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Biomedical subjects

H Wachter

Publications and source records attributed to H Wachter.

At least 91 records · Page 5Linked to original sources
PubMed1995

2,4-Diamino-6-hydroxypyrimidine, an inhibitor of tetrahydrobiopterin synthesis, downregulates the expression of iNOS protein and mRNA in primary murine macrophages.

2,4-diamino-6-hydroxy-pyrimidine (DAHP), an inhibitor of GTP cyclohydrolase I, blocks the synthesis of tetrahydrobiopterin (BH4), which is a known cofactor of inducible nitric oxide synthase (iNOS). Previously, DAHP was shown to suppress the production of nitric oxide by cytokine-activated fibroblasts, smooth muscle cells or endothelial cells which could be attributed to its function as a cofactor antagonist. Here, we demonstrate that in interferon-gamma-activated murine peritoneal macrophages DAHP suppresses the expression of iNOS mRNA and protein in a BH4-independent manner and, thus, acts by a novel mechanism.

Amino Acid Oxidoreductases↗
PubMed1995

Neopterin and soluble tumor necrosis factor receptor type I in alcohol-induced cirrhosis.

Alcohol-induced cirrhosis (AC) is accompanied by disturbances of immune function and cytokine production. To better define the pattern of cytokine synthesis in this disease and to relate it to the immune activation state, we measured circulating levels of soluble tumor necrosis factor receptor p55 (sTNFR-55) and neopterin in a group of 85 patients with AC (classified according to the Child-Pugh score of severity of liver disease) and 43 healthy volunteers. Serum concentrations of sTNFR-55 and neopterin were significantly raised in patients with AC. Moreover, concentrations of sTNFR-55 were significantly higher in patients with more severe disease compared with the group with lower severity. There were significant correlations between sTNFR-55 and neopterin levels in patients and controls. The results contribute to affirm the existence of an immune activation state in AC that could be responsible for the development of the disease and clinical complications.

Biopterins↗
PubMed1995

Serum-soluble receptors for tumor necrosis factor-alpha and interleukin-2, and neopterin in acute rheumatic fever.

Immune activation may play an important role in the pathogenesis of acute rheumatic fever (ARF). The objective of the present study was to investigate serum concentrations of various markers of immune activation in ARF patients. Sera of 32 patients with ARF were investigated, 20 of them in follow-up. Radioimmunoassay was used to quantify neopterin and ELISA for the measurement of 55-kDa-type soluble tumor necrosis factor receptor (sTNF-R) and soluble interleukin-2 receptor (sIL2-R). Markers of immune activation were found to be raised in 48% (sTNF-R), 28% (sIL2-R), and 78% (neopterin) of patients at the onset of ARF. There were significant correlations between the concentrations of neopterin and sTNF-R (rs = 0.60, P < 0.001) or sIL2-R (rs = 0.35, P < 0.05). Higher neopterin concentrations were found in patients with combined aortic and mitral insufficiency than in patients with mitral valve lesions alone (U = 2.67, P < 0.05) or without valve lesion (U = 2.36, P < 0.05). Increased concentrations of neopterin, sTNF-R, and sIL2-R demonstrate activation of the cellular immune system in patients with ARF. Higher serum neopterin concentrations are associated with development of combined aortic and mitral insufficiency during the first episode of ARF.

Acute Disease↗
PubMed1995

Brain biopterin metabolism in chronic experimental hepatic encephalopathy.

Chronic hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with a substantial increase in the brain L-tryptophan (L-TRP) level. Moreover, a supranormal L-TRP hydroxylating activity in the brain suggests an induced enzymatic process in chronic HE. GTP-cyclohydrolase I (GTPCHI) and tetrahydrobiopterin (BH4) are two major factors besides L-TRP that are involved in regulating the brain L-TRP hydroxylating activity. We therefore determined the GTPCHI activity, the total biopterin and the BH4 concentrations in the neocortex and mesencephalon-pons of portacaval shunted (PCS) rats. The encephalopathic component in PCS rats was accounted for by studying open field behaviour. The acute effects of a single parenteral L-TRP challenge were also evaluated. The basal GTPCHI activities in PCS rats were decreased bu 50% (p < 0.05) compared to controls in both investigated brain regions. No significant alterations in brain total biopterin or BH4 levels were present. The PCS rats exhibited a clearly reduced spontaneous locomotor activity. After the exogenous L-TRP load only a lower GTPCHI activity in the neocortex of PCS rats was recorded. We conclude that a perturbation in the brain biopterin metabolism is concomitantly present with behavioural abnormalities in the chronic PCS condition and that the acute effects of a superimposed L-TRP load do not aggravate these disturbances.

Animals↗
PubMed1995

Linkage of cell-mediated immunity to iron metabolism.

Iron is essential for growing microorganisms and tumour cells, and is also crucial for the proliferation of immune cells. In this review, Günter Weiss, Helmut Wachter and Dietmar Fuchs focus on the complex network of interactions that link iron metabolism with cellular immune effector functions involving cytokines and nitric oxide, and draw a suitable model for the pathogenesis of anaemia of chronic disease.

Animals↗
PubMed1995

Effects of pteridines on luminol-dependent chemiluminescence induced by chloramine-T.

Pteridines are ubiquitous in living organisms, but little is known about their biological functions. Different pteridines were tested for their ability to modulate luminol-dependent chemiluminescence induced by chloramine-T at pH = 7.5 and at a concentration of 100 microM for each pteridine. We observed striking differences between the compounds; whereas reduced pteridine species were generally potent scavengers, aromatic pteridines were weak to strong enhancers of the chemiluminescence. Taking into account the detailed chemical structure of the molecules, by multiple linear regression analysis a simple index was constructed that allows prediction of the effects of the different pteridines with high accuracy (linear correlation coefficient between predicted and observed values r = 0.89). The effects of different pteridines on free radical-induced chemiluminescence might bear biological significance since, for example, certain pteridines take part in enzymic reactions involving free-radical intermediates, or are related to the activation of macrophages in close relationship with the oxidative burst.

Animals↗
PubMed1995

Serum nitrite plus nitrate in infection with human immunodeficiency virus type-1.

To get a measure of the extent of induction of nitric oxide synthase in infection with human immunodeficiency virus type-1 (HIV-1) in vivo, we estimated serum nitrite plus nitrate concentrations in 110 HIV-1 infected individuals compared to 76 blood donors. To monitor cytokine action and to measure induction of pteridine synthesis, we determined in parallel neopterin, biopterin, soluble tumor necrosis factor-alpha receptor 55 and 75, and beta 2-microglobulin. Serum nitrite plus nitrate concentrations were elevated in patients as compared to blood donor controls. In sera of patients, nitrite plus nitrate levels correlated significantly with neopterin, soluble tumor necrosis factor receptor 55 and 75, and beta 2-microglobulin. Nitrite plus nitrate levels were higher and correlations were stronger in groups of patients with lower CD4+ cell count. These results suggest that cytokine-mediated nitric oxide synthesis occurs in individuals with HIV-1 infection.

Adult↗
PubMed1995

Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis.

Soluble tumour necrosis factor receptors (sTNF-Rs) play a role as modulators of the biological function of tumour necrosis factor-alpha (TNF-alpha) in an agonist/antagonist pattern. In various pathologic states the production and release of sTNF-Rs may mediate host response and determine the course and outcome of disease by interacting with TNF-alpha and competing with cell surface receptors. The determination of sTNF-Rs in body fluids such as plasma or serum is a new tool to gain information about immune processes and provides valuable insight into a variety of pathological conditions. Regarding its immediate clinical use, sTNF-Rs levels show high accuracy in the follow-up and prognosis of various diseases. In HIV infection and sepsis, sTNF-Rs concentrations strongly correlate with the clinical stage and the progression of disease and can be of predictive value. Determination of sTNF-Rs also gives useful information for monitoring cancer and autoimmune diseases. The information provided is often even superior to that obtained with classical disease markers, probably due to the direct involvement of the "TNF system" in the pathogenetic mechanisms in these patients. The available data imply that the measurement of sTNF-Rs, especially of the sTNF-R 75kD type, is a useful adjunct for quantification of the Th1-type immune response, similar to other immune activation markers such as neopterin and beta 2-microglobulin. Endogenous sTNF-Rs concentrations appear to reflect the activation state of the TNF-alpha/TNF receptor system.

Communicable Diseases↗
PubMed1995

Detection of bacterial pyrogens on the basis of their effects on gamma interferon-mediated formation of neopterin or nitrite in cultured monocyte cell lines.

In a number of mammalian cell types, pteridine biosynthesis from guanosine 5'-triphosphate and formation of nitric oxide from L-arginine are induced by gamma interferon (IFN-gamma) and bacterial lipopolysaccharide (LPS). We assessed the possibility of using such metabolic alterations for the in vitro detection of pyrogens. Products from gram-negative and gram-positive bacteria and related synthetic compounds were tested for their potential to induce either of these pathways. Stimulation of pteridine biosynthesis was monitored as the formation of neopterin in the human myelomonocytic cell line THP-1. The formation of nitric oxide was determined as nitrite in murine J774A.1 macrophage cultures. The substances tested included toxic and detoxified parts of LPS and lipid A from Escherichia coli, Salmonella typhimurium, Salmonella minnesota, and Klebsiella pneumoniae as well as lipoteichoic acid and toxic shock syndrome toxin 1 from Staphylococcus aureus. Furthermore, two cell wall compounds from Mycobacterium tuberculosis, trehalose 6,6'-dimycolate and N-acetylmuramyl-L-alanyl-D-isoglutamine, which are active components of Freund's adjuvant, were used. When applied as a single stimulus, only the whole LPS molecule potently stimulated neopterin or nitrite formation. Lipid A and products from gram-positive bacteria were weakly active. For neopterin formation, lipid A required the presence of fetal calf serum. Besides detoxified LPS and independently from the presence of serum, all bacterial compounds tested strongly increased the effects mediated by IFN-gamma. Our results show that bacterial pyrogens can be detected by monitoring the formation of neopterin or nitrite. This may provide a basis for the development of an in vitro assay for the detection of pyrogenic contamination with the aim of replacing the currently used animal test.

Animals↗
PubMed1995

Reactivation of human immunodeficiency virus type 2 in macaques after simian immunodeficiency virus SIVmac superinfection.

By superinfection of human immunodeficiency virus type 2 (HIV-2) strain HIV-2ben-infected macaques with simian immunodeficiency virus (SIV) strain SIVmac, we investigated the mutual influences of an apathogenic and a pathogenic virus in vivo. Four rhesus and two cynomolgus monkeys were infected with HIV-2ben in 1988 and 1989, respectively. Virus could be reisolated from five of six animals 6 weeks after infection. The monkeys remained healthy over the next 2 to 3 years. PCR for viral RNA became negative, and virus could no longer be reisolated by coculture. All six macaques were superinfected with the pathogenic SIVmac251/32H. Subsequently, five monkeys became persistently viremic, while one animal was protected against the SIVmac infection. In the peripheral blood mononuclear cells and cocultures of the five viremic animals, DNA from both HIV-2 and SIVmac was present. The plasma contained RNA from both viruses. Thus, superinfection with SIVmac activated HIV-2. A proliferative T-cell response against both HIV-2 and SIVmac was measured in all animals after superinfection. Such a response was regularly seen after infection with the apathogenic HIV-2 but never when the pathogenic SIVmac alone was administered. While naive control monkeys inoculated with SIVmac251/32H regularly develop AIDS-like symptoms soon after infection and have to be killed, none of the preinfected animals has developed AIDS-like symptoms, but two of six animals developed tumors. After the SIVmac challenge, however, apoptotic lymphocytes were detected in the peripheral blood mononuclear cells of all animals. Thus, the presence of an apathogenic viral variant seems to retard the disease occurring after infection with a pathogenic virus rather than to confirm total protection. This partial protection appears to depend on a specific proliferative T-cell response early after infection.

Animals↗
PubMed1995

Serum soluble markers of immune activation and disease activity in systemic lupus erythematosus.

We investigated a possible association between markers of immune activation and disease activity in 52 patients with systemic lupus erythematosus (SLE). Serum concentrations of neopterin, beta-2-microglobulin, 55 kD-type soluble tumor necrosis factor receptor, soluble interleukin-2 receptor and soluble CD8 were compared to the Index of European Consensus Lupus Activity Measurement (ECLAM). All markers of immune activation, except sCD8, significantly correlated with ECLAM. Stepwise multiple linear regression analysis revealed erythrocyte sedimentation rate and neopterin to correlate best with ECLAM (multiple correlation coefficient = 0.74, P < 0.001). The study shows that serum neopterin concentrations are a useful independent index for disease activity in SLE. The finding of enhanced concentrations of various parameters of immune activation in patients confirm a role of the T cell and macrophage activation in the pathogenesis of SLE.

Adolescent↗
PubMed1995

Predictive value of urinary neopterin in patients with lung cancer.

Concentrations of neopterin, which is produced by human monocytes/macrophages when stimulated by gamma-interferon, were measured in urine specimens from 72 patients with lung cancer at diagnosis. Other routine clinical and laboratory variables were concomitantly determined. Neither neopterin nor any other laboratory variable studied showed a significant correlation with clinical indicators of the disease (morphologic type, tumour stage, grading, lymph node status, presence of distant metastases). The cancer patients were followed up for up to 10 years, and the abilities of all variable to predict fatal outcome were assessed. In univariate survival analyses, all clinical indicators except morphologic type (P = 0.86) were significant predictors of survival (P < 0.002), but of all the laboratory variables studies, only neopterin was significantly predictive (P = 0.0013). By multivariate survival analysis, a combination of four variables was found to jointly predict survival: lymph node status (P = 0.003), multivariate model), tumour stage (P = 0.0006), grading (P = 0.0047) and neopterin (P = 0.0047). The data suggest that certain aspects of immune activation may have adverse consequences for the prognosis of patients with lung cancer.

Adult↗
PubMed1995

7,8 Dihydroneopterin inhibits low density lipoprotein oxidation in vitro. Evidence that this macrophage secreted pteridine is an anti-oxidant.

Neopterin and its reduced form, 7,8 dihydroneopterin are pteridines released from macrophages and monocytes when stimulated with interferon gamma in vivo. The function of this response is unknown though there is an enormous amount of information available on the use of these compounds as clinical markers of monocyte/macrophage activation. We have found that in vitro 7,8-dihydroneopterin dramatically increases, in a dose dependent manner, the lag time of low density lipoprotein oxidation mediated by Cu++ ions or the peroxyl radical generator 2,2'-azobis (2-amidino propane) dihydrochloride (AAPH). 7,8-Dihydroneopterin also inhibits AAPH mediated oxidation of linoleate. The kinetic of the inhibition suggests that 7,8-dihydroneopterin is a potent chain breaking antioxidant which functions by scavenging lipid peroxyl radicals. No anti-oxidant activity was observed in any of the oxidation systems studied with the related compounds neopterin and pterin.

Adult↗
PubMed1995

Longitudinal immunological follow-up of HIV infected haemophiliacs in Hungary.

Twenty-five haemophiliacs who had been infected with HIV in 1982 or 1983 were followed up from 1986 to 1993. The absolute number of the CD4+ and CD8+ cells, neopterin levels and more recently the percentage of activated, DR+ T lymphocytes were determined twice a year. In most patients a permanent decline in the CD4+ cell count was observed whereas in two HIV-infected haemophiliacs the absolute number of CD4+ cells did not change during the observation period. In these long-term non-progressor patients no clinical symptoms and no increased neopterin levels were observed. T cells subset and neopterin measurements were found to predict the development of AIDS. AIDS developed only in those patients who exhibited both a CD4+ cell count of < 350/microliter and a serum neopterin concentration of > 20 nmol/l. A negative correlation was observed between the percentage of activated. DR+ T lymphocytes and the CD4+ cell counts.

Adolescent↗
PubMed1994

Pteridine biosynthesis and nitric oxide synthase in Physarum polycephalum.

Physarum polycephalum, an acellular slime mould, serves as a model system to study cell-cycle-dependent events since nuclear division is naturally synchronous. This organism was shown to release isoxanthopterin which is structurally related to tetrahydrobiopterin, a cofactor of aromatic amino acid hydroxylases and of nitric oxide synthases (NOSs) (EC 1.14.13.39). Here, we studied Physarum pteridine biosynthesis in more detail and found that high amounts of tetrahydrobiopterin are produced and NOS activity is expressed. Physarum pteridine biosynthesis is peculiar in as much as 7,8-dihydroneopterin aldolase (EC 4.1.2.25), an enzyme of folic acid biosynthesis usually not found in organisms producing tetrahydrobiopterin, is detected in parallel. NOS purified from Physarum depends on NADPH, tetrahydrobiopterin and flavins. Enzyme activity is independent of exogenous Ca2+ and is inhibited by arginine analogues. The purified enzyme (with a molecular mass of 130 kDa) contains tightly bound tetrahydrobiopterin and flavins. During the synchronous cell cycle of Physarum, pteridine biosynthesis increases during S-phase whereas NOS activity peaks during mitosis, drops at telophase and peaks again during early S-phase. Our results characterize Physarum pteridine biosynthesis and NOS and suggest a possible link between NOS activity and mitosis.

Amino Acid Oxidoreductases↗
PubMed1994

Synthesis and characterization of 3H-labelled tetrahydrobiopterin.

We synthesized [3'-3H]-5,6,7,8-tetrahydrobiopterin from [8,5'-3H]guanosine 5'-triphosphate ([8,5'-3H]GTP) using GTP cyclohydrolase (EC 3.5.4.16), 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase (EC 1.1.1.153). After purification by cation-exchange h.p.l.c. a solution of radiochemically pure (> 95%) [3'-3H]-5,6,7,8-tetrahydrobiopterin with a specific activity of 9.2 Ci/mmol was obtained. The product proved well suited for studying the binding of tetrahydrobiopterin to nitric-oxide synthase.

Amino Acid Oxidoreductases↗
PubMed1994

Neopterin derivatives together with cyclic guanosine monophosphate induce c-fos gene expression.

We have previously shown that neopterin enhances hydrogen peroxide and chloramine T activity in a luminol-dependent chemiluminescence assay and strengthens toxicity of these agents against bacteria at slightly alkaline pH (pH 7.5), while 7,8-dihydroneopterin was shown to be a scavenger independent of the pH value. Besides various oxidants, phenolic antioxidants were shown to specifically induce expression of the c-fos and c-jun mRNAs. Using an inducible cfosCAT reporter transactivation system we studied the function of the pteridine derivatives on c-fos transactivation. For the first time, we demonstrate that neopterin and 7,8-dihydroneopterin, particularly together with cyclic guanosine monophosphate, induce c-fos gene expression. In humans, interferon-gamma induces the release of neopterin and 7,8-dihydroneopterin and also the synthesis of nitric oxide radical which in turn stimulate the formation of cGMP. Thus, in certain situations all three substances, namely neopterin, 7,8-dihydroneopterin and cGMP, may be present locally and even in the circulation at the same time. Based on our findings this constellation would significantly enhance the risk of c-fos gene expression and therefore promote tumour growth and development.

3T3 Cells↗