Biomedical subjects

Noriyuki Koibuchi

Publications and source records attributed to Noriyuki Koibuchi.

28 records · Page 2Linked to original sources

PubMed2004

Polychlorinated biphenyls suppress thyroid hormone receptor-mediated transcription through a novel mechanism.

Polychlorinated biphenyls (PCBs) are environmental compounds that disrupt the endocrine system, and exposure to low doses causes abnormalities, particularly in the developing central nervous system. Because they are structurally similar to thyroid hormone (TH), PCBs might affect systems involving this hormone. We previously found, using reporter assays, that hydroxylated-PCB at doses as low as 10(-10) m suppress TH-induced transcriptional activation of TH receptor (TR). To understand the molecular mechanisms of this process, we examined whether PCBs alter coactivator or corepressor interaction with TR. Polychlorinated biphenyls suppressed steroid receptor coactivator-1 enhanced TR-mediated transcription, but did not reduce TR/steroid receptor coactivator-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. Thus, the suppression was probably not caused by coactivator dissociation. Nuclear receptor co-repressor was not recruited to TR by PCBs either in vivo or in vitro, indicating that TR corepressor binding did not induce the suppression. We then examined whether PCB influences TR binding to the thyroid hormone-response element (TRE). Electrophoretic mobility shift assays revealed that the TR/retinoid X receptor heterodimer complex was partially dissociated from TRE in the presence of PCB. These results indicate that partial dissociation of TR/retinoid X receptor heterodimer complex from the TRE is involved in the suppression of transcription induced by PCB.

Environmental Pollutants↗

PubMed2004

Phosphorylation of JNK is involved in regulation of H(+)-induced c-Jun expression.

Cells respond to physical and chemical stimulations mediated by pH, osmolarity, and oxidative and mechanical stresses. Various signal transduction pathways cooperate and participate in these responses. Here we describe the role of c-Jun NH2-terminal kinase (JNK) in regulation of gene transcription after an increase in extracellular H+. When cells were incubated in low pH medium, the promotion of JNK phosphorylation and c-Jun expression was clearly observed in cells in an extracellular pH- and time-dependent manner. Activation of p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) was extremely weak compared with that of JNK. An increase in extracellular H+ led to enhanced nuclear translocation of phosphorylated JNK leading to augmentation of the transcriptional activity of c-Jun. Nimodipine, a blocker of voltage-gated Ca2+ ion channels, prevented the phosphorylation of JNK and expression of c-Jun in a dose-dependent manner. These results suggest a novel intracellular signalling pathway for H+-induced c-Jun expression: an increase of extracellular H+ induces JNK phosphorylation and c-Jun expression via partly extracellular Ca2+ influx through voltage-gated Ca2+ channels.

Animals↗

PubMed2004

Impact of thyroid hormone deficiency on the developing CNS: cerebellar glial and neuronal protein expression in rat neonates exposed to antithyroid drug propylthiouracil.

The developing rat cerebellum is vulnerable to thyroid hormone (TH) deficiency. The present study addresses the molecular mechanisms involved in this response. Specifically, the study focuses on the expression of selected cerebellar proteins that are known to be directly [protein expressing 3-fucosyl-N-acetyl-lactosamine antigen (CD15), neuronal cell adhesion molecule (L1)] or indirectly [glial fibrillary acidic protein (GFAP)], involved in glial-neuronal interactions and thus regulation of cell proliferation and granule cell migration. Cerebellar mass, structure, and protein expression in rat neonates exposed to antithyroid drug propylthiouracil (PTU) from the embryonic day (E) 16 to postnatal day (P) 21 were compared against rat neonates that received replacement of thyroxin (T4) starting on day P1 or untreated controls. Cerebellar proteins were analyzed by quantitative Western blots. PTU-treated rats lagged in growth and showed reduction in cerebellar mass and alterations in cerebellar structure on P15. Daily treatment of neonates with T4 restored normal cerebellum-to-body-mass ratio, cerebellar structure, and cerebellar protein expression. Densitometric analysis of Western blots revealed altered expression of selected proteins in the cerebella of hypothyroid neonates. A decrease of CD15 (46%, p = 0.031) was observed on P10 and was accompanied by a decrease in GFAP expression (64%, p = 0.039). Furthermore, a shift in the developmental GFAP profile was observed in the PTU-treated cerebellum. L1 expression was not significantly affected in the hypothyroid cerebellum. Altered expression of cerebellar proteins is likely to affect cell-cell interactions and consequently cell proliferation and migration and contribute to structural and functional alterations seen in the hypothyroid rat neonates.

Age Factors↗

PubMed2004

Effect of hyperbaric oxygen on the ligament healing process in rats.

Animal experiments were done to investigate whether administration of hyperbaric oxygen promotes scar tissue formation, increases expression of the Type I procollagen gene, and improves the tensile properties of healing ligament. In 76 Sprague-Dawley rats, a 2-mm segment of the medial collateral ligament was removed. Thirty-eight rats were exposed to hyperbaric oxygen at 2.5 atmospheres absolute for 2 hours 5 days per week (Group H), whereas the remaining rats were exposed to room air (Group C). The animals were sacrificed at 3, 7, 14, and 28 days postoperatively. In situ hybridization histochemistry was done to examine the Type I procollagen gene expression in healing ligaments in 40 rats, whereas a tensile failure test was done in the remaining rats. The amount of scar tissue was greater in Group H than in Group C. Type I procollagen gene expression at 7 or 14 days was significantly greater in Group H than in Group C. The ultimate load and stiffness in Group H were significantly greater than in Group C at 14 days. Administration of hyperbaric oxygen promotes scar tissue formation and increases Type I procollagen gene expression in healing ligaments. These effects are associated with the improvement of their tensile properties.

Analysis of Variance↗

PubMed2004

Apoptosis in the epididymal epithelium of adult male golden hamster exposed to diethylstilbestrol.

Apoptosis in the testis and prostate exposed to disrupters of endocrine function, including diethylstilbestrol (DES), during neonatal or postnatal periods has repeatedly been demonstrated, but not in the mature epididymis. We investigated the effects of DES, a potent and synthetic estrogen, on apoptosis in the adult. Adult male golden hamsters received an SC injection of DES and were then sacrificed to collect epididymides after 1, 4, or 7 days of treatment. A significant decrease in epididymal weight and an increase in apoptotic cells were shown on the first day after DES injection. Flow cytometry showed that DES treatment (1 mg/kg) for 1, 4, or 7 days induced significant apoptosis both in the caput and the cauda epididymides. Greater numbers of apoptotic cells were detected in the caput than in the cauda at a fixed time after DES treatment. Serum levels of testosterone decreased markedly within 24 hr after DES administration, reaching undetectable levels of 0.1 ng/ml at 4 days and thereafter. These results indicate that DES administration can increase epididymal apoptosis with a decrease in serum testosterone levels. Because DES used to be injected into domestic animals, adult males also have a chance to take this substance through food. Our study indicates that exposure to DES in adults is as toxic as that in the perinatal period.

Animals↗

PubMed2003

Current perspectives on the role of thyroid hormone in growth and development of cerebellum.

The thyroid hormone (TH) is essential for growth and development of brain, including the cerebellum. Deficiency of TH during the perinatal period results in abnormal cerebellar development, which is well documented in rodent animal models. TH exerts its major effect by binding to the nuclear TH receptor (TR), a ligand-regulated transcription factor. Although TR is highly expressed in many brain regions, including the cerebellum, TH-target genes that likely play critical roles in brain development have not yet been fully clarified. At present, however, expression of many cerebellar genes is known to be altered by perinatal hypothyroidism. Interestingly, after the critical period of TH action (first 2 weeks of postnatal life in rodent cerebellum), the activities of many genes that are altered by perinatal hypothyroidism return to the same levels as those of euthyroid animal despite morphological alterations. Several prominent candidate genes that may play key roles in TH-mediated cerebellar development are discussed in this review. On the other hand, TR-mediated transcription may be modulated by various substances. The nuclear hormone receptor superfamily contains more than 40 transcriptional factors and, most of these receptors are present in the brain. Possible interactions between TR and such transcription factors are also discussed. Further, several additional issues that need to be clarified are discussed. One such issue is the discrepancy of phenotypes among TR-knockout and perinatal hypothyroid mice. Recent studies have provided several important clues to address this issue. Another current area that needs attention is the effect of endocrine disruptors on brain development. Since the molecular structures of TH and several endocrine disrupting chemicals are similar, the effect of such chemicals on brain may be exerted at least in part through the TH system. Recent studies have shown the possible interaction between TR and such chemicals. Overall, this review provides current findings regarding molecular mechanisms on TH action in cerebellar development.

Animals↗

PubMed2002

Polychlorinated biphenyls suppress thyroid hormone-induced transactivation.

Polychlorinated biphenyls (PCBs) have been known as environmental endocrine disrupting chemical that causes various abnormalities in many organs including the central nervous system (CNS). To examine the effect of PCBs on thyroid hormone (T3)-mediated transcription, transfection-based reporter assays were performed. Surprisingly, as low as 10(-10)M of 4(OH)-2('),3,3('),4('),5(')-pentachloro biphenyl suppressed T3-induced transactivation by thyroid hormone receptor (TR) in various cell lines. Interestingly, among the cell lines that we tested, brain-derived cell line TE671 cells showed strong suppression by the PCB. The suppression of TR action by the PCB was not likely due to the ligand competition with T3. Various compounds of PCBs showed similar suppression. However, PCBs did not suppress glucocorticoid receptor-mediated transcription. Finally, we showed that PCBs suppress TR/coactivator (SRC-1) complex-mediated transactivation. In summary, our results suggest that very low dose of PCBs can potentially interfere with TR-mediated transactivation by influencing on TR/coactivator complex. As such, PCBs may disturb growth and development of TH target organ, particularly in the CNS.

Cell Line↗

PubMed2002

Past-A, a novel proton-associated sugar transporter, regulates glucose homeostasis in the brain.

The ventral medullary surface (VMS) of the medulla oblongata is known to be the site of the central chemosensitive neurons in mammals. These neurons sense excess H+/CO2 dissolved in the CSF and induce hyperventilation. To elucidate the mechanism of neuronal cell adaptation to changes of H+/CO2, we screened for hypercapnia-induced genes in the VMS. Here, we report cloning and characterization of a novel gene called proton-associated sugar transporter-A (Past-A), which is induced in the brain after hypercapnia and mediates glucose uptake along the pH gradient. Past-A comprises 751 amino acid residues containing 12 membrane-spanning helices, several conserved sugar transport motifs, three proline-rich regions, and leucine repeats. Past-A transcript was expressed predominantly in the brain. Moreover, the Past-A-immunoreactive neural cells were found in the VMS of the medulla oblongata, and the number of immunoreactive cells was increased by hypercapnic stimulation. Transient transfection of Past-A in COS-7 cells leads to the expression of a membrane-associated 82 kDa protein that possesses a glucose transport activity. The acidification of extracellular medium facilitated glucose uptake, whereas the addition of carbonyl cyanide m-chlorophenylhydrazone, a protonophore, inhibited glucose import. Together, our results indicate that Past-A is a brain-specific glucose transporter that may represent an adaptation mechanism regulating sugar homeostasis in neuronal cells after hypercapnia.

Administration, Inhalation↗

PubMed2002

Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics.

Cytochrome P450 monooxygenase 3A4 (CYP3A4) is responsible for the metabolism of endogenous steroids and drugs in liver. Many inducers of human CYP3A4, such as rifampicin, bind to the orphan nuclear receptor SXR (steroid and xenobiotic receptor) as ligands and stimulate transcription on xenobiotic response elements located in the CYP3A4 promoter. Conversely, it is not known whether SXR mediates the transcriptional repression. We thus examined transcriptional repression of SXR and its interaction with corepressors, NCoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid receptors) using reporter assays in the absence and presence of ligand. Cotransfection of SMRT, but not NCoR, inhibited not only basal but also rifampicin-induced transcriptional activity of SXR on the CYP3A4 promoter through specific SMRT-SXR interaction in HepG2 cells. Interestingly, rifampicin also increased the interaction of SXR with SMRT as well as with coactivator SRC-1. On the other hand, the anti-fungal agent ketoconazole decreased SXR interaction with both SRC-1 and SMRT. Ketoconazole partially inhibited corticosterone-induced SXR-mediated transcription on the CYP3A4 promoter. Taken together, our results suggest that the differential interaction of coactivators and corepressors induced by various xenobiotics may alter SXR-mediated transcription. Further, the effects of ketoconazole on the CYP3A4 gene suppression may explain, in part, drug-induced inhibition of the CYP3A4 action at the transcriptional level.

Adrenal Cortex Hormones↗

PubMed2002

Vulnerability of monoaminergic neurons in the brainstem of the zitter rat in oxidative stress.

In the monograph of Santiago Ramon y Cajal, he provided a detailed description about the morphological changes in degeneration and regeneration of peripheral and central nervous systems following lesions. He discussed factors that may promote or inhibit axonal growth after peripheral and/or central nerve injury. Cajal with a brilliant insight anticipated the existence of several factors acting on degeneration and regeneration. Free radicals have been proposed to be one of such factors. These highly reactive oxygen species-derived free radicals play a pathogenetic role in neurological disorders, including ischemia, trauma, Alzheimer's disease and Parkinson's disease (PD). In this review we will discuss the similarities and differences between the morphological changes under oxidant stress and Cajal's drawings of degeneration and regeneration following the central injury. The monoaminergic neuron systems in the brainstem appear vulnerable to these free radicals, which have also been implicated in the selective degeneration of the nigrostriatal DA system. We analyzed the degeneration of fibers and the neuronal cell death of brainstem monoaminergic neuron systems in a mutant rat, which has abnormal metabolism of oxygen species in the brain. The degeneration of DA cell bodies and fibers was characterized by swollen varicosities and clustered fibers.

Animals↗