Search Results (84)

This study investigated the systemic metabolic effects of feeding a Fusarium-contaminated diet to early-lactation Holstein cows, with or without a mycotoxin-deactivating product (MDP; Mycofix^® Plus, BIOMIN Holding GmbH, Tulln, Austria). Thirty cows were divided into three dietary groups: a mildly contaminated control (CTR), a moderately contaminated diet containing zearalenone and deoxynivalenol (MTX), and the same contaminated diet supplemented with MDP. Plasma collected at 56 days in milk was analyzed by untargeted ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS), and multivariate models identified discriminant metabolites and pathways. MTX-fed cows showed alterations in sphingolipid metabolism, including accumulation of ceramide (t18:0/16:0), lactosylceramide, and sphinganine 1-phosphate, consistent with ceramide synthase inhibition and lipid remodeling stress. Increases in estradiol, estrone, and cholesterol sulfate suggested endocrine disruption, while elevated 8-oxo-dGMP indicated oxidative DNA damage. MDP supplementation mitigated these alterations, reducing sphingolipid intermediates, modulating tryptophan and glycerophospholipid pathways, and lowering oxidative stress markers. Metabolites such as riboflavin, pipecolic acid, and N-acetylserotonin could be likely associated with an improved mitochondrial function and redox homeostasis, although future studies are required to confirm this hypothesis. Additionally, MDP-fed cows exhibited distinct shifts in pyrimidine and nucleotide metabolism. Overall, MDP effectively counteracted Fusarium-related metabolic disturbances, supporting its protective role in maintaining lipid balance, hormonal stability, oxidative control, and metabolic resilience. Full article

Marek’s disease (MD), induced by the highly contagious Marek’s disease virus (MDV), remains a significant challenge to global poultry health despite extensive vaccination efforts. This study employed integrated transcriptomic and metabolomic analyses to investigate liver responses in naturally MDV-infected Wenchang chickens during late infection stages. RNA sequencing identified 959 differentially expressed genes (DEGs) between the infected and uninfected groups. Functional enrichment analysis demonstrated that these DEGs were primarily associated with canonical pathways related to metabolism and cellular processes, including lipid, carbohydrate, and amino acid metabolism, as well as the p53 signaling pathway, cell cycle, and apoptosis. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) detected 561 differentially expressed metabolites (DEMs), showing near-significant enrichment (p = 0.069) in phenylalanine metabolism. Integrated analysis of transcriptomics and metabolomics data highlighted that critical gene–metabolite pairs such as SGPL1-palmitaldehyde–sphinganine-1-phosphate and ME1-NADP+–malic acid potentially mediate functional crosstalk between sphingolipid metabolism and cellular redox homeostasis during viral oncogenesis. This comprehensive mapping of regulatory networks provides insights into host–virus interactions during MDV pathogenesis, offering potential applications in immunomodulation approaches, targeted therapeutic strategies, and vaccine adjuvant development. Full article

Background/Objectives: Individuals with childhood obesity exhibit significant metabolic heterogeneity, necessitating precise biomarkers for risk stratification and assessment. This multi-omics investigation characterizes metabolic and microbial signatures underlying divergent metabolic phenotypes in the context of pediatric obesity. Methods: We analyzed 285 Chinese children (5–7 years) stratified into five groups: wasting (WAS, n = 55), metabolically healthy/unhealthy and normal weight (MHWH, n = 54; MUWH, n = 67), and metabolically healthy/unhealthy obesity (MHO, n = 36; MUO, n = 73). Untargeted metabolomics (Orbitrap ID-X Tribrid™) and 16S rRNA sequencing were integrated with multivariate analyses (OPLS-DA with VIP > 1, FDR < 0.05; Maaslin 2 with TSS normalization and BH correction, FDR < 0.10). Results: Analysis identified 225 differential metabolites and 12 bacterial genera. The proportion of steroids and their derivatives among differential metabolites in the MUO/MHO group was significantly lower than that in the OVOB/NOR and OVOB/WAS groups (2.12% vs. 7.9–14.1%). MUO displayed elevated C17 sphinganine and LysoPC (O-18:0) levels but reduced PI (16:0/14:1) levels. In contrast, OVOB showed upregulated glycerol phospholipids (LPCs and PSs) and downregulated PE species (e.g., PE(16:0/16:0)) as well as gut microbiota dysbiosis characterized by a higher Firmicutes/Bacteroidetes (F/B) ratio (2.07 vs. 1.24 in controls, p = 0.009) and reduced α diversity (Ace index, Chao1 index, and Shannon index values were lower in the OVOB group, Shannon index: 2.96 vs. 3.45, p = 0.03). SCFA-producing genera were negatively correlated with the OVOB group, while positively associated with PE(16:0/16:0). Internal validation showed differential metabolites had potential predictive efficacy for MUO/MHO (AUC = 0.967) and OVOB/NOR (AUC = 0.888). Conclusions: We identified distinct lipid disruptions characterizing obesity subtypes, including steroid/terpene deficits and sphingolipid/ether lipid dysregulation in the MUO/MHO groups as well as phospholipid imbalance (↑LPC/PS↓PE) in the OVOB/NOR groups. The gut microbiota exhibited a profile characterized by low diversity, an increased F/B ratio, and a reduced abundance of SCFA-producing genera. These findings suggest potential biomarkers for childhood obesity stratification, though further validation is warranted. Full article

Measles, hepatitis C, and COVID-19 are significant human diseases caused by RNA viruses. While vaccines exist to prevent infections, there are a small number of currently available therapeutic agents that can effectively treat these diseases after infection occurs. This study explores a new therapeutic strategy using a small molecule designated polyprenyl immunostimulant (PI) to increase innate immune responses and combat viral infections. Using a multi-disciplinary approach, this study quantifies the effects of PI in mice and THP-1 cells using flow cytometry to identify immune phenotypic markers and mass spectroscopy to monitor the metabolomic profiles of immune cells perturbed by PI treatment. The metabolomic studies identified that sphinganine and ceramide, which are precursors of sphingosine-1-phosphate (S1P), were the common metabolites upregulated in THP-1 and mice blood. Sphingosine-1-phosphate can mediate the trafficking of T cells, whereas ceramide can signal the activation and proliferation of T cells, thereby modulating the mammalian host’s immunity. To demonstrate proof-of-principle, a case study was conducted to examine the benefit of administering PI to improve the outcomes of a feline co-infected with two distinct RNA viruses—feline leukemia virus and feline infectious peritonitis virus. Both viruses produce deadly symptoms that closely resemble RNA viruses that infect humans. The results identify quantifiable cellular and metabolic markers arising from PI treatment that can be used to establish a platform measuring the efficacy of PI in modulating the innate immune system. Full article

The gut–liver axis is essential in animal disease and health. However, the role of the gut–liver axis in the anti-disease mechanism of disease-resistant grass carp (DRGC) derived from the backcross of female gynogenetic grass carp (GGC) and male grass carp (GC) remains unclear. This study analyzed the changes in gut histopathology, fecal intestinal microflora and metabolites, and liver transcriptome between GC and DRGC. Histological analysis revealed significant differences in the gut between DRGC and GC. In addition, microbial community analyses indicated that hybridization induced gut microbiome variation by significantly increasing the proportion of Firmicutes and Bacteroidota in DRGC. Metabolomic data revealed that the hybridization-induced metabolic change was probably characterized by being related to taurocholate and sphinganine in DRGC. Transcriptome analysis suggested that the enhanced disease resistance of DRGC was primarily attributed to immune-related genes (SHMT2, GOT1, ACACA, DLAT, GPIA, TALDO1, G6PD, and FASN). Spearman’s correlation analysis revealed a significant association between the gut microbiota, immune-related genes, and metabolites. Collectively, the gut–liver axis, through the interconnected microbiome–metabolite–gene pathway, may play a crucial role in the mechanism of greater disease resistance in DRGC, offering valuable insights for advancing the grass carp cultivation industry. Full article

Background/Objectives: The objective of this study was to analyze the profiles of sphingosine (Sph), sphinganine (SPA), sphingosine-1-phosphate (S1P), and ceramides (C14 Cer, C16 Cer, C18:1 Cer, C18 Cer, C20 Cer, C22 Cer, C24:1 Cer, and C24 Cer), along with caspases (CAS-3, CAS-6, and CAS-9), in serum and in the periosteum of the maxilla and mandible in patients with dentofacial deformities undergoing treatment with titanium fixations (miniplates and miniscrews). Methods: The study group comprised 20 patients who underwent bilateral jaw osteotomy due to dentofacial deformities. The osteotomy segments were stabilized with titanium alloy miniplates and screws. The control group consisted of 20 patients who had not yet received surgical treatment for maxillofacial defects. Results: Sphinganine (SPA) and ceramide C22 (C22 Cer) were the only compounds found to be significantly elevated in the serum of the study group compared to the control group. The concentrations of Sph, SPA, C14 Cer, C16 Cer, C18 1 Cer, C18 Cer, C22 Cer, C24 1 Cer, C24 Cer, and S1P were significantly lower in the maxillary periosteum of patients in the study group compared to those in the control group. The concentration of C20 Cer was significantly higher in the maxillary periosteum of patients in the study group compared to the control group. In contrast, the concentrations of Sph, SPA, C14 Cer, C16 Cer, C18 1 Cer, C22 Cer, C24 1 Cer, and C24 Cer were significantly lower in the mandibular periosteum of the study group compared to the control group. The concentrations of C20 Cer and S1P were significantly elevated in the mandibular periosteum of patients in the study group compared with the control group. The activity of CAS-3 was significantly higher in the mandibular periosteum of patients in the study group compared to those in the control group. Conclusions: Titanium fixations induce local changes in the sphingolipid profile within the periosteum of the maxilla and mandible, while no systemic impact on this metabolism was observed. Full article

Background: The role of the indoor microbiome in sick building syndrome (SBS) is well-recognized, yet prior studies have been limited to single-center analyses, limiting a broader understanding and applicability of their findings. Methods: We conducted a multicenter indoor microbiome and metabolome investigation for SBS, involving 1139 middle school students across three regions in Malaysia (Johor Bahru, Terengganu, and Penang). Using high-throughput amplicon sequencing and untargeted LC-MS, indoor microbiome and metabolites were characterized from classroom dust samples. Results: The study found that the prevalence of SBS symptoms was high across all three centers (51.0% to 54.6%). Environmental characteristics, including indoor NO₂ and CO₂ concentrations and total weight of indoor dust, were positively associated with SBS (p < 0.01, linear regression). Curtobacterium in Terengganu was negatively associated with SBS, and Clostridium perfringens in Johor Bahru was positively associated with SBS (p < 0.01, FDR < 0.05). Whereas all identified fungal taxa, including an uncharacterized uc_f_Auriculariaceae_sp., Duportella kuehneroides, and Wallemia mellicola, were positively associated with SBS (p < 0.01, FDR < 0.05) in Johor Bahru and Terengganu. Mediation analysis revealed that the adverse health effects of NO₂ on SBS were partially mediated by the increased abundance of uc_f_Auriculariaceae_sp. (p < 0.05, total effect mediated 51.40%). Additionally, potential protective metabolites (S-adenosylmethionine, N-acetylserotonin, sphinganine, 4-hydroxy-2-quinolone, and (2E,4Z,8E)-Colneleic acid) were mainly derived from environmental microorganisms, conferring protective effects against nasal symptoms and tiredness. In contrast, synthetic chemicals were associated with higher SBS symptoms, inducing eye and nasal symptoms. Conclusions: This study emphasizes both the significance of fostering a balanced indoor microbiome/metabolite and the necessity to reduce exposure to deleterious substances, providing new insights for future targeted intervention strategies. Full article

Background: Cigarette smoking is a leading cause of preventable mortality, largely due to the absence of effective, non-invasive biomarkers for early disease detection. Profiling serum metabolomics to identify metabolic changes holds the potential to accelerate the detection process and identify individuals at risk of developing smoking-related diseases. Objectives: This study investigated the biochemical and metabolomic changes induced by nicotine exposure, with a focus on disruptions in amino acid, lipid, and carbohydrate metabolism. Methods: Liquid chromatography–tandem mass spectrometry (LC-MS/MS) was employed to observe significant disruptions in lipid and amino acid metabolism, along with alterations in key metabolic pathways. A total of 400 smokers and 100 non-smokers were included to evaluate the biomarkers related to insulin resistance, blood lipid profile, inflammation, and kidney and liver function. Results: The results demonstrated significantly elevated (p < 0.05) levels of glycemic markers in smokers, including fasting blood glucose; glycated hemoglobin (HbA1c); and inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP). Smokers also exhibited dyslipidemia, with increased total cholesterol (154.888 ± 35.565) and LDL levels (117.545 ± 24.138). Impaired liver and kidney function was evident, with significantly higher levels (p < 0.05) of AST, ALP, ALT, blood urea nitrogen, and creatinine in smokers. A total of 930 metabolites were identified, of which 343 exhibited significant alterations (p < 0.05) in smokers compared to non-smokers. Among these, 116 metabolites were upregulated, and 127 were downregulated. Metabolomic pathway analysis revealed eight significant pathways. The study also identified three lipid metabolites specific to smokers and seven unique to non-smokers. Through LC-MS/MS, fragments of phenylalanine, tryptophan, valine, histidine, carnitine, and sphinganine were detected. Several lipidomic changes associated with insulin resistance and cardiovascular complications were observed. Cadmium (Cd) levels were higher in smokers than non-smokers (1.264 ppb vs. 0.624 ppb) and showed a strong negative correlation (R² = 0.8061, p-value = 0.015) with serum zinc (Zn), likely due to Cd displacing Zn in proteins and causing nephrotoxicity through accumulation. Conclusions: This study highlights the distinct metabolic disruptions caused by smoking that could serve as potential biomarkers for the early detection of metabolic diseases. It emphasizes the importance of metabolomics in identifying systemic indicators of smoking-related health issues, providing new opportunities for preventive and therapeutic interventions. Full article

Sphingolipidomic mass spectrometry has provided valuable information—and surprises—about sphingolipid structures, metabolism, and functions in normal biological processes and disease. Nonetheless, many noteworthy compounds are not routinely determined, such as the following: most of the sphingoid bases that mammals biosynthesize de novo other than sphingosine (and sometimes sphinganine) or acquire from exogenous sources; infrequently considered metabolites of sphingoid bases, such as N-(methyl)_n-derivatives; “ceramides” other than the most common N-acylsphingosines; and complex sphingolipids other than sphingomyelins and simple glycosphingolipids, including glucosyl- and galactosylceramides, which are usually reported as “monohexosylceramides”. These and other subspecies are discussed, as well as some of the circumstances when they are likely to be seen (or present and missed) due to experimental conditions that can influence sphingolipid metabolism, uptake from the diet or from the microbiome, or as artifacts produced during extraction and analysis. If these compounds and factors are kept in mind during the design and interpretation of lipidomic studies, investigators are likely to be surprised by how often they appear and thereby advance knowledge about them. Full article

Although dysregulated sphingolipid metabolism was observed in many malignant tumors, bladder cancer has not yet been examined in this regard. This study aims to investigate the metabolism of bioactive sphingolipids across different stages of urothelial urinary bladder cancer (UBC). Forty-eight patients with UBC were included in this study. The neoplasms were classified as either non-muscle-invasive (NMIBC, n = 24) or muscle-invasive (MIBC, n = 24). Samples of the healthy bladder tissue were taken from the patients who underwent radical cystectomy. The content of sphingolipids was measured using an HPLC method, and the mRNA expression of sphingolipid transporters and metabolizing enzymes was evaluated using RT-PCR. Compared to the healthy bladder tissue, the UBC, regardless of the stage, showed an elevated expression of SphK1, Spns2, and ABCC1. The changes in the level of bioactive sphingolipids were strongly stage-dependent. MIBC showed accumulation of sphingosine-1-phosphate (S1P) and ceramide, whereas the content of these sphingolipids in the NMIBC tumor was not different from that of healthy tissue. Moreover, MIBC, compared to NMIBC, was characterized by higher levels of sphingosine and dihydroceramide. We conclude that profound alterations in sphingolipid metabolism develop upon UBC transition from non-muscle-invasive to muscle-invasive. They include the accumulation of S1P, resulting from the increased availability of sphingosine generated from ceramide, which also builds up due to a further activation of its de novo synthesis. We hypothesize that the dysregulation of S1P metabolism leading to the accumulation of this tumor-promoting sphingolipid contributes to the progression of UBC. Full article

Identification of disease and therapeutic biomarkers remains a significant challenge in the early diagnosis and effective treatment of juvenile idiopathic arthritis (JIA). In this study, plasma metabolomic profiling was conducted to identify disease-related metabolic biomarkers associated with JIA. Plasma samples from treatment-naïve JIA patients and non-JIA reference patients underwent global metabolomic profiling across discovery (60 JIA, 60 non-JIA) and replication (49 JIA, 38 non-JIA) cohorts. Univariate analysis identified significant metabolites (q-value ≤ 0.05), followed by enrichment analysis using ChemRICH and metabolic network mapping with MetaMapp and Cytoscape. Receiver operating characteristic (ROC) analysis determined the top discriminating biomarkers based on area under the curve (AUC) values. A total of over 800 metabolites were measured, consisting of 714 known and 155 unknown compounds. In the discovery cohort, 587 metabolites were significantly altered in JIA patients compared with the reference population (q < 0.05). In the replication cohort, 288 metabolites were significantly altered, with 78 overlapping metabolites demonstrating the same directional change in both cohorts. JIA was associated with a notable increase in plasma levels of sphingosine metabolites and fatty acid ethanolamides and decreased plasma levels of sarcosine, iminodiacetate, and the unknown metabolite X-12462. Chemical enrichment analysis identified cycloparaffins in the form of naproxen and its metabolites, unsaturated lysophospholipids, saturated phosphatidylcholines, sphingomyelins, ethanolamines, and saturated ceramides as the top discriminating biochemical clusters. ROC curve analysis identified 11 metabolites classified as highly discriminatory based on an AUC > 0.90, with the top discriminating metabolite being sphinganine-1-phosphate (AUC = 0.98). This study identifies specific metabolic changes in JIA, particularly within sphingosine metabolism, through both discovery and replication cohorts. Plasma metabolomic profiling shows promise in pinpointing JIA-specific biomarkers, differentiating them from those in healthy controls and Crohn’s disease, which may improve diagnosis and treatment. Full article

Plant–microbe interactions are key to nutrient-use efficiency. Root microbes are influenced by rhizosphere soil and plant cultivars. The impact of cultivar-by-nitrogen (N) interactions on the maize-root microbiome remains unclear, yet it is crucial for understanding N use efficiency in maize. This study evaluated the effects of maize cultivars and N forms, along with their interactions, on the diversity and composition of root bacteria and fungi. Additionally, we examined correlations between soil microbes and root metabolites. The maize cultivar Zhengdan 958 (ZD958) showed a positive response to the mixture of nitrate and ammonium N, resulting in increased in biomass, grain yield, shoot N content, grain N content, and root area. In contrast, the cultivar Denghai605 (DH605) did not exhibit a similar response. The diversity and composition of root bacteria and fungi differed between ZD958 and DH605. The N form primarily affected the community structure of rhizospheric fungi in ZD958 and rhizospheric bacteria in DH605, rather than endophytic microbes. A mixed N supply increased the relative abundance of Basidiomycota, which was positively correlated with ZD958 yield. For DH605, a mixed N treatment enhanced nitrification functions involving Bacteroidetes and Proteobacteria, while it reduced the effects of ammonium N supply. The dominant rhizospheric microbes in DH605 showed a stronger response to changes in root metabolites compared to those in ZD958. A mixed N supply increased the content of palmitoleic acid in ZD958 root exudates, facilitating the recruitment of beneficial rhizospheric microbes, which promotes maize growth. In DH605, a mixed N supply decreased the concentration of sphinganine, which is significantly correlated with Acidobacteria (negatively), Proteobacteria (negatively), Bacteroidetes (positively), and TM7 (positively). Our findings suggest that different maize cultivars respond differently to N forms, causing distinct rhizospheric microbial effects, and that root metabolites send metabolic signals to regulate and recruit key bacterial and fungal communities. Full article

Fusarium verticillioides produces fumonisins, which are mycotoxins inhibiting sphingolipid biosynthesis in humans, animals, and other eukaryotes. Fumonisins are presumed virulence factors of plant pathogens, but may also play a role in interactions between competing fungi. We observed higher resistance to added fumonisin B₁ (FB₁) in fumonisin-producing Fusarium verticillioides than in nonproducing F. graminearum, and likewise between isolates of Aspergillus and Alternaria differing in production of sphinganine-analog toxins. It has been reported that in F. verticillioides, ceramide synthase encoded in the fumonisin biosynthetic gene cluster is responsible for self-resistance. We reinvestigated the role of FUM17 and FUM18 by generating a double mutant strain in a fum1 background. Nearly unchanged resistance to added FB₁ was observed compared to the parental fum1 strain. A recently developed fumonisin-sensitive baker’s yeast strain allowed for the testing of candidate ceramide synthases by heterologous expression. The overexpression of the yeast LAC1 gene, but not LAG1, increased fumonisin resistance. High-level resistance was conferred by FUM18, but not by FUM17. Likewise, strong resistance to FB₁ was caused by overexpression of the presumed F. verticillioides “housekeeping” ceramide synthases CER1, CER2, and CER3, located outside the fumonisin cluster, indicating that F. verticillioides possesses a redundant set of insensitive targets as a self-resistance mechanism. Full article

Excessive lipid deposition affects hepatic homeostasis and contributes to the development of insulin resistance as a crucial factor for the deterioration of simple steatosis to steatohepatitis. So, it is essential to search for an effective agent for a new therapy for hepatic steatosis development before it progresses to the more advanced stages. Our study aimed to evaluate the potential protective effect of α-lipoic acid (α-LA) administration on the intrahepatic metabolism of sphingolipid and insulin signaling transduction in rats with metabolic dysfunction-associated steatotic liver disease (MASLD). The experiment was conducted on male Wistar rats subjected to a standard diet or a high-fat diet (HFD) and an intragastrically α-LA administration for eight weeks. High-performance liquid chromatography (HPLC) was used to determine sphingolipid content. Immunoblotting was used to measure the expression of selected proteins from sphingolipid and insulin signaling pathways. Multiplex assay kit was used to assess the level of the phosphorylated form of proteins from PI3K/Akt/mTOR transduction. The results revealed that α-LA decreased sphinganine, dihydroceramide, and sphingosine levels and increased ceramide level. We also observed an increased the concentration of phosphorylated forms of sphingosine and sphinganine. Changes in the expression of proteins from sphingolipid metabolism were consistent with changes in sphingolipid pools. Treatment with α-LA activated the PI3K/Akt/mTOR pathway, which enhanced the hepatic phosphorylation of Akt and mTOR. Based on these data, we concluded that α-lipoic acid may alleviate glucose intolerance and may have a protective influence on the sphingolipid metabolism under HFD; thus, this antioxidant appears to protect from MASLD development and steatosis deterioration. Full article

Edible fungi polysaccharides are widely sourced and have various physiological activities, including hypoglycemic. Current studies mainly focus on the hypoglycemic activity of polysaccharides themselves, while the strength of the hypoglycemic activity of edible fungi polysaccharides from different sources remained elusive. This study compared the hypoglycemic activity of different edible fungi polysaccharides after in vitro fermentation by fecal bacteria, combined with non-targeted metabolomics and 16S rDNA analysis, to screen out potential key metabolites related to the hypoglycemic activity. The results show that the fermentation supernatants of all four edible fungi polysaccharides significantly increased the glucose consumption and glycogen synthesis of IR-HepG2, also up-regulated the level of hexokinase and down-regulated the level of phosphoenolpyruvate carboxylase. All fermentation supernatants could alleviate the insulin resistance of IR-HepG2 cells by regulating the expression levels of genes related to the IRS-1/PI3K/Akt signaling pathway. Gingerglycolipid A, sphinganine 1-phosphate, matricin, tricarballylic acid, N-carbamoylputrescine, nomega-acetylhistamine, tyramine, and benzamide could be considered as potential key metabolites to evaluate the hypoglycemic effects. Their levels were strongly positively correlated with the abundance of Candidatus_Stoquefichu, Faecalibacterium, Coprococcus, Bacteroides, Eubacterium_ventriosum_group, Anaerostipes, Parabacteroides, and Agathobacter. These metabolites and microorganisms are closely related to the hypoglycemic activity of edible fungi polysaccharides. Full article