KATP channel-independent glucose action: an elusive pathway in stimulus-secretion coupling of pancreatic beta-cell.
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Adenosine Triphosphate↗
Biomedical subjects
K Hashizume
Publications and source records attributed to K Hashizume.
An ectopic ACTH-producing carcinoid tumor localized by the measurement of ACTH in the bronchial lavage.
We report a case of an ectopic ACTH-producing carcinoid in the lung. Typical Cushingoid appearance, elevated plasma ACTH and serum cortisol, bilateral enlargement of the adrenal glands, absence of pituitary adenoma and negativity in petrosus sinus venous sampling indicated the ectopic ACTH syndrome. Venous samplings from a lung tumor which was detected by the chest X-ray, did not show any step-up of ACTH. However, ACTH concentration in the bronchoscopic lavage was as high as that in the peripheral blood. Removal of the tumor, which was an ACTH producing carcinoid, resulted in normalization of ACTH and cortisol concentrations. Measurement of ACTH in the bronchoscopic lavage was useful for the diagnosis of ectopic ACTH-producing tumor.
ACTH Syndrome, Ectopic↗
Glutamate is not a major conveyer of ATP-sensitive K+ channel-independent glucose action in pancreatic islet beta cell.
Insulinotropic action of glucose can be categorized as 1) triggering of release, 2) augmentation of exocytosis elicited by Ca2+, and 3) time-dependent potentiation (TDP) of the exocytotic machinery. Glucose-induced closure of ATP-sensitive K+ (K+ATP) channel is required for the first but not for the latter two. We examined the legitimacy of a novel hypothesis that glutamate is a conveyer of the K+ATP channel-independent glucose action, using intact rat pancreatic islets. To this end, we compared glucose and cell permeable glutamate donors such as dimethylglutamate and glutamine for their potency of augmentation and TDP in the presence of diazoxide (250 micromol/l), a K+ATP channel opener. One millimolar leucine was employed as an activator of glutamate dehydrogenase (GDH) as needed. A high concentration (16.7 mmol/l) of glucose applied simultaneously with a depolarizing concentration (50 mmol/l) of K+ augmented (5.80 fold) insulin release elicited by the latter. Pretreatment of the islets with 16.7 mmol/l glucose caused TDP so that insulin release subsequently elicited by 50 mmol/l K+ alone was enhanced (4.70 fold). The augmentation and TDP caused by dimethylglutamate and glutamine (10 mmol/l each), respectively, were very weak (12% of the glucose effect utmost), and dramatically enhanced upon activation of GDH by leucine. Insulinotropic effect of the glutamate donors, but not that of 50 mmol/l K+, was eliminated by 2 mmol/l NaN3, a mitochondrial poison. Glutamate per se serves as a weakly metabolizable mitochondrial fuel, but not a direct conveyer of the K+ATP channel-independent glucose action in the islet beta cell.
Adenosine Triphosphate↗
A case of familial isolated hyperparathyroidism with ectopic parathyroid cancer.
We report the kindred with familial isolated hyperparathyroidism with parathyroid cancer. The proband was diagnosed as having primary hyperparathyroidism at age 43. The same disorder was also found in his daughter who had low bone mass. His son was found to have primary hyperparathyroidism by family screening. The pathological diagnosis of the resected parathyroid in both father and daughter was parathyroid cancer, and that in son was parathyroid adenoma. The right lower gland of the proband and the left lower gland of the son were present in thymus. No mutations were found in the sequences of MEN1 gene, hence gene(s) other than MEN1 gene may have contributed to the malignant potency in our cases.
Adenoma↗
Norepinephrine inhibits glucose-stimulated, Ca2+-independent insulin release independently from its action on adenylyl cyclase.
Inhibition of insulin release by norepinephrine has been attributed to activation of ATP-sensitive K+ channels, inactivation of voltage-dependent Ca2+ channels, and inhibition of adenylyl cyclase. However, direct inhibitory action of norepinephrine at a distal site of stimulus-secretion coupling has also been suggested. To obtain more direct evidence for norepinephrine inhibition of insulin release at a distal site, we performed experiments in intact, non-permeabilized beta cells. In rat pancreatic islets, a combination of glucose, phorbol ester and forskolin under stringent Ca2+-free conditions was used as a trigger of insulin exocytosis at a distal site. Norepinephrine inhibited this Ca2+-independent insulin release in a concentration-dependent manner, with an IC50 of 50 nM. The inhibition was complete, reversible, and pertussis toxin-sensitive, and not associated with any reduction of cAMP content in the islet cells. In conclusion, norepinephrine strongly, yet reversibly, inhibits insulin release in intact beta cells at a late step of exocytosis, through pertussis toxin-sensitive, G protein-mediated mechanism(s).
Adenylate Cyclase Toxin↗
IgA-kappa type multiple myeloma affecting proximal and distal renal tubules.
A 45-year-old male was admitted because of chest pain, lumbago, and bilateral ankle pain. Examination disclosed hypophosphatemic osteomalacia, acquired Fanconi syndrome, and abnormalities in distal nephron such as distal renal tubular acidosis and renal diabetes insipidus. Further exploration revealed IgA kappa multiple myeloma excreting urinary Bence Jones protein (kappa-light chain). Renal biopsy revealed thick basement membranes and elec-tron-dense crystals in proximal tubular epithelial cells. Immunofluorescent studies revealed deposition of kappa-light chain in renal tubular epithelial cells that caused the renal tubular damage. Although the osteomalacia was relieved by medical treatment, the urinary Bence Jones protein and the renal tubular defects were not improved by the chemotherapy for the myeloma. The patient died of exacerbation of multiple myeloma at 50 years of age.
Biopsy↗
Long-term follow-up of asymptomatic patients with major artery occlusion: rate of symptomatic change and evaluation of cerebral hemodynamics.
BACKGROUND AND PURPOSE: The natural history of asymptomatic major cerebral artery occlusive disease is unclear. Rate of symptomatic change, appearance of new lesions on MR images, and cerebral hemodynamics were analyzed for patients with asymptomatic major cerebral artery occlusion. METHODS: This prospective study included asymptomatic patients who had occlusive disease between 1992 and 1995. MR imaging and MR angiography were used to detect internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion in 3965 neurologically asymptomatic patients and for follow-up of affected patients for 67 to 105 months (mean, 79 months). Regional cerebral blood flow and cerebrovascular reserve capacity were examined by xenon-enhanced CT at rest and after the administration of acetazolamide, respectively. RESULTS: Eighteen patients had MCA occlusion and 17 had ICA occlusion. During the follow-up period, five patients became symptomatic (four with MCA occlusion and one with ICA occlusion), with no significant difference (P = .332) in the rate of symptomatic change. Among these five patients, new infarction occurred on the ipsilateral side in three patients, contralateral side in one, and bilateral sides in one. New stenotic or occlusive changes occurred in three patients. The patients were divided into groups: group A, without new lesions on MR images (n = 23), and group B, with new lesions (n = 12). There was no significant difference in regional cerebral blood flow value between groups A and B in the whole hemisphere, anterior cerebral artery territory, or MCA territory. There was a significant difference in cerebrovascular reserve capacity between groups A and B between the affected side (P = .00051 and P = .00068, respectively) and the contralateral side (P = .00101 and P = .00115, respectively) for the whole hemisphere and MCA territory, and the difference was more severe on the affected side in both regions. CONCLUSION: These pilot data suggest that asymptomatic MCA occlusion has a worse prognosis than does ICA occlusion. Silent events are common bilaterally. This may be because of hemodynamic factors or perhaps MCA occlusion is a marker for a more progressive type of atherosclerosis. A prospective study involving assessment of hemodynamics and baseline stroke risk factors in patients with MCA occlusion is indicated.
Aged↗
Automated immunohistochemical staining of formalin-fixed and paraffin-embedded tissues using a catalyzed signal amplification method.
An immunohistochemical assay using catalyzed signal amplification (CSA), which is based on the peroxidase catalyzed deposition of biotinylated tyramide, is a highly sensitive method to visualize weak immunohistochemical signals originating from rare antigens or masked antigens in formalin-fixed, paraffin-embedded (FFPE) tissues. However, CSA methods are hampered by poor reproducibility and the complexity of their staining procedures. In this study, we aimed to apply the CSA procedure to a capillary gap-based, automated immunostainer, TechMate Horizon, to perform immunohistochemical signal amplification effectively and reproducibly. A variety of cellular antigens previously considered to be undetectable in FFPE human specimens were selected and examined with the automated immunostainer. Compared with the manual CSA staining method that takes more than 2 hours, the automated CSA method took less than 2 hours to complete. The staining results from the automated CSA method presented higher reproducibility, as well as lower background owing to well-regulated, punctual staining and washing at every step of the procedure. Conclusively, the automation of the CSA method enabled us to perform the time-consuming and complicated CSA amplification technique with minimal effort in an accurate, consistent, and reproducible manner.
Antigens↗
Expression of heparanase mRNA in bovine placenta during gestation.
This study reports the identification and sequence of a partial cDNA for bovine heparanase and the expression of its mRNA in the placenta during gestation. The 364 amino acid residues deduced from the 1092 bp cDNA fragment share 81.9% and 80.5% identity with amino acid sequences of human and rat heparanase, respectively. Northern blot hybridization showed that two mRNAs (2.0 and 3.5 kb) are strongly expressed in placenta, and weakly expressed in the kidney, lung, spleen and non-pregnant uterus. In the placenta, these transcripts were detected in the cotyledon at all stages of gestation examined, and in the intercotyledonary fetal membrane and caruncle on day 60, day 120 and day 260. Quantitative real-time RT-PCR analysis showed very low expression of heparanase mRNA in the conceptus before implantation (day 17), but high expression in the cotyledon-containing fetal membrane (days 27-34) after implantation. Furthermore, heparanase mRNA was detected in the cotyledon, intercotyledonary fetal membrane and caruncle after days 60-64 of gestation. However, no significant expression of heparanase mRNA was observed in intercaruncular endometrium at all stages of gestation examined. These results demonstrate that heparanase mRNA is expressed in the placentome, indicating that heparanase may play a role in implantation, and in placental development and function.
Amino Acid Sequence↗
Frequent deletions and mutations of the beta-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma.
Hepatoblastoma (HBL) is the most common malignant liver tumor in young children. Recent reports have shown that the beta-catenin gene was frequently mutated or deleted in HBLS: To elucidate the role of beta-catenin abnormalities in HBLs, we searched for mutations of beta-catenin and APC as well as expression of the target genes, cyclin D1, c-myc, and fibronectin, in 68 primary HBLS: The mutation analysis revealed that 44 (65%) tumors carried missense mutations or deletions of beta-catenin, all of which were somatic and targeted to the exon 3 encoding the amino acid residues involved in its degradation. However, no loss of function mutation of the APC gene was detected by the yeast functional assay. Of interest, beta-catenin mutation was significantly correlated with overexpression of the target genes, cyclin D1 and fibronectin, but not with that of c-myc in HBLs as measured by quantitative real-time reverse transcription-PCR. The immunohistochemical studies in 15 HBLs demonstrated that the nuclear/cytoplasmic accumulation of beta-catenin was positive in 13 tumors, 9 of which had the deletion or mutation of the gene. The significant correlation between the beta-catenin gene abnormality and the positive staining of cyclin D1 was also confirmed. Furthermore, the nuclear accumulation of beta-catenin was strongly associated with the poorly differentiated tumor cell components as well as with the positive staining of cyclin D1 within the tumor. Thus, our present results suggested that the gain of function mutation of beta-catenin played a crucial role in the malignant progression of HBL in vivo.
Adenomatous Polyposis Coli Protein↗
Free right internal thoracic artery as a second arterial conduit: modification of proximal anastomosis for improvement of graft patency.
The applicability of the right internal thoracic artery (RITA) for coronary artery bypass grafting is higher when used as a free graft than as a pedicled graft. However, the technical difficulty of directly connecting the proximal end of the free RITA to the much larger aorta leads to poor patency. To overcome this technical limitation, we have used a modification that places the proximal end of this artery onto the hood of an accompanying vein graft at the aortic anastomosis instead of directly onto the aorta. We performed isolated coronary artery bypass grafting on 43 patients using the free RITA as a second arterial graft following pedicled left internal thoracic artery grafting. The mean patient age was 60 years and 38 patients were male. There was no mortality and no incidence of morbidity related to free RITA use. Postoperative coronary angiography performed in all patients revealed that all proximal anastomoses were widely patent, making the patency rate of the free RITA 100%. With these encouraging results, the free RITA graft with the described modification is thought to be a more promising second arterial graft with greater versatility than the pedicled graft. The long-term evaluation of a large patient population will determine the significance of this modification.
Adolescent↗
[Herpes zoster and post-herpetic neuralgia].
Pain associated with herpes zoster arise from the virul neuritis of the suffered trigeminal or spinal dorsal ganglion. Prolonged neuritis makes an irreversible nerve injury and continuous pain impulse develops a central sensitization. A post-herpetic neuralgia is thought to be a neuropathic pain due to the irreversible nerve injury and sensitization. It is important to treat herpetic pain completely before the development of the post-herpetic neuralgia, because there are few effective therapies to cure post-herpetic neuralgia. A sympathetic nerve block increases the nerve blood flow supply, and may improve the nerve injury. It is also known that some sympathetic mechanisms relate to the development of the sensitization. A sensory nerve block reduces pain impulse to the dorsal horn, and may interfere the sensitization. A cortico-steroid administrated with a nerve block can reduce the neuritis, and may improve the nerve injury.
Anticonvulsants↗
Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue.
PURPOSE: Activation of transcription factor nuclear factor-kappaB (NF-kappaB) has been shown to play a role in cell proliferation, apoptosis, cytokine production, and oncogenesis. The purpose of this study was to determine whether NF-kappaB is constitutively activated in human gastric carcinoma tissues and, if so, to determine any correlation between NF-kappaB activity and clinicopathological features of gastric carcinoma. EXPERIMENTAL DESIGN: NF-kappaB activation was determined by immunohistochemical analysis of formalin-fixed, paraffin-embedded specimens from 64 gastric carcinoma patients. We quantified nuclear staining of RelA as a marker of NF-kappaB activation. RESULTS: Nuclear translocation of RelA was significantly high in tumor cells in comparison to that in adjacent normal epithelial cells (22.5 +/- 2.4% versus 8.6 +/- 1.5%, P < 0.0001). There was a significant correlation between NF-kappaB activation (nuclear translocation of RelA) and expression of urokinase-type plasminogen activator, an invasion-related factor and target of NF-kappaB in tumor cells (rho = 0.393; P = 0.0013). NF-kappaB activation was correlated with tumor invasion-related clinicopathological features such as lymphatic invasion of tumor cells (P = 0.0126), depth of invasion (P = 0.0539), peritoneal metastases (P = 0.0538), and tumor size (P = 0.0164). CONCLUSIONS: Collectively, the data show that NF-kappaB is constitutively activated in human gastric carcinoma tissues and suggest that NF-kappaB activity is related to tumor progression due to its transcriptional regulation of invasion-related factors such as urokinase-type plasminogen activator.
Active Transport, Cell Nucleus↗
Silencing mediator for retinoid and thyroid hormone receptors interacts with octamer transcription factor-1 and acts as a transcriptional repressor.
Octamer transcription factor-1 (Oct-1) is a member of the POU (Pit-1, Oct-1, unc-86) family of transcription factors and is involved in the transcriptional regulation of a variety of gene expressions related to cell cycle regulation, development, and hormonal signals. It has been shown that Oct-1 acts not only as a transcriptional activator but also as a transcriptional repressor for certain genes. The mechanism of the repressive function of Oct-1 has not been well understood. Here we demonstrate by using the glutathione S-transferase pull-down assays and coimmunoprecipitation assays that the POU domain of Oct-1 directly interacts with a silencing mediator for retinoid and thyroid hormone receptors (SMRT). The interaction surfaces are located in the C-terminal region of SMRT, which are different from previously described silencing domains I and II or receptor interacting domains I and II. In transient transfection assays in COS1 cells, overexpression of SMRT attenuated the augmentation of Oct-1 transcriptional activity by OBF-1/OCA-B, activator for Oct-1. In pull-down assays, increasing amounts of SMRT could compete the binding of OCA-B to Oct-1 POU domain. The activity of Oct-1 could be determined by a regulated balance between SMRT and OCA-B. Furthermore, cotransfected unliganded thyroid hormone receptor enhanced the transactivation by Oct-1, and addition of 3,3',5-tri-iodo-l-thyronine obliterated the stimulatory effects. Consequently, in the presence of cotransfected thyroid hormone receptor, the octamer response element acts as an element negatively regulated by 3,3',5-tri-iodo-l-thyronine. The results suggest that the transcriptional activity of Oct-1 can be modulated by interaction through its POU domain by a silencing mediator SMRT resulting in the cross-talk between Oct-1 and nuclear receptors.
Animals↗
Solar wind record on the moon: deciphering presolar from planetary nitrogen.
Ion microprobe analyses show that solar wind nitrogen associated with solar wind hydrogen implanted in the first tens of nanometers of lunar regolith grains is depleted in 15N by at least 24% relative to terrestrial atmosphere, whereas a nonsolar component associated with deuterium-rich hydrogen, detected in silicon-bearing coatings at the surface of some ilmenite grains, is enriched in 15N. Systematic enrichment of 15N in terrestrial planets and bulk meteorites relative to the protosolar gas cannot be explained by isotopic fractionation in nebular or planetary environments but requires the contribution of 15N-rich compounds to the total nitrogen in planetary materials. Most of these compounds are possibly of an interstellar origin and never equilibrated with the 15N-depleted protosolar nebula.
Argon↗
Characterization of two DNase gamma-specific monoclonal antibodies and the in situ detection of DNase gamma in the nuclei of apoptotic rat thymocytes.
Two novel monoclonal antibodies (mAbs), hg302 and hg303, raised against a synthetic peptide corresponding to the basic domain of human DNase gamma, are characterized in detail. In Western blot analysis, hg303 recognizes both wild type and C-terminal Myc-His-tagged human DNase gamma, but does not cross-react with human DNase I family members, DNase I, DNase X, or DNAS1L2. On the other hand, dot blot analysis reveals the fine specificity of hg302; it recognizes human, mouse, and rat DNase gamma, but not other DNase I family DNases under non-denaturing conditions. Furthermore, hg302 efficiently immunoprecipitates wild type, but not C-terminal Myc-His-tagged, human DNase gamma from cell lysates. In immunohistochemical analysis, hg302 strongly recognizes DNase gamma in the nuclei of X-ray irradiation-induced apoptotic, but not normal rat thymocytes. The specific detection of DNase gamma in apoptotic nuclei is confirmed by indirect-immunofluorescence analysis using TNF-alpha-induced apoptotic HeLa S3 cells transfected with DNase gamma. These results, together with the observations that DNase gamma is present in normal thymocytes and its activity is unchanged during the apoptosis, suggest that some molecular change(s), which triggers the activation of DNase gamma, occurs in response to apoptotic stimuli in the basic domain, and hg302 specifically recognizes the activated DNase gamma in immunohistochemical analysis.
Amino Acid Sequence↗
[Severe myopathy in patients with thyrotoxicosis] [In Process Citation]
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Journal Article↗
Selective attenuation of metabolic branch of insulin receptor down-signaling by high glucose in a hepatoma cell line, HepG2 cells.
The effects of a high concentration of glucose on the insulin receptor-down signaling were investigated in human hepatoma (HepG2) cells in vitro to delineate the molecular mechanism of insulin resistance under glucose toxicity. Treatment of the cells with high concentrations of glucose (15-33 mm) caused phosphorylation of serine residues of the insulin receptor substrate 1 (IRS-1), leading to reduced electrophoretic mobility of it. The phosphorylation of IRS-1 with high glucose treatment was blocked only by protein kinase C (PKC) inhibitors. The high glucose treatment attenuated insulin-induced association of IRS-1 and phosphatidylinositol 3-kinase and insulin-stimulated phosphorylation of Akt. A metabolic effect of insulin, stimulation of glycogen synthesis, was also inhibited by the treatment. In contrast, insulin-induced association of Shc and Grb2 was not inhibited. Treatment of the cells with high glucose promoted the translocation of PKCepsilon and PKCdelta from the cytosol to the plasma membrane but not that of other PKC isoforms. Finally, PKCepsilon and PKCdelta directly phosphorylated IRS-1 under cell-free conditions. We conclude that a high concentration of glucose causes phosphorylation of IRS-1, leading to selective attenuation of metabolic signaling of insulin. PKCepsilon and PKCdelta are involved in the down-regulation of insulin signaling, and they may lie in a pathway regulating the phosphorylation of IRS-1.
Adaptor Proteins, Signal Transducing↗