Possible liver damage by biosynthetic human insulin.
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Chemical and Drug Induced Liver Injury↗
Biomedical subjects
T Iriuchijima
Publications and source records attributed to T Iriuchijima.
Primary culture of cells from hyperfunctioning thyroid adenoma with an activating mutation of G alphas.
We analyzed cultured cells from hyperfunctioning thyroid adenoma and its surrounding thyroid tissue from a Japanese woman and determined the nucleotide sequences of genes encoding the alpha subunit of the stimulatory G-protein 1 (G alphas) and thyrotropin (TSH) receptor in its tumor tissue. Primary culture of cells from hyperfunctioning thyroid adenoma and its surrounding thyroid tissue revealed that cAMP production was constitutively activated while intracellular Ca2+ concentration was suppressed both at the basal level and in the response to TSH stimulation in the cells from tumor tissue compared with those from non-tumor tissue. Nucleotide sequence analysis demonstrated the somatic missense mutation at codon 201 (CGT(Arg)-CAT(His)) of G alphas gene in tumor tissue but not in its surrounding tissue. No mutation was observed in the transmembrane region of TSH receptor. These results suggest that cAMP regulatory cascade is constitutively activated while phospholipase C-Ca2+ signaling cascade is suppressed in hyperfunctioning thyroid adenoma with an activating mutation of G alphas gene in the present case.
Adenoma↗
Northern analysis of type II iodothyronine deiodinase mRNA in rat Harderian gland.
It has been known that type II iodothyronine deiodinase activity is present in rat Harderian gland and the activity is significantly increased by isoproterenol administration. We have performed Northern analyses to study whether the transcript for type II iodothyronine deiodinase is expressed in rat Harderian gland and whether the isoproterenol stimulation of type II iodothyronine deiodinase activity in rat Harderian gland is due to the change in its mRNA level. Northern analyses have demonstrated that type II iodothyronine deiodinase mRNA, approximately 7.5 kb in size, is expressed in rat Harderian gland, and the mRNA levels as well as the deiodinase activities are greater in hypothyroid rats than those in euthyroid rats. Type II iodothyronine deiodinase mRNA levels and the deiodinase activities in Harderian gland were increased by isoproterenol administration, and the increase in the mRNA levels preceded that in the deiodinase activities. These results indicate that 7.5 kb transcript for type II iodothyronine deiodinase is expressed in rat Harderian gland and beta-adrenergic stimulation of type II iodothyronine deiodinase activity is due at least in part to the increase in its mRNA level.
Actins↗
Expression and nocturnal increase of type II iodothyronine deiodinase mRNA in rat pineal gland.
It has been demonstrated that thyroxine deiodinating activity is present in rat pineal gland, and its activity increases significantly during the night time. We have studied whether mRNA for type II iodothyronine deiodinase is expressed in rat pineal gland and whether the nocturnal rise of pineal T4 deiodinating activity is due to the change in type II iodothyronine deiodinase mRNA level. Reverse transcription-polymerase chain reaction amplification and Northern blot analyses have demonstrated that type II iodothyronine deiodinase mRNA is expressed in rat pineal gland and its mRNA level increases markedly at midnight. These results suggest that the nocturnal rise in pineal T4 deiodinating activity is due to the change in type II iodothyronine deiodinase mRNA level.
Animals↗
Decreased pulmonary perfusion in hypersensitivity pneumonitis caused by Shiitake mushroom spores.
Hypersensitivity pneumonitis is an occupational hazard of mushroom workers. We describe a patient with severe hypersensitivity pneumonitis caused by spores of the Shiitake mushroom (Lentinus edodes) who showed a marked decrease in pulmonary perfusion, as demonstrated by pulmonary scintigraphy. This patient was treated successfully with prednisolone. These results suggest that pulmonary vasculitis may be associated with patients with hypersensitivity pneumonitis, and that steroid therapy may be clinically useful in treatment.
Alveolitis, Extrinsic Allergic↗
Thymic hyperplasia in patients with Graves' disease. Identification of thyrotropin receptors in human thymus.
Thymic size and density were studied in 23 untreated patients with Graves' disease and 38 control subjects using computed tomography. Both thymic size and density were higher in untreated patients with Graves' disease than in control subjects in the age-matched group. After treatment with antithyroid drugs, both thymic size and density were significantly reduced, with a concomitant decrease in thyrotropin receptor antibodies. PCR of human thymic cDNA using primers for human thyrotropin receptor amplified a fragment in a size expected for the receptor, and its nucleotide sequence was identical to human thyrotropin receptor cDNA in the thyroid. Northern blot analysis of human thymic poly(A)+ RNA demonstrated the presence of the full length form of thyrotropin receptor mRNA. Western blot analysis of human thymic membrane using anti-thyrotropin receptor peptide antibodies demonstrated a band of 100 kD that was also observed in the thyroid membrane. Immunohistochemistry of thymic tissue using mouse antihuman thyrotropin receptor monoclonal antibodies demonstrated the immunostaining of epithelial cells. These results indicate that thymic hyperplasia is apparently associated with Graves' disease and suggest that thymic thyrotropin receptor may act as an autoantigen that may be involved in the pathophysiology of development of Graves' disease.
Adult↗
Sex and age differences in soluble guanylate cyclase activity in human platelets.
Soluble guanylate cyclase is a key enzyme of nitric oxide (NO)-related intracellular signal transduction in platelets. In the present study, we investigated the effects of sex and age on the enzyme activity in human platelets. Soluble guanylate cyclase activity was determined by generation of cyclic GMP in platelet cytosol. No significant differences in the basal activity of soluble guanylate cyclase were observed between in men and women, and between in young and old subjects. However, soluble guanylate cyclase activity in response to sodium nitroprusside, an exogenous NO donor, was higher in young men than in young and old women. Furthermore, the enzyme activity was lower in old than in young men, but there were no differences in female platelets between from young and old subjects. The present data suggest that NO-related signal transduction system in the platelet is affected by sex and age, which, to certain extent, contributes to different sensitivity of human platelets.
Adult↗
Nitric oxide-dependent soluble guanylate cyclase activity is decreased in platelets from male NIDDM patients.
To elucidate the underlying mechanisms of platelet dysfunction in diabetes mellitus, we examined the activity of soluble guanylate cyclase (sGC), a key enzyme in the nitric oxide (NO)-related signalling pathway, in platelets from NIDDM (non-insulin dependent diabetes mellitus) patients. The sGC activity was determined by measuring the amount of cyclic GMP produced in platelet cytosol. In the first study, we investigated the platelet sGC activity in untreated NIDDM patients without diabetic complications. In the male NIDDM patients, sodium nitroprusside (SNP) caused a significantly lower sGC response than that in age-matched control male subjects, while the enzyme activity of female diabetics did not differ from that in the controls. Secondly, we investigated effects of diabetic-associated factors on the enzyme activity in the male NIDDM patients. There was no difference in the SNP-stimulated sGC activity in platelets from male diabetics between with and without retinopathy. In the male diabetic patients with retinopathy, however, the platelet sGC activity was slightly increased by treatment with insulin. Interestingly, the changes in enzyme activity did not correlate with plasma glycosylated hemoglobin A1c levels in diabetic patients. The impairment of the NO-related signalling pathway may contribute to the platelet dysfunction observed in patients with diabetes mellitus.
Adult↗
Discrete characteristics of antibodies raised against thyrotropin receptor-related peptides whose sequences are not conserved in the luteinizing hormone/chorionic gonadotropin receptor.
In order to identify the specific regions in the human TSH receptor for TSAb and thyroid stimulation-blocking antibody (TSBAb), we produced rabbit antibodies raised against several peptides of the extracellular domain of the human TSH receptor, where sequences are not conserved in the LH/CG receptor, and measured the TSAb activity and TSBAb activity of those antibodies using Chinese hamster ovary cells expressing human TSH receptors. Only antisera from rabbits that were immunized with a peptide of amino acid 32-56, including the small insertion near the N-terminal end of the extracellular domain, showed apparent TSAb activities and have been shown to be significantly precipitated by IgG of patients with Graves' disease. TSAb activity positively correlated with the antibody titers against the peptide in those rabbits. In contrast, antisera from rabbits immunized with a peptide of amino acid 352-378, including a part of the large insertion near the C-terminal end of the extracellular domain, showed the obvious TSBAb activities. TSBAb activity also positively correlated with the degree of antibody titers against the peptide in those rabbits. Moreover, this peptide was significantly immunoprecipitated by the IgG from hypothyroid patients who had TSBAb, and the immunoprecipitation of this peptide positively correlated with TSBAb activities. These results suggest that the epitope responsible for TSAb is quite different from that for TSBAb in the extracellular domain of the human TSH receptor.
Amino Acid Sequence↗
Regulation of rat liver type 1 iodothyronine deiodinase mRNA levels by testosterone.
To investigate the underlying mechanisms of sex-related differences in liver type 1 iodothyronine deiodinase (ID1), we studied the sex-related differences and roles of sex steroids in liver ID1 mRNA levels in the rat. In both euthyroid and thyroidectomized rats, liver ID1 activity and ID1 mRNA levels in female rats were less than those in male rats. A positive correlation was observed between liver ID1 activity and ID1 mRNA levels. Liver ID1 activity and ID1 mRNA levels in male rats decreased after orchiectomy, and were increased to control levels by testosterone administration. Ovariectomy of beta-estradiol administration did not alter liver ID1 activity or ID1 mRNA levels in female rats. ID1 mRNA levels in cultured rat hepatocytes were significantly increased by testosterone, but not by beta-estradiol. These results suggest that the sex-related differences in liver ID1 activity are attributable to differences in ID1 mRNA levels, and that testosterone plays an important role in the sex-related differences in liver ID1 mRNA levels.
Animals↗
Activation of the thyrotropin-releasing hormone (TRH) receptor by a direct precursor of TRH, TRH-Gly.
We studied the mechanism by which thyrotropin-releasing hormone (TRH)-Gly stimulated prolactin and thyrotropin (TSH) secretion in pituitary, using a pituitary mammotropic cell line, GH3 cells, and a cell line stably expressing a human TRH receptor (TRH-R). In GH3 cells expressing endogenous TRH-R, an addition of TRH-Gly evoked an immediate rise of intracellular calcium concentration, indicating that TRH-Gly reacted directly without converting from TRH-Gly to TRH. In order to determine whether this reaction might occur through TRH-R, we established a cell line stably expressing a human TRH-R, by transfecting a human TRH-R cDNA into Chinese hamster ovary cells (CHO cells). In this cell line, 10 nM TRH elevated intracellular calcium significantly; the Kd for MeTRH was 1.7 nM. One micromolar and 100 nM TRH-Gly also elevated intracellular concentration of calcium significantly, but not in CHO cells which were not transfected with the TRH-R cDNA. Competition studies further revealed that TRH-Gly displaced MeTRH binding (IC50, 12 microM). These data indicate that at high concentration, TRH-Gly interacts directly with TRH-R to activate signal transduction pathway, and that release of prolactin and TSH induced by TRH-Gly in vitro may be due, at least in part, to the direct effect of TRH-Gly on the TRH-R.
Animals↗
Diabetes mellitus and interferon-alpha therapy.
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Aged↗
Clinical usefulness of thyroid-stimulating antibody measurement using Chinese hamster ovary cells expressing human thyrotropin receptors.
Human thyrotropin (TSH) receptors were expressed in Chinese hamster ovary (CHO) cells using eukaryotic expression plasmid pCXN2, which contains beta-actin promoter. We measured cAMP stimulation in CHO cells expressing human TSH receptors (CHO-hTSH-R cells) by immunoglobulin G (IgG) of patients with Graves' disease and Hashimoto's thyroiditis, and compared the results with a conventional thyroid-stimulating antibody (TS-Ab) assay using porcine thyroid cells and a TSH-binding inhibiting immunoglobulin (TBII) assay. Nineteen untreated patients with Graves' disease, including a case who developed hyperthyroidism after interferon -alpha therapy for chronic hepatitis C, and 13 treated patients with Graves' disease, 10 patients with Hashimoto's thyroiditis and 8 control subjects were studied. In 19 untreated patients with Graves' disease, 17 patients showed positive CHO-hTSH-R cell stimulation, 11 patients showed positive porcine thyroid cell stimulation and 15 patients showed positive TBII. All the untreated patients showed positive results in at least one assay. Although significantly positive correlations were observed among CHO-hTSH-R cell stimulation, porcine thyroid cell stimulation and TBII activities, the IgG of several patients showed significant discrepancy in the assay results. In a patient with interferon-induced hyperthyroidism only CHO-hTSH-R cell stimulation was positive, while porcine thyroid cell stimulation and TBII were negative. After the treatment with propylthiouracil for 6 months, CHO-hTSH-R cell stimulation became negative. The IgG of patients with Hashimoto's thyroiditis did not show significant stimulation of CHO-hTSH-R cells. These results suggest that the CHO-hTSH-R cell stimulation assay is clinically useful for the diagnosis and follow-up of patients with Graves' disease.
Animals↗
Precipitations of thyrotropin receptor-related peptides by immunoglobulin G of patients with Hashimoto's thyroiditis.
In order to study whether specific binding sites for Hashimoto's IgG exist in TSH receptor, we have examined the TSH receptor binding activity of IgG of patients with Hashimoto's thyroiditis using synthetic peptides corresponding to the amino acid sequences in the extracellular domain of human TSH receptor. Eight different peptides were synthesized, radiolabeled and examined by immunoprecipitation assay. Among the peptides studied, peptide (352-378) was significantly precipitated by IgG of patients with Hashimoto's thyroiditis compared with control subjects. Ten out of twenty patients with Hashimoto's thyroiditis showed more precipitations of peptide (352-378) than mean + 2SD of those of control subjects. Peptide (352-378) was precipitated by IgG in a dose dependent manner and the binding of peptide (352-378) to IgG was displaced by the addition of increased amount of cold peptide (352-378). Precipitations of peptide (352-378) positively correlates with both TGHA and MCHA titers. Two out of fourteen patients with Graves' disease, one out of seven patients with subacute thyroiditis and none of eleven patients with thyroid tumor showed more precipitations of peptide (352-378) than mean + 2SD of those of control subjects. These results suggest that one of binding sites for Hashimoto's IgG is present in the amino acid sequence of 352-378 in the extracellular domain of TSH receptor.
Amino Acid Sequence↗
Diabetic scleredema and scleroderma-like changes in a patient with maturity onset type diabetes of young people.
A 21-year-old housewife with maturity onset type diabetes of young people developed scleredema diabeticorum, scleroderma-like skin thickness on forearms and dorsum of hands, digital sclerosis and cheiroarthropathy. She had diabetes mellitus since the age of 11 years. Her grandfather on the mother's side, her mother and 3 of 5 her mother's brothers and sisters have diabetes mellitus. Blood glucose was 295 mg/dl. Urinary glucose was 5.3 g/day. Nail fold capillary microscopy revealed a progressive systemic sclerosis pattern. Histologically, hematoxylin and eosin sections from back and forearm skin demonstrated broad collagen bundles separated by widened clear spaces throughout the thickened dermis.
Adult↗
[TRH receptor-related signal transduction mechanism].
TRH receptor-related signal transduction mechanism in the pituitary cells and the central nervous system was reviewed. In pituitary cells, TRH binds to its specific receptor on the cell membrane, followed by hydrolysis of inositol phospholipids by activation of phospholipase C leading to an increase in inositol 1,4,5-trisphosphates (IP3) and diacylglycerol (DG). IP3 mobilizes intracellular Ca2+, which activates Ca2+ and Calmodulin dependent protein kinase (Ca-CaM kinase) and DG activates protein kinase C (PKC). Both Ca-CaM kinase and PKC phosphorylates several proteins in the nucleus, plasma membranes, and cytosol resulting in cell responses including hormone secretion and gene expression. Protein dephosphorylation is also involved in TRH action in the pituitary. In the central nervous system, TRH possesses different intracellular signaling systems, which vary with brain regions.
Animals↗
Histidyl-proline diketopiperazine. Novel formation that does not originate from thyrotropin-releasing hormone.
We asked whether cyclo(His-Pro) may arise from a substance other than the initially found progenitor thyrotropin-releasing hormone (TRH). Incubation of TRH-Gly (pGlu-His-Pro-Gly), a TRH precursor, with brain hypothalamic cytosols caused significant formation of His-Pro-Gly followed by the generation of histidyl-proline diketopiperazine (cyclo(His-Pro)), whereas TRH was not formed. The addition of purified pyroglutamyl aminopeptidase resulted in the transformation of TRH-Gly to His-Pro-Gly and cyclo (His-Pro) but not to TRH. Neither TRH nor cyclo(His-Pro) was produced from TRH-Gly in the presence of alpha-amidating enzyme under the present conditions. Nonenzymatic conversion of His-Pro-Gly to cyclo(His-Pro) occurred. The present results provide evidence that cyclo(His-Pro) can emanate from a direct predecessor form of TRH by pyroglutamyl aminopeptidase action, not through TRH formation.
Amino Acid Sequence↗
Pituitary adenomas of patients with acromegaly express thyrotropin-releasing hormone receptor messenger RNA: cloning and functional expression of the human thyrotropin-releasing hormone receptor gene.
We cloned a human thyrotropin-releasing hormone receptor (TRH-R) gene and its pituitary cDNA, and examined whether TRH-R mRNA may be expressed and function in the GH-secreting pituitary adenomas of patients with acromegaly. The human TRH-R consists of 398 amino acids and is a member of the G protein-coupled receptor family. The gene has a single intron in the coding sequence. An addition of TRH caused an obvious increase in intracellular calcium concentration in chinese hamster ovary cells expressing this receptor. Although highly homologous to the rat and mouse TRH-Rs, the human TRH-R has several differences in the carboxyl-terminal structure. The sequence and functioning analyses showed the same expression of TRH-R mRNA in the pituitary adenomas as that in the normal pituitaries, indicating that 1) some adenomas of patients with acromegaly express an intact and functional TRH-R, and that 2) the paradoxical response of GH secretion to TRH found in the patients might be a direct effect of TRH on TRH-R expressed in the adenoma.
Acromegaly↗