Ganoderma lucidum is a valuable medical macrofungus with a myriad of diverse secondary metabolites,in which triterpenoids are the major constituents.This paper introduced the germplasm resources of genus Ganoderma fro...Ganoderma lucidum is a valuable medical macrofungus with a myriad of diverse secondary metabolites,in which triterpenoids are the major constituents.This paper introduced the germplasm resources of genus Ganoderma from textual research,its distribution and identification at the molecular level.Also we overviewed G.lucidum in the components,the biological activities and biosynthetic pathways of ganoderic acid,aiming to provide scientific evidence for the development and utilization of G.lucidum germplasm resources and the biosynthesis of ganoderic acid.展开更多
The relevance of constipation to the development and progression of colorectal cancer(CRC)is currently a controversial issue.Studies have shown that changes in the composition of the gut microbiota,a condition known a...The relevance of constipation to the development and progression of colorectal cancer(CRC)is currently a controversial issue.Studies have shown that changes in the composition of the gut microbiota,a condition known as ecological imbalance,are correlated with an increasing number of common human diseases,including CRC and constipation.CRC is the second leading cause of cancerrelated deaths worldwide,and constipation has been receiving widespread attention as a risk factor for CRC.Early colonoscopy screening of constipated patients,with regular follow-ups and timely intervention,can help detect early intestinal lesions and reduce the risks of developing colorectal polyps and CRC.As an important regulator of the intestinal microenvironment,the gut microbiota plays a critical role in the onset and progression of CRC.An increasing amount of evidence supports the thought that gut microbial composition and function are key determinants of CRC development and progression,with alterations inducing changes in the expression of host genes,metabolic regulation,and local and systemic immunological responses.Furthermore,constipation greatly affects the composition of the gut microbiota,which in turn influences the susceptibility to intestinal diseases such as CRC.However,the crosstalk between the gut microbiota,constipation,and CRC is still unclear.展开更多
The use of traditional chemical catalysis to produce chemicals has a series of drawbacks,such as high dependence on fossil resources,high energy consumption,and environmental pollution.With the development of syntheti...The use of traditional chemical catalysis to produce chemicals has a series of drawbacks,such as high dependence on fossil resources,high energy consumption,and environmental pollution.With the development of synthetic biology and metabolic engineering,the use of renewable biomass raw materials for chemicals synthesis by constructing efficient microbial cell factories is a green way to replace traditional chemical catalysis and traditional microbial fermentation.This review mainly summarizes several types of bulk chemicals and high value-added chemicals using metabolic engineering and synthetic biology strategies to achieve efficient microbial production.In addition,this review also summarizes several strategies for effectively regulating microbial cell metabolism.These strategies can achieve the coupling balance of material and energy by regulating intracellular material metabolism or energy metabolism,and promote the efficient production of target chemicals by microorganisms.展开更多
Alterations in cellular metabolism may contribute to tumor proliferation and survival.Upregulation of the facilitative glucose transporter(GLUT)plays a key role in promoting cancer.GLUT5 mediates modulation of fructos...Alterations in cellular metabolism may contribute to tumor proliferation and survival.Upregulation of the facilitative glucose transporter(GLUT)plays a key role in promoting cancer.GLUT5 mediates modulation of fructose utilization,and its overexpression has been associated with poor prognosis in several cancers.However,its metabolic regulation remains poorly understood.Here,we demonstrated elevated GLUT5 expression in human cholangiocarcinoma(CCA),using RNA sequencing data from samples of human tissues and cell lines,as compared to normal liver tissues or a cholangiocyte cell line.Cells exhibiting highexpression of GLUT5 showed increased rates of cell proliferation and ATP production,particularly in a fructose-supplemented medium.In contrast,GLUT5 silencing attenuated cell proliferation,ATP production,cell migration/invasion,and improved epithelialemesenchymal transition(EMT)balance.Correspondingly,fructose consumption increased tumor growth in a nude mouse xenograft model,and GLUT5 silencing suppressed growth,supporting the tumor-inhibitory effect of GLUT5 downregulation.Furthermore,in the metabolic pathways of fructolysis-Warburg effect,the expression levels of relative downstream genes,including ketohexokinase(KHK),aldolase B(ALDOB),lactate dehydrogenase A(LDHA),and monocarboxylate transporter 4(MCT4),as well as hypoxia-inducible factor 1 alpha(HIF1A),were altered in a GLUT5 expression-dependent manner.Taken together,these findings indicate that GLUT5 could be a potential target for CCA therapeutic approach via metabolic regulation.展开更多
The metabolic cycle firstly considered here is composed of a unique initial substrate, six enzymes, and five empty boxes to accommodate the substrates derived from the transformation of the initial substrate. This cyc...The metabolic cycle firstly considered here is composed of a unique initial substrate, six enzymes, and five empty boxes to accommodate the substrates derived from the transformation of the initial substrate. This cycle was considered as a pre-Closed Metabolic Cycle (CMC). Using this model, the influence of changing the kinetic constant values of any enzyme on the substrate concentration was explored. This model was transformed into an open metabolic cycle (OMC) by the input and output of two metabolites catalyzed by two external enzymes. In this case, the relative rates of input and output of metabolites were also examined;it can be concluded that the OMC cycles form delicate and fragile structures which can be theoretically disrupted, making them metabolically unfeasible.展开更多
The ginsenoside Rgfound in Panax species has extensive pharmacological properties,in particular anti-cancer effects.However,its natural yield in Panax plants is limited.Here,we report a multimodular strategy to improv...The ginsenoside Rgfound in Panax species has extensive pharmacological properties,in particular anti-cancer effects.However,its natural yield in Panax plants is limited.Here,we report a multimodular strategy to improve yields of Rgin a Panax ginseng chassis,combining engineering of triterpene metabolism and overexpression of a lignin biosynthesis gene,phenylalanine ammonia lyase(PAL).We first performed semi-rational design and site mutagenesis to improve the enzymatic efficiency of Pq3-O-UGT2,a glycosyltransferase that directly catalyzes the biosynthesis of Rgfrom Rh.Next,we used clustered regularly interspaced palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)gene editing to knock down the branch pathway of protopanaxatriol-type ginsenoside biosynthesis to enhance the metabolic flux of the protopanaxadiol-type ginsenoside Rg.Overexpression of PAL accelerated the formation of the xylem structure,significantly improving ginsenoside Rgaccumulation(to 6.19-fold higher than in thecontrol).Wecombinedoverexpression of the ginsenoside aglycon synthetic genes squalene epoxidase,Pq3-O-UGT2,and PAL with CRISPR/Cas9-based knockdown of CYP716A53v2 to improve ginsenoside Rgaccumulation.Finally,we produced ginsenoside Rgat a yield of 83.6 mg/L in a shake flask(7.0 mg/g dry weight,21.12-fold higher than with wild-type cultures).The highproduction system established in this study could be a potential platform to produce the ginsenoside Rgcommercially for pharmaceutical use.展开更多
Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life.Multiple signaling pathways that regulate metabolism also play critical roles in aging,such as PI3K/AKT,mTOR,AMPK,and s...Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life.Multiple signaling pathways that regulate metabolism also play critical roles in aging,such as PI3K/AKT,mTOR,AMPK,and sirtuins(SIRTs).Among them,sirtuins are known as a protein family with versatile functions,such as metabolic control,epigenetic modification and lifespan extension.Therefore,by understanding how sirtuins regulate metabolic processes,we can start to understand how they slow down or accelerate biological aging from the perspectives of metabolic regulation.Here,we review the biology of SIRT3,SIRT4,and SIRT5,known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix.First,we will discuss canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation.Then,we will summarize the current knowledge about functional differences between SIRT3,SIRT4,and SIRT5 in metabolic control and integration in signaling networks.Finally,we will discuss how mitochondrial sirtuins regulate processes associated with aging and aging-related diseases.展开更多
Thyroid hormone plays pivotal roles in growth,differentiation,development and metabolic homeostasis via thyroid hormone receptors(TRs)by controlling the expression of TR target genes.The transcriptional activity of TR...Thyroid hormone plays pivotal roles in growth,differentiation,development and metabolic homeostasis via thyroid hormone receptors(TRs)by controlling the expression of TR target genes.The transcriptional activity of TRs is modulated by multiple factors including various TR isoforms,diverse thyroid hormone response elements,different heterodimeric partners,coregulators,and the cellular location of TRs.In the present review,we summarize recent advance in understanding the molecular mechanisms of thyroid hormone action obtained from human subject research,thyroid hormone mimetics application,TR isoform-specific knock-in mouse models,and mitochondrion study with highlights in metabolic regulations.Finally,as future perspectives,we share our thoughts about current challenges and possible approaches to promote our knowledge of thyroid hormone action in metabolism.展开更多
Diterpenoid lactones(DLs),a group of furan-containing compounds found in Dioscorea bulbifera L.(DB),have been reported to be associated with hepatotoxicity.Different hepatotoxicities of these DLs have been observed in...Diterpenoid lactones(DLs),a group of furan-containing compounds found in Dioscorea bulbifera L.(DB),have been reported to be associated with hepatotoxicity.Different hepatotoxicities of these DLs have been observed in vitro,but reasonable explanations for the differential hepatotoxicity have not been provided.Herein,the present study aimed to confirm the potential factors that contribute to varied hepatotoxicity of four representative DLs(diosbulbins A,B,C,F).In vitro toxic effects were evaluated in various cell models and the interactions between DLs and CYP3 A4 at the atomic level were simulated by molecular docking.Results showed that DLs exhibited varied cytotoxicities,and that CYP3 A4 played a modulatory role in this process.Moreover,structural variation may cause different affinities between DLs and CYP3 A4,which was positively correlated with the observation of cytotoxicity.In addition,analysis of the glutathione(GSH)conjugates indicated that reactive intermediates were formed by metabolic oxidation that occurred on the furan moiety of DLs,whereas,GSH consumption analysis reflected the consistency between the reactive metabolites and the hepatotoxicity.Collectively,our findings illustrated that the metabolic regulation played a crucial role in generating the varied hepatotoxicity of DLs.展开更多
The progression of many diseases is accompanied by inflammation,in which inflammasomes play an important role.Inflammasomes are large multimolecular complexes present in the cytosol of stimulated immune cells,which me...The progression of many diseases is accompanied by inflammation,in which inflammasomes play an important role.Inflammasomes are large multimolecular complexes present in the cytosol of stimulated immune cells,which mediate the activation of caspase-1 and the secretion of cytokines,leading to cellular pyroptosis.During this process,metabolic regulation of the inflammasome is gaining increasing attention in this field.This review focuses on a major inflammasome,NOD-,LRR-and pyrin domain-containing protein 3(NLRP3),and discusses the role and significance of its metabolic regulation.展开更多
Prodigiosin is a secondary metabolite mainly produced at 30°C in Serratia marcescens,but it can hardly be synthetized at 37°C or higher.In this study,we provide insight into the metabolic regulation of prodi...Prodigiosin is a secondary metabolite mainly produced at 30°C in Serratia marcescens,but it can hardly be synthetized at 37°C or higher.In this study,we provide insight into the metabolic regulation of prodigiosin synthesis in response to temperature through transcriptome sequencing.The analysis of the function of differentially expressed genes suggested that temperature resulted in significant alteration of the metabolic pathways between 30 and 37°C.Specifically,30°C favored transcriptional expression of the pig gene cluster.At the same time,the carbon flux was redistributed to pathways of pyruvate,proline,serine,especially homoserine,cystathionine,homocysteine,methionine,and s-adenosylmethionine metabolism,all involved in prodigiosin biosynthesis,and was finally increased towards the prodigiosin synthesis pathway in S.marcescens at 30°C.Interestingly,results further confirmed increased transcriptional level of five regulators(LuxS,RpoS,Hfq,EepR,CRP),and decreased content of hexS through qPCR.Finally,successful co-overexpression of mmuM and metK,related to homocysteine,methionine,and s-adenosylmethionine metabolism,in the chromosome of JNB5-1(JNB5-1/MK)resulted in increased prodigiosin titer up to 7.57 g/L in JNB5-1/MK at 30°C,which was 41.2%higher than that in JNB5-1.Our transcriptome analysis provides further insight into the strain’s response to temperature changes at the transcription level,which is of great significance for improving the production of prodigiosin.展开更多
Over 300 billion of cells die every day in the human body,producing a large number of endogenous apoptotic extracellular vesicles(apoEVs).Also,allogenic stem cell transplantation,a commonly used therapeutic approach i...Over 300 billion of cells die every day in the human body,producing a large number of endogenous apoptotic extracellular vesicles(apoEVs).Also,allogenic stem cell transplantation,a commonly used therapeutic approach in current clinical practice,generates exogenous apoEVs.It is well known that phagocytic cells engulf and digest apoEVs to maintain the body’s homeostasis.In this study,we show that a fraction of exogenous apoEVs is metabolized in the integumentary skin and hair follicles.Mechanistically,apoEVs activate the Wnt/β-catenin pathway to facilitate their metabolism in a wave-like pattern.The migration of apoEVs is enhanced by treadmill exercise and inhibited by tail suspension,which is associated with the mechanical force-regulated expression of DKK1 in circulation.Furthermore,we show that exogenous apoEVs promote wound healing and hair growth via activation of Wnt/β-catenin pathway in skin and hair follicle mesenchymal stem cells.This study reveals a previously unrecognized metabolic pathway of apoEVs and opens a new avenue for exploring apoEV-based therapy for skin and hair disorders.展开更多
Interactions between diet and the intestinal microbiome play an important role in human health and disease development.It is well known that such interactions,whether direct or indirect,trigger a series of metabolic r...Interactions between diet and the intestinal microbiome play an important role in human health and disease development.It is well known that such interactions,whether direct or indirect,trigger a series of metabolic reactions in the body.Evidence suggests that intestinal stem cells(ISCs),which are phenotypic precursors of various intestinal epithelial cells,play a significant role in the regulation of intestinal barrier function and homeostasis.The advent and evolution of intestinal organoid culture techniques have presented a key opportunity to study the association between the intestinal microenvironment and ISCs.As a result,the effects exerted by dietary factors,intestinal microbiomes,and their metabolites on the metabolic regulation of ISCs and the potential mechanisms underlying such effects are being gradually revealed.This review summarises the effects of different dietary patterns on the behaviour and functioning of ISCs and focuses on the crosstalk between intestinal microbiota,related metabolites,and ISCs,with the aim of fully understanding the relationship between these three factors and providing further insights into the complex mechanisms associated with ISCs in the human body.Gaining an understanding of these mechanisms may lead to the development of novel dietary interventions or drugs conducive to intestinal health.展开更多
The B7/CD28 families of immune checkpoints play vital roles in negatively or positively regulating immune cells in homeostasis and various diseases.Recent basic and clinical studies have revealed novel biology of the ...The B7/CD28 families of immune checkpoints play vital roles in negatively or positively regulating immune cells in homeostasis and various diseases.Recent basic and clinical studies have revealed novel biology of the B7/CD28 families and new therapeutics for cancer therapy.In this review,we discuss the newly discovered KIR3DL3/TMIGD2/HHLA2 pathways,PD-1/PD-L1 and B7-H3 as metabolic regulators,the glycobiology of PD-1/PD-L1,B7x(B7-H4)and B7-H3,and the recently characterized PD-L1/B7-1 cis-interaction.We also cover the tumor-intrinsic and-extrinsic resistance mechanisms to current anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapies in clinical settings.Finally,we review new immunotherapies targeting B7-H3,B7x,PD-1/PD-L1,and CTLA-4 in current clinical trials.展开更多
Microorganisms are important sources of various natural products that have been commercialized for human medicine and animal healthcare.Bacitracin is an important antibacterial natural product predominantly pro-duced ...Microorganisms are important sources of various natural products that have been commercialized for human medicine and animal healthcare.Bacitracin is an important antibacterial natural product predominantly pro-duced by Bacillus licheniformis and Bacillus subtilis,and it is characterized by a broad antimicrobial spectrum,strong activity and low resistance,thus bacitracin is extensively applied in animal feed and veterinary medicine industries.In recent years,various strategies have been proposed to improve bacitracin production.Herein,we systematically describe the regulation of bacitracin biosynthesis in genus Bacillus and its associated mechanism,to provide a theoretical basis for bacitracin overproduction.The metabolic engineering strategies applied for bacitracin production are explored,including improving substrate utilization,using an enlarged precursor amino acid pool,increasing ATP supply and NADPH generation,and engineering transcription regulators.We also present several approaches of fermentation process optimization to facilitate the industrial large-scale production of bacitracin.Finally,the challenges and prospects associated with microbial bacitracin synthesis are discussed to facilitate the establishment of high-yield and low-cost biological factories.展开更多
Adoptive cell therapy(ACT)has emerged with remarkable efficacies for tumor immunotherapy.Chimeric antigen receptor(CAR)T cell therapy,as one of most promising ACTs,has achieved prominent effects in treating malignant ...Adoptive cell therapy(ACT)has emerged with remarkable efficacies for tumor immunotherapy.Chimeric antigen receptor(CAR)T cell therapy,as one of most promising ACTs,has achieved prominent effects in treating malignant hematological tumors.However,the insufficient killing activity and limited persistence of T cells in the immunosuppressive tumor microenvironment limit the further application of ACTs for cancer patients.Many studies have focused on improving cytotoxicity and persistence of T cells to achieve improved therapeutic effects.In this study,we explored the potential function in ACT of ginsenoside Rg1,the main pharmacologically active component of ginseng.We introduced Rg1 during the in vitro activation and expansion phase of T cells,and found that Rg1 treatment upregulated two T cell activation markers,CD69 and CD25,while promoting T cell differentiation towards a mature state.Transcriptome sequencing revealed that Rg1 influenced T cell metabolic reprogramming by strengthening mitochondrial biosynthesis.When co-cultured with tumor cells,Rg1-treated T cells showed stronger cytotoxicity than untreated cells.Moreover,adding Rg1 to the culture endowed CAR-T cells with enhanced anti-tumor efficacy.This study suggests that ginsenoside Rg1 provides a potential approach for improving the anti-tumor efficacy of ACT by enhancing T cell effector functions.展开更多
Target of rapamycin(TOR)is an evolutionarily conserved protein kinase that functions as a central signaling hub to integrate diverse internal and external cues to precisely orchestrate cellular and organismal physiolo...Target of rapamycin(TOR)is an evolutionarily conserved protein kinase that functions as a central signaling hub to integrate diverse internal and external cues to precisely orchestrate cellular and organismal physiology.During evolution,TOR both maintains the highly conserved TOR complex compositions,and cellular and molecular functions,but also evolves distinctive roles and strategies to modulate cell growth,proliferation,metabolism,survival,and stress responses in eukaryotes.Here,we review recent discoveries on the plant TOR signaling network.We present an overview of plant TOR complexes,analyze the signaling landscape of the plant TOR signaling network from the upstream signals that regulate plant TOR activation to the downstream effectors involved in various biological processes,and compare their conservation and specificities within different biological contexts.Finally,we summarize the impact of dysregulation of TOR signaling on every stage of plant growth and development,from embryogenesis and seedling growth,to flowering and senescence.展开更多
Mango leaves have been widely used in the clinical practice for thousands of years in traditional Chinese medicine. Mangiferin,an effective constituent in the mango leaves,has multiple pharmacological actions involved...Mango leaves have been widely used in the clinical practice for thousands of years in traditional Chinese medicine. Mangiferin,an effective constituent in the mango leaves,has multiple pharmacological actions involved in some basic pathological processes,such as inflammation,oxidative injury,tumor growth,micro-organism infections, metabolic regulations,and immunological regulations.The pharmacological effects of mangiferin from some published data are reviewed in this article.展开更多
The core G protein signaling module,which consists of Gαand extra-large Gα(XLG)subunits coupled with the Gβγdimer,is a master regulator of various stress responses.In this study,we compared the basal and salt stre...The core G protein signaling module,which consists of Gαand extra-large Gα(XLG)subunits coupled with the Gβγdimer,is a master regulator of various stress responses.In this study,we compared the basal and salt stress-induced transcriptomic,metabolomic and phenotypic profiles in Gα,Gβ,and XLG-null mutants of two plant species,Arabidopsis thaliana and Marchantia polymorpha,and showed that G protein mediates the shift of transcriptional and metabolic homeostasis to stress readiness status.We demonstrated that such stress readiness serves as an intrinsic protection mechanism against further stressors through enhancing the phenylpropanoid pathway and abscisic acid responses.Furthermore,WRKY transcription factors were identified as key intermediates of G protein-mediated homeostatic shifts.Statistical and mathematical model comparisons between A.thaliana and M.polymorpha revealed evolutionary conservation of transcriptional and metabolic networks over land plant evolution,whereas divergence has occurred in the function of plant-specific atypical XLG subunit.Taken together,our results indicate that the shifts in transcriptional and metabolic homeostasis at least partially act as the mechanisms of G protein-coupled stress responses that are conserved between two distantly related plants.展开更多
Metabolic-dysfunction-associated fatty liver disease(MAFLD)is a group of highly heterogeneous multi-system diseases,which is closely related to metabolic dysfunction and is one of the most important public health prob...Metabolic-dysfunction-associated fatty liver disease(MAFLD)is a group of highly heterogeneous multi-system diseases,which is closely related to metabolic dysfunction and is one of the most important public health problems in the world.Studies have shown that paracrine fibroblast growth factors(FGFs)play an important role in the occurrence and development of MAFLD by regulating glucose and lipid metabolism,inflammation,and fibrosis.This article reviews the latest progress in understanding of the distribution,function,and metabolic regulation of paracrine FGFs,which paves the way for future FGF-based therapies targeting MAFLD.展开更多
基金supported by the Key Scientific and Technological Grant of Zhejiang for Breeding New Agricultural Varieties(No.2021C02074 and 2021C02073)Zhejiang Provincial Natural Science Foundation of China(No.LR21H280002)Zhejiang Key Agricultural Enterprise Institute(No.2017Y20001)。
文摘Ganoderma lucidum is a valuable medical macrofungus with a myriad of diverse secondary metabolites,in which triterpenoids are the major constituents.This paper introduced the germplasm resources of genus Ganoderma from textual research,its distribution and identification at the molecular level.Also we overviewed G.lucidum in the components,the biological activities and biosynthetic pathways of ganoderic acid,aiming to provide scientific evidence for the development and utilization of G.lucidum germplasm resources and the biosynthesis of ganoderic acid.
基金Supported by National Natural Science Foundation of China,No. 82000511 and 82170558Scientific and Technological Projects of Tianjin,No. 21JCQNJC01120+3 种基金Health Science and Technology Project of Tianjin,No. TJWJ2021QN006Scientific Research Project of Tianjin Education Commission,No. 2019KJ197Natural Science Foundation of Zhejiang Province,No. LQ23H050005Scientific Research Project of Zhejiang Provincial Education Department,No. Y202250731
文摘The relevance of constipation to the development and progression of colorectal cancer(CRC)is currently a controversial issue.Studies have shown that changes in the composition of the gut microbiota,a condition known as ecological imbalance,are correlated with an increasing number of common human diseases,including CRC and constipation.CRC is the second leading cause of cancerrelated deaths worldwide,and constipation has been receiving widespread attention as a risk factor for CRC.Early colonoscopy screening of constipated patients,with regular follow-ups and timely intervention,can help detect early intestinal lesions and reduce the risks of developing colorectal polyps and CRC.As an important regulator of the intestinal microenvironment,the gut microbiota plays a critical role in the onset and progression of CRC.An increasing amount of evidence supports the thought that gut microbial composition and function are key determinants of CRC development and progression,with alterations inducing changes in the expression of host genes,metabolic regulation,and local and systemic immunological responses.Furthermore,constipation greatly affects the composition of the gut microbiota,which in turn influences the susceptibility to intestinal diseases such as CRC.However,the crosstalk between the gut microbiota,constipation,and CRC is still unclear.
基金This work was financially supported by the National Natural Science Foundation of China(Grant Nos.21811530003,21861132017,U1663227,21706006)。
文摘The use of traditional chemical catalysis to produce chemicals has a series of drawbacks,such as high dependence on fossil resources,high energy consumption,and environmental pollution.With the development of synthetic biology and metabolic engineering,the use of renewable biomass raw materials for chemicals synthesis by constructing efficient microbial cell factories is a green way to replace traditional chemical catalysis and traditional microbial fermentation.This review mainly summarizes several types of bulk chemicals and high value-added chemicals using metabolic engineering and synthetic biology strategies to achieve efficient microbial production.In addition,this review also summarizes several strategies for effectively regulating microbial cell metabolism.These strategies can achieve the coupling balance of material and energy by regulating intracellular material metabolism or energy metabolism,and promote the efficient production of target chemicals by microorganisms.
基金This work was supported by JSPS KAKENHI,Japan[No.JP16H05255,JP19H03884(MM),JP17H04654(NM)]scholarship support from the Japanese Government(MEXT)provided to the author(NS).
文摘Alterations in cellular metabolism may contribute to tumor proliferation and survival.Upregulation of the facilitative glucose transporter(GLUT)plays a key role in promoting cancer.GLUT5 mediates modulation of fructose utilization,and its overexpression has been associated with poor prognosis in several cancers.However,its metabolic regulation remains poorly understood.Here,we demonstrated elevated GLUT5 expression in human cholangiocarcinoma(CCA),using RNA sequencing data from samples of human tissues and cell lines,as compared to normal liver tissues or a cholangiocyte cell line.Cells exhibiting highexpression of GLUT5 showed increased rates of cell proliferation and ATP production,particularly in a fructose-supplemented medium.In contrast,GLUT5 silencing attenuated cell proliferation,ATP production,cell migration/invasion,and improved epithelialemesenchymal transition(EMT)balance.Correspondingly,fructose consumption increased tumor growth in a nude mouse xenograft model,and GLUT5 silencing suppressed growth,supporting the tumor-inhibitory effect of GLUT5 downregulation.Furthermore,in the metabolic pathways of fructolysis-Warburg effect,the expression levels of relative downstream genes,including ketohexokinase(KHK),aldolase B(ALDOB),lactate dehydrogenase A(LDHA),and monocarboxylate transporter 4(MCT4),as well as hypoxia-inducible factor 1 alpha(HIF1A),were altered in a GLUT5 expression-dependent manner.Taken together,these findings indicate that GLUT5 could be a potential target for CCA therapeutic approach via metabolic regulation.
文摘The metabolic cycle firstly considered here is composed of a unique initial substrate, six enzymes, and five empty boxes to accommodate the substrates derived from the transformation of the initial substrate. This cycle was considered as a pre-Closed Metabolic Cycle (CMC). Using this model, the influence of changing the kinetic constant values of any enzyme on the substrate concentration was explored. This model was transformed into an open metabolic cycle (OMC) by the input and output of two metabolites catalyzed by two external enzymes. In this case, the relative rates of input and output of metabolites were also examined;it can be concluded that the OMC cycles form delicate and fragile structures which can be theoretically disrupted, making them metabolically unfeasible.
基金financial support from the National Key Research and Development Program(2020YFA0907903)a key project at the central government level:“The ability to establish a sustainable use for valuable Chinese medicine resources”(2060302)+2 种基金the National Science Foundation of China(91954112 and 31900501)the Young Elite Scientists Sponsorship Program of Tianjin(TJSQNTJ-2020-19)the Scientific Research Transformation Foundation of the Wenzhou Safety(Emergency)Institute of Tianjin University。
文摘The ginsenoside Rgfound in Panax species has extensive pharmacological properties,in particular anti-cancer effects.However,its natural yield in Panax plants is limited.Here,we report a multimodular strategy to improve yields of Rgin a Panax ginseng chassis,combining engineering of triterpene metabolism and overexpression of a lignin biosynthesis gene,phenylalanine ammonia lyase(PAL).We first performed semi-rational design and site mutagenesis to improve the enzymatic efficiency of Pq3-O-UGT2,a glycosyltransferase that directly catalyzes the biosynthesis of Rgfrom Rh.Next,we used clustered regularly interspaced palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)gene editing to knock down the branch pathway of protopanaxatriol-type ginsenoside biosynthesis to enhance the metabolic flux of the protopanaxadiol-type ginsenoside Rg.Overexpression of PAL accelerated the formation of the xylem structure,significantly improving ginsenoside Rgaccumulation(to 6.19-fold higher than in thecontrol).Wecombinedoverexpression of the ginsenoside aglycon synthetic genes squalene epoxidase,Pq3-O-UGT2,and PAL with CRISPR/Cas9-based knockdown of CYP716A53v2 to improve ginsenoside Rgaccumulation.Finally,we produced ginsenoside Rgat a yield of 83.6 mg/L in a shake flask(7.0 mg/g dry weight,21.12-fold higher than with wild-type cultures).The highproduction system established in this study could be a potential platform to produce the ginsenoside Rgcommercially for pharmaceutical use.
基金supported by the National Natural Science Foundation of China (91949209, 91749202, 92149301, 92168201)the National Key Research and Development Program of China (2018YFC2000100, 2020YFA0804000)+5 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010000)the National Natural Science Foundation of China (81921006, 81625009, 82125011)the Key Research Program of the Chinese Academy of Sciences (KFZD-SW-221)the 14th Five-year Network Security and Informatization Plan of Chinese Academy of Sciences (WX145XQ0718)Informatization Plan of Chinese Academy of Sciences (CASWX2021SF-0301)the Milky Way Research Foundation (MWRF)
文摘Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life.Multiple signaling pathways that regulate metabolism also play critical roles in aging,such as PI3K/AKT,mTOR,AMPK,and sirtuins(SIRTs).Among them,sirtuins are known as a protein family with versatile functions,such as metabolic control,epigenetic modification and lifespan extension.Therefore,by understanding how sirtuins regulate metabolic processes,we can start to understand how they slow down or accelerate biological aging from the perspectives of metabolic regulation.Here,we review the biology of SIRT3,SIRT4,and SIRT5,known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix.First,we will discuss canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation.Then,we will summarize the current knowledge about functional differences between SIRT3,SIRT4,and SIRT5 in metabolic control and integration in signaling networks.Finally,we will discuss how mitochondrial sirtuins regulate processes associated with aging and aging-related diseases.
基金supported by grants from the One Hundred Talents Program of the Chinese Academy of Sciencesthe National Basic Research Program(973 Program)(Grant Nos.2009CB919000 and 2010CB912500)+1 种基金the National Natural Science Foundation of China(Grant Nos.30970587 and 31070679)the Science and Technology Commission of Shanghai Municipality(10ZR1435000).
文摘Thyroid hormone plays pivotal roles in growth,differentiation,development and metabolic homeostasis via thyroid hormone receptors(TRs)by controlling the expression of TR target genes.The transcriptional activity of TRs is modulated by multiple factors including various TR isoforms,diverse thyroid hormone response elements,different heterodimeric partners,coregulators,and the cellular location of TRs.In the present review,we summarize recent advance in understanding the molecular mechanisms of thyroid hormone action obtained from human subject research,thyroid hormone mimetics application,TR isoform-specific knock-in mouse models,and mitochondrion study with highlights in metabolic regulations.Finally,as future perspectives,we share our thoughts about current challenges and possible approaches to promote our knowledge of thyroid hormone action in metabolism.
基金supported by the National Natural Science Foundation of China(No.81773993)
文摘Diterpenoid lactones(DLs),a group of furan-containing compounds found in Dioscorea bulbifera L.(DB),have been reported to be associated with hepatotoxicity.Different hepatotoxicities of these DLs have been observed in vitro,but reasonable explanations for the differential hepatotoxicity have not been provided.Herein,the present study aimed to confirm the potential factors that contribute to varied hepatotoxicity of four representative DLs(diosbulbins A,B,C,F).In vitro toxic effects were evaluated in various cell models and the interactions between DLs and CYP3 A4 at the atomic level were simulated by molecular docking.Results showed that DLs exhibited varied cytotoxicities,and that CYP3 A4 played a modulatory role in this process.Moreover,structural variation may cause different affinities between DLs and CYP3 A4,which was positively correlated with the observation of cytotoxicity.In addition,analysis of the glutathione(GSH)conjugates indicated that reactive intermediates were formed by metabolic oxidation that occurred on the furan moiety of DLs,whereas,GSH consumption analysis reflected the consistency between the reactive metabolites and the hepatotoxicity.Collectively,our findings illustrated that the metabolic regulation played a crucial role in generating the varied hepatotoxicity of DLs.
基金This work was supported by the National Natural Science Foundation of China(81930042,81730047,31670926,and 31800759)the National Key Research and Development Program of China(2018YFC1105203 and 2016YFC1100204).
文摘The progression of many diseases is accompanied by inflammation,in which inflammasomes play an important role.Inflammasomes are large multimolecular complexes present in the cytosol of stimulated immune cells,which mediate the activation of caspase-1 and the secretion of cytokines,leading to cellular pyroptosis.During this process,metabolic regulation of the inflammasome is gaining increasing attention in this field.This review focuses on a major inflammasome,NOD-,LRR-and pyrin domain-containing protein 3(NLRP3),and discusses the role and significance of its metabolic regulation.
基金This work was supported by the National Key Research and Development Program of China(2018YFA0900300)the National Natural Science Foundation of China(31870066,21778024)+1 种基金National First-Class Discipline Program of Light Industry Technology and Engineering(LITE2018-06)the Program of Introducing Talents of Discipline to Universities(111-2-06).
文摘Prodigiosin is a secondary metabolite mainly produced at 30°C in Serratia marcescens,but it can hardly be synthetized at 37°C or higher.In this study,we provide insight into the metabolic regulation of prodigiosin synthesis in response to temperature through transcriptome sequencing.The analysis of the function of differentially expressed genes suggested that temperature resulted in significant alteration of the metabolic pathways between 30 and 37°C.Specifically,30°C favored transcriptional expression of the pig gene cluster.At the same time,the carbon flux was redistributed to pathways of pyruvate,proline,serine,especially homoserine,cystathionine,homocysteine,methionine,and s-adenosylmethionine metabolism,all involved in prodigiosin biosynthesis,and was finally increased towards the prodigiosin synthesis pathway in S.marcescens at 30°C.Interestingly,results further confirmed increased transcriptional level of five regulators(LuxS,RpoS,Hfq,EepR,CRP),and decreased content of hexS through qPCR.Finally,successful co-overexpression of mmuM and metK,related to homocysteine,methionine,and s-adenosylmethionine metabolism,in the chromosome of JNB5-1(JNB5-1/MK)resulted in increased prodigiosin titer up to 7.57 g/L in JNB5-1/MK at 30°C,which was 41.2%higher than that in JNB5-1.Our transcriptome analysis provides further insight into the strain’s response to temperature changes at the transcription level,which is of great significance for improving the production of prodigiosin.
基金supported by grants from the National Key R&D Program of China(2021YFA1100600 to S.S.)the Guangdong Financial Fund for High-Caliber Hospital Construction(174-2018-XMZC-0001-03-0125,D-07 to S.S.,D-11 to X.K.)+5 种基金the Pearl River Talent Recruitment Program(2019ZT08Y485)the National Science and Technology Major Project of the Ministry of Science and Technology of China(2018ZX10302207-001-002)the Sun Yat-sen University Young Teacher Key Cultivation Project(18ykzd05 to X.K.)the Natural Science Foundation of Guangdong(2016A030313262 to X.M.)the National Natural Science Foundation of China(82170924 to X.K.,81700928 to L.M.)the Youth Teacher Training Project of Sun Yat-sen University(17ykpy71 to L.M.).
文摘Over 300 billion of cells die every day in the human body,producing a large number of endogenous apoptotic extracellular vesicles(apoEVs).Also,allogenic stem cell transplantation,a commonly used therapeutic approach in current clinical practice,generates exogenous apoEVs.It is well known that phagocytic cells engulf and digest apoEVs to maintain the body’s homeostasis.In this study,we show that a fraction of exogenous apoEVs is metabolized in the integumentary skin and hair follicles.Mechanistically,apoEVs activate the Wnt/β-catenin pathway to facilitate their metabolism in a wave-like pattern.The migration of apoEVs is enhanced by treadmill exercise and inhibited by tail suspension,which is associated with the mechanical force-regulated expression of DKK1 in circulation.Furthermore,we show that exogenous apoEVs promote wound healing and hair growth via activation of Wnt/β-catenin pathway in skin and hair follicle mesenchymal stem cells.This study reveals a previously unrecognized metabolic pathway of apoEVs and opens a new avenue for exploring apoEV-based therapy for skin and hair disorders.
基金supported by the National Natural Science Foundation of China(81973837)Scientific and technological innovation project of China Academy of Chinese Medical Sciences(CI2021A016)National Key projects for international cooperation on science,technology and innovation(2021YFE0201100).
文摘Interactions between diet and the intestinal microbiome play an important role in human health and disease development.It is well known that such interactions,whether direct or indirect,trigger a series of metabolic reactions in the body.Evidence suggests that intestinal stem cells(ISCs),which are phenotypic precursors of various intestinal epithelial cells,play a significant role in the regulation of intestinal barrier function and homeostasis.The advent and evolution of intestinal organoid culture techniques have presented a key opportunity to study the association between the intestinal microenvironment and ISCs.As a result,the effects exerted by dietary factors,intestinal microbiomes,and their metabolites on the metabolic regulation of ISCs and the potential mechanisms underlying such effects are being gradually revealed.This review summarises the effects of different dietary patterns on the behaviour and functioning of ISCs and focuses on the crosstalk between intestinal microbiota,related metabolites,and ISCs,with the aim of fully understanding the relationship between these three factors and providing further insights into the complex mechanisms associated with ISCs in the human body.Gaining an understanding of these mechanisms may lead to the development of novel dietary interventions or drugs conducive to intestinal health.
基金NIH R01CA175495 and R01CA262132the Department of Defense(PC210331 and BC190403)the Price Family Foundation.M.C.P.is supported by NIH 5TL1TR002557.A.T.M.is supported by Scandinavia/Borge.
文摘The B7/CD28 families of immune checkpoints play vital roles in negatively or positively regulating immune cells in homeostasis and various diseases.Recent basic and clinical studies have revealed novel biology of the B7/CD28 families and new therapeutics for cancer therapy.In this review,we discuss the newly discovered KIR3DL3/TMIGD2/HHLA2 pathways,PD-1/PD-L1 and B7-H3 as metabolic regulators,the glycobiology of PD-1/PD-L1,B7x(B7-H4)and B7-H3,and the recently characterized PD-L1/B7-1 cis-interaction.We also cover the tumor-intrinsic and-extrinsic resistance mechanisms to current anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapies in clinical settings.Finally,we review new immunotherapies targeting B7-H3,B7x,PD-1/PD-L1,and CTLA-4 in current clinical trials.
基金supported by National Key Research and Development Program of China(2022YFA0911800)Knowledge Innovation Program of Wuhan-Shuguang Project(2022020801020334)Science and Technology Project of Hubei Tobacco Company(027Y2021-023,027Y2020-013).
文摘Microorganisms are important sources of various natural products that have been commercialized for human medicine and animal healthcare.Bacitracin is an important antibacterial natural product predominantly pro-duced by Bacillus licheniformis and Bacillus subtilis,and it is characterized by a broad antimicrobial spectrum,strong activity and low resistance,thus bacitracin is extensively applied in animal feed and veterinary medicine industries.In recent years,various strategies have been proposed to improve bacitracin production.Herein,we systematically describe the regulation of bacitracin biosynthesis in genus Bacillus and its associated mechanism,to provide a theoretical basis for bacitracin overproduction.The metabolic engineering strategies applied for bacitracin production are explored,including improving substrate utilization,using an enlarged precursor amino acid pool,increasing ATP supply and NADPH generation,and engineering transcription regulators.We also present several approaches of fermentation process optimization to facilitate the industrial large-scale production of bacitracin.Finally,the challenges and prospects associated with microbial bacitracin synthesis are discussed to facilitate the establishment of high-yield and low-cost biological factories.
基金supported by the National Natural Science Foundation of China(No.82020108004 and 81873424)the Natural Science Foundation of Chongqing,China(No.CSTB2022NSCQ-MSX1287)+2 种基金Special Funding for the Frontiers of Military Medical Basics(No.2018YQYLY002)Key Technical Innovation Projects in Clinical Fields of Xinqiao Hospital(No.2018JSLC0020)the Young Doctor Talent Incubation Program of Xinqiao Hospital(No.2022YQB016).
文摘Adoptive cell therapy(ACT)has emerged with remarkable efficacies for tumor immunotherapy.Chimeric antigen receptor(CAR)T cell therapy,as one of most promising ACTs,has achieved prominent effects in treating malignant hematological tumors.However,the insufficient killing activity and limited persistence of T cells in the immunosuppressive tumor microenvironment limit the further application of ACTs for cancer patients.Many studies have focused on improving cytotoxicity and persistence of T cells to achieve improved therapeutic effects.In this study,we explored the potential function in ACT of ginsenoside Rg1,the main pharmacologically active component of ginseng.We introduced Rg1 during the in vitro activation and expansion phase of T cells,and found that Rg1 treatment upregulated two T cell activation markers,CD69 and CD25,while promoting T cell differentiation towards a mature state.Transcriptome sequencing revealed that Rg1 influenced T cell metabolic reprogramming by strengthening mitochondrial biosynthesis.When co-cultured with tumor cells,Rg1-treated T cells showed stronger cytotoxicity than untreated cells.Moreover,adding Rg1 to the culture endowed CAR-T cells with enhanced anti-tumor efficacy.This study suggests that ginsenoside Rg1 provides a potential approach for improving the anti-tumor efficacy of ACT by enhancing T cell effector functions.
基金supported by the National Natural Science Foundation of China(31870269 to Y.X.,31800199 and 32170273 to Y.L.)the funding from Fujian Agriculture and Forestry University(Y.X.)。
文摘Target of rapamycin(TOR)is an evolutionarily conserved protein kinase that functions as a central signaling hub to integrate diverse internal and external cues to precisely orchestrate cellular and organismal physiology.During evolution,TOR both maintains the highly conserved TOR complex compositions,and cellular and molecular functions,but also evolves distinctive roles and strategies to modulate cell growth,proliferation,metabolism,survival,and stress responses in eukaryotes.Here,we review recent discoveries on the plant TOR signaling network.We present an overview of plant TOR complexes,analyze the signaling landscape of the plant TOR signaling network from the upstream signals that regulate plant TOR activation to the downstream effectors involved in various biological processes,and compare their conservation and specificities within different biological contexts.Finally,we summarize the impact of dysregulation of TOR signaling on every stage of plant growth and development,from embryogenesis and seedling growth,to flowering and senescence.
文摘Mango leaves have been widely used in the clinical practice for thousands of years in traditional Chinese medicine. Mangiferin,an effective constituent in the mango leaves,has multiple pharmacological actions involved in some basic pathological processes,such as inflammation,oxidative injury,tumor growth,micro-organism infections, metabolic regulations,and immunological regulations.The pharmacological effects of mangiferin from some published data are reviewed in this article.
基金This study was supported by the Agency for Science,Technology and Research(A*STAR)Singapore under the Industry Alignment Fund Pre-positioning Program,the High Performance Precision Agriculture(HiPPA)system(A19E4a0101)the Singapore-MIT Aliance for Research and Technology,and Disruptive&Sustainable Technologies for Agricul-tural Precision(DISTAP)(to D.U.)a discovery grant from the Natural Sciences and Engineering Research Council of Canada(ARGPIN-2020-07097)(to K-LL)。
文摘The core G protein signaling module,which consists of Gαand extra-large Gα(XLG)subunits coupled with the Gβγdimer,is a master regulator of various stress responses.In this study,we compared the basal and salt stress-induced transcriptomic,metabolomic and phenotypic profiles in Gα,Gβ,and XLG-null mutants of two plant species,Arabidopsis thaliana and Marchantia polymorpha,and showed that G protein mediates the shift of transcriptional and metabolic homeostasis to stress readiness status.We demonstrated that such stress readiness serves as an intrinsic protection mechanism against further stressors through enhancing the phenylpropanoid pathway and abscisic acid responses.Furthermore,WRKY transcription factors were identified as key intermediates of G protein-mediated homeostatic shifts.Statistical and mathematical model comparisons between A.thaliana and M.polymorpha revealed evolutionary conservation of transcriptional and metabolic networks over land plant evolution,whereas divergence has occurred in the function of plant-specific atypical XLG subunit.Taken together,our results indicate that the shifts in transcriptional and metabolic homeostasis at least partially act as the mechanisms of G protein-coupled stress responses that are conserved between two distantly related plants.
基金This work was supported by the National Natural Science Foundation of China(Grant number 82070593)。
文摘Metabolic-dysfunction-associated fatty liver disease(MAFLD)is a group of highly heterogeneous multi-system diseases,which is closely related to metabolic dysfunction and is one of the most important public health problems in the world.Studies have shown that paracrine fibroblast growth factors(FGFs)play an important role in the occurrence and development of MAFLD by regulating glucose and lipid metabolism,inflammation,and fibrosis.This article reviews the latest progress in understanding of the distribution,function,and metabolic regulation of paracrine FGFs,which paves the way for future FGF-based therapies targeting MAFLD.