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Biomedical subjects

H Kaneto

Publications and source records attributed to H Kaneto.

At least 19 recordsLinked to original sources
PubMed1999

Effects of Tyr-MIF-1 on stress-induced analgesia and the blockade of development of morphine tolerance by stress in mice.

The role of Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) in biological responses to stress exposure was examined in mice. Intraperitoneal or intracerebroventricular administration of Tyr-MIF-1 attenuated not only footshock (FS)- and forced swimming (SW)-stress-induced analgesia (SIA) but also socio-psychological (PSY)-SIA that, when using the communication box, is produced without any direct physical nociceptions. Tyr-MIF-1 also disrupted the suppressive effect of concurrent exposure to FS- and PSY-stress on the development of morphine antinociceptive tolerance. In elevated-plus-maze tests, mice treated with Tyr-MIF-1 tended to spend more time in the open arms compared with the control group, suggesting the anxiolytic properties of the peptide. Thus, the finding that Tyr-MIF-1 modulates these stress responses suggests that the peptide regulates an endogenous biological alert system responding to stress exposure, perhaps, counteracting the excessive response of the system. Furthermore, Tyr-MIF-1, in the case of PSY-stress, through the attenuation of emotional factors such as fear and anxiety, may suppress PSY-SIA and inhibition by PSY-stress of the development of morphine tolerance.

Analgesics, Opioid↗
PubMed1999

Characterization of socio-psychological stress-induced antinociception in the formalin test in mice.

The antinociceptive effect induced by exposure to socio-psychological (PSY) stress using a communication box was assessed by the formalin test in mice, compared with those by exposure to footshock (FS) stress and forced swimming (SW) stress. After the termination of stress exposure, whereas exposure to FS- and SW-stress resulted in the attenuation of the formalin-induced biphasic pain response over 15 min, no appreciable antinociceptive effect was found in the case of PSY stress. When exposure to PSY stress was started during the period of early or late phase of pain after the formalin injection, the antinociceptive effect was maintained for 5-15 min; however, further exposure to PSY stress was not effective for producing antinociception. In the tail-pinch test, likewise, exposure to PSY stress longer than 5 min rather decreased the intensity of antinociception. We conclude that PSY stress in this tonic pain paradigm produces antinociception, but further continuous exposure to the emotional stress caused mice to become recuperative even in such a fear-inducing situation.

Analgesia↗
PubMed1998

Attempts to classify dependence-liable drugs by using a simple drug-discrimination test in mice.

1. In a simple discrimination test using a two-compartment shuttle box with mice, we examined the action properties of dependence-liable drugs. In mice trained to discriminate morphine from saline, neither methamphetamine (MAP) nor cocaine (COCA) was generalized to the discriminative stimulus effects of morphine. 2. Similarly, in mice trained to discriminate MAP from saline, COCA, which is known to have neuronal mechanisms in common with MAP, was generalized to the stimulus effects of MAP, but morphine was not. 3. Dihydroetorphine (DHE), which has receptor mechanisms in common with morphine, was generalized to the discriminative stimulus effects of morphine, whereas it was not generalized to the effects of MAP. Thus, the present discrimination test might be useful for the first screening of compounds with unknown neuronal mechanisms, particularly for classification into groups having separate neuropharmacological mechanisms in common.

Analgesics, Opioid↗
PubMed1998

Ischemia induces a reduction in the content of ulinastatin-like substance in the murine hippocampus.

Effects of ischemia on the content of a ulinastatin (UT)-like substance in the murine cerebral cortex and hippocampus were studied. At 24 h post-ischemia, a significant (p < 0.05) decrease in the content of UT-like substance in the hippocampus but not the cerebral cortex and a concurrent increase in the activity of micro-calpain were observed. In in vitro experiments, a decrease was registered in the content of UT-like substance in the hippocampus in the presence of calcium. This decrease was inhibited by both EDTA and calpastatin treatments. These results implicate the destruction of UT-like substance by micro-calpain in the ischemic hippocampus.

Animals↗
PubMed1998

Antiamnesic action of cromakalim, a potassium channel opener, in mice treated with hypoxia- and cerebral ischemia-type stress stimuli.

1. The amnesia induced by various stress stimuli through hypoxia and cerebral ischemia was evaluated by the shortening of the response latency in a step-through task in mice. 2. The hypoxia-induced amnesia was reduced by cromakalim, a K+ channel opener (KCO), given 10 min before or immediately after the hypoxic treatment. 3. Similarly, the ischemia-induced amnesia was also reduced by cromakalim given 30 min before the occlusion. 4. In ischemic-induced amnesic mice, pyknotic cells, indicating the condensation of chromatin, were observed histochemically at the dentate gyrus granule cells in hippocampal regions 96 hr after ischemic treatment. In addition, cromakalim inhibited the induction of pyknotic cells. 5. These results suggest that KCOs might produce prophylactically neuroprotective effects against hypoxia- and cerebral ischemia-induced amnesia.

Amnesia↗
PubMed1998

Osteopontin expression in the kidney during unilateral ureteral obstruction.

Osteopontin is a bone protein also expressed in other tissues. Increased osteopontin is thought to be associated with tissue inflammation. We used immunocytochemical analyses and polymerase chain reaction amplification of mRNA to examine osteopontin expression and regulation in unilateral ureteral obstruction (UUO) in rats, a model of inflammatory kidney disease. In the obstructed kidney, osteopontin mRNA and protein were significantly increased. The increase reached 4-fold after 1 day of UUO and persisted at this level for the 5-day duration of UUO. Immunocytochemical analyses showed increased osteopontin protein in tubular cells of the obstructed kidney cortex from days 1 through 5 of UUO. No such significant increase was apparent in the glomerulus or interstitium. Increased osteopontin mRNA and protein likewise occurred in the tubular cells of the obstructed kidney of rats that had undergone whole-body irradiation to eliminate macrophage infiltration into the experimental kidney. Purified osteopontin was found to be a chemoattractant for macrophages isolated from the rat peritoneum. Enalapril treatment, which decreases macrophage infiltration of the obstructed kidney, had no effect on the increase in osteopontin mRNA but significantly attenuated the increase in protein in tubular cells. Western blot analysis of whole cortical homogenates revealed that the osteopontin antibody recognized one protein of 67 kD. The amount of this protein was substantially decreased in kidney homogenates obtained from enalapril-treated compared to untreated animals. Increased osteopontin synthesis may, therefore, contribute in part to the inflammatory response that characterizes obstructive nephropathy.

Animals↗
PubMed1997

Expression of heparin-binding epidermal growth factor-like growth factor during pancreas development. A potential role of PDX-1 in transcriptional activation.

The development of the pancreas appears to be regulated by various growth factors. We report here the expression of heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) in the developing pancreas. Immunostaining of fetal and neonatal rat pancreata, in which endocrine cells are visible as cell clusters often associated with primitive ducts or ductular cells, revealed that most of the cluster-forming cells and primitive ducts or ductular cells express HB-EGF protein. In contrast, the exocrine pancreas lacked HB-EGF expression. Based on findings that the expression pattern was similar to that of the homeodomain-containing transcription factor PDX-1 (IDX-1/STF-1/IPF1) and that the regulatory region of the HB-EGF gene contained sequences similar to the PDX-1-binding A element, we examined whether PDX-1 could be a potential activator of HB-EGF gene expression. The results of reporter gene analyses suggested that the HB-EGF gene promoter is PDX-1-responsive and that the activity of the promoter in pancreatic beta cell-derived betaTC1 cells depends on the PDX-1 binding site-like sequences. Gel-mobility shift analyses using an anti-PDX-1 antibody indicated that PDX-1 is a specific and dominant binding factor for an A element-like sequence in the HB-EGF gene. These observations suggest the possible involvement of HB-EGF in pancreas development. While PDX-1 is essential for pancreas development, HB-EGF may function as a mediator of PDX-1 and thus be involved in the development of the endocrine pancreas.

Animals↗
PubMed1997

Suppression of transcription factor PDX-1/IPF1/STF-1/IDX-1 causes no decrease in insulin mRNA in MIN6 cells.

The insulin gene transcription factor PDX-1/IPF1/STF-1/ IDX-1 plays a key role in directing beta cell-specific gene expressions. Recently, impairment of PDX-1 expression or activity has been observed in beta cell-derived HIT cells cultured under high glucose concentrations, and this has been suggested as a possible cause of the decrease in insulin gene transcription. To investigate the pathophysiological significance of PDX-1 as a determinant of the rate of insulin gene transcription, we suppressed its expression in beta cell-derived MIN6 cells using an antisense oligodeoxynucleotide (ODN) and searched for possible changes in the beta cell-specific gene expression. Treatment of MIN6 cells with an 18-mer phosphorothioate ODN complementary to a sequence starting at the translation initiation codon of PDX-1 caused a potent, concentration-dependent reduction in PDX-1 expression; addition of 2 microM antisense ODN could reduce PDX-1 expression to 14+/-4% of the control. There was also a decrease in its DNA binding to the insulin gene A element. Despite such suppression of PDX-1, Northern blot analysis revealed no decrease in the amount of insulin mRNA in the MIN6 cells. Similarly, no changes were detected in the transcription of the glucokinase or islet amyloid polypeptide gene, for which PDX-1 was shown to function as a transcription factor. Thus, our findings dispute the physiological significance of PDX-1 in determining the rate of insulin gene transcription. This means that other components constituting the transcription-controlling machinery need to be evaluated in order to understand the molecular basis of impaired insulin biosynthesis such as that observed due to glucose toxicity.

Binding Sites↗
PubMed1997

Selective induction of heparin-binding epidermal growth factor-like growth factor by methylglyoxal and 3-deoxyglucosone in rat aortic smooth muscle cells. The involvement of reactive oxygen species formation and a possible implication for atherogenesis in diabetes.

Methylglyoxal (MG) and 3-deoxyglucosone (3-DG), reactive dicarbonyl metabolites in the glyoxalase system and glycation reaction, respectively, selectively induced heparin-binding epidermal growth factor (HB-EGF)-like growth factor mRNA in a dose- and time-dependent manner in rat aortic smooth muscle cells (RASMC). A nuclear run-on assay revealed that the dicarbonyl may regulate expression of HB-EGF at the transcription level. The dicarbonyl also increased the secretion of HB-EGF from RASMC. However, platelet-derived growth factor, another known growth factor of smooth muscle cells (SMC), was not induced by both dicarbonyls. The dicarbonyl augmented intracellular peroxides prior to the induction of HB-EGF mRNA as judged by flow cytometric analysis using 2',7'-dichlorofluorescin diacetate. N-Acetyl-L-cysteine and aminoguanidine suppressed both dicarbonyl-increased HB-EGF mRNA and intracellular peroxide levels in RASMC. DL-Buthionine-(S, R)-sulfoximine increased the levels of 3-DG-induced HB-EGF mRNA. Furthermore, hydrogen peroxide alone also induced HB-EGF mRNA in RASMC. These results indicate that MG and 3-DG induce HB-EGF by increasing the intracellular peroxide levels. In addition, the pretreatment with 12-O-tetra-decanoylphorbol-13-acetate failed to alter dicarbonyl-induced HB-EGF mRNA expression in RASMC, suggesting that the signal transducing mechanism is not mediated by protein kinase C. Since HB-EGF is known as a potent mitogen for smooth muscle cells and is abundant in atherosclerotic plaques, the induction of HB-EGF by MG and 3-DG, as well as the concomitant increment of intracellular peroxides, may trigger atherogenesis during diabetes.

Acetylcysteine↗
PubMed1997

Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells.

Prolonged poor glycemic control in non-insulin-dependent diabetes mellitus patients often leads to a decline in insulin secretion from pancreatic beta cells, accompanied by a decrease in the insulin content of the cells. As a step toward elucidating the pathophysiological background of the so-called glucose toxicity to pancreatic beta cells, we induced glycation in HIT-T15 cells using a sugar with strong deoxidizing activity, D-ribose, and examined the effects on insulin gene transcription. The results of reporter gene analyses revealed that the insulin gene promoter is more sensitive to glycation than the control beta-actin gene promoter; approximately 50 and 80% of the insulin gene promoter activity was lost when the cells were kept for 3 d in the presence of 40 and 60 mM D-ribose, respectively. In agreement with this, decrease in the insulin mRNA and insulin content was observed in the glycation-induced cells. Also, gel mobility shift analyses using specific antiserum revealed decrease in the DNA-binding activity of an insulin gene transcription factor, PDX-1/IPF1/STF-1. These effects of D-ribose seemed almost irreversible but could be prevented by addition of 1 mM aminoguanidine or 10 mM N-acetylcysteine, thus suggesting that glycation and reactive oxygen species, generated through the glycation reaction, serve as mediators of the phenomena. These observations suggest that protein glycation in pancreatic beta cells, which occurs in vivo under chronic hyperglycemia, suppresses insulin gene transcription and thus can explain part of the beta cell glucose toxicity.

Acetylcysteine↗
PubMed1997

Learning/memory processes under stress conditions.

Using mice, changes in the learning/memory processes under various stress conditions were investigated in one-trial step-through type passive avoidance learning task. Pre-, post-training and pre-test foot shock (FS)-stress induced long-lasting, at least 96 h, facilitation of test trial latencies. Pre-training psychological (PSY)-stress induces facilitation and pre-test swimming (SW)-stress provokes impairment of test trial latencies. These effects of FS-, PSY- and SW-stress are all dependent on the timing of their exposure and due to their acute effect. Intraperitoneal administration of 1 mg/kg scopolamine 30 min pre-training caused impairment of test latencies in naive and pre-test FS-stressed animals but failed to affect both pre- and post-training FS-induced enhancement. Taken all these data together, it seems that cholinergic mechanism is partly involved in the FS-stress induced facilitation of test latencies, though the research on the changes in ACh levels at the action site in brain after FS-stress exposure is necessary for a definite conclusion.

Animals↗
PubMed1997

TGF-beta1 triggers oxidative modifications and enhances apoptosis in HIT cells through accumulation of reactive oxygen species by suppression of catalase and glutathione peroxidase.

Transforming growth factor-beta1 (TGF-beta1) is a multifunctional polypeptide that is related to the progression of chronic pancreatitis. However, the mechanism of beta-cell damage by TGF-beta1 is unknown. Treatment with TGF-beta1 enhanced internucleosomal DNA cleavage caused by exogenous hydrogen peroxide in a hamster pancreatic beta-cell line (HIT). TGF-beta1 also induced protein oxidation, assessed by measuring carbonyl groups in proteins, and was involved in reactions that lead to lipid peroxidation. This eventually destructs membrane lipids and forms malondialdehyde. We have investigated its effects on two major antioxidative enzymes, catalase and glutathione peroxidase (GPx). TGF-beta1 suppressed mRNA expression as well as reduced the activities of catalase and GPx. The decrease in the catalase and GPx activities in TGF-beta1-treated cells resulted in an increase in intracellular peroxides as judged by flow cytometric analysis using a peroxide-sensitive dye, 2',7'-dichlorofluorescin diacetate. These data suggest that the augmented production of reactive oxygen species by TGF-beta1 through suppression of antioxidative enzymes may cause cellular damage and consequent apoptosis and induce pancreatitis or diabetes.

Adenoma, Islet Cell↗
PubMed1997

Unicalyceal kidney associated with ureteral anomalies.

A unicalyceal kidney is a very rare anomaly of the urinary system. We report 4 cases of unicalyceal kidneys in infants. All cases were associated with ureteral anomalies: megaureter on the involved side, and/or ectopic ureter with vesicoureteral reflux or renal agenesis on the contralateral side. In order to preserve renal function we recommend surgical treatment for patients with unicalyceal kidney when they have ureteral anomalies.

Abnormalities, Multiple↗
PubMed1996

Involvement of the homeodomain-containing transcription factor PDX-1 in islet amyloid polypeptide gene transcription.

The AT-rich cis-motif A elements of the insulin gene promoter contribute to directing the gene's expression to pancreatic beta-cells, bound by a homeodomain-containing transcription factor, PDX-1/IPF1/STF-1/IDX-1. The islet amyloid polypeptide (IAPP; amylin) gene, which is also expressed in limited tissues such as pancreatic beta- and delta-cells, contained similar AT-rich sequences in its regulatory sequences. To understand the molecular basis of IAPP gene regulation, we evaluated the possible physiological significance of the motif in human IAPP gene regulation. All of the three typical A element-like sequences that matched the CT-box consensus (AT-1, -207/-202; AT-2, -154/-142; and AT-3, -88/-83) were shown to bind specifically to a nuclear factor in the beta-cell-derived MIN6 cells, which was subsequently identified immunologically as the insulin gene transcription factor PDX-1. When the promoter activity was examined in MIN6 cells, the disruption of AT-1 or AT-3 but not of AT-2 caused a marked reduction in the IAPP gene promoter. Thus, despite the observation that all the three A element-like regions could bind to PDX-1, the AT-2 site may not be involved in mediating the PDX-1 action in vivo. These observations suggest the involvement of PDX-1 in human IAPP gene regulation, which seems to be mediated through at least two A element-like cis-motifs in the gene promoter.

Amyloid↗
PubMed1996

Reducing sugars trigger oxidative modification and apoptosis in pancreatic beta-cells by provoking oxidative stress through the glycation reaction.

Several reducing sugars brought about apoptosis in isolated rat pancreatic islet cells and in the pancreatic beta-cell-derived cell line HIT. This apoptosis was characterized biochemically by inter-nucleosomal DNA cleavage and morphologically by nuclear shrinkage, chromatin condensation and apoptotic body formation. N-Acetyl-L-cysteine, an antioxidant, and aminoguanidine, an inhibitor of the glycation reaction, inhibited this apoptosis. We also showed directly that proteins in beta-cells were actually glycated by using an antibody which can specifically recognize proteins glycated by fructose, but not by glucose. Furthermore, fluorescence-activated cell sorting analysis using dichlorofluorescein diacetate showed that reducing sugars increased intracellular peroxide levels prior to the induction of apoptosis. Levels of carbonyl, an index of oxidative modification, and of malondialdehyde, a lipid peroxidation product, were also increased. Taken together, these results suggest that reducing sugars trigger oxidative modification and apoptosis in pancreatic beta-cells by provoking oxidative stress mainly through the glycation reaction, which may explain the deterioration of beta-cells under conditions of diabetes.

Acetylcysteine↗
PubMed1996

Glycation and inactivation of sorbitol dehydrogenase in normal and diabetic rats.

Sorbitol dehydrogenase (SDH) is involved in the polyol pathway, which plays an important role in the pathogenesis of diabetic complications. We have measured the tissue distributions of SDH mRNA, both the immunoreactive enzyme levels and the enzyme activity. SDH mRNA was especially abundant in liver, kidney and testis. Both the activity and enzyme content are high in liver and kidney but not in testis. The discrepancy between mRNA and immunoreactive enzyme levels and the activity of SDH observed in testis was also seen in livers of streptozotocin-induced diabetic rats. SDH was found to exist in both glycated and non-glycated forms, with larger amounts of the glycated protein in the diabetic liver. Moreover, after incubation of purified enzyme with glucose or fructose, its activity was markedly decreased. These results indicate that glycation causes a decrease in SDH activity in liver under diabetic conditions. The same post-transcriptional event might occur to decrease the activity of SDH in testis in normal animals.

Animals↗