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PubMed1984

Apolipoprotein E Bethesda. Isolation and partial characterization of a variant of human apolipoprotein E isolated from very low density lipoproteins.

A variant of apolipoprotein E, denoted E Bethesda, has been identified in the plasma of a 72-year-old woman with type III hyperlipoproteinemia. An offspring of the proband also has this variant and type III hyperlipoproteinemia. Apolipoprotein E Bethesda was isolated by preparative isoelectrofocusing followed by preparative SDS-polyacrylamide gel electrophoresis from the very low density lipoproteins of the proband's son. The purity and the identity of the preparation were analyzed by analytical SDS-polyacrylamide gel electrophoresis, two-dimensional gel electrophoresis and by immunochemical analysis. Apolipoprotein E Bethesda migrates in the E 1 position and its electrophoretic mobility is not affected by neuraminidase treatment. The protein is shifted to the E3 position after cysteamine treatment. The amino acid composition revealed the presence of two cysteine residues. These data support the concept that the apolipoprotein E Bethesda allele is derived from a mutation of the E2 or E2* allele.

Aged↗

PubMed1982

Inhibition of glycolysis of mammalian cells by misonidazole and other radiosensitizing drugs. prevention by thiols.

Prolonged anaerobic incubation of Ehrlich ascites tumor cells and Chinese hamster V79-379A cells with misonidazole, desmethylmisonidazole, or niridazole led to inhibition of both glucose consumption and lactate formation. This effect was measured in cells washed free of the nitro compounds and resuspended in fresh buffer or medium. The degree of inhibition of glucose utilization was related to drug concentration, and to the rate of metabolic reduction, as measured under aerobic conditions by KCN-insensitive oxygen consumption. Misonidazole-induced inhibition of glycolysis developed concurrently with depletion of intracellular non-protein thiol (NPSH) and was protected against by the presence of cysteamine, cysteine and, to some extent, GSH in the cell incubate. These findings suggest diethyl maleate was used to deplete 90% of the endogenous NPSH, but this depletion did not alter the effects of misonidazole on glycolysis.

Anaerobiosis↗

PubMed1995

Degradation of 2-(3-aminopropylamino)-ethanethiol (WR-1065) by Cu-dependent amine oxidases and influence on glutathione status of Chinese hamster ovary cells.

The radioprotective drug 2-(3-aminopropylamino)ethanethiol (WR-1065) can be degraded when incubated in cell culture medium in vitro. The degradation reaction consumes oxygen and results from the action of Cu-dependent amine oxidases present in the serum content of the medium. Analysis of the degradation products of WR-1065 demonstrates the formation of cysteamine, acrolein and H2O2. WR-2721, the inactive prodrug of WR-1065, is not a substrate for these enzymes. Extracellular degradation of WR-1065 by Cu-dependent amine oxidases leads to an intracellular depletion of glutathione (GSH) in Chinese hamster ovary (CHO) cells and to reduction of clonogenic cell survival. Addition of aminoguanidine, an inhibitor of Cu-dependent amine oxidases, protects CHO cells from the toxic effects of WR-1065 and under these conditions an increase of intracellular GSH levels occurs. These data demonstrate that WR-1065 can be degraded to toxic compounds by the presence of Cu-dependent amine oxidases which might have further implications for the clinical use of WR-2721.

Acrolein↗

PubMed1995

The interaction of nitroaromatic drugs with aminothiols.

The effect of cysteamine and glutathione addition on the redox behaviour of metronidazole, chloramphenicol, M&B 4998, nitrofurazone, and nifuroxime has been studied by electrochemical techniques. The presence of thiol influences the redox behaviour of the nitro compound in a number of ways. In aqueous media, the single-step nitro/hydroxylamine reduction shows a decrease in current and a shift to more positive potentials, which is assigned to the thiol acting as the reducing agent, but only after the formation of the nitro radical anion. In addition, the reversible RNO/RNHOH couple is greatly diminished or removed. In a dimethylformamide/H2O solvent, the nitro radical anion can be selectively generated. The effect of thiol addition on the stability of the radical anion is strongly dependent on the drug, the identity of the thiol, and the concentration of the supporting electrolyte. The presence of thiol can result in an increase or a decrease in the lifetime of the radical with no apparent correlation with the redox couple of the nitro compound, or can act as an oxidizing agent and regenerate the original nitro compound. These disparate routes by which thiol can modify the redox characteristics of nitro compounds suggest that the traditional role of thiol as a radical scavenger needs to be extended.

Buffers↗

PubMed1985

Localization and characterization of brain somatostatin receptors as studied with somatostatin-14 and somatostatin-28 receptor radioautography.

The localization and characterization of receptors for somatostatin-14 (S-14) and somatostatin-28 (S-28) were studied in the rat brain using the iodinated agonists [Tyr0,D-Trp8]S-14 and [Leu8,D-Trp22,Tyr25]S-28 as tracers. Slide-mounted frozen sections were used for the radioautographic localization and biochemical characterization of somatostatin receptors. In the latter case counting was performed on scraped off serial sections from rostral regions of the brain. Specificity studies demonstrated that either tracer could be displaced with S-28, S-14 or their agonists. The N-terminus fragment (1-12) of S-28 as well as a number of unrelated peptides were unable to compete with either tracer, indicating that the binding capacity for ligand-receptor recognition is located in the C-terminal portion of S-28. Scatchard analysis of saturation curves gave a one-site interaction with Kd values of 0.42 +/- 0.09 nM and 0.32 +/- 0.04 nM for the S-14 and S-28 iodinated agonists, respectively. By radioautography, the distribution of receptors for both S-14 and S-28 appeared very similar with high levels of binding in the deep layers of the cortex, the cingulate cortex, the claustrum, the locus coeruleus and most structures of the limbic system. Treatment with cysteamine, which caused a somatostatin depletion in the brain, was required to observe labeling in the hypothalamus. In some caudal areas of the brain, especially in the cerebellar nuclei, the solitary tract nucleus and the nucleus of the vagus nerve, only labeling with the S-28 agonist could be detected. This S-28 binding could be displaced by native S-14 (10(-6) M). Generally, there was a correlation between the localization of somatostatin receptors and that of immunoreactive somatostatin, as evaluated by immunocytochemistry. However, in some areas, an inverse correlation between receptor and peptide concentrations was observed. These results are in agreement with previous data suggesting that somatostatin could act as a neurotransmitter or neuromodulator in several brain areas.

Animals↗

PubMed1986

Intracerebroventricular infusion of somatostatin selectively increases paradoxical sleep in rats.

Chronic intracerebroventricular (i.c.v.) infusion of somatostatin (SRIF) elicited a specific increase of the daily duration of paradoxical sleep (PS) in rats. I.c.v. administration of cysteamine, a selective SRIF depletor, brought about a dose-dependent reduction of PS. Slow wave sleep (SWS) remained unaffected in both cases. These results suggest that SRIF may be involved in the regulation of PS.

Animals↗

PubMed1993

Bilateral induction of NADPH-diaphorase activity in neocortical and hippocampal neurons by unilateral injury.

Unilateral injury of the cerebral cortex or hippocampus induced a bilateral appearance of NADPH-diaphorase in some pyramidal neuronal and glial cells of both structures. Only in the cerebral cortex, near the needle track, did some V layer pyramidal neurons contain so much of this enzyme that they looked to be stained by the Golgi method. The induction of NADPH-diaphorase in a subset of cortical and hippocampal neurons in both hemispheres after unilateral injections of either cysteamine or artificial cerebro-spinal fluid suggests the existence in the isocortex and the hippocampus of a selective signalling system which may play a role in recovery of function following local brain damage.

Animals↗

PubMed1983

Mechanism of augmentation of the antibody response in vitro by 2-mercaptoethanol in murine lymphocytes. II. A major role of the mixed disulfide between 2-mercaptoethanol and cysteine.

Five thiol compounds including 2-mercaptoethanol (2-ME) were examined for their augmenting effects on in vitro antibody response to sheep erythrocytes. Three compounds were effective with the following order of activity; 2-ME greater than dithiothreitol greater than cysteamine. Glutathione and thioglycollate failed to enhance the response. The same order or effectiveness was seen in the stimulation of [35S]cystine uptake by murine lymphocytes by these thiols. Murine lymphocytes took up cysteine five to six times more rapidly than cystine. It is, however, unlikely that 2-ME stimulation of cystine uptake is solely due to the reduction of cystine into cysteine, because 2-ME was still stimulatory after free thiol groups had disappeared in the medium containing 2-ME and [35S]cystine. The mixed disulfide of cysteine with 2-ME (Cys-2-ME) was found to be an only product after free thiols had been oxidized. [35S]Cys-2-ME was taken up by the lymphocytes with a comparable rate to cysteine via a transport system common to that of leucine and phenylalanine. Cysteine was, however, transported via a different route. It was observed that Cys-2-ME was readily metabolized to cysteine and glutathione after the uptake. Cys-2-ME added to cystine-free RPMI 1640 medium could support the antibody response as efficiently as cystine plus 2-ME. These observations strongly suggest that 2-Me stimulates cystine uptake and, therefore, enhances the antibody response through the formation of the mixed disulfide with cysteine.

Adjuvants, Immunologic↗

PubMed1995

(Z)-3-(4-bromophenyl)-3-(3-pyridyl)allylamine as substrate for studies of myeloperoxidase activity.

(Z)-3-(4-Bromophenyl)-3-(3-pyridyl)allylamine (CPP 200) is transformed to the corresponding chloroimine by hypochlorite ion (ClO-) formed in the presence of myeloperoxidase. A scheme for this transformation is given. The influence of various compounds on this process has been studied. Cysteamine, cysteine and 6-chloro-3-hydrazino-pyridazine inhibited the transformation of CPP 200, while some p-hydroxyphenyl derivatives increased the rate of transformation of CPP 200. The increase seen on addition of the p-hydroxyphenyl derivatives is not a chloride-dependent reaction. Various mechanisms for the inhibiting effect as well as for the activating effect on the transformation of CPP 200 are discussed.

Acetaminophen↗

PubMed1989

Duodenal ulcers are associated with a depletion of duodenal calcitonin gene-related peptide-like immunoreactivity in rats.

Calcitonin gene-related peptide-like immunoreactivity (CGRP-li) was decreased in duodenal samples from animals treated with ulcerogens such as dulcerozine, cysteamine or mepirizole. The degree of these experimental ulcers was inversely correlated with the levels of duodenal CGRP-li. These findings show that endogenous CGRP may play an important role in duodenal ulcerogenesis.

Animals↗

PubMed1990

Reduction of the severity of experimental gastric and duodenal ulceration by interleukin-1 beta.

Interleukin-1 beta (IL-1 beta) has been reported to stimulate prostaglandin synthesis by the rat stomach in vitro and to inhibit gastric acid secretion in vivo. We have therefore tested the hypothesis that IL-1 beta might have protective actions in experimental models of gastroduodenal ulceration. IL-1 beta, given i.p., dose and time dependently reduced the severity of ethanol-induced gastric damage. A pretreatment time of 90 min was found to produce the greatest reduction of damage, while doses of 0.1 micrograms/kg or greater were found to produce significant effects. The protective actions of IL-1 beta were abolished by prior boiling or by pretreatment of the animals with indomethacin, and were not shared by the nonapeptide fragment 163-171. IL-1 beta also reduced the severity of gastric damage induced by indomethacin and the duodenal ulceration induced by cysteamine. The results indicate that IL-1 beta has protective actions in three separate experimental models of gastroduodenal ulceration. The mechanism of action of IL-1 beta is not entirely clear, but contributions of endogenous prostaglandin synthesis and inhibition of gastric acid secretion cannot be excluded.

Animals↗

PubMed1991

BAY P 1455, a thiazolylaminobenzimidazole derivative with gastroprotective properties in the rat.

The antiulcer activity of BAY P 14551 a thiazolylaminobenzimidazole derivative, was evaluated in different experimental ulcer models and its antiulcer activity was compared to that of different reference drugs. The overall activity of the compound was equal to or more potent than that of reference antiulcer drugs, such as pirenzepine, cimetidine and carbenoxolone, but it was not as potent as rioprostil. The ED50 values (expressed as mumol/kg p.o.) were 68 (confidence limits: 51-91) for indomethacin-induced ulcers, 21 (confidence limits: 13-31) for stress-induced ulcers and 1260 mumol/kg p.o. (confidence limits: 412-3800) for ulcers induced by absolute ethanol. The compound had no activity against cysteamine-induced duodenal ulcers and lost its cytoprotective activity in adrenalectomised rats. Since inhibition of gastric acid secretion was seen, if at all, only with the higher doses, the gastro-protective action of BAY P 1455 seemed not to be due to an antisecretory effect, but more likely to a gastroprotective action as hypothesised for prostaglandins.

Adrenalectomy↗

PubMed1993

Protective effects of calcitonin gene-related peptide in different experimental models of gastric ulcers.

Intravenous administration of calcitonin gene-related peptide (CGRP) prevented in a dose-dependent manner reserpine-induced gastric mucosal damage, but failed to affect the lesions produced by ethanol administration. In pylorus-ligated rats, CGRP significantly reduced gastric volume, total acid and peptic activity output as well as ulcer formation. These protective effects of CGRP were not present when rats were pretreated with cysteamine. Our data suggest that CGRP exerts its antisecretory and antiulcer activity, at least in part, by interfering with somatostatin transmission.

Animals↗

PubMed1993

Role of somatostatin in the augmentation of hippocampal long-term potentiation by FR121196, a putative cognitive enhancer.

N-(4-Acetyl-1-piperazinyl)-4-fluorobenzenesulfonamide (FR121196), a newly introduced putative cognitive enhancer of a derivative of piperazine, was investigated for its effects on long-term potentiation in guinea-pig hippocampal slices. The magnitude of long-term potentiation of population spikes recorded in CA3 pyramidal neurons was significantly augmented by perfusing FR121196 (10(-9)-10(-6) M) for 25 min before and during tetanic stimulation of the mossy fibers; the basal amplitude of population spikes before tetanus was hardly affected by the drug. The dose-response curve was bell-shaped with a maximal augmentation at 10(-7) M. Similar activity and bell-shaped dose-response curve were observed with methamphetamine (10(-8)-10(-6) M). Physostigmine (10(-8)-10(-6) M) also facilitated long-term potentiation of this pathway and the magnitude of augmentation was concentration-dependent. Scopolamine (10(-6) M) per se had little effect on the magnitude of long-term potentiation in the mossy fiber-CA3 pathway, but significantly attenuated its enhancement by FR121196 (10(-7) M) and physostigmine (10(-6) M), although it failed to influence that by methamphetamine (10(-7) M). In hippocampal slices from animals treated with cysteamine, which was shown to deplete hippocampal somatostatin, FR121196 (10(-7) M) hardly affected long-term potentiation generation, whereas physostigmine (10(-6) M) and methamphetamine (10(-7) M) augmented it significantly. These results suggest that FR121196 enhances the development of long-term potentiation in the mossy fiber-CA3 pathway through activation of somatostatinergic neurons in the hippocampal formation.

Animals↗

PubMed1994

The role of endogenous nitric oxide in the gastroprotective action of morphine.

Morphine in a dose of 1 mg/kg s.c. decreased mucosal lesions induced by 100% ethanol or acidified aspirin by 79% and 85%, respectively, in rats. When the animals were pretreated with NG-nitro-L-arginine (40 mg/kg i.v.), the mucosal lesions were aggravated in both tests and the gastroprotective action of morphine decreased to 17% and 20%, respectively. This decrease in morphine protection was antagonized by L-arginine but not by D-arginine in the case of ethanol-induced lesions; however, L-arginine failed to restore the gastroprotective effect of morphine when the mucosal damage was induced by acidified aspirin. The protective action of either prostaglandin E2 (0.1 mg/kg orally) or cysteamine (50 mg/kg orally) was not influenced by NG-nitro-L-arginine (L-NNA). When L-NNA was given simultaneously with either indomethacin (10 mg/kg p.o.) or N-ethyl-maleimide (50 mg/kg s.c.), compounds which also reduced the gastroprotective action of morphine, almost complete inhibition of the gastroprotective action of morphine against 100% ethanol-induced lesions was observed as a result of the addition of the inhibitory activities of the latter substances. These results suggest that: (1) Endogenous nitric oxide is likely to be involved in the gastroprotective action of morphine. (2) The protective action of nitric oxide is independent of both mucosal prostaglandins and sulfhydryls.

Animals↗

PubMed1987

Irreversible inactivation of calcium-dependent proteinases from rat liver by biological disulfides.

The effect of low-molecular-mass biological disulfides and their related reduced compounds on the activity of two calcium-dependent neutral proteinases (calpains) from rat liver has been investigated. L-Cystine and L-cystamine bring about the inactivation of both enzymes, while the related reduced compounds L-cysteine and L-cysteamine are without effect. Calpain II is more sensitive to the inactivating effect of glutathione disulfide in comparison with calpain I. The inactivation rates of both calpains depend on the concentration of glutathione disulfide. Reduced glutathione, added at physiological concentration (5 mM), neither affects the proteinase activities nor protects the enzymes from the inactivating effect of glutathione disulfide. The enzymes inactivated by biological disulfides cannot be restored by a large excess of a reducing thiolic compound (dithiothreitol). It is suggested that calcium-dependent proteinases might be inactivated also in vivo by enhanced level of glutathione disulfide.

Animals↗

PubMed1986

Oral administration of synthetic human urogastrone promotes healing of chronic duodenal ulcers in rats.

The effect of oral administration of synthetic human epidermal growth factor/urogastrone (EGF/URO) on healing of chronic duodenal ulcers induced by cysteamine in rats was investigated and compared with that of cimetidine, a H2-receptor antagonist. After 25 and 50 days of treatment, synthetic human EGF/URO significantly increased healing of chronic duodenal ulcers to the same extent as cimetidine. Combined treatment with synthetic human EGF/URO and cimetidine for 25 days was more effective than synthetic human EGF/URO given alone, whereas combined treatment for 50 days was significantly more effective than cimetidine alone. These results show that a combination of an agent inhibiting gastric acid secretion and the cytoprotective and growth-stimulating peptide EGF/URO seems to be more effective with regard to duodenal ulcer healing than individual administration of the two substances. Synthetic human EGF/URO is a potent inhibitor of gastric acid secretion when administered intravenously, but had no effect on acid secretion when given intraduodenally, which suggests that the effect of synthetic human EGF/URO is a direct action on the duodenal mucosa. In conclusion, this study showed that oral synthetic human EGF/URO has a significant effect on healing of duodenal ulcers in rats. The amount of synthetic human EGF/URO administered is comparable to that found in saliva during stimulation of the salivary glands. Our results, therefore, suggest that EGF/URO is one of the endogenous factors participating in healing of duodenal ulcers.

Animals↗

PubMed1990

Oxytocin inhibits infanticide in female house mice (Mus domesticus).

Between 60 and 90% of female house mice spontaneously kill unrelated young. A previous report indicated that subcutaneous administration of oxytocin significantly reduced the frequency of infanticide by virgin and pregnant females. However, in this study a distinction could not be made between an action of oxytocin on the CNS versus a secondary effect such as an enhanced release of prolactin by oxytocin. In the current experiment, oxytocin administered intracerebroventricularly was equally as effective at inhibiting infanticide as sc oxytocin. There was no difference in the effectiveness of oxytocin between groups of infanticidal females that were gonadally intact, ovariectomized, or estrogen treated. Pretreatment of infanticidal females with the prolactin inhibitors, bromocriptine and cysteamine, was also without effect on the ability of oxytocin to inhibit infanticide. Last, prolactin-inhibiting drugs had no significant effect on spontaneous parenting behavior by female mice. These data suggest that oxytocin acts directly on the CNS to alter behavior toward pups and that prolactin may not play a role in the maternal behavior of the house mouse.

Animals↗