Biomedical subjects

J Hoshino

Publications and source records attributed to J Hoshino.

At least 37 records · Page 2Linked to original sources

PubMed1995

Recombinant human erythropoietin stimulates tubular reabsorption of sodium in anesthetized rabbits.

To determine whether recombinant human erythropoietin (rHuEPO) exerts a direct vasoconstrictive effect on renal arteries or affects renal function, we measured renal hemodynamics and renal function during a 30-min intrarenal infusion of rHuEPO in anesthetized rabbits without renal failure. Intrarenal infusion of rHuEPO at a rate of 100 U/min did not alter mean arterial pressure, renal blood flow, or renal vascular resistance, as compared with controls treated with vehicle. There were no significant rHuEPO-associated changes in glomerular filtration rate, filtration fraction, or arterial hematocrit. However, urine volume, urinary excretion of sodium and potassium, and fractional sodium excretion were significantly reduced by intrarenal infusion of rHuEPO. These observations indicate that rHuEPO has no direct effects on mean arterial pressure or renal hemodynamics, but that it stimulates net tubular sodium reabsorption, and reduces urine volume and urinary excretion of sodium and potassium in anesthetized rabbits without renal failure.

Animals↗

PubMed1995

Creatine phosphokinase-linked immunoglobulin associated with hypokalemic myopathy.

We present three women with hypokalemic myopathy in whom serum creatine phosphokinase (CPK) was bound to serum immunoglobulin (macro-CPK). In all three cases, CPK isozyme electrophoresis demonstrated an extra CPK band between CPK-MM and CPK-MB. The bound immunoglobulins were identified as IgA/A-kappa and lambda, IgA-lambda and IgA-kappa and lambda, respectively. In all cases, histological examination of the biopsied muscles revealed necrotic and/or regenerating fibers. In each patient, potassium replacement therapy returned the macro-CPK as well as the marked elevations of serum muscle enzymes to normal. Taken together with other recent reports, our findings suggested that CPK-immunoglobulin binding may be related to the emergence of pathophysiology of hypokalemic myopathy.

Aged↗

PubMed1995

[Remission and relapse of acute eosinophilic pneumonia].

A 46-year-old man presented with progressive dyspnea of acute onset, nonproductive coughing, and a high fever. He had been in his usual good health until symptoms began on the previous day. The chest roentgenogram revealed Kerley A and B lines, perivascular cuffing, hilar haze, and bilateral pleural effusins. Body temperature was 37 degrees C and PaO2 was 42 Torr. All clinical and radiographic signs improved. On the 12th hospital day, dyspnea and diffuse infiltration shadows on the chest roentgenogram suddenly occurred again. Acute eosinophilic pneumonia was strongly suspected because of increasing peripheral eosinophilia, and from the results of histologic examination of a specimen obtained by transbronchial lung biopsy. Without steroid treatment, the patient's condition gradually improved. Most cases of eosinophilic pneumonia have been diagnosed as pulmonary infiltration with eosinophilia (PIE). However, this patient did not have PIE syndrome, but instead was given a diagnosis of acute eosinophilic pneumonia, which was first described in 1990. This case may help establish criteria for the diagnosis and steroid treatment of acute eosinophilic pneumonia.

Acute Disease↗

PubMed1994

3-Aminobenzamide enhances dexamethasone-mediated mouse thymocyte depletion in vivo: implication for a role of poly ADP-ribosylation in the negative selection of immature thymocytes.

3-Aminobenzamide (3-ABAm), an inhibitor of poly ADP-ribosylation, was here found to remarkably enhance the dexamethasone (Dex)-mediated depletion of total mouse thymocytes within 24 h post-injection, when given i.p. in combination with Dex. After treatment the total thymocytes were fractionated by Percoll gradient centrifugation into two mitogen-unresponsive (high- and medium-density) and one mitogen-reactive (low-density) subpopulations and these were analyzed for the phenotypic expression of CD4 and CD8 antigens. Treatment with Dex alone most extensively depleted the high- and medium-density thymocytes and also those expressing both CD4 and CD8 double positive (DP) phenotypes in all three subpopulations. The CD4+ and CD8+ single positive (SP) and CD4-CD8- double negative (DN) subsets, in the low-density subpopulation in particular, were most resistant to the Dex-mediated depletion, thus giving rise to an enrichment of SP (2-fold) and particularly DN subset in the medium- and low-density populations (5-fold) recovered. 3-ABAm, which alone increased the total thymocyte number up to 2-fold, had no effect on the distribution of phenotypic subsets. However, the inhibitor, when given in combination with Dex, additionally depleted all four phenotypic subsets up to one-third of the levels with Dex alone, except for those of medium-density subpopulation. Because the non-inhibitor, 3-aminobenzoate, had no potentiating effect, our present results, together with our previous in vitro studies, indicate a role for the DNA repair cofactor poly ADP-ribose in the intrathymic death by apoptosis and depletion of thymocytes, especially those of DP subset in the high-density, functionally immature population.

Animals↗

PubMed1994

Effect of vasopressin V (OPC-21268) and V2 (OPC-31260) antagonists on renal hemodynamics and excretory function.

Our objective was to assess the effect of endogenous AVP on renal hemodynamics and excretory function. We measured mean arterial pressure (MAP), renal blood flow (RBF), glomerular filtration rate (GFR) and urine osmolality before and after the intravenous infusion of a V1 antagonist (OPC-21268), a V2 antagonist (OPC-31260) and their vehicle (saline) in anesthetized male Wistar rats. The infusion of the V2 antagonist increased the urine flow rate and reduced the urine osmolality significantly (p < 0.05). The infusion of saline and the V1 antagonist did not change the urine flow rate or the urine osmolality. The infusion of saline, the V1 antagonist and the V2 antagonist had no effect on MAP, RBF or GFR. These results suggest that endogenous AVP plays a critical role in the regulation of renal water reabsorption mediated through the V2 receptor.

Animals↗

PubMed1994

Exaggerated vascular response due to endothelial dysfunction and role of the renin-angiotensin system at early stage of renal hypertension in rats.

We investigated whether endothelial dysfunction might contribute to the exaggerated vasoconstriction that was induced by the administration of norepinephrine at the early stage of one-kidney, one-clip renal hypertension (1K1C) in rats. We also studied the role of the renin-angiotension system in this phenomenon. Male Wistar rats were killed 48 hours after the induction of renal artery stenosis or sham operation, and ring preparations of the thoracic aorta were obtained. The isometric contraction and relaxation of aortic strips produced by norepinephrine and acetylcholine, respectively, were recorded with a force-displacement transducer. The aorta of 1K1C rats showed a significantly (P < .05) exaggerated contractile response to norepinephrine as compared with that of control rats. Rubbing the endothelium and treatment with methylene blue or NG-monomethyl L-arginine acetate augmented the contractile responses to norepinephrine to a greater extent in control rats than in 1K1C rats; therefore, the responses of the groups did not differ significantly. In the second experiment, rats received 0.05% captopril, 0.02% enalapril, or 0.02% nicardipine in the drinking water for 1 day before and for 48 hours after the induction of renal artery stenosis or sham operation. The increased contractile responses of the aorta to norepinephrine in 1K1C rats were normalized to the level of the control rats by treatment with either captopril or enalapril but not with nicardipine. These results suggest that the endothelial dysfunction may contribute to the exaggerated norepinephrine-induced vasoconstriction observed in the 1K1C rats and that angiotensin I-converting enzyme inhibitors can restore the endothelial function.

Acetylcholine↗

PubMed1994

Lecithinized superoxide dismutase enhances its pharmacologic potency by increasing its cell membrane affinity.

We performed the present study to clarify whether lecithinized superoxide dismutase (PC-SOD) enhanced its pharmacologic potency by increasing its cell membrane affinity. PC-SOD, in which 4 molecules of a phosphatidylcholine (PC) derivative were covalently bound to each dimer of recombinant human CuZn-SOD (rhCuZn-SOD), was shown to have a high membrane affinity using a laser confocal imaging technique. PC-SOD efficiently scavenged superoxide anion (O2-) produced by phorbol myristate acetate (PMA)-stimulated human neutrophils (IC50 0.60 U/ml), and it exerted a dose-dependent scavenging effect (IC50 1.27 U/ml) even when the neutrophils were washed after incubation with PC-SOD. In contrast, neither unmodified SOD nor polyethylene glycol-bound SOD (PEG-SOD) showed a scavenging effect for washed neutrophils, even at a high concentration (100 U/ml). PC-SOD also showed a strong protective effect against human vascular endothelial cell damage caused by O2- generated by stimulated neutrophils, and PC-SOD was approximately 100-fold more potent than unmodified SOD (in vitro IC50 100 U/ml for PC-SOD and > 10,000 U/ml for unmodified SOD). Moreover, PC-SOD (50,000 U/kg) had an inhibitory effect on ischemia-reperfusion paw edema in mice, whereas neither unmodified SOD nor PEG-SOD had any effect. These results suggest that PC-SOD (designed to target for cell membranes) exerted a far higher pharmacologic activity by increasing cell membrane affinity than unmodified SOD and may be potentially useful for various clinical applications.

Animals↗

PubMed1994

Interleukin 1 beta enhances the response of rabbit synovial fibroblasts in vitro to dexamethasone injury: implication for the role of increased nuclear hypersensitive sites and the number of dexamethasone receptors.

OBJECTIVE: As a model system to understand the efficacy of patients with glucocorticoid (GC) treatment of joint inflammation of rheumatoid arthritis, we stimulated confluent rabbit synovial fibroblasts in culture with interleukin 1 beta (IL-1 beta) and studied the effects of dexamethasone (Dex). METHODS: Twenty-four h after IL stimulation Dex was added and the response of cells to Dex was estimated by [3H]thymidine uptake, cell count and lactate dehydrogenase release. Cellular and nuclear binding of [3H] Dex as well as the DNase sensitivity of isolated nuclei were estimated. RESULTS: Dex strongly inhibited the [3H]thymidine uptake by the stimulated cells in a dose dependent manner with Ki of lower than 10(-12) M, whereas it only slightly inhibited the unstimulated cells. With stimulation the sensitivity of cells increased 10-fold as estimated by lactate dehydrogenase release and 85-fold by counting the final cell density. We found also a 5-fold increase in the DNase I hypersensitive sites in the nuclei and a 2 to 3-fold increase in the cellular as well as the nuclear Dex binding sites following stimulation. CONCLUSION: In addition to the well documented inhibition of degradative enzyme production by the stimulated synovium, the efficacy of GC treatment of patients could be explained also on the basis of the sensitization of stimulated synovium to the GC mediated injury.

Animals↗

PubMed1993

3-aminobenzamide protects the mouse thymocytes in vitro from dexamethasone-mediated apoptotic cell death and cytolysis without changing DNA strand breakage.

Exposure of mouse thymocytes to 1 microM dexamethasone (Dex) resulted in a dramatic increase in the degree of DNA strand breakage up to 80% between 4 to 6 h postincubation. During incubation a marked decrease in the number of total and viable cells as well as an increase in the release of lactate dehydrogenase into medium were detectable, indicating a strong cytotoxicity of Dex on the mouse thymocytes. Agarose gel electrophoresis of DNA from cells exposed to Dex for 6 h clearly demonstrated an increased laddering of DNA fragments multiple of approx. 200 base pairs as a characteristic feature of an apoptosis or programmed cell death. The cytotoxicity of Dex, as judged by the decrease in the viability and increase in the cell lysis, was effectively prevented by 3-aminobenzamide, a potent inhibitor of poly(ADP-ribose) synthesis. Furthermore, the lowering of intracellular NAD levels, which was observable in the present study most probably as a result of activation of poly(ADP-ribose) synthesis due to Dex-mediated DNA strand breakage, was also specifically prevented by the inhibitor, although the DNA strand breakage itself was not affected under these conditions. Our present results indicate that the Dex-mediated thymocyte death and cytolysis and probably intrathymic apoptotic thymocytolysis could be attributable primarily to the loss of intracellular NAD.

Animals↗

PubMed1992

Lecithinization of superoxide dismutase potentiates its protective effect against Forssman antiserum-induced elevation in guinea pig airway resistance.

We synthesized lecithinized superoxide dismutase (PC-SOD), in which a lecithin derivative was covalently bound to recombinant human SOD. We selected PC4-SOD (4 molecules of the lecithin derivative bound to each SOD dimer) and PC10-SOD (10 molecules of the derivative to each SOD dimer) for our study. Both of these PC-SOD retained SOD activity in vitro and showed delayed plasma disappearance in vivo in rats. PC-SOD also had 4 to 20 times higher affinity in vitro for several kinds of cells than that of unmodified SOD. Because Forssman antiserum is known to induce bronchial obstruction in guinea pigs via actions of O2-, we studied the effect of PC-SOD on Forssman antiserum-induced respiratory resistance. Unmodified SOD was ineffective at the doses of 1,000 to 30,000 U/kg, whereas PC-SOD showed a dose-dependent inhibitory effect over the range of 10 to 1,000 U/kg. The ED50 of PC4-SOD and PC10-SOD were 140 and 240 U/kg, respectively, at 30 min after the challenge with Forssman antiserum. These findings suggest that the pharmacological potency of PC-SOD is over 200 times more than that of unmodified SOD, and that PC-SOD may have the potential for various clinical applications.

Airway Resistance↗

PubMed1992

Sensitivity in vitro of mature and immature mouse thymocytes to dexamethasone cytotoxicity and its correlation to poly ADP-ribosylation.

Mouse thymocytes were fractionated into heavy (subtype I, 79% of total cell number), medium (subtype II, 18%) and light (subtype III, 3%) ones by Percoll density centrifugation and they were identified as immature (subtype I and II) and mature (subtype III) thymocytes based on their proliferative response to mitogens. Whereas the nuclear activity of poly (ADP-ribose) polymerase (EC 2.4.2.30) in the subtype III was only one half that of denser subtypes, it increased two-fold upon mitogen stimulation. The sensitivity of three thymocyte subtypes to the dexamethasone cytotoxicity, as judged by the extent of the DNA cleavage, depletion of NAD and cell viability, was highest in the subtype I and lowest in the subtype III. The possible involvement of poly ADP-ribosylation in the apoptotic (programmed) cell death during intrathymic development of immature to mature thymocytes is discussed.

Animals↗

PubMed1990

Suppression of nuclear ADP-ribosyltransferase activity in Ehrlich ascites tumor cells by 5-azacytidine. Modification of DNA as a cause of suppression.

Exposure of Ehrlich ascites tumor cells to 5-azacytidine for 5 h resulted in a partial loss of ability of DNA to stimulate ADP-ribosyltransferase activity, as assessed in a reconstituted in vitro enzyme system consisting of purified calf thymus enzyme, calf thymus whole histone and DNA isolated from the cells. The degree of suppression in vitro varied depending on the amount of histone and DNA added and it reached a maximum with a value of 83% and 62% of control for DNAs from cells exposed to 10 microM and 30 microM 5-azacytidine, respectively, at a histone/DNA mass ratio of 0.4. In the absence of histone (conditions of auto-ADP-ribosylation of the enzyme), no suppression was detectable.

Animals↗

PubMed1990

Influence of ADP-ribosyltransferase inhibitors on the intracellular NAD and ATP levels in Ehrlich ascites tumor cells: implication for the altered NAD + ATP-dependent cellular sensitivity to the cytotoxic agents.

Exposure of Ehrlich ascites tumor cells to 3-aminobenzamide for 60 min resulted in a dose-dependent increase of cellular NAD and ATP levels at a concentration range of 0.3-5 mM. In the cells exposed to 5-methylnicotinamide there was a decrease of both nucleotide levels. As a possible cause for these changes we found a marked inhibition of microsomal NAD glycohydrolase activity by 3-aminobenzamide and a moderate stimulation of this enzyme by 5-methylnicotinamide. Furthermore, 3-aminobenzamide significantly enhanced the cellular uptake of nicotinamide and NAD synthesis, probably by the stimulation of nuclear ATP-NMN adenylyltransferase activity. We show also that the cells containing elevated NAD and ATP levels by the exposure to 3-aminobenzamide became resistant to the 5-azacytidine cytotoxicity.

Adenosine Triphosphate↗

PubMed1987

Suppression of nuclear ADP-ribosyltransferase activity in Ehrlich ascites tumor cells by 5-azacytidine and its analogs.

The exposure of freshly isolated, activity growing Ehrlich ascites tumor cells to the antileukemic agent 5-azacytidine and its analogs, 5-azacytosine (but not 6-azacytosine), 5-aza-2'-deoxycytidine and, in particular, 5-fluorocytidine in the serum-free medium caused a time- and dose-dependent suppression of the nuclear ADP-ribosyltransferase activity. The azacytidine suppression was apparently dependent on the cellular activity of DNA synthesis but not related to the nuclear activity of DNA methylation, indicating the 5-azacytidine incorporation into DNA, but not drug-induced hypomethylation of DNA, being responsible for the 5-azacytidine-suppression of chromatin-bound ADP-ribosyltransferase.

Animals↗

PubMed1987

Suppression of nuclear ADP-ribosyltransferase activity in regenerating rat liver by 5-azacytidine and its relevance to the nuclear methylating activities.

A single administration of 5-azacytidine (5-ACR) to partially hepatectomized rats 24 h following operation resulted in a dose-dependent reduction of nuclear ADP-ribosyltransferase (ADPRT) activity in the liver, when assayed after the nuclei were isolated 22 h after injection. No such a suppression by 5-ACR was observed in the liver of intact rats. Cytidine, a known agent which prevents the incorporation of 5-ACR into DNA, abolished the suppression of ADPRT, when it was given in combination with 5-ACR. The 5-ACR suppressed nuclei from regenerating liver showed no decreased DNA methylating activity, as estimated from the rate of radiolabel transfer from [methyl-3H]SAM to the bulk DNA. The methylation of nuclear RNA and protein was markedly reduced. These results suggest that the incorporation of 5-ACR into nucleic acids inactivates chromatin-bound ADPRT without inhibition of DNA methylation.

Animals↗

PubMed1986

Suppressed mutagenicity of benzo[a]pyrene by the liver S9 fraction and microsomes from eugenol-treated rats.

The mutagenicity of benzo[a]pyrene (B[a]P) in the Ames test using liver S9 fraction prepared from rats pretreated with eugenol (4-allyl-2-methoxyphenol) was suppressed to a lower level than that obtained using liver S9 from untreated rats. There was a reverse correlation between the mutagenicity of B[a]P and the dose of eugenol administered to the animals. Similarly suppressed mutagenicity was observed when liver microsomes, instead of the S9 fraction, were used in the Ames test. The mutagenic activity of B[a]P and arylhydrocarbon hydroxylase (AHH) could not be inhibited by the direct addition of eugenol into the assay mixtures. In eugenol-treated microsomes, cytochrome P-450 content, AHH activity and total B[a]P hydroxylase activity were decreased to 81, 29 and 48% of the control values, respectively. The mutagenicity of B[a]P catalyzed by microsomes from rats fed ad libitum on a diet containing 5% eugenol in the Ames test was significantly decreased. AHH activity and total B[a]P hydroxylase activity were also decreased in these liver microsomes. These results indicate that the activation of B[a]P in rat liver by cytochrome P-450, which metabolizes B[a]P to ultimate mutagens or carcinogens, is reduced by the administration of eugenol.

Administration, Oral↗

PubMed1984

Nicotinamide methylation and its relation to NAD synthesis in rat liver tissue culture. Biochemical basis for the physiological activities of 1-methylnicotinamide.

The mode of [14C]nicotinamide conversion to NAD and 1-methylnicotinamide and the effects of exogenous 1-methylnicotinamide on this metabolic conversion were studied using rat liver slices incubated in a chemically defined culture medium. It was shown that at the physiological nicotinamide concentrations tested (11-500 microM), 1-methylnicotinamide is preferentially produced, rather than NAD. Upon increasing nicotinamide concentration to the levels that cause cytotoxicity (1-10 mM and higher), the rate of NAD synthesis dramatically increased and reached a level 6-fold higher than that of 1-methylnicotinamide. A dose-dependent inhibition (up to 60%) of NAD synthesis was seen by the exogenous addition of 1-methylnicotinamide; the degree of inhibition is affected also by the concentration of nicotinamide present as a precursor. A large depletion of intracellular ATP, associated with a marked accumulation of NAD, occurred in slices in response to the addition of high amounts of nicotinamide. However, the loss of ATP was overcome, when nicotinamide was given together with 1-methylnicotinamide. Finally, 1-methylnicotinamide per se was proven active in regulating cell growth by comparing the cytosolic activity of 1-methylnicotinamide oxidation of cultured RLC cells with that of rat liver. Thus, the previously observed growth stimulation of hepatic cells by 1-methylnicotinamide can reasonably been explained by its ATP-sparing effect due to the inhibition of NAD synthesis, a reaction which requires ATP.

Adenosine Triphosphate↗

PubMed1984

Nicotinamide methylation. Tissue distribution, developmental and neoplastic changes.

The distribution of cytosolic activity of nicotinamide:S-adenosylmethionine methyltransferase (nicotinamide methylase, EC 2.1.1.1) in normal tissues from adult rat and mouse and in tumors and the change in the enzyme activity during the development of rat tissues were studied. (1) Rat liver exhibited the highest nicotinamide methylase activity among all adult tissues tested; other rat tissues, like adrenal, pancreas, kidney, brain and mouse tissues, had only less than 15% of the adult rat liver activity. (2) 3 days before birth, fetal liver showed a very low nicotinamide methylase activity (2% of adult rat liver), which, however, increased already 1 day before birth and reached the adult level on the day 28 after birth. (3) In a variety of hepatomas and ascites tumors, an inverse correlation, with some exceptions, between tumor growth rate and nicotinamide methylase activity could be seen. In all hepatomas, with the exception of Morris hepatoma 5123tc, nicotinamide methylase activity was significantly decreased in comparison to normal adult rat liver. The highly malignant Zajdela hepatoma, Yoshida sarcoma, sarcoma 180 and Ehrlich ascites tumor methylated nicotinamide only at a negligibly low rate. (4) Cultured RLC cells (an established rat liver cell line) from the stationary growth phase or G1-arrested RLC cells had about half of the adult rat liver activity, yet the activity was 70% higher than that of the logarithmically growing RLC cells.

Aging↗