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PubMed1993

An amplified assay for thiols based on reactivation of papain.

A sensitive spectrophotometric assay has been developed for thiol (sulfhydryl) groups using an inactive disulfide derivative of papain (papain-S-SCH3). The thiol-disulfide interchange reaction of a thiol with papain-S-SCH3 results in the stoichiometric formation of active papain (papain-SH). The reactivated papain catalyzes the hydrolysis of a chromogenic substrate, resulting in an amplified spectrophotometric signal proportional to the initial amount of thiol. A variety of thiols, e.g., cysteine, glutathione, penicillamine, cysteine methyl ester, and cysteamine, yield similar linear plots for the activity of papain vs the initial amount of thiol. An unknown concentration of a thiol is measured using a standard plot for the activity of papain vs the amount of thiol, obtained for the same thiol or for a similar thiol. Thiol groups on proteins and thiol groups of high values of pKa (2-mercaptoethanol, 3-mercaptopropanoic acid) can also be assayed using papain-S-SCH3 in the presence of excess cystamine. The assay is about 100-fold more sensitive than that using Ellman's reagent [5,5'-dithiobis(2-nitrobenzoic acid)]. A 0.4 microM solution of cysteine produces an absorbance change of 0.55 at 410 nm after 30 min in the assay, compared to a predicted change in absorbance of 0.0054 using Ellman's assay.

Aniline Compounds↗
PubMed2000

Modulation of lens glycolytic pathway by thioltransferase.

The observation that the level of S-thiolated proteins (protein-thiol mixed disulfides) was transiently increased in the lens epithelial cells correlation with the transient inactivation of glyceraldehyde-3-phosphate dehydrogenase (G-3PD), a key glycolytic enzyme, when the cells were treated with a bolus of hydrogen peroxide, prompted our speculation that G-3PD may have been transiently thiolated at the SH sensitive active center. In the meantime, thioltransferase (TTase), a thiol regulating enzyme, whose activity remained constant under the same condition, may be regulating G-3PD and other sulfhydryl-sensitive glycolytic enzymes through thiol-disulfide exchange reactions ( Lou et al., 1998 ). To prove this hypothesis, several purified glycolytic enzymes from a commercial source, including hexokinase (HK), G-3PD, pyruvate kinase (PK) and fructose 1,6-bisphosphatase (FBPase), an enzyme in gluconeogenesis, were made into protein-thiol mixed disulfide and used for this study. Glycolytic enzymes in cultured rabbit lens epithelial cells pre-exposed to H(2)O(2)(0.5 m M for 15 min) were also studied for this purpose. Recombinant human lens thioltransferase (RHLT), which was isolated and purified previously in this laboratory, reactivated these pure glycolytic enzymes inactivated by forming protein-S-S-gluthathione (PSSG), protein-S-S-cysteine (PSSC) or, protein-S-S-cysteamine after thiolating with oxidized glutathione, cystine or cystamine respectively. RHLT also reactivated these enzymes in the cell extract of cultured rabbit lens epithelial cells after being briefly exposed to 0.5 m M H(2)O(2). The S-thiolation and dethiolation of FBPase however, showed an opposite effect to that of glycolytic enzymes. These results suggest that TTase may participate in the repair process of glycolytic enzymes during oxidative stress and restore their activities in situ.

Adenosine Triphosphate↗
PubMed1999

Renal metabolism of acrylonitrile to cyanide: in vitro studies.

Acrylonitrile (VCN) is a widely used industrial chemical. The present work examines the mechanism of its renal toxicity. In renal centrifugal fractions from Sprague-Dawley rats, the metabolism of VCN to cyanide (CN(-)) was highest in the microsomal fraction and required a NADPH-generating system in the presence of magnesium ions for maximum activity. This biotransformation of VCN to CN(-)was characterised with respect to time (15 min), microsomal protein concentration (3 mg ml(-1)), pH (7.5) and temperature (37 degrees C). The V(max)of the reaction was 118.2 pmol CN(-)mg(-1)protein min(-1)and K(m)was 160.2 micromol VCN. Activation of VCN to CN(-)was markedly increased in microsomes obtained from phenobarbital (PB), ethanol, 4-methylpyrazole and 3-methylcholanthrene-treated rats by 161.5, 89.6, 71.0 and 50.2%, respectively. Addition of SKF 525-A (5x10(-4)m) or benzimidazole (2 m m) to the incubation mixtures significantly inhibited VCN metabolism by 66.6 and 78.8%, respectively. VCN metabolism to CN(-)was enhanced significantly by the addition of 10 m m of glutathione (GSH), l -cysteine, d -penicillamine, cysteamine or 2-mercaptoethanol to 389.5, 886.5, 611. 1, 145.5 and 384.0% of control, respectively. These findings indicate that VCN is metabolised in the kidney via cytochrome P-450-dependent mixed function oxidase system. 1999 Academic Press.

Acrylonitrile↗
PubMed1986

Improved method for determination of cellular thiols, disulfides and protein mixed disulfides using HPLC with electrochemical detection.

The role of glutathione in cellular responses to toxic insult is well established in the literature and is largely based on chemical determinations of GSH. Although these methods have proved to be adequate to demonstrate the relationships between cellular levels of GSH and xenobiotic toxicity, they may be inadequate for careful investigations regarding the regulation of cellular concentrations of GSH, GSSG and GSSProt. Enzymatic and chromatographic methods provide increased specificity and sensitivity, but the problems of variable accuracy or tedious derivitization steps remain. The HPLC-EC method constitutes a significant improvement over previous methods by satisfying the requirements for selectivity, sensitivity, accuracy and convenience. The utility of the HPLC-EC method has been described in two systems of toxicological interest, particularly with regard to the determination of GSSProt. In further studies, the HPLC-EC method has been useful in investigating the mechanism(s) of alternate nucleophiles, such as cysteamine. The capability to determine various thiols simultaneously in a given biological sample greatly facilitates these investigations. In view of its power as an analytical tool, the HPLC-EC method has the potential for widespread application to the study of cellular thiols.

Animals↗
PubMed1989

Cytotoxicities of two disulfide-bond-linked conjugates of methotrexate with monoclonal anti-MM46 antibody.

In studies on (antitumor antibody)-drug conjugates as potential antitumor agents, the amide derivatives of methotrexate (MTX) with cysteine and with 2-mercaptoethylamine (cysteamine) (MTX-Cys and MTX-MEA, respectively) were linked via a disulfide bond with a monoclonal antibody (alpha MM46) to a mouse mammary tumor MM46 with attached 3-(2-pyridyldithio) propionyl groups to give conjugates of MTX with alpha MM46 (MTX-Cys-SS-alpha MM46 and MTX-MEA-SS-alpha MM46, respectively). These two conjugates are both linked by a disulfide bond and are very similar in structure, but MTX-MEA-SS-alpha MM46 showed only weak in vitro cytotoxicity against MM46 cells, whereas MTX-Cys-SS-alpha MM46 had strong cytotoxicity. The cytotoxicity of the latter was comparable to that of the conventional direct MTX-alpha MM46 conjugate prepared with an MTX-active ester. However, this conjugate had a greater selectivity than that of the direct conjugate, calculated as the IC50 (concentration of a conjugate by MTX equivalence required for suppression of the number of viable MM46 cells to 50% of that of the untreated control) for the corresponding nonspecific conjugate divided by the IC50 for the alpha MM46 conjugate. The inhibitory activities of MTX-Cys and MTX-MEA on dihydrofolate reductase were similar. The cytotoxicity of MTX-Cys-SS-alpha MM46 was not affected by thiamine pyrophosphate, an inhibitor of the active transport of MTX across the cell membrane, but was decreased significantly by ammonium chloride, a lysosomotropic amine. However, the cytotoxicity was decreased only to a small extent by leupeptin, an inhibitor of lysosomal cysteine proteases cathepsins B, H, and L. These results suggest that the cytotoxicity is mediated by lysosomes, and may involve lysosomal enzymes other than cathepsins B, H, and L.

Animals↗
PubMed1986

Immunohistochemical localization of thioredoxin and thioredoxin reductase in mouse exocrine and endocrine pancreas.

Thioredoxin and thioredoxin reductase (NADPH-oxidized thioredoxin oxidoreductase, E.C. 1.6.4.5) have been proposed to be involved in several thiol-dependent reduction-oxidation reactions in cells. Both proteins have been immunohistochemically demonstrated in the periphery of the cytoplasm and in cytoplasmic granules of acinar and islet cells in mouse pancreas. In animals fed ad libitum, the staining for thioredoxin was more intense in the exocrine acinar cells than in the islet cells, whereas that for thioredoxin reductase was more intense in the endocrine than in the exocrine pancreas. In the islets of fed mice all endocrine cell types showed about the same staining intensity for thioredoxin, while thioredoxin reductase was greatly enriched in the somatostatin-containing D cells. Starvation overnight caused an increased staining for both proteins in the acinar cells as well as in the islets. Under conditions of starvation, thioredoxin reductase, in contrast to thioredoxin, appeared to increase preferentially in the islet B cells, as compared with the D cells. Cysteamine treatment reduced the staining for somatostatin and for thioredoxin reductase in the D cells without any obvious effect on the other pancreatic cells. The results are compatible with a role for thioredoxin and thioredoxin reductase in secretion.

Aging↗
PubMed1984

DNA lysis is involved in the simplified fluorescence plus Giemsa method for differential staining of sister chromatids.

The DNA labelling of the bifilarly 5-bromodeoxyuridine- to-substituted chromatid decreased relative to that of the unifilarly substituted chromatid with increasing duration of HB pretreatment (Hoechst 33258 plus black light at 55 degrees C). Sister chromatid differential staining was detected by Giemsa as well as a DNA-specific dye, ethidium bromide, after 4 s of HB pretreatment. The contrast of sister chromatid differential staining was improved with increased duration of HB pretreatment or by incubation with exonucleases. Hydrogen donors such as cysteamine, cysteine, and L-ascorbic acid inhibited the HB pretreatment, but this inhibition could be overcome by increasing the duration of HB pretreatment.

Animals↗
PubMed1986

The effects of mucus on the binding of cationized ferritin by human and animal gastrointestinal epithelium.

Human gallbladder and gastric epithelial cells are normally covered with a layer of mucus. When specimens were exposed to cationized ferritin (CF) in vitro, they did not regularly bind nor internalise it. If the tissues were first exposed to the mucolytic agents cysteamine or pepsin, then the gallbladder epithelium readily bound CF and the gastric epithelium irregularly. The in vivo binding of CF by guinea pig gallbladder could be abolished by the induction of mucous hypersecretion by the antibiotic lincomycin. The removal of the mucus by mucolytic agents restored the binding of CF. The irregular binding of CF by gastric mucosa after the use of mucolytic agents suggests other factors may be at play.

Animals↗
PubMed1989

Relationship between lipids and aflatoxin biosynthesis.

This paper describes the key role of lipids on fungal growth and of lipoperoxidation on the output of aflatoxin biosynthesis both 'in vitro' and 'in vivo'. 'In vitro' BHA, BHT and cysteamine, depending their concentration, are capable of reducing or blocking aflatoxin output induced by lipoperoxides or halomethanes in cultures of Aspergillus flavus or A. parasiticus without affecting fungal growth. 'In vivo' BHA and BHT significantly reduced aflatoxin production on wheat, maize and sunflower inoculated with aflatoxigenic Aspergilli essentially by preventing fungal growth. 'In vivo' the seeds surface lipids represent a very important carbon source for fungal growth.

Aflatoxins↗
PubMed1994

Experimental study of laparoscopic selective proximal vagotomy using a carbon dioxide laser.

This study investigated the effectiveness of laparoscopic selective proximal vagotomy using a CO2 laser. Irradiation of the stomach was performed from the serosal aspect using a defocused CO2 laser beam. In the first experiment, the inhibitory effect on cysteamine ulcers in rats was compared between surgical vagotomy and CO2 laser vagotomy using three different irradiation fields. The results suggested that irradiation near the lesser curvature provided sufficient denervation. In the second experiment, CO2 laser vagotomy was performed laparoscopically in dogs. The procedure lasted less than 1 h and a postoperative endoscopic Congo red test confirmed its effectiveness. Subserosal tissues including the vagus nerve branches showed degeneration and were replaced by fibrosis 3 months postoperatively, but the deeper tissues were spared. In conclusion, laparoscopic CO2 laser vagotomy may be as effective for reducing acid secretion as standard surgical vagotomy. Its simplicity and safety suggest that a clinical trial in humans may be warranted.

Animals↗
PubMed1987

Ocular changes in some progressive hereditary nephropathies.

Ocular involvement is a common feature of three hereditary nephropathies: cystinosis, nephronophthisis and Alport's syndrome. The follow-up of 25 cases of infantile cystinosis over a period of 26 years demonstrated that the corneal and retinal epithelium were affected in the same way as the kidney epithelium. Corneal involvement induced photophobia and discomfort, but actual blindness was mainly due to retinal involvement, and therefore no corneal graft was performed. The use of topical cysteamine appears to be promising, but its production raises many questions so no definitive conclusions may be made. Since 1965, 51 patients with nephronophthisis have had ocular examinations; all patients had characteristic clinical symptoms and histological findings. The first group, which consisted of 18 children, all under 10 years of age, was found to have obvious chorioretinal degeneration. The second group, which consisted of 11 children, had a normal ocular examination and normal electroretinogram (ERG). The third group, consisting of 22 children, had a normal clinical examination but ERG tracings with variable alterations. In 28 instances of Alport's syndrome, two types of ocular abnormalities have been observed. In six cases, an anterior lenticonus was noted, which caused a major decline in visual acuity. Retinopathy, which did not affect vision, was observed in 13 cases.

Adolescent↗
PubMed1975

Molecur mechanism of action of the radioprotective substance WR 2721.

The radioprotective effect of WR 2721 on catalase and the type and loci of its interaction with the enzyme have been investigated by means of spectrophotometric and electron spin resonance, (ESR) methods. The radiation damage, indicated by a change in enzymatic activity and in the Soret absorption band, has been the less the larger the WR 2721 concentration. In the case of ESR investigations, addition of WR 2721 has resulted in a reduction of the spin concentration of Cu-2+. Since cysteamine has exhibited similar results, however, to a lesser extent, it can be assumed that the RS-ions are responsible for the protective effect. From the results obtained it can be concluded that (the dephosphorilized) WR 2721 forms a complex with the enzyme and acts as an electron donor.

Animals↗
PubMed1979

The formation of peptides from glycine thioesters.

The condensation products obtained from 0.01M S-glycyl-N-acetyl-cysteamine at different pH's were investigated. The highest yields of diketopiperazine (approx. 50%) were observed in phosphate buffers between pH 7.5 and 8.5. The highest yields of diglycine (46%), triglycine (10%) and tetraglycine (2%) were observed in carbonate buffers at pH 9.5. At pH 8.0, over 90% of the glycyl residues of 0.15M S-glycyl-N-acetylcysteamine were incorporated into condensation products, mainly DKP (60--70%). The yields of products from the condensation of S-glycyl-ethanethiol under similar conditions closely resembled those obtained with S-glycyl-N-acetylcysteamine.

Esters↗
PubMed1994

Gastric and duodenal anti-ulcer activity of sulpiride, a dopamine D2 receptor antagonist, in rats.

The gastric and duodenal anti-ulcer activity of sulpiride, a dopamine D2 receptor antagonist, was studied on various types of experimentally induced ulcers in rats, viz., pylorus ligation and water immersion + restraint stress-induced gastric ulcers, gastric mucosal damage induced by nonsteroidal anti-inflammatory drugs and reserpine, and duodenal ulcers induced by cysteamine hydrochloride. It has been found to possess significant anti-ulcer activity against all these models. In 19 h pylorus ligated rats, it significantly reduced the gastric secretion, increased the fucose and sialic acid concentration of the gastric juice and reduced its protein content, thus increasing the total carbohydrate:protein (TC/PR) ratio. These results suggest that the antisecretory and gastric mucosal barrier strengthening effects of sulpiride may be responsible for its anti-ulcer activity. A central component also appears to be involved in its anti-ulcer action against water immersion + restraint stress model. The results of this study provide a rationale for its beneficial effect seen in the therapy of peptic ulcer disease.

Animals↗
PubMed1992

Formation of formaldehyde and malonaldehyde by photooxidation of squalene.

Formaldehyde and malonaldehyde were identified upon exposure of squalene to ultraviolet (UV) irradiation at 300 nm. Formaldehyde was derivatized by reaction with cysteamine to form thiazolidine; malonaldehyde was derivatized by reaction with N-methylhydrazine to produce N-methylpyrazole. The derivatives were subsequently analyzed with a gas chromatograph equipped with a fused silica capillary column and a nitrogen/phosphorus detector. The levels of formaldehyde and malonaldehyde produced increased with irradiation time. The amount of formaldehyde produced reached a maximum of 3.40 nmol/mg squalene after 7 hr irradiation; the maximum amount of malonaldehyde generated, 0.92 nmol/mg, was found after 5 hr of irradiation. Prior to this study, formaldehyde had not been reported as a photoproduct of squalene. Acetaldehyde and acetone were also detected in the irradiated squalene, which may be formed via a 6-methyl-5-hepten-2-one intermediate. 6-Methyl-5-hepten-2-one can also undergo breakdown to form malonaldehyde.

Formaldehyde↗
PubMed1993

An increased incidence of apolipoprotein E2/E2 and E4/E4 in retinitis pigmentosa.

Previous studies from our laboratory have shown that retinitis pigmentosa (RP), a family of hereditary retinal degenerations, is often accompanied by abnormal levels of cholesterol or polyunsaturated fatty acids. The requirement of the retina for n-3 fatty acids is well known, and a defect in the supply of these lipids (e.g., by apolipoproteins) could affect the course of the disease. The present study confirms and extends a report on apolipoprotein E (apo E) isoforms in German RP patients [Jahn, Oette, Esser, Bergmann, and Leiss, (1987) Ophthalmic Res. 19, 285-288] which showed a tenfold increased frequency of the E2/E2 phenotype compared to the average German population. In our study, apo E phenotypes were determined in the probands of 100 Scottish RP families. The findings revealed a 4-fold increase in the incidence of E2/E2 and an 8-fold increase in E4/E4 compared to a Scottish control population. These increases were statistically significant at the P < 0.05 and P < 0.01 levels, respectively. To investigate the possibility that some of these apparent E2/E2 or E4/E4 phenotypes might actually be new apo E mutations, we examined the behavior of the apo E on sodium dodecyl sulfate-polyacrylamide gels (E2 migrates anomalously) and on isoelectric focusing gels following cysteamine modification of cysteines. These studies showed that two RP patients possibly had new apo E mutations, though amino-terminal sequence analysis revealed no changes in the sequence of the first 19 residues; further sequence analysis is obviously warranted.

Apolipoproteins E↗
PubMed1990

Febrile effects of polyriboinosinic acid: polyribocytidylic acid and interferon: relationship to somatostatin in rat hypothalamus.

The changes in thermoregulatory effectors produced by an injection of polyriboinosinic acid: polyribocytidylic acid (Poly I:C) or interferon were assessed and compared in control rats, in rats with hypothalamic somatostatin (SS) receptor blockade and in rats with hypothalamic SS depletion. Intrahypothalamic (i.h., 0.05-0.50 microgram) or intraperitoneal (i.p., 100-600 micrograms) administration of Poly I:C caused a dose-related rise in colon temperature in control rats at all ambient temperatures (Ta) studied. A Poly I:C-induced fever was produced by increased metabolism at a Ta of 8 degrees C, whereas at 30 degrees C, it was caused by cutaneous vasoconstriction. At a Ta of 22 degrees C, the fever was caused by increased metabolism and cutaneous vasoconstriction. On the other hand, i.h. administration of SS-14 antagonist (0.1-0.5 ng) caused a dose-related fall in colon temperature at Ta of 8 degrees C or 22 degrees C. At a Ta of 8 degrees C, the hypothermia was caused by decreased metabolism, whereas at 22 degrees C, it was caused by decreased metabolism and cutaneous vasodilation. At a Ta of 30 degrees C, the thermoregulatory effectors were not affected by SS-14 antagonist treatment. Furthermore, the fever induced by Poly I:C or interferon was significantly reduced by pretreatment of rats with an i.p. dose of cysteamine (30 mg. kg-1) or an i.h. dose of SS-14 antagonist (0.1 ng). The results indicate that a somatostatinergic pathway in rat hypothalamus may mediate the fever induced by interferon or its inducer Poly I:C.

Animals↗
PubMed1999

Glial HO-1 expression, iron deposition and oxidative stress in neurodegenerative diseases.

The mechanisms responsible for the pathological deposition of brain iron in Parkinson's disease, Alzheimer's disease and other human neurodegenerative disorders remain poorly understood. In rat primary astrocyte cultures, we demonstrated that dopamine, cysteamine, H(2)O(2) and menadione rapidly induce heme oxygenase-1 (HO-1) expression (mRNA and protein) followed by sequestration of non-transferrin-derived (55)Fe by the mitochondrial compartment. The effects of dopamine on HO-1 expression were inhibited by ascorbate implicating a free radical mechanism of action. Dopamine-induced mitochondrial iron trapping was abrogated by administration of the heme oxygenase inhibitors, tin mesoporphyrin (SnMP) or dexamethasone (DEX) indicating that HO-1 upregulation is necessary for subsequent mitochondrial iron deposition in these cells. Overexpression of the human HO-1 gene in cultured rat astroglia by transient transfection also stimulated mitochondrial (55)Fe deposition, an effect that was again preventible by SnMP or DEX administration. We hypothesize that free ferrous iron and carbon monoxide generated by HO-1-mediated heme degradation promote mitochondrial membrane injury and the deposition of redox-active iron within this organelle. We have shown that the percentages of GFAP-positive astrocytes that co-express HO-1 in Parkinson-affected substantia nigra and Alzheimer-diseased hippocampus are significantly increased relative to age-matched controls. Stress-induced up-regulation of HO-1 in astroglia may be responsible for the abnormal patterns of brain iron deposition and mitochondrial insufficiency documented in various human neurodegenerative disorders.

Journal Article↗