Blood Metabolic Signatures of Body Mass Index: A Targeted Metabolomics Study in the EPIC Cohort.

Metabolomics is now widely used to characterize metabolic phenotypes associated with lifestyle risk factors such as obesity. The objective of the present study was to explore the associations of body mass index (BMI) with 145 metabolites measured in blood samples in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolites were measured in blood from 392 men from the Oxford (UK) cohort (EPIC-Oxford) and in 327 control subjects who were part of a nested case-control study on hepatobiliary carcinomas (EPIC-Hepatobiliary). Measured metabolites included amino acids, acylcarnitines, hexoses, biogenic amines, phosphatidylcholines, and sphingomyelins. Linear regression models controlled for potential confounders and multiple testing were run to evaluate the associations of metabolite concentrations with BMI. 40 and 45 individual metabolites showed significant differences according to BMI variations, in the EPIC-Oxford and EPIC-Hepatobiliary subcohorts, respectively. Twenty two individual metabolites (kynurenine, one sphingomyelin, glutamate and 19 phosphatidylcholines) were associated with BMI in both subcohorts. The present findings provide additional knowledge on blood metabolic signatures of BMI in European adults, which may help identify mechanisms mediating the relationship of BMI with obesity-related diseases.

Early metabolomics changes in heart and plasma during chronic doxorubicin treatment in B6C3F1 mice.

The present study aimed to identify molecular markers of early stages of cardiotoxicity induced by a potent chemotherapeutic agent, doxorubicin (DOX). Male B6C3F1 mice were dosed with 3 mg kg(-1) DOX or saline via tail vein weekly for 2, 3, 4, 6 or 8 weeks (cumulative DOX doses of 6, 9, 12, 18 or 24 mg kg(-1) , respectively) and euthanized a week after the last dose. Mass spectrometry-based and nuclear magnetic resonance spectrometry-based metabolic profiling were employed to identify initial biomarkers of cardiotoxicity before myocardial injury and cardiac pathology, which were not noted until after the 18 and 24 mg kg(-1) cumulative doses, respectively. After a cumulative dose of 6 mg kg(-1) , 18 amino acids and four biogenic amines (acetylornithine, kynurenine, putrescine and serotonin) were significantly increased in cardiac tissue; 16 amino acids and two biogenic amines (acetylornithine and hydroxyproline) were significantly altered in plasma. In addition, 16 acylcarnitines were significantly increased in plasma and five were significantly decreased in cardiac tissue compared to saline-treated controls. Plasma lactate and succinate, involved in the Krebs cycle, were significantly altered after a cumulative dose of 6 mg kg(-1) . A few metabolites remained altered at higher cumulative DOX doses, which could partly indicate a transition from injury processes at 2 weeks to repair processes with additional injury happening concurrently before myocardial injury at 8 weeks. These altered metabolic profiles in mouse heart and plasma during the initial stages of injury progression due to DOX treatment may suggest these metabolites as candidate early biomarkers of cardiotoxicity. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

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

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.

[Cerebral metabolism and the exchange of biogenic amines in the brain of patients under various types of anesthesia in the surgery of intracranial aneurysms].

During intracranial surgical interventions, the major tasks of an anesthetic procedure are to maintain cerebral perfusion, adequate oxygen delivery, and brain tissue metabolism at all surgical stages. The authors have compared cerebral metabolism and the exchange of biogenic amines that regulate cerebral oxygen consumption and cerebral blood flow, by using neuroleptic anesthesia and balanced anesthesia on the basis of enflurane during operations on intracranial vessels. There is evidence for the equal efficiency of both types of anesthesias and for a unidirectional impact on the body's neurohumoral systems.

Effects of monoamines formed in the cecum of horses on equine digital blood vessels and platelets.

OBJECTIVE: To determine in vitro vasoactive potency of monoamines formed in the cecum and found in the systemic circulation of horses. SAMPLE POPULATION: Segments of digital blood vessels obtained from 6 healthy mixed-breed horses and ponies euthanatized at an abattoir and platelets isolated from 4 healthy ponies. PROCEDURE: Paired rings of digital artery and vein from the same horse were examined, and isometric tension was recorded. Concentration-response curves for tryptamine (TRP), tyramine (TYR), phenylethylamine (PEA), isoamylamine (IAA), and isobutylamine (IBA) were obtained. Vasoconstrictor mechanisms were investigated for TRP and TYR by the use of antagonists. Washed platelets loaded with [3H]-5-hydroxytryptamine (5-HT) were incubated with monoamines; the amount of radioactivity displaced after 30 minutes was estimated. RESULTS: TRP, TYR, and PEA were potent constrictors of arteries and veins, with TRP and TYR being more potent in veins than arteries. Constrictions induced by TYR were inhibited by benextramine (alpha-antagonist) and nisoxetine (neuronal-uptake blocker), whereas TRP responses were inhibited by ketanserin (5-HT receptor antagonist). All 5 amines displaced 5-HT from platelets with the order of potency being TYR > TRP > PEA > IAA > IBA. CONCLUSIONS AND CLINICAL RELEVANCE: Amines from the equine cecum cause digital vasoconstriction. The most potent (TRP and TYR) cause selective venoconstriction. Tyrosine activates predominantly alpha-adrenoceptors through the release of neuronal norepinephrine, whereas TRP activates 5-HT receptors. All amines tested released 5-HT from platelets. Amines formed in the cecum and released into the systemic circulation warrant additional investigation as trigger factors for digital ischemia and subsequent laminitis.

In vivo effects of high phenylalanine blood levels on Na+,K+-ATPase, Mg2+-ATPase activities and biogenic amine concentrations in phenylketonuria.

OBJECTIVE: To evaluate the activities of Na+,K+-ATPase and Mg2+-ATPase in erythrocyte membranes from phenylketonuric (PKU) patients and to correlate the enzyme activities with their blood phenylalanine (Phe) levels, biogenic amines as well as with their precursors tyrosine (Tyr) and tryptophan (Try). DESIGN AND METHODS: Twenty three PKU patients were divided into group A (n = 12) on a restricted diet (Phe 1.57 +/- 0.52 mg/dL or 0.10 +/- 0.03 mM) and group B (n = 11) on a "loose" diet (Phe 24.45 +/- 1.50 mg/dL or 1.72 +/- 0.09 mM). The enzyme activities were measured spectrophotometrically, the amino acids with an automatic amino analyser and the biogenic amines with HPLC methods. RESULTS: In group B, plasma amino acids (Tyr, Try), their biogenic amines [adrenaline (A), noradrenaline (NA), dopamine (DA) and serotonin (5HT)], (Na+,K+)-ATPase and Mg2+-ATPase activities were found remarkably decreased (p < 0.001). CONCLUSIONS: High Phe and/or low NA, DA, 5HT plasma levels may indirectly inhibit the erythrocyte membrane Na+,K+-ATPase and Mg2+-ATPase in PKU patients. The observed enzyme inhibitions could be a very informative peripheral marker as regards the neurotoxic Phe brain effects.

[The change of biogenic amine blood level under the influence of the low intensity laser infrared radiation]. / Izmeneniia soderzhaniia biogennykh aminov v krovi pri vozdeistvii nizkointensivnogo lazernogo izlucheniia infrakrasnogo diapazona.

The dynamics of the biogenic amines level in the blood of patients after performance of hemorrhoidectomy was dependent on severity of an organism stress-reaction predicting the wound healing outcome. When the wound irradiation using the low-energy laser of infrared diapason is performed in patients with the lowered reactivity of organism the histamine and serotonin contents dynamics is the same as in the patients with normal reactivity.

Measurement of nitrite and nitrate in plasma, serum and urine of humans by high-performance liquid chromatography, the Griess assay, chemiluminescence and gas chromatography-mass spectrometry: interferences by biogenic amines and N(G)-nitro-L-arginine analogs.

In this paper, the HPLC method for the measurement of nitrite and nitrate in serum of humans newly reported by E1 Menyawi et al. is discussed, especially in regard to the extremely low nitrate levels measured in serum of healthy humans. From the discussion, it is concluded that: (1) Biogenic amines at physiological concentrations do not significantly interfere with the batch Griess assay. (2) The HPLC method of E1 Menyawi et al. does not reveal accurate levels for serum nitrate. (3) In serum and plasma of healthy humans, nitrate ranges within 15-70 microM. (4) Exogenous NG-nitro-L-arginine analogs can interfere with the measurement of nitrate in human plasma and urine by the batch Griess assay, chemiluminescence and GC-MS; interferences can be effectively eliminated by solid-phase extraction on cation-exchangers.

Recent advances in diagnosis and therapy of neuroendocrine tumors of the gastrointestinal tract.

Neuroendocrine tumors of the gastrointestinal tract are rare tumors that can be classified as APU-Domas (amine precursor uptake and decarboxylation). They can be subdivided into the carcinoid tumors of the gastrointestinal submucosa and the islet cell endocrine tumors of the pancreas. Although the majority of tumors that become clinically apparent are malignant, they are frequently slow growing. Despite this, neuroendocrine tumors may generate disabling hormonal syndromes requiring aggressive treatment to achieve palliation. Recent advances in understanding the pathophysiology of these tumors has led to better radiographic imaging and more accurate localization techniques. Medical therapies with somatostatin analogues, omeprazole, and locoregional tumor ablation have made a positive impact on curative and palliative therapy. This review updates the recent efforts made in the radiographic imaging and therapeutics of the gastrointestinal neuroendocrine tumors.

Changes in circulatory biogenic amines during head-up tilt testing in neurocardiogenic syncope.

The pathogenesis of neurocardiogenic syncope is not completely understood. To examine the possible role of biogenic amines in patients with neurocardiogenic syncope, 18 consecutive patients (age 30 +/- 13 years, 15 males, 3 females) of unexplained syncope were subjected to Head-Up Tilt Testing (HUTT). Blood was sampled by an indwelling cannula at baseline, end of tilt test (or at syncope) and 1 min after returning to the supine position. Biogenic amines, epinephrine (E), norepinephrine (NE), serotonin (5-HT) and their metabolites, homovanillic acid (HVA) and 5-hydroxy indole acetic acid (5-HIAA), were measured in the serum after serial organic phase extraction by high-performance liquid chromatography (HPLC) using ultraviolet detection at a wavelength of 280 nm. Twelve patients were found to be HUTT negative while 6 patients were HUTT positive. Baseline E, NE and 5-HT levels were significantly greater in the HUTT positive patients [E 510 +/- 154 versus 302 +/- 96 pg/ml (p < 0.01), NE 253 +/- 99 versus 159 +/- 62 pg/ml (p < 0.05), 5-HT 174 +/- 32 versus 118 +/- 22 pg/ml (p < 0.01)]. E and HVA levels at the end of the test were significantly higher in HUTT positive patients [E 788 +/- 268 versus 465 +/- 119 pg/ml (p < 0.01), HVA 308 +/- 91 versus 112 +/- 12 pg/ml (p < 0.001)]. A significantly greater rise of E from the baseline was observed in HUTT positive patients (510 +/- 154 versus 112 +/- 12 pg/ml (p < 0.01)]. The increase in the levels of E and HVA both at baseline and after the tilt test, without a corresponding rise in NE levels indicates enhanced activity of the adrenomedullary axis which is not paralleled by NE release from sympathetic nerve endings in patients of neurocardiogenic syncope.

Separación de aminas biogénicas mediante cromatografía líquida de alta resolución / High-performance liquid chromatographic determination of biogenic amines

En este trabajo se han compilado los distintos modos cromatográficos y sistemas de detección utilizados en la cromatografía líquida de alta resolución de aminas biogénicas. Se indican las características generales del intercambio catiónico, fase reversa, fase reversa de pares iónicos y cromatografía de partición con fase reversa de pares iónicos. También se analizan comparativamente la detección UV, detección fluorimétrica usando fluorescencia nativa o bien derivatización pre- y postcolumna y detección electroquímica de gran utilidad para esta extensa familia de compuestos. Se dan ejemplos de aplicación de interés en el campo bioquímico-clínico, con el análisis de ácido homovainillínico, ácido 3,4-dihidroxifenilacético y ácido 5-hidroxiindolacético en líquido cefalorraquídeo, metanefrinas, ácido 3,4-dihidroxifenilacético, catecolaminas, ácidos urinarios y 3-metoxi-4-hidroxifenilglicol en orina, catecolaminas y 3-metoxi-4-hidroxifenilglicol en plasma, catecolaminas, 3-metoxi-4-hidroxifenilglicol y otros neurotransmisores en cerebro de rata. Se discuten, también, los tratamientos previos requeridos especialmente para orina y plasma, así como las condiciones de conservación y su incidencia en los resultados obtenidos

[Biogenic amines in the differential diagnosis of erythrocytes]. / Biogennye aminy v differentsial'noi diagnostike éritrotsitov.

Free histamine (FH) and free serotonin (FS) were studied fluorometrically in blood serum of 26 patients with genuine polycythemia (GP), 52 patients with chronic obstructive bronchitis (COB) associated with secondary erythrocytosis (SE) and 29 healthy subjects. On the grounds of the results of the study criteria of GP and COB-related SE were suggested. Diagnosis of GP can be considered valid if content of FH is no more than 3.1 times, FS content no less than 3 times and FH/FS ratio is no more than 2.65 times as much as normal. Levels of FH and FS and FH/FS ratio in SE related to COB are characterized by 4-fold and more, 2.9 and less and 4.64 and more increase respectively.

[The effect of the one-time and long-term administration of preparations acting on biogenic amine metabolism on the blood level of pressor peptide hormones]. / Vliianie odnokratnogo i dlitel'nogo priema preparatov, deistvuiushchikh na obmen biogennykh sminov, na so9derzhanie v krovi pressornykh peptidnykh gornonov.

Blood contents of pressor peptide hormones vasopressin and angiotonin II were studied in patients with neuro-endocrine syndrome before and after single intake and prolonged treatment with anti-serotonin drug peritol and cholinergic agent parlodel which affect biogenic amine metabolism and, consequently, influence blood pressure. Single doses of the drugs were established to cause different blood dynamics of vasopressin and angiotonin II which classified as marked and paradoxic reactions on peritol and parlodel used separately and associatively. Fall of blood vasopressin content induced by single dose of parlodel was accompanied by blood pressure decrease. Tree-week treatment with peritol and parlodel exerted hypotensive effect and significantly reduced vasopressin blood content.

High-performance liquid chromatographic separation of biogenic polyamines using 2-(1-pyrenyl)ethyl chloroformate as a new fluorogenic derivatizing reagent.

The application of a new fluorogenic pre-column derivatizing reagent, 2-(1-pyrenyl)ethyl chloroformate (PEOC), is reported for the separation and detection of biogenic polyamines using column liquid chromatography. The development of the method included the optimization of excitation and emission wavelengths, efficient gradient programming, derivatization temperature, time, and pH. Minimum detection limits, linear ranges, reproducibility, and recovery from analyzed samples were determined. The procedure was applied to hydrolyzed serum samples taken from healthy individuals and cancer patients. Separation of PEOC-derivatized polyamines from the serum hydrolysis by-products was successful and detection limits were more favorable than those previously reported for 9-fluorenyl-methyl chloroformate-derivatized polyamines.

Serum catecholamine levels determined by high performance liquid chromatography coupled with electrochemical detection

Este trabalho apresenta um método rápido para a quantificaçäo de catecolaminas utilizando a técnica de cromatografia líquida de fase reversa acoplada à detecçäo eletroquímica. Separaçäo isocrática rápida foi obtida empregando como fase móvel a soluçäo: 0,02M de fosfato de sódio dibásico, 0,02M de ácido nítrico, pH 2,64, metanol a 10 por cento, 0,12mM de EDTA sódico e 556 mg/L de ácido heptanosulfônico. Delineou-se o procedimento de preparaçäo das amostras com extraçäo das monoaminas em alumina, para melhorar a recuperaçäo e diminuir fatores de diluiçäo. O tempo total de análise é de 15 minutos, com boa separaçäo dos picos de monoaminas. O limite de detecçäo obtido para as monoaminas séricas é de 40 a 50 pg/mL, com uma taxa de recuperaçäo de 70-75 por cento.

[The combined action of ionizing radiation and a heat load on the content of biogenic amines in the blood of guinea pigs with anaphylactic shock]. / Kombinirovannoe deistvie ioniziruiushchego izlucheniia i teplovoi nagruzki na soderzhanie biogennykh aminov v krovi morskikh svinok pri anafilaticheskom shoke.

The anaphylactic shock and alterations in the epinephrine and norepinephrine content of the blood were inhibited in guinea pigs which were repeatedly kept at high temperature (50 degrees C). Preirradiation with a dose of 1 Gy prevented this effect.

Serotonin, histamine and platelets in vascular disease with special reference to peripheral vascular disease

Cardiovascular disease is a major cause of death. There is evidence that this disease is predicted and its progression influenced by various factors (e.g. hyperlipidaemia). In this review, we consider aspects of platelet structure and function which may explain how this cell type contributes to the pathogenesis of vascular disease. The platelet also contains bioamines (serotonin, 5-HT; histamine) which are potent vasoactive substances. Studies involving patients with peripheral vascular disease (PVD) where abnormalities in platelet function (platelet aggregation and platelet shape change) and in bioamine status (vascular, platelet and plasma bioamine concentrations) are reviewed. We also discuss how platelet activation (in vitro) and plasma lipids influence intraplatelet bioamine status. Finally, we report in vitro evidence of the effect of two drugs prescribed to PVD patients: aspirin and naftidrofuryl. Aspirin is an ineffective inhibitor of 5-HT-induced whole blood platelet aggregation whereas naftidrofuryl is effective in the presence or absence of aspirin. By identifying and altering the factors which contribute to the pathogenesis of atherosclerosis we will be better equipped to prevent, reverse or retard this process

Blood bioamines, cortisol and aminoacid levels in leukemic patients.

In patients of chronic myeloid leukemia blood adrenaline, noradrenaline, dopamine and glutamate level were significantly elevated. The GABA levels were decreased along with no significant alterations in aspartate levels in these patients. In cases of acute myeloid leukemia only adrenaline and glutamate levels were enhanced with decreased GABA levels. However, plasma cortisol levels were significantly enhanced in both chronic and acute myeloid leukemia patients. These observations suggest that the circulating bioamines, cortisol and certain aminoacids level are considerably altered in chronic and acute myeloid leukemia. All these changes may possibly be attributed to the stress induced by the disease.

[Mechanism of changes in amine binding to plasma proteins during allergy]. / O mekhanizme izmeneniia sviazyvaniia aminov belkami plazmy krovi pri allergii.

Blood plasma of healthy persons bound 13.13 +/- 1.07 mmol/l of p-phenylene diamine (PDA), histamine pectic index constituted 33.3 +/- 2.18%. In patients with neurodermitis and eczema both these patterns were markedly reduced. Unitiol (10(-3) mol/l) increased PDA binding and histamine level in vitro. The same concentration of cystamine decreased histamine pectic index in healthy persons. Importance of protein SH-groups in binding of amines is discussed.

Platelet alpha 2- and leucocyte beta 2-adrenoceptors in phaeochromocytoma: effect of tumour removal.

Platelet alpha 2- and leucocyte beta 2-adrenoceptors (as well as noradrenaline and adrenaline plasma levels) were studied in five patients with confirmed phaeochromocytoma using tritiated yohimbine and iodated cyanopindolol, respectively, before and after tumour removal. Patients with phaeochromocytoma had a lower leucocyte iodated cyanopindolol binding than control subjects, but no change in platelet tritiated yohimbine binding. Plasma catecholamine levels were higher than controls. Tumour removal induced a return to normal values of leucocyte iodated cyanopindolol binding and a decrease in plasma catecholamine levels. These results underline the potential interest of leucocyte beta-adrenoceptor quantification in the diagnosis and the follow-up of phaeochromocytoma. Pharmacologically, they show that down-regulation occurs in vivo for leucocyte beta 2-adrenoceptors but not for platelet alpha 2-adrenoceptors.