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At least 55 records · Page 3Linked to original sources
PubMed1993

The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates.

While the production of melatonin in higher vertebrates occurs in other organs and tissues besides the pineal, the contribution of extrapineal sites of melatonin synthesis such as the retina, the Harderian glands and the gut to circulating melatonin levels is still a matter of debate. The amount of melatonin found in the gastrointestinal tract is much higher than in any other organ including the pineal and the gut appears to make a significant contribution to circulating melatonin at least under certain conditions. The gut has been identified to be the major source of the elevated plasma concentrations of melatonin seen after tryptophan administration and of the changes of circulating melatonin level induced by the feeding regimen. Whereas the circadian and circannual fluctuations of the concentration of melatonin in the blood seem to be triggered by changes of the photoenvironment and its effect of pineal melatonin formation, basal daytime melatonin levels and the extent of their elevation at nighttime appear to be additionally controlled by nutritional factors, such as the amount and the composition of ingested food and therefore availability of tryptophan as a rate-limiting precursor of melatonin formation by the enterochromaffin cells of the gastrointestinal tract.

Animals↗
PubMed1997

Teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture.

Congenital malformations are more common in offspring of diabetic mothers than offspring of non-diabetic mothers. The precise cell biological mechanism leading to the increased incidence of congenital malformations in diabetic pregnancy is not known. In previous studies increased glucose and beta-hydroxybutyrate concentrations were found to cause embryonic dysmorphogenesis. We have previously shown that rat embryos, cultured in serum from insulin-treated diabetic rats, develop malformations, despite normalisation of glucose and beta-hydroxybutyrate concentration, thereby suggesting a multifactorial teratological nature of the diabetic environment. In the present study, therefore, we aimed to characterise the teratogenic activity of various components of diabetic serum and in addition to study the possible anti-teratogenic effects of supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture. We found that diabetic serum has a teratogenic effect on embryo development, a capacity residing in the alteration of several serum components in addition to glucose. Improving the embryonic capability to scavenge oxygen radicals, either by increasing superoxide dismutase activity or by supplying a rate-limiting precursor (N-acetylcysteine) for the enhanced synthesis of reduced glutathione, blocks the embryonic dysmorphogenesis.

Acetylcysteine↗
PubMed1996

The synovial-like membrane at the bone interface in loose total hip replacements contains high levels of extracellular group II phospholipase A2.

Progressive lysis of bone in loose total hip replacement has been ascribed to the capacity of the synovial-like membrane present at the bone interface to produce prostaglandin E2 and cytokines such as tumor necrosis factor (TNF alpha). Phospholipase A2 (PLA2) produces rate limiting precursor i.e. arachidonic acid in the biosynthesis of various types of biologically active lipids including prostaglandins. It has been shown that extracellular human group II phospholipase A2 is present in large amount in synovial fluid of patients with synovitis and that the expression of this enzyme is under the control of cytokines such as TNF alpha. Furthermore, the human extracellular enzyme has been also shown to induce in an experimental animal model to cause disruption of a synovial like membrane without increasing prostaglandin production. Here we have evaluated PLA2 and TNF alpha levels in the supernatant of homogenate of the synovial-like membrane present at the bone interface retrieved from six patients with a loose non septic failed total hip replacement. In all the membranes examined were found high levels of both TNF alpha (856 +/- 211 units/ml) and extracellular phospholipase A2 (2616 +/- 862 ng/ml). These findings suggest that extracellular PLA2 may play a major role in the process that cause disruption of the membrane at the bone-prosthesis interface.

Bone and Bones↗
PubMed1992

Overexpression of oskar directs ectopic activation of nanos and presumptive pole cell formation in Drosophila embryos.

In Drosophila, a small group of maternal effect genes, including oskar, defines a shared pathway leading to the provision of two determinants at the posterior pole of the embryo. One determinant is the posterior body patterning morphogen nanos, and the other directs germ cell formation. Overexpression of oskar causes the shared pathway to be hyperactivated, with excess nanos activity present throughout the embryo and a superabundance of posterior pole cells. In addition, presumptive pole cells appear at a novel anterior position. Strikingly, formation of these ectopic pole cells is enhanced in nanos mutants. This observation may reflect competition between nanos and the germ cell determinant for a shared and limiting precursor.

Animals↗
PubMed1985

Kallikrein gene expression in the rat anterior pituitary.

The report of 'kallikrein-like' activity in the rat neuro-intermediate lobe (N-IL) and its possible involvement in pro-opiomelanocortin processing led us to explore the expression of the kallikrein gene(s) in the pituitary. Using 32P-labelled rat pancreatic kallikrein cDNA, we have shown positive hybridization for rat anterior pituitary poly(A)+ RNA, of identical size on Northern blots (approximately 1.0 kb) to rat kidney poly(A)+ RNA run in parallel. Prior adrenalectomy or ovariectomy decreased the level of kallikrein mRNA seen in the anterior pituitary; total RNA from rat N-IL showed no significant hybridization. On hybridization histochemistry the anterior pituitary was strongly positive, and the neural and intermediate lobes negative. The previously reported kallikrein-like activity in the N-IL is therefore probably due to a non-kallikrein kininogenase; in the anterior pituitary, kallikrein may have a physiological role in limited precursor proteolysis, but lack kininogen activity.

Animals↗
PubMed2005

Seizure-induced changes in mitochondrial redox status.

The aim of this study was to determine seizure-induced oxidative stress by measuring hippocampal glutathione (GSH) and glutathione disulfide (GSSG) levels in tissue and mitochondria. Kainate-induced status epilepticus (SE) in rats resulted in a time-dependent decrease of GSH/GSSG ratios in both hippocampal tissue and mitochondria. However, changes in GSH/GSSG ratios were more dramatic in the mitochondrial fractions compared to hippocampal tissue. This was accompanied by a mild increase in glutathione peroxidase activity and a decrease in glutathione reductase activity in hippocampal tissue and mitochondria, respectively. Since coenzyme A (CoASH) and its disulfide with GSH (CoASSG) are primarily compartmentalized within mitochondria, their measurement in tissue was undertaken to overcome problems associated with GSH/GSSG measurement following subcellular fractionation. Hippocampal tissue CoASH/CoASSG ratios were decreased following kainate-induced SE, the time course and magnitude of change paralleling mitochondrial GSH/GSSG levels. Cysteine, a rate-limiting precursor of glutathione was decreased following kainate administration in both hippocampal tissue and mitochondrial fractions. Together these changes in altered redox status provide further evidence for seizure-induced mitochondrial oxidative stress.

Animals↗
PubMed2004

The effect of oral 5-HTP administration on 5-HTP and 5-HT immunoreactivity in monoaminergic brain regions of rats.

5-Hydroxytryptophan (5-HTP), which is the rate-limiting precursor in serotonin (5-hydroxytryptamine (5-HT)) biosynthesis, is used as an oral supplement to enhance serotonin levels in humans. To evaluate its effects on serotonin levels and localization, 5-hydroxytryptophan was administered to Sprague-Dawley rats either orally or via intraperitoneal injection. 5-Hydroxytryptophan-immunoreactivity was co-localized with serotonin-immunoreactivity in the serotonergic dorsal raphe nucleus of control animals and this was not changed in animals given 5-hydroxytryptophan. Oral 5-HTP administration increased the intensity of both 5-HTP and serotonin immunoreactivity in raphe neurons. However, 5-HTP treatment also caused ectopic 5-hydroxytryptophan-immunoreactivity and serotonin-immunoreactivity in normally dopaminergic neurons of the substantia nigra par compacta. Serotonin-immunoreactivity was confined to neurons that also displayed amino acid decarboxylase immunoreactivity, but in a small percentage of substantia nigra neurons, serotonin immunoreactivity was not co-localized with tyrosine hydroxylase-immunoreactivity. The intensity of the immunoreactivity to serotonin and 5-hydroxytryptophan in the substantia nigra was maximal within 2h of 5-hydroxytryptophan administration and returned to control levels by 24h. This time course mirrored changes in HPLC measurements of 5-hydroxytryptophan, serotonin, and the metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the urine. 5-Hydroxytryptophan administration did not cause ectopic appearance of either serotonin or 5-hydroxytryptophan in the noradrenergic locus coeruleus. These results suggest that a single oral dose of 5-HTP increases the 5-HTP and serotonin content of serotonergic neurons and causes the transient ectopic appearance of serotonin in some normally non-serotonergic neurons.

5-Hydroxytryptophan↗
PubMed2003

Stimulation of CDP-choline synthesis by uridine or cytidine in PC12 rat pheochromocytoma cells.

Oral administration of CDP-choline to rats raises plasma and brain cytidine levels and increases brain levels of phosphatidylcholine (PC). In contrast, in humans oral CDP-choline increases plasma levels of uridine. To determine whether uridine can also enhance PC synthesis, we developed an assay for CDP-choline, an immediate and rate-limiting precursor in PC synthesis, and measured this intermediate in clonal PC12 rat pheochromocytoma cells incubated with various concentrations of uridine or cytidine. Addition of uridine (50-100 microM) to the incubation medium caused significant elevations in UTP, CT, USAP and CDP-choline levels in PC12 cells. Uridine had no effect on the synthesis of diacylglycerol (DAG) or the activity of the phosphotransferase which catalyzes the synthesis of PC from DAG and CDP-choline. Hence uridine treatment was unlikely to inhibit the conversion of endogenous CDP-choline to PC. These results suggest the possibility that uridine may also enhance PC synthesis in intact brain.

Animals↗
PubMed1998

Nerve growth factor stimulates diacylglycerol de novo synthesis and phosphatidylinositol hydrolysis in pheochromocytoma cells.

Induction of neurite outgrowth by treating pheochromocytoma cells (PC12 cells) with nerve growth factor (NGF) is associated with major increases in cellular levels of diacylglycerol (DAG), an essential and probably limiting precursor in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) syntheses. To identify the sources of this DAG we examined the effects of NGF treatment on the conversion of [3H]oleic acid (OA) or [3H]glycerol to [3H]glycerolipids, and the turnover of these products in PC12 cells. In kinetic studies on [3H]OA incorporation, most of the radioactivity in the cells initially was free [3H]OA; then it appeared predominantly as [3H]DAG and, eventually, as large amounts of [3H]phospholipids (PLs). In NGF pre-treated cells, the increases in the levels of [3H]DAG (which were most prominent) and PLs were similar to those in unlabeled DAG and PLs. These effects of NGF could be partially blocked by an inhibitor (triacsin C) of long chain acyl-CoA synthetase. NGF pre-treatment also significantly enhanced the incorporation of [3H]glycerol into lipids, a pathway for de novo synthesis of glycerolipids. In studies on the degradation of [3H]OA-labeled lipids, the disappearance of [3H]OA-labeled neutral lipids exhibited an initial rapid phase and a subsequent stable phase. NGF treatment transiently promoted the hydrolysis of [3H]PI to [3H]DAG. These data suggest that the increases in DAG levels observed in PC12 cells exposed to NGF derive mainly from de novo synthesis and, to a lesser and transient extent, from the hydrolysis of [3H]PI.

Animals↗
PubMed1998

High concentration of glucose causes impairment of the function of the glutathione redox cycle in human vascular smooth muscle cells.

We demonstrated that high glucose reduced H2O2 scavenge activity in human vascular smooth muscle cells. In the cells exposed to high glucose, the intracellular glutathione content decreased, although the NADPH content was unchanged. The rate of uptake of cystine, which is a rate-limiting precursor of the glutathione synthesis, decreased in the high glucose group compared with the control group. These decreases were shown to be dependent on glucose concentration. It was suggested that high glucose causes impairment of the function of the glutathione redox cycle in human vascular smooth muscle cells, resulting in reduced H2O2 scavenge activity.

Aorta↗
PubMed2002

Receptor modeling application framework for particle source apportionment.

Receptor models infer contributions from particulate matter (PM) source types using multivariate measurements of particle chemical and physical properties. Receptor models complement source models that estimate concentrations from emissions inventories and transport meteorology. Enrichment factor, chemical mass balance, multiple linear regression, eigenvector. edge detection, neural network, aerosol evolution, and aerosol equilibrium models have all been used to solve particulate air quality problems, and more than 500 citations of their theory and application document these uses. While elements, ions, and carbons were often used to apportion TSP, PM10, and PM2.5 among many source types, many of these components have been reduced in source emissions such that more complex measurements of carbon fractions, specific organic compounds, single particle characteristics, and isotopic abundances now need to be measured in source and receptor samples. Compliance monitoring networks are not usually designed to obtain data for the observables, locations, and time periods that allow receptor models to be applied. Measurements from existing networks can be used to form conceptual models that allow the needed monitoring network to be optimized. The framework for using receptor models to solve air quality problems consists of: (1) formulating a conceptual model; (2) identifying potential sources; (3) characterizing source emissions; (4) obtaining and analyzing ambient PM samples for major components and source markers; (5) confirming source types with multivariate receptor models; (6) quantifying source contributions with the chemical mass balance; (7) estimating profile changes and the limiting precursor gases for secondary aerosols; and (8) reconciling receptor modeling results with source models, emissions inventories, and receptor data analyses.

Air Pollutants↗
PubMed1996

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides.

Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure--activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.

Animals↗
PubMed1981

Effect of allylisopropylacetamide on glutathione metabolism in the rat liver. The possible role of glutathione in the induction of 5-aminolaevulinate synthase.

Administration of allylisopropylacetamide to rats caused a marked decline in the concentrations of reduced and oxidized glutathione in the liver. However, this decrease occurred in the presence of uninhibited activities of gamma-glutamylcysteine synthase and glutathione reductase, and unaltered activities of glutathione transferases A, B and C. The administration of cysteine, the rate-limiting precursor of glutathione formation, to rats treated with allylisopropylacetamide potentiated the inductive effects of the agent on 5-aminolaevulinate synthase, and markedly decreased the extent of decrease in glutathione concentrations by the agent. Conversely, the administration of diethyl maleate, which depletes the hepatic glutathione concentrations, to allylisopropylacetamide-pretreated rats (1h) diminished the extent of 5-aminolaevulinate synthase induction and the production of porphyrins by nearly 50%, when measured at 16h. This treatment did not alter the extent of non-enzymic degradation of liver haem by allylisopropylacetamide. When diethyl maleate was administered to the animals possessing high 5-aminolaevulinate synthase activity (at 3, 7 and 15h after allylisopropylacetamide), in 1h the enzyme activity was markedly decreased. Diethyl maleate had no effect on induction of 5-aminolaevulinate synthase by 3,5-diethoxycarbonyl-1,4-dihydrocollidine, also a potent porphyrinogenic agent. Diethyl maleate alone neither inhibited 5-aminolaevulinate synthase activity nor decreased the cellular content of porphyrins and haem. The data suggest that the decreases observed in the glutathione concentrations after allylisopropylacetamide administration are not the result of decreased production of the tripeptide. Rather, they most likely reflect the increased utilization of glutathione. The findings further suggest that the inhibition by diethyl maleate of allylisopropylacetamide-stimulated 5-aminolaevulinate synthase involves the inhibition of induction processes.

5-Aminolevulinate Synthetase↗
PubMed2002

Exogenous cysteine and cystine promote cell proliferation in CaCo-2 cells.

Previous studies have shown that intracellular glutathione, a ubiquitous intracellular thiol, is related to cell proliferation and that cysteine or its disulphide form, cystine, also induces cell proliferation. Cysteine is a thiol containing amino acid and a rate-limiting precursor of glutathione. Therefore, it is still unresolved as to whether the proliferative effect of cysteine or cystine is entirely mediated by a change in the intracellular glutathione status. The objective of this study was to delineate the relationship among cysteine/cystine (thereafter referred to as cyst(e)ine), intracellular glutathione and cell proliferation in the human colon cancer CaCo-2 cell line. CaCo-2 cells were cultured in cyst(e)ine-free Dulbecco's Modified Eagle Medium without serum, and treated with 200 microm cysteine and/or 200-400 microm cystine for 24 h. In the presence of DL-buthionine-[S, R]-sulfoximine (BSO), a glutathione synthesis inhibitor, exogenously administered cyst(e)ine did not change the intracellular glutathione content, but increased the intracellular cysteine as well as cystine level. Addition of exogenous cyst(e)ine following 5 mm BSO treatment significantly increased cell proliferation as measured by 3H-thymidine incorporation and protein content. Cell cycle analyses revealed that cyst(e)ine promoted cell progression from the G1 phase to the S phase. Correspondingly, cyst(e)ine treatment induced expression of cyclin D1 and phosphorylation of retinoblastoma protein (Rb). In conclusion, these data indicate that both cysteine and cystine have proliferative effects in CaCo-2 cells independent of an increase in intracellular glutathione. Induction of cyclin D1, phosphorylation of Rb, and subsequent facilitation of G1-to-S phase transition were involved in the proliferative effect of exogenous cyst(e)ine.

Antimetabolites↗
PubMed2000

Astrocytes provide cysteine to neurons by releasing glutathione.

Cysteine is the rate-limiting precursor of glutathione synthesis. Evidence suggests that astrocytes can provide cysteine and/or glutathione to neurons. However, it is still unclear how cysteine is released and what the mechanisms of cysteine maintenance by astrocytes entail. In this report, we analyzed cysteine, glutathione, and related compounds in astrocyte conditioned medium using HPLC methods. In addition to cysteine and glutathione, cysteine-glutathione disulfide was found in the conditioned medium. In cystine-free conditioned medium, however, only glutathione was detected. These results suggest that glutathione is released by astrocytes directly and that cysteine is generated from the extracellular thiol/disulfide exchange reaction of cystine and glutathione: glutathione + cystine<-->cysteine + cysteine-glutathione disulfide. Conditioned medium from neuron-enriched cultures was also assayed in the same way as astrocyte conditioned medium, and no cysteine or glutathione was detected. This shows that neurons cannot themselves provide thiols but instead rely on astrocytes. We analyzed cysteine and related compounds in rat CSF and in plasma of the carotid artery and internal jugular vein. Our results indicate that cystine is transported from blood to the CNS and that the thiol/disulfide exchange reaction occurs in the brain in vivo. Cysteine and glutathione are unstable and oxidized to their disulfide forms under aerobic conditions. Therefore, constant release of glutathione by astrocytes is essential to maintain stable levels of thiols in the CNS.

Animals↗
PubMed2000

Glucosamine for migraine prophylaxis?

Following a fortuitous observation that migraine headaches ceased in a patient receiving glucosamine therapy for osteoarthritis, a further ten patients with migraine or migraine-like vascular headaches, refractory to established preventive or abortive therapies, have been treated with daily oral glucosamine. After a lag of 4-6 weeks, a substantial reduction in headache frequency and/or intensity has been noted; in some cases, the benefit appears to be dose-dependent. Since glucosamine can be a rate-limiting precursor for mucopolysaccharide synthesis, it is germane to note previous reports that heparin and pentosan polysulfate may have migraine-preventive activity. There is reason to suspect that mast cells are central mediators of the neurogenic inflammation associated with migraine and cluster headaches. The heparin produced by mast cells may function to provide feedback down-regulation of mast cell activation, and exerts a range of other anti-inflammatory effects. We postulate that supplemental glucosamine can boost mast cell heparin synthesis - perhaps correcting a functional heparin deficiency - thereby preventing or ameliorating the neurogenic inflammation that mediates pain in vascular headache. Whether or not this idea has validity, a controlled study of glucosamine for migraine prophylaxis appears to be warranted.

Glucosamine↗
PubMed1990

Purification of a 110-kilodalton cytosolic phospholipase A2 from the human monocytic cell line U937.

The major dithiothreitol-resistant phospholipase A2 activity present in the cytosol of U937 cells has been purified greater than 200,000-fold by sequential chromatography on phenyl-5PW, heparin-Sepharose CL-6B, high-performance hydroxylapatite, TSK-gel G3000-SW, and Mono Q columns. This 110-kDa cytosolic phospholipase A2 is distinct from the relatively small (14-kDa) dithiothreitol-sensitive phospholipases A2 that are secreted from many cell types. This additional phospholipase A2 selectively hydrolyzes fatty acid at the sn-2 position of the glycerol and favors phospholipids containing arachidonic acid, which is the rate-limiting precursor for prostaglandin and leukotriene production. Interestingly, a greater than 5-fold increase in phospholipase A2 activity is noted as the calcium concentration increases from the levels found in resting cells to those observed in activated macrophages. We suggest that this enzyme and not the previously described secretory phospholipase A2 is activated by cytosolic effectors such as GTP-binding regulatory proteins and protein kinases to initiate the production of prostaglandins, leukotrienes, and platelet-activating factor. To distinguish this cytosolic enzyme from the previously described secretory ones, we suggest referring to it as cPLA2 for cytosolic phospholipase A2 and collectively referring to the secretory phospholipases A2 as sPLA2s.

Calcium↗
PubMed2002

Visibility: science and regulation.

The 1999 Regional Haze Rule provides a context for this review of visibility, the science that describes it, and the use of that science in regulatory guidance. The scientific basis for the 1999 regulation is adequate. The deciview metric that tracks progress is an imperfect but objective measure of what people see near the prevailing visual range. The definition of natural visibility conditions is adequate for current planning, but it will need to be refined as visibility improves. Emissions from other countries will set achievable levels above those produced by natural sources. Some natural events, notably dust storms and wildfires, are episodic and cannot be represented by annual average background values or emission estimates. Sulfur dioxide (SO2) emission reductions correspond with lower sulfate (SO4(2-)) concentrations and visibility improvements in the regions where these have occurred. Non-road emissions have been growing more rapidly than emissions from other sources, which have remained stable or decreased since 1970. Simpler models representing transport, limiting precursor pollutants, and gas-to-particle equilibrium should be used to understand where and when emission reductions will be effective, rather than large complex models that have insufficient input and validation measurements. Examples of model-based source attribution show large differences among estimates from various modeling systems and with ambient measurements.

Air Pollutants↗