Diagnostic performance of automated red cell parameters in predicting bone marrow iron stores.

OBJECTIVES: The aim of the study was to determine the diagnostic performance of novel automated red cell parameters for estimating bone marrow iron stores. METHODS: The study was a retrospective single-centre study based on data from an automated haematology analyser and results of bone marrow iron staining. Red cell parameters were measured on a Sysmex XN-series haematology analyser. Bone marrow iron stores were assessed semiquantitatively by cytochemical reaction according to Perls. RESULTS: The analysis included 429 bone marrow aspirate smears from 393 patients. Median age of patients was 67 years, 52 % of them were female. The most common indication for bone marrow examination was a plasma cell dyscrasia (n=104; 24 %). Median values of percentage of hypochromic and hyperchromic red blood cells (%HYPO-He, %HYPER-He), reticulocyte haemoglobin equivalent (RET-He) and microcytic red blood cells (MicroR) were statistically significantly different between cases with iron deplete and iron replete bone marrow. In a logistic regression model, ferritin was the best predictor of bone marrow iron stores (AUC=0.891), outperforming RET-He and %HYPER-He (AUC=0.736 and AUC=0.722, respectively). In a combined model, ferritin/MicroR index achieved the highest diagnostic accuracy (AUC=0.915), outperforming sTfR/log ferritin index (AUC=0.855). CONCLUSIONS: While single automated red cell parameters did not show improved diagnostic accuracy when compared to traditional iron biomarkers, a novel index ferritin/MicroR has the potential to outperform ferritin and sTfR/log ferritin index for predicting bone marrow iron stores. Further research is needed for interpretation and implementation of novel parameters and indices, especially in the context of unexplained anaemia and myelodysplastic syndromes.

Impacts of methyl jasmonate on Selaginella martensii: volatiles, transcriptomics, phytohormones, and gas exchange.

Methyl jasmonate (MeJA) induces various defence responses in seed plants, but for early plant lineages, information on the potential of jasmonates to elicit stress signalling and trigger physiological modifications is limited. The spikemoss Selaginella martensii was exposed to a range of MeJA concentrations (0, 10, 25, and 50 mM), and biogenic volatile organic compound (BVOC) emissions, photosynthetic rate (A), and stomatal conductance (gs) were continuously measured. In addition, changes in phytohormone concentrations and gene expression were studied. Enhancement of methanol, lipoxygenase pathway volatiles and linalool emissions, and reductions in A and gs, were MeJA dose-dependent. Before MeJA treatment, the concentration of 12-oxo-phytodienoic acid (OPDA) was 7-fold higher than jasmonic acid (JA). MeJA treatment rapidly increased OPDA and JA concentrations (within 30 min), with the latter more responsive. Some genes involved in BVOC biosynthesis and OPDA-specific response were up-regulated at 30 min after MeJA spraying, whereas those in the JA signalling pathway were not affected. Although JA was synthesized in S. martensii, OPDA was prioritized as a signalling molecule upon MeJA application. MeJA inhibited primary and enhanced secondary metabolism; we propose that fast-emitted linalool could serve as a marker of elicitation of stress-induced metabolism in lycophytes.

Stomatal VPD Response: There Is More to the Story Than ABA.

Guard cells shrink and close stomatal pores when air humidity decreases (i.e. when the difference between the vapor pressures of leaf and atmosphere [VPD] increases). The role of abscisic acid (ABA) in VPD-induced stomatal closure has been studied using ABA-related mutants that respond to VPD in some studies and not in others. The importance of ABA biosynthesis in guard cells versus vasculature for whole-plant stomatal regulation is unclear as well. Here, we show that Arabidopsis (Arabidopsis thaliana) lines carrying mutations in different steps of ABA biosynthesis as well as pea (Pisum sativum) wilty and tomato (Solanum lycopersicum) flacca ABA-deficient mutants had higher stomatal conductance compared with wild-type plants. To characterize the role of ABA production in different cells, we generated transgenic plants where ABA biosynthesis was rescued in guard cells or phloem companion cells of an ABA-deficient mutant. In both cases, the whole-plant stomatal conductance, stunted growth phenotype, and leaf ABA level were restored to wild-type values, pointing to the redundancy of ABA sources and to the effectiveness of leaf ABA transport. All ABA-deficient lines closed their stomata rapidly and extensively in response to high VPD, whereas plants with mutated protein kinase OST1 showed stunted VPD-induced responses. Another strongly ABA-insensitive mutant, defective in the six ABA PYR/RCAR receptors, responded to changes in VPD in both directions strongly and symmetrically, indicating that its VPD-induced closure could be passive hydraulic. We discuss that both the VPD-induced passive hydraulic stomatal closure and the stomatal VPD regulation of ABA-deficient mutants may be conditional on the initial pretreatment stomatal conductance.

In vitro culture and non-invasive metabolic profiling of single bovine embryos.

Selecting high-quality embryos for transfer has been a difficult task when producing bovine embryos invitro. The most used non-invasive method is based on visual observation. Molecular characterisation of embryo growth media has been proposed as a complementary method. In this study we demonstrate a culture medium sampling method for identifying potential embryonic viability markers to predict normal or abnormal embryonic development. During single embryo culture, 20µL culture media was removed at Days 2, 5 and 8 after fertilisation from the same droplet (60µL). In all, 58 samples were analysed using liquid chromatography-mass spectrometry. We demonstrate that it is possible to remove samples from the same culture medium droplets and not significantly affect blastocyst rate (25.2%). Changes in any single low molecular weight compound were not predictive enough. Combining multiple low molecular weight signals made it possible to predict Day 2 and 5 embryo development to the blastocyst stage with an accuracy of 64%. Elevated concentrations of lysophosphatidylethanolamines (m/z=453, 566, 588) in the culture media of Day 8 well-developing embryos were observed. Choline (104m/z) and citrate (215m/z) concentrations were increased in embryos in which development was retarded. Metabolic profiling provides possibilities to identify well-developing embryos before transfer, thus improving pregnancy rates and the number of calves born.

Phenotyping of Chronic Obstructive Pulmonary Disease Based on the Integration of Metabolomes and Clinical Characteristics.

Apart from the refined management-oriented clinical stratification of chronic obstructive pulmonary disease (COPD), the molecular pathologies behind this highly prevalent disease have remained obscure. The aim of this study was the characterization of patients with COPD, based on the metabolomic profiling of peripheral blood and exhaled breath condensate (EBC) within the context of defined clinical and demographic variables. Mass-spectrometry-based targeted analysis of serum metabolites (mainly amino acids and lipid species), untargeted profiles of serum and EBC of patients with COPD of different clinical characteristics (n = 25) and control individuals (n = 21) were performed. From the combined clinical/demographic and metabolomics data, associations between clinical/demographic and metabolic parameters were searched and a de novo phenotyping for COPD was attempted. Adjoining the clinical parameters, sphingomyelins were the best to differentiate COPD patients from controls. Unsaturated fatty acid-containing lipids, ornithine metabolism and plasma protein composition-associated signals from the untargeted analysis differentiated the Global Initiative for COPD (GOLD) categories. Hierarchical clustering did not reveal a clinical-metabolomic stratification superior to the strata set by the GOLD consensus. We conclude that while metabolomics approaches are good for finding biomarkers and clarifying the mechanism of the disease, there are no distinct co-variate independent clinical-metabolic phenotypes.

Alterations of bronchial epithelial metabolome by cigarette smoke are reversible by an antioxidant, O-methyl-L-tyrosinyl-γ-L-glutamyl-L-cysteinylglycine.

Human bronchial epithelial cells (HBECs) have first-line contact with harmful substances during smoking, and changes in their metabolism most likely represent a defining factor in coping with the stress and development of airway diseases. This study was designed to determine the dynamics of metabolome changes in HBECs treated with cigarette smoke condensate (CSC), and to test whether normal metabolism can be restored by synthetic antioxidants. Principal component analysis, based on untargeted mass spectra, indicated that treatment of CSC-exposed HBECs with O-methyl-L-tyrosinyl-γ-L-glutamyl-L-cysteinylglycine (UPF1) acted faster than did N-acetylcysteine to revert the effect of CSC. The maximum effect of 10 µg/ml CSC itself on HBEC cell line, BEAS-2B, metabolism was seen at 2 hours after treatment, with return to the baseline level by 7 hours. In primary HBECs, the initial maximum effect was seen at 1 hour after CSC exposure. Certain metabolites associated with redox pathways and energy production were affected by CSC. Subsequent restoration of their content by UPF1 supports the hypothetical protective capacity of UPF1 against the oxidative stress and increased energy demand, respectively. Furthermore, UPF1 up-regulated the contents of phospholipid species identified as phosphatidylcholines and phosphatidylethanolamines in the CSC-exposed HBECs, indicating possible suppression of inflammatory processes along with an increase in spermidine as an endogenous cytoprotector. In conclusion, with this dynamic metabolomics study, we characterize the durability of the CSC-induced metabolic changes in BEAS-2B line cells and primary HBECs, and demonstrate the ability of UPF1 to significantly accelerate the recovery of HBECs from CSC insult.

A Novel Bifidobacterium longum ssp. longum Strain with Pleiotropic Effects.

Postbiotics are gaining increasing interest among the scientific community as well as at the level of food processing enterprises. The aim of this preliminary study was to characterise the metabolic diversity of a novel Bifidobacterium longum strain, BIOCC 1719, of human origin. The change after 24 h cultivation in three media was assessed using a metabolomic approach. Milk-based substrates favoured the activity of the strain, promoting the production of B vitamins, essential amino acids, bile acids, and fatty acids. Vitamins B1, B2, B6, B7, and B12 (with an average increase of 20-30%) were produced in both whole milk and whey; the increased production in the latter was as high as 100% for B7 and 744% for B12. The essential amino acids methionine and threonine were produced (>38%) in both milk and whey, and there was an increased production of leucine (>50%) in milk and lysine (126%) in whey. Increases in the content of docosahexaenoic acid (DHA) by 20%, deoxycholic acid in milk and whey (141% and 122%, respectively), and cholic acid (52%) in milk were recorded. During the preliminary characterisation of the metabolic diversity of the novel B. longum strain, BIOCC 1719, we identified the bioactive compounds produced by the strain during fermentation. This suggests its potential use as a postbiotic ingredient to enrich the human diet.

Associations of the Single Bovine Embryo Growth Media Metabolome with Successful Pregnancy.

This study investigated whether metabolomic fingerprints of bovine embryo growth media improve the prediction of successful embryo implantation. In this prospective cohort study, the metabolome from in vitro-produced day 7 blastocysts with successful implantation (n = 11), blastocysts with failed implantation (n = 10), and plain culture media without embryos (n = 5) were included. Samples were analyzed using an AbsoluteIDQ® p180 Targeted Metabolomics Kit with LC-MS/MS, and a total of 189 metabolites were analyzed from each sample. Blastocysts that resulted in successful embryo implantation had significantly higher levels of methionine sulfoxide (p < 0.001), DOPA (p < 0.05), spermidine (p < 0.001), acetylcarnitine-to-free-carnitine ratio (p < 0.05), C2 + C3-to-free-carnitine ratio (p < 0.05), and lower levels of threonine (nep < 0.001) and phosphatidylcholine PC ae C30:0 (p < 0.001) compared to control media. However, when compared to embryos that failed to implant, only DOPA, spermidine, C2/C0, (C2 + C3)/C0, and PC ae C30:0 levels differentiated significantly. In summary, our study identifies a panel of differential metabolites in the culture media of bovine blastocysts that could act as potential biomarkers for the selection of viable blastocysts before embryo transfer.

Investigation of Effects of Novel Bifidobacterium longum ssp. longum on Gastrointestinal Microbiota and Blood Serum Parameters in a Conventional Mouse Model.

Representatives of the genus Bifidobacterium are widely used as probiotics to modulate the gut microbiome and alleviate various health conditions. The action mechanisms of probiotics rely on their direct effect on the gut microbiota and the local and systemic effect of its metabolites. The main purpose of this animal experiment was to assess the biosafety of the Bifidobacterium longum strain BIOCC1719. Additional aims were to characterise the influence of the strain on the intestinal microbiota and the effect on several health parameters of the host during 15- and 30-day oral administration of the strain to mice. The strain altered the gut microbial community, thereby altering luminal short-chain fatty acid metabolism, resulting in a shift in the proportions of acetic, butyric, and propionic acids in the faeces and serum of the test group mice. Targeted metabolic profiling of serum revealed the possible ability of the strain to positively affect the hosts' amino acids and bile acids metabolism, as the cholic acid, deoxycholic acid, aspartate, and glutamate concentration were significantly higher in the test group. The tendency to increase anti-inflammatory polyamines (spermidine, putrescine) and neuroprotective 3-indolepropionic acid metabolism and to lower uremic toxins (P-cresol-SO4, indoxyl-SO4) was registered. Thus, B. longum BIOCC1719 may exert health-promoting effects on the host through modulation of the gut microbiome and the host metabolome via inducing the production of health-promoting bioactive compounds. The health effects of the strain need to be confirmed in clinical trials with human volunteers.

Mutations in the SLAC1 anion channel slow stomatal opening and severely reduce K+ uptake channel activity via enhanced cytosolic [Ca2+] and increased Ca2+ sensitivity of K+ uptake channels.

The Arabidopsis guard cell anion channel SLAC1 is essential for stomatal closure in response to various endogenous and environmental stimuli. Interestingly, here we reveal an unexpected impairment of slac1 alleles on stomatal opening. We report that mutations in SLAC1 unexpectedly slow stomatal opening induced by light, low CO(2) and elevated air humidity in intact plants and that this is caused by the severely reduced activity of inward K(+) (K(+)(in)) channels in slac1 guard cells. Expression of channels and transporters involved in stomatal opening showed small but significant reductions in transcript levels in slac1 guard cells; however, this was deemed insufficient to explain the severely impaired K(+)(in) channel activity in slac1. We further examined resting cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) and K(+)(in) channel sensitivity to [Ca(2+)](cyt) in slac1. These experiments showed higher resting [Ca(2+)](cyt) in slac1 guard cells and that reducing [Ca(2+)](cyt) to < 10 nM rapidly restored the activity of K(+)(in) channels in slac1 closer to wild-type levels. These findings demonstrate an unanticipated compensatory feedback control in plant stomatal regulation, which counteracts the impaired stomatal closing response of slac1, by down-regulating stomatal opening mechanisms and implicates enhanced [Ca(2+)](cyt) sensitivity priming as a mechanistic basis for the down-regulated K(+)(in) channel activity.

On the methodological limitations of detecting oxidative stress: effects of paraquat on measures of oxidative status in greenfinches.

Oxidative stress (OS) is widely believed to be responsible for the generation of trade-offs in evolutionary ecology by means of constraining investment into a number of components of fitness. Yet, progress in understanding the true role of OS in ecology and evolution has remained elusive. Interpretation of current findings is particularly hampered by the scarcity of experiments demonstrating which of the many available parameters of oxidative status respond most sensitively to and are relevant for measuring OS. We addressed these questions in wild-caught captive greenfinches (Carduelis chloris) by experimental induction of OS by administration of the pro-oxidant compound paraquat with drinking water. Treatment induced 50% mortality, a significant drop in body mass and an increase in oxidative DNA damage and glutathione levels in erythrocytes among the survivors of the high paraquat (0.2 g l(-1) over 7 days) group. Samples taken 3 days after the end of paraquat treatment showed no effect on the peroxidation of lipids (plasma malondialdehyde), carbonylation of proteins (in erythrocytes), parameters of plasma antioxidant protection (total antioxidant capacity and oxygen radical absorbance), uric acid or carotenoids. Our findings of an increase in one marker of damage and one marker of protection from the multitude of measured variables indicate that detection of OS is difficult even under the most stringent experimental induction of oxidative insult. We hope that this study highlights the need for reconsideration of over-simplistic models of OS and draws attention to the limitations of detection of OS due to time-lagged and hormetic upregulation of protective mechanisms. This study also underpins the diagnostic value of measurement of oxidative damage to DNA bases and assessment of erythrocyte glutathione levels.

Crude glycerol as glycogenic precursor in feed; effects on milk coagulation properties and metabolic profiles of dairy cows.

As grain prices rise, the search for alternative glycogenic precursors in animal feed becomes increasingly important, and this study was conducted to determine if the replacement of starch with glycerol, as an alternative glycogenic precursor, affects the milk metabolic profile and milk coagulation ability, and therefore the quality of the milk. Eight primiparous mid-lactation Holstein cows were fed during a replicated 4 × 4 Latin square trial with four different isoenergetic rations: (1) control (T0) fed a total mixed ration (TMR) with barley meal; (2) group T1, decreased barley content, replaced isoenergetically with 1 kg crude glycerol; (3) group T2, the barley meal was replaced with 2 kg of crude glycerol; and (4) group T3 the barley meal was replaced with 3 kg of crude glycerol. Rumen, blood and milk samples were collected at the end of every 21-d treatment period. Rumen samples were analysed for proportion of total volatile fatty acid (VFA), blood samples for insulin and glucose, and milk for metabolites (e.g. citric-acid cycle compounds). The change in glycogenic precursors had a positive effect on rumen VFA proportions; the proportion of propionic acid increased (P < 0.001). Milk protein (P < 0.001) and curd firmness (P < 0.001) both increased. The increase in milk protein concentration may have been due to an increase in microbial protein. Regarding the milk metabolic profiles, different signals were positively associated with coagulation ability and change in the diet. Based on this study, changing the glycogenic precursor in animal diet in this way is possible, and may have no immediate deleterious consequences on milk quality or cow health. Indeed, there is evidence for benefits from this substitution.

Effects of RIPC on the Metabolomical Profile during Lower Limb Digital Subtraction Angiography: A Randomized Controlled Trial.

Remote ischemic preconditioning (RIPC) has demonstrated protective effects in patients with lower extremity arterial disease (LEAD) undergoing digital subtraction angiography (DSA) and/or percutaneous transluminal angioplasty (PTA). This study aimed to investigate the impact of RIPC on the metabolomical profile of LEAD patients undergoing these procedures and to elucidate its potential underlying mechanisms. A total of 100 LEAD patients were enrolled and randomly assigned to either the RIPC group (n = 46) or the sham group (n = 54). Blood samples were drawn before and 24 h after intervention. Targeted metabolomics analysis was performed using the AbsoluteIDQ p180 Kit, and changes in metabolite concentrations were compared between the groups. The RIPC group demonstrated significantly different dynamics in nine metabolites compared to the sham group, which generally showed a decrease in metabolite concentrations. The impacted metabolites included glutamate, taurine, the arginine-dimethyl-amide-to-arginine ratio, lysoPC a C24:0, lysoPC a C28:0, lysoPC a C26:1, PC aa C38:1, PC ae C30:2, and PC ae C44:3. RIPC exhibited a 'stabilization' effect, maintaining metabolite levels amidst ischemia-reperfusion injuries, suggesting its role in enhancing metabolic control. This may improve outcomes for LEAD patients. However, additional studies are needed to definitively establish causal relationships among these metabolic changes.

Kynurenine pathway dynamics in patients with schizophrenia spectrum disorders across the disease trajectory.

The aim of this study was to evaluate how schizophrenia spectrum disorders (SSD) and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum levels of tryptophan (Trp) metabolites. A total of 112 adults (54 first-episode psychosis [FEP] patients and 58 control subjects [CSs]) participated in the study. The investigated changes in the metabolite levels appeared against a background of persistent increase in BMI and waist circumference among the patients. Regarding the kynurenine (KYN) pathway, the strongest changes were seen in AP-naïve FEP patients. Trp, KYN, kynurenic acid (KYNA), and anthranilic acid (ANT) levels were significantly reduced in blood samples from patients in the early stage of the disease. Furthermore, 3-OH-kynurenine (3-HK) and quinolinic acid (QUIN) levels were somewhat lower in these patients. Most of these changes in the KYN pathway became weaker with AP treatment. The levels of serotonin and its metabolite 5-HIAA tended to be higher at 5.1 years in patients showing the relation of elevated serotonin turnover to increased BMI and waist circumference. The similar trend was evident for the ratio between xanthurenic acid (XA) and KYNA with strong link to the elevated BMI. Altogether, the present study supports the role of Trp-metabolites in the development of obesity and metabolic syndrome in SSD patients.

Apnoea-hypopnoea index of 5†events·h-1 as a metabolomic threshold in patients with sleep complaints.

Background: The apnoea-hypopnoea index (AHI) forms the basis for severity of obstructive sleep apnoea (OSA), a condition expected to reprogramme metabolic pathways in humans. We aimed to identify the AHI breakpoint from which the majority of significant changes in the systemic metabolome of patients with sleep complaints occur. Methods: In a prospective observational study on symptomatic individuals, who underwent polysomnography for the diagnosis of OSA, profiles of 187 metabolites including amino acids, biogenic amines, acylcarnitines, lysophosphatidylcholines, phosphatidylcholines and sphingomyelins were analysed with liquid chromatography mass spectrometry in peripheral blood drawn at three different time points overnight. Comparisons of rank-transformed data using a general linear model for repeated measures after dichotomising the study group at different AHI levels were applied to define the best cut-off based on Cohen's f. Results: 65 subjects were recruited with a median AHI of 15.6 events·h-1. The mean Cohen's f over the metabolites was highest (0.161) at an AHI level of 5 events·h-1 representing the metabolomic threshold. Of the particular between-group differences, eight phosphatidylcholines, nine acylcarnitines and one amino acid (threonine) had significantly lower concentrations in the individuals with an AHI level equal to or above the metabolomic threshold. The metabolomic changes at AHI levels defining moderate and severe OSA were smaller than at an AHI of 5 events·h-1. Conclusions: The metabolomic threshold for patients with sleep complaints described in this report for the first time coincides with the AHI threshold required to confirm the diagnosis of OSA.

Silencing of STE20-type kinase TAOK1 confers protection against hepatocellular lipotoxicity through metabolic rewiring.

BACKGROUND: NAFLD has become the leading cause of chronic liver disease worldwide afflicting about one quarter of the adult population. NASH is a severe subtype of NAFLD, which in addition to hepatic steatosis connotes liver inflammation and hepatocyte ballooning. In light of the exponentially increasing prevalence of NAFLD, it is imperative to gain a better understanding of its molecular pathogenesis. The aim of this study was to examine the potential role of STE20-type kinase TAOK1 -a hepatocellular lipid droplet-associated protein-in the regulation of liver lipotoxicity and NAFLD etiology. METHODS: The correlation between TAOK1 mRNA expression in liver biopsies and the severity of NAFLD was evaluated in a cohort of 62 participants. Immunofluorescence microscopy was applied to describe the subcellular localization of TAOK1 in human and mouse hepatocytes. Metabolic reprogramming and oxidative/endoplasmic reticulum stress were investigated in immortalized human hepatocytes, where TAOK1 was overexpressed or silenced by small interfering RNA, using functional assays, immunofluorescence microscopy, and colorimetric analysis. Migration, invasion, and epithelial-mesenchymal transition were examined in TAOK1-deficient human hepatoma-derived cells. Alterations in hepatocellular metabolic and pro-oncogenic signaling pathways were assessed by immunoblotting. RESULTS: We observed a positive correlation between the TAOK1 mRNA abundance in human liver biopsies and key hallmarks of NAFLD (i.e., hepatic steatosis, inflammation, and ballooning). Furthermore, we found that TAOK1 protein fully colocalized with intracellular lipid droplets in human and mouse hepatocytes. The silencing of TAOK1 alleviated lipotoxicity in cultured human hepatocytes by accelerating lipid catabolism (mitochondrial ß-oxidation and triacylglycerol secretion), suppressing lipid anabolism (fatty acid influx and lipogenesis), and mitigating oxidative/endoplasmic reticulum stress, and the opposite changes were detected in TAOK1-overexpressing cells. We also found decreased proliferative, migratory, and invasive capacity, as well as lower epithelial-mesenchymal transition in TAOK1-deficient human hepatoma-derived cells. Mechanistic studies revealed that TAOK1 knockdown inhibited ERK and JNK activation and repressed acetyl-CoA carboxylase (ACC) protein abundance in human hepatocytes. CONCLUSIONS: Together, we provide the first experimental evidence supporting the role of hepatic lipid droplet-decorating kinase TAOK1 in NAFLD development through mediating fatty acid partitioning between anabolic and catabolic pathways, regulating oxidative/endoplasmic reticulum stress, and modulating metabolic and pro-oncogenic signaling.

The Expanded Endocannabinoid System Contributes to Metabolic and Body Mass Shifts in First-Episode Schizophrenia: A 5-Year Follow-Up Study.

Alterations in the expanded endocannabinoid system (eECS) and cell membrane composition have been implicated in the pathophysiology of schizophrenia spectrum disorders. We enrolled 54 antipsychotic (AP)-naïve first-episode psychosis (FEP) patients and 58 controls and applied a targeted metabolomics approach followed by multivariate data analysis to investigate the profile changes in the serum levels of endocannabinoids: 2-arachidonoylglycerol (2-AG) and anandamide, endocannabinoids-like N-acylethanolamines (NAEs: linoleoylethanolamide, oleoylethanolamide, and palmitoylethanolamide), and their dominating lipid precursor's phosphatidylcholines. Biomolecule profiles were measured at the onset of first-episode psychosis (FEP) and 0.6 years and 5.1 years after the initiation of AP treatment. The results indicated that FEP might be characterized by elevated concentrations of NAEs and by decreased 2-AG levels. At this stage of the disease, the NAE-mediated upregulation of peroxisome proliferator-activated receptors (PPARs) manifested themselves in energy expenditure. A 5-year disease progression and AP treatment adverse effects led to a robust increase in 2-AG levels, which contributed to strengthened cannabinoid (CB1) receptor-mediated effects, which manifested in obesity. Dynamic 2-AG, NAEs, and their precursors in terms of phosphatidylcholines are relevant to the description of the metabolic shifts resulting from the altered eECS function during and after FEP.

A Marked Low-Grade Inflammation and a Significant Deterioration in Metabolic Status in First-Episode Schizophrenia: A Five-Year Follow-Up Study.

The objective of this study was to evaluate how schizophrenia spectrum disorders and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum level of acylcarnitines (ACs), cytokines and metabolic biomarkers and to characterize the dynamics of inflammatory and metabolic changes in the early course of the disorder. A total of 112 adults participated in the study (54 patients with first-episode psychosis (FEP) and 58 control subjects). Biomolecule profiles were measured at the onset of first-episode psychosis and 0.6 years and 5.1 years after the initiation of APs. The results of the present study confirmed that specific metabolic-inflammatory imbalance characterizes AP-naïve patients. Short-term (0.6-years) AP treatment has a favourable effect on psychotic symptoms, as well as the recovery of metabolic flexibility and resolution of low-level inflammation. However, 5.1 years of AP treatment resulted in weight gain and increased serum levels of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon-γ, hexoses, acetylcarnitine, short-chain ACs (C3, C4) and long-chain ACs (C16:2, C18:1, C18:2). In conclusion, despite the improvement in psychotic symptoms, 5.1 years of AP treatment was accompanied by a pronounced metabolic-inflammatory imbalance, which was confirmed by the presence of enhanced pro-inflammatory activity and increased obesity with changes in the metabolism of carbohydrates, lipids, and their metabolites.

Effects of RIPC on the Metabolome in Patients Undergoing Vascular Surgery: A Randomized Controlled Trial.

BACKGROUND: remote ischemic preconditioning (RIPC) is a phenomenon in which short episodes of ischemia are applied to distant organs to prepare target organs for more prolonged ischemia and to induce protection against ischemia-reperfusion injury. This study aims to evaluate whether preoperatively performed RIPC affects the metabolome and to assess whether metabolomic changes correlate with heart and kidney injury markers after vascular surgery. METHODS: a randomized sham-controlled, double-blinded trial was conducted at Tartu University Hospital. Patients undergoing elective open vascular surgery were recruited and RIPC was applied before operation. Blood was collected preoperatively and 24 h postoperatively. The metabolome was analyzed using the AbsoluteIDQ p180 Kit. RESULTS: final analysis included 45 patients from the RIPC group and 47 from the sham group. RIPC did not significantly alter metabolites 24 h postoperatively. There was positive correlation of change in the kynurenine/tryptophan ratio with change in hs-troponin T (r = 0.570, p < 0.001), NT-proBNP (r = 0.552, p < 0.001), cystatin C (r = 0.534, p < 0.001) and beta-2-microglobulin (r = 0.504, p < 0.001) only in the RIPC group. CONCLUSIONS: preoperative RIPC did not significantly affect the metabolome 24 h after vascular surgery. The positive linear correlation of kynurenine/tryptophan ratio with heart and kidney injury markers suggests that the kynurenine-tryptophan pathway can play a role in RIPC-associated cardio- and nephroprotective effects.

Depression-Associated Negr1 Gene-Deficiency Induces Alterations in the Monoaminergic Neurotransmission Enhancing Time-Dependent Sensitization to Amphetamine in Male Mice.

In GWAS studies, the neural adhesion molecule encoding the neuronal growth regulator 1 (NEGR1) gene has been consistently linked with both depression and obesity. Although the linkage between NEGR1 and depression is the strongest, evidence also suggests the involvement of NEGR1 in a wide spectrum of psychiatric conditions. Here we show the expression of NEGR1 both in tyrosine- and tryptophan hydroxylase-positive cells. Negr1-/- mice show a time-dependent increase in behavioral sensitization to amphetamine associated with increased dopamine release in both the dorsal and ventral striatum. Upregulation of transcripts encoding dopamine and serotonin transporters and higher levels of several monoamines and their metabolites was evident in distinct brain areas of Negr1-/- mice. Chronic (23 days) escitalopram-induced reduction of serotonin and dopamine turnover is enhanced in Negr1-/- mice, and escitalopram rescued reduced weight of hippocampi in Negr1-/- mice. The current study is the first to show alterations in the brain monoaminergic systems in Negr1-deficient mice, suggesting that monoaminergic neural circuits contribute to both depressive and obesity-related phenotypes linked to the human NEGR1 gene.