Biomedical subjects

K Higashino

Publications and source records attributed to K Higashino.

At least 73 records · Page 4Linked to original sources

PubMed1997

IL-18 accounts for both TNF-alpha- and Fas ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in mice.

When LPS is administered to heat-killed Propionibacterium acnes-primed BALB/c nude mice, they develop endotoxin-induced liver injury. As previously reported, this liver injury can be prevented by treatment with an Ab against IL-18, a novel cytokine with the ability to induce IFN-gamma production and up-regulate functional Fas ligand (FasL) expression. To identify the pathologic role of IL-18 in this liver injury, we investigated the hepatic cytokine network and FasL induction after LPS challenge. After LPS challenge to BALB/c nude mice, their livers expressed IL-12 mRNA, followed by the induction of IFN-gamma and FasL mRNA and then by the late elevation of TNF-alpha mRNA, but stably expressed IL-18 mRNA. The TNF-alpha induction curve had two peaks. The first peak was the result of the direct reaction to LPS, and the late peak might have been induced, since P. acnes-elicited Kupffer cells showed one-peak TNF-alpha kinetics in response to LPS stimulation in vitro. LPS-activated P. acnes-elicited Kupffer cells secreted both IL-12 and IL-18, as determined by ELISA and bioassay, respectively. The in vivo administration of anti-IL-18 just before an LPS challenge suppressed not only the induction of IFN-gamma and the late TNF-alpha elevation, but also the FasL induction, resulting in the total prevention of liver injury, whereas such an anti-IL-12 treatment did not. Anti-IFN-gamma treatment reduced the late increase in TNF-alpha, but not FasL, resulting in a partial prevention of the liver injury. The administration of anti-TNF-alpha just before elevation of the late TNF-alpha peak also markedly, but incompletely, suppressed the LPS-induced liver injury. These data suggested that IL-18 activates both TNF-alpha- and FasL-mediated hepatocytotoxic pathways in endotoxin-induced liver injury.

Animals↗

PubMed1997

The tumor-derived fetal-intestinal alkaline phosphatase cDNA is identical in sequence to the adult intestinal alkaline phosphatase isozyme gene.

The alkaline phosphatase (AP) of Caco-2 cells, a cell line derived from a human adenocarcinoma of the colon, is quite similar to fetal intestinal AP in its enzymatic properties. The nucleotide sequence of a cDNA encoding AP produced in Caco-2 cells was examined. The sequence was identical to one of the three sequences of adult intestinal AP reported previously. We further investigated the entire nucleotide sequence of cDNA of intestinal-type AP produced in cancer cell lines such as HuH-7 cells, FL-amnion cells, and HuG-1 cells. The sequence of these cell APs was identical to that of Caco-2 cell AP. These results indicate that cancer cells producing intestinal-type AP have the same nucleotide sequence as that of adult intestinal AP, and suggest that the differences in electrophoretic mobilities of these cell APs compared with adult intestinal AP may be due to post-translational modifications.

Adult↗

PubMed1997

Propionibacterium acnes treatment diminishes CD4+ NK1.1+ T cells but induces type I T cells in the liver by induction of IL-12 and IL-18 production from Kupffer cells.

LPS injection into normal mice does not induce liver injury, while the same treatment of Propionibacterium acnes-primed mice induces severe liver injury, indicating that P. acnes treatment renders the mice susceptible to LPS. Since IFN-gamma sensitizes macrophages to LPS, we investigated the mechanism of induction and activation of IFN-gamma-producing (type 1) T cells by P. acnes. Twenty percent of liver lymphocytes of C57BL/6 mice are CD4+ NK1.1+ T cells that promptly produce IL-4 in response to anti-CD3 in vitro. However, P. acnes treatment diminished these lymphocytes. Therefore, liver lymphocytes from P. acnes-primed mice showed reduced IL-4 production. Furthermore, P. acnes treatment induced CD4- type 1 T cells in the liver. Isolated P. acnes-elicited Kupffer cells produced IL-12 and to a lesser degree IL-18 in vitro. Injection of anti-IL-12 Ab totally abrogated these actions of P. acnes, while injection of anti-IL-18 Ab caused only partial abrogation. Thus, administration of P. acnes diminished CD4+ NK1.1+ T cells, but induced type 1 T cells in the liver by induction of IL-12 and IL-18 production. Injection of IL-12 (approximately 1,000 ng) dose dependently diminished CD4+ NK1.1+ T cells, but induced type 1 T cells. In contrast, injection of IL-18 (approximately 1,000 ng) failed, although injection of a much larger dose of IL-18 (10,000 ng) or IL-18 (approximately 1,000 ng) with suboptimal doses of IL-12 (1-100 ng) diminished CD4+ NK1.1+ T cells in a dose-dependent manner. Thus, P. acnes treatment renders the mice highly susceptible to LPS by induction and activation of type 1 T cells.

Animals↗

PubMed1997

Requirement of gamma-carboxyglutamic acid residues for the biological activity of Gas6: contribution of endogenous Gas6 to the proliferation of vascular smooth muscle cells.

Gas6 (encoded by growth-arrest-specific gene 6) is a gamma-carboxyglutamic acid (Gla)-containing protein which is released from growth-arrested vascular smooth muscle cells (VSMCs) and potentiates VSMC proliferation induced by Ca2+-mobilizing growth factors, but not that induced by receptor tyrosine kinases. In this study we examined the importance of Gla residues for the biological activities of Gas6 and tried to assess the importance of endogenous Gas6 in VSMC proliferation. We demonstrated that Gla-deficient Gas6 lacked receptor-binding and growth-potentiating activities. Therefore the vitamin K-dependent modification of Gas6 appeared to be essential for its biological activities. Next we used warfarin, an inhibitor of vitamin K-dependent gamma-carboxylation, to estimate the contribution of endogenous Gas6 to VSMC proliferation. Warfarin markedly inhibited the thrombin-induced proliferation of VSMC without affecting the mRNA or protein expression of Gas6. Therefore the inhibition seems to be due to prevention of the vitamin K-dependent modification of Gas6. However, warfarin did not affect epidermal growth factor-induced proliferation. A neutralizing antibody against Gas6 gave a similar result, i.e. it inhibited thrombin-induced VSMC proliferation but not that induced by epidermal growth factor. These results indicate that endogenously produced Gas6 is very important for VSMC proliferation induced by Ca2+-mobilizing growth factors.

1-Carboxyglutamic Acid↗

PubMed1997

Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme.

The interleukin-1beta (IL-1beta) converting enzyme (ICE) processes the inactive IL-1beta precursor to the proinflammatory cytokine. ICE was also shown to cleave the precursor of interferon-gamma inducing factor (IGIF) at the authentic processing site with high efficiency, thereby activating IGIF and facilitating its export. Lipopolysaccharide-activated ICE-deficient (ICE-/-) Kupffer cells synthesized the IGIF precursor but failed to process it into the active form. Interferon-gamma and IGIF were diminished in the sera of ICE-/- mice exposed to Propionibacterium acnes and lipopolysaccharide. The lack of multiple proinflammatory cytokines in ICE-/- mice may account for their protection from septic shock.

Animals↗

PubMed1997

The tumor-bearing state induces augmented responses of organ-associated lymphocytes to high-dose interleukin-2 therapy in mice.

A high-dose bolus regimen for interleukin(IL)-2 administration to cancer patients frequently causes serious side-effects in which various organs are involved. In order to reveal the mechanism of toxicities associated with this regimen, we compared the augmenting effect of high-dose IL-2 on murine organ-associated lymphocytes between neoplastic and non-neoplastic states. Intraperitoneal administration of IL-2 at a dose of 10(5) JRU (Japanese Reference Units) twice daily for 3 days led to the death of all the syngeneic MH134-hepatoma- or X5563-myeloma-bearing mice, whereas it had no lethal effect on non-tumor-bearing mice. Histological and morphometric analyses demonstrated that tumor-bearing mice displayed more extensive infiltration of large granular lymphocytes and agranular lymphocytes in the liver and lungs than did the non-tumor-bearing mice. Large granular lymphocytes had the ultrastructural characteristics of lymphokine-activated killer cells. Lymphocytes often underwent extravasation into the interstitial space and exhibited local proliferation without causing any direct injury to apposed parenchymal cells. Flow-cytometric analysis of hepatic mononuclear cells demonstrated that IL-2-receptor-beta (IL-2R beta)-bearing lymphocytes, i.e., natural killer cells and intermediate CD3 cells, were increased in number in the neoplastic state before the IL-2 injection. The present study indicates that the tumor-bearing state increases the number of organ-associated IL-2R beta + lymphocytes, which are then greatly amplified by the challenge of high-dose IL-2, leading to the functional disturbance of organs. We have further demonstrated here that an intermittent low-dose IL-2 regimen has a potential therapeutic effect on tumor regression without causing lethal side-effects.

Animals↗

PubMed1997

S-8921, an ileal Na+/bile acid cotransporter inhibitor decreases serum cholesterol in hamsters.

The ileal Na+/bile acid cotransporter (IBAT) maintains the reabsorption of bile acids from the intestine in the enterohepatic circulation of bile acids. In the present study, we showed that S-8921 could dose-dependently inhibit the uptake of [3H] taurocholate in the COS7 cell line which constitutively expresses hamster IBAT. The IC50 value of S-8921 against 60 microM of [3H] taurocholate uptake was 66 +/- 8 microM and kinetic analysis revealed that the inhibition by 100 microM of S-8921 was a mixture of competitive and non-competitive types. In vivo administration of S-8921 by its incorporation into diet (0.001-0.1%) caused dose-dependent decrease of serum cholesterol concentrations accompanied by increased fecal excretion of bile acids in hamsters which were not loaded with cholesterol and bile acid. These data suggest that the inhibition of IBAT could decrease serum cholesterol in the non-cholesterol and -bile acid loaded normal condition.

Absorption↗

PubMed1997

Is the plasma uridine level a marker of the overproduction of uric acid?

To determine whether the plasma level of uridine can be used to identify patients with gout, the plasma concentration of uridine was determined in patients with gout and normal subjects. Plasma uridine was significantly higher in patients with gout than in normal subjects. It was also significantly higher in patients with gout of the overexcretion (of uric acid) type than in those with gout of the underexcretion type. Plasma uridine was used to classify gout patients into underexcretion and overexcretion types, with a diagnostic accuracy of 92.5%. Results indicate that the plasma uridine concentration may be a marker of uric acid production and can be used to separate hyperuricemia into the overexcretion and underexcretion types.

Adult↗

PubMed1997

Effect of allopurinol and benzbromarone on the concentration of uridine in plasma.

To investigate whether allopurinol and benzbromarone affect the concentration of uridine in plasma, allopurinol or benzbromarone were administered to patients with gout for 3 to 6 months. Allopurinol decreased the concentrations of uridine and uric acid in plasma and the urinary excretion of uric acid, but increased the plasma concentration and urinary excretion of oxypurines and orotidine. Benzbromarone decreased the concentration of uric acid in plasma and increased the excretion of uric acid in urine. However, it did not affect the plasma concentration of uridine or oxypurines or the urinary excretion of oxypurines or orotidine. These results suggest that orotidilytic decarboxylase was inhibited by allopurinol and oxypurinol ribonucleotides and/or that phosphoribosyl pyrophosphate (PRPP) was consumed by conversion from hypoxanthine, allopurinol, and oxypurinol to the respective ribonucleotides, resulting in a decrease in the de novo synthesis of pyrimidine leading to the decreased concentration of uridine in plasma. Furthermore, it was suggested that benzbromarone did not affect the de novo synthesis of pyrimidine or purine.

Adult↗

PubMed1997

Effect of ethanol and fructose on plasma uridine and purine bases.

To determine whether both ethanol and fructose increase the plasma concentration of uridine, we administered ethanol (0.6 g/kg) or fructose (1.0 g/kg) to seven normal subjects. Both ethanol and fructose increased the plasma concentration of uridine together with an increase in the plasma concentration of oxypurines, whereas fructose also increased the plasma concentration of uric acid, but ethanol did not. In ethanol ingestion and fructose infusion, an increase in the plasma concentration of purine bases correlated with that of uridine. These results strongly suggest that an increase in the plasma concentration of uridine is ascribable to increased pyrimidine degradation following purine degradation increased by ethanol and fructose.

Adult↗

PubMed1997

Close correlation between visceral fat accumulation and uric acid metabolism in healthy men.

We evaluated the effect of accumulation of intraabdominal visceral fat on the metabolism of uric acid in 50 healthy male subjects to elucidate any relationship between such obesity and hyperuricemia. The area of abdominal fat (visceral fat and subcutaneous fat) was measured at the level of the umbilicus by abdominal computed tomographic scanning. Serum and urinary concentrations of uric acid and creatinine were determined with an autoanalyzer. Uric acid clearance and the ratio of urinary uric acid to creatinine excreted in urine were calculated. Univariate and multivariate analyses were used to evaluate the relationship between uric acid metabolism and body fat. The size of the area of visceral fat was significantly correlated with the serum concentration of uric acid (r = .37, P < .01), uric acid clearance (r = -.34, P < .05), and the urinary uric acid to creatinine ratio (r = .65, P < .0001). The size of the area of subcutaneous fat was significantly correlated only with the urinary uric acid to creatinine ratio (r = .38, P < .01). Multivariate analyses, including body mass index (BMI), showed that the size of the visceral fat area was the strongest contributor to an elevated serum concentration of uric acid, a decrease in uric acid clearance, and an increase in the urinary uric acid to creatinine ratio. These results suggest that accumulation of visceral fat may have a greater adverse effect on the metabolism of uric acid than BMI or accumulation of subcutaneous fat. Clearly, patients with hyperuricemia should lose weight to reduce excessive visceral fat stores, to help avoid attacks of gout.

Abdomen↗

PubMed1997

Effect of muscular exercise on the concentration of uridine and purine bases in plasma--adenosine triphosphate consumption-induced pyrimidine degradation.

To identify whether muscular exercise increases the plasma concentration of uridine and of purine bases, the effect of rigorous muscular exercise was determined in five healthy men with a bicycle ergometer. Twenty-five-minute muscular exercise at 65% maximum O2 consumption increased the concentration of uridine, purine bases, and inorganicphosphate in plasma and of NH3 and lactic acid in blood. These results suggest that exercise-induced excessive adenosine triphosphate (ATP) consumption enhanced not only purine degradation but also pyrimidine degradation (uridine triphosphate [UTP]-->uridine diphosphate [UDP]-->uridine monophosphate [UMP]-->uridine) in exercising muscles.

Adenosine Triphosphate↗

PubMed1997

Urine viscosity after injections of iotrolan or iomeprol.

PURPOSE: Previous observations in rats caused us to speculate whether the injection of iotrolan, a nonionic dimeric contrast medium (CM), would increase urine viscosity enough to obstruct urine outflow in the collecting duct. MATERIAL AND METHODS: The urine viscosity in dogs was measured directly with a viscosimeter after injections of iotrolan or of iomeprol, a nonionic monomeric CM. RESULTS AND CONCLUSION: The injection of iotrolan increased urine viscosity considerably whereas iomeprol had little effect on this variable. The osmolality-dependent adverse reactions of CM have previously been emphasized but viscosity-dependent adverse reactions must also be considered when the CM is a polymer with a low osmolality.

Animals↗

PubMed1997

Permeability of contrast media through hemodialysis membrane.

PURPOSE: To compare the permeability of 10 contrast media (CM) through the hemodialysis membrane. MATERIAL AND METHODS: An experimental model was constructed from clinical hemodialysis equipment. The 10 CM that were used were: diatrizoate, iothalamate, iopamidol, iohexol, iopromide, ioversol, iomeprol, ioxaglate, iodixanol and iotrolan. They were dissolved into the dialysate. Each solution ran into the blood circuit of the dialyzer at a rate of 200 ml/min and into the dialysate circuit of the dialysis machine at a rate of 500 ml/min. Permeability was expressed as clearance, calculated from the iodine concentration at the afferent and efferent lines of the dialyzer, and from the blood-flow rate. RESULTS: The clearance of all the monomeric CM was superior to that of all the dimeric CM. Values of clearance and molecular weight correlated well. CONCLUSION: The molecular weight of a contrast medium is the main factor that influences the efficiency of CM removal by hemodialysis.

Cellulose↗

PubMed1997

Familial hypocholinesterasemia found in a family and a new confirmed mutation.

A 45-year-old man was hospitalized because of acute hepatitis. His serum cholinesterase (ChE) was below 10 IU/l (normal range: 105-240 IU/l) during the disease course and after his recovery. The patient was suspected of having familial hypocholinesterasemia. His family members were healthy except that his father had hypertension and gall stones. Analysis of ChE gene in the propositus and his family revealed three point mutations at nucleotides 298 (CCA to TCA), 1,410 (CGT to CGG) and 1,615 (GCA to ACA). The first mutation caused an amino acid change at codon 100 from proline to serine, which was a new mutation not previously reported, but the second one was a silent mutation. The third mutation resulted in an amino acid alteration from alanine to threonine at codon 539 in exon 4 of the ChE gene. The mode of transmission of these mutations is described.

Adult↗

PubMed1997

Early loss of serum hepatitis C virus RNA can predict a sustained response to interferon therapy in patients with chronic hepatitis C.

OBJECTIVES: We evaluated whether the loss of serum hepatitis C virus (HCV) RNA early in interferon (IFN) therapy would indicate a subsequent response to IFN therapy. METHODS: One hundred fourteen patients with chronic hepatitis C were treated with IFN-alpha for 24 weeks. All patients were positive for anti-HCV antibodies and serum HCV RNA. Serum HCV RNA was measured by highly sensitive and specific RT-PCR (modified Amplicor HCV). RESULTS: Of 114 patients who were treated with IFN-alpha for 24 weeks, 22 of 29 patients (75.9%) who lost HCV RNA at the first week of treatment, 5 of 14 patients (35.7%) who lost HCV RNA at the second week, and 2 of 16 patients (12.5%) who lost HCV RNA at fourth week were judged as sustained responder (SR). The SR rate was significantly higher in patients who lost HCV RNA at the first week of therapy (p < 0.05). On the contrary, none of 55 patients who retained HCV RNA during the first 4 weeks of IFN therapy were judged as SR. Concerning the patients who lost HCV RNA at the first week of therapy, there were no significant differences in the SR rate in either HCV genotype (1b, 2a, and 2b). CONCLUSIONS: Our study confirms that the early response to IFN (loss of HCV RNA at the end of the first week of IFN therapy) can be a predictor of the subsequent sustained response to IFN therapy. Additionally, positivity of HCV RNA at the fourth week of IFN therapy can be a predictor of the subsequent nonsustained response to IFN therapy.

Adolescent↗

PubMed1997

Effect of glucagon on renal excretion of oxypurinol and purine bases.

OBJECTIVE: To investigate whether glucagon increases the urinary excretion of oxypurinol and purine bases. METHODS: We administered 1 mg glucagon intravenously to 5 healthy subjects taking 300 mg allopurinol orally, and determined plasma concentrations and urinary excretion of oxypurinol and purine bases. RESULTS: Glucagon increased the urinary excretion and fractional clearances of uric acid, xanthine, and oxypurinol, together with an increase in creatinine clearance, while it decreased plasma concentrations of xanthine and hypoxanthine. CONCLUSION: Glucagon-induced increases in urinary excretion of uric acid, xanthine, and oxypurinol were attributable to increases in the fractional clearances of uric acid, xanthine, and oxypurinol in addition to an increase in glomerular filtration rate. It is suggested that glucagon affects the renal common transport pathway of uric acid, xanthine, and oxypurinol by stimulating the release of a liver derived renal vasodilator.

Adult↗

PubMed1997

Distribution and pathophysiologic role of molybdenum-containing enzymes.

The importance of molybdenum-containing enzymes in the pathophysiology of a number of clinical disorders necessitates a comprehensive understanding of their histological localization and expression. The objectives of this review are to cover such enzymes so far reported and their enzyme- and immunohistochemical localization in various tissues and species, and to discuss their possible pathophysiological effects. The molybdenum cofactor is essential for the activity of the three molybdenum-containing enzymes, sulfite oxidase, xanthine oxidase and aldehyde oxidase. Sulfite oxidase serves as the terminal enzyme in the pathway of the oxidative degradation of sulfur amino acids, and is also involved in preventing the toxic effects of sulfur dioxide. Biochemical study has revealed a high activity of sulfite oxidase mainly in the liver, heart and kidney with lesser activity observed in other tissues. Subcellular observations have shown that this enzyme is present in the mitochondrial intermembraneous spaces. Xanthine oxidase is the final enzyme in the conversion of hypoxanthine to xanthine, and subsequently, to uric acid. Unlike sulfite and aldehyde oxidases, xanthine oxidase can be converted to xanthine dehydrogenase, and vice versa. Xanthine oxidase has been widely investigated for its role in post-ischemic reperfusion tissue injury. Enzyme- and immunohistochemical studies of its localization in various animal species and tissues have shown its ubiquitous distribution in the liver, small and large intestine, lung and kidney, and other tissues. Aldehyde oxidase shares a similar substrate specificity with xanthine oxidase. Although the tissue localization of this enzyme has not been studied as thoroughly as that of xanthine oxidase, aldehyde oxidase is reportedly found in the digestive gland of terrestrial gastropods, the antennae of certain moths as well as the mammalian liver. Recently, the ubiquitous distribution of aldehyde oxidase has been demonstrated in rat tissues. The aldehyde oxidase activity of herbivores exceeds that of carnivores, suggesting a possible role of this enzyme as a protection against the effects of toxic plants. The relationship between the tissue localization of these enzymes and their pathophysiological roles is reviewed.

Animals↗