THE USE OF PROTECTIVE SUBSTANCES FOR DIFFERENTIAL CHANGES OF RADIOSENSITIVITY IN NORMAL AND TUMOR TISSUES.
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Animals↗
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T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase.
Celiac disease is an HLA-DQ2-associated disorder characterized by intestinal T cell responses to ingested wheat gliadins. Initial studies used gliadin that had been subjected to non-enzymatic deamidation during pepsin/trypsin digestion to enrich for the gliadin-specific T cells in small intestinal celiac biopsies. These T cells recognized synthetic gliadin peptides only after their deamidation in vitro by purified tissue transglutaminase (tTG). However, as these studies used a deamidated antigen for re-stimulation prior to testing for antigen specificity, this raised the possibility that T cells specific for native epitopes had not been expanded in vitro and had thus been overlooked. To address this possibility and to look for more direct evidence that endogenous tTG mediates deamidation of gluten in the celiac lesions, we have here used a minimally deamidated chymotrypsin-digest of gliadin to challenge biopsies and then investigated the specificity of the T cell lines derived from them. Interestingly, these T cell lines only barely responded to the chymotrypsin-digested gliadins, but efficiently recognized the in vitro tTG-treated variants of the same gliadins. Moreover, the addition of a tTG-inhibitor during the gliadin challenge often resulted in T cell lines with abolished or reduced responses to deamidated gliadin. These data demonstrate that DQ2-restricted T cells within adult celiac lesions predominantly recognize deamidated gliadin epitopes that are formed in situ by endogenous tTG.
Amides↗
Investigating the reaction of a number of gel electrophoresis cross-linkers with beta-lactoglobulin by matrix assisted laser desorption/ionization-mass spectrometry.
A number of cross-linkers that are commonly used in polyacrylamide gels have been incubated with bovine beta-lactoglobulin B and the resulting reaction mixtures were examined by matrix assisted laser desorption/ionization-mass spectrometry. At concentrations of 0.1, 1, and 20 mM of each cross-linker incubated for 1 h with 50 pmol/microL of the protein, a reactivity scale can be expressed as polyethylene glycol diacrylate > N,N'-bisacrylylcystamine > bisacrylyl piperazine > N,N'-methylenebisacrylamide >> N,N'-diallyltartardiamide (PEGDA>BAC>BAP>Bis>>DATD). Relatively short incubation times indicated one of the five Cys residues as the target of reaction, which was confirmed by post-source decay measurements. Longer incubation times (24 h) with bisacrylamide extended the reaction to all five Cys residues and a number of Lys residues. A second consequence of longer reaction time is the involvement of both terminals of the cross-linker in the observed reaction. This experimental evidence is the first to demonstrate a different reactivity of both ends of one of the most commonly used cross-linkers. Investigation of solutions containing a cross-linker and acrylamide monomers provided useful information on the competition between the two identities for reaction with the protein. Possible implications of these experimental observations for isoelectric focusing separations in polyacrylamide gels are discussed.
Acrylamide↗
Transglutaminase activity in aging articular chondrocytes and articular cartilage vesicles.
OBJECTIVE: Transglutaminases (TGases) (E.C. 2.3.2.13) catalyze a posttranslational modification of proteins and are associated with biomineralization in growth plate cartilage. Type II TGase participates in the activation of latent transforming growth factor beta (TGFbeta), a crucial factor for both normal cartilage mineralization and the pathologic mineralization that results in calcium pyrophosphate dihydrate (CPPD) crystal formation in aging articular cartilage. To explore a possible association between TGase levels and CPPD crystal formation in mature articular cartilage, TGase activity in articular chondrocytes from old and young pigs and in the articular cartilage vesicle (ACV) fraction of porcine articular cartilage was examined. In addition, the effects of TGase inhibitors on the production of inorganic pyrophosphate (PPi), a process necessary for CPPD crystallogenesis, were determined. METHODS: TGase activity was measured with a radiometric assay in cultured articular chondrocytes from the knee joints of old (3-5 years old) and young (2-6 weeks old) pigs and in the ACVs. PPi levels were measured in chondrocyte-conditioned media in the presence of TGase inhibitors or control compounds. RESULTS: Levels of TGase activity in the cytosolic fraction of old chondrocytes were 7-fold higher than those in identically cultured young chondrocytes. The mean +/- SD activity level in the membrane fraction of lysed chondrocytes was 6.0 +/- 0.6 units/mg protein in old articular chondrocytes and was undetectable in young chondrocytes. In ACVs, the mean +/- SD TGase activity level was 1.23 +/- 0.1 units/mg protein. Type II TGase protein was present in chondrocyte cytosol and in ACVs. TGase activity was increased by TGFbeta to 120% of control values (P < 0.01), and decreased by insulin-like growth factor 1 to 80% of control values (P < 0.01). TGase inhibitors blocked media accumulation of PPi, an essential precursor of CPPD crystal formation, and a sensitive marker of TGFbeta effect. CONCLUSION: These data suggest a potential link between TGase activity and processes of pathologic biomineralization that result in CPPD crystal formation in aging articular cartilage.
Aging↗
Correlation between contractility and proliferation in human fibroblasts.
The contractile power of human fibroblasts was checked through their life span in vitro, using a plasma clot retraction test. It was found to decline with a pattern analogous to that of the different phases identifiable by the study of the kinetics of proliferation of these cells. The capacity to retract a plasma clot was higher in cells harvested during active growth than in cells harvested in resting phase. The decreased ability to retract during aging becomes apparent when cells are harvested in resting phase. Decreased retractile activity was also observed in postnatal cells as compared with embryonic cells. The results support a correlation between the initiation of DNA synthesis and the turnover of cytoskeletal elements. The data fit our previous results showing that the early proliferative disturbance during cellular senescence consists of a decline in the probability of initiating the division cycle linked to impaired cell attachment and spreading.
Cell Division↗
Effects of drugs on pituitary fine structure in laboratory animals.
Although an increasing number of chemicals are reported to affect endocrine glands, only a few studies are dealing with their toxic effect on pituitary. The drugs can induce lesions acting directly on endocrine cells or indirectly by interfering with the regulation of their endocrine activities. Some drugs stimulate pituitary cell proliferation leading to hyperplasia and tumor formation; other chemicals have an inhibitory effect on adenohypophysial cells; and only one drug, hexadimethrine bromide, has been found to induce pituitary necrosis. Although complex toxicologic studies have been carried out on many chemicals, the mechanism of action of most drugs is not completely elucidated and further studies are necessary to establish structure function correlations.
Acrylonitrile↗
Inhibition of influenza A virus replication by rifampicin and selenocystamine.
The effects of selenocystamine, an inhibitor of influenza virus RNA-dependent RNA polymerase in vitro activity, in the antibiotic rifampicin were studied on influenza A/PR/8/34 (HON1) infection in embryonated eggs. Both drugs completely inhibited hemagglutinating and infective virus yields when added at relatively early times postinfection. Maximal inhibition was produced by apparently noncytotoxic concentrations of 50 microgram of selenocystamine, or of 400 microgram of rifampicin, per egg.
Animals↗
Effect of antiviral substances on hepatitis A virus replication in vitro.
The effect of protamine, atropine, selenocystamine, taxifolin, and catechin on the infectivity and antigenicity of the cell culture-adapted hepatitis A virus (HAV) strain CF 53 was studied. The toxicity on uninfected PLC/PRF/5 cells was examined for each antiviral compound by morphological and biochemical methods, in order to determine concentrations without cytotoxic effect. At these concentrations, protamine and taxifolin, added to infected cells for a 15-day period, caused concentration-dependent reductions in the infectivity and antigenicity of HAV. Atropine also caused a concentration-dependent reduction of HAV infectivity but did not affect the antigenicity of the virus. At the highest concentration used, 50 micrograms/ml of protamine, 59 micrograms/ml of taxifolin, and 50 micrograms/ml of atropine, the infectious viral titer reduction was 1.56, 0.77, and 0.68 log10, respectively. Selenocystamine and catechin had no effect on HAV replication.
Antigens, Viral↗
Polymethylene tetraamines: a novel class of cardioselective M2-antagonists.
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Amines↗
Catalysis of reduction of disulfide by selenol.
The reduction of a disulfide to thiols, using sodium borohydride or dithiothreitol as reductant, is catalyzed by selenol. The rates of reduction of oxidized glutathione and bis(2-hydroxyethyl) disulfide by sodium borohydride are accelerated using a catalytic amount of selenol (8 mol% of the disulfide), by factors of 10 and 12, respectively. A rapid and convenient assay for disulfide has been developed, which involves its reduction with sodium borohydride in the presence of a catalytic amount of selenol, followed by acid quench and measurement of the resulting thiol by Ellman's assay. The disulfide bonds in proteins are reduced rapidly using excess dithiothreitol (5 mM) and selenol (0.8 mM), which can be separated conveniently from the reduced protein by gel filtration. The rates of reduction of disulfide bonds in immunoglobulin and alpha-chymotrypsinogen A by dithiothreitol are enhanced by a factor of 90 in the presence of selenol. The rate-determining step is the reaction of selenolate anion with disulfide. Selenocystamine, a commercially available diselende, is used as the precursor of the catalyst; it is reduced to its selenol in situ.
Borohydrides↗
Alpha and beta adrenergic receptor involvement in catecholamine-induced growth of gram-negative bacteria.
The effect of a number of adrenergic receptor agonists and antagonists on the growth of Escherichia coli and Yersinia enterocolitica was examined in order to delineate possible receptor mechanism(s) by which the catecholamines influence the growth of gram-negative bacteria. Neither alpha or beta adrenergic receptor agonists or antagonists affected growth in a dose-dependent manner similar to that observed for norepinephrine. The physiological less active enantiomer of norepinephrine, (+)-norepinephrine, did not affect catecholamine-induced growth to a similar degree as that observed with the active enantiomer. These results suggest that a non-alpha, non-beta adrenergic receptor mediated process may play a role in catecholamine-induced growth of gram-negative bacteria.
Alprenolol↗
Seleno compounds and glutathione peroxidase catalyzed decomposition of S-nitrosothiols.
Seleno compounds such as selenocystamine and seleno-D, L-cystine were found to catalyze the decomposition of S-nitrosothiols (e.g. S-nitroso-glutathione and S-nitroso-N-acetyl-D, L-penicillamine) in the presence of different thiols (e.g. glutathione, N-acetyl-D-penicillamine and 2-mercaptoethanol), and liberate nitric oxide. It was also found that glutathione peroxidase itself can catalyze the decomposition of S-nitrosoglutathione without the presence of any thiol or H2O2.
Catalysis↗
Modulation of inflammatory paw oedema by cysteamine in the rat.
Cysteamine, a potent somatostatin depletor, was used in the present study to investigate the role of endogenous somatostatin in acute peripheral inflammation. The acute inflammation was induced by intraplantar injection of carrageenan (1%), histamine (5 micromol), or formalin (2.5%) in the rat hind paw. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Given subcutaneously (s.c.) 1 h before carrageenan, cysteamine caused significant, dose-dependent and long-lasting inhibition of rat paw oedema induced by carrageenan. At doses of 12.5, 25, 50 or 100 mg kg (-1), cysteamine significantly inhibited the carrageenan-induced paw oedema at 4 h by 52.3, 40, 40.7 or 26.3%. Cysteamine given at 300 mg kg (-1), a dose well known to deplete tissue somatostatin, reduced oedema by only 16.2% vs control values. Significant inhibition of the carrageenan-induced rat paw oedema was still evident 24 h post-injection at cysteamine doses of 12.5, 25, 50 or 100 mg kg (-1). Given s.c. at 300 mg kg (-1), 4 h prior to carrageenan, cysteamine decreased rat paw oedema at 4 h by 14.9%. Cysteamine (300 mg kg (-1)), 4 h beforehand, had little modulatory effect on the oedema induced by formalin (2.5%) but reduced that caused by intraplantar histamine (5 micromol). The anti-oedematogenic effect of indomethacin, but not that of the selective COX-2 inhibitor celecoxib, was less marked in rats pre-treated with cysteamine at 300 mg kg (-1). Cysteamine (0.3 microg- 0.3 mg paw (-1)) co-administered with carrageenan was devoid of anti-inflammatory effect and even promoted inflammation at low concentrations. Cysteamine given locally alone induced slight paw oedema. These data indicate that systemic cysteamine possesses potent and long-lasting anti-inflammatory effects and modulates the anti-inflammatory effect of cyclooxygenase inhibitors in a model of peripheral inflammation in the rat. The effect of cysteamine is likely to be mediated via central action.
Animals↗
Inactivation of glutathione peroxidase by benzaldehyde.
Chronic benzaldehyde exposure is known to cause central nervous system (CNS) disturbances. Previous studies have shown that benzaldehyde causes the formation of reactive oxygen species (ROS) in rat synaptosomal fractions. Benzaldehyde has also been implicated in ROS formation in the CNS of rats treated with toluene. We have found that benzaldehyde effectively inactivates the antioxidant enzyme glutathione peroxidase (Ki approximately 15 microM), but has no effect on the other antioxidant enzymes tested: catalase, superoxide dismutase, and glutathione reductase. This effect has been found to be specific to benzaldehyde since other structurally related and unrelated aldehydes tested were found to be devoid of inactivating capacity toward glutathione peroxidase. Since glutathione peroxidase is the main enzyme responsible for removal of hydrogen peroxide and organic hydroperoxides in brain, its inactivation by benzaldehyde may be a main contributor to the observed ROS formation and the observed neurotoxicity caused by either benzaldehyde or toluene exposure.
Animals↗
In vitro reactions of hypotaurine.
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Chromatography, Thin Layer↗
Some ideas concerning the mode of action of radioprotective agents.
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Adrenal Glands↗
Effects of the irreversible alpha-adrenoceptor antagonists phenoxybenzamine and benextramine on the effectiveness of nifedipine in inhibiting alpha 1- and alpha 2-adrenoceptor mediated vasoconstriction in pithed rats.
In pithed normotensive rats, i.v. injection of the selective alpha 1-adrenoceptor agonist cirazoline produced vasoconstriction which was largely resistant to inhibition by nifedipine. On the other hand, the pressor effects of the selective alpha 1-adrenoceptor agonists St 587 and Sgd 101/75 were much more effectively blocked by nifedipine, although not as effectively as the pressor effects to the selective alpha 2-adrenoceptor agonist B-HT 920. The sensitivity to inhibition of vasoconstriction in pithed rats to the different agonists increased in the order cirazoline much less than St 587 less than Sgd 101/75 less than B-HT 920. Phenoxybenzamine (3-300 micrograms/kg, i.v., -60 min) irreversibly antagonized the vasoconstriction to cirazoline, St 587, Sgd 101/75 and B-HT 920. After treatment of the rats with phenoxybenzamine the potency and efficacy of nifedipine in antagonizing vasoconstriction to alpha 1-, but not to alpha 2-adrenoceptor activation was dose-dependently enhanced. The potency of nifedipine to inhibit alpha 1-adrenoceptor-mediated vasoconstriction by cirazoline, St 587 and Sgd 101/75 was increased maximally to the level of efficacy at which nifedipine antagonized B-HT 920-induced vasoconstriction. The dose of phenoxybenzamine required to maximally increase the potency and efficacy of nifedipine to antagonize vasoconstriction of the alpha 1-adrenoceptor agonists was inversely related to the level of sensitivity to blockade by nifedipine of the vasoconstriction they produced. In contrast, pretreatment of rats with the irreversible antagonist, benextramine (10 mg/kg, i.v., -100 to -60 min) did not increase the potency or efficacy of nifedipine to antagonize vasoconstriction to cirazoline, St 587, Sgd 101/75 or B-HT 920, despite irreversible blockade of alpha 1- and alpha 2-adrenoceptors. These data suggest that phenoxybenzamine, but not benextramine, selectively inhibits the alpha 1-adrenoceptor mediated vasoconstrictor mechanism that is independent of influx of extracellular calcium. Moreover, the results show that the existence of receptor reserve or the number of alpha 1-adrenoceptors activated does not determine the relative contribution of calcium influx-independent mechanisms in alpha 1-adrenoceptor-mediated vasoconstriction.
Animals↗
Evidence for a receptor mediated action of norepinephrine distinct from alpha- and beta-adrenoceptors.
The mode of action of (-) norepinephrine (NE) and UK-14,304-18 has been investigated using the cholinergically-evoked 'twitch' response of the electrically stimulated guinea-pig ileum. St 587 and benextramine were employed as antagonists. St 587 acted as a competitive antagonist toward UK-14,304-18, yielding an apparent pA2 value of 7.3. In contrast, St 587 failed to act competitively toward NE. Similarly, benextramine (1 X 10(-5) mol/l) blocked the inhibitory responses to UK-14,304-18 but was considerably less active toward NE. Remaining responses to NE after benextramine were not antagonized by St 587, even at a concentration of 3 X 10(-5) mol/l. It is postulated that NE acts to inhibit the 'twitch' response be evoking two different receptor-mediated events: 1. agonism at the alpha 2-adrenoceptor and 2. agonism at a site which is distinct from the alpha- and beta-subtypes. In the concentrations studied, UK-14,304-18, St 587 and benextramine are postulated to lack affinity for the proposed site. The effect of NE and UK-14,304-18 was also investigated on the contractile responses to exogenously applied histamine. These experiments were done in the presence of muscarinic cholinergic and adrenoceptor blockade. NE inhibited responses to histamine but UK-14,304-18 was inactive. Furthermore, the inhibitory action of NE was stereoselective with the (-) form being 25 times more potent than the (+) enantiomer. These findings suggest the presence of a receptor site for NE which is distinct from cholinergic mechanisms and established alpha and beta-adrenoceptors.
Adrenergic alpha-Agonists↗