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.

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.

Peroxisome proliferator-activated receptor agonists:A new hope towards the management of alcoholic liver disease

In this editorial,we examine a paper by Koizumi et al,on the role of peroxisome proliferator-activated receptor(PPAR)agonists in alcoholic liver disease(ALD).The study determined whether elafibranor protected the intestinal barrier and reduced liver fibrosis in a mouse model of ALD.The study also underlines the role of PPARs in intestinal barrier function and lipid homeostasis,which are both affected by ALD.Effective therapies are necessary for ALD because it is a critical health issue that affects people worldwide.This editorial analyzes the possibility of PPAR agonists as treatments for ALD.As key factors of inflammation and metabolism,PPARs offer multiple methods for managing the complex etiology of ALD.We assess the abilities of PPARα,PPARγ,and PPARβ/δagonists to prevent steatosis,inflammation,and fibrosis due to liver diseases.Recent research carried out in preclinical and clinical settings has shown that PPAR agonists can reduce the severity of liver disease.This editorial discusses the data analyzed and the obstacles,advantages,and mechanisms of action of PPAR agonists for ALD.Further research is needed to understand the efficacy,safety,and mechanisms of PPAR agonists for treating ALD.

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.

A Research Overview on Arachidonic Acid:Fermentation Regulation and Purification

Arachidonic acid （ARA or AA）, one of the most important polyunsaturated fatty acids （PUFAs）, has various physiological activities and positive effects on human health. ARA production by Mortierella alpina has become a hot topic in recent years, owing to that it is effective, safe and easy to control. How to improve ARA yield and purification efficiency is important to ARA production in M. alpina. Therefore, in this review, we summarized some methods to improve ARA yield： optimization of culture conditions, mycelium aging technologies and metabolic regulation, and the commonly used methods for ARA isolation and purification, to provide a theoretical basis for ARA production by M. alpina fermentation.

Progress of Alzheimer＇s disease related glucose metabolism regulating hormones and a research perspective in nootropics of herbal medicine

Alzheimer’s disease as one of the neurodegenerative diseases, its pathological mechanisms still remains unclear. There’s evidence that diabetes is associated with Alzheimer’s disease. However, the fundamental cause of diabetes is abnormal glucose metabolism. There may be an inseparable relationship between glucose metabolism regulating hormones and Alzheimer’s disease. Here, we review the studies that connect the glucose metabolism regulating hormones to Alzheimer’s disease, and that suggest the quality of Alzheimer’s patients is improved by regulating glucose metabolism.

The secretory function of adipose tissues in metabolic regulation

In addition to their pivotal roles in energy storage and expenditure,adipose tissues play a crucial part in the secretion of bioactive molecules,including peptides,lipids,metabolites,and extracellular vesicles,in response to physiological stimulation and met-abolic stress.These secretory factors,through autocrine and paracrine mechanisms,regulate various processes within adipose tissues.These processes include adipogenesis,glucose and lipid metabolism,inflammation,and adaptive thermogenesis,all of which are essential for the maintenance of the balance and functionality of the adipose tissue micro-environment.A subset of these adipose-derived secretory factors can enter the circulation and target the distant tissues to regulate appetite,cognitive function,energy expenditure,insulin secretion and sensitivity,gluconeogenesis,cardiovascular remodeling,and exercise capac-ity.In this review,we highlight the role of adipose-derived secretory factors and their signaling pathways in modulating meta-bolic homeostasis.Furthermore,we delve into the alterations in both the content and secretion processes of these factors under various physiological and pathological conditions,shedding light on potential pharmacological treatment strategies for related diseases.

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.

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.

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.

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.

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.

Inhibiting Human Copper Transfer and Tumor Growth

Copper is a trace element that is required by almost all forms of life.Acting as cofactors for various key metabolism enzymes,copper takes part in many vital biological processes.Previous studies have found the concentration of copper is significantly higher in tumor cells than in normal cells.In addition,copper can promote angiogenesis by activating VEGF and FGF signaling.

Engineering of triterpene metabolism and overexpression of the lignin biosynthesis gene PAL promotes ginsenoside Rg3 accumulation in ginseng plant chassis

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.

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.

Mitochondrial sirtuins,metabolism,and aging

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.

Sensing Sulfur Conditions： Simple to Complex Protein Regulatory Mechanisms in Plant Thiol Metabolism

Sulfur is essential for plant growth and development, and the molecular systems for maintaining sulfur and thiol metabolism are tightly controlled. From a biochemical perspective, the regulation of plant thiol metabolism high- lights nature＇s ability to engineer pathways that respond to multiple inputs and cellular demands under a range of con- ditions. In this review, we focus on the regulatory mechanisms that form the molecular basis of biochemical sulfur sensing in plants by translating the intracellular concentration of sulfur-containing compounds into control of key metabolic steps. These mechanisms range from the simple （substrate availability, thermodynamic properties of reactions, feedback inhi- bition, and organelle localization） to the elaborate （formation of multienzyme complexes and thiol-based redox switches）. Ultimately, the dynamic interplay of these regulatory systems is critical for sensing and maintaining sulfur assimilation and thiol metabolism in plants.

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.