Search Results (1,563)

Per- and polyfluoroalkyl substances (PFASs) are widespread in the environment, bioaccumulate in humans, and lead to disease and organ injury, such as liver steatosis. However, we lack a clear understanding of how these chemicals cause organ-level toxicity. Here, we aimed to analyze PFAS-induced metabolic perturbations in male and female rat livers by combining a genome-scale metabolic model (GEM) and toxicogenomics. The combined approach overcomes the limitations of the individual methods by taking into account the interaction between multiple genes for metabolic reactions and using gene expression to constrain the predicted mechanistic possibilities. We obtained transcriptomic data from an acute exposure study, where male and female rats received a daily PFAS dose for five consecutive days, followed by liver transcriptome measurement. We integrated the transcriptome expression data with a rat GEM to computationally predict the metabolic activity in each rat’s liver, compare it between the control and PFAS-exposed rats, and predict the benchmark dose (BMD) at which each chemical induced metabolic changes. Overall, our results suggest that PFAS-induced metabolic changes occurred primarily within the lipid and amino acid pathways and were similar between the sexes but varied in the extent of change per dose based on sex and PFAS type. Specifically, we identified that PFASs affect fatty acid-related pathways (biosynthesis, oxidation, and sphingolipid metabolism), energy metabolism, protein metabolism, and inflammatory and inositol metabolite pools, which have been associated with fatty liver and/or insulin resistance. Based on these results, we hypothesize that PFAS exposure induces changes in liver metabolism and makes the organ sensitive to metabolic diseases in both sexes. Furthermore, we conclude that male rats are more sensitive to PFAS-induced metabolic aberrations in the liver than female rats. This combined approach using GEM-based predictions and BMD analysis can help develop mechanistic hypotheses regarding how toxicant exposure leads to metabolic disruptions and how these effects may differ between the sexes, thereby assisting in the metabolic risk assessment of toxicants. Full article

Atherosclerosis is a multifactorial, chronic inflammatory disorder characterized by the progressive accumulation of plaque within the arterial wall. Recent research has highlighted the pivotal role of bioactive peptides in modulating vascular homeostasis and inflammation. Among these, salusin-α and salusin-β have emerged as critical regulators of atherogenesis. These peptides are generated via differential proteolytic processing of preprosalusin: an amino acid precursor encoded by the torsin family 2 member A gene. Despite their common origin, salusin-α and salusin-β exhibit divergent biological activities. Salusin-β promotes vascular inflammation by enhancing oxidative stress, activating the nuclear factor kappa B signaling pathway, and upregulating proinflammatory cytokines as well as adhesion molecules, and it also facilitates foam cell formation by increasing the expression of acyl-CoA/cholesterol acyltransferase 1 and scavenger receptors, thereby contributing to plaque progression. In contrast, salusin-α appears to exert protective, anti-inflammatory, and anti-atherogenic effects by increasing the expression of the interleukin-1 receptor antagonist and inhibiting key proinflammatory mediators. Additionally, these peptides modulate the proliferation of vascular smooth muscle cells and fibroblasts, with salusin-β promoting cellular proliferation and fibrosis via calcium and 3′,5′-cyclic adenosine monophosphate-mediated pathways, while the role of salusin-α in these processes is less well defined. Altered plasma levels of salusins have been correlated with the presence and severity of atherosclerotic lesions, suggesting their potential as diagnostic biomarkers and therapeutic targets. This review provides a comprehensive overview of biosynthesis, tissue distribution, and dual roles of salusins in vascular inflammation and remodeling, emphasizing their significance in the pathogenesis and early detection of atherosclerotic cardiovascular disease. Full article

Background: Oxidative stress and inflammation are major drivers of metabolic inflammatory diseases, and natural antioxidant peptides represent promising therapeutic agents. Antioxidant peptides derived from Cyperus protein (CAOP) exhibit high digestibility and bioavailability, but their antioxidant and anti-inflammatory mechanisms remain unclear. Methods: We employed in vitro experiments, non-targeted metabolomics, peptide omics, and molecular docking techniques to explore how CAOP exerts dual antioxidant and anti-inflammatory effects. Results: The in vitro experiments showed that in LPS-induced RAW264.7 cells, CAOP not only significantly increased the levels of superoxide dismutase (SOD) and catalase (CAT) but also significantly reduced the gene expression and secretion of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), as well as the phagocytic ability of cells. Metabolomics studies indicate that CAOP protects cells from LPS-induced damage by enhancing intracellular glutathione metabolism pathways, glyceraldehyde and dicarboxylic acid metabolism pathways, pantothenic acid and coenzyme A biosynthesis metabolism pathways, and thiamine metabolism pathways while inhibiting the ferroptosis pathway. CAOP was purified using Sephadex G-25 column chromatography, and its amino acid sequence was determined using LC-MS/MS technology. Subsequently, 25 peptide sequences were screened through bioinformatics analysis. These peptides can target Keap1. Among them, DLHMFVWS (-ICE = 62.8072) and LGHPWGNAPG (-ICE = 57.4345) are most likely to activate the Nrf2-Keap1 pathway. Conclusions: CAOP exerts antioxidant and anti-inflammatory effects by regulating the key metabolic networks, demonstrating its therapeutic promise for associated with oxidative damage and metabolic inflammation disorders. Full article

Mastitis is a common disease for dairy cows that exerts tremendously detrimental impacts on the productivity of cows and economic viability of pasture. Dihydromyricetin (DMY) is a flavonoid monomeric compound that possesses anti-inflammatory and antioxidant activity. This study aimed at dissecting the effects of DMY on the lactation performance, blood parameters, gut microbiota, and metabolite profiles of dairy cows with subclinical mastitis (SM). The results showed that dietary supplementation with DMY resulted in a reduction in milk somatic cell count, an increase in serum T-AOC and CAT activity, as well as a decrease in serum MDA content. DMY significantly enhanced the prevalence of Coprococcus and Roseburia and reduced the proportion of Cyanobacteria, Proteobacteria, and Dehalobacterium. The amino acid degradation, antibiotic resistance, and O-antigen building blocks biosynthesis (E. coli) capacity of gut microbes were notably diminished by DMY supplementation in cows with SM. Moreover, fecal and plasma metabolomic analysis revealed that DMY intervention reduced the abundance of pro-inflammatory metabolites including arachidonic acid analogues, ω-6 PUFA, and structural components of bacteria. Nevertheless, the levels of anti-inflammatory and antioxidant metabolites involving secondary bile acids, antioxidant vitamins, specific amino acid analogues, etc. were elevated by DMY administration. Overall, DMY might ameliorate SM via enhancing antioxidant capacity and improving the structure of the hindgut microbial community and metabolite profiles in dairy cows. These findings underscore the potential of DMY as a valuable dietary supplement for the improvement of mammary inflammatory diseases in dairy cows. Full article

The hydrocoral Millepora complanata (fire coral) plays a critical role in reef structure and relies on a symbiotic relationship with Symbiodiniaceae algae. Environmental stressors derived from climate change, such as UV radiation and elevated temperatures, disrupt this symbiosis, leading to bleaching and threatening reef survival. To gain insight into the thermal stress response of this reef-building hydrocoral, this study investigates the proteomic response of M. complanata to bleaching during the 2015–2016 El Niño event. Fragments from non-bleached and bleached colonies of the hydrocoral M. complanata were collected from a coral reef in the Mexican Caribbean, and proteomic extracts were analyzed using nano-liquid chromatography–tandem mass spectrometry (nano-LC-MS/MS). Uni- and multivariate analyses were applied to identify significant differences in protein abundance. A total of 52 proteins showed differential abundance, including 24 that showed increased expression and 28 whose expression decreased in bleached fragments. Differentially abundant proteins were associated with amino acid biosynthesis, carbohydrate metabolism, cytoskeleton organization, DNA repair, extracellular matrix composition, redox homeostasis, and protein modification. These molecular alterations reflect critical physiological adaptations that may influence stress sensitivity or tolerance in hydrocorals. The findings indicate that heat stress induces molecular responses involving protein refolding, enhanced vesicular transport, cytoskeletal reorganization, and modulation of redox activity. This contributes to a deeper understanding of the molecular mechanisms underlying bleaching in reef-building hydrozoans and broadens current knowledge beyond the more extensively studied anthozoan corals. Full article

Lambda-cyhalothrin (LCY), a widely used pyrethroid insecticide, is toxic to bees—vital pollinators experiencing global declines; however, its molecular effects during early development remain poorly understood. We investigated the molecular mechanisms underlying chronic sublethal exposure to LCY in the larval and adult stages. Larvae were exposed to LCY (0.004 µg active ingredient/larva), with four groups examined: solvent-treated larvae group (SLG), solvent-treated adult group (SAG), LCY-treated larvae group (LLG), and LCY-treated adult group (LAG). We identified 1128 and 168 significantly altered genes in LLG vs. SLG and LAG vs. SAG, respectively, with 125 larval- and 25 adult-specific DEGs, indicating stage-dependent toxicity. LCY dysregulated processes such as cuticle formation, sulfur metabolism, oxidoreductase activity, and neuropeptide signaling in larvae, while adults exhibited altered redox balance, peptide receptor signaling, and monoamine transport. Neuroactive signaling disruptions were observed in both stages, with additional effects on motor function, amino acid metabolism, and glycolysis in larvae; whereas adults exhibited altered lipid biosynthesis and energy metabolism. Downregulated genes involved in chitin metabolism and antioxidant defenses in larvae suggested compromised exoskeletal integrity and increased vulnerability. Overall, our findings highlight the long-term molecular consequences of early-life exposure and emphasize the need for safer pesticide practices to protect pollinator health. Full article

Obesity and related metabolic disorders are major global health challenges. Postbiotics, such as heat-inactivated probiotics, have attracted attention for their improved safety, stability, and potential metabolic benefits compared to live probiotics. However, the comparative anti-obesity effects and mechanisms of live versus heat-inactivated Lactiplantibacillus plantarum FRT4 remain unclear, so this study systematically evaluated their effects and mechanisms in high-fat-diet-induced obese mice. Mice received oral administration of live or heat-inactivated FRT4 (prepared by heating in a water bath at 80 °C for 5 min) for 16 weeks. Comprehensive analyses included metabolic profiling, histological evaluation, serum and liver biomarkers, gut microbiota composition, liver metabolomics, and transcriptomics. Both live and inactivated FRT4 significantly reduced body weight gain, adiposity, hepatic steatosis, and dyslipidemia, with inactivated FRT4 exhibiting comparable or superior efficacy. Notably, inactivated FRT4 restored gut microbiota composition, increased short-chain fatty acid production, and regulated hepatic metabolic pathways. Multi-omics analyses revealed modulation of lipid biosynthesis, amino acid metabolism, and energy utilization pathways. Specifically, the “biosynthesis of unsaturated fatty acids” pathway was downregulated in metabolomics and significantly enriched in transcriptomics, highlighting its central role in FRT4M-mediated metabolic reprogramming. These findings demonstrate that heat-inactivated Lp. plantarum FRT4 exerts systemic anti-obesity effects via gut–liver axis modulation, supporting its potential as a promising postbiotic intervention for obesity and metabolic dysfunction. Full article

Off-white or yellowish shoots are common in tea plants (Camellia sinensis L.), and such albino variations are often accompanied by metabolic reprogramming, including increased contents of amino acids and lower levels of polyphenols. Nonetheless, the molecular mechanisms that underlie these albino variations remain to be fully clarified. Here, we examined the ultrastructural characteristics of novel, naturally occurring, yellowish mutated tea leaves and performed metabolomic analyses on green and albino leaves and stems. Then, transcriptomic analyses were also conducted on green and albino leaves to investigate the mechanistic basis of the albino variation. As expected, the cells of albino tea leaves contained fewer and smaller chloroplasts with disorganized thylakoids and smaller starch granules. Widely targeted metabolomics analysis revealed 561 differentially abundant metabolites between green and albino leaves and stems, but there was little difference between green and albino stems. Then, RNA sequencing of green and albino leaves revealed downregulation of genes associated with light harvesting and photosynthesis, and integration of the metabolomic and transcriptomic results indicated that biosynthesis of aromatic amino acids (AAAs) was strongly upregulated in albino leaves. To gain additional insight into the molecular basis of the increased AAA levels, Oxford Nanopore long-read sequencing was performed on green and albino leaves, which enabled us to identify differences in long non-coding RNAs (lncRNAs) and alternatively spliced transcripts between green and albino leaves. Interestingly, the amino acid biosynthesis genes arogenate dehydratase/prephenate dehydratase (ADT) and serine hydroxymethyltransferase (SHMT) were highlighted in the lncRNA and alternative splicing analyses, and the transcription factor genes PLATZ, B3 Os04g0386900, and LRR RLK At1g56140 showed significant changes in both expression and alternative splicing in albino leaves. Together, our data suggest that biosynthesis of AAAs might be crucial for albino mutations in tea plants and could be coordinated with the regulation of lncRNAs and alternative splicing. This is a complex regulatory network, and further exploration of the extensive metabolic reprogramming of albino tea leaves will be beneficial. Full article

Continuous planting results in a higher occurrence rate of oriental melon Fusarium wilt caused by Fusarium oxysporum f. sp. melonis (FOM), and treatment with Trichoderma can considerably alleviate the incidence of disease. However, the tripartite interaction mechanisms among T. harzianum–melon–rhizosphere microorganisms remain poorly understood in current research. Pot experiments elucidate the growth-promoting, antagonistic, and rhizosphere-regulating effects of T. harzianum on oriental melon. The experiment consisted of two treatments: (1) water control (CK), and (2) T. harzianum inoculation (MM) with three repetitions per treatment. Illumina high-throughput sequencing was employed to analyze the microbial community and associated metabolic pathways. Additionally, a comprehensive correlation analysis clarified how T. harzianum-modulated physiological factors regulate soil microbial communities to enhance melon resistance to FOM. T. harzianum inoculation significantly promoted plant growth, decreased the incidence rate of Fusarium wilt by 41.85%, and increased rhizosphere nitrate-N, pH, EC, and soil enzyme activity (e.g., sucrose and alkaline phosphatase). Notably, T. harzianum inoculation altered the rhizosphere microbial community’s relative abundance and structure, with the most striking changes in the fungal community. Principal coordinate analysis showed this fungal restructuring accounted for 44.9% of total community variation (37% from PCo1, 7.9% from PCo2). Soil-borne pathogens (e.g., Fusarium, Verticillium, Phytophthora) decreased in relative abundance with the inoculation of T. harzianum. Meanwhile, the microbial community shifted from a “fungal-dominated” to “bacterial-dominated” state: fungal proportion decreased by 9.47% (from 23.95% in CK to 14.48% in MM), while bacterial proportion increased by 9.47% (from 76.05% in CK to 85.52% in MM). Microbial abundance shifts primarily impacted amino acid and cofactor biosynthesis metabolic pathways. The application of T. harzianum modified the soil environment, restructuring microbial communities through these changes, which in turn regulated microbial metabolic pathways, creating a soil environment conducive to melon growth and thereby enhancing oriental melon resistance to FOM, while mitigating the obstacles of continuous cropping. Full article

Soil salinization limits the growth of agricultural crops in the world, requiring the use of methods to increase the tolerance of agricultural crops to salinity–alkali stress. Arbuscular mycorrhizal fungi (AMF) enhance plant stress adaptation through symbiosis and offer a promising strategy for remediation. However, in non-model crops such as oat (Avena sativa L.), research has mainly focused on physiological assessments, while the key genes and metabolic pathways involved in AMF-mediated growth and saline–alkali tolerance remain unclear. In this study, we employed integrated multi-omics and physiological analyses to explore the regulatory mechanisms of AMF in oats under normal and saline–alkali stress. The results indicated that AMF symbiosis significantly promoted oat growth and physiological performance under both normal and saline–alkali stress conditions. Compared to the non-inoculated group under normal conditions, AMF increased plant height and biomass by 8.5% and 15.3%, respectively. Under saline–alkali stress, AMF enhanced SPAD value and relative water content by 16.7% and 7.3%, reduced MDA content by 35.8%, increased soluble protein by 21.8%, and decreased proline by 13.3%. In addition, antioxidant enzyme activities (SOD, POD, and CAT) were elevated by 18.4%, 18.2%, and 14.8%, respectively. Transcriptomic analysis revealed that AMF colonization under saline–alkali stress induced about twice as many differentially expressed genes (DEGs) as under non-saline–alkali stressed conditions. These DEGs were primarily associated with Environmental Information Processing, Genetic Information Processing, and Metabolic Processes. According to metabolomic analysis, a total of 573 metabolites were identified across treatments, mainly comprising lipids (29.3%), organic compounds (36.8%), and secondary metabolites (21.5%). Integrated multi-omics analysis indicated that AMF optimized energy utilization and antioxidant defense by enhancing phenylpropanoid biosynthesis and amino acid metabolism pathways. This study provides new insights into how AMF may enhance oat growth and tolerance to saline–alkali stress. Full article

Lyophyllum decastes, a common edible mushroom, is prized for its exceptional taste and rich nutritional composition. The concentrations of amino acids and polysaccharides in the fruiting body exhibited a dynamic increase throughout development, reaching their highest levels in the maturation stages, with values of 45,107.39 μg/g and 13.66 mg/g, respectively. Integrated metabolomic and transcriptomic analyses uncovered dynamic metabolites changing during the transition from vegetative growth to reproductive development. Several differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) were identified, associated with secondary metabolite, amino acid, and carbohydrate metabolism. The shift in metabolites was linked to key nutrient synthesis, explaining the abundant production of amino acids and polysaccharides at maturity. Our results provide novel insights into the developmental biology of L. decastes, demonstrating that this mushroom is a valuable source of bioactive compounds and contributing to the optimization of cultivation strategies, as well as improving research into its application as a functional food and nutraceutical source. Full article

Forest ginseng (FG) is a rare medicinal and culinary plant in China, and its drying quality is heavily dependent on the drying method. This study investigated the effects of traditional hot air drying (HAD) and the self-developed negative-pressure circulating airflow-assisted desiccator drying (PCAD) method on the quality of FG using metabolomics and enzyme activity. The results revealed that the enzyme activities of dried FG were reduced considerably. PCAD preserved higher enzyme activity than HAD. Metabolomics data demonstrate that HAD promotes the formation of primary metabolites (amino acids, lipids, nucleotides, etc.), whereas PCAD promotes the formation of secondary metabolites (terpenoids, phenolic acids, etc.). A change-transformation network was built by combining the metabolites listed above and their biosynthetic pathways, and it was discovered that these biosynthetic pathways were primarily associated with the mevalonate (MVA) pathway, lipid metabolism, phenylpropane biosynthesis, and nucleotide metabolism. It is also believed that these findings are related to the chemical stimulation induced by thermal degradation and the ongoing catalysis of enzyme responses to drought stress. The facts presented above will give a scientific basis for the selection of FG drying processes, as well as helpful references for increasing the nutritional quality of processed FG. Full article

Antibiotic resistance is considered to be one of the most complex health obstacles of our time. Methicillin-resistant Staphylococcus aureus (MRSA) represents a global health challenge due to its broad treatment resistance capacity, resulting in high mortality rates. The shikimate pathway (SP) is responsible for the biosynthesis of chorismate from glycolysis and pentose phosphate pathway intermediates. This pathway plays a crucial role in producing aromatic amino acids, folates, ubiquinone, and other secondary metabolites in bacteria. Notably, SP is absent in humans, which makes it a specific and potential therapeutic target to explore for discovering new antibiotics against MRSA. The present study characterized in vitro and in silico natural products as inhibitors of the shikimate dehydrogenase from methicillin-resistant S. aureus (SaSDH). The results showed that, from the set of compounds studied, phloridzin, rutin, and caffeic acid were the most potent inhibitors of SaSDH, with IC₅₀ values of 140, 160, and 240 µM, respectively. Furthermore, phloridzin showed a mixed-type inhibition mechanism, whilst rutin and caffeic acid showed non-competitive mechanisms. The structural characterization of the SaSDH–inhibitor complex indicated that these compounds interacted with amino acids from the catalytic site and formed stable complexes. In biological activity studies against MRSA, caffeic acid showed an MIC of 2.2 mg/mL. Taken together, these data encourage using these compounds as a starting point for developing new antibiotics based on natural products against MRSA. Full article

Ericoid mycorrhizal fungi (EMF) enhance plant fitness and metabolic regulations in nutrient-poor soils, though the mechanisms diving these interactions require further elucidation. This study investigated the physiological and metabolic responses of blueberry seedlings following 2- and 3-weeks inoculation with Oidiodendron maius H14. The results indicated that EMF could significantly increases plant biomass, improve the accumulation of osmoregulatory substances in leaves. Additionally, the colonization rate of EMF are 26.18% and 30.22% after 2- and 3-weeks, respectively. The Metabolomics analysis identified 758 (593 up- and 165 down-regulated) and 805 (577 up- and 228 down-regulated) differential metabolites in roots at 2- and 3-weeks inoculation with O. maius H14, respectively. KEGG pathway annotation revealed that O. maius H14 triggered various amino acid metabolism pathways, including tryptophan metabolism and arginine and proline metabolism. These findings suggested that O. maius H14 stimulated root-specific biosynthesis of growth-promoting compounds and antimicrobial compounds. Concomitant downregulation of stress-associated genes and upregulation of glutamine synthetase suggest EMF modulates host defense responses to facilitate symbiosis. Thus, our results demonstrated that O. maius H14 orchestrates a metabolic reprogramming in blueberry roots, enhancing growth and stress tolerance through coordinated changes in primary and specialized metabolism, which could inform strategies for improving symbiosis and metabolic engineering in horticultural practices. Full article

Background/Objectives: Medulloblastoma is the most common malignant brain tumor in children and comprises four molecular subtypes—WNT, SHH, Group 3, and Group 4—each with distinct genetic, epigenetic, and metabolic features. Increasing evidence highlights the critical role of metabolic reprogramming and epigenetic alterations in driving tumor progression, therapy resistance, and clinical outcomes. This review aims to explore the interplay between metabolic and epigenetic mechanisms in medulloblastoma, with a focus on their functional roles and therapeutic implications. Methods: A comprehensive literature review was conducted using PubMed and relevant databases, focusing on recent studies examining metabolic pathways and epigenetic regulation in medulloblastoma subtypes. Particular attention was given to experimental findings from in vitro and in vivo models, as well as emerging preclinical therapeutic strategies targeting these pathways. Results: Medulloblastoma exhibits metabolic adaptations such as increased glycolysis, lipid biosynthesis, and altered amino acid metabolism. These changes support rapid cell proliferation and interact with the tumor microenvironment. Concurrently, epigenetic mechanisms—including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation—contribute to tumor aggressiveness and treatment resistance. Notably, metabolic intermediates often serve as cofactors for epigenetic enzymes, creating feedback loops that reinforce oncogenic states. Preclinical studies suggest that targeting metabolic vulnerabilities or epigenetic regulators—and particularly their combination—can suppress tumor growth and overcome resistance mechanisms. Conclusions: The metabolic–epigenetic crosstalk in medulloblastoma represents a promising area for therapeutic innovation. Understanding subtype-specific dependencies and integrating biomarkers for patient stratification could facilitate the development of precision medicine approaches that improve outcomes and reduce long-term treatment-related toxicity in pediatric patients. Full article