Metabolism Biosynthesis Research Articles

Interrelationship between altered metabolites and the gut microbiota in people living with HIV with different immune responses to antiretroviral therapy.

Antiretroviral therapy (ART) effectively reduces opportunistic infections and mortality in people living with HIV (PLWH); however, some patients exhibit poor immune recovery. This study explores the connections among immune responses, metabolites, and the gut microbiota in PLWH with differing reactions to ART. We analyzed the gut microbiota composition, metabolites, and immune markers in 38 PLWH who showed an immunological response (IR) and 32 who did not (INR), as classified according to CD4+ T-cell levels after 24 months of ART. Additionally, in vitro assays using cell counting kit 8, flow cytometry, and quantitative real-time reverse transcription PCR were employed to assess the effects of the metabolites on cell viability, immune marker expression, and cytokine levels. Gut microbiota and metabolic profiles differed significantly between the IR and INR groups. Enterococcus was more abundant in the INR group, whereas [Ruminococcus]_gnavus_group levels were reduced. Significant metabolic pathway alterations included decreased folate biosynthesis and biotin metabolism. We observed negative associations of Parabacteroides with activation markers on CD4+ T-cells, and positive correlations with CD4/CD8 ratios. Enterococcus showed inverse relationships with these markers. Indole-3-acetyl-beta-1-D-glucoside (area under the curve value = 0.8931), had the best discriminatory ability. Further experiments showed that Indole-3-acetyl-beta-1-D-glucoside significantly decreased the proportions of CD4+CD57+, effector CD4+, CD4+PD1+, CD8+CD57+, effector CD8+, and CD8+HLA-DR+ T cells. Moreover, mRNA expression analysis showed that Indole-3-acetyl-beta-1-D-glucoside treatment led to a suppression of pro-inflammatory cytokines. The multi-omics approach highlighted potential biomarkers for immune recovery in HIV, suggesting avenues for further research into treatment strategies.

Physiological and multi-omics analysis revealed the mechanism of arbuscular mycorrhizal fungi to cadmium toxicity in green onion.

Cadmium (Cd) is a highly toxic agricultural pollutant that inhibits the growth and development of plants. Arbuscular mycorrhizal fungi (AMF) can enhance plant tolerance to Cd, but the regulatory mechanisms in Allium fistulosum (green onion) are unclear. This study used a Cd treatment concentration of 1.5 mg·kg-1, which corresponds to the risk control threshold for soil pollution in Chinese agricultural land, to examine the effects and molecular mechanisms of AMF inoculation on the growth and physiology of green onion under Cd stress. AMF formed an effective symbiotic relationship with green onion roots under Cd stress, increased plant biomass, improved root structure and enhanced root vitality. AMF-colonized green onion had reduced Cd content in roots and leaves by 63.00 % and 46.50 %, respectively, with Cd content being higher in the roots than in the leaves. The ameliorative effect of AMF on Cd toxicity was mainly due to a reduction in malondialdehyde content in leaves (30.12 %) and an enhancement of antioxidant enzyme activities (peroxidase, catalase, superoxide dismutase, glutathione reductase and reduced glutathione) that mitigated damage from excessive reactive oxygen species. In addition, AMF induced secretion of easily extractable glomalin soil protein and total glomalin-related soil protein and inhibited the translocation of Cd to the shoots. Transcriptomic and metabolomic correlation analyses revealed that differentially expressed genes and metabolites in AMF-inoculated green onion under Cd stress were predominantly enriched in the "phenylpropanoid biosynthesis" and "phenylalanine metabolism" pathways, upregulated the expression of the HCT, PRDX6, HPD, MIF, and HMA3 genes, and accumulation of the phenylalanine, L-tyrosine, and 1-O-sinapoyl-β-glucose metabolites. Thus, AMF enhance Cd tolerance in green onions by sequestering Cd in roots, restricting its translocation, modulating antioxidant defenses and inducing the expression of genes involved in the phenylpropanoid biosynthesis and phenylalanine metabolism pathways. Collectedly, we for the first time revealed the mechanism of AMF alleviating the toxicity of Cd to green onion, providing a theoretical foundation for the safe production and sustainable cultivation of green onion in Cd-contaminated soils.

Decoding gene expression dynamics during seed development in sesame (Sesamum indicum L.) through RNA-Seq analysis.

Sesame (Sesamum indicum L., 2n = 2× = 26) from the Pedaliaceae family is primarily grown for its high oil content, rich in unsaturated fatty acids like linoleic acid (LA) and alpha-linolenic acid (ALA). However, the molecular mechanisms of sesame oil accumulation remain poorly understood. This study analyzed transcriptomes at two seed development stages: Young Stage (YS, pods 1.5-2.5 cm) and Mature Stage (MS, brown pods >2.5 cm), to explore regulatory mechanisms and identify key genes involved in lipid biosynthesis. From 25,173 genes, 18,820 with expression values >10 CPM in at least 70 % of replicates were included in differential expression (DE) analysis. Active expression (LFC > 0) was observed in 9372 and 9448 genes at YS and MS, respectively. DEGs were annotated, revealing roles in various biological processes, (e.g., mRNA metabolic process, reproduction-related developmental processes, seed development), molecular functions (e.g., aminoacyltransferase activity, ubiquitin-like protein and ubiquitin-protein transferase activities), and cellular components (e.g., peroxisome, microbody, lipid droplet). KEGG analysis highlighted genes involved in fatty acid synthesis (e.g., fabG, fabZ), TAG biosynthesis (DGAT1, GPAT), and alpha-linolenic acid metabolism (AOS, LCAT3). Key genes upregulated at MS included SIN_1025205 (protein transport), SIN_1006853 (acetylajmalan esterase), and SIN_1003267 (gamma-cadinene synthase). The study generated a valuable transcriptome dataset and gene list for seed development and lipid biosynthesis, which will be validated through functional studies. An interactive webpage is provided for data exploration.

Recent advances in synthetic biology toolkits and metabolic engineering of Ralstonia eutropha H16 for production of value-added chemicals.

Ralstonia eutropha H16, a facultative chemolithoautotrophic Gram-negative bacterium, demonstrates remarkable metabolic flexibility by utilizing either diverse organic substrates or CO2 as the sole carbon source, with H2 serving as the electron donor under aerobic conditions. The capacity of carbon and energy metabolism of R. eutropha H16 enabled development of synthetic biology technologies and strategies to engineer its metabolism for biosynthesis of value-added chemicals. This review firstly outlines the development of synthetic biology tools tailored for R. eutropha H16, including construction of expression vectors, regulatory elements, and transformation techniques. The availability of comprehensive omics data (i.e., transcriptomic, proteomic, and metabolomic) combined with the fully annotated genome sequence provides a robust genetic framework for advanced metabolic engineering. These advancements facilitate efficient reprogramming metabolic network of R. eutropha. The potential of R. eutropha as a versatile microbial platform for industrial biotechnology is further underscored by its ability to utilize a wide range of carbon sources for the production of value-added chemicals through both autotrophic and heterotrophic pathways. The integration of state-of-the-art genetic and genomic engineering tools and strategies with high cell-density fermentation processes enables engineered R. eutropha as promising microbial cell factories for optimizing carbon fluxes and expanding the portfolio of bio-based products.

INVESTIGATING MEDIATORS OF SYSTEMIC MITOCHONDRIAL BIOENERGETICS IN COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE

Abstract We previously showed peripheral blood mononuclear cell (PBMC) and platelet mitochondrial bioenergetic capacities are lower in older adults with Alzheimer’s disease (AD), with notable changes in fatty acid oxidation (FAO)-mediated respiration. The metabolic pathways underlying mitochondrial functional differences remain un-identified. This study investigated lipid metabolites that are differently expressed across different stages of cognitive impairment (CI). Targeted lipidomics analyzed 51 fatty acids (FAs) in PBMCs and platelets of older adults with normal cognition (NC), mild cognitive impairment (MCI), and AD dementia (DEM). 10 FAs were selected in each cell type based on significant concentration differences between different cognitive groups. In PBMCs, 9 FAs exhibited higher concentrations in MCIs than NC and DEM, with significantly lower concentration in DEM than MCI, while 1 FA exhibited progressively declining concentrations from NC to MCI to DEM. Significant positive correlations were observed between FA concentrations and FAO and maximal mitochondrial respiration (Max). In platelets, 7 FAs showed progressively declining concentrations from NC to MCI to DEM, and significant positive correlations with FAO and Max, while 3 FAs showed progressively increasing concentrations with cognitive impairment, and significant negative correlations with FAO and Max. Significant negative correlations were also observed with mPACC5 cognitive assessment scores and hippocampal volumes. Pathway analyses identified FA biosynthesis, alpha-linolenic acid, and alpha-linoleic acid metabolism as involved pathways differently impacted across cognitive groups. These findings emphasize the importance of FAs and related metabolic pathways in systemic bioenergetic decline in CI, and may facilitate development of preventative, diagnostic, and therapeutic approaches in AD.

Integrated analysis of physiological and metabolic data uncovers essential dynamic mechanisms involved in the maturation of cigar tobacco leaves

The quality of cigar tobacco leaves is profoundly affected by the timing of their harvest, with both early and late collections resulting in inferior characteristics. While the relationship between maturity and physiological metabolic processes is acknowledged, a comprehensive understanding of the physiological behavior of cigar leaves harvested at different stages remains elusive. This research investigated the physiological and metabolomic profiles of the cigar tobacco variety CX-014, grown in Danjiangkou City, Hubei Province, with leaves sampled at 35 (T1), 42 (T2), 49 (T3), and 56 (T4) days post-inflorescence removal. Leaf color transitioned from green to yellow, accompanied by the appearance of white mature spots. Notable increases in photosynthetic pigments and gas exchange parameters occurred between T1 and T2, followed by decline at T3 and T4. The optimal sugar-to-nicotine and potassium-to-chlorine ratios, critical determinants of smoking quality and tobacco combustibility, were observed at T3, indicating a superior chemical balance in leaves harvested at this stage. Metabolomic analysis revealed 2153 distinct metabolites, with the most significant changes occurring between T2 and T3, highlighting critical physiological transformations during this interval. Pathway enrichment analysis via KEGG pinpointed notable shifts in amino acid synthesis pathways, particularly those involving tryptophan, alanine, and aspartate. Tryptophan metabolism and zeatin biosynthesis were substantially altered, with compounds like indolepyruvic acid, N-formylpurine nucleotide, isopentenyladenine nucleotide, and dihydrozeatin showing marked reductions at T3. This study also explored how the timing of lower leaf harvest influences the physiological processes of middle leaves, finding that a plethora of metabolites associated with the breakdown of arachidonic acid—a primitive metazoan signaler implicated in plant stress and defense networks—were abundant in T3 leaves when lower leaves were harvested 43–38 days prior. Overall, these findings elucidates the complex physiological dynamics of cigar leaves during maturation, highlighting critical metabolites involved in essential metabolic pathways.

Genome Combination Improvement Strategy Promotes Efficient Spinosyn Biosynthesis in Saccharopolyspora spinosa.

Spinosyns are secondary metabolites produced by Saccharopolyspora spinosa known for their potent insecticidal properties and broad pesticidal spectrum. We report significant advancements in spinosyn biosynthesis achieved through a genome combination improvement strategy in S. spinosa. By integrating modified genome shuffling with ultraviolet mutation and multiomics analysis, we developed a high-yield spinosyn strain designated as YX2. The levels of most proteins and metabolites linked to primary metabolism and spinosyn biosynthesis were greater in this strain than those in S. spinosa. Based on these insights, we overexpressed 15 relevant functional genes to enhance the conversion of fatty acids into acetyl-coenzyme A. Notably, the overexpression of acd (YX2_3432) significantly increased the spinosyn yield, reaching 1120 ± 108 mg/L, which is about 12 times higher than that produced by S. spinosa. This study presents a valuable and straightforward strategy that can be broadly applied to enhance the production of secondary metabolites in actinomycetes.

Rumen-Degradable Starch Improves Rumen Fermentation, Function, and Growth Performance by Altering Bacteria and Its Metabolome in Sheep Fed Alfalfa Hay or Silage.

Alfalfa silage due to its high protein can lead to easier feeding management, but its high proportion of rumen-degradable protein can reduce rumen nitrogen utilization. Nevertheless, increasing dietary energy can enhance ruminal microbial protein synthesis. Thirty-two Suffolk female sheep were used in this study, with a 2 × 2 factorial arrangement of treatment. The four treatments were a combination of two forage types (alfalfa hay; AH vs. alfalfa silage; AS) and two rumen-degradable starch levels (low RDS; LR vs. high RDS; HR) with a 15 d adaptation and 60 d experimental period. The rumen content and rumen epithelium samples were collected after slaughter. Feeding AS increased the rumen isobutyrate, valerate, ammonia-N (NH3-N) concentration, urase activity, and papillae height (p < 0.05) and reduced the feed to gain (F:G), rumen bacterial protein (BCP), rumen lactic acid concentration, and papillae width (p < 0.05) of sheep. Increased RDS in the diet improved the daily matter intake, average daily gain, and rumen weight, reduced the F:G, and enhanced the rumen nitrogen capture rate by decreasing total amino acids and the NH3-N concentration to increase BCP, aquaporins 3 gene, and protein expression. The rumen microbiota also changed as the HR diet reduced the Chao index (p < 0.05). The metabolomics analysis showed that feeding AS upregulated the rumen tryptophan metabolism and steroid hormone biosynthesis, while the purine metabolism, linoleic acid metabolism, and amino acid biosynthesis were downregulated. Furthermore, increased RDS in the diet upregulated rumen lysine degradation and sphingolipid metabolism, while aromatic amino acid biosynthesis was downregulated. Additionally, the correlation analysis results showed that ADG was positively correlated with 5-aminopentanoic acid, and three microorganisms (unclassified_f__Selenomonadaceae, Quinella, Christensenellaceae_R-7_group) were positively correlated with the rumen isobutyrate, valerate, NH3-N concentration, urase activity, tryptophan metabolism, and steroid hormone biosynthesis and negatively correlated with linoleic acid metabolism and amino acid biosynthesis in sheep. In summary, increased RDS in the diet improved the growth performance and rumen N utilization and reduced bacterial diversity in sheep. The alfalfa silage diet only increased feed efficiency; it did not affect growth performance. Additionally, it decreased rumen nitrogen utilization, linoleic acid, and amino acid biosynthesis. Nevertheless, there were limited interactions between forage and RDS; increased RDS in the AS diet enhanced the nitrogen capture rate of rumen microorganisms for alfalfa silage, with only slight improvements in the purine metabolism, linoleic acid, and amino acid synthesis.

Comprehensive Metabolomic Profiling in Adults with X-Linked Hypophosphatemia: A Case-Control Study.

X-linked hypophosphatemia (XLH) is a rare disorder characterized by elevated levels of fibroblast growth factor 23 (FGF-23), leading to hypophosphatemia and complications in diagnosis due to its clinical heterogeneity. Metabolomic analysis, which examines metabolites as the final products of cellular processes, is a powerful tool for identifying in vivo biochemical changes, serving as biomarkers of pathological abnormalities, and revealing previously uncharted metabolic pathways. A multicenter cross-sectional case-control study of adult patients diagnosed with XLH was conducted. Serum metabolomic analysis was performed with an Ultra-Performance Liquid Chromatography equipment (UPLC) coupled to a high-resolution mass spectrometer (MS). An analysis of metabolic pathways using MetaboAnalyst version 5.0 and a quantitative enrichment analysis (QEA) was performed. We employed multivariate statistical models, including a principal component analysis (PCA) and an orthogonal partial least squares discriminant analysis (OPLS-DA) regression model. A cohort of 20 XLH patients and 19 control subjects were recruited. A total of 104 metabolites were identified. The differential metabolites identified included glycine, taurine, hypotaurine, phosphoethanolamine, pyruvate, guanidoacetic acid, serine, succinate, 2-aminobutyric acid, glutamine, 2-hydroxyvaleric acid, methionine, ornithine, phosphorylcholine, hypoxanthine, lysine, and N-methylnicotinamide. Enrichment analysis identified disturbances in key metabolic pathways, including phosphatidylethanolamine biosynthesis, sphingolipid metabolism, and phosphatidylcholine biosynthesis. Additionally, pathways related to cysteine metabolism, glycolysis, and pyruvate metabolism. This study identified significant differences in the metabolic profiles of individuals with XLH compared to healthy controls. These findings enhance understanding of potential pathogenic mechanisms and offer a metabolic basis for further in-depth investigations into XLH.

Effects of seasonal climates and MIPS1 mutations on soybean germination through multi-omics analysis

This study delves into the combined effects of seasonal climate variations and MIPS1 gene mutations on the germination rates of soybean cultivars TW-1 and TW75. Through comprehensive metabolomic and transcriptomic analyses, we identified key KEGG pathways significantly affected by these factors, including starch and sucrose metabolism, lipid metabolism, and amino acid biosynthesis. These pathways were notably disrupted during the spring, leading to an imbalance in metabolic reserves critical for seedling development. Additionally, MIPS1 gene mutations further altered these pathways, exacerbating the metabolic disturbances. Our results underscore the intricate network of environmental and genetic interactions influencing soybean seed vigor and underscore the importance of understanding these pathways to enhance agricultural resilience and seed quality in fluctuating climates.

Targeting ACAT1 for Precision Chemo‐Immunoprevention in Lung Cancer

AbstractLung cancer (LC) is a leading cause of cancer‐related deathworldwide, and altered cholesterol metabolism is a hallmark of cancer cells. Acyl‐CoA:cholesterol acyltransferase 1(ACAT1), or Sterol O‐acyltransferase 1 (SOAT1), isa key cholesterol esterification enzyme. Its overexpression promotes tumorprogression by accumulating cholesterol esters. Inhibition of ACAT1 also potentiatesCD8+ T cells medicated anti‐tumor immunity by increasing plasma membranecholesterol level. This study, as the first of its kind, shows the ACAT1/SOAT1 overexpressioncorrelates with poor prognosis in early‐stage lung adenocarcinoma (LUAD) patients.Long‐term treatment with ACAT1 inhibitor avasimibe suppresses tumorigenesis inboth Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growthfactor receptor (EGFR) mutation‐induced LC mouse models without overttoxicity. ACAT1 inhibition reduces tumor cell proliferation, migration, andinvasion and causes G0/G1 cell cycle arrest, while boosting CD8+ T cells'effector function and memory phenotype. Single‐cell RNA sequencing reveals thatACAT1 inhibition downregulates cholesterol biosynthesis and central carbon andnitrogen metabolism pathways in tumor cells, while upregulating genes relatedto oxidative phosphorylation and fatty acid oxidation in CD8+ T cells. Finally, avasimibe improves the efficacy of a human EGFR vaccine in preventing LCprogression. These novel findings suggest potential strategies for cancer preventionand therapy.

Integrated metabolomic and transcriptomic analysis reveals the role of root phenylpropanoid biosynthesis pathway in the salt tolerance of perennial ryegrass

Perennial ryegrass (Lolium perenne) is a widely cultivated forage and turf grass species. Salt stress can severely damage the growth of grass plants. The genome-wide molecular mechanisms of salt tolerance have not been well understood in perennial grass species. In this study, the salt sensitive genotype P1 (PI265351, Chile) and the salt tolerant genotype P2 (PI368892, Algeria) of perennial ryegrass were subjected to 200 mM NaCl, and transcriptomics and metabolomics analyses were performed. A total of 5,728 differentially expressed genes (DEGs) were identified through pairwise comparisons. Antioxidant enzyme encoding genes (LpSOD1, LpCAT1), ion channel gene LpCaC1 and transcription factors (LpERFs, LpHSF1 and LpMYB1) were significantly upregulated in P2, suggesting their involvement in regulating expression of salt-responsive genes for salt tolerance. Functional analysis of DEGs revealed that biosynthesis of secondary metabolites, carbohydrate metabolism and signal transduction were the main pathways in response to salt stress. Weighted gene co-expression network analysis (WGCNA) based on RNA-Seq data showed that membrane transport and ABC transporters were significantly correlated with salt tolerance-related traits. The combined transcriptomics and metabolomics analysis demonstrated that the phenylpropanoid biosynthesis pathway was a major secondary metabolic pathway in the salt response of perennial ryegrass. Especially, the tolerant genotype P2 had greater amounts of upregulated phenylpropanoids, flavonoids and anthocyanins and higher expressions of relevant genes in the pathway than the sensitive genotype P1, indicating a role of phenylpropanoid biosynthesis for perennial ryegrass to adapt to salt stress. The results provided insights into the molecular mechanisms of perennial ryegrass adaptation to salinity and laid a base for genetic improvement of salt tolerance in perennial grass species.

Analysis of Immunosuppression and Antioxidant Damage in Diploid and Triploid Crucian Carp (Carassius auratus) Induced by Saline-Alkaline Environmental Stress: From Metabolomic Insight.

Objectives: The salinization of the water environment worldwide is increasing, which has brought great challenges to the sustainability of fish farming of aquatic animals. Methods: Three NaHCO3 concentration groups (0 mmol/L, 20 mmol/L, and 60 mmol/L) were set up in this study to investigate growth and metabolic differences between diploid and triploid crucian carp under saline-alkaline stresses. Purpose: This study utilized UPLC-QTOF/MS metabolomics to analyze significant metabolites and metabolic pathways in the serum of diploid and triploid crucian carp, exposing them to different NaHCO3 concentrations in saline-alkaline habitats, elucidating the mechanism of their metabolic differences. Results: Results revealed that in the CA20 group, diploid and triploid crucian carp shared 69 differential metabolites, primarily enriched in pathways such as sphingolipid metabolism, glycerophospholipid metabolism, and linoleic acid metabolism. In the CA60 group, 46 differentially metabolites (DMs) were identified, mainly enriched in pathways such as linoleic acid metabolism, unsaturated fatty acid biosynthesis and sphingolipid metabolism. Conclusions: The analysis indicated that under different carbonate-saline-alkaline concentrations, diploid and triploid crucian carp primarily enriched in metabolic pathways such as glycerophospholipid metabolism, sphingolipid metabolism, and unsaturated fatty acid biosynthesis. With increasing carbonate-alkaline concentrations, hemolytic phospholipids associated with cell apoptosis were significantly upregulated and sphingolipid metabolism related to inflammation was more significantly enriched in triploid crucian carp, indicating that triploid crucian carp exhibited significant sensitivity to high carbonate-saline-alkaline stress and poorer carbonate-saline-alkaline tolerance. The results of this study provided a scientific theoretical basis for the later cultivation and aquaculture research of saline-alkaline-tolerant fish species.

Ecological factors affecting toluene biosynthesis from bacterial communities.

As a highly emitted volatile organic compound, toluene significantly contributes to atmospheric pollution and poses high risks to human health. Its anthropogenic source is well understood, while its biosynthesis remains poorly understood, especially by bacterial communities. This research attempted to reveal the temporal changes of bacterial community structure during toluene biosynthesis and identify key bacterial factors using 16S rRNA sequencing gene and machine learning methods. The results showed that toluene biosynthesis by the bacterial consortium nonlinearly increased with phenylacetic acid concentration with the optimal temperature of 25-30°C and pH of 7-7.5. Diversity and richness of the bacterial communities increased over time, as well as the abundance and composition of phyla (e.g. Bacteroidota and Synergistota), families (e.g. Acidaminococcaceae and Oscillospiraceae), species (e.g. Bacteroides and Parabacteroides), and functional genes (e.g. phenylalanine, tyrosine, and tryptophan biosynthesis and fatty acid metabolism). They were significantly related to toluene biosynthesis, of which the Shannon and Simpson indices and the abundances of Synergistaceae, Bacteroidaceae, and Spirochaetaceae species and functional genes related to metabolic pathways, biosynthesis of secondary metabolites, and alanine aspartate and glutamate metabolism were identified as key factors. Findings of this study contributed to new understandings of the underlying mechanisms of toluene biosynthesis by the bacterial community.

Response of human metabolism to ultra-low and high nicotine cigarettes based on urine metabolomics and bioinformatic analysis.

This study aimed to evaluate the metabolomic profiles of urine samples obtained from smokers who smoked cigarettes with low and high nicotine content. Three smokers participated in this study. They were given low-nicotine (LN) cigarettes, and urine was collected at the end of the third day for the LN group. After 1 week of not smoking, they were given high-nicotine (HN) cigarettes, and urine was collected for the HN group. Untargeted metabolomics and bioinformatic analysis methods were used for urine analysis. PCA showed a high degree of similarity between samples within the group and a large distance between samples between groups, indicating a significant difference between the two groups. A total of 1150 significantly differential metabolites were selected between the HN and LN groups, such as cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol-N-glucuronide. Two-way hierarchical clustering analysis also suggested noticeable differences between the two comparison groups Enrichment analysis indicates that the differential metabolites between the two groups were mainly enriched in 19 pathways, such as the protein kinase G (cGMP)-protein kinase G (PKG) signaling pathway, adenosine monophosphate (AMP)-activated protein kinase signaling pathway, mammalian target of rapamycin signaling pathway, and Parkinson's disease. Cigarettes with different nicotine content may alter the metabolism of smokers. A total of 1150 significantly different metabolites were identified between the HN and LN groups, which were mainly enriched in ABC transporters, protein kinase G (cGMP)-protein kinase G (PKG) signaling pathway, caffeine metabolism, and arginine biosynthesis pathways.

Metabolomic analysis reveals an important role of sphingosine 1-phosphate in the development of HFMD due to EV-A71 infection.

Hand, foot, and mouth disease (HFMD) is a serious pediatric infectious disease that causes immeasurable physical and mental health burdens. Currently, there is a lack of information on the mechanisms of HFMD severity and early diagnosis. We performed metabolomic profiling of sera from 84 Enterovirus A71 (EV-A71) infections and 45 control individuals. Targeted metabolomics assays were employed to further validate some of the differential metabolic molecules. We identified significant molecular changes in the sera of HFMD patients compared to healthy controls (HCs). A total of 54, 60, 35, and 62 differential metabolites were screened between mild cases and HCs, severe cases and HCs, severe cases and mild cases, and among the three groups, respectively. These differential metabolites implicated dysregulation of the tricarboxylic acid cycle, alanine, aspartate, and glutamate metabolism, and valine, leucine, and isoleucine biosynthesis. The diagnostic panel based on some overlapped differential metabolites could effectively discriminate severe cases from mild cases with an AUC of 0.912 (95% CI: 0.85-0.97) using the logistic regression model. Next, we found the elevation of serum sphingosine 1-phosphate (S1P) level in EV-A71 infection mice, which was similar to clinical observation. Importantly, after blocking the release of S1P by MK571, the clinical symptoms and survival of mice were significantly improved, involving the reduction of leukocyte infiltration in infected brain tissues. Collectively, our data provided a landscape view of metabolic alterations in EV-A71 infected children and revealed regulating S1P metabolism was an exploitable therapeutic target against EV-A71 infection.

Genetic and biochemical determinants in potentially toxic metals resistance and plant growth promotion in Rhizobium sp LBMP-C04.

The association of bacteria resistant to potentially toxic metals (PTMs) with plants to remove, transfer, or stabilize these elements from the soil is an appropriate tool for phytoremediation processes in metal-contaminated environments. The objective of this study was to evaluate the potential ofRhizobiumsp. LBMP-C04 forphytoremediation processes and plant growth promotion in metal-contaminated soils. Functional annotation allowed us to predict a variety of genes related to PTMs resistance and plant growth promotion in the bacterial genome. Resistance genes are mainly associated with DNA repair, and the import or export of metals in bacterial cells to maintain cell homeostasis. Genes that promote plant growth are related to mechanisms of osmotic stress tolerance, phosphate solubilization, nitrogen metabolism, biological nitrogen fixation, biofilm formation, heat shock responses, indole-3-acetic acid (IAA) biosynthesis, tryptophan, and organic acids metabolism. Biochemical tests indicated thatRhizobiumsp. LBMP-C04 can solubilize calcium phosphate and produce siderophores and IAAin vitroin the presence of the PTMs Cd2+,Cu2+,Cr3+,Cr6+, Zn2+, and Ni2+. Results indicate the possibility of usingRhizobiumsp. LBMP-C04 as a potentially efficient bacterium in phytoremediation processesin environments contaminated by PTMs and simultaneously promote plant growth.

Exploring the mechanism of seed shattering in Psathyrostachys juncea through histological analysis and comparative transcriptomics

BackgroundSeed shattering (SS) negatively impacts seed yield in Psathyrostachys juncea. Understanding and improving the SS trait requires elucidating the regulatory mechanisms of SS and identifying the key genes involved.ResultsThis study presents a comprehensive analysis of the abscission zone (AZ) structures at four developmental stages in two P. juncea genotypes. High-SS P. juncea (H) exhibited a significantly higher SS rate than low-SS P. juncea (L) at all four developmental stages. Anatomical analysis revealed that the degree of lignification in the AZ cell walls is related to the integrity of the abscission structure. The degradation of the AZ in H occurred earlier and was more severe compared to L. At different developmental stages of the AZ, H exhibited higher cellulase and polygalacturonase activities and higher abscisic acid contents compared to L. Conversely, L showed higher lignin, cytokinin, auxin, and gibberellin contents than H. Transcriptomic analysis identified key metabolic pathways related to SS in P. juncea, such as phenylpropanoid biosynthesis, fructose and mannose metabolism, galactose metabolism, and pentose and glucuronate interconversions. The integration of morphological, histological, physiochemical, and metabolic data led to the identification of critical genes, including AUX1, CKX, ABF, GH3, 4CL, CCoAOMT, BGAL, Gal, and PG. The roles of these genes were involved in the regulation of plant hormones and in the synthesis and degradation of cell walls within the AZ.ConclusionsThis study provides an in-depth understanding of the regulatory mechanisms of SS in P. juncea through comparative transcriptomic analysis. The SS in P. juncea may result from the degradation of the cell wall regulated by cell wall hydrolases genes. The genes identified in this study provide a basis for the genetic improvement of SS traits and serve as a reference for research on other grass species.

Exosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptors

Cancer cells acquire the ability to reprogram their phenotype in response to targeted therapies, yet the transition from dormancy to proliferation in drug-resistant cancers remains poorly understood. In prostate cancer, we utilized high-plasticity mouse models and enzalutamide-resistant (ENZ-R) cellular models to elucidate NR2F1 as a key factor in lineage transition and ENZ resistance. Depletion of NR2F1 drives ENZ-R cells into a relative dormancy state, characterized by reduced proliferation and heightened drug resistance, while NR2F1 overexpression yields contrasting outcomes. Transcriptional sequencing analysis of NR2F1-silenced prostate cancer cells and tissues from the Cancer Genome Atlas-prostate cancer and SU2C cohorts indicated exosomes as the most enriched cell component, with pathways implicated in steroid hormone biosynthesis and drug metabolism. Moreover, NR2F1-AS1 forms a complex with SRSF1 to upregulate NR2F1 expression, facilitating its binding with ESR1 to sustain hormonal receptor expression and enhance proliferation in ENZ-R cells. Furthermore, HnRNPA2B1 interacts with NR2F1 and NR2F1-AS1, assisting their packaging into exosomes, wherein exosomal NR2F1 and NR2F1-AS1 promote the proliferation of dormant ENZ-R cells. Our works offer novel insights into the reawaking of dormant drug-resistant cancer cells governed by NR2F1 upregulation triggered by exosome-derived NR2F1-AS1 and NR2F1, suggesting therapeutic potential for phenotype reversal.Graphical

Unraveling the Molecular Mechanisms of Blueberry Root Drought Tolerance Through Yeast Functional Screening and Metabolomic Profiling.

Blueberry plants are among the most important fruit-bearing shrubs, but they have shallow, hairless roots that are not conducive to water and nutrient uptake, especially under drought conditions. Therefore, the mechanism underlying blueberry root drought tolerance should be clarified. Hence, we established a yeast expression library comprising blueberry genes associated with root responses to drought stress. High-throughput sequencing technology enabled the identification of 1475 genes potentially related to drought tolerance. A subsequent KEGG enrichment analysis revealed 77 key genes associated with six pathways: carbon and energy metabolism, biosynthesis of secondary metabolites, nucleotide and amino acid metabolism, genetic information processing, signal transduction, and material transport and catabolism. Metabolomic profiling of drought-tolerant yeast strains under drought conditions detected 1749 differentially abundant metabolites (DAMs), including several up-regulated metabolites (organic acids, amino acids and derivatives, alkaloids, and phenylpropanoids). An integrative analysis indicated that genes encoding several enzymes, including GALM, PK, PGLS, and PIP5K, modulate key carbon metabolism-related metabolites, including D-glucose 6-phosphate and β-D-fructose 6-phosphate. Additionally, genes encoding FDPS and CCR were implicated in terpenoid and phenylalanine biosynthesis, which affected metabolite contents (e.g., farnesylcysteine and tyrosine). Furthermore, genes for GST and GLT1, along with eight DAMs, including L-γ-glutamylcysteine and L-ornithine, contributed to amino acid metabolism, while genes encoding NDPK and APRT were linked to purine metabolism, thereby affecting certain metabolites (e.g., inosine and 3',5'-cyclic GMP). Overall, the yeast functional screening system used in this study effectively identified genes and metabolites influencing blueberry root drought tolerance, offering new insights into the associated molecular mechanisms.