PubMed

Related Articles Adaptive antibody diversification through N-linked glycosylation of the immunoglobulin variable region. Proc Natl Acad Sci U S A. 2018 02 20;115(8):1901-1906 Authors: van de Bovenkamp FS, Derksen NIL, Ooijevaar-de Heer P, van Schie KA, Kruithof S, Berkowska MA, van der Schoot CE, IJspeert H, van der Burg M, Gils A, Hafkenscheid L, Toes REM, Rombouts Y, Plomp R, Wuhrer M, van Ham SM, Vidarsson G, Rispens T Abstract A hallmark of B-cell immunity is the generation of a diverse repertoire of antibodies from a limited set of germline V(D)J genes. This repertoire is usually defined in terms of amino acid composition. However, variable domains may also acquire N-linked glycans, a process conditional on the introduction of consensus amino acid motifs (N-glycosylation sites) during somatic hypermutation. High levels of variable domain glycans have been associated with autoantibodies in rheumatoid arthritis, as well as certain follicular lymphomas. However, the role of these glycans in the humoral immune response remains poorly understood. Interestingly, studies have reported both positive and negative effects on antibody affinity. Our aim was to elucidate the role of variable domain glycans during antigen-specific antibody responses. By analyzing B-cell repertoires by next-generation sequencing, we demonstrate that N-glycosylation sites are introduced at positions in which glycans can affect antigen binding as a result of a specific clustering of progenitor glycosylation sites in the germline sequences of variable domain genes. By analyzing multiple human monoclonal and polyclonal (auto)antibody responses, we subsequently show that this process is subject to selection during antigen-specific antibody responses, skewed toward IgG4, and positively contributes to antigen binding. Together, these results highlight a physiological role for variable domain glycosylation as an additional layer of antibody diversification that modulates antigen binding. PMID: 29432186 [PubMed - indexed for MEDLINE]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/07/26PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Integrated approach of eco-epigenetics and eco-metabolomics on the stress response of bisphenol-A exposure in the aquatic midge Chironomus riparius. Ecotoxicol Environ Saf. 2018 Jul 21;163:111-116 Authors: Lee SW, Chatterjee N, Im JE, Yoon D, Kim S, Choi J Abstract The stress response mechanisms of Bisphenol A (BPA), an endocrine disrupting compound, remain to be elucidated. In this study, we explored the effects of BPA on the non-biting midge Chironomus riparius through basic ecotoxicity assays, DNA damage (comet assay), eco-epigenetics (global DNA and histone methylations) and non-targeted global metabolomics (NMR based) approaches. The reproduction failure, increase in DNA damage, global DNA hyper-methylation, and increased global histone modification (H3K36) status were evident due to BPA exposure at 10% lethal concentration (LC10: 1 mg/L, based on 48 h acute toxicity). Moreover, non-targeted global metabolomics followed by pathway analysis identified alterations of energy metabolism, amino acids, and methionine metabolisms etc. Most importantly, we found a potential cross-talk between altered epigenetics and metabolites, such as, increase in methionine and o-phosphocholine metabolites corresponds with the phenomena of global hyper-methylation in DNA and H3K36 mark. Overall, our results suggests that the crosstalk of global metabolomics and epigenetic modification was fundamental of the underlying mechanisms in BPA-induced stress response in C. riparius. PMID: 30041127 [PubMed - as supplied by publisher]

Aphid infestation leads to plant part-specific changes in phloem sap chemistry, which may indicate niche construction. New Phytol. 2018 Jul 24;: Authors: Jakobs R, Schweiger R, Müller C Abstract Phloem sap quality can differ between and within plants, and affect the performance of aphids. In turn, aphid infestation may change the chemical composition and nutritional value of phloem sap. However, the effects of different aphid species on the overall phloem sap composition of distinct parts within plant individuals in relation to aphid performance remain unclear. To test the specificity of plant responses to aphids, we used two chemotypes of Tanacetum vulgare plants and placed the monophagous aphids Macrosiphoniella tanacetaria and Uroleucon tanaceti on different plant parts (stems close to the inflorescence, young and old leaves). Aphid population growth was determined and sugars, organic acids, amino acids and metabolic fingerprints of phloem exudates were analysed. Macrosiphoniella tanacetaria performed best on stems, whereas U. tanaceti performed best on old leaves, indicating differences in niche conformance. Aphid infestation led to distinct changes in the phloem exudate composition of distinct metabolite classes, differing particularly between plant parts but less between chemotypes. In summary, plant responses to aphids are highly specific for the chemotype, plant part, metabolite class and aphid species. These changes may indicate that aphids construct their own niche, optimizing the food quality on the plant parts they prefer. PMID: 30040116 [PubMed - as supplied by publisher]

Cognition, psychosis risk and metabolic measures in two adolescent birth cohorts. Psychol Med. 2018 Jul 24;:1-15 Authors: Ramsay H, Barnett JH, Murray GK, Miettunen J, Mäki P, Järvelin MR, Smith GD, Ala-Korpela M, Veijola J Abstract BACKGROUND: Psychoses, especially schizophrenia, are often preceded by cognitive deficits and psychosis risk states. Altered metabolic profiles have been found in schizophrenia. However, the associations between metabolic profiles and poorer cognitive performance and psychosis risk in the population remain to be determined. METHODS: Detailed molecular profiles were measured for up to 8976 individuals from two general population-based prospective birth cohorts: the Northern Finland Birth Cohort 1986 (NFBC 1986) and the Avon Longitudinal Study of Parents and Children (ALSPAC). A high-throughput nuclear magnetic resonance spectroscopy platform was used to quantify 70 metabolic measures at age 15-16 years in the NFBC 1986 and at ages 15 and 17 years in ALSPAC. Psychosis risk was assessed using the PROD-screen questionnaire at age 15-16 years in the NFBC 1986 or the psychotic-like symptoms assessment at age 17 years in ALSPAC. Cognitive measures included academic performance at age 16 years in both cohorts and general intelligence and executive function in ALSPAC. Logistic regression measured cross-sectional and longitudinal associations between metabolic measures and psychosis risk and cognitive performance, controlling for important covariates. RESULTS: Seven metabolic measures, primarily fatty acid (FA) measures, showed cross-sectional associations with general cognitive performance, four across both cohorts (low density lipoprotein diameter, monounsaturated FA ratio, omega-3 ratio and docosahexaenoic acid ratio), even after controlling for important mental and physical health covariates. Psychosis risk showed minimal metabolic associations. CONCLUSIONS: FA ratios may be important in marking risk for cognitive deficits in adolescence. Further research is needed to clarify whether these biomarkers could be causal and thereby possible targets for intervention. PMID: 30039772 [PubMed - as supplied by publisher]

Related Articles Phenylalanine hydroxylase: A biomarker of disease susceptibility in Parkinson's disease and Amyotrophic lateral sclerosis. Med Hypotheses. 2018 Sep;118:29-33 Authors: Steventon GB, Mitchell SC Abstract The S-oxidation of S-carboxymethyl-l-cysteine has been reported previously to be a biomarker of disease susceptibility in Parkinson's disease and Amyotrophic lateral sclerosis. In this investigation, the original observations have been confirmed with the incidence of the poor metaboliser phenotype (no urinary recovery of S-oxide metabolites) being found to be 3.9% within healthy control population. However, 38.3% of the Parkinson's disease subjects and 39.0% of the Amyotrophic lateral sclerosis group were phenotyped as poor metabolisers. The consequent odds risk ratio of developing Parkinson's disease was calculated to be 15.5 (95% CI 9.5-25.3) and for Amyotrophic lateral sclerosis was 15.2 (95% CI 8.8-26.5). Thus, the possible role of the enzyme responsible for the S-oxidation biotransformation reaction, phenylalanine hydroxylase, must be further investigated to elucidate the mechanism(s) of toxicity in susceptible individuals displaying these diseases. A dual role potentially explaining of the role of phenylalanine hydroxylase as a biomarker of disease susceptibility is presented together with the observation that metabolomics is a possible way forward in the identification of potential pro-toxins/toxins in those individuals phenotyped as poor metabolisers (Controls, Parkinson's disease and Amyotrophic lateral sclerosis subjects). PMID: 30037610 [PubMed - in process]

Related Articles Microbiome-metabolomics Analysis of the Impacts of Long-term Dietary Advanced Glycation End Products Consumption on the C57BL/6 Mouse Fecal Microbiota and Metabolite Perturbation. J Agric Food Chem. 2018 Jul 23;: Authors: Qu W, Nie C, Zhao J, Ou X, Zhang Y, Yang S, Bai X, Wang Y, Wang J, Li J Abstract Thermal-processed diets are widely consumed, although advanced glycation end products (AGEs) are unavoidably formed. AGEs, a cluster of protein-cross-linking products, become less digestible for they impair intestinal peptidase proteolysis. We characterized the impacts of dietary AGEs on gut microbiota through microbiome-to-metabolome association study. C57BL/6 mice were fed heated-treated diet (H-AGEs), or standard AIN-93G diet (L-AGEs) for 8 months. Fecal microbiota composition was examined by 16S rDNA sequencing, and fecal metabolome profile was evaluated by gas chromatography tandem time-of-flight mass spectrometry (GC-TOF-MS). Reduced α-diversity and altered microbiota composition with elevated Helicobacter were found in H-AGEs group, and protein fermentation products (i.e., p-cresol, putrescine) were increased among 57 perturbed metabolites. Major dysfunctional metabolic pathways were associated with carbohydrate and amino acid metabolism in two groups. Moreover, high correlations were found between fluctuant gut microbiota and metabolites. These findings might reveal underlying mechanisms of the detrimental impacts of dietary AGEs on host health. PMID: 30037223 [PubMed - as supplied by publisher]

Related Articles Insights into Tissue-specific Specialized Metabolism in Tieguanyin Tea Cultivar by Untargeted Metabolomics. Molecules. 2018 Jul 21;23(7): Authors: Chen S, Lin J, Liu H, Gong Z, Wang X, Li M, Aharoni A, Yang Z, Yu X Abstract Tea plants produce extremely diverse and abundant specialized metabolites, the types and levels of which are developmentally and environmentally regulated. However, little is known about how developmental cues affect the synthesis of many of these molecules. In this study, we conducted a comparative profiling of specialized metabolites from six different tissues in a premium oolong tea cultivar, Tieguanyin, which is gaining worldwide popularity due to its uniquely rich flavors and health benefits. UPLC-QTOF MS combined with multivariate analyses tentatively identified 68 metabolites belonging to 11 metabolite classes, which exhibited sharp variations among tissues. Several metabolite classes, such as flavonoids, alkaloids, and hydroxycinnamic acid amides were detected predominantly in certain plant tissues. In particular, tricoumaroyl spermidine and dicoumaroyl putrescine were discovered as unique tea flower metabolites. This study offers novel insights into tissue-specific specialized metabolism in Tieguanyin, which provides a good reference point to explore gene-metabolite relationships in this cultivar. PMID: 30037120 [PubMed - in process]

Related Articles Succinate Accumulation Is Associated with a Shift of Mitochondrial Respiratory Control and HIF-1α Upregulation in PTEN Negative Prostate Cancer Cells. Int J Mol Sci. 2018 Jul 21;19(7): Authors: Weber A, Klocker H, Oberacher H, Gnaiger E, Neuwirt H, Sampson N, Eder IE Abstract The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostate cancer (PCa) cells. In particular, we found that PCa cells had a higher total respiratory activity than benign cells. Moreover, PCa cells showed a substantial shift towards succinate-supported mitochondrial respiration compared to benign cells, indicating a re-programming of respiratory control. This study aimed to investigate the role of succinate and its main plasma membrane transporter NaDC3 (sodium-dependent dicarboxylate transporter member 3) in PCa cells and to determine whether targeting succinate metabolism can be potentially used to inhibit PCa cell growth. Using high-resolution respirometry analysis, we observed that ROUTINE respiration in viable cells and succinate-supported respiration in permeabilized cells was higher in cells lacking the tumor suppressor phosphatase and tensin-homolog deleted on chromosome 10 (PTEN), which is frequently lost in PCa. In addition, loss of PTEN was associated with increased intracellular succinate accumulation and higher expression of NaDC3. However, siRNA-mediated knockdown of NaDC3 only moderately influenced succinate metabolism and did not affect PCa cell growth. By contrast, mersalyl acid-a broad acting inhibitor of dicarboxylic acid carriers-strongly interfered with intracellular succinate levels and resulted in reduced numbers of PCa cells. These findings suggest that blocking NaDC3 alone is insufficient to intervene with altered succinate metabolism associated with PCa. In conclusion, our data provide evidence that loss of PTEN is associated with increased succinate accumulation and enhanced succinate-supported respiration, which cannot be overcome by inhibiting the succinate transporter NaDC3 alone. PMID: 30037119 [PubMed - in process]

Related Articles Phospholipase A2 activity during the replication cycle of the flavivirus West Nile virus. PLoS Pathog. 2018 04;14(4):e1007029 Authors: Liebscher S, Ambrose RL, Aktepe TE, Mikulasova A, Prier JE, Gillespie LK, Lopez-Denman AJ, Rupasinghe TWT, Tull D, McConville MJ, Mackenzie JM Abstract Positive-sense RNA virus intracellular replication is intimately associated with membrane platforms that are derived from host organelles and comprised of distinct lipid composition. For flaviviruses, such as West Nile virus strain Kunjin virus (WNVKUN) we have observed that these membrane platforms are derived from the endoplasmic reticulum and are rich in (at least) cholesterol. To extend these studies and identify the cellular lipids critical for WNVKUN replication we utilized a whole cell lipidomics approach and revealed an elevation in phospholipase A2 (PLA2) activity to produce lyso-phosphatidylcholine (lyso-PChol). We observed that the PLA2 enzyme family is activated in WNVKUN-infected cells and the generated lyso-PChol lipid moieties are sequestered to the subcellular sites of viral replication. The requirement for lyso-PChol was confirmed using chemical inhibition of PLA2, where WNVKUN replication and production of infectious virus was duly affected in the presence of the inhibitors. Importantly, we could rescue chemical-induced inhibition with the exogenous addition of lyso-PChol species. Additionally, electron microscopy results indicate that lyso-PChol appears to contribute to the formation of the WNVKUN membranous replication complex (RC); particularly affecting the morphology and membrane curvature of vesicles comprising the RC. These results extend our current understanding of how flaviviruses manipulate lipid homeostasis to favour their own intracellular replication. PMID: 29709018 [PubMed - indexed for MEDLINE]

Related Articles Sirt4 is a mitochondrial regulator of metabolism and lifespan in Drosophila melanogaster. Proc Natl Acad Sci U S A. 2018 02 13;115(7):1564-1569 Authors: Wood JG, Schwer B, Wickremesinghe PC, Hartnett DA, Burhenn L, Garcia M, Li M, Verdin E, Helfand SL Abstract Sirtuins are an evolutionarily conserved family of NAD+-dependent deacylases that control metabolism, stress response, genomic stability, and longevity. Here, we show the sole mitochondrial sirtuin in Drosophila melanogaster, Sirt4, regulates energy homeostasis and longevity. Sirt4 knockout flies have a short lifespan, with increased sensitivity to starvation and decreased fertility and activity. In contrast, flies overexpressing Sirt4 either ubiquitously or specifically in the fat body are long-lived. Despite rapid starvation, Sirt4 knockout flies paradoxically maintain elevated levels of energy reserves, including lipids, glycogen, and trehalose, while fasting, suggesting an inability to properly catabolize stored energy. Metabolomic analysis indicates several specific pathways are affected in Sirt4 knockout flies, including glycolysis, branched-chain amino acid metabolism, and impaired catabolism of fatty acids with chain length C18 or greater. Together, these phenotypes point to a role for Sirt4 in mediating the organismal response to fasting, and ensuring metabolic homeostasis and longevity. PMID: 29378963 [PubMed - indexed for MEDLINE]

Related Articles Identification of the lipid biomarkers from plasma in idiopathic pulmonary fibrosis by Lipidomics. BMC Pulm Med. 2017 Dec 06;17(1):174 Authors: Yan F, Wen Z, Wang R, Luo W, Du Y, Wang W, Chen X Abstract BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an irreversible interstitial pulmonary disease featured by high mortality, chronic and progressive course, and poor prognosis with unclear etiology. Currently, more studies have been focusing on identifying biomarkers to predict the progression of IPF, such as genes, proteins, and lipids. Lipids comprise diverse classes of molecules and play a critical role in cellular energy storage, structure, and signaling. The role of lipids in respiratory diseases, including cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD) has been investigated intensely in the recent years. The human serum lipid profiles in IPF patients however, have not been thoroughly understood and it will be very helpful if there are available molecular biomarkers, which can be used to monitor the disease progression or provide prognostic information for IPF disease. METHODS: In this study, we performed the ultraperformance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-QTOF/MS) to detect the lipid variation and identify biomarker in plasma of IPF patients. The plasma were from 22 IPF patients before received treatment and 18 controls. RESULTS: A total of 507 individual blood lipid species were determined with lipidomics from the 40 plasma samples including 20 types of fatty acid, 159 types of glycerolipids, 221 types of glycerophospholipids, 47 types of sphingolipids, 46 types of sterol lipids, 7 types of prenol lipids, 3 types of saccharolipids, and 4 types of polyketides. By comparing the variations in the lipid metabolite levels in IPF patients, a total of 62 unique lipids were identified by statistical analysis including 24 kinds of glycerophoslipids, 30 kinds of glycerolipids, 3 kinds of sterol lipids, 4 kinds of sphingolipids and 1 kind of fatty acids. Finally, 6 out of 62 discriminating lipids were selected as the potential biomarkers, which are able to differentiate between IPF disease and controls with ROC analysis. CONCLUSIONS: Our results provided vital information regarding lipid metabolism in IPF patients and more importantly, a few potentially promising biomarkers were firstly identified which may have a predictive role in monitoring and diagnosing IPF disease. PMID: 29212488 [PubMed - indexed for MEDLINE]

Related Articles Diet-induced obesity and weight loss alter bile acid concentrations and bile acid-sensitive gene expression in insulin target tissues of C57BL/6J mice. Nutr Res. 2017 Oct;46:11-21 Authors: La Frano MR, Hernandez-Carretero A, Weber N, Borkowski K, Pedersen TL, Osborn O, Newman JW Abstract Bile acids (BAs) influence the metabolism of glucose, lipids, and energy expenditure. We hypothesized that BA concentrations and related gene expression would be altered in lean (low-fat diet fed; LFD) vs diet-induced obese (high-fat diet fed; HFD) groups of mice and that some detected changes would remain after weight loss in an HFD group switched to the LFD (SW). Taurine conjugates dominated the bile acid composition of the liver, epididymal white adipose tissue (eWAT), and hypothalamus, with the latter having lower levels (~95%, ~95%, and ~80%, respectively; P<.05). Plasma conjugated bile acids were elevated in the HFD relative to the LFD and SW animals. Total hepatic BA concentrations decreased in obese mice fed HFD, and levels returned to preobese levels in the SW group. Subtle changes in unconjugated bile acids were detected in the eWAT, hypothalamus, and muscle. Liver expression of a variety of enzymes involved in BA synthesis (eg, Cyp27a1, Acox2), BA transport (eg, Slc22a8), and BA-sensitive receptors (Fxr, Tgr5) were unchanged by HFD feeding but decreased with SW. Other hepatic enzymes were induced in the SW group (eg, Amacr and Bal). In eWAT, Cyp27a1 and Acox2 also declined in the SW group, whereas the HFD group showed reduced expression of BA transporters (eg, Abcc3), and changes in Fxr and Tgr5 were unclear. Therefore, although most detectable changes in BA metabolism associated with diet-induced obesity are reversed by diet-induced weight loss, some effects on BA composition, concentrations, and gene expression can persist after weight loss. PMID: 29173647 [PubMed - indexed for MEDLINE]

Related Articles Doses Lactobacillus reuteri depend on adhesive ability to modulate the intestinal immune response and metabolism in mice challenged with lipopolysaccharide. Sci Rep. 2016 06 21;6:28332 Authors: Gao K, Liu L, Dou X, Wang C, Liu J, Zhang W, Wang H Abstract The objective of this study was to evaluate the modulatory effects of Lactobacillus reuteri ZJ617 and ZJ615, which have high and low adhesive abilities, respectively, and Lactobacillus rhamnosus GG (LGG) on immune responses and metabolism in mice stimulated with lipopolysaccharide (LPS). Six C57BL/6 mice per group were orally inoculated with ZJ617, ZJ615 or LGG for one week (1 × 10(8) CFU/mouse) and i.p. injected with LPS (10 mg/kg) for 24 h. Compared with the LPS stimulation group, ZJ615, ZJ617 and LGG significantly decreased TNF-α levels in the sera of mice stimulated by LPS. ZJ615 and LGG significantly down-regulated mRNA levels of cytokines and Toll-like receptors, and suppressed activation of MAPK and NF-κB signaling, while ZJ617 up-regulated anti-inflammatory cytokine IL-10 mRNA levels in the ilea of mice stimulated by LPS. Correlation analysis confirmed that adhesive ability is relative with the immunomodulation in the ilea of mice. There were 24, 7 and 10 metabolites and 10, 9 and 8 major metabolic pathways with significant differences (VIP > 1, P < 0.05) between the LPS and ZJ617 + LPS groups, the LPS and ZJ615 + LPS groups, and the ZJ617 + LPS and ZJ615 + LPS groups, respectively. The results indicated that both ZJ617 and ZJ615 could modulate the intestinal immune responses and metabolism in LPS-stimulated mice. PMID: 27323686 [PubMed - indexed for MEDLINE]

Related Articles Can Metabolic Profiles Be Used as a Phenotypic Readout of the Genome to Enhance Precision Medicine? Clin Chem. 2016 05;62(5):676-8 Authors: Contrepois K, Liang L, Snyder M PMID: 26960666 [PubMed - indexed for MEDLINE]

22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/07/24PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

MoDentify: phenotype-driven module identification in metabolomics networks at different resolutions. Bioinformatics. 2018 Jul 19;: Authors: Do KT, Rasp DJN, Kastenmüller G, Suhre K, Krumsiek J Abstract Summary: Associations of metabolomics data with phenotypic outcomes are expected to span functional modules, which are defined as sets of correlating metabolites that are coordinately regulated. Moreover, these associations occur at different scales, from entire pathways to only a few metabolites; an aspect that has not been addressed by previous methods. Here we present MoDentify, a free R package to identify regulated modules in metabolomics networks at different layers of resolution. Importantly, MoDentify shows higher statistical power than classical association analysis. Moreover, the package offers direct interactive visualization of the results in Cytoscape. We present an application example using complex, multifluid metabolomics data. Due to its generic character, the method is widely applicable to other types of data. Availability and Implementation: https://github.com/krumsieklab/MoDentify (vignette includes detailed workflow). Supplementary Information: Supplementary materials are available at Bioinformatics online. PMID: 30032270 [PubMed - as supplied by publisher]

Human exposure to polycyclic aromatic hydrocarbons: Metabolomics perspective. Environ Int. 2018 Jul 19;119:466-477 Authors: Gao P, da Silva E, Hou L, Denslow ND, Xiang P, Ma LQ Abstract Polycyclic aromatic hydrocarbons (PAHs) are organic contaminants exhibiting carcinogenic toxicity. They are widespread in the environment, especially in urban areas. Humans are exposed to PAHs via inhalation, ingestion and dermal contact. Though much research has investigated their toxicity, little is known regarding the metabolic responses in humans after exposing to PAHs. However, those studies are important since PAHs become carcinogenic after metabolic activation by humans as indirect-acting carcinogens. As such, it is important to study their metabolism in humans based on metabolomics analysis. The goal of metabolomics study is to obtain a comprehensive view of metabolic reactions in humans after exposing to PAHs to better control the underlying metabolisms and reduce their genotoxicity. This article reviewed the biomarkers, analytical techniques including nuclear magnetic resonance and mass spectrometry, big data multivariate statistical analysis, and animal models that have been utilized to better understand the biological effects of PAHs, PAH-derivatives, and their metabolites and biotransformation products on humans. PMID: 30032012 [PubMed - as supplied by publisher]

Dose-dependent target diversion of Danhong injection on the Glu-GLT-1/Gly-GlyRα dynamic balance module of cerebral ischemia. Pharmacol Res. 2018 Jul 19;: Authors: Xu W, Zhang Y, Yu Y, Li B, Liu J, Wang P, Wu H, Liu Q, Wei Z, Xiao H, Wang Z Abstract Function-oriented modular structure analysis is a great challenge in module-based pharmacological studies. A strategy to uncover target-target interaction (TTI) and dynamic balance regularity (DBR) was established to discover the structural factors influencing modular functions and explore the mechanism of Danhong injection (DHI) in treating cerebral ischemia. The dose-related metabolic features of DHI intervention were investigated using metabolomics and modular pharmacology. The findings indicated that Glu/Gly was a biomarker and Glu-GLT-1/Gly-GlyRα was the core unit regulated by DHI. Gly and Glu displayed opposite patterns and functional roles, representing intra-modular balance. GlyRα was identified as the upstream target and GLT-1 as the downstream target by inhibiting or activating GlyRα, indicating that DHI has two dose-dependent regulatory modes. GlyRα was the major target at low doses, while GLT-1 was activated as the dominant target as doses accumulated. Our study reveals that target-target interaction and dynamic balance regularity are the key factors influencing modular functions, which is a promising breakthrough for module-based pharmacological studies. PMID: 30031913 [PubMed - as supplied by publisher]

Supplementing phytogenic compounds or autolyzed yeast modulates ruminal biogenic amines and plasma metabolome in dry cows experiencing subacute ruminal acidosis. J Dairy Sci. 2018 Jul 18;: Authors: Humer E, Kröger I, Neubauer V, Schedle K, Reisinger N, Zebeli Q Abstract Subacute ruminal acidosis (SARA) causes ruminal dysbiosis, thereby increasing the risk of systemic metabolic disorders in cattle. We recently showed that supplementation with phytogenic compounds (PHY) or autolyzed yeast (AY) counteracted negative effects of SARA by improving ruminal pH and microbiome. This study investigated the effects of an intermittent SARA challenge on the ruminal concentration of biogenic amines (BA) and lipopolysaccharides (LPS), as well as on the blood metabolome. We also evaluated effects of PHY and AY on the latter variables. Eight rumen-cannulated nonlactating Holstein cows were arranged in an incomplete 4 × 3 Latin square design with 4 experimental runs and 3 treatment groups. During each run, cows were switched from an all-forage diet (baseline) to an intermittent concentrate-challenge diet with a forage:concentrate ratio of 35:65 (dry matter basis) to induce SARA for 1 (SARA1) or 2 (SARA2) wk, separated by 1 wk of forage-only feeding. The 3 treatment groups were no additive as control, PHY, or AY. During baseline, SARA1 and SARA2 rumen fluid samples were collected for analysis of BA and LPS. Blood samples were taken during baseline and SARA1 for a targeted metabolomics approach. High-concentrate feeding caused a 9-fold increase in ruminal LPS during SARA1 and an 11-fold increase in SARA2 compared with the baseline. Elevated concentrations of ruminal BA were found during both SARA periods, with histamine showing the strongest increase during SARA1. Moreover, a decrease in phosphatidylcholines, lysophosphatidylcholines, sphingomyelines, and several AA in the blood during SARA1 were detected. Supplementation of PHY decreased concentrations of LPS (-43%), histamine (-66%), pyrrolidine (-38%), and spermine (-54%) in SARA1 and cadaverine in SARA2 (-50%). Moreover, cows that received PHY had higher concentrations of cholesterol (+26%), several AA, and phosphatidylcholines in SARA1 compared with control cows. For AY, decreases in ruminal ethanolamine (-21%), methylamine (-52%), histamine (-54%), spermidine (-44%), and spermine (-80%) in SARA1 were observed, whereas in the blood an increase in tryptophan was noticed. In conclusion, the SARA was associated with markedly increased concentrations of LPS and BA in the rumen fluid and undesirable shifts in the plasma metabolome. Supplementation of PHY and AY counteracted some of these changes and therefore may help in attenuating negative effects of high-concentrate feeding in dairy cattle. PMID: 30031584 [PubMed - as supplied by publisher]