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Biomedical subjects

I Saito

Publications and source records attributed to I Saito.

At least 127 records · Page 7Linked to original sources
PubMed2000

Risk factors associated with persistent postoperative hypertension in Cushing's syndrome.

The aim of the present study was to assess the long-term results of adrenalectomy and to evaluate potential risk factors for the persistence or recurrence of hypertension. Forty-five patients with Cushing's syndrome caused by benign cortisol-producing adrenocortical adenomas were evaluated before and for a period of 1 year after surgical cure. When the patients were classified into two groups according to whether their preoperative BP was more (HBP group) or less (NBP group) than 140/90 mmHg, the BP level was found to be continuously higher in the HBP group than in the NBP group during the year after surgery. This finding suggests that the preoperative BP level in Cushing's syndrome may be a determinant factor for persistent hypertension after surgery (P<0.05). In addition, a correlation was found between postoperative BP level and duration of hypertension (P<0.05), but no relationships were found between postoperative BP levels and other factors, including age, BMI, tumor size, serum cortisol, aldosterone, potassium, total cholesterol, or glucose levels. The above findings indicate that intensive control of preoperative BP to maintain it below 140/90 mmHg with antihypertensive medication is a very important means of improving prognosis for postoperative BP. Immediate diagnosis and surgical treatment to reduce the duration of hypertension are also crucial for the long-term BP prognosis.

Adrenalectomy↗
PubMed2000

Expression and regulation of BCL-2 family genes in human adrenocortical adenomas in comparison with adrenal hyperplasia of Cushing's disease.

The significance of increases in the expression of apoptosis-suppressing genes such as bcl-2 and mcl-1/EAT in human adrenal tumors has not yet been fully elucidated. Furthermore the roles of these genes in cell proliferation may involve interaction with steroidogenesis in the tumors via intracellular second messengers. Cyclic AMP (cAMP) caused human adrenocortical H295R cells to overexpress hCYP17 resulting in hypersecretion of cortisol. At the same time, however, expression of bcl-2, which has a cAMP response element (CRE), was not affected. Furthermore, in vivo Bcl-2 protein analysis showed its down-regulation in adrenal hyperplasia of Cushing's disease despite ACTH stimulation. Exogenous addition of glucocorticoid did not affect the expression of bcl-2 family genes. Expressions of Mcl-1/EAT and Bax did not differ markedly among human adrenal glands affected by various pathologies. In conclusion the down-regulation of Bcl-2 in Cushing's disease did not agree with no induction of this gene by cAMP in H295R cells, suggesting that expression of Bcl-2 protein was not regulated mainly by cAMP-protein kinase (PKA) pathways in human adrenal hyperplasia.

Adenoma↗
PubMed2000

Transcriptional regulation of steroid receptor coactivator-1 (SRC-1) in glucocorticoid action.

Diverse mechanisms of steroid receptor action have been clarified in recent years, as a consequence of the discovery of multiple coactivators. Among them, steroid receptor coactivator-1 (SRC-1) is a member of the p160 coactivator families, which are 160 kDa proteins that interact with steroid receptors in a hormone-sensitive manner. Since coactivators function as transcriptional power boosters, subtle changes in coactivator expression levels in certain cells markedly change of receptor-mediated transcriptional activity. Expression of the glucocorticoid receptor (GR) has been shown to be autoregulated in glucocorticoid action, i.e., GR is downregulated by its cognate ligand, indicating that this autoregulation of GR may protect target cells against excessive hormone action. In the present study, we examined whether coactivator expression levels are also regulated by glucocorticoids. Among several coactivators, the SRC-1 mRNA level was downregulated by dexamethasone treatment in rat tissues, such as liver, heart, kidney, stomach, and cerebrum, in vivo. We also demonstrated dexamethasone-mediated downregulation of SRC-1 mRNA and its protein levels in rat renal mesangial cells in vitro. These results suggest that ligand-mediated downregulation of SRC-1 is crucial in the physiology of glucocorticoid action.

Animals↗
PubMed2000

Orphan receptors COUP-TF and DAX-1 as targets in disordered CYP17 expression in adrenocortical tumors.

CYP17 gene transcription is activated by SF-1 binding to a cyclic AMP-responsive sequence within the promoter region of the gene, and its transcription is inhibited by COUP-TF binding to the sequence. Another orphan receptor, DAX-1, is shown to act as a suppressor of SF-1-mediated transcription. We examined the expression level of these orphan receptors in adrenocortical tumors and compared the results with CYP17 expression. CYP17 was highly expressed in cortisol-producing adenomas, whereas COUP-TF and DAX-1 expression levels were very low. In deoxycorticosterone-producing adenomas, on the other hand, CYP17 expression was extremely low, whereas DAX-1 was highly expressed and SF-1 expression was slightly decreased. In conclusion, the reciprocal expression of CYP17 and the transcriptional repressors COUP-TF and DAX-1 indicates that these orphan receptors have a pathophysiologic role in the excessive hormone production in cortisol- and deoxycorticosterone-producing adrenocortical tumors.

Adrenal Cortex Neoplasms↗
PubMed2000

Structure of IL-10 and its role in autoimmune exocrinopathy.

Cytokines are implicated in the pathogenesis of a variety of autoimmune disorders. Whether the presence of cytokines is primary or secondary and the extent to which these factors may contribute to the development and progression of clinicopathologic alterations in these disorders remain largely unknown but are highly important questions. Our research focuses on evaluating these issues by using a transgenic approach to direct the constitutive expression of cytokines to epithelial cells in the intact exocrine glands of mice. Our recent studies have focused on the potential of the regulatory cytokine IL-10 produced by type 2 T-helper cells to inhibit inflammation and the development of autoimmue diseases. Using targeted introduction of this molecule into the exocrine gland epithelial cells, we found that IL-10 induced apoptosis of glandular tissues destruction and lymphocyte infiltration consisting primarily of Fas-ligand+ CD4+ T cells, as well as in vitro upregulation of FasL expression on T cells. These results suggest that IL-10 is necessary and sufficient for exocrine gland dysfunction in the transgenic mice. This article discusses recent advances in IL-10 and its role in the pathological conditions of autoimmune exocrinopathy.

Animals↗
PubMed1999

Site-specific oxidation at GG and GGG sequences in double-stranded DNA by benzoyl peroxide as a tumor promoter.

Benzoyl peroxide (BzPO), a free-radical generator, has tumor-promoting activity. As a method for approaching the mechanism of tumor promoter function, the ability of oxidative DNA damage by BzPO was investigated by using (32)P-labeled DNA fragments obtained from the human p53 tumor suppressor gene and c-Ha-ras-1 protooncogene. BzPO induced piperidine-labile sites at the 5'-site guanine of GG and GGG sequences of double-stranded DNA in the presence of Cu(I), whereas the damage occurred at single guanine residues of single-stranded DNA. Both methional and dimethyl sulfoxide (DMSO) inhibited DNA damage induced by BzPO and Cu(I), but typical hydroxyl radical ((*)OH) scavengers, superoxide dismutase (SOD) and catalase, did not inhibit it. On the other hand, H(2)O(2) induced piperidine-labile sites at cytosine and thymine residues of double-stranded DNA in the presence of Cu(I). Phenylhydrazine, which is known to produce phenyl radicals, induced Cu(I)-dependent damage at thymine residues but not at guanine residues. These results suggest that the BzPO-derived reactive species causing DNA damage is different from (*)OH and phenyl radicals generated from benzoyloxyl radicals. BzPO/Cu(I) induced 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation in double-stranded DNA more effectively than that in single-stranded DNA. Furthermore, we observed that BzPO increased the amount of 8-oxodG in human cultured cells. Consequently, it is concluded that benzoyloxyl radicals generated by the reaction of BzPO with Cu(I) may oxidize the 5'-guanine of GG and GGG sequences in double-stranded DNA to lead to 8-oxodG formation and piperidine-labile guanine lesions, and the damage seems to be relevant to the tumor-promoting activity of BzPO.

5' Untranslated Regions↗
PubMed1999

Site-specific DNA methylation and apoptosis: induction by diabetogenic streptozotocin.

Streptozotocin (STZ) is known to induce insulin-dependent diabetes mellitus via DNA damage in experimental animals. The mechanism of induction of DNA damage by STZ was investigated in vitro, using a human cell line and 32P-labeled DNA fragments isolated from human genes. STZ induced cellular DNA damage and apoptosis, and frequently initiated DNA modification at guanines, especially at the middle guanine in runs of three and at the guanine at the 3'-end of runs of two guanines, similar to N-methyl-N-nitrosourea, a typical methylating agent. Scavengers for reactive oxygen species or nitric oxide did not inhibit the induction of DNA damage by STZ. On the other hand, damage induction was inhibited by sodium acetate and sodium chloride, which can reduce the reactivity of methylating agents to DNA via the sodium cation. These results suggest that STZ induces DNA damage by methylation of guanines via methyl cations. This alkylation may be responsible for triggering apoptosis, and subsequently diabetes.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1999

Postsynaptic expression of Ca2+-permeable AMPA-type glutamate receptor channels by viral-mediated gene transfer.

The ability to artificially express a particular receptor protein in the postsynaptic sites of neurons in the central nervous system (CNS) would be useful for the study of synaptic function of cloned receptor genes as well as for gene therapy of neurological disorders caused by dysfunction of postsynaptic receptors. In this study, we aimed to express the cDNA of unedited GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor that forms inwardly rectifying and Ca2+-permeable channel in CNS neurons by using adenoviral-mediated gene transfer. For this purpose, we have constructed a recombinant adenovirus bearing an expression-switching unit, where the unedited GluR2 cDNA can be activated by the Cre recombinase-mediated excisional deletion of a stuffer DNA interposed between the promotor and the coding region. When PC12 cells were infected with this recombinant adenovirus together with an adenovirus expressing Cre recombinase, the inwardly rectifying and Ca2+-permeable AMPA receptor channels were expressed in nearly 100% of infected cells. Two days after co-infection of cultured rat hippocampal neurons with these adenoviruses, fast excitatory neurotransmission in the glutamatergic synapse was mediated predominantly by the inwardly rectifying and Ca2+-permeable AMPA receptor channels. This indicates that the native AMPA receptors in the postsynaptic sites of the glutamatergic synapse are replaced rapidly with recombinant receptors newly produced by the viral-mediated gene transfer.

2-Amino-5-phosphonovalerate↗