Project description:The rapidly increasing number of engineered nanoparticles (NPs), and products containing NPs, raises concerns for human exposure and safety. With this increasing, and ever changing, catalogue of NPs it is becoming more difficult to adequately assess the toxic potential of new materials in a timely fashion. It is therefore important to develop methods which can provide high-throughput screening of biological responses. The use of omics technologies, including metabolomics, can play a vital role in this process by providing relatively fast, comprehensive, and cost-effective assessment of cellular responses. These techniques thus provide the opportunity to identify specific toxicity pathways and to generate hypotheses on how to reduce or abolish toxicity.We have used untargeted metabolome analysis to determine differentially expressed metabolites in human lung epithelial cells (A549) exposed to copper oxide nanoparticles (CuO NPs). Toxicity hypotheses were then generated based on the affected pathways, and critically tested using more conventional biochemical and cellular assays. CuO NPs induced regulation of metabolites involved in oxidative stress, hypertonic stress, and apoptosis. The involvement of oxidative stress was clarified more easily than apoptosis, which involved control experiments to confirm specific metabolites that could be used as standard markers for apoptosis; based on this we tentatively propose methylnicotinamide as a generic metabolic marker for apoptosis.Our findings are well aligned with the current literature on CuO NP toxicity. We thus believe that untargeted metabolomics profiling is a suitable tool for NP toxicity screening and hypothesis generation.
Project description:Attention Deficit Hyperactivity Disorder (ADHD) is a clinically common neurodevelopmental disorder of the brain. In addition to genetic factors, an imbalance in gut flora may also play a role in the development of ADHD. Currently, it is critical to investigate the function of gut flora and related metabolites, which may form the fundamental basis of bidirectional cross-linking between the brain and the gut, in addition to focusing on the changed gut flora in ADHD. This study aimed to investigate the possible relationship between changes in gut flora and metabolites and ADHD by analyzing metagenome and untargeted metabolomics of fecal samples from ADHD patients. Specifically, we attempted to identify key metabolites and the metabolic pathways they are involved in, as well as analyze in detail the structure and composition of the gut flora of ADHD patients. In order to further investigate the relationship between gut flora and ADHD symptoms, some behavioral studies were conducted following the transplantation of gut flora from ADHD patients into rats. The results of the metagenome analysis revealed several distinct strains, including Bacteroides cellulosilyticus, which could be important for diagnosing ADHD. Additionally, the ADHD group showed modifications in several metabolic pathways and metabolites, including the nicotinamide and nicotinic acid metabolic pathways and the metabolite nicotinamide in this pathway. The behavioral results demonstrated that rats with ADHD gut flora transplants displayed increased locomotor activity and interest, indicating that the onset of behaviors such as ADHD could be facilitated by the flora associated with ADHD. This research verified the alterations in gut flora and metabolism observed in ADHD patients and provided a list of metabolites and flora that were significantly altered in ADHD. Simultaneously, our findings revealed that modifications to the microbiome could potentially trigger behavioral changes in animals, providing an experimental basis for comprehending the function and influence of gut flora on ADHD. These results might provide new perspectives for the development of novel treatment strategies.
Project description:l-Carnitine is a candidate therapeutic for the treatment of septic shock, a condition that carries a ?40% mortality. Responsiveness to l-carnitine may hinge on unique metabolic profiles that are not evident from the clinical phenotype. To define these profiles, we performed an untargeted metabolomic analysis of serum from 21 male sepsis patients enrolled in a placebo-controlled l-carnitine clinical trial. Although treatment with l-carnitine is known to induce changes in the sepsis metabolome, we found a distinct set of metabolites that differentiated 1-year survivors from nonsurvivors. Following feature alignment, we employed a new and innovative data reduction strategy followed by false discovery correction, and identified 63 metabolites that differentiated carnitine-treated 1-year survivors versus nonsurvivors. Following identification by MS/MS and database search, several metabolite markers of vascular inflammation were determined to be prominently elevated in the carnitine-treated nonsurvivor cohort, including fibrinopeptide A, allysine, and histamine. While preliminary, these results corroborate that metabolic profiles may be useful to differentiate l-carnitine treatment responsiveness. Furthermore, these data show that the metabolic signature of l-carnitine-treated nonsurvivors is associated with a severity of illness (e.g., vascular inflammation) that is not routinely clinically detected.
Project description:Thermal ablation is widely used in the treatment of lung cancer and is beneficial for the overall survival of patients in clinic. However, there is barely a priority in which ablation system should be chosen under different periods of tumor progression in lung cancer. The present study investigated different modes of thermal ablation systems in mice with transplanted Lewis lung carcinoma tumors and their various biological effects in local regions using untargeted metabolomics. The results showed that thermal ablation could significantly suppress tumor growth and the differentially expressed metabolites of tumors after ablation relative to untreated tumors concentrated on organic compounds, organic acids and derivatives, nucleosides, nucleotides, and lipids. The upregulated metabolites indicated an inflammatory reaction in the ablation groups at an early stage after ablation. Steroid hormone and tryptophan metabolism, which are associated with immune responses, were modulated after both cryoablation and hyperthermal ablation. Characteristically, the results also indicated that cryoablation suppressed glucose oxidation and carbohydrate metabolism of tumor, while hyperthermal ablation suppressed lipid metabolism of tumor. In conclusion, thermal ablation could inhibit tumor growth under either freezing or heating modes with characteristic different biological effects on tumors.
Project description:The prohibition of the use of growth-promoting drug additives in feeds was implemented in China in 2020. However, rabbits can experience symptoms of intestinal disease, such as diarrhea and flatulence, when switching from standard normal diets with antibiotics to antibiotic-free diets. The molecular mechanisms related to the occurrence of these diseases as well as associated physiological and metabolic changes in the intestine are unclear. Thus, the objectives of this study were to study the pathogenesis of intestinal inflammation using untargeted metabolomics. This was done to identify differential metabolites between a group of antibiotic-free feed Hyplus rabbits (Dia) whose diet was abruptly changed from a standard normal diet with antibiotics to an antibiotic-free diet, and an antibiotic diet group Hyplus rabbits (Con) that was fed a standard normal diet with antibiotics. Morphological damage to the three intestinal tissues was determined through visual microscopic examination of intestinal Dia and Con tissue samples stained with hematoxylin and eosin (HE). A total of 1969 different metabolites were identified in the three intestinal tissues from Dia and Con rabbits. The level of 1280 metabolites was significantly higher and the level of 761 metabolites was significantly lower in the Dia than in the Con group. These differential metabolites were involved in five metabolic pathways associated with intestinal inflammation (tryptophan metabolism, pyrimidine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, lysine degradation, and bile secretion). Rabbits in the Dia group developed metabolic disorders that affected the intestinal microbiota and changed the permeability of the intestinal tract, thereby triggering intestinal inflammation, affecting feed utilization, reducing production performance, and activating the intestinal tract self-repair mechanism. Thus, the abrupt transition from a diet with antibiotics to an antibiotic-free diet affected the structure and metabolism of the intestinal tract in Hyplus rabbits. Consequently, to avoid these problems, the antibiotic content in a rabbit diet should be changed gradually or alternative antibiotics should be found.
Project description:Oncogene-associated metabolic signatures in prostate cancer, identified by an integrative analysis of cultured cells and murine and human tumors, suggest that AKT activation results in a glycolytic phenotype whereas MYC induces aberrant lipid metabolism. Heterogeneity in human tumors makes this simplistic interpretation obtained from experimental models more challenging. Metabolic reprogramming as a function of distinct molecular aberrations has major diagnostic and therapeutic implications.