Biomedical Research on Trace Elements
Online ISSN : 1880-1404
Print ISSN : 0916-717X
ISSN-L : 0916-717X
Volume 16, Issue 4
Displaying 1-25 of 25 articles from this issue
Reveiw Article
  • Jun-ichi Chikawa
    2005 Volume 16 Issue 4 Pages 265-275
    Published: 2005
    Released on J-STAGE: July 19, 2006
    JOURNAL FREE ACCESS
    Homeostasis in concentration of essential elements and its abnormality due to the development of cancer have been observed for single hair samples by fluorescent x-ray analysis using synchrotron radiation. Ca and K play important roles as messengers in the universal cellular signal transduction. Their concentrations in hair were found to have two levels of high and low concentrations due to open and close of their ion channels of hair matrix cells, which exhibit the status of their metabolisms. The analysis of patient hair from its root to tip revealed that breast cancer accompanies the characteristic long-term change from the high to low level of the hair Ca concentration that had started 8 to 12 months before finding the cancer; breast cancer originates from disturbance of the cellular signal transduction by the high Ca level in cells. In contrast to the case of Ca, K concentration in cells must be much higher than that in serum. However, K deficiency to cause hypertension was found for 50% of the hair donors; this rate is nearly equal to the population of hypertension in Japan. Most of elements such as Fe, Cu, Zn, etc. are controlled with their excretion as bile in the liver. When this function is disordered by diseases such as hepatocellular carcinoma, the elemental profiles in hair were strongly disturbed by unusual increases of element concentrations and appearance of other elements such as Ge, depending upon dietary element intakes.
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Review Articles
  • Kin-ichi Tsunoda
    2005 Volume 16 Issue 4 Pages 276-280
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Aluminum, especially, cationic form of A3+, is toxic to animals and plants. In this mini-review, after the toxicity of aluminum toward plants and its neurotoxicity in human beings are briefly reviewed, the present status of the speciation analysis for aluminum in biological and environmental samples is introduced. Some plants have evolved mechanisms resistant to aluminum toxicity where organic acids such as malate, citrate and oxalate may play a central role. The potentialities of electrospray ionization mass spectrometry for identifying such aluminum-organic acid complexes are discussed.
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  • Yuki Munebayashi, Masatoshi Kinugasa, Seiji Nakatsuka, Chiharu Minami
    2005 Volume 16 Issue 4 Pages 281-284
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    The first mesoscale iron-enrichment experiments in the northwest subarctic Pacific were conducted in July-August 2001 (SEEDS2001) and July-August 2004 (SEEDS II). During these experiments, the dynamics of dissolved and acid-dissolvable trace metals were studied. For SEEDS2001, seawater samples were collected from the upper water column (5-70 m) of In- and Out-patch stations. Immediately after the collection, an aliquot of seawater for dissolved species was filtered through a 0.2μm filter and acidified to pH 2.2. An aliquot for acid-dissolvable species was acidified without filtration and stored for 3 years at an ambient temperature. Before the Fe enrichment, the concentration of dissolved Fe in the surface mixed layer was <0.13 nM (the detection limit) and that of acid-dissolvable Fe was 4.7 nM. The difference was a particulate fraction. Since the photochemical quantum efficiency of algal photosystem II was low, Fe in this fraction was not easily available to phytoplankton. After the Fe enrichment, acid-dissolvable Fe in the patch decreased from 9.6 nM on day 2 to 4.6 nM on day 13 after starting the experiment, which was still ∼3 nM higher than that at the Out-patch station. Dissolved Fe was 1.4 nM on day 2 and decreased exponentially to <0.13 nM on day 11. The concentration ratio of the acid-dissolvable fraction to the dissolved fraction for the other trace metals was lower than that for Fe. The acid- dissolvable concentrations for Co, Ni, Cu, Zn and Cd did not show significant changes. The dissolved concentrations in the surface layer decreased exponentially. The molar ratio of the concentration difference between days 2 and 13 was similar to the elemental ratio reported for phytoplankton. These are the first data showing that mesoscale iron-enrichment alters the dynamics of dissolved Co, Ni, Cu and Zn. On the contrary, significant decrease in the dissolved concentration was not detected except for Cd during SEEDS II.
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Original Article
  • Hiroshi Yasuda, Toshie Yonashiro, Kazuya Yoshida, Tomiko Ishii, Toyoha ...
    2005 Volume 16 Issue 4 Pages 285-292
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    In order to investigate any role of minerals in autistic disorders, we measured 24 mineral contents in scalp hair samples of 360 autistic children and compared with those of healthy controls. In the male autistic group aged 4-9 years (N=200), the geometric means of many element levels, namely not only essential minerals such as cobalt, chromium, iodine, molybdenum and phosphorus, but also nickel, boron, cadmium and lead were significantly lower than those in the control group (p<0.001). In contrast, selenium level was significantly higher in the autistic group. On the mercury levels, no significant difference was observed between the two groups, though with a tendency of low concentration in the autistic group. Similar mineral imbalance profiles with a global mineral deficiency were observed in the other autistic groups aged 0-3 and 10-15 years (N=85 and 20) and also in the female autistic groups. In addition, high accumulation of a few elements such as iron, manganese, chromium, copper, sodium, aluminum, cadmium, lead, or mercury was observed in some autistic individuals. These findings indicate that autistic children are suffered from a global mineral deficiency in various trace elements, with some individuals being exposed to a marked accumulation of several elements. Autistic children may be classified to sub-groups, based on their mineral imbalance profile in hair.
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Short Communications
  • Noriyuki Shiraishi, Wenxiang Bi, Morimitsu Nishikimi
    2005 Volume 16 Issue 4 Pages 293-295
    Published: 2005
    Released on J-STAGE: July 19, 2006
    JOURNAL FREE ACCESS
    Prion protein (PrP) consists of an amino-terminal domain containing a series of octapeptide repeats with the consensus sequence PHGGGWGQ and a carboxyl-terminal domain composed of three α-helices and two short β-strands. Several studies have shown that the amino-terminal domain binds five Cu2+ ions. In this study, we have investigated the effect of reactive oxygen species (ROS) on PrP and copper-loaded PrP. In the presence of H2O2 or O2-, copper-loaded PrP, either an N-terminal fragment or a full-length molecule, underwent degradation and polymerization, whereas PrP without copper did not suffer any oxidative damage upon incubation with the ROS. The oxidative damage on copper-loaded PrP was decreased in the presence of the copper chelators and catalase, but not in the presence of hydroxyl radical scavengers. Together, these results indicate that the copper bound to PrP causes oxidative damage by ROS.
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  • Tetsuro Agusa, Suguru Inoue, Takashi Kunito, Reiji Kubota, Tu Binh Min ...
    2005 Volume 16 Issue 4 Pages 296-298
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    High As concentrations over the World Health Organization (WHO) drinking water guideline were recently found in groundwater of Gia Lam District and Thanh Tri District, Hanoi, located in the center of the Red River Delta, Vietnam. To reveal the distribution of As contamination in groundwater of the Red River Delta, contamination status of As in other two regions, Ha Nam Province and Ha Tay Province, was examined. Concentrations of As in the groundwater from both regions ranged from 3.0 to 486 μg/l and most of the samples exceeded the WHO drinking water guideline of 10 μg/l. These results suggest that human health risk in both provinces is of concern and that As pollution may be widely distributed in the Red River Delta. Inorganic arsenicals and their methylated compounds such as monomethylarsonic acid [MMA] and dimethylarsinic acid [DMA] were found in urine of residents in the Ha Nam Province and Ha Tay Province. Concentrations of As in groundwater were positively correlated with inorganic arsenicals and DMA in human urine, suggesting that residents are exposed to As through consumption of groundwater.
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  • Masaya Kawase, Noritaka Kagaya, Akiko Kamiyoshi, Yoh-ichi Tagawa, Kiyo ...
    2005 Volume 16 Issue 4 Pages 299-301
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    αl-Acid glycoprotein (AGP) prevented primary hepatocytes from undergoing cell death induced by the chemical toxin, bromobenzene at range from 0.1 to 0.2 mg/ml. Addition of zinc (0.2 mM) to medium containing AGP (0.02 mg/ml) was found to prevent the cell death by bromobenzene. Zinc is shown to enhance the hepatoprotective effect of AGP. Circular dichroism and thermal analysis were done to investigate the mechanism of the effect of zinc mentioned above. The results suggest that zinc stabilizes the conformation of AGP.
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  • Yuriko Yasuhara, Hiroyuki Yasui, Hiromu Sakurai
    2005 Volume 16 Issue 4 Pages 302-305
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    UVA-induced reactive oxygen species (ROS) generation is well known to cause cutaneous lesion in the skin, therefore, it is important to prevent the skin from UV damage due to ROS generation. In 2000, we reported first the in vivo detection and imaging by chemiluminescence (CL) method of the generated ROS in the skin of live mice following UVA-irradiation [1]. Using this method, we found that superoxide anion radical (•O2¯) was intrinsically generated in the skin of live mice and singlet oxygen (1O2) was exclusively produced in the skin following UVA-irradiation. In our previously report, we found that topical application and oral administration of zinc compounds to the skin of live mice reduce the formation of UVA-induced ROS [2-3]. Then, in the present study, we examined whether metallogluconates (zinc gluconate (ZnGA) and copper gluconate (CuGA)) topically applied and orally administered reduce the intrinsic and UVA-induced ROS generations in the skin of live mice or not. We found that topical application and oral supplementation of CuGA reduced CL intensities in terms of the formation of UVA-induced ROS and ZnGA suppressed inflammation caused UVA-exposure.
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  • Kunio SHIRAISHI, Susumu KO, Sarata Kumar SAHOO, Hideki Arae, Kyoko Aya ...
    2005 Volume 16 Issue 4 Pages 306-310
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Daily intakes of twelve elements in Ukrainian subjects were estimated in relation to the health effects on habitants after the Chernobyl accident. Total diets were collected from one hundred twenty-three locations for children and adult males by a duplicate portion method. Elements were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES) or inductively coupled plasma mass spectrometry (ICP-MS). Geometric mean and median (in parentheses) of daily intake in Ukrainians are as follows: Co 10.3 (9.83) μg; Cu 0.688 (0.701) mg; Zn 5.73 (5.44) mg; Mn 2.26 (2.28) mg; Fe 8.15 (7.25) mg; Rb 2.74 (2.58) mg; Mg 0.210 (0.219) g; Ca 0.584 (0.606) g; P 0.839 (0.815) g; K 2.80 (2.75) g; and Na 3.76 (3.57) g. The intakes of Cu, Mn, and Zn in Ukrainians were lower than those of Japanese and worldwide reported values.
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  • Susumu Ko, Kunio Shiraishi, Sarata K. Sahoo, Hideki Arae, Kyoko Ayama, ...
    2005 Volume 16 Issue 4 Pages 311-314
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Within the framework of a comprehensive study on trace element intakes of Ukrainian residents after the Chernobyl accident, an investigation was made for Cs, Sr, 232Th and 238U with respect to radiation exposure from released radionuclides. From 1997 to 2001, the north part of Ukraine had median daily dietary intakes of Sr, Cs, 232Th and 238U which were 1.9mg, 6.3μg, 0.53μg and 0.58μg per person, respectively. Intakes of Sr and Cs were about same as the global averages, while those of 232Th and 238U were about half the global averages. The variation of Cs intake among districts may indicate that high 137Cs exposure was accompanied by high Cs intake.
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  • Norikazu Shimizu, Yukiko Takeshita, Atsuko Watanabe, Hiromichi Hemmi, ...
    2005 Volume 16 Issue 4 Pages 315-317
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Wilson disease is a genetic disorder of copper metabolism characterized by hepatic and/or neurological manifestations. This disease is caused by mutations in the gene of copper transporting ATPase (ATP7B). Early diagnosis is very important to improve the prognosis of this disease. However, biochemical studies are not sufficiently effective for the definitive diagnosis of young patients. This study presents the molecular diagnosis of presymptomatic patients with Wilson disease. Three patients, two infants and one young child without any symptoms, and one carrier, were diagnosed by ATP7B gene analysis. We conclude that the molecular diagnosis of Wilson disease is very useful for the identification of young patients and familial analysis.
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  • Yasutomo Nomura, Atsuo Aragane, Zhonggang Feng, Takao Nakamura
    2005 Volume 16 Issue 4 Pages 318-320
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Increase in hypoxia-inducible factor-1α (HIF-1α) expression is caused by some essential trace elements such as vanadium and cobalt even under normoxic conditions. The mechanism of HIF-1α activation caused by vanadium is not documented well whereas several authors proposed that by cobalt. When HEK293 cells were treated with 100 μM sodium orthovanadate, HIF-1α expression increased within 6 to 12 hours. The increase was suppressed by HIF-1α-specific inhibitors, YC-1 for the metal-related oxygen sensing pathway, and 17-AAG for the Hsp90-dependent pathway. The results suggest that orthovanadate increases HIF-1α expression via both oxygen-dependent and -independent pathways.
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  • Suguru Kurokawa, Hisaaki Mihara, Masanori Takehashi, Seigo Tanaka, Tat ...
    2005 Volume 16 Issue 4 Pages 321-324
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Selenocysteine lyase (SCL), which specifically catalyzes the decomposition of L-selenocysteine into Se and L-alanine, is proposed to function as a Se delivery protein to selenophosphate synthetase in selenoprotein biosynthesis. However, the physiological role of SCL has not been established. To address the role of SCL in mammalian cells, we have used RNA-interference (RNAi) to deplete SCL in a HeLa cell line. RNAi-mediated depletion of SCL resulted in growth inhibition in cells cultivated with a serum-containing medium. The similar growth inhibition was observed in SCL-depleted cells cultivated with a serum-free medium supplemented with selenite, selenomethionine, or selenocysteine, indicating that these selenium-containing compounds can not rescue the growth inhibition. These results suggest a physiological importance of SCL in normal cell function. Depletion of SCL may reduce the biosynthesis levels of selenoproteins which are essential for cell proliferation.
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  • Katsumasa Abe, Ichiro Ebata, Takayuki Kazuoka, Hisaaki Mihara, Tatsuo ...
    2005 Volume 16 Issue 4 Pages 325-327
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Selenophosphate synthetase (SelD) catalyzes the production of selenophosphate from selenide and ATP. Selenophosphate is required for synthesis of selenoprotein and 5-methylaminomethyl-2-selenouridine. Cysteine desulfurase IscS, which provides sulfur atoms for Fe-S cluster biosynthesis, has been proposed to be a selenium-delivery protein for selenophosphate biosynthesis. We have found specific interaction between SelD and IscS in vitro. SelD inhibited the IscS-mediated reconstitution of Fe-S cluster in ferredoxin. These findings support the proposal that IscS supplies a selenium substrate for SelD through direct protein-protein interaction.
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  • Tapan Kumar Saha, Yutaka Yoshikawa, Yusuke Adachi, Hiromu Sakurai
    2005 Volume 16 Issue 4 Pages 328-331
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Diabetes mellitus (DM) is one of the life style-related diseases as well as one of the widespread diseases in the world. DM is classified mainly into two types; type 1 insulin-dependent DM is associated with absolute insulin deficiency and type 2 non-insulin dependent DM is associated with lowering of insulin sensitivity in all organs, which ultimately follows absolute insulin deficiency. We first reported that vanadyl-cysteinemethylester complex with the VO(S2N2) coordination mode is very useful in the treatment of streptozotocin (STZ)-induced type 1 diabetic rats by daily oral administrations in 1990. Since then, many types of insulinomimetic vanadyl complexes with different coordination modes around vanadyl, such as VO(O4), VO(S4), VO(S2O2), VO(S2N2) and VO(N2O2) have been proposed, however, few complexes with the VO(N4) coordination mode have been examined. Recently, we found that meso-tetrakis({1-methylpyridinium-4-yl}porphyrinato)oxovanadium(IV), VOTMPyP, with the VO(N4) coordination mode, is a potential insulinomimetic vanadyl complex for the treatment of type 1 diabetic model STZ-rats in the presence of sodium ascorbate. This important finding promoted us to find more active insulinomimetic vanadyl-porphyrin complexes. In this study, we have synthesized, characterized and estimated in vitro insulinomimetic activity of the (protoporphyrinato IX)oxovanadium(IV), VOPP, and meso-tetrakis({4-sulfonatophenyl}porphyrinato)oxovanadium(IV), VOTPPS, complexes, comparing with those of previously proposed insulinomimetic VOTMPyP. VOTPPS was very stable in both 4% bovine serum albumin (BSA) and rat blood serum (RBS) for 48 h without ascorbate. The IC50 value, which is a 50% inhibitory concentration of the complex for FFA-release from the adipocytes, was estimated to be 488.3 ± 49.1 μM for VOTMPyP and 18.6 ± 13.0 μM for VOTPPS, respectively. The EC50 value, which is a 50% enhancing concentration of the compound with respect to the maximal glucose-uptake concentration in epinephrine-treated adipocytes, was not detected for VOTMPyP, but found for VOTPPS as 46.3 ± 6.4 μM. The complex VOPP, which is insoluble in water, exhibited no in vitro insulinomimetic activity in the concentration range examined. Based on these observations, VOTPPS was proposed to be an insulinomimetic vanadyl porphyrin complex having a potential for treating insulin-dependent and noninsulin-dependent diabetic mellitus.
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  • importance of selenium
    Yoshihiro Saito, Daisuke Umemoto, Yasuhiro Kidera, Takaji Sato, Masahi ...
    2005 Volume 16 Issue 4 Pages 332-335
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    To investigate the antioxidant property of several selenocompounds we synthesized, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity was determined by ESR. In this study, the experimental conditions for ESR measurement were also examined. Phosphate-buffered saline (PBS) was a better solvent for DPPH than dimethylsulfoxide (DMSO) or ethanol to obtain the strong signal intensity and the high S/N ratio. Among absolute signal intensity, absolute signal area, relative signal intensity to MnO, and relative signal area to MnO, the most suitable parameter corresponding to the concentration of DPPH was absolute signal intensity, because the correlation coefficient between absolute signal intensity and DPPH concentration was the highest. In low-molecular-weight selenocompounds, diethyldithiocarbamate selenotrisulfide (DEDC-SeT) had almost the same degree of DPPH radical scavenging activity as reduced glutathione or dithiothreitol, which are reference antioxidant compounds. The activity of DEDC-SeT was higher than that of sodium diethyldithiocarbamate or its disulfide form. Four polysaccharide- selenocystamine (SeCyst) conjugates, heparin-cystamine (Hep-Cyst), pullulan-selenocystamine (Pul-SeCyst), laminarin-selenocystamine (Lam-SeCyst), fucoidan-selenocystamine (Fuc-SeCyst) had DPPH radical scavenging activity which was similar to that of ascorbic acid or reduced glutathione. The activity of Hep-Cyst was higher than that of heparin or heparin-cystamine conjugate which has sulfur instead of selenium in the molecule. These results suggest that selenium is involved in the antioxidant activity of DEDC-SeT and polysaccharide-SeCyst conjugates.
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  • Emi DOTE, Tomotaro DOTE, Kan USUDA, Hiroyasu SHIMIZU, Go MITSUI, Kazuy ...
    2005 Volume 16 Issue 4 Pages 336-340
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Cadmium nitrate (CN) is generally used for Ni-Cd batteries in industrial fields. However, there are no reports on the acute lethal toxicity of CN. LD50 and LD90 were 7.2 mg/kg and 8.1 mg/kg, respectively, after a single intravenous injection of CN in rats. A dose of CN (2.7, 5.4, 8.1 (mg/kg)) or saline (control) was intravenously administered to investigate the kinetics of cadmium (Cd) in blood and bile and dose-dependent hepatic damage after 5 hours. Liver dysfunction was caused in a dose-dependent manner and hepatic injury was severe in the 8.1 mg/kg group. The changes in serum Cd concentrations and kinetic parameters indicated that the clearance of Cd was significantly altered in the 8.1 mg/kg group. The excretion of Cd in the bile increased in the 8.1 mg/kg group. It indicated that Cd was transported in blood and Cd induces the synthesis of metallothionein and would be stored in the liver as a Cd-MT complex; however, when the Cd dose greatly exceeds the its ability to accumulate in the liver, bile excretion of cadmium increases. We suggest that the Cd binding sites in the liver were saturated and that more Cd was available for biliary excretion in the 8.1 mg/kg group. Detoxication after acute CN exposure would be dependent upon accumulation of Cd in the liver. Severe liver dysfunction was caused by acute exposure to high concentration of CN that exceed the accumulation of the liver and it caused reduction of clearance of Cd.
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  • H. Hashimoto, K. Matsumoto, Y. Yoshikawa, H. Taniguchi, Y. Kojima, N. ...
    2005 Volume 16 Issue 4 Pages 341-343
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    The objective of this study is to investigate the effects of zinc(II)molecular complex with ascorbic acid (Zn(VC)2), carnitine (Zn(Car)2Cl2), and glutamine (Zn(Gln)2) on obesity and blood fluidity. We fed the high fat diet which consisted of 40% fat in the energy ratio to the male Wistar rats from 8 weeks of age for 10 weeks of period with or without Zn (II) complexes. Zinc(II) complexes were mixed to the diet as 30∼50 mg Zn/kg body weight. The body weight and body fat composition have been intactly measured once a week. The remarkable body weight reduction was observed by Zn(VC)2 and Zn(Car)2Cl2 mixed diet groups compared to the control groups. The accumulation of abdominal adipose tissues was diminished in Zn(VC)2 and Zn(Car)2Cl2 groups compared to the control groups. We observed the tendency of improved blood fluidity at the 18th week of age measured by micro channel array analyzer (Bloody 6-7) in three Zn (II) complexes groups compared to control groups. These results suggested that zinc (II) complexes with vitamin C, carnitine, and glutamine have suggest the preventive effects of life-style related diseases such as obesity and diabetes.
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  • in vitro and in vivo anti-oxidative activities, and absorption of copper
    T. Fujimori, S. Yamada, H. Yasui, H. Sakurai
    2005 Volume 16 Issue 4 Pages 344-347
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Since it is proposed that reactive oxygen species (ROS) is involved in the pathogenesis of various diseases, low-molecular weight superoxide dismutase (SOD) mimetic complexes have been intensively studied. We prepared a Cu2(aspirin)4 complex consisting of Cu(II), active center of Cu, Zn-SOD, and aspirin, which has been in use for many years as an antipyretic, an analgestic, and as an anti-inflammatory agent. The ROS scavenging activities of Cu2(aspirin)4 and Cu(salicylic acid)2, for comparison, have been evaluated in in vitro and in vivo. We have ever proposed that Cu2(aspirin)4 has SOD mimetic activity and defense activity against skin injury caused by an ultraviolet radiation. The suppressive effect of ROS generation following UVA irradiation on the skin of hairless mice, who received oral administration of the complexes for three consecutive days, was observed, the effect being significantly higher than that of Cu(II) ion. Further, the Cu concentration in the skin and blood of ICR mice who received complexes were measured using atomic absorption spectrometry. The Cu concentration in the skin of ICR mice treated with Cu2(aspirin)4 was slightly increased, probably due to lipophilicity of Cu2(aspirin)4 complex. The Cu2(aspirin)4 complex was thus observed to be an orally active anti-oxidative complex, proposing a potent anti-oxidative agent for clinical use in future to treat diseases relevant to ROS.
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  • Kojiro Tayama, Yusuke Adachi, Hiroyuki Yasui, Hiromu Sakurai
    2005 Volume 16 Issue 4 Pages 348-351
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Vanadyl ion and its complexes have been found to normalize the blood glucose levels in both type 1 and 2 diabetic animals. We have developed various types of vanadyl complexes, and found that the bis (picolinato) oxovanadium (IV) [VO(pa)2] complex is an effective agent for treating diabetes mellitus. Then, we used VO(pa)2 as a leading compound for developing more active agents with hypoglycemic effects. By introducing an electron-withdrawing group such as a halogen atom into the pyridine ring of picolinic acid, seven kinds of vanadyl picolinate complexes were prepared. The structures of these complexes were characterized by elemental analysis and physical methods such as visible, IR, and ESR absorption spectra, and magnetic susceptibility. Introduction of an iodine to the picolinic acid gave a stronger insulinomimetic activity than that of VO(pa)2. The hyperglycemia of streptozotocin-induced insulin dependent diabetic mice was normalized when bis(4-chloropicolinato)oxovanadium(IV) [VO(4cpa)2] or bis(4-iodopicolinato)oxovanadium(IV) [VO(4ipa)2] was given by a single intraperitoneal injection. The metallokinetic features of vanadyl species in the blood were examined by using the blood circulation monitoring-electron paramagnetic resonance (BCM-EPR) method. Vanadyl concentrations in the blood of normal rats given VO(4cpa)2 and VO(4ipa)2 remained higher and longer than those of VO(pa)2 because of their slower clearance rates. On the basis of the results, we conclude that introduction of a halogen atom to 4th position of picolinic acid enhances insulinomimetic activities and reduces clearance rate of the vanadyl species from the blood.
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  • Sayo Horibe, Riichi Tawa, Hiromu Sakurai
    2005 Volume 16 Issue 4 Pages 352-354
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    Increased metallothionein (MT)-IIA transcription is found in some cells with acquired resistance to cisplatin (CDDP). It is also known that mammalian MT is induced by copper. MT induction by TPA (12-O-tetradecanoyl phorbol-13-acetate) and TNFα (tumor necrosis factor α has been demonstrated. In previous study, we found Cu(II) ion dependency on binding of the nuclear protein of HeLa cells stimulated with TPA or TNFα to the metal responsive elements (MREs) sequences in the MT-IIA promoter gene, which was investigated by the gel shift assay using the plasmid pKB8 constructed the human MT-IIA promoter gene in pUC19. Therefore, it was suggested that the nuclear protein bound specificically to the MT-IIA promoter region in the presence of Cu(II) ion contributes to CDDP resistance by regulation of MT-IIA gene expression. In this study Cu(II) ion dependency on binding of the nuclear protein from the CDDP-resistant cells to the DNA fragments containing MREs in the MT-IIA promoter gene was examined in connection with observation of the MT-IIA gene expression (mRNAs) in CDDP-resistant cells.
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  • Tetsuya MAEGAWA, Mamoru HARATAKE, Masahiro ONO, Morio NAKAYAMA
    2005 Volume 16 Issue 4 Pages 355-357
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    We synthesized a 1 : 2 complex between the vanadyl(IV)or vanadate(V)ion and benzohydroxamic acid (BHA), and assessed their insulin-like activity in terms of the inhibitory effects on free fatty acid release from the isolated rat adipocytes when stimulated with epinephrine. The vanadyl-BHA complex showed similar insulin-like activity to the inorganic vanadyl ion, while the vanadate complex was more effective than the vanadate ion. In addition, the vanadium contents of isolated rat adipocytes treated with the two complexes were determined by the graphite furnace atomic absorption spectrometry. The vanadyl- and vanadate-BHA treatments provided lower vanadium contents than the corresponding inorganic ions with the same oxidation states. Thus, the observed insulin-like activity did not necessarily correspond to the vanadium contents in the adipocytes. These results reflect the difference in the insulin-like activity in the subcellular region between the two complexes and the inorganic compounds in the IV and V oxidation states.
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  • —in vitro and in vivo studies—
    Yutaka Yoshikawa, Hiromu Sakurai
    2005 Volume 16 Issue 4 Pages 358-360
    Published: 2005
    Released on J-STAGE: July 19, 2006
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    It is already known that some metal ions and its complexes involving Zn(II) to treat diabetes mellitus (DM) in model animals. To find Zn(Il) complexes that treat DM at low doses, six novel Zn(II)-dithiocarbamate complexes with Zn(S4) coordination mode were prepared and their insulinomimetic in vitro and anti-diabetic in vivo activity were evaluated. Bis (pyrrolidine-N-dithiocarbamate; pyd) zinc(II) (Zn(pyd)2) complex was found to be the most effective in terms of inhibition of free fatty acid release in adipocytes compared with those of other Zn(II)-dithiocarbamate complexes. Thus, Zn(pyd)2 complex was administrated orally in KK-Ay mice with type 2 DM. Blood glucose levels of hyperglycemic KK-Ay mice lowered to 250 mg/dL within 5 days, and the effect was maintained during the administration period with average dose of 12.2 mg Zn/kg body weight (n=3). In those mice, HbA1c level and glucose tolerance were improved. Indications of the insulin resistance such as serum insulin, leptin, and triglyceride levels were also improved compared with those of untreated KK-Ay mice. In addition, Zn(pyd)2 complex decreased the fat pads weight around the epididymides and liver. From these results, Zn(pyd)2 complex is indicated to be a good agent to treat insulin resistance in type 2 DM model animals.
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  • Shigeru Saito, Shuiti Hiyamuta, Masaaki Kurasaki, Toshiyuki Hosokawa, ...
    2005 Volume 16 Issue 4 Pages 361-363
    Published: 2005
    Released on J-STAGE: July 19, 2006
    JOURNAL FREE ACCESS
    The present study was carried out to investigate the effect of gold (Au) injection on copper (Cu) and two types of ceruloplasmin (Cp), total Cp (ID1) and active Cp (ID2), metallothionein (MT) in the serum, kidney and liver, and 8-hydroxydeoxyguanosine (8-OHdG) in the rat kidney. The Cu contents in sera and kidneys of Au-injected rats were 1.7 and 5.5 times higher than those in sera and kidneys of control rats, respectively. Significant increases of ID1 and ID2 were found in the sera of the control rats and Au-injected rats. The immunoreactivity of 8-OHdG was located in the cortex of the Au-injected rat. These findings suggested that the oxidative DNA damage in the kidneys of rats injected with Au is associated with Cu except Cu-MT.
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  • —Detection of tissue cadmium by in-air micro-PIXE system—
    Kyoumi Nakazato, Keiji Suzuki, Takeaki Nagamine, Katuyuki Nakajima, Ta ...
    2005 Volume 16 Issue 4 Pages 364-366
    Published: 2005
    Released on J-STAGE: July 19, 2006
    JOURNAL FREE ACCESS
    ICR female mice were allowed free access to water to which Cd (CdCl2) was added at levels of 100mg/l. Mice were sacrificed and liver and kidney were removed immediately after 18 and 24 months. Three μm paraffin sections of the organs were prepared for HE stain and immunohistochemical stain for metallothionein (MT). Ten μm frozen sections of the organs were prepared for detection of Cd using In-air micro-PIXE system. Histological changes and MT expression were observed in the liver cells and the renal proximal tubular epithelium after Cd administration for 18 and 24 months. Using in-air micro-PIXE, Cd accumulation in the liver and kidney were detected in the mouse administratied Ca for 24 months but not detected in the mouse administratied Ca for 18 months.
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