bims-metlip Biomed News
on Methods and protocols in metabolomics and lipidomics
Issue of 2025–03–09
twenty-two papers selected by
Sofia Costa, Matterworks



  1. Talanta. 2025 Feb 28. pii: S0039-9140(25)00343-1. [Epub ahead of print]291 127853
      Herein, we aim to establish a straightforward and versatile reversed-phase liquid chromatography/mass spectrometry (RP-LC/MS) methodology for analyzing a wide range of polar and mid-polar metabolites utilizing a single instrument, column, and mobile phase. We present a comprehensive evaluation of three C18 columns compatible with aqueous solutions using 19 mobile phases in terms of the number of detected metabolites, chromatographic performance, and MS response. The RP-LC/MS platform utilizes the HSS T3 column with a mobile phase consisting of 0.2 % formic acid, acetonitrile, and propan-2-ol, effectively separating polar and mid-polar metabolites through various mobile phase gradients. Our developed method outperforms the conventional hydrophilic interaction liquid chromatography metabolomic method, yielding a higher number of detected metabolites and better chromatographic performance. The RP-LC/MS platform demonstrates excellent intrabatch and interbatch retention time repeatability (<0.8 %). Furthermore, the determined concentrations of metabolites show strong agreement with certified and published concentrations of metabolites in the SRM 1950 plasma sample. We successfully annotate 71 polar metabolites, 36 acylcarnitines, 23 endocannabinoids, 42 oxylipins, and 16 fatty acids in plasma, placenta, and brain samples. The developed RP-LC/MS approach represents a robust and adaptable technique for the targeted or untargeted analysis of polar and mid-polar metabolites employing a single chromatographic column and mobile phase. This is achieved through the simple modification of the gradient program and MS conditions. Consequently, this methodology offers a highly valuable tool for conducting comprehensive, large-scale metabolomic investigations on a variety of biological samples.
    Keywords:  Liquid chromatography; Mass spectrometry; Metabolomics; Reversed-phase; Targeted analysis; Untargeted analysis
    DOI:  https://doi.org/10.1016/j.talanta.2025.127853
  2. Se Pu. 2025 Mar;43(3): 228-236
      Animal-derived foods are essential sources of vitamin D and 25-hydroxyvitamin D in the human diet. Currently, the relevant regulatory methods in China are limited to using non-derivatization methods to determine vitamin D content. In this study, 4-phenyl-1,2,4-triazoline-3-5-dione (PTAD) was used as a derivative reagent, and the ionization efficiencies of vitamin D and 25-hydroxyvitamin D were improved by introducing readily ionizable groups via the Diels-Alder reaction. This method allowed for the simultaneous determination of vitamin D and 25-hydroxyvitamin D in animal-derived foods using derivatization and ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The conditions for derivatization, sample pretreatment, chromatographic separation, and MS detection were optimized. The results showed that the derivatization reaction was effective in acetonitrile solvent at a target compound to PTAD mass ratio of 1∶10000 and stabilized after 1 h. Compared with Silica and C18 solid-phase extraction (SPE) columns, hydrophilic lipophilic balanced (HLB) SPE columns yielded higher recoveries of the target compounds, while simultaneously reducing the matrix effect. The detection sensitivity was significantly improved by adding 5 mmol/L methylamine to the water-methanol mobile phase system. An isotopic internal standard was added to the homogenized samples, which were saponified with alkali solution, extracted and concentrated, purified using a SPE column, derivatized, and separated on a Waters Acquity UPLC BEH C18 column (100 mm×2.1 mm, 1.7 μm) with a gradient elution using 0.1% formic acid-5 mmol/L methylamine aqueous solution and 0.1% formic acid-5 mmol/L methylamine of methanol as the mobile phases. The analytes were determined by multiple reaction monitoring (MRM) in positive electrospray ionization mode (ESI+) and quantified using the internal standard method. The results for both vitamin D and 25-hydroxyvitamin D showed good linearity in the range of 0.2-50 μg/L, with correlation coefficients of 0.9995-0.9999. The limits of detection (LODs) and limits of quantification (LOQs) were in the range of 0.018-0.066 and 0.06-0.22 μg/kg, respectively. Recoveries were 92.6%-99.4% at three spiked levels (0.20, 1.0, and 5.0 μg/kg), and the relative standard deviations (RSDs) were 3.6%-6.2%. This highly sensitive method yields reproducible and accurate results for the quantitative determination of vitamin D and 25-hydroxyvitamin D in animal-derived foods.
    Keywords:  25-hydroxyvitamin D; 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD); derivatization; tandem mass spectrometry (MS/MS); ultra performance liquid chromatography (UPLC); vitamin D
    DOI:  https://doi.org/10.3724/SP.J.1123.2024.02003
  3. Se Pu. 2025 Mar;43(3): 252-260
      Perfluorinated/polyfluoroalkyl compounds (PFASs) are a group of synthetic chemicals. Since the 1940s, PFASs have been widely used in industrial and daily consumer fields. PFASs can enter the human body through various pathways, such as drinking water, food, and air. Toxicological studies have shown that PFASs feature developmental and reproductive toxicity. Thus, the accurate assessment of PFAS exposure levels plays an important role in determining the health risks of these compounds. Biological monitoring is considered the most ideal means of monitoring and evaluating PFAS levels in the human body. The concentration of PFASs in serum can directly reflect their level of absorption in the human body after exposure; therefore, serum is widely used as a biological matrix for evaluating PFASs. In this study, a high-throughput solid-phase extraction (SPE)-ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was developed for the determination of 17 PFASs in serum. A laboratory-made straight-through SPE column was used to purify serum samples. The SPE column used a new inorganic material with a low perfluorinated compound background. Unlike traditional SPE columns, the extraction column does not require activation before use, and the sample can be directly loaded into it for purification. The straight-through SPE column adopts a stepped design, which does not require a large sample volume and is suitable for the pretreatment of precious biological samples such as serum. The serum sample size adopted in this study was only 50 μL, which is much lower than that required by other extraction methods. The straight-through SPE column can be used in conjunction with a 96-well plate, and the purification treatment of 96 serum samples can be completed within 30 min with high efficiency. The mass spectrometry parameters were optimized, and the results indicated that the electrospray ionization source temperature had a significant impact on the PFASs with later elution peaks. The effects of ion-source temperatures of 400 and 500 ℃ on the peak shapes and response values of the target compounds were compared, and 400 ℃ was selected. The sample pretreatment and ultra-high performance liquid chromatographic conditions were optimized. Briefly, 50 μL of the sample was loaded into the SPE column and extracted twice using 200 μL of acetonitrile each time. The purified solution was collected, blown with nitrogen at 40 ℃ to near dryness, dissolved in a 50% methanol aqueous solution, and then separated on a Poroshell 120 EC-C18 chromatographic column (100 mm×3 mm, 2.7 μm) with 5 mmol/L ammonium acetate aqueous solution and methanol as mobile phases. Detection was conducted in multiple-reaction monitoring mode, and quantification was performed using an isotope internal standard method. The 17 detected PFASs had good linear relationships within the corresponding mass concentration ranges (r2>0.995), with limits of detection ranging from 3.6 ng/L to 14 ng/L and limits of quantification ranging from 11 ng/L to 42 ng/L. The recoveries in spiked serum samples were 89.3%-110.2%, the intra-day RSDs were 2.5%-9.8%, and the inter-day RSDs were 3.6%-10.2%. The method was applied to the detection of 20 human serum samples, and all 17 compounds were successfully detected. The proposed method is easy to operate, highly sensitive, has a small sample size and high detection efficiency, and is suitable for the large-scale monitoring and exposure assessment of PFASs in human serum samples.
    Keywords:  perfluorinated/polyfluoroalkyl compounds (PFASs); serum; solid-phase extraction (SPE); ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)
    DOI:  https://doi.org/10.3724/SP.J.1123.2024.03007
  4. J Chromatogr B Analyt Technol Biomed Life Sci. 2025 Feb 21. pii: S1570-0232(25)00076-5. [Epub ahead of print]1256 124524
      The issue of drug abuse is increasingly becoming a significant concern worldwide. However, the simultaneous detection of a wide spectrum of drug of abuse (DOA), especially in biofluids, is challenging due to their diverse and varied physicochemical properties and matrix effects. Herein, we have developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous detection of 203 DOAs, including amphetamines, opiates, cathinones, phencyclidines, synthetic cannabinoids, cocaine, and metabolites, in 100 μL of urine. A mass analysis was performed using multiple reaction monitoring mode with an electrospray ionization source. The run time of the developed method was 16 min. Two sample preparation methods were compared for urine samples: enzymatic hydrolysis followed by either dilution or QuEChERS. Both methods demonstrated good linearity and low matrix effects; however, the dilution method showed superior accuracy and precision. Method validation was conducted to assess the efficacy of the developed method. The LC-MS/MS method with the dilution method demonstrated good linearity with the coefficients of determination (R2) above 0.99 for 200 compounds. The limit of quantification (LOQ) ranged from 0.1 to 20.0 ng/mL. The inter-day precision was below 20 % for all 203 compounds, with a bias of ±20 % for 198 compounds. This method was successfully applied to 40 real urine samples. The developed method allows the simultaneous separation and detection of a variety of DOAs with diverse physicochemical properties in a small amount of urine. Furthermore, the technique could be adapted to fit the practical requirements of forensic investigations, thereby enhancing its effectiveness and reliability.
    Keywords:  Drug of abuse; Liquid chromatography-tandem mass spectrometry; Multi-class method; Simultaneous analysis; Urine sample
    DOI:  https://doi.org/10.1016/j.jchromb.2025.124524
  5. Nat Protoc. 2025 Feb 28.
      Untargeted metabolomics is evolving into a field of big data science. There is a growing interest within the metabolomics community in mining tandem mass spectrometry (MS/MS)-based data from public repositories. In traditional untargeted metabolomics, samples to address a predefined question are collected and liquid chromatography with MS/MS data are generated. We then identify metabolites associated with a phenotype (for example, disease versus healthy) and elucidate or validate their structural details (for example, molecular formula, structural classification, substructure or complete structural annotation or identification). In reverse metabolomics, we start with MS/MS spectra for known or unknown molecules. These spectra are used as search terms to search public data repositories to discover phenotype-relevant information such as organ/biofluid distribution, disease condition, intervention status (for example, pre- and postintervention), organisms (for example, mammals versus others), geography and any other biologically relevant associations. Here we guide the reader through a four-part process: (1) obtaining the MS/MS spectra of interest (Universal Spectrum Identifier) and (2) Mass Spectrometry Search Tool searches to find the files associated with the MS/MS that are in available databases, (3) using the Reanalysis Data User Interface framework to link the files with their metadata and (4) validating the observations. Parts 1-3 could take from hours to days depending on the method used for collecting MS/MS spectra. For example, we use MS/MS spectra from three small molecules: phenylalanine-cholic acid (a microbially conjugated bile acid), phenylalanine-C4:0 and histidine-C4:0 (two N-acyl amides). We leverage the Global Natural Products Social Molecular Networking-based framework to explore the microbial producers of these molecules and their associations with health conditions and organ distributions in humans and rodents.
    DOI:  https://doi.org/10.1038/s41596-024-01136-2
  6. Clin Chem Lab Med. 2025 Mar 06.
       OBJECTIVES: Isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC MS/MS)-based candidate reference measurement procedures (RMPs) for the quantification of 24,25(OH)2D2 and 24,25(OH)2D3 in human serum and plasma are presented.
    METHODS: Quantitative nuclear magnetic resonance (qNMR) spectroscopic methodology was utilized to assign absolute content (g/g) and SI-traceability to reference materials used as primary calibrators. For liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis a two-dimensional heart cut LC approach, in combination with a supported liquid extraction protocol, was established to mitigate matrix effects and prevent co-elution of interferences. Selectivity was determined by spiking the internal standards and similar compounds, in human serum. A post-column infusion experiment and comparison of standard line slopes was performed to evaluate matrix effects. Precision and accuracy were assessed via a multi-day validation experiment, utilizing certified secondary reference materials from the National Institute of Standards and Technology (NIST). Measurement uncertainty (MU) was evaluated per the Guide to the Expression of Uncertainty in Measurement (GUM). To demonstrate equivalence with the JCTLM-listed RMP, certified secondary reference materials were utilized. Additionally, a method comparison study was conducted with the 24,25(OH)2D3 method used by the CDC Vitamin D Reference Laboratory.
    RESULTS: The RMP allowed quantification of 24,25(OH)2D2 and 24,25(OH)2D3 within the range of 0.150-18.0 ng/mL (0.350-42.0 nmol/L 24,25(OH)2D2 and 0.360-43.2 nmol/L 24,25(OH)2D3) without interference from structurally-related compounds and no evidence of matrix effects. Intermediate precision was ≤2.3 % for 24,25(OH)2D2 and ≤2.9 % for 24,25(OH)2D3; repeatability was ≤1.4 % for 24,25(OH)2D2 and ≤2.1 % for 24,25(OH)2D3, across all concentration levels. The relative mean bias was -4.5 to 2.9 % for 24,25(OH)2D2, and -3.7 to 3.6 % for 24,25(OH)2D3. Expanded MU for reference value assignment for 24,25(OH)2D2 and 24,25(OH)2D3 for reference value assignment was ≤2.5 %, regardless of concentration level and sample type. Passing-Bablok regression revealed strong agreement between the 24,25(OH)2D3 results from the candidate RMPs and those provided by the CDC Vitamin D Reference Laboratory.
    CONCLUSIONS: These RMPs permit accurate and reproducible determination of 24,25(OH)2D2 and 24,25(OH)2D3. Implementation of these methods supports routine assay standardization and patient sample measurement with confirmed traceability.
    Keywords:  24(R),25-dihydroxyvitamin D2; 24(R),25-dihydroxyvitamin D3; SI units; isotope dilution-liquid chromatography-tandem mass spectrometry; qNMR characterization; reference measurement procedure
    DOI:  https://doi.org/10.1515/cclm-2024-1139
  7. J Am Soc Mass Spectrom. 2025 Mar 07.
      The analysis of small carboxyl-containing metabolites (CCMs), such as tricarboxylic acid (TCA) cycle intermediates, provides highly useful information about the metabolic state of cells. However, their detection using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) methods can face sensitivity and specificity challenges given their low ionization efficiency and the presence of isomers. Ion mobility spectrometry (IMS), such as trapped ion mobility spectrometry (TIMS), provides additional specificity, but further signal loss can occur during the mobility separation process. We, therefore, developed a solution to boost CCM ionization and chromatographic separation as well as leverage specificity of IMS. Inspired by carbodiimide-mediated coupling of carboxylic acids with 4-bromo-N-methylbenzylamine (4-BNMA) for quantitative analysis, we newly report the benefits of this reagent for TIMS-based measurement. We observed a pronounced (orders of magnitude) increase in signal and enhanced isomer separations, particularly by LC. We found that utilization of a brominated reagent, such as 4-BNMA, offered unique benefits for untargeted CCM measurement. Derivatized CCMs displayed shifted mobility out of the metabolite and lipid region of the TIMS-MS space as well as characteristic isotope patterns, which were leveraged for data mining with Mass Spectrometry Query Language (MassQL) and indication of the number of carboxyl groups. The utility of our LC-ESI-TIMS-MS/MS method with 4-BMA derivatization was demonstrated via the characterization of alterations in CCM expression in bone marrow-derived macrophages upon activation with lipopolysaccharide. While metabolic reprogramming in activated macrophages has been characterized previously, especially with respect to TCA cycle intermediates, we report a novel finding that isomeric itaconic, mesaconic, and citraconic acid increase after 24 h, indicating possible roles in the inflammatory response.
    DOI:  https://doi.org/10.1021/jasms.5c00023
  8. J Proteome Res. 2025 Mar 05.
      The clustering of tandem mass spectra (MS/MS) is a crucial computational step to deduplicate repeated acquisitions in data-dependent experiments. This technique is essential in untargeted metabolomics, particularly with high-throughput mass spectrometers capable of generating hundreds of MS/MS spectra per second. Despite advancements in MS/MS clustering algorithms in proteomics, their performance in metabolomics has not been extensively evaluated due to the lack of database search tools with false discovery rate control for molecule identification. To bridge this gap, this study introduces the MS1-retention time (MS-RT) method to assess MS/MS clustering performance in metabolomics data sets. Here, we validate MS-RT by comparing MS-RT to established proteomics clustering evaluation approaches that utilize database search identifications. Additionally, we evaluate the performance of several MS/MS clustering tools on metabolomics data sets, highlighting their advantages and drawbacks. This MS-RT method and the MS/MS clustering tool benchmarking will provide valuable real world practical recommendations for tools and set the stage for future advancements in metabolomics MS/MS clustering.
    Keywords:  MS-RT method; benchmark clustering; clustering tools; completeness; metabolomics; purity; tandem mass spectrometry
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00881
  9. bioRxiv. 2025 Feb 17. pii: 2025.02.12.637912. [Epub ahead of print]
       Background: Clustering analysis is a foundational step in exploratory data analysis workflows, with dimensionality reduction methods commonly used to visualize multidimensional data in lower-dimensional spaces and infer sample clustering. Principal Component Analysis (PCA) is widely applied in metabolomics but is often suboptimal for clustering visualization. Metabolomics data often require specialized manipulations such as blank removal, quality control adjustments, and data transformations that demand efficient visualization tools. However, the lack of user-friendly tools for clustering without computational expertise presents a challenge for metabolomics researchers. ClusterApp addresses this gap as a web application that performs Principal Coordinate Analysis (PCoA), expanding clustering alternatives in metabolomics. Built on a QIIME 2 Docker image, it enables PCoA computation and Emperor plot visualization. The app supports data input from GNPS, GNPS2, or user-provided spreadsheets. Freely available, ClusterApp can be locally installed as a Docker image or integrated into Jupyter notebooks, offering accessibility and flexibility to diverse users.
    Results: To demonstrate the data preprocessing techniques available in ClusterApp, we analyzed two Liquid Chromatography coupled to Tandem Mass Spectrometry (LC-MS/MS) metabolomics datasets: one exploring metabolomic differences in mouse tissue samples and another investigating coral life history stages. Among the dissimilarity measures available, the Bray-Curtis measure effectively highlighted key metabolomic variations and patterns across both datasets. Targeted filtering significantly enhanced data reliability by retaining biologically relevant features, 10,617 in the coral dataset and 7,341 in the mouse dataset while eliminating noise. The combination of Total Ion Current (TIC) normalization and auto-scaling improved clustering resolution, revealing distinct separations in tissue types and life stages. ClusterApp's flexible features, such as customizable blank removal and group selection, provided tailored analyses, enhancing visualization and interpretation of metabolomic profiles.
    Conclusion: ClusterApp addresses the need for accessible, dynamic tools for exploratory data analysis in metabolomics. By coupling data transformation capabilities with PCoA on multiple dissimilarity matrices, it provides a versatile solution for clustering analysis. Its web interface and Docker-based deployment offer flexibility, accommodating a wide range of use cases through graphical or programmatic interactions. ClusterApp empowers researchers to uncover meaningful patterns and relationships in metabolomics data without requiring cumbersome data manipulation or advanced bioinformatics expertise.
    DOI:  https://doi.org/10.1101/2025.02.12.637912
  10. Anal Chim Acta. 2025 Apr 15. pii: S0003-2670(25)00185-0. [Epub ahead of print]1347 343791
       BACKGROUND: Robust tissue pre-treatment and lipid extraction workflows are crucial to metabolic phenotyping studies and accurate interpretation of lipid profiles. Numerous methods for lipid extraction from tissues have been developed, and the choice of technique influences analysis. This study provides a comprehensive evaluation of six liquid-liquid extraction methods (three biphasic and three monophasic) used for lipidomic tissue analysis by liquid chromatography-mass spectrometry. Extraction methods were assessed for their suitability for comprehensive lipid profiling across diverse tissue types: adipose, liver, and heart. These techniques were compared using lyophilised and fresh frozen samples.
    RESULTS: The study revealed significant differences in the coverage and reliability of lipid species extracted using each technique, dependent on the tissue type. The optimal extraction method for adipose tissue was butanol:methanol (BUME) (3:1) which achieved the highest lipid coverage, yield and reproducibility (886 lipids with a coefficient of variation (CV) < 30 %); methyl tert-butyl ether (MTBE) with ammonium acetate was most effective for liver tissue (707 lipids CV < 30 %) and BUME (1:1) for heart tissue (311 lipids CV < 30 %). These findings showed that the most effective lipid extraction methods are highly tissue-specific, underscoring the critical need for bespoke protocols tailored to each tissue type. The optimised tissue-specific methods were validated using an intervention study in C57BL/6 mice to investigate diet-induced metabolic changes. The results demonstrated distinct discriminating lipid profiles unique to each tissue type, with 374 lipid species from 13 subclasses significantly different between high-fat diet (HFD) and normal diet (ND) in adipose tissue, while 485 lipid species from 17 subclasses were significantly different between HFD and ND in liver tissue.
    SIGNIFICANCE AND NOVELTY: This study presents a new approach to studying lipid profiles derived from diverse tissues that substantially improve comprehensive lipid species' detection sensitivity and reliability. Our systematic evaluation provides evidence that tailored tissue-specific extraction protocols are highly valuable in comprehensive lipidomics studies, offering robust tools for reliably identifying lipid changes and facilitates a deeper understanding of tissue-specific metabolic processes in diverse research and clinical applications.
    Keywords:  Extraction solvents; Lipidomics∗; Lipids∗; Mass spectrometry; Murine tissue; Sample preparation
    DOI:  https://doi.org/10.1016/j.aca.2025.343791
  11. Se Pu. 2025 Mar;43(3): 220-227
      Bile acids (BAs), the primary components of bile, play significant roles in sugar, lipid, and cholesterol metabolism. Normal BA metabolism maintains a dynamic equilibrium by regulating gut microbiota to effectively protect the liver and intestines, thereby sustaining overall health. Conversely, abnormal BA metabolism can cause intestinal tissue and liver damage, disruption of enterohepatic circulation homeostasis, dysbiosis of gut microbiota, and gastrointestinal and hepatic diseases. Although largemouth bass (Micropterus salmoides) and grass carp (Ctenopharyngodon idella) are important freshwater fish species in China, their BA profiles have not been fully characterized. Elucidating these profiles could provide valuable data to support the aquaculture industry. In this study, a qualitative and quantitative method for the simultaneous determination of 30 BAs in the gallbladders of M. salmoides and C. idella was developed using ultra-high performance liquid chromatography-triple quadrupole mass spectrometry. The samples were centrifuged and then the supernatant was extracted, vortex-mixed with methanol, and filtered through a 0.22 μm membrane. Various mobile phase systems commonly used in liquid chromatography-mass spectrometry were investigated, including formic acid, acetic acid, ammonium formate, acetic acid-ammonium, and methanol-acetonitrile. Based on the response intensity, chromatographic separation, and peak shape of each substance, the optimal mobile phase was acetic acid and acetonitrile, and the concentration of acetic acid in water was optimized. To improve the ionization efficiency, the most effective ion scanning mode was selected by comparing the response intensities and peak conditions of each BA during mass spectrometry in positive and negative ion modes. Furthermore, the interface voltage for each BA and the ion source interface temperature were investigated to determine the optimal mass spectrometry conditions. Ultimately, separation was performed using a Shim-pack Velox SP-C18 column (100 mm×2.1 mm, 1.8 μm) with gradient elution of 0.01% acetic acid aqueous solution and acetonitrile, and the total analysis time was 14 min. The column temperature was 50 ℃ and the injection volume was 2 μL. Multiple reaction monitoring of 8 positive ions and 22 negative ions was carried out using electrospray ionization. Different series of mixed standard working solutions, prepared based on the response intensity of each BA, were used to construct standard curves. All 30 BAs exhibited good linearities within the investigated concentration ranges, with correlation coefficients (R2) of 0.9975-0.9997, indicating high accuracy. Spiked recoveries were 72.3%-117.2%, and the inter-day precisions were in the range of 0.46%-13.23%. The limits of detection and quantification were 0.01-0.75 ng/mL and 0.02-2.28 ng/mL, respectively, enabling the precise detection of low-concentration BAs. Using the established method, 19 BAs were successfully detected in the bile of M. salmoides, and 16 BAs were detected in the bile of C. idella, enriching the BA profiles of both species. Notably, five BAs present in the gallbladder of M. salmoides were undetected in the gallbladder of C. idella, whereas two BAs found in the gallbladder of C. idella were absent from the gallbladder of M. salmoides, demonstrating differences between the BA compositions of these species. The developed method is characterized by simplicity, speed, high sensitivity, and accuracy, harnessing the high-throughput advantages of ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC-MS/MS), and is suitable for the simultaneous detection of the 30 BAs in the gallbladders of M. salmoides and C. idella.
    Keywords:  Ctenopharyngodon idella; Micropterus salmoides; bile; bile acids; ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC-MS/MS)
    DOI:  https://doi.org/10.3724/SP.J.1123.2024.03004
  12. Sci Rep. 2025 Mar 01. 15(1): 7310
      The report presents first high performance liquid chromatography coupled with ultraviolet detection (HPLC-UV) based method for the determination of homocysteine thiolactone (HTL) in human urine. Sample preparation procedure chiefly involves chloroform liquid-liquid extraction of HTL and its re-extraction with hydrochloric acid, followed by evaporation to dryness and treatment of the residue with 1-benzyl-2-chloropyridinium bromide and perchloric acid. The chromatographic separation of obtained UV-absorbing 2-S-pyridinium derivative is achieved within 6 min at 25 °C on Zorbax SB-C18 (150 × 4.6 mm, 5 μm) column using gradient elution. The eluent consists of 0.1% acetic acid in a mixture with acetonitrile delivered at a flow rate of 1 mL/min. The analyte is quantified by monitoring at 316 nm. The assay linearity was observed within 0.1-1.0 µmol/L in urine. The limit of quantification was found to be 100 nmol/L. The accuracy ranged from 92.56 to 112.51% and 92.56-114.31%, while precision varied from 5.89 to 11.27% and 3.85-14.25% for intra- and inter-assay measurements, respectively. The method was successfully applied to urine samples delivered by apparently healthy donors. The presence of HTL was confirmed in twelve of eighteen study samples. The HTL concentration ranged from 36.67 to 693.12 nmol/L.
    Keywords:  1-benzyl-2-chloropyridinium bromide; Homocysteine Thiolactone; Liquid-liquid extraction; Reversed phase liquid chromatography; Ultraviolet detection; Urine
    DOI:  https://doi.org/10.1038/s41598-025-92323-y
  13. Heliyon. 2025 Feb 28. 11(4): e42461
       Background: The chromatographic measurement of polar molecules is often surprisingly complicated. On the one hand, the standard experiments use C18 columns, which is usually unsuitable. On the other hand, these types of molecules can behave vastly differently despite their similarities. Thus, finding the right chromatographic conditions is challenging. HILIC can be an obvious choice, but C18 is still used with suitable analytes. Comparing the two methods would be advantageous, but a numerical comparison can be problematic. Thus, a simple comparing and ranking system is needed and put to use to find the best method for the separation of polar basic molecules.
    Results: In this paper, nine columns with different stationary phases, from reversed-phase to hydrophilic interaction, are compared and ranked in gradient elution. The effect of pH was also considered. The measurements were repeated in acidic, near-to-neutral, and basic conditions. A straightforward system is developed to rank different stationary phases. Its foundation was peak shapes and resolutions. Every measurement condition with all the columns on the available pHs is evaluated by each property. The testing solution consisted of ten components, which aimed to cover a wide range of polar basic molecules. The comparison also focuses on these analytes. We highlighted which analyte is adaptable to different methods or which needed exclusive conditions. The resulting best column with the optimal conditions is presented and proven highly efficient for their separation.
    Significance: A straightforward comparison and ranking system is developed to test multiple chromatographic columns with different stationary phases, from reversed-phase to hydrophilic interaction in gradient elution, seeking the best method for separating polar basic molecules. Nine columns were compared in multiple conditions. The best setup resulting in the competition is presented in detail, which can be applied to a wide range of analytes.
    Keywords:  Column comparison; Hydrophilic interaction liquid chromatography; Mass spectrometry; Polar basic analytes; Reversed-phase liquid chromatography
    DOI:  https://doi.org/10.1016/j.heliyon.2025.e42461
  14. Anal Chem. 2025 Mar 06.
      Suspect screening strives to rapidly monitor a large number of substances in a sample using mass spectral libraries. For hydrophobic organic contaminants (HOCs), these libraries are traditionally based on electron ionization mass spectra. However, with the growing use of state-of-the-art mass spectrometers, which often use alternative ionization approaches and separation techniques, new suspect screening workflows and libraries are urgently needed. This study established a new suspect screening library for 1,590 HOCs, including exact mass and a combination of measured and model-predicted values for retention time (RT) and collision cross section (CCS). The accuracy of in silico predictions was assessed using standards for 102 HOCs. Thereafter, using gas chromatography-atmospheric pressure chemical ionization-ion mobility-mass spectrometry, a suspect screening workflow constrained by the full scan mass spectrum of (quasi-)molecular ions (including isotope patterns), RT, CCS, and fragmentation mass spectra, together with a continuous scoring system, was established to reduce false positives and improve identification confidence. Application of the method to fortified and standard reference sediment samples demonstrated true positive rates of 79% and 64%, respectively, with all false positives attributed to suspect isomers. This study offers a new workflow for improved suspect screening of HOCs using multidimensional information and highlights the need to enrich mass spectral databases and extend the applicable chemical space of current in silico tools to hydrophobic substances.
    DOI:  https://doi.org/10.1021/acs.analchem.4c06234
  15. J Chromatogr B Analyt Technol Biomed Life Sci. 2025 Feb 05. pii: S1570-0232(25)00058-3. [Epub ahead of print]1256 124506
      The integration of free-range beef livestock into the human food chain has been continuously threatened by outbreaks of babesiosis, which is propagated by ticks that vector the protozoans that cause the disease. The protozoans are spread among livestock by certain species of ticks, known collectively as cattle fever ticks (CFT). Although eliminated from the US in the 1940s, CFT continue to infiltrate the US by crossing the US/Mexico border on stray livestock and wildlife, and infest cattle herds. Orally administered acaricides are part of the strategy to control CFT. Parallel dosing studies, utilizing oral administration of the benzoylphenyl urea (BPU) compound diflubenzuron (DFB), were conducted in cattle and white tailed deer (WTD). We developed and validated a sensitive (<1 ppb) liquid chromatography/ tandem mass spectrometry (LC-MS/MS) method for DFB quantification in toxicology specimens. In fit-for-purpose testing, the method demonstrated accuracies within ±9 % of QC targets, and coefficient of variation percentages (%CV) of 14.8 % for whole blood, 9.0 % for plasma, and 8.7 % for serum. This work outlines the extraction and instrumental method for DFB analysis in these matrices. LC-MS/MS had not previously been used to detect and quantify DFB in whole blood, plasma, or serum. This is also the first method to employ carbon-13 labeled DFB (13C6) as an internal standard for measuring DFB in blood matrices from bovine dosing studies.
    Keywords:  Acaricides; Acetonitrile extraction; Benzoylphenyl ureas; Blood matrices; Diflubenzuron; LC-MS/MS; Tandem mass spectrometry
    DOI:  https://doi.org/10.1016/j.jchromb.2025.124506
  16. Sci Data. 2025 Mar 04. 12(1): 377
      The profiling of metabolites provides an immediate snapshot that depicts crucial physiological information, holding immense potential for the early diagnosis and prognosis of diseases, including diabetes. Herein, we proposed an optimized and in-depth target-based metabolome platform through an integration of six distinct conditions, including a normal phase, a pre-column chemical derivatization and four reversed phase separation methods for the quantification of a total of 1609 small molecules (32 sub-classes) in serum after normalization using isotope-labeled internal standards. After undergoing rigorous methodological validation and comprehensive comparison with untargeted strategies, we present a new dataset of metabolomic profile encompassing a cohort of 200 healthy individuals and 100 newly diagnosed Type 2 diabetes mellitus (T2DM) patients from the northern region of China. The overall differential analysis results indicated obvious metabolic disturbance of amino acid, fatty acids, lysophosphatidyl-choline and triacylglycerol in T2DM. We hereby make these technical validation results and the profiling dataset publicly available to the scientific community, showcasing its exceptional sensitivity and robustness as an invaluable tool for the comprehensive targeted metabolome analysis.
    DOI:  https://doi.org/10.1038/s41597-025-04652-2
  17. Anal Chem. 2025 Mar 05.
      Non-targeted analysis (NTA) using high-resolution mass spectrometry (HRMS) is a global chemical screening approach that generates information-rich data which can be used to detect and identify unknown chemicals. NTA is a powerful approach which is increasingly being used for a variety of sample types, research fields, and goals. However, there are challenges associated with accurate assessments of data quality and method performance, comparability across laboratories/instruments/methods, and communication of results/confidence. A standard mixture containing a sufficient number and diversity of chemicals would help address these needs, but is not yet commercially available. Thus, we conducted a survey of 146 NTA researchers to examine desired requirements for the broad fields, studies, and goals where NTA can be applied. We also compare this feedback to previously published in-house standard mixtures, which, we argue, are models for a standard that can be adjusted to fit the NTA community's needs and possibly commercialized. Reversed-phase liquid chromatography HRMS is one of the most common methods used for NTA; therefore, this survey is focused on characteristics necessary for these types of methods. We intend this information to communicate the need for an interdisciplinary NTA standard mixture, the importance of implementing standards, and to lower the barriers for chemical vendor standard mixture development and distribution.
    DOI:  https://doi.org/10.1021/acs.analchem.4c05710
  18. J Am Soc Mass Spectrom. 2025 Mar 05.
      Profiling of steroid hormones is incredibly valuable in clinical settings for diagnosing endocrine disorders. However, the presence of matrix effects and labor-intensive manual work in LC-MS/MS analysis has hindered its routine application. In the present study, a highly efficient and automated magnetic bead extraction method was developed to address matrix effects and quantitatively profile 15 steroid hormones in human serum. Octadecyl (C18) and N-vinylpyrrolidone divinylbenzene (HLB) modified magnetic beads were compared for enriching steroids from human serum. Following enrichment, the beads were separated using a magnetic field; the matrix was cleaned, and the steroid hormones were eluted from the beads for LC-MS/MS analysis. This entire process of enrichment, cleanup, and elution was conducted automatically, making it simple, fast, and cost-effective. The results indicated that steroid hormones could be selectively enriched from human serum in just 1 min using C18 magnetic beads. The absolute matrix effect, evaluated as the relative response between human serum matrix and methanol solution, ranged from 89.2% to 113.1% for low levels, from 82.3% to 112.0% for medium levels, and from 91.7% to 111.0% for high levels. The intrabatch coefficients of variation (CVs) and interbatch CVs were between 3.1% and 13.4% and between 3.0% and 13.7%, respectively. Recoveries were between 87.6% and 114.3% for low levels, 94.0% and 105.0% for medium levels, and 91.9% and 111.7% for high levels. The clinical application was demonstrated by profiling steroid hormones in 160 pregnant women at various gestational weeks. The results suggested that the automated magnetic bead extraction method for LC-MS/MS could effectively address matrix effects in profiling steroid hormones. To our knowledge, this is the first automated magnetic bead extraction method for LC-MS/MS profiling of steroid hormones in clinical practice.
    Keywords:  automation; liquid chromatography−tandem mass spectrometry; magnetic bead extraction; matrix effect; steroid hormone
    DOI:  https://doi.org/10.1021/jasms.4c00338
  19. Talanta. 2025 Feb 25. pii: S0039-9140(25)00322-4. [Epub ahead of print]290 127832
      Glycolic acid and allantoin are known to be responsible, at least in part, for the main activities of snail slime, such as moisturizing, skin regeneration, antioxidant, soothing and anti-inflammatory. Accordingly, a hydrophilic interaction liquid chromatography (HILIC) method for the analysis of allantoin and glycolic acid in snail slime samples was developed by a conventional UV-Vis detector and the diol-type Luna® HILIC column. An optimized eluent made up of acetonitrile/water/methanol/formic acid (90:5:5:0.1 v/v/v/v) allowed the separation of the two investigated compounds from each other and from lactic acid and hydantoin used as internal standards. Being allantoin a chiral compound, an enantioselective HPLC protocol was also developed. The chiral analysis of allantoin was performed with the Lux® 3 μm i-Amilose-3 chiral stationary phase using the same mobile phase as for the achiral analysis. The chiral method was efficiently transferred to a HPLC system coupled to triple-quadrupole mass spectrometry (MS/MS). HPLC-MS/MS analysis revealed the racemic nature of allantoin in the pure snail slime. The same profile was also observed in a prototype hydrogel prepared with snail slime. Moreover, the same method allowed to measure the amount of glycolic acid in the two investigated samples (pure snail slime and gel) and ascertain a valuable extraction recovery. The enantiomeric elution order (S)<(R) with the amylose-based phase was established coupling the results of experimental electronic circular dichroism analysis to time-dependent density functional theory simulations.
    Keywords:  Amylose-based chiral stationary phase; Diol-type stationary phase; Enantioselective analysis; Hydrophilic interaction liquid chromatography; Snail slime-based hydrogel
    DOI:  https://doi.org/10.1016/j.talanta.2025.127832
  20. Talanta. 2025 Feb 27. pii: S0039-9140(25)00345-5. [Epub ahead of print]291 127855
      Lipidomics, a rapidly evolving field within metabolomics, provides comprehensive insights into lipid profiles and their roles in health and disease. Advances in lipidomics have enabled the discovery of novel biomarkers with significant clinical applications, revolutionizing the diagnosis, prognosis, and therapeutic monitoring of various diseases. Emerging methodologies, including high-resolution mass spectrometry (HRMS), Ion mobility spectrometry (IMS), and Supercritical Fluid Chromatography (SFC) have enhanced lipid identification and quantification with remarkable analytical whip hands. These advancements are complemented by innovative sample preparation techniques ensuring the recovery of diverse lipid species with minimal degradation. Biomarker discovery with lipidomics has illuminated critical pathways in numerous diseases, including cardiovascular disorders, neurodegenerative conditions, metabolic syndromes, and cancers. Specific lipid classes, such as sphingolipids (SLs) and phospholipids (PLs) have been linked to Alzheimer's disease and diabetes, respectively, while oxylipins and eicosanoids are emerging as inflammatory biomarkers. Furthermore, lipidomic profiles have shown promise in personalized medicine, enabling the stratification of patient sub-populations and tailoring treatment strategies. This review emphasizes the latest innovative developments in analytical technologies, advanced sample preparation techniques and challenges for lipidomics research including bioinformatic tools on multiple clinical conditions. By exploring these cutting-edge developments, this review highlights the transformative potential of lipidomics in biomarker discovery across diverse clinical applications.
    Keywords:  Desorption electrospray ionization (DESI); Lipid biomarkers; Lipidomics; Pseudo-targeted lipidomics
    DOI:  https://doi.org/10.1016/j.talanta.2025.127855
  21. Biomed Chromatogr. 2025 Apr;39(4): e70043
      Apixaban is an oral anticoagulant classified as a direct factor Xa inhibitor. It is widely utilized for prophylaxis and management of thromboembolic conditions, including stroke, deep vein thrombosis, and pulmonary embolism, as a primary therapeutic option. Apixaban is subjected to stringent testing for potential genotoxic impurities during its manufacturing, due to its structure indicating the possibility of such impurity's formation. Setting limits in accordance with ICH M7 guidelines is essential to reduce patient exposure and also recommended an advanced analytical tool for testing. The present study aims to establish limits based on computational toxicological evaluation, and develop and validate a highly sensitive LS-MS/MS method for quantifying three novel genotoxic impurities of apixaban, namely impurities F, G, and H. The method was established utilizing a mobile phase comprising a pH 5.5 acetate buffer and acetonitrile in a gradient mode. Used a C18 column, of 150 mm (length) × 3.0 mm (width), 2.7 μm of particle size as stationary phase. Quantification was performed with multi-response monitoring in mass spectrometry, employing precursor ions of m/z 437.2, 525.2, and 569.1 for impurities F, G, and H, respectively. The established method is validated for its intended use in accordance with regulatory guidelines and found suitable.
    Keywords:  LC‐MS/MS; apixaban; factor Xa inhibitor; genotoxic impurities
    DOI:  https://doi.org/10.1002/bmc.70043
  22. J Proteome Res. 2025 Mar 04.
      Liquid chromatography-tandem mass spectrometry employing data-dependent acquisition (DDA) is a mature, widely used proteomics technique routinely applied to proteome profiling, protein-protein interaction studies, biomarker discovery, and protein modification analysis. Numerous tools exist for searching DDA data and myriad file formats are output as results. While some search and post processing tools include data visualization features to aid biological interpretation, they are often limited or tied to specific software pipelines. This restricts the accessibility, sharing and interpretation of data, and hinders comparison of results between different software pipelines. We developed Limelight, an easy-to-use, open-source, freely available tool that provides data sharing, analysis and visualization and is not tied to any specific software pipeline. Limelight is a data visualization tool specifically designed to provide access to the whole "data stack", from raw and annotated scan data to peptide-spectrum matches, quality control, peptides, proteins, and modifications. Limelight is designed from the ground up for sharing and collaboration and to support data from any DDA workflow. We provide tools to import data from many widely used open-mass and closed-mass search software workflows. Limelight helps maximize the utility of data by providing an easy-to-use interface for finding and interpreting data, all using the native scores from respective workflows.
    Keywords:  DDA; data visualization; mass spectrometry; proteomics; server; software development
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00968