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At least 1,243 records · Page 69Linked to original sources
PubMed1989

Double inhibition of L-threonine dehydratase by aminothiols.

The inhibition of highly purified rat liver L-threonine dehydratase (L-threonine hydro-lyase (deaminating), EC 4.2.1.16) by aminothiols (L-cysteine, D-cysteine, cysteamine) has been studied. Single inhibition experiments evaluated by Lineweaver-Burk and Dixon plots showed, in a given concentration range, partially (parabolic) competitive inhibitions, indicating two binding sites for each inhibitor. Double inhibition experiments revealed that the inhibition was antagonistic, the two inhibitors weakening each other's effect. Formation of EI1 and EI2 binary complexes, and ESI1, ESI2 and EI1I2 ternary complexes was demonstrated, while formation of the quaternary complex ESI1I2 was ruled out. It is assumed that one inhibitor-binding site coincides with the substrate-binding center while the second inhibitor-binding (allosteric, regulatory) site may comprise the pyridoxal-phosphate-binding SH group(s). The comparison between Km and Ki values and the evaluation of intracellular concentrations of L-threonine, L-cysteine and cysteamine suggest a possible physiological role of the inhibition.

Animals↗
PubMed1990

Inhaled thiol and phosphorothiol radioprotectors fail to protect the mouse lung.

Pretreatment with an inhaled aerosol of WR 2721, cysteamine or N-acetylcysteine failed to influence the development of radiation-induced lung damage at 14-16 weeks as assessed by a rise in breathing rate in the mouse. In contrast, intraperitoneal WR 2721 400 mg/kg and cysteamine 230 mg/kg were effective indicating that, unlike N-acetylcysteine, they are effective radioprotectors if correctly delivered.

Acetylcysteine↗
PubMed1990

Modulation of m-dinitrobenzene and m-nitrosonitrobenzene toxicity in rat Sertoli--germ cell cocultures.

Previous work has shown that m-dinitrobenzene is a testicular toxicant in rats in vivo, and in vitro produces comparable morphological changes in rat testicular Sertoli-germ cell cocultures. m-Dinitrobenzene is metabolized both in vivo and in the in vitro system to m-nitroaniline m-nitroaniline and m-nitroacetanilide. These metabolites do not provoke testicular toxicity in vivo or in vitro. We have therefore proposed a pathway for the metabolism of m-dinitrobenzene to m-nitroaniline and m-nitroacetanilide, which involved the intermediate m-nitrosonitrobenzene (1-nitroso-3-nitrobenzene, NNB). When tested, m-nitrosonitrobenzene, at equimolar doses to m-dinitrobenzene, produced similar morphological changes in the culture system to those exhibited by m-dinitrobenzene. However, m-nitrosonitrobenzene produced a greater toxicity than did m-dinitrobenzene (as measured by germ cell detachment). When the intracellular thiol levels were reduced in the cocultures pretreated with diethyl maleate, the toxicity of both m-dinitrobenzene and m-nitrosonitrobenzene was enhanced. In contrast, pretreatment of cocultures with agents known to increase cellular thiol (cysteamine) or scavenge reactive intermediates (cysteamine or ascorbate) reduced the toxicity of m-dinitrobenzene and m-nitrosonitrobenzene. We propose that m-dinitrobenzene requires metabolic activation before it can exert its toxicity to Sertoli cells, and it appears that the toxic species is m-nitrosonitrobenzene or a further metabolite of m-nitrosonitrobenzene.

Animals↗
PubMed1992

Some recent data on chemical protection against ionizing radiation.

Once introduced in the organism, the radioprotectors are fastly degraded and that increases their toxicity, shortens their duration of action and renders them inactive after oral delivery. So, it was tried to protect them by their incorporation in vectors. When a cysteamine-liposomal suspension was orally delivered, it showed a radioprotective activity for about 4 hours. By using 35S cysteamine, it was noted that its plasmatic concentration was increased. Freeze-drying of these preparations was a good mean of conservation if the samples were stored at 4 degrees C. A good and sustained activity was also obtained after oral delivery of WR-2721 entrapped in microspheres. Otherwise, it was shown that after interacting with the polar heads of phospholipids, under determined conditions of pH and in fluid phase, aminothiols can penetrate inside the membrane and be entrapped in the internal medium of liposomes and as they penetrate, they can lessen the diffusion of oxygen in the lipidic bilayers.

Administration, Oral↗
PubMed1991

Ultrasonic cavitation indirectly induces single strand breaks in DNA of viable cells in vitro by the action of residual hydrogen peroxide.

Direct exposure of cells to vigorous ultrasonic cavitation results predominantly in mechanical cell lysis, but latent effects due to production of toxic sonochemicals can also be present. Phosphate buffered saline (PBS) was exposed to 1.61 MHz ultrasonic cavitation at 20 degrees C in a rotating tube exposure system to build up sonochemical products. Single strand DNA breaks (SSBs) were then induced by treating Chinese hamster ovary (CHO) cells with the cavitated PBS for 30 min on ice. The SSBs resided in viable cells, as evidenced by their ability to repair the breaks when warmed. This indirect effect could be explained by the action of cavitation-generated hydrogen peroxide that had built up (e.g., to 16 microM after 30 min exposure) in the PBS. Dissolution of argon gas in the PBS before exposure enhanced the SSB effect and the H2O2 production. Addition of catalase to the cavitated PBS before cell treatment eliminated the H2O2 and the SSB gamma effect. Tests with hydrogen peroxide showed that 16 microM H2O2 treatment for 30 on ice was as effective as 1 Gy dose of 60Co gamma rays in producing single strand breaks. The SSB effect of H2O2 and gamma rays was reduced by addition of the radical scavenger cysteamine to the cells before treatment, but cysteamine did not reduce the SSB effect of direct exposure to ultrasonic cavitation. These results help to clarify the potential for genetic effects from ultrasonic cavitation. These effects help to clarify the potential for genetic effects from ultrasonic cavitation.

Animals↗
PubMed1991

A facilitatory role of endogenous somatostatin in long-term potentiation of the mossy fiber-CA3 system in guinea-pig hippocampus.

To estimate the functional role of endogenous somatostatin in the production of long-term potentiation (LTP) in mossy fiber-CA3 system, an influence of depletion of somatostatin on the magnitude of it was examined in guinea-pig hippocampal slices. Administration of cysteamine (200 mg/kg, s.c.), a depletor of somatostatin, to guinea-pigs 13 h prior to preparing slices resulted in a significant decrease in the magnitude of LTP of population spikes in mossy fiber-CA3 system, being associated with a significant depletion of the content of somatostatin in the hippocampus. Furthermore, bath-applied somatostatin (1-14) at a concentration, at which the substance did not influence LTP in slices prepared from saline-treated animals, significantly augmented LTP in slices from cysteamine-treated animals. Cyclo-somatostatin (0.32 and 3.2 microM), a putative antagonist of somatostatin receptors, failed to affect the magnitude of LTP of mossy fiber-CA3 system when applied alone; however, the combined application of cyclo-somatostatin with somatostatin (0.32 microM) significantly inhibited the augmenting action of somatostatin on LTP. From these observations, it is suggested that endogenous somatostatin plays a facilitatory role in the production of LTP in mossy fiber-CA3 system in guinea-pig hippocampus.

Animals↗
PubMed1978

Enzymatic degradation of succinyl-coenzyme A by rat liver homogenates.

When a dilute suspension of the mitochondrial fraction of rat liver homogenates was incubated with chemically synthesized succinyl-CoA, a product was rapidly formed which was retained at pH 3.9 on Dowex 50 (H+). Although its acid-base properties were indistinguishable from those of epsilon-aminolevulinic acid, the product did not form a pyrrole with acetylacetone, nor was its enzymatic formation dependent on added glycine. The enzyme which cleaved succinyl-CoA to the epsilon-aminolevulinic acid-like product was inhibited by phenylmethyl sulfonylfluoride. The first substance formed by the peptidase was the unstable thioester of succinic acid and cysteamine which underwent rearrangement to the more stable N-succinyl cysteamine above pH 4.0. It is apparent that the assay of epsilon-aminolevulinic acid synthetase (EC 2.3.1.37) by the ion-exchange method of Ebert et al. (Ebert, P.S., Tschudy, D.P., Choudhry, J.N. and Chirigos, M.A. (1970) Biochim. Biophys. Acta 208, 236--250) can yield erroneous results with succinyl-coenzyme A as substrate, especially when incubations are carried out for less than 25 min.

Acyl Coenzyme A↗
PubMed1986

Combined radiation-protective and radiation-sensitizing agents. III: Radiosensitization by misonidazole as a function of concentrations of endogenous glutathione or exogenous thiols.

Radiosensitization of V79 Chinese hamster fibroblasts by 0.5 mM misonidazole is a smooth function of endogenous glutathione (GSH) levels as modulated upwards by pre-incubation in medium containing cysteamine, or downwards by pre-incubation in medium containing buthionine sulfoximine. The enhancement ratio (radiation sensitivity in nitrogen/radiation sensitivity in nitrogen +/- sensitizer or thiol) varies from 1.3 at 12 mM to 2.25 at less than 0.1 mM endogenous GSH. The enhanced radiosensitivity of thiol-depleted hypoxic cells is reversed when exogenous thiols are added, and for equivalent ER, the exogenous thiol concentrations are much lower than the endogenous GSH concentrations. Measurement of intracellular drug concentrations amplified rather than diminished the above discrepancy, since intracellular concentrations of cysteamine were lower and glutathione much lower than the extracellular concentrations. Three possible explanations are addressed: an external membrane component of damage is involved, long-range protection to DNA target radicals is possible from outside the cell (e.g., donation of electrons), and (c) endogenous glutathione is not in a free or exchangeable state (e.g., bound).

Animals↗
PubMed1980

Effects of sulphur-containing compounds on paracetamol activation and covalent binding in a mouse hepatic microsomal system.

The interactions of cysteamine, N-acetylcysteine, 2-mercaptopropionylglycine and methionine with N-acetyl 4-aminophenol (paracetamol) have been examined during its metabolism to a covalently bound product in an in vitro mouse hepatic microsomal system. Of the compounds used only methionine failed to reduce the amount of covalently bound [3H]paracetamol-derived radioactivity. These results indicate that the effecitveness of methionine in reducing paracetamol hepatotoxicity in vivo is achieved by mechanisms other than those involving direct interactions with the hepatic mixed-function oxidase system or its oxidation products. In contrast, cysteamine, N-acetylcysteine and 2-mercaptopropionylglycine can directly inhibit the binding of [3H]paracetamol-derived radioactivity in vitro, and may do so by processes which affect both the formation and the subsequent binding of a reactive paracetamol metabolite.

Acetaminophen↗
PubMed1996

Comparative study of DNA radiolysis by fast neutrons and gamma-rays.

The effect of fast neutrons on cells is different from that of gamma-rays: the relative (to gamma) biological effect (RBE) is higher than one and the oxygen enhancement ratio (OER) is lower than that of gamma-rays. We searched for differences between the effects of the two radiations on DNA, the critical target of radiations. Using a model plasmid DNA we observed that for the same absorbed dose, fast neutrons induce twice fewer single strand breaks (SSB) and 1.5 more double strand breaks (DSB) than gamma-rays. A transition metal ion, the Cu++, is a better sensitizer of DNA breakage with fast neutrons than with gamma-rays. In anoxia, cysteamine, a positively charged thiol, is a better radioprotector against neutrons than against gamma-rays. In presence of cysteamine, the OER is lower for neutrons than for gamma-rays. These results are discussed in terms of different physical properties of the two types of radiation.

Copper↗
PubMed1985

Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in the rat.

The hypothesis that vascular injury contributes to the development of hemorrhagic erosions after intragastric administration of ethanol has been examined in the rat using vascular tracers. Extravasation of intravenously injected Evans blue into the gastric wall and into gastric contents was used as an indicator of vascular permeability. India ink and monastral blue, which label damaged blood vessels, were used to demonstrate vascular injury morphologically. Intragastric instillation of 75% and 100% ethanol induced increased vascular permeability within 1-3 min and resulted in monastral blue labeling of vessels in 13% and 17%, respectively, of the glandular mucosa within 1 min. After 1 h of 100% ethanol exposure, the areal density of monastral blue-stained blood vessels did not increase compared with that seen at 1 min, but the areal density of grossly visible hemorrhagic lesions increased strikingly and approximated that of vessel staining. The hemorrhagic erosions consistently occurred in regions of glandular mucosa where vessels were stained with monastral blue. Pretreatment with prostaglandin F2 beta or cysteamine reduced ethanol-induced Evans blue extravasation and monastral blue staining of mucosal blood vessels but did not reduce histologic evidence of gastric surface cell damage in the glandular mucosa. As increased vascular permeability and morphologically detectable vascular lesions consistently preceded the development of grossly visible hemorrhagic erosions in the glandular mucosa, we suggest that vascular injury is an early pathogenetic factor in the development of ethanol-induced gastric hemorrhagic erosions. The data also indicate that the degree of vascular damage, unlike the injury to surface epithelial cells, is reduced by pretreatment with prostaglandin F2 beta or the sulfhydryl cysteamine.

Animals↗
PubMed2001

Gastric antisecretory and antiulcer activity of oxytocin in rats and guinea pigs.

The effect of oxytocin (1 mg/kg s.c) on gastric acid secretion and on different experimentally induced gastric and duodenal ulcers was studied. The acute gastric ulcer models used were pylorus ligation, indomethacin, ethanol and histamine induced acute gastric ulcers. Chronic gastric ulcers were induced using acetic acid and duodenal ulcers by cysteamine hydrochloride. Oxytocin showed significant antisecretory and antiulcer activity in pylorus ligated rats. Similarly oxytocin reduced the ulcer index in histamine induced gastric ulcers in guinea pigs and cysteamine induced duodenal ulcers in rats. The antiulcer and antisecretory effect was comparable to that of ranitidine (50mg/kg, i.p) though less in intensity. However, it did not show any gastric cytoprotective effect in ethanol and indomethacin induced ulcer models but ranitidine showed protection (p<0.05) in later model. Oxytocin enhanced gastric ulcer healing in acetic acid induced chronic gastric ulcer model. The reversal of oxytocin effect by atosiban, an oxytocin receptor antagonist indicates a role for oxytocin receptors. The antiulcer activity of oxytocin can be attributed to its antisecretory effect.

Acetic Acid↗
PubMed1997

Radiation protection by alpha-methyl-homocysteine thiolactone in vitro.

The radiation protective effect of thiol compounds is unequivocal and their use is only limited by their toxic effects. We used the principle of alpha alkylation, which renders amino acids unmetabolizable, to reduce the toxicity of homocysteine. This product, alpha-methyl-homocysteine thio-lactone, was tested for toxicity and radiation protective effect along with known protectors L-cysteine, cysteamine and WR 1065 in cell culture using V79-4 Chinese hamster lung cells. The three-day growth curve assays, useful to measure overall effects on cell growth, revealed lowest toxicity for alpha-methyl-homocysteine thiolactone (GL-2). Clonogenic survival tests, used to evaluate the retention of reproductive integrity, were carried out and revealed that GL-2 had no adverse effects in this test system. Radiation protection tests showed that GL-2 exhibited protective activity against radiation induced lethality above that seen with cysteine and cysteamine, but below WR 1065. However, GL-2 showed little or no negative effects toward the cell itself, in direct contrast to WR 1065. Our findings show a potentially important tool and principle to reduce toxicity of radiation protectors with analogous structures.

Animals↗
PubMed2000

Reduction of gastrointestinal toxicity of NSAIDs via molecular modifications leading to antioxidant anti-inflammatory drugs.

Reactive oxygen species and free radical reactions are related to several pathologic conditions including inflammation and gastric ulceration. The latter is the major undesired side-effect of almost all NSAIDs. Since this effect of NSAIDs is greatly influenced not only by the type of cyclooxygenase which is inhibited but also by the acidic nature of the molecule, we considered it interesting to modify their structure in such a way that it would lead to an antioxidant, neutral molecule or a molecule with greatly reduced acidic character. Thus, we synthesized amide derivatives of four well-known NSAIDs, i.e. diclofenac acid, tolfenamic acid, ibuprofen and indomethacin, with cysteamine, a well-known antioxidant. The synthesized derivatives, with demonstrated good anti-inflammatory and antioxidant activities, showed very significant reduction of ulcerogenicity in the investigation of gastrointestinal (GI) toxicity. As indices of ulcerogenic toxicity in rats, we used the mortality (%), the incidence of GI ulcers (%), body weight reduction (g/100 g BW) and the incidence of melena. All amide derivatives of the NSAIDs with cysteamine were almost non-toxic in the GI tract, under our experimental conditions, in contrast to their parent NSAIDs. These results are attributed to the acquired antioxidant activity as well as to the reduction of acidic character compared with the parent compounds. Therefore, it can be concluded that the combination of these two properties, anti-inflammatory and antioxidant activity, with a simultaneous drastic reduction of acidic character, may lead to the development of novel, useful anti-inflammatory and cytoprotective pharmacomolecules, with potentially important therapeutic applications.

Amides↗
PubMed2001

An electrochemical evidence of free radicals formation from flutamide and its reactivity with endo/xenobiotics of pharmacological relevance.

This paper reports the feasibility of free radicals formation from flutamide by using cyclic voltammetry. The electrochemical characteristics and the reactivity of the one-electron reduction product from flutamide in mixed media with thiol compounds and the nuclei acid bases are characterized. Results from this paper show the thermodynamic feasibility of free radical formation expressed for both the cathodic peak potential and the second-order rate constant values. The reactivity of the radical towards thiol compounds (glutathione, cysteamine, N-acetylcysteine) and the nuclei acid base, adenine, thymine and uracil were quantitatively assessed through the calculation of the respective interaction rate constants. Based on these results, the following tentative order of reactivity towards the xeno/endobiotics is as follows: cysteamine > uracil > glutathione > adenine > N-acetylcysteine > thymine. The stability of the nitro radical anion electrochemically generated from flutamide showed a linear dependence with pH.

Acetylcysteine↗
PubMed2003

Electrochemical detection of DNA immobilized on gold colloid particles modified self-assembled monolayer electrode with silver nanoparticle label.

The target DNA was immobilized successfully on gold colloid particles associated with a cysteamine monolayer on gold electrode surface. Self-assembly of colloidal Au onto a cysteamine modified gold electrode can enlarge the electrode surface area and enhance greatly the amount of immobilized single stranded DNA (ssDNA). The electron-transfer processes of [Fe(CN)6](4-)/[Fe(CN)6](3-) on the gold surface were blocked due to the procedures of the target DNA immobilization, which was investigated by impedance spectroscopy. Then single stranded target DNA immobilized on the gold electrode hybridized with the silver nanoparticle-oligonucleotide DNA probe, followed by the release of the silver metal atoms anchored on the hybrids by oxidative metal dissolution, and the indirect determination of the released solubilized Ag(I) ions by anodic stripping voltammetry (ASV) at a carbon fiber microelectrode. The results show that this method has good correlation for DNA detection in the range of 10-800 pmol/l and allows the detection level as low as 5 pmol/l of the target oligonucleotides.

Cross-Linking Reagents↗
PubMed1997

Formation of free radicals and protein mixed disulfides in rat red cells exposed to dapsone hydroxylamine.

The hemolytic activity of dapsone is well known to reside in its N-hydroxylamine metabolites. Addition of dapsone hydroxylamine (DDS-NOH) to red cell suspensions causes damage such that when reintroduced into the circulation of isologous rats, the injured cells are rapidly removed by the spleen. Hemolytic activity is associated with the extensive formation of disulfide-linked hemoglobin adducts on red cell membrane skeletal proteins. To determine if free radicals could be involved in this process, rat red cells were incubated with DDS-NOH in the presence of the spin trap, 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) and subjected to EPR analysis. Addition of DDS-NOH (25-50 microM) to a red cell suspension gave rise to a four-line (1:2:2:1) EPR spectrum with coupling constants identical to those of a DMPO-hydroxyl radical adduct (DMPO-OH) standard. No other radicals were detected; however, preincubation of red cells with cysteamine caused the DDS-NOH-generated DMPO-OH signal to be replaced by a cysteamine thiyl radical adduct signal. DDS-NOH-treated red cells were also found to contain ferrylhemoglobin, indicating the presence of hydrogen peroxide. Furthermore, DDS-NOH was found to stimulate salicylate hydroxylation in red cell suspensions, confirming the presence of oxygen radicals. These data support the hypothesis that oxygen radicals are involved in the mechanism underlying dapsone-induced hemolytic anemia.

Animals↗
PubMed2005

Biophysical and biological studies of end-group-modified derivatives of Pep-1.

Pep-1 is a tryptophane-rich cell-penetrating peptide (CPP) that has been previously proposed to bind protein cargoes by hydrophobic assembly and translocate them across cellular membranes. To date, however, the molecular mechanisms responsible for cargo binding and translocation have not been clearly identified. This study was conducted to gain insight into the interaction between Pep-1 with its cargo and the biological membrane to identify the thereby involved structural elements crucial for translocation. We studied three peptides differing in their N- and C-termini: (i) Pep-1, carrying an acetylated N-terminus and a C-terminal cysteamine elongation, (ii) AcPepWAmide, with an acetylated N-terminus and an amidated C-terminus, and (iii) PepW, with two free termini. Thioredoxin (TRX) and beta-galactosidase were used as protein cargoes. To study CPP-membrane interactions, we performed biophysical as well as biological assays. To mimic biological membranes, we used phospholipid liposomes in a dye leakage assay and surfactant micelles for high-resolution NMR studies. In addition, membrane integrity, cell viability, and translocation efficiency were analyzed in HeLa cells. An alpha-helical structure was found for all peptides in the hydrophobic N-terminal region encompassing residues 4-13, whereas the hydrophilic region remained unstructured in the presence of micelles. Our results show that the investigated peptides interacted with the micelles as well as with the protein cargo via their tryptophan-rich domain. All peptides displayed an orientation parallel to the micelle surface. The C-terminal cysteamine group formed an additional membrane anchor, leading to more efficient translocation properties in cells. No membrane permeabilization was observed, and our data were largely compatible with an endocytic pathway for cellular uptake.

Cell Survival↗