methylthiouracil and Disease-Models--Animal

Topics: Animals; Bile; Bile Acids and Salts; Chickens; Cholelithiasis; Cholesterol; Cholestyramine Resin; Clofibrate; Cricetinae; Diet; Dietary Carbohydrates; Dietary Fats; Disease Models, Animal; Fatty Acids, Essential; Female; Gallbladder; Glucose; Guinea Pigs; Haplorhini; Humans; Lipid Metabolism; Liver; Male; Methylthiouracil; Mice; Phosphatidylcholines; Progesterone; Rabbits; Solubility; Thyroid Hormones

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as an attractive therapeutic strategies in the management of severe sepsis or septic shock. Here, we examined the effects of methylthiouracil (MTU), used as antithyroid drug, by monitoring the effects on lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-mediated release of HMGB1, and on the modulation of HMGB1-mediated inflammatory responses. The anti-inflammatory activities of MTU were determined by measuring permeability, leukocyte adhesion and migration, and the activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice. MTU inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. MTU also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with MTU reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury. Our results indicate that MTUs could be candidate therapeutic agents for various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Cell Movement; Disease Models, Animal; HMGB1 Protein; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Leukocytes; Lipopolysaccharides; Male; Methylthiouracil; Mice; Mice, Inbred C57BL; Sepsis; Signal Transduction

Drug repositioning is used to discover drug candidates to treat human diseases, through the application of drugs or compounds that are approved for the treatment of other diseases. This method can significantly reduce the time required and cost of discovering new drug candidates for human diseases. Previous studies have reported pro-inflammatory responses of endothelial cells to the release of polyphosphate (PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of methylthiouracil (MTU), which is an antithyroid drug, and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behaviour of human neutrophils and vascular permeability were determined in PolyP-activated HUVECs and mice. MTU suppressed the PolyP-mediated vascular barrier permeability, up-regulation of inflammatory biomarkers, adhesion/migration of leucocytes, and activation and/or production of nuclear factor-κB, tumour necrosis factor-α and interleukin-6. Furthermore, MTU demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of MTU on various systemic inflammatory diseases, such as sepsis or septic shock.

Topics: Animals; Blood Vessels; Capillary Permeability; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Human Umbilical Vein Endothelial Cells; Inflammation; Interleukin-6; Methylthiouracil; Mice, Inbred C57BL; Neutrophils; NF-kappa B; Polyphosphates; Protective Agents; Tumor Necrosis Factor-alpha

Chronic investigations (up to 3 years) conducted in dogs have evidenced that periodic disturbances of vascular permeability produced by using dicoumarin with a long-term blocking of the thyroid function greatly aggravate pathological manifestations induced by the action of 6-methylthiouracil. They result in the development in the animals of endogenous hypercholesterinemia, elevated content in the blood of beta-lipoproteins and in a periodic rise of the arterial pressure. These changes were particularly spectacular at the final stage of the experiment in animals with marked manifestations of atherosclerosis and were accompanied by reduced stand-by potentialities of the adrenal gland, disruption of metabolic processes in the myocardium along with the slowed down resorption of NaI131 from the heart muscle. The sensitivity of the heart to adrenalin was down too.

Topics: 17-Hydroxycorticosteroids; Adrenal Cortex; Animals; Arteriosclerosis; Capillary Permeability; Dicumarol; Disease Models, Animal; Dogs; Lipids; Methylthiouracil

Topics: Animals; Blood Glucose; Disease Models, Animal; Gluconeogenesis; Glucose Tolerance Test; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Methylthiouracil; Rats; Thyroid Gland; Thyroxine

Topics: Adrenocorticotropic Hormone; Anabolic Agents; Animals; Dermatitis, Atopic; Disease Models, Animal; Guinea Pigs; Methods; Methylthiouracil; Solanine; Thyroid Hormones

Topics: Amphetamine; Animals; Arteriosclerosis; Cholesterol; Disease Models, Animal; Humans; Mathematics; Methylthiouracil; Models, Theoretical; Oils; Rabbits