Shinzo Kato - Academia.edu (original) (raw)

Papers by Shinzo Kato

Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2008

We examined the effects of various NO inhibitors on the healing of DSS-induced rat colitis. Exper... more We examined the effects of various NO inhibitors on the healing of DSS-induced rat colitis. Experimental colitis was induced by feeding rats for 6 days with 2.5% DSS in drinking water. After DSS treatment, the animals were fed normally and killed various days up to 7 days later. L-NAME (a nonselective NOS inhibitor) or aminoguanidine (a selective iNOS inhibitor) was given p.o. twice daily for 6 days starting from the termination of DSS treatment. The area of lesions, colon length and MPO activity were measured on day 7 after DSS treatment. DSS treatment caused severe lesions in the colon, accompanied by an increase in MPO activity and a decrease in colon length. The lesions healed gradually after discontinuation of DSS treatment, with a histological restoration and subsidence of inflammation. The healing of DSS-induced colonic lesions was significantly impaired by daily administration of L-NAME or aminoguanidine, the effects being all but equivalent between these drugs, and the effe...

Alcohol and Alcoholism, 1993

The formation of acetaldehyde (AcH) adducts was immunohistochemically demonstrated in the livers ... more The formation of acetaldehyde (AcH) adducts was immunohistochemically demonstrated in the livers of experimental animals after chronic ethanol consumption. Recently, we established a hybridoma producing monoclonal antibody against the adduct. Although the polyclonal antibody obtained from a rabbit immunized with adducts had affinities for AcH adducts produced with 20 microM, 1 mM and 10 mM of AcH, the monoclonal antibody could recognize only those produced with 1 and 10 mM of AcH, suggesting that there is a difference of antigenicity between the adducts formed with a high concentration of AcH and those modified with a low concentration of AcH. AcH adducts in the liver of guinea-pigs fed ethanol for 90 days were detected by immunohistochemical staining with the polyclonal and monoclonal antibodies. The staining of liver specimens with polyclonal antibody was observed around both the portal and perivenular areas, whereas the reactions to monoclonal antibody were localized only in the perivenular area. These data suggest that AcH adducts are able to be formed around both portal and perivenular areas in the liver and that the perivenular area might be exposed to a higher concentration of AcH than the portal area after ethanol intake.

Gastroenterology, 1992

Intralobular heterogeneity of oxidative stress and its topographic relationship with cell death d... more Intralobular heterogeneity of oxidative stress and its topographic relationship with cell death during low-flow hypoxia were shown in perfused rat liver by digital microfluorography using dichlorofluorestin diacetate, a fluorochrome sensitive to intracellular hydroperoxide formation, and propidium iodide, which labels the nuclei of nonviable cells. The surface of the liver loaded with two precursors was microscopically visualized, and the fluorescence of dichlorofluorescein, a highly fluorescent molecule generated by hydroperoxide-mediated dichlorofluorescin oxidation, was digitally processed. Dichlorofluorescein fluorescence significantly increased in midzonal regions as early as 20 minutes after starting the 25% low-flow hypoxia. At 40 minutes the fluorograph showed multiple dotted patferns, and the intensity peaked at 60 minutes. The onset of cell death studied by propidium iodide was observed at 40 minutes, and its topographic distribution corresponded to the dichlorofluorescein-enhanced midzonal regions. Allopurinol diminished the early midzonal oxidative stress and retarded the onset of cell death. The current findings show that xanthine oxidase-dependent oxidative stress and the resultant cell death during low-flow hypoxia are spatially restricted in the intermediate zone between the periportal and pericentral regions.

The Journal of Toxicological Sciences, 1991

Oxidative Damage & Repair, 1991

Pharmacology Biochemistry and Behavior, 1983

Hepatology, 2003

Cirrhosis with ascites is frequently resistant to the effects of i.v. administered endogenous nat... more Cirrhosis with ascites is frequently resistant to the effects of i.v. administered endogenous natriuretic peptides (ENPs). Neutral endopeptidase (NEP) inhibitors potentiate the actions of ENPs by minimizing their degradation in the lumen of the proximal renal tubule, avoiding in the meantime the hypotensive effects observed when ENPs are administered intravenously. To test the diuretic and aquaretic properties of NEP inhibitors in ascitic cirrhosis, we administered intravenously single bolus doses of Candoxatrilat (Pfizer Central Research, Sussex, England), a specific NEP-inhibitor, to 10 control rats and 30 cirrhotic rats with ascites, according to the following schedule: two groups of controls were administered 5% glucose solution (vehicle) alone or containing 3 mg/kg b.w. Candoxatrilat; three groups of cirrhotic rats were administered vehicle alone or containing 3 or 10 mg/kg b.w. Candoxatrilat. The effects of i.v. Candoxatrilat on renal plasma flow (RPF, measured as para-aminohippurate clearance), glomerular filtration rate (GFR, measured as inulin clearance), diuresis, urinary sodium, potassium and chloride excretions, free water clearance, ANP and cGMP urinary excretions and ADH plasma concentrations were then evaluated. A further group of cirrhotic rats was studied to determine the single effect of 10 mg/kg b.w. Candoxatrilat on mean arterial pressure by means of tail sphygmomanometry. Compared with the cirrhotic group receiving vehicle, in the 60-rain period following 10 mg/Kg i.v. Candoxatrilat administration the cirrhotic rats showed higher values of urine volume (P<0.03), urinary sodium excretion (P<0.03), fractional sodium excretion (P<0.02), urinary atrial natriuretic peptide (ANP) and cGMP excretions (respectively, P<0.01 and P<0.003) and reduced tubular solute-free water reabsorption (P<0.05). We observed no difference in GFR, RPF, or plasma ADH concentrations between any of the groups of rats. Mean arterial pressure remained unchanged after Candoxatrilat administration. In conclusion, i.v. candoxatrilat has diuretic, natriuretic and aquaretic effects in cirrhotic rats with ascites without affecting arterial pressure or renal perfusion or glomerular filtration.

Hepatology, 1993

The influence of endogenous nitric oxide, which is generated by stimulation with lipopolysacchari... more The influence of endogenous nitric oxide, which is generated by stimulation with lipopolysaccharide, on the mitochondrial energization of rat hepatocytes was investigated in vitro and ex vivo. Using a fluorescence microscope equipped with a silicon intensifier target camera, we visualized fluorescence of rhodamine-123, a mitochondrial energization-sensitive fluorescence probe, in individual hepatocytes and measured the fluorescence intensity with a digital imaging processor. Although addition of Kupffer cells or lipopolysaccharide in a range of 0.1 to 1.0 microgram/ml caused no significant alteration in the fluorescence in hepatocytes, Kupffer cells plus 1.0 microgram/ml lipopolysaccharide reduced fluorescence intensity in the cocultured hepatocytes. The alteration of rhodamine-123 fluorescence in the hepatocytes induced by lipopolysaccharide-activated Kupffer cells was significantly inhibited by the addition of NG-monomethyl-L-arginine, a selective inhibitor of nitric oxide synthesis. The transportal infusion of lipopolysaccharide also decreased rhodamine-123 fluorescence in perfused rat liver. The decrease was significantly enhanced in the pericentral regions. Autofluorescence of NADH was elicited by continuous infusion of lipopolysaccharide; this reaction was also enhanced in the pericentral regions. We showed the main site of uptake of infused lipopolysaccharide in the hepatic lobule to be in the periportal regions with fluorescein isothiocyanate-labeled lipopolysaccharide. Our results indicate that the inhibition of mitochondrial energization occurs mainly in pericentral regions, which are distant from the lipopolysaccharide uptake site. The continuous administration of NG-monomethyl-L-arginine significantly attenuated the lipopolysaccharide-induced decrease in rhodamine-123 fluorescence and increase of the NADH contents of the hepatic lobule.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastroenterology, 2001

chemoradiation (40Gy + 5-fluorouracil); (ii) is there a role for chemotherapy (5-fluorouracil +fo... more chemoradiation (40Gy + 5-fluorouracil); (ii) is there a role for chemotherapy (5-fluorouracil +folinic acid). Methods: 541 patients with pancreatic ductal adenocarcinoma were randomised from 83 clinicians in 11 countries. Presently, 227 patients (42%) are alive with median followup of 10 months (inter-quartile range 1-25). Secondary endpoints include OoL which was assessed by patient questionnaires (EORTC QLO-C30/ESPAC-QLQ32) completed at 3 monthly intervals. Fifteen QoL dimensions measured by the questionnaire were analysed. Results: Preliminary results show no evidence of a survival benefit for chemoradiation treatment (median survival 15.5 months with chemoradiation vs 16.1 months without, p = 0.24). There is some evidence of a benefit for patients having chemotherapy (median survival 19.7 months with chemotherapy vs 14.0 months without, p<0.001). However, this treatment benefit was not seen in the 285 patients randomisad via the original 2x2 factorial design (median survival 17.4 months with chemotherapy vs 15.9 months without, p=0.19). A total of 211 patients have completed 644 questionnaires within 12 months of surgery. The QoL patients were a representative sample of the main study in terms of patient characteristics and survival. Changes in dimension scores within 3 months from surgery were compared between treatments. Initial analysis suggests, that for 2 of the 15 dimensions, change within 3 months differs depending upon treatment: role functioning is improved in patients not having chemotherapy; cognitive functioning is improved in patients not having chemoradiation. The global QoL score was analysed accounting for survival by calculating Qualify Adjusted Life Months (QALM) as the area under the curve per patient, where OoL was assumed to be zero at time of death. No significant differences in OALM were found between chemoradiotherapy and no chemoradiotherapy (p = 0.59) or chemotherapy and no chemotherapy (p = 0.74).

Biochemical Pharmacology, 1988

Acknowledgernenrs-We thank M. Ohara of Kyushu University for critical reading of the manuscript.

Biochemical and Biophysical Research Communications, 1989

The contribution of peroxisomal fatty acid beta-oxidation to ethanol metabolism was examined in d... more The contribution of peroxisomal fatty acid beta-oxidation to ethanol metabolism was examined in deermice hepatocytes. Addition of 1 mM oleate to hepatocytes isolated from fasted alcohol dehydrogenase (ADH)-positive deermice in the presence of 4-methylpyrazole or to hepatocytes from fasted or fed ADH-negative deermice produced only a slight and statistically not significant increase in ethanol oxidation. Lactate (10 mM), which is not a peroxisomal substrate, showed a greater effect on ethanol oxidation. There was also a lack of oleate effect on the oxidation of ethanol by hepatocytes of ADH-positive deermice. Furthermore, in ADH-negative deermice, the catalase inhibitor azide (0.1 mM) did not inhibit the increase in ethanol oxidation by oleate and lactate. The rate of oleate oxidation by hepatocytes from fasted ADH-negative deermice was much lower than that of ethanol. These results indicate that in deermice hepatocytes, peroxisomal fatty acid oxidation does not play major role in ethanol metabolism.

Archives of Biochemistry and Biophysics, 1989

Archives of Biochemistry and Biophysics, 1987

Annals of Internal Medicine, 2003

The Chinese herbal dietary supplements Chaso and Onshido are marketed for weight loss in Japan. T... more The Chinese herbal dietary supplements Chaso and Onshido are marketed for weight loss in Japan. The safety of these weight loss aids is unknown. To describe patients who developed liver injury while taking Chaso or Onshido. Case series. Keio University Hospital, Tokyo, Japan, and other hospitals in Japan. 6 patients who took Chaso and 6 patients who took Onshido before presenting with liver injury. Pathologic, clinical, and laboratory evaluations and chemical analysis of the herbal weight loss aids. All 12 patients developed acute liver injury characterized by a marked increase in serum liver chemistry values (mean alanine aminotransferase level, 1978 U/L [range, 283 to 4074 U/L]) after ingesting these products. Two patients developed fulminant hepatic failure: 1 patient required liver transplantation, and the other patient died. N-nitroso-fenfluramine, a variant of the appetite-depressant drug fenfluramine, was present in these products. The use of the weight loss aids Chaso and Onshido may be associated with acute liver injury. N-nitroso-fenfluramine is a possible hepatotoxic ingredient.

Alcoholism: Clinical & Experimental Research, 2004

The objective of this study was to determine whether Cardiotopic Pills (CP) affects fatty liver i... more The objective of this study was to determine whether Cardiotopic Pills (CP) affects fatty liver in rats fed ethanol chronically. Male Wistar rats were treated with liquid diet that contained ethanol (36% of total calories) or an isocaloric carbohydrate instead of ethanol for 6 weeks. CP, an oral herbal medicine including Danshen (Salviae Miltiorrhiza), Panax notoginseny and Dyroblanops aromatica gaertn, have been clinically used for vascular diseases such as coronary diseases and cerebral infarction. CP was administered orally with the liquid diets for 2 weeks 0.4 mg/kg body weight/day with the liquid diet thereafter. Serum triglyceride and total cholesterol levels, total protein, albumin, and AST and ALT activities are measured. Histological examination was also carried out. In another set of experiments, autofluorescence of NAD(P)H, an indicator of mitochondrial O2 consumption and redox status, was measured by an intravital microscopy, and peroxisome proliferators-activated receptor-(PPAR)-alpha and gamma mRNA levels were evaluated by real time quantitative PCR methods. Chronic ethanol consumption elevated serum triglyceride level, and caused fatty degeneration of liver. After administration of CP, fatty degeneration was not observed in rats fed ethanol chronically. Elevation of serum triglyceride level was not noted after treatment with CP (Ethanol: 79.4 +/- 9.3 mg/dl, Ethanol+CP: 48.0 +/- 4.4, respectively, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). CP did not affect any other laboratory data or NAD(P)H levels. Chronic ethanol consumption did not affect PPAR-gamma mRNA levels, while it decreased PPAR-alpha mRNA levels in the liver. CP prevented the ethanol-induced decrease in PPAR-alpha mRNA levels. CP and its components could enhance expression of PPAR-alpha mRNA levels. These results suggest that CP may be useful to prevent alcoholic fatty liver via enhanced expression of PPAR-alpha.

Alcoholism: Clinical and Experimental Research, 1996

We have previously reported that the Kupffer cell has antitumor activity through mitochondrial da... more We have previously reported that the Kupffer cell has antitumor activity through mitochondrial damage to tumor cells by nitric oxide production. In this study, the effect of chronic ethanol feeding on antihepatoma cell activity of the Kupffer cell was examined in rats. Male rats of the Wistar strain were fed ethanol chronically for 8 weeks by liquid diets. Kupffer cells were isolated from the control rat or the ethanol-fed rat, and cocultured with AH 70 cells, a rat hepatoma cell line. Fluorescence of rhodamine 123 or propidium iodide was observed as indicators of the mitochondrial damage or cell membrane injury, respectively, by a laser scanning confocal microscopy. Mitochondrial damage of AH 70 cells as indicated by reduction of rhodamine 123 fluorescence was smaller by the coculture with Kupffer cell from the ethanol rat than that from the control. Cell membrane barrier dysfunction of AH 70 cell was less frequently observed with the Kupffer cell from ethanol-fed rats. A metabolite of nitric oxide (nitrite and nitrate) was less in the cultured medium with the ethanol Kupffer cell than with the control Kupffer cell. Ca2+ mobilization, which induces inducible nitric oxide synthase and observed by the fluorescence of fluo-3, in Kupffer cells cocultured with AH 70 cells was suppressed in ethanol-fed rats. These result suggests that chronic ethanol feeding suppresses antitumor cell activity of Kupffer cell through the impairment of Ca2+ mobilization and nitric oxide production.

Alcoholism: Clinical and Experimental Research, 1996

Alcoholism: Clinical and Experimental Research, 1996

Kupffer cells contribute to the important role of the liver defense mechanism through nitric oxid... more Kupffer cells contribute to the important role of the liver defense mechanism through nitric oxide (NO) production. In this study, the effect of chronic ethanol administration on the ability of Kupffer cells to synthesize and release NO was investigated after stimulation with lipopolysaccharide (LPS). Male Wistar rats were chronically fed ethanol for 8 weeks according to the method described by DeCarli and Lieber et al. (J Nufr. 91:331-336, 1967). Kupffer cells were isolated and cultured with LPS (1 pg/ml) for 24 hr. The levels of nitrite and nitrate, metabolites of NO, were determined in the culture medium. NO synthase (NOS) activity in Kupffer cells was determined by the method that measures conversion of ['4C]arginine into ['*C]citrulline. In control rats, a significant increase of nitrite and nitrate levels in culture medium was observed after LPS treatment. The magnitude of this increase was significantly smaller in chronic ethanol-fed rats. When the activity of NOS was determined, inducible NOS (iNOS) activity was higher than that of constitutive NOS, and LPS administration produced a significant elevation of iNOS activity in both control and chronic ethanol-fed rats. However, the elevation of iNOS activity by LPS stimulation was diminished by chronic ethanol administration. Distribution of iNOS in Kupffer cells as determined by an immunofluorescence method using a laser scanning confocal image system showed a lower expression of iNOS in chronic ethanol-fed rats even in the presence of LPS. These results demonstrate that the excessive production of NO by increased iNOS activity in Kupffer cells is diminished by chronic ethanol administration.

Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2008

We examined the effects of various NO inhibitors on the healing of DSS-induced rat colitis. Exper... more We examined the effects of various NO inhibitors on the healing of DSS-induced rat colitis. Experimental colitis was induced by feeding rats for 6 days with 2.5% DSS in drinking water. After DSS treatment, the animals were fed normally and killed various days up to 7 days later. L-NAME (a nonselective NOS inhibitor) or aminoguanidine (a selective iNOS inhibitor) was given p.o. twice daily for 6 days starting from the termination of DSS treatment. The area of lesions, colon length and MPO activity were measured on day 7 after DSS treatment. DSS treatment caused severe lesions in the colon, accompanied by an increase in MPO activity and a decrease in colon length. The lesions healed gradually after discontinuation of DSS treatment, with a histological restoration and subsidence of inflammation. The healing of DSS-induced colonic lesions was significantly impaired by daily administration of L-NAME or aminoguanidine, the effects being all but equivalent between these drugs, and the effe...

Alcohol and Alcoholism, 1993

The formation of acetaldehyde (AcH) adducts was immunohistochemically demonstrated in the livers ... more The formation of acetaldehyde (AcH) adducts was immunohistochemically demonstrated in the livers of experimental animals after chronic ethanol consumption. Recently, we established a hybridoma producing monoclonal antibody against the adduct. Although the polyclonal antibody obtained from a rabbit immunized with adducts had affinities for AcH adducts produced with 20 microM, 1 mM and 10 mM of AcH, the monoclonal antibody could recognize only those produced with 1 and 10 mM of AcH, suggesting that there is a difference of antigenicity between the adducts formed with a high concentration of AcH and those modified with a low concentration of AcH. AcH adducts in the liver of guinea-pigs fed ethanol for 90 days were detected by immunohistochemical staining with the polyclonal and monoclonal antibodies. The staining of liver specimens with polyclonal antibody was observed around both the portal and perivenular areas, whereas the reactions to monoclonal antibody were localized only in the perivenular area. These data suggest that AcH adducts are able to be formed around both portal and perivenular areas in the liver and that the perivenular area might be exposed to a higher concentration of AcH than the portal area after ethanol intake.

Gastroenterology, 1992

Intralobular heterogeneity of oxidative stress and its topographic relationship with cell death d... more Intralobular heterogeneity of oxidative stress and its topographic relationship with cell death during low-flow hypoxia were shown in perfused rat liver by digital microfluorography using dichlorofluorestin diacetate, a fluorochrome sensitive to intracellular hydroperoxide formation, and propidium iodide, which labels the nuclei of nonviable cells. The surface of the liver loaded with two precursors was microscopically visualized, and the fluorescence of dichlorofluorescein, a highly fluorescent molecule generated by hydroperoxide-mediated dichlorofluorescin oxidation, was digitally processed. Dichlorofluorescein fluorescence significantly increased in midzonal regions as early as 20 minutes after starting the 25% low-flow hypoxia. At 40 minutes the fluorograph showed multiple dotted patferns, and the intensity peaked at 60 minutes. The onset of cell death studied by propidium iodide was observed at 40 minutes, and its topographic distribution corresponded to the dichlorofluorescein-enhanced midzonal regions. Allopurinol diminished the early midzonal oxidative stress and retarded the onset of cell death. The current findings show that xanthine oxidase-dependent oxidative stress and the resultant cell death during low-flow hypoxia are spatially restricted in the intermediate zone between the periportal and pericentral regions.

The Journal of Toxicological Sciences, 1991

Oxidative Damage & Repair, 1991

Pharmacology Biochemistry and Behavior, 1983

Hepatology, 2003

Cirrhosis with ascites is frequently resistant to the effects of i.v. administered endogenous nat... more Cirrhosis with ascites is frequently resistant to the effects of i.v. administered endogenous natriuretic peptides (ENPs). Neutral endopeptidase (NEP) inhibitors potentiate the actions of ENPs by minimizing their degradation in the lumen of the proximal renal tubule, avoiding in the meantime the hypotensive effects observed when ENPs are administered intravenously. To test the diuretic and aquaretic properties of NEP inhibitors in ascitic cirrhosis, we administered intravenously single bolus doses of Candoxatrilat (Pfizer Central Research, Sussex, England), a specific NEP-inhibitor, to 10 control rats and 30 cirrhotic rats with ascites, according to the following schedule: two groups of controls were administered 5% glucose solution (vehicle) alone or containing 3 mg/kg b.w. Candoxatrilat; three groups of cirrhotic rats were administered vehicle alone or containing 3 or 10 mg/kg b.w. Candoxatrilat. The effects of i.v. Candoxatrilat on renal plasma flow (RPF, measured as para-aminohippurate clearance), glomerular filtration rate (GFR, measured as inulin clearance), diuresis, urinary sodium, potassium and chloride excretions, free water clearance, ANP and cGMP urinary excretions and ADH plasma concentrations were then evaluated. A further group of cirrhotic rats was studied to determine the single effect of 10 mg/kg b.w. Candoxatrilat on mean arterial pressure by means of tail sphygmomanometry. Compared with the cirrhotic group receiving vehicle, in the 60-rain period following 10 mg/Kg i.v. Candoxatrilat administration the cirrhotic rats showed higher values of urine volume (P<0.03), urinary sodium excretion (P<0.03), fractional sodium excretion (P<0.02), urinary atrial natriuretic peptide (ANP) and cGMP excretions (respectively, P<0.01 and P<0.003) and reduced tubular solute-free water reabsorption (P<0.05). We observed no difference in GFR, RPF, or plasma ADH concentrations between any of the groups of rats. Mean arterial pressure remained unchanged after Candoxatrilat administration. In conclusion, i.v. candoxatrilat has diuretic, natriuretic and aquaretic effects in cirrhotic rats with ascites without affecting arterial pressure or renal perfusion or glomerular filtration.

Hepatology, 1993

The influence of endogenous nitric oxide, which is generated by stimulation with lipopolysacchari... more The influence of endogenous nitric oxide, which is generated by stimulation with lipopolysaccharide, on the mitochondrial energization of rat hepatocytes was investigated in vitro and ex vivo. Using a fluorescence microscope equipped with a silicon intensifier target camera, we visualized fluorescence of rhodamine-123, a mitochondrial energization-sensitive fluorescence probe, in individual hepatocytes and measured the fluorescence intensity with a digital imaging processor. Although addition of Kupffer cells or lipopolysaccharide in a range of 0.1 to 1.0 microgram/ml caused no significant alteration in the fluorescence in hepatocytes, Kupffer cells plus 1.0 microgram/ml lipopolysaccharide reduced fluorescence intensity in the cocultured hepatocytes. The alteration of rhodamine-123 fluorescence in the hepatocytes induced by lipopolysaccharide-activated Kupffer cells was significantly inhibited by the addition of NG-monomethyl-L-arginine, a selective inhibitor of nitric oxide synthesis. The transportal infusion of lipopolysaccharide also decreased rhodamine-123 fluorescence in perfused rat liver. The decrease was significantly enhanced in the pericentral regions. Autofluorescence of NADH was elicited by continuous infusion of lipopolysaccharide; this reaction was also enhanced in the pericentral regions. We showed the main site of uptake of infused lipopolysaccharide in the hepatic lobule to be in the periportal regions with fluorescein isothiocyanate-labeled lipopolysaccharide. Our results indicate that the inhibition of mitochondrial energization occurs mainly in pericentral regions, which are distant from the lipopolysaccharide uptake site. The continuous administration of NG-monomethyl-L-arginine significantly attenuated the lipopolysaccharide-induced decrease in rhodamine-123 fluorescence and increase of the NADH contents of the hepatic lobule.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastroenterology, 2001

chemoradiation (40Gy + 5-fluorouracil); (ii) is there a role for chemotherapy (5-fluorouracil +fo... more chemoradiation (40Gy + 5-fluorouracil); (ii) is there a role for chemotherapy (5-fluorouracil +folinic acid). Methods: 541 patients with pancreatic ductal adenocarcinoma were randomised from 83 clinicians in 11 countries. Presently, 227 patients (42%) are alive with median followup of 10 months (inter-quartile range 1-25). Secondary endpoints include OoL which was assessed by patient questionnaires (EORTC QLO-C30/ESPAC-QLQ32) completed at 3 monthly intervals. Fifteen QoL dimensions measured by the questionnaire were analysed. Results: Preliminary results show no evidence of a survival benefit for chemoradiation treatment (median survival 15.5 months with chemoradiation vs 16.1 months without, p = 0.24). There is some evidence of a benefit for patients having chemotherapy (median survival 19.7 months with chemotherapy vs 14.0 months without, p<0.001). However, this treatment benefit was not seen in the 285 patients randomisad via the original 2x2 factorial design (median survival 17.4 months with chemotherapy vs 15.9 months without, p=0.19). A total of 211 patients have completed 644 questionnaires within 12 months of surgery. The QoL patients were a representative sample of the main study in terms of patient characteristics and survival. Changes in dimension scores within 3 months from surgery were compared between treatments. Initial analysis suggests, that for 2 of the 15 dimensions, change within 3 months differs depending upon treatment: role functioning is improved in patients not having chemotherapy; cognitive functioning is improved in patients not having chemoradiation. The global QoL score was analysed accounting for survival by calculating Qualify Adjusted Life Months (QALM) as the area under the curve per patient, where OoL was assumed to be zero at time of death. No significant differences in OALM were found between chemoradiotherapy and no chemoradiotherapy (p = 0.59) or chemotherapy and no chemotherapy (p = 0.74).

Biochemical Pharmacology, 1988

Acknowledgernenrs-We thank M. Ohara of Kyushu University for critical reading of the manuscript.

Biochemical and Biophysical Research Communications, 1989

The contribution of peroxisomal fatty acid beta-oxidation to ethanol metabolism was examined in d... more The contribution of peroxisomal fatty acid beta-oxidation to ethanol metabolism was examined in deermice hepatocytes. Addition of 1 mM oleate to hepatocytes isolated from fasted alcohol dehydrogenase (ADH)-positive deermice in the presence of 4-methylpyrazole or to hepatocytes from fasted or fed ADH-negative deermice produced only a slight and statistically not significant increase in ethanol oxidation. Lactate (10 mM), which is not a peroxisomal substrate, showed a greater effect on ethanol oxidation. There was also a lack of oleate effect on the oxidation of ethanol by hepatocytes of ADH-positive deermice. Furthermore, in ADH-negative deermice, the catalase inhibitor azide (0.1 mM) did not inhibit the increase in ethanol oxidation by oleate and lactate. The rate of oleate oxidation by hepatocytes from fasted ADH-negative deermice was much lower than that of ethanol. These results indicate that in deermice hepatocytes, peroxisomal fatty acid oxidation does not play major role in ethanol metabolism.

Archives of Biochemistry and Biophysics, 1989

Archives of Biochemistry and Biophysics, 1987

Annals of Internal Medicine, 2003

The Chinese herbal dietary supplements Chaso and Onshido are marketed for weight loss in Japan. T... more The Chinese herbal dietary supplements Chaso and Onshido are marketed for weight loss in Japan. The safety of these weight loss aids is unknown. To describe patients who developed liver injury while taking Chaso or Onshido. Case series. Keio University Hospital, Tokyo, Japan, and other hospitals in Japan. 6 patients who took Chaso and 6 patients who took Onshido before presenting with liver injury. Pathologic, clinical, and laboratory evaluations and chemical analysis of the herbal weight loss aids. All 12 patients developed acute liver injury characterized by a marked increase in serum liver chemistry values (mean alanine aminotransferase level, 1978 U/L [range, 283 to 4074 U/L]) after ingesting these products. Two patients developed fulminant hepatic failure: 1 patient required liver transplantation, and the other patient died. N-nitroso-fenfluramine, a variant of the appetite-depressant drug fenfluramine, was present in these products. The use of the weight loss aids Chaso and Onshido may be associated with acute liver injury. N-nitroso-fenfluramine is a possible hepatotoxic ingredient.

Alcoholism: Clinical & Experimental Research, 2004

The objective of this study was to determine whether Cardiotopic Pills (CP) affects fatty liver i... more The objective of this study was to determine whether Cardiotopic Pills (CP) affects fatty liver in rats fed ethanol chronically. Male Wistar rats were treated with liquid diet that contained ethanol (36% of total calories) or an isocaloric carbohydrate instead of ethanol for 6 weeks. CP, an oral herbal medicine including Danshen (Salviae Miltiorrhiza), Panax notoginseny and Dyroblanops aromatica gaertn, have been clinically used for vascular diseases such as coronary diseases and cerebral infarction. CP was administered orally with the liquid diets for 2 weeks 0.4 mg/kg body weight/day with the liquid diet thereafter. Serum triglyceride and total cholesterol levels, total protein, albumin, and AST and ALT activities are measured. Histological examination was also carried out. In another set of experiments, autofluorescence of NAD(P)H, an indicator of mitochondrial O2 consumption and redox status, was measured by an intravital microscopy, and peroxisome proliferators-activated receptor-(PPAR)-alpha and gamma mRNA levels were evaluated by real time quantitative PCR methods. Chronic ethanol consumption elevated serum triglyceride level, and caused fatty degeneration of liver. After administration of CP, fatty degeneration was not observed in rats fed ethanol chronically. Elevation of serum triglyceride level was not noted after treatment with CP (Ethanol: 79.4 +/- 9.3 mg/dl, Ethanol+CP: 48.0 +/- 4.4, respectively, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). CP did not affect any other laboratory data or NAD(P)H levels. Chronic ethanol consumption did not affect PPAR-gamma mRNA levels, while it decreased PPAR-alpha mRNA levels in the liver. CP prevented the ethanol-induced decrease in PPAR-alpha mRNA levels. CP and its components could enhance expression of PPAR-alpha mRNA levels. These results suggest that CP may be useful to prevent alcoholic fatty liver via enhanced expression of PPAR-alpha.

Alcoholism: Clinical and Experimental Research, 1996

We have previously reported that the Kupffer cell has antitumor activity through mitochondrial da... more We have previously reported that the Kupffer cell has antitumor activity through mitochondrial damage to tumor cells by nitric oxide production. In this study, the effect of chronic ethanol feeding on antihepatoma cell activity of the Kupffer cell was examined in rats. Male rats of the Wistar strain were fed ethanol chronically for 8 weeks by liquid diets. Kupffer cells were isolated from the control rat or the ethanol-fed rat, and cocultured with AH 70 cells, a rat hepatoma cell line. Fluorescence of rhodamine 123 or propidium iodide was observed as indicators of the mitochondrial damage or cell membrane injury, respectively, by a laser scanning confocal microscopy. Mitochondrial damage of AH 70 cells as indicated by reduction of rhodamine 123 fluorescence was smaller by the coculture with Kupffer cell from the ethanol rat than that from the control. Cell membrane barrier dysfunction of AH 70 cell was less frequently observed with the Kupffer cell from ethanol-fed rats. A metabolite of nitric oxide (nitrite and nitrate) was less in the cultured medium with the ethanol Kupffer cell than with the control Kupffer cell. Ca2+ mobilization, which induces inducible nitric oxide synthase and observed by the fluorescence of fluo-3, in Kupffer cells cocultured with AH 70 cells was suppressed in ethanol-fed rats. These result suggests that chronic ethanol feeding suppresses antitumor cell activity of Kupffer cell through the impairment of Ca2+ mobilization and nitric oxide production.

Alcoholism: Clinical and Experimental Research, 1996

Alcoholism: Clinical and Experimental Research, 1996

Kupffer cells contribute to the important role of the liver defense mechanism through nitric oxid... more Kupffer cells contribute to the important role of the liver defense mechanism through nitric oxide (NO) production. In this study, the effect of chronic ethanol administration on the ability of Kupffer cells to synthesize and release NO was investigated after stimulation with lipopolysaccharide (LPS). Male Wistar rats were chronically fed ethanol for 8 weeks according to the method described by DeCarli and Lieber et al. (J Nufr. 91:331-336, 1967). Kupffer cells were isolated and cultured with LPS (1 pg/ml) for 24 hr. The levels of nitrite and nitrate, metabolites of NO, were determined in the culture medium. NO synthase (NOS) activity in Kupffer cells was determined by the method that measures conversion of ['4C]arginine into ['*C]citrulline. In control rats, a significant increase of nitrite and nitrate levels in culture medium was observed after LPS treatment. The magnitude of this increase was significantly smaller in chronic ethanol-fed rats. When the activity of NOS was determined, inducible NOS (iNOS) activity was higher than that of constitutive NOS, and LPS administration produced a significant elevation of iNOS activity in both control and chronic ethanol-fed rats. However, the elevation of iNOS activity by LPS stimulation was diminished by chronic ethanol administration. Distribution of iNOS in Kupffer cells as determined by an immunofluorescence method using a laser scanning confocal image system showed a lower expression of iNOS in chronic ethanol-fed rats even in the presence of LPS. These results demonstrate that the excessive production of NO by increased iNOS activity in Kupffer cells is diminished by chronic ethanol administration.