bluuebunny/crossref_metadata_2025 huggingface dataset:
Pteridines, XC Syntheses, Oxidations, Properties, and Reactions of 2-Thiopteridine-4,6, 7- trione Derivatives
Authors: Bartke Michael , Pfleiderer Wolfgang
Published: March 2013

A new efficient synthesis for 2-thiopteridine-4,6,7-triones (6-10, 15) has been found in the condendation of the appropriate 5,6-diaminopyrimidine (1-5, 14) with oxalic acid in DMF. Analogous condensations with dimethyl oxalate led to S-alkylation probably via an intermediate O-methylation of the DMF. 8-Methyl-2- thiopteridine-4,6,7-trione (10) shows a ring contraction to 9-methyl-2-thioxanthine (13) on base treatment. Oxidations by H20 2 and KMn04 respectively lead to the corresponding 2-sulfinate 22 and the 2-sulfonates 17 -19. Oxidative desulfurization takes place in formic acid with H 20 2 forming first the sulfinate 22, which then eliminates S02 to give pteridine-4,6,7-trione (23). Nucleophilic displacements of the 2-sulfonate group by ammonia and amines form the corresponding leucopterin derivatives 20, 21 and 24. The newly synthesized compounds have been characterized by elemental analyses, UV-spectra and pKa-determinations. The ionization sequences of the acidic hydrogens have been assigned based on these physical data .
Synthesis of the Folylpolyglutamate Synthetase Inhibitor Nα-Pteroyl-Lornithine and its Nδ-Benzoyl and Nδ-Hemiphthaloyl Derivatives, and an Improved Synthesis of Nα-( 4-Amino-4-deoxypteroy1)-Nδ-hemiphthaloyl-Lornithine
Authors: Rosowsky Andre , Bader Henry , Forsch Ronald A.
Published: March 2013

N10-Formylpteroic acid may be prepared from folic acid by sequentially heating with formic acid and cleaving the glutamate side chain with carboxypeptidase G1. Condensation of the product with the Nα,O bis( trimethylsilyl) derivative of Nδ-(tert-butyloxycarbonyl)-L-ornithine via a modification of the carboxyliccarbonic anhydride peptide synthesis, followed by stepwise removal of the N10-formyl group with NaOH and of the Nδ-tert-butyloxycarbonyl group with trifluoroacetic acid affords Nα-pteroyl-L-ornithine. A similar sequence, starting from methyl Nδ-benzoyl-L-ornithinate and methyl Nδ-phthaloyl-L-ornithinate and using gentle treatment with sodium hydroxide in DMSO to selectively remove the methyl ester and N10-formyl groups while hydrolyzing only one of the phthaloyl amide bonds, gives the hitherto undescribed compounds Nδ-benzoyl- and Nδ-hemiphthaloyl-Nα-pteroyl-L-ornithine, respectively. An improved synthesis of Nδ-hemiphthaloyl- Nα-(4-amino-4-deoxypteroyl)-L-ornithine, based on the same chemistry but using 4-amino-4-deoxyN10- formylpteroic acid and methyl Nδ-phthaloyl-L-ornithinate, is also described.
Purification and Characterization of a Carbonyl Reductase from Human Liver, which is Competent in the Reduction of 6-Pyruvoyl-Tetrahydropterin
Authors: Steinerstauch Petra , Sawada Yoshitomo , Leimbacher Walter , Ghisla Sandro , Curtius Hans-Christoph
Published: March 2013

An enzyme which reduces 6-pyruvoyl-tetrahydropterin has been purified to apparent homogeneity from human liver. It consists of a single polypeptide chain with a molecular weight of 35 kDa, has an isoelectric point of 5.9 ± 0.1 and contains no glycosyl residues. The pure enzyme has a specific activity of 450 mU/mg protein at pH 7.0 in 10 mM potassium phosphate buffer. It converts 6-pyruvoyl-tetrahydropterin to 6-lactoyltetrahydropterin by transfer of the pro 4R-hydrogen of NADPH to form the side chain -OH at position C(2') of the substrate. Km values are 1.8 J..lM for 6-pyruvoyl-tetrahydropterin and 5.5 J..lM for NADPH. Polyclonal antibodies raised against the purified enzyme recognize 6-pyruvoyl-tetrahydropterin reductase in Western blot and ELISA but do not cross-react with human sepiapterin reductase. The enzyme appears to be identical with aldose reductase.
Four Different Markers for Activated Cell Mediated Immunity Compared with the Clinical Stages of HIV Infection
Authors: Caruso Arnaldo , Francesco Maria de , Gonzales Rosanna , Pollara Patrizia , Zanoni Lorenzo , Foresti Ida , Turano Adolfo
Published: March 2013

Activated cell-mediated immunity, as defined by four markers, has been studied in HIV-infected patients, and compared with the clinical stages of HIV infection. All the values obtained with such markers (interferon-y expressed on lymphocytes, soluble CD8, soluble IL-2 receptor, and serum neopterin) were observed to increase with the progressive stages of HIV infection, with the highest figures occurring in stage IV-C patients. Since the replication of HIV depend strictly on the stimulation of infected cells, T-cell activation in vitro might contribute to a further spread of HIV-1 in infected subjects. Thus permanent or multiple stimulation of the cellular immune system could be an important cofactor in the progression of this syndrome.
Nucleosides, XLVII. Syntheses, Reactions and Properties of 6- and 7-p-Bromophenyllumazine N-1-Nucleosides
Authors: Al-Masoudi Najim A. L. , Pfleiderer Wolfgang
Published: March 2013

Glycosylation of 6-(2) and 7-p-bromophenyllumazine (3) by the silyl method using 1-O-acetyl-2.3 ,5-tri-O-benzoyl-β-D-ribofuranose (6) and trimethylsilyl trifluoromethanesulfonate as catalyst proceeded regioselectively in high yields to the N-1 nucleosides (7, 11). Thiations by P4S10 or Lawesson’s reagent led to the corresponding 4-thiolumazine ribosides (9, 13). Deblocking to the free nucleosides (8, 10, 12. 14) worked best with K2CO3, in MeOH. Treatment of 9 and 13 respectively by methanolic NH3 afforded debenzoylation and di splacement of the thio-function to give the corresponding isopterin N-1 ribofuranosides (15.16). 2,2ʹ-Anhydro- nucleoside formation was achieved with 8 and 10 respectively to give 17 and 18, which formed on acid hydrolysis the 6- and 7-substituted l-~-D-arabinofuranosyl-lumazines 19 and 20.
Pregnancy Increases Urinary Neopterin Levels in Human Immunodeficiency Virus Type 1 Infection
Authors: Mayr Peter , Fuchs Dietmar , Fuith Lothar C. , Reibnegger Gilbert , Werner Ernst R. , Dapunt Otto , Wachter Helmut
Published: March 2013

Eleven mothers of 12 infants with human immunodeficiency virus type 1 (HIV-1) infection (all intravenous drug users) were followed throughout their pregnancies for evidence of clinical and immunological abnormalities. Intrauterine death occurred in one, growth retardation in 7/12 pregnancies. Moderate progression of HIV-l infection according to the Walter Reed Staging Classification was observed in 5/ 11 women during pregnancy. Two of them developed AIDS during follow up after delivery. Mean neopterin levels in the first, second and third trimester were significantly higher as compared to HIV-l seronegative pregnant women. Furthermore, concentrations of urinary neopterin increased significantly with the time of pregnancy in all HIV-1 seropositive women. Since higher urinary neopterin concentrations are predictive for more rapid disease progression in HIV infected patients the data may indicate that pregnancy increases the risk for developing AIDS. However, a possible influence of continuous drug use has to be considered.
Preparation of Isotope-labeled Dihydroneopterin 3'-Triphosphate with High Specific Activity
Authors: Katzenmeier Gerd , Schwarzkopf Bruno , Van Quang Le , Schmid Cornelia , Bacher Adelbert
Published: March 2013

Isotope-labeled dihydroneopterin 3'-triphosphate with 3H at positions C-1' and C-2', respectively, has been prepared from isotope-labeled glucose as starting material. Glucose was first converted enzymatically to ribose 5-phosphate. GMP was subsequently obtained by the action of phosphoribosylpyrophosphate synthetase and guanosine phosphoribosyl transferase. It was subsequently phosphorylated to GTP in two steps using adenylate kinase and guanylate kinase. Dihydroneopterin triphosphate was prepared from GTP by the action of recombinant GTP-cyclohydrolase I from Escherichia coli. The method allows the incorporation of 3H and 14C isotope labels into any desired position of dihydroneopterin triphosphate. Rapid purfication procedures for phosphoribosylpyrophosphate synthetase and guanosine phosphoribosyl transferase as well as HPLC assays for their determinations are described.
Neopterin and the Acute Phase Response In Human Immunodeficiency Virus Type 1 (HIV -1) Infection
Authors: Zangerle R. , Fuchs D. , Reibnegger G. , Artner-Dworzak E. , Fritsch P. , Wachter H.
Published: March 2013

Three markers of acute phase response - C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin - and two markers of immune activation - urinary neopterin, β2-microglobulin - were measured in 60 HIV-l infected individuals; β2microglobulin and ferritin increased mainly in the later stages WR 5 and WR 6 but identical in WR 1 - WR 4. The data indicate that chronic bacterial infections are unlikely to be the cause of immune activation in patients with HIV-l infection.
Neopterin and Tumor Necrosis Factor-α : Two Markers of Monocyte/ Macrophage Activation in a Septic Baboon Model
Authors: Strohmaier W. , Bahrami S. , Davies J. , Redl H. , Schlag G.
Published: March 2013

A hyperdynamic sepsis model in adult baboons was set up to follow the time course of TNF-Cl, endotoxin and neopterin. Continuous intravenous administration of 5.108 CFU/kg live E. coli over 2 hours was followed by a seventy hours observation period. In this experimental set up TNF -Cl shows a pronounced peak after 2 hours and a return to baseline after 4 hours. By 20 - 24 hours neopterin peaks in this subchronic set up and shows only a reduction to half maximum values during the observation period. Another finding is the fast clearance of bacteria and consecutively LPS from the circulation. We conceive that monocyte/macrophage activation seems to occur on at least two levels. The diagnostic usefulness of neopterin in routine measurement is in part explained by these findings.
Pteridines IC. Chemical Synthesis and Structural Proof of Photinuspterin
Authors: Sugimoto Takashi , Pfleiderer Wolfgang
Published: March 2013

The proposed structure of Photinuspterin isolated from the firefly Photinus pyralis has been proven by two unambiguous syntheses to be 6-(1-hydroxypropyl)-8-methylisoxanthopteIin (15), 8-MethylisoxanthopteIin (7) can be substituted in 6-position in a homolytic nucleophilie substitution reaction either by the 1-hydroxypropyl radical to give 15 directly or by the propionyl radical leading first to 8-methyl-6-propionyl-isoxanthopteIin (9) which was easily converted into 15 by sodium borohydlide reduction. These two approaches are of general nature and can be applied to synthesize a broad variety of 6-substituted 8-methylisoxanthopterins (8-19). The newly synthesized compounds have been characterized by elemental analysis. pKa determinations, UV and NMR spectra.
Regulation of Folate Metabolizing Enzymes In Fungus Aspergillus nidulans
Authors: Balińska Malgorzata , Natorff Renata , Paszewski Andrzej
Published: March 2013

The regulation of methionine synthase. serine hydroxymethyltransferase. methylenetetrahydrofolate oxidorelluctase and dihydrofolate reductase in Aspergillus nidulans have been found to be controlled by endogenous pools methionine and homocysteine. Mutants impaired in sulfur metaholite repression. which have highly elevated pools of these amino acids. also show elevated levels of folate metabolizing enzymes mentioned above. This effect was found to he the result of the accumulation of endogenous homocysteine. which induces folate enzymes. High concentration (up to 5 mM) or methionine in growth medium leads to repression of these enzymes. It appears. therefore. that the levels of folate metaholizing enzymes arc determined by the ratio of cellular levels or methionine and homocysteine.
Nucleosides LIII Syntheses and Reactions of 6,7-Dipyridyllumazine and 2' -Deoxylumazine N-1 Nucleosides
Authors: Al-Masoudi Najim AL. , Pfleiderer Wolfgang
Published: March 2013

The chemical syntheses of 6,7-(α-pyridyl)-1-(2,3,5-tri-O-benzoy-β-D-ribofuranosyl)-lumazine (6) and the corresponding free nucleoside 7 are described. Thiation of 6 with P4S10 gave a salt type adduct derivative of 4-thiolumazine 8 which afforded the free nucleoside 9 on deblocking. Treatment of 8 with methanolic NH3 gave the isopterin-N-1 nucleoside 10. 2,2' -Anhydro compound 13 was obtained by the diphenyl carbonate technique and characterised as the diacetate 14. Acid hydrolysis of 14 gave the arabino-nucleoside 15. which was isolated also from hydrolysis of 14 with hydroxide ion. Reaction of 7 with acetyl bromide gave the 2'-bromo-2'-deoxy derivative 11 as minor product together with triacetate 12 as the main analogue. Reduction of the bromo function in 11 into the expected 2'-deoxy analogue during the treatment with tri-n-butyltin hydride has failed and the 2.2' -anhydro compound 15 was the only product isolated. Alternatively. the 6,7-bis-(α-pyridyl)-1-(2-deoxy-3.5-di-O-toloulyl-α and β-D-ribofuranosyl)-Iumazine (17) and (19) were synthesized from direct condensation of sugar 16 and the silylated base 4. Debolcking of 17 and 19 with sodium methoxide gave the free analogues 18 and 20 respectively.
Influence of Kynurenine, Neopterin, Noradrenaline and Pyridoxal-5-Phosphate on Cholesterol and Phospholipid Content and Phospholipid Biosynthesis in vitro
Authors: Rudzite Vera , Jurika Edite , Reibnegger Gilbert , Weiss Günter , Wachter Helmut , Fuchs Dietmar
Published: March 2013

Incorporation of fatty acids into phospholipids has been investigated using samples of rat liver tissue homogenate, Krebs-Ringer-phosphate buffer (pH = 7.4) containing 0.3% albumin, fatty acid mixture and glyceroL The addition of L-kynurenine (4 nmol/g wet weight), D-eryhro-neopterin (5 and 30 pmol/g wet weight) and noradrenaline (4 nmol/g wet weight) to incubation medium induced an increase of saturated (palmitic acid) and decrease of poly-unsaturated (linoleic and arachidonic acid) fatty acids incorporation into phospholipids. The increase of saturated fatty acids incorporation into phospholipids was more pronounced after addition of neopterin and noradrenaline to the incubation medium while the decrease of linoleic and arachidonic acid synthesis was stimulated most with kynurenine. Moreover, kynurenine stimulated whereas neopterin depressed the oleic acid incorporation into phospholipids. These changes of fatty acid incorporation into phospholipids were followed by increase of cholesterol content in samples containing kynurenine, neopterin or noradrenalin. In contrast, phospholipid content decreased in samples containing kynurenine or noradrenalin, hut was not altered by supplementation of neopterin. Since the addition of kynurenine and neopterin to incubation medium for isolated fog heart resulted in an increased noradrenaline and decreased pyridoxal-5-phosphate content in the tissue, we also added pyridoxal-5-phosphate (4 nmol/g wet weight) to incubation medium for phospholipid biosynthesis. No change of the fatty acid incorporation into phospholipids as welI as the content of phospholipids and cholesterol in samples was observed.
Neopterin, PMN Elastase, and Complement Components as Monitoring Parameters in Women with the Syndrome of Hemolysis, Elevated Liver Enzymes and Low Platelet Count
Authors: Haeger Magnus , Unander Margareta , Bengtsson Anders
Published: March 2013

Preeclampsia is a pregnancy induced hypertensive disease with an incidence of about 5% in primigravida and it significantly contributes to maternal and neonatal morbidity and mortality. The primary cause remains unknown but might be immunologic. Our previous studies have shown that complement neutrophils and macrophages are activated in preeclampsia. The present study evaluated whether the extension of the macrophage, the neutrophil and the complement activation is related to the severity of preeclampsia. Patients with severe preeclampsia. complicated by the syndrome of hemolysis. elevated liver enzymes and low platelet count (HELLP) and women with preeclampsia were studied. Women with uncomplicated pregnancies were controls. To detect activation of macrophages and polymorphonuclear neutrophils (PMN), respectively. the formations of neopterin and PMN elastase were analyzed. For evaluation of complement activation. the biologically active components C5a and the terminal C5b-9 complement complex (TCC) were determined in plasma. Patients with the HELLP syndrome had significantly elevated plasma concentrations of neopterin and C5a at delivery compared to women with preeclampsia. and compared to the controls, the HELLP group had significantly raised plasma levels of neopterin. PMN elastase. C5a and TCC. Women with preeclampsia had significantly higher plasma concentrations of neopterin and TeC at delivery as compared to the controls. In preeclamptics and HELLP patients, the plasma concentrations at delivery of PMN elastase, C5a and TCC were normalized within one week. but the plasma levels of neopterin remained elevated after one week. Neopterin, PMN
Dihydropteridine Reductase
Authors: Whiteley John M. , Varughesej Kottayil I. , Xuong Nguyen H. , Matthews David A. , Grimshaw Charles E.
Published: March 2013

During the past decade numerous advances have been made in understanding the structure, mechanism and clinical properties of dihydropteridine reductase. An attempt is made here to delineate the current status of this essential enzyme by describing its structural features, its kinetic mechanism, the cloning and expression of both rat and human enzyme forms, the solution of their crystal structures, their classification as members of a large family of short chain dehydrogenases, and finally a brief description is included indicating how current molecular biological applications have allowed the clinical definition of the aberrant form of phenylketonuria caused by a defective reductase.
Neopterin Levels In Thyroid Pseudocysts
Authors: Zaknun J. , Mayersbach P. , Moncayo R. , Fridrich L. , Wachter H. , Fuchs D.
Published: March 2013

Cystic changes of the thyroid remain a diagnostic dilemma with regard to malignancy due to insufficient information gained by fine needle aspiration, sonography and routine nuclear medicine procedures. As complementary soluble parameters we measured neopterin and thyroglobin levels in cyst fluids and in serum of 81 patients with disorders of the thyroid. Based on clinical, cytological and histological information, patients were divided into five groups. (I): Serous cysts (n=41), (II): hemorrhagic cysts (N=18), (III): cysts ' with evidence for inflammation clinically or by histology (n= 11), (IV): malignancy in cysts by histology (n = 6), (V): cysts containing "honey" like, brownish fluid of high viscosity (n = 5). Neopterin concentration in cyst fluids vs. serum in group (I) were not different, 8.8± 4.3 nmol/l in vs. 6.67± 3.34 nmol/l. In groups II-V neopterin concentration in cysts were higher than in serum, (II): 21.1 ± 18.7 nmol/l vs. 5.6± 2.56 nmol/l, (III): 30.6± 24.9 nmol/l vs. 6.1 ± 2.9 nmol/l, in (IV): 35± 23.5 vs. 10.98± 7.0 nmol/l and (V): 36.0± 23.9 vs. 5.9± 3.32 nmol/l respectively. In patients with proven benign histology at surgery, neopterin levels in cystic fluid were significantly lower than in cysts harbouring malignancy, 8.5±4.6 vs. 35.4±23.5 (Z=3,17, p=O. 0015). There were no significant differences between groups II, III IV and V regarding neopterin concentrations in cysts. Elevated serum neopterin levels were observed in 2/6 patients with aggressive thyroid cancer (group IV). However, average neopterin concentrations in serum of patients of group IV were not higher than in 15 patients from group I with benign histology (P=O.l). Significantly lower levels of thyroglobin in cyst fluid were found in group V ("honey" cysts) in comparison to all other groups pooled, 2.67± 1.82 f..lg/rnl vs. 6.76± 3.97 f..lg/ml, (Z=2.l5, p=0.031), four of five cysts in group V resolved after fine needle aspiration. We found no correlation between thyroglobin levels in cyst fluid and in serum.

Our data suggest that low neopterin concentrations in cystic fluid have high negative predictive value with regard to inflammation and malignancy in thyroid cysts. In clinical settings neopterin may provide further' valuable information in the evaluation of such lesions.
Early Diagnosis of 6-Pyruvoyl-tetrahydropterin Synthase Deficiency
Authors: Shintaku Haruo
Published: March 2013

6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, which used to be called dihydrobiopterin synthase deficiency, is the most common kind of tetrahydrobiopterin deficiency. Early treatment by administration of tetrahydrobiopterin and neurotransmitter precursors helps to prevent neurological injury, so prompt diagnosis of neonates with hyperphenylalaninemia discovered by screening for phenylketonuria is necessary. Three patients with PTPS deficiency were diagnosed by pteridine analysis. All patients had low biopterin and high neopterin levels in the urine, resulting in a neopterin to biopterin ratio (N/B)much higher than that of age-matched controls. The mean NIB in the parents of these patients was twice that of healthy unrelated adults. PTPS activity was measured in one of these patients with PTPS deficiency and in his family members; the patient was homozygous and his parents were heterozygous for PTPS deficiency. This result meant that N/Bcould be used as an index of PTPS activity. In healthy subjects studied cross-sectionally, urinary levels of pteridine decreased in groups of increasing age, and the same change was found in subjects with hyperphenylalaninemia studied cross-sectionally. Thus, pteridine values of patients can be compared meaningfully only with age-matched controls. The urinary N/Bis useful for the diagnosis of homozygotes and heterozygotes for PTPS deficiency.
Applicability of an Enzyme-linked Immunosorbant Assay for Neopterin Detection for Screening of Blood Donations
Authors: Mayersbach Peter , Augustin Roman , Schennach Harald , Fuchs Dietmar , Werner Ernst R. , Schonitzer Diether , Wachter Helmut , Reibnegger Gilbert
Published: March 2013

We have evaluated a new commercially available enzyme-linked immunorsorbant assay for neopterin :or its suitability in the context of screening of voluntary blood donors. The assay was performed on 1040 consecutive blood donors, and compared with radioimmunoassay and. in a fraction of 142 donors . . : Iso with high performance liquid chromatography. On repetitive assays of all donations showing a concentration exceeding 8.0 nmol/L in the initial assay. three of the radioimmunoassay results were identified as gross outliers. No such gross outliers were detected for the enzyme-linked immunosorbant assay. RegarJing the reproducibility of results exceeding a cut-off limit of \0 nmol/L neopterin. the enzyme-linked ;mmunosorbant assay was better than the radioimmunoassay. Moreover. the enzyme-linked immunosorbant assay was slightly superior to radioimmunoassay when both tests were compared with high performance liquid chromatography (based on linear regression analysis. evaluation of frequencies of concentrations bant assay was slightly superior to radioimmunoassay when both tests were compared with high performance liquid chromatography (based on linear regression analysis. evaluation of frequencies of concentrations rations. Its slight superiority compared to the conventional radioimmunoassay likely results from the higher degree of automatization employed.
Neopterin Determinations in Tuberculous Bone Infections
Authors: Peters K. M. , Schweitzer K. , Zimmermann S. , Zilkens K. W.
Published: March 2013

In patients with tuberculous chest infections caused by intracellular Mycobacteria elevated serum neopterin levels could be found. In the present study neopterin levels were elevated in 5/6 patients with proven tuberculous bone infections as well. Neopterin determinations in serum were especially helpful for the drug monitoring of these patients. After a sufficient antituberculous therapy initially elevated neopterin levels decreased and remained within normal range. Persistent elevation of neopterin may be a hint for a resistance of the Mycobacteria.
Role of Folate in the Modulation of Lipids, Lipoproteins and Eicosanoids in Hypertension and Diabetes
Authors: Katki Khurshed A. , Viswanathan Gomathy , Noronha John M.
Published: March 2013

Besides elevated levels of lipids and lipoproteins, ievels of the physiological amino acid homocysteine as well as whole blood folates are now known to play a role in atherogenesis. The role of folates in atherosclerosis is rather peculiar in that it helps to catalyse the remethylation of homocysteine (a proatherogenic agent) to methionine thus preventing the accumulation of homocysteine in plasma and hence its antiatherogenic role. We estimated whole blood folate levels of 69 normotensive, 34 diabetic and 94 hypertensive individuals and have attempted to correlate these values with lipid and non-lipid parameters. Whole blood levels of simple, conjugated and total folates were significantly higher among the diabetics as well as the hypertensives when compared to the normotensives. In all the study groups, levels of conjugated folates correlated significantly to those of total folates even after adjustments for age and body mass index were introduced. Among the normotensive individuals the significance of the inverse correlation between simple folates and total cholesterol/high density lipoprotein cholesterol ratio was lost after adjusting for age and body mass index. Levels of total and conjugated folates were positively correlated to plasma levels of thromboxane B2 among the diabetics. In the same group the positive correlation between total folates and thromboxane B2 and that between total folates and the eicosanoid ratio remained significant even after adjustments for age and body mass index were introduced. None of the other metabolic variables correlated with whole blood levels of simple folates in any of the study groups.
Degeneration of Rat Retina is Paralleled by an Imbalance of the Redox Mechanism of Pteridines
Authors: Cremer-Bartels Gertrud
Published: March 2013

The RCS rat suffers from a genetic degeneration of retinal cell We have examined the pattern of oxidized and reduced monapterin and biopterin in retinas from RCS retinas and controls. The ratio of oxidized monapterin to reduced monapterin was significantly increased compared to controls. Since oxidized pterins have been shown to affect the enzyme (HIOMT) to successivly increase the content of melatonin, it can be suggested that destruction of visual cells by light exposure is based on an increase in melatonin content. Consequently, a lack of dihydro-d-monapterin reductase is postulated to be causative in the pathway for blinding in RCS rats.
Time Course of Neopterin and Cytokines After an Extreme Bicycle Race at Moderate Altitude
Authors: Deetjen Christian , Mair Johannes , Herold Manfred , Wiedermann Franz , Hobisch-Hagen Petra , Jelkmann Wolfgang , Hoffmann Georg , Schobersberger Wolfgang
Published: March 2013

Endurance exercise induces several alterations in the immune and hematological system. At present it is unknown whether exercise under hypoxic conditions can modulate these changes. We investigated the effects of a prolonged endurance bicycle exercise in 8 healthy athletes (Oetztal Bicycle Marathon, OEBM; distance 230 km; vertical displacement 5000 m) on serum concentrations of interleukin-I[3 (IL-If3), interleukin- 6 (IL-6), tumor necrosis factor-a (TNF-a), neopterin as well as erythropoietin (EPO). Blood was collected before (A), immediately after the race (B), one (C), two (D), three (E) as well as five (F) days after the OEBM. We could demonstrate that IL-6 was increased significantly after exercise termination, whereas IL-I[3 and TNF-a were unchanged. Neopterin was significantly elevated from B to D, indicating an activation of the cellular immune system. Serum EPO was significantly increased from day 1 to day 5 after exercise which might reflect the combination of hypoxia and postexercise hemodilution.
The Influence of Kynurenine and Its Metabolites on Lipid Metabolism
Authors: Rudzite Vera , Jurika Edite , Jirgensons Janis , Herpfer Inga , Weiss Günter , Wachter Helmut , Fuchs Dietmar
Published: March 2013

Incorporation of fatty acids into phospholipids has been investigated using samples of rat liver tissue homogenate, Krebs-Ringer-phosphate buffer (pH=7.4) containing 0.3% albumin, fatty acid mixture and glycerol. The addition of L-kynurenine (4 nmoljg wet weight) to incubation medium induced an increase of palmitic, oleic and linolenic acid and decrease of linoleic and arachidonic acid incorporation into phospholipids. These changes of fatty acid incorporation into phospholipids were followed by increase of cholesterol and decrease of phospholipids content in samples. The addition of 3-hydroxykynurenine (1.8 and 4 nmoljg wet weight), 3-hydroxyanthranilic acid (2.2 and 4 nmoljg wet weight) ,1n..:l quinolinic acid (2.4 and 4 nmoljg wet weight) to incubation medium for phospholipid biosynthesis ill vitro induced a decrease of stearic, palrnitic and linoleic acid and an increase of oleic and especially arachidonic acid incorporation into phospholipids. These changes were accompanied by a decrease of cholesterol content in samples. The influence of kynurenine on fatty acid incorporation into phospholipids was similar to that of neopterin observed earlier. The other tryptophan degradation products behaved similar to the reduced pteridine derivatives. Our results allow to suggest that L-kynurenine decreases, while 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid increase membrane fluidity in the studied concentrations.
Influence of an Aromatic Amino Acid Decarboxylase Inhibitor on GTP Cyclohydrolase I Activity in the Rat Brain
Authors: Sakamoto Hideo , Fujita Ko , Kuzuya Hiroshi
Published: March 2013

Based on the hypothesis that catecholamine decreases may cause increases in biopterin, we measured the GTP cyclohydrolase I(GTPCH-I) activity and biopterin content in the cerebral cortex, midbrain/diencephalon, cerebeilum, pons/medulla oblongata, striatum , and hippocampus of brains from rats given NSDlOIS, an inhibitor for aromatic amino acid decarboxylase . The catecholamine contents decreased in all the regions tested. The changes in the GTPCH -I activity and bioptcrin content were different among the regions; they decreased in some regions contrary to expectations and increased in other regions. However, either the enzyme activity or biopterin content increased in the midbrain/ diencephalon and pons/ medulla oblongata, in which similar levels of catecholamines, GTPCH -I activity and biopterin were detected. These results suggest that for the midbrain/diencephalon and pons/medulla oblongata the surmise that a decrease in catecholamines causes an increase in the biopterin synthesis may be correct.
Auto-oxidation of 5,6,7 ,8-tetrahydroneopterin
Authors: Arai Toshiyuki , Mori Hiroko , Ishii Hisanari , Suzuki Toshinori , Kojima Shuji , Mori Kenjiro
Published: March 2013

Auto-oxidation of 5,6,7,8-tetrahydroneopterin (NPH4 ) in phosphate buffer solution (PBS) was examined using reversed-phase high-performance liquid chromatography. In the chromatograms obtained every 30 min after NPH4 was dissolved in PBS, the peak of NPH4 gradually decreased and almost disappeared 90 min after the dissolution. In contrast, another peak of an unidentified substance (one of dihydroneopterins), appeared from the first time, gradually increased and became most dominant among various peaks 60 min after. The peak of 7,8-dihydroneopterin (7,8-NPH2) appeared 30 min after and gradually increased, but its height was less than that of the above-mentioned peak from first to last. These results indicate that NPH4 is readily oxidized by dissolved oxygen in PBS to produce 7,8-NPH2 and other dihydroneopterins before the reaction with oxygen free radicals and that the substances which actually serve as antioxidants in vivo are these dihydroneopterins.
Pteridines and Lipid Metabolism
Authors: Rudzite Vera , Jurika Edite , Baier-Bitterlich Gabriele , Widner Bernhard , Reibnegger Gilbert , Fuchs Dietmar
Published: March 2013

The effect of 9 different pteridines on fatty acid incorporation into phospholipids as well as on cholesterol and phospholipid content was compared in vitro using rat liver homogenate, Krebs-Ringer phosphate buffer containing 0.3 % albumin (pH=7.4), fatty acid mixture and glycerol. D-neopterin (5-30 pmol/g) induced an increase of saturated, a decrease of unsaturated fatty acids incorporation into phospholipids and elevated the cholesterol content in samples. The phospholipid amount in samples remained unchanged. Sepiapterin, 7,8-dihydrobiopterin, 5,6,7,8-tetrahydrobiopterin, biopterin, monapterin and 7,8-dihydroneopterin addition to samples induced an inverse relationship: a decrease of saturated, an increase of unsaturated fatty acid, especially arachidonic acid, incorporation into phospholipids and the decrease of cholesterol content in samples. The phospholipid amount in samples remained unchanged or increased. Lipid metabolism was not altered after addition of xanthopterin and isoxanthopterin to samples. It was suggested that neopterin decreased membrane fluidity, prevented cell cycle, induced cell dystrophy and apoptosis, and promoted the cholesterol precipitation while tetrahydrobiopterin, its precursors, biopterin, monapterin and dihydroneopterin increased membrane fluidity, stimulated cell cycle, prevented cholesterol precipitation. The data point to a potential role of increased neopterin concentrations in vivo to support atherosclerosis development and progression whereas the other pteridines may have a protective effect. Moreover, these pteridines can also promote cell transformation.
Difference and Similarity of Serotonin and Pteridines to Act on Lipid Metabolism
Authors: Rudzite Vera , Jurika Edite , Jirgensons Janis , Widner Bernhard , Weiss Guenter , Fuchs Dietmar
Published: March 2013

Incorporation of fatty acids into phospholipids has been investigated using samples of rat liver homogenate, Krebs-Ringer phosphate buffer (pH=7.4) containing 0.3% albumin, fatty acid mixture and glycerol. The addition of neopterin, serotonin (0.2 and 2.0 nmoljg wet weight) without iproniasid and 5- hydroxyindoleacetic acid (20.0 nmoljg wet weight) induced an increase of saturated and a decrease of unsaturated, especially arachidonic acid, incorporation into phospholipids. These changes were accompanied with elevated cholesterol content in samples. The addition of 5,6,7,8-tetrahydrobiopterin (5 and 30 pmolj g wet weight) and serotonin (0.2 and 2.0 nmoljg wet weight) together with iproniasid (10 nmoljg wet weight) to incubation medium for phospholipid biosynthesis in vitro induced a decrease of saturated and an increase of unsaturated, especially arachidonic acid, incorporation into phospholipids. These changes were accompanied with decreased cholesterol content in samples. The influence of serotonin without iproniasid and 5-hydroxyindoleacetic acid was similar to that of neopterin, kynurenine and noradrenaline observed earlier, while the influence of serotonin together with iproniasid was similar to that of 5,6,7,8- tetrahydrobiopterin and its precursors found earlier. Our results allow to suggest that in the studied concentrations serotonin increases, while 5-hydroxyindoleacetic acid decreases membrane fluidity.
Serum Biopterin as a Marker of Immune Activation in the Spontaneously Diabetic BB Rat
Authors: Galloway Tamara , Braven Jim , Barley Jas , Rokos Hartmut , Wilkin Terence
Published: March 2013

Tetrahydrobiopterin (BH4), is a pteridine product which is released by rodent macrophages and fibroblasts upon activation by cytokines. It has previously been reported as a potentially useful marker for monitoring immune activation during the prediabetic prodrome in the spontaneously diabetic BB rat. We have used serial serum BH4 measurements, first to confirm the hypothesis that serum BH4 is elevated as a result of immunostimulation, and second to monitor more closely the serum BH4 levels during the prediabetic prodrome in a cohort of diabetes prone BB rats. A modified biopterin radioimmunoassay protocol was used to establish a reference range of 25.5-80.1 nmolll (95% confidence limits) for 70 Wistar rats of mean age six months. When eight adult Wistar rats were treated with sic BCG there was a significant increase in serum BH4 level (p<O.Ol) which returned to pre-treatment levels by day 16, coincident with the disappearance of visible signs of inflammation. A cohort of 26 diabetes prone BB rats, their diabetes resistant controls (n=20) and a cohort of Wistar controls (n=20) were then used to monitor serum BH4 levels from 30-120 days of age, at frequent intervals. The diabetes incidence in the diabetes prone animals was 100% with a mean age of onset of 80 days. The serum tetrahydrobiopterin level was significantly higher at day 30 in all three groups (p< 0.05) than at any other time point. The serum BH4 level in the diabetes prone group was significantly higher at day 30 (p<O.Ol ) and day 60 (p<0.05) than in either control group. These results show that serum BH4 is a sensitive marker for immune activation following subcubaneous injection of BCG in the rat, and is detectable using RIA. Serum BH4 was maximum in this study at day 30, but the significantly higher levels at days 30 and 60 in the diabetes prone compared with the diabetes resistant animals suggest that the immune activation characteristic of prediabetes can be detected biochemically in blood samples.
Cerebrospinal Fluid Levels of Neopterin in Child Patients with Neurological Diseases-In Correlation with IFN-γ or TNF-α
Authors: Kawakami Yasuhiko , Fukunaga Yoshitaka , Kuwabara Kentaro , Fujita Takehisa , Fujino Osamu , Hashimoto Kiyoshi
Published: March 2013

Cerebrospinal fluid (CSF) neopterin levels were measured in child patients with neurological diseases. CSF neopterin levels on admission were significantly higher in patients with bacterial meningitis than in those with aseptic meningitis or in those with non-pleocytotic CSF. CSF neopterin levels in patients with bacterial meningitis one day after admission were higher than those on admission and were markedly elevated with high levels of CSF IFN-γ and TNF-α. CSF neopterin levels in patients with bacterial meningitis one day after admission were related to the period of positive serum C-reactive protein. In patients with non-pleocytotic CSF, CSF neopterin and CSF IFN-y levels were higher in patients with febrile convulsion (FC) than in those with pyrexia only or convulsion (including epilepsy) only. These results suggest that elevation of CSF neopterin in bacterial meningitis results from monocytes/ macrophages costimulated with IFN-γ and TNF-α and that immunological activation in the central nervous system is one of the mechanisms of onset with FC.
Neopterin and Cytokines in Hereditary Dystonia and Parkinson's Disease
Authors: Nagatsu T. , Ichinose H. , Mogi M. , Togari A.
Published: March 2013

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Both neopterin and biopterin concentrations in cerebrospinal fluid from patients with Parkinson's disease, in which the nigrostriatal dopamine neurons degenerate, were lower than those from age-matched older control subjects. However, the decrease in biopterin was more marked than that in neopterin, resulting in the increase in the neopterin/ biopterin ratio in Parkinson's disease. These results suggests that neopterin in cerebrospinal fluid in Parkinson's disease may partly be derived from immunoactivated glial cells, besides catecholamine or serotonin n eurons including nigrostriatal dopamine neurons. In accordance to this hypothesis, cytokines (TNF-α, IL-1, IL-2 , IL-6, EGF, TGF-α, TGF-β1) were found to be increased in the striatum and/or in cerebrospinal fluid. The increment of cytokines in the brain in Parkinson's disease may be related to the mechanism of neurodegeneration of dopaminergic neurons in Parkinson's disease . In contrast to Parkinson's disease, in hereditary progressive dystonia/ dopa-responsive dystonia, which is a dopamine deficiency caused by mutations in GTP cyclohydrolase I without neuronal cell death (Segawa's disease), neopterin and biopterin in cerebrospinal fluid decreases in parallel owing to the decreased activity in GTP cyclohydrolase I .
Neopterin in Autoimmune Rheumatic Diseases
Authors: Nassonov Eugeney L. , Samsonov Mikhail Y. , Wirleitner Barbara , Tilz Gernot P. , Fuchs Dietmar
Published: March 2013

Neopterin concentrations in body fluids allow to monitor the activation status of the cellular ( =Thl-type) llnmune system in an easy but also sensitive way. Autoimmune disease result from deterioration of almost .1,1 immune system compartments. Rheumatic disorders comprise an important group of diseases featuring several aspects of autoimmune disorders. Already several years ago increased neopterin concentrations were Jemonstrated in patients with rheumatoid arthritis and later on in patients with systemic lupus erythemarosus. Neopterin concentrations were fowld to correlate with the activity of the diseases and to conveniently indicate effects of therapy. Similar data were obtained in patients with acute rheumatic fever, and more recently, the utility of neopterin determination was also demonstrated in patients with Wegeners granulomatosis and with polymytositis/dermatomyositis. In this article we intend to summarize the current knowledge about the usefulness of neopterin measurements in patients with rheumatic diseases.
Similarity Between the Action of Pteridines and Tryptophan Metabolites on Lipid Metabolism
Authors: Rudzite Vera , Jurika Edite , Widner Bernhard , Fuchs Dietmar
Published: March 2013

Incorporation of fatty acids into phospholipids has been investigated using samples of rat liver tissue homogenate, Krebs-Ringer-phosphate buffer (pH=7.4) containing 0.3% albumin, fatty acid mixture and glycerol. The addition of anthranilic acid (2.2 and 4 nmol/g wet weight), kynurenic acid (4 and 40 nmol/ g wet weight), xanthurenic acid (4 and 40 nmol/g wet weight), picolinic acid (0.2 and 2 nmol/g wet weight) induced an increase of saturated and a decrease of polyunsaturated fatty acids incorporation into phospholipids as well as an eleyation of choksterol concentration in samples used for phospholipid biosynthesis in vitro. These changes were similar to those observed after addition of kynurenine and neopterin to the same test system, An inverse relationship has been observed after addition of nicotinic acid to samples used for phospholipid biosynthesis in vitro. Nicrotinic acid induced .1 decrease of saturated and an increase of unsaturated fatty acids incorporation into phospholipids as well as decrease of cholesterol concentration in samples, These changes were similar to those observed after addition of 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic, acid, 5,6],8-tetrahydrobiopterin and its precursors to the same test system used rex phospholipid biosynthesis in vitro. In parallel anthranilic acid, kynurenic acid, xanthurenic acid and picolinic acid decrease while nicotinic acid increases membrane fluidity in the studied concentrations.
Natural durability of organomodified layered silicate filled wood flour reinforced polypropylene nanocomposites
Authors: Kord Behzad
Published: March 2013

The effect of organomodified montmorillonite (OMMT) loading on the natural durability properties of polypropylene/wood flour composites exposed to brown-rot fungi (Coniophora puteana) was studied. To meet this objective, the blend composites were prepared through the melt mixing of polypropylene/wood flour at 50% weight ratios, with various amounts of OMMT (0, 3 and 6 per hundred compounds [phc]) in a hake internal mixer. The samples were then made by injection molding. The amount of coupling agent was fixed at 2 phc for all formulations. After specimen and culture medium preparation, the specimens were exposed to the purified fungus at 25°C and 75% relative humidity for 14 weeks. Identical specimens of the same composite, without being exposed to the fungus, were provided as the control specimens. After the discussed periods; weight loss, flexural strength, flexural modulus, hardness, water absorption, and thickness swelling of specimens were measured. Results indicated that OMMT had significant effects on the natural durability of the studied composite formulations. All mechanical properties were affected by the fungus, to a greater extent in the case of specimens without OMMT than the specimens with OMMT. Furthermore, the flexural strength and modulus increased with an increase of OMMT up to 3 phc and then decreased. However, the impact strength, water absorption and thickness swelling was decreased with increase of OMMT loading. Also, the lowest weight loss and the highest hardness were observed in the composite containing 6 phc organoclay. The morphology of the nanocomposites was examined by using X-ray diffraction (XRD) and transmission electron microscopy (TEM). Morphological findings revealed that intercalation came from the sample with 3 phc concentration of OMMT, which implies the formation of intercalation morphology and better dispersion than 6 phc.
Strategies of International Community-Building in Early Twentieth-Century Metabolism Research: The Foreign Laboratory Visits of Francis Gano Benedict
Authors: Neswald Elizabeth
Published: March 2013

In the early twentieth century, nutrition was a developing science, emerging at the intersection of physiological questions and the public health concerns and approaches embodied by the field of hygiene. Its rising status as an independent research field converged with the growing self-confidence of American physiology and with the expansion of international scientific communities. In these crucial decades for American physiology, Francis Gano Benedict, director of the Carnegie Nutrition Laboratory, made seven extended tours of European laboratories that specialized in the study of nutrition, biocalorimetry, metabolism, and respiration gas analysis. The reports of his tours show the strategies and challenges of establishing a new laboratory with leadership intentions in the international arena and of creating and coordinating a community of researchers across the boundaries of language, politics, laboratories, and methods.
Development of a specific method to evaluate 8-hydroxy,2-deoxyguanosine in sperm nuclei: relationship with semen quality in a cohort of 94 subjects
Authors: Cambi M , Tamburrino L , Marchiani S , Olivito B , Azzari C , Forti G , Baldi E , Muratori M
Published: March 2013

Oxidative stress (OS) is involved in many disoders including male infertility. Human spermatozoa are very sensitive targets of reactive oxygen species (ROS) and most sperm functions are impaired in the case of OS. In addition unbalanced production of ROS is considered one of the most important causes of sperm DNA fragmentation, a semen trait of infertile men. The relationship between oxidative damage and semen quality is partially controversial, probably due to the different methods and/or targets used to reveal the OS. In this study, by fluorescence microscopy and flow cytometry, we compared two methods to reveal 8-hydroxy,2-deoxyguanosine (8-OHdG), the hallmark of oxidative DNA damage: an immunofluorescence method and the commercial OxyDNA kit. We found that although both methods localized the labelling in sperm nuclei they yielded different measures, and only with the immunofluorescence method was the labelling specific for sperm 8-OHdG. The immunofluorescence method, coupled to flow cytometry, was thus selected to analyse the 8-OHdG content in semen samples from 94 subfertile patients and to investigate the relationship with semen quality. We found that the percentages of spermatozoa with 8-OHdG (mean±s.d., 11.4±6.9%) were related to sperm count (Pearson's correlation coefficient (r)=−0.27,P=0.04 (ANOVA and student'st-test)), motility (progressive:r=−0.22,P=0.04; non-progressive:r=0.25,P=0.01), and normal morphology (r=−0.27,P=0.01). In conclusion, we demonstrate that immunofluorescence/flow cytometry is a reliable and specific method to detect 8-OHdG at single-cell level and show that oxidative damage only partially overlaps poor semen quality, suggesting that it could provide additional information on male fertility with respect to routine semen analysis.