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Biomedical subjects

Kiyoshi Hashizume

Publications and source records attributed to Kiyoshi Hashizume.

At least 19 recordsLinked to original sources
PubMed2006

Synergistic regulation of the mouse orphan nuclear receptor SHP gene promoter by CLOCK-BMAL1 and LRH-1.

Small heterodimer partner (SHP; NR0B2) is an orphan nuclear receptor and acts as a repressor for wide variety of nuclear hormone receptors. We demonstrated here that mouse SHP mRNA showed a circadian expression pattern in the liver. Transient transfection of the mSHP promoter demonstrated that CLOCK-BMAL1, core circadian clock components, bound to E-box (CACGTG), and stimulated the promoter activity by 4-fold. Liver receptor homologue-1 (LRH-1; NR5A2) stimulated the mSHP promoter, and CLOCK-BMAL1 synergistically enhanced the LRH-1-mediated transactivation. Interestingly, SHP did not affect the CLOCK-BMAL1-mediated promoter activity, but strongly repressed the synergistic activation of CLOCK-BMAL1 and LRH-1. Furthermore, in vitro pull-down assays revealed the existence of direct protein-protein interaction between LRH-1 and CLOCK. In summary, this study shows that CLOCK-BMAL1, LRH-1 and SHP coordinately regulate the mSHP gene to generate the circadian oscillation. The cyclic expression of mSHP may affect daily activity of other nuclear receptors and contribute to circadian liver functions.

ARNTL Transcription Factors↗
PubMed2006

Inhibition of LXRalpha signaling by vitamin D receptor: possible role of VDR in bile acid synthesis.

The expression of cholesterol 7alpha-hydroxylase (CYP7alpha), the rate-limiting enzyme in the catabolism of cholesterol to bile acid, is stimulated by oxysterol receptor, liver X receptor alpha (LXRalpha) and negatively regulated by a bile acid receptor, farnesoid X receptor. In the current study, we demonstrated that 1,25-(OH)(2)D3 blunted the LXRalpha-mediated induction of CYP7alpha mRNA in H4IIE rat hepatoma cells. In co-transfection experiments in HepG2 cells, VDR repressed the activity of rat CYP7alpha promoter in a ligand-dependent manner through inhibition of LXRalpha signaling. We also confirmed the ability of VDR to repress LXRalpha transcriptional activation using a synthetic LXRalpha responsive reporter. Deletion analyses revealed that the ligand-binding domain of VDR was required for the suppression and the DNA-binding domain was dispensable. Given the fact that VDR can be activated by the secondary bile acid as well as 1,25-(OH)(2)D3, the crosstalk between LXRalpha and VDR signaling in regulation of bile acid metabolism provides a possible contribution of VDR to modulate bile acid and cholesterol homeostasis, and highlights a physiological function of VDR beyond calcium metabolism in the body.

Animals↗
PubMed2006

Novel 14 base-pair deletion of the MEN1 gene in a patient with recurrent primary hyperparathyroidism.

MEN1 is the causative gene for multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome characterized by hyperplastic and neoplastic disorder of endocrine organs such as parathyroid, anterior pituitary and gastroenteropancreatic endocrine tissues. More than 300 germline mutations have already been reported in patients with MEN1. We here report a novel deletional mutation identified in a Japanese woman with apparently sporadic recurrent hyperparathyroidism. Genetic testing revealed a heterozygous deletion involving 14 bp in exon 6 (starting at amino acid codon 293) of MEN1, which results in early termination of the protein. This deletional mutation has not previously been described elsewhere.

Base Pairing↗
PubMed2006

Metabolic syndrome and age-related dementia: endocrinological aspects of adaptation to aging.

Metabolic syndrome is one of the determinants of lifespan in Japan. In order to prevent the acute vascular events, intervention is recommended. However, management of patients with this syndrome increased the number of patients with cognition decline and depressive state. Endocrinological studies with human and experimental animals showed that there is a negative relationship between progression of metabolic syndrome and occurrence of mental disorders. In this review, we summarize our clinical and experimental data, and discuss on the mechanism of the metabolic syndrome prevention of progression of age-related mental disorder.

Adaptation, Physiological↗
PubMed2006

Familial neuroendocrine tumor syndromes: from genetics to clinical practice.

Thanks to recent developments in molecular biology and cancer genetics, genetic testing has become widely available and useful in several kinds of familial tumor syndrome. However, the impact of genetic testing on medical management is not always straightforward. Clinicians have to consider the psychological impact and ethical complexities of communicating hereditary cancer risk information to families. This review notes some points on genetic counseling before and after genetic testing for familial neuroendocrine tumor syndromes.

Adult↗
PubMed2006

Angiotensin II regulates migration in mouse cultured mesangial cells: evidence for the presence of receptor subtype-specific regulation.

The biological effects of angiotensin II (AngII) are mediated by two major subtypes of AngII receptors, type 1 (AT1R) and type 2 (AT2R). In this study, we attempted to elucidate the role of AngII subtype receptor-specific regulation in migration and proliferation of mouse cultured mesangial (MSG) cells. We found that 100 nM AngII stimulated weak migration of MSG cells. Cell motility increased more in the presence of AT2R than in the presence of AT1R, and it was suppressed by guanylate cyclase inhibitors. On the other hand, the activation of AT1R resulted in increased cell numbers, while AT2R activation inhibited cell proliferation. Moreover, high concentrations of glucose (25 mM) stimulated the expression of AT2R but not AT1R. These results indicate that there are receptor subtype-specific roles in MSG cells, and it is therefore possible that the activation of AT2R stimulates repair of glomerular tissue defect, by regulation of migration and proliferation of MSG cells. Taken together, these results suggest that the relative concentrations of AT1R and AT2R are important factors in the regulation of AngII function in glomerular tissue, and alterations in the concentrations of these receptors may contribute to progression of or protection from diabetic nephropathy.

Angiotensin II↗
PubMed2006

[Knack of treatment with oral hypoglycemic drugs in the elderly].

In the treatment of elderly type 2 diabetes, it is important to detect hypoglycemia correctly, because the elderly patients often exhibit atypical symptoms from hypoglycemia. Oral hypoglycemic agents (OHA), which do not stimulate insulin release from pancreas, is rather safe and may be the first choice for the elderly patients. OHAs that stimulate insulin secretion weakly or temporally might be useful drug for controlling elderly diabetic patients characterized by post-prandial hyperglycemia. Strong-acting sulfonylurea must be use with a great caution. Importantly, once glycemic control comes to a fail even after an appropriate combination of OHAs, initiation of insulin injection therapy must be considered.

Aged↗
PubMed2005

Octreotide as a rapid and effective painkiller for metastatic carcinoid tumor.

Octreotide is one of the somatostatin analogue used for the treatment of endocrine tumors principally to suppress hormone secretion and to inhibit tumor growth. We experienced a case with multiple endocrine neoplasia type 1 who small amount of octreotide dramatically relieved the lumber pain caused by metastatic bone tumor. He had recurrent bronchial carcinoid tumors that metastasized to liver and bones. The spontaneous and radiated pain by bone tumors subsided within a few minutes after the initial injection of octreotide and the effect persisted for several hours. Combination therapy of octreotide and interferon alpha-2b significantly reduced the size of metastatic liver tumors and inhibited further growth of metastatic bone tumors for the last 27 months. The use of octreotide may be a good option for controlling pain by metastatic bone disease and combination therapy of octreotide and interferon alpha-2b is worth to try for patients with inoperable metastatic carcinoid tumor.

Analgesics↗
PubMed2005

[Aging and the endocrine system].

Blood pressure is maintained for preventing from the progression of damage of central nervous system. Endocrine system plays important roles in the prevention from the damage through the functional deviation. Hypertension is one of the results of the endocrinological deviation. Although the hypertension induced by the endocrinological deviation is a risk for the progression of metabolic syndrome, it is important in the maintaining activity of central nervous system.

Aged↗
PubMed2005

[A successful treatment of percutaneous radio frequency ablation for advanced thyroid cancer].

The patient was a 69-year-old woman. She received chemotherapy and radiation for thyroid tumor (undifferentiated cancer) following an operation in 1998. The chemotherapy was regularly repeated for relapse. The tumor increased gradually and came to cause dysphagia. She initially rejected nutritional management that depends on intravenous hyper alimentation or gastrostomy. After receiving an informed consent, we performed percutaneous radio frequency ablation (RFA) for the tumor using a Cool-tip needle on April 2, 2003. The algorithm of RFA was 9 min: 30 --> 120 W, 12 min: 50 --> 110 W, 9 min: 50 --> 100 W. After 2 days, the covered stent was implanted in the esophagus and an oral intake was started. Although the operation for undifferentiated thyroid cancer is controversial, we performed RFA and esophageal stenting for improving of QOL. This is the first case report in Japan.

Aged↗
PubMed2004

Vascular endothelial cell growth factor attenuates actions of transforming growth factor-beta in human endothelial cells.

Because vascular endothelial cell growth factor (VEGF) and transforming growth factor-beta (TGF-beta) are both involved in cellular growth and differentiation, we examined whether VEGF modifies TGF-beta signaling cascade in human umbilical cord vein endothelial cells (HUVEC). Production of plasminogen activator inhibitor-1 (PAI-1), which is under the specific control of TGF-beta, was strongly enhanced (3.5-fold) by TGF-beta treatment. Remarkably, physiological concentration of VEGF (30 nm) profoundly (by 60%) attenuated the TGF-beta stimulation of PAI-1 production without an effect on the basal PAI-1 production. In HUVECs transiently transfected with an expression construct containing a PAI-1 promoter fused to luciferase reporter gene, TGF-beta-stimulation of transcription of PAI-1 was clearly (by 60%) inhibited by VEGF. TGF-beta phosphorylation of Smad2/3, an obligatory step of intracellular TGF-beta signaling, was also suppressed by VEGF. VEGF attenuation of TGF-beta action was also demonstrated in two other endothelial cell lines. In conclusion, VEGF attenuates TGF-beta action in the human endothelial cell, specifically at the level of transcription of PAI-1 gene and Smad2/3 phosphorylation.

Androstadienes↗
PubMed2004

A kindred with Cockayne syndrome caused by multiple splicing variants of the CSA gene.

Cockayne syndrome (CS) is an autosomal recessive disorder, which is associated with abnormal UV hypersensitivity, growth retardation, and psycho-neural abnormalities. Recently, CSA protein was found to be associated with CS. We obtained mRNAs from immortal lymphoblasts derived from members of the kindred, and sequenced the CSA gene of all family members after reverse transcription (RT) of the coding region. The intact length of the CSA transcript was found in all family members except the proband with CS. Multiple abnormal splicing variant forms were revealed in all cases. No mutation was found in the sequences of the splice donor and acceptor sites of each exon in the CSA gene. UVA irradiation suppressed cell growth in the proband. There was no significant alteration of UVA sensitivity among the normal control and the family members except for the proband. These data suggest that multiple splicing variant forms of CSA mRNA, in the absence of the full-length form of the mRNA, are associated with CS.

Adult↗
PubMed2004

Primacy of beta-cell dysfunction in the development of hyperglycemia: a study in the Japanese general population.

To elucidate the hierarchy in the evolution of glucose intolerance in the general population, the relationship between plasma glucose (PG), beta-cell function (insulinogenic index [II] = DeltaIRI(0-30)/DeltaPG(0-30) on 75 g oral glucose tolerance test [OGTT], where IRI is immunoreactive insulin), insulin sensitivity (Si; determined by quantitative insulin sensitivity check index [QUICKI]), age, and body mass index (BMI) were analyzed in 504 Japanese health examinees (men/women: 347/157). The mean (+/-SD) age was 53 (+/-11) years, BMI 23.6 (+/-3.2) kg/m2, fasting PG (FPG) 5.61 (+/-0.97) mmol/L, 2-hour PG 7.42 (+/-3.1) mmol/L, II 74.2 (+/-169.3) [pmol/L]. [mmol/l](-1), and QUICKI 0.385 (+/-0.057) [log (microU/mL) + log (mg/100 mL)](-1). Higher FPG and 2-hour PG, respectively, were independently correlated with lower II, lower QUICKI, higher age, and higher BMI; the standardized correlation coefficient was largest for the correlation between PG and II. Based on the multiple linear regression, FPG = 8.565 - 1.201. log [II] - 5.374. QUICKI + 0.007. age + 0.030. BMI (r2 = 0.442), and 2-hour PG = 14.239 - 4.206. log [II] - 0.141. QUICKI + 0.034 - age + 0.141. BMI (r2 = 0.493). Thus, elevation of PG correlated most prominently with beta-cell dysfunction and less prominently with decreased Si, higher age, and BMI (especially so in the case of 2-hour PG). In conclusion, the primacy of beta-cell dysfunction in the process of developing glucose intolerance was strongly suggested in the Japanese general population.

Adult↗
PubMed2004

Adenovirus-mediated tumor-specific combined gene therapy using Herpes simplex virus thymidine/ganciclovir system and murine interleukin-12 induces effective antitumor activity against medullary thyroid carcinoma.

The present treatment of advanced and metastatic medullary thyroid carcinoma (MTC) is unsatisfactory. Tissue-specific cancer gene therapy is a novel alternative approach. We developed a recombinant adenovirus expressing Herpes simplex type 1 thymidine kinase (HSVtk) driven by a modified CALC-I promoter TCP (AdTCPtk). Infection with this virus showed efficient cytotoxic effect on MTC cell lines (rMTC and TT cells) after treatment with ganciclovir (GCV) in vitro. In a syngenic WAG/Rij rat model, the combination of AdTCPtk/GCV treatment with administration of murine interleukin-12 (mIL-12) expressing adenovirus under control of TCP (AdTCPmIL-12) resulted in effective growth suppression of tumor at the treated site and also at a distant untreated site, in comparison to treatment with AdTCPtk/GCV or AdTCPmIL-12 alone. Moreover, intravenous injection of AdTCPtk, or AdTCPtk+AdTCPmIL-12, followed by administration of GCV, did not cause evident toxicity after administration of GCV. These results indicate that this combined system can provide an effective therapy for metastatic MTC with minimal toxicity.

Adenoviridae↗
PubMed2004

Clinical and genetic features of patients with multiple endocrine tumors who have neither family history nor MEN1 germline mutations.

Multiple endocrine neoplasia type 1 (MEN1) is an hereditary tumor syndrome that involves specific endocrine organs such as parathyroids, anterior pituitary gland, and endocrine pancreas. The responsible gene for this syndrome, MEN1, has been isolated and that enabled genetic diagnosis for patients with endocrine tumors and early detection of asymptomatic gene carriers in affected families. Nevertheless, there are a considerable number of patients with MEN1 who have neither family history nor germline MEN1 mutations. In this article, clinical features of such patients are described. Among 53 MEN1 patients we have seen during the last 20 yr, five patients who did not have either MEN1 germline mutation or family history were categorized as MEN1 phenocopy. During the same period, we have also experienced three patients who had primary hyperparathyroidism and adrenocortical tumor but had no apparent family history of endocrine tumors. These patients were considered as MEN1 phenocopy variants and included in the study. The mean age of MEN1 phenocopy patients (including variants) at diagnosis was 48 yr, which was not significantly different from that of probands of familial MEN1 (46 yr) who carry heterozygous MEN1 gene mutations. In the majority of MEN1 phenocopy patients, primary hyperparathyroidism was due to a single parathyroid adenoma. In contrast to a previous report, we found that MEN1 phenocopy patients are not necessarily older than probands of familial MEN1. Phenotypic expression of such patients is variable, thus differentiation of familial MEN1 and MEN1 phenocopy cannot be made based on age and clinical phenotype alone.

Adrenal Gland Neoplasms↗
PubMed2004

JunD-menin interaction regulates c-Jun-mediated AP-1 transactivation.

The gene responsible for multiple endocrine neoplasia type 1, MEN1, encodes the 610-amino acid-protein, menin. Although menin has been reported to bind AP-1 transcription factor JunD and suppress its transcriptional activity, little is known about its molecular mechanisms and physiological role. To better understand the function of menin and its significance in tumorigenesis, we investigated the effect of wild-type and mutant menin proteins on AP-1 transactivation. In COS cells, wild-type menin suppressed JunD-mediated transactivation in a dose-dependent manner, while it augmented c-Jun-mediated transactivation also in a dose-dependent manner. These effects were lost or reduced in all menin mutants examined. Electrophoretic mobility shift assay using AP-1 binding elements as a probe revealed that menin does not affect binding of c-Jun to DNA. Coexpression of menin mutants did not affect the function of wild-type menin. Coexpression of JunD amino-terminal fragment abolished menin-mediated enhancement of c-Jun transactivation, suggesting that Menin-JunD interaction may negatively regulate the enhancing effect of menin on c-Jun-mediated transactivation in COS cells.

Animals↗
PubMed2004

Multiple endocrine neoplasia type 1 with unusual concomitance of various neoplastic disorders.

A patient with multiple endocrine neoplasia type 1 (MEN1) who manifested various MEN1-unrelated tumors was reported. The patient was a 43-year-old woman who manifested typical features of MEN1 including primary hyperparathyroidism, prolactinoma, adrenal adenoma and visceral lipomas. During the course, she also manifested chondrosarcoma, B cell lymphoma and mesothelioma. The patient had no apparent family history of MEN1 or any other neoplastic diseases. Genetic analysis of DNA from peripheral mononuclear cells of the patient revealed no germline mutations in MEN1 gene. Genetic instability due to yet unidentified cause is the possible explanation of occurrence of multiple tumors. Careful periodic screening of endocrine and other disorders for her siblings and children as well as for the patient is warranted.

Adenoma↗