SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
S-Aryl-S-DABO derivatives, a novel subclass of S-DABO anti-HIV-1 agents, were synthesized via Ullmann type reaction starting from the corresponding 2-thiouracils by the aid of microwave irradiation. The results of their evaluation as inhibitors of RT are reported together with their antiviral activity in cellular assays.
Guanidine-based peptide nucleic acid (GPNA) monomers and oligomers containing all four natural (adenine (A), cytosine (C), guanine (G), and thymine (T)) and two unnatural (2-thiouracil (sU) and 2,6-diaminopurine (D)) nucleobases have been synthesized. Thermal denaturation study showed that GPNA oligomers containing alternate D-backbone configuration bind sequence-specifically to DNA and, when incubated with mammalian cells, localized specifically to the endoplasmic reticulum (ER).
Thyroid hormones are critical for the maturation and function of the central nervous system. Insufficiency of thyroid hormones in the adulthood causes a wide range of cognitive dysfunctions, including deficits in learning and memory. The present study investigated whether adult-onset hypothyroidism would alter synaptic functions in the dorsal hippocampo-medial prefrontal cortex (mPFC) pathway, a neural pathway important for learning and memory. Adult hypothyroidism was induced by oral administration of 1% (g/l) antithyroid acting drug 6-n-propyl-2-thiouracil (PTU) to adult male Sprague-Dawley rats for 4 weeks. Postsynaptic potentials (PSP) were recorded in the mPFC by stimulating the dorsal hippocampal CA1 region in vivo. Basal synaptic transmission was evaluated by comparing input-output relationships. Paired-pulse facilitation and long-term potentiation were recorded to examine short- and long-term synaptic plasticity. Adult-onset hypothyroidism did not change the basal synaptic transmission, but significantly reduced paired-pulse facilitation and long-term potentiation of PSP. These inhibitions can be restored by thyroid hormone replacement. The results suggest that such alterations in synaptic plasticity of the dorsal hippocampo-mPFC pathway might contribute to understanding basic mechanisms underlying learning and memory deficits associated with adult-onset hypothyroidism.
BACKGROUND: The association of atherosclerosis and hypercholesterolemia is well known. Hypercholesterolemic diet-induced atherogenesis is a widely accepted experimental model that is amenable to exploration of both the disease as well as therapeutic interventions. We evaluated the role of low molecular weight heparin (LMWH) in modulating the early biochemical changes in atherogenesis. METHODS: Male Wistar rats (140 +/- 10 g) were fed an atherogenic diet comprising of normal rat chow supplemented with 4% cholesterol, 1% cholic acid and 0.5% thiouracil (CCT diet) for 2 weeks. While one of the CCT diet-fed group served as the untreated pathologic model, the other group received LMWH (Certoparin sodium, Troparin; 300 microg/day/rat s.c.) treatment, commencing on day 8 and continued for 1 week. RESULTS: Decreased concentrations of serum albumin and increased serum urea, uric acid and creatinine concentrations were normalized by LMWH treatment. The atherogenic diet induced abnormal rise in the activities of lactate dehydrogenase, aminotransferases and alkaline phosphatase, as well as the high serum cholesterol and triglyceride concentrations were restored to near control values in the treated group. LMWH administration prevented the hypertrophic cardiac histology and fatty changes in the liver in early atherogenesis. CONCLUSION: The present study encapsulates the early cellular abnormalities in the heart, liver and kidney tissues of atherogenic diet fed rats. Treatment with LMWH affords considerable protection to the tissues challenged by hypercholesterolemia, evidenced by its correction of lipemia and restoration of serum and tissue indices of injury, to normalcy. LMWH intervention minimized the atherogenic diet-induced histopathological lesions in heart, liver and kidney tissues.
BACKGROUND: The present work explores the myriad of biochemical and cellular changes that are featured in the early stages of atherosclerosis; if unchecked these changes lead to the complicated atherosclerotic plaque formation. The influence of a low-molecular-weight heparin derivative on the aortic aberrations and lipoprotein oxidation has been assessed in an experimental model of hypercholesterolemic atherogenesis. METHODS: Two groups of male Wistar rats (140+/-10 g) were fed a hypercholesterolemic atherogenic diet (rat chow supplemented with 4% cholesterol, 1% cholic acid and 0.5% thiouracil; CCT diet) for 2 weeks; one of these groups received LMWH (Certoparin) treatment of 300 microg/day/rat, s.c. for 7 days. An untreated control and a LMWH drug control group were also included. RESULTS: Abnormal increase in the aortic lipids -glycosaminoglycans levels (p<0.001) in CCT-diet fed group was circumvented by the exogenous glycosaminoglycan (LMWH) treatment (p<0.001). The escalation of oxidative stress (markers-lipid peroxidation and thiol levels, superoxide dismutase and catalase activities) in the atherogenic aorta was minimised by LMWH treatment. Further, an increased susceptibility of the apo B-containing lipoproteins (LDL+VLDL) to oxidation in vitro, induced by copper ions and Fenton's reagent, was observed in the untreated CCT diet fed group. This paper reports the favorable modulation of these oxidative changes by LMWH administration. Vascular protection by LMWH is further substantiated by the normal aortic histologic findings as against the appearance of foam cells in the untreated atherogenic group. CONCLUSION: The exogenous heparin-derivative (LMWH) treatment attempted in this experimental model of hypercholesterolemic atherogenesis affords substantial protection against abnormal levels of aortic lipids and glycosaminoglycans, aortic oxidative stress and also stunts the lipoprotein peroxidative process, thereby proving its multi-faceted anti-atherogenic effects.
BACKGROUND: In the hypercholesterolemic state, the net result of combined oxidative and nitrosative stress is a pro-inflammatory phenotype that is manifested as increased adhesion molecule expression, enhanced leucocyte trafficking, and increased vascular permeability. The present work explores the inflammatory aspects of hypercholesterolemic atherogenesis, and also evaluates the role of a low-molecular-weight heparin derivative (LMWH), Certoparin, on a biochemical basis. METHODS AND RESULTS: Two groups of male Wistar rats were fed an atherogenic diet (normal rat chow plus 4% cholesterol, 1% cholic acid and 0.5% thiouracil-CCT diet) for 2 weeks. While one was left untreated, the other was administered LMWH (300 microg/day/rat commencing on day 8 and continued for a week). Increased concentrations of plasma C-reactive protein and fibrinogen and cardiac TNF-alpha indicated severe inflammation in the atherogenic diet fed rats. In comparison, these biochemical indices of inflammation diminished significantly in the LMWH treated group (p < 0.001). Significant depletion of thiols, along with accentuated activities of the glutathione metabolising was observed in the cardiac and hepatic tissues of the untreated atherogenic rats, indicating heightened oxidative response. Tissue damage was marked by elevated levels of plasma and tissue hexose, hexosamine, hexuronic acid and sialic acid, which were reversed towards normalcy on LMWH administration. The activities of lysosomal enzymes (N-acetyl glucosaminidase, beta-glucuronidase, beta-galactosaminidase and cathepsin-D) showed a marked increase in the CCT-diet fed rats, while LMWH treated rats showed normal activities (p < 0.001). The osmotic fragility test revealed that the untreated hyperlipidemic rat erythrocytes were significantly fragile at high salt concentrations, while the response was normalized in the LMWH treated group (p < 0.05). Further, hypercholesterolemia induced downregulation of physiological nitric oxide levels was corrected upon treatment with heparin-derivative. CONCLUSION: The results of this work highlight the inflammatory changes in atherogenic conditions and that the low-molecular-weight heparin derivative affords substantial protection.
Psoriasis is a common skin disorder associated with significant morbidity. Many agents are used in the medical management of this debilitating condition with the newer anti-cytokine agents being the most recent addition to the pharmacological armamentarium to battle the disorder. Cost concerns are very important with the newer "biologic" treatments costing in excess of 10,000 US dollars annually. The need for cheaper, orally administered agents is therefore imperative. This paper addresses the potential role of anti-thyroid thioureylenes, propylthiouracil and methimazole, in the treatment of psoriasis and reviews the possible mechanism of action of these drugs in this disorder. It is hypothesized that the beneficial effect of anti-thyroid thioureylenes in psoriasis is linked to their effect as anti-proliferative agents as reflected by significant decrease in markers of cellular proliferation such as proliferative cell nuclear antigen in biopsy specimens after treatment with these drugs. Propylthiouracil has been shown to bind to the hepatic T 3 receptor and it is possible that propylthiouracil (6-n-propyl-2-thiouracil) binding to the ligand-binding site normally occupied by T 3 impairs transcription by inactivating the effect of T 3 as well as by squelching retinoic X receptor heterodimer formation with other receptors of the steroid receptor superfamily such as the peroxisome proliferator-activated receptor, retinoic acid receptor and vitamin D receptors.
Synthesis and characterization of [o-carboxy phenylazo] moiety of barbituric acid, thiobarbituric acid, thiouracil, citrazinic acid, and disodium chromotropate and their complexes derived from cobalt (II), nickel (II), and copper (II) salts were done. The stereochemistry and the mode of bonding of the complexes were achieved based on elemental analysis, NMR, UV-Vis, IR and ESR. The dissociation constants of the free azo ligands are evaluated by spectrophotometric methods.
EPR spectroscopy was used to study the complex formed in crystals of 5-methyl-2-thiouracil (2-thiothymine) containing traces of copper. The copper impurities, originally present as Cu(I)-complex of 2-thiothymine in the lattice of 2-thiothymine, are transformed into paramagnetic Cu(II)-complex by ionizing radiation. It was found that the complex is planar, the plane being defined by two pairs of S and N atoms, from two adjacent 2-thiothymine molecules. The structure of the complex suggests that a pair of hydrogen bonds between two neighboring molecules is replaced by a stronger Cu-coordination bonding, with two sulfur and two nitrogen atoms as ligands. The spectroscopic parameters (g-tensor, A(63Cu) and A(14N) tensors) are essentially similar to those earlier observed for copper planar centers in other systems.
The electronic absorption spectra of 5-(o-substituted phenylazo)-6-amino-2-thiouracils and 6-(o-substituted phenylazo)-5-aminouracils containing different substituents are studied at different pH's. The dissociation constants are evaluated and discussed. Phenomenon of tautomerism is more supported by (1)H NMR and (13)C NMR spectra. The electrical conductivity of some ligands and their Co(II), Ni(II) and Cu(II) complexes in the temperature range 293-150K favoured their semiconducting properties where the metal ion forms a bridge to facilitate the flow of the current. The biological activity of some ligands and their complexes are tested against a number of Gram-positive and Gram-negative bacteria. The results showed that some of the compounds have a well considerable activity against some of the organisms.
Polybrominated diphenyl ethers (PBDEs), used as flame retardants in textiles, plastics and electrical appliances, have been shown to interfere with thyroid homeostasis. We evaluated the effects of environmentally relevant concentrations (low doses) of 2,2',4, 4',5-pentabromodiphenyl ether (PBDE-99) on the female reproductive system. A single dose of either 60 microg or 300 microg PBDE-99/kg body weight (BW) was administered on gestation day 6 to gravid Wistar rats. A reference control was treated with 6-n-propyl-2-thiouracil (PTU) on gestation days 7-21. Ultrastructural changes compatible with altered mitochondrial morphology were observed in the ovaries of the F1 offspring. No statistically significant changes in ovarian follicle counts were observed. Mating of the F1 females with untreated males revealed resorption rates in the PBDE groups greater than the limits considered normal for our controls. External and skeletal anomalies were detected in offspring (F2) from two different dams (F1) with early developmental exposure to 300 microg PBDE-99/kg BW. Exposure to PBDE-99 resulted in female reproductive tract changes in the F1 generation which were apparent at adulthood.
Altered thyroid statuses are associated with autonomic disorders. Thyrotropin-releasing hormone (TRH) synthesized in medullary raphe pallidus (Rpa), raphe obscurus (Rob) and the parapyramidal regions (PPR) regulates vagal and sympathetic preganglionic motoneurons. Hypothyroidism increased TRH gene expression and c-Fos immunoreactivity (IR) in these nuclei. Whether these increases represent a direct action of thyroid hormone was studied by detecting the presence of thyroid hormone receptor beta2 (TRbeta2) in pro-TRH-synthesizing neurons in the Rpa, Rob and the PPR using immunohistochemistry with specific TRbeta2 antiserum and in situ hybridization with digoxigenin-labeled pro-TRH cRNA probe. TRbeta2 IR was widely distributed throughout the medulla and primarily localized within the cell nuclei. Particularly intense immunostaining was presented in the Rpa, Rob and the PPR neurons. The combination of immunohistochemistry with in situ hybridization revealed that all pro-TRH mRNA-positive neurons in these ventral medullary nuclei were also TRbeta2 IR positive. The numbers of TRbeta2 IR-positive neurons in each nucleus were identical in both euthyroid rats and hypothyroid rats induced by 6-n-propyl-2-thiouracil in drinking water for 4 weeks. The finding that TRbeta2 localized in pro-TRH-synthesizing neurons in the ventral medullary nuclei provides an anatomical substrate for a direct thyroid hormone action on these neurons in the regulation of TRH gene expression, which may contribute to the altered autonomic activity in different thyroid statuses.
OBJECTIVE: The aim of the present study was to characterize the relationships between the thyroid-hormone-dependent changes in sarcoplasmic reticulum (SR) Ca2+ handling and contractile performance in atria. METHODS: Hypothyroidism in rats was induced by adding 0.05% 6-n-propyl-2-thiouracil to their drinking water for 6 weeks. Hyperthyroidism was induced by daily subcutaneous injections of L-thyroxine (1 microgram/g body weight) to euthyroid rats for 1 week. Left atria from the hearts with different thyroid states were examined by means of contractile measurements, SR oxalate-supported Ca(2+)-uptake, and Western blot of SR proteins. RESULTS: The tissue level of SR Ca(2+)-pump protein decreased in hypothyroid (46 +/- 6%) atria, but remained unchanged in hyperthyroid (110 +/- 8%) atria as compared with euthyroid atria. Hypothyroidism was associated with increased phospholamban expression (141 +/- 25%), whereas it was drastically downregulated under hyperthyroidism (21 +/- 4%). The rate of SR Ca(2+)-uptake, measured in the presence of the protein kinase A inhibitor, H-89, was higher in hyperthyroid atria and lower in hypothyroid atria than in euthyroid atria (397 +/- 40, 55 +/- 6 and 194 +/- 17 nmol Ca2+/g protein/min, respectively). However, the stimulation of SR Ca(2+)-uptake by the catalytic subunit of protein kinase A was relatively weaker in hyperthyroid (130 +/- 20% over control level without catalytic subunit) and stronger in hypothyroid (640 +/- 60%) than in euthyroid atria (280 +/- 40%). The rates of inotropic contraction (+dT/dt) were higher in the hyperthyroid atria (133 +/- 10 mN/s), but lower in hypothyroid atria (15 +/- 3 mN/s) than in their euthyroid counterparts (95 +/- 13 mN/s). Inversely, hypothyroid atria responded to isoproterenol with much larger increases in contractility (883 +/- 164% over the control values for the same muscle before addition of isoproterenol) and hyperthyroid with smaller increases (25 +/- 9%) than euthyroid preparations (207 +/- 17%) CONCLUSIONS: Thyroid hormones increase the contractility, but decrease the inotropic response to isoproterenol through decreasing the phospholamban/SR Ca(2+)-pump ratio in rat atria.
OBJECTIVE: The aim was to analyze the early postnatal changes in myocardial density, subsarcolemmal localization and isoform expression of dihydropyridine receptors in rat ventricle and the influence of thyroid status on these changes. METHODS: Newborn rats were treated from postnatal day 2 with L-triiodothyronine (T3) or 6-n-propyl-2-thiouracil )PTU) and ventricles were collected on day 1, 7 and 14. Radioligand binding and cell fractionation (density gradient centrifugation) techniques were used to determine the tissue density of various receptors and their subcellular localization. To analyze dihydropyridine receptor alpha 1 subunit isoform expression, cDNA fragments corresponding to a large portion of motif IV were amplified by reverse transcriptase-polymerase chain reaction and treated with appropriate restriction endonucleases to determine the frequency of splicing events at the level of motif IV. RESULTS: The myocardial density of dihydropyridine receptors increased 3-fold from day 1 to day 14 in control rats, and this increase occurred predominantly in membrane entities equilibrating at high densities in sucrose gradient, that is, presumably, in junctional structures (dyadic couplings). This maturation was delayed after PTU-treatment, and somewhat accelerated by excess T3. The proportion of mRNA variants typical of foetal heart (IVS3A variant and 'deleted' variant, showing a 33-nucleotide deletion at the level of the extracellular loop between IVS3 and IVS4) decreased with age in control rats. This reduction was delayed after treatment with PTU but was not influenced by excess T3. CONCLUSION: Hypothyroidism impaired the early postnatal maturation of dihydropyridine receptors as regards both their concentration into junctional structures and the decrease in the relative expression of alpha 1-subunit mRNA variants typical of foetal heart.
Cryopreserved human hepatocytes were extensively characterized in our laboratory. The post-thaw viability, measured via dye exclusion, ranged from 55 to 83%, for hepatocytes cryopreserved from 17 donors. Post-thaw viability and yield (viable cells per vial) were found to be stable up to the longest storage duration evaluated of 120 days. Drug-metabolizing enzyme activities of the cryopreserved hepatocytes (mean of ten donors) as percentages of the freshly isolated cells were: 97%, for cytochrome P450 isoform (CYP) 1A2, 78% for CYP2A6, 96% for CYP2C9. 86% for CYP2Cl9, 90% for CYP2D6, 164% for CYP3A4, 76% for UDP-glucuronidase, and 88% for umbelliferone sulfotransferase. Known species-differences in 7-ethoxycoumarin (7-EC) metabolism were reproduced by cryopreserved hepatocytes from human, rat, rabbit, dog, and monkey, illustrating the utility of cryopreserved hepatocytes from multiple animal species in the evaluation of species-differences in drug metabolism. Higher throughput screening (HTS) assays were developed using cryopreserved human hepatocytes for hepatotoxicity, metabolic stability, and inhibitory drug-drug interactions. Dose-dependent cytotoxicity, measured using MTT metabolism as an endpoint, was observed for the known hepatotoxic chemicals tamoxifen, clozapine, cadmium chloride, diclofenac, amiodarone, tranylcypromine, precocene II, but not for 2-thiouracil. Cell density- and time-dependent metabolism of 7-EC and dextromethorphan were observed in the HTS assay for metabolic stability. Known CYP isoform-specific inhibitors were evaluated in the HTS assay for inhibitory drug-drug interactions. Furafylline, sulfaphenazole, quinidine, and ketoconazole were found to be specific inhibitors of CYP1A2, CYP2C9, CYP2D6, and CYP3A4, respectively. Tranylcypromine and diethyldithiocarbamate were found to be less specific, with inhibitory effects towards several CYP isoforms, including CYP2A6, CYP2C9, CYP2C19, and CYP2E1. These results suggest that cryopreserved human hepatocytes represent a useful experimental tool for the evaluation of drug metabolism, toxicity, and inhibitory drug-drug interaction potential.
Alterations in the superoxide dismutase (SOD) content of thyroid tissues occurring in association with thyroid dysfunction have been reported. In this study, the Mn-SOD content was found to increase in thyroid tissues of rats administered thyroid stimulating hormone (TSH) and in thyrocytes cultured in medium supplemented with TSH. Furthermore, in the thyroid glands of rats whose serum TSH level was elevated by inhibiting the synthesis of T3 and T4 by 6-methyl-2-thiouracil, the Mn-SOD increased as the TSH concentration increased. In the cultured thyrocytes, the increase in Mn-SOD induced by TSH was inhibited by the C-kinase inhibitor H7. These findings suggest the induction of Mn-SOD by TSH in thyroid cells and point to a role of C-kinase in this process, thereby indicating that a close relationship exists between the serum TSH level and the change in Mn-SOD content in thyrocytes with thyroid dysfunction.
This paper describes a method for extraction of tapazol, thiouracil, methylthiouracil, propylthiouracil and mercaptobenzimidazol (MBI) from thyroid tissue. The solid-phase extraction procedure is optimized to obtain the maximum results for the main thyreostats including MBI. Different combinations of sample application, column conditioning and wash steps were tested. The analytes were extracted from the matrix with methanol. After solid-phase extraction they were derivatised with 7-chloro-4-nitrobenzo-2-furazan. Determination is carried out using liquid chromatography-electrospray mass spectrometry. The identification of the analytes was performed according to the final revision of the EU criteria (93/256/EC decision). The detection capability was 20 microg kg(-1) for all mentioned thyreostats.
In the present study, we describe the modifications in the expression of type II 5'deiodinase activity (5'D) in Xenopus laevis oocytes by injection of polyadenylated (poly A) mRNA from hypothyroid rat Harderian gland. The time-course study showed that the expression of the enzyme was dependent on time. Thus, enzyme activity was observed in oocytes 6 and 12 hours after the injection with poly A mRNA, reaching a maximal value at 24 hours. The activity was partially inhibited by 6-n-propyl-thiouracil, completely inhibited by iopanoic acid and exhibited a higher affinity for the T4 (Km=1.5 nM) than rT3 (Km=20 nM). The expression of the enzyme was modified in different experimental conditions: (a) exhibited diurnal variations with maximal peak values at night, (b) was inhibited by light at night and, (c) was activated by isoproterenol. On the other hand, we have also identified, for the first time, the size of mRNA capable of inducing 5'D in rats.