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Biomedical subjects

Kozo Hashimoto

Publications and source records attributed to Kozo Hashimoto.

At least 19 recordsLinked to original sources
PubMed2007

High glucose activates pituitary proopiomelanocortin gene expression: possible role of free radical-sensitive transcription factors.

BACKGROUND: Hyperglycemia is recognized as a metabolic stress, and indeed it is known to stimulate hypothalamo-pituitary-adrenal (HPA) axis, a representative anti-stress system, in patients with diabetes mellitus or in animal models of hyperglycemia. Thus, we tried to clarify the molecular mechanism of glucose-induced HPA axis activation. METHODS: We studied the effect of high glucose on the transcriptional regulation of proopiomelanocortin (POMC) gene that encodes adrenocorticotropic hormone, a central mediator of HPA axis, using AtT20 corticotroph cell line in vitro. RESULTS: We found that high glucose concentration (24 mM) significantly stimulated the 5'-promoter activity of POMC gene. The effect was promoter-specific, and was mimicked by nuclear factor-kappaB (NF-kappaB)- or AP1-responsive promoters but not by cAMP-responsive element or serum-response element-containing promoters. Furthermore, the stimulatory effect of high glucose on POMC gene was eliminated by NF-kappaB and AP1 inhibitors, suggesting the involvement of the transcriptional factors. The POMC 5'-promoter has the canonical NF-kappaB consensus sequence, and gel shift assay showed the binding of NF-kappaB to the element. Finally, the effect of high glucose was completely abolished by treatment with a radical quencher 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL). CONCLUSIONS: Our data suggest that hyperglycemia activates POMC gene expression, at least partly, via NF-kappaB/AP1, and that high-glucose-induced free radical generation may mediate the activation of these transcription factors, which in turn stimulates the transcription of POMC gene.

Animals↗
PubMed2006

Molecular mechanisms for corticotropin-releasing hormone gene repression by glucocorticoid in BE(2)C neuronal cell line.

The molecular mechanisms for the suppression of corticotropin-releasing hormone (CRH) gene expression by glucocorticoid remain to be clarified albeit the well-known physiological role of the glucocorticoid-induced negative feedback regulation of the gene. In this study, we examined the effect of glucocorticoid on CRH gene transcription using the human BE(2)C neuronal cell line, which expresses the CRH gene and produces CRH peptide intrinsically. Dexamethasone, a specific ligand for the glucocorticoid receptor (GR), potently suppressed human CRH 5'-promoter activity. The effect was GR-dependent, and was completely antagonized by antiglucocorticoid RU38486. Treatment with neither sodium butyrate nor trichostatin A abolished the suppression, thus making the possible involvement of histone deacetylase (HDACs) unlikely. The suppression was not influenced by the deletion or mutation of the proposed negative glucocorticoid-response element (nGRE) but was completely eliminated by that of cAMP-response element. Finally, overexpression of protein kinase A catalytic subunit antagonized the glucocorticoid suppression, whereas overexpression of GR enhanced it. Taken together, our data suggest that: (1) glucocorticoid exerts its negative effect on CRH gene transcription in a GR-dependent manner, but the GR-mediated inhibition appears to be independent of the nGRE; (2) HDACs do not play a significant role in the glucocorticoid repression; (3) some of the inhibitory events may take place through transrepression of protein kinase A by GR.

Cell Line, Tumor↗
PubMed2006

Regulation of proopiomelanocortin gene transcription during single and repeated immobilization stress.

We have previously reported that repeated immobilization produces persistent activation of the hypothalamic-pituitary-adrenocortical axis in rats. In an attempt to assess whether any adaptational responses occur at the pituitary level, we examined the detailed time courses of proopiomelanocortin (POMC) gene transcription in the anterior pituitary (AP) in comparison with those of corticotropin-releasing hormone (CRH) gene transcription in the hypothalamic paraventricular nucleus (PVN) during single and repeated immobilization using both intronic and exonic probes. During single immobilization, there was a robust and rapid increase in both CRH heteronuclear RNA (hnRNA) in the PVN and POMC hnRNA in the AP, together with a slower increase in CRH mRNA, but no significant increase in POMC mRNA. Single immobilization also caused significant increases in the plasma concentrations of both ACTH and corticosterone. Daily immobilization for 6 days increased the basal levels of CRH hnRNA and CRH mRNA in the PVN and POMC mRNA in the AP. Both CRH hnRNA and POMC hnRNA responded rapidly to a final episode of acute immobilization on day 7, whereas the peak values of CRH hnRNA and POMC hnRNA after 15 min of the final stress were smaller than those during single immobilization. In contrast to single stress, CRH mRNA did not change significantly, whereas POMC mRNA robustly increased after the final immobilization on day 7. Plasma ACTH increased to a similar degree to single stress, but its initial increase at 5 min was significantly higher than that during single immobilization. The increase in the plasma corticosterone concentration was higher during final immobilization than during single stress. These results suggest that, in response to the hypothalamic drive during repeated immobilization stress, pituitary corticotrophs are capable of upregulating the basal and stress-induced POMC mRNA levels via increased efficiency of the posttranscriptional processing of the hnRNA and/or increased mRNA stability.

Adrenocorticotropic Hormone↗
PubMed2006

Association between serum ferritin and circulating oxidized low-density lipoprotein levels in patients with type 2 diabetes.

The oxidative modification of low-density lipoproteins (LDL) plays a central role in the initiation and acceleration of atherosclerosis. Iron plays a part in the formation of highly toxic free radicals such as hydroxide and superoxide anions, which can induce lipid peroxidation. We investigated whether serum iron status was associated with circulating oxidized LDL (oxLDL) levels in type 2 diabetic patients, in whom oxidative stress and susceptibility to lipid oxidation were supposedly increased. Serum ferritin levels were significantly correlated with plasma oxLDL concentrations in both male and female patients (p<0.02 and p<0.05, respectively). No correlation was detected between ferritin and LDL-cholesterol (LDL-C) concentrations despite the close correlation between LDL-C and oxLDL concentrations (p<0.0001). Stepwise regression analysis showed that ferritin concentration was an independent positive determinant of oxLDL level, in addition to triglyceride concentration, body mass index and sex. This is the first report to show that serum ferritin is associated with circulating oxLDL levels in patients with type 2 diabetes. Further work is required to establish a causative link between iron excess and the development of diabetic vascular complications.

Aged↗
PubMed2006

Longitudinal study of patients with idiopathic isolated TSH deficiency: possible progression of pituitary dysfunction in lymphocytic adenohypophysitis.

The relationship between isolated TSH deficiency and hypophysitis was studied. Six patients (five women and one man) with idiopathic isolated TSH deficiency were longitudinally investigated with an interval of 31 to 60 months. Clinical symptoms, laboratory results and endocrine function were investigated as well as pituitary magnetic resonance imaging (MRI) at the start and the end of the study. Clinically, initial symptoms due to hypothyroidism were ameliorated by the thyroid hormone replacement in all patients. Oligomenorrhea newly appeared during the study in three patients, although no other symptoms appeared. Serum fT3 and fT4 levels were within the reference ranges, and serum TSH level and its response to TRH stimulation remained low in all patients. Peak plasma GH level during GRH stimulation was significantly (p<0.03) decreased, at the end of the study as compared with the start. Peak plasma FSH level to LHRH stimulation was significantly (p<0.03) decreased as well as basal FSH level. In contrast, peak of prolactin during TRH stimulation was significantly (p<0.03) increased at the end of the study as compared with the start as well as basal prolactin level. Endocrine features at the end of the study were compatible with those of lymphocytic adenohypophysitis (LAH). MRI of the pituitary gland showed empty sella in one patient and slight swelling in two patients. These findings remained unchanged during the study period. One patient underwent pituitary biopsy, with histological examination showing atypical form of LAH. LAH can cause idiopathic isolated TSH deficiency and can functionally progress to combine dysfunction of the pituitary gland.

Adult↗
PubMed2006

Spontaneous remission of small cell lung cancer: a case report and review in the literature.

Spontaneous remission (SR) of cancer, especially of lung tumor, is a rare biological event. Only seven cases in which small cell lung cancer (SCLC) regressed spontaneously had been previously reported. We report here a rare case of complete SR of SCLC in an 86-year-old man. Paraneoplastic sensory neuronopathy (PSN) is a rare syndrome, which is associated with malignancy such as SCLC and starts with dysesthetic pain and numbness in the distal extremities, then spreading all four limbs and trunk causing severe sensory ataxia. In the previous reports, SR of SCLC is suggested to result from surgical trauma or PSN, which may be able to enhance anti-tumoral immunity. Our report is the case of SR of SCLC, without any therapies nor any invasive examinations. Although the reason of SR of SCLC in the present case is unknown, PSN could be one of the diagnosis by exclusion.

Aged, 80 and over↗
PubMed2006

Identification of a functional AP1 element in the rat vasopressin gene promoter.

Arginine vasopressin (AVP) is expressed in paraventricular, supraoptic, and suprachiasmatic nuclei of the hypothalamus, where transcription of the AVP gene is activated by various forms of stress, such as hyperosmolality, inflammation, and photic stimulation. In vasopressinergic neurons, the expression of the Fos/Jun family proteins is known to be rapidly induced after these stimuli as well. However, it is still unknown whether these proteins actually mediate AVP gene expression. In this study we examined in vitro the role of Fos/Jun protein in transcriptional regulation of the AVP gene using the BE(2)M17 neuroblastoma cell line. We found that 5'-promoter activity of the rat AVP gene (-803/+26) markedly increased when all combinations of the Fos/Jun family proteins were overexpressed. Coexpression of the cAMP-responsive element-binding protein-binding protein and steroid receptor coactivator-1a further enhanced the Fos/Jun-mediated transcription. Using site-directed mutagenesis and EMSA techniques, we identified an activation protein 1 (AP1)-like element (-134/-128; TGAATCA) in the AVP gene 5'-promoter region, which is the sole responsible site for the Fos/Jun-mediated transcription. We also found that 12-O-tetradecarbonyl phorbol 13-acetate stimulates AVP gene transcription partly via the AP1 site through the activation of ERK signaling. Together, these results suggest that a variety of Fos/Jun family member proteins stimulate transcription of the AVP gene through the AP1 site we identified. Furthermore, this effect may be activated by both protein kinase A and protein kinase C signaling pathways.

Animals↗
PubMed2006

Pleural dissemination of thymoma showing tumor regression after combined corticosteroid and tacrolimus therapy.

We present the case of an elderly woman with myasthenia gravis who had pleural dissemination of thymoma reduced by treatments with a moderate dose of corticosteroids and a conventional dose of tacrolimus. A maintenance dose of prednisolone for myasthenia gravis could not shrink the size of the disseminated thymoma, but prednisolone (>30 mg daily) succeeded in reducing the size of the tumor. Moreover, a combination with tacrolimus enabled the daily dose of prednisolone to be tapered off without recurrence of myasthenia gravis, and the disseminated thymoma almost disappeared. A moderate or higher dosage of corticosteroids with tacrolimus may, in some cases, be an effective procedure for pleural dissemination of thymoma. Treatment should be undertaken on a trial basis for patients not indicated for surgery, radiotherapy, or chemotherapy.

Journal Article↗
PubMed2006

Edaravone inhibits rheumatoid synovial cell proliferation and migration.

Rheumatoid arthritis (RA) is characterized by synovial proliferation and migration which is induced by proinflammatory cytokines or oxidative stress, followed by joint destruction. Edaravone, clinically available free radical scavenger in Japan, is confirmed to be beneficial in the acute stage of cerebral infarction. We aimed to investigate whether edaravone suppressed in vitro proliferation and migration of synovial cells (SC) induced by IL-1beta. SC proliferation and migration induced by IL-1beta were dose-dependently suppressed by edaravone at the clinically available concentration. These data suggest that edaravone has potential effects to suppress SC proliferation and migration, followed by suppression of synovial proliferation in RA. Therefore, edaravone, an antioxidant agent, might be a novel therapeutic agent which develops the new strategy for treatment of RA, and more detailed studies are required to establish the therapeutic effect of edaravone on RA in vivo.

Aged↗
PubMed2006

Obstructive sleep apnoea syndrome, plasma adiponectin levels, and insulin resistance.

OBJECTIVE: To investigate whether sleep-disordered breathing and/or plasma adiponectin levels are associated with insulin resistance independent of obesity or fat distribution in obstructive sleep apnoea syndrome (OSAS). DESIGN: Cross-sectional clinical study. PATIENTS: Two-hundred and thirteen Japanese patients with OSAS aged 27-80 years were divided into three groups: 30 with mild OSAS [apnoea-hypopnoea index (AHI) = 10.3 +/- 0.9 episodes/h, minimum oxygen saturation (min SpO2) = 87.3 +/- 0.9%], 98 with moderate OSAS (AHI = 28.9 +/- 0.6 episodes/h, min SpO2 = 82.1 +/- 0.7%), and 85 with severe OSAS (AHI = 68.1 +/- 2.8 episodes/h, min SpO2 = 72.3 +/- 1.6%). Twenty-one patients undergoing diabetic treatments (two mild, nine moderate and 10 severe) were excluded from the assessment of insulin resistance and plasma adiponectin measurements. MEASUREMENTS: Fat distribution [evaluated according to visceral (V) and subcutaneous (S) fat areas using computed tomography scanning at the umbilical level], blood pressure, metabolic parameters and hormones including insulin and adiponectin were measured. After full polysomnography, venous blood was collected between 0600 and 0700 h. RESULTS: Severe OSAS patients were more hypertensive than mild and moderate OSAS. Fasting plasma glucose (FPG) and fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR) levels were all higher in severe OSAS than mild and moderate OSAS patients. HOMA-IR was correlated not only with obesity [body mass index (BMI), V and S areas] but also with apnoea (AHI, min SpO2 and desaturation time). Additionally, HOMA-IR was correlated positively with haemoglobin (Hb)A1c, systolic (SBP) and diastolic blood pressure (DBP), triglycerides and free fatty acids (FFA), and negatively with high density lipoprotein (HDL)-cholesterol, suggesting that insulin resistance is a key component of the metabolic syndrome in OSAS. Plasma adiponectin levels were not different between mild, moderate and severe OSAS groups. Plasma adiponectin levels were correlated with HOMA-IR and V area, but not AHI or min SpO2. Stepwise multiple regression analysis, however, revealed that BMI, AHI and plasma adiponectin were independently associated with HOMA-IR. CONCLUSION: Sleep-disordered breathing was associated with insulin resistance independent of obesity. Although plasma adiponectin was also an independent determinant of HOMA-IR in OSAS patients, plasma adiponectin was more closely related to obesity than to sleep apnoea. Although treatment of sleep-disordered breathing with nasal continuous positive airway pressure reportedly improves insulin sensitivity, our findings suggest that treatment of obesity is also essential in ameliorating insulin resistance at least through increased plasma adiponectin levels in OSAS.

Adiponectin↗
PubMed2006

Edaravone inhibits the disease activity in rheumatoid arthritis.

A male patient with rheumatoid arthritis (RA) developed acute stroke and was treated with the free radical scavenger, edaravone. Polyarthralgia improved with a reduction in serum C-reactive protein concentration soon after the start of edaravone administration. The disease activity score 28 (DAS28) also decreased. Edaravone appears to be effective for the control of RA. The usefulness of this potentially novel therapeutic agent should be tested in a well designed randomized controlled trial.

Antipyrine↗
PubMed2006

A case with insulinoma diagnosed and localized preoperatively using contrast-enhanced ultrasonography (CEUS) and arterial stimulation and venous sampling (ASVS).

We report a case with insulinoma diagnosed and localized preoperatively using a combination of contrast-enhanced ultrasonography (CEUS) and arterial stimulation and venous sampling (ASVS). A 76-year-old woman was admitted to our hospital because of hypoglycemic attacks, delirium, and dementia. Fajans' ratio, Grunt's ratio, and Turner's ratio, which are reported to be indexes for endogenous hyperinsulinemia in insulinoma, were all negative. Imaging tests, including computed tomography, magnetic resonance imaging and angiography, failed to detect any abnormalities. CEUS showed a small low echoic lesion in the pancreatic body with blood flow and ASVS showed that the insulin levels in the hepatic vein were extremely increased by calcium injection to the splenic artery, indicating an insulinoma in the pancreatic body preoperatively. An open intra-abdominal operation was performed and an insulinoma was confirmed in the pancreatic body. Enucleation of tumor was undertaken and symptomatic hypoglycemia improved.

Aged↗
PubMed2005

Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and DQB1 in autoimmune polyglandular syndrome type III in Japanese population.

BACKGROUND: It has been reported that HLA class II haplotypes DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0901-DQA1*0302-DQB1*0303 are major susceptibility haplotypes for type 1 diabetes mellitus (DM) in Japanese population. However, little has been reported on the susceptibility HLA class II haplotypes in Japanese patients with autoimmune polyglandular syndrome type II and type III (APS III). PATIENTS AND METHODS: HLA class II haplotypes of DRB1-DQA1-DQB1 in 31 patients with APS III, 14 patients with Hashimoto's thyroiditis alone, and 15 patients with Graves' disease alone were examined in Japanese population. APS III patients were divided into three groups (A, B, and C) depending on the combination of autoimmune endocrine diseases. RESULTS: In 13 APS III patients with both Hashimoto's thyroiditis and type 1 DM (group A), the haplotype frequencies of the HLA DRB1*0802-DQA1*0401-DQB1*0402 and DRB1*0901-DQA1*0302-DQB1*0303 were significantly higher than in the controls. In patients with Hashimoto's thyroiditis alone, the haplotype frequency of DRB1*0901-DQA1*0302-DQB1*0303 was significantly higher than in controls, whereas the frequency of DRB1*0802-DQA1*0401-DQB1*0402 did not differ significantly from those in the controls. In 11 APS III patients with both Graves' disease and type 1 DM (group B), the haplotype frequencies of HLA DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0802-DQA1*0301-DQB1*0302 were significantly higher than in controls. In patients with Graves' disease alone, the haplotype frequency of DRB1*0803-DQA1*0103-DQB1*0601 were significantly higher than those in controls, suggesting that the susceptibility haplotypes for group B APS III differed from those for Graves' disease alone. In 7 APS III patients with both autoimmune thyroid diseases and pituitary disorders (group C), the haplotype frequency of HLA DRB1*0405-DQA1*0303-DQB1*0401 was significantly higher than in controls. CONCLUSIONS: Susceptible HLA class II haplotypes of DRB1-DQA1-DQB1 for APS III differ between the Japanese and Caucasian populations. More interestingly, the susceptible HLA class II haplotypes differ among the three types of Japanese APS III and are not merely a combination of susceptibility haplotypes of each endocrine disease.

Adult↗
PubMed2005

Inhibition of 11beta-hydroxysteroid dehydrogenase eliminates impaired glucocorticoid suppression and induces apoptosis in corticotroph tumor cells.

Cushing's disease is characterized by persistent ACTH secretion under hypercortisolemia. In an attempt to clarify the molecular mechanism, we examined the effect of 11beta-hydroxysteroid dehydrogenase (HSD) inhibition on glucocorticoid suppression of ACTH release using murine corticotroph tumor cells. We found that 11beta-HSD2, as well as -HSD1, was expressed in the cells and that its inhibition by carbenoxolone significantly improved the negative feedback effect of glucocorticoid. Carbenoxolone also enhanced apoptosis induced by cortisol. These effects are most likely attributable to inhibition of 11beta-HSD2 because only cortisol, a substrate of 11beta-HSD2, was present in these experimental conditions. We conclude that ectopic expression of 11beta-HSD2 is, at least in part, responsible for the impaired glucocorticoid suppression in corticotroph adenoma. Inhibition of 11beta-HSD2 may be applicable to the medical therapy for Cushing's disease.

11-beta-Hydroxysteroid Dehydrogenases↗