thiourea and tetramethylthiourea

The synthesis of strained polycyclic systems from readily available precursors with a minimum number of steps and with regio- and stereochemical control constitutes an important synthetic challenge. Herein, we report a tandem reaction comprising Co-TMTU (tetramethyl thiourea)-catalyzed Pauson-Khand (PK) and 6π-electrocyclization reactions for the formation of the highly strained core of presilphiperfolanols. The developed chemistry has been applied to the total syntheses of 4-epi-presilphiperfolan-8-ol and 7-epi-presilphiperfolan-1-ol.

Topics: Catalysis; Crystallography, X-Ray; Cyclization; Molecular Conformation; Sesquiterpenes; Stereoisomerism; Thiourea

The reaction between tetramethylthiourea (TTTU) and slightly acidic chlorite has been studied. The reaction is much faster than comparable oxidations of the parent thiourea compound as well as other substituted thioureas. The stoichiometry of the reaction in excess oxidant showed a complete desulfurization of the thiocarbamide to yield the corresponding urea and sulfate: 2ClO2(-) + (Me2N)2C ═ S + H2O → (Me2N)2C ═ O + SO4(2-) + 2Cl(-) + 2H(+). The reaction mechanism is unique in that the most stable metabolite before formation of the corresponding urea is the S-oxide. This is one of the rare occasions in which a low-molecular-weight S-oxide has been stabilized without the aid of large steric groups. ESI-MS data show almost quantitative formation of the S-oxide and negligible formation of the sulfinic and sulfonic acids. TTTU, in contrast to other substituted thioureas, can only stabilize intermediate oxoacids, before formation of sulfate, in the form of zwitterions. With a stoichiometric excess of TTTU over oxidant, the TTTU dimer is the predominant product. Chlorine dioxide, which is formed from the reaction of excess chlorite and HOCl, is a very important reactant in the overall mechanism. It reacts rapidly with TTTU to reform ClO2(-). Oxidation of TTTU by chlorite has a complex dependence on acid as a result of chlorous acid dissociation and protonation of the thiol group on TTTU in high-acid conditions, which renders the thiol center a less effective nucleophile.

Topics: Catalysis; Chlorides; Chlorine Compounds; Drug Combinations; Free Radicals; Ions; Kinetics; Molecular Structure; Oils; Oxidation-Reduction; Oxides; Phenols; Spectrum Analysis; Thiourea; Ultraviolet Rays; Water

An organic redox couple tetramethylthiourea/tetramethylformaminium disulfide (TMTU/TMFDS(2+) ) is evaluated in dye-sensitized solar cells in conjunction with a series of indoline and ruthenium-based dyes. Of these, devices with indoline dye D205 show the best performance, with an optimized power conversion efficiency of 7.6 % under AM 1.5G 1 sun illumination. Charge collection and injection are highly efficient in all TMTU-based DSCs studied. Regeneration of indoline dyes is highly efficient, whereas regeneration of ruthenium dyes by TMTU is less efficient, accounting for their inferior performance. Impedance spectroscopy results reveal that using an optimized TMTU/TMFDS(2+) electrolyte solution, the TiO2 conduction band edge is 300-400 meV lower than when an optimized I3 (-) /I(-) electrolyte is used. The would-be loss in open-circuit voltage caused by the downward conduction band shift is mostly compensated by approximately the 200 meV lower redox level of the TMTU/TMFDS(2+) electrolyte and up to 1000 times slower recombination rates. This makes TMTU/TMFDS(2+) a promising redox couple in the development of highly efficient solar energy conversion devices.

Topics: Coloring Agents; Electric Power Supplies; Indoles; Kinetics; Optical Phenomena; Oxidation-Reduction; Ruthenium; Sunlight; Thiourea

A cobalt-TMTU complex, derived from the in situ reduction of CoBr(2) with Zn in the presence of TMTU, can catalyze Pauson-Khand reaction at a balloon pressure of CO, which enables the synthesis of structurally diverse cyclopentenones. This catalytic system works efficiently for both intermolecular and intramolecular PK reactions.

Topics: Bromides; Catalysis; Cobalt; Molecular Structure; Thiourea; Zinc

The rate of displacement of the aqua ligands by three neutral nucleophiles (Nu) of different steric demands, namely thiourea (tu), N,N'-dimethylthiourea (dmtu) and N,N,N',N'-tetramethylthiourea (tmtu) and an anionic nucleophile (I(-)) in complexes of the form [{Pt(H(2)O)}(2)(N,N,N',N'-tetrakis(2-pyridylmethyl)-N(CH(2))(n)N](CF(3)SO(3))(4), n = 2 (En); 3 (Prop); 4 (But); 6 (Hex); 8 (Oct) and 10 (Dec), was studied under pseudo first-order conditions as a function of concentration, temperature and pressure using stopped-flow techniques and UV-visible spectrophotometry. The pseudo first-order rate constants, k(obs(1(st)/2(nd))), for the simultaneous substitution of the aqua ligands and the proposed subsequent dechelation of the pyridyl units, respectively, agreed well to the rate law: k(obs(1(st)/2(nd))) = k(2(1(st)/2(nd)))[Nu]. High negative activation entropies, negative volumes of activation and second-order kinetics for the displacement reactions all support an associative mode of activation. Except for Prop, the rate of the simultaneous substitution of the aqua ligands in the complexes was found to increase as the chain length of the linker increases from En to Hex, beyond which any further increase in chain length is not accompanied by a further increase in reactivity. The reactivity trend of the even-bridged complexes with C(2h) symmetry is ascribed to a concomitant decrease in axial steric influences imposed on one side of the square-planar picolyl chelates by the other as the chain length increases. Based on the model structures of the complexes, this kind of steric imposition occurs only in complexes with an even number of CH(2) groups within the linker. The Prop complex, having a C(2v) symmetry showed exceptional high reactivity towards the nucleophiles. A cage effect, evolving from its bowl-shaped molecular structure, is proposed to explain this high reactivity. The order of reactivity of the nucleophiles increased in the order I(-) >> tu approximately dmtu > tmtu, in line with the strong electrostatic interactions between the highly polarizable iodide nucleophile and the Pt centers, steric retardation effects in the case of tmtu and dominating positive inductive effects for the dmtu nucleophile.

Topics: Chelating Agents; Coordination Complexes; Diamines; Kinetics; Ligands; Molecular Conformation; Platinum; Spectrophotometry, Ultraviolet; Thiourea

N-Acetylcysteine (NAC) has been widely used as an antioxidant in research, however, it has also been found to reduce the binding of TNF to its receptor independent of its antioxidative role. In this study, we investigated the effect of NAC on NF-kappaB activation. In HeLa cells, Hep3B cells, and A549 cells, DNA-binding activity of NF-kappaB was induced by NAC without any other stimulation but not by tetramethylthiourea (TMTU) or vitamin C, suggesting that ROS is not involved in the effect of NAC. The degradation of IkappaBalpha and nuclear translocation of NF-kappaB were not induced by NAC. The phosphorylation of p65 at serine 536 was induced by NAC, which is known to contribute to the enhancement of DNA-binding activity of NF-kappaB, however, NAC did not directly phosphorylate p65. The NAC-induced DNA-binding activity of NF-kappaB and phosphorylation of p65 were sensitive to a phosphatidylinositol (PI) 3-kinase inhibitor, partially sensitive to an IkappaB kinase (IKK) inhibitor, but not sensitive to a Bruton's tyrosine kinase (Btk) inhibitor. Moreover, both the DNA-binding activity and phosphorylation induced by NAC were reduced by the overexpression of a dominant negative Akt in HeLa cells. These results suggest that NAC activates mainly PI3K to phosphorylate p65 and subsequently induces DNA-binding activity of NF-kappaB, independent of its antioxidative function.

Topics: Acetylcysteine; Active Transport, Cell Nucleus; Agammaglobulinaemia Tyrosine Kinase; Antioxidants; Ascorbic Acid; Cell Line; Cell Nucleus; DNA; Humans; NF-kappa B; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Binding; Protein-Tyrosine Kinases; Reactive Oxygen Species; Signal Transduction; Thiourea; Transcription Factor RelA

N,N,N',N'-Tetramethylthiourea (TMTU) is a rat goitrogen inducing thyroid hyperplasia, hypertrophy, and tumor formation. Little is known about the exact underlying mechanism of action. As thyroid peroxidase (TPO) and type I iodothyronine deiodinase (ID-I) have been established as targets of goitrogenic thiourea derivatives, we investigated interactions of TMTU with target enzymes using a partially purified fraction from hog thyroids or solubilized hog thyroid microsomes and 10,000g supernatant from rat liver homogenate, respectively, as enzyme sources. For comparison, comprehensively characterized goitrogenic thiourea derivatives were studied as well. In contrast to propylthiouracil (PTU), and like ethylenethiourea (ETU), TMTU only marginally affected TPO-catalyzed oxidation of guaiacol. TMTU, like ETU, concentration-dependently suppressed TPO-catalyzed iodine formation with concomitant oxidative metabolism. Suppression ceased upon consumption of thiourea derivatives, the rate of the reappearing iodine formation was similar to that of controls. TMTU, like ETU, also suppressed non-enzymatic and TPO-catalyzed monoiodination of l-tyrosine with a stoichiometry of 2:1, i.e., one molecule of thiourea derivative suppressed two times monoiodination. TMTU and ETU were unable to irreversibly inhibit TPO. In contrast to PTU, TMTU did not inhibit ID-I. These findings provide evidence that TMTU interferes with thyroid hormone synthesis at the level of iodination and demonstrate a metabolic route for the oxidative detoxification of TMTU in the thyroid suggesting that low-level or intermittent exposure to TMTU would have only minimal effects on thyroid hormone synthesis. Finally, it can be concluded that meaningful toxicological studies on TPO inhibition can be performed without a need for highly purified TPO.

Topics: Amitrole; Animals; Antithyroid Agents; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ethylenethiourea; Goiter; Guaiacol; Hydrogen Peroxide; Iodide Peroxidase; Iodine; Oxidation-Reduction; Propylthiouracil; Rats; Swine; Thiourea; Time Factors; Tyrosine

A Pauson-Khand type of conversion of enynes to bicyclic cyclopentenones employing the commercially available Co2(CO)8 and tetramethylthiourea (TMTU) as catalysts is described. This method allows a variety of enynes with diverse functional groups to be cyclized into cyclopentenones of interest. [reaction: see text]

Topics: Carbon Monoxide; Catalysis; Cyclization; Pressure; Thiourea

Small airway remodeling (SAR) is an important cause of airflow obstruction in cigarette smokers, but whether SAR represents a response to smoke-evoked inflammation or is directly mediated by smoke-induced growth factor production is disputed. To examine this process, we exposed rat tracheal explants, a model free of exogenous inflammatory cells, to cigarette smoke in vitro. Cigarette smoke caused release of active transforming growth factor (TGF)-beta1, and this was prevented by the oxidant scavenger tetramethythiourea. Nuclear immunostaining for phospho-Smad2, a TGF-beta downstream signaling molecule, was present in epithelial and interstitial cells within 1 h after exposure. Smoke caused upregulation of gene expression of connective tissue growth factor (CTGF), a mediator of TGF-beta fibrogenic effects, within 2 h, and upregulation of procollagen gene expression at 24 h; both changes could be prevented by the TGF-beta antagonist fetuin (alpha2-HS-glycoprotein). In a cell-free system, recombinant human TGF-beta latency-associated peptide was oxidized by cigarette smoke, and smoke released active TGF-beta1 from recombinant latent TGF-beta1 via an oxidant mechanism. These experiments suggest that SAR in cigarette smokers may be caused by direct, smoke-mediated, oxidant-driven induction of growth factor signaling in the airway wall, and that SAR does not necessarily require exogenous inflammatory cells.

Topics: Animals; Collagen Type I; Connective Tissue Growth Factor; Culture Media, Conditioned; DNA-Binding Proteins; Gene Expression Regulation; Humans; Immediate-Early Proteins; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Macrophages; Procollagen; Rats; Rats, Sprague-Dawley; Smad2 Protein; Smoking; Thiourea; Trachea; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factor beta1

Air pollution particles (PM) are known to elicit an acute inflammatory response in vivo that is mediated in part through PM-induced activation of the NF-kappaB signaling pathway. Many of the details of this process and particularly where in the cell it occurs are unclear. To determine whether contact of PM particles with an epithelial cell surface activates NF-kappaB, rat tracheal explants were exposed to Ottawa Urban Air Particles or iron-loaded fine TiO2, a model PM particle, for up to 2 h. During this period, there was no evidence of particle entry into the tracheal epithelial cells by light or electron microscopy, but both types of particle activated NF-kappaB as assayed by gel shifts. NF-kappaB activation could be inhibited by the active oxygen species scavenger, tetramethylthiourea; the redox-inactive metal chelator, deferoxamine; the Src inhibitor, PP2; and the epidermal growth factor (EGF) receptor inhibitor AG1478. An iron-containing citrate extract of both dusts also produced NF-kappaB activation. Both dusts and a citrate extract caused phosphorylation of the EGF receptor on tyrosine 845, an indicator of Src activity. We conclude that iron-containing PM particles can activate NF-kappaB via a pathway involving Src and the EGF receptor. This process does not require entry of particles into the airway epithelial cells but is dependent on the presence of iron and generation of active oxygen species by the dusts. These findings imply that even brief contact of PM with a pulmonary epithelial cell surface may produce deleterious effects in vivo.

Topics: Air Pollutants; Animals; Binding, Competitive; Biological Transport; Deferoxamine; Dust; Epithelial Cells; Ferric Compounds; Free Radical Scavengers; In Vitro Techniques; NF-kappa B; Particle Size; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Rats; Rats, Sprague-Dawley; Signal Transduction; Thiourea; Time Factors; Titanium; Trachea; Tyrphostins

The oxidation of tetramethylthiourea (TMTU) at gold electrodes in acetonitrile, leading to dissolution of the electrode, has been studied by electrochemical methods and by an electrochemical quartz crystal microbalance (EQCM). TMTU in acetonitrile readily adsorbs at gold electrodes and an estimated coverage of 5.5 x 10(-10) mol cm(-2) (30 A2 per molecule) was measured electrochemically. Nevertheless, the oxidation of TMTU in solution is a diffusion-controlled process and is strongly influenced by the electrode material, as observed by comparison of gold electrodes with glassy carbon and platinum working electrodes. In the absence of TMTU, EQCM cyclic voltammetry experiments showed dissolution of gold through a 1e- oxidation process at potentials more positive than 1.20 V vs saturated calomel electrode (SCE). Potential step and cyclic voltammetry EQCM experiments performed using gold surfaces in the presence of TMTU revealed TMTU-assisted etching of gold at potentials as low as 0.35 V vs SCE. In the potential region from 0.35 to 1.20 V the current response of TMTU oxidation mimics the response expected for a redox-active species in solution, including the presence of a mass-transfer-limited region, which supports the conclusion that the etching process in this potential region is initiated by the oxidation of TMTU at the gold surface. The current efficiency of the TMTU-assisted etching was found to vary between 12 electrons per gold atom dissolved (e/Au) (E = 0.50 V vs SCE) and 2 e/Au (0.90 V < E < 1.20 V). At potentials <0.90 V the dominant electrochemical process is the formation of TMTU+, whereas at higher potentials the etching of the gold surface by formation of a Au(I)-TMTU+ species becomes equally important. At potentials above 1.20 V the etching is no longer dependent on the diffusion of TMTU and the e/Au value approaches 1.

Topics: Acetonitriles; Electrochemistry; Gold; Microchemistry; Oxidation-Reduction; Quartz; Surface Properties; Thiourea

There is evidence that chronic exposure to high levels of ambient particulate pollutants (PM) is associated with chronic airflow obstruction, but how this occurs is not known. We exposed rat tracheal explants to Ottawa urban air particles (ECH93) or diesel exhaust particles. After 7 d in air organ culture, both types of PM increased explant procollagen and transforming growth factor (TGF)-beta 1 gene expression, and markedly increased tissue hydroxyproline. For both types of particle, nuclear factor-kappa B inhibitor SN50 completely blocked increased gene expression. With EHC93, procollagen expression was inhibited by the oxidant scavenger, tetramethylthiourea, and by the iron chelator, deferoxamine, but TGF-beta1 expression was not inhibited by deferoxamine. Inhibitors of extracellular signal regulated kinase and p38 kinase did not affect EHC93-induced gene expression. With diesel exhaust particles, tetramethylthiourea and deferoxamine had no effect, but extracellular signal regulated kinase and p38 inhibitors completely blocked effects on procollagen and TGF-beta 1. Fetuin, an inhibitor of TGF-beta receptor binding, prevented increases in procollagen gene expression. We conclude that two common types of PM can directly induce expression of genes involved in fibrogenesis and actual airway wall fibrosis through nuclear factor-kappa B- and TGF-beta-mediated mechanisms. PM-induced airway wall remodeling may play an important role in producing airflow obstruction in individuals living in high PM regions.

Topics: Air Pollution; alpha-Fetoproteins; Animals; Cells, Cultured; Chelating Agents; Collagen; Deferoxamine; DNA, Complementary; Enzyme Inhibitors; Fibrosis; Flavonoids; Gene Expression Regulation; Hydroxyproline; Imidazoles; Iron; Mitogen-Activated Protein Kinases; NF-kappa B; Organ Culture Techniques; Oxidants; p38 Mitogen-Activated Protein Kinases; Peptides; Procollagen; Promoter Regions, Genetic; Pyridines; Rats; Thiourea; Time Factors; Trachea; Transforming Growth Factor beta; Transforming Growth Factor beta1

Crystalline silica has been classified as a group 1 human carcinogen in the lung. However, its mechanisms of action on pulmonary epithelial cells which give rise to lung cancers are unclear. Using a nontransformed alveolar type II epithelial cell line (C10), we show that alpha-quartz silica causes persistent dose-related increases in phosphorylation of c-Jun-NH2-terminal amino kinases (JNKs) that are inhibited by antioxidants (P < or = 0.05). Increases in activator protein-1 (AP-1) binding to DNA and transactivation of AP-1-dependent gene expression by silica were accompanied by increases in steady-state mRNA levels of the AP-1 family members, c-jun, junB, fra-1, and c-fos at 8 h and elevated mRNA levels of fra-1 at 24 h (P < or = 0.05). Addition of tetramethylthiourea inhibited silica-associated increases infra-1 and proportions of cells in S-phase (P < or = .05). Our findings indicate that silica induces JNK activity, AP-1-dependent gene expression, ie., fra-1, and DNA synthesis via oxidative stress. Moreover, they suggest that silica may act mechanistically as a mitogen or tumor promoter, rather than a genotoxic carcinogen, in the development of lung cancers.

Topics: Animals; Cell Line; DNA; Dose-Response Relationship, Drug; Enzyme Activation; Epithelial Cells; Free Radical Scavengers; Gene Expression Regulation; Hydroxyl Radical; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Oxidative Stress; Phosphorylation; Proto-Oncogene Mas; Proto-Oncogene Proteins c-fos; Pulmonary Alveoli; RNA, Messenger; S Phase; Silicon Dioxide; Thiourea; Transcription Factor AP-1

Accumulation of immune complexes in the mesangium is a common finding. Since migration of macrophages (Mphi) in the mesangium has been demonstrated to be an important event in the development of glomerular lesions, we studied the role of immune complexes and mesangial cell (MC) interaction in the transmigration (Tm) of Mphi.. To determine the effect of MC and immune complexes (aggregated IgG, IgGAg) on transmigration of Mphi. MC were incubated with or without IgGAg in the lower compartment of a modified Boyden Chamber. To determine the effects of the secretory products (as a result of endocytosis of IgGAg by mesangial cells), MC-IgAg conditioned media was prepared and placed in the lower compartment of the Boyden chamber. We evaluated the effects of MC alone, MC + IgGAg, or MC-IgGAg conditioned media on the transmigration of macrophages across a filter. To determine the effect of free radicals on MC-IgAg endocytosis-induced Mphi migration we evaluated the effect of free radical scavengers such as dimethyl thiourea (DMTU) and tetramethylthiourea (TMTU) in MC-IgAg endocytosis-induced Mphi migration. To determine the role of chemokines in MC-IgAs endocytosis-induced Mphi migration we evaluated the effect of ani-MCP-1 antibodies on MC-IgAg endocytosis-induced Mphi migration, and also studied the effects of IgAg on MC mRNA expression of MCP-1 and RANTES. In addition, we evaluated the role of Fc receptors and actin cytoskeleton of MC in transmigration of Mphi.. Mesangial cell endocytosis of IgG aggregates (IgGAg) is associated with enhanced (P < 0.001) transmigration of Mphi (control, 11.2 +/- 0.2 vs. MC + IgGAg, 22.1 +/- 0.9 migrated Mphi/field). IgGAg also induced MC mRNA expression for RANTES and MCP-1 on MC. DMTU and TMTU attenuated (P < 0.001) the MC + IgGAg-induced migration of Mphi as well as IgGAg-induced mRNA expression for RANTES and MCP-1. MC and IgGAg interaction products (MC-IgGAg conditioned media) also increased (P < 0.01) transmigration of Mphi (control, 18.3 +/- 1.7 vs. MC-IgGAg conditioned media, 30.7 +/- 0.6 Mphi/field). This effect of MC-IgGAg conditioned media on the migration of macrophages was dose dependent. Anti-MCP-1 antibody partially inhibited MC-IgGAg-induced migration of macrophages. MC and monomeric IgG (MIgG) interaction (MC-MIgG conditioned media) showed a lower (P < 0.05) migration of Mphi, when compared to the MC-IgGAg conditioned media. MC-IgGAg conditioned media prepared from cytochalasin B pretreated MCs also showed a lower (P < 0.001) migration of Mphi when compared with MC-IgGAg conditioned media-induced migration.. These results indicate that MC-IgGAg conditioned media-induced transmigration of macrophages may be mediated through the generation of RANTES and MCP-1 by MC.

Topics: Animals; Antibodies; Cell Line; Cell Movement; Chemokine CCL2; Chemokine CCL5; Culture Media, Conditioned; Cytochalasin B; Endocytosis; Free Radical Scavengers; Glomerular Mesangium; Immunoglobulin G; Macrophages; Mice; Microscopy, Electron; Receptors, Cell Surface; RNA, Messenger; Thiourea

The most important stimulus for the enhanced synthesis of erythropoietin (Epo) is a lowered O2 tension in the tissue. However, the mechanism by which an impaired O2 supply is transduced into appropriate Epo production is still not fully understood. Recently, studies in human hepatoma cells (line HepG2) indicate that reactive O2 species are involved in the signal transduction from the cellular O2 sensor to the Epo gene. To clarify the role of reactive O2 species in the regulation of Epo synthesis in the kidney, the principal Epo-producing organ in vivo, we investigated the influence of potent pro- and antioxidants on Epo production in isolated perfused rat kidneys. Under normoxic conditions, the iron chelator desferrioxamine and the antioxidant vitamin A increased renal Epo production, mimicking hypoxic induction. In contrast, supplementation of the perfusion medium of hypoxically perfused kidneys with the prooxidant compounds H2O2 or pyrogallol caused a significant reduction of Epo synthesis. The inhibition of Epo formation by reactive O2 species could be completely antagonized by desferrioxamine and the hydroxyl radical-(OH*)-scavenger tetramethylthiourea. Vitamin A also antagonized the H2O2-dependent inhibition of hypoxically induced Epo synthesis. Interestingly, the addition of the antioxidant vitamin A to hypoxically perfused kidneys also induced Epo production significantly. Our data strongly support the idea that reactive O2 species, especially H2O2, are part of the signaling chain of the cellular O2-sensing mechanism regulating the renal synthesis of Epo.

Topics: Animals; Antioxidants; Chelating Agents; Deferoxamine; Erythropoietin; Free Radical Scavengers; Hydrogen Peroxide; Hypoxia; In Vitro Techniques; Kidney; Male; Oxidants; Pyrogallol; Rats; Rats, Sprague-Dawley; Reference Values; RNA, Messenger; Thiourea; Vitamin A

Obesity is associated with hyperinsulinemia and elevated concentrations of tumor necrosis factor-alpha (TNF-alpha) in adipose tissue. TNF-alpha has been implicated as an inducer of the synthesis of plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of fibrinolysis, mediated by plasminogen activators in cultured adipocytes. To identify mechanism(s) through which TNF-alpha induces PAI-1, 3T3-L1 preadipocytes were differentiated into adipocytes and exposed to TNF-alpha for 24 h. TNF-alpha selectively increased the synthesis of PAI-1 without increasing activity of plasminogen activators. Both superoxide (generated by xanthine oxidase plus hypoxanthine) and hydrogen peroxide were potent inducers of PAI-1, and hydroxyl radical scavengers completely abolished the TNF-alpha induction of PAI-1. Exposure of adipocytes to TNF-alpha or insulin alone over 5 days increased PAI-1 production. These agonists exert synergistic effects. Results obtained suggest that TNF-alpha stimulates PAI-1 production by adipocytes, an effect potentiated by insulin, and that adipocyte generation of reactive oxygen centered radicals mediates the induction of PAI-1 production by TNF-alpha. Because induction of PAI-1 by TNF-alpha is potentiated synergistically by insulin, both agonists appear likely to contribute to the impairment of fibrinolytic system capacity typical in obese, hyperinsulinemic patients.

Topics: 3T3 Cells; Adipocytes; Animals; Cells, Cultured; Drug Synergism; Insulin; Mice; Plasminogen Activator Inhibitor 1; Reactive Oxygen Species; Thiourea; Tumor Necrosis Factor-alpha

Topical application of anthralin, used in the treatment of psoriasis, is often accompanied by severe skin inflammation, presumably due to free radical products of the drug. The role of inflammatory cytokines and their induction by anthralin-derived reactive oxygen species were studied in cultures of normal human keratinocytes (NHKs).. Anthralin was added to cultures of NHKs in the presence or absence of various antioxidants, including superoxide dismutase, tetramethylthiourea, N-acetylcysteine and vitamin E and relative changes in cytokine secretion and in the number of mRNA transcripts were examined. In addition, NHKs were either treated with neutralizing antibodies to tumor necrosis factor (TNF)-alpha or transfected with a CAT-linked IL-8 promoter to establish the direct effects of anthralin on chemokine synthesis.. Anthralin, at concentrations between 5 microM and 25 microM, caused a marked increase in granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-6, IL-8 and TNFalpha synthesis that was selectively inhibited by specific antioxidants. Furthermore, anthralin induced chemokine secretion without the need of primary cytokines.. Taken together, these studies suggest that oxygen radicals generated from anthralin are responsible for the induction of inflammatory cytokines which, in turn contributes to their dermal toxicity.

Topics: Acetylcysteine; Administration, Topical; Anthralin; Anti-Inflammatory Agents; Antibodies; Antioxidants; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-6; Interleukin-8; Keratinocytes; Reactive Oxygen Species; RNA, Messenger; Superoxide Dismutase; Thiourea; Transcription, Genetic; Transfection; Tumor Necrosis Factor-alpha; Vitamin E

A number of compounds of pharmaceutical importance from a variety of chemical families, including thiocyanates, isothiocyanates, thiourea and derivatives, imidazoles, and various amines, were found to form charge transfer complexes with iodine. Parallel studies were carried out to investigate the actions of these drugs on lactoperoxidase and thyroid activity in vivo in the rat (assays of T3 and T4 and histology of the thyroid gland). The results showed that there was a good correlation between the value of Kc (the formation constant of the iodinated complex) and antithyroid activity in vivo. The higher the electron donor power of the compound, the higher the Kc value and the stronger the action on the thyroid. The results indicated that a number of drugs could have secondary antithyroid activity. Some compounds, such as levamisole, tetramethylthiourea, tetrahydrozoline, phenothiazines, and imipramines, with no action on peroxidase had high Kc values (tetramethylthiourea, 13,825 liters/M) and had strong antithyroid activity in the rat. These results suggest that synthetic antithyroid agents may act either on peroxidase and/or the molecular iodine which may be produced by oxidation of iodides (2I(-)----I2----2I+). It has been shown that oxidation of I- can occur in the absence of thyroglobulin. In the absence of a suitable receptor, significant amounts of I2 may, thus, accumulate. The action of such drugs on molecular iodine may have considerable pharmacological significance.

Topics: Absorption; Animals; Antithyroid Agents; Biomechanical Phenomena; Chemical Phenomena; Chemistry; Enzyme Activation; Iodides; Iodine; Lactoperoxidase; Male; Oxidation-Reduction; Rats; Thiourea; Thyroxine; Triiodothyronine; Ultraviolet Rays

The proliferation of Schwann cells in the sciatic nerve of chick was studied from day 11 to day 27 of development in control and thyroid-deficient embryos. Hypothyroidism was induced by tetramethylthiourea injection on days 8 and 19 of incubation. The parameters of the cell cycle were determined using autoradiographs (tritiated thymidine) and by image analysis of Feulgen-stained nuclear smears. The duration of the cell cycle was lengthened and the growth fraction was reduced in hypothyroid animals, at 11 and 15 days of incubation. At later stages (days 21 and 27), these parameters were not significantly different from the controls as if the sensitivity of Schwann cells to thyroid hormones was scheduled to occur during a limited period of development. The total number of axons was the same in control and hypothyroid animals suggesting that the slowing down of Schwann cell proliferation is not a consequence of neuronal cell death. The consequence of that slowing down is a delay in the isolation of promyelin axons and a reduction in the proportion of myelinated axons at all the stages studied.

Topics: Animals; Autoradiography; Cell Count; Cell Division; Chick Embryo; Embryonic and Fetal Development; Hypothyroidism; Schwann Cells; Sciatic Nerve; Thiourea; Thyroxine

A morphometric analysis of Purkinje cells in the developing cerebellar cortex of the chick was performed in normal animals and embryos made hypothyroid by one or two spaced injections of tetramethylthiourea. Profiles of 162 Purkinje cells, from Golgi-Cox treated sections were analysed. Soma area, perimeter and circularity index, cumulative length of the dendrites and number of dendritic bifurcations were studied. The results showed significant differences between control and hypothyroid animals. There were no important differences between birds rendered transiently hypothyroid with a single injection and those made chronically hypothyroid with dual injections. This confirms that the Purkinje cell is very dependent on thyroid hormone especially during the early phases of its morphogenesis. The development of the Purkinje cell was the most affected process of cerebellar cortex maturation in the thyroid-deficient chick. The dendritic arborization was particularly hypoplastic. Moreover, a dynamic balance appeared to exist between the development of the dendritic arborization and that of the perikaryon.

Topics: Animals; Cell Count; Cerebellar Cortex; Chick Embryo; Chickens; Dendrites; Hypothyroidism; Purkinje Cells; Thiourea; Thyroid Hormones

The mesonephros of the chick embryo normally begins to regress during the second half of embryonic life. Experimental methods, such as adenohypophysis grafting, hypophysectomy or use of antithyroid drugs, which stimulate or depress the thyroid function of the embryo, modified accordingly the regressive processes occurring in the mesonephric Malpighian corpuscles, particularly at the level of the glomerular basement laminae. These results as well as the known sensitivity of the mesonephros to thyroxine and the concordance between the steps of embryonic thyroid development and the mesonephric modifications show that the thyroid normally plays a major determining role in this phenomenon.

Topics: Animals; Antithyroid Agents; Chick Embryo; Hypophysectomy; Mesonephros; Morphogenesis; Nephrons; Pituitary Gland, Anterior; Thiourea; Thyroid Gland; Thyroxine

Topics: Animals; Axons; Chick Embryo; Chickens; Hypothyroidism; Myelin Sheath; Nervous System; Schwann Cells; Skin; Thiourea

Tetramethyl and ethylene thiourea are collected from air using midget impingers containing 15 mL water. Ethylene thiourea may also be collected from air using PVC or cellulose ester membrane filters which are then extracted with water. Pentacyanoamineferrate reagent is added to the filter-extract or to the impinger contents to form a colored coordination complex. The absorbance of the solution is measured spectrophotometrically at 590 nm, and the unknown concentration of tetramethyl or ethylene thiourea samples is determined from calibration curves. The detection limit is 0.75 microg/sample for ethylene thiourea and 3 microg/sample for tetramethyl thiourea. Experimental results indicate that this method can be used as a general analytical method for the analysis of other thiourea-derived compounds.

Topics: Ethylenethiourea; Spectrum Analysis; Thiourea