Plasma Levels Of Metabolites Research Articles

Habitual intakes of sugar-sweetened beverages associated with gut microbiota-related metabolites and metabolic health outcomes in young Chinese adults

Background and aimsReducing consumption of sugar-sweetened beverages (SSBs) is a global public health priority because of their limited nutritional value and associations with increased risk of obesity and metabolic diseases. Gut microbiota-related metabolites emerged as quintessential effectors that may mediate impacts of dietary exposures on the modulation of host commensal microbiome and physiological status. Methods and resultsThis study assessed the associations among SSBs, circulating microbial metabolites, and gut microbiota–host co-metabolites, as well as metabolic health outcomes in young Chinese adults (n = 86), from the Carbohydrate Alternatives and Metabolic Phenotypes study in Shaanxi Province. Five principal component analysis-derived beverage drinking patterns were determined on self-reported SSB intakes, which were to a varying degree associated with 143 plasma levels of gut microbiota-related metabolites profiled by untargeted metabolomics. Moreover, carbonated beverages, fruit juice, energy drinks, and bubble tea exhibited positive associations with obesity-related markers and blood lipids, which were further validated in an independent cohort of 16,851 participants from the Regional Ethnic Cohort Study in Northwest China in Shaanxi Province. In contrast, presweetened coffee was negatively associated with the obesity-related traits. A total of 79 metabolites were associated with both SSBs and metabolic markers, particularly obesity markers. Pathway enrichment analysis identified the branched-chain amino acid catabolism and aminoacyl-tRNA biosynthesis as linking SSB intake with metabolic health outcomes. ConclusionOur findings demonstrate the associations between habitual intakes of SSBs and several metabolic markers relevant to noncommunicable diseases, and highlight the critical involvement of gut microbiota-related metabolites in mediating such associations.

Peculiarities of relationships between plasma levels of nitrogenous metabolites and EEG & HRV parameters in patients with postradiation encephalopaty

Background. Recently we shown that nitrogenous plasma metabolites (uric acid, bilirubin, urea and creatinine), even in the absence of uremia, are able to influence the state of the anxiety, autonomic and central nervous and endocrine systems, apparently through aryl hydrocarbon and adenosine receptors of neurons and endocrine cells and/or directly. Sexual dimorphism in the neurotropic effects of uric acid in neurologically healthy patients was also revealed. The purpose of this study is to compare nitrogenous-neural relationships in neurologically healthy men and those with post-radiation encephalopathy (PREP). Materials and Methods. The object of observation were neurologically healthy 31 men (24÷69 y) and 19 patients (26÷61 y) with PREP. The relationships between plasma levels of nitrogenous metabolites, on the one hand, and EEG and HRV parameters, on the other, were analyzed. Results. By constructing regression models with stepwise elimination it was found that the multiple correlation coefficient (R±µ) of creatinine with neural parameters in patients with PREP significantly exceeded that of control patients (0,762±0,069 vs 0,409±0,107; t=2,62; p=0,011). With regard to urea, the differences are insignificant (0,801±0,059 vs 0,694±0,066; t=1,17; p>0,2), and with regard to bilirubin (0,548±0,115 vs 0,402±0,107; t=0,94) and uric acid (0,496±0,124 vs 0,549±0,089; t=0,32), there are practically no differences. Conclusion. Post-radiation encephalopathy is accompanied not only by deviations from the norm of a number of EEG and HRV parameters, but also by their increased sensitivity to creatinine and, to a lesser extent, urea, but not to bilirubin and uric acid.

Effects of a 12-week whole-grain or refined wheat intervention on plasma acylcarnitines, bile acids and signaling lipids, and association with liver fat: A post-hoc metabolomics study of a randomized controlled trial.

We previously showed that whole-grain wheat (WGW) consumption had beneficial effects on liver fat accumulation, as compared to refined wheat (RW). The mechanisms underlying these effects remain unclear. In this study, we investigated the effects of WGW vs. RW consumption on plasma metabolite levels to explore potential underlying mechanisms of the preventive effect of WGW consumption on liver fat accumulation. Targeted metabolomics of plasma obtained from a concluded 12-week double-blind, randomized controlled trial was performed. Fifty overweight or obese men and women aged 45-70 years with mildly elevated levels of plasma cholesterol were randomized to either 98 g/d of WGW or RW products. Before and after the intervention, a total of 89 fasting plasma metabolite concentrations including acylcarnitines, trimethylamine-N-oxide (TMAO), choline, betaine, bile acids, and signaling lipids were quantified by UPLC-MS/MS. Intrahepatic triglycerides (IHTG) were quantified by 1H-MRS, and multiple liver markers, including circulating levels of β-hydroxybutyrate, alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (γ-GT), serum amyloid A (SAA), and C-reactive protein, were assessed. The WGW intervention increased plasma concentrations of four out of 52 signaling lipids-lysophosphatidic acid C18:2, lysophosphatidylethanolamine C18:1 and C18:2, and platelet-activating factor C18:2-and decreased concentrations of the signaling lipid lysophosphatidylglycerol C20:3 as compared to RW intervention, although these results were no longer statistically significant after false discovery rate (FDR) correction. Plasma concentrations of the other metabolites that we quantified were not affected by WGW or RW intervention. Changes in the above-mentioned metabolites were not correlated to change in IHTG upon the intervention. Plasma acylcarnitines, bile acids, and signaling lipids were not robustly affected by the WGW or RW interventions, which makes them less likely candidates to be directly involved in the mechanisms that underlie the protective effect of WGW consumption or detrimental effect of RW consumption on liver fat accumulation. [www.ClinicalTrials.gov], identifier [NCT02385149].

Bifidobacterium breve MCC1274 Supplementation Increased the Plasma Levels of Metabolites with Potential Anti-Oxidative Activity in APP Knock-In Mice.

We previously reported the effects of a probiotic strain, Bifidobacterium breve MCC1274, in improving cognitive function in preclinical and clinical studies. Recently, we demonstrated that supplementation of this strain led to decreased amyloid-β production, attenuated microglial activation, and suppressed inflammation reaction in the brain of APP knock-in (AppNL-G-F) mice. In this study, we investigated the plasma metabolites to reveal the mechanism of action of this probiotic strain in this Alzheimer's disease (AD)-like model. Three-month-old mice were orally supplemented with B. breve MCC1274 or saline for four months and their plasma metabolites were comprehensively analyzed using CE-FTMS and LC-TOFMS. Principal component analysis showed a significant difference in the plasma metabolites between the probiotic and control groups (PERMANOVA, p = 0.03). The levels of soy isoflavones (e.g., genistein) and indole derivatives of tryptophan (e.g., 5-methoxyindoleacetic acid), metabolites with potent anti-oxidative activities were significantly increased in the probiotic group. Moreover, there were increased levels of glutathione-related metabolites (e.g., glutathione (GSSG)_divalent, ophthalmic acid) and TCA cycle-related metabolites (e.g., 2-Oxoglutaric acid, succinic acid levels) in the probiotic group. Similar alternations were observed in the wild-type mice by the probiotic supplementation. These results suggest that the supplementation of B. breve MCC1274 enhanced the bioavailability of potential anti-oxidative metabolites from the gut and addressed critical gaps in our understanding of the gut-brain axis underlying the mechanisms of the probiotic action of this strain in the improvement of cognitive function.

Associations of microbial and indoleamine-2,3-dioxygenase-derived tryptophan metabolites with immune activation in healthy adults.

Background Tryptophan (Trp) metabolites from intestinal bacteria (indole, indole acetic acid [IAA] and indole propionic acid [IPA]), and the Trp metabolite kynurenine (Kyn) from the indoleamine 2,3-dioxygenase (IDO) pathway, are aryl hydrocarbon receptor (AhR) agonists and thus, can regulate immune activity via the AhR pathway. We hypothesized that plasma concentrations of these metabolites would be associated with markers of immune activation in a cohort of healthy adults in a manner consistent with AhR-mediated immune-regulation. We also hypothesized that the plasma Kyn/Trp ratio, a marker of IDO activity, would be associated with immune markers reflecting IDO activation in innate immune cells. Finally, we hypothesized that some intestinal bacteria would be associated with plasma indole, IPA and IAA, and that these bacteria themselves would be associated with immune markers.MethodsA novel set of 88 immune markers, and plasma Trp metabolites, were measured in 362 healthy adults. Bacterial taxa from stool were identified by 16S rRNA gene analysis. Multiple linear regression analysis was used to identify significant associations with immune markers.ResultsThe sum of indole and IAA was positively associated with natural killer T-cells levels. Kyn and Kyn/Trp were positively associated with neopterin and IP-10, markers of type 1 immunity, and TNF-α and C-reactive protein (CRP), markers of the acute phase response, and the regulatory cytokine IL-10. Three bacteria negatively associated with Trp metabolites were associated with markers of immune activation: the family Lachnospiraceae with higher lymphocyte counts but lower level of activated CD4 T-cells, the genus Dorea with higher production of IFN-γ by T-cells in PBMC cultures, and the genus Ruminococcus with higher production IL-6 in PBMC cultures stimulated with bacterial lipopolysaccharide (LPS).ConclusionsIn this cohort of healthy adults bacterial Trp metabolites were not strongly associated with immune markers. Conversely, the Kyn/Trp ratio was strongly associated with markers of systemic inflammation and the acute phase response, consistent with IDO activation in innate immune cells. Finally, commensal bacteria associated with lower plasma (and perhaps intestinal) levels of bacterial Trp metabolites were associated with greater immune activation, possibly reflecting decreased regulatory immune activity related to lower intestinal levels of bacterial indole metabolites.

Circulating metabolites in the early stage of breast cancer were not related to cancer stage or subtypes but associated with ki67 level. Promising statistical discrimination from controls

It was documented that the presence of malignancy in an organism causes metabolomic alterations in blood plasma which applies also to breast cancer. Breast cancer is a heterogeneous disease and there are only limited known relations of plasma metabolomic signatures with the tumour characteristics in early BC and knowing them would be of great advantage in noninvasive diagnostics. In this study, we focused on the metabolic alterations in early BC in blood plasma with the aim to identify metabolomic characteristics of BC subtypes. We used 50 early BC patients (FIGO stage I and II), where no additional metabolomic changes from metastatically changed remote organs were to be expected. We compared plasma levels of metabolites against controls and among various molecular and histological BC subtypes. BC patients showed decreased plasma levels of branched-chain amino acids BCAAs (and related keto-acids), histidine pyruvate and alanine balanced with an increased level of 3-hydroxybutyrate. The levels of circulating metabolites were not related to BC molecular subtypes (luminal A/luminal B), histological finding or grade, eventually stage, which indicate that in early BC, the BC patients share common metabolomics fingerprint in blood plasma independent of grade, stage or molecular subtype of BC. We observed statistically significant correlations between tumour proliferation marker Ki-67 level and circulating metabolites: alanine, citrate, tyrosine, glutamine, histidine and proline. This may point out the metabolites those levels could be associated with tumour growth, and conversely, the rate of tumour proliferation could be potentially estimated from plasma metabolites. When analyzing metabolomic changes in BC, we concluded that some of them could be associated with the metabolomic features of cancer cells, but the other observed alterations in blood plasma are the results of the complex mutual biochemical pathways in the comprehensive inter-organ metabolic exchange and communication. In the end, statistical discrimination against controls performed with AUC >0.91 showed the very promising potential of plasma metabolomics in the search for biomarkers for oncologic diseases.

Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

ObjectivePerfluoroalkyl substances (PFAS) are man-made chemicals with demonstrated endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to disturbed metabolism via the liver, although the exact mechanism is not clear. Moreover, information on the metabolic effects of the new PFAS alternative GenX is limited. We examined whether exposure to low-dose PFOA and GenX induces metabolic disturbances in mice, including NAFLD, dyslipidemia, and glucose tolerance, and studied the involvement of PPARα. MethodsMale C57BL/6J wildtype and PPARα−/− mice were given 0.05 or 0.3 mg/kg body weight/day PFOA, or 0.3 mg/kg body weight/day GenX while being fed a high-fat diet for 20 weeks. Glucose and insulin tolerance tests were performed after 18 and 19 weeks. Plasma metabolite levels were measured next to a detailed assessment of the liver phenotype, including lipid content and RNA sequencing. ResultsExposure to high-dose PFOA decreased body weight and increased liver weight in wildtype and PPARα−/− mice. High-dose but not low-dose PFOA reduced plasma triglycerides and cholesterol, which for triglycerides was dependent on PPARα. PFOA and GenX increased hepatic triglycerides in a PPARα-dependent manner. RNA sequencing showed that the effects of GenX on hepatic gene expression were entirely dependent on PPARα, while the effects of PFOA were mostly dependent on PPARα. In the absence of PPARα, the involvement of PXR and CAR became more prominent. ConclusionOverall, we show that long-term and low-dose exposure to PFOA and GenX disrupts hepatic lipid metabolism in mice. Whereas the effects of PFOA are mediated by multiple nuclear receptors, the effects of GenX are entirely mediated by PPARα. Our data underscore the potential of PFAS to disrupt metabolism by altering signaling pathways in the liver.

​Study of the Relationship between the Levels of L-carnitine and NO Metabolites in Blood Plasma and Seminal Plasma in Stallions

Background: Artificial insemination with chilled sperm is a reproductive biotechnology often used in horse breeding. However, maintaining the acceptable sperm quality after cooling, which affects the frequency of pregnancy, remains an urgent problem at the present time. Therefore, clarifying the role of important physiological metabolites, such as L-carnitine and nitric oxide, is a significant aspect in terms of possible improvement of the quality of cryopreserved sperm. Methods: The study included 35 breeding stallions, 27 of which were stallions of the Arabian breed and 8 were of the Soviet heavy draft breed. The content of total, free and bound carnitine and NO metabolites was determined by photometric method in the samples of seminal plasma and blood plasma. The correlation coefficient between the content of L-carnitine and the level of NO metabolites was also determined. Result: We have found a direct moderate correlation between the level of total and free L-carnitine in the seminal plasma and blood plasma. The study has also revealed a positive correlation between the level of all L-carnitine fractions and NO metabolites in seminal plasma. In addition, there was a positive correlation between the total L-carnitine of blood plasma and NO metabolites in seminal plasma.

Determination of Lipoxygenase, CYP450, and Non-Enzymatic Metabolites of Arachidonic Acid in Essential Hypertension and Type 2 Diabetes.

Type 2 diabetes (T2D) and hypertension (HTN) are common risk factors of cardiovascular diseases (CVD) characterized by chronic low-grade systemic inflammation and impaired endothelial function. This study aimed to assess whether levels of non-enzymatic, lipoxygenase (LOX)- and cytochrome P450 (CYP)-derived arachidonic acid (ARA) metabolites, which are known regulators of vascular homeostasis, are affected by HTN and T2D. For this objective, 17 plasma level derivatives of ARA were quantitated by chromatography coupled with mass spectrometry in 44 patients (12 healthy, 8 HTN, 7 T2D, and 17 HTN + T2D). Effects of hyperglycemic and hyperinsulinemic clamps on ARA metabolite levels were assessed in seven healthy subjects. No significant differences in the plasma levels of ARA metabolites were observed for T2D patients compared with healthy volunteers. HTN was associated with an alteration of ARA metabolite correlation patterns with increased 20-, 19-, 15-, and 8-hydroxyeicosatrienoic acid (HETE). A decrease of 20-HETE was also observed during both hyperglycemic and hyperinsulinemic clamps. Additional experiments are needed to assess whether the modulation of HETE metabolites in HTN may be of interest. Furthermore, although not affected by T2D, it remains to investigate whether the decrease of 20-HETE observed during clamps may be related to the regulation of glucose tolerance and insulin signaling.

Evaluation of quantitative-qualitative levels of blood pressure by Tensioregulom

Background. Earlier we showed that the qualitative-quantitative clusters of blood pressure (BP) are very clearly different from each other by age, sex and the constellation of neuro-endocrine, immune and metabolic variables, which we called the Tensioregulome by analogy with the metabolome and the microbiome. The purpose of this study is detailing this concept. Materials and methods. Under an observations were 44 patients with chronic pyelonephritis and cholecystitis in the phase of remission. Testing was performed twice - on admission and after 7-10 days of standard balneotherapy. The main object of the study was BP. We determined parameters of EEG and HRV, plasma levels of adaptation hormones, electrolytes, lipids, and nitrogenous metabolites, components of humoral, cellular, and phagocytic links of immunity and microbiota as well as markers of pyelonephritis. Results. The forward stepwise program identified 42 Tensioregulome parameters as characteristic of quantitative-qualitative blood pressure clusters: 25 EEGs, sympathetic tone, cortisol, calcitonin, Bifidobacteria faeces, 5 metabolic and 5 immune parameters as well as sex and age. The accuracy of patient classification is 97,7%. Another 15 parameters were found to be characteristic, but were outside the discriminant model. Non-linear correlations between the BP and Tensioregulome parameters were revealed. Conclusion. The Tensioregulome allows us to reliably evaluate quantitative-qualitative levels of blood pressure without measuring it with a tonometer.

Influence of CYP2D6, CYP2C19 and CYP3A5 polymorphisms on plasma levels of tamoxifen metabolites in Algerian women with ER+ breast cancer

BackgroundTamoxifen, a selective estrogen receptor modulator, is indicated for breast cancer developed in response to estrogen.FindingsIn the current study we explored the relationship between the different variants of CYP2D6, CYP2C19, CYP3A5 and plasma Endoxifen levels in Algerian patients with ER + breast cancer. We further conducted the relationship between the candidate genes and the recurrences rate. Endoxifen levels differed significantly (p < .005) between carriers of two functional alleles and patients genotyped as CYP2D6*10, CYP2D6*17, CYP2D6*41 or CYP2D6*5/*5. Patients with elevated Endoxifen concentrations were significantly more likely to not report recurrences than patients with reduced or nul alleles. Such nul/nul, red/red, and red/nul diplotypes have been associated with a higher rate of recurrences than other genotypes during treatment.ConclusionOur findings suggest that the CYP2D6 genotype should be considered in tamoxifen-treated women. While quantitatively, CYP2D6 represents only a minor fraction of the total drug metabolizing capacity of the liver, it is polymorphic and, therefore, may alter the balance of metabolism of tamoxifen toward the activation pathways. Breast cancer patients with the CYP2D6 nul/nul or red/nul diplotype may benefit less from Tamoxifen treatment and are more likely to develop recurrences. Comprehensive CYP2D6 genotyping has a good predictive value for CYP2D6 activity. Common variants in CYP2C19 and CYP3A5 did not have a significant impact on the recurrences in this cohort of patients with ER + breast cancer.

Melatonin Regulates the Daily Levels of Plasma Amino Acids, Acylcarnitines, Biogenic Amines, Sphingomyelins, and Hexoses in a Xenograft Model of Triple Negative Breast Cancer.

Metabolic dysregulation as a reflection of specific metabolite production and its utilization is a common feature of many human neoplasms. Melatonin, an indoleamine that is highly available during darkness, has a variety of metabolic functions in solid tumors. Because plasma metabolites undergo circadian changes, we investigated the role of melatonin on the profile of amino acids (AAs), biogenic amines, carnitines, sphingolipids, and hexoses present in the plasma of mice bearing xenograft triple negative breast cancer (MDA-MB-231 cells) over 24 h. Plasma concentrations of nine AAs were reduced by melatonin, especially during the light phase, with a profile closer to that of non-breast cancer (BC) animals. With respect to acylcarnitine levels, melatonin reduced 12 out of 24 molecules in BC-bearing animals compared to their controls, especially at 06:00 h and 15:00 h. Importantly, melatonin reduced the concentrations of asymmetric dimethylarginine, carnosine, histamine, kynurenine, methionine sulfoxide, putrescine, spermidine, spermine, and symmetric dimethylarginine, which are associated with the BC metabolite sets. Melatonin also led to reduced levels of sphingomyelins and hexoses, which showed distinct daily variations over 24 h. These results highlight the role of melatonin in controlling the levels of plasma metabolites in human BC xenografts, which may impact cancer bioenergetics, in addition to emphasizing the need for a more accurate examination of its metabolomic changes at different time points.

Evolocumab on top of empagliflozin improves endothelial function of individuals with diabetes: randomized active-controlled trial

BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2i) improve endothelial dysfunction and reduce cardiovascular events in individuals with type 2 diabetes (T2D). Proprotein convertase subtilisin/kexin 9 (PCSK9i) inhibitors reduce cardiovascular events in high-risk patients. Whether the addition of PCSK9i to SGLT2i treatment adds benefits is not known.ObjectivesTo assess the PCSK9-i effect on the endothelial function of T2D individuals under treatment with SGLT2-i.MethodsIndividuals with T2D were randomized in a 1:1 ratio to a 16-week treatment with either empagliflozin (E) or empagliflozin plus evolocumab (EE). The primary endpoint was post-treatment change from baseline in flow-mediated dilation (FMD) at 1-min. Secondary outcomes included changes in plasma levels of nitric oxide metabolites and isoprostane.ResultsA total of 110 patients were enrolled, the mean age was 58 years, and 71% were men. The median post-treatment change in FMD at 1-min was 2.7% (interquartile range [IQR]: 0.9%) and 0.4% (IQR: 0.9%) in the EE and E groups, respectively (p < 0.001). There was a greater increase in plasma levels of nitrate [5.9 (16.5) vs. 2.6 (11.8); p = 0.001] and nitrite [0.14 (0.72) vs. 0.02 (0.74); p = 0.025] in the EE group than in the E group, respectively. Isoprostane reduction was more pronounced in the EE group when compared to the E group [−1.7 (5.9) vs. −1.1 (5.3); p < 0.001).ConclusionsIn individuals with T2D, the addition of evolocumab on top of empagliflozin improves endothelial function.

Abstract P3046: Deletion Of Sarm1 Nad Hydrolase Ameliorates Diabetic Cardiomyopathy

Diabetes is a risk factor for heart disease. NAD depletion has emerged as a hallmark of cardiometabolic diseases, and hence, elevating NAD level alleviates diabetic cardiomyopathy. On the other hand, inhibition of NAD consumption also maintains NAD homeostasis. SARM1 is a novel intracellular NAD hydrolase that contributes to diabetic neuropathy; however, its role in heart disease has never been described. We assayed 243 plasma metabolites from wild-type (WT) and SARM1-KO (KO) mice by quantitative metabolomics, and found that SARM1 deficiency caused changes in more (67) metabolites in male mice than in female mice (28). Only 5 of these metabolites overlapped between male and female, indicating sex-dependent effect of SARM1 deletion on plasma metabolites. SARM1 deficiency may alter susceptibility of male mice to metabolic stress, since metabolites associated with diabetes and impaired metabolism were altered, e.g. pyridoxic acid, alloisoleucine, LPC/PC, ceramide etc. Despite the differences in plasma metabolite levels, KO mice from either sex did not show changes in cardiac structure and function at baseline. We next tested a hypothesis that SARM1 deficiency protects mice against diabetic cardiomyopathy. WT and KO mice were challenged with streptozotocin (STZ) to induce diabetic stress. 16-week diabetes promoted progressive systolic (fractional shortening) and diastolic dysfunction (E’/A’, e/E’) in WT male mice. SARM1 deficiency attenuated diabetes-induced cardiac dysfunction, although fasting glucose levels were similarly elevated in diabetic WT and KO mice. Diabetic WT hearts showed declined NAD level, which was elevated by SARM1 deficiency. The restored NAD level in KO hearts did not change expression of other NAD hydrolases (Bst1 and CD38). Diabetic WT hearts up-regulated cardiomyopathy markers such as nppb and Nox4 mRNAs, and myh7/myh6 ratio, that were normalized by SARM1 deficiency. Chronic diabetes promoted cardiac fibrosis and upregulation of profibrotic gene expression such as ctgf and Inhbb, that were suppressed by SARM1 deficiency. Our data suggest a protective effect of SARM1 deficiency on diabetic cardiomyopathy in male mice. The effects of SARM1 deficiency on diabetic hearts could be sex-dependent and remain to be determined.

Association Between the Gut Microbiome and Their Metabolites With Human Blood Pressure Variability.

Blood pressure (BP) variability is an independent risk factor for cardiovascular events. Recent evidence supports a role for the gut microbiota in BP regulation. However, whether the gut microbiome is associated with BP variability is yet to be determined. Here, we aimed to investigate the interplay between the gut microbiome and their metabolites in relation to BP variability. Ambulatory BP monitoring was performed in 69 participants from Australia (55.1% women; mean±SD, 59.8±7.26 years; body mass index, 25.2±2.83 kg/m2). These data were used to determine nighttime dipping, morning BP surge (MBPS) and BP variability as SD. The gut microbiome was determined by 16S ribosomal RNA (rRNA) sequencing and metabolite levels by gas chromatography. We identified specific taxa associated with systolic BP variability, nighttime dipping, and MBPS. Notably, Alistipesfinegoldii and Lactobacillus spp. were only present in participants within the normal ranges of BP variability, MBPS and dipping, while Prevotella spp. and Clostridium spp., were found to be present in extreme dippers and the highest quartiles of BP SD and MBPS. There was a negative association between MBPS and microbial α-diversity (r=-0.244, P=0.046). MBPS was also negatively associated with plasma levels of microbial metabolites called short-chain fatty acids (r=-0.305, P=0.020), particularly acetate (r=-0.311, P=0.017). Gut microbiome diversity, levels of microbial metabolites, and the bacteria Alistipesfinegoldii and Lactobacillus were associated with lower BP variability and Clostridium and Prevotella with higher BP variability. Thus, our findings suggest the gut microbiome and metabolites may be involved in the regulation of BP variability.

Oxidative physiology is weakly associated with pigmentation in birds

The mechanistic link between avian oxidative physiology and plumage coloration has attracted considerable attention in past decades. Hence, multiple proximal hypotheses were proposed to explain how oxidative state might covary with the production of melanin and carotenoid pigments. Some hypotheses underscore that these pigments (or their precursors, e.g., glutathione) have antioxidant capacities or function as molecules storing the toxic excess of intracellular compounds, while others highlight that these pigments can act as pro‐oxidants under specific conditions. Most studies addressing these associations are at the intraspecific level, while phylogenetic comparative studies are still scarce, though needed to assess the generality of these associations. Here, we tested whether plumage and bare part coloration were related to oxidative physiology at an interspecific level by measuring five oxidative physiology markers (three nonenzymatic antioxidants and two markers of lipid peroxidative damage) in 1387 individuals of 104 European bird species sampled during the breeding season, and by scoring plumage eumelanin, pheomelanin, and carotenoid content for each sex and species. Only the plasma level of reactive oxygen metabolites was related to melanin coloration, being positively associated with eumelanin score and negatively with pheomelanin score. Thus, our results do not support the role of antioxidant glutathione in driving variation in melanin synthesis across species. Furthermore, the carotenoid scores of feathers and bare parts were unrelated to the measured oxidative physiology parameters, further suggesting that the marked differences in pigmentation across birds does not influence their oxidative state.

Clinical significance of plasma tryptophan, kynurenine, and kynurenine/tryptophan ratio in rheumatoid arthritis patients

BackgroundThe catabolism of tryptophan (Trp) in the kynurenine (Kyn) pathway is thought to have a critical immunosuppressive effect. Aim of the workTo evaluate plasma Trp and metabolite levels to identify their diagnostic potential in rheumatoid arthritis (RA). Patients and methods50 RA patients and 41 control were included in this study. The Trp and Kyn were analyzed and the Kyn\\Trp ratio was calculated to estimate Indolamine 2,3 dioxygenase (IDO) enzyme activity involved in Trp degradation. ResultsThe 50 patients had a mean age of 58·5 ± 10·6 years; 37 females and 13 males, F:M 2.8:1 and median disease duration was 10·1 (7–16) years. Rheumatoid factor was positive in 64 %. The median Trp value was significantly lower in RA (11120·7; 3259–16352 ng/ml) compared to control (12372·3; 7217–31,936 ng/ml) (p = 0·001). Kyn/Trp was significantly higher in RA (4·04; 2·5-12·3) compared to control (3.2; 2·1-4·7) (p < 0·0001). The median Kyn value was higher in RA (451·02; 264–1292 ng/ml) than in control (391·4; 236–1494 ng/ml) (p = 0·04). Trp significantly inversely correlated with the morning stiffness (r = −0·32, p = 0·025), Kyn significantly correlated with the C-reactive protein (CRP) (r = 0·31, p = 0·028) and erythrocyte sedimentation rate (ESR) (r = 0·41, p = 0·003) and the Kyn/Trp ratio correlated with the morning stiffness, CRP and ESR (r = 0·26, p = 0·045; r = 0·32, p = 0·025 and r = 0.32, p = 0·024 respectively). Kyn/Trp, Kyn and Trp significantly predicted RA at a cut-off value of 4.72, 589.1 ng/ml and 9921.1 ng/ml (p < 0.0001, p = 0.04 and p = 0.001 respectively). ConclusionOur study showed that there is a significant relationship between RA and Kyn and Trp levels and IDO enzyme activity.

Cytochrome P450 oxidase 2J inhibition suppresses choroidal neovascularization in mice

IntroductionChoroidal neovascularization (CNV) in age-related macular degeneration (AMD) leads to blindness. It has been widely reported that increased intake of ω−3 long-chain polyunsaturated fatty acids (LCPUFA) diets reduce CNV. Of the three major pathways metabolizing ω−3 (and ω−6 LCPUFA), the cyclooxygenase and lipoxygenase pathways generally produce pro-angiogenic metabolites from ω−6 LCPUFA and anti-angiogenic ones from ω−3 LCPUFA. Howevehr, cytochrome P450 oxidase (CPY) 2C produces pro-angiogenic metabolites from both ω−6 and ω−3 LCPUFA. The effects of CYP2J2 products on ocular neovascularization are still unknown. Understanding how each metabolic pathway affects the protective effect of ω−3 LCPUFA on retinal neovascularization may lead to therapeutic interventions. ObjectivesTo investigate the effects of LCPUFA metabolites through CYP2J2 pathway and CYP2J2 regulation on CNV both in vivo and ex vivo. MethodsThe impact of CYP2J2 overexpression and inhibition on neovascularization in the laser-induced CNV mouse model was assessed. The plasma levels of CYP2J2 metabolites were measured by liquid chromatography and tandem mass spectroscopy. The choroidal explant sprouting assay was used to investigate the effects of CYP2J2 inhibition and specific LCPUFA CYP2J2 metabolites on angiogenesis ex vivo. ResultsCNV was exacerbated in Tie2-Cre CYP2J2-overexpressing mice and was associated with increased levels of plasma docosahexaenoic acids. Inhibiting CYP2J2 activity with flunarizine decreased CNV in both ω−6 and ω−3 LCPUFA-fed wild-type mice. In Tie2-Cre CYP2J2-overexpressing mice, flunarizine suppressed CNV by 33 % and 36 % in ω−6, ω−3 LCPUFA diets, respectively, and reduced plasma levels of CYP2J2 metabolites. The pro-angiogenic role of CYP2J2 was corroborated in the choroidal explant sprouting assay. Flunarizine attenuated ex vivo choroidal sprouting, and 19,20-EDP, a ω−3 LCPUFA CYP2J2 metabolite, increased sprouting. The combined inhibition of CYP2J2 with flunarizine and CYP2C8 with montelukast further enhanced CNV suppression via tumor necrosis factor-α suppression. ConclusionsCYP2J2 inhibition augmented the inhibitory effect of ω−3 LCPUFA on CNV. Flunarizine suppressed pathological choroidal angiogenesis, and co-treatment with montelukast inhibiting CYP2C8 further enhanced the effect. CYP2 inhibition might be a viable approach to suppress CNV in AMD.

Circulating Metabolites in Relation to the Kidney Allograft Function in Posttransplant Patients.

End-stage kidney disease is preferably treated by kidney transplantation. The suboptimal function of the allograft often results in misbalances in kidney-controlled processes and requires long-term monitoring of allograft function and viability. As the kidneys are organs with a very high metabolomic rate, a metabolomics approach is suitable to describe systematic changes in post-transplant patients and has great potential for monitoring allograft function, which has not been described yet. In this study, we used blood plasma samples from 55 patients after primary kidney transplantation identically treated with immunosuppressants with follow-up 50 months in the mean after surgery and evaluated relative levels of basal plasma metabolites detectable by NMR spectroscopy. We were looking for the correlations between circulating metabolites levels and allograft performance and allograft rejection features. Our results imply a quantitative relationship between restricted renal function, insufficient hydroxylation of phenylalanine to tyrosine, lowered renal glutamine utilization, shifted nitrogen balance, and other alterations that are not related exclusively to the metabolism of the kidney. No link between allograft function and energy metabolism can be concluded, as no changes were found for glucose, glycolytic intermediates, and 3-hydroxybutyrate as a ketone body representative. The observed changes are to be seen as a superposition of changes in the comprehensive inter-organ metabolic exchange, when the restricted function of one organ may induce compensatory effects or cause secondary alterations. Particular differences in plasma metabolite levels in patients with acute cellular and antibody-mediated allograft rejection were considered rather to be related to the loss of kidney function than to the molecular mechanism of graft rejection since they largely follow the alterations observed by restricted allograft function. In the end, we showed using a simple mathematical model, multilinear regression, that the basal plasmatic metabolites correlated with allograft function expressed by the level of glomerular filtration rate (with creatinine: p-value = 4.0 × 10−26 and r = 0.94, without creatinine: p-value = 3.2 × 10−22 and r = 0.91) make the noninvasive estimation of the allograft function feasible.

The Influence of Orthopedic Surgery on Circulating Metabolite Levels, and their Associations with the Incidence of Postoperative Delirium.

The mechanisms underlying the occurrence of postoperative delirium development are unclear and measurement of plasma metabolites may improve understanding of its causes. Participants (n = 54) matched for age and gender were sampled from an observational cohort study investigating postoperative delirium. Participants were ≥65 years without a diagnosis of dementia and presented for primary elective hip or knee arthroplasty. Plasma samples collected pre- and postoperatively were grouped as either control (n = 26, aged: 75.8 ± 5.2) or delirium (n = 28, aged: 76.2 ± 5.7). Widespread changes in plasma metabolite levels occurred following surgery. The only metabolites significantly differing between corresponding control and delirium samples were ornithine and spermine. In delirium cases, ornithine was 17.6% higher preoperatively, and spermine was 12.0% higher postoperatively. Changes were not associated with various perioperative factors. In binary logistic regression modeling, these two metabolites did not confer a significantly increased risk of delirium. These findings support the hypothesis that disturbed polyamine metabolism is an underlying factor in delirium that warrants further investigation.