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Biomedical subjects

S Sugiyama

Publications and source records attributed to S Sugiyama.

At least 19 recordsLinked to original sources
PubMed1992

Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts.

Some mutations in mitochondrial DNA (mtDNA) causing a number of neuromuscular diseases are suggested to arise spontaneously during the life of an individual. To substantiate the extent and the rate of these somatic mutations, mtDNA specimens from post-mortem human heart muscles of subjects in differing age groups were hydrolyzed. 8-Hydroxy-deoxyguanosine (8-OH-dG), a hydroxyl-radical adduct of deoxyguanosine, in mtDNA, was quantitatively determined using a micro high-performance liquid chromatography/mass spectrometry system. In each specimen, the mtDNA with a 7.4 kilo base-pair deletion was quantified by the kinetic polymerase chain reaction method. In association with age, the 8-OH-dG content accumulated exponentially up to 1.5% with a correlative increase in the content of the deleted mtDNA up to 7%. Clear correlation between the 8-OH-dG content in mtDNA and the population of mtDNA with a deletion (r = 0.93, P < 0.01) gives insight into the mechanism for the generation of a large deletion. These results indicate that accumulation of somatically acquired oxygen damage together with age-associated mutations in mtDNA which lead to bioenergetic deficiency and the heart muscle weakness are inevitable in human life.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1992

Age-associated decreases in prostaglandin contents in human gastric mucosa.

This study was designed to clarify effects of ageing on human gastric mucosal prostaglandin (PG) contents. Forty examinees were divided into 5 age groups of 8 persons each, as follows: age under 40, age 40-49, age 50-59, age 60-69, and age over 70. PG contents in human gastric mucosa were measured by microcolumn high performance liquid chromatography (HPLC) with helium/cadmium laser induced fluorescence detection using biopsy samples obtained by endoscopy. The contents of 6-keto-PGF1 alpha, PGF2 alpha, PGE2, and PGD2 in the under 40 group were 638 +/- 39, 97 +/- 16, 468 +/- 68, 497 +/- 86 (pg/mg tissue), respectively. No significant differences in PG contents among groups aged under 70 were observed. In contrast, significantly low PG contents in the over 70 group were observed, i.e., the contents of 6-keto-PGF1 alpha, PGF2 alpha, PGE2, and PGD2 were 311 +/- 58, 36 +/- 8, 196 +/- 48, 171 +/- 40, respectively, and their contents were significantly lower than those in other age groups. In conclusion, gastric mucosal PG contents decrease significantly in over 70 years-old and this might be a contributing factor in the pathogenesis of gastric ulcers in elderly people.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

The effects of a high dose of ascorbate on ischemia-reperfusion-induced mitochondrial dysfunction in canine hearts.

The cardioprotective effects of a high dose of ascorbate on ischemia-reperfusion-induced myocardial damage were investigated using open chest anesthetized dogs. Two-hour occlusion of the left anterior descending coronary artery (LAD) induced mitochondrial dysfunction with a depletion of mitochondrial glutathione (GSH) concentration. Two-hour LAD occlusion followed by 1-h reperfusion worsened the ischemia-induced mitochondrial dysfunction together with a marked depletion of mitochondrial GSH concentration. Ascorbate reduced the mitochondrial dysfunction and prevented the depletion of mitochondrial GSH concentration after 2-h LAD occlusion and 1-h reperfusion. Activities of mitochondrial glutathione peroxidase and glutathione reductase did not change significantly in each group. Administration of ascorbate also prevented reperfusion arrhythmias without affecting blood pressure or heart rate. These results suggest that coronary reperfusion induces mitochondrial dysfunction and a depletion of mitochondrial GSH concentration, and that a high dose of ascorbate prevents reperfusion damage.

Animals↗
PubMed1992

Extensive varices of ileocecum. Report of a case.

A man was admitted to our hospital because of intestinal reddish bleeding. Colonic varices were found at the cecum by colonoscopy. Angiography of the superior mesenteric artery showed that blood vessels were scant from the end of the ileum to the ascending colon. An operative view revealed the varices, but there was no trace of the ileocecal vein. This case, presenting a deficit of the ileocecal vein, indicated that the blood flow could not return via the ileocecal vein, and therefore there was an outflow through the varices to the surrounding intestine or abdominal veins. Such a case is probably unrepresented in the literature because it was caused by the total deficiency of the ileocecal vein and it was in the right colon.

Angiography↗
PubMed1992

Point mutations in mitochondrial DNA in patients with hypertrophic cardiomyopathy.

Recent advances suggest that mutations in nuclear DNA are involved in the etiology of autosomal dominant hypertrophic cardiomyopathy. Mitochondria have their own DNA, and mutations in mitochondrial DNA have been shown to contribute to the genesis of various diseases. In this study, we developed rapid sequencing methods with the use of a fluorescence-based sequencing system and analyzed total mitochondrial DNA of seven patients with nonautosomal dominant hypertrophic cardiomyopathy. Multiple point mutations were observed in all patients with hypertrophic cardiomyopathy, although some of them were common among the subjects examined and the others are unique to each subject. Point mutations in transfer RNA genes were observed in five of the seven patients, and point mutations that replaced conserved amino acids were also observed. These mutations may result in the impairment of mitochondrial function. According to these results, mutations in mitochondrial DNA may contribute to the genesis of some cases of nonautosomal dominant hypertrophic cardiomyopathy, and our methods may be useful for the detection of point mutations in mitochondrial DNA.

Adult↗
PubMed1992

Ultrastructural localization and semiquantitative analysis of glycoconjugates in the tectorial membrane.

The tectorial membrane of the gerbil cochlea was analyzed with lectin-gold cytochemical methods for demonstrating and characterizing glycoconjugates (GCs) in situ. Binding of lectins from Limax flavus (LFA), Lens culinaris (LCA), Datura stramonium (DSA), Ricinus communis (RCA I), Ulex europeus (UEA I) and Phaseolus vulgaris (PHA L) was assayed semiquantitatively on ultrathin sections. Binding occurred throughout the tectorial membrane with all lectins except UEA I but the labelling density with a given lectin differed among substructures. The cover net disclosed the highest level of GC with four lectins whereas the fibrous layer revealed the lowest level. DSA, LCA and PHA L demonstrated considerable similarity between the cover net and the marginal band in content of GC with N-linked oligosaccharide. The cover net differed from the marginal band, however, in containing more RCA I reactive GC with terminal lactosamine. Hensen's stripe, with which inner hair cell stereocilia are thought to interact, differed from other substructures in containing the highest level of PHA L-reactive traintennate N-linked chains and except for the basal layer the lowest concentration of GC with terminal lactosamine. Fucosylated GC detectable with UEA I-gold was present at low levels in all substructures except the cover net and marginal band. Distribution of GCs in the fibrous layer and less consistently in the cover net differed between limbal and middle zones. The differences observed here in the carbohydrate composition among substructures in the tectorial membrane support and extend previous cytochemical observations and imply a role for different classes of GCs in determining the biophysical and physiological properties of the tectorial membrane.

Animals↗
PubMed1992

Beneficial effects of cyclosporine on postischemic liver injury in rats.

The discovery of cyclosporine has had a significant impact on preventing the rejection of transplanted organs in humans. In this study, we present another positive aspect of cyclosporine. Rats were pretreated with cyclosporine (10 mg/kg, i.v.), or untreated. After 2-hr ischemia or 1 hr of reperfusion following 2-hr ischemia, livers were isolated and liver adenine nucleotide concentrations were determined. Liver mitochondria were prepared and their function was estimated polarographically. Leakage of AST, ALT, LDH, and adenine nucleotides into the hepatic vein just after reperfusion was also measured. Cyclosporine treatment did not affect ischemia-induced mitochondrial dysfunction, nor did it prevent the associated decrease in adenosine triphosphate concentration. However, treatment with cyclosporine accelerated the recovery of mitochondrial function and of tissue adenosine triphosphate concentrations. Cyclosporine treatment also mitigated leakage of AST, ALT, LDH, and adenine nucleotides after reperfusion. These results indicate that cyclosporine shows a potent protective effect on ischemia-reperfusion-related liver injury.

Adenine Nucleotides↗
PubMed1992

The effects of gamma-glutamylcysteine ethyl ester, a prodrug of glutathione, on ischemia-reperfusion-induced liver injury in rats.

This study was designed to clarify the effects of changes in liver tissue glutathione (GSH) concentration on postischemic liver injury together with the effects of gamma-glutamylcysteine ethyl ester (GCE), a prodrug of GSH, and GSH. Rats were pretreated with GSH (50 mg/kg, i.v.), or GCE (50 mg/kg, i.v.), or untreated. In each rat, liver was isolated, and liver mitochondria were prepared after 2 h of ischemia or 1 h of reperfusion following 2 h of ischemia. Mitochondrial function was measured polarographically. Liver adenine nucleotide concentrations were also determined using high-performance liquid chromatography. Liver tissue GSH, an oxidized form of glutathione (GSSG) concentrations, and activities of GSH peroxidase and GSSG reductase were determined enzymatically. Liver hypoxanthine and xanthine concentrations were determined by HPLC. Liver tissue concentration of lipid peroxide was measured. Leakages of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and adenine nucleotides into the hepatic vein after reperfusion were also measured. Administration of GCE improved the recovery of mitochondrial function and maintained tissue GSH concentration concomitantly. Increases in liver lipid peroxide concentration after reperfusion, and leakage of liver cell enzymes and adenine nucleotides were mitigated by administration of GCE. Administration of GSH itself failed to maintain tissue GSH concentration and had no protective effects. From these results, it is concluded that in the postischemic process, free radical formation might be enhanced, and the radical scavenging system deteriorated. To enhance the radical scavenging system is a possible maneuver to prevent radical-related cell damage associated with reperfusion, because pharmacological reduction of breakdown of ATP to hypoxanthine and xanthine seems to be difficult. GCE maintained liver GSH concentrations and mitigated postischemic liver injury, concomitantly. Clinical use of GCE might be recommended.

Adenine Nucleotides↗
PubMed1992

A prospective study of human herpesvirus-6 infection in renal transplantation.

Sixty-five kidney transplant recipients and their (22 living related and 43 cadaveric) donors were studied prospectively to determine the relationship between kidney transplantation and human herpesvirus-6 (HHV-6) infection. The virus isolation from peripheral blood and other tissues and sequential determination of neutralizing antibodies to HHV-6 were performed during 3 months following the transplantation. All of the donors and their recipients examined had neutralizing antibodies to HHV-6 at the time of renal transplantation and the virus was not isolated from them. HHV-6 was isolated from 3 renal tissues (2 living related and 1 cadaveric) obtained during transplant surgery, but not from their blood at that time. HHV-6 viremia occurred in 9 (14%) of the 65 recipients around 2 to 4 weeks after the transplantation. An additional 27 recipients showed a significant rise in the antibody titer. Thus, the infection with HHV-6 was confirmed in 36 (55%) of the 65. These results indicate that the virus is activated in many cases in the early posttransplant period and that HHV-6 establishes in vivo latency in the kidney tissue. There was no correlation between HHV-6 infection and acute rejection or the antirejection prophylaxis.

Adolescent↗
PubMed1992

Polyoxyethylene-modified superoxide dismutase reduces side effects of adriamycin and mitomycin C.

Polyoxyethylene-modified superoxide dismutase (SOD-POE) is a newly developed long-acting superoxide dismutase. Adriamycin (ADR) and mitomycin C (MMC) generate superoxide, which contributes to their cytocidal effects or side effects. We examined whether SOD-POE could prevent the side effects induced by superoxide generated by antitumor agents, and the following results were obtained. SOD-POE did not influence the antitumor effects of ADR and MMC either in vitro or in vivo, but prevented the toxic death of BALB/c, nu/nu male mice caused by overdoses of ADR or MMC. As for its effective sites, SOD-POE prevented a decrease in the specific activity of rotenone-sensitive NADH-ubiquinone oxido-reductase (complex I) in heart muscle mitochondrial respiratory chain function in BALB/c male mice administered 10 mg/kg ADR, and prevented damage to the sarcoplasmic reticulum and mitochondria of mouse heart muscle by ADR as observed by electron microscopy. Furthermore, SOD-POE prevented bone marrow suppression induced by MMC in Donryu rats. The above results suggest that combination chemotherapy with SOD-POE would make it possible to increase the maximum permissible doses of antitumor agents, improving the efficacy of these agents.

Animals↗
PubMed1992

Mechanism and prevention of chronic colonic inflammation with trinitrobenzene sulfonic acid in rats.

1. The role of prostanoids in experimental colitis with trinitrobenzene sulfonic acid (TNBS) in rats was investigated. The effects of cyclosporine A (CsA) on the development of experimental colitis were also examined. 2. Five kinds of prostanoids were detected in rat colonic tissue by high performance liquid chromatography. These were 6-keto-prostaglandin (PG) F1 alpha, PGF2 alpha, PGE2, PGD2 and thromboxane B2. 3. In TNBS-induced experimental colitis, all prostanoid concentrations except PGD2 increased, although the time courses differed from each other. 4. Medication with indomethacin markedly reduced prostanoid concentrations in TNBS-induced colitis. However, indomethacin did not show any effect on damage scores. 5. Cyclosporine A reduced damage scores 14 days after TNBS treatment, and the protective effects were observed, whereas CsA did not affect colonic tissue prostanoid concentrations. 6. Prostanoids might be produced secondarily in the genesis of TNBS-induced colitis, although they may attenuate the inflammatory response. It was also suggested that CsA was likely to have therapeutic effects on experimental colitis by inhibiting the immune reaction with TNBS, which induced the chronic inflammation.

Animals↗
PubMed1992

Induction of irreversible glomerulosclerosis in the rat by repeated injections of a monoclonal anti-Thy-1.1 antibody.

The present experiment demonstrated that an irreversible glomerulosclerosis could be induced in the rat through repeated intravenous administrations of OX-7 (a monoclonal anti-Thy-1.1 antibody). Rats were injected with 0.2 mg of affinity-purified OX-7 at 1-week intervals for a period of 4 weeks. Glomerular damage was periodically examined at light-microscopic level. Thirty-five days after the initial injection (7 days after the final injection), capillary aneurysms and expansion of the mesangial areas with hypercellularity were frequently observed. Similar glomerular damage was also observed in rats 7 days after they received a single injection of either 1.0 or 0.2 mg of OX-7. After repeated injections, 112 days from the initial administration (84 days after the final injection), approximately 60% of the glomeruli had expanded mesangial areas with an apparent increase in the mesangial matrix. The result contrasts sharply with that obtained from a single injection of OX-7 in that more than 85% of the glomeruli showed no abnormalities 84 days after the injection. This chronic model, as a result of repeated injections of the antibody, could serve as a potential for further investigation of the mechanisms involved in the development of chronic glomerulonephritis.

Animals↗
PubMed1992

Lysophosphatidylcholine inhibits surface receptor-mediated intracellular signals in endothelial cells by a pathway involving protein kinase C activation.

Lysophosphatidylcholine (lysoPC) transferred from oxidatively modified low density lipoprotein (Ox-LDL) to the endothelial surface membrane has been shown to produce a selective unresponsiveness to cell surface receptor-regulated endothelium-dependent relaxation (EDR) in the rabbit aorta. To determine its mechanism we examined the effects of lysoPC on endothelial surface receptor-mediated transmembrane signals. Incubation for 1 minute with palmitoyl lysoPC (5-10 microM) decreased thrombin (Th, 2 units/ml)- or histamine (His, 0.1 mM)-stimulated inositol 1,4,5-trisphosphate (IP3) production in primary cultures of human umbilical vein endothelial cells (HUVECs). LysoPC also decreased Th- or His-induced intracellular calcium ([Ca2+]i, fura 2) elevation. Pretreatment with protein kinase C (PKC) inhibitors staurosporine (100 nM) or H-7 (50 microM) prevented the inhibitory actions of lysoPC, but HA-1004 had no effect. Incubation for 5 minutes with phorbol 12-myristate 13-acetate (PMA, 100 nM) produced the inhibitory actions on the Th- or His-induced intracellular signals, which closely mimic those exhibited by lysoPC. However, the inhibitory effect of lysoPC was lost in cells that were depleted of PKC by pretreatment for 24 hours with 100 nM PMA. Furthermore, incubation of the cells for 1 minute with lysoPC stimulated PKC activity in the membrane fraction. In organ chamber experiments with porcine coronary artery rings, pretreatment with staurosporine (20 nM) attenuated lysoPC-induced impairment of EDR in response to Th. These results indicate that lysoPC, which accumulates in Ox-LDL and atherosclerotic arterial walls, inhibits the early transmembrane signaling pathway in endothelial cells, and PKC activation could at least partially be involved in the negative regulation by lysoPC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Implication of oxygen radicals on airway hyperresponsiveness after ovalbumin challenge in guinea pigs.

We elucidated the implication of oxygen radicals on airway hyperresponsiveness after ovalbumin (OA) challenge in guinea pigs. Ten days OA exposure increased airway responsiveness, i.e., a significant decrease in log [acetylcholine (Ach) PC200] (2.445 +/- 0.227) was observed compared with the control group (3.398 +/- 0.269). After OA exposure, the number of beta-adrenoceptors decreased by 38%, and adenylate cyclase activity decreased by 36% (isoproterenol stimulated) and 28% (basal). Significant increases in xanthine oxidase activities in lung tissue, bronchoalveolar lavage fluid (BALF), and serum were observed after the tenth OA exposure (49.1 +/- 11.7 mU/g tissue, 12.6 +/- 3.16 mU/ml, and 11.5 +/- 2.66 mU/ml, respectively) compared with those in the control group (7.35 +/- 6.48 mU/g tissue, 2.85 +/- 1.17 mU/ml, and 3.51 +/- 1.15 mU/ml, respectively). Administration of long-acting superoxide dismutase (SOD) (5,000 U/kg twice a day intraperitoneally) or gamma-glutamylcysteine ethyl ester (gamma-GCE) (10 mg/kg, twice a day, intraperitoneally), a prodrug of glutathione, maintained log [Ach PC200] (3.248 +/- 0.415 and 3.298 +/- 0.246, respectively) in spite of 10 days OA exposure. Decreases in the number of beta-adrenoceptors and adenylate cyclase activity were prevented by long-acting SOD or gamma-GCE. In contrast, long-acting SOD or gamma-GCE inhibited significantly, but not completely, the elevation of xanthine oxidase activities. These results support suggestions that oxygen radicals might be involved in the underlying mechanism of airway hyperresponsiveness after OA challenge in guinea pigs.

Adenylyl Cyclases↗
PubMed1992

Age-related decrease in respiratory muscle mitochondrial function in rats.

The purpose of this study was to elucidate the effects of aging on diaphragmatic mitochondrial function. Diaphragm mitochondria were prepared from specific pathogen-free rats aged 7 wk (n = 7), 35 wk (n = 7), and 55 wk (n = 7). The activities of various portions of the mitochondrial electron transport chain, i.e., complexes I, II, III, and IV, were measured enzymatically. The specific activities of complex I decreased significantly (P less than 0.01) in 35-wk-old rats (726 +/- 90 nmol/min/mg protein) compared with 7-wk-old rats (1,018 +/- 121), and the decrease was more remarkable in 35-wk-old rats (565 +/- 64; P less than 0.01 versus 35-wk-old). The activities of complex IV also decreased significantly (P less than 0.01) in 55-wk-old rats (1,222 +/- 191) compared with 7-wk-old rats (1,797 +/- 208); however, no significant changes in complex IV activities between 7-wk-old rat and 35-wk-old rats were observed. In contrast, the activities of complex II and III were not affected by aging. Limb muscle, heart, and liver mitochondria were also prepared from the same rats. The same tendency was observed in limb muscle mitochondria; however, in heart and liver mitochondria, activities of all four complexes were not changed in rats of all age groups. These results indicate that vulnerability of mitochondrial electron transport chain to aging differs from organ to organ and that it also differs from portion to portion in the electron transport chain and the most vulnerable site was complex I.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Aging-associated deletions of human diaphragmatic mitochondrial DNA.

It is known that respiratory function deteriorates with age. Endogenous damage to DNA is thought to contribute to the aging process. The mitochondrial oxidative phosphorylation system, a bio-engine, consists of five complexes, and 13 subunits of those complexes are biosynthesized from information encoded in mitochondrial DNA. Mitochondrial DNA is shown to have a much higher mutation rate than nuclear DNA. We examined the diaphragms obtained at autopsy from 34 humans, 23 men and 11 women, ranging in age from 25 to 85 yr, for mitochondrial DNA deletions using the polymerase chain reaction method. Multiple mitochondrial DNA deletions were detected particularly among the elderly; the number of deletions in those over age 70 was significantly higher than in those under age 40. The occurrence of a 3.4-kbp deletion of mitochondrial DNA increased with age, i.e., 0% of those under age 30, 20.0% of those in their forties, 25.0% of those in their fifties, 28.6% of those in their sixties, 72.7% of those in their seventies, and in all of those over age 80. The mutation was based on the directly repeated sequence, 5'-TCACCCC-3', which exists in both the CO3 gene and the ND5 gene. Replication impairment occurred at that directly repeated sequence, which caused the elimination of a genome between the CO3 gene and the ND5 gene, and information for biosynthesis of four subunits in complex I (ND3, ND4L, ND4, and ND5), one in complex IV (CO3), and five transfer RNA genes was missing.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗