Biosynthesis of Trimethylammonium Compounds in Aquatic Animals: IV. Precursors of Trimethylamine Oxide and Betaine in Marine Teleosts

1964 ◽  
Vol 21 (4) ◽  
pp. 765-771 ◽  
Author(s):  
E. Bilinski
Keyword(s):  
Metabolic Pathways ◽  
Sodium Acetate ◽  
Sodium Formate ◽  
Whole Body ◽  
Platichthys Stellatus ◽  
Trimethylamine Oxide ◽  
Dragendorff Reagent ◽  
Limited Degree ◽  
Parophrys Vetulus

An in-vivo study was made of potential precursors of trimethylamine oxide (TMAO) in marine teleosts (lemon sole, Parophrys vetulus, and starry flounder, Platichthys stellatus). C14-labelled compounds were administered intraperitoneally and the incorporation of tracer into TMAO, isolated from the whole body, was determined. Trimethylamine (TMA)-C14 was found to be a much better precursor than the other compounds tested. A limited labelling of TMAO was observed after administration of γ-butyrobetaine-methyl-C14, betaine-methyl-C14 and methionine-methyl-C14. There was little or no incorporation of C14 into TMAO after administration of methylamine-C14, carnitine-methyl-C14, gIycine-2-C14, sodium formate-C14, sodium acetate-1-C14, sodium acetate-2-C14 and NaHCO3-C14. The conversion of choline-methyl-C14 to TMAO was higher after intraperitoneal than after intramuscular injection and only trace amounts of radioactivity were found after intravenous injection. The results provide support for formation of TMAO in fish by oxidation of TMA but they give no clear indication for metabolic pathways leading to this oxidative step.Betaine was isolated from fish after administration of choline-methyl-C14, methionine-methyl-C14 and glycine-2-C14. Evidence of extensive conversion of choline to betaine was obtained. Betaine also was found to be labelled after administration of methionine-methyl-C14, but only a limited degree of labelling was observed after administration of glycine-2-C14. The results indicate that betaine is formed by oxidation of choline in fish.A modification of the Dragendorff reagent for use as a spray for detecting trimethylammonium compounds on paper chromatograms is described.

scholarly journals Arginine metabolism in vascular biology and disease

2005 ◽  
Vol 10 (2_suppl) ◽  
pp. S83-S87 ◽  
Author(s):  
Sidney M Morris
Keyword(s):  
Metabolic Pathways ◽  
Whole Body ◽  
Cardiovascular Physiology ◽  
Arginine Metabolism ◽  
Complex Interplay ◽  
End Products ◽  
Health And Disease ◽  
Enzyme Families ◽  
Dependent Processes

Arginine metabolism plays a major role in cardiovascular physiology and pathophysiology, largely via nitric oxide (NO)-dependent processes. It is becoming increasingly apparent, however, that arginine metabolic enzymes other than the NO synthases can also play important roles via both NO-dependent and -independent processes. There are three sources of arginine in vivo and at least five mammalian enzymes or enzyme families that utilize arginine as substrate. Changes in arginine availability or in production of the different end products of the various arginine metabolic pathways can have distinct and profound physiologic consequences. However, our knowledge regarding the complex interplay between these pathways at the level of the whole body, specific tissues, and even individual cells, is incomplete. This review will highlight recent findings in this area that may suggest additional avenues of investigation that will allow a fuller understanding of cardiovascular physiology in health and disease.

Biosynthesis of Trimethylammonium Compounds in Aquatic Animals: I. Formation of Trimethylamine Oxide and Betaine from C14-labelled Compounds by Lobster (Homarus americanus)

1960 ◽  
Vol 17 (6) ◽  
pp. 895-902 ◽  
Author(s):  
E. Bilinski
Keyword(s):  
Homarus Americanus ◽  
Abdominal Muscle ◽  
Whole Body ◽  
Aquatic Animals ◽  
Radioactive Carbon ◽  
Trimethylamine Oxide ◽  
Good Precursor

The formation of trimethylamine oxide and betaine in lobster has been studied in vivo with radioactive carbon. C14-labelled compounds, tested as possible precursors, were administered to lobsters by injection into the abdominal muscle. Incorporation of the tracer into trimethylamine oxide and betaine, isolated from the whole body, was followed after a metabolic period of 24 and 72 hours.Administration of Na formate-C14, DL-serine-3-C14and glycine-2-C14does not lead to labelling of trimethylamine oxide. L-methionine-methyl-C14was a poor precursor of trimethylamine oxide, compared with choline-methyl-C14. These findings suggest a possible function for choline or a derivative in trimethylamine oxide biosynthesis.It appears that the formation of betaine in lobster takes place by oxidation of choline rather than by methylation of glycine. Choline-methyl-C14was found to be a very good precursor, whereas glycine-2-C14was not converted to betaine.

Arginine metabolism in vascular biology and disease

2005 ◽  
Vol 10 (1_suppl) ◽  
pp. S83-S87 ◽  
Author(s):  
Sidney M Morris
Keyword(s):  
Metabolic Pathways ◽  
Whole Body ◽  
Arginine Metabolism ◽  
Complex Interplay ◽  
Vascular Physiology ◽  
Health And Disease ◽  
Enzyme Families ◽  
Cardio Vascular ◽  
Dependent Processes

Arginine metabolism plays a major role in cardiovascular physiology and pathophysiology, largely via nitric oxide (NO)-dependent processes. It is becoming increasingly apparent, however, that arginine metabolic enzymes other than the NO synthases can also play important roles via both NO-dependent and -independent processes. There are three sources of arginine in vivo and at least five mammalian enzymes or enzyme families that utilize arginine as substrate. Changes in arginine availability or in production of the different end products of the various arginine metabolic pathways can have distinct and profound physiologic consequences. However, our knowledge regarding the complex interplay between these pathways at the level of the whole body, specific tissues, and even individual cells, is incomplete. This review will highlight recent findings in this area that may suggest additional avenues of investigation that will allow a fuller understanding of cardio vascular physiology in health and disease.

Maintenance and accumulation of trimethylamine oxide by winter skate (Leucoraja ocellata): reliance on low whole animal losses rather than synthesis

2006 ◽  
Vol 291 (6) ◽  
pp. R1790-R1798 ◽  
Author(s):  
Jason R. Treberg ◽  
William R. Driedzic
Keyword(s):  
Whole Body ◽  
In Vitro Techniques ◽  
Organic Osmolyte ◽  
Trimethylamine Oxide ◽  
Endogenous Synthesis

Trimethylamine oxide (TMAO) is typically accumulated as an organic osmolyte in marine elasmobranchs to levels second only to urea (which can reach >400 mM); however, little is known about the whole animal regulation of TMAO in elasmobranchs. In the present study on the winter skate ( Leucoraja ocellata), we determine whether this species can maintain levels of TMAO in the absence of feeding, and if so, is this due to endogenous synthesis or low whole animal losses. Winter skates maintain plasma TMAO levels for up to 45 days without feeding. The liver displays methimazole oxidation, which is consistent with the presence of flavin-containing monooxygenase (E.C. 1.14.13.8 ) activity, the class of enzymes responsible for the physiological oxygenation of trimethylamine (TMA) to TMAO in mammals. However, no evidence for TMA oxygenation by winter skates was found using in vivo or in vitro techniques, indicating no significant capacity for endogenous TMAO synthesis. Fed skates displayed low, but measurable (∼4–13 μmol·kg−1·h−1), efflux of TMAO (plus TMA), whereas fasted skates did not. Using the loss of injected [14C]TMAO, it was determined that whole animal TMAO losses are likely <1% of whole body TMAO per day. These results demonstrate that winter skates utilize low whole animal TMAO losses, rather than endogenous synthesis, to maintain TMAO levels when not feeding.

Use of Toxicokinetics in Risk Assessment Based on In Vitro Data

1993 ◽  
Vol 21 (2) ◽  
pp. 173-180
Author(s):  
Gunnar Johanson
Keyword(s):  
Risk Assessment ◽  
Whole Body ◽  
External Exposure ◽  
Target Dose ◽  
Toxic Response ◽  
Route Of Exposure ◽  
Vitro Data ◽  
In Vitro Data

This presentation addresses some aspects of the methodology, advantages and problems associated with toxicokinetic modelling based on in vitro data. By using toxicokinetic models, particularly physiologically-based ones, it is possible, in principle, to describe whole body toxicokinetics, target doses and toxic effects from in vitro data. Modelling can be divided into three major steps: 1) to relate external exposure (applied dose) of xenobiotic to target dose; 2) to establish the relationship between target dose and effect (in vitro data, e.g. metabolism in microsomes, partitioning in tissue homogenates, and toxicity in cell cultures, are useful in both steps); and 3) to relate external exposure to toxic effect by combining the first two steps. Extrapolations from in vitro to in vivo, between animal and man, and between high and low doses, can easily be carried out by toxicokinetic simulations. In addition, several factors that may affect the toxic response by changing the target dose, such as route of exposure and physical activity, can be studied. New insights concerning the processes involved in toxicity often emerge during the design, refinement and validation of the model. The modelling approach is illustrated by two examples: 1) the carcinogenicity of 1,3-butadiene; and 2) the haematotoxicity of 2-butoxyethanol. Toxicokinetic modelling is an important tool in toxicological risk assessment based on in vitro data. Many factors, some of which can, and should be, studied in vitro, are involved in the expression of toxicity. Successful modelling depends on the identification and quantification of these factors.

scholarly journals Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
KyeongJin Kim ◽  
Jin Ku Kang ◽  
Young Hoon Jung ◽  
Sang Bae Lee ◽  
Raffaela Rametta ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Whole Body ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Ph Domain ◽  
Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

The Hemostatic Effect of 51Cr-Labelled Platelets

1975 ◽  
Author(s):  
J. Björnson ◽  
I. Aursnes
Keyword(s):  
Whole Body ◽  
Platelet Concentrates ◽  
Platelet Aggregability ◽  
Hemostatic Effect ◽  
Normal Platelet ◽  
Labelling Procedure

In the interpretation of data obtained with 51Cr-labelled platelets it is vital to know whether they are functionally normal. Although survival of 51Cr-labelled platelets in vivo appears to be normal, platelet aggregability- has recently been shown to be reduced after the labelling procedure (Björnson, J., Sc and. J. Haemat. 13, 252–259).The aim of the present study was to examine the hemostatic effect of labelled platelets. Rabbits were made thrombocytopenic (< 35,000/μ1) by whole body irradiation. Bleeding times were recorded after standardized cuts on the inner side of the ear, a method showing an acceptable reproducibility (< 3 min in normals). The animals were then transfused with labelled platelet concentrates, increasing the platelet levels to about 200,000/μ) blood. Bleeding times of more than 15 min before transfusion were almost normalized 1 and 4 hours after transfusion. In controls transfusion of PRP led to similar shortening of bleeing time.It is concluded that platelets subjected to the 51Cr-labelling procedure to a large extent retain their hemostatic ability.

scholarly journals Integrated multi-omics analysis of RB-loss identifies widespread cellular programming and synthetic weaknesses

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Swetha Rajasekaran ◽  
Jalal Siddiqui ◽  
Jessica Rakijas ◽  
Brandon Nicolay ◽  
Chenyu Lin ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Human Cells ◽  
Cellular Reprogramming ◽  
Hallmarks Of Cancer ◽  
Compensatory Mechanisms ◽  
Response Factors ◽  
Cancer Data ◽  
Cell Stress Response ◽  
Metabolic Output

AbstractInactivation of RB is one of the hallmarks of cancer, however gaps remain in our understanding of how RB-loss changes human cells. Here we show that pRB-depletion results in cellular reprogramming, we quantitatively measured how RB-depletion altered the transcriptional, proteomic and metabolic output of non-tumorigenic RPE1 human cells. These profiles identified widespread changes in metabolic and cell stress response factors previously linked to E2F function. In addition, we find a number of additional pathways that are sensitive to RB-depletion that are not E2F-regulated that may represent compensatory mechanisms to support the growth of RB-depleted cells. To determine whether these molecular changes are also present in RB1−/− tumors, we compared these results to Retinoblastoma and Small Cell Lung Cancer data, and identified widespread conservation of alterations found in RPE1 cells. To define which of these changes contribute to the growth of cells with de-regulated E2F activity, we assayed how inhibiting or depleting these proteins affected the growth of RB1−/− cells and of Drosophila E2f1-RNAi models in vivo. From this analysis, we identify key metabolic pathways that are essential for the growth of pRB-deleted human cells.

scholarly journals Fetal hemoglobin induction by acetate, a product of butyrate catabolism [see comments]

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3198-3204 ◽  
Author(s):  
G Stamatoyannopoulos ◽  
CA Blau ◽  
B Nakamoto ◽  
B Josephson ◽  
Q Li ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Sickle Cell Disease ◽  
Umbilical Cord Blood ◽  
Sodium Acetate ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Gamma Globin ◽  
Hbf Induction ◽  
Globin Synthesis

Abstract Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of erythroid progenitors, in primates, and in man. The mechanism by which this compound stimulates gamma-globin synthesis is unknown. In the course of butyrate catabolism, beta oxidation by mitochondrial enzymes results in the formation of two acetate molecules from each molecule of butyrate. Studies were performed to determine whether acetate itself induces HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures from normal persons, and individuals with sickle cell disease and umbilical-cord blood, dose-dependent increases in gamma-globin protein and gamma mRNA were consistently observed in response to increasing acetate concentrations. In BFU-E cultures from normal adults and patients with sickle cell disease, the ratio of gamma/gamma + beta mRNA increased twofold to fivefold in response to acetate, whereas the percentage of BFU-E progeny staining with an anti-gamma monoclonal antibody (MoAb) increased approximately twofold. Acetate-induced increases in gamma-gene expression were also noted in the progeny of umbilical cord blood BFU-E, although the magnitude of change in response to acetate was less because of a higher baseline of gamma- chain production. The effect of acetate on HbF induction in vivo was evaluated using transgenic mouse and primate models. A transgenic mouse bearing a 2.5-kb mu locus control region (mu LCR) cassette linked to a 3.3-kb A gamma gene displayed a near twofold increase in gamma mRNA during a 10-day infusion of sodium acetate at a dose of 1.5 g/kg/d. Sodium acetate administration in baboons, in doses ranging from 1.5 to 6 g/kg/d by continuous intravenous infusion, also resulted in the stimulation of gamma-globin synthesis, with the percentage of HbF- containing reticulocytes (F reticulocytes) approaching 30%. Surprisingly, a dose-response effect of acetate on HbF induction was not observed in the baboons, and HbF induction was not sustained with prolonged acetate administration. These results suggest that both two- carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of HbF in vivo.

scholarly journals IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii111-ii111
Author(s):  
Lan Hoang-Minh ◽  
Angelie Rivera-Rodriguez ◽  
Fernanda Pohl-Guimarães ◽  
Seth Currlin ◽  
Christina Von Roemeling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
T Cell Therapy ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

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