The tobacco alkaloid nicotine is known for its activation of neuronal nicotinic acetylcholine receptors. Nicotine is consumed in different ways such as through conventional smoking, e-cigarettes, snuff or nicotine pouches. The use of snuff has been associated with several adverse health effects, such as inflammatory reactions of the oral mucosa and oral cavity cancer. We performed a metabolomic analysis of nicotine-exposed THP-1 human monocytes. Cells were exposed to 5 mM of the alkaloid for up to 4 h, and cell extracts and medium subjected to untargeted liquid chromatography high-resolution mass spectrometry. Raw data processing revealed 17 nicotine biotransformation products. Among these, cotinine and nornicotine were identified as the two major cellular biotransformation products. The application of multi- and univariate statistical analyses resulted in the annotation, up to a certain level of identification, of 12 compounds in the cell extracts and 13 compounds in the medium that were altered by nicotine exposure. Of these, four were verified as methylthioadenosine, cytosine, uric acid, and L-glutamate. Methylthioadenosine levels were affected in both cells and the medium, while cytosine, uric acid, and L-glutamate levels were affected in the medium only. The effects of smoking on the pathways involving these metabolites have been previously demonstrated in humans. Most of the other discriminating compounds, which were merely tentatively or not fully identified, were amino acids or amino acid derivatives. In conclusion, our preliminary data suggest that some of the potentially adverse effects related to smoking may also be expected when nicotine is consumed via snuff or nicotine pouches.

Cyanobacterial blooms have emerged as a significant environmental issue worldwide in recent decades. However, the toxic effects of microcystin-LR (MC-LR) on aquatic organisms, such as frogs, have remained poorly understood. In this study, frogs (Pelophylax nigromaculatus) were exposed to environmentally relevant concentrations of MC-LR (0, 1, and 10 μg/L) for 21 days. Subsequently, we assessed the impact of MC-LR on the histomorphology of the frogs\' livers and conducted a global MS-based nontarget metabolomics analysis, followed by the determination of substances involved in lipid metabolism. Results showed that MC-LR significantly induced histological alterations in the frogs\' hepatopancreas. Over 200 differentially expressed metabolites were identified, primarily enriched in lipid metabolism. Biochemical analysis further confirmed that MC-LR exposure led to a disorder in lipid metabolism in the frogs. This study laid the groundwork for a mechanistic understanding of MC-LR toxicity in frogs and potentially other aquatic organisms.

BACKGROUND: CDD-2103 is an herbal prescription used to treat ulcerative colitis (UC). This study aimed to uncover its mechanism by integrating metabolomics and serum-feces pharmacochemistry-based network pharmacology.
METHODS: A DSS-induced chronic colitis mice model was used to evaluate the anti-colitis effect of CDD-2103. Serum and feces metabolomics were conducted to identify differential metabolites and pathways. In the serum-feces pharmacochemistry study, biological samples were collected from rats treated with CDD-2103. Then, network pharmacology was utilized to predict the targets of the identified compounds. Critical genes were extracted through the above-integrated analysis. The interactions between targets, CDD-2103, and its compounds were validated through molecular docking, immunoblotting, and enzyme activity assays.
RESULTS: CDD-2103 alleviated ulcerous symptoms and colonic injuries in colitis mice. Metabolomics study identified differential metabolites associated with tryptophan, glycerophospholipid, and linoleic acid metabolisms. The serum-feces pharmacochemistry study revealed twenty-three compounds, which were subjected to network pharmacology analysis. Integration of these results identified three key targets (AHR, PLA2, and PTGS2). Molecular docking showed strong affinities between the compounds and targets. PTGS2 was identified as a hub gene targeted by most CDD-2103 compounds. Immunoblotting and enzyme activity assays provided further evidence that CDD-2103 alleviates UC, potentially through its inhibitory effect on cyclooxygenase-2 (COX-2, encoded by PTGS2), with alkaloids and curcuminoids speculated as crucial anti-inflammatory compounds.
CONCLUSIONS: This integrated strategy reveals the mechanism of CDD-2103 and provides insights for developing herbal medicine-based therapies for UC.

Pig bile- and Fructus Evodiae sauce-processed Rhizoma Coptidis (Danhuanglian, DHL; Yuhuanglian, YHL, respectively) are two types of processed Rhizoma Coptidis (Huanglian, HL) in traditional Chinese medicine (TCM). DHL and YHL are representative of HL generated from the subordinate and counter system processing methods, respectively, both noted for their anti-inflammatory effects. How these processing methods can affect the medicinal efficacy of HL remains a hot topic. Here, we discussed the influence of the two methods on the efficacy of final HL products (i.e., DHL and YHL) by comparing their components and anti-inflammatory mechanisms. Enzyme-linked immunosorbent assay was employed to measure inflammatory factors in RAW264.7 cells induced by lipopolysaccharide, and UPLC-Q-Exactive Orbitrap-MS was utilized to analyze the endogenous differential metabolites of RAW264.7 cells treated with HL, YHL, and DHL, and thus to identify the related metabolic pathways. Finally, using network pharmacology, we constructed a \"disease-target-differential metabolites-active ingredients\" network map. Compared with the control, all three products, HL, YHL, and DHL, significantly reduced IL-6, TNF-α, and IL-1β levels. 12 differential metabolites related to inflammation were identified and 25 target proteins were overlapping among the three groups. Notably, the anti-inflammatory effects of DHL and YHL were mediated by metabolic pathways such as aminoacyl-tRNA biosynthesis, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and arginine biosynthesis. Specifically, DHL significantly impacted free fatty acid levels, which was not observed with HL and YHL. On screening, DHL had 9 active ingredients, including three from pig bile, and YHL had 12 active ingredients, with six from the processing excipient Fructus Evodiae. The distinct anti-inflammatory mechanisms and material basis of YHL and DHL were characterized by consistency and distinctiveness. Thus, this study underscores the significant influence of processing methods on the medicinal efficacy of TCMs by revealing their regulatory mechanisms and material bases.

Chromium (Cr) exposure is associated with various respiratory system diseases, but there are limited studies investigating its impact on lung function in young adults. The Cr exposure-related metabolomic changes are not well elucidated. This study recruited 608 students from a university in Shandong Province, China in 2019. We used cohort design fitted with linear mixed-effects models to assess the association between blood Cr concentration and lung function. In addition, we performed metabolomic and lipidomic analyses of baseline serum samples (N = 582) using liquid chromatography-mass spectrometry. Two-step statistical analysis (analysis of variance and mixed-linear effect model) was used to evaluate the effect of blood Cr exposure on metabolites. We found that blood Cr was associated with decreased lung function in young adults. Each 2-fold increase in blood Cr concentrations was significantly associated with decreased FEV1 and FVC by 35.26 mL (95 % CI: -60.75, -9.78) and 38.56 mL (95 % CI: -66.60, -10.51), respectively. In the metabolomics analysis, blood Cr exposure was significantly associated with 14 key metabolites. The changed metabolites were mainly enriched in six pathways including lipid metabolism, amino acid metabolism, and cofactor vitamin metabolism. Blood Cr may affect lung function through oxidative stress and inflammation related pathways.

BACKGROUND: Exploring metabolic changes within host E. coli through an untargeted metabolomic study of T7L variants overexpression to optimize engineered endolysins for clinical/therapeutic use.
OBJECTIVE: This study aims to assess the impact of overexpressing T7L variants on the metabolic profiles of E. coli. The two variants considered include T7L-H37A, which has enhanced lytic activity compared to its wild-type protein, and T7L-H48K, a dead mutant with no significant activity.
METHODS: 1H NMR-based metabolomics was employed to compare the metabolic profiles of E. coli cells overexpressing T7L wild-type protein and its variants.
RESULTS: Overexpression of the T7L wild-type (T7L-WT) protein and its variants (T7L-H48K and T7L-H37A) was compared to RNAP overexpression in E. coli cells using 1H NMR-based metabolomics, analyzing a total of 75 annotated metabolites, including organic acids, amino acids, sugars, and nucleic acids. The results showed distinct clustering patterns for the two T7L variant groups compared with the WT, in which the dead mutant (H48K) group showed clustering close to that of RNAP. Pathway impact analysis revealed different effects of T7L variants on E. coli metabolic profiles, with T7L-H48K showing minimal alterations in energy and amino acid pathways linked to osmotic stress compared to noticeable alterations in these pathways for both T7L-H37A and T7L-WT.
CONCLUSIONS: This study uncovered distinct metabolic fingerprints when comparing the overexpression of active and inactive mutants of T7L lytic enzymes in E. coli cells. These findings could contribute to the optimization and enhancement of suitable endolysins as potential alternatives to antibiotics.

BACKGROUND: Metabolomics data is often complex due to the high number of metabolites, chemical diversity, and dependence on sample preparation. This makes it challenging to detect significant differences between factor levels and to obtain accurate and reliable data. To address these challenges, the use of Design of Experiments (DoE) techniques in the setup of metabolomic experiments is crucial. DoE techniques can be used to optimize the experimental design space, ensuring that the maximum amount of information is obtained from a limited sample space.
OBJECTIVE: This review aims at providing a baseline workflow for applying DoE when generating metabolomics data.
UNASSIGNED: The review provides insights into the theory of DoE. The review showcases the theory being put into practice by highlighting different examples DoE being applied in metabolomics throughout the literature, considering both targeted and untargeted metabolomic studies in which the data was acquired using both nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry techniques. In addition, the review presents DoE concepts not currently being applied in metabolomics, highlighting these as potential future prospects.

BACKGROUND: Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma associated with Plasmodium falciparum and Epstein-Barr virus, both of which affect metabolic pathways. The metabolomic patterns of BL is unknown.
METHODS: We measured 627 metabolites in pre-chemotherapy treatment plasma samples from 25 male children (6-11 years) with BL and 25 cancer-free area- and age-frequency-matched male controls from the Epidemiology of Burkitt Lymphoma in East African Children and Minors study in Uganda using liquid chromatography-tandem mass spectrometry. Unconditional, age-adjusted logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for the BL association with 1-standard deviation increase in the log-metabolite concentration, adjusting for multiple comparisons using false discovery rate (FDR) thresholds and Bonferroni correction.
RESULTS: Compared to controls, levels for 42 metabolite concentrations differed in BL cases (FDR < 0.001), including triacylglyceride (18:0_38:6), alpha-aminobutyric acid (AABA), ceramide (d18:1/20:0), phosphatidylcholine ae C40:6 and phosphatidylcholine C38:6 as the top signals associated with BL (ORs = 6.9 to 14.7, P < 2.4✕10- 4). Two metabolites (triacylglyceride (18:0_38:6) and AABA) selected using stepwise logistic regression discriminated BL cases from controls with an area under the curve of 0.97 (95% CI: 0.94, 1.00).
CONCLUSIONS: Our findings warrant further examination of plasma metabolites as potential biomarkers for BL risk/diagnosis.

Dental caries, a prevalent global infectious condition affecting over 95% of adults, remains elusive in its precise etiology. Addressing the complex dynamics of caries demands a thorough exploration of taxonomic, potential, active, and encoded functions within the oral ecosystem. Metabolomic profiling emerges as a crucial tool, offering immediate insights into microecosystem physiology and linking directly to the phenotype. Identified metabolites, indicative of caries status, play a pivotal role in unraveling the metabolic processes underlying the disease. Despite challenges in metabolite variability, the use of metabolomics, particularly via mass spectrometry and nuclear magnetic resonance spectroscopy, holds promise in caries research. This review comprehensively examines metabolomics in caries prevention, diagnosis, and treatment, highlighting distinct metabolite expression patterns and their associations with disease-related bacterial communities. Pioneering in approach, it integrates singular and combinatory metabolomics methodologies, diverse biofluids, and study designs, critically evaluating prior limitations while offering expert insights for future investigations. By synthesizing existing knowledge, this review significantly advances our comprehension of caries, providing a foundation for improved prevention and treatment strategies.

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