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Developmental Medicine and Child... May 2021To explore the cerebrospinal fluid (CSF) metabolite features in acute neuroinflammatory diseases and identify potential biomarkers to diagnose and monitor...
AIM
To explore the cerebrospinal fluid (CSF) metabolite features in acute neuroinflammatory diseases and identify potential biomarkers to diagnose and monitor neuroinflammation.
METHOD
A cohort of 14 patients (five females, nine males; mean [median] age 7y 9mo [9y], range 6mo-13y) with acute encephalitis (acute disseminated encephalomyelitis n=6, unknown suspected viral encephalitis n=3, enteroviral encephalitis n=2, seronegative autoimmune encephalitis n=2, herpes simplex encephalitis n=1) and age-matched non-inflammatory neurological disease controls (n=14) were investigated using an untargeted metabolomics approach. CSF metabolites were analyzed with liquid chromatography coupled to high resolution mass spectrometry, followed by subsequent multivariate and univariate statistical methods.
RESULTS
A total of 35 metabolites could be discriminated statistically between the groups using supervised orthogonal partial least squares discriminant analysis and analysis of variance. The tryptophan-kynurenine pathway contributed nine key metabolites. There was a statistical increase of kynurenine, quinolinic acid, and anthranilic acid in patients with encephalitis, whereas tryptophan, 3-hydroxyanthrnailic acid, and kynurenic acid were decreased. The nitric oxide pathway contributed four metabolites, with elevated asymmetric dimethylarginine and argininosuccinic acid, and decreased arginine and citrulline in patients with encephalitis. An increase in the CSF kynurenine/tryptophan ratio (p<0.001), anthranilic acid/3-hydroxyanthranilic acid ratio (p<0.001), asymmetric dimethylarginine/arginine ratio (p<0.001), and neopterin (p<0.001) strongly predicted neuroinflammation.
INTERPRETATION
The combination of alterations in the tryptophan-kynurenine pathway, nitric oxide pathway, and neopterin represent a useful potential panel for neuroinflammation and holds potential for clinical translation practice.
WHAT THIS PAPER ADDS
The kynurenine/tryptophan and anthranilic acid/3-hydroxyanthranilic acid ratios hold great potential as biomarkers of neuroinflammation. Elevation of the asymmetric dimethylarginine/arginine ratio in acute brain inflammation shows dysregulation of the nitric oxide pathway.
Topics: Adolescent; Biomarkers; Child; Child, Preschool; Encephalitis, Viral; Encephalomyelitis, Acute Disseminated; Female; Humans; Infant; Kynurenine; Male; Nitric Oxide; Tryptophan
PubMed: 33336374
DOI: 10.1111/dmcn.14774 -
British Journal of Cancer Dec 2017Uterine leiomyomas can be classified into molecularly distinct subtypes according to their genetic triggers: MED12 mutations, HMGA2 upregulation, or inactivation of FH....
BACKGROUND
Uterine leiomyomas can be classified into molecularly distinct subtypes according to their genetic triggers: MED12 mutations, HMGA2 upregulation, or inactivation of FH. The aim of this study was to identify metabolites and metabolic pathways that are dysregulated in different subtypes of leiomyomas.
METHODS
We performed global metabolomic profiling of 25 uterine leiomyomas and 17 corresponding myometrium specimens using liquid chromatography-tandem mass spectroscopy.
RESULTS
A total of 641 metabolites were detected. All leiomyomas displayed reduced homocarnosine and haeme metabolite levels. We identified a clearly distinct metabolomic profile for leiomyomas of the FH subtype, characterised by metabolic alterations in the tricarboxylic acid cycle and pentose phosphate pathways, and increased levels of multiple lipids and amino acids. Several metabolites were uniquely elevated in leiomyomas of the FH subtype, including N6-succinyladenosine and argininosuccinate, serving as potential biomarkers for FH deficiency. In contrast, leiomyomas of the MED12 subtype displayed reduced levels of vitamin A, multiple membrane lipids and amino acids, and dysregulation of vitamin C metabolism, a finding which was also compatible with gene expression data.
CONCLUSIONS
The study reveals the metabolomic heterogeneity of leiomyomas and provides the requisite framework for strategies designed to target metabolic alterations promoting the growth of these prevalent tumours.
Topics: Adenosine; Amino Acids; Argininosuccinic Acid; Ascorbic Acid; Citric Acid Cycle; Female; Fumarate Hydratase; HMGA2 Protein; Humans; Leiomyoma; Lipid Metabolism; Mediator Complex; Metabolic Networks and Pathways; Metabolome; Pentose Phosphate Pathway; Uterine Neoplasms; Vitamin A
PubMed: 29073636
DOI: 10.1038/bjc.2017.361 -
Pharmaceutical Biology Dec 2023Hydroxysafflor yellow A (HSYA) is the main bioactive ingredient of safflower ( L., [Asteraceae]) for traumatic brain injury (TBI) treatment.
CONTEXT
Hydroxysafflor yellow A (HSYA) is the main bioactive ingredient of safflower ( L., [Asteraceae]) for traumatic brain injury (TBI) treatment.
OBJECTIVE
To explore the therapeutic effects and underlying mechanisms of HSYA on post-TBI neurogenesis and axon regeneration.
MATERIALS AND METHODS
Male Sprague-Dawley rats were randomly assigned into Sham, controlled cortex impact (CCI), and HSYA groups. Firstly, the modified Neurologic Severity Score (mNSS), foot fault test, hematoxylin-eosin staining, Nissl's staining, and immunofluorescence of Tau1 and doublecortin (DCX) were used to evaluate the effects of HSYA on TBI at the 14th day. Next, the effectors of HSYA on post-TBI neurogenesis and axon regeneration were screened out by pathology-specialized network pharmacology and untargeted metabolomics. Then, the core effectors were validated by immunofluorescence.
RESULTS
HSYA alleviated mNSS, foot fault rate, inflammatory cell infiltration, and Nissl's body loss. Moreover, HSYA increased not only hippocampal DCX but also cortical Tau1 and DCX following TBI. Metabolomics demonstrated that HSYA significantly regulated hippocampal and cortical metabolites enriched in 'arginine metabolism' and 'phenylalanine, tyrosine and tryptophan metabolism' including l-phenylalanine, ornithine, l-(+)-citrulline and argininosuccinic acid. Network pharmacology suggested that neurotrophic factor (BDNF) and signal transducer and activator of transcription 3 (STAT3) were the core nodes in the HSYA-TBI-neurogenesis and axon regeneration network. In addition, BDNF and growth-associated protein 43 (GAP43) were significantly elevated following HSYA treatment in the cortex and hippocampus.
DISCUSSION AND CONCLUSIONS
HSYA may promote TBI recovery by facilitating neurogenesis and axon regeneration through regulating cortical and hippocampal metabolism, BDNF and STAT3/GAP43 axis.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; Brain-Derived Neurotrophic Factor; Axons; Nerve Regeneration; Brain Injuries, Traumatic; Quinones; Chalcone; Metabolomics
PubMed: 37416997
DOI: 10.1080/13880209.2023.2229379 -
Scientific Reports Nov 2023A multi-class classification model for acute coronary syndrome (ACS) remains to be constructed based on multi-fluid metabolomics. Major confounders may exert spurious...
A multi-class classification model for acute coronary syndrome (ACS) remains to be constructed based on multi-fluid metabolomics. Major confounders may exert spurious effects on the relationship between metabolism and ACS. The study aims to identify an independent biomarker panel for the multiclassification of HC, UA, and AMI by integrating serum and urinary metabolomics. We performed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics study on 300 serum and urine samples from 44 patients with unstable angina (UA), 77 with acute myocardial infarction (AMI), and 29 healthy controls (HC). Multinomial machine learning approaches, including multinomial adaptive least absolute shrinkage and selection operator (LASSO) regression and random forest (RF), and assessment of the confounders were applied to integrate a multi-class classification biomarker panel for HC, UA and AMI. Different metabolic landscapes were portrayed during the transition from HC to UA and then to AMI. Glycerophospholipid metabolism and arginine biosynthesis were predominant during the progression from HC to UA and then to AMI. The multiclass metabolic diagnostic model (MDM) dependent on ACS, including 2-ketobutyric acid, LysoPC(18:2(9Z,12Z)), argininosuccinic acid, and cyclic GMP, demarcated HC, UA, and AMI, providing a C-index of 0.84 (HC vs. UA), 0.98 (HC vs. AMI), and 0.89 (UA vs. AMI). The diagnostic value of MDM largely derives from the contribution of 2-ketobutyric acid, and LysoPC(18:2(9Z,12Z)) in serum. Higher 2-ketobutyric acid and cyclic GMP levels were positively correlated with ACS risk and atherosclerosis plaque burden, while LysoPC(18:2(9Z,12Z)) and argininosuccinic acid showed the reverse relationship. An independent multiclass biomarker panel for HC, UA, and AMI was constructed using the multinomial machine learning methods based on serum and urinary metabolite signatures.
Topics: Humans; Acute Coronary Syndrome; Argininosuccinic Acid; Chromatography, Liquid; Tandem Mass Spectrometry; Biomarkers; Myocardial Infarction; Angina, Unstable; Cyclic GMP
PubMed: 37996510
DOI: 10.1038/s41598-023-47783-5 -
Journal of Mass Spectrometry and... Aug 2022Amino acids are critical biomarkers for many inborn errors of metabolism, but amino acid analysis is challenging due to the range of chemical properties inherent in...
INTRODUCTION
Amino acids are critical biomarkers for many inborn errors of metabolism, but amino acid analysis is challenging due to the range of chemical properties inherent in these small molecules. Techniques are available for amino acid analysis, but they can suffer from long run times, laborious derivatization, and/or poor resolution of isobaric compounds.
OBJECTIVE
To develop and validate a method for the quantitation of a non-derivatized free amino acid profile in both plasma and urine samples using mixed-mode chromatography and tandem mass spectrometry.
METHODS
Chromatographic conditions were optimized to separate leucine, isoleucine, and allo-isoleucine and maintain analytical runtime at less than 15 min. Sample preparation included a quick protein precipitation followed by LC-MS/MS analysis. Matrix effects, interferences, linearity, carryover, acceptable dilution limits, precision, accuracy, and stability were evaluated in both plasma and urine specimen types.
RESULTS
A total of 38 amino acids and related compounds were successfully quantitated with this method. In addition, argininosuccinic acid was qualitatively analyzed. A full clinical validation was performed that included method comparison to a reference laboratory for plasma and urine with Deming regression slopes ranging from 0.38 to 1.26.
CONCLUSION
This method represents an alternative to derivatization-based methods, especially in urine samples where interference from metabolites and medications is prevalent.
PubMed: 35637738
DOI: 10.1016/j.jmsacl.2022.05.002 -
Scientific Reports Mar 2021Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a severe multisystemic disease characterized by immunological abnormalities and dysfunction of energy...
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a severe multisystemic disease characterized by immunological abnormalities and dysfunction of energy metabolism. Recent evidences suggest strong correlations between dysbiosis and pathological condition. The present research explored the composition of the intestinal and oral microbiota in CFS/ME patients as compared to healthy controls. The fecal metabolomic profile of a subgroup of CFS/ME patients was also compared with the one of healthy controls. The fecal and salivary bacterial composition in CFS/ME patients was investigated by Illumina sequencing of 16S rRNA gene amplicons. The metabolomic analysis was performed by an UHPLC-MS. The fecal microbiota of CFS/ME patients showed a reduction of Lachnospiraceae, particularly Anaerostipes, and an increased abundance of genera Bacteroides and Phascolarctobacterium compared to the non-CFS/ME groups. The oral microbiota of CFS/ME patients showed an increase of Rothia dentocariosa. The fecal metabolomic profile of CFS/ME patients revealed high levels of glutamic acid and argininosuccinic acid, together with a decrease of alpha-tocopherol. Our results reveal microbial signatures of dysbiosis in the intestinal microbiota of CFS/ME patients. Further studies are needed to better understand if the microbial composition changes are cause or consequence of the onset of CFS/ME and if they are related to any of the several secondary symptoms.
Topics: Adult; Case-Control Studies; Chromatography, High Pressure Liquid; Dysbiosis; Fatigue Syndrome, Chronic; Feces; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Mass Spectrometry; Metabolomics; Microbiota; Middle Aged; Pilot Projects; RNA, Ribosomal, 16S
PubMed: 33782445
DOI: 10.1038/s41598-021-86425-6 -
Journal of Inherited Metabolic Disease Jul 2018Urea cycle disorders often present as devastating metabolic conditions, resulting in high mortality and significant neuropsychological damage, despite treatment. The...
Urea cycle disorders often present as devastating metabolic conditions, resulting in high mortality and significant neuropsychological damage, despite treatment. The Urea Cycle Disorders Longitudinal Study is a natural history study that collects data from regular clinical follow-up and neuropsychological testing. This report examines links between biochemical markers (ammonia, glutamine, arginine, citrulline) and primary neuropsychological endpoints in three distal disorders, argininosuccinic acid synthetase deficiency (ASD or citrullinemia type I), argininosuccinic acid lyase deficiency (ASA or ALD), and arginase deficiency (ARGD). Laboratory results and test scores from neuropsychological evaluations were assessed in 145 study participants, ages 3 years and older, with ASD (n = 64), ASA (n = 65) and ARGD (n = 16). Mean full scale IQ was below the population mean of 100 ± 15 for all groups: (ASD = 79 ± 24; ASA = 71 ± 21; ARGD = 65 ± 19). The greatest deficits were noted in visual performance and motor skills for all groups. While ammonia levels remain prominent as prognostic biomarkers, other biomarkers may be equally valuable as correlates of neuropsychological functioning. Cumulative exposure to the biomarkers included in the study proved to be highly sensitive indicators of neuropsychological outcomes, even when below the cut-off levels generally considered toxic. Blood levels of biomarkers obtained on the day of neuropsychological evaluations were not correlated with measures of functioning for any disorder in any domain. The importance of cumulative exposure supports early identification and confirms the need for well-controlled management of all biochemical abnormalities (and not just ammonia) that occur in urea cycle disorders.
Topics: Adolescent; Adult; Ammonia; Arginine; Argininosuccinic Aciduria; Biomarkers; Child; Child, Preschool; Citrulline; Citrullinemia; Female; Glutamine; Humans; Hyperargininemia; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Young Adult
PubMed: 29423830
DOI: 10.1007/s10545-017-0132-5 -
International Journal of Neonatal... Jul 2021To minimize false-positive cases in newborn screening by tandem mass spectrometry in Japan, practical second-tier liquid chromatography-tandem mass spectrometry analyses...
To minimize false-positive cases in newborn screening by tandem mass spectrometry in Japan, practical second-tier liquid chromatography-tandem mass spectrometry analyses have been developed using a multimode ODS column with a single set of mobile phases and different gradient elution programs specific to the analysis of acylcarnitines, acylglycines, amino acids, and organic acids. Most analyses were performed using underivatized samples, except for analysis of methylcitric acid, and careful conditioning of the column was necessary for analyses of organic acids. Our second-tier tests enabled us to measure many metabolites useful for detection of target disorders, including allo-isoleucine, homocysteine, methylmalonic acid, and methylcitric acid. We found that accumulation of 3-hydroxyglutaric acid was specific to glutaric acidemia type I and that the ratio of 3-hydroxyisovaleric acid to 3-hydroxyisovalerylcarnitine was useful to detect newborns of mothers with 3-methylcrotonyl-CoA carboxylase deficiency. Data from the analysis of short-chain acylcarnitine and acylglycine were useful for differential diagnosis in cases positive for C5-OH-acylcarnitine or C5-acylcarnitine.
PubMed: 34287228
DOI: 10.3390/ijns7030044 -
Molecular Genetics and Metabolism... Sep 2018Expanded newborn screening (ENBS) utilizing tandem mass spectrometry (MS/MS) for inborn metabolic diseases (IMDs), such as organic acidemias (OAs), fatty acid oxidation...
Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening vs. expanded newborn screening.
BACKGROUND
Expanded newborn screening (ENBS) utilizing tandem mass spectrometry (MS/MS) for inborn metabolic diseases (IMDs), such as organic acidemias (OAs), fatty acid oxidation disorders, (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in many Asian countries. This study aimed to determine the incidence rates of OAs, FAODs, and AAs in Asian countries and Germany using selective screening and ENBS records.
MATERIALS AND METHODS
Selective screening for IMDs using gas chromatography-mass spectrometry and MS/MS was performed among patients suspected to be afflicted in Asian countries (including Japan, Vietnam, China, and India) between 2000 and 2015, and the results from different countries were compared. Similarly, ENBS results from Japan, South Korea, Taiwan, and Germany were compared. Additionally, the results of selective screening and ENBS in Japan were compared.
RESULTS
Among 39,270 patients who underwent selective screening, IMDs were detected in 1170. Methylmalonic acidemia was frequently identified in several countries, including Japan (81/377 diagnosed IMDs), China (94/216 IMDs), and India (72/293 IMDs). In Vietnam, however, β-ketothiolase deficiency was particularly frequent (33/250 IMDs). ENBS yielded differences in overall IMD rates by country: 1:8557 in Japan, 1:7030 in Taiwan, 1:13,205 in South Korea, and 1:2200 in Germany. Frequently discovered diseases included propionic acidemia (PPA) and phenylketonuria (PKU) in Japan, 3-methylcrotonyl-CoA carboxylase deficiency (MCCD) and PKU in Taiwan, MCCD and citrullinemia type I in South Korea, and PKU and medium-chain acyl-CoA dehydrogenase deficiency in Germany. Furthermore, in Japan, selective screening and ENBS yielded respective PPA frequencies of 14.7% and 49.4% among all organic acidemias.
CONCLUSION
The incidence rates of IMDs vary by country. Moreover, the disease spectra of IMDs detected via selective screening differ from those detected via ENBS.
PubMed: 29946514
DOI: 10.1016/j.ymgmr.2018.05.003 -
Molecular Genetics and Metabolism... Dec 2021The urea cycle generates arginine that is one of the major precursors for creatine biosynthesis. Here we evaluate levels of creatine and guanidinoacetate (the precursor...
The urea cycle generates arginine that is one of the major precursors for creatine biosynthesis. Here we evaluate levels of creatine and guanidinoacetate (the precursor in the synthesis of creatine) in plasma samples (n = 207) of patients (n = 73) with different types of urea cycle disorders (ornithine transcarbamylase deficiency (n = 22; n = 7), citrullinemia type 1 (n = 60; n = 22), argininosuccinic aciduria (n = 81; n = 31), arginase deficiency (n = 44; n = 13)). The concentration of plasma guanidinoacetate positively correlated ( < 0.001, R = 0.64) with levels of arginine, but not with glycine in all patients with urea cycle defects, rising to levels above normal in most samples (34 out of 44) of patients with arginase deficiency. In contrast to patients with guanidinoacetate methyltransferase deficiency (a disorder of creatine synthesis characterized by elevated guanidinoacetate concentrations), creatine levels were normal (32 out of 44) or above normal (12 out of 44) in samples from patients with arginase deficiency. Creatine levels correlated significantly, but poorly ( < 0.01, R = 0.1) with guanidinoacetate levels and, despite being overall in the normal range in patients with all other urea cycle disorders, were occasionally below normal in some patients with argininosuccinic acid synthase and lyase deficiency. Creatine levels positively correlated with levels of methionine ( < 0.001, R = 0.16), the donor of the methyl group for creatine synthesis. The direct correlation of arginine levels with guanidinoacetate in patients with urea cycle disorders explains the increased concentration of guanidino compounds in arginase deficiency. Low creatine levels in some patients with other urea cycle defects might be explained by low protein intake (creatine is naturally present in meat) and relative or absolute intracellular arginine deficiency.
PubMed: 34471603
DOI: 10.1016/j.ymgmr.2021.100791