scholarly journals Mice with Impaired Extrathyroidal Thyroxine to 3,5,3′-Triiodothyronine Conversion Maintain Normal Serum 3,5,3′-Triiodothyronine Concentrations

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 954-960 ◽  
Author(s):  
Marcelo A. Christoffolete ◽  
Rafael Arrojo e Drigo ◽  
Fernanda Gazoni ◽  
Susana M. Tente ◽  
Vanessa Goncalves ◽  
...  
Keyword(s):  
Biological Effects ◽  
Elevated Serum ◽  
Normal Growth ◽  
Normal Serum ◽  
C3h Mice ◽  
Serum T3 ◽  
Serum T4 ◽  
Hormone Homeostasis ◽  
Type 3

For T3 to mediate its biological effects, the prohormone T4 must be activated by removal of an outer-ring iodine by the type 1 or 2 deiodinases (D1 and D2) with approximately 60% of the daily T3 production in rodents being produced extrathyroidally through this pathway. To further define the role of these enzymes in thyroid hormone homeostasis, we backcrossed the targeted disruption of the Dio2 gene into C3H/HeJ (C3H) mice with genetically low D1 expression to create the C3H-D2KO mouse. Remarkably, these mice maintain euthyroid serum T3 levels with normal growth and no decrease in expression of hepatic T3-responsive genes. However, serum T4 is increased 1.2-fold relative to the already elevated C3H levels, and serum TSH is increased 1.4-fold. Despite these increases, thyroidal 125I uptake indicates no difference in thyroidal activity between C3H-D2KO and C3H mice. Although C3H-D2KO hepatic and renal D1 activities were well below those observed in wild-type mice (∼0.1-fold for both), they were 8-fold and 2-fold higher, respectively, relative to C3H mice. Thyroidal D1 and cerebral cortical type 3 deiodinase activity were unchanged between C3H-D2KO and C3H mice. In conclusion, C3H-D2KO mice have notably elevated serum T4 levels, and this, in conjunction with residual D1 activity, is likely an important role in the maintenance of euthyroid serum T3 concentrations.

scholarly journals Tissue-Specific Alterations in Thyroid Hormone Homeostasis in Combined Mct10 and Mct8 Deficiency

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 315-325 ◽  
Author(s):  
Julia Müller ◽  
Steffen Mayerl ◽  
Theo J. Visser ◽  
Veerle M. Darras ◽  
Anita Boelen ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Elevated Serum ◽  
Normal Serum ◽  
Monocarboxylate Transporter ◽  
Cellular Transport ◽  
Tissue Specific ◽  
Serum T3 ◽  
Serum T4 ◽  
Mct8 Deficiency

The monocarboxylate transporter Mct10 (Slc16a10; T-type amino acid transporter) facilitates the cellular transport of thyroid hormone (TH) and shows an overlapping expression with the well-established TH transporter Mct8. Because Mct8 deficiency is associated with distinct tissue-specific alterations in TH transport and metabolism, we speculated that Mct10 inactivation may compromise the tissue-specific TH homeostasis as well. However, analysis of Mct10 knockout (ko) mice revealed normal serum TH levels and tissue TH content in contrast to Mct8 ko mice that are characterized by high serum T3, low serum T4, decreased brain TH content, and increased tissue TH concentrations in the liver, kidneys, and thyroid gland. Surprisingly, mice deficient in both TH transporters (Mct10/Mct8 double knockout [dko] mice) showed normal serum T4 levels in the presence of elevated serum T3, indicating that the additional inactivation of Mct10 partially rescues the phenotype of Mct8 ko mice. As a consequence of the normal serum T4, brain T4 content and hypothalamic TRH expression were found to be normalized in the Mct10/Mct8 dko mice. In contrast, the hyperthyroid situation in liver, kidneys, and thyroid gland of Mct8 ko mice was even more severe in Mct10/Mct8 dko animals, suggesting that in these organs, both transporters contribute to the TH efflux. In summary, our data indicate that Mct10 indeed participates in tissue-specific TH transport and also contributes to the generation of the unusual serum TH profile characteristic for Mct8 deficiency.

scholarly journals Defective binding of the third component of complement (C3) to Streptococcus pneumoniae in multiple myeloma

Blood ◽  
1984 ◽  
Vol 63 (4) ◽  
pp. 949-957 ◽  
Author(s):  
BD Cheson ◽  
HS Walker ◽  
ME Heath ◽  
RJ Gobel ◽  
J Janatova
Keyword(s):  
Multiple Myeloma ◽  
Streptococcus Pneumoniae ◽  
Elevated Serum ◽  
Normal Serum ◽  
Complement C3 ◽  
Complement Pathway ◽  
Serum Factors ◽  
Increased Risk ◽  
History Of ◽  
Type 3

Abstract Patients with multiple myeloma (MM) are at an increased risk for infections with bacteria that require opsonization with complement. Because Streptococcus pneumoniae is the most frequently encountered pathogen in these patients, we investigated the ability of serum from patients with MM to mediate the binding of C3b, the major opsonin of the complement system, to S. pneumoniae. S. pneumoniae types 3, 14, and 25 were chosen for study, since S. pneumoniae type 3 activates primarily the classical complement pathway (CCP), type 25 primarily the alternative complement pathway (ACP), and type 14 both pathways. S. pneumoniae were treated with normal serum or serum from 17 patients with MM, and the bound C3b was quantified with fluorescein-conjugated anti-C3 in a spectrophotofluorometric assay. Despite normal or elevated serum concentrations of C3, total hemolytic complement, and C-reactive protein in all of the MM sera, factor B in 16/17 such sera, and C4 in 14/17 MM sera studied, all 17 sera demonstrated a defect in C3b binding to type 3 (32.7% +/- 6% of normal). In addition, serum from 15/17 patients bound decreased amounts of C3b to types 14 (39.6% +/- 8%) and 25 (52.2% +/- 8%). Mixing normal serum with MM serum restored MM C3b binding activity to all three S. pneumoniae types, suggesting that the defect was related to a deficiency rather than an inhibitor of C3 activation. Although MM patients are unable to produce specific antibodies to bacterial antigens, the addition of anti-S. pneumoniae antibodies to MM serum did not enhance C3b binding to any of the S. pneumoniae types. However, when S. pneumoniae were opsonized in a mixture of MM serum and C3-depleted normal serum, C3b binding was restored to all three S. pneumoniae types, demonstrating that MM C3 functions normally in the presence of other normal serum factors. In the present studies, the MM C3b binding defect appeared to correlate with the incidence of S. pneumoniae infections. Serum from patients with a history of an S. pneumoniae infection bound significantly less C3 (20.5% +/- 4%) than those study patients without a history of an S. pneumoniae infection (55.8% +/- 8%) (p less than 0.0025). Thus, MM serum has a defect in the activation of C3, and this may contribute to the increased susceptibility of MM patients to S. pneumoniae infections.

scholarly journals Defective binding of the third component of complement (C3) to Streptococcus pneumoniae in multiple myeloma

Blood ◽  
1984 ◽  
Vol 63 (4) ◽  
pp. 949-957
Author(s):  
BD Cheson ◽  
HS Walker ◽  
ME Heath ◽  
RJ Gobel ◽  
J Janatova
Keyword(s):  
Multiple Myeloma ◽  
Streptococcus Pneumoniae ◽  
Elevated Serum ◽  
Normal Serum ◽  
Complement C3 ◽  
Complement Pathway ◽  
Serum Factors ◽  
Increased Risk ◽  
History Of ◽  
Type 3

Patients with multiple myeloma (MM) are at an increased risk for infections with bacteria that require opsonization with complement. Because Streptococcus pneumoniae is the most frequently encountered pathogen in these patients, we investigated the ability of serum from patients with MM to mediate the binding of C3b, the major opsonin of the complement system, to S. pneumoniae. S. pneumoniae types 3, 14, and 25 were chosen for study, since S. pneumoniae type 3 activates primarily the classical complement pathway (CCP), type 25 primarily the alternative complement pathway (ACP), and type 14 both pathways. S. pneumoniae were treated with normal serum or serum from 17 patients with MM, and the bound C3b was quantified with fluorescein-conjugated anti-C3 in a spectrophotofluorometric assay. Despite normal or elevated serum concentrations of C3, total hemolytic complement, and C-reactive protein in all of the MM sera, factor B in 16/17 such sera, and C4 in 14/17 MM sera studied, all 17 sera demonstrated a defect in C3b binding to type 3 (32.7% +/- 6% of normal). In addition, serum from 15/17 patients bound decreased amounts of C3b to types 14 (39.6% +/- 8%) and 25 (52.2% +/- 8%). Mixing normal serum with MM serum restored MM C3b binding activity to all three S. pneumoniae types, suggesting that the defect was related to a deficiency rather than an inhibitor of C3 activation. Although MM patients are unable to produce specific antibodies to bacterial antigens, the addition of anti-S. pneumoniae antibodies to MM serum did not enhance C3b binding to any of the S. pneumoniae types. However, when S. pneumoniae were opsonized in a mixture of MM serum and C3-depleted normal serum, C3b binding was restored to all three S. pneumoniae types, demonstrating that MM C3 functions normally in the presence of other normal serum factors. In the present studies, the MM C3b binding defect appeared to correlate with the incidence of S. pneumoniae infections. Serum from patients with a history of an S. pneumoniae infection bound significantly less C3 (20.5% +/- 4%) than those study patients without a history of an S. pneumoniae infection (55.8% +/- 8%) (p less than 0.0025). Thus, MM serum has a defect in the activation of C3, and this may contribute to the increased susceptibility of MM patients to S. pneumoniae infections.

scholarly journals Functional Analysis of Monocarboxylate Transporter 8 Mutations Identified in Patients with X-Linked Psychomotor Retardation and Elevated Serum Triiodothyronine

2007 ◽  
Vol 92 (6) ◽  
pp. 2378-2381 ◽  
Author(s):  
Jurgen Jansen ◽  
Edith C. H. Friesema ◽  
Monique H. A. Kester ◽  
Carmelina Milici ◽  
Maarten Reeser ◽  
...  
Keyword(s):  
Elevated Serum ◽  
Splice Site Mutation ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Missense Mutations ◽  
Wild Type ◽  
Site Mutation ◽  
Central Neurons ◽  
Serum T3 ◽  
Type 3

Abstract Context: T3 action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T3 uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T3 levels. Objective: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T3. Design: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T3 uptake, 2) T3 metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry. Results: The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8. Conclusion: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T3 levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T3 in central neurons.

scholarly journals Regulation of Dio2 gene expression by thyroid hormones in normal and type 1 deiodinase-deficient C3H mice

2007 ◽  
Vol 193 (3) ◽  
pp. 435-444 ◽  
Author(s):  
Marcia S Wagner ◽  
Simone M Wajner ◽  
José M Dora ◽  
Ana Luiza Maia
Keyword(s):  
Marked Decrease ◽  
Elevated Serum ◽  
Fold Increase ◽  
Activity Levels ◽  
Mrna Levels ◽  
Brown Adipose ◽  
C3h Mice

The C3H/HeJ mouse presents an inherited type 1 deiodinase (D1) deficiency that results in elevated serum thyroxine (T4), whereas TSH and tri-iodothyronine (T3) concentrations are normal when compared with those in the C57BL/6J strain. Here, we evaluated the expression of the type 2 (D2), the other T4-activating enzyme, in C3H mice. A comparative analysis revealed that D2 mRNA levels in C3H are similar to those in C57 animals. The D2 activity in C3H pituitary and brain are reduced when compared with those in the C57 strain (3.75 ± 1.08 vs 5.78 ± 0.33 and 0.17 ± 0.05 vs 0.26 ± 0.07 fmol/min per mg protein respectively). However, no differences on D2 activity levels were observed in the brown adipose tissue (BAT) between both strains (0.34 ± 0.06 vs 0.36 ± 0.09 fmol/min per mg protein). Experiments using different T4 doses showed that higher levels of serum T4 than those of the C3H mouse are required to downregulate D2 activity in this tissue. T3 administration to euthyroid mice resulted in a two- to four-fold increase on D2 activity in BAT and brain of both strains, despite a marked decrease in BAT D2 transcripts and no changes in brain D2 mRNA levels. The increase in D2 activity was preceded by a decrease in serum T4 levels, which appears to reduce D2 degradation. Indeed, administration of T3 plus T4 abolished the T3-induced D2 upregulation. In conclusion, our results demonstrated that D2 activity is mainly regulated at posttranslational level in a tissue-specific manner. These observations further characterize and provide insights into the complex and dual regulatory role of the iodothyronines in D2 regulation.

scholarly journals The Expression of Prolactin Receptors in Benign Breast Tumors Is Not Associated with Serum Prolactin Level

2021 ◽  
Vol 10 (24) ◽  
pp. 5866
Author(s):  
Olena Kolomiiets ◽  
Oleksandr Yazykov ◽  
Artem Piddubnyi ◽  
Mykola Lyndin ◽  
Ivan Lukavenko ◽  
...  
Keyword(s):  
Breast Tissue ◽  
Elevated Serum ◽  
Breast Tumors ◽  
Serum Prolactin ◽  
Ki 67 ◽  
Cystic Fluid ◽  
Significant Difference ◽  
Hormone Homeostasis ◽  
Benign Breast Tumors

The role of prolactin (PRL) and its receptors in the initiation and development of benign breast tumors (BBT) has not been sufficiently studied. An imbalance in the system of hormone homeostasis is crucial in the development of BBT. In particular, an association between elevated prolactin levels and the development of BBT has been reported. Our study showed no significant differences between PRL receptor (PRL-R) expression in BBT tissue under normal and elevated serum PRL levels. There was also no significant correlation between age, PRL-R expression in BBT tissue, intact tissue, and PRL level in the serum. There was a strong significant correlation (p < 0.01; r = 0.92) between PRL-R expression in BBT samples and intact breast tissue, which did not depend on the serum PRL level. There was also no significant difference in the expression of the proliferative marker Ki-67 in BBT tissues from women with normal and elevated levels of serum PRL (p > 0.05). No signs of PRL and its receptors were detected in the BBT cystic fluid women with elevated serum PRL levels. In summary, our prospective study showed that the expression of PRL-R in the tissue of BBT and physiological breast tissue does not depend on the level of serum PRL.

The Role of Zinc in Thyroid Hormones Metabolism

2019 ◽  
Vol 89 (1-2) ◽  
pp. 80-88 ◽  
Author(s):  
Juliana Soares Severo ◽  
Jennifer Beatriz Silva Morais ◽  
Taynáh Emannuelle Coelho de Freitas ◽  
Ana Letícia Pereira Andrade ◽  
Mayara Monte Feitosa ◽  
...  
Keyword(s):  
Thyroid Hormones ◽  
Scientific Evidence ◽  
Thyroid Stimulating Hormone ◽  
Zinc Transporters ◽  
Serum Concentrations ◽  
Metabolic Adaptations ◽  
Serum T3 ◽  
Regulatory Effects ◽  
Shed Light

Abstract. Thyroid hormones play an important role in body homeostasis by facilitating metabolism of lipids and glucose, regulating metabolic adaptations, responding to changes in energy intake, and controlling thermogenesis. Proper metabolism and action of these hormones requires the participation of various nutrients. Among them is zinc, whose interaction with thyroid hormones is complex. It is known to regulate both the synthesis and mechanism of action of these hormones. In the present review, we aim to shed light on the regulatory effects of zinc on thyroid hormones. Scientific evidence shows that zinc plays a key role in the metabolism of thyroid hormones, specifically by regulating deiodinases enzymes activity, thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) synthesis, as well as by modulating the structures of essential transcription factors involved in the synthesis of thyroid hormones. Serum concentrations of zinc also appear to influence the levels of serum T3, T4 and TSH. In addition, studies have shown that Zinc transporters (ZnTs) are present in the hypothalamus, pituitary and thyroid, but their functions remain unknown. Therefore, it is important to further investigate the roles of zinc in regulation of thyroid hormones metabolism, and their importance in the treatment of several diseases associated with thyroid gland dysfunction.

Hepatitis G Viral RNA in Serum and in Peripheral Blood Mononuclear Cells and Its Relation to HCV-RNA in Patients with Clotting Disorders

1997 ◽  
Vol 77 (05) ◽  
pp. 0868-0872 ◽  
Author(s):  
Li Sheng ◽  
Ann Soumillion ◽  
Kathelijne Peerlinck ◽  
Chris Verslype ◽  
Lan Lin ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Elevated Serum ◽  
Normal Serum ◽  
Hcv Rna ◽  
Peripheral Blood Mononuclear ◽  
Hepatitis G Virus ◽  
Blood Mononuclear Cells ◽  
Hepatitis G

SummaryThe hepatitis G virus (HGV) has recently been identified as a new member of the Flaviviridae family. Infection by this virus is thought to be associated with blood borne hepatitis. In this study, the presence of HCV- and HGV-RNAs in serum or plasma (175 patients) and in peripheral blood mononuclear cells (PBMC) (133 patients) was investigated in patients with clotting disorders using a sensitive reverse transcriptase polymerase chain reaction (RT-PCR). HGV-RNA was detected in serum of 26 patients (14.8%). In apparently healthy blood donors, serum HGV-RNA was detected in 4 of 358 individuals investigated (1.12%). Ninety two percent of the 26 serum HGV-RNA positive patients had coinfection with the hepatitis C virus (HGV), especially with HCV genotype lb, the most common genotype in Belgium. Of these coinfected patients, 15 (62.5%) showed elevated serum ALT levels. Two patients who were solely infected with HGV had normal serum ALT. HGV-RNA in PBMC was found in 18 patients, of whom 3 were negative for serum HGV-RNA. As in case of HCV, HGV-RNA in PBMC is preferentially sensitive to interferon treatment. Nevertheless, rapid reappearance of HGV-RNA in PBMC was observed after cessation of treatment. In one patient, persistent serum ALT elevation seems to be associated with continued HGV viremia, despite the disappearance of serum HCV-RNA.

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