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PubMed1981

Activation of murine lymphocytes by 2-mercaptoethanol and related thiol compounds and its mechanism. I. Relationship between mitogenic activities and augmenting effects on antibody synthesis in vitro.

Seven thiol compounds, namely, 2-mercaptoethanol (2-ME), alpha -thioglycerol (alpha -TG), dithiothreitol (DTT), cysteamine, L-cysteine (Cys), glutathione (GSH), and sodium thioglycollate (TGL) were examined for their mitogenic activities, the effects on mitogen-induced 3H-thymidine uptake, and the effects on antibody synthesis in vitro in murine spleen lymphocytes. All these thiols showed mitogenic activities in RPMI-1640 medium containing 10% fetal calf serum (FCS) with the following order of effectiveness: 2-ME greater than or equal to alpha -TG greater than DTT greater than cysteamine greater than Cys greater than or equal to GSH greater than TGL. A close correlation was observed between the enhancement of the response to lipopolysaccharide (LPS) and the mitogenic activities of these thiol compounds in their magnitude and dose-response profiles. The primary antibody response in vitro to sheep red blood cells (SRBC) (thymus-dependent) or dinitrophenyl (DNP)-Ficoll (thymus-independent) was augmented in a similar fashion by these compounds. T-cells depletion did not influence the enhancement by 2-ME of the antibody response to DNP-Ficoll. There was a discrepancy between the dose-response profiles of mitogenic activities of these compounds and their augmenting effects on antibody responses. Particularly, 2-ME and DTT significantly enhanced the antibody response to DNP-Ficoll or SRBC even at the nonmitogenic doses. Ethyl mercaptan (HSCH2 CH3) showed similar activities to 2-ME, but methylthioethanol (CH3 SCH2 CH2 OH) and ethanol (CH3 CH2 OH) were inactive, thus indicating that the thiol group would play an essential role in the above activities of 2-ME.

Animals↗
PubMed1986

Gastric antisecretory, gastric and duodenal anti-ulcer and cytoprotective properties of Ro 22-6923, a synthetic trimethyl prostanoid in rats.

Ro 22-6923, a synthetic trimethyl prostanoid, has been studied for its ability to inhibit gastric secretion and to protect the gastroduodenal mucosa against the injuries caused by pyloric ligation, hypothermic restraint stress, nonsteroidal anti-inflammatory drugs (NSAIDs), reserpine, dimaprit, cysteamine and the cytodestructing agents--80% ethanol, 0.6 M HCl, 0.2 M NaOH, 25% NaCl, aspirin 30 mg in 0.35 M HCl and 100 mM sodium taurocholate in 0.2 M HCl. The results of this study demonstrate that Ro 22-6923 has both prophylactic and curative effects on various experimental models. It produces a dose dependent inhibition of the gastric mucosal damage induced by pyloric ligation, hypothermic restraint stress, NSAIDs, reserpine, dimaprit and cytodestructing agents and that of duodenal ulcers induced by cysteamine. It also produces a dose dependent healing of the acetic acid induced chronic gastric ulcers. These observations suggest that Ro 22-6923 exerts its anti-ulcer effects by its antisecretory, gastric mucosal resistance increasing and cytoprotective activities and that it may be a useful therapeutic agent for the treatment of peptic ulcer disease in humans.

Animals↗
PubMed1995

Bacterial expression of human chorionic gonadotropin alpha subunit: studies on refolding, dimer assembly and interaction with two different beta subunits.

Human chorionic gonadotropin (hCG) is a member of a family of heterodimeric glycoprotein hormones that have a common alpha subunit but differ in their hormone-specific beta subunit. The common alpha subunit contains two asparagine (N)-linked oligosaccharides. To study the function of carbohydrates on in vitro refolding of alpha subunit and dimer assembly, we generated recombinant non-glycosylated hCG alpha subunit (rNGl-hCGalpha) from E. coli. The expression vector was constructed by inserting hCGalpha cDNA coding for the mature form in-frame into a pQE-30 vector, which contains a 6 x His sequence immediately before the 5'-end of hCGalpha cDNA for subsequent purification of rNG-hCGalpha. The rNG-hCGalpha expressed in inclusion bodies was efficiently purified by immobilized metal chelate affinity chromatography on Ni-NTA resin. SDS-PAGE, solid-phase binding assay and immunoblotting demonstrated the expression of rNG-hCG. Its alpha molecular weight on SDS-PAGE was 14.7 kDa under reducing conditions and 15 kDa for a monomer accompanied with some higher molecular weight oligomer under non-reducing conditions. Reconstitution of rNG-hCGalpha with native hCGbeta and oFSHbeta occurred in very low yield under standard conditions. However, the oxidation-reduction system cystamine (1.34 mM) and cysteamine (7.3 mM) facilitated both the refolding of rNG-hCGalpha and reconstitution of rNG-hCGalpha with native hCGbeta to regain partially correct conformation. These were revealed by conformationally sensitive antibody and receptor binding assays. Cystamine and cysteamine were more effective in the recombination of rNG-hCGalpha with oFSHbeta as indicated by a 22-36-fold decrease in the amount required to cause a 50% competitive inhibition in radioreceptor assay. They have no effect on assembly of rNG-hCGalpha with oLHbeta. Our results suggest the carbohydrate moieties confer greater conformational flexibility to the backbone of the beta subunit and the relative rigidity of the beta subunit may serve as a conformational template of the alpha subunit. The present approach has made it possible to prepare the non-glycosylated gonadotropin alpha subunit in adequate amounts for further study on their biological and topographical features in complete absence of carbohydrate.

Amino Acid Sequence↗
PubMed1986

Systemic administration of antioxidants does not protect mice against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP).

We examined whether DA neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) can be prevented by combined systemic administration of antioxidants. C57 black mice were injected s.c. with MPTP (30 mg/kg), once daily for two days, alone, or with ascorbic acid (1 g/kg), alpha-tocopherol (100 mg/kg), or dimethylsulfoxide (50 microliters) i.p. for two days before, two days with and two days after MPTP, and decapitated 30 days later. MPTP once (30 mg/kg), alone, or with ascorbic acid (200 mg/kg) or cysteamine (75 mg/kg), two days before, one day with and 4 days after, and decapitated 10 days post-MPTP. MPTP once (15 mg/kg), alone, or with ascorbic acid (500 mg/kg, alpha-tocopherol (100 mg/kg), cysteamine (50 mg/kg) or sodium selenite (2.5 mg/kg), 90 min before and again 90 min after MPTP, and decapitated 7 days later. In all experiments, the marked striatal DA depletions produced by MPTP alone (by 40-70% from controls) were unchanged by cotreatments with the various antioxidants. Findings do not favor intraneuronal generation of superoxides and related cytotoxic free radicals as a major factor in the DA neurotoxicity of MPTP. They suggest that if natural Parkinson's disease is caused by an MPTP-like neurotoxin, early treatment with antioxidants is unlikely to protect nigrostriatal neurons and prevent disease progression.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Separation of urinary thiols as tributyltinmercaptides and determination using capillary isotachophoresis.

The essential steps in the assay included electrolytic reduction of disulphides, neutralization, extraction of thiols with 0.1 M tributyltin hydroxide in octane, stripping of the extract with 2% acetic acid, fixing the washed-out amino thiols to a cation exchanger, elution with 2 M hydrochloric acid, oxidation with bromine and evaporation. The remaining octane extract was decomposed by dodecanethiol, the mercapto acids were washed out, oxidized with bromine and evaporated. Both residues were dissolved in water and analysed using capillary isotachophoresis at pH 3.0. Cysteamine was extracted from reduced urine at ca. pH 10, decomposed by dodecanethiol and re-extracted to boric acid followed by determination as a cation. The presence of the following thiols in urine has been confirmed: mercaptoacetic acid, 3-mercaptolactic acid, 2-mercaptopropionic acid, acetylcysteine, mercaptoethanol, cysteine, homocysteine and an un-identified amino thiol. Cysteamine and 3-mercaptopropionic acid could not be detected. Captopril, homocysteine and cysteine were determined quantitatively.

Antidotes↗
PubMed1990

Evaluation of turmeric (Curcuma longa) for gastric and duodenal antiulcer activity in rats.

An ethanol extract of turmeric was studied in rats for its ability to inhibit gastric secretion and to protect gastroduodenal mucosa against the injuries caused by pyloric ligation, hypothermic-restraint stress, indomethacin, reserpine and cysteamine administration and cystodestructive agents including 80% ethanol, 0.6 M HCl, 0.2 M NaOH and 25% NaCl. An oral dose of 500 mg/kg of the extract produced significant anti-ulcerogenic activity in rats subjected to hypothermic-restraint stress, pyloruic ligation and indomethacin and reserpine administration. The extract had a highly significant protective effect against cystodestructive agents. The reduction in the intensity of ulceration of cysteamine-induced duodenal ulcers was not found to be statistically significant. Turmeric extract not only increased the gastric wall mucus significantly but also restored the non-protein sulfhydryl (NP-SH) content in the glandular stomachs of the rats.

Animals↗
PubMed1989

Determination of thiols of biological and pharmacological interest by high-performance thin-layer chromatography and fluorescence scanning densitometry.

The application of high-performance thin-layer chromatography (HPTLC) with fluorescence scanning densitometry provides a simple, rapid and reliable system for the qualitative and quantitative determination of several thiols of biological and pharmacological interest. The determination of a mixture of thiols (captopril, coenzyme A, cysteamine, cysteine and glutathione), together with their disulphides may readily be performed by pre-chromatographic derivatization with the thiol-specific fluorobenzoxadiazole reagents SBD-F and ABD-F, followed by HPTLC separation on silica gel plates using isopropyl ether-methanol-water-acetic acid (9:8:2:1, v/v/v/v) as the developing solvent, and fluorodensitometric measurement of the fluorescing derivatives. Detection limits of about 30 pg (coenzyme A) to 6 pg (cysteamine) per spot were achieved; the relative standard deviation (RSD) of the complete procedure was 1.16-3.2%.

Acetates↗
PubMed1996

A novel cystathionine beta-synthase from Panagrellus redivivus (Nematoda).

The free-living nematode Panagrellus redivivus can be used as a biochemical model for parasitic nematodes in the search for new chemotherapeutic agents. A novel cystathionine beta-synthase has been purified 3600-fold from the cytosol of P. redivivus. The enzyme catalyses the synthesis of cystathionine from homocysteine plus serine or cysteine. The enzyme, native M(r) 71.7 kDa, pI 4.7, is a dimer and also catalyses the replacement of the beta-SH group of cysteine with 2-mercaptoethanol to yield a thioether, S-(2-hydroxyethyl) cysteine and H2S. This reaction proceeds much faster than cystathionine synthesis and L-cysteine cannot be replaced by D-cysteine, L-cystine, N-acetyl L-cysteine, cysteamine of D,L-homocysteine. 2-Mercaptoethanol in the assay can be replaced by monothiolglycerol and to a lesser extent by cysteamine. The absolute K(m) values for L-cysteine and 2-mercaptoethanol were 0.13 +/- 0.05 mM and 1.72 +/- 0.24 mM, respectively, the absolute V(max) was 55 +/- 4.9 mumol.min(-1).mg protein(-1). The enzyme had a pH optimum of approx. 8.5 and did not require metal ions for activity. The enzyme was inhibited by a series of substrate analogues, anthelmintics and plant phenols. The P. redivivus enzyme differs markedly from its mammalian equivalent and suggests distinctive differences in sulphur amino acid metabolism in nematodes.

Animals↗
PubMed2007

Amperometric glucose biosensor based on multilayer films via layer-by-layer self-assembly of multi-wall carbon nanotubes, gold nanoparticles and glucose oxidase on the Pt electrode.

A novel amperometric glucose biosensor based on the nine layers of multilayer films composed of multi-wall carbon nanotubes (MWCNTs), gold nanoparticles (GNp) and glucose oxidase (GOD) was developed for the specific detection of glucose. MWCNTs were chemically modified with the H(2)SO(4)-HNO(3) pretreatment to introduce carboxyl groups which were used to interact with the amino groups of poly(allylamine) (PAA) and cysteamine via 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide cross-linking reaction, respectively. A cleaned Pt electrode was immersed in PAA, MWCNTs, cysteamine and GNp, respectively, followed by the adsorption of GOD, assembling the one layer of multilayer films on the surface of Pt electrode (GOD/GNp/MWCNTs/Pt electrode). Repeating the above process could assemble different layers of multilayer films on the Pt electrode. PBS washing was applied at the end of each assembly deposition for dissociating the weak adsorption. Film assembling and characterization were studied by transmission electron microscopy and quartz crystal microbalance, and properties of the resulting glucose biosensors were measured by electrochemical measurements. The marked electrocatalytic activity of Pt electrode based on multilayer films toward H(2)O(2) produced during GOD enzymatic reactions with glucose permitted effective low-potential amperometric measurement of glucose. Taking the sensitivity and selectivity into consideration, the applied potential of 0.35 V versus Ag/AgCl was chosen for the oxidation detection of H(2)O(2) in this work. Among the resulting glucose biosensors, the biosensor based on nine layers of multilayer films was best. It showed a wide linear range of 0.1-10mM glucose, with a remarkable sensitivity of 2.527 microA/mM, a detection limit of 6.7 microM estimated at a signal-to-noise ratio of 3 and fast response time (within 7s). Moreover, it exhibited good reproducibility, long-term stability and the negligible interferences of ascorbic acid, uric acid and acetaminophen. The study can provide a feasible approach on developing new kinds of oxidase-based amperometric biosensors, and can be used as an illustration for constructing various hybrid structures.

Biosensing Techniques↗
PubMed2005

Antioxidant treatment inhibited glutamate-evoked NF-kappaB activation in primary astroglial cell cultures.

In glial cells, glutamate exposure causes alterations in cell redox status, mainly mediated by glutathione depletion and reactive oxygen species generation. These effects finally lead to astrocyte dysfunction which contributes to the pathogenesis of several neurological disorders. This study was aimed to investigate the involvement of the NF-kappaB pathway in oxidative stress induced by glutamate exposure in primary cultures of astrocytes. Further, we evaluated the power of the antioxidants genistein (0.1-10 microM) and IRFI 016 (20-80 microM), a synthetic tocopherol analogue, compared with glutathione ethyl ester (10-50 microM) and cysteamine-HCl (100-500 microM), to antagonize the effects elicited by glutamate (500 microM). Alterations of cell redox status were reduced, in a dose-dependent way, by antioxidants; in particular, 80 microM IRFI 016 and 10 microM genistein almost completely restored glutathione basal levels and significantly diminished ROS production, as well as 100 microM glutathione ethyl ester. These antioxidant effects were stronger than those caused by 500 microM cysteamine-HCl. Further, glutamate promoted the up-regulation of p50 and p65 NF-kappaB subunits and their nuclear translocation, as revealed by Western blot analysis and electrophoretic mobility shift assay of both subunits. The activation of p50 and p65 NF-kappaB subunits induced by glutamate exposure was significantly reduced by IRFI 016, acting in a dose-dependent manner. Altogether, these data confirm that the NF-kappaB pathway is involved in cell response to oxidative stress induced by glutamate injury in primary astrocyte cultures, and suggest that the use of antioxidants, such as IRFI 016, may be a helpful pharmacological strategy for neuroprotection.

Animals↗
PubMed1999

Kinetics of oxidation of aliphatic and aromatic thiols by myeloperoxidase compounds I and II.

Myeloperoxidase (MPO) is the most abundant protein in neutrophils and plays a central role in microbial killing and inflammatory tissue damage. Because most of the non-steroidal anti-inflammatory drugs and other drugs contain a thiol group, it is necessary to understand how these substrates are oxidized by MPO. We have performed transient kinetic measurements to study the oxidation of 14 aliphatic and aromatic mono- and dithiols by the MPO intermediates, Compound I (k3) and Compound II (k4), using sequential mixing stopped-flow techniques. The one-electron reduction of Compound I by aromatic thiols (e.g. methimidazole, 2-mercaptopurine and 6-mercaptopurine) varied by less than a factor of seven (between 1.39 +/- 0.12 x 10(5) M(-1) s(-1) and 9.16 +/- 1.63 x 10(5) M(-1) s(-1)), whereas reduction by aliphatic thiols was demonstrated to depend on their overall net charge and hydrophobic character and not on the percentage of thiol deprotonation or redox potential. Cysteamine, cysteine methyl ester, cysteine ethyl ester and alpha-lipoic acid showed k3 values comparable to aromatic thiols, whereas a free carboxy group (e.g. cysteine, N-acetylcysteine, glutathione) diminished k3 dramatically. The one-electron reduction of Compound II was far more constrained by the nature of the substrate. Reduction by methimidazole, 2-mercaptopurine and 6-mercaptopurine showed second-order rate constants (k4) of 1.33 +/- 0.08 x 10(5) M(-1) s(-1), 5.25 +/- 0.07 x 10(5) M(-1) s(-1) and 3.03 +/- 0.07 x 10(3) M(-1) s(-1). Even at high concentrations cysteine, penicillamine and glutathione could not reduce Compound II, whereas cysteamine (4.27 +/- 0.05 x 10(3) M(-1) s(-1)), cysteine methyl ester (8.14 +/- 0.08 x 10(3) M(-1) s(-1)), cysteine ethyl ester (3.76 +/- 0.17 x 10(3) M(-1) s(-1)) and alpha-lipoic acid (4.78 +/- 0.07 x 10(4) M(-1) s(-1)) were demonstrated to reduce Compound II and thus could be expected to be oxidized by MPO without co-substrates.

Cysteine↗
PubMed2000

Unusual arrangement of catalytic domains in head-to-tail associated homodimer of 6-hydroxymellein synthase, a multifunctional polyketide biosynthetic enzyme.

6-Hydroxymellein synthase, a multifunctional polyketide synthetic enzyme in carrot, is organized as a homodimer, and the activity of the synthase was appreciably inhibited upon the specific alkylation of cysteine- and cysteamine-SHs at the reaction center with iodoacetoamide and chloroacetyl-CoA, respectively. Dissociation and stoichiometric recombination of the unmodified and the SH-modified enzyme subunits yielded a combination of unmodified-unmodified, unmodified-modified and modified-modified hybrid dimers that together exhibit 50% activity. In contrast, hybrid dimers obtained by reconstruction of the two modified enzymes showed essentially no catalytic activity. These results suggest that the two subunits of 6-hydroxymellein synthase are aligned in head-to-tail orientation to organize two reaction centers which are comprised of a cysteine and a complementary cysteamine SH group, belonging to and contributed from the same subunit in the homodimer structure.

Journal Article↗
PubMed2004

Nile red-adsorbed gold nanoparticles for selective determination of thiols based on energy transfer and aggregation.

For the first time, an aqueous solution of 32-nm gold nanoparticles (GNPs), to which Nile red (NR) has been noncovalently adsorbed, has been used for sensing thiols. The as-prepared NRGNPs fluoresce weakly as a result of fluorescence resonance energy transfer between NR and the GNPs. The fluorescence of a solution containing NRGNPs at pH 4.0 increases upon the addition of thiols, but not when amines, acids, alcohols, bovine serum albumin, or hemoglobin are added. This phenomenon allows for the selective determination of thiols such as cysteamine and homocysteine, which have limits of detection of 10.2 and 10.9 nM, respectively, at a signal-to-noise ratio of 3. Interestingly, we have found that the excitation (lambda(ex) = 480 nm), emission (lambda(em) = 610 nm), and mass spectra (m/z 282) of the substance that desorbs from the GNPs in the presence of thiols are different from those of NR (lambda(ex) = 580 nm; lambda(em) = 652 nm; m/z 318), which indicates that a new product forms. When simultaneously conducting fluorescence and colorimetric assays, the selectivity of this approach further improves because at pH 4.0, the color of the NRGNPs does not change in the presence of negatively charged thiols, (e.g., N-(2-mercaptopropionyl)glycine), but changes from maroon to purple and lavender in the presence of neutral thiols (e.g., 3-mercapto-1,2-propanediol) and positively charged thiols (e.g., cysteamine), respectively, as a result of aggregation. This feature allows the types of thiols to be determined at concentrations >1.0 and 0.1 microM by the naked eye and by UV-vis absorption, respectively. Depending on the rate at which the NRGNP color changes, reduced glutathione (slow) is readily distinguishable from oxidized glutathione (no aggregation and no displacement) and from cysteine and homocysteine (fast).

Adsorption↗
PubMedDate not supplied

Application of cystamine and N,N'-Bis(glycyl)cystamine as linkers in polysaccharide-protein conjugation.

Pneumococcal polysaccharide type 6B, 14, or 23F (35-70 kDa) was activated with cyanogen bromide and modified with cystamine. After reduction of the spacer, the thiol-containing (i.e. cysteamine-modified) polysaccharide obtained was added in a 5-10-fold molar excess to bromoacetylated tetanus toxoid to give thioether-linked polysaccharide-protein conjugates in a yield of 10-20%. This approach failed for preparing a type 19F polysaccharide-protein conjugate, possibly due to intramolecular elimination of cysteamine from the reduced 19F polysaccharide. When N,N'-bis(glycyl)cystamine was introduced as a spacer molecule, the elimination of the reduced spacer was suppressed, thus allowing preparation of a 19F polysaccharide-tetanus toxoid conjugate (15%).

Carbohydrate Conformation↗
PubMed2005

Isolation, catalytic properties, and competitive inhibitors of the zinc-dependent murine glutaminyl cyclase.

Murine glutaminyl cyclase (mQC) was identified in the insulinoma cell line beta-TC 3 by determination of enzymatic activity and RT-PCR. The cloned cDNA was expressed in the secretory pathway of the methylotrophic yeast Pichia pastoris and purified after fermentation using a new three-step protocol. mQC converted a set of various substrates with very similar specificity to human QC, indicating a virtually identical catalytic competence. Furthermore, mQC was competitively inhibited by imidazole derivatives. A screen of thiol reagents revealed cysteamine as a competitive inhibitor of mQC bearing a Ki value of 42 +/-2 microM. Substitution of the thiol or the amino group resulted in a drastic loss of inhibitory potency. The pH dependence of catalysis and inhibition support that an uncharged nitrogen of the inhibitors and the substrate is necessary in order to bind to the active site of the enzyme. In contrast to imidazole and cysteamine, the heterocyclic chelators 1,10-phenanthroline, 2,6-dipicolinic acid, and 8-hydroxyquinoline inactivated mQC in a time-dependent manner. In addition, citric acid inactivated the enzyme at pH 5.5. Inhibition by citrate was abolished in the presence of zinc ions. A determination of the metal content by total reflection X-ray fluorescence spectrometry and atomic absorption spectroscopy in mQC revealed stoichiometric amounts of zinc bound to the protein. Metal ion depletion appeared to have no significant effect on protein structure as shown by fluorescence spectroscopy, suggesting a catalytic role of zinc. The results demonstrate that mQC and probably all animal QCs are zinc-dependent catalysts. Apparently, during evolution from an ancestral protease, a switch occurred in the catalytic mechanism which is mainly based on a loss of one metal binding site.

Amino Acid Sequence↗
PubMed2006

Structural diversity within analogous compounds: syntheses and studies of M(SCH2CH2NH2)Cl (M = Zn, Cd, Hg).

The novel complexes [Zn(L)Cl] (1), [Cd(L)Cl] (2), [Hg(L)Cl] (3), {[Hg(L)Cl].NaOH.2H2O} (3.NaOH.2H2O), and {[Hg3(HL)2Cl6].2H2O} (4) (L = -SCH2CH2NH2) were prepared and investigated by means of IR spectroscopy and single-crystal X-ray diffraction. The crystal structures of 1, 2, and 3.NaOH.2H2O show chelating N,S-coordination of the cysteaminate ligand, bridging S, and terminally coordinating Cl. Apart from these common features, the coordination geometries and modes of intermolecular association are different. 1 forms a cyclic tetramer with a Zn4S4 ring, and 3.NaOH.2H2O contains one-dimensional [Hg(L)Cl]n chains with S-bridged Hg atoms. Zn and Hg atoms in 1 and 3.NaOH.2H2O are tetracoordinate with a distorted tetrahedral M(ClNS2) geometry (M = Zn, Hg). Each Cd atom of 2 binds to three S atoms and vice versa, such that layers of distorted Cd3S3 hexagons are formed. 2 is the first example for a compound exhibiting a group 12-group 16 layer structure, which can be described as an analogue of a graphite layer. Additionally, each Cd atom binds to a chlorine atom and a nitrogen atom from a cysteaminate ligand resulting in pentacoordination with a distorted trigonal bipyramidal Cd(ClNS3) geometry. 4 contains two differently coordinate Hg atoms. One displays a distorted trans-octahedral Hg(Cl4S2) geometry, while the other is coordinated by four Cl atoms and one S atom and additionally forms a long Hg...Cl contact.

Journal Article↗
PubMed2001

Gastrointestinal damage induced by celecoxib and rofecoxib in rats.

Five experimental models were developed in different groups of Wistar rats (N = 15) to study selective COX-2-inhibitor NSAIDs such as celecoxib and rofecoxib, as follows: (1) dose-dependent oral Celecoxib and Rofecoxib for 5 days, and 24 hr after oral indomethacin; (2) Same as 1 but subcutaneously; (3) gastric ulcer induced by glacial acetic acid; (4) duodenal ulcer induced by cysteamine; and (5) stress by immobilization and immersion in water at 15 degrees C for 6 hr. Celecoxib and Rofecoxib, either orally or subcutaneously, did not produce necrotic lesions in healthy gastrointestinal mucosa (0%), showing normal histology. In contrast, previously indomethacin-induced lesions were aggravated (90%, P < 0.001). Total necrosis in the small intestine as well as increased ulcers and perforation of gastric and duodenal ulcers induced by acetic acid and cysteamine were observed. There was also aggravation of the necrotic gastric area in stress (60-90%, P < 0.05). Celecoxib and rofecoxib showed neutrophilia (5000/mm3) similar to that with indomethacin. In contrast, there was no leukocyte infiltration in the gastric múcosa; thus, we can consider it a selective COX-2 NSAID. In conclusion, celecoxib and rofecoxib at doses causing COX-2 but not COX-1 inhibition did not produce toxic lesions in healthy gastrointestinal mucosa, yielding a broad therapeutic margin. In contrast, when administered in altered gastrointestinal mucosa, they aggravated and complicated gastric ulcers as well as necrosis in the small intestine, consequently restricting their clinical use.

Animals↗
PubMed2002

Electrochemical and spectroelectrochemical behavior of the main photodegradation product of nifedipine: the nitrosopyridine derivative.

PURPOSE: To characterize the electrochemical behavior of the photodegradation product of nifedipine, i.e., 2,6-dimethyl-4-(2-nitrosophenyl)-3,5-pyridine-carboxylic acid dimethyl ester (NPD) in different electrolytic media. We also evaluated the interaction between free radicals generated from NPD and xeno/endobiotics. METHODS: Tast polarography, differential pulse polarography, and cyclic voltammetry were used for the characterization. Controlled potential electrolysis and ultraviolet-visible spectroscopy were used to generate and to detect the nitroso radical anion. RESULTS: In protic media, the NPD derivative gave a reversible well-defined peak either on Hg or glassy carbon electrodes in a reaction involving two electrons and two protons to give the hydroxylamine derivative. In mixed aqueous-organic media (pH 9) and in aprotic media, nitroso radical anion was isolated and characterized, exhibiting second-order dimerization rate constant (k2) values of 11,300 +/- 210 [Ms](-1) and 8,820 +/- 78 [Ms](-1), respectively. Reactivity of the nitroso radical anion with relevant pharmacologic targets revealed a significant interaction with the tested endo/xenobiotics (cysteamine, GSH, N-acetylcysteine, and adenine). CONCLUSIONS: Both in mixed and aprotic media, NPD generated free-radical species, the nitroso radical anion. Taking into account their respective interaction rate constants, the following tentative rank order of reactivity can be established as follows: cysteamine > N-acetylcysteine > GSH > adenine.

Electrochemistry↗