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Article ; Online: Accurate redox state indication by in situ derivatization with N-ethylmaleimide - Profiling of transsulfuration and glutathione pathway metabolites by UPLC-MS/MS.

Langner, Mathias / Fröbel, Dennis / Helm, Jana / Chavakis, Triantafyllos / Peitzsch, Mirko / Bechmann, Nicole

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences

2024 Volume 1236, Page(s) 124062

Abstract: Background: Reduced and oxidized glutathione play an important role for the intracellular detoxification of reactive oxygen species. The iron-dependent formation of such reactive oxygen species in conjunction with the inhibition of the redox-balancing ... ...

Abstract	Background: Reduced and oxidized glutathione play an important role for the intracellular detoxification of reactive oxygen species. The iron-dependent formation of such reactive oxygen species in conjunction with the inhibition of the redox-balancing enzyme glutathione peroxidase 4 underlie an imbalance in the cellular redox state, thereby resulting in a non-apoptotic form of cell death, defined as ferroptosis, which is relevant in several pathologies. Methods: Here we present a rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) based method providing the accurate quantification of 12 glutathione pathway metabolites after in situ derivatization with N-Ethylmaleimide (NEM). The method was validated regards linearity, recovery and accuracy as well as precision. The assay includes glutathione and its oxidized form glutathione disulfide. Furthermore, the related precursors cysteine, cystine, glutamic acid, γ-glutamylcysteine and cysteinylglycine, biomarkers of protein crosslinking such as cystathionine and lanthionine, as well as metabolites of the transsulfuration pathway, methionine, homocysteine and serine are simultaneously determined. Results: Twelve glutathione pathway metabolites were simultaneously analyzed in four different human cell line extracts within a total LC run time of 5.5 min. Interday coefficients of variation (1.7 % to 12.0 %), the mean observed accuracy (100.0 % ± 5.2 %), linear quantification ranges over three orders of magnitude for all analytes and sufficient metabolite stability after NEM-derivatization demonstrate method reliability. Immediate derivatization with NEM at cell harvesting prevents autooxidation of glutathione, ensures accurate results for the GSH/GSSG redox ratio and thereby allows interpretation of cellular redox state. Conclusion: The described UPLC-MS/MS method provides a sensitive and selective tool for a fast and simultaneous analysis of glutathione pathway metabolites, its direct precursors and related compounds. Assay performance characteristics demonstrate the suitability of the method for applications in different cell cultures. Therefore, by providing glutathione related functional metabolic readouts, the method enables investigations in mechanisms of ferroptosis and alterations in oxidative stress levels in several pathophysiologies.
MeSH term(s)	Humans ; Ethylmaleimide ; Chromatography, Liquid/methods ; Liquid Chromatography-Mass Spectrometry ; Tandem Mass Spectrometry/methods ; Reactive Oxygen Species ; Reproducibility of Results ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Oxidation-Reduction
Chemical Substances	Ethylmaleimide (O3C74ACM9V) ; Reactive Oxygen Species ; Glutathione (GAN16C9B8O) ; Glutathione Disulfide (ULW86O013H)
Language	English
Publishing date	2024-02-27
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1180823-8
ISSN	1873-376X ; 0378-4347 ; 1570-0232 ; 1387-2273
ISSN (online)	1873-376X
ISSN	0378-4347 ; 1570-0232 ; 1387-2273
DOI	10.1016/j.jchromb.2024.124062
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Article: Biochemical Diagnosis of Catecholamine-Producing Tumors of Childhood: Neuroblastoma, Pheochromocytoma and Paraganglioma.

Eisenhofer, Graeme / Peitzsch, Mirko / Bechmann, Nicole / Huebner, Angela

Frontiers in endocrinology

2022 Volume 13, Page(s) 901760

Abstract: Catecholamine-producing tumors of childhood include most notably neuroblastoma, but also pheochromocytoma and paraganglioma (PPGL). Diagnosis of the former depends largely on biopsy-dependent histopathology, but this is contraindicated in PPGL where ... ...

Abstract	Catecholamine-producing tumors of childhood include most notably neuroblastoma, but also pheochromocytoma and paraganglioma (PPGL). Diagnosis of the former depends largely on biopsy-dependent histopathology, but this is contraindicated in PPGL where diagnosis depends crucially on biochemical tests of catecholamine excess. Such tests retain some importance in neuroblastoma though continue to largely rely on measurements of homovanillic acid (HVA) and vanillylmandelic acid (VMA), which are no longer recommended for PPGL. For PPGL, urinary or plasma metanephrines are the recommended most accurate tests. Addition of methoxytyramine to the plasma panel is particularly useful to identify dopamine-producing tumors and combined with normetanephrine also shows superior diagnostic performance over HVA and VMA for neuroblastoma. While use of metanephrines and methoxytyramine for diagnosis of PPGL in adults is established, there are numerous pitfalls for use of these tests in children. The establishment of pediatric reference intervals is particularly difficult and complicated by dynamic changes in metabolites during childhood, especially in infants for both plasma and urinary measurements, and extending to adolescence for urinary measurements. Interpretation of test results is further complicated in children by difficulties in following recommended preanalytical precautions. Due to this, the slow growing nature of PPGL and neglected consideration of the tumors in childhood the true pediatric prevalence of PPGL is likely underappreciated. Earlier identification of disease, as facilitated by surveillance programs, may uncover the true prevalence and improve therapeutic outcomes of childhood PPGL. For neuroblastoma there remain considerable obstacles in moving from entrenched to more accurate tests of catecholamine excess.
MeSH term(s)	Adolescent ; Adrenal Gland Neoplasms/diagnosis ; Adult ; Child ; Humans ; Infant ; Metanephrine ; Neuroblastoma/diagnosis ; Paraganglioma/diagnosis ; Pheochromocytoma/diagnosis
Chemical Substances	Metanephrine (5001-33-2)
Language	English
Publishing date	2022-07-26
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2022.901760
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Article ; Online: Liquid chromatography-tandem mass spectrometry based simultaneous quantification of tryptophan, serotonin and kynurenine pathway metabolites in tissues and cell culture systems.

Fröbel, Dennis / Stanke, Daniela / Langner, Mathias / Žygienė, Gintare / Bechmann, Nicole / Peitzsch, Mirko

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences

2023 Volume 1229, Page(s) 123870

Abstract: Background: Kynurenine and respective metabolites exhibit bioactivity as well as tryptophan, an essential amino acid, and the neurotransmitter serotonin. Dysregulations in the kynurenine pathway are involved in neurodegenerative/neuropsychiatric ... ...

Abstract	Background: Kynurenine and respective metabolites exhibit bioactivity as well as tryptophan, an essential amino acid, and the neurotransmitter serotonin. Dysregulations in the kynurenine pathway are involved in neurodegenerative/neuropsychiatric disorders and diabetes mellitus type 2 but also in cancer. Therefore, measurements of kynurenine-related metabolites will improve the general understanding for kynurenine pathway relevance in disease pathogenesis. Methods: Tryptophan, serotonin, picolinic acid, quinolinic acid, 3-OH-kynurenine, kynurenine, 3-OH-anthranilic acid, kynurenic acid, anthranilic acid as well as nicotinic acid and the redox cofactor NAD Results: A simple and sensitive UPLC-MS/MS method for simultaneous quantification of up to 10 kynurenine-related metabolites in four biological matrices was developed. Within a run time of 6.5 min, chromatographic separation of kynurenine-related metabolites, including the isomers nicotinic acid and picolinic acid, was achieved without derivatization. Validation parameters, including interday precision (<14.8%), mean accuracy (102.4% ± 12.9%) and linear detection ranges of more than three orders of magnitude, indicate method reliability. Depending the investigated sample matrix, the majority of metabolites were successfully detected and quantified in native murine and cell culture derived sample materials. Furthermore, the method allowed to monitor the impact of a tryptophan-2,3-dioxygenase-inhibitor on kynurenine pathway in a cellular system and is suitable for multi-assay analyses using aliquots from the same cell extract. Conclusion: The described UPLC-MS/MS method provides a simple tool for the simultaneous quantification of kynurenine pathway metabolites. Due to its suitability for many physiological matrices, the method provides wide application for disease-related experimental settings.
MeSH term(s)	Mice ; Animals ; Tryptophan/metabolism ; Kynurenine ; Chromatography, Liquid/methods ; Serotonin ; Tandem Mass Spectrometry/methods ; Reproducibility of Results ; Niacin ; Dioxygenases
Chemical Substances	Tryptophan (8DUH1N11BX) ; Kynurenine (343-65-7) ; anthranilic acid (0YS975XI6W) ; Serotonin (333DO1RDJY) ; Niacin (2679MF687A) ; Dioxygenases (EC 1.13.11.-)
Language	English
Publishing date	2023-09-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1180823-8
ISSN	1873-376X ; 0378-4347 ; 1570-0232 ; 1387-2273
ISSN (online)	1873-376X
ISSN	0378-4347 ; 1570-0232 ; 1387-2273
DOI	10.1016/j.jchromb.2023.123870
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Article: Long-Term Excessive Dietary Phosphate Intake Increases Arterial Blood Pressure, Activates the Renin-Angiotensin-Aldosterone System, and Stimulates Sympathetic Tone in Mice.

Latic, Nejla / Peitzsch, Mirko / Zupcic, Ana / Pietzsch, Jens / Erben, Reinhold G

Biomedicines

2022 Volume 10, Issue 10

Abstract: Increased dietary phosphate intake has been associated with severity of coronary artery disease, increased carotid intima-media thickness, left ventricular hypertrophy (LVH), and increased cardiovascular mortality and morbidity in individuals with normal ...

Abstract	Increased dietary phosphate intake has been associated with severity of coronary artery disease, increased carotid intima-media thickness, left ventricular hypertrophy (LVH), and increased cardiovascular mortality and morbidity in individuals with normal renal function as well as in patients suffering from chronic kidney disease. However, the underlying mechanisms are still unclear. To further elucidate the cardiovascular sequelae of long-term elevated phosphate intake, we maintained male C57BL/6 mice on a calcium, phosphate, and lactose-enriched diet (CPD, 2% Ca, 1.25% P, 20% lactose) after weaning them for 14 months and compared them with age-matched male mice fed a normal mouse diet (ND, 1.0% Ca, 0.7% P). Notably, the CPD has a balanced calcium/phosphate ratio, allowing the effects of elevated dietary phosphate intake largely independent of changes in parathyroid hormone (PTH) to be investigated. In agreement with the rationale of this experiment, mice maintained on CPD for 14 months were characterized by unchanged serum PTH but showed elevated concentrations of circulating intact fibroblast growth factor-23 (FGF23) compared with mice on ND. Cardiovascular phenotyping did not provide evidence for LVH, as evidenced by unchanged LV chamber size, normal cardiomyocyte area, lack of fibrosis, and unchanged molecular markers of hypertrophy (
Language	English
Publishing date	2022-10-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10102510
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Article ; Online: False-positive results for pheochromocytoma associated with norepinephrine reuptake blockade.

Schürfeld, Robin / Pamporaki, Christina / Peitzsch, Mirko / Rayes, Nada / Sabri, Osama / Rohm, Silvio / Biemann, Ronald / Sandner, Benjamin / Tönjes, Anke / Eisenhofer, Graeme

Endocrine-related cancer

2023 Volume 31, Issue 1

Abstract: Measurements of plasma metanephrines and methoxytyramine provide a sensitive test for diagnosis of pheochromocytoma/paraganglioma. False-positive results remain a problem, particularly in patients taking norepinephrine reuptake-blocking drugs. Therefore, ...

Abstract	Measurements of plasma metanephrines and methoxytyramine provide a sensitive test for diagnosis of pheochromocytoma/paraganglioma. False-positive results remain a problem, particularly in patients taking norepinephrine reuptake-blocking drugs. Therefore, in this retrospective observational study, we measured plasma metanephrines and methoxytyramine in 61 patients taking norepinephrine reuptake blockers (tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors) and 17 others taking selective serotonin reuptake inhibitors, all without pheochromocytoma/paraganglioma. We highlight a singular case with strongly elevated plasma normetanephrine and methoxytyramine concentrations associated with norepinephrine reuptake blockade. Data were compared to results from 252 and 1804 respective patients with and without tumors. Plasma normetanephrine was 40% higher (P < 0.0001) in patients on norepinephrine reuptake blockers and methoxytyramine was 127% higher (P = 0.0062) in patients taking tricyclic antidepressants compared to patients not taking uptake blockers and without tumors. The corresponding false-positive rates rose (P < 0.0001) from 4.8% to 23.0% for normetanephrine and from 0.9% to 28.6% for methoxytyramine. Selective serotonin reuptake inhibitors did not increase plasma concentrations of metabolites. In the highlighted case, plasma normetanephrine and methoxytyramine were elevated more than six times above upper reference limits. A pheochromocytoma/paraganglioma, however, was excluded by functional imaging. All biochemical test results normalized after discontinuation of norepinephrine reuptake blockers. These findings clarify that norepinephrine reuptake blockers usually result in mild elevations of normetanephrine and methoxytyramine that, nevertheless, significantly increase the number of false-positive results. There can, however, be exceptions where increases in normetanephrine and methoxytyramine reach pathological levels. Such exceptions may reflect failure of centrally mediated sympathoinhibition that normally occurs with the norepinephrine reuptake blockade.
MeSH term(s)	Humans ; Pheochromocytoma/drug therapy ; Pheochromocytoma/diagnosis ; Normetanephrine ; Antidepressive Agents, Tricyclic ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; Metanephrine ; Paraganglioma/drug therapy ; Paraganglioma/diagnosis ; Norepinephrine ; Adrenal Gland Neoplasms/drug therapy ; Adrenal Gland Neoplasms/diagnosis
Chemical Substances	Normetanephrine (0J45DE6B88) ; 3-methoxytyramine (JCH2767EDP) ; Antidepressive Agents, Tricyclic ; Selective Serotonin Reuptake Inhibitors ; Metanephrine (5001-33-2) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2023-12-01
Publishing country	England
Document type	Observational Study ; Journal Article
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1530/ERC-23-0063
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Zs.A 4192: Show issues

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Article ; Online: Age-specific pediatric reference intervals for plasma free normetanephrine, metanephrine, 3-methoxytyramine and 3-O-methyldopa: Particular importance for early infancy.

Peitzsch, Mirko / Mangelis, Anastasios / Eisenhofer, Graeme / Huebner, Angela

Clinica chimica acta; international journal of clinical chemistry

2019 Volume 494, Page(s) 100–105

Abstract: Background: Availability of appropriately established reference intervals for biochemical tests can be troublesome in pediatrics. Here we establish age-specific continuous reference intervals for catecholamine O-methylated metabolites in children ... ...

Abstract	Background: Availability of appropriately established reference intervals for biochemical tests can be troublesome in pediatrics. Here we establish age-specific continuous reference intervals for catecholamine O-methylated metabolites in children evaluated for catecholamine producing tumors, particularly younger children with suspected neuroblastoma. Methods: Plasma concentrations of 3-methoxytyramine, normetanephrine, metanephrine, and 3-O-methyldopa were analyzed by liquid chromatography tandem mass spectrometry in 533 children aged 2 days to 18 years. Results: Concentrations of plasma free normetanephrine, 3-methoxytyramine and 3-O-methyldopa were higher in neonates up until six months of age, but thereafter declined steeply to levels after one year that were <38% those of neonatal concentrations and to further lower concentrations in teenagers that were <23% those in neonates. In contrast, concentrations of plasma free metanephrine showed a reciprocal pattern with 50% lower concentrations in infants below one year compared to later in childhood. Conclusion: The dynamic reciprocal changes in plasma concentrations of normetanephrine, 3-methoxytyramine and 3-O-methyldopa compared to metanephrine during early childhood suggest underlying developmental changes in extra-adrenal and adrenal chromaffin tissue that must be considered for pediatric reference intervals, particularly in infants. With such reference intervals at hand, biochemical testing for catecholamine producing tumors in young children is substantially improved.
MeSH term(s)	Adolescent ; Adrenal Gland Neoplasms/blood ; Aging/blood ; Blood Chemical Analysis ; Catecholamines/biosynthesis ; Child ; Child, Preschool ; Chromatography, Liquid ; Dopamine/analogs & derivatives ; Dopamine/blood ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Metanephrine/blood ; Normetanephrine/blood ; Paraganglioma/blood ; Pheochromocytoma/blood ; Reference Values ; Tandem Mass Spectrometry ; Tyrosine/analogs & derivatives ; Tyrosine/blood
Chemical Substances	Catecholamines ; Normetanephrine (0J45DE6B88) ; Tyrosine (42HK56048U) ; Metanephrine (5001-33-2) ; 3-methoxytyramine (JCH2767EDP) ; 3-methoxytyrosine (V3O7J20DWN) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2019-03-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80228-1
ISSN	1873-3492 ; 0009-8981
ISSN (online)	1873-3492
ISSN	0009-8981
DOI	10.1016/j.cca.2019.03.1620
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Ud II Zs.173: Show issues

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Article ; Online: Zona Glomerulosa-Derived Klotho Modulates Aldosterone Synthase Expression in Young Female Mice.

Daryadel, Arezoo / Tang, Cong / Xie, Ye / Peitzsch, Mirko / Fisi, Viktoria / Hantel, Constanze / Loffing-Cueni, Dominique / Breault, David T / Penton, David / Loffing, Johannes / Beuschlein, Felix

Endocrinology

2024 Volume 165, Issue 5

Abstract: Klotho plays a critical role in the regulation of ion and fluid homeostasis. A previous study reported that haplo-insufficiency of Klotho in mice results in increased aldosterone synthase (CYP11B2) expression, elevated plasma aldosterone, and high blood ... ...

Abstract	Klotho plays a critical role in the regulation of ion and fluid homeostasis. A previous study reported that haplo-insufficiency of Klotho in mice results in increased aldosterone synthase (CYP11B2) expression, elevated plasma aldosterone, and high blood pressure. This phenotype was presumed to be the result of diminished Klotho expression in zona glomerulosa (zG) cells of the adrenal cortex; however, systemic effects on adrenal aldosterone production could not be ruled out. To examine whether Klotho expressed in the zG is indeed a critical regulator of aldosterone synthesis, we generated a tamoxifen-inducible, zG-specific mouse model of Klotho deficiency by crossing Klotho-flox mice with Cyp11b2-CreERT mice (zG-Kl-KO). Tamoxifen-treated Cyp11b2-CreERT animals (zG-Cre) served as controls. Rosa26-mTmG reporter mice were used for Cre-dependent lineage-marking. Two weeks after tamoxifen induction, the specificity of the zG-Cre line was verified using immunofluorescence analysis to show that GFP expression was restricted to the zG. RNA in situ hybridization revealed a 65% downregulation of Klotho messenger RNA expression in the zG of zG-Kl-KO female mice at age 12 weeks compared to control mice. Despite this significant decrease, zG-Kl-KO mice exhibited no difference in plasma aldosterone levels. However, adrenal CYP11B2 expression and the CYP11B2 promotor regulatory transcription factors, NGFIB and Nurr1, were enhanced. Together with in vitro experiments, these results suggest that zG-derived Klotho modulates Cyp11b2 but does not evoke a systemic phenotype in young adult mice on a normal diet. Further studies are required to investigate the role of adrenal Klotho on aldosterone synthesis in aged animals.
MeSH term(s)	Female ; Mice ; Animals ; Zona Glomerulosa/metabolism ; Cytochrome P-450 CYP11B2/genetics ; Cytochrome P-450 CYP11B2/metabolism ; Aldosterone/metabolism ; Adrenal Cortex/metabolism ; Hyperaldosteronism/genetics ; Tamoxifen/pharmacology
Chemical Substances	Cytochrome P-450 CYP11B2 (EC 1.14.15.4) ; Aldosterone (4964P6T9RB) ; Tamoxifen (094ZI81Y45)
Language	English
Publishing date	2024-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqae040
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Article: Liquid chromatography-tandem mass spectrometry based quantification of arginine metabolites including polyamines in different sample matrices

Langner, Mathias / Mateska, Ivona / Bechmann, Nicole / Wielockx, Ben / Chavakis, Triantafyllos / Alexaki, Vasileia Ismini / Peitzsch, Mirko

Journal of chromatography. 2022 May 24, v. 1671

2022

Abstract: The conditionally essential amino acid arginine and its metabolic products play an important role in different biological processes, such as metabolic regulation of the immune response, including macrophage activation and polarization and regulation of T ...

Abstract	The conditionally essential amino acid arginine and its metabolic products play an important role in different biological processes, such as metabolic regulation of the immune response, including macrophage activation and polarization and regulation of T cell function. Furthermore, the polyamine spermidine has a role in aging and age-related diseases. Additionally, altered polyamine metabolism may be associated with neurodegenerative diseases, while polyamine levels may present useful biomarkers associated with severity of Parkinson's disease or with progression of non-alcoholic fatty liver disease. In the present study, a simple, derivatization-free hydrophilic interaction liquid chromatography based tandem mass spectrometry (LC-MS/MS) method is described, that allows the accurate quantification of arginine and related amine, polyamine and acetylated polyamine metabolites in different experimental sample matrices, such as cell lysates, cell culture supernatants and tissues. Ten arginine metabolites, including citrulline, agmatine, ornithine, putrescine, spermidine, spermine, N1-acetylspermidine, N1-acetylspermine, N1,N12-diacetylspermine and arginine in conjunction with the metabolic cofactors S-adenosylhomocysteine and S-adenosylmethionine are simultaneously analyzed within a total LC-MS/MS run time of 9.5 min. The assay is suitable to quantify concentration ranges over multiple orders of magnitude for all metabolites with averaged accuracies observed at 103.2% ± 6.8%, 99.0% ± 4.2% and 100.4% ± 4.3% in cell lysates, cell culture supernatant and tissue extracts, respectively. Inter-day coefficients of variation ranged from 5.9 to 14.8% in cell lysates, 6.7 to 14.6% in cell culture supernatants and 5.3 to 12.0% in tissue extracts. The method was successfully applied to cell culture systems of different origin as well as different murine tissues and organs. The herein described LC-MS/MS method provides a simple tool for a fast and simultaneous analysis of arginine metabolites, including polyamines and their respective metabolic cofactors. Assay performance characteristics demonstrate suitability for applications in different experimental and preclinical settings.
Keywords	Parkinson disease ; S-adenosylmethionine ; T-lymphocytes ; agmatine ; arginine ; biomarkers ; cell culture ; citrulline ; essential amino acids ; fatty liver ; hydrophilic interaction chromatography ; macrophage activation ; metabolism ; metabolites ; mice ; ornithine ; putrescine ; spermidine ; spermine ; tandem mass spectrometry
Language	English
Dates of publication	2022-0524
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	218139-3
ISSN	0021-9673 ; 0378-4355 ; 0376-737X
ISSN	0021-9673 ; 0378-4355 ; 0376-737X
DOI	10.1016/j.chroma.2022.463021
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Integration of artificial intelligence and plasma steroidomics with laboratory information management systems: application to primary aldosteronism.

Constantinescu, Georgiana / Schulze, Manuel / Peitzsch, Mirko / Hofmockel, Thomas / Scholl, Ute I / Williams, Tracy Ann / Lenders, Jacques W M / Eisenhofer, Graeme

Clinical chemistry and laboratory medicine

2022 Volume 60, Issue 12, Page(s) 1929–1937

Abstract: Objectives: Mass spectrometry-based steroidomics combined with machine learning (ML) provides a potentially powerful approach in endocrine diagnostics, but is hampered by limitations in the conveyance of results and interpretations to clinicians. We ... ...

Abstract	Objectives: Mass spectrometry-based steroidomics combined with machine learning (ML) provides a potentially powerful approach in endocrine diagnostics, but is hampered by limitations in the conveyance of results and interpretations to clinicians. We address this shortcoming by integration of the two technologies with a laboratory information management systems (LIMS) model. Methods: The approach involves integration of ML algorithm-derived models with commercially available mathematical programming software and a web-based LIMS prototype. To illustrate clinical utility, the process was applied to plasma steroidomics data from 22 patients tested for primary aldosteronism (PA). Results: Once mass spectrometry data are uploaded into the system, automated processes enable generation of interpretations of steroid profiles from ML models. Generated reports include plasma concentrations of steroids in relation to age- and sex-specific reference intervals along with results of ML models and narrative interpretations that cover probabilities of PA. If PA is predicted, reports include probabilities of unilateral disease and mutations of Conclusions: The outlined process for integrating plasma steroidomics data and ML with LIMS may facilitate improved diagnostic-decision-making when based on higher-dimensional data otherwise difficult to interpret. The approach is relevant to other diagnostic applications involving ML.
MeSH term(s)	Male ; Female ; Humans ; Hyperaldosteronism/diagnosis ; Artificial Intelligence ; Steroids ; Mass Spectrometry ; Information Management ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics
Chemical Substances	Steroids ; KCNJ5 protein, human ; G Protein-Coupled Inwardly-Rectifying Potassium Channels
Language	English
Publishing date	2022-07-18
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1418007-8
ISSN	1437-4331 ; 1434-6621 ; 1437-8523
ISSN (online)	1437-4331
ISSN	1434-6621 ; 1437-8523
DOI	10.1515/cclm-2022-0470
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Zs.A 121: Show issues

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Article ; Online: Liquid chromatography-tandem mass spectrometry based quantification of arginine metabolites including polyamines in different sample matrices.

Langner, Mathias / Mateska, Ivona / Bechmann, Nicole / Wielockx, Ben / Chavakis, Triantafyllos / Alexaki, Vasileia Ismini / Peitzsch, Mirko

Journal of chromatography. A

2022 Volume 1671, Page(s) 463021

Abstract	The conditionally essential amino acid arginine and its metabolic products play an important role in different biological processes, such as metabolic regulation of the immune response, including macrophage activation and polarization and regulation of T cell function. Furthermore, the polyamine spermidine has a role in aging and age-related diseases. Additionally, altered polyamine metabolism may be associated with neurodegenerative diseases, while polyamine levels may present useful biomarkers associated with severity of Parkinson's disease or with progression of non-alcoholic fatty liver disease. In the present study, a simple, derivatization-free hydrophilic interaction liquid chromatography based tandem mass spectrometry (LC-MS/MS) method is described, that allows the accurate quantification of arginine and related amine, polyamine and acetylated polyamine metabolites in different experimental sample matrices, such as cell lysates, cell culture supernatants and tissues. Ten arginine metabolites, including citrulline, agmatine, ornithine, putrescine, spermidine, spermine, N1-acetylspermidine, N1-acetylspermine, N1,N12-diacetylspermine and arginine in conjunction with the metabolic cofactors S-adenosylhomocysteine and S-adenosylmethionine are simultaneously analyzed within a total LC-MS/MS run time of 9.5 min. The assay is suitable to quantify concentration ranges over multiple orders of magnitude for all metabolites with averaged accuracies observed at 103.2% ± 6.8%, 99.0% ± 4.2% and 100.4% ± 4.3% in cell lysates, cell culture supernatant and tissue extracts, respectively. Inter-day coefficients of variation ranged from 5.9 to 14.8% in cell lysates, 6.7 to 14.6% in cell culture supernatants and 5.3 to 12.0% in tissue extracts. The method was successfully applied to cell culture systems of different origin as well as different murine tissues and organs. The herein described LC-MS/MS method provides a simple tool for a fast and simultaneous analysis of arginine metabolites, including polyamines and their respective metabolic cofactors. Assay performance characteristics demonstrate suitability for applications in different experimental and preclinical settings.
MeSH term(s)	Animals ; Arginine ; Chromatography, Liquid/methods ; Mice ; Polyamines ; Spermidine/metabolism ; Tandem Mass Spectrometry/methods ; Tissue Extracts
Chemical Substances	Polyamines ; Tissue Extracts ; Arginine (94ZLA3W45F) ; Spermidine (U87FK77H25)
Language	English
Publishing date	2022-04-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1171488-8
ISSN	1873-3778 ; 0021-9673
ISSN (online)	1873-3778
ISSN	0021-9673
DOI	10.1016/j.chroma.2022.463021
Database	MEDical Literature Analysis and Retrieval System OnLINE

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