{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T19:22:12Z","timestamp":1788463332204,"version":"build-2803163510"},"reference-count":83,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005274","name":"North-West University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005274","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Metabolomics"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tuberculous meningitis (TBM), caused by Mycobacterium tuberculosis, is the most severe form of extrapulmonary tuberculosis and isassociated with high morbidity and mortality, particularly when diagnosis is delayed. Improved understanding of the metabolic alterations associated withTBM may support the development of novel diagnostic biomarkers and provide insights into disease pathophysiology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>In this study, we applied anuntargeted two-dimensional gas chromatography\u2013time-of-flight mass spectrometry (GC\u00d7GC-TOFMS) metabolomics approach to formalin-fixed, paraffin-embedded (FFPE) postmortem human brain tissue from 41 TBM cases and 36 tissue sections from 6 non-TBM control cases. Metabolomics data wereprocessed, normalized, and analyzed using multivariate and univariate statistical approaches, including principal component analysis (PCA) and partialleast squares\u2013discriminant analysis (PLS-DA), with variable importance in projection (VIP) scores. These results were further correlated with patient clinical data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Distinct metabolic profiles were observed between TBM and control tissues. Several metabolites were significantly reduced in TBM samples, particularly within the alkane and alkene classes, with additional decreases observed in metabolites associated with alcohols, fatty acids, lipids, carbohydrates, and amino acids. These metabolic alterations suggest substantial perturbations, primarily in the host lysine degradation pathway (linked to the kynurenine pathway), in TBM-affected brain tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, these findings provide insight into the metabolic landscape of terminalTBM and suggest potential metabolic pathways that may contribute to disease pathophysiology. Further investigation of these metabolic signatures in accessible patient tissue and biofluids may support the development of biomarkers and inform future therapeutic strategies for TBM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11306-026-02511-8","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:03:01Z","timestamp":1786111381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic insights into the pathophysiology of tuberculous meningitis in FFPE postmortem human brain tissue"],"prefix":"10.1007","volume":"22","author":[{"given":"Abisola R.","family":"Isaiah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Du Toit","family":"Loots","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelia A.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan Dan","family":"Zaharie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Marceline Tutu","family":"van Furth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn","family":"van der Kuip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shayne","family":"Mason","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"issue":"10","key":"2511_CR1","doi-asserted-by":"publisher","first-page":"933","DOI":"10.3390\/metabo12100933","volume":"12","author":"F Amalia","year":"2022","unstructured":"Amalia, F., Syamsunarno, M. R. A., Triatin, R. D., Fatimah, S. N., Chaidir, L., & Achmad, T. H. (2022). The role of amino acids in tuberculosis infection: A literature review. Metabolites, 12(10), 933.","journal-title":"Metabolites"},{"issue":"10","key":"2511_CR2","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1093\/bioinformatics\/btx012","volume":"33","author":"S Basu","year":"2017","unstructured":"Basu, S., Duren, W., Evans, C. R., Burant, C. F., Michailidis, G., & Karnovsky, A. (2017). Sparse network modeling and metscape-based visualization methods for the analysis of large-scale metabolomics data. Bioinformatics, 33(10), 1545\u20131553.","journal-title":"Bioinformatics"},{"issue":"10","key":"2511_CR3","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1042\/BCJ20200194","volume":"477","author":"SM Batt","year":"2020","unstructured":"Batt, S. M., Minnikin, D. E., & Besra, G. S. (2020). The thick waxy coat of mycobacteria, a protective layer against antibiotics and the host\u2019s immune system. Biochemical Journal, 477(10), 1983\u20132006.","journal-title":"Biochemical Journal"},{"issue":"1","key":"2511_CR4","doi-asserted-by":"publisher","first-page":"2875","DOI":"10.1038\/s41598-018-37816-9","volume":"9","author":"D Beri","year":"2019","unstructured":"Beri, D., Ramdani, G., Balan, B., et al. (2019). Insights into physiological roles of unique metabolites released from Plasmodium-infected RBCs and their potential as clinical biomarkers for malaria. Scientific Reports, 9(1), 2875.","journal-title":"Scientific Reports"},{"issue":"1","key":"2511_CR5","doi-asserted-by":"publisher","first-page":"e8614","DOI":"10.1371\/journal.pone.0008614","volume":"5","author":"M Berney","year":"2010","unstructured":"Berney, M., & Cook, G. M. (2010). Unique flexibility in energy metabolism allows mycobacteria to combat starvation and hypoxia. PloS One, 5(1), e8614.","journal-title":"PloS One"},{"issue":"4","key":"2511_CR6","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1111\/j.1471-4159.1977.tb07781.x","volume":"29","author":"J Bourre","year":"1977","unstructured":"Bourre, J., Cassagne, C., Larrouquere-Regnier, S., & Darriet, D. (1977). Occurrence of alkanes in brain myelin. Comparison between normal and quaking mouse. Journal of Neurochemistry, 29(4), 645\u2013648.","journal-title":"Journal of Neurochemistry"},{"issue":"4","key":"2511_CR7","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1158\/1541-7786.MCR-16-0262","volume":"15","author":"S Cacciatore","year":"2017","unstructured":"Cacciatore, S., Zadra, G., Bango, C., et al. (2017). Metabolic profiling in formalin-fixed and paraffin-embedded prostate cancer tissues. Molecular Cancer Research, 15(4), 439\u2013447.","journal-title":"Molecular Cancer Research"},{"key":"2511_CR8","unstructured":"Chang, I. J., Lam, C., & Vockley, J. (2024). Medium-chain acyl-coenzyme A dehydrogenase deficiency. GeneReviews\u00ae."},{"issue":"2","key":"2511_CR9","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1128\/AEM.65.2.549-552.1999","volume":"65","author":"SA Churchill","year":"1999","unstructured":"Churchill, S. A., Harper, J. P., & Churchill, P. F. (1999). Isolation and characterization of a Mycobacterium species capable of degrading three-and four-ring aromatic and aliphatic hydrocarbons. Applied and Environmental Microbiology, 65(2), 549\u2013552.","journal-title":"Applied and Environmental Microbiology"},{"issue":"2","key":"2511_CR10","doi-asserted-by":"publisher","first-page":"191","DOI":"10.5114\/aoms.2013.33181","volume":"9","author":"M Coelho","year":"2013","unstructured":"Coelho, M., Oliveira, T., & Fernandes, R. (2013). State of the art paper Biochemistry of adipose tissue: An endocrine organ. Archives of Medical Science, 9(2), 191\u2013200.","journal-title":"Archives of Medical Science"},{"key":"2511_CR12","doi-asserted-by":"crossref","unstructured":"Cooper, G., & Adams, K. W. (2022). The cell: A molecular approach. Oxford University Press.","DOI":"10.1093\/hesc\/9780197583746.001.0001"},{"key":"2511_CR11","doi-asserted-by":"publisher","first-page":"1427472","DOI":"10.3389\/fimmu.2024.1427472","volume":"15","author":"SK Cooper","year":"2024","unstructured":"Cooper, S. K., Ackart, D. F., Lanni, F., Henao-Tamayo, M., Anderson, G. B., & Podell, B. K. (2024). Heterogeneity in immune cell composition is associated with Mycobacterium tuberculosis replication at the granuloma level. Frontiers in Immunology, 15, 1427472.","journal-title":"Frontiers in Immunology"},{"issue":"2","key":"2511_CR13","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1002\/JLB.MR0318-102R","volume":"105","author":"AG Davis","year":"2019","unstructured":"Davis, A. G., Rohlwink, U. K., Proust, A., Figaji, A. A., & Wilkinson, R. J. (2019). The pathogenesis of tuberculous meningitis. Journal of Leukocyte Biology, 105(2), 267\u2013280.","journal-title":"Journal of Leukocyte Biology"},{"issue":"2","key":"2511_CR14","doi-asserted-by":"publisher","first-page":"e96","DOI":"10.1016\/S1473-3099(25)00364-0","volume":"26","author":"J Donovan","year":"2026","unstructured":"Donovan, J., Cresswell, F. V., Tucker, E. W., et al. (2026). A clinical practice guideline for tuberculous meningitis. The Lancet Infectious Diseases, 26(2), e96\u2013e111.","journal-title":"The Lancet Infectious Diseases"},{"issue":"6","key":"2511_CR15","doi-asserted-by":"publisher","first-page":"700","DOI":"10.4103\/ijmr.IJMR_1441_16","volume":"146","author":"M Druszczynska","year":"2017","unstructured":"Druszczynska, M., Wawrocki, S., Szewczyk, R., & Rudnicka, W. (2017). Mycobacteria-derived biomarkers for tuberculosis diagnosis. Indian Journal of Medical Research, 146(6), 700\u2013707.","journal-title":"Indian Journal of Medical Research"},{"issue":"3","key":"2511_CR16","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.tube.2013.02.008","volume":"93","author":"I Du Preez","year":"2013","unstructured":"Du Preez, I., & Loots, D. (2013). New sputum metabolite markers implicating adaptations of the host to Mycobacterium tuberculosis, and vice versa. Tuberculosis, 93(3), 330\u2013337.","journal-title":"Tuberculosis"},{"key":"2511_CR17","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.jtbi.2013.03.008","volume":"328","author":"M El-Kebir","year":"2013","unstructured":"El-Kebir, M., Van der Kuip, M., Van Furth, A., & Kirschner, D. (2013). Computational modeling of tuberculous meningitis reveals an important role for tumor necrosis factor-\u03b1. Journal of Theoretical Biology, 328, 43\u201353.","journal-title":"Journal of Theoretical Biology"},{"issue":"7989","key":"2511_CR18","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1038\/s41586-023-06749-3","volume":"623","author":"H Fan","year":"2023","unstructured":"Fan, H., Xia, S., Xiang, J., et al. (2023). Trans-vaccenic acid reprograms CD8\u2009+\u2009T cells and anti-tumour immunity. Nature, 623(7989), 1034\u20131043.","journal-title":"Nature"},{"issue":"1-2","key":"2511_CR19","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/S0009-8981(99)00129-1","volume":"287","author":"T Fujita","year":"1999","unstructured":"Fujita, T., Hada, T., & Higashino, K. (1999). Origin of D-and L-pipecolic acid in human physiological fluids: A study of the catabolic mechanism to pipecolic acid using the lysine loading test. Clinica Chimica Acta, 287(1-2), 145\u2013156.","journal-title":"Clinica Chimica Acta"},{"key":"2511_CR20","doi-asserted-by":"crossref","unstructured":"Gouzy, A., Healy, C., Black, K. A., Rhee, K. Y., & Ehrt, S. (2021). Growth of Mycobacterium tuberculosis at acidic pH depends on lipid assimilation and is accompanied by reduced GAPDH activity. Proceedings of the National Academy of Sciences,  118(32): e2024571118.","DOI":"10.1073\/pnas.2024571118"},{"key":"2511_CR21","doi-asserted-by":"crossref","unstructured":"Gray, R. M., Hunt, D. M., Silva dos Santos, M. (2025). Mycobacterium tuberculosis overcomes phosphate starvation by extensively remodelling its lipidome with phosphorus-free lipids. Nature Communications.","DOI":"10.1101\/2024.09.27.615480"},{"issue":"1","key":"2511_CR22","doi-asserted-by":"publisher","first-page":"4215","DOI":"10.1038\/s41467-019-12224-3","volume":"10","author":"EJ Hasenoehrl","year":"2019","unstructured":"Hasenoehrl, E. J., Rae Sajorda, D., Berney-Meyer, L., et al. (2019). Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection. Nature Communications, 10(1), 4215.","journal-title":"Nature Communications"},{"key":"2511_CR23","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez, J. A., L\u00f3pez-S\u00e1nchez, R. C., & Rend\u00f3n-Ram\u00edrez, A. (2016). Lipids and oxidative stress associated with ethanol-induced neurological damage. Oxidative Medicine and Cellular Longevity, 2016(1), 1543809.","DOI":"10.1155\/2016\/1543809"},{"issue":"3","key":"2511_CR24","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1111\/j.2042-3306.1984.tb01893.x","volume":"16","author":"A Higgins","year":"1984","unstructured":"Higgins, A., & Lees, P. (1984). The acute inflammatory process, arachidonic acid metabolism and the mode of action of anti-inflammatory drugs. Equine Veterinary Journal, 16(3), 163\u2013175.","journal-title":"Equine Veterinary Journal"},{"issue":"3","key":"2511_CR25","doi-asserted-by":"publisher","first-page":"248","DOI":"10.3390\/brainsci15030248","volume":"15","author":"BY Hollingworth","year":"2025","unstructured":"Hollingworth, B. Y., Pallier, P. N., Jenkins, S. I., & Chen, R. (2025). Hypoxic neuroinflammation in the pathogenesis of multiple sclerosis. Brain Sciences, 15(3), 248.","journal-title":"Brain Sciences"},{"key":"2511_CR26","doi-asserted-by":"crossref","unstructured":"Hundemer, G. L., & Fenves, A. Z. (2017). Acquired 5-oxoproline acidemia successfully treated with N-acetylcysteine. Baylor University Medical Center Proceedings (pp. 169\u2009\u2013\u200970). Taylor & Francis.","DOI":"10.1080\/08998280.2017.11929570"},{"issue":"4","key":"2511_CR29","doi-asserted-by":"publisher","first-page":"103442","DOI":"10.1016\/j.xpro.2024.103442","volume":"5","author":"AR Isaiah","year":"2024","unstructured":"Isaiah, A. R., Luies, L., Williams, A. A., et al. (2024). Protocol for unified metabolomics and proteomics analysis of formalin-fixed paraffin-embedded tissue. STAR Protocols, 5(4), 103442.","journal-title":"STAR Protocols"},{"issue":"1","key":"2511_CR31","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1186\/s12879-025-11740-6","volume":"25","author":"AR Isaiah","year":"2025","unstructured":"Isaiah, A. R., Williams, M., Loots, D. T., et al. (2025). Potential biomarkers for tuberculous meningitis diagnosis using metabolomics and proteomics: A systematic review. BMC Infectious Diseases, 25(1), 1298.","journal-title":"BMC Infectious Diseases"},{"issue":"5","key":"2511_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11306-025-02304-5","volume":"21","author":"S Isaiah","year":"2025","unstructured":"Isaiah, S., Loots, D. T., van Furth, A., et al. (2025). Exploratory investigation of urinary alkanes and other volatile organic compounds in paediatric patients with tuberculous meningitis. Metabolomics, 21(5), 1\u201311.","journal-title":"Metabolomics"},{"key":"2511_CR28","doi-asserted-by":"publisher","first-page":"1253983","DOI":"10.3389\/fmolb.2024.1253983","volume":"11","author":"S Isaiah","year":"2024","unstructured":"Isaiah, S., Loots, D. T., van Reenen, M., et al. (2024). Urinary metabolic characterization of advanced tuberculous meningitis cases in a South African paediatric population. Frontiers in Molecular Biosciences, 11, 1253983.","journal-title":"Frontiers in Molecular Biosciences"},{"issue":"1","key":"2511_CR30","doi-asserted-by":"publisher","first-page":"19471","DOI":"10.1038\/s41598-024-70419-1","volume":"14","author":"S Isaiah","year":"2024","unstructured":"Isaiah, S., Westerhuis, J. A., Loots, D. T., et al. (2024). The diagnostic potential of urine in paediatric patients undergoing initial treatment for tuberculous meningitis. Scientific Reports, 14(1), 19471.","journal-title":"Scientific Reports"},{"issue":"6","key":"2511_CR32","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1038\/s41590-018-0119-x","volume":"19","author":"SK Jain","year":"2018","unstructured":"Jain, S. K., Tobin, D. M., Tucker, E. W., et al. (2018). Tuberculous meningitis: A roadmap for advancing basic and translational research. Nature Immunology, 19(6), 521\u2013525.","journal-title":"Nature Immunology"},{"key":"2511_CR33","doi-asserted-by":"crossref","unstructured":"Kalia, N. P., Singh, S., Hards, K. (2023). M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments. Cell Reports ; 42(5).","DOI":"10.1016\/j.celrep.2023.112444"},{"issue":"4","key":"2511_CR34","doi-asserted-by":"publisher","first-page":"254","DOI":"10.3390\/membranes11040254","volume":"11","author":"IS Kleinw\u00e4chter","year":"2021","unstructured":"Kleinw\u00e4chter, I. S., Pannwitt, S., Centi, A., et al. (2021). The bacteriostatic activity of 2-phenylethanol derivatives correlates with membrane binding affinity. Membranes, 11(4), 254.","journal-title":"Membranes"},{"key":"2511_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1559-0275-9-12","volume":"9","author":"GSS Kumar","year":"2012","unstructured":"Kumar, G. S. S., Venugopal, A. K., Mahadevan, A., et al. (2012). Quantitative proteomics for identifying biomarkers for tuberculous meningitis. Clinical Proteomics, 9, 1\u201313.","journal-title":"Clinical Proteomics"},{"key":"2511_CR36","doi-asserted-by":"publisher","first-page":"e71946","DOI":"10.7554\/eLife.71946","volume":"10","author":"T Laval","year":"2021","unstructured":"Laval, T., Pedr\u00f3-Cos, L., Malaga, W., et al. (2021). De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis. Elife, 10, e71946.","journal-title":"Elife"},{"key":"2511_CR37","doi-asserted-by":"publisher","first-page":"100703","DOI":"10.1016\/j.medj.2025.100703","volume":"6","author":"THN Le","year":"2025","unstructured":"Le, T. H. N., van Abeelen, K. C., Ardiansyah, E., et al. (2025). Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis uncovers pathways associated with mortality. Med, 6, 100703.","journal-title":"Med"},{"issue":"2","key":"2511_CR38","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1080\/19768354.2021.1901781","volume":"25","author":"H Lee","year":"2021","unstructured":"Lee, H., Jang, J-H., & Kim, S-J. (2021). Malonic acid suppresses lipopolysaccharide-induced BV2 microglia cell activation by inhibiting the p38 MAPK\/NF-\u03baB pathway. Animal Cells and Systems, 25(2), 110\u2013118.","journal-title":"Animal Cells and Systems"},{"issue":"7","key":"2511_CR39","doi-asserted-by":"publisher","first-page":"102110","DOI":"10.1016\/j.jbc.2022.102110","volume":"298","author":"YC Lin","year":"2022","unstructured":"Lin, Y. C., Cheung, G., Porter, E., & Papadopoulos, V. (2022). The neurosteroid pregnenolone is synthesized by a mitochondrial P450 enzyme other than CYP11A1 in human glial cells. Journal of Biological Chemistry, 298(7), 102110.","journal-title":"Journal of Biological Chemistry"},{"issue":"1","key":"2511_CR40","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1186\/s12866-014-0242-2","volume":"14","author":"P Liu","year":"2014","unstructured":"Liu, P., Cheng, Y., Yang, M., et al. (2014). Mechanisms of action for 2-phenylethanol isolated from Kloeckera apiculata in control of Penicillium molds of citrus fruits. BMC Microbiology, 14(1), 242.","journal-title":"BMC Microbiology"},{"key":"2511_CR41","doi-asserted-by":"publisher","first-page":"1427559","DOI":"10.3389\/fimmu.2024.1427559","volume":"15","author":"J Lyu","year":"2024","unstructured":"Lyu, J., Narum, D. E., Baldwin, S. L., et al. (2024). Understanding the development of tuberculous granulomas: Insights into host protection and pathogenesis, a review in humans and animals. Frontiers in Immunology, 15, 1427559.","journal-title":"Frontiers in Immunology"},{"issue":"9","key":"2511_CR42","doi-asserted-by":"publisher","first-page":"295","DOI":"10.3390\/biomedicines8090295","volume":"8","author":"AJ L\u00f3pez-Gambero","year":"2020","unstructured":"L\u00f3pez-Gambero, A. J., Sanjuan, C., Serrano-Castro, P. J., Su\u00e1rez, J., & Rodr\u00edguez de Fonseca, F. (2020). The biomedical uses of inositols: A nutraceutical approach to metabolic dysfunction in aging and neurodegenerative diseases. Biomedicines, 8(9), 295.","journal-title":"Biomedicines"},{"key":"2511_CR43","doi-asserted-by":"crossref","unstructured":"Mancini, M., Andreassi, A., Salvioni, M., Pelliccione, F., Mantellassi, G., & Banderali, G. (2016). Myoinositol and D-chiro inositol in improving insulin resistance in obese male children: Preliminary data. International Journal of Endocrinology, 2016(1), 8720342.","DOI":"10.1155\/2016\/8720342"},{"issue":"6","key":"2511_CR44","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1080\/1354750X.2022.2071991","volume":"27","author":"CM Manyelo","year":"2022","unstructured":"Manyelo, C. M., Solomons, R. S., Snyders, C. I., et al. (2022). Validation of host cerebrospinal fluid protein biomarkers for early diagnosis of tuberculous meningitis in children: A replication and new biosignature discovery study. Biomarkers, 27(6), 549\u2013561.","journal-title":"Biomarkers"},{"issue":"1","key":"2511_CR45","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.chembiol.2013.11.011","volume":"21","author":"H Marrakchi","year":"2014","unstructured":"Marrakchi, H., Lan\u00e9elle, M-A., & Daff\u00e9, M. (2014). Mycolic acids: Structures, biosynthesis, and beyond. Chemistry & Biology, 21(1), 67\u201385.","journal-title":"Chemistry & Biology"},{"issue":"1","key":"2511_CR46","first-page":"798764","volume":"2011","author":"GE Marx","year":"2011","unstructured":"Marx, G. E., & Chan, E. D. (2011). Tuberculous meningitis: Diagnosis and treatment overview. Tuberculosis Research and Treatment, 2011(1), 798764.","journal-title":"Tuberculosis Research and Treatment"},{"issue":"1","key":"2511_CR48","doi-asserted-by":"publisher","first-page":"e385","DOI":"10.1002\/edm2.385","volume":"6","author":"E Mason","year":"2023","unstructured":"Mason, E., Hindmarch, C. C., & Dunham-Snary, K. J. (2023). Medium\u2010chain Acyl\u2010COA dehydrogenase deficiency: Pathogenesis, diagnosis, and treatment. Endocrinology Diabetes & Metabolism, 6(1), e385.","journal-title":"Endocrinology Diabetes & Metabolism"},{"issue":"4","key":"2511_CR47","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1007\/s11306-014-0741-z","volume":"11","author":"S Mason","year":"2015","unstructured":"Mason, S., van Furth, A. M., Mienie, L. J., et al. (2015). A hypothetical astrocyte\u2013microglia lactate shuttle derived from a 1H NMR metabolomics analysis of cerebrospinal fluid from a cohort of South African children with tuberculous meningitis. Metabolomics, 11(4), 822\u2013837.","journal-title":"Metabolomics"},{"key":"2511_CR49","doi-asserted-by":"publisher","first-page":"534","DOI":"10.3389\/fnins.2017.00534","volume":"11","author":"S Mason","year":"2017","unstructured":"Mason, S., Reinecke, C. J., & Solomons, R. (2017). Cerebrospinal fluid amino acid profiling of pediatric cases with tuberculous meningitis. Frontiers in Neuroscience, 11, 534.","journal-title":"Frontiers in Neuroscience"},{"issue":"2","key":"2511_CR50","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1111\/j.1574-6968.2011.02493.x","volume":"328","author":"R McNerney","year":"2012","unstructured":"McNerney, R., Mallard, K., Okolo, P. I., & Turner, C. (2012). Production of volatile organic compounds by mycobacteria. FEMS Microbiology Letters, 328(2), 150\u2013156.","journal-title":"FEMS Microbiology Letters"},{"key":"2511_CR51","doi-asserted-by":"crossref","unstructured":"Mori, T., & Hodgson, J. (2013). Fatty acids: Health effects of omega-6 polyunsaturated fatty acids. Elsevier.","DOI":"10.1016\/B978-0-12-375083-9.00100-8"},{"issue":"4","key":"2511_CR52","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1046\/j.1365-2958.2003.03900.x","volume":"51","author":"F Movahedzadeh","year":"2004","unstructured":"Movahedzadeh, F., Smith, D. A., Norman, R. A., et al. (2004). The Mycobacterium tuberculosis ino1 gene is essential for growth and virulence. Molecular Microbiology, 51(4), 1003\u20131014.","journal-title":"Molecular Microbiology"},{"issue":"1","key":"2511_CR53","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/1471-2180-10-50","volume":"10","author":"F Movahedzadeh","year":"2010","unstructured":"Movahedzadeh, F., Wheeler, P. R., Dinadayala, P., et al. (2010). Inositol monophosphate phosphatase genes of Mycobacterium tuberculosis. BMC Microbiology, 10(1), 50.","journal-title":"BMC Microbiology"},{"issue":"12","key":"2511_CR54","doi-asserted-by":"publisher","first-page":"4596","DOI":"10.1074\/jbc.RA118.005543","volume":"294","author":"S Murugan","year":"2019","unstructured":"Murugan, S., Jakka, P., Namani, S., Mujumdar, V., & Radhakrishnan, G. (2019). The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation. Journal of Biological Chemistry, 294(12), 4596\u20134607.","journal-title":"Journal of Biological Chemistry"},{"issue":"1","key":"2511_CR55","doi-asserted-by":"publisher","first-page":"54","DOI":"10.3390\/cells14010054","volume":"14","author":"L M\u00fcller","year":"2025","unstructured":"M\u00fcller, L., Di Benedetto, S., & M\u00fcller, V. (2025). From homeostasis to neuroinflammation: Insights into cellular and molecular interactions and network dynamics. Cells, 14(1), 54.","journal-title":"Cells"},{"key":"2511_CR56","doi-asserted-by":"publisher","first-page":"937946","DOI":"10.3389\/fpls.2022.937946","volume":"13","author":"M Nabi","year":"2022","unstructured":"Nabi, M., Tabassum, N., & Ganai, B. A. (2022). Phytochemical screening and antibacterial activity of Skimmia anquetilia NP Taylor and Airy Shaw: A first study from Kashmir Himalaya. Frontiers in Plant Science, 13, 937946.","journal-title":"Frontiers in Plant Science"},{"issue":"24","key":"2511_CR57","doi-asserted-by":"publisher","first-page":"2909","DOI":"10.2174\/1381612826666200612163326","volume":"26","author":"KO Ndjoubi","year":"2020","unstructured":"Ndjoubi, K. O., Sharma, R., & Hussein, A. A. (2020). The potential of natural diterpenes against tuberculosis: An updated review. Current Pharmaceutical Design, 26(24), 2909\u20132932.","journal-title":"Current Pharmaceutical Design"},{"key":"2511_CR58","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.neures.2018.08.013","volume":"139","author":"N Ohno","year":"2019","unstructured":"Ohno, N., & Ikenaka, K. (2019). Axonal and neuronal degeneration in myelin diseases. Neuroscience Research, 139, 48\u201357.","journal-title":"Neuroscience Research"},{"key":"2511_CR59","unstructured":"Organization, W. H. (2024). Global tuberculosis report 2024. World Health Organization."},{"key":"2511_CR60","doi-asserted-by":"publisher","first-page":"961","DOI":"10.3389\/fmicb.2018.00961","volume":"9","author":"C Pac\u00edfico","year":"2018","unstructured":"Pac\u00edfico, C., Fernandes, P., & De Carvalho, C. C. (2018). Mycobacterial response to organic solvents and possible implications on cross-resistance with antimicrobial agents. Frontiers in Microbiology, 9, 961.","journal-title":"Frontiers in Microbiology"},{"key":"2511_CR61","doi-asserted-by":"crossref","unstructured":"Pandey, A. K., & Sassetti, C. M. (2008). Mycobacterial persistence requires the utilization of host cholesterol. Proceedings of the National Academy of Sciences, 105(11): 4376-80.","DOI":"10.1073\/pnas.0711159105"},{"issue":"6","key":"2511_CR62","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1111\/j.1742-7843.2004.t01-1-pto950505.x","volume":"95","author":"GI Panoutsopoulos","year":"2004","unstructured":"Panoutsopoulos, G. I., Kouretas, D., Gounaris, E. G., & Beedham, C. (2004). Enzymatic oxidation of 2-phenylethylamine to phenylacetic acid and 2\u2010phenylethanol with special reference to the metabolism of its intermediate phenylacetaldehyde. Basic & Clinical Pharmacology & Toxicology, 95(6), 273\u2013279.","journal-title":"Basic & Clinical Pharmacology & Toxicology"},{"key":"2511_CR63","doi-asserted-by":"crossref","unstructured":"Pintaudi, B., Di Vieste, G., & Bonomo, M. (2016). The effectiveness of Myo-inositol and D\u2010chiro inositol treatment in type 2 diabetes. International Journal of Endocrinology, 2016(1), 9132052.","DOI":"10.1155\/2016\/9132052"},{"issue":"1","key":"2511_CR64","doi-asserted-by":"publisher","first-page":"29366","DOI":"10.1038\/s41598-025-15000-0","volume":"15","author":"ON Plaatjie","year":"2025","unstructured":"Plaatjie, O. N., van Furth, A. M. T., Solomons, R., van der Kuip, M., & Mason, S. (2025). CSF carnitine is a potential biomarker in paediatric tuberculous meningitis. Scientific Reports, 15(1), 29366.","journal-title":"Scientific Reports"},{"key":"2511_CR65","doi-asserted-by":"crossref","unstructured":"Plaatjie, O. N., van Furth, A. M. T., Solomons, R., van der Kuip, M., & Mason, S. (2025). Characterization of CSF tryptophan metabolites in South African children with tuberculous meningitis. International Journal of Infectious Diseases, 108219.","DOI":"10.1016\/j.ijid.2025.108219"},{"key":"2511_CR66","doi-asserted-by":"crossref","unstructured":"Reichlen, M. J., Leistikow, R. L., Scobey, M. S., Born, S. E., & Voskuil, M. I. (2017). Anaerobic Mycobacterium tuberculosis cell death stems from intracellular acidification mitigated by the DosR regulon. Journal of Bacteriology, 199(23). 10.1128\/jb. 00320\u2009\u2013\u200917.","DOI":"10.1128\/JB.00320-17"},{"issue":"3","key":"2511_CR67","doi-asserted-by":"publisher","first-page":"e216","DOI":"10.1038\/emm.2016.4","volume":"48","author":"E Roh","year":"2016","unstructured":"Roh, E., Song, D. K., & Kim, M-S. (2016). Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism. Experimental & Molecular Medicine, 48(3), e216.","journal-title":"Experimental & Molecular Medicine"},{"key":"2511_CR68","doi-asserted-by":"crossref","unstructured":"Saavedra, J. M., & Axelrod, J. (1973). Demonstration and distribution of phenylethanolamine in brain and other tissues. Proceedings of the National Academy of Sciences, 70(3), 769\u2009\u2013\u200972.","DOI":"10.1073\/pnas.70.3.769"},{"issue":"14","key":"2511_CR69","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.3390\/foods13142164","volume":"13","author":"L Sanjulian","year":"2024","unstructured":"Sanjulian, L., Lamas, A., Barreiro, R., et al. (2024). Investigating the dietary impact on trans-vaccenic acid (Trans-C18: 1 n-7) and other beneficial fatty acids in breast milk and infant formulas. Foods, 13(14), 2164.","journal-title":"Foods"},{"key":"2511_CR70","doi-asserted-by":"crossref","unstructured":"Schmitzer, V., Choo, W. S., & Urbanek Krajnc, A. (2022). Phytochemicals in ornamental plants: Synthesis, nutraceutical prospects and applied focus\u2014women in plant science series. Frontiers Media SA, 13, 1016968.","DOI":"10.3389\/fpls.2022.1016968"},{"issue":"8","key":"2511_CR71","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1038\/s12276-024-01273-4","volume":"56","author":"KC Shin","year":"2024","unstructured":"Shin, K. C., Ali Moussa, H. Y., & Park, Y. (2024). Cholesterol imbalance and neurotransmission defects in neurodegeneration. Experimental & Molecular Medicine, 56(8), 1685\u20131690.","journal-title":"Experimental & Molecular Medicine"},{"key":"2511_CR72","doi-asserted-by":"publisher","first-page":"804838","DOI":"10.3389\/fneur.2022.804838","volume":"13","author":"AR Sholeye","year":"2022","unstructured":"Sholeye, A. R., Williams, A. A., Loots, D. T., van Tutu, A. M., van der Kuip, M., & Mason, S. (2022). Tuberculous granuloma: Emerging insights from proteomics and metabolomics. Frontiers in Neurology, 13, 804838.","journal-title":"Frontiers in Neurology"},{"issue":"12","key":"2511_CR73","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1023\/A:1014289232039","volume":"26","author":"A Silva","year":"2001","unstructured":"Silva, A., Silva, C., Ruschel, C., et al. (2001). L-pyroglutamic acid inhibits energy production and lipid synthesis in cerebral cortex of young rats in vitro. Neurochemical Research, 26(12), 1277\u20131283.","journal-title":"Neurochemical Research"},{"key":"2511_CR74","doi-asserted-by":"crossref","unstructured":"Snow, N. (2024). From detector to decision, Part III: Fundamentals of calibration in gas chromatography.","DOI":"10.56530\/lcgc.int.gc8481s2"},{"issue":"1","key":"2511_CR75","doi-asserted-by":"publisher","first-page":"10732","DOI":"10.1038\/s41598-019-47057-z","volume":"9","author":"J Song","year":"2019","unstructured":"Song, J., Kim, Y-S., Lee, D. H., et al. (2019). Neuroprotective effects of oleic acid in rodent models of cerebral ischaemia. Scientific Reports, 9(1), 10732.","journal-title":"Scientific Reports"},{"issue":"2","key":"2511_CR76","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s11306-024-02098-y","volume":"20","author":"A Thirion","year":"2024","unstructured":"Thirion, A., Loots, D. T., Williams, M. E., Solomons, R., & Mason, S. (2024). An exploratory investigation of the CSF metabolic profile of HIV in a South African paediatric cohort using GCxGC-TOF\/MS. Metabolomics, 20(2), 33.","journal-title":"Metabolomics"},{"issue":"5","key":"2511_CR83","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/j.jinf.2020.06.078","volume":"81","author":"CDW Van Zyl","year":"2020","unstructured":"Van Zyl, C. D. W., Solomons, R., Van Reenen, M., & Mason, S. (2020). Metabolic characterization of tuberculous meningitis in a South African paediatric population using 1H NMR metabolomics. Journal of Infection, 81(5), 743\u2013752.","journal-title":"Journal of Infection"},{"key":"2511_CR77","doi-asserted-by":"crossref","unstructured":"Venkataraman, S. S., Regone, R., Ammar, H. M., & Govindu, R. R. (2019). Pyroglutamic acidemia: An underrecognized and underdiagnosed cause of high anion gap metabolic acidosis-a case report and review of literature. Cureus , 11(7).","DOI":"10.7759\/cureus.5229"},{"key":"2511_CR78","doi-asserted-by":"crossref","unstructured":"Vockley, J. (2021). Organic acidemias and disorders of fatty acid oxidation. Emery and Rimoin\u2019s principles and practice of medical genetics and genomics (pp. 279\u2013333). Elsevier.","DOI":"10.1016\/B978-0-12-812535-9.00008-X"},{"issue":"1\u20132","key":"2511_CR79","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.jneuroim.2006.11.014","volume":"184","author":"Q Wang","year":"2007","unstructured":"Wang, Q., Tang, X. N., & Yenari, M. A. (2007). The inflammatory response in stroke. Journal of Neuroimmunology, 184(1\u20132), 53\u201368.","journal-title":"Journal of Neuroimmunology"},{"key":"2511_CR80","doi-asserted-by":"publisher","first-page":"6","DOI":"10.3389\/fncel.2019.00006","volume":"13","author":"G Xu","year":"2019","unstructured":"Xu, G., Li, C., Parsiola, A. L., et al. (2019). Dose-dependent influences of ethanol on ischemic stroke: Role of inflammation. Frontiers in Cellular Neuroscience, 13, 6.","journal-title":"Frontiers in Cellular Neuroscience"},{"issue":"4","key":"2511_CR81","doi-asserted-by":"publisher","first-page":"e233306","DOI":"10.1136\/bcr-2019-233306","volume":"13","author":"A Zand Irani","year":"2020","unstructured":"Zand Irani, A., Almuwais, A., & Gibbons, H. (2020). Acquired pyroglutamic acidosis due to long-term dicloxacillin and paracetamol use. BMJ Case Reports, 13(4), e233306.","journal-title":"BMJ Case Reports"},{"issue":"1","key":"2511_CR82","doi-asserted-by":"publisher","first-page":"3103","DOI":"10.1038\/s41467-024-47458-3","volume":"15","author":"N Zhang","year":"2024","unstructured":"Zhang, N., Wang, X., Feng, M., et al. (2024). Early-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice. Nature Communications, 15(1), 3103.","journal-title":"Nature Communications"}],"container-title":["Metabolomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11306-026-02511-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11306-026-02511-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11306-026-02511-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T19:02:19Z","timestamp":1788462139000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11306-026-02511-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,7]]},"references-count":83,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["2511"],"URL":"https:\/\/doi.org\/10.1007\/s11306-026-02511-8","relation":{},"ISSN":["1573-3890"],"issn-type":[{"value":"1573-3890","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,7]]},"assertion":[{"value":"14 May 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"138"}}