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Biomedical subjects

Shigeru Okada

Publications and source records attributed to Shigeru Okada.

At least 55 records · Page 3Linked to original sources
PubMed2003

Targeting superoxide dismutase to renal proximal tubule cells attenuates vancomycin-induced nephrotoxicity in rats.

Vancomycin hydrochloride (VCM), a glycopeptide antibiotic, has a broad spectrum against methicillin-resistant Staphylococcus aureus (MRSA). As it is known to induce renal dysfunction, the dose and the duration of its administration are limited. Moreover, the mechanism of VCM-induced renal dysfunction remains to be unclear. To evaluate the involvement of free radical on VCM-induced renal dysfunction, we carried out analysis with a hexamethylenediamine-conjugated superoxide dismutase (AH-SOD) which rapidly accumulates in renal proximal tubule cells and inhibits oxidative injury of the kidney. Male Wistar rats (weighing 200-210 g) were intraperitonealy administered with 200 mg/kg of VCM twice a day for 7 days. AH-SOD 5 mg/kg/day was subcutaneously injected 5 min before every VCM injection. VCM induced renal injury dose-dependently. Biochemical analyses revealed that plasma levels of blood urea nitrogen and creatinine significantly increased in the VCM-treated group by an AH-SOD-inhibitable mechanism. VCM simultaneously elicited an increase of 8-OHdG levels and chemiluminescence intensity of free radical generation in the kidney. Histological examination revealed that VCM also elicited a marked destruction of glomeruli and necrosis of proximal tubules. AH-SOD inhibited these phenomena in the kidney. These results suggested that oxidative stress might underlie the pathogenesis of VCM-induced nephrotoxicity and targeting SOD and/or related antioxidants to renal proximal tubules might permit the administration of higher doses of VCM sufficient for eradication of MRSA without causing renal injury.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

Induction of NAD(P)H:quinone reductase by probucol: a possible mechanism for protection against chemical carcinogenesis and toxicity.

Dietary antioxidants protect laboratory animals against induction of tumours by a variety of chemical carcinogens. Among possible mechanism, protection against chemical carcinogenesis could be mediated via antioxidant-dependent induction of detoxifying enzymes, including quinone reductase and glutathione S-transferase (GSH transferase). Probucol is used cholesterol-lowering drug used in the clinic, with pronounced antioxidant effect that protect against chemical carcinogenesis and toxicity. In the present study we therefore examined the ability of probucol to induce activities of quinone reductase in the cytosolic fractions of various tissues of mice. Quinone reductase activity was increased significantly in 6 of 8 tissues examined from probucol-fed mice. The greatest proportionate increase, to 1.8 times control levels, was observed in liver. Probucol also increased quinone reductase activities of forestomach, heart, kidney, lungs and spleen. Quinone reductase is a major enzyme of xenobiotic metabolism that carries out obligatory two-electron reductions and thereby protects cells against toxicity of quinones. It is induced in many tissues coordinately with other enzymes that protect against electrophilic toxicity. The protective effects of probucol appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the non-oxidative metabolism of a wide variety of xenobiotics. The induction of such enzyme, quinone reductase by probucol suggests the potential value of this compound as a protective agent against chemical carcinogenesis and other forms of electrophilic toxicity. The significance of these results can be implicated in relation to cancer chemopreventive effects of probucol in various target organs.

Animals↗
PubMed2003

Protective role of zinc-metallothionein (Zn-MT) in iron nitrilotriacetate (Fe-NTA)-induced renal oxidative damage.

Several studies have shown the role of thiol-rich proteins especially metallothionein (MT) in the therapeutic interventions against oxidative damage. Previously, we have provided strong evidence for the involvement of ROS in iron nitrilotriacetate (Fe-NTA)-induced renal toxicity, which may have relevance to its carcinogenicity. The purpose of this study was to evaluate the role of zinc metallothionein (Zn-MT) on the protection against Fe-NTA-induced renal oxidative damage. The results demonstrate that Zn-MT pretreatment provided protection against Fe-NTA-induced mortality in mice (40% protection). Similarly, Zn-MT pretreatment also provided protection against Fe-NTA-induced lipid peroxidation (26% inhibition, P < 0.001). It is proposed that Zn-MT protects kidney tissue against the noxious effect of Fe-NTA primarily by interference with lipid peroxides. It is concluded that Zn-MT may serve as an excellent physiological antioxidant against Fe-NTA-mediated renal oxidative damage.

Animals↗
PubMed2003

Mediation of arachidonic acid metabolite(s) produced by endothelial cytochrome P-450 3A4 in monkey arterial relaxation.

We investigated mechanisms of endothelium-dependent relaxation by acetylcholine resistant to indomethacin and N(G)-nitro-L-arginine and sensitive to cytochrome P-450 (CYP) inhibitors or charybdotoxin + apamin in the monkey lingual artery. Treatment with quinacrine, an inhibitor of phospholipase A2, abolished the relaxation by acetylcholine. However, treatment with alpha-glycyrrhetinic acid, an inhibitor of gap junctions, or catalase, an enzyme which dismutates hydrogen peroxide to form water and oxygen, did not affect the relaxation by acetylcholine. Immunohistochemistry demonstrated the presence of CYP3A4 in endothelial cells of the artery. Anti-CYP3A4 antibody inhibited relaxations by products of arachidonic acid incubated with human liver microsomes rich in CYPs in the endothelium-denuded artery. Purified CYP3A4 produced epoxyeicosatrienoic acids (EETs) from arachidonic acid, and the production was abolished by a selective CYP3A inhibitor, ketoconazole. It may be concluded that endothelium-derived relaxing substance(s) other than nitric oxide and prostanoids in the monkey lingual artery opens charybdotoxin + apamin-sensitive K+ channels in smooth muscle cells, and arachidonic acid metabolite(s) produced by endothelial CYP3A4 is likely to be the major substance.

Acetylcholine↗
PubMed2003

CD56-positive cells with or without synaptophysin expression are recognized in the pancreatic duct epithelium: a study with adult and fetal tissues and specimens from chronic pancreatitis.

We observed the distribution of CD56+ epithelial cells in the pancreatic duct system using 25 fetal, one infantile, 3 normal adult, 4 diabetic, and 8 chronically inflamed pancreatic tissue samples. In the early stage of gestation (12 to 17 weeks), CD56+ cells were commonly seen in the immature tubular structures. They were often continuous to pancreatic islets, and their distribution was similar to that of synaptophysin (Syn)+ cells, suggesting that they are precursors of islet neogenesis. Their number decreased in proportion to gestational age. Instead, from 24 weeks of gestation, luminal cell clusters that were common in interlobular ducts revealed CD56+. These cell clusters were unrelated to islet neogenesis and Syn expression. Similar CD56+ luminal cell clusters were also observed in cases of chronic pancreatitis, whereas they were scarce in normal adult and diabetic tissues. CD56+ cells were also occasionally seen in intralobular ducts, intercalated ducts, and centroacinar cells in cases of chronic pancreatitis. We conclude that there are two types of CD56+ epithelial cells in the pancreatic duct system: CD56+ endocrine cells are numerous during the early stage of gestation, when islet neogenesis appears, while CD56+ luminal cells may represent developmental and regenerative changes of pancreatic ducts.

CD56 Antigen↗
PubMed2002

Amelioration of cisplatin toxicity by a fermented grain food product.

The most noticeable hypothesis regarding the pathogenesis of cisplatin toxicity, seen mainly in kidney and intestine, is oxidative stress, an imbalance between free-radical generating cisplatin and radical scavenging systems. This paper describes the role of the antioxidant system in cisplatin-induced toxicity and the protective effect by a processed grain food (Antioxidant Biofactor: AOB), which has been shown to exhibit strong antioxidant activity. Male Fischer 344 rats were used. They were pre-fed either a basal diet (control, 15 g/day) or the diet supplemented with AOB to provide 6.5% or 20% of total diet throughout the experiment. Cisplatin (5 mg/kg, i.v.) was administered at the start of the experiment, and the animals were sacrificed 5 days later. Blood urea nitrogen (BUN) and plasma creatinine, NO2(-) and NO3(-) (NOx) were determined from the plasma. The levels of 4-hydroxy-2-nonenal (a lipid peroxidation product), 8-hydroxy-deoxyguanosine (8-OHdG, an oxidatively modified DNA adduct) and nitrotyrosine were histologically analyzed. The cisplatin administration resulted in a loss of body weight and elevations of BUN, serum creatinine and NOx levels, whereas AOB supplement reversed these effects. The severe morphological damages induced in the kidney and intestine by the cisplatin administration were markedly improved in the AOB group. The levels of lipid peroxidation, 8-OHdG, and nitrotyrosine all paralleled the morphological damage. The AOB effect was dose dependent. In conclusion, the present study suggests that certain food additives like AOB may be of benefit against the side effects of cisplatin.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2002

A wider molecular spectrum of beta-thalassaemia in Myanmar.

Two hundred and nine beta-thalassaemia (beta-Thal) alleles of 158 unrelated Myanmar patients (107 HbE-beta-Thal; 51 beta-Thal major) were analysed for beta-globin gene mutations. Amplification refractory mutation system (ARMS) characterized six beta-thal mutations known to Myanmar [betaIVSI-1(G-->T), codon 41/42(-TCTT), betaIVSI-5(G-->C), codon 17(A-->T), betaIVS II-654(C-->T), and -28 Cap (A-->G)] in 166/209 (79.4%) alleles. DNA sequencing of 24 alleles from 43 ARMS-negative samples (20.6%) identified an additional 12 new mutations, to produce a total of 18 different mutations. Nineteen alleles (9.1%) remained for further characterization. The molecular spectrum of Myanmar beta-Thal is wider and more heterogeneous than previously reported.

Adolescent↗
PubMed2002

Expression of thyroid transcription factor-1 in strumal carcinoid and struma ovarii: an immunohistochemical study.

Strumal carcinoid is an ovarian teratoma composed of thyroid tissue and carcinoid, intimately admixed in variable proportions. To further elucidate the histogenesis of strumal carcinoid, the expression pattern of thyroid transcription factor-1 (TTF-1) was evaluated in two cases of strumal carcinoid using immunohistochemical techniques. TTF-1 is a nuclear transcription protein that is selectively expressed in the thyroid and respiratory epithelium, and is thought to be expressed specifically in pulmonary and thyroid neoplasms. While the follicular lining cells of the strumal carcinoid showed positive staining for TTF-1, the carcinoid element was, for the most part, negative. These results confirm that TTF-1 is expressed in the thyroidal element of ovarian teratomas and also provide further evidence that the carcinoid component of the strumal carcinoid bears no relation to thyroidal differentiation.

Adult↗
PubMed2002

Monochloramine inhibits the expression of E-selectin and intercellular adhesion molecule-1 induced by TNF-alpha through the suppression of NF-kappaB activation in human endothelial cells.

Reactive oxygen species have various effects on the expression of cell adhesion molecules induced by proinflammatory cytokines, such as tumor necrosis factor a (T-NF-alpha). We studied the effects of monochloramine (NH2Cl), a physiological oxidant derived from activated neutrophils, on the TNF-alpha-induced expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells (HUVEC). HUVEC were pretreated with or without NH2Cl (20-90 microM for 20 min), then stimulated with TNF-alpha (10 ng/ml), and the expression of E-selectin and ICAM-1 was measured. Without NH2Cl, TNF-alpha induced marked expression of e-selectin and ICAM-1. Pretreatment with NH2Cl resulted in a significant, but transient inhibition of the expression of adhesion molecules. Higher dose of NH2Cl showed more pronounced inhibition, and the inhibitory effect lasted for 8h when 70 microM of NH2Cl was added. TNF-alpha stimulation also induced marked activation of nuclear factor KB (NF-kappaB). Notably, NH2Cl also inhibited this NF-kappaB activation in a dose- and time-dependent manner, which was similar to the inhibition of E-selectin and ICAM-1 expression. In addition, IkappaB-alpha phosphorylation and degradation were also inhibited by NH2Cl pretreatment. These observations indicated that NH2Cl inhibited TNF-alpha-induced expression of E-selectin and ICAM-1 through the inhibition of NF-kappaB activation. We speculate that neutrophil-derived chloramines may have a regulatory role in the recruitment of leukocytes.

Blotting, Western↗
PubMed2002

Inhibition of vancomycin-induced nephrotoxicity by targeting superoxide dismutase to renal proximal tubule cells in the rat.

Vancomycin, a glycopeptide antibiotic, has a broad spectrum against methicillin-resistant Staphylococcus aureus (MRSA). Because vancomycin induces renal dysfunction, the dose and the duration of its administration are limited. The mechanism of vancomycin-induced renal dysfunction is not known. We recently synthesized a hexamethylenediamine-conjugated cationic superoxide dismutase (AH-SOD) which rapidly accumulates in renal proximal tubule cells and inhibits oxidative injury of the kidney. The present work reports the protective effects of AH-SOD against vancomycin-induced renal dysfunction. Male Wistar rats (200-210 g) were intraperitoneally administered with either 200 or 400 mg/kg of vancomycin twice a day for 7 days. Either 5 mg/kg/day AH-SOD or saline was subcutaneously injected 5 min before every vancomycin injection. Biochemical analysis revealed that plasma levels of blood urea nitrogen and creatinine increased significantly in vancomycin-treated group by an AH-SOD-inhibitable mechanism. Histological examination revealed that vancomycin also elicited a marked destruction of glomeruli and necrosis of proximal tubule by an AH-SOD inhibitable mechanism. These results suggest that oxidative stress underlies the pathogenesis of vancomycin-induced nephrotoxicity and that targeting SOD and/or related antioxidants to renal proximal tubule cells might permit the administration of higher doses of vancomycin sufficient for eradication of MRSA without causing renal injury.

Animals↗
PubMed2002

Organic nitrate tolerance is induced by degradation of some cytochrome P450 isoforms.

The mechanism of nitrate tolerance is poorly defined. We studied the rat P450 (CYP)-catalyzed conversion of organic nitrate to nitric oxide (NO) by purified CYP isoforms and the relationship between P450 expression and nitrate tolerance following continuous infusion of organic nitrates in rats. CYP1A2 effectively formed NO from isosorbide dinitrate and nitroglycerine (NTG). The hypotensive effect of an NTG bolus injection was abolished in rats which had been previously given a continuous 48 h infusion of NTG. Nitrate tolerance was reversible to control levels 2 days after cessation of the continuous infusion. At 48 h after infusion, NTG-induced NO generation of the vessels increased in acetone (a P450 inducer)-pretreated rats, and nitrite and nitrate levels were markedly greater than in normal rats. The appearance and disappearance of P450 isoforms paralleled the conversion of organic nitrates to NO as assessed by immunohistochemistry and Western blotting. Our observations indicate that nitrate tolerance is in large part the result of decreased P450 expression and activity. Interventions that maintain or increase P450 activity may be a useful strategy to provide sustained relief from ischemic conditions in humans.

Animals↗
PubMed2002

Effects of phlebotomy on the growth of ferric nitrilotriacetate-induced renal cell carcinoma.

The ferric nitrilotriacetate-induced carcinogenesis model is unique in that reactive oxygen species-free radicals are involved in the carcinogenic process. But the effects of iron-withdrawal in the progression of renal cell carcinoma are not well understood. We performed repeated phlebotomies on animals that had been administered ferric nitrilotriacetate in the initiation stage of renal cell carcinoma (phlebotomy group), and compared the development of renal tumors with those not receiving repeated phlebotomies (non-phlebotomy group). Ferric nitrilotriacetate-treated male Wistar rats were randomly divided into 2 groups: a phlebotomy group (21 rats) and a non-phlebotomy group (17 rats). Ten age-adjusted normal rats were also observed as a normal group. Hematocrit was maintained under 25% in the phlebotomy group. Hematocrit levels in the normal group and in the non-phlebotomy group were not significantly different. As a result, the incidence of renal cell carcinoma was not significantly different between phlebotomy and non-phlebotomy animals. However, the total weight of the renal cell carcinoma was significantly heavier in the animals from non-phlebotomy group than in those from the phlebotomy group (23.64 g +/- 18.54 vs. 54.40 g +/- 42.40, P < 0.05). The present study demonstrated that phlebotomy after the administration of ferric nitrilotriacetate did not reduce the incidence of renal cell carcinoma. In addition, we showed that iron withdrawal at the promotion stage of carcinogenesis will retard tumor growth.

Animals↗
PubMed2002

Evaluation of tumor markers for the detection of hepatocellular carcinoma in Yangon General Hospital, Myanmar.

Levels of alpha-fetoprotein (AFP), its glycoforms AFP-L3 and AFP-P4, and proteins induced by vitamin K absence or antagonist-II (PIVKA-II) were determined in sera obtained from patients in Yangon General Hospital (20 with hepatocellular carcinoma (HCC), 29 with chronic liver diseases, including 3 with chronic hepatitis and 26 with cirrhosis of the liver, and 9 with other hepatobiliary diseases). Forty-five percent of the patients with HCC had serum AFP levels above 10,000 ng/ml, indicating that nearly half of the HCC patients were at an advanced stage of the disease. Thus, the AFP sensitivity was as high as 70% with 100% specificity for a cutoff level of 200 ng/ml. The sensitivity of AFP-L3 was 75% and a specificity 90% for a cutoff level of 15%. AFP-P4 showed a higher sensitivity of 80% and a similar specificity of 86% for a cutoff level of 12%. Combined evaluation of AFP-L3 and/or AFP-P4 increased the sensitivity to 90% with the same specificity of 86%, indicating that AFP-L3 and AFP-P4 are useful as adjuncts for diagnosis of HCC in the present population. PIVKA-II had a high sensitivity of 90%, although the specificity was lower than 45%, probably due to the low cutoff level, as some cholestatic patients were included in the control group.

Biomarkers↗
PubMed2002

Feasibility and limitations of acridine orange fluorescence technique using a Malaria Diagnosis Microscope in Myanmar.

We studied parasite detectability in thick films by an acridine orange fluorescence technique (AO) to test its applicability and the use of a Malaria Diagnosis Microscope (MDM)-ESL in the detection of parasites, compared to the conventional Giemsa staining method. This study was conducted on 1,390 clinically suspected malaria cases of Thaton township, Myanmar. We found sensitivities of 82.8% for Plasmodium falciparum (P. falciparum) and 100% for Plasmodium vivax (P. vivax) and specificities of 97.1% for P. falciparum and 98.6% for P. vivax. AO had a higher sensitivity than Giemsa-stained films at low levels of parasitemia (< 1,000/microl). AO showed lower sensitivity and higher specificity than the Giemsa method at parasite levels of more than 1,000/microl. The results of using the AO method, achieved by both novice and experienced observers, showed no significant difference and required less practice to perform the test as well as to identify the parasite. The acridine orange fluorescence technique using a malaria diagnosis microscope MDM-ESL series is simple, rapid and cost effective. The microscope is conveniently operable using standard AC power or a 12-V DC car battery, and it is easily convertible to a conventional biological microscope. With the exception of species differentiation, which is not possible with this method, this method would be appropriate for both clinical and epidemiological studies.

Acridine Orange↗
PubMed2002

Localization of S100C immunoreactivity in various human tissues.

Using 2-dimensional gel electrophoresis, we previously demonstrated that the S100C protein remarkably decreased after immortalization of normal human fibroblasts, and that this protein caused growth inhibition of human tumor cells when forcibly expressed in these cells, suggesting that S100C plays a significant role in tumor suppression. The present study was carried out to determine what type of human tissues express S100C protein, and, subsequently, whether the S100C content in these tissues changes after normal cells have been transformed into cancer cells. We found that ductal cells in various tissues were positively stained with the S100C protein. In comparison, epithelial cells in digestive organs such as the stomach, small intestine, and colon were not stained as strongly. When 14 pairs of human normal and cancerous tissues were stained with the antibody, decreases in the staining levels of S100C were observed in 6 kinds of cancerous tissues--from the bronchus, mammary duct, renal tubule, prostate, uterus, and testis--in comparison with staining in their normal counterparts. These results suggest that S100C is a new tumor marker protein, the expression of which significantly decreases after malignant transformation of human tissues.

Antibodies↗
PubMed2000

Hemoglobinopathies, Iron Overload and Chronic Viral Hepatitis in Patients with Hepatocellular Carcinoma in Myanmar.

To assess the relevance of altered iron metabolism, hemoglobin electrophoresis by isoelectric focusing was performed for 16 cases of hepatocellular carcinoma (HCC) from the Liver Unit, Yangon General Hospital. Serum iron, total iron binding capacity, serum ferritin and free iron were also determined. Hemoglobin A (HbA) was found in all of the cases. Four cases had one extra band, hemoglobin A(2) in three cases, and hemoglobin F in one case. No abnormal hemoglobin was detected. Anemias due to chronic disorders or associated with liver disease were observed in all of the cases. Iron overload was documented in 83% and free iron was detected in all cases. Viral markers like HBsAg, AntiHBc, and AntiHCV singly or in combination were found in all cases. HCC occurring at young age was seen in this study; the youngest patient was 23 years old and four cases (25%) were under 40 years, with a mean age of 49 years. The findings support the hypothesis that free iron and iron overload is a potential promoter of the development of HCC, especially if underlying chronic viral infection is present.

Journal Article↗
PubMed1996

Enhancing and Inhibiting Effect of Vitamin C on Lipid Peroxidation in the Linoleic Acid Micelle System.

Vitamin C (Vc), a reductant in the body can function as an antioxidant by scavenging free radicals. However, with the coexistence of the transition metal iron (Fe), Vc can induce lipid peroxidation reaction resulting in the production of conjugated diene which has a peek absorbance at UV 234 nm. In order to clarify the proportion of Vc to Fe on the two different effects mentioned above, the authors detected conjugated diene production by means of spectrophotometer in linoleic acid micelles induced by Fe with different amount of Vc. The results showed that in the presence of Te or Vc alone there was no induction of lipid peroxidation. In the presence of some Fe (20 &mgr;M), Vc induced lipid peroxidation at a concentration of 80 &mgr;M or lower, but inhibited lipid peroxidation at concentration of 100 &mgr;M or higher. The pH of the experimental system clearly affected the lipid peroxidation induced by Fe-Vc, with the production of conjugated diene at acidic pH, but none at physiological pH.

Journal Article↗