This review introduces the development of metal-containing pharmaceutics (metallopharmaceutics) such as anticancer agents containing platinum (Pt) and ruthenium (Ru), and superoxide dismutase (SOD) mimetic, focusing on the recent topics on antidiabetic vanadium (V) and zinc (Zn) complexes as well as antioxidative copper (Cu) and Zn complexes. From the ancient ages, people used many types of inorganic compounds to treat physical disorders or diseases. Since the modern concept of chemotherapy was achieved by Paul Ehrlich, who developed the arsenic (As)-containing compound to treat syphilis in 1910, a wide variety of metallopharmaceutics have been proposed and clinically used worldwide. This review is described for the researchers who are interested in the current states for the development of metallopharmaceutics.

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The physiological roles of vitamin A have been elucidated based on a knowledge of the relatioships between vitamin A and health. However, this knowledge is not complete and it still remains to be studied what the actions of vitamin A are and the mechanisms behind its actions. Vitamin A, including β-carotene, is consumed from diet, are metabolized and transported within the body. Vitamin A is stored as retinyl ester in the liver, and vitamin A metabolites (retinal and retinoic acid) exert their actions in various target cells (organs). The mechanisms of action of these agents depend on nuclear retinoid receptors and protein modifications. This review provides a comprehensive survey of vitamin A and new insights into the latter's mechanisms of action.

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Hyphenated analytical techniques, such as high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) and HPLC-electrospray ionization (ESI)-MS, are powerful tools for evaluating the elemental (HPLC-ICP-MS) and molecular (ESI-MS) speciation of metalloids, such as selenium (Se) and arsenic (As). Because the toxicity of metalloids is highly dependent upon the chemical forms that are present in vivo, toxicological assessment must include both the intact compound and its metabolites. We investigated the metabolic pathways of Se and As compounds and their metabolites using HPLC-ICP-MS and HPLC-ESI-MS.

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The expression of metallothionein (MT), a heavy-metal-binding protein, is induced by heavy metals such as zinc, copper, cadmium, and mercury. This induction of MT maintains zinc homeostasis and defends against toxic heavy metals by sequestering these metals and lowering their concentrations at critical intracellular sites. However, MT cannot bind chromium(VI), a heavy metal that has been known for over 100 years to be a human carcinogen. Chromium(VI) enters cells via the sulfate anion transporter system and is reduced to intermediate oxidation states, such as chromium(V) and chromium(IV), in the process of forming stable chromium(III) forms. Chromium(VI) is known to inhibit MT gene transcription, and recently my colleagues and I reported that chromium(VI) inhibits zinc-induced MT gene transcription by modifying the transactivation potential of metal response element-binding transcription factor-1 (MTF-1), a zinc-finger transcription factor. Inhibition of MT gene transcription may therefore be involved in the carcinogenicity of chromium(VI). In this review, I briefly summarize the molecular mechanisms of heavy metal-induced MT gene transcription and discuss the current status of research on chromium(VI) toxicity and chromium(VI)-mediated inhibition of MT gene transcription.

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We studied the in vitro antioxidant activities of neutral aqueous solution systems (water products marketed as drinks) containing hydrogen gas (H₂), 2-carboxyethyl germanium sesquioxide (Ge-132), and platinum (Pt) nanocolloid as additives. We evaluated the abilities of these aqueous solutions to inhibit the oxidation of biomolecules catalyzed by an enzyme and induced by reactive oxygen species (ROS) and also to scavenge ROS directly using electron spin resonance (ESR) spectrometry. The concentrations of inorganic elements including Ge and Pt were measured by inductively coupled plasma-mass spectrometry (ICP-MS) and inductively coupled plasma-atomic emission spectrometry (ICP-AES). All the water products examined more or less inhibited the oxidation of 3,4-dihydroxyphenylalanine by tyrosinase and that of L-histidine in an L-ascorbic acid/Cu²⁺ reaction system. The results of ICP-MS and ICP-AES analyses revealed that Ge, Pt, and some major minerals existed in the water products at concentrations approximately equivalent to those reported by their manufacturers. The ESR spectra indicated that the dissolved Ge-132 molecules and the supplemented Pt nanocolloid particles reduced hydroxyl and superoxide anion radicals. However, under the conditions employed, aqueous H₂ did not display such a scavenging ability for these ROS. Our results suggest that H₂, Ge-132 and Pt nanocolloid dissolved or supplemented in neutral aqueous media exhibited antioxidant activities in vitro due to the direct scavenging of ROS and/or by other mechanisms.

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The large numbers of environmental chemicals that now exist have made assessing their neurodevelopmental risks challenging. In this study, we quantified neurodevelopmental toxicity of bisphenol A, using a neurosphere assay in vitro. Neurosphere was isolated from rat E16 mesencephalone. A neurosphere assay was carried out in the amine-coated plates. Cells emerged from the neurosphere and migrated along the radial axis from the sphere. The migrating populations comprised cells that were positive for nestin, microtubule-associated proteins, and glial fibrillary acidic protein. Exposure to bisphenol A inhibited cell migration and decreased proliferative cells in dose-dependent manner. Quantitative analyses revealed a linear function between the inhibition of migration and the logarithm of bisphenol A concentration (0-100 μM); the percent inhibition by 1 μM bisphenol A of migration was 35% (p<0.05). Thus, we showed for first time that bisphenol A inhibited migration as well as proliferation of neural stem cells in vitro and that a neurosphere assay in vitro is very useful to rapidly quantify neurodevelopmental toxicity of environmental chemicals.

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Pueraria candollei (Leguminosae) has long been used as a traditional medicine for rejuvenation, and the major constituents in the tuberous root are isoflavonoids. The effects of the root cultures of P. candollei (r-PC) on cytochrome P450 enzymes in mouse liver and antioxidant activity in mouse brain including gross anatomy were examined. r-PC significantly enlarged the uterus length while no change in weight was noted. The total P450 content was not significantly altered by either estradiol benzoate (ES) or r-PC. Benzyloxyresorufin O-dealkylase activity was significantly increased by r-PC, comparable to the increase induced by ES. Correspondingly, r-PC demonstrated a tendency to upregulate CYP2B9 mRNA expression. Furthermore, assessment of lipid peroxidation in mouse brain using the thiobarbituric acid assay demonstrated that r-PC remarkably decreased the level of malondealdehyde formation. These observations suggest r-PC as a potential alternative to ES with the extrabenefit of its antioxidant activity.

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By adopting a rapid and sensitive method for simultaneous detection of nivalenol (NIV), deoxynivalenol (DON), fusarenon-X (FX), 3-acetyl deoxinivalenol (3ADON), HT-2 toxin (HT-2), T-2 toxin (T-2) and zearalenone (ZEN), the natural occurrence of these mycotoxins in biscuits made of wheat (201 samples) in Japan was surveyed. Samples were analyzed by LC/MS with atmospheric pressure photo ionization (APPI). Further confirmation was performed by liquid chromatography/time of flight mass spectrometry (LC/TOFMS). The average contamination of each Fusarium mycotoxin was 3.1, 23, 0.7, 0.1 and 4.2 ng/g for NIV, DON, HT-2, T-2 and ZEN, respectively. Multiple toxins were observed in 120 samples while FX and 3ADON were not detected. The incidence of these toxins was 41% for NIV, 98% for DON, 19% for HT-2, 11% for T-2 and 2% for ZEN. There were no significant differences in the concentration and incidence between conventional biscuits made of wheat and biscuits made of wheat for infants. This is the first report concerning the presence of NIV, DON, HT-2, T-2 and ZEN in biscuits in Japan.

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Reactive oxygen species play an important role in the development of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and stroke. The present study investigated the neuroprotective action of geniposide and its signaling pathway in peroxynitrite induced PC12 cells. After coculture of PC12 cells with geniposide in the presence or absence of 3-morpholinosydnonmine hydrochloride (SIN-1), a donor of peroxynitrite, Bcl-2, Bcl-2 associated X protein (Bax) and the phosphorylation of mitogen-activated protein kinase (MAPK) were probed with Western blotting. The results showed that geniposide enhanced the expression of Bcl-2 to prevent the peroxynitrite damage induced by SIN-1 in PC12 cells. U0126, a selective inhibitor of MAPK/ERK, attenuated the protective effects of geniposide by inhibiting the phosphorylation of MAPK and expression of Bcl-2. All these data indicate that geniposide prevents PC12 cells from peroxynitrite damage induced by SIN-1 involved in the MAPK signaling pathway.

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Polycyclic aromatic hydrocarbon (PAH) emissions from diesel vehicles have been reduced by recent regulations further dropping the permissible levels of regulated substances. We analyzed emissions of 13 PAHs from cold- or hot-start test cycles in three diesel vehicles complying with these stringent regulations, and we estimated cancer risk in terms of toxic equivalency factors (TEFs). Two vehicles were equipped with oxidation catalysts and one with a urea-selective catalytic reduction (SCR) system. Most PAH emissions were lower from the compliant vehicles than from other diesel vehicles with no aftertreatment devices. For the three vehicles, naphthalene (Naph) was emitted at the highest rate (2.92-376 μg/km); by mass it constituted 51.1-84.8% (mean 73.0%, S.D.±12.2%) of all PAH emissions. However, in the SCR system, Naph emissions probably decomposed during collection, because the percentage recoveries of surrogate were low, suggesting the presence of specific reactive substances in the SCR system exhaust. The cancer risk of PAH emissions was reduced by application of the emission-control devices. Most benzo[a]pyrene-equivalent (B[a]P_eq) emissions of two-ring PAHs (Naph) or total emissions of five-ring PAHs like benzo[a]pyrene were greater than those of other-ring PAHs. Although Naph has a low TEF (0.001), it constituted a high proportion of the total B[a]P_eq (26-74%; mean 54%, S.D.±15%). The contents of particulate five-ring PAHs, which pose high cancer risks, are decreasing because of improvements in emissions-reduction technology. Hence, the relative contribution of Naph as a gaseous PAH to the TEF-determined risk of carcinogenesis is increasing.

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We investigated the preventive effects of a saccharified solution of rice, Oryza sativa subsp. japonica, against type IV and type I allergy in mice. The oral and/or percutaneous administration of the saccharified rice solution prevented type IV allergy at doses of 0.3 and 0.5 ml/mouse and at a dose of 10 μl/ear, respectively. With oral administration, the solution also suppressed type I allergy at doses of 0.25 and 0.5 ml/mouse. In the case of type IV allergy, administration of the saccharified rice solution suppressed the ear levels of tumor necrosis factor-α and tended to suppress the ear levels of interleukin-12. The non-dialysate prepared from the saccharified solution showed similar effects to the original solution, suggesting that the molecular weights of the active components are higher than ca. 14000. The saccharified rice solution also enhanced the antioxidative activities in the serum of mice with type IV allergy. These results suggest that the saccharified rice solution may be a convenient beneficial food material for prevention of allergies based on suppression of the increases in some proinflammatory cytokines and promotion of antioxidative activity.

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The purpose of this study was to elucidate the effects of dexamethasone, a synthetic glucocorticoid, on the immune system by analyzing the number of white blood cells (WBCs) over the course of hours and days of dexamethasone administration. Dexamethasone was given as either a single dosage [1.0 mg/kg body weight (BW); subcutaneous injection (s.c.)] or as a daily dosage (1.0 mg/kg BW per day; s.c.) for 10 days for the hourly and daily assessment of changes in the number of white blood cells, respectively. A single administration of dexamethasone markedly decreased the number of total WBCs, as well as the number of lymphocyte, monocyte, neutrophil and eosinophil subsets with a nadir at 8 hr post-injection. The number of these cells recovered to the control levels at 24 hr. The numbers of total WBCs, lymphocytes, monocyte, eosinophil and basophil were reduced by the daily administration of dexamethasone. However, the number of neutrophil was significantly higher at days 2 and 8 after the injection. These results suggest that glucocorticoid-mediated immunosuppressions are at least partly attributable to quantitative changes in the number of circulating WBCs.

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