Makoto Akashi

National Institute of Radiological Sciences, Tiba, Chiba, Japan

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Publications (83)262.03 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: One of the important mechanisms for gastrointestinal (GI) injury following high-dose radiation exposure is apoptosis of epithelial cells. X-linked inhibitor of apoptosis (XIAP) and cellular IAP2 (cIAP2) are intrinsic cellular inhibitors of apoptosis. In order to study the effects of exogenously added IAPs on apoptosis in intestinal epithelial cells, we constructed bacterial expression plasmids containing genes of XIAP (full-length, BIR2 domain and BIR3-RING domain with and without mutations of auto-ubiquitylation sites) and cIAP2 proteins fused to a protein-transduction domain (PTD) derived from HIV-1 Tat protein (TAT) and purified these cell-permeable recombinant proteins. When the TAT-conjugated IAPs were added to rat intestinal epithelial cells IEC6, these proteins were effectively delivered into the cells and inhibited apoptosis, even when added after irradiation. Our results suggest that PTD-mediated delivery of IAPs may have clinical potential, not only for radioprotection but also for rescuing the GI system from radiation injuries.
    Journal of radiation research. 10/2014;
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    ABSTRACT: A huge earthquake struck the northeast coast of the main island of Japan on 11 March 2011, triggering a tsunami with more than 10-m-high waves hitting the area. The earthquake was followed by numerous sustained aftershocks. The earthquake and aftershocks left almost 16,000 people dead and more than 2,800 missing (as of 11 March 2014). The earthquake affected the Fukushima Daiichi Nuclear Power Plant (NPP) of Tokyo Electric Power Company (TEPCO), causing serious damage to the NPP and resulting in large amounts of radioactive materials being released into not only controlled areas but also the environment. Damage was caused to the cooling systems of the NPP, although they automatically shut down after the earthquake. The trouble with the cooling systems led to hydrogen explosions and core meltdown. The major nuclides released on land were I, Cs, and Cs. The release of these radioactive materials resulted in contamination of first responders and workers and also a high ambient dose of radiation around the NPP. The local hospital system, including that for radiation emergency medicine, was dysfunctional. Hospitals that had been designated as radiation emergency facilities were not able to function because the earthquake and tsunami had caused damage to their facilities; some of these were located within a 20-km radius of the NPP and in the evacuation areas. Local fire department personnel were also ordered to evacuate. Fukushima prefecture changed the screening level required for decontamination from 13,000 to 100,000 cpm, with decontamination by wiping being performed for over 13,000 cpm. However, as hospitals and fire departments had to abide by lower levels than that of the prefecture for receiving or transporting contaminated patients, these personnel could not accept or transport contaminated people from the NPPs. In addition, hospitals not designated as radiation emergency facilities would not receive patients from the NPPs because of concerns about the health effects of radiation. From this disaster, it was learned that basic knowledge of radiation and its effects is extremely important for health care providers.
    Health physics 06/2014; 106(6):630-7. · 0.92 Impact Factor
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    ABSTRACT: A huge earthquake struck the northeast coast of the main island of Japan on March 11, 2011, triggering a tsunami with 14-15 meter-high waves hitting the area. The earthquake was followed by numerous sustained aftershocks. The earthquake affected the nuclear power plant (NPP) in Fukushima prefecture, resulting in large amounts of radioactive materials being released into the environment. The major nuclides released on land were (131) I, (134) Cs, and (137) Cs. Therefore, almost 170 000 people had to be evacuated or stay indoors. Besides the NPP and the telecommunications system, the earthquake also affected infrastructures such as the supplies of water and electricity as well as the radiation monitoring system. The local hospital system was dysfunctional; hospitals designated as radiation-emergency facilities were not able to function because of damage from the earthquake and tsunami, and some of them were located within a 20 km radius of the NPP, the designated evacuation zone. Local fire department personnel were also asked to evacuate. Furthermore, the affected hospitals had not established their evacuation plans at that time. We have learned from this "combined disaster" that the potential for damage to lifelines as well as the monitoring systems for radiation in case of an earthquake requires our intense focus and vigilance, and that hospitals need comprehensive plans for evacuation, including patients requiring life support equipment during and after a nuclear disaster. There is an urgent need for a "combined disaster" strategy, and this should be emphasized in current disaster planning and response.
    Drug Development Research 02/2014; 75(1):3-9. · 0.87 Impact Factor
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    ABSTRACT: Accidental exposure of the abdomen to high-dose radiation leads to severe consequences initiated by disruption of the mucosa in the small intestine. Therapeutic options are limited, even though various treatments have been investigated, particularly in the field of regenerative therapy. In order to identify readily available treatment methods, we included several current pharmaceutical drugs, for which the clinical trials have already been completed, in tests on mice that had undergone severe mucosal damage by radiation. The drugs were injected into mice 24 h after exposure to 15.7 Gy X-rays. The effects of the drugs on the damaged mucosa of the small intestine were evaluated using early regeneration indices [the expression of c-myb mRNA, and proliferation of epithelial cells in the form of microcolonies (MCs) by Days 4 and 5 post-irradiation] and the survival rate of the mice. Enhancement of mucosal regeneration at Day 4 (c-myb: P < 0.01, MC: P < 0.05) and improvement of the survival rate (P < 0.05) were observed when a clinical dose of gonadotropin, a stimulator of androgen, was injected. Similarly, a clinical dose of thiamazole (which prevents secretion of thyroid hormone) stimulated mucosal growth by Day 5 (c-myb: P < 0.01, MC: P < 0.05) and also improved the survival rate (P < 0.05). The nonclinical drugs histamine and high-dose octreotide (a growth hormone antagonist) also gave significant survival-enhancing benefits (P < 0.01 and P < 0.05, respectively). These results can be used to construct therapeutic programs and applied in various experimental studies to control the regeneration of damaged mucosa.
    Journal of Radiation Research 05/2013; · 1.45 Impact Factor
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    ABSTRACT: Although radiation exposure accidents fortunately occur only rarely, potential sources for exposure accidents can be found anywhere. When persons are accidentally exposed to radiation, physicians may be involved in their assessment and care; of course, their early diagnosis and dose assessment are crucial. After the criticality accident at Tokaimura in 1999, the system of radiation emergency medical preparedness has been further strengthened for nuclear facilities in Japan. In the revised system, hospitals involved were classified into three levels, depending on their locations and capabilities. The Great East Japan Earthquake attacked the Pacific coast area of eastern Japan on 11 March 2011. This earthquake and tsunami caused serious damage to the nuclear power plants of Tokyo Electric Power Co.(TEPCO) in Fukushima Prefecture; a large amount of radionuclides such as iodine and cesium were released into the environment. Since the revised system was focused on treatment of heavily exposed patients and knowledge on radiation was not enough for medical staff, many problems were raised at hospitals and fire departments in this disaster.
    Nippon rinsho. Japanese journal of clinical medicine 03/2012; 70(3):469-74.
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    ABSTRACT: The vascular endothelium is important for the early and late effects observed in lethally irradiated tissue and organs. We examined the effects of exogenously added superoxide dismutase on cell survival and angiogenesis in lethally irradiated human primary umbilical vein endothelial cells. Cell survival was significantly improved in superoxide dismutase-treated cells; the addition of superoxide dismutase to cells after irradiation was also effective for increased survival, as it was before irradiation. Moreover, treatment of cells with superoxide dismutase enhanced the phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase/extracellular signal regulated kinases 1 and 2 in human primary umbilical vein endothelial cells. The addition of superoxide dismutase to cells after irradiation attenuated the reduction of angiogenesis by irradiation, and inhibition of the mitogen-activated protein/extracellular signal-regulated kinase/extracellular signal regulated kinases signaling pathway abrogated the rescue effect of superoxide dismutase. Our results suggest that superoxide dismutase rescues human primary umbilical vein endothelial cells from endothelial dysfunction caused by irradiation via a pathway requiring activation of mitogen-activated protein/extracellular signal-regulated kinase/extracellular signal regulated kinases 1 and 2.
    Journal of Clinical Biochemistry and Nutrition 01/2012; 50(1):78-83. · 2.25 Impact Factor
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    ABSTRACT: The extracellular effect of fibroblast growth factor-12 (FGF12) remains unknown because FGF12 cannot activate any fibroblast growth factor receptors (FGFRs), and FGF12 is not currently thought to be released from cells. We reported previously that FGF12 plays an intracellular role in the inhibition of radiation-induced apoptosis. In this study, we demonstrated that recombinant FGF12 was able to be internalized into the cytoplasm of a rat intestinal epithelial cell line, IEC6, and this process was dependent on two novel cell-penetrating peptide (CPP) domains (CPP-M and CPP-C). In particular, CPP-C, composed of ∼10 amino acids, was identified as a specific domain of FGF12 and its subfamily in the C-terminal region (residues 140–149), although CPP-M was a common domain in the internal region of the FGF family. The absence of CPP-C from FGF12 or a mutation (E142L) in the CPP-C domain drastically reduced the internalization of FGF12 into cells. Therefore, CPP-C played an essential role in the internalization of FGF12. In addition, CPP-C was able to deliver other polypeptides into cells as a CPP because an FGF1/CPP-C chimeric protein was internalized into IEC6 cells more efficiently than wild-type FGF1. Finally, intraperitoneally added FGF12 inhibited radiation-induced apoptosis in the intestinal epithelial cells of BALB/c mice, and deletion of the CPP-C domain decreased the inhibition of the apoptosis. These findings suggest that exogenous FGF12 can play a role in tissues by translocating into cells through the plasma membrane, and the availability of this novel CPP provides a new tool for the intracellular delivery of bioactive molecules.
    Journal of Biological Chemistry 07/2011; 286(29):25823-25834. · 4.65 Impact Factor
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    ABSTRACT: The extracellular effect of fibroblast growth factor-12 (FGF12) remains unknown because FGF12 cannot activate any fibroblast growth factor receptors (FGFRs), and FGF12 is not currently thought to be released from cells. We reported previously that FGF12 plays an intracellular role in the inhibition of radiation-induced apoptosis. In this study, we demonstrated that recombinant FGF12 was able to be internalized into the cytoplasm of a rat intestinal epithelial cell line, IEC6, and this process was dependent on two novel cell-penetrating peptide (CPP) domains (CPP-M and CPP-C). In particular, CPP-C, composed of ∼10 amino acids, was identified as a specific domain of FGF12 and its subfamily in the C-terminal region (residues 140-149), although CPP-M was a common domain in the internal region of the FGF family. The absence of CPP-C from FGF12 or a mutation (E142L) in the CPP-C domain drastically reduced the internalization of FGF12 into cells. Therefore, CPP-C played an essential role in the internalization of FGF12. In addition, CPP-C was able to deliver other polypeptides into cells as a CPP because an FGF1/CPP-C chimeric protein was internalized into IEC6 cells more efficiently than wild-type FGF1. Finally, intraperitoneally added FGF12 inhibited radiation-induced apoptosis in the intestinal epithelial cells of BALB/c mice, and deletion of the CPP-C domain decreased the inhibition of the apoptosis. These findings suggest that exogenous FGF12 can play a role in tissues by translocating into cells through the plasma membrane, and the availability of this novel CPP provides a new tool for the intracellular delivery of bioactive molecules.
    Journal of Biological Chemistry 04/2011; 286(29):25823-34. · 4.65 Impact Factor
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    ABSTRACT: Damage to intestine is a serious problem after accidental radiation exposure. To examine substances to ameliorate damage by postirradiation administration, we focused on the regeneration process after irradiation of the intestine. Using experimental systems, the effects of clinically used sex hormones on regeneration were compared. An anabolic steroid, nandrolone (19-nortestosterone), stimulated proliferation in IEC-6 epithelial cells. A single injection of 19-nortestosterone ester with prolonged action into mice 24 h after abdominal irradiation at a lethal dose of 15.7 Gy showed significant life-saving effects. Regeneration indicators such as microcolonies of BrdU-incorporated cells at day 5 and c-myb mRNA expression levels at day 4 were enhanced by 19-nortestosterone administration. In contrast, high concentrations of estradiol inhibited growth of IEC-6 cells. Treatment of abdominally irradiated mice with estradiol ester decreased levels of regeneration indicators and survival. These results suggest the effectiveness of the anabolic steroid as well as the importance of manipulation of steroid receptors in the recovery of mucosa damaged by radiation.
    Radiation Research 03/2011; 175(3):367-74. · 2.70 Impact Factor
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    ABSTRACT: Although carbon ion therapy facilities are expensive, the biological effects of carbon ion beam treatment may be better against cancer (and cancer stem cells) than the effects of a photon beam. To investigate whether a carbon ion beam may have a biological advantage over X-rays by targeting cancer stem-like cells, human colon cancer cells were used in vitro and in vivo. The in vitro relative biological effectiveness (RBE) values of a carbon ion beam relative to X-rays at the D10 values were from 1.63 to 1.74. Cancer stem-like CD133(+), CD44(+)/ESA(+) cells had a greater ability for colony and spheroid formation, as well as in vivo tumorigenicity compared with the CD133(-), CD44(-)/ESA(-) cells. FACS (fluorescence-activated cell sorting) data showed that cancer stem-like cells were more highly enriched after irradiation with X-rays than carbon ion at doses that produced the same level of biological efficacy. A colony assay for cancer stem-like cells showed that RBE values calculated by the D10 levels were from 2.05 to 2.28 for the carbon ion beam relative to X-rays. The in vivo xenotransplant assay showed an RBE of 3.05 to 3.25, calculated from the slope of the dose-response curve for tumor growth suppression. Carbon ion irradiation with 15 Gy induced more severe xenograft tumor cell cavitation and fibrosis without significant enhancement of cells with putative cancer stem cell markers, CD133, ESA, and CD44, compared with 30 Gy X-rays, and marker positive cells were significantly decreased following 30 Gy carbon ion irradiation. Taken together, carbon ion beam therapy may have an advantage over photon beam therapy by improved targeting of putative colon cancer stem-like cells.
    Cancer Research 03/2011; 71(10):3676-87. · 9.28 Impact Factor
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    ABSTRACT: A fibroblast growth factor (FGF) 1-FGF2 chimera (FGFC) was created previously and showed greater structural stability than FGF1. This chimera was capable of stimulating epithelial cell proliferation much more strongly than FGF1 or FGF2 even without heparin. Therefore FGFC was expected to have greater biologic activity in vivo. This study evaluated and compared the protective activity of FGFC and FGF1 against radiation-induced intestinal injuries. We administered FGFC and FGF1 intraperitoneally to BALB/c mice 24 h before or after total-body irradiation (TBI). The numbers of surviving crypts were determined 3.5 days after TBI with gamma rays at doses ranging from 8 to 12 Gy. The effect of FGFC was equal to or slightly superior to FGF1 with heparin. However, FGFC was significantly more effective in promoting crypt survival than FGF1 (p < 0.01) when 10 μg of each FGF was administered without heparin before irradiation. In addition, FGFC was significantly more effective at promoting crypt survival (p < 0.05) than FGF1 even when administered without heparin at 24 h after TBI at 10, 11, or 12 Gy. We found that FGFC post treatment significantly promoted 5-bromo-2'-deoxyuridine incorporation into crypts and increased crypt depth, resulting in more epithelial differentiation. However, the number of apoptotic cells in FGFC-treated mice decreased to almost the same level as that in FGF1-treated mice. These findings suggest that FGFC strongly enhanced radioprotection with the induction of epithelial proliferation without exogenous heparin after irradiation and is useful in clinical applications for both the prevention and post treatment of radiation injuries.
    International journal of radiation oncology, biology, physics 11/2010; 78(3):860-7. · 4.59 Impact Factor
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    ABSTRACT: An earthquake measuring 6.8 on the Richter scale struck the Niigata-Chuetsu region of Japan at 10:13 on 16 July 2007. The earthquake was followed by the sustained occurrence of numerous aftershocks, delaying the reconstruction of community lifelines. The earthquake affected the Kashiwazaki-Kariwa nuclear power plants (NPPs), the biggest NPP site in the world. The earthquake caused damage to NPPs, resulting in a small amount of radioactive materials being released into the air and the sea. However, no significant effects were detected in the public and the environment. As medical response to this earthquake, 42 Disaster Medical Assistance Teams (DMATs) were sent to hospitals and first-aid care centers at the NPP site. In order to evaluate the perceptions of the deployed DMAT personnel regarding concerns about the health effects of radiation and information about the damage to NPPs, questionnaires were sent to 40 facilities that dispatched DMATs to the earthquake area. Most of them were concerned with the effects of radiation, and adequate information about the problems at the NPPs was not communicated to them. This preliminary study suggests that communication of information is extremely important for DMAT members in the case of disasters, in particular if there exists a possibility of radiation exposure, since radiation cannot be detected by our senses. DMAT members are critical to any mass casualty incident, whether caused by humans or nature. We have learned from this earthquake that there is urgent need for an all-hazards approach, including a "combined disaster" strategy, which should be emphasized for current disaster planning and response. This is the first report on DMATs deployed to an earthquake site with damage to NPPs.
    Health physics 06/2010; 98(6):804-9. · 0.92 Impact Factor
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    ABSTRACT: Molecular mechanisms of intracellular response after DNA-damage by exposure to ionizing radiation have been studied. In the case of cells isolated from living body of human and experimental animals, alteration of the responsiveness by physiological oscillation such as circadian rhythm must be considered. To examine the circadian variation in the response of p53-responsible genes p21, mdm2, bax, and puma, we established a method to quantitate their mRNA levels with high reproducibility and accuracy based on real-time RT-PCR and compared the levels of responsiveness in mouse hemocytes after diurnal irradiation to that after nocturnal irradiation. Augmentations of p21 and mdm2 mRNA levels with growth-arrest and of puma mRNA before apoptosis were confirmed by time-course experiment in RAW264.7, and dose-dependent increases in the peak levels of all the RNA were shown. Similarly, the relative RNA levels of p21, mdm2, bax, and puma per GAPDH also increased dose-dependently in peripheral blood and bone marrow cells isolated from whole-body-irradiated mice. Induction levels of all messages reduced by half after nighttime irradiation as compared with daytime irradiation in blood cells. In marrow cells, nighttime irradiation enhanced the p21 and mdm2 mRNA levels than daytime irradiation. No significant difference in bax or puma mRNA levels was observed between nighttime and daytime irradiation in marrow cells. This suggests that early-stage cellular responsiveness in DNA damage-induced genes is modulated between diurnal and nocturnal irradiation.
    Journal of Radiation Research 03/2010; 51(3):265-75. · 1.45 Impact Factor
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    ABSTRACT: Several members of the fibroblast growth factor (FGF) family have the potential to protect the intestine against the side effects of radiation therapy. FGF1 is capable of signaling through all subtypes of FGF receptors (FGFRs), whereas FGF7 and FGF10 activate only the epithelial-specific subtype, FGFR2IIIb (FGFR2b). The present study compared the protective activity of FGF1, FGF7 and FGF10 and examined the profiles of FGFR expression in the jejunum of BALB/c mice given total-body irradiation (TBI) with gamma rays. TBI caused drastic increases in FGFR1-4 transcript levels in the jejunum. However, FGFR2b protein temporarily decreased at 12 and 24 h after irradiation. FGF1 pretreatment minimized the number of apoptotic cells in jejunal crypts at 16 and 24 h after irradiation and increased crypt survival most effectively. In addition, pretreatment with FGF7 or FGF10 decreased FGFR1 transcript levels. The greater effectiveness of FGF1 to enhance crypt survival was also observed even when each FGF was administered 1 h after irradiation. These findings indicate that FGF1 is more potent than FGF7 or FGF10 for protection of the intestine against radiation exposure and suggest that the profiles of FGFR expression in the intestine favor the FGF1 signaling pathway before and during the initial period after irradiation.
    Radiation Research 08/2009; 172(1):58-65. · 2.70 Impact Factor
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    ABSTRACT: Radiation-induced hair loss is a clinically important, but under-researched topic. The aim of the study was to develop an in vivo assay system for radiation-induced apoptosis in hair follicles to promote hair research and exploit new radioprotectors. BALB/c mice received total body irradiation (TBI) with gamma-rays at doses in the range from 8 to 16 Gy at 6 days after depilation. Pathological changes were detected progressively in the hair follicles over the time course after TBI and the dystrophy was evaluated on the basis of stage-specific parameters reported previously, which were found to be well-suited for classification of the radiation-induced hair follicle dystrophy. As a result, regression from anagen to catagen was determined in these follicles after irradiation. In addition, radiation-induced apoptosis was a good early dystrophic parameter. In this system, it was found that fibroblast growth factor-1 effectively prevented hair follicle apoptosis in mice.
    Experimental Dermatology 04/2009; 18(10):889-92. · 3.58 Impact Factor
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    ABSTRACT: Human promonocytic cell line U937 cells can be induced to differentiate into macrophages by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). TPA treatment induced the expression of the monocytic differentiation markers CD11b and CD36, with concomitant morphological changes. Moreover, TPA enhanced reactive oxygen species (ROS) generation in these cells, and phagocytic ability was also stimulated during differentiation. The antioxidant agent N-acetyl-L-cysteine inhibited the TPA-induced differentiation of U937 cells. TPA treatment decreased the expression level of catalase, which catalyzes the decomposition of hydrogen peroxide (H(2)O(2)) to H(2)O and O(2). In contrast, TPA increased the level of manganese superoxide dismutase, which catalyzes the dismutation of superoxide into H(2)O(2) and O(2) without affecting the levels of copper-zinc superoxide dismutase or glutathione peroxidase 1, which removes H(2)O(2) using glutathione as substrate. Treatment of U937 cells with catalase inhibited the enhancement of ROS generation induced by TPA, and blocked the TPA-induced differentiation of U937 cells. Human promyelocytic cell line HL60 cells were also induced to differentiate into macrophages by TPA. However, HP100-1 cells, its variant cell line overexpressing catalase, were resistant to TPA-induced differentiation. Our results suggest that catalase inhibits monocytic differentiation by TPA; the decrease in catalase level and the accumulation of H(2)O(2) are significant events for monocyte/macrophage differentiation by TPA.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2009; 23(4):761-9. · 10.16 Impact Factor
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    ABSTRACT: Panax ginseng has been shown to have a protective effect for irradiated animals or cells. Ginsenosides are the most active components isolated from ginseng, and ginsenoside Rd has been identified as one of the effective compounds responsible for the pharmaceutical actions of ginseng. In the present study, we studied the molecular mechanisms for the radio-protective action of ginsenoside Rd in rat intestinal epithelial IEC-6 cells. Cells were irradiated with gamma-ray, and apoptosis was examined using Hoechst staining and Western blot analysis. Treatment with ginsenoside Rd before gamma-irradiation inhibited irradiation-induced apoptosis in IEC-6 cells. Administration of Rd after irradiation also inhibited apoptosis in these cells. Irradiation of IEC-6 cells resulted in inactivation of Akt phosphorylation that was abrogated by Rd. On the other hand, irradiation activated phosphorylation of ERK1/2 but did not affect that of p38 MAPK. Inhibition of Akt phosphorylation prevented the reduction of apoptosis by Rd following irradiation. Pretreatment with an inhibitor of the MEK pathway further decreased the number of apoptotic cells. Rd decreased the ratios of Bax/Bcl-2 and Bax/Bcl-xL, the levels of cytochrome c, and the cleaved form of caspase-3 in irradiated IEC-6 cells. Our results suggest that ginsenoside Rd protects and rescues rat intestinal epithelial cells from irradiation-induced apoptosis through a pathway requiring activation of PI3K/Akt, inactivation of MEK, and also inhibition of a mitochondria/caspase pathway.
    Food and Chemical Toxicology 09/2008; 46(9):3080-9. · 3.01 Impact Factor
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    ABSTRACT: Several fibroblast growth factors (FGFs) are able to reduce and improve radiation-induced tissue damage through the activation of surface fibroblast growth factor receptors (FGFRs). In contrast, some FGFs lack classical signal sequences, which play roles in the release of FGFs, and the intracellular function of these FGFs is not well clarified. In this study, we evaluated the transcript levels of 22 FGFs in a human mast cell line, HMC-1, using quantitative RT-PCR and found that FGF2 and FGF12 were expressed in HMC-1 cells. FGF12 not only lacks classical signal sequences but also fails to activate FGFRs. HMC-1 cells were transfected with an expression vector of FGF12 to clarify the intracellular function of FGF12 after irradiation. The overexpression of FGF12 in HMC-1 cells decreased ionizing radiation-induced apoptosis, and siRNA-mediated repression of FGF12 expression augmented apoptosis in HMC-1 cells. The overexpression of FGF12 strongly suppressed the marked augmentation of apoptosis induced by inhibition of the MEK/ERK pathway with PD98059. In contrast, the mitogen-activated protein kinase (MAPK) scaffold protein islet brain 2 (IB2), which was reported to bind to FGF12, did not interfere with the anti-apoptotic effect of FGF12. The expression of FGF12 transcripts was also detected in murine cultured mast cells derived from bone marrow or fetal skin. These findings suggest that FGF12 intracellularly suppresses radiation-induced apoptosis in mast cells independently of IB2.
    Journal of Radiation Research 09/2008; 49(5):491-501. · 1.45 Impact Factor
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    ABSTRACT: Structural instability of wild-type fibroblast growth factor (FGF)-1 and its dependence on exogenous heparin for optimal activity diminishes its potential utility as a therapeutic agent. Here we evaluated FGFC, an FGF1:FGF2 chimeric protein, for its receptor affinity, absolute heparin-dependence, stability and potential clinical applicability. Using BaF3 transfectants overexpressing each FGF receptor (FGFR) subtype, we found that, like FGF1, FGFC activates all of the FGFR subtypes (i.e., FGFR1c, FGFR1b, FGFR2c, FGFR2b, FGFR3c, FGFR3b and FGFR4) in the presence of heparin. Moreover, FGFC activates FGFRs even in the absence of heparin. FGFC stimulated keratinocytes proliferation much more strongly than FGF2, as would be expected from its ability to activate FGFR2b. FGFC showed greater structural stability, biological activity and resistance to trypsinization, and less loss in solution than FGF1 or FGF2. When FGFC was intraperitoneally administered to BALB/c mice prior to whole body gamma-irradiation, survival of small intestine crypts was significantly enhanced, as compared to control mice. These results suggest that FGFC could be useful in a variety of clinical applications, including promotion of wound healing and protection against radiation-induced damage.
    Biochimica et Biophysica Acta 09/2008; 1780(12):1432-40. · 4.66 Impact Factor
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    ABSTRACT: Arsenic, a known human carcinogen, can induce tumors of the skin, urinary bladder, liver and lung etc.. On the other hand, arsenic is also a novel promising anticancer agent, and can be used effectively to treat acute promyelocytic leukemia (APL) and some other tumors. These paradoxical effects of arsenic not only result from direct or indirect influences on the genetic and epigenetic levels, but are also closely correlated with unique arsenic metabolism. This article reviews our recent studies as well as other reports on arsenic metabolism and epigenetic changes of DNA methylation during its metabolism. We also summarize the clinical use of arsenic trioxide (As2O3) to date and discuss new therapeutic strategies such as concurrent arsenic-radiation therapy to achieve local tumor control and enhance the radiosensitivity of solid tumors.
    Current Medicinal Chemistry 02/2008; 15(22):2293-304. · 3.72 Impact Factor

Publication Stats

972 Citations
262.03 Total Impact Points

Institutions

  • 1993–2013
    • National Institute of Radiological Sciences
      • • Research Center for Charged Particle Therapy
      • • Research Center for Radiation Protection
      Tiba, Chiba, Japan
  • 1991–1996
    • Cedars-Sinai Medical Center
      • • Division of Hematology and Oncology
      • • Department of Medicine
      Los Angeles, CA, United States
  • 1989–1990
    • University of California, Los Angeles
      • • Division of Hematology and Medical Oncology
      • • Department of Medicine
      Los Angeles, CA, United States