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PubMed2000

[Expression of autoantibodies to ICA512 and GAD in the sera of patients with diabetic ketoacidosis or ketonemia].

To explore the expression of the autoantibodies to ICA512 and GAD65 in the sera of diabetic patients who will be diagnosed as Type 1 diabetes, autoantibody assays were carried out in 15 diabetic patients complicated with ketonemia or ketoacidosis and in 19 healthy controls. The results were that the positive ratios of these autoantibodies were higher in the patient's sera than in the control's, and were higher in patients with shorter disease duration than those with longer disease duration. It is suggested that detecting these autoantibodies is helpful to the classification of diabetes and the disease duration affects the antibody's positive ratio.

Adult↗
PubMed1977

Recent developments in the clinical assessment of the metabolism of aromatics by high-performance, reversed-phase chromatography with amperometric detection.

High-performance liquid chromatography with electrochemical detection has developed into a tool with excellent capability to monitor picomole amounts of individual metabolites in both tissue and body-fluid specimens. Significant technical advances in the area of microparticle chemically-bonded stationary phases have led to dramatic improvements in both sensitivity and resolution. Reversed-phase systems can be modified to include charged exchange sites by addition of detergents to the mobile phase. Adjustment of the surface charge in this manner permits capacity factors for ionic sample components to be increased or decreased. This concept is quite compatible with electrochemical detection and has provided the foundation for several clinical assays now in routine use. Examples of additional applications are presented for the determination of catecholamines in tissue, 3-methoxy-4-hydroxyphenylglycol in urine, and dopamine-beta-hydroxylase activity in human serum.

Animals↗
PubMed1997

Autoimmune diabetes. The role of autoantibody markers in the prediction and prevention of insulin-dependent diabetes mellitus.

In general, reliable and reproducible ICA results are available only from research laboratories that routinely perform ICA testing. Regarding IAA testing, IAA ELISA must be avoided. There are numerous GADA procedures available that definitely have different sensitivities for GADA detection. IA-2A testing is very new and is performed in only a few research laboratories. Islet autoantibody testing should be performed only as part of research protocols. At the present time, we know much more about the prediction of IDDM than its prevention. Once safe and credible methods are available to prevent IDDM, islet autoantibody screening may become as common as childhood immunizations.

Adolescent↗
PubMed2004

Molecular detection of dopamine decarboxylase expression by means of reverse transcriptase and polymerase chain reaction in bone marrow and peripheral blood: utility as a tumor marker for neuroblastoma.

A highly sensitive molecular method was used to evaluate the presence of dopamine decarboxylase (DDC) mRNA in the bone marrow and peripheral blood of patients with neuroblastoma (NB). DDC, like tyrosine hydroxylase (TH), is an enzyme involved in the catecholamine synthesis pathway and has recently been proposed as a specific marker of NB among pediatric malignancies. DDC transcript was detected in five of five NB cell lines, 10 of 10 NB primary tumors, 17 of 18 (94%) bone marrow samples, and 12 of 18 (66%) blood samples drawn at diagnosis in 18 patients affected by disseminated NB. In contrast, no PCR signal was found in 20 bone marrow samples obtained from patients with other malignancies or in eight of nine marrow and blood samples drawn from patients with localized NB (two stage 2 and seven stage 3). In addition, all marrow and blood samples obtained from NB patients at relapse revealed DDC mRNA. Furthermore, the percentage of DDC-positive samples was lower among the samples drawn from these patients during treatment. By comparison with conventional methods for disease evaluation, DDC transcript research can increase the sensitivity of NB cell detection in marrow and blood samples at diagnosis and during the treatment and follow-up of NB patients. These results suggest that finding DDC mRNA in NB patients could be a potential marker for minimal residual disease study.

Biomarkers, Tumor↗
PubMed1980

Production of melanin precursors by a mutant of Tetrahymena thermophila.

A mutant of Tetrahymena thermophila, "pig," excretes melanin precursors into the culture medium where spontaneous polymerization to melanin occurs. The precursors, probably oxidation products of catecholamines, are produced in large amounts by the mutant by decarboxylation of tyrosine and hydroxylation of the resulting tyramine. Overproduction and excretion of precursors by the mutant appears to result from elevated specific activity of L-aromatic amino acid decarboxylase (DOPA decarboxylase) (E.C. 4.1.1.26).

Animals↗
PubMed1994

Growth signaling and JAK2 association mediated by membrane-proximal cytoplasmic regions of prolactin receptors.

Prolactin (PRL) has recently been demonstrated to induce tyrosine phosphorylation and activation of the cytoplasmic tyrosine kinase JAK2 in PRL-dependent Nb2 lymphoma cells. The present study represents an initial effort to identify cytoplasmic regions of the PRL receptor (PRLR) that are critical to growth signal generation and JAK2 activation. Variably truncated rat PRLRs were stably expressed in the murine 32D cell line. PRL-induced proliferation was mediated by the full-length receptor and the mutant G328, which contains the membrane-proximal Homology Boxes 1 and 2 characteristic of hematopoietin receptors. In contrast, mutant receptors lacking either Box 2 or both Boxes 1 and 2 were not capable of transmitting a growth signal. The mitogenic capacity of the PRLR variants correlated with JAK2 association and activation, as well as with induction of mRNA levels for the growth-related gene ornithine decarboxylase. We conclude that mitogenic competence of rat PRLRs resides within the first 94 amino acids of the cytoplasmic domain. The data suggest that Homology Box 1/Box 2 region is critical to JAK2 phosphorylation and association with the PRLR. These findings will serve as a basis for more detailed molecular characterization of PRLR domains essential for JAK2 interaction and growth signal generation.

Amino Acid Sequence↗
PubMed2000

Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group.

Recent prospective studies have documented serologically an increased frequency of enterovirus infections in prediabetic children, indicating that these infections may initiate and accelerate the beta-cell damaging process several years before the clinical manifestation of type 1 diabetes. The aim of the present study was to establish whether these serological findings would be supported by the detection of enterovirus RNA in a unique prospective series of sera collected from prediabetic children 0-10 years before the manifestation of clinical type 1 diabetes. Reverse transcription followed by polymerase chain reaction employing highly conserved primers among enteroviruses were used to amplify enteroviral sequences. Viral RNA was found in 22% (11/49) of follow-up samples from prediabetic children but in only 2% (2/105) of those from controls (OR 14.9, P < 0.001). Persisting RNA positivity was not observed in any of these children. The presence of enterovirus RNA was associated with concomitant increases in the levels of autoantibodies against islet cells (OR 21.7, P < 0.01) and glutamic acid decarboxylase (OR 15.4, P < 0.05), but not in the levels of antibodies against insulin or the tyrosine phosphatase-like IA-2 protein. In contrast to the prediabetic children, those with newly diagnosed type 1 diabetes were negative for enterovirus RNA. The results thus complement previous serological data, suggesting that enterovirus infections are an important risk factor underlying type 1 diabetes and associated with the induction of beta-cell autoimmunity even years before symptoms appear.

Adolescent↗
PubMed1999

Differential effect of immobilization stress on in vivo synthesis rate of monoamines in medial prefrontal cortex and nucleus accumbens of conscious rats.

We have used microdialysis to measure the in vivo hydroxylation level of tyrosine and tryptophan in the medial prefrontal cortex and nucleus accumbens of conscious rats that were subjected to immobilization. The brain was perfused with an inhibitor of aromatic L-amino acid decarboxylase, 3-hydroxybenzylhydrazine, and the amount of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) accumulating in the dialysate was measured as an index of the in vivo hydroxylation rate of tyrosine and tryptophan. One hour of immobilization caused a significant increase in extracellular DOPAin the medial prefrontal cortex but not nucleus accumbens. The same manipulation produced a significant and more prolonged elevation in extracellular 5-HTP in the nucleus accumbens as well as medial prefrontal cortex. The observed profile of stress-induced 5-HTP response was comparable in two brain regions. The results suggest that in vivo catecholamine synthesis is heterogenous, whereas in vivo serotonin synthesis is homogenous, with respect to responsiveness to stress in the medial prefrontal cortex and nucleus accumbens.

5-Hydroxytryptophan↗
PubMed2005

A developmental role for catecholamines in Drosophila behavior.

Tyrosine hydroxylase (TH), the enzyme which catalyzes the conversion of tyrosine to L-DOPA and is the rate limiting step in catecholamine biosynthesis, is genetically expressed during development in Drosophila. Null mutant alleles of the single copy gene which codes for this enzyme are developmentally lethal as is a conditional TH mutant at its restrictive temperature. In adult flies, inhibition of TH by alpha-methyl-p-tyrosine (alphaMT) decreases locomotor activity in a dose-dependent manner. This behavioral effect is accompanied by reductions in brain levels of dopamine, the primary CNS catecholamine in Drosophila, and can be prevented by the coadministration of L-DOPA. Similar effects are found with reserpine and at the restrictive temperature in flies with a temperature conditional mutation for TH. In agreement with published studies in mammals, inhibition of TH by alphaMT during Drosophila development results in enhanced expression of this enzyme in the progeny of surviving adults. This biochemical outcome is accompanied behaviorally by increased sensitivity to the locomotor effects of both alphaMT and reserpine, drugs which act via depletion of brain catecholamines. Since TH is the rate limiting enzyme responsible for the conversion of tyrosine to L-DOPA and L-DOPA is converted to dopamine by aromatic amino acid decarboxylase (AAAD), the results indicate that depletion of catecholamine levels in the fly embryo results in increased dopamine biosynthesis in the next generation accompanied by alterations in behavior.

Animals↗
PubMed2000

Metabolism of tryptophan in the liver: interference with decarboxylation of other aromatic amino acids.

Decarboxylation of aromatic amino acid in mammalian tissues is catalyzed by aromatic amino acid decarboxylase (EC. 4.1.1.28, AAD). The enzyme differs in its affinity to individual aromatic amino acids, the best substrates being 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytroptophan. Surprisingly, AAD is abundant in the liver, where the substrates with rather low affinity to AAD as tryptophan, phenylalanine, and tyrosine are offered to decarboxylation. In the present paper, the possibility of interference of tryptophan with decarboxylation of phenylalanine, tyrosine as well as dopa in the liver was investigated. The AAD activity was measured radiometrically with 1-14C-labeled aromatic amino acid substrates using the rat liver enzyme. The influence of tryptophan on decarboxylation of tyrosine was formally competitive with Ki = 9.2 x 10(-3) M, while the inhibition of decarboxylation of phenylalanine by tryptophan was non-competitive with Ki at 2.75 x 10(-2) M. The effect of tryptophan on decarboxylation of dopa was small and it could not be expressed in terms of inhibition kinetics and inhibition constant. At physiological concentrations of aromatic amino acids in plasma, tryptophan does not seem to have remarkable effects on decarboxylation of phenylalanine, tyrosine, and dopa in the liver.

Amino Acids↗
PubMed1990

Effects of dietary tyrosine on L-dopa- and amphetamine-induced changes in locomotor activity and neurochemistry in mice.

Recent findings suggest that intraperitoneal injections of L-tyrosine at high doses (100 mg/kg) alters amphetamine-induced changes in behavior by restoring amphetamine-induced decreases in whole brain norepinephrine (NE). The present study examined the motor effects of L-dihydroxyphenylalanine (L-dopa) and d-amphetamine sulfate in mice after treatment with a basal casein diet supplemented with L-tyrosine. The basal diet supplemented with 1-4% L-tyrosine, or 1-4% L-phenylalanine, produced no changes in motor activity in otherwise untreated mice. Whereas L-dopa (25-100 mg/kg) following inhibition of extracerebral decarboxylase by Ro 4-4602 (25 mg/kg) slightly decreased activity in diet control (casein) animals, this drug treatment enhanced motor activity in a dose-related fashion when L-tyrosine was added to the diet. Increases in motor activity following low doses of amphetamine (0.75-1.5 mg/kg) in casein control mice were antagonized by dietary L-tyrosine, but a higher dose of d-amphetamine (3 mg/kg) interacted with the addition of L-tyrosine producing an increase in motor activity. Neurochemical changes observed in brain concentrations of tyrosine, dopamine (DA), norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), tryptophan, serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) following drug and diet treatments suggest that 5-HT systems, in addition to catecholamine systems, may be involved in mediating these effects.

Animals↗
PubMed1998

[3H]DOPA formed from [3H]tyrosine in living rat brain is not committed to dopamine synthesis.

Tyrosine hydroxylase of catecholamine neurons catalyzes the synthesis of 3,4-dihydroxphenylalanine (DOPA), which is subsequently metabolized to dopamine by DOPA decarboxylase (DDC). However, DOPA is not committed to decarboxylation in vivo because export of DOPA from brain and metabolism of DOPA other than decarboxylation are possible. To estimate the relative magnitudes of the several fates of DOPA, the kinetics of the uptake and metabolism of L-[3H]tyrosine ([3H]Tyr, intravenous infusion) was measured in brain of rats pretreated with NSD 1015, an inhibitor of DDC. Some rats were pretreated with haloperidol before the blockade of DDC. The [3H]Tyr was incorporated into brain protein at a rate constant of 0.03 min(-1). The relative tyrosine hydroxylase activity in striatum was 0.005 min(-1) at 30 minutes after NSD 1015, 0.011 min(-1) 3 hours later, and 0.020 min(-1) after haloperidol treatment. The rate constant for the clearance of DOPA from brain (0.06 min(-1)) and earlier estimates of the rate constant of DDC activity in striatum (0.26 min(-1)) together predict that 80% of DOPA formed in normal rat striatum normally is available for dopamine synthesis. It follows that modulation of DDC activity can influence the rate of DA synthesis by affecting the relative magnitude of the several fates of DOPA in living brain.

Animals↗
PubMed1993

Tyrosine-hydroxylase-containing vagal afferent neurons in the rat nodose ganglion are independent from neuropeptide-Y-containing populations and project to esophagus and stomach.

Immunoreactivity to the rate limiting enzyme of catecholamine synthesis, tyrosine hydroxylase, has been described in the inferior sensory (= nodose) ganglion of the vagal nerve in the rat. The aim of the present study was to characterize further this neuronal population. The neurons do not represent displaced autonomic efferent neurons, since they do not receive synaptic input, as indicated by the absence of synaptophysin-immunoreactive terminals. In addition to the immunoreactivity to tyrosine hydroxylase, a tyrosine hydroxylase cRNA probe hybridizes with nodose ganglion neurons as demonstrated by in situ hybridization and Northern blotting. Many but not all of the tyrosine hydroxylase-immunoreactive neurons are also immunoreactive to the dopamine synthesizing enzyme, aromatic-L-amino-acid-decarboxylase, but lack the noradrenaline-synthesizing enzyme, dopamine-beta-hydroxylase, thus favoring synthesis of dopamine. Neuropeptide Y, which is often colocalized with catecholamines, is also present in a subset of nodose ganglion neurons, as indicated by immunohistochemistry, in situ hybridization and Northern blotting. However, double-labeling immunofluorescence has revealed that these two antigens are localized in different cell populations. Retrograde neuronal tracing utilizing fluorescent dyes (Fast blue, Fluoro-gold) combined with tyrosine hydroxylase immunohistochemistry has demonstrated that the esophagus and stomach are peripheral targets of tyrosine-hydroxylase-containing vagal viscero-afferent neurons.

Animals↗
PubMed2006

L-tyrosine contributes to (+)-3,4-methylenedioxymethamphetamine-induced serotonin depletions.

The specific mechanisms underlying (+)-3,4-methylenedioxymethamphetamine (MDMA)-induced damage to 5-HT terminals are unknown. Despite the hypothesized role for dopamine (DA) and DA-derived free radicals in mediating this damage, it remains unclear why MDMA produces long-term depletions of 5-HT in brain regions that are sparsely innervated by DA neurons. We hypothesized that the precursor to DA biosynthesis, tyrosine, mediates MDMA-induced 5-HT depletions. Extracellular tyrosine concentrations increased fivefold in striatum and 2.5-fold in hippocampus during the administration of neurotoxic doses of MDMA. In vitro results show that L-tyrosine can be hydroxylated nonenzymatically to the DA precursor l-3,4-dihydroxyphenylalanine (DOPA) under pro-oxidant conditions. The local infusion of L-tyrosine into the striatum or hippocampus during MDMA administration potentiated the acute increase in extracellular DA and the long-term depletion of 5-HT after MDMA. Coinfusion of the aromatic amino acid decarboxylase (AADC) inhibitor m-hydroxybenzylhydrazine attenuated these effects in hippocampus and decreased basal extracellular DA in the striatum. In contrast, the reverse dialysis of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine into the hippocampus did not affect MDMA-induced increases in extracellular DA or the long-term depletion in 5-HT. These results show that MDMA increases the concentration of tyrosine in the brain to cause a long-term depletion of 5-HT via the nonenzymatic, tyrosine hydroxylase-independent, hydroxylation of tyrosine to DOPA and subsequently to DA via AADC. Overall, the findings suggest that MDMA depletes 5-HT by increasing tyrosine and its eventual conversion to DA within 5-HT terminals.

Animals↗
PubMed1983

Alterations of catecholamine enzymes in several brain regions of victims of sudden infant death syndrome.

Dopamine-beta-Hydroxylase (DBH) activity is decreased and tyrosine hydroxylase activity is increased in three brain regions (hypothalamus, putamen, and caudate nucleus) from victims of Sudden Infant Death Syndrome (SIDS) when compared to values in the same regions from infants dying of known causes. No stastically significant difference was detected in tyrosine hydroxylase activity in the thalamus and brain stem although DBH was 20% lower in the former region of the SIDS victims. Two other enzymes of biogenic amine metabolism, catechol-o-methyl transferase and Dopa-decarboxylase, were essentially the same in both groups. These data are consistent with the hypothesis that an alteration in the central nervous system may be a factor in the pathophysiology of SIDS.

Brain↗
PubMed2006

New striatal dopamine neurons in MPTP-treated macaques result from a phenotypic shift and not neurogenesis.

We investigated whether there is neurogenesis in the striatum of aged monkeys, and whether dopamine (DA) depletion induces the genesis of new DA neurons in this structure. Six aged macaques received repeated intraperitoneal injections of bromodeoxyuridine (BrdU) over a 3 week period to label dividing cells. Three macaques were injected in parallel with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to decrease dopaminergic innervation of the striatum. The brains were analysed 3 weeks after the last BrdU injection. In MPTP-treated aged macaques, the number of tyrosine hydroxylase (TH) immunoreactive (ir) striatal neurons increased 2.3-fold compared with controls. These TH-ir striatal cells did not express dopamine beta hydroxylase (DBH) but the dopamine transporter (DAT), suggesting that they are functional DA neurons. They were also negative for calbindin (CB), neuropeptide Y (NPY) and parvalbumin (PV), and a small proportion expressed calretinin (CR). This suggests that these cells stained for TH are interneurons. All these cells also co-expressed glutamic acid decarboxylase (GAD). They thus resemble the small, aspiny, GABAergic interneurons. None of the BrdU-labelled cells in the striatum expressed the neuronal markers neuronal nuclei (NeuN), or GAD or TH, and none of TH-ir cells incorporated BrdU. These data indicate that neurogenesis did not occur in the striatum of aged macaques. The new striatal TH-ir neurons observed after DA depletion was therefore derived from pre-existing GABAergic interneurons. Understanding of the molecular signals mediating this phenotypic shift might help in developing novel and elegant strategies for a cell-based therapy for Parkinson's disease that would avoid many of the drawbacks of cell transplantation.

Aging↗