Publications by authors named "Evangelos Papakonstantinou"

11 Publications

  • Page 1 of 1

Metabolic profiling of organic and fatty acids in chronic and autoimmune diseases.

Adv Clin Chem 2021 15;101:169-229. Epub 2020 Jul 15.

Metabolomic Medicine Clinic, Athens, Greece; European Institute of Nutritional Medicine, E.I.Nu.M, Rome, Italy. Electronic address:

Metabolomics is a powerful tool of omics that permits the simultaneous identification of metabolic perturbations in several autoimmune and chronic diseases. Several parameters can affect a metabolic profile, from the population characteristics to the selection of the analytical method. In the current chapter, we summarize the main analytical methods and results of the metabolic profiling of fatty and organic acids performed in human metabolomic studies for asthma, COPD, psoriasis and Hashimoto's thyroiditis. We discuss the most significant metabolic alterations associated with these diseases, after comparison of either a single patient's group with healthy controls or several patient's subgroups of different disease severity and phenotype with healthy controls or of a patient's group before and after treatment. Finally, we present critical metabolic patterns that are associated with each disease and their potency for the unraveling of disease pathogenesis, prediction, diagnosis, patient stratification and treatment selection.
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http://dx.doi.org/10.1016/bs.acc.2020.06.003DOI Listing
July 2021

Prediction of Autoimmune Diseases by Targeted Metabolomic Assay of Urinary Organic Acids.

Metabolites 2020 Dec 8;10(12). Epub 2020 Dec 8.

Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania.

Autoimmune diseases (ADs) are chronic disorders characterized by the loss of self-tolerance, and although being heterogeneous, they share common pathogenic mechanisms. Self-antigens and inflammation markers are established diagnostic tools; however, the metabolic imbalances that underlie ADs are poorly described. The study aimed to employ metabolomics for the detection of disease-related changes in autoimmune diseases that could have predictive value. Quantitative analysis of 28 urine organic acids was performed using Gas Chromatography-Mass Spectrometry in a group of 392 participants. Autoimmune thyroiditis, inflammatory bowel disease, psoriasis and rheumatoid arthritis were the most prevalent autoimmune diseases of the study. Statistically significant differences were observed in the tricarboxylate cycle metabolites, succinate, methylcitrate and malate, the pyroglutamate and 2-hydroxybutyrate from the glutathione cycle and the metabolites methylmalonate, 4-hydroxyphenylpyruvate, 2-hydroxyglutarate and 2-hydroxyisobutyrate between the AD group and the control. Artificial neural networks and Binary logistic regression resulted in the highest predictive accuracy scores (66.7% and 74.9%, respectively), while Methylmalonate, 2-Hydroxyglutarate and 2-hydroxybutyrate were proposed as potential biomarkers for autoimmune diseases. Urine organic acid levels related to the mechanisms of energy production and detoxification were associated with the presence of autoimmune diseases and could be an adjunct tool for early diagnosis and prediction.
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http://dx.doi.org/10.3390/metabo10120502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764183PMC
December 2020

Application of metabolomics part II: Focus on fatty acids and their metabolites in healthy adults.

Int J Mol Med 2019 Jan 14;43(1):233-242. Epub 2018 Nov 14.

Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, 71003 Heraklion, Greece.

Fatty acids (FAs) play critical roles in health and disease. The detection of FA imbalances through metabolomics can provide an overview of an individual's health status, particularly as regards chronic inflammatory disorders. In this study, we aimed to establish sensitive reference value ranges for targeted plasma FAs in a well‑defined population of healthy adults. Plasma samples were collected from 159 participants admitted as outpatients. A total of 24 FAs were analyzed using gas chromatography‑mass spectrometry, and physiological values and 95% reference intervals were calculated using an approximate method of analysis. The differences among the age groups for the relative levels of stearic acid (P=0.005), the omega‑6/omega‑3 ratio (P=0.027), the arachidonic acid/eicosapentaenoic acid ratio (P<0.001) and the linoleic acid‑produced dihomo‑gamma‑linolenic acid (P=0.046) were statistically significant. The majority of relative FA levels were higher in males than in females. The levels of myristic acid (P=0.0170) and docosahexaenoic acid (P=0.033) were significantly different between the sexes. The reference values for the FAs examined in this study represent a baseline for further studies examining the reproducibility of this methodology and sensitivities for nutrient deficiency detection and investigating the biochemical background of pathological conditions. The application of these values to clinical practice will allow for the discrimination between health and disease and contribute to early prevention and treatment.
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http://dx.doi.org/10.3892/ijmm.2018.3989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257830PMC
January 2019

Longitudinal Profiles of Metabolism and Bioenergetics Associated with Innate Immune Hormonal Inflammatory Responses and Amino-Acid Kinetics in Severe Sepsis and Systemic Inflammatory Response Syndrome in Children.

JPEN J Parenter Enteral Nutr 2018 Aug 16;42(6):1061-1074. Epub 2018 Jan 16.

Pediatric Intensive Care Unit, University Hospital, Medical School, University of Crete, Heraklion, Greece.

Background: Experimental data indicate that sepsis influences the mitochondrial function and metabolism. We aim to investigate longitudinal bioenergetic, metabolic, hormonal, amino-acid, and innate immunity changes in children with sepsis.

Methods: Sixty-eight children (sepsis, 18; systemic inflammatory response syndrome [SIRS], 23; healthy controls, 27) were enrolled. Plasma amino acids were determined by high-performance liquid chromatography (HPLC); flow-cytometry expressed as mean fluorescence intensity (MFI) of heat shock protein (HSP) levels from monocytes (m) and neutrophils (n); resistin, adiponectin, and extracellular (e) HSPs evaluated by ELISA; ATP levels in white blood cells by luciferase luminescent assay; lipid peroxidation products (TBARS) by colorimetric test; nitrite and nitrate levels by chemiluminescent assay; biliverdin reductase (BVR) activity by enzymatic assay; and energy-expenditure (EE) by E-COVX.

Results: Resistin, eHSP72, eHSP90α, and nitrate were longitudinally higher in sepsis compared with SIRS (p<0.05); mHSP72, nHSP72, VO , VCO , EE, and metabolic pattern were repressed in sepsis compared with SIRS (p<0.05). Septic patients had lower ATP and TBARS compared with controls on day 1, lower ATP compared with SIRS on day 3 (p<0.05), but higher levels of BVR activity. Sepsis exhibited higher phenylalanine levels on day 1, serine on day 3; lower glutamine concentrations on days 3 and 5 (p<0.05). Resistin, inversely related to ATP, was independently associated with sepsis, along with mHSP72 and eHSP90α (p<0.05); TBARS and VO were independently associated with organ failure (p<0.05)). Septic nonsurvivors had malnutrition, persistently repressed metabolism, mHSP72, and induced resistin and adiponectin (p<0.05).

Conclusions: A pattern of early longitudinal induction of metabolic-hormones and eHSP72/HSP90α, repression of bioenergetics and innate immunity, hypo-metabolism, and amino-acid kinetics changes discriminate sepsis from SIRS; malnutrition, hypo-metabolism, and persistently increased resistin and adiponectin are associated with poor outcome.
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http://dx.doi.org/10.1002/jpen.1050DOI Listing
August 2018

Application of metabolomics: Focus on the quantification of organic acids in healthy adults.

Int J Mol Med 2017 Jul 10;40(1):112-120. Epub 2017 May 10.

Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, Heraklion 71003, Greece.

Metabolomics, a 'budding' discipline, may accurately reflect a specific phenotype which is sensitive to genetic and epigenetic interactions. This rapidly evolving field in science has been proposed as a tool for the evaluation of the effects of epigenetic factors, such as nutrition, environment, drug and lifestyle on phenotype. Urine, being sterile, is easy to obtain and as it contains metabolized or non‑metabolized products, is a favored study material in the field of metabolomics. Urine organic acids (OAs) reflect the activity of main metabolic pathways and have been used to assess health status, nutritional status, vitamin deficiencies and response to xenobiotics. To date, a limited number of studies have been performed which actually define reference OA values in a healthy population and as reference range for epigenetic influences, and not as a reference to congenital metabolic diseases. The aim of the present study was thus the determination of reference values (RVs) for urine OA in a healthy adult population. Targeted metabolomics analysis of 22 OAs in the urine of 122 healthy adults by gas chromatography‑mass spectrometry, was conducted. Percentile distributions of the OA concentrations in urine, as a base for determining the RVs in the respective population sample, were used. No significant differences were detected between female and male individuals. These findings can facilitate the more sensitive determination of OAs in pathological conditions. Therefore, the findings of this study may contribute or add to the information already available on urine metabolite databases, and may thus promote the use of targeted metabolomics for the evaluation of OAs in a clinical setting and for pathophysiological evaluation. However, further studies with well‑defined patients groups exhibiting specific symptoms or diseases are warranted in order to discern between normal and pathological values.
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http://dx.doi.org/10.3892/ijmm.2017.2983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466383PMC
July 2017

Evidence for the participation of the stimulated sympathetic nervous system in the regulation of carnitine blood levels of soccer players during a game.

Metabolism 2009 Aug 18;58(8):1080-6. Epub 2009 Jun 18.

Institute of Child Health, Research Center, "Aghia Sophia" Children's Hospital, GR-11527 Athens, Greece.

Catecholamines and carnitine blood levels are closely implicated with training. The aim of the study was to investigate the effect of sympathetic nervous system stimulation on carnitine and its fraction levels during training. Blood was obtained from 14 soccer players pregame, at intermission, and postgame. Catecholamines were measured with high-performance liquid chromatography methods; muscle enzymes creatine kinase and lactate dehydrogenase as well as lactate, pyruvate, and total antioxidant status with commercial kits; and carnitine and fraction levels with tandem mass spectrometry. Total antioxidant status (2.97 +/- 0.13 vs 0.96 +/- 0.10 mmol/L, P < .01) as well as free carnitine levels (20.47 +/- 4.0 vs 12.30 +/- 2.8 micromol/L, P < .001) were remarkably decreased especially postgame. Total acylcarnitines (5.20 +/- 1.8 vs 9.42 +/- 3.0 micromol/L, P < .001) and especially total very long-chain acylcarnitines (0.80 +/- 0.01 vs 1.85 +/- 0.03 micromol/L, P < .001) as well as catecholamine levels (adrenaline: 230 +/- 31 vs 890 +/- 110 pmol/L, P < .01; noradrenaline: 1.53 +/- 0.41 vs 3.7 +/- 0.6 nmol/L, P < .01) were significantly increased in players postgame. A statistically significant inverse correlation was found between adrenaline and free carnitine (r = -0.51, P < .01); and a positive correlation was found between adrenaline, total acylcarnitines (r = 0.58, P < .01), and total long-chain acylcarnitine (r = 0.49, P < .01). The significant positive correlation of adrenaline levels with total acylcarnitine and total long-chain acylcarnitine blood levels in athletes as well as the inverse correlation with free carnitine levels may indicate participation of the stimulated sympathetic nervous system in the regulation of some carnitine fraction levels during exercise.
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http://dx.doi.org/10.1016/j.metabol.2009.04.001DOI Listing
August 2009

Maternal-neonatal amino acid blood levels in relation to the mode of delivery.

Acta Obstet Gynecol Scand 2009 ;88(1):71-6

Institute of Child Health, Research Centre, Aghia Sophia Children's Hospital, Athens, Greece.

Objective: To investigate the effect of the mode of delivery on maternal-neonatal amino acid levels as high blood levels of some amino acids are implicated with endurance exercise.

Design: Comparative study.

Sample: Thirty women in normal pregnancy divided into two groups: Group A (n=15) with normal labor and vaginal delivery and group B (n=15) with scheduled cesarean section.

Material And Methods: Blood was obtained from the mothers pre- versus post-delivery as well as from the umbilical cord. Routine laboratory tests (liver enzymes, muscle enzyme, etc.) and the amino acid blood levels were measured with a clinical chemistry analyzer and tandem mass spectrometry methods, respectively.

Results: Routine laboratory tests and the amino acid blood levels were similar in the two groups of mothers pre-delivery. Total antioxidant status levels were reduced, whereas the branched-chain amino acids (BCAAs) and alanine levels were remarkably elevated in the sera of group A post-delivery, whereas they remained unaltered in group B at the same time of study. The mentioned BCAAs and alanine levels were higher in the umbilical cord blood of group A than those in group B. The rest of the amino acids were similar.

Conclusions: The increased BCAAs and alanine blood levels in mothers of group A may be related to uterine and skeletal muscle contractions during the vaginal delivery process and the high levels in the umbilical cord blood of their neonates may mirror those of the mothers. The elevation of BCAAs both in mothers of group A and their neonates may exclude or minimize tyrosine and tryptophane levels from entry in the brain resulting in decreased biogenic amine and increased prolactin production in the central nervous system of these mothers and their infants.
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http://dx.doi.org/10.1080/00016340802578098DOI Listing
February 2009

The effect of the mode of delivery on maternal-neonatal interleukin-6, biogenic amine and their precursor amino acid concentrations.

Clin Chem Lab Med 2008 ;46(11):1624-30

Institute of Child Health, Research Center, "Aghia Sophia" Children's Hospital, Athens, Greece.

Background: Biogenic amine, adrenaline, noradrenaline, dopamine and 5-hydroxy-tryptamine (5-HT) levels are related to interleukin-6 (IL-6) plasma concentrations and endurance exercise. The aim of our study was to investigate the effect of the mode of delivery on maternal-neonatal IL-6, biogenic amine and their precursor amino acid levels.

Methods: Some women with normal pregnancy (n=56) were divided into two groups: group A (n=26) with normal labor and vaginal delivery, and group B (n=30) with scheduled cesarean section. Blood was obtained from the mothers at the beginning of labor and immediately after delivery (pre- vs. post-delivery), as well as from the umbilical cord (CB). Total antioxidant status (TAS) and IL-6 levels were measured with commercial kits, the precursor amino acids, tyrosine and tryptophan with tandem mass spectrometry and the biogenic amine blood levels with HPLC methods, respectively.

Results: TAS, IL-6, biogenic amine and their precursor amino acid blood levels were similar in the two groups of mothers pre-delivery. TAS levels were reduced, whereas the amino acids, the catecholamine, 5-HT and IL-6 levels were increased post-delivery and in the CB of group A and unaltered in group B at the same time of the study.

Conclusions: During a vaginal delivery process, the low TAS, the increased levels of the studied amino acids, the catecholamines, 5-HT and IL-6 may be due to the activation of the neuroendocrine system and the participation of skeletal and uterine muscles. The mode of delivery may be taken into account when IL-6 plasma levels are evaluated as an anti-inflammatory index perinatally.
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http://dx.doi.org/10.1515/CCLM.2008.305DOI Listing
February 2009

The effect of the mode of delivery on the maternal-neonatal carnitine blood levels and antioxidant status.

Clin Chem Lab Med 2008 ;46(5):680-6

Institute of Child Health, Research Center, Aghia Sophia Children's Hospital, Athens, Greece.

Background: Carnitine blood levels are closely related to beta-oxidation and implicated with strenuous muscle contractions. Normal delivery process is characterized by the participation of the uterus and most skeletal muscles.

Methods: Women with normal pregnancy (n = 56) were divided into two groups. Group A (n = 26) with normal labor and vaginal delivery and group B (n = 30) with scheduled cesarean section. Blood was obtained from the mothers at the beginning of labor and immediately after delivery (pre- vs. post-delivery), as well as from the cord blood (CB). Total antioxidant status (TAS) was measured with a commercial kit and carnitine was measured in blood spots on Guthrie cards with tandem-mass spectrometry.

Results: TAS and carnitine levels were similar in all the groups pre-delivery. In contrast, TAS and carnitine levels were significantly lower in group A than in group B post-delivery. Remarkably lower TAS and carnitine levels were measured in the CB of neonates of group A as compared to the CB of neonates of group B.

Conclusions: The lower TAS and carnitine levels measured in group A as compared to group B postdelivery may be due to uterus and skeletal muscle contraction during a normal labor process. Infants born with scheduled cesarean section are benefited with high carnitine levels to face oxidation perinatally.
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http://dx.doi.org/10.1515/cclm.2008.100DOI Listing
November 2008

Maternal chronic hepatitis B virus does not affect neonatal biotinidase activity.

Acta Paediatr 2008 Mar 31;97(3):362-5. Epub 2008 Jan 31.

First Department of Obstetrics and Gynecology, Alexandra Hospital, Athens University Medical School, Athens, Greece.

Background: Biotinidase activity is closely related to liver function.

Aim: To evaluate whether maternal chronic hepatitis B virus (HBV) infection affects neonatal biotinidase activity.

Patients And Methods: Twenty-three asymptomatic pregnant women with HBV (group A) and 28 healthy pregnant women (controls) in the delivery room and their newborns (cord blood) underwent laboratory examinations. Serological HBV and liver function tests were performed with standard techniques, while biotinidase activity was measured with an HPLC method.

Results: Serological HBV tests and HBV DNA showed chronic HBV (precore mutant G1896A) in group A, whereas anti-HBc and anti-HBe were detected in their neonates. Liver function chemistry was found normal in controls and both groups of newborns. Moderately increased transaminases were found in the infected mothers. Interestingly, albumin levels did not differ among the studied groups. Biotinidase activity in HBV mothers (5.76+/-0.6 nmol/min/mL) was significantly decreased (p<0.001) as compared to controls (8.43+/-0.65 nmol/min/mL). The enzyme activity did not differ among the neonates. Biotinidase activity inversely correlated with transaminases but not with albumin or with HBV-DNA levels.

Conclusions: Decreased biotinidase activities were evaluated in mothers with HBV and normal in their neonates. Biotin supplementation in the diseased mothers may prevent possible symptoms due to biotin recycling impairment.
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http://dx.doi.org/10.1111/j.1651-2227.2007.00636.xDOI Listing
March 2008

The effect of diet on Paraoxonase 1/Arylesterase activities in patients with disorders of galactose metabolism.

Clin Endocrinol (Oxf) 2007 Nov 25;67(5):687-92. Epub 2007 Jun 25.

Institute of Child Health, Research Centre, 'Aghia Sophia' Children's Hospital, Athens, Greece.

Objective: To investigate the effects of diet on the antiatherogenic enzyme Paraoxonase 1/Arylesterase (PON1/Aryl) activities in patients with disorders of galactose metabolism.

Patients And Methods: Eleven poorly dietary controlled children with classical galactosaemia (GALT deficiency), 7 with epimerase deficiency and 12 with duarte 1 variant 'off diet' underwent clinical and laboratory investigations before and after 10 days on galactose restricted diet whereas controls (N = 20) were examined once. Serum lipids, lipoproteins and apolipoprotein A1 (ApoA1) were measured with routine methods, PON1/Aryl activities and total antioxidant status (TAS) spectrophotometrically, and galactose-1-phosphate (Gal-1-P) enzymatically.

Results: Lipids, lipoproteins, ApoA1, PON1/Aryl, TAS remained unaltered in all groups, except in those with classical galactosaemia pre- versus postdiet. In patients with classical galactosaemia, TAS, PON1, Aryl (0.98 +/- 0.2 mmol/l, 60 +/- 12 U/min/ml, 56 +/- 16 KU/min/ml, respectively) were significantly reduced prediet as compared with those postdiet (1.63 +/- 0.2 mmol/l, 136 +/- 15 U/min/ml, 112 +/- 18 KU/min/ml, respectively; P < 0.001) and controls. The enzyme activities positively correlated with TAS (r = 0.56, P < 0.001) in all groups and negatively with Gal-1-P (r = -0.54, P < 0.001) in group with GALT deficiency.

Conclusions: Low TAS and high Gal-1-P levels may reduce PON1/Aryl activities. Patients with classical galactosaemia, when on strict diet, may benefit with a generous antiatherogenic capacity.
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http://dx.doi.org/10.1111/j.1365-2265.2007.02946.xDOI Listing
November 2007
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