Pathway Metabolites Research Articles

A time-course transcriptomic analysis reveals the key responses of a resistant rice cultivar to brown planthopper infestation.

The brown planthopper (BPH) is one of the most problematic pests affecting rice (Oryza sativa L.) yields in Asia. Breeding rice varieties containing resistance genes is the most economical and effective means of controlling BPH. In this study, the key factors in resistance to BPH were investigated between the high-resistance rice variety "R26" and the susceptible variety "TN1" using RNA-sequencing. We identified 9527 differentially expressed genes (DEGs) between the rice varieties under BPH-induced stress. Weighted time-course gene co-expression network analysis (WGCNA) indicated that the increased expression of genes is associated with plant hormones, MAPK signaling pathway and biosynthesis of other secondary metabolites, which were involved in disease resistance. A connection network identified a hub gene, OsREM4.1 (BGIOSGA024059), that may affect rice resistance to the BPH. Knocking out OsREM4.1 in rice can lead to a decrease in callose, making it less resistant to BPH. Overall, the expression of differentially expressed genes varies among rice varieties with different resistance in BPH invasion. Inaddition, R26 enhances resistance to BPH by upregulating genes and secondary metabolites related to stress resistance and plant immunity. In summary, our study provides valuable insights into the genome-wide expression profile of DEGs in rice under BPH invasion through high-throughput sequencing, and further suggests that R26 can be used to develop high resistance rice lines in BPH resistant breeding programs.

Immunometabolic Chaos in Septic Shock.

Septic shock is associated with over 40% mortality. The immune response in septic shock is tightly regulated by cellular metabolism and transitions from early hyper-inflammation to later hypo-inflammation. Patients are susceptible to secondary infections during hypo-inflammation. The magnitude of the metabolic dysregulation and the effect of plasma metabolites on the circulating immune cells in septic shock are not reported. We hypothesized that the accumulated plasma metabolites affect the immune response in septic shock during hypo-inflammation. Our study took a unique approach. Using peripheral blood from adult septic shock patients and healthy controls, we studied: 1. Whole blood stimulation ± E. Coli lipopolysaccharide (LPS: endotoxin) to analyze plasma TNF protein, and 2. Plasma metabolomic profile by Metabolon. Inc. 3. We exposed peripheral blood mononuclear cells (PBMCs) from healthy controls to commercially available carbohydrate, amino acid, and fatty acid metabolites and studied the response to LPS. We report that: 1. The whole blood stimulation of the healthy control group showed a significantly upregulated TNF protein, while the septic shock group remained endotoxin tolerant, a biomarker for hypo-inflammation. 2. A significant accumulation of carbohydrate, amino acid, fatty acid, ceramide, sphingomyelin, and TCA cycle pathway metabolites in septic shock plasma. 3. In vitro exposure to five metabolites repressed while two metabolites upregulated the inflammatory response of PBMCs to LPS. We conclude that the endotoxin-tolerant phenotype of septic shock is associated with a simultaneous accumulation of plasma metabolites from multiple metabolic pathways, and these metabolites fundamentally influence the immune response profile of circulating cells.

Insights into flavor quality and metabolites profiles of fresh cheese with different probiotics by SPME-GC-MS and untargeted metabolomics

In this study, fresh cheeses produced with four novel probiotics (Lactobacillus casei PB-LC39, Lactobacillus rhamnosus PB-LR76, Lactobacillus helveticus HH-LH17, and Lactobacillus plantarum HH-LP56) were named as LC, LR, LH, and LP, respectively. SPME-GC-MS and untargeted metabolomics were used to compare and analyze the flavor quality, metabolites and metabolic pathways of LC, LR, LH and LP, and the potential function of differential metabolites was emphasized. The results demonstrated that the incorporation of probiotics resulted in a significant increase in the number of volatile flavor compounds and varying flavor profiles within the cheese. Especially LC, exhibited aromas reminiscent of wine, fruit and rose, and displayed the most favorable flavor qualities among all probiotic cheeses. The results of differential metabolite screening and metabolic pathway demonstrated that probiotic cheese could result in the production of 146–192 differential metabolites, mainly carbohydrates, proteins and acids. Arginine biosynthesis was a key differential metabolite pathway made by probiotics. The LC, LR, LH, and LP groups contained 22, 27, 23, and 24 functional metabolites, including L-carnitine, naringenin, and turanose et al., which might confer anti-inflammatory and improve lipid metabolism functions. These findings provide a theoretical basis for the further functional evaluation and development of probiotic cheese.

Circulating tryptophan–kynurenine pathway metabolites are associated with all‐cause mortality among patients with stage I–III colorectal cancer

AbstractAlterations within the tryptophan–kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan–kynurenine pathway metabolites and all‐cause mortality among CRC patients. This study utilizes data from 2102 stage I–III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3‐hydroxykynurenine (HK), xanthurenic acid (XA), 3‐hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography–tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above‐mentioned metabolites with all‐cause mortality, adjusted for potential confounders. During a median follow‐up of 3.2 years (interquartile range: 2.2–4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all‐cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine‐to‐tryptophan ratio, a marker of cell‐mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan–kynurenine pathway metabolites may be prognostic markers of survival in CRC patients.

Mediterranean Diet Prior to Ischemic Stroke and Potential Circulating Mediators of Favorable Outcomes.

Background/Objectives. A Mediterranean diet (MD) has been associated with neuroprotective effects. We aimed to assess the MD's association with stroke prognosis and the potential mediators involved. Methods. Seventy patients with acute anterior circulation ischemic stroke were included. Dietary patterns were evaluated using the MEDAS scale, a food-frequency questionnaire, and a 24 h recall. Circulating biomarkers including insulin resistance (HOMA index), adipokines (resistin, adiponectin, leptin), choline pathway metabolites (TMAO, betaine, choline), and endothelial progenitor cells (EPCs) were measured. Early neurological improvement (ENI) at 24 h, final infarct volume, and functional outcome at 3 months were assessed. Results. Adherence to MD and olive oil consumption were associated with a lower prevalence of diabetes and atherothrombotic stroke, and with lower levels of fasting glycemia, hemoglobinA1C, insulin resistance, and TMAO levels. Monounsaturated fatty acids and oleic acid consumption correlated with lower resistin levels, while olive oil consumption was significantly associated with EPC mobilization. Multivariate analysis showed that higher MD adherence was independently associated with ENI and good functional prognosis at 3 months. EPC mobilization, lower HOMA levels, and lower resistin levels were associated with ENI, a smaller infarct volume, and good functional outcome. Conclusions. MD was associated with better prognosis after ischemic stroke, potentially mediated by lower insulin resistance, increased EPC mobilization, and lower resistin levels, among other factors.

Transcriptomics and metabolomics analyses of Rosa hybrida to identify heat stress response genes and metabolite pathways

BackgroundGlobal warming has greatly increased the impact of high temperatures on crops, resulting in reduced yields and increased mortality. This phenomenon is of significant importance to the rose flower industry because high-temperature stress leads to bud dormancy or even death, reducing ornamental value and incurring economic losses. Understanding the molecular mechanisms underlying the response and resistance of roses to high-temperature stress can serve as an important reference for cultivating high-temperature-stress-resistant roses.ResultsTo evaluate the impact of high temperatures on rose plants, we measured physiological indices in rose leaves following heat stress. Protein and chlorophyll contents were significantly decreased, whereas proline and malondialdehyde (MDA) contents, and peroxidase (POD) activity were increased. Subsequently, transcriptomics and metabolomics analyses identified 4,652 common differentially expressed genes (DEGs) and 57 common differentially abundant metabolites (DAMs) in rose plants from four groups. Enrichment analysis showed that DEGs and DAMs were primarily involved in the mitogen-activated protein kinases (MAPK) signaling pathway, plant hormone signal transduction, alpha-linolenic acid metabolism, phenylpropanoid biosynthesis, and flavonoid biosynthesis. The combined analysis of the DEGs and DAMs revealed that flavonoid biosynthesis pathway-related genes, such as chalcone isomerase (CHI), shikimate O-hydroxycinnamoyl transferase (HCT), flavonol synthase (FLS), and bifunctional dihydroflavonol 4-reductase/flavanone 4-reductase (DFR), were downregulated after heat stress. Moreover, in the MAPK signaling pathway, the expression of genes related to jasmonic acid exhibited a decrease, but ethylene receptor (ETR/ERS), P-type Cu + transporter (RAN1), ethylene-insensitive protein 2/3 (EIN2), ethylene-responsive transcription factor 1 (ERF1), and basic endochitinase B (ChiB), which are associated with the ethylene pathway, were mostly upregulated. Furthermore, heterologous overexpression of the heat stress-responsive gene RcHSP70 increased resistance to heat stress in Arabidopsis thaliana.ConclusionThe results of this study indicated that the flavonoid biosynthesis pathway, MAPK signaling pathway, and plant hormones may be involved in high-temperature resistance in roses. Constitutive expression of RcHSP70 may contribute to increasing high-temperature tolerance. This study provides new insights into the genes and metabolites induced in roses in response to high temperature, and the results provide a reference for analyzing the molecular mechanisms underlying resistance to heat stress in roses.

Novel mechanisms of intestinal flora regulation in high-altitude hypoxia

BackgroundThis study investigates the molecular mechanisms behind firmicutes-mediated macrophage (Mψ) polarization and glycolytic metabolic reprogramming through HIF-1α in response to intrinsic mucosal barrier injury induced by high-altitude hypoxia. MethodsEstablishing a hypoxia mouse model of high altitude, we utilized single-cell transcriptome sequencing to identify key cell types involved in regulating intestinal mucosal barrier damage caused by high-altitude hypoxia. Through proteomic analysis of colonic tissue Mψ and metabolomic analysis of Mψ metabolites, we determined crucial proteins and metabolic pathways influencing intestinal mucosal barrier damage induced by high-altitude hypoxia. Mechanistic validation was conducted using RAW264.7 Mψ in vitro by assessing cell viability with CCK-8 assay following treatment with different metabolites. The hypoxia mouse model was further validated in vivo by transplanting gut microbiota of Firmicutes. Histological examinations through H&E staining assessed colonic cell morphology and structure, while the FITC-dextran assay evaluated intestinal tissue permeability. Hypoxia probe signal intensity in mouse colonic tissue was assessed via metronidazole staining. Various experimental techniques, including flow cytometry, immunofluorescence, ELISA, Western blot, and RT-qPCR, were employed to study the impact of HIF-1α/glycolysis pathway and different gut microbiota metabolites on Mψ polarization. ResultsBioinformatics analysis revealed that single-cell transcriptomics identified Mψ as a key cell type, with their polarization pattern playing a crucial role in the intestinal mucosal barrier damage induced by high-altitude hypoxia. Proteomics combined with metabolomics analysis indicated that HIF-1α and the glycolytic pathway are pivotal proteins and signaling pathways in the intestinal mucosal barrier damage caused by high-altitude hypoxia. In vitro cell experiments demonstrated that activation of the glycolytic pathway by HIF-1α led to a significant upregulation of mRNA levels of IL-1β, IL-6, and TNFα while downregulating mRNA levels of IL-10 and TGFβ, thereby promoting M1 Mψ activation and inhibiting M2 Mψ polarization. Further mechanistic validation experiments revealed that the metabolite butyric acid from Firmicutes bacteria significantly downregulated the protein expression of HIF-1α, GCK, PFK, PKM, and LDH, thus inhibiting the HIF-1α/glycolytic pathway that suppresses M1 Mψ and activates M2 Mψ, consequently alleviating the hypoxic symptoms in RAW264.7 cells. Subsequent animal experiments confirmed that Firmicutes bacteria inhibited the HIF-1α/glycolytic pathway to modulate Mψ polarization, thereby mitigating intestinal mucosal barrier damage in high-altitude hypoxic mice. ConclusionThe study reveals that firmicutes, through the inhibition of the HIF-1α/glycolysis pathway, mitigate Mψ polarization, thereby alleviating intrinsic mucosal barrier injury in high-altitude hypoxia.

Ketamine Prevents Inflammation-Induced Reduction of Human Hippocampal Neurogenesis via Inhibiting the Production of Neurotoxic Metabolites of the Kynurenine Pathway.

Understanding the precise mechanisms of ketamine is crucial for replicating its rapid antidepressant effects without inducing psychomimetic changes. Here, we explore whether the antidepressant-like effects of ketamine enantiomers are underscored by protection against cytokine-induced reductions in hippocampal neurogenesis and activation of the neurotoxic kynurenine pathway in our well-established in vitro model of depression in a dish. We used the fetal hippocampal progenitor cell line (HPC0A07/03C) to investigate ketamine's impact on cytokine-induced reductions in neurogenesis in vitro. Cells were treated with interleukin- 1beta (IL-1b) (10ng/mL) or IL-6 (50 pg/mL), alone or in combination with ketamine enantiomers arketamine (R-ketamine, 400nM) or esketamine (S-ketamine, 400nM) or antidepressants sertraline (1mM) or venlafaxine (1mM). Resembling the effect of antidepressants, both ketamine enantiomers prevented IL-1b- and IL-6-induced reduction in neurogenesis and increase in apoptosis. This was mediated by inhibition of IL-1b-induced production of IL-2 and IL-13 by R-ketamine and of IL-1b-induced tumor necrosis factor-alpha by S-ketamine. Likewise, R-ketamine inhibited IL-6-induced production of IL-13, whereas S-ketamine inhibited IL-6-induced IL-1b and IL-8. Moreover, both R- and S-ketamine prevented IL-1b-induced increases in indoleamine 2,3-dioxygenase expression as well as kynurenine production, which in turn was shown to mediate the detrimental effects of IL-1b on neurogenesis and apoptosis. In contrast, neither R- nor S-ketamine prevented IL-6-induced kynurenine pathway activation. Results suggest that R- and S-ketamine have pro-neurogenic and anti-inflammatory properties; however, this is mediated by inhibition of the kynurenine pathway only in the context of IL-1b. Overall, this study enhances our understanding of the mechanisms underlying ketamine's antidepressant effects in the context of different inflammatory phenotypes, ultimately leading to the development of more effective, personalized therapeutic approaches for patients suffering from depression.

Metabolomics, phytohormone and transcriptomics strategies to reveal the mechanism of barley heading date regulation to responds different photoperiod

BackgroundThe correlation between heading date and flowering time significantly regulates grain filling and seed formation in barley and other crops, ultimately determining crop productivity. In this study, the transcriptome, hormone content detection, and metabolome analysis were performed systematically to analyze the regulatory mechanism of heading time in highland barley under different light conditions. The heading date of D18 (winter highland barley variety, Dongqing18) was later than that of K13 (vernal highland barley variety) under normal growth conditions or long-day (LD) treatment, while this situation will reverse with short-day (SD) treatment.ResultsThe circadian rhythm plant, plant hormone signaling transduction, starch and sucrose metabolism, and photosynthesis-related pathways are significantly enriched in barley under SD and LD to influence heading time. In the plant circadian rhythm pathway, the key genes GI (Gigantea), PRR (Pesudoresponseregulator), FKF1 (Flavin-binding kelch pepeat F-Box 1), and FT (Flowering locus T) are identified as highly expressed in D18SD3 and K13SD2, while they are significantly down-regulated in K13SD3. These genes play an important role in regulating the heading date of D18 earlier than that of K13 under SD conditions. In photosynthesis-related pathways, a-b binding protein and RBS were highly expressed in K13LD3, while NADP-dependent malic enzyme, phosphoenolpyruvate carboxylase, fructose-bisphosphate aldolase, and triosephosphate isomerase were significantly expressed in D18SD3. In the starch and sucrose metabolism pathway, 41 DEGs (differentially expressed genes) and related metabolites were identified as highly expressed and accumulated in D18SD3. The DEGs SAUR (Small auxin-up RNA), ARF (Auxin response factor), TIR1 (Transport inhibitor response 1), EIN3 (Ethylene-insensitive 3), ERS1 (Ethylene receptor gene), and JAZ1 (Jasmonate ZIM-domain) in the plant hormone pathway were significantly up-regulated in D18SD3. Compared with D18LD3, the content of N6-isopentenyladenine, indole-3-carboxylic acid, 1-aminocyclopropanecarboxylic acid, trans-zeatin, indole-3-carboxaldehyde, 1-O-indol-3-ylacetylglucose, and salicylic acid in D18SD3 also increased. The expression levels of vernalization genes (HvVRN1, HvVRN2, and HvVRN3), photoperiod genes (PPD), and PPDK (Pyruvate phosphate dikinase) that affect photosynthetic efficiency in barley are also analyzed, which play important regulatory roles in barley heading date. The WGCNA analysis of the metabolome data and circadian regulatory genes identified the key metabolites and candidate genes to regulate the heading time of barley in response to the photoperiod.ConclusionThese studies will provide a reference for the regulation mechanism of flowering and the heading date of highland barley.

Metabolic phenotypes and vitamin D response in the critically ill: A metabolomic cohort study

Background & AimsAlthough vitamin D deficiency is common in critically ill patients, randomized controlled trials fail to demonstrate benefits of supplementation. We aimed to identify distinct vitamin D3 responsive metabolic phenotypes prior to trial intervention of high-dose vitamin D3 by applying machine learning clustering method to metabolomics data from the Correction of Vitamin D Deficiency in Critically Ill Patients (VITdAL-ICU) trial. MethodsIn the randomized, placebo-controlled VITdAL-ICU trial, critically ill adults received placebo or high-dose vitamin D3. To distinguish vitamin D3 responsive metabolic phenotypes prior to intervention, we implemented consensus clustering with partitioning around medoids algorithm to the plasma metabolome data before randomization. Individual metabolite differences were determined utilizing linear mixed-effects regression models stratified for metabolomic phenotypes with false discovery rate adjustment. The association between vitamin D3 supplementation and 180-day mortality was evaluated in each metabolic phenotype, applying multivariable logistic regression analysis. ResultsIn 453 critically ill adults, the study identified 4 distinct metabolic phenotypes (clusters A. N=134; B. N=123; C. N=92; D. N=104). We found differential metabolic pathway patterns in the four clusters. Specifically, branched chain amino acid catabolic metabolites, long-chain acylcarnitines and diacylglycerol species are significantly increased in a specific metabolic phenotype (cluster D) following high-dose vitamin D3. Further, in cluster D high-dose vitamin D3 supplementation had a significantly lower adjusted odds of 180-day mortality after controlling age, sex, Simplified Acute Physiology Score II, admission diagnosis, and baseline 25-hydroxyvitamin D (OR 0.28 (95%CI, 0.09–0.89); P=0.03). In metabotype A, B, and C, high-dose vitamin D3 supplementation was not significantly associated with lower 180-day mortality following multivariable adjustment. ConclusionIn this post-hoc cohort study of the VITdAL-ICU trial, the clustering analysis of plasma metabolome data identified biologically distinct metabolic phenotypes. Among clusters, we found the different associations between high-dose vitamin D3 supplementation and specific metabolite pathways as well as 180-day mortality. Our findings facilitate further research to validate metabolic phenotype-targeted strategies for critical illness treatments.

ROS regulation in Dunaliella salina by fulvic acid: induction of enzymes related to the ascorbate–glutathione pathway and antioxidant metabolites

ROS regulation in Dunaliella salina by fulvic acid: induction of enzymes related to the ascorbate–glutathione pathway and antioxidant metabolites

The 1400 metabolite-mediated relationship between 91 inflammatory cytokines and migraine: An exploratory two-step Mendelian randomization study.

Inflammatory cytokines and migraines have been associated in previous research, but the underlying mechanisms of action are still elusive. The biological functions of metabolites are crucial in the onset of migraine. Our goals were to clarify the cause-and-effect connection between inflammatory cytokines and migraines and explore the potential mediating function of metabolites. Utilizing summary-level data from genome-wide association studies (GWAS), we conducted two-sample Mendelian randomization (MR) analyses to evaluate the possible causal connection between inflammatory cytokines and migraines. A two-step MR analysis was employed to further investigate the potential mediating pathways of metabolites. MR analysis identified a total of 9 inflammatory cytokines that were genetically associated with migraines, and we subsequently identified 21 mediated relationships, with 20 metabolites (13 metabolites, 7 ratios) acting as potential mediators between 8 inflammatory cytokines and migraine. The 9 inflammatory cytokines were beta-nerve growth factor levels (β-NGF), T-cell surface glycoprotein CD5 levels (CD5), T-cell surface glycoprotein CD6 isoform levels (CD6), C-X-C motif chemokine 11 levels (CXCL11), interleukin-4 levels (IL-4), oncostatin-M levels (OSM), signalling lymphocytic activation molecule levels (SLAM), C-C motif chemokine 25 levels (CCL25) and monocyte chemoattractant protein-1 levels (MCP-1). Our research findings provide evidence for both a causal connection between inflammatory cytokines and migraines, as well as a metabolite-mediated pathway. These biomarkers facilitate the detection, diagnosis and treatment of migraines while offering fresh perspectives on their underlying mechanisms.

7 Role of the preovulatory follicle in oocyte metabolic and developmental competence for pregnancy

Abstract A majority of bovine pregnancy loss occurs in the first 7 d of gestation. The oocyte is a key driver of embryo viability during this time, and its competence for embryo development and pregnancy establishment is greatly influenced by the surrounding microenvironment during oocyte maturation. Assisted reproductive technologies allow for more efficient propagation of superior genetics and improved reproductive management of the cattle herd; however, many assisted reproductive technologies alter the normal microenvironment of the maturing oocyte and negatively impact oocyte competence for early embryo development. For example, oocytes induced to ovulate from preovulatory follicles of lesser physiological maturity (decreased estradiol production and smaller diameter) have reduced blastocyst development, poorer embryo quality, and a hastened rate of embryo development compared with those ovulated from follicles of greater maturity. Our overarching hypothesis is that the intrafollicular milieu of physiologically mature preovulatory follicles provides the necessary microenvironment to metabolically program maturing oocytes for successful embryo development. Studies by our team have demonstrated that the follicular fluid metabolite milieu during in vivo oocyte maturation differs between preovulatory follicles of greater and lesser maturity and that such differences have direct effects on the maturing oocyte. Numerous follicular fluid metabolites involved in glucose and amino acid metabolism were more abundant in preovulatory follicles of greater versus lesser physiological maturity. Additionally, abundance of transcripts encoding glycolytic enzymes was higher in cumulus cells from follicles of greater maturity, and both ATP and levels of key transcripts in the mitochondrial respiratory chain were higher in oocytes collected from preovulatory follicles of greater versus lesser maturity. We supplemented in vitro maturing oocytes with follicular fluid from preovulatory follicles of greater or lesser maturity to determine causality of differing follicular fluid milieu on cumulus-oocyte metabolism and oocyte competence for early embryo development. Follicle maturity status had robust effects on cumulus-oocyte complex consumption or production of key metabolites in glucose, purine, and amino acid metabolism pathways during oocyte maturation. We also observed hastened development rate in embryos arising from in vitro matured oocytes supplemented with lesser maturity follicular fluid, mirroring past in vivo findings by others. Furthermore, RNA-sequencing of resulting blastocysts of identical stage and quality suggested more efficient metabolism and Wnt/β-catenin signaling in blastocysts derived from oocytes matured in preovulatory follicular fluid from greater maturity follicles. In contrast, transcriptome profiles of blastocysts from oocytes matured in preovulatory follicular fluid from lesser maturity follicles indicated oxidative stress and dysregulated cell division. These recent findings by our lab indicate that impacts of follicle maturity and the resulting follicular fluid microenvironment on the maturing oocyte withstand throughout early embryo development and hold promising roles to improve reproductive efficiency in cattle.

169 Vitamin and mineral supplementation to gestating beef heifers: Fetal physiology and metabolic programming

Abstract Vitamins and minerals have key roles in hormone production and action, enzyme activity, tissue synthesis, oxygen transport, and energy production. These micronutrients are efficiently transferred from the dam to the fetus during gestation to be partitioned for metabolic use and stored as postnatal mineral reserves. Maternal nutrient intake is one of the main factors that influence the availability of vitamins and minerals to the fetus. Thus, an inadequate supply of these critical nutrients can have a long-lasting impact on offspring growth and health. Evidence suggests that biological processes regulating normal growth, development, and nutrient utilization are programmed in utero, even during the earliest developmental stages. Therefore, there is a critical need to evaluate the effects of micronutrient supplementation during gestation on fetal physiology and metabolic programming. Our research group has developed research models examining the impact of maternal vitamin and mineral supplementation (VTM, supplemented vs. NoVTM, not supplemented) during the periconceptual period or throughout gestation in beef heifers. A metabolomic analysis revealed that metabolites in the oxidative phosphorylation pathway were more abundant in the liver of fetuses from VTM than NoVTM dams, suggesting that a greater supply of micronutrients during the periconceptual period and first trimester of pregnancy may positively modulate mitochondrial energy metabolism in offspring. These changes in the abundance of metabolites suggested physiological adaptations to meet fetal metabolic needs. Further, high-resolution respirometry analysis revealed greater efficiency of energy utilization in small intestinal samples of neonatal calves from VTM dams. In fact, VTM offspring were heavier from weaning to breeding phase than NoVTM offspring, suggesting that maternal nutrition affects physiological mechanisms in utero that modulate offspring energetics and efficiency of nutrient utilization in the postnatal period. Furthermore, we reported increased concentrations of histidine, aspartate, and 12 out of 14 neutral amino acids in the allantoic fluid of VTM-supplemented dams. Finally, genes involved with amino acid transport in fetal liver were upregulated in response to VTM supplementation, highlighting the intricate relationship between maternal and fetal nutrition. Vitamin and mineral supplementation were also associated with changes in gene expression, biological processes and pathways in placental tissue at d 83 of gestation. We observed an upregulation of genes in the calcium signaling and cyclic guanosine monophosphate (CGMP)-PKG signaling pathways in response to micronutrient supplementation. Calcium-mediated systems may modulate cell proliferation and steroidogenic activity in bovine placentomes, while CGMP-PKG plays a key role in vascular homeostasis. Placental blood vessel vascularity at term was indeed increased in heifers supplemented throughout gestation, emphasizing the importance of micronutrient supplementation beyond early pregnancy. Altogether, our findings suggest that vitamin and mineral supplementation in the periconceptual period and during gestation play a pivotal role in fetal metabolic programming with consequences extending to the postnatal period.

Functional impacts of PtrMYB203 on phenylpropanoid pathway regulation and wood properties in hybrid poplar

The phenylpropanoid pathway is vital for plant growth and development, producing lignin and flavonoids. This study investigates PtrMYB203, a homolog of MYB repressors of proanthocyanidin (PA) biosynthesis in Populus trichocarpa, as a transcriptional repressor in the phenylpropanoid pathway of hybrid poplar (Populus alba x P. glandulosa). Overexpression of PtrMYB203 (35S::PtrMYB203) in hybrid poplar detrimentally impacted plant growth and development. Histological analysis revealed irregular xylem vessel formation and decreased lignin content, corroborated by Klason lignin assays. Moreover, 35S::PtrMYB203 transgenic poplars exhibited significant decreases in anthocyanin and PA accumulations in callus tissues, even under high light conditions. Quantitative RT-PCR analysis and protoplast-based transcriptional activation assay confirmed the downregulation of lignin and flavonoid biosynthesis genes. This genetic modification also alters the expression of several MYB transcription factors, essential for phenylpropanoid pathway regulation. Remarkably, saccharification efficiency in the 35S::PtrMYB203 poplar was improved by over 34% following hot water treatment alone. These findings suggest PtrMYB203 as a potential genetic target for enhancing wood properties for bioenergy production, providing valuable insights into the manipulation of metabolite pathways in woody perennials to advance wood biotechnology.

The use of metagenomic and untargeted metabolomics in the analysis of the effects of the Lycium barbarum glycopeptide on allergic airway inflammation induced by Artemesia annua pollen

Ethnopharmacological relevanceThe prevalence of allergic airway inflammation (AAI) worldwide is high. Artemisia annua L. pollen is spread worldwide, and allergic diseases caused by its plant polysaccharides, which are closely related to the intestinal microbiota, have anti-inflammatory effects. Further isolation and purification of Lycium barbarum L. yielded its most effective component Lycium barbarum L. glycopeptide (LbGP), which can inhibit inflammation in animal models. However, its therapeutic effect on AAI and its mechanism of regulating the intestinal flora have not been fully investigated. Aim of the studyTo explore LbGP in APE-induced immunological mechanisms of AAI and the interaction mechanism of the intestinal flora and metabolites. MethodsA mouse model of AAI generated from Artemisia annua pollen was constructed, and immunological indices related to the disease were examined. A combination of macrogenomic and metabolomic analyses was used to investigate the effects of LbGP on the gut microbial and metabolite profiles of mice with airway inflammation. ResultsLbGP effectively alleviated Artemisia. annua pollen extract (APE)-induced AAI, corrected Th1/Th2 immune dysregulation, decreased Th17 cells, increased Treg cells, and altered the composition and function of the intestinal microbiota. LbGP treatment increased the number of OdoribacterandDuncaniella in the intestines of the mice, but the numble of Alistipes and Ruminococcus decreased. Metabolite pathway enrichment analysis were used to determine the effects of taurine and hypotaurine metabolism, bile acid secretion, and pyrimidine metabolism pathways on disease. ConclusionOur results revealed significant changes in the macrogenome and metabolome following APE and LbGP intervention, revealed potential correlations between gut microbial species and metabolites, and highlighted the beneficial effects of LbGP on AAI through the modulation of the gut microbiome and host metabolism.

Polysaccharides from Lanzhou Lily Attenuate Nonalcoholic Fatty Liver Disease Modifying the Gut Microbiota and Metabolite Profile.

Nonalcoholic fatty liver disease (NAFLD) is closely related to gut microbiota due to the hepatic portal system, and utilizing natural polysaccharides as prebiotics has become a prospective strategy for treating NAFLD. However, the therapeutic effects and potential molecular mechanisms of Lanzhou Lily polysaccharides (LLP) on NAFLD remains unclear. Therefore, the alleviating effects of LLP on NAFLD induced by high-fat diet (HFD) were investigated. LLP treatment greatly ameliorated NAFLD by significantly reducing lipid accumulation and the levels of liver function markers in HFD-induced NAFLD mice, as evidenced by decreased serum levels of TG, TC, HDL-C and LDL-C. Furthermore, LLP administration reduced hepatic steatosis, as shown by H&E and Oil red O staining. LLP also inhibited the TNF-α and IL-1β expression, thereby reducing levels of hepatic proinflammatory cytokines. Furthermore, LLP restored gut microbiota dysbiosis (up-regulated Bacteroidota, Proteobacteria, Alistipes and Lachnospiraceae abundances, down-regulated Firmicutes, Verrucomicrobiota, Desulfobacterota and Turicibacter abundances), and regulated microbial metabolic pathways such as primary bile acid biosynthesis and amino acid metabolism. In addition, the resultes of Spearman's correlation analysis found that some key metabolites in these metabolic pathways were associated with intestinal microorganisms such as Desulfobacterota, Prevotellaceae-UCG-001, Colidextribacter and Alistipes. Therefore, our study suggests that LLP may has potential applications in the treatment of NAFLD by regulating gut microbiota and its metabolite profile.

Assessment of Urinary Dopamine and Serotonin Metabolites in Relation to Dysbiosis Indicators in Patients with Functional Constipation.

The causes of functional constipation (FC) in adults are unclear, but changes in the gut microbiome may play an important role. The present study aimed to assess the relationship between urinary metabolites of dopamine and serotonin and some dysbiosis indicators in patients with FC. The study included 40 healthy women and 40 women with FC aged 21-46 years. Urinary levels of homovanillic acid (HVA), 5-hydoxyindoleacetic acid (5-HIAA), p-hydroxyphenylacetic acid (PhAc), and 3-indoxyl sulfate, as final metabolites of dopamine, serotonin, and indole pathway, respectively, were determined using the LC-Ms/Ms method. However, hydrogen-methane and ammonia breath tests were performed. The GA-map Dysbiosis Test was used to identify and characterize the dysbiosis index (DI). In patients with FC, the DI was significantly higher than in the control group: 4.05 ± 0.53 vs. 1.52 ± 0.81 points (p < 0.001), but the number of many types of bacteria varied among individuals. The levels of HVA were higher, while 5-HIAA levels were lower in patients. Moreover, the HVA/5-HIAA ratio had a positive correlation with DI as well as with the severity of symptoms. In patients with functional constipation, the balance in dopamine and serotonin secretion is disturbed, which is associated with changes in the gut microbiome.

Recent progress of methods for cuproptosis detection.

Varying from other identified cell death pathways, cuproptosis is a new type of regulated cell death characterized by excess Cu ions, abnormal aggregation of lipoylated proteins in TCA cycle, loss of Fe-S cluster proteins, upregulation of HSP70, leading to proteotoxic and oxidative stress. Cuproptosis is highly concerned by scientific community and as the field of cuproptosis further develops, remarkable progress has been made in the verification and mechanism of cuproptosis, and methods used to detect cuproptosis have been continuously improved. According to the characteristic changes of cuproptosis, techniques based on cell death verification, Cu content, morphology, molecular biology of protein levels of cuproptosis-related molecules and biochemical pathways of cuproptosis-related enzyme activity and metabolites of oxidative stress, lipoic acid, TCA cycle, Fe-S cluster proteins, oxidative phosphorylation, cell respiration intensity have been subject to cuproptosis verification and research. In order to further deepen the understanding of detecting cuproptosis, the principle and application of common cuproptosis detection methods are reviewed and categorized in cellular phenomena and molecular mechanism in terms of cell death, Cu content, morphology, molecular biology, biochemical pathways with a flow chart. All the indicating results have been displayed in response to the markers of cuproptosis, their advantages and limitations are summaried, and comparison of cuproptosis and ferroptosis detection is performed in this study. Our collection of methods for cuproptosis detection will provide a great basis for cuproptosis verification and research in the future.

Proanthocyanidins and β-Glucan Synergistically Regulate Intestinal Inflammation in Dextran Sulfate Sodium-Induced Colitis Mice.

Proanthocyanidins (PA) have been proven to have an anti-inflammation effect in multiple models by regulating oxidative stress. β-glucan (BG) could alleviate colitis from the perspectives of intestinal permeability and gut microbiota. In the present study, the synergistic anti-inflammatory function of PA and BG was explored from multiple aspects including immune response, intestinal barrier, gut microbiota, and differential metabolites. The results showed that the supplementation of PA and BG improved the colitis symptoms including atrophy of the colon, body weight loss, and organ index increase. Additionally, inflammatory cytokine levels and oxidative stress status were significantly regulated with the intake of PA and BG. Moreover, PA and BG intervention improved intestinal permeability and promoted the expression of barrier proteins. The microbiome and metabolic profile of cecal contents showed that PA and BG supplementation increased the abundance of anti-inflammatory bacteria and decreased the abundance of pro-inflammatory bacteria. Furthermore, some beneficial metabolites involved in amino acid metabolism, carbohydrate metabolism, and biosynthesis of other secondary metabolite pathways were increased. Overall, these findings have demonstrated the regulation of the inflammatory response and remodel of metabolite profiles by PA and BG complexes, indicating that it may serve as a new strategy for inflammatory bowel disease treatment in the future.