[How should we accept the risk from low level radiation?].
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Apoptosis↗
Biomedical subjects
Kazuo Sakai
Publications and source records attributed to Kazuo Sakai.
[Biological responses to low dose radiation--hormesis and adaptive responses].
"Hormesis" is defined, originally in the field of toxicology, as a phenomenon in which a harmful substance gives stimulating effects to living organisms when the quantity is small. The concept was extended and applied to ionizing radiation, high doses of which are harmful. Although radiation has been thought to be, based on findings in high dose ranges, harmful no matter low the dose is, recent investigation revealed that living organisms possess the ability to respond to low-dose radiation in very sophisticated ways. A good example of such responses is the so-called radiation adaptive response, a process in which acquired radioresistance is induced by low-dose radiation given in advance. The stimulation of certain bioprotective functions, including antioxidative capacity, DNA repair functions, apoptosis, and immune functions are thought to underly the adaptive response. The adaptive response is effective for chromosome induction, acute death, and tumorigenesis induced by high doses of radiation. Radiation hormesis and adaptive response provide a new scope in the risk assessment and medical application of ionizing radiation.
Adaptation, Biological↗
Activation of antioxidative enzymes induced by low-dose-rate whole-body gamma irradiation: adaptive response in terms of initial DNA damage.
An adaptive response induced by long-term low-dose-rate irradiation in mice was evaluated in terms of the amount of DNA damage in the spleen analyzed by a comet assay. C57BL/ 6N female mice were irradiated with 0.5 Gy of (137)Cs gamma rays at 1.2 mGy/h; thereafter, a challenge dose (0.4, 0.8 or 1.6 Gy) at a high dose rate was given. Less DNA damage was observed in the spleen cells of preirradiated mice than in those of mice that received the challenge dose only; an adaptive response in terms of DNA damage was induced by long-term low-dose-rate irradiation in mice. The gene expression of catalase and Mn-SOD was significantly increased in the spleen after 23 days of the low-dose-rate radiation (0.5 Gy). In addition, the enzymatic activity of catalase corresponded to the gene expression level; the increase in the activity was observed at day 23 (0.5 Gy). These results suggested that an enhancement of the antioxidative capacities played an important role in the reduction of initial DNA damage by low-dose-rate radiation.
Adaptation, Physiological↗
Activation of immunological network by chronic low-dose-rate irradiation in wild-type mouse strains: analysis of immune cell populations and surface molecules.
PURPOSE: To analyse the effects of chronic whole body low-dose-rate irradiation on the immune system in various wild-type mouse strains in comparison with the effects from acute high-dose-rate irradiation. MATERIALS AND METHODS: Wild-type mouse strains (C57BL/6, BALB/c, C3H/He, DBA/1, DBA/2 and CBA) were observed after chronic low-dose-rate gamma irradiation at 1.2 mGy hour(-1) by intensive analysis of immune cell populations and their various surface molecules, together with antibody-producing activity both with and without immunization by sheep red blood cells (SRBC). The cell surface functional molecules [cluster of differentiation (CD) 3, CD4, CD8, CD19, CD45R/B220, intercellular adhesion molecule (ICAM)-1, Fas, natural killer (NK)-1.1, chemokine [C-X-C motif] receptor 4 (CXCR4) and chemokine [C-C motif] receptor 5 (CCR5)] and activation molecules [thymocyte-activating molecule (THAM), CD28, CD40, CD44H, CD70, B7-1, B7-2, OX-40 antigen, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD30 ligand and CD40 ligand] were studied in the bone marrow, thymus, spleen, lymph nodes and peripheral blood by flow cytometry. RESULTS: By chronic low-dose-rate irradiation alone, CD4+ T cells and CD8 molecule expression increased significantly by a maximum of 30%, while CD40+ B cells decreased significantly. Increases of CD4+ T cells, CD40+ B cells and anti-SRBC antibody-producing cells by immunization were significantly enhanced by continuous low-dose-rate irradiation at 1.2 mGy hour(-1). CD3- CD4+ T cells, representative of abnormal immune cells, were absent in the chronically low-dose-rate-irradiated mice, while a dose-dependent increase of these cells was found in acutely high-dose-rate-irradiated mice given the same total doses. CONCLUSION: Chronic low-dose-rate radiation activated the immune system of the whole body.
Animals↗
Effect of chitobiose and chitotriose on carbon tetrachloride-induced acute hepatotoxicity in rats.
The purpose of the present study was to examine whether chitobiose and chitotriose can protect rats from CCl4-induced hepatic toxicity when given orally. We studied the effects of the 2 chitooligosaccharides given orally to rats on the acute hepatotoxicity induced by CCl4-dependent lipid peroxidation. The increase in the sum of malondialdehyde and 4-hydroxy-2-alkenals, a marker of lipid peroxidation, in both plasma and liver of CCl4-treated rats was suppressed by oral administration of chitobiose or chitotriose. The elevation in the levels of plasma aspartate transaminase and alanine transaminase activities, markers of hepatic injury, induced by CCl4 intoxication was also counteracted by oral administration of either chitooligosaccharide. The results indicate that chitobiose and chitotriose have the ability to exert a protective action against CCl4-induced acute hepatoxicity, probably by their antioxidant activity.
Alanine Transaminase↗
Pharmacokinetics of chitobiose and chitotriose administered intravenously or orally to rats.
Chitooligosaccharides have attracted much attention as new biomedical materials. The biologic availability of each of these chitooligosaccharides, however, has not yet been studied. In the present study, we found that chitobiose and chitotriose appeared in the blood of rats with maximum plasma concentrations at around 1 h after administration when given orally at a dose of 30 mg/kg. However, chitotetraose and chitopentaose did not appear in the blood when given at a dose of 300 mg/kg. Pharmacokinetic analysis of chitobiose and chitotriose after intravenous administration at 100 mg/kg revealed that both sugars were eliminated from the body following a one-compartment model and that the former relative to the latter was higher for both the total body clearance (224+/-43 vs. 155+/-26 ml/h/kg) and the distribution volume (107+/-15 vs. 65+/-9 ml/kg). The absolute oral bioavailability of chitobiose was higher than that of chitotriose at all doses (30, 100, and 300 mg/kg) examined. The first-order absorption rate constants for chitobiose and chitotriose at all doses were less than 1.0 h(-1) and smaller than the elimination rate constants (2.2+/-0.3, 2.7+/-0.1 h(-1), respectively). The absorption was slow, resulting in flip-flop kinetics. This study indicates that among various chitooligosaccharides, only chitobiose and chitotriose can be appreciably absorbed from the gastrointestinal tract.
Administration, Oral↗
Suppression of thymic lymphoma induction by life-long low-dose-rate irradiation accompanied by immune activation in C57BL/6 mice.
The induction of thymic lymphomas by whole-body X irradiation with four doses of 1.8 Gy (total dose: 7.2 Gy) in C57BL/6 mice was suppressed from a high frequency (90%) to 63% by preirradiation with 0.075 Gy X rays given 6 h before each 1.8-Gy irradiation. This level was further suppressed to 43% by continuous whole-body irradiation with 137Cs gamma rays at a low dose rate of 1.2 mGy/h for 450 days, starting 35 days before the challenging irradiation. Continuous irradiation at 1.2 mGy/h resulting in a total dose of 7.2 Gy over 258 days yielded no thymic lymphomas, indicating that this low-dose-rate radiation does not induce these tumors. Further continuous irradiation up to 450 days (total dose: 12.6 Gy) produced no tumors. Continuously irradiated mice showed no loss of hair and a greater body weight than unirradiated controls. Immune activities of the mice, as measured by the numbers of CD4+ T cells, CD40+ B cells, and antibody-producing cells in the spleen after immunization with sheep red blood cells, were significantly increased by continuous 1.2-mGy/h irradiation alone. These results indicate the presence of an adaptive response in tumor induction, the involvement of radiation-induced immune activation in tumor suppression, and a large dose and dose-rate effectiveness factor (DDREF) for tumor induction with extremely low-dose-rate radiation.
Adaptation, Physiological↗
Further study of prolongation of life span associated with immunological modification by chronic low-dose-rate irradiation in MRL-lpr/lpr mice: effects of whole-life irradiation.
MRL-lpr/lpr mice carry a deletion in the apoptosis-regulating Fas gene that markedly shortens life due to multiple severe diseases. In our previous study (Radiat. Res. 161, 168- 173, 2004), chronic low-dose-rate gamma irradiation of mice at 0.35 or 1.2 mGy/h for 5 weeks markedly prolonged the life span, accompanied by immunological activation. This report shows that extension of the irradiation period to the entire life of the mice at the same dose rates improved survival further. The 50% survival time for untreated mice, 134 days, was prolonged to 502 days by 1.2 mGy/h life-long irradiation. Also obtained were a time course and a radiation dose-rate response for the activation of the immune system as indicated by a significant increase in CD4+ CD8+ T cells in the thymus and CD8+ T cells in the spleen and also by a significant decrease in CD3+ CD45R/B220+ cells and CD45R/B220+ CD40+ cells in the spleen. Drastic ameliorations of multiple severe diseases, i.e. total-body lymphadenopathy, splenomegaly and serious autoimmune diseases including proteinuria, and kidney and brain-central nervous system syndromes, were found in parallel with these immunological activations, with lifelong low-dose-rate irradiation being more effective than 5-week irradiation at low dose rates.
Adaptation, Physiological↗
Enhancement of radiation-induced apoptosis by preirradiation with low-dose X-rays in human leukemia MOLT-4 cells.
The effects of low-dose preirradiation on the process of radiation-induced cell death were investigated in human leukemic MOLT-4 cells. By 0.2 Gy of X-rays given 12 h prior to a challenge dose of 5 Gy, the process of apoptosis was accelerated. The acceleration was associated with a certain increase in caspase 3 activity, a disruption of the mitochondrial transmembrane potential, and an accumulation of p53 proteins. This finding is in contrast to the radiation adaptive responses in which a small dose of preirradiation would induce certain radiation resistance and decrease the cell death after irradiation with higher doses.
Adaptation, Physiological↗
Prolongation of life span associated with immunological modification by chronic low-dose-rate irradiation in MRL-lpr/lpr mice.
Chronic low-dose-rate gamma irradiation at 0.35 or 1.2 mGy/h prolonged the life span of MRL-lpr/lpr mice carrying a deletion in the apoptosis-regulating Fas gene that markedly shortens life due to severe autoimmune disease. Immunological modifications as indicated by a significant increase of CD8(+) T cells and a significant decrease of CD3(+) CD45R/B220(+) as well as CD45R/B220(+) CD40(+) cells were found in parallel with amelioration of total-body lymphadenopathy, splenomegaly, proteinuria, and kidney and brain syndromes.
AIDS-Related Complex↗
A threshold exists in the dose-response relationship for somatic mutation frequency induced by X irradiation of Drosophila.
The dose-response relationship of ionizing radiation and its stochastic effects has been thought to be linear without any thresholds. The basic data for this model were obtained from mutational assays in the male germ cells of the fruit fly Drosophila melanogaster. However, it is more appropriate to examine carcinogenic activity in somatic cells than in germ cells. Here the dose-response relationship of X irradiation and somatic mutation was examined in Drosophila. A threshold at approximately 1 Gy was observed in DNA repair-proficient flies. In the repair-deficient siblings, the threshold was smaller and the inclination of the dose-response curve was much steeper. These results suggest that the dose-response relationship between X irradiation and somatic mutation has a threshold and that the DNA repair function contributes to its formation.
Animals↗
[Urinary 8-OHdG (8-hydroxy-2'-deoxyguanosine)].
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8-Hydroxy-2'-Deoxyguanosine↗
Novel variants of murine serotonin transporter mRNA and the promoter activity of its upstream site.
Three variants of murine serotonin transporter (5-HTT) mRNA, which consist of a different exon-one (exon 1a, exon 1b or exon 1c) and the same exon-two to exon-five, were identified. The promoter region for each exon 1 (p1a, p1b and p1c, respectively), ligated to pGL-3 enhancer vector, had activities significantly higher than the empty vector in all cell lines tested except p1c in PC-12, whereas the activity of p1c was significantly lower than the others. Effects of the treatment of dibutyryl-cyclic AMP, human interferon-alpha or mouse interferon-gamma have different profiles among COS-7, PC-12, C6 glioma and immortalized rat serotonergic raphe neurons, RN46A. These three promoter regions may play a role in the transcription of the 5-HTT and could offer a model of the regulation of 5-HTT production in humans and further the pathogenesis of depression.
Alternative Splicing↗
Antioxidant activities of chitobiose and chitotriose.
Chitooligosaccharides, the oligomers made up of beta-1,4-linked D-glucosamine, are obtained by partial hydrolysis of chitosan, a deacetylation product of chitin. The antioxidant activity of various chitooligosaccharides was tested in vitro with aminoguanidine, pyridoxamine, and Trolox as reference compounds. Hydroxylation of benzoate to salicylate by H2O2 in the presence of Cu(2+) was effectively inhibited by chitobiose, chitotriose, aminoguanidine, pyridoxamine, and Trolox (their IC(50) values=18, 80, 85, 10, and 95 microM, respectively), whereas glucosamine and N-acetylchito-oligosaccharides (di-N-acetylchitobiose and tri-N-acetylchitotriose) did not show any inhibitory activity. Chitobiose and chitotriose were more potent than the 3 reference compounds in scavenging hydroxyl radicals produced by photolysis of zinc oxide: IC(50) values of the 2 oligomers were 30 and 55 microM, respectively. Such a scavenging activity of these 2 chitooligomers was also shown by the use of another system, a mixture of Fe(3+)/EDTA/ascorbate/H2O2, for producing hydroxyl radicals. Only chitobiose and Trolox, of the 10 compounds tested, had the ability to scavenge superoxide radicals generated by a non-enzymatic system using phenazine methosulfate and NADH. Taken together with our unpublished observation that chitobiose and chitotriose are appreciably absorbed from the intestine of rats, the present results suggest that these 2 chitooligosaccharides would act as effective antioxidants in vivo when orally ingested.
Antioxidants↗
Wortmannin-enhanced X-ray-induced apoptosis of human T-cell leukemia MOLT-4 cells possibly through the JNK/SAPK pathway.
We demonstrated that enhancement of X-ray-induced apoptosis/rapid cell death by wortmannin accompanied by increased activation of JNK/SAPK in human leukemia MOLT-4 cells. Rapid cell death/apoptosis was determined either by the dye exclusion test or by the appearance of Annexin V-positive cells and cleaved PARP fragments. Enhancement was observed only at higher concentrations of wortmannin, i.e. 1 microM or more. At these high concentrations, both DNA-PK and ATM were inhibited. X-ray-induced phosphorylation of Ser 15 of p53/TP53, accumulation of both p53/TP53 and p21/WAF1/CDKN1A, and phosphorylation of XRCC4 were all suppressed. The enhancement of apoptosis/rapid cell death by wortmannin was prevented by addition of caspase inhibitors, Z-VAD-FMK or Ac-DEVD-CHO, or by transfection and overexpression of mouse Bcl2, which is known as an anti-apoptosis protein. The requirement for a high concentration of wortmannin, i.e. 1 microM or more, indicates that inhibition of both DNA-PK and ATM was necessary for the enhanced apoptosis/rapid cell death. Phosphorylation of AKT/PKB was completely suppressed at a much lower concentration, i.e. 0.1 microM wortmannin, where no enhancement of X-ray-induced apoptosis/rapid cell death was observed. On the other hand, X-ray-induced phosphorylation of JNK and its kinase activity as well as apoptosis/rapid cell death were all significantly enhanced only at high concentrations of wortmannin, i.e. 1 microM or more. Furthermore, the extent of enhancement of both JNK phosphorylation and of apoptosis/rapid cell death by wortmannin was less in Rh1a cells, which are ceramide- and radiation-resistant variant cells compared to the parental MOLT-4 cells. Therefore, activation of the JNK pathway was considered important for the enhancement of X-ray-induced apoptosis/rapid cell death of MOLT-4 cells by wortmannin, because of the requirement for a higher concentration of wortmannin than that required for inhibition of AKT phosphorylation. The suppression of the AKT-dependent pathway by wortmannin may have some underlying role in activating the JNK pathway toward the enhancement of cell death in the current system.
Androstadienes↗
[Oxidative stress profile: OSP].
Oxidative stress is known to be related to various diseases such as inflammation, carcinogenesis, arteriosclerosis and ischemia-reperfusion injury, and is also a major cause of aging. For the prevention of diseases and control of aging, evaluation and control of oxidative stress in vivo may become essential. We have developed the new Oxidative Stress Profile(OSP), a total diagnostic system which provides information about oxidative stress inside human body. The OSP system consists of a number of biomakers including oxidative damage markers, prooxidant factors, antioxidants and life style-related markers. The result is shown in a two dimensional plot form. We measured a combination of biomarkers for oxidative damage of biological components, serum antioxidants and analyzed oxidative stress. The result show that oxidative stress was elevated in diabetic patients in comparison with normal controls. Oxidative stress is also elevated in smokers in comparison with non-smokers. It is also interesting to find that oxidative stress can be greatly reduced by the improvement of life style such as diet. Oxidative Stress Profile system may become a powerful tool for the evaluation of oxidative stress in vivo, and may be useful in prevention of diseases, "mi-byo"(possible cause of diseases)-diagnosis and the control of aging.
8-Hydroxy-2'-Deoxyguanosine↗
[Measurement of plasma von Willebrand factor cleaving protease in patients with varied thrombotic microangiopathy].
Thrombotic thrombocytopenic purpura(TTP) is a multisystem disorders characterized by thrombocytopenia, microangiopathic hemolytic anemia associated with red cell fragmentation, and neurological and renal symptoms. Plasma of patients with TTP has been shown to contain unusually large von Willebrand factor(vWF) multimers that may cause platelet agglutination in vivo. Recently, a metalloprotease responsible for cleavage of vWF multimers has been isolated from normal human plasma and was found to be deficient in some patients with TTP. We examined the activity of the vWF-cleaving protease(vWF-CP), by modified Furlan's method, in plasma from patients with a familial TTP, 3 acquired TTP, 4 thrombotic microangiopathy(TMA) and 2 veno-occlusive disease(VOD) associated after allo-BMT. Diluted plasma samples of patients were incubated with protease-free vWF purified from normal human plasma, in the presence of urea and barium ions. The extent of vWF degradation was assayed by electrophoresis in SDS-agarose gels and immunoblotting. Activity of vWF-CP from 12 normal plasma have been shown as 77-180%(average 115%), whereas, no vWF-CP(below 5%) was observed in plasma from familial TTP, before and after plasma exchange, although FFP infusion therapy has been effective for this patient to recover thrombocytopenia. In 3 acquired TTP, 2 patients showed lack of vWF-CP activity in plasma, and inhibitors against vWF-CP have been elucidated by plasma cross-mixing test. After extensive plasma exchange and FFP infusion followed by corticosteroid therapy, normal vWF-CP was recovered in plasma from 2 acquired TTP patients. Among BMT patients, plasma from 4 BMT-TMA showed normal vWF-CP activities as 55-111%, whereas plasma from 2 BMT-VOD revealed low vWF-CP activity, as 24% and 37%, respectively. Thus, measurement of vWF-CP is crucial to predict differentiation of primary forms of TMA to establish the pathogenesis in varied endothelial dysfunction.
ADAM Proteins↗
Chitin synthesis in chlorovirus CVK2-infected chlorella cells.
Hyaluronan synthesis in chlorovirus PBCV-1-infected Chlorella cells was previously reported (DeAngelis et al., 1997). In contrast, we report here on the detection, characterization, and expression of a gene for chitin synthase (chs) encoded by chlorovirus CVK2 isolated in Kyoto, Japan. The CVK2 chs gene encoding an open reading frame of 516 aa was expressed as early as 10 min postinfection (p.i.), peaked at 20-40 min p.i., and disappeared at 120-180 min p.i. The chitin polysaccharide began to accumulate as chitinase-sensitive, hair-like fibers on the outside of the virus-infected Chlorella cell wall by 30 min p.i. All chloroviruses without the gene for hyaluronan synthase (has) alternatively contained the chs gene, suggesting the importance of polysaccharide production in the course of virus infection. A few chloroviruses possessed both the chs and has genes and produced chitin and hyaluronan simultaneously. Polysaccharide accumulation on the algal surface may protect virus-infected algae from uptake by other organisms, such as protozoa. Since CVK2 was reported to encode two chitinases and one chitosanase, CVK2 is a very peculiar virus that encodes enzymes required for both the synthesis and the degradation of chitin materials.
Amino Acid Sequence↗