Metabolic Regulation of Mammary Gland Epithelial Cells of Dairy Cow by Galactopoietic Compound Isolated from Vaccariae segetalis

In previous experiment, we isolated a compound dibutyl phthalate （DBP） from Vaccaria segetalis which had galactopoietic function on mammary gland epithelial cells of dairy cow （DCMECs）. In this experiment, we ascertained the metabolic regulation function of DBP on DCMECs. Many genes related to lactation including Stat5, AMPK, b-casein, Glut1, SREBP-1, PEPCK, and ACC were detected by real-time PCR. Furthermore, Stat5 and AMPK were detected by Western blot and immunofluorescence co-localization, respectively. The results showed that DBP stimulates the expression of Stat5 and p-Stat5, thus activates Stat5 cell signal transduction pathway and stimulates b-casein synthesis. DBP also raises the activities of Glut1 and AMPK to stimulate glucose uptake and glycometabolism and activates the expression of AMPK downstream target genes PEPCK and ACC and expression of SREBP-1 to stimulate milk fat synthesis. In addition, the activities of HK, G-6-PDH, ICDH, ATPase, and energy charges were stimulated by DBP to increase the energy metabolism level of DCMECs. The results showed DBP stimulates energy metabolism related to galactopoietic function in DCMECs.

Thyroid hormone action in metabolic regulation

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.

The crucial role of metabolic regulation in differential hepatotoxicity induced by furanoids in Dioscorea bulbifera

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.

Metabolic Regulation of the NLRP3 Inflammasome

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.

Comparative transcriptome analysis reveals metabolic regulation of prodigiosin in Serratia marcescens

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.

Microbiota regulation in constipation and colorectal cancer

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.

Efficient production of chemicals from microorganism by metabolic engineering and synthetic biology

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.

Metabolic Cycles: Effect of a Simultaneous Input and Output of Two Substrates

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.

Effect of Insulin on the Differential Expression of VLDL Receptor Isoforms of SGC7901 Cell and Its Biological Implication

This study examined the effect of insulin on the expression of very low density lipoprotein receptor (VLDLR) subtypes of SGC7901 cells and discussed its biological implication.In vitro, moderately or poorly-differentiated human gastric adenocarcinoma cell line SGC7901 was incubated with insulin for different lengths of time, and then the expression of protein and RNA level in VLDLR subtypes were detected by Western blotting and real-time PCR, respectively.The results showed that, at certain time interval, insulin could down-regulate expression of type Ⅰ VLDLR and up-regulate the expression of type Ⅱ VLDLR in SGC7901 cells, at both protein and RNA level.We are led to conclude that insulin serves as a regulator in maintaining the balance between glucose and lipid metabolism in vivo, possibly through its effect on the differential expression of VLDLR subtypes.

Germplasm resources and secondary metabolism regulation in Reishi mushroom(Ganoderma lucidum)

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.

Regulation of Sulfate Uptake and Assimilation——the Same or Not the Same？

Plant take up the essential nutrient sulfur as sulfate from the soil, reduce it, and assimilate into bioorganic compounds, with cysteine being the first product. Both sulfate uptake and assimilation are highly regulated by the demand for the reduced sulfur, by availability of nutrients, and by environmental conditions. In the last decade, great prog- ress has been achieved in dissecting the regulation of sulfur metabolism. Sulfate uptake and reduction of activated sulfate, adenosine 5＇-phosphosulfate （APS）, to sulfite by APS reductase appear to be the key regulatory steps. Here, we review the current knowledge on regulation of these processes, with special attention given to similarities and differences.

Energy Signaling in the Regulation of Gene Expression during Stress

Maintenance of homeostasis is pivotal to all forms of life. In the case of plants, homeostasis is constantly threatened by the inability to escape environmental fluctuations, and therefore sensitive mechanisms must have evolved to allow rapid perception of environmental cues and concomitant modification of growth and developmental patterns for adaptation and survival. Re-establishment of homeostasis in response to environmental perturbations requires reprog- ramming of metabolism and gene expression to shunt energy sources from growth-related biosynthetic processes to defense, acclimation, and, ultimately, adaptation. Failure to mount an initial ＇emergency＇ response may result in nutrient deprivation and irreversible senescence and cell death. Early signaling events largely determine the capacity of plants to orchestrate a successful adaptive response. Early events, on the other hand, are likely to be shared by different conditions through the generation of similar signals and before more specific responses are elaborated. Recent studies lend credence to this hypothesis, underpinning the importance of a shared energy signal in the transcriptional response to various types of stress. Energy deficiency is associated with most environmental perturbations due to their direct or indirect deleterious impact on photosynthesis and/or respiration. Several systems are known to have evolved for monitoring the available resources and triggering metabolic, growth, and developmental decisions accordingly. In doing so, energy-sensing systems regulate gene expression at multiple levels to allow flexibility in the diversity and the kinetics of the stress response.

PLEIOTROPIC REGULATORY LOCUS 1 （PRL1） Integrates the Regulation of Sugar Responses with Isoprenoid Metabolism in Arabidopsis

The biosynthesis of isoprenoids in plant cells occurs from precursors produced in the cytosol by the mevalonate （MVA） pathway and in the plastid by the methylerythritol 4-phosphate （MEP） pathway, but little is known about the mechanisms coordinating both pathways. Evidence of the importance of sugar signaling for such coordination in Arabi- dopsis thaliana is provided here by the characterization of a mutant showing an increased accumulation of MEP-derived isoprenoid products （chlorophylls and carotenoids） without changes in the levels of relevant MEP pathway transcripts, proteins, or enzyme activities. This mutant was found to be a new loss-of-function allele of PRL1 （Pleiotropic Regulatory Locus 1）, a gene encoding a conserved WD-protein that functions as a global regulator of sugar, stress, and hormone responses, in part by inhibition of SNFl-related protein kinases （SnRK1）. Consistent with the reported role of SnRK1 kinases in the phosphorylation and inactivation of the main regulatory enzyme of the MVA pathway （hydroxymethylglutaryl coenzyme-A reductase）, its activity but not transcript or protein levels was reduced in prll seedlings. However, the accumulation of MVA-derived end products （sterols） was unaltered in mutant seedlings. Sucrose supplementation to wild- type seedlings phenocopied the prll mutation in terms of isoprenoid metabolism, suggesting that the observed isoprenoid phenotypes result from the increased sugar accumulation in the prll mutant. In summary, PRL1 appears to coordinate isoprenoid metabolism with sugar, hormone, and stress responses.

Complex Assembly and Metabolic Profiling of Arabidopsis thaliana PlantsOverexpressing Vitamin B6 Biosynthesis Proteins

In plants, vitamin B6 biosynthesis requires the activity of PDX1 and PDX2 proteins. Arabidopsis thaliana encodes for three PDX1 proteins, named PDXI.1, 1.2, and 1.3, but only one PDX2. Here, we show in planta complex assembly of PDX proteins, based on split-YFP and FPLC assays, and can demonstrate their presence in higher complexes of around 750 kDa. Metabolic profiling of plants ectopically expressing the different PDX proteins indicates a negative influence of PDX1.2 on vitamin Be biosynthesis and a correlation between aberrant vitamin B6 content, PDX1 gene expression, and light sensitivity specifically for PDX1.3. These findings provide first insights into in planta vitamin B6 synthase complex assembly and new information on how the different PDX proteins affect plant metabolism.

Analysis of Short-Term Metabolic Alterations in Arabidopsis Following Changes in the Prevailing Environmental Conditions

Although a considerable increase in our knowledge concerning the importance of metabolic adjustments to unfavorable growth conditions has been recently provided, relatively little is known about the adjustments which occur in response to fluctuation in environmental factors. Evaluating the metabolic adjustments occurring under changing environmental conditions thus offers a good opportunity to increase our current understanding of the crosstalk between the major pathways which are affected by such conditions. To this end, plants growing under normal conditions were transferred to different light and temperature conditions which were anticipated to affect （amongst other processes） the rates of photosynthesis and photorespiration and characterized at the physiological, molecular, and metabolic levels following this transition. Our results revealed similar behavior in response to both treatments and imply a tight connec- tivity of photorespiration with the major pathways of plant metabolism. They further highlight that the majority of the regulation of these pathways is not mediated at the level of transcription but that leaf metabolism is rather pre-poised to adapt to changes in these input parameters.

G protein controls stress readiness by modulating transcriptional and metabolic homeostasis in Arabidopsis thaliana and Marchantia polymorpha

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.

Targeting fructose metabolism by glucose transporter 5 regulation in human cholangiocarcinoma

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.

Paracrine Fibroblast Growth Factor-Based Therapy:An Unexpected Panacea for Metabolic-DysfunctionAssociated Fatty Liver Disease(MAFLD)

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.

Key regulators of intestinal stem cells:diet,microbiota,and microbial metabolites

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.

Microbial synthesis of bacitracin:Recent progress,challenges,and prospects

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.