triiodothyronine--reverse and Disease-Models--Animal

Thyroid hormone action in the brain is strictly regulated, since these hormones play a crucial role in the development and physiological functioning of the central nervous system. Hormone kinetics and molecular events at the nuclear receptor level during the adaptation of the brain of chicken to hypothyroidism were simultaneously investigated. Data obtained by Oldendorff's 'single-pass' technique showed a significantly higher labelled 3,3'5-triiodothyronine (125I-T3) uptake into the brain of surgically thyroidectomized (TX) 2-week-old broilers after 1 week of surgery in comparison to sham-operated (SH) and t3 supplemented (TX + T3) controls in the 10th second after the bolus injection. Telencephalons showed the highest, while cerebellum the lowest uptake intensity in all groups. In a similar arrangement of experiments the expression of the TR alpha- and TR beta nuclear thyroid receptors in the telencephalon of TX and control chickens was investigated by a semiquantitative RT-PCR-based approach for beta-actin, then amplified for thyroid receptors. The level of both the TR alpha and TR beta coding mRNA was elevated in hypothyroidism. In conclusion, the presented hormone kinetics and TR expression data provide further details of the cellular and molecular events occurring during the adaptation to hypothyroidism of the brain of chicken.

Topics: Animals; Brain; Chickens; Disease Models, Animal; Hypothyroidism; Poultry Diseases; Triiodothyronine, Reverse

Prolonged critically ill patients have low circulating thyroid hormone (TH) levels without a rise in TSH, a condition labeled 'the low tri-iodothyronine (T(3)) syndrome'. Currently, it is not clear whether this represents an adaptive response. We examined the role of TH transporters monocarboxylate transporter 8 (MCT8, also known as SLC16A2) and MCT10 in the pathogenesis of the low T(3) syndrome in prolonged critical illness.. A clinical observational study in critically ill patients and an intervention study in an in vivo animal model of critical illness. Gene expression levels of MCT8 and MCT10 were measured by real-time PCR.. In prolonged critically ill patients, we measured increased MCT8 but not MCT10 gene expression levels in liver and skeletal muscle as compared with patients undergoing acute surgical stress. In a rabbit model of prolonged critical illness, gene expression levels of MCT8 in liver and of MCT10 in skeletal muscle were increased as compared with healthy controls. Treatment of prolonged critically ill rabbits with TH (thyroxine+T(3)) resulted in a downregulation of gene expression levels of MCT8 in liver and of MCT10 in muscle. Transporter expression levels correlated inversely with circulating TH parameters.. These data suggest that alterations in the expression of TH transporters do not play a major role in the pathogenesis of the 'low T(3) syndrome' but rather reflect a compensatory effort in response to hypothyroidism.

Topics: Aged; Amino Acid Transport Systems, Neutral; Animals; Base Sequence; Critical Illness; Disease Models, Animal; Euthyroid Sick Syndromes; Female; Humans; Liver; Male; Molecular Sequence Data; Monocarboxylic Acid Transporters; Muscle, Skeletal; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Symporters; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

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

Topics: Animals; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Diiodothyronines; Disease Models, Animal; Gene Knockdown Techniques; Humans; Immunoblotting; Immunohistochemistry; In Vitro Techniques; Mental Retardation, X-Linked; Mice; Mice, Knockout; Models, Molecular; Monocarboxylic Acid Transporters; Muscle Hypotonia; Muscular Atrophy; Sequence Alignment; Symporters; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Thyroid hormone plays an important role in brain development and adult brain function, and may influence neuronal recovery after Traumatic Brain Injury (TBI). We utilized both animal and cell culture models to determine the effects of thyroid hormone treatment, post TBI or during hypoxia, on genes important for neuronal survival and neurogenesis. We show that TBI in rats is associated with a reduction in serum thyroxine (T4) and triiodothyronine (T3). A single dose of levothyroxine (T4), one hour after injury, increased serum T4 and normalized serum T3 levels. Expression of genes important for thyroid hormone action in the brain, MCT8 and Type 2 deiodinase (Dio2) mRNA, diminished after injury, but were partially restored with T4 treatment. mRNA from the Type 3 deiodinase (Dio3) gene, which inactivates T4 to reverse T3 (rT3), was induced 2.7 fold by TBI, and further stimulated 6.7-fold by T4 treatment. T4 treatment significantly increased the expression of mRNA from Bcl2, VEGFA, Sox2 and neurotrophin, genes important for neuronal survival and recovery. The cortex, compared to the hippocampus and cerebellum, sustained the greatest injury and had the most significant change in gene expression as a result of injury and the greatest response to T4 treatment. We utilized hypoxia to study the effect of neuronal injury in vitro. Neuroblastoma cells were exposed to reduced oxygen tension, 0.2%, and were compared to cells grown at control oxygen levels of 21%. T3 treatment significantly increased hypoxia inducible factor (HIF)-2α protein, but not HIF-1α. In a hypoxia time course exposure, expression of hypoxia-mediated genes (VEGF, Enolase, HIF2α, c-Jun) peaked at least 8 h earlier with T3-treatment, compared to cells grown without T3. The early induction of these genes may promote cellular growth after injury. After hypoxic injury, T3 induced mRNA expression of the genes, KLF9 and hairless, important for T3-mediated brain function. The findings from both in vitro and in vivo studies support a role of thyroid hormone in activating pathways important for neuronal protection and promotion of neuronal recovery after injury.

Topics: Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Brain Edema; Brain Injuries; Cell Line; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia, Brain; Male; Neurogenesis; Neurons; Rats; Rats, Sprague-Dawley; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Thyroid hormones are essential for a variety of developmental and metabolic processes. Congenital hypothyroidism (CHT) results in severe defects in the development of different tissues, in particular brain. As an animal model for CHT, we studied Pax8(-/-) mice, which are born without a thyroid gland. We determined the expression of iodothyronine deiodinase D1 in liver and kidney, D2 in brain and pituitary, and D3 in brain, as well as serum T(4), T(3), and rT(3) levels in Pax8(-/-) vs. control mice during the first 3 wk of life. In control mice, serum T(4) and T(3) were undetectable on the day of birth (d 0) and increased to maximum levels on d 15. In Pax8(-/-) mice, serum T(4) and T(3) remained below detection limits. Serum rT(3) was high on d 0 in both groups and rapidly decreased in Pax8(-/-), but not in control mice. Hepatic and renal D1 activities and mRNA levels were low on d 0 and increased in control mice roughly parallel to serum T(4) and T(3) levels. In Pax8(-/-) mice, tissue D1 activities and mRNA levels remained low. Cerebral D2 activities were low on d 0 and increased to maximum levels on d 15, which were approximately 10-fold higher in Pax8(-/-) than in control mice. D2 mRNA levels were higher in Pax8(-/-) than in control mice only on d 21. Cerebral D3 activities and mRNA levels were high on d 0 and showed a moderate decrease between d 3 and 15, with values slightly lower in Pax8(-/-) than in control mice. One day after the injection of 200 ng T(4) or 20 ng T(3)/g body weight, tissue deiodinase activities and mRNA levels were at least partially restored toward control levels, with the exception of cerebral D3 activity. In conclusion, these findings show dramatic age and thyroid state-dependent changes in the expression of deiodinases in central and peripheral tissues of mice during the first 3 wk of life.

Topics: Aging; Animals; Brain; Congenital Hypothyroidism; Disease Models, Animal; DNA-Binding Proteins; Female; Gene Expression Regulation, Enzymologic; Growth Disorders; Hypothyroidism; Iodide Peroxidase; Kidney; Liver; Male; Mice; Mice, Knockout; Nuclear Proteins; Paired Box Transcription Factors; PAX8 Transcription Factor; Pituitary Gland; RNA, Messenger; Thyroxine; Trans-Activators; Triiodothyronine; Triiodothyronine, Reverse

HyLine Brown laying hens at 30 weeks of age were treated twice daily with Fadrozole, a non-steroidal aromatase inhibitor (AI; 1 mg/kg body weight; i.m.) for six consecutive days; control hens received saline. Blood was collected every day 0.5 h after oviposition, i.e. just before AI treatment. Ovarian steroids: progesterone (P4), testosterone (T) and estradiol (E2), and iodothyronines: thyroxine (T4), triiodothyronine (T3) and reverse-triiodothyronine (rT3) were measured in blood plasma by radioimmunoassay methods. In AI-treated hens a gradual delay in oviposition time was observed. AI significantly decreased P4 and E2 levels, maximally by 43% on day 4 and by 74% on day 5, respectively, and elevated T level, maximally by 248% on day 4. Simultaneously, the increases in T4 and T3 levels with no changes in rT3 levels were observed. The maximal effect of AI on T4 and T3 levels was found on day 4 (60% increase) and day 5 (312% increase), respectively. Moreover, statistically significant, negative coefficient of correlation between E2 and T3 (r = -0.51), and positive coefficient of correlation between T and T3 (r = 0.42) in AI-treated hens were found. The results obtained indicate that in mature laying hens there is a strong relationship between ovarian steroids and thyroid hormones, and suppression of E2 synthesis not only disrupts ovarian function but also affects the activity of the thyroid gland and peripheral metabolism of thyroid hormones.

Topics: Animals; Chickens; Disease Models, Animal; Enzyme Inhibitors; Estradiol; Fadrozole; Female; Hormones; Oviposition; Pregnancy; Progesterone; Testosterone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Hyperthyroidism is known to affect multiple organ functions, and thyroid hormone has been known to improve myocardial function in a failing heart. The purpose of this study is to elucidate the functional and metabolic effects of thyroid hormone on myocardium in a rat model exposed to long-term excess thyroid hormone, particularly focusing on the SR Ca(2+)-ATPase (SERCA2) function. 3,5,3'-Triiodo-L-thyronine (T3), or the vehicle, was subcutaneously given for 4 weeks (T3 and control [C] group). Bolus I.V. Thapsigargin (TG) was used to test the SERCA2 function (C-TG and T3-TG) in Langendorff perfused heart. Myocardial functions such as LV-developed pressure (LVDP; mmHg), +/- dP/dt (mmHg/s), tau (ms), and oxygen consumption (MVO(2); ml/min/g wt) were measured. SERCA2 and GLUT4 protein level were also evaluated by Western immunoblotting. Left ventricle to body weight (LV/BW) ratio was significantly higher in the T3 group. Both negative dP/dt and tau were significantly decreased by TG. It is interesting that the decrement of negative dP/dt and tau attained by TG was significantly larger in the hyperthyroid group (T3-TG) than in a normal heart (C-TG). SERCA2 and GLUT4 protein levels were not significantly different between control and the T3 group. We conclude that prolonged exposure to thyroid hormone causes hypertrophy of the myocardium and an augmentation of the SR Ca(2+) ATPase activity. Care must be taken in hyperthyroid heart during the ischemia-reperfusion process where the SRECA2 function is inhibited.

Topics: Animals; Calcium-Transporting ATPases; Disease Models, Animal; Heart Ventricles; Hyperthyroidism; Myocardial Contraction; Myocardium; Rats; Rats, Wistar; Reperfusion Injury; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Thyroid Hormones; Triiodothyronine, Reverse

This study was conducted to determine whether the administration of tri-iodothyronine (T3) to brain-dead donor pigs would improve hemodynamic instability, serum levels of thyroid hormones, or the outcome of transplantation of donor livers. Brain death was caused in young pigs (25-38 kg) by rapid inflation of an intracranially implanted balloon catheter. The animals were maintained on a ventilator and frequent measurements of acid/base balance, electrolytes, and glucose were made. At the end of 16 hr, livers were removed and implanted into prepared recipients. Serum-free tri-iodothyronine fell to zero at the end of 16 hr, and there was a 4-6-fold decline in free thyroxine (T4). The levels of serum reverse T3 (rT3) however, increased up to 6-fold. In animals treated with tri-iodothyronine 2 micrograms/hr, the serum levels of free T3 and T4 were not changed but the levels of serum reverse T3 (rT3) increased further. There were no apparent correlations between any hemodynamic parameter and serum thyroid hormone levels in the donors. After the liver transplants, recipients could be divided into those that survived longer than 6 days and those that did not. Although there were significant differences in the plasma levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, there was no correlation between survival and whether the donor had received tri-iodothyronine. Although other hormones, including insulin and cortisol, may also be necessary, there is no indication from these studies that the administration of tri-iodothyronine to brain-dead donors of liver grafts benefits the serum hormone levels in the donors or the subsequent survival of the recipients.

Topics: Animals; Brain Death; Disease Models, Animal; Hemodynamics; Liver; Liver Transplantation; Swine; Thyroid Hormones; Thyroxine; Time Factors; Triiodothyronine; Triiodothyronine, Reverse