thiourea and Body-Weight

Topics: Abnormalities, Drug-Induced; Abortion, Veterinary; Administration, Oral; Allyl Compounds; Animals; Body Weight; Chickens; Economics; Estrus; Female; Guinea Pigs; Horses; Hydrazines; Injections, Intramuscular; Injections, Subcutaneous; Lactation; Male; Medication Errors; Periodicity; Pituitary Gland; Pregnancy; Pregnancy, Animal; Rats; Reproduction; Swine; Thiourea; Time Factors

Topics: Animals; Animals, Newborn; Body Weight; Bromodeoxyuridine; Cerebral Cortex; Chick Embryo; DNA; DNA Nucleotidyltransferases; Environment; Female; Growth Hormone; Hexoses; Hormones; Male; Maternal-Fetal Exchange; Mice; Nutrition Disorders; Nutritional Physiological Phenomena; Organ Size; Pregnancy; Seasons; Sex Factors; Species Specificity; Thiourea; Thyroxine

Osteoporosis is a major skeletal disease with low bone mineral density, which leads to an increased risk of bone fracture. Salubrinal is a synthetic chemical that inhibits dephosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) in response to endoplasmic reticulum (ER) stress. To understand possible linkage of osteoporosis to ER stress, we employed an unloading mouse model and examined the effects of salubrinal in the pathogenesis of disuse osteoporosis. The results presented several lines of evidence that osteoclastogenesis in the development of osteoporosis was associated with ER stress, and salubrinal suppressed unloading-induced bone loss. Compared to the age-matched control, unloaded mice reduced the trabecular bone area/total area (B.Ar/T.Ar) as well as the number of osteoblasts, and they increased the osteoclasts number on the trabecular bone surface in a time-dependent way. Unloading-induced disuse osteoporosis significantly increased the expression of Bip, p-eIF2α and ATF4 in short-term within 6h of tail suspension, but time-dependent decreased in HU2d to HU14d. Furthermore, a significant correlation of ER stress with the differentiation of osteoblasts and osteoclasts was observed. Administration of salubrinal suppressed the unloading-induced decrease in bone mineral density, B.Ar/T.Ar and mature osteoclast formation. Salubrinal also increased the colony-forming unit-fibroblasts and colony-forming unit-osteoblasts. It reduced the formation of mature osteoclasts, suppressed their migration and adhesion, and increased the expression of Bip, p-eIF2α and ATF4. Electron microscopy showed that rough endoplasmic reticulum expansion and a decreased number of ribosomes on ER membrane were observed in osteoblast of unloading mice, and the abnormal ER expansion was significantly improved by salubrinal treatment. A TUNEL assay together with CCAAT/enhancer binding protein homologous protein (CHOP) expression indicated that ER stress-induced osteoblast apoptosis was rescued by salubrinal. Collectively, the results support the notion that ER stress plays a key role in the pathogenesis of disuse osteoporosis, and salubrinal attenuates unloading-induced bone loss by altering proliferation and differentiation of osteoblasts and osteoclasts via eIF2α signaling.

Topics: Animals; Apoptosis; Body Weight; Bone Resorption; Cell Count; Cell Differentiation; Cell Survival; Cinnamates; Colony-Forming Units Assay; Endoplasmic Reticulum Stress; Female; Femur; Fibroblasts; Hindlimb Suspension; Mice, Inbred C57BL; Muscular Disorders, Atrophic; NFATC Transcription Factors; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Thiourea; X-Ray Microtomography

The cardioprotective role of histamine H3 receptor (H3R) agonist imetit (IMT) in isoproterenol (ISO)-induced alterations of hemodynamic and oxidative stress was investigated in Wistar rats. In this study, rats were treated with IMT (5 and 10 mg/kg, per orally [p.o.]), carvedilol (10 mg/kg, p.o.) and ISO control group (normal saline) for 7 d, with concurrent subcutaneous administration of ISO (85 mg/kg) at 24 h interval on last two consecutive days whereas control group was administered with vehicle only. ISO significantly attenuated cardiac antioxidant enzymes superoxide dismutase, catalase and increased plasma cardiac injury biomarkers creatine kinase-MB, alanine transaminase and aspartate transaminase. ISO also altered cardiac activity as evidenced by decrease in blood pressure (34.60%) and increase in heart rate (11.40%). The damage due to oxidative stress was revealed by histopathology alterations such as myocyte necrosis, myofibrillar degeneration and pyknotic nucleus. However, pre-treatment with IMT demonstrated restoration of hemodynamic alterations along with significant preservation of antioxidants and myocyte injury-specific marker enzymes. Furthermore, protective effect of IMT was reconfirmed by the histopathological salvage of myocardium. Results of the present study demonstrated the cardioprotective potential of IMT, as evidenced by favorable improvement in ISO-induced hemodynamic, plasma cardiac biomarkers and tissue antioxidant status along with maintenance of integrity of myocardium.

Topics: Adrenergic beta-Agonists; Animals; Antioxidants; Biomarkers; Blood Pressure; Body Height; Body Weight; Carbazoles; Cardiotonic Agents; Carvedilol; Heart Diseases; Heart Rate; Hemodynamics; Histamine Agonists; Humans; Imidazoles; Isoproterenol; Male; Myocardium; Oxidative Stress; Propanolamines; Rats; Rats, Wistar; Thiourea

Phosphorylation of eukaryotic initiation factor 2α (eIF2α), transiently activated by various cellular stresses, is known to alleviate stress-induced cellular damage. Here, we addressed a question: does elevation of eIF2α phosphorylation by salubrinal (a pharmacological inhibitor of eIF2α dephosphorylation) enhance healing of bone wounds? We hypothesized that salubrinal would accelerate a closure of surgically generated bone holes by modifying expression of stress-sensitive genes. To examine this hypothesis, we employed a rat wound model. Surgical wounds were generated on anterior and posterior femoral cortexes, and salubrinal was locally administered on the anterior side. The results showed that, compared to a contralateral control, the size of surgical wounds was reduced by 10.8 % (day 10) and 18.0 % (day 20) on the anterior side (both p < 0.001), and 4.1 % (day 10; p < 0.05) and 11.1 % (day 20; p < 0.001) on the posterior side. In addition, salubrinal locally elevated cortical thickness and increased BMD and BMC. Pharmacokinetic analysis revealed that subcutaneous injection of salubrinal transiently increased its concentration in plasma followed by a rapid decrease within 24 h, and its half-life in plasma was 1.2 h. Salubrinal altered the phosphorylation level of eIF2α as well as the mRNA levels of ATF3, ATF4, and CHOP, and suppressed cell death induced by stress to the endoplasmic reticulum. In summary, the results herein demonstrate that subcutaneous administration of salubrinal accelerates healing of surgically generated bone holes through the modulation of eIF2α phosphorylation.

Topics: Animals; Apoptosis; Body Weight; Cells, Cultured; Cinnamates; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; Female; Femur; Half-Life; Phosphorylation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stress, Physiological; Thiourea; Wound Healing

Dengue virus (DENV) is the etiologic agent for dengue fever, for which there is no approved vaccine or specific anti-viral drug. As a remedy for this, we explored the use of compounds that interfere with the action of required host factors and describe here the characterization of a kinase inhibitor (SFV785), which has selective effects on NTRK1 and MAPKAPK5 kinase activity, and anti-viral activity on Hepatitis C, DENV and yellow fever viruses. SFV785 inhibited DENV propagation without inhibiting DENV RNA synthesis or translation. The compound did not cause any changes in the cellular distribution of non-structural 3, a protein critical for DENV RNA synthesis, but altered the distribution of the structural envelope protein from a reticulate network to enlarged discrete vesicles, which altered the co-localization with the DENV replication complex. Ultrastructural electron microscopy analyses of DENV-infected SFV785-treated cells showed the presence of viral particles that were distinctly different from viable enveloped virions within enlarged ER cisternae. These viral particles were devoid of the dense nucleocapsid. The secretion of the viral particles was not inhibited by SFV785, however a reduction in the amount of secreted infectious virions, DENV RNA and capsid were observed. Collectively, these observations suggest that SFV785 inhibited the recruitment and assembly of the nucleocapsid in specific ER compartments during the DENV assembly process and hence the production of infectious DENV. SFV785 and derivative compounds could be useful biochemical probes to explore the DENV lifecycle and could also represent a new class of anti-virals.

Topics: Animals; Antiviral Agents; Azocines; Body Weight; Cell Line; Cell Line, Tumor; Chlorocebus aethiops; Dengue Virus; Endoplasmic Reticulum; Hepacivirus; Humans; Mice; Mice, Inbred ICR; Microscopy, Electron; Microscopy, Fluorescence; Molecular Structure; Nucleocapsid; Protein Kinase Inhibitors; Thiourea; Vero Cells; Viral Envelope Proteins; Virion; Virus Assembly; Virus Replication

Previous studies have shown that inherited taste blindness to bitter compounds like 6-n-propylthiouracil (PROP) may be a risk factor for obesity, but this literature has been highly controversial. The objectives of this study were (i) to confirm findings that show an interaction between PROP status and sex on BMI z-score, and (ii) to determine if sex also interacts with variations in TAS2R38 (phenylthiocarbamide (PTC) genotype) to influence weight status in 4-6 year olds. Also, we tested whether nontaster children consumed more fat and total energy at laboratory-based meals. Seventy-two ethnically diverse children who ranged in weight status were classified as tasters (N = 52) or nontasters (N = 20) using a standard PROP screening solution. Anthropometric measures were taken, and at the end of each visit, children ate ad libitum from test meals intended for exploratory purposes. Genomic DNA was extracted from saliva and alleles at TAS2R38 were genotyped for A49P polymorphisms. In 75.8% of children, PTC genotype predicted PROP phenotype, whereas in 24.4%, genotype did not predict phenotype. PROP nontaster males had higher BMI z-scores than taster-males and females in both groups (P < 0.05), but due to a three-way interaction between PROP phenotype, TAS2R38 genotype, and sex, this relationship was only true for children who were homozygous for the bitter-insensitive allele (P < 0.0005). There were no differences in test-meal intake as a function of PROP phenotype or TAS2R38 genotype. These results suggest that the TAS2R38 variation, PROP phenotype, and sex interact to impact obesity risk in children. Future studies should be done to determine how this trait influences energy balance.

Topics: Body Mass Index; Body Weight; Child; Child, Preschool; Female; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Male; Obesity; Propylthiouracil; Receptors, G-Protein-Coupled; Risk; Sex Characteristics; Taste; Taste Disorders; Thiourea

Our previous studies show that a decrease in endogenous nitric oxide (NO) is involved in the blunted outward K(+) currents in carotid body (CB) glomus cells from chronic heart failure (CHF) rabbits. In the present study, we measured the effects of the neuronal nitric oxide synthase (nNOS) transgene on the K(+) currents in CB glomus cells from pacing-induced CHF rabbits. Using single-cell real-time RT-PCR and immunofluorescent techniques, we found that nNOS mRNA and protein are expressed in the rabbit CB glomus cells and CHF decreased the expression of nNOS mRNA and protein in CB glomus cells. After 3 days of an adenoviral nNOS (Ad.nNOS) gene transfection, the expression of nNOS protein was increased to the level found in sham CB glomus cells. In whole cell patch-clamp experiments, Ad.nNOS markedly reversed the attenuated K(+) currents in CB glomus cells from CHF rabbits. The specific nNOS inhibitor (S-methyl-l-thiocitrulline [SMTC]) and large-conductance Ca(2+)-activated K(+) (BK) channel blocker (iberiotoxin) fully abolished the effect of Ad.nNOS on the K(+) currents in the CB glomus cells from CHF rabbits. However, neither CHF nor Ad.nNOS altered the protein expression of BK channel alpha-subunit. These results suggest that a decrease of NO induced by an attenuated nNOS activity lowers the activation of the BK channels but not the protein expression of the BK channel alpha-subunit in the CB glomus cells during CHF.

Topics: Analysis of Variance; Animals; Body Weight; Calcium; Carotid Body; Chemoreceptor Cells; Citrulline; Disease Models, Animal; Enzyme Inhibitors; Genetic Vectors; Green Fluorescent Proteins; Heart Failure; Large-Conductance Calcium-Activated Potassium Channels; Male; Membrane Potentials; Nitric Oxide Synthase Type I; Pacemaker, Artificial; Patch-Clamp Techniques; Peptides; Potassium Channel Blockers; Rabbits; RNA, Messenger; Thiourea; Transduction, Genetic; Tyrosine 3-Monooxygenase

This study sought to determine whether oxygen radical scavengers of dimethylthiourea (DMTU), superoxide dismutase (SOD), or catalase (CAT) pretreatment attenuated ischemia-reperfusion (I/R)-induced lung injury. After isolation from a Sprague-Dawley rat, the lungs were perfused through the pulmonary artery cannula with rat whole blood diluted 1:1 with a physiological salt solution. An acute lung injury was induced by 10 minutes of hypoxia with 5% CO2-95% N2 followed by 65 minutes of ischemia and then 65 minutes of reperfusion. I/R significantly increased microvascular permeability as measured by the capillary filtration coefficient (Kfc), lung weight-to-body weight ratio (LW/BW), and protein concentration in bronchoalveolar lavage fluid (PCBAL). DMTU pretreatment significantly attenuated the acute lung injury. The capillary filtration coefficient (P<.01), LW/BW (P<.01) and PCBAL (P<.05) were significantly lower among the DMTU-treated rats than hosts pretreated with SOD or CAT. The possible mechanisms of the protective effect of DMTU in I/R-induced lung injury may relate to the permeability of the agent allowing it to scavenge intracellular hydroxyl radicals. However, whether superoxide dismutase or catalase antioxidants showed protective effects possibly due to their impermeability of the cell membrane not allowing scavenging of intracellular oxygen radicals.

Topics: Animals; Body Weight; Edema; Free Radical Scavengers; Lung; Lung Injury; Microcirculation; Organ Size; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thiourea

Cancers and hepatoprotective prevention using traditional medicines have attracted increasing interest. The aim of our study was to characterize the putative protective effects of ethanol and chloroform extracts of Peganum harmala on thiourea-induced diseases in adult male rat. We seek to determine the effects of these plant extracts on body weight, thyroid and endocrine cancer parameters. In addition the putative hepatoprotective effect was checked by the determination of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the bilirubin level in the blood. Our data show that ethanol and chloroform extracts of Peganum harmala protected the animal against the carcinogenic effects induced by thiourea since neuron-specific enolase (NSE) and thyroglobulin (TG) levels were back to the normal range. In addition, the observed-hepatocytotoxicity after thiourea treatment was greatly reduced (AST and ALT activities were respectively 270 IU/l and 60 IU/l and in the same order of magnitude as in the untreated rats) as well as the bilirubin levels (6 micromol/l) especially for animals receiving the choroform preparation. Therefore we may suggest that extracts of Peganum harmala are efficient to reduce the toxicity induced by thiourea in male rat as far as the above parameters are concerned.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Bilirubin; Body Weight; Chloroform; Ethanol; Male; Multiple Endocrine Neoplasia; Peganum; Phosphopyruvate Hydratase; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Thiourea; Thyroglobulin; Thyroid Neoplasms; Time Factors

Leptin is a key signal linking peripheral adiposity levels to the regulation of energy homeostasis in the brain. The injection of leptin decreases body weight and food intake in lean rodents; however, in a rodent model of high fat diet-induced obesity (DIO), the exogenous leptin cannot improve adiposity. This ineffectiveness is known as leptin resistance, and the factors downstream of leptin signaling have received attention as viable targets in the treatment of obesity. We previously reported that the histaminergic system is one of the targets of leptin. In the present study, the effect of an H(3)-receptor inverse agonist on hypothalamic histamine release and energy intake was investigated in normal and DIO mice. Leptin (1.3 mg/kg, i.p.) significantly increased hypothalamic histamine release and reduced 12 h-energy intake in normal mice, but had no such effects in DIO mice. In contrast, clobenpropit (5 mg/kg, i.p.), an H(3)-inverse agonist, elicited a significant increase in histamine release in both types of mice. Clobenpropit did not reduce 12 h-energy intake; however, it decreased 3 h-energy intake in both types of mice. These results suggest that lack of the activation of the histaminergic system partly contributes to obesity in DIO mice and direct activation of the histaminergic system circumvents leptin resistance.

Topics: Analysis of Variance; Animals; Behavior, Animal; Body Weight; Chromatography, High Pressure Liquid; Electrochemistry; Energy Intake; Fats; Histamine; Histamine H3 Antagonists; Hypothalamus; Imidazoles; Leptin; Male; Mice; Mice, Inbred C57BL; Microdialysis; Obesity; Thiourea; Time Factors

Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.

Topics: Animals; Appetite; Body Weight; Diabetes Mellitus; Histamine Agonists; Imidazoles; Insulin; Leptin; Mice; Mice, Knockout; Obesity; Piperidines; Receptors, Histamine H3; Thiourea

The inducible nitric oxide synthase (iNOS) generates a high concentration of nitric oxide (NO) in tissues. Increased NO production is associated with many disorders including esophageal cancer. Previous studies in our laboratory demonstrated an association between increased iNOS expression and the development of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. On the basis of these observations, we initiated a bioassay to evaluate the ability of S,S'-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), a selective iNOS inhibitor, to prevent the progression of esophageal tumors in rats preinitiated with NMBA. Rats were given s.c. injections of NMBA (0.25 mg/kg body weight) three times per week for 5 weeks. One week later, they were fed a synthetic diet containing either 50 or 100 ppm PBIT until the end of the bioassay (25 weeks). PBIT reduced the incidence of esophageal cancer from 96% in NMBA-treated rats to 83% and 77% (P < 0.05) in rats treated with 50 and 100 ppm PBIT, respectively. Tumor multiplicity was reduced from 3.64 +/- 0.42 tumors per esophagus in NMBA-treated rats to 1.79 +/- 0.25 (P < 0.001) and 1.50 +/- 0.24 (P < 0.0001) in rats treated with 50 and 100 ppm PBIT, respectively. PBIT reduced the production of NO in NMBA-induced preneoplastic and papillomatous esophageal lesions when compared with comparable lesions in rats treated with NMBA only. iNOS mRNA expression was not modulated by PBIT. These observations suggest that iNOS plays a role in tumor development and that its selective inhibitor, PBIT, significantly inhibits esophageal tumor progression presumably through reducing the production of NO.

Topics: Animals; Anticarcinogenic Agents; Body Weight; Carcinogens; Dimethylnitrosamine; Eating; Enzyme Inhibitors; Esophageal Neoplasms; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Thiourea

Physiopathological discrepancies exist between the most widely used models of pulmonary hypertension (PH), namely monocrotaline- and hypoxia-induced PH. The development of a new model could help in the understanding of underlying mechanisms. Repeated alpha-naphthylthiourea (ANTU) injections (5 mg/kg weekly, 3 wk) induced pulmonary vascular remodeling, which was associated with development of PH and right ventricular hypertrophy. ANTU followed by granulocyte colony-stimulating factor (G-CSF; 25 microgram. kg(-1). day(-1) subcutaneously, 3 days/wk) induced higher pulmonary arterial pressures and right ventricular hypertrophy than ANTU alone. Lidocaine, which inhibits neutrophil functions, inhibited PH exacerbation by G-CSF. Endothelial nitric oxide synthase expression, measured to assess ANTU-related endothelial toxicity, decreased significantly in ANTU-treated rats and fell even more sharply when G-CSF was given. This occurred despite a significant increase in vascular endothelial cell growth factor expression in lung and right ventricle in rats given ANTU alone and even more in rats given ANTU plus G-CSF. Repeated ANTU administration induces PH with vascular remodeling that can be further aggravated by the neutrophil activator G-CSF.

Topics: Animals; Blood Vessels; Blotting, Western; Body Weight; Chronic Disease; Drug Synergism; Granulocyte Colony-Stimulating Factor; Hypertension, Pulmonary; Hypertrophy; Lung; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Organ Size; Rats; Rats, Sprague-Dawley; Thiourea; Vascular Endothelial Growth Factor A

We attempted to evaluate whether the antioxidants 1,3-dimethyl-2-thiourea (DMTU) and hexa(sulfobutyl)fullerenes (FC(4)S) attenuate monocrotaline (MCT)-induced pulmonary hypertension (PH) by lowering lung substance P (SP) in Wistar rats. Sixty-three rats weighing 297 +/- 8 g were divided into six groups: control; MCT; capsaicin + MCT; MCT + DMTU-1; MCT + DMTU-2; and MCT + FC(4)S. Three weeks before the functional study, saline was injected into each control rat, whereas each MCT rat received 60 mg/kg sc MCT. Rats in the third group received capsaicin pretreatment followed by MCT. A 3-day injection of DMTU was performed during the early (DMTU-1) or the late (DMTU-2) post-MCT period. For the last group, each MCT-treated rat received a daily FC(4)S injection until the commencement of the functional study. Compared to the control group, MCT caused significant increases in pulmonary arterial pressure (Ppa), right ventricular hypertropy, pulmonary arterial medial thickness, lung SP level, and luminol-enhanced chemiluminescence counts in bronchoalveolar lavage. Both capsaicin and antioxidants significantly attenuated the above MCT-induced alterations. SP-induced acute increase in Ppa was exaggerated in MCT-treated rats. These results suggest that oxygen radicals play an important role in MCT-induced PH via elevating lung SP level.

Topics: Animals; Body Weight; Carbon; Free Radical Scavengers; Hematocrit; Hypertension, Pulmonary; Immunoenzyme Techniques; Luminescent Measurements; Male; Monocrotaline; Muscle, Smooth, Vascular; Poisons; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Wistar; Reactive Oxygen Species; Substance P; Thiourea

In our previous investigation, which focused on two-stage carcinogenicity in the thyroid, rats were administered N-bis(2-hydroxypropyl)nitrosamine (DHPN), followed by thiourea (TU) over an experimental period of 19 weeks. Simultaneous treatment with a high level of vitamin A (VA) enhanced the induction of proliferative lesions that originated from the thyroidal follicular epithelium. To examine whether hormone synthesis in the thyroid could be inhibited by simultaneous treatment with a large amount of VA and TU, all of the rats were initially given a single subcutaneous injection of 2,800 mg DHPN/kg followed by a supply of 0% TU + 0% VA (DHPN only, control group), 0.2% TU in their drinking water (DHPN/TU group), 0.1% VA in their diet (DHPN/VA group), or 0.2% TU + 0.1% VA (DHPN/TU + VA group) during an experimental period of 4 weeks. Results obtained indicate that the iodine uptake and organification, namely iodination of tyrosine residue in thyroglobulin, of the thyroid, were significantly decreased in the DHPN/TU group compared to the DHPN control group. The variation in these values was attributable to the inhibitory effect of TU upon thyroid hormone synthesis. Results obtained from the DHPN/TU + VA and DHPN/TU groups were comparable. Therefore, the possibility that modification of hormone synthesis contributes to the enhancing effect of simultaneous treatment with a large amount of VA on thyroidal tumor induction by TU is considered to be very minimal.

Topics: Adenoma; Animals; Body Weight; Bromodeoxyuridine; Carcinogens; Drug Synergism; Hyperplasia; Iodine; Liver; Nitrosamines; Organ Size; Pituitary Gland; Rats; Rats, Inbred F344; Thiourea; Thyroid Gland; Thyroid Hormones; Thyroid Neoplasms; Vitamin A

Oxidative stress might play an important role in the progression of left ventricular (LV) remodeling and failure that occur after myocardial infarction (MI). We determined whether reactive oxygen species (ROS) are increased in the LV remodeling and failure in experimental MI with the use of electron spin resonance spectroscopy and whether the long-term administration of dimethylthiourea (DMTU), hydroxyl radical (.OH) scavenger, could attenuate these changes. We studied 3 groups of mice: sham-operated (sham), MI, and MI animals that received DMTU (MI+DMTU). Drugs were administered to the animals daily via intraperitoneal injection for 4 weeks.OH was increased in the noninfarcted myocardium from MI animals, which was abolished in MI+DMTU. Fractional shortening was depressed by 65%, LV chamber diameter was increased by 53%, and the thickness of noninfarcted myocardium was increased by 37% in MI. MI+DMTU animals had significantly better LV contractile function and smaller increases in LV chamber size and hypertrophy than MI animals. Changes in myocyte cross-sectional area determined with LV mid-free wall specimens were concordant with the wall thickness data. Collagen volume fraction of the noninfarcted myocardium showed significant increases in the MI, which were also attenuated with DMTU. Myocardial matrix metalloproteinase-2 activity, measured with gelatin zymography, was increased with MI after 7 and 28 days, which was attenuated in MI+DMTU. Thus, the attenuation of increased myocardial ROS and metalloproteinase activity with DMTU may contribute, at least in part, to its beneficial effects on LV remodeling and failure. Therapies designed to interfere with oxidative stress might be beneficial to prevent myocardial failure.

Topics: Animals; Body Weight; Cyclic N-Oxides; Echocardiography; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Hemodynamics; Male; Matrix Metalloproteinases; Mice; Myocardial Infarction; Myocardium; Organ Size; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Spin Labels; Thiourea; Ventricular Dysfunction, Left; Ventricular Remodeling

Antioxidants attenuate noncholinergic airway constriction. To further investigate the relationship between tachykinin-mediated airway constriction and oxygen radicals, we explored citric acid-induced bronchial constriction in 48 young Hartley strain guinea-pigs, divided into six groups: control; citric acid; hexa(sulphobutyl)fullerenes + citric acid; hexa(sulphobutyl)fullerenes + phosphoramidon + citric acid; dimethylthiourea (DMTU) + citric acid; and DMTU + phosphoramidon + citric acid. Hexa(sulphobutyl)fullerenes and DMTU are scavengers of oxygen radicals while phosphoramidon is an inhibitor of the major degradation enzyme for tachykinins. Animals were anaesthetized, paralyzed, and artificially ventilated. Each animal was given 50 breaths of 4 ml saline or citric acid aerosol. We measured dynamic respiratory compliance (Crs), forced expiratory volume in 0.1 (FEV0.1), and maximal expiratory flow at 30% total lung capacity (Vmax30) to evaluate the degree of airway constriction. Citric acid, but not saline, aerosol inhalation caused marked decreases in Crs, FEV0.1 and Vmax30, indicating marked airway constriction. This constriction was significantly attenuated by either hexa(sulphobutyl)fullerenes or by DMTU. In addition, phosphoramidon significantly reversed the attenuating action of hexa(sulphobutyl)fullerenes, but not that of DMTU. Citric acid aerosol inhalation caused increases in both lucigenin- and t-butyl hydroperoxide-initiated chemiluminescence counts, indicating citric acid-induced increase in oxygen radicals and decrease in antioxidants in bronchoalveolar lavage fluid. These alterations were significantly suppressed by either hexa(sulphobutyl)fullerenes or DMTU. An elastase inhibitor eglin-c also significantly attenuated citric acid-induced airway constriction, indicating the contributing role of elastase in this type of constriction. We conclude that both oxygen radicals and elastase play an important role in tachykinin-mediated, citric acid-induced airway constriction.

Topics: Animals; Body Weight; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Chelating Agents; Citric Acid; Forced Expiratory Volume; Free Radical Scavengers; Guinea Pigs; Pancreatic Elastase; Peak Expiratory Flow Rate; Proteins; Reactive Oxygen Species; Respiratory Function Tests; Serpins; tert-Butylhydroperoxide; Thiourea; Vital Capacity

Because chronic hypoxia increases the production of oxygen radicals, we hypothesized that antioxidants attenuate chronic hypoxic pulmonary hypertension. In part 1, we examined the temporal progress in chronic hypoxic pulmonary hypertension in 46 Wistar rats exposed to hypoxia from 0-3 weeks. In part 2, we tested whether antioxidants attenuated chronic hypoxic pulmonary hypertension in 82 rats divided into 10 groups: control, fullerenol-1, U-83836E, dimethylthiourea-1, dimethylthiourea-2, hypoxia, hypoxia + fullerenol-1, hypoxia + U83836E, hypoxia + dimethylthiourea-1, and hypoxia + dimethylthiourea-2. Control animals breathed room air and were injected intraperitoneally with saline for 2 weeks. Fullerenol-1, U-83836E, and dimethylthiourea are antioxidants and were administered intraperitoneally for 2 weeks, except that dimethylthiourea was given either on days 3, 5, and 7 (dimethylthiourea-1), or on days 8, 10, and 12 (dimethylthiourea-2). Hypoxic animals were placed into a hypobaric chamber with a barometric pressure of 380 Torr for 2 weeks. Hypoxia + antioxidant groups were administered antioxidants during hypoxic exposure. We observed a gradual increase in pulmonary artery pressure, the weight ratio of right ventricle to left ventricle plus septum, and hematocrit during the 3 weeks of chronic hypoxia. These hypoxia-induced alterations were significantly attenuated by U-83836E and dimethylthiourea, but not by fullerenol-1. Neither the temporal alterations nor the antioxidant effects can be explained by the change in either tracheal neutral endopeptidase activity or the lung or plasma substance P level, perhaps because of the time lag in sampling. These results indicate that oxygen radicals play an important role in the development of chronic hypoxic pulmonary hypertension.

Topics: Animals; Antioxidants; Body Weight; Chronic Disease; Free Radicals; Hypertension, Pulmonary; Hypoxia; Male; Rats; Rats, Wistar; Substance P; Thiourea

The mechanisms underlying enhanced cell proliferation in thyroid proliferative lesions of rats simultaneously treated with large amounts of vitamin A (VA) and thiourea (TU) were investigated. Male F344 animals were initiated with N-bis(2-hydroxypropyl)nitrosamine (2800 mg/kg body weight, single s.c. injection). Starting 1 week later, groups received water containing 0.2% TU (TU group), diet containing 0.1% VA (VA group), both 0.2% TU and 0.1% VA (TU + VA group) or tap water/basal diet without supplement (control group) for 10 weeks. The serum levels of triiodothyronine (T3) and thyroxine (T4) were decreased and the thyroid stimulating hormone (TSH) levels were elevated in the TU and TU + VA groups, with the degree of change being significantly greater in the combined treatment group. The induction of P450 isoenzymes by TU was not enhanced by VA supplementation, but uridine diphosphate glucuronosyltransferase (UDP-GT) activity in the liver was significantly increased in the TU + VA group compared to the TU group. Thyroid weights were increased in both the TU and TU + VA groups, this being more pronounced with VA supplementation. Thyroid follicular cell hyperplasias and neoplasias were induced to similar extents in both TU treated groups, but their cell proliferation appeared to be increased by the VA supplementation. The results of the present study suggest that enhanced cell proliferation is due to increased TSH stimulation, resulting from the decrease in serum T3/T4 levels brought about by induction of liver UDP-GT activity with the combined action of TU + VA as well as inhibition by TU of thyroid hormone synthesis in the thyroid.

Topics: Animals; Antithyroid Agents; Blotting, Western; Body Weight; Carcinogens; Cell Division; Glucuronosyltransferase; Isoenzymes; Liver; Male; Microsomes, Liver; Organ Size; Rats; Rats, Inbred F344; Thiourea; Thyroid Neoplasms; Triiodothyronine; Vitamin A

In order to examine modifying effects of simultaneous treatment with large amounts of vitamin A (VA) and thiourea (TU) on the thyroid tumorigenesis in rats, male F344 rats were initiated with N-bis(2-hydroxypropyl)nitrosamine (2800 mg/kg body weight, single s.c. injection), and starting 1 week later received diet containing 0.1% VA (VA group), drinking water containing 0.2% TU (TU group), 0.2% TU + 0.1% VA (TU + VA group) or tap water/basal diet (control group) for 19 weeks. Serum T3 and T4 in the TU and TU + VA groups were significantly decreased as compared to the control group, while serum TSH levels were remarkably increased. The ratios of T3 and T4 decrease and TSH increase in the TU + VA group were remarkably more pronounced than in the TU group. Thyroid neoplastic lesions were only induced in the TU and TU + VA groups. The multiplicity of intracapsular follicular cell proliferative foci in the TU + VA group was significantly increased as compared to the TU group value. Cell proliferation of hypertrophic and subcapsular follicular cells, as well as in hyperplasias, and neoplasias with adenomatous growth pattern was significantly higher in the combined treatment case than after TU alone. In the liver, centrilobular hypertrophy of hepatocytes was seen in the TU and TU + VA groups, this being especially marked in the latter group. In the combined group case the affected cells were strongly positive for GST-P antibody binding. The results of the present study suggest that cell proliferation of thyroid follicular cell proliferative lesions in rats is enhanced by strong TSH stimulation with simultaneous treatment of TU and large amounts of VA.

Topics: Adenoma; Animals; Body Weight; Carcinogens; Cell Division; Drug Synergism; Male; Nitrosamines; Rats; Rats, Inbred F344; Reference Values; Thiourea; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Thyroxine; Triiodothyronine; Vitamin A

Alpha-naphthylthiourea when injected intraperitoneally to rats (10 mg kg-1 i.p.) produced lung oedema as indicated by an increase in lung weight/body ratio and pleural effusion reaching a maximum within 4 hours. Prior intravenous single bolus injection of endothelin-1 elicited a significant and dose-dependent inhibition in both parameters. However, prior i.v. injection of angiotensin II using relatively higher doses did not alter the oedema-producing effect of alpha-naphthylthiourea indicating a characteristic for endothelin-1. The inhibitory effect of endothelin-1 on pleural effusion is more prominent than lung weight/body weight ratio. The resolution of lung oedema by single bolus i.v. injection of endothelin-1 is probably due to the acute long-lasting and potent vasoconstrictor effect of the peptide and its large accumulation in lung tissue. Phosphoramidon, an inhibitor of endothelin converting enzyme, did not alter the oedema producing effect of alpha-naphthylthiourea indicating the lack of the participation of endothelin-peptide cascade to this pathological event. Bosentan, a non-selective receptor blocker of endothelin-1, did not inhibit the preventive effect of the peptide against alpha-naphthylthiourea-induced lung oedema. Possible mechanisms of the acute effect of endothelin-1 on lung oedema are discussed.

Topics: Angiotensin II; Animals; Aspartic Acid Endopeptidases; Body Weight; Bosentan; Endothelin-1; Endothelin-Converting Enzymes; Glycopeptides; Male; Metalloendopeptidases; Organ Size; Pleural Effusion; Protease Inhibitors; Pulmonary Edema; Rats; Sulfonamides; Thiourea

Long-term treatment with dimethylthiourea (DMTU), a scavenger of hydroxyl radical (.OH) and hypochlorous acid (HOCl), suppressed the age-related development of autoimmune disease in NZB x NZWF1 mice. Treatment reduced autoantibody production, retarded increase in blood urea nitrogen, and prolonged life. The results suggest that .OH and HOCl may, at least in part, enhance the development of autoimmune diseases in NZB x NZWF1 mice.

Topics: Animals; Antibodies, Antinuclear; Autoimmune Diseases; Blood Urea Nitrogen; Body Weight; Female; Free Radical Scavengers; Mice; Mice, Inbred NZB; Survival Rate; Thiourea

Whether a reduction in urinary protein excretion in rats coadministered puromycin aminonucleoside and antioxidants was associated with a reduction in alterations to glomerular epithelial cell (podocyte) ultrastructure was examined. Daily urinary protein excretion was measured in rats that received a single i.v. injection of saline or puromycin aminonucleoside with or without coadministration of antioxidants. The coadministration of alpha-tocopherol/ascorbic acid, dimethyl thiourea, or superoxide dismutase to puromycin aminonucleoside-treated rats reduced proteinuria by approximately 90, 40, and 60%, respectively, over the 18-day period studied. For a second group of rats, daily urinary protein excretion was measured and kidneys were processed for light microscopy and transmission and scanning electron microscopy 4, 5, and 10 days after injection. Transmission electron microscopic morphometric analysis of glomeruli from puromycin aminonucleoside-treated rats coadministered antioxidants revealed significantly reduced foot process effacement on Days, 4, 5, and 10 compared with rats that received puromycin aminonucleoside alone. Thus, at Day 10, puromycin aminonucleoside-treated rats coadministered alpha-tocopherol/ascorbic acid, dimethyl thiourea, or superoxide dismutase contained 90, 74, and 88% (P < 0.01 in all cases) more glomerular epithelial cell filtration slits per unit length of glomerular basement membrane than rats treated with puromycin aminonucleoside alone. In contrast, by scanning electron microscopy, the antioxidants were found to provide no protection against the changes occurring in glomerular epithelial cell bodies and major processes. These results provide further evidence of a role for reactive oxygen species in puromycin aminonucleoside nephrosis and indicate that the antioxidants provide protection against the changes occurring in glomerular epithelial cell foot processes.

Topics: Animals; Antioxidants; Ascorbic Acid; Body Weight; Diuresis; Female; Kidney Glomerulus; Microscopy, Electron; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thiourea; Vitamin E

Time course changes in serum TSH and quantitative data for thyroid proliferative lesions in male F344 rats administered N-bis(2-hydroxypropyl)nitrosamine (DHPN: 2000 mg/kg body weight, single s.c. injection) followed by 0.1% thiourea (TU), were assessed at weeks 1, 2, 4, 8, 12 and 16 of treatment. The serum T4 level in the TU group was markedly decreased at week 1 and remained significantly lowered throughout the experiment. Serum TSH levels, in contrast, were elevated up to a peak at around week 4 with a return to the normal range at week 12. Thyroid weights in the TU group were increased significantly in a treatment period-dependent manner. Histopathologically, marked hypertrophy of thyroid follicular cells occurred at the early stage of TU treatment. Proliferative lesions, such as hyperplasia and adenomas, occurred from weeks 2 and 4, respectively, and increased with the later treatment period. The cell proliferative activity of follicular cells, assessed by BrdU incorporation, was high until week 2, but then returned to normal. The initially appearing hyperplasias and adenomas were characterized by marked proliferation but this also greatly decreased at later stages when TSH was no longer elevated. The results of our study thus suggest that a high serum TSH level plays an important role in the early phase of thyroid tumorigenesis and 8 weeks treatment with test substances is sufficient for detection of thyroid tumor promoter potential in two-stage thyroid carcinogenesis models.

Topics: Adenoma; Animals; Body Weight; Carcinogens; Cell Division; Drug Administration Schedule; Hyperplasia; Male; Nitrosamines; Organ Size; Pituitary Gland; Rats; Rats, Inbred F344; Thiourea; Thyroid Diseases; Thyroid Gland; Thyrotropin; Time Factors

Study was made to determine whether oxygen free radicals mediate uranium-induced acute renal failure (ARF). Superoxide dismutase (SOD), a superoxide anion scavenger, did not prevent uranium acetate (UA) (5 mg/kg, i.v.)-induced renal injury 48 h after injection. In contrast, dimethylthiourea (DMTU), a hydroxyl radical scavenger, significantly attenuated UA-induced rise in serum creatinine concentration (1.11 +/- 0.05 (DMTU) vs. 1.40 +/- 0.06 mg/dl (control), p < .05), and tubular necrosis. Dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger, decreased UA-induced tubular damage. UA injection caused no increase in renal cortical malondialdehyde (MDA) content. DMTU and DMSO did not modify intrarenal MDA content. UA administration brought about significant increase in plasma renin activity but not in renal cortical renin content. Treatment with DMTU and DMSO had no effect on plasma renin activity or intrarenal renin content. It follows from these findings that DMTU and DMSO may attenuate UA-induced renal injury. Such a protective effect would not be mediated through modulation of lipid peroxidation or renin activity.

Topics: Acute Kidney Injury; Analysis of Variance; Animals; Blood Urea Nitrogen; Body Weight; Creatinine; Dimethyl Sulfoxide; Free Radical Scavengers; Hematocrit; Kidney; Kidney Cortex; Male; Malondialdehyde; Rats; Rats, Sprague-Dawley; Renin; Superoxide Dismutase; Systole; Thiourea; Uranium

Dimethylthiourea (DMTU) is a small, highly diffusible molecule that effectively scavenges toxic oxygen metabolites in vitro and reduces oxidative injury in many biologic systems. Nonetheless, for unknown reasons, DMTU has occasionally failed to decrease damage in some systems where injury is presumed to be mediated by oxygen metabolites. We hypothesized that the inconsistent pattern of protection might partially reflect a direct toxicity of DMTU. Our results supported this premise. We found that rats treated with commonly used doses of highly purified DMTU had increased lung accumulation of intravenously injected iodine 125-labeled albumin (4 hours after DMTU treatment) and decreased blood glutathione levels (24 hours after DMTU treatment) when compared with saline-injected control rats. In contrast, rats treated with dimethylurea, a analog of DMTU, did not develop increased accumulation of labeled albumin in the lungs or decreased blood glutathione levels. We conclude that DMTU has intrinsically toxic effects in rats and that DMTU toxicity may at times obscure its protective action.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Glutathione; Lung; Male; Methylurea Compounds; Organ Size; Rats; Rats, Sprague-Dawley; Serum Albumin; Stomach; Thiourea

A rat model of endotoxic shock was used to evaluate the effects of dimethylthiourea, a putative hydroxyl radical scavenger, in the alterations of lung phosphatidylcholine biosynthesis found during endotoxemia. Treatment of rats with dimethylthiourea, just before lipopolysaccharide injection, resulted in a decreased lipid peroxidation and an increase in phosphatidylcholine biosynthesis, although it did not prevent the body weight loss or the increase in lung weight and lung protein content associated with the lung injury induced by lipopolysaccharide. Our results suggest that phosphatidylcholine biosynthesis is impaired by processes in which hydroxyl radicals are implicated, although other oxygen free radical species, not removed by dimethylthiourea, can be also involved in lipopolysaccharide mediated lung injury.

Topics: Animals; Body Weight; Hydroxyl Radical; Lipid Peroxidation; Lipopolysaccharides; Lung; Male; Organ Size; Phosphatidylcholines; Rats; Rats, Wistar; Shock, Septic; Superoxide Dismutase; Thiourea

We tested the hypothesis that free radicals play a role in the selective destruction of pancreatic beta-cells in BB/Wor rats. Diabetes-prone BB rats of both sexes and 40 days of age were divided into three groups. The control group was fed ad libitum Purina rat chow powder, while the experimental group was fed ad libitum the rat chow powder blended with a mixture of four known free radical scavengers: allopurinol, mercaptopropionylglycine, dimethylthiourea and Vitamin E. A third group was pair-fed 10 g chow powder/rat/day, since in earlier experiments we observed that rats on the experimental diet consumed only about 10 g/rat/day. All rats were studied up to age 120 days. Body weight and food intake were measured daily. Urine was tested for glucose beginning at age 60 days. When glucosuria appeared, blood glucose and urinary ketones were measured. Body weight gain in the experimental and pair-fed groups was similar, but lower than the control group. Life table analysis of the data showed a decreased and a delayed onset of diabetes in the rats fed free radical scavengers. Thus, the results of this study demonstrated that calorie restriction and the related impaired growth did not affect the incidence of diabetes in the BB rat. In addition, the results suggested a role for free radicals in the spontaneous destruction of pancreatic beta-cells in the BB rat.

Topics: Allopurinol; Animals; Body Weight; Diabetes Mellitus, Type 1; Diet; Female; Free Radical Scavengers; Male; Rats; Rats, Inbred BB; Thiourea; Tiopronin; Vitamin E; Weight Gain

Sprague-Dawley rats were administered ethylenethiourea (ETU), 1,3-dimethyl-2-thiourea (DMT), 1,3-dibutyl-2-thiourea (DBT), or 1,3-diphenyl-2-thiourea (DPT) by gavage from Days 6 to 20 of gestation. Daily dosage levels (mg/kg/day) were ETU at 0, 15, 25 and 35; DMT at 0, 15, 25, 50, 100, and 200; DBT at 0, 15, 25, 50, 100, and 200; and DPT at 0, 25, 50, 100, and 200. There was evidence of maternal toxicity at all doses of DMT and at doses greater than or equal to 50 mg DBT/kg/day. DPT was embryolethal at 200 mg/kg/day. Fetotoxicity was observed at doses greater than or equal to 15 mg DMT/kg/day, greater than or equal to 15 mg DBT/kg/day, and greater than or equal to 100 mg DPT/kg/day. ETU was the only chemical tested that proved to be teratogenic.

Topics: Animals; Behavior, Animal; Body Weight; Embryo, Mammalian; Ethylenethiourea; Female; Gestational Age; Intubation, Gastrointestinal; Pregnancy; Rats; Rats, Inbred Strains; Reproduction; Teratogens; Thiourea

2,4-Dithiobiuret (DTB) exposure causes a delayed onset muscle weakness in rats that has been attributed to depressed neuromuscular transmission. The present study compares the effects of DTB on both sensory and motor function in rats. Adult male Long-Evans hooded rats were exposed to saline, 0.25, 0.5, or 1.0 mg/kg/day DTB, ip, for 5 consecutive days (Days 1-5). Body weights were monitored throughout the experiment. Motor activity was measured for 1 hr in figure-eight mazes on Days 0, 6, 13, and 27. Forelimb and hindlimb grip strength were assessed on Days 6, 13, and 27. Auditory thresholds were determined for 5- and 40-kHz tones using reflex modification of the startle response on Days 0, 7, 14, and 28. Visual function was examined on Day 6 in animals exposed at 0.5 mg/kg/day using flash- and pattern-elicited visual evoked potentials (FEPs and PEPs, respectively). Thermal sensitivity was measured using the hot plate procedure. All motor endpoints were decreased in a dosage- and time-dependent manner; the higher the dosage the longer the effects lasted. There were no effects on any measure of sensory function with the exception of peak N2 of the FEP. Both the amplitude and latency of FEP N2 were altered by DTB exposure. Decreases in body weight were maximal on Day 9 at 1.0 mg/kg/day (20% from control), but recovered by Day 22. Motor activity was suppressed on Day 6 only, whereas grip strength measures were decreased on both Days 6 and 13. Auditory thresholds were not significantly altered; however, baseline startle amplitude was decreased at the highest dosage on Days 7 and 14, but recovered by Day 28. Hot plate latencies were not altered by DTB treatment. These data demonstrate that DTB produces a reversible impairment of motor function, without altering auditory, thermal, or pattern visual function. FEP N2, which is thought to arise from activity generated in the superficial layers of visual cortex, was diminished by DTB treatment, indicating that DTB can alter the function of the CNS, although effects on the motor system are more pronounced.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Electroencephalography; Evoked Potentials; Evoked Potentials, Visual; Male; Motor Activity; Motor Neurons; Neurons, Afferent; Psychomotor Performance; Rats; Reflex; Reflex, Startle; Sensory Thresholds; Thiourea

To evaluate the mechanism of the promoting effect of goitrogens on thyroid tumorigenesis, well-known goitrogens having different pharmacologic action, i.e., thiourea, phenobarbital sodium (PB), potassium thiocyanate (KSCN), and 3,4,5,6-tetrachloro-2',4',5',7'-tetraiodo-fluorescein sodium salt (Rose Bengal B, FD&C Red No. 105) (FR105) were administered to the DHPN-initiated and non-initiated F344 male rats in the drinking water for 25 weeks. Remington's iodine deficient diet (I-def) was fed as a positive control. These goitrogens showed significant tumor promoting effect or promoting tendency on the rat thyroids. According to the changes in thyroid morphology and thyroid-related hormone titers observed in the present study, we proposed to classify goitrogens at least into 2 groups, i.e., iodine deficiency-type promoters and the iodine excess-type promoters. The former contains goitrogens inducing TSH-stimulated diffuse goiter composed of uniform follicles with activated tall follicular epithelial cells, such as thiourea, KSCN and PB, and the latter contains goitrogens inducing colloid goiter composed of a mixture of colloid-rich follicles with flat follicular cells and normal-looking follicles with cuboidal follicular cells, such as FR105. This classification may be useful for the risk assessment of goitrogens.

Topics: Animals; Antithyroid Agents; Body Weight; Carcinogens; Male; Nitrosamines; Organ Size; Phenobarbital; Rats; Rats, Inbred F344; Rose Bengal; Thiocyanates; Thiourea; Thyroid Gland; Thyroid Hormones; Thyrotropin

We studied the effects of a hydroxyl radical scavenger, dimethylthiourea (DMTU), on syngeneic islet grafts. Six hundred fresh islets taken from two Wistar rats were transplanted intraportally into other Wistar rats made diabetic with streptozotocin. DMTU was given to five recipients intraperitoneally for a month while nine controls received only intraperitoneal saline. The DMTU-treated group had significantly lower fasting plasma glucose levels at 1.5, 4.5, 5, 5.5, 6, 7, 9 and 11 weeks and had higher mean fasting body weights between the 2.5th week and their eventual sacrifice. Their islets also survived significantly longer than did those of the controls (73.6 +/- 3.4 vs. 21.6 +/- 9.4 days). This suggests that oxygen free radical production endangers graft survival and that the hydroxyl radical scavenger DMTU protects syngeneic islet grafts.

Topics: Animals; Blood Glucose; Body Weight; Graft Survival; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Rats; Rats, Inbred Strains; Reference Values; Thiourea; Transplantation, Isogeneic

N-Methylthiobenzamide (NMTB) and alpha-naphthylthiourea (ANTU) are pneumotoxicants which cause pulmonary edema and hydrothorax. Recently a role was assigned to serotonin (5-hydroxytryptamine, 5-HT) in the pneumotoxic response to ANTU (D.E. Mais and T.R. Bosin, 1984, Toxicol. Appl. Pharmacol. 74, 185-194). We therefore investigated the participation of 5-HT in NMTB-induced pneumotoxicity. Pulmonary clearance of 5-HT was studied after NMTB or ANTU using the rat isolated perfused lung. Lung 5-HT uptake was not depressed 5 hr after ANTU or NMTB, but was depressed 12 hr after compound administration. At both time points lungs were edematous as judged by lung wet weight to body weight ratios. Pretreatment with reserpine, a drug known to deplete 5-HT, did not affect the NMTB-induced decrease in lung 5-HT uptake, but did diminish the increased lung wet weight to dry weight ratios seen after NMTB administration in rats and mice and the increased lung wet weight to body weight ratios in mice. NMTB induces a dose-dependant increase in the incorporation of [14C]thymidine into mouse pulmonary DNA. This increase was attenuated, but not abolished, by pretreatment with reserpine. Reserpine did not alter survival time after NMTB or ANTU and did not shift the 14-day LD50 of NMTB. These data suggest that 5-HT is not a primary mediator in the pneumotoxic response to these thiono-containing compounds.

Topics: Amides; Animals; Body Weight; Hydroxyindoleacetic Acid; Lethal Dose 50; Lung; Male; Organ Size; Rats; Rats, Inbred Strains; Reserpine; Serotonin; Thioamides; Thiourea; Thymidine

Lung injury induced by phorbol myristate acetate (PMA) is closely associated with toxic oxidants released from activated granulocytes. But the major toxic oxidant causing lung damage is not really known. We have, therefore, conducted investigations using various oxygen radical scavengers. The intravenous administration of dimethylthiourea (DMTU), a potent hydroxyl radical scavenger, or of superoxide dismutase (SOD), a superoxide anion scavenger, plus catalase, a hydrogen peroxide scavenger, to rabbits intravenously injected with PMA prevented biochemical data and cellularity indicative of lung damage in lung lavages. Morphologically, the lungs of PMA-injected rabbits revealed mild interstitial edema, aggregates of granulocytes within the interstitial capillaries, and the increase of granulocytes in alveolar spaces. Furthermore, there was direct morphologic evidence of pulmonary endothelial cell disruption. In rabbits treated with DMTU or SOD plus catalase, there was no evidence of destructive changes in the lungs. SOD-treated rabbits did not show evidence of protection from PMA-induced lung injury. Only a little protection was provided by catalase treatment. Moreover, in the ultracytochemical study for examination of hydrogen peroxide (H2O2) generation, the number of H2O2-generated granulocytes remarkably decreased in lung lavages of catalase-treated rabbits, but destructive changes were observed in the lungs. In contrast, though the number of H2O2-generated granulocyte was not decreased in lung lavages of DMTU-treated rabbits, treatment with DMTU could afford protection from lung injury. These data indicate that the hydroxyl radical, a toxic oxidant derived from stimulated granulocytes, is deeply involved in the pathogenesis of PMA-induced lung injury.

Topics: Animals; Body Weight; Bronchoalveolar Lavage Fluid; Catalase; Cell Count; Free Radicals; Granulocytes; Histocytochemistry; Hydrogen Peroxide; Hydroxides; Hydroxyl Radical; Lung; Lung Diseases; Male; Organ Size; Rabbits; Superoxide Dismutase; Superoxides; Tetradecanoylphorbol Acetate; Thiourea

The rate and sequence of interstitial and alveolar fluid removal from the lung after the occurrence of pulmonary edema were examined. Rats were given intraperitoneal injections of 20 mg/kg alpha-naphthylthiourea (ANTU), resulting in an increased permeability edema with alveolar flooding. Animals were killed at intervals between 2 and 48 hours after ANTU for the gravimetric determination of extravascular lung water (Qwl/dQl) and histologic study of the lung. Interstitial fluid volume was quantified by a morphometric technique. The assumptions were made that edema fluid equaled the experimental Qwl/dQl minus the normal Qwl/dQl, and that the edema fluid volume equaled the sum of interstitial and alveolar fluid volume. It was found that between 2 and 4 hours after the induction of pulmonary edema, fluid was removed from the alveolar space faster than it was removed from the interstitial space. Between 4 and 48 hours after ANTU, the fluid removal rate from both compartments was much slower, and interstitial fluid was removed at a faster rate than alveolar fluid. It is hypothesized that the later phase of fluid removal from the lung is dependent on the removal of protein.

Topics: Animals; Biological Transport; Body Weight; Extracellular Space; Male; Pulmonary Alveoli; Pulmonary Edema; Rats; Thiourea; Time Factors

Treating chick embryos with high doses of thiourea (32.8 mumol) on day 17 of incubation resulted in prevention of hatching and of active breathing. Furthermore, thiourea also prevented the increase of O2 consumption and the marked increase of somatic activity associated with the final hatching act. These findings provide evidence for the importance of active breathing in the prenatal period to initiate pipping and hatching of the avian embryo.

Topics: Animals; Body Weight; Carbon Dioxide; Chick Embryo; Gases; Lung; Oxygen Consumption; Respiration; Thiourea; Time Factors

Acute lung injury due to alpha-naphthylthiourea (ANTU) is associated with increased permeability edema, transient pulmonary hypertension, and increased vascular reactivity. We sought to determine whether repeated administration of ANTU caused right ventricular hypertrophy. Rats were injected weekly for 4 wk with ANTU or an equivalent volume of the vehicle Tween 80. Rats injected repeatedly with ANTU in doses of 5-10 mg/kg body wt had increased ratios of right ventricular to left ventricular plus septal weights. The right ventricular hypertrophy in ANTU-treated rats was associated with right ventricular systolic hypertension. Repeated injections of ANTU also caused transient pulmonary edema after each dose, as evidenced by increased wet-to-dry lung weight ratios after 4 h, which returned to normal by 24 h. Lungs isolated from ANTU-injected rats had greater pressor responses to hypoxia and to angiotensin II than lungs from Tween 80-injected rats. Pressure-flow curves of isolated lungs, arterial blood gases, and hematocrits were similar in rats treated repetitively with ANTU or Tween alone. Lung histology was also similar in ANTU and control lungs, as were measurements of arterial medial thickness and ratios of numbers of arteries/100 alveoli, indicating that substantial vascular remodeling had not occurred. Thus, four weekly ANTU injections in rats caused right ventricular hypertrophy, probably due to pulmonary hypertension. We speculate that the pulmonary hypertension was due, at least in part, to sustained vasoconstriction, which somehow resulted from repeated acute lung injury.

Topics: Animals; Blood Pressure; Body Weight; Cardiomegaly; Heart Ventricles; Lung; Lung Injury; Male; Organ Size; Polysorbates; Pulmonary Artery; Rats; Rats, Inbred Strains; Thiourea

Administration of both thyroxine (1 microgram/g body wt) and thiourea (0.5 mg/10 g body wt) to young male garden lizards for a period of 2 weeks led to changes in morphometric/biochemical parameters. Percentages of increase in body weight and snout-to-vent length of thyroxine-treated lizards during this period were significantly lower than the percentages of increase observed in control lizards. Thiourea-induced inhibition of increase in body weight was marginal but not significant statistically. The total collagen content of tendons decreased upon thyroxine treatment and increased following thiourea administration. Thyroxine treatment led to an increase in salt solubility of bone and skin collagens and thiourea showed a reverse effect. On the other hand, the acid solubility of tendon collagen increased after thyroxine administration and decreased following thiourea treatment.

Topics: Aging; Animals; Body Weight; Collagen; Lizards; Male; Solubility; Thiourea; Thyroxine

The effect of prolonged metiamide administration on serum gastrin, gastrin content of the antrum and gastric corpus, and G-cell population was studied in the rat. A single subcutaneous injection of metiamide (200 mg/kg) at the onset of 16 days of continous treatment with three daily injections was followed by a fivefold increase in serum gastrin level at 4 hr in fasted and at 4 and 6 hr in fed rats. After 16 days of metiamide, the fed rats showed a peak in serum gastrin level of the same magnitude as on day 1, but only at 4 hr. Two hours later, the levels decreased rapidly to basal values. In the fasted animals, the response to metiamide was reduced to a threefold increase at 2 hr. There was no difference in gastrin content of the antrum and gastric corpus nor in volume density of the G-cells after the prolonged treatment compared with the controls. It is concluded that in spite of rises in serum gastrin, prolonged metiamide medication has no effect on the gastrin content of the antrum and gastric corpus nor on the G-cell population in the rat. Furthermore, after prolonged treatment, metiamide-induced gastrin release is diminished.

Topics: Animals; Body Weight; Cell Count; Fasting; Gastric Mucosa; Gastrins; Male; Metiamide; Organ Size; Pyloric Antrum; Rats; Stomach; Thiourea

The effect of administration of thiourea (5 g/kg in diet) alone or simultaneously with thyroxine (1 mg/l in drinking water) on the frequency of hyperplastic benign osteoma of the skull was studied in AkR mice. Animals treated with both thiourea and thyroxine were in hyperthyroidism: the thyroxine dose received was higher that that required to prevent thiourea-induced thyroid gland hypertrophy. A significant increase of the intracranial bone tumour (IBT) frequency was observed both in mice treated with thiourea alone and those which received thiourea and thyroxine simultaneously. Increase of IBT frequency was not due to the antithyroid effect of thiourea but seems due to a direct toxic action of thiourea on the pituitary.

Topics: Animals; Body Weight; Female; Male; Mice; Mice, Inbred AKR; Neoplasms, Experimental; Osteoma; Pituitary Gland; Skull Neoplasms; Thiourea; Thyroid Gland; Thyroxine

1. Synergistic action of alpha-chlorohydrin with methallibure (ICI, 33828) on the testicular function of Presbytis entellus entellus Dufresne has been studied. 2. Chronic administration of alpha-chlorohydrin alone (140 mg/day for 40 days) caused testicular lesion resulting in a massive atrophy of the spermatogenic elements. Epididymal epithelium was regressed and the lumen was devoid of spermatozoa. 3. alpha-Chlorohydrin inhibited the synthesis of RNA and sialic acid in the testes and epididymides. Total cholesterol per gram of testis and alkaline phosphatase activity were increased after alpha-chlorohydrin administration. 4. These effects could be achieved with a lower dose of alpha-chlorohydrin (1/4) when administered in combination with a gonadotrophin inhibitor, i. e. ICI, 33828 (Methallibure). Methallibure alone (200 mg/kg: total dose) has no damaging effects on the testes and epididymides. But it altered testicular cholesterol and enzyme activity. 5. In conclusion, an effective inhibition of spermatogenesis could be achieved by synergistic action of the two different drugs i. e. alpha-chlorohydrin and ICI, 33828 (Methallibure).

Topics: Alkaline Phosphatase; alpha-Chlorohydrin; Animals; Body Weight; Chlorohydrins; Cholesterol; Drug Synergism; Epididymis; Haplorhini; Histocytochemistry; Leydig Cells; Male; Methallibure; Organ Size; Seminiferous Tubules; Sialic Acids; Sterilization, Reproductive; Testis; Thiourea

The influence of thyroid deficiency and the administration of thyroxine on pituitary-testicular function were studied in male albino rats from weaning age (22 days old) up to 82 days of age. The results showed that the hyperthyroid state induced by a daily injection of 2.5 or 5 microng L-thyroxine resulted in acceleration of growth, a comparative increase in size and number of spermatogenic and interstitial cells, an increase in the STH cells, particularly at the earlier age (42 days old), and in a decrease in the number and size of TSH cells. Gonadotrophic FSH and LH and prolactin cells exhibited an increase in their granular content. The hypothyroid state induced by thyroidectomy or thiourea feeding, at the levels of 0.1 and 0.2% resulted in the depression of growth rate, destructive changes of the spermatogenic and interstitial cells and also in the lumen of the seminiferous tubules. A decrease in the STH, gonadotrophic FSH and LH and prolactin cells and hypertrophy of TSH cells accompanied by degranulation were also observed.

Topics: Age Factors; Animals; Body Weight; Growth; Hyperthyroidism; Hypothyroidism; Male; Pituitary Gland; Rats; Rats, Inbred Strains; Spermatogenesis; Testis; Thiourea; Thyroid Gland; Thyroidectomy; Thyroxine

Methallibure administration caused reduction of gonadal weights in female rats and mice indicative of suppression of pituitary gonadotrophins. In the ovaries of the methallibure treated females, there was a great atresia of the follicles and of the corpora lutea. Methalbure caused atrophic changes in the endometrial lining of the vagina. Uterine horns became thin after methallibure treatment. A significant decrease in protein, RNA and sialic acid concentration in uterus and vagina was observed following methallibure treatment. Uterus of treated animals showed decreased glycogen contents. Histological and biochemical changes in the female genital tract of rats and mice suggested that the drug caused antifertility effect due to its possible antiestrogenic action.

Topics: Adrenal Glands; Animals; Body Weight; Female; Genitalia, Female; Methallibure; Mice; Organ Size; Rats; Thiourea

Topics: Aging; Animals; Body Weight; Drug Tolerance; Glucose; Glucosephosphate Dehydrogenase; In Vitro Techniques; Lung; Male; Mice; Oxygen; Oxygen Consumption; Paraquat; Rats; Species Specificity; Thiourea

Topics: Animals; Blood Cell Count; Body Weight; Carcinogens; Female; Hemoglobinometry; Hyperplasia; Iodine; Iodine Radioisotopes; Male; Organ Size; Rats; Thiourea; Thyroid Gland; Thyroid Neoplasms; Time Factors

Topics: Analysis of Variance; Animals; Antithyroid Agents; Body Weight; Organ Size; Potassium; Quail; Selection, Genetic; Sulfadiazine; Sulfaguanidine; Thiocyanates; Thiouracil; Thiourea; Thyroid Gland

Two groups of five female store pigs, weighing an average of 60 kg at the start of the experiment, were given either 1 or 10 mg metallibure zinc complex (SUISYNCHRON) per kg body weight once daily for six months, in the form of a 2% talcum premix added to concentrates. Clinical inspection, weight gain, haematological findings, blood sugar, serum transaminases, properties of urine and faeces, carcass examination and histological study (internal organs, endocrine glands, skeletal muscle) showed that the 1 mg/kg dosage had no toxic effect. The 10 mg/kg dosage resulted in considerable depression in appetite and some apathy in the pigs, but there was no evidence of a toxic effect.

Topics: Alanine Transaminase; Animals; Appetite; Aspartate Aminotransferases; Blood Cells; Blood Glucose; Body Weight; Dose-Response Relationship, Drug; Erythrocytes; Feces; Female; Hematocrit; Hemoglobins; Hypothalamo-Hypophyseal System; Leukocytes; Long-Term Care; Methallibure; Swine; Thiourea; Urine; Zinc

Topics: Allyl Compounds; Animals; Body Weight; Canaries; Castration; Estradiol; Female; Gonadotropins; Light; Luteinizing Hormone; Nesting Behavior; Organ Size; Ovary; Oviducts; Periodicity; Radioimmunoassay; Seasons; Thiourea

Metallibure (TURISYNCHRON, VEB Jenapharm, GDR) at 40 mg per kg of food, given for 14 days, completely suppressed laying, and in a shorter time than that produced by conventional methods. Turkeys tolerated TURISYNCHRON well, and no adverse effects were seen. Egg production after TURISYNCHRON treatment was higher than that of untreated controls. This preliminary trial will be followed by more extensive trials.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Female; Methallibure; Oviposition; Ovulation; Thiourea; Turkeys

Acute, subacute and chronic toxicity of TURISYNCHRON and its zinc complex (SUISYNCHRON) was tested in mice, rats and dogs. The acute toxicity of SUISYNCHRON was lower than that of TURISYNCHRON in mice and rats. Ulcerative lesions in the duodenum produced by high doses of SUISYNCHRON were quantitatively less pronounced than those produced by similar doses of TURISYNCHRON. Subacute toxicity testing in rats showed that neither preparation had any toxic effect on haematological, clinical chemical or histological criteria in the dosages selected. Chronic toxicity testing of TURISYNCHRON in dogs did not reveal any evidence of toxic damage.

Topics: Acute Disease; Administration, Oral; Animals; Atropine; Body Weight; Chlorpromazine; Chronic Disease; Duodenal Diseases; Female; Injections, Subcutaneous; Lethal Dose 50; Maternal-Fetal Exchange; Methallibure; Mice; Organ Size; Papaverine; Peptic Ulcer; Poisoning; Pregnancy; Rats; Sex Factors; Structure-Activity Relationship; Thiourea; Zinc

Topics: Allyl Compounds; Animals; Body Weight; Depression, Chemical; Female; Follicle Stimulating Hormone; Hypothalamo-Hypophyseal System; Luteinizing Hormone; Nutritional Physiological Phenomena; Organ Size; Ovary; Pituitary Gland; Prolactin; Rats; Thiourea; Uterus

Topics: Animals; Body Weight; Capillary Permeability; Dactinomycin; Dose-Response Relationship, Drug; Drug Synergism; Intubation, Intratracheal; Lung; Male; Organ Size; Peritoneal Diseases; Pleural Effusion; Pulmonary Edema; Rats; Thiourea; Time Factors

Topics: Animals; Body Weight; Cartilage; Chick Embryo; Epiphyses; Osteogenesis; Thiourea; Thyroxine; Tibia

Topics: Allyl Compounds; Animals; Body Weight; Corpus Luteum; Estrus; Female; Fertilization; Fetus; Gestational Age; Gonadotropins, Equine; Ovulation; Pregnancy; Pregnancy, Animal; Swine; Thiourea

Topics: Allyl Compounds; Animals; Body Weight; Connective Tissue; Connective Tissue Cells; Cyprinidae; Gonadotropins; Gonadotropins, Pituitary; Male; Radioimmunoassay; Sertoli Cells; Spermatogenesis; Testis; Thiourea

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Animals; Body Weight; Bone and Bones; Brain; Clubfoot; Dose-Response Relationship, Drug; Embryo, Mammalian; Embryonic and Fetal Development; Ethylenes; Female; Fetal Death; Fetus; Fungicides, Industrial; Germ Cells; Hindlimb; Imidazoles; Kidney Tubules; Lens, Crystalline; Male; Meninges; Micrognathism; Osteogenesis; Pregnancy; Rabbits; Rats; Rats, Inbred Strains; Spinal Cord; Tail; Teratogens; Thiourea

Topics: Administration, Oral; Aerosols; Aniline Compounds; Animals; Antifungal Agents; Birds; Body Weight; Carbamates; Cyprinidae; Dogs; Female; Fungicides, Industrial; Guinea Pigs; Injections, Intraperitoneal; Lethal Dose 50; Male; Mice; Mice, Inbred Strains; Photosensitivity Disorders; Rabbits; Rats; Salmonidae; Sex Factors; Skin; Species Specificity; Thiourea

Topics: Allyl Compounds; Animals; Body Weight; Chorionic Gonadotropin; Estrus; Female; Fertilization; Follicle Stimulating Hormone; Hydrazines; Pregnancy; Swine; Thiourea; Time Factors

Topics: Allyl Compounds; Animals; Animals, Newborn; Body Weight; Female; Hair; Hydrazines; Lactation; Milk; Pregnancy; Rats; Thiourea

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Brain; Diencephalon; Female; Fetus; Gestational Age; Goiter; Hypophysectomy; Hypothalamus; Maternal-Fetal Exchange; Organ Size; Pituitary Gland; Pregnancy; Propylthiouracil; Rats; Thiourea; Thyroid Gland; Thyrotropin-Releasing Hormone; Vitamin A

Topics: Acid Phosphatase; Alcohols; Animals; Body Weight; Caseins; Cell Fractionation; Colon; Esterases; Esters; Hyperthyroidism; Hypothyroidism; Iodine; Iodoproteins; Liver; Lysosomes; Male; Oxidoreductases; Palmitic Acids; Rats; Spectrophotometry; Sulfatases; Thiourea; Thyroid Gland; Ultraviolet Rays; Vitamin A

Topics: Animals; Body Weight; Chick Embryo; Female; Incubators; Organ Size; Respiration; Temperature; Thiourea; Thyrotropin; Thyroxine; Time Factors; Vitelline Membrane

Topics: Animals; Animals, Newborn; Body Weight; Injections, Intraperitoneal; Mice; Nitrogen Dioxide; Organ Size; Pulmonary Edema; Rats; Thiourea

Topics: Animals; Behavior, Animal; Body Weight; Carcinogens; DDT; Diet; Drug Synergism; Female; Growth; Kidney; Liver; Liver Neoplasms; Lung; Male; Organ Size; Pesticides; Rats; Spleen; Thiourea

Topics: Anabolic Agents; Animals; Body Weight; Endocrine Glands; Growth; Guinea Pigs; Methandrostenolone; Thiourea

Topics: Animals; Body Weight; Body Weights and Measures; Iodides; Iodine; Rats; Thiourea; Thyroid Gland; Thyroxine; Viscera