiation and disease pathogenesis.This regulatory function entails the involvement of the cytoskeleton,nucleoskeleton,integrin,focal adhesions(FAs),and the integration of multiple signaling pathways,including extracellular signal-regulated kinase(ERK),wingless/integrated(WNT),and Hippo signaling.Furthermore,emerging evidence substantiates the implication of long non-coding RNAs(lncRNAs)as mechanosensitive molecules in cellular mechanotransduction.In this review,we discuss the mechanisms through which YAP/TAZ and lncRNAs serve as effectors in responding to mechanical stimuli.Additionally,we summarize and elaborate on the crucial signal molecules involved in mechanotransduction.展开更多
Gaining a better understanding of autoprotection against drug-induced liver injury(DILI)may provide new strategies for its prevention and therapy.However,little is known about the underlying mechanisms of this phenome...Gaining a better understanding of autoprotection against drug-induced liver injury(DILI)may provide new strategies for its prevention and therapy.However,little is known about the underlying mechanisms of this phenomenon.We used single-cell RNA sequencing to characterize the dynamics and functions of hepatic non-parenchymal cells(NPCs)in autoprotection against DILI,using acetaminophen(APAP)as a model drug.Autoprotection was modeled through pretreatment with a mildly hepatotoxic dose of APAP in mice,followed by a higher dose in a secondary challenge.NPC subsets and dynamic changes were identified in the APAP(hepatotoxicity-sensitive)and APAP-resistant(hepatotoxicity-resistant)groups.A chemokine(C-C motif)ligand 2^(+)endothelial cell subset almost disappeared in the APAP-resistant group,and an R-spondin 3^(+)endothelial cell subset promoted hepatocyte proliferation and played an important role in APAP autoprotection.Moreover,the dendritic cell subset DC-3 may protect the liver from APAP hepatotoxicity by inducing low reactivity and suppressing the autoimmune response and occurrence of inflammation.DC-3 cells also promoted angiogenesis through crosstalk with endothelial cells via vascular endothelial growth factor-associated ligand-receptor pairs and facilitated liver tissue repair in the APAP-resistant group.In addition,the natural killer cell subsets NK-3 and NK-4 and the Sca-1^(-)CD62L^(+)natural killer T cell subset may promote autoprotection through interferon-γ-dependent pathways.Furthermore,macrophage and neutrophil subpopulations with anti-inflammatory phenotypes promoted tolerance to APAP hepatotoxicity.Overall,this study reveals the dynamics of NPCs in the resistance to APAP hepatotoxicity and provides novel insights into the mechanism of autoprotection against DILI at a high resolution.展开更多
Panax ginseng(PG)and Panax notoginseng(PN)are highly valuable Chinese medicines(CM).Although both CMs have similar active constituents,their clinical applications are clearly different.Over the past decade,RNA sequenc...Panax ginseng(PG)and Panax notoginseng(PN)are highly valuable Chinese medicines(CM).Although both CMs have similar active constituents,their clinical applications are clearly different.Over the past decade,RNA sequencing(RNA-seq)analysis has been employed to investigate the molecular mechanisms of extracts or monomers.However,owing to the limited number of samples in standard RNA-seq,few studies have systematically compared the effects of PG and PN spanning multiple conditions at the transcriptomic level.Here,we developed an approach that simultaneously profiles transcriptome changes for multiplexed samples using RNA-seq(TCM-seq),a high-throughput,low-cost workflow to molecularly evaluate CM perturbations.A species-mixing experiment was conducted to illustrate the accuracy of sample multiplexing in TCM-seq.Transcriptomes from repeated samples were used to verify the robustness of TCM-seq.We then focused on the primary active components,Panax notoginseng saponins(PNS)and Panax ginseng saponins(PGS)extracted from PN and PG,respectively.We also characterized the transcriptome changes of 10 cell lines,treated with four different doses of PNS and PGS,using TCM-seq to compare the differences in their perturbing effects on genes,functional pathways,gene modules,and molecular networks.The results of transcriptional data analysis showed that the transcriptional patterns of various cell lines were significantly distinct.PGS exhibited a stronger regulatory effect on genes involved in cardiovascular disease,whereas PNS resulted in a greater coagulation effect on vascular endothelial cells.This study proposes a paradigm to comprehensively explore the differences in mechanisms of action between CMs based on transcriptome readouts.展开更多
The progression from gastric mucosal inflammation to cancer signifies a pivotal event in the trajectory of gastric cancer(GC)development.Chinese medicine(CM)exhibits unique advantages and holds significant promise in ...The progression from gastric mucosal inflammation to cancer signifies a pivotal event in the trajectory of gastric cancer(GC)development.Chinese medicine(CM)exhibits unique advantages and holds significant promise in inhibiting carcinogenesis of the gastric mucosa.This review intricately examines the critical pathological events during the transition from gastric mucosal inflammation-cancer transformation(GMICT),with a particular focus on pathological evolution mechanisms of spasmolytic polypeptide-expressing metaplasia(SPEM).Moreover,it investigates the pioneering applications and advancements of CM in intervening within the medical research domain of precancerous transformations leading to GC.Furthermore,the analysis extends to major shortcomings and challenges confronted by current research in gastric precancerous lesions,and innovative studies related to CM are presented.We offer a highly succinct yet optimistic outlook on future developmental trends.This paper endeavors to foster a profound understanding of forefront dynamics in GMICT research and scientific implications of modernizing CM.It also introduces a novel perspective for establishing a collaborative secondary prevention system for GC that integrates both Western and Chinese medicines.展开更多
Chimeric antigen receptor(CAR)-T-cell therapy has revolutionized cancer treatment.However,its long-term efficacy and broader application are limited because of its antigen insensitivity,poor persistence,and T-cell exh...Chimeric antigen receptor(CAR)-T-cell therapy has revolutionized cancer treatment.However,its long-term efficacy and broader application are limited because of its antigen insensitivity,poor persistence,and T-cell exhaustion.A recent study published by Xu et al.revealed a novel CAR engineering strategy that overcomes these difficulties by incorporating a modified CD3εintracellular domain,EB6I,into the conventional CAR structure[1].This modification enhances antigen sensitivity and sustains the cytotoxic activity of CAR-T cells,demonstrating promising efficacy in treating various tumor models,including solid tumors and hematological malignancies.This strategy could be applied to different CAR types,including 28Z and BBZ CARs,underscoring its transformative potential in overcoming current limitations and broadening the therapeutic scope of CAR-T-cell immunotherapy.展开更多
Extensive genome profiling studies have identified thousands of long non-coding RNAs(lncRNAs)associated with human cancer.LncRNAs are emerging elements through which the complex process of cancer development and progr...Extensive genome profiling studies have identified thousands of long non-coding RNAs(lncRNAs)associated with human cancer.LncRNAs are emerging elements through which the complex process of cancer development and progression can be understood.Thus,it is crucial to include an examination of lncRNAs when studying human cancer,especially when researching the clinical challenges of relapse and recurrence following targeted therapy[1].展开更多
Dear editor,Cas13,a class Ⅱ type Ⅵ CRISPR‒Cas endonuclease with two higher eukaryotes and prokaryotes nucleotide-binding(HEPN)domains,exclusively binds to and cleaves single-stranded RNA by a complementary guide RNA...Dear editor,Cas13,a class Ⅱ type Ⅵ CRISPR‒Cas endonuclease with two higher eukaryotes and prokaryotes nucleotide-binding(HEPN)domains,exclusively binds to and cleaves single-stranded RNA by a complementary guide RNA(gRNA)(Makarova et al.,2020).RfxCas13d(also known as CasRx)is an ortholog of CRISPR‒Cas13 with a relatively small size and robust RNA knockdown capability in mammalian cells(Konermann et al.,2018).Owing to its simplicity and high efficiency,CasRx has been applied for RNA targeting in various types of cells and organisms.Nevertheless,most of these studies failed to control the nuclease activity of CasRx spatiotemporally.The re-engineered split-Cas9 system enables inducible genome editing and epigenetic modulation through chemical-induced reassembly of the Cas9 protein(Zetsche et al.,2015).However,tools that allow for efficient and controllable RNA knockdown by a split-Cas13 system remain to be established.展开更多
基金the Natural Science Foundation of Zhejiang Province(No.LZ20H290002)the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(No.ZYYCXTD-D-202002)+2 种基金the Fundamental Research Funds for the Central Universities(No.226-2022-00226)the Science and Technological Innovation Project for College Students in Zhejiang Province(Xinmiao Talent Plan 2022R424A005)Zhejiang Provincial Administration of Traditional Chinese Medicine(Nos.2022ZQ022,2023ZF083).
文摘Pharmacodynamics material basis and effective mechanisms are the two main issues to decipher the mechnisms of action of Traditional Chinese medicines(TCMs)for the treatment of diseases.TCMs,in“multi-component,multi-target,multi-pathway”paradigm,show satisfactory clinical results in complex diseases.New ideas and methods are urgently needed to explain the complex interactions between TCMs and diseases.Network pharmacology(NP)provides a novel paradigm to uncover and visualize the underlying interaction networks of TCMs against multifactorial diseases.The development and application of NP has promoted the safety,efficacy,and mechanism investigations of TCMs,which then reinforces the credibility and popularity of TCMs.The current organcentricity of medicine and the“one disease-one target-one drug”dogma obstruct the understanding of complex diseases and the development of effective drugs.Therefore,more attentions should be paid to shift from“phenotype and symptom”to“endotype and cause”in understanding and redefining current diseases.In the past two decades,with the advent of advanced and intelligent technologies(such as metabolomics,proteomics,transcriptomics,single-cell omics,and artificial intelligence),NP has been improved and deeply implemented,and presented its great value and potential as the next drug-discovery paradigm.NP is developed to cure causal mechanisms instead of treating symptoms.This review briefly summarizes the recent research progress on NP application in TCMs for efficacy research,mechanism elucidation,target prediction,safety evaluation,drug repurposing,and drug design.
基金supported by the National Natural Science Foundation for Distinguished Young Scholars of China(No.32225014)the“Lingyan”R&D Research and Development Project(No.2023C03023)+2 种基金the National Key R&D Program of China(No.2021YFC2700903)the National Natural Science Foundation of China(Nos.81672791 and 81872300)the Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholars of China(No.LR18C060002)。
文摘Cells within tissues are subject to various mechanical forces,including hydrostatic pressure,shear stress,compression,and tension.These mechanical stimuli can be converted into biochemical signals through mechanoreceptors or cytoskeleton-dependent response processes,shaping the microenvironment and maintaining cellular physiological balance.Several studies have demonstrated the roles of Yes-associated protein(YAP)and its homolog transcriptional coactivator with PDZ-binding motif(TAZ)as mechanotransducers,exerting dynamic influence on cellular phenotypes including differentiation and disease pathogenesis.This regulatory function entails the involvement of the cytoskeleton,nucleoskeleton,integrin,focal adhesions(FAs),and the integration of multiple signaling pathways,including extracellular signal-regulated kinase(ERK),wingless/integrated(WNT),and Hippo signaling.Furthermore,emerging evidence substantiates the implication of long non-coding RNAs(lncRNAs)as mechanosensitive molecules in cellular mechanotransduction.In this review,we discuss the mechanisms through which YAP/TAZ and lncRNAs serve as effectors in responding to mechanical stimuli.Additionally,we summarize and elaborate on the crucial signal molecules involved in mechanotransduction.
基金supported by the National Natural Science Foundation of China(Grant No.:81870426)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.:ZYYCXTD-D-202002)the Fundamental Research Funds for the Central Universities(Grant No.:226-2023-00059),and the Fundamental Research Funds for the Central Universities.
文摘Gaining a better understanding of autoprotection against drug-induced liver injury(DILI)may provide new strategies for its prevention and therapy.However,little is known about the underlying mechanisms of this phenomenon.We used single-cell RNA sequencing to characterize the dynamics and functions of hepatic non-parenchymal cells(NPCs)in autoprotection against DILI,using acetaminophen(APAP)as a model drug.Autoprotection was modeled through pretreatment with a mildly hepatotoxic dose of APAP in mice,followed by a higher dose in a secondary challenge.NPC subsets and dynamic changes were identified in the APAP(hepatotoxicity-sensitive)and APAP-resistant(hepatotoxicity-resistant)groups.A chemokine(C-C motif)ligand 2^(+)endothelial cell subset almost disappeared in the APAP-resistant group,and an R-spondin 3^(+)endothelial cell subset promoted hepatocyte proliferation and played an important role in APAP autoprotection.Moreover,the dendritic cell subset DC-3 may protect the liver from APAP hepatotoxicity by inducing low reactivity and suppressing the autoimmune response and occurrence of inflammation.DC-3 cells also promoted angiogenesis through crosstalk with endothelial cells via vascular endothelial growth factor-associated ligand-receptor pairs and facilitated liver tissue repair in the APAP-resistant group.In addition,the natural killer cell subsets NK-3 and NK-4 and the Sca-1^(-)CD62L^(+)natural killer T cell subset may promote autoprotection through interferon-γ-dependent pathways.Furthermore,macrophage and neutrophil subpopulations with anti-inflammatory phenotypes promoted tolerance to APAP hepatotoxicity.Overall,this study reveals the dynamics of NPCs in the resistance to APAP hepatotoxicity and provides novel insights into the mechanism of autoprotection against DILI at a high resolution.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.:81973701 and 81903767)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.:ZYYCXTD-D-202002)the Natural Science Foundation of Zhejiang Province(Grant No.:LZ20H290002).
文摘Panax ginseng(PG)and Panax notoginseng(PN)are highly valuable Chinese medicines(CM).Although both CMs have similar active constituents,their clinical applications are clearly different.Over the past decade,RNA sequencing(RNA-seq)analysis has been employed to investigate the molecular mechanisms of extracts or monomers.However,owing to the limited number of samples in standard RNA-seq,few studies have systematically compared the effects of PG and PN spanning multiple conditions at the transcriptomic level.Here,we developed an approach that simultaneously profiles transcriptome changes for multiplexed samples using RNA-seq(TCM-seq),a high-throughput,low-cost workflow to molecularly evaluate CM perturbations.A species-mixing experiment was conducted to illustrate the accuracy of sample multiplexing in TCM-seq.Transcriptomes from repeated samples were used to verify the robustness of TCM-seq.We then focused on the primary active components,Panax notoginseng saponins(PNS)and Panax ginseng saponins(PGS)extracted from PN and PG,respectively.We also characterized the transcriptome changes of 10 cell lines,treated with four different doses of PNS and PGS,using TCM-seq to compare the differences in their perturbing effects on genes,functional pathways,gene modules,and molecular networks.The results of transcriptional data analysis showed that the transcriptional patterns of various cell lines were significantly distinct.PGS exhibited a stronger regulatory effect on genes involved in cardiovascular disease,whereas PNS resulted in a greater coagulation effect on vascular endothelial cells.This study proposes a paradigm to comprehensively explore the differences in mechanisms of action between CMs based on transcriptome readouts.
基金Supported by the National Natural Science Foundation of China(No.82274511)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(No.CI2021A01004)+1 种基金the China Postdoctoral Science Foundation General Project(No.2021M693541)China Postdoctoral Science Foundation Special Project(No.2022T150731)。
文摘The progression from gastric mucosal inflammation to cancer signifies a pivotal event in the trajectory of gastric cancer(GC)development.Chinese medicine(CM)exhibits unique advantages and holds significant promise in inhibiting carcinogenesis of the gastric mucosa.This review intricately examines the critical pathological events during the transition from gastric mucosal inflammation-cancer transformation(GMICT),with a particular focus on pathological evolution mechanisms of spasmolytic polypeptide-expressing metaplasia(SPEM).Moreover,it investigates the pioneering applications and advancements of CM in intervening within the medical research domain of precancerous transformations leading to GC.Furthermore,the analysis extends to major shortcomings and challenges confronted by current research in gastric precancerous lesions,and innovative studies related to CM are presented.We offer a highly succinct yet optimistic outlook on future developmental trends.This paper endeavors to foster a profound understanding of forefront dynamics in GMICT research and scientific implications of modernizing CM.It also introduces a novel perspective for establishing a collaborative secondary prevention system for GC that integrates both Western and Chinese medicines.
基金supported by grants from the National Natural Science Foundation of China(32350007 and 32441096 to LL).
文摘Chimeric antigen receptor(CAR)-T-cell therapy has revolutionized cancer treatment.However,its long-term efficacy and broader application are limited because of its antigen insensitivity,poor persistence,and T-cell exhaustion.A recent study published by Xu et al.revealed a novel CAR engineering strategy that overcomes these difficulties by incorporating a modified CD3εintracellular domain,EB6I,into the conventional CAR structure[1].This modification enhances antigen sensitivity and sustains the cytotoxic activity of CAR-T cells,demonstrating promising efficacy in treating various tumor models,including solid tumors and hematological malignancies.This strategy could be applied to different CAR types,including 28Z and BBZ CARs,underscoring its transformative potential in overcoming current limitations and broadening the therapeutic scope of CAR-T-cell immunotherapy.
基金supported by the National Natural Science Fund for Distinguished Young Scholars(32225014)the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2023ZD0507500)+4 种基金the National Natural Science Foundation of China(81672791,81872300,and 82172899)the National Key R&D Program of China(2021YFC2700903)the“Lingyan”R&D Research and Development Project(2023C03023)the Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China(LR18C060002 and LR22H160002)the Fundamental Research Funds for the Central Universities(K20220228).
文摘Extensive genome profiling studies have identified thousands of long non-coding RNAs(lncRNAs)associated with human cancer.LncRNAs are emerging elements through which the complex process of cancer development and progression can be understood.Thus,it is crucial to include an examination of lncRNAs when studying human cancer,especially when researching the clinical challenges of relapse and recurrence following targeted therapy[1].
基金supported by the National Natural Science Foundation of China(82203444 and 82273161)the Natural Science Foundation of Jiangsu Province(BK20220672)。
文摘Dear editor,Cas13,a class Ⅱ type Ⅵ CRISPR‒Cas endonuclease with two higher eukaryotes and prokaryotes nucleotide-binding(HEPN)domains,exclusively binds to and cleaves single-stranded RNA by a complementary guide RNA(gRNA)(Makarova et al.,2020).RfxCas13d(also known as CasRx)is an ortholog of CRISPR‒Cas13 with a relatively small size and robust RNA knockdown capability in mammalian cells(Konermann et al.,2018).Owing to its simplicity and high efficiency,CasRx has been applied for RNA targeting in various types of cells and organisms.Nevertheless,most of these studies failed to control the nuclease activity of CasRx spatiotemporally.The re-engineered split-Cas9 system enables inducible genome editing and epigenetic modulation through chemical-induced reassembly of the Cas9 protein(Zetsche et al.,2015).However,tools that allow for efficient and controllable RNA knockdown by a split-Cas13 system remain to be established.
