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Biomedical subjects

K Oka

Publications and source records attributed to K Oka.

At least 37 records · Page 2Linked to original sources
PubMed2001

Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector.

Ideally, somatic gene therapy should result in lifetime reversal of genetic deficiencies. However, to date, phenotypic correction of monogenic hyperlipidemia in mouse models by in vivo gene therapy has been short-lived and associated with substantial toxicity. We have developed a helper-dependent adenoviral vector (HD-Ad) containing the apolipoprotein (apo) E gene. A single i.v. injection of this vector completely and stably corrected the hypercholesterolemia in apoE-deficient mice, an effect that lasted the natural lifespan of the mice. At 2.5 years, control aorta was covered 100% by atherosclerotic lesion, whereas aorta of treated mice was essentially lesion-free. There was negligible toxicity associated with the treatment. We also developed a method for repeated HD-Ad vector administration that could be applied to organisms, e.g., humans, with life spans longer than 2-3 years. These studies indicate that HD-Ad is a promising system for liver-directed gene therapy of metabolic diseases.

Adenoviridae↗
PubMed2001

MRNA and enzyme activity of hepatic 11beta-hydroxysteroid dehydrogenase type 1 are elevated in C57BL/KsJ-db/db mice.

To evaluate the importance of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in insulin resistant diabetic C57BL/KsJ-db/db mice, we measured the activity and mRNA level of 11beta-HSD1 in the liver of db/db mice and their heterozygote litter mates, db/+m mice. The blood glucose, plasma insulin, and corticosterone levels of db/db mice were significantly higher than those of db/+m mice. Despite hyperinsulinemia, the activity level of this enzyme was significantly higher in db/db mice, and the mRNA level of hepatic 11beta-HSD1 was also significantly higher in db/db mice. Since hepatic 11beta-HSD1 in vivo mainly functions as 11-keto-reductase and does not work as 11beta-oxidase, these results suggest that the rate of hepatic conversion of 11-dehydrocorticosterone to corticosterone is increased in db/db mice, resulting in higher glucocorticoid activity in the liver. The increased hepatic corticosterone concentration due to the elevation of 11beta-HSD1 and high plasma corticosterone concentration may antagonize the action of insulin and cause insulin resistance. These findings have a potentially important implication for relationships between increased hepatic 11beta-HSD1 and insulin resistance in db/db mice. The present paper is the first to demonstrate the increased activities and mRNA level of hepatic 11beta-HSD1 in db/db mice.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2001

Therapeutic effect of glycyrrhetinic acid in MRL lpr/lpr mice: implications of alteration of corticosteroid metabolism.

Glycyrrhetinic acid (GA) inhibits 11beta-hydroxysteroid dehydrogenase and increases the levels and thus the action of endogenous glucocorticoid. We considered that GA could be used effectively for treatment of autoimmune diseases that have been treated by synthetic glucocorticoids. In this report, we demonstrated that GA delayed the development of autoimmune disease in spontaneously autoimmune strain MRL lpr/lpr (referred to as lpr) mice. GA was administered via drinking water at approximately 5 mg/kg/day for 170 days. An increase of urine protein levels in the mice treated with GA was delayed as compared to the control mice. After GA treatment began, urinary protein levels in the GA-treated mice were found to be significantly lower than vehicle-treated mice (p<0.05) between days 18 to 50. At 3 weeks of GA treatment serum IgG levels were lowered significantly in comparison with the control mice (p<0.03). In this circumstance, 11beta-HSD activities in liver and kidney were significantly inhibited by GA treatment (p<0.03, p<0.04 respectively). Concentration of corticosterone and dehydrocorticosterone in liver significantly increased after 3 weeks of GA treatment (p<0.02, p<0.01 respectively). In contrast to the local tissue levels of corticosteroids, the serum concentration of dehydrocorticosterone significantly decreased with GA treatment (p<0.02). These data suggest that GA could modify the local and systemic homeostasis of steroid metabolism in lpr mice. We concluded that the continuous treatment of GA is able to retard the development of autoimmune disease by suppressing urinary protein excretion and serum IgG levels in lpr mice. Modulation of local tissue levels as well as serum levels of corticosteroid by GA may thus be implicated in the therapeutic efficacy of GA.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2001

Doubling of the bands in overdoped Bi2Sr2CaCu2O(8+delta): evidence for c-axis bilayer coupling.

We present high resolution angle resolved photoemission data of the bilayer superconductor Bi(2)Sr(2)CaCu(2)O(8+delta) (Bi2212) showing a clear doubling of the near E(F) bands. This splitting approaches zero along the (0,0)-->(pi,pi) nodal line and is not observed in single layer Bi(2)Sr(2)CuO(6+delta) (Bi2201), indicating that the splitting is due to the long sought after bilayer splitting effect. The splitting has a magnitude of approximately 75 meV near the middle of the zone, extrapolating to about 110 meV near the (pi,0) point. The existence of these two bands also helps to clear up the recent controversy concerning the topology of the Fermi surface.

Journal Article↗
PubMed2001

Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer.

Although apoptosis plays an essential role in the embryogenesis and homeostasis of multicellular organisms, this mechanism has not yet been fully clarified. We isolated a novel human apoptosis-inducing gene, ASY, which encodes an endoplasmic reticulum-targeting protein without any known apoptosis-related motifs. This gene is identical to the Nogo-B, a splice variant of the Nogo-A which has recently been shown to be an inhibitor of neuronal regeneration in the central nervous system. Ectopic expression of the ASY gene led to extensive apoptosis, particularly in cancer cells. Furthermore, transcription of the ASY gene was suppressed in small cell lung cancer. These results suggest that a new type of apoptosis-inducing gene, namely, ASY, may be involved in the development of certain types of cancer.

Amino Acid Motifs↗
PubMed2001

Oxidized glucocorticoids counteract glucocorticoid-induced apoptosis in murine thymocytes in vitro.

11Beta-hydroxyglucocorticoids (HGCs) are known to induce apoptosis in immature T cells. Here we show that 11-oxoglucocorticoids (OGCs), which are oxidized metabolites of HGCs, counteract the apoptosis-inducing effects of HGC in murine thymocytes in vitro. Corticosterone at concentrations ranging from 0.1-100 microM induced apoptosis in thymocytes obtained from C57BL/6J mice aged 4 weeks, as demonstrated by cell staining with anti-phosphatidylserine antibody, a decrease in mitochondrial membrane potential, and DNA fragmentation. Co-culture of the cells with 10-100 microM of OGCs, dehydrocorticosterone, cortisone, and prednisone significantly inhibited thymocyte apoptosis induced by 1 microM corticosterone, (p<0.006). Among the other 6 physiological metabolites of the HGCs we tested, 20alpha-dehydrocortisol also showed considerable inhibitory effect on corticosterone-induced thymocyte apoptosis. Corticosterone-treatment of thymocytes in vitro decreased the number of CD4 and CD8 double positive cells, while co-culturing the cells with dehydrocorticosterone significantly attenuated this corticosterone effect (p<0.0001). Numbers of double-negative cells and single-positive cells were not significantly affected by corticosterone, dehydrocorticosterone, or both together. These results raised the possibility that OGCs and probably other HGC metabolites can regulate apoptotic cell death of immature double-positive thymocytes induced by HGC.

Animals↗
PubMed2001

Long-term stable correction of low-density lipoprotein receptor-deficient mice with a helper-dependent adenoviral vector expressing the very low-density lipoprotein receptor.

BACKGROUND: Familial hypercholesterolemia (FH) that results from LDL receptor (LDLR) deficiency affects approximately 1 in 500 persons in the heterozygous state and approximately 1 in 1 million persons in the homozygous state. We tested a novel gene therapy strategy for the treatment of FH in a mouse model. METHODS AND RESULTS: We delivered the VLDL receptor (VLDLR) to the liver of LDLR-deficient mice and compared the effect of a helper-dependent adenoviral vector with all viral coding sequences deleted (HD-Ad-mVLDLR) with a first-generation vector (FG-Ad-mVLDLR), an HD-Ad (HD-Ad-0) that contained no expression cassette, and dialysis buffer (DB). A single intravenous injection of HD-Ad-mVLDLR led to a lowering of plasma cholesterol that lasted >/=6 months. Acute liver toxicity (as measured with liver enzyme elevation) occurred after FG-Ad-mVLDLR but not after HD-Ad-mVLDLR, HD-Ad-0, or DB treatment. At 6 months, VLDLR was detected in the liver with Western blotting and with immunofluorescence staining only in HD-Ad-mVLDLR-treated mice. Aortic atherosclerosis was almost completely prevented in these animals. CONCLUSIONS: HD-Ad-mediated intravenous delivery of VLDLR to hepatocytes is well tolerated. It produces long-term lowering of plasma cholesterol and prevents atherosclerosis development in LDLR-deficient mice. These data provide support for the feasibility and safety of this approach for therapy of human subjects.

Adenoviridae↗
PubMed2001

Visualization of nitric oxide production in the earthworm ventral nerve cord.

Distribution of nitric oxide (NO)-producible neurons in the ventral nerve cord (VNC) of the earthworm was investigated by nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry. Some neurons (20-30 microm in diameter) were intensely stained and were localized in areas between the 1st and 2nd lateral nerves in the ventral side of VNC. In contrast, no neurons including giant fibers were stained in the dorsal side. Endogenous NO production from VNC was visualized using a fluorescent dye, diaminofluorescein-2 diacethyl (DAF-2 DA). When VNC was incubated in a saline, a relative high level of NO was produced from the ventral side, especially from NADPH-d-positive neurons. Under high-K+ stimulation, NO was also detected in the giant fibers in the dorsal side of VNC. Our results suggest that the earthworm VNC constantly and relative highly produces NO as a neuromodulator, and that NO produced from the ventral side sometimes reaches and affects the giant fibers. In conclusion, we successfully visualized NO in the earthworm VNC by clarifying both the distribution of NO-producible neurons and the endogenous NO production.

Animals↗
PubMed2001

Serotonin-induced nitric oxide production in the ventral nerve cord of the earthworm, Eisenia fetida.

Effect of serotonin on nitric oxide (NO) production in the ventral nerve cord (VNC) of the earthworm Eisenia fetida was investigated by a bio-imaging and an electrochemical technique. In the bio-imaging, the spatial pattern of NO production in VNC was visualized using an NO-specific fluorescent dye, diaminofluorescein-2 diacethyl (DAF-2 DA). Application of serotonin (100 microM) increased NO production in VNC by about 65% (P<0.05), compared with basal NO production. The increase was mainly from the nitergic neurons in the ventral side of VNC. In the electrochemical technique, real-time basal and serotonin-induced NO production was estimated with an NO-specific electrode. On the ventral surface of VNC, the estimated basal NO production was stable at 200+/-52 nM, and was transiently augmented to 840+/-193 nM by the addition of 10 microM serotonin. In conclusion, the estimated basal NO production in the earthworm VNC is relatively high compared with other nervous systems earlier reported, and transiently augmented by serotonin. Our results suggest that NO signaling in VNC is involved in neuromodulation by serotonin.

Animals↗
PubMed2001

Cortisone counteracts apoptosis-inducing effect of cortisol in human peripheral-blood mononuclear cells.

Glucocorticoids (GCs) have been considered to regulate immune cell systems through induction of apoptosis in thymocytes and mature peripheral-blood lymphocytes. Here we report that apoptosis induced by cortisol in mitogen-activated peripheral-blood mononuclear cells (PBMC) is suppressed by cortisone, an oxidized metabolite of cortisol. Apoptosis in PBMCs is quantified by a cell death ELISA procedure, which can specifically detect fragmented DNA. Cortisol induced PBMC-apoptosis at concentrations more than 10 ng/ml (28 nM) in concanavalin A-stimulated PBMCs and cortisone suppressed this apoptosis at a concentration range of 1-10,000 ng/ml (2.8-28,000 nM) dose-dependently. Prednisone, a synthetic oxidized-GC, also suppressed the apoptosis-inducing effect of cortisol in a dose-dependent manner. Suppression of cortisol-induced apoptosis by cortisone was consistently observed in PBMCs derived from 16 healthy subjects. Examination for inhibitory activities of the steroids against [3H]dexamethasone binding to PBMCs suggested that cortisone can bind cellular GC-receptors (GC-Rs), but the affinity of cortisone to GCRs is 1/30 or less than that of cortisol. The results raised a possible role of cortisone in cortisol-mediated regulation of apoptosis in activated human PBMCs. The counteracting action of cortisone against cortisol-induced apoptosis may take place partially through intervention of GC-receptors (GC-Rs), but may also be due to unknown pathway(s) different from those mediated by cellular GC-Rs.

Adult↗
PubMed2001

The differences between late graft loss group and long-term graft survival group in renal transplantation.

In renal transplantation, the long-term graft survival rate has not been improved. Until now, the differences between late graft loss and long-term graft survival have still not been estimated thoroughly. We have attempted to define clinical risk factors and parameters for late graft loss by comparing the differences in these two groups. Data from the Osaka University Database were assessed on 156 renal allografts during a 7-yr period. Thirty-six patients comprised the late graft loss group (patients in this group had graft function without need for dialysis for more than 3 yr post-transplantation, afterwards lost the allograft: 'loss group'). One hundred and twenty patients comprised the long-term graft survival group (patients in this group had graft function without need for dialysis until 31 December 1999: 'survival group'). Various immunological and non-immunological parameters were included in an univariate regression analysis. This analysis showed that donor age (P < 0.01), HLA mismatch number (P < 0.01) and a repeat of acute rejection (P < 0.01) were significant factors. Serum creatinine levels at 3 months (P = 0.01), proteinuria at 1 yr (P < 0.01) and antihypertensive treatment at 2 yr (P = 0.03) after transplantation were predictive of the risk of late graft loss. CsA trough concentration at 3-6 months (P < 0.05) and body mass index increase at 1 yr (P = 0.046) were elevated in the loss group. These results from a single centre suggest that immunological as well as non-immunological factors are associated with the pathogenesis of late graft loss.

Adult↗
PubMed2001

A case of tacrolimus nephrotoxicity appearing in a second renal transplantation patient.

We experienced a case of a second renal transplantation patient. With the use of cyclosporin, he lost his first graft because of chronic rejection; with the use of tacrolimus, his second graft suffered from drug nephrotoxicity. On his second renal transplantation, his graft function deteriorated and required haemodialysis with the use of tacrolimus. Repeated biopsies did not reveal the typical characteristics of acute tacrolimus nephrotoxicity and acute rejection. His tacrolimus trough level was not high during the clinical course; however, by reducing tacrolimus dosage, his graft function eventually recovered to mild renal dysfunction. This observation was helpful for clinical diagnosis of the functional toxicity of tacrolimus. The case is interesting in considering the functional toxicity of tacrolimus and the difference between tacrolimus and cyclosporin in terms of immunosuppressive and nephrotoxic actions.

Biopsy↗
PubMed2001

Hypoleptinemia, but not hypoinsulinemia, induces hyperphagia in streptozotocin-induced diabetic rats.

To assess the dominance between hypoinsulinemia and hypoleptinemia as factors in the development of hyperphagia in streptozotocin (STZ)-induced diabetes mellitus (STZ-DM) rodents with respect to hormone-neuropeptide interactions, changes in gene expression of agouti gene-related protein (AGRP) in the arcuate nucleus of the hypothalamus were investigated using STZ-DM rats, fasting Zucker fa/fa rats and STZ-DM agouti (STZ-DM A(y)/a) mice. AGRP mRNA and neuropeptide Y mRNA were both significantly up-regulated in STZ-DM rats, which are associated with body weight loss, hyperglycemia, hypoinsulinemia and hypoleptinemia. We proceeded to analyze whether insulin or leptin played the greater role in the regulation of AGRP using Zucker fa/fa rats. The AGRP mRNA did not differ significantly between fasted fa/fa rats, which have both leptin-insensitivity and hypoinsulinemia, and fed Zuckers, which have leptin-insensitivity and hyperinsulinemia. We further found that up-regulation of AGRP expression was normalized by infusion of leptin into the third cerebroventricle (i3vt), but not by i3vt infusion of insulin, although up-regulation of AGRP was partially corrected by systemic insulin infusion. The latter finding supports hypoleptinemia as a key-modulator of STZ-DM-induced hyperphagia because systemic insulin infusion, at least partially, restored hypoleptinemia through its acceleration of fat deposition, as demonstrated by the partial recovery of lost body weight. After STZ-DM induction, A(y)/a mice whose melanocortin-4 receptor (MC4-R) was blocked by ectopic expression of agouti protein additionally accelerated hyperphagia and up-regulated AGRP mRNA, implying that the mechanism is triggered by a leptin deficit rather than by the main action of the message through MC4-R. Hypoleptinemia, but not hypoinsulinemia per se, thus develops hyperphagia in STZ-DM rodents. These results are very much in line with evidence that hypothalamic neuropeptides are potently regulated by leptin as downstream targets of its actions.

Agouti Signaling Protein↗
PubMed2001

Assessing systemic 11beta-hydroxysteroid dehydrogenase with serum cortisone/cortisol ratios in healthy subjects and patients with diabetes mellitus and chronic renal failure.

11beta-hydroxysteroid dehydrogenase (11beta-HSD), an enzyme regulating mineralocorticoid like action of glucocorticoid, oxidizes active cortisol to inactive cortisone. Impaired activity of this enzyme is associated with apparent mineralocorticoid excess (AME) syndrome and is characterized by hypertension and hypokalemia. Recent investigations suggest the presence of hypertensive subjects with low activity of 11beta-HSD. The blood concentration ratio of cortisone/cortisol reflects the overall conversion of cortisol to cortisone and may be an index to assess the systemic activity of 11beta-HSD. We evaluated the peripheral blood concentration ratio of cortisone/cortisol as a possible marker to identify subjects with hypertension thought to represent impaired 11beta-HSD activity. We compared this ratio in healthy subjects and patients with diabetes mellitus (DM) or chronic renal failure (CRF). Peripheral blood samples were collected from 69 healthy subjects, 44 DM, and 36 CRF patients in the morning (9:00 to 11:00 AM). Twenty-six DM patients (59%) and 32 CRF patients (89%) met the criteria for having hypertension. Serum cortisol and cortisone concentrations were determined by high performance liquid chromatography (HPLC). All values for serum cortisone and cortisol levels were within the normal range. Serum cortisone/cortisol ratio in the healthy subjects was distributed with a range of 0.113 to 0.494 (median, 0.243). Compared with healthy subjects, DM and CRF patients had significantly low (P <.01) serum cortisone/cortisol levels (median, 0.188 [range, 0.092 to 0.313] in DM and 0.088 [range, 0.031 to 0.140] in CRF). Bimodal distribution of cortisone/cortisol, found in DM patients with hypertension, represented high- and low-ratio groups around the border of the ratio 0.2. Kidney function, DM duration, and complications varied between the high- and low-ratio groups. The low ratio group (<0.2), whose 11beta-HSD activity was considered low, had an increase in blood urea nitrogen (BUN) levels and experienced nephropathy, neuropathy, retinopathy, and prolonged DM duration when compared with the group with a ratio greater than 0.2. The data suggest that the serum cortisone/cortisol ratio reflects the change in 11beta-HSD activity and is dependent kidney function. This is a possible marker to evaluate glucocorticoid excess hypertension observed in DM and CRF patients.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2001

Magnolol from Magnolia officinalis inhibits 11beta-hydroxysteroid dehydrogenase without increases of corticosterone and thymocyte apoptosis in mice.

Magnolol is an 11beta-hydroxysteroid dehydrogenase (11beta-HSD) inhibitor contained in Magnolia officinalis which is used in Chinese remedies. We have reported that glycyrrhetinic acid, a strong 11beta-HSD inhibitor isolated from licorice, induces apoptosis of murine thymocytes via accumulation of corticosterone. In this paper, we report that magnolol inhibited 11beta-HSD without increases in the blood concentration of corticosterone and in thymocyte apoptosis in mice. Oxidative activities of the enzyme (from corticosterone to 11-dehydrocorticosterone) in liver, kidney and thymus in vitro were examined 24 h after a single administration of magnolol. Magnolol inhibited the enzyme activity in kidney (P < 0.0001) and thymus (P < 0.002), while the activity in liver was not affected. Blood concentrations of corticosterone in the magnolol-treated mice were unexpectedly lower than those in the control animals (P < 0.002). This means that the inhibition of 11beta-HSD by magnolol did not increase the systemic level of corticosterone which is relevant to thymocyte apoptosis. Accordingly, our flow cytometric analysis of thymocytes after magnolol treatment showed no change in the number of apoptotic cells. We concluded that unlike glycyrrhetinic acid, magnolol selectively inhibited 11beta-HSD in kidney and thymus but not in liver, so that the blood concentrations of corticosterone could not exceed the control level.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2001

[Transcultural study of the altruistic anxiety - comparison between sociophobia and Tai-jin-kyôfu].

We feel guilty to whom we have injured. So the guiltiness has an aspect, namely, "to whom". In the transcultural psychiatry this aspect is often discussed, because it shows directly, which ethical value is supposed to be violated. In comparison with that less attention was paid to another aspect, namely, "through which" we fall into guilt. Therefore this aspect can still give a new viewpoint for problems of the guilt to the transcultural psychiatry. In order to focus this rather neglected aspect, the altruistic anxiety of the German sociophobic patient is compared with that of the Japanese "Tai-jin-kyôfu" patient. In this study we find a transcultural difference in a proportion of two basic ways of the human life, namely, voluntary doing and involuntary becoming.

Adult↗