Regulation Of Metabolites Research Articles

Maternal soybean diet on prevention of obesity-related breast cancer through early-life gut microbiome and epigenetic regulation

Overnutrition-induced obesity and metabolic dysregulation are considered major risk factors contributing to breast cancer. The origin of both obesity and breast cancer can retrospect to early development in human lifespan. Genistein (GE), a natural isoflavone enriched in soybean products, has been proposed to associate with a lower risk of breast cancer and various metabolic disorders. Our study aimed to determine the effects of maternal exposure to soybean dietary GE on prevention of overnutrition-induced breast cancer later in life and explore potential mechanisms in different mouse models. Our results showed that maternal dietary GE treatment improved offspring metabolic functions by significantly attenuating high-fat diet-induced body fat accumulation, lipid panel abnormalities and glucose intolerance in mice offspring. Importantly, maternal dietary GE exposure effectively delayed high-fat diet-simulated mammary tumor development in female offspring. Mechanistically, we found that maternal dietary GE may exert its chemopreventive effects through affecting essential regulatory gene expression in control of metabolism, inflammation and tumor development via, at least in part, regulation of offspring gut microbiome, bacterial metabolites and epigenetic profiles. Altogether, our findings indicate that maternal GE consumption is an effective intervention approach leading to early-life prevention of obesity-related metabolic disorders and breast cancer later in life through dynamically influencing the interplay between early-life gut microbiota, key microbial metabolite profiles and offspring epigenome.

Combined transcriptome and metabolome analysis of the resistance mechanism of quinoa seedlings to Spodoptera exigua.

Quinoa has attracted considerable attention owing to its unique nutritional, economic, and medicinal values. The damage intensity of Spodoptera exigua at the seedling stage of quinoa fluctuates with the crop’s biological cycle and the environmental changes throughout the growing season. In this study, we used independently selected quinoa seedling resistant and susceptible cultivars to investigate the difference between insect resistance and insect susceptibility of quinoa at the seedling stage. Samples were collected when Spodoptera exigua 45 days after planting the seedlings, and broad targeted metabolomics studies were conducted using liquid chromatography-mass spectrophotometry combined with transcriptomic co-analysis. The metabolomic and genomic analyses of the insect-resistant and insect-susceptible quinoa groups revealed a total of 159 differential metabolites and were functionally annotated to 2334 differential genes involved in 128 pathways using the Kyoto Encyclopedia of Genes and Genomes analysis. In total, 14 metabolites and 22 genes were identified as key factors for the differential accumulation of insect-resistant metabolites in quinoa seedlings. Among them, gene-LOC110694254, gene-LOC110682669, and gene-LOC110732988 were positively correlated with choline. The expression of gene-LOC110729518 and gene-LOC110723164, which were notably higher in the resistant cultivars than in the susceptible cultivars, and the accumulations of the corresponding metabolites were also significantly higher in insect-resistant cultivars. These results elucidate the regulatory mechanism between insect resistance genes and metabolite accumulation in quinoa seedlings, and can provide a basis for the breeding and identification of new insect-resistant quinoa cultivars as well as for screening potential regulatory metabolites of quinoa insect-resistant target genes.

Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis.

Tryptophan is an essential amino acid from dietary proteins. It can be metabolized into different metabolites in both the gut microbiota and tissue cells. Tryptophan metabolites such as indole-3-lactate (ILA), indole-3-acrylate (IAC), indole-3-propionate (IPA), indole-3-aldehyde (IAID), indoleacetic acid (IAA), indole-3-acetaldehyde and Kyn can be produced by intestinal microorganisms through direct Trp transformation and also, partly, the kynurenine (Kyn) pathway. These metabolites play a critical role in maintaining the homeostasis of the gut and systematic immunity and also potentially affect the occurrence and development of diseases such as inflammatory bowel diseases, tumors, obesity and metabolic syndrome, diseases in the nervous system, infectious diseases, vascular inflammation and cardiovascular diseases and hepatic fibrosis. They can not only promote the differentiation and function of anti-inflammatory macrophages, Treg cells, CD4+CD8αα+ regulatory cells, IL-10+ and/or IL-35+B regulatory cells but also IL-22-producing innate lymphoid cells 3 (ILC3), which are involved in maintaining the gut mucosal homeostasis. These findings have important consequences in the immunotherapy against tumor and other immune-associated diseases. We will summarize here the recent advances in understanding the generation and regulation of tryptophan metabolites in the gut microbiota, the role of gut microbiota-derived tryptophan metabolites in different immune cells, the occurrence and development of diseases and immunotherapy against immune-associated diseases.

Transcriptome and Metabonomic Analysis of Tamarix ramosissima Potassium (K+) Channels and Transporters in Response to NaCl Stress.

Potassium ion (K+) channels and transporters are key components of plant K+ absorption and transportation and play an important role in plant growth and development. This study revealed that K+ channels and transporters are involved in the salt tolerance molecular mechanism and metabolites of the halophyte representative plant Tamarix ramosissima (T. ramosissima) in response to NaCl stress, providing a theoretical basis for the mitigation of salt stress using halophytes. Through transcriptome sequencing and metabolite detection analysis of 0 h, 48 h and 168 h by applying exogenous K+ to the roots of T. ramosissima under NaCl stress, 15 high-quality Clean Data bases were obtained, Q20 reached more than 97%, Q30 reached more than 92%, and GC content reached 44.5%, which is in line with further bioinformatics analysis. Based on the Liquid chromatography–mass spectrometry (LC-MS) analysis, the roots of T. ramosissima were exposed to exogenous potassium for 48 h and 168 h under NaCl stress, and 1510 and 1124 metabolites were identified in positive and negative ion mode, respectively. Through orthogonal projections to latent structures discriminant analysis (OPLS-DA) model analysis, its metabolomic data have excellent predictability and stability. The results of this study showed that there were 37 differentially expressed genes (DEGs) annotated as Class 2 K+ channels (Shaker-like K+ channel and TPK channel) and Class 3 K+ transporters (HAK/KUP/KT, HKT and CPAs transporter families). Among them, 29 DEGs were annotated to the gene ontology (GO) database, and the most genes were involved in the GO Biological Process. In addition, the expression levels of Unigene0014342 in the HAK/KUP/KT transporter and Unigene0088276 and Unigene0103067 in the CPAs transporter both first decreased and then increased when treated with 200 mM NaCl for 48 h and 168 h. However, when treated with 200 mM NaCl + 10 mM KCl for 48 h and 168 h, a continuous upward trend was shown. Notably, the expression level of Unigene0016813 in CPAS transporter continued to increase when treated with 200 mM NaCl and 200 mM NaCl + 10 mM KCl for 48 h and 168 h. 3 DEGs, Unigene0088276, Unigene0016813 and Unigene0103067, were dominated by the positive regulation of their related metabolites, and this correlation was significant. The results showed that these DEGs increased the absorption of K+ and the ratio of K+/Na+ under NaCl stress at 48 h and 168 h after adding exogenous potassium and enhanced the salt tolerance of T. ramosissima. Notably, the expression level of Unigene0103067 in the CPAs transporter was consistently upregulated when 200 mM NaCl + 10 mM KCl was treated for 48 h and 168 h. The positive regulatory metabolites were always dominant, which better helped T. ramosissima resist salt stress. Unigene0103067 plays an important role in enhancing the salt tolerance of T. ramosissima and reducing the toxicity of NaCl in roots. Additionally, phylogenetic tree analysis showed that Unigene0103067 and Reaumuria trigyna had the closest genetic distance in the evolutionary relationship. Finally, 9 DEGs were randomly selected for quantitative real-time PCR (qRT-PCR) verification. Their expression trends were completely consistent with the transcriptome sequencing analysis results, proving that this study’s data are accurate and reliable. This study provides resources for revealing the molecular mechanism of NaCl stress tolerance in T. ramosissima and lays a theoretical foundation for cultivating new salt-tolerant varieties.

Aging Relevant Metabolite Itaconate Inhibits Inflammatory Bone Loss.

Progressive bone loss during aging makes osteoporosis one of the most common and life impacting conditions in geriatric populations. The bone homeostasis is maintained through persistent remodeling mediated by bone-forming osteoblast and bone-resorbing osteoclast. Inflammaging, a condition characterized by increased pro-inflammatory markers in the blood and other tissues during aging, has been reported to be associated with skeletal stem/progenitor cell dysfunction, which will result in impaired bone formation. However, the role of age-related inflammation and metabolites in regulation of osteoclast remains largely unknown. In the present study, we observed dichotomous phenotypes of anti-inflammatory metabolite itaconate in responding to inflammaging. Itaconate is upregulated in macrophages during aging but has less reactivity in responding to RANKL stimulation in aged macrophages. We confirmed the inhibitory effect of itaconate in regulating osteoclast differentiation and activation, and further verified the rescue role of itaconate in lipopolysaccharides induced inflammatory bone loss animal model. Our findings revealed that itaconate is a crucial regulatory metabolite during inflammaging that inhibits osteoclast to maintain bone homeostasis.

Advances in studies on transcription factors in regulation of secondary metabolites in Chinese medicinal plants

Advances in studies on transcription factors in regulation of secondary metabolites in Chinese medicinal plants

Quorum Sensing Inhibitory and Quenching Activity of Bacillus cereus RC1 Extracts on Soft Rot-Causing Bacteria Lelliottia amnigena.

The quorum sensing (QS) system of bacteria helps them to communicate with each other in a density-dependent manner and regulates pathogenicity. The concentrations of autoinducers, peptides, and signaling factors are required for determining the expression of virulence factors in many pathogens. The QS signals of the pathogen are regulated by the signal transduction pathway. The binding of signal molecules to its cognate receptor brings changes in the structure of the receptor, makes it more accessible to the DNA, and thus regulates diverse expression patterns, including virulence factors. Degrading the autoinducer molecules or disturbing the quorum sensing network could be exploited to control the virulence of the pathogen while avoiding multidrug-resistant phenotypes. The rhizosphere is a tremendous source of beneficial microbes that has not yet been explored properly for its anti-quorum sensing potential. Lelliottia amnigena causes soft rot diseases in onion, potato, and other species. The present investigation was carried out with the aim of isolating the anti-quorum sensing metabolites and elucidating their role in controlling the virulence factors of the pathogen by performing a maceration assay. The ethyl acetate extracts of various bacteria are promising for violacein inhibition assay using Chromobacterium violaceum MTCC2656 and pyocyanin inhibition of Pseudomonas aeruginosa MTCC2297. Therefore, the extract was used to deduce its role in attenuation of soft rot in potato, carrot, and cucumber. The maximum reduction of macerated tissue in carrot, potato, and cucumber was given by Bacillus cereus RC1 at 91.22, 97.59, and 88.78%, respectively. The concentration-dependent inhibition of virulence traits was observed during the entire experiment. The quorum quenching potential of the bacterial extract was used to understand the regulatory metabolites. The data of the diffusible zone and gas chromatography–mass spectrometry (GC–MS) analysis showed that diketopiperazines, viz. Cyclo(d-phenylalanyl-l-prolyl), Cyclo Phe-Val, Cyclo(Pro-Ala), Cyclo(l-prolyl-l-valine), Cyclo (Leu-Leu), and Cyclo(-Leu-Pro), are prominent metabolites that could modulate the pathogenicity in L. amnigena RCE. The interaction of bacterial extracts regulates various metabolites of the pathogens during their growth in liquid culture compared to their control counterparts. This study might help in exploiting the metabolites from bacteria to control the pathogens, with concurrent reduction in the pathogenicity of the pathogens without developing antibiotic resistance.

Proteomining-Based Elucidation of Natural Product Biosynthetic Pathways in Streptomyces

The genus Streptomyces is known to harbor numerous biosynthetic gene clusters (BGCs) of potential utility in synthetic biology applications. However, it is often difficult to link uncharacterized BGCs with the secondary metabolites they produce. Proteomining refers to the strategy of identifying active BGCs by correlating changes in protein expression with the production of secondary metabolites of interest. In this study, we devised a shotgun proteomics-based workflow to identify active BGCs during fermentation when a variety of compounds are being produced. Mycelia harvested during the non-producing growth phase served as the background. Proteins that were differentially expressed were clustered based on the proximity of the genes in the genome to highlight active BGCs systematically from label-free quantitative proteomics data. Our software tool is easy-to-use and requires only 1 point of comparison where natural product biosynthesis was significantly different. We tested our proteomining clustering method on three Streptomyces species producing different compounds. In Streptomyces coelicolor A3(2), we detected the BGCs of calcium-dependent antibiotic, actinorhodin, undecylprodigiosin, and coelimycin P1. In Streptomyces chrestomyceticus BCC24770, 7 BGCs were identified. Among them, we independently re-discovered the type II PKS for albofungin production previously identified by genome mining and tedious heterologous expression experiments. In Streptomyces tenebrarius, 5 BGCs were detected, including the known apramycin and tobramycin BGC as well as a newly discovered caerulomycin A BGC in this species. The production of caerulomycin A was confirmed by LC-MS and the inactivation of the caerulomycin A BGC surprisingly had a significant impact on the secondary metabolite regulation of S. tenebrarius. In conclusion, we developed an unbiased, high throughput proteomics-based method to complement genome mining methods for the identification of biosynthetic pathways in Streptomyces sp.

Astaxanthin absorption modulated antioxidant enzyme activity and targeted specific metabolic pathways in rats.

Saponification contributed to an increase in the in vitro antioxidant activity of astaxanthin (Asta) extracts derived from Penaeus sinensis (Solenocera crassicornis) by-products. However, the influence of non-saponification (N-Asta) and saponification Asta (S-Asta) absorption on antioxidant activity in vivo was limited. The antioxidant properties of N-Asta and S-Asta were therefore compared in Sprague Dawley male rats after 6 h and 12 of absorption using biochemistry assays combined with an untargeted metabonomics strategy. Non-saponified Asta and S-Asta showed similar digestive properties in a stimulated gastrointestinal tract. Increased glutathione content and decreased malondialdehyde content were measured in the liver tissues of N-Asta and S-Asta treated rats after 12 h of absorption. Absorption of N-Asta increased liver total superoxide dismutase, glutathione peroxidase, and catalase activity. Treatment with S-Asta up-regulated NAD(P)H: quinine oxidoreductase-1, and heme oxygenase-1 expression was associated with the nuclear erythroid 2-related factor 2/antioxidant responsive element pathway at the end of 12 h absorption. With partial least square-discriminant analysis and metabolite heatmap profiles, the S-Asta group was clearly separated from the N-Asta group. The S-Asta treatment also demonstrated stronger influences on plasma metabolites than the N-Asta treatment. Both N-Asta and S-Asta absorption showed critical roles in the regulation of specific metabolites, and 15 potential biomarkers were identified in eight key pathways to separate these experimental groups after 12 h of absorption. However, an increased serotonin level was only detected in the S-Asta group after 12 h absorption. Absorption of N-Asta and S-Asta induced different antioxidant effects in normal rats, which were associated with metabolite changes. © 2022 Society of Chemical Industry.

Metabolomic Profiles of Multidrug-Resistant Salmonella Typhimurium from Humans, Bovine, and Porcine Hosts.

Simple SummaryThe global threat that is imposed by the resistance the pathogens develop to antimicrobial drugs is escalating. Tools to detect the resistance (with evidence on molecular and cellular outcomes) would reveal intricate mechanisms through which novel drugs could be developed. Approaches such as metabolomics, which involve metabolite detection, provide scientific evidence of metabolite expression of antimicrobial-resistant pathogens. The current study involved metabolomics of antimicrobial-resistant Salmonella Typhimurium collected from various hosts (human, porcine, bovine) and were exposed to antimicrobial drugs—ampicillin, chloramphenicol, streptomycin, sulfisoxazole, and tetracycline—as one set of the experiment. The same isolates were also cultured with no drug exposure as a comparison. There are certain pathways of metabolite expression that are impacted by drug exposure when compared to no drug exposure, meaning that the expressed metabolites could be potential targets for drug companies for the treatment of antimicrobial-resistant pathogens.Antimicrobial resistance (AMR) is a global public health threat, yet tools for detecting resistance patterns are limited and require advanced molecular methods. Metabolomic approaches produce metabolite profiles and help provide scientific evidence of differences in metabolite expressions between Salmonella Typhimurium from various hosts. This research aimed to evaluate the metabolomic profiles of S. Typhimurium associated with AMR and it compares profiles across various hosts. Three samples, each from bovine, porcine, and humans (total n = 9), were selectively chosen from an existing library to compare these nine isolates cultured under no drug exposure to the same isolates cultured in the presence of the antimicrobial drug panel ACSSuT (ampicillin, chloramphenicol, streptomycin, sulfisoxazole, tetracycline). This was followed by metabolomic profiling using UPLC and GC–mass spectrometry. The results indicated that the metabolite regulation was affected by antibiotic exposure, irrespective of the host species. When exposed to antibiotics, 59.69% and 40.31% of metabolites had increased and decreased expressions, respectively. The most significantly regulated metabolic pathway was aminoacyl-tRNA biosynthesis, which demonstrated increased expressions of serine, aspartate, alanine, and citric acid. Metabolites that showed decreased expressions included glutamate and pyruvate. This pathway and associated metabolites have known AMR associations and could be targeted for new drug discoveries and diagnostic methods.

Construction strategies and prospect of the Global Medicinal Plant Stem Cell Bank

Medicinal plant stem cells are separated from the meristem and vascular cambium of medicinal plants, which can produce active components for preventing and treating diseases and improving body physical functions under certain conditions. Medicinal plant stem cells come from a broad category of medicinal plants, including ethnic medicinal plants, folk medicinal plants, original plants of health products, vegetables, fruits, and other potential medicinal plants. At present, the techniques for the isolation, identification, preservation and culture of medicinal plant stem cells have become increasingly mature, and the mechanism of stem cell differentiation, growth and regulation of secondary metabolites has been studied in depth. Medicinal plant stem cells have a broad application prospect in medicine, health food, food and medical beauty products. As a strategic resource, the construction of the "Global Medicinal Plant Stem Cell Bank" was first proposed to preserve various kinds of medicinal plant resources in the world, and it will go global relying on the internationalization strategy of traditional Chinese medicine. The bank should follow safety, environmental protection, advanced and practical design principles. The main construction contents include the original plant bank, stem cell bank, component resource bank, gene bank, database and resource sharing system, with genetic and data resources incorporated into the scope of protection and utilization. The bank will establish a new strategy for medicinal plant resources protection and regeneration, and provide a new resource for natural products drug discovery and a technology sharing platform for various medicinal plant stem cells. As a resource treasury, a source of innovative technologies and a center of cooperation, it will become the core driving force of the global medicinal plant stem cell industry.

Metabolomic Analysis of Key Regulatory Metabolites in the Urine of Flavivirus-Infected Mice.

Objective Dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV) are several important flaviviruses, and infections caused by these flaviviruses remain worldwide health problems. Different flaviviruses exhibit different biological characteristics and pathogenicity. Metabolomics is an emerging research perspective to uncover and observe the pathogenesis of certain infections. Methods To improve the understanding of the specific metabolic changes that occur during infection with different flaviviruses, considering the principle of noninvasive sampling, this article describes our comprehensive analysis of metabolites in urine samples from the three kinds of flavivirus-infected mice using a liquid chromatography tandem mass spectrometry method to better understand their infection mechanisms. Results The urine of DENV-, JEV-, and ZIKV-infected mice had 68, 64, and 47 different differential metabolites, respectively, compared with the urine of control mice. Among the metabolic pathways designed by these metabolites, ABC transporters, arginine and proline metabolism, and regulation of lipolysis play an important role. Furthermore, we predicted and fitted potential relationships between metabolites and pathways. Conclusions These virus-specific altered metabolites may be associated with their unique biological properties and pathogenicity. The metabolomic analysis of urine is very important for the analysis of flavivirus infection.

Dissecting the Regulation of Arachidonic Acid Metabolites by Uncaria rhynchophylla (Miq). Miq. in Spontaneously Hypertensive Rats and the Predictive Target sEH in the Anti-Hypertensive Effect Based on Metabolomics and Molecular Docking.

Uncaria rhynchophylla (Miq). Miq. (UR), as a traditional Chinese medicine, was employed in treating hypertension as a safe and effective therapy. The pharmacological properties of UR have characteristics of multiple biological targets and multiple functional pathways. Hypertension is related to impaired metabolic homeostasis and is especially associated with the abnormal regulation of arachidonic acid metabolites, the classical cardiovascular active compounds. This study aimed to examine the anti-hypertensive effect of UR extract (URE) and its regulating role in differential metabolic pathways. The results showed that daily administration of URE at a dose of 4 g crude drug/kg orally could exert hypotensive effects on spontaneously hypertensive rats (SHRs) for 8 weeks. Non-targeted metabolomics analysis of the plasma samples suggested that the anti-hypertension effect of URE in SHRs was associated with the reorganization of the perturbed metabolic network, such as the pathways of glycerophospholipid metabolism, linoleic acid metabolism, and arachidonic acid metabolism. For the targeted metabolomics, twenty-eight arachidonic acid metabolites in SHRs were quantitatively analyzed for the first time based on ultra-high performance liquid chromatography-tandem mass spectrometry method after URE administration. URE restored the functions of these cardiovascular active compounds and rebalanced the dynamics of arachidonic acid metabolic flux. Among them, the inhibition of soluble epoxide hydrolase (sEH) enzyme activity and up-regulation of vasodilators epoxyeicosatrienoic acids (EETs) were identified as contributors to the anti-hypertension effect of URE on SHRs, and sEH represented an attractive and promising drug-binding target of URE. With the molecular docking approach, 13 potential anti-hypertension ingredients as well as sEH inhibitors were discovered, which were worthy of further investigation and verification in future studies.

Regulatory mutants of Serratia with modulated antibiotic production due to intergenic transposon insertions

Antibiotic resistance is an increasing problem, exacerbated by global dissemination of drug resistance genes under selection pressure. Moreover, the rate of new antibiotic discovery declined over previous decades and so there is a growing need for new antibiotic discovery and a deeper appreciation of the various genetic and physiological factors that influence antibiotic biosynthesis. The enterobacterium Serratia sp. ATCC 39006 (Serratia) is a useful model for studies on the biosynthesis and regulation of bioactive secondary metabolites, including two antibiotics - a carbapenem and prodigiosin. Both compounds are tightly regulated in response to various physiological and environmental signals, including quorum sensing. We have identified novel regulators of antibiotic production after random transposon mutagenesis. Multiple regulatory mutations mapped to a small locus defining an intergenic region (IGR). These IGR insertion mutants display elevated production of both the carbapenem and prodigiosin antibiotics and they also exhibit reduced motility, confirming pleiotropic impacts. Exploiting phage transduction, we constructed double mutants with 15 known Serratia regulators and showed that the IGR mutant phenotype was epistatic over several of these. Further analysis suggested the presence of a putative gene encoded within the IGR locus, which may play an impactful role in the intricate regulatory network. Functional characterisation of the IGR region and its physiological impacts in both the modulation of antibiotic production and in wider pleiotropy were dissected. Mechanistic understanding of the regulatory mechanisms involved may prove exploitable in enhancing controlled antibiotic hyperproduction.

Multi-dimensional "projection" - the impact of abiotic stresses on the content of seven active compounds and expression of related genes in Glycyrrhiza uralensis Fisch

Triterpenoids and flavonoids from licorice ( Glycyrrhiza uralensis Fisch.) are known to have a wide range of applications in the pharmaceutical, skin care, and food industries. The effects of various types of abiotic stresses and associated phytohormones - polyethylene glycol, sodium chloride, ultraviolet, cadmium, abscisic acid, and methyl jasmonate - on both the content of these secondary metabolites and the transcript levels of genes encoding enzymes of important biosynthetic pathways were evaluated in hydroponic seedlings of G. uralensis . In these treatments, abscisic acid induced a substantial increase in the levels of the four active compounds, compared to the control. Analysis of the expression of genes involved in the biosynthetic pathways of these compounds, such as FPPS , showed that their transcript levels were significantly up-regulated in the four stresses. These findings suggested that the multi-stress superposition pattern of the content of active compounds and the gene expression of their biosynthetic pathways may provide insights to explore the management of secondary metabolite synthesis pathways in medicinal plants. It could facilitate a better understanding of the formation patterns of active compounds in licorice in artificial cultivation. Further insights may also be provided to increase the yield of these high value components. • Exogenous abscisic acid has a positive effect on the active compounds of licorice. • Glycyrrhizic acid-related gene expression was uprated in PEG and UV treatments. • Hydroponic system can be used to study the effect of abiotic stresses on licorice. • Multi-stress has potential in regulation and production of secondary metabolites.

Multi-Omic Profiling of Multi-Biosamples Reveals the Role of Amino Acid and Nucleotide Metabolism in Endometrial Cancer.

BackgroundEndometrial cancer (EC) is one of the most common gynecological cancers. The traditional diagnosis of EC relies on histopathology, which, however, is invasive and may arouse tumor spread. There have been many studies aiming to find the metabolomic biomarkers of EC to improve the early diagnosis of cancer in a non-invasive or minimally invasive way, which can also provide valuable information for understanding the disease. However, most of these studies only analyze a single type of sample by metabolomics, and cannot provide a comprehensive view of the altered metabolism in EC patients. Our study tries to gain a pathway-based view of multiple types of samples for understanding metabolomic disorders in EC by combining metabolomics and proteomics.MethodsForty-four EC patients and forty-three controls were recruited for the research. We collected endometrial tissue, urine, and intrauterine brushing samples. Untargeted metabolomics and untargeted proteomics were both performed on the endometrial tissue samples, while only untargeted metabolomics was performed on the urine and intrauterine brushing samples.ResultsBy integrating the differential metabolites and proteins between EC patients and controls detected in the endometrial tissue samples, we identified several EC-related significant pathways, such as amino acid metabolism and nucleotide metabolism. The significance of these pathways and the potential of metabolite biomarker-based diagnosis were then further verified by using urine and intrauterine brushing samples. It was found that the regulation of metabolites involved in the significant pathways showed similar trends in the intrauterine brushings and the endometrial tissue samples, while opposite trends in the urine and the endometrial tissue samples.ConclusionsWith multi-omics characterization of multi-biosamples, the metabolomic changes related to EC are illustrated in a pathway-based way. The network of altered metabolites and related proteins provides a comprehensive view of altered metabolism in the endometrial tissue samples. The verification of these critical pathways by using urine and intrauterine brushing samples provides evidence for the possible non-invasive or minimally invasive biopsy for EC diagnosis in the future.

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells.

Butyrate (B) is a short-chain fatty acid produced by dietary fiber, known to inhibit histone deacetylases (HDACs) and possess cancer-preventive/anticancer effects. However, the role of B in metabolic rewiring, epigenomic reprogramming, transcriptomic network, NRF2 signaling, and eliciting cancer-preventive effects in colorectal cancer (CRC) HCT116 cell remains unclear. Sodium butyrate (NaB) dose-dependently inhibits the growth of CRC HCT116 cells. NaB inhibits NRF2/NRF2-target genes and blocks NRF2-ARE signaling. NaB increases NRF2 negative regulator KEAP1 expression through inhibiting its promoter methylation. Associative analysis of DEGs (differentially expressed genes) from RNA-seq and DMRs (differentially methylated regions) from CpG methyl-seq identified the tumor suppressor gene ABCA1 and tumor promote gene EGR3 are correlated with their promoters' CpG methylation indicating NaB regulates cancer markers through modulating their promoter methylation. NaB activated the mitochondrial tricarboxylic acid (TCA) cycle while inhibited the methionine metabolism which are both tightly coupled to the epigenetic machinery. NaB regulates the epigenetic enzymes/genes including DNMT1, HAT1, KDM1A, KDM1B, and TET1. Altogether, B's regulation of metabolites coupled to the epigenetic enzymes illustrates the potential underlying biological connectivity between metabolomics and epigenomics. B regulates KEAP1/NRF2 signaling, drives metabolic rewiring, CpG methylomic, and transcriptomic reprogramming contributing to the overall cancer-prevention/anticancer effect in the CRC cell model.

Regulation of gut microbiota and intestinal metabolites by Poria cocos oligosaccharides improves glycolipid metabolism disturbance in high-fat diet-fed mice

In this study, we aimed to explore the effect of Poria cocos oligosaccharides (PCO) on glucolipid metabolism disorder. Based on a high-fat diet (HFD)-induced obese mouse model, we demonstrated that PCO ameliorated glucose intolerance and insulin resistance, decreased the levels of blood glucose (187.8±19.8 mg/dL) and insulin (566.3±53.34 ng/L) in HFD-fed mice compared to the Ctrl group (140.4±7.942 mg/dL for glucose, 423.2±19.56 ng/L for insulin). Moreover, PCO treatment suppressed the mRNA expressions of fatty acid synthesis regulators (decreases of 68.8%, 62.8%, and 32.0% for G6Pase, FASN, and DGAT, respectively, vs. HFD group) and pro-inflammatory cytokines in epididymal fat (decreases of 71.9%, 81.5%, 76.0%, 29.3%, and 63.9% for TNF-α, IL-1β, IL-6, COX-5b, and MCP-1, respectively, vs. HFD group). Also, PCO treatment alleviated damage to the intestinal barrier of HFD-fed mice. By 16S rDNA gene sequencing, PCO partly restored the imbalance of gut microbiota in HFD-fed mice, accompanied by the reversal of several intestinal metabolites, including bile acids (BAs), short-chain fatty acids (SCFAs), and tryptophan metabolites. By Spearman's correlation analysis, we found that the changed gut microbiota and their metabolites were significantly correlated with the alteration of metabolic markers. Finally, the significance of gut microbiota in PCO-mediated improvement on glucolipid metabolism disorder was confirmed by an antibiotic depletion experiment and fecal microbiota transplantation. In summary, PCO may be used as a novel prebiotic in the treatment of glucolipid disorders by reshaping intestinal bacteria structure. Our studies also point towards the potential of Poria cocos as a healthy food in the clinical application to metabolic diseases in the future.

Emerging landscape of molecular interaction networks: Opportunities, challenges and prospects

Network biology finds application in interpreting molecular interaction networks and providing insightful inferences using graph theoretical analysis of biological systems. The integration of computational bio-modelling approaches with different hybrid network-based techniques provides additional information about the behaviour of complex systems. With increasing advances in high-throughput technologies in biological research, attempts have been made to incorporate this information into network structures, which has led to a continuous update of network biology approaches over time. The newly minted centrality measures accommodate the details of omics data and regulatory network structure information. The unification of graph network properties with classical mathematical and computational modelling approaches and technologically advanced approaches like machine-learning- and artificial intelligence-based algorithms leverages the potential application of these techniques. These computational advances prove beneficial and serve various applications such as essential gene prediction, identification of drug–disease interaction and gene prioritization. Hence, in this review, we have provided a comprehensive overview of the emerging landscape of molecular interaction networks using graph theoretical approaches. With the aim to provide information on the wide range of applications of network biology approaches in understanding the interaction and regulation of genes, proteins, enzymes and metabolites at different molecular levels, we have reviewed the methods that utilize network topological properties, emerging hybrid network-based approaches and applications that integrate machine learning techniques to analyse molecular interaction networks. Further, we have discussed the applications of these approaches in biomedical research with a note on future prospects.

Red light-transmittance bagging promotes carotenoid accumulation of grapefruit during ripening

Light, a crucial environmental signal, is involved in the regulation of secondary metabolites. To understand the mechanism by which light influences carotenoid metabolism, grapefruits were bagged with four types of light-transmitting bags that altered the transmission of solar light. We show that light-transmitting bagging induced changes in carotenoid metabolism during fruit ripening. Compared with natural light, red light (RL)-transmittance treatment significantly increases the total carotenoid content by 62%. Based on weighted gene co-expression network analysis (WGCNA), ‘blue’ and ‘turquoise’ modules are remarkably associated with carotenoid metabolism under different light treatment (p < 0.05). Transcriptome analysis identifies transcription factors (TFs) bHLH128, NAC2-like/21/72, MYB-like, AGL11/AGL61, ERF023/062, WRKY20, SBPlike-7/13 as being involved in the regulation of carotenoid metabolism in response to RL. Under RL treatment, these TFs regulate the accumulation of carotenoids by directly modulating the expression of carotenogenic genes, including GGPPS2, PDS, Z-ISO, ZDS2/7, CRTISO3, CYP97A, CHYB, ZEP2, CCD1-2. Based on these results, a network of the regulation of carotenoid metabolism by light in citrus fruits is preliminarily proposed. These results show that RL treatments have great potential to improve coloration and nutritional quality of citrus fruits.