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PubMed2002

Effect of sperm survival and CTC staining pattern on in vitro fertilization of porcine oocytes.

Polyspermy in pig oocytes fertilized in vitro remains unacceptably high. In this study, we evaluated the effects of gamete coincubation time, and determined if the proportion of capacitated spermatozoa would be predictive of the fertilizing ability of frozen-thawed semen in vitro. Cumulus-oocyte complexes were collected from slaughterhouse prepubertal gilt ovaries and matured in vitro for 44 h in TCM199, with EGF, FSH, cysteamine and follicular fluid. Fertilization was induced with 2 x 10(5) frozen-thawed spermatozoa/ml in TBM. Penetration of oocytes as well as polyspermic fertilization occurred 2 h after insemination. A strong correlation between penetration and polyspermic fertilization rates has been demonstrated, but there was no correlation between the proportion of capacitated spermatozoa, as assessed by chlortetracycline staining, at the time of insemination and fertilization rates. We also compared the results of IVF in three IVF media: TBM, m199 and TALP. Penetration and polyspermy were very different in these three media: 71 +/- 19% and 25 +/- 13% in TBM, 37 +/- 11% and 6 +/- 2% in m199, 10 +/- 2% and 0% in TALP, respectively. Nevertheless, survival of spermatozoa or modifications of the capacitation status were not different in these media after 6 h incubation. We concluded that survival and capacitation characteristics of the semen used for IVF could not be predictive of the IVF results. It seems necessary to act at the oocyte level to control both variability between replicates and the incidence of polyspermy. Improving the spermatozoa penetration blocking system of the oocytes and reducing the number of sperm-binding sites on the zona pellucida (ZP) are our further objectives.

Animals↗
PubMed1977

Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine.

Fifteen patients with paracetamol (acetaminophen) poisoning were treated with intravenous N-acetylcystein (300 mg/kg given over 20 h). Mean admission and 4 h plasma-paracetamol concentrations were 262 and 369 microgram/ml, respectively. Liver-function tests remained normal or were only slightly disturbed in 11 of 12 patients treated within 10 h of paracetamol ingestion. Severe liver damage developed in the other patient and in the three in whom treatment was started more than 10 h after paracetamol ingestion. In contrast to cysteamine, N-acetylcysteine was very well tolerated and has the advantage of being available as a pharmaceutical preparation in a 20% sterile solution.

Acetaminophen↗
PubMed1997

Redox regulation of the mitogen-activated protein kinase pathway during lymphocyte activation.

We have previously demonstrated an obligatory requirement for intracellular reactive oxygen species generation during T lymphocyte activation, and have proposed that intracellular reactive oxygen species may act as signalling agents in the regulation of certain cellular processes, for example, during cell cycle entry. To test this hypothesis, we have been interested to determine which, if any, cell cycle entry events are affected by oxidative signalling. In earlier studies, we have identified the transcription factors NF-kappa B and AP-1 as molecular targets for oxidative signalling processes during cell cycle entry, and have shown that oxidative signalling is involved in the regulation of early changes in gene expression during the G0 to G1 phase transition. To extend these initial observations, we have examined the effect of antioxidant treatment on the activity of the mitogen-activated protein kinases erk1 and erk2, as members of a signal transduction pathway known to directly regulate transcription factor function. Using as a probe cysteamine, an aminothiol compound with both antioxidant and antiproliferative activity, we have identified erk2, a key element of the MAP kinase pathway, as being responsive to oxidative signalling during lymphocyte activation. These observations provide further evidence to suggest a role for intracellular oxidant generation as a regulatory mechanism during cell cycle entry, and establish a link between oxidative signalling and other aspects of the intracellular signalling network that is activated in response to mitogenic stimulation.

Alkaloids↗
PubMed2002

Gastroprotective effect of adrenomedullin administered subcutaneously in the rat.

Subcutaneous injections of adrenomedullin prevented reserpine-induced gastric mucosal damage in a dose-dependent manner (1-1000 ng/kg), but did not interfere with the lesions produced by ethanol administration. In pylorus-ligated rats adrenomedullin significantly reduced gastric volume, total and free acid output as well as ulcer formation. The gastroprotective activity of adrenomedullin was not present in rats pretreated with cysteamine. These results suggest that adrenomedullin exerts its antiulcer effect, when it is administered subcutaneously (s.c.), probably by a mechanism which involves somatostatin related transmission.

Adrenomedullin↗
PubMed2000

Reversible protection of disulfide bonds followed by oxidative folding render recombinant hCGbeta highly immunogenic.

Active immunization of women against human chorionic gonadotropin (hCG) has been considered as a promising option for contraception. However, prototype hCG vaccines based on natural sources of antigen are expected to be costlier for use by common people. In the present report, a functionally active, cost-effective antigen of bacterial origin has been described. Sulfonation of thiol groups of the protein, anion-exchange purification, refolding with concomitant formation of disulfide bonds in the presence of cysteamine-cystamine redox buffer, and slow removal of denaturant resulted in 95% homogeneous, monomeric form of the antigen. The recombinant processed antigen [CGbeta(p)] obtained this way was highly immunopotent. Cellular DNA and endotoxin contaminants were appreciably low in the final product. The immunogenic response was drastically reduced with the unprocessed antigen. This finding envisages better prospect of a cost-effective hCG vaccine for birth control.

Animals↗
PubMed2003

Ultrasound-enhanced transgene expression in vascular cells is not dependent upon cavitation-induced free radicals.

Although acoustic cavitation is clearly important in ultrasound (US)-enhanced gene delivery (UEGD), the relative importance of mechanical and sonochemical (free radical) bioeffects remains unclear, as does the mechanism of gene delivery at the cellular level. Porcine vascular smooth muscle cells (VSMC) were transfected with luciferase or green fluorescent protein (GFP) plasmid +/- pulsed 956 kHz US (2.0 mechanical index (MI), 128 W cm(-2) spatial peak pulse average intensity, ISPPA) for 60 s, in the presence or absence of 20 mM cysteamine or N-acetyl-L-cysteine. Both compounds effectively scavenged free radical production following US, leaving unaffected the 50- to 100-fold enhancements in luciferase expression seen in US-treated VSMC. US exposure enhanced plasmid uptake (25 +/- 4.6 vs. 3 +/- 1.9 cells/field, n=4, p<0.05), most likely directly into the cytoplasm, and increased both the total number (>sevenfold) and average fluorescence intensity (>sixfold) of GFP-transfected cells. UEGD is not dependent upon cavitation-induced free radical generation and has potential for use with a wide range of therapeutic transgenes.

Acoustics↗
PubMed1978

The need for a mammalian test system for mutagens: action of some reducing agents.

Reducing agents and cysteine, cysteamine, glutathione, ascorbic acid and H2O2 with and without the addition of Cu2+ did not increase significantly the frequency of mutations in the Salmonella test at non-toxic concentrations but triggered a marked DNA repair synthesis and induced a relatively high frequency of chromosome aberrations in cultured mammalian cells. Both latter effects were reduced by the addition of catalase to solutions of the reducing agents plus Cu2+. To avoid 'False Negatives' in mutagenicity screening the use of several test subjects including mammalian cells seems to be required.

Animals↗
PubMed2003

Biochemical studies on the anti-ulcerogenic potential of Hemidesmus indicus R.Br. var. indicus.

Roots of Hemidesmus indicus var. indicus are used for various ailments in Indian traditional medicines. The present study evaluated the antiulcerogenic property of aqueous ethanolic extracts of the roots in animal models. Modified pyloric ligated (Shay) rat model and aspirin-induced ulcerogenesis in pylorus ligated rat models were used for this study and analysed for gastric volume, ulcer score, pH, free and total acidity and sodium and potassium ion output. Bio-chemical estimations like total proteins, total hexoses, hexosamine, fucose, sialic acid and pepsin were also made. Ulcer score was calculated for cysteamine-induced duodenal ulcer model. Roots collected during flowering season were found to be more effective than that collected during vegetative seasons.

Animals↗
PubMed1997

Effects of Cistus laurifolius L. flowers on gastric and duodenal lesions.

The flowers and flower buds of Cistus laurifolius L. are used for the treatment of peptic ulcers. Through the bioassay-guided fractionation of the material, using water immersion and immobilisation-induced stress ulcer model, the EtOH-precipitated part from the aqueous extract (E-H2O decreases) was determined to be the active fraction. For the evaluation of the mode of action, the activity of E-H2O decreases was tested using various ulcer models in rats and mice and this fraction was found active against pylorus ligation-, abs. ethanol-, indomethacin-, indomethacin plus HCl/EtOH-induced gastric and cysteamine-induced duodenal lesions while ineffective against serotonin-induced gastric lesions. The active fraction showed its activity not only on per os administration but also after subcutanous injection. According to the results of biochemical studies, the active fraction showed a potent antiacid activity. In addition, histopathological, and toxicological studies were conducted with the active fraction.

Animals↗
PubMed2000

Noninvasive study of radiation-induced oxidative damage using in vivo electron spin resonance.

Nitroxyl radicals injected into a whole body indicate the disappearance of signal intensity of in vivo electron spin resonance (ESR). The signal decay rates of nitroxyl have reported to be influenced by various types of oxidative stress. We examined the effect of X-irradiation on the signal decay rate of nitroxyl in the upper abdomen of mice using in vivo ESR. The signal decay rates increased 1 h after 15 Gy irradiation, and the enhancement was suppressed by preadministration of cysteamine, a radioprotector. These results suggest that the signal decay of nitroxyl in whole mice is enhanced by radiation-induced oxidative damage. The in vivo ESR system probing the signal decay of nitroxyl could provide a noninvasive technique for the study of oxidative stress caused by radiation in a living body.

Animals↗
PubMed2001

Attenuation of radiation-induced genomic instability by free radical scavengers and cellular proliferation.

To investigate the mechanisms of radiation-induced chromosomal instability, cells were irradiated in the presence of the free radical scavengers DMSO, glycerol, or cysteamine, in the presence of DMSO while frozen, or held in confluence arrest post-irradiation to permit cells to repair potentially lethal DNA damage. Clones derived from single progenitor cells surviving each treatment were then analyzed for the subsequent development of chromosomal instability. The presence of scavengers (+/- freezing) during irradiation, and the recovery from potentially lethal damage after irradiation led to an increase in cell survival that was accompanied by a decrease in the initial yield of chromosomal rearrangements. Furthermore, analysis of over 400 clones and 80,000 metaphases indicates that these same treatments reduced the incidence of instability at equitoxic doses when compared to controls irradiated in the absence of scavengers at ambient temperature. Results suggest that preventing reactive species from damaging DNA, promoting chemical repair of ionized DNA intermediates, or allowing enzymatic removal of genetic lesions, represent measures that reduce the total burden of DNA damage and reduce the subsequent onset of radiation-induced genomic instability.

Animals↗
PubMed1997

In vivo electron paramagnetic resonance studies on oxidative stress caused by X-irradiation in whole mice.

The effect of x-irradiation on the reduction rates of nitroxyl radicals was examined in whole mice using in vivo EPR. One hour after irradiation, the reduction rates of nitroxyl increased up to 15 Gy irradiation, but decreased over this dose. The enhancement of the reduction rate of nitroxyl was suppressed by preadministration of a radioprotector, cysteamine, suggesting that the enhancement of nitroxyl reduction is related to the radiation damage. Thiobarbituric acid-reactive substances (TBARS) in liver homogenate were increased by x-irradiation, indicating that x-irradiation induced oxidative stress in mice. Endogenous antioxidant, alpha-tocopherol, and the activities of antioxidative enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase were not induced by x-irradiation under these experimental conditions. Eventually the nitroxyl reduction in whole mice should be enhanced by the oxidative stress due to x-irradiation. An in vivo EPR system probing the nitroxyl reduction should be applicable to the noninvasive study on the oxidative stress caused by radiation.

Animals↗
PubMed1997

Increased transcription of the astrocyte gene GFAP during middle-age is attenuated by food restriction: implications for the role of oxidative stress.

Glial fibrillary acidic protein (GFAP), an intermediate filament of astrocytes, shows increased expression during aging. Because we found that chronic food restriction retards the increase of GFAP mRNA in aging rats and because food restriction decreases the load of oxidized proteins and lipids in association with increased life span, we investigated the regulation of GFAP during oxidative stress and aging. First, we showed that food restriction decreased the transcription of GFAP in aging rats. This result generalizes effects of food restriction on age changes of transcription; whether transcription decreases during aging as in hepatic genes, or increases during aging as in astrocytic GFAP, food restriction attenuates the age change. Moreover, food restriction decreased microglial activation during aging, which suggested the hypothesis that GFAP expression is sensitive to oxidative stress. Because GFAP transcription in cultured glia is increased by oxidative stress in response to hydrogen peroxide and cysteamine whether or not microglia were present, we conclude that responses of GFAP to oxidative stress in astrocytes do not depend on microglial activation. The results implicate oxidative stress in the increased expression of GFAP during aging, but also in responses to brain injury.

Aging↗
PubMed1999

Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide.

The reactivities of glutathione, cysteine, cysteamine, penicillamine, N-acetylcysteine, dithiothreitol and captopril with superoxide generated from xanthine oxidase and hypoxanthine, and with reagent hydrogen peroxide, have been investigated. Rates of thiol loss on adding hydrogen peroxide, and superoxide-dependent thiol loss and oxygen uptake were measured. The relative reactivities of the different thiols with both oxidants were inversely related to the pK of the thiol group, such that at pH 7.4, penicillamine was the most reactive. N-acetylcysteine weakly reactive and no reaction was seen with captopril. For hydrogen peroxide, the calculated rate constants for the reaction with the thiolate anion all fell within the range 18-26 M(-1) s(-1). With superoxide, our results are consistent with each thiol reacting via a short chain that consumes oxygen and regenerates superoxide. Only with some of the thiols, was the consumed oxygen recovered as hydrogen peroxide. Reported values for the rate constant for the reaction of thiols with superoxide vary over four orders of magnitude, with the highest being > 10(5) M(-1) s(-1). Due to the complexity of the chain reaction, no study so far has been able to obtain accurate values and we consider the best estimates to be in the 30 to 1000 M(-1) s(-1) range.

Acetylcysteine↗
PubMed1995

Differential proliferation of somatostatin and glucagon cells in rat pancreatic islets submitted to various stimuli.

The populations of endocrine cells in pancreatic islets are subjected to striking fluctuations in their size when subjected to sustained stimulation and/or inhibition of their secretory activity. The stimulation of a specific endocrine secretion is followed by proliferation of its producing cell, a situation that is reversed after interruption or inhibition of the stimulus. Morphometric and cytological modifications of somatostatin and glucagon producing cells (D and A cells respectively) in the islets of Langerhans have been studied by electron microscopy, immunocytochemistry and morphometry in pancreas of rats submitted to the following experimental conditions: 1) Adrenalectomized (ADX), 2) ADX treated with hydrocortisone, 3) Diabetic and 4) Cysteamine (CSH) treated rats. In addition to ultrastructural changes, the populations of A and D cells were analyzed morphometrically applying a computerized system for light microscopy of paraffin sections immunostained with peroxidase-antiperoxidase (PAP) technique. Glucagon cell population displayed striking alterations in fine structural features and in the volume density in the different experimental conditions examined. By contrast, the cytological organization and the size of somatostatin cell population were little or not affected except in the diabetic rats where the massive degeneration of beta cells grossly distorted the structure of the islets. These observations led to the conclusion that the population of D cells constitutes a stable of endocrine system, at variance to the profound modifications occurring in A cells when they are submitted to various experimental conditions that stimulate or inhibit their secretory activity.

Adrenalectomy↗
PubMed1998

Importance of the two ester functions for the brain retention of 99mTc-labelled ethylene dicysteine diethyl ester (99mTc-ECD).

99mTc-ethylene dicysteine diethyl ester (99mTc-L,L-ECD) is a neutral lipophilic tracer agent that crosses the blood-brain barrier and is retained in the brain of primates following enzymatic hydrolysis of one of the ester functions to the ionized mono-ester, mono-acid metabolite. Up to now, it is not clear whether the second ethylcarboxylate group is essential for brain uptake and retention. Therefore, we have synthesized and studied two derivatives of 99mTc-L,L-ECD that contain only one ethylcarboxylate function, namely 99mTc-labelled L- and D-ethylene cysteamine cysteine ethyl ester (99mTc-ECCE). Direct labelling of L- or D-ECCE at neutral pH and room temperature resulted for each of them in the formation of two probably diastereomeric 99mTc-complexes in a 1:1 ratio. This means that four different isomers could be isolated. The 99mTc-labelled complexes formed after labelling ECCE (A and B, in order of elution during HPLC) are slightly less lipophilic than 99mTc-L,L-ECD. In mice, all four isomers show a low brain activity at 10 min post injection (p.i.), approximately 0.1% to 0.3% of the injected dose versus 0.9% for 99mTc-L,L-ECD. The clearance from the blood is comparable with (isomers LA and LB) or slower (isomers DA and DB) than that of 99mTc-L,L-ECD. Isomers LA and DA show high liver uptake and rapid excretion to the intestines. Both 99mTc-ECCE-LB and 99mTc-ECCE-DB, the most lipophilic isomers, are cleared from the blood mainly by the kidneys and excreted more efficiently to the urine. 99mTc-ECCE-LB is characterized by a surprisingly high heart uptake (about 1.5% of i.d.) at 10 min p.i. versus 1.0% for 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) and 0.2-0.3% for the other isomers, but also lung uptake is relatively high. In the baboon, brain and heart uptake of isomers LA and LB of 99mTc-ECCE were negligible. Activity concentrated mostly in the hepatobiliary system for isomer LA and in the renal system for isomer LB. The results indicate a clear difference in biological behaviour between 99mTc-L,L-ECD and the four isomers of 99mTc-ECCE. This shows that the presence of both ester functions in 99mTc-L,L-ECD is an essential structural requirement for its brain uptake and retention in primates.

Animals↗
PubMed2002

Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat.

The present study aimed to evaluate the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Acute inflammation was induced by sub-plantar injection of carrageenan (1%) in the rat hind paw. The rats received vehicle or drug 30 min before carrageenan administration and were evaluated for paw oedema at 1, 2, 3, and 4 h post-carrageenan. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Nociception was tested by determining vocalization following electrical stimulation of the tail. Given intraperitoneally (i.p.) 30 min before carrageenan, melatonin caused significant and a dose-dependent reduction of hind paw swelling induced by carrageenan. At doses of 0.5 and 1 mg kg(-1), melatonin inhibited the carrageenan-induced oedema by 20.5 and 29.6% versus control values at 4 h post-carrageenan, respectively. Melatonin (0.5 and 1 mg kg(-1), i.p.) 30 min beforehand displayed anti-nociceptive effect in the electric stimulation of the rat tail test, increasing nociceptive thresholds to electrically-induced pain at 4 h post-treatment by 29.6 and 39.5%, respectively. Melatonin given simultaneously with the non-selective COX-1 and COX-2 inhibitor indomethacin (5 mg kg(-1), i.p.) 30 min prior to carrageenan, enhanced the anti-inflammatory effect of the latter in the carrageenan-induced paw oedema model by 23%. Melatonin (0.5 mg kg(-1), i.p.) increased the anti-nociceptive effect of indomethacin (5 mg kg(-1), i.p.). Meanwhile, the anti-inflammatory and anti-nociceptive effect of the highly selective COX-2 inhibitor rofecoxib (2.25 mg kg(-1), i.p.) was only slightly increased by melatonin administration at 0.5 mg kg(-1). Melatonin enhanced the anti-inflammatory effect of cysteamine (300 mg kg(-1), s.c.) in the carrageenan-induced paw oedema. Melatonin (20 and 40 microg per paw) given prior to carrageenan into the rat hind paw was devoid of anti-inflammatory effect. These results indicate that melatonin possesses anti-inflammatory and anti-nociceptive properties in the rat and enhance those of indomethacin. This effect is likely to be centrally mediated.

Administration, Topical↗
PubMed2002

The effects of lysosomotropic agents on normal and INCL cells provide further evidence for the lysosomal nature of palmitoyl-protein thioesterase function.

Fatty acylation of proteins on cysteine residues is a common post-translational modification that plays roles in protein-membrane and protein-protein interactions. Recently, we described a lysosomal palmitoyl-protein thioesterase that removes long-chain fatty acids from lipid-modified cysteine residues in proteins. Deficiency in palmitoyl-protein thioesterase results in a human lysosomal storage disorder, infantile neuronal ceroid lipofuscinosis (INCL), which primarily affects the central nervous system. The pathological hallmark of the disorder is the accumulation of granular osmiophilic deposits (GROD) that resemble lipofuscin, or aging pigment. In previous work, we have shown that [35S]cysteine-labeled lipid thioesters derived from fatty acylated proteins accumulate in cultured cells derived from palmitoyl-protein thioesterase-deficient patients. In the present work, we show that the lipid cysteine thioesters accumulate in the lysosomal fraction, and we further show that the appearance of these compounds in the organic phase is blocked by inhibitors of lysosomal proteolysis, demonstrating through biochemical means the lysosomal nature of the site of palmitoyl-protein thioesterase action. Furthermore, substrates for palmitoyl-protein thioesterase accumulate even in normal cells after leupeptin or chloroquine treatment. This was demonstrated by subjecting extracts of treated cells to exhaustive proteolysis to release protein-bound cysteine lipid for analysis. Cysteamine, a lysosomotropic drug recently proposed for the treatment of INCL, was found to have effects similar to leupeptin and chloroquine, suggesting that its mechanism of action may be more complex than previously understood.

Cell Line, Transformed↗