A heavy-metal-binding protein, metallothionein (MT), is induced by heavy metal overload and reactive oxygen species (ROS). The metals and ROS are rendered harmless by binding to MT or by oxidizing MT, respectively. This is a well-known role of MT. MT is also induced by glucocorticoids and cytokines. Induced MT may increase intracellular free zinc and modulate the activity of transcription factors. Changes in MT levels are thought to help in adaptation to changes in environmental conditions. MT modulates inflammatory reactions, including lipopolysaccharide (LPS)-induced expression of cytokines, nitric oxide production from macrophages in response to LPS, and resistance to LPS/D-galactosamine-induced lethality. In this review, we focus on a newly found protective role of MT, which acts mainly via changes in intracellular zinc levels or modulation of gene expression.

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Control of the intracellular localization of the constitutive androstane receptor (CAR, NR1I3) has more impact on the transcriptional activation of target genes by CAR ligands/activators, including medicines, environmental contaminants and endogenous metabolites, than the conformational change induced by ligand binding, because CAR, unlike other members of nuclear receptor superfamily, is constitutively active. Human CAR (hCAR) and rat CAR (rCAR) were comparatively studied, in primary hepatocytes and in immortal cells, to assess the functional domains controlling nucleo-cytoplasmic shuttling and/or intracellular localization. There are two nuclear localization signals (NLSs) and two nuclear export signals (NESs) in rCAR as well as a cytoplasmic retention region (CRR), whereas hCAR has a single NLS and two NESs. A xenochemical response signal (XRS) controls the neighboring NLS, in a phenobarbital-responsive manner, in both rCAR and hCAR in vivo, but not in immortal cells.

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Electrophiles readily bind to nucleophilic centers on intracellular macromolecules such as DNA and proteins. Electrophilic attack on DNA results in the formation of an adduct, leading to depurination due to hydrolysis of a purine base such as adenine or guanine. On the other hand, electrophiles also attack proteins, with the thiolate function as the most attractive site. Many protein cysteine (Cys) thiols are affected by their proximity to basic amino acids, which results a decrease in the thiol pKa value. This paper discusses the role of electrophile-nucleophile interactions in the adverse health effects of electrophilic environmental chemicals such as arsenic compounds (groundwater contaminant), methylmercury (MeHg; a fish contaminant), and 1,2-naphthoquinone (1,2-NQ; an atmospheric contaminant).

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The estrogenic chemical bisphenol A (BPA) has multiple hormonal activities, but its effects on thyroid hormone (TH) action are not fully understood. TH is required for the metamorphosis of tadpoles into frogs, and thus tadpole tail regression, one of the most spectacular events in metamorphosis, can be used for studying the effect of BPA and related compounds (BPAs) on TH action. We found that 3,3',5-triiodothyronine (T₃)-induced tadpole tail regression in the wrinkled frog Rana rugosa (R. rugosa) is suppressed by BPA, tetrabromobisphenol A (TBBPA), tetrachlorobisphenol A (TCBPA), and tetramethylbisphenol A (TMBPA). BPAs also inhibited spontaneous metamorphosis in the tropical clawed frog Silurana tropicalis (S. tropicalis) controlled by endogenous circulating TH. These results indicate that BPAs are TH antagonists. For the African clawed frog Xenopus laevis (X. laevis), transgenic tadpoles carrying plasmid DNA containing TH response element (TRE) and 5'-upstream promoter region of the TH receptor (TR) βA1 gene linked to an enhanced green fluorescent protein (EGFP) gene, T₃ induced a strong EGFP expression in the hind limbs. This expression was suppressed by BPA, TBBPA, TCBPA and TMBPA, suggesting BPAs all act as antagonists to prevent the binding of T₃ to TR, resulting in inhibition of TR-mediated gene expression. Much work has been done in examining the apoptotic and other detrimental effects of polychlorinated biphenyls (PCBs), but the role of mitochondrial damage in such toxic action remains obscure. There is evidence however that mitochondrial membrane permeability transition (MPT) plays a crucial role in apoptosis. We investigated the effect of 4-hydroxy-3,3',4',5-tetrachlorobiphenyl (4-OH-TCB) on isolated rat liver mitochondria. In order to help clarify this, biochemical analysis revealed that 4-OH-TCB induced calcium release, reactive oxygen species (ROS) generation, depolarization, swelling and cytochrome c (Cyt. c) release in a time- and concentration-dependent manner. These 4-OH-TCB-induced changes in mitochondrial function were found to be inhibited by the presence of cyclosporin A (CsA), a specific inhibitor of MPT, suggesting a classic type of MPT. It is concluded that 4-OH-TCB induces MPT together with ROS generation, causing apoptosis in certain cells.

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The methanolic extract of Antigonon leptopus Hook. et Arn roots was evaluated for analgesic and anti-inflammatory activity at the doses of 200 and 400 mg/kg body weight. The hot-plate and acetic acid writhing response in mice were used to assess analgesic activity. Carrageenan-induced paw edema in rats, which is an acute model, was used to evaluate the anti-inflammatory activity of A. leptopus Hook. et Arn root extract. The extract inhibited paw edema in a dose-related manner. A dose-dependent analgesic action was obtained against chemical (writhing test) and thermic (hot-plate test) stimuli indicating antinociceptive activity may involve inhibition of pain by peripheral and central mechanisms. Further, an acute toxicity study with the extract showed no sign of toxicity up to a dose level of 2000 mg/kg body weight. Thus, the extract of A. leptopus Hook. et Arn root possesses significant analgesic and anti-inflammatory properties.

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The development of effective utilization methods of Shochu distillation remnants is desirable from the viewpoint of environmental protection and biomass. In this study, we examined inhibitory effects of the powder (barley-powder) obtained from the barley-Shochu distillation remnants on the various tumor cells in vitro and immunostimulation effect in vivo. Remarkable inhibitory effects on the growth of human lung tumor cells along with the induction of apoptosis were obtained for barley-powder in vitro. On the other hand, the barley-powder induced the production of serum Interferon (IFN)-γ for normal rats in vivo, and increased natural killer (NK) activity. Furthermore, the barley-powder showed no acute toxicity in the tail vein administration to normal rats. It was found that the barley-powder had not only an antitumor effect but also an immunostimulation effect for the first time.

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Bidens pilosa L. var. radiata SCHERFF (Tachiawayukisendangusa: Musashino Miyako Bidens Pilosa (MMBP)) has been reported to have antiinflammatory and antiallergic properties in the treatment of experimental diseases. We studied the antiinflammatory and anti-allergic effects of enzymatic digested MMBP (eMMBP), MMBP treated with Cellulosine, using an experimental inflammatory and allergic model. Oral administration of eMMBP suspension in carboxy-methyl-cellulose sodium solution inhibited the production of IgE 10 days after immunization with 2,4-dinitrophenylate (DNP)-ascaris in mice. Oral administration of eMMBP suspension inhibited dye exudation in rat skin induced by passive cutaneous anaphylaxis (PCA) and chemical mediators (histamine and substance P). The effects of eMMBP on the inhibition of histamine release from mast cells induced by compound 48/80 or antigen-antibody reaction was stronger than that of the hot-water extract (HWex). Caffeic acid and flavonoids (hyperin and isoquercitrin) in eMMBP are increased more than those in HWex of MMBP, as estimated using HPLC. These results suggest that eMMBP has antiinflammatory and antiallergic activity, and that enzymatic digestion enhances its antiallergic activity by the inhibition of histamine release from the mast cells due mainly to an increase in caffeic acid and flavonoids. The enzymatic digestion of MMBP might be useful in enhancing its antiinflammatory and antiallergic activities.

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Recent animal and human studies suggest that chlorogenic acids, which are the main component of the class of polyphenols in coffee, reduce blood pressure, and that hydroxyhydroquinone (HHQ), produced by roasting green coffee beans, inhibits the antihypertensive effect of chlorogenic acids in brewed coffee. To examine the effects of 4 weeks of daily ingestion of HHQ-reduced coffee in patients with essential hypertension undergoing treatment with antihypertensive drugs. Patients being treated for essential hypertension with antihypertensive drugs participated in a randomized, double-blind, crossover controlled trial. After a 2-week run-in phase, participants consumed two cans of either HHQ-reduced coffee or Control coffee daily for 4 weeks. After a 2-week washout period, subjects were crossed over to the other treatment. Blood pressure and pulse rate were measured once a week. Blood biochemistry and hematology analysis was performed before and after the test beverage ingestion periods. A 4-week ingestion period of HHQ-reduced coffee did not significantly change systolic blood pressure (SBP) or diastolic blood pressure (DBP) compared to the Control coffee. There were no significant changes in pulse rate and body weight during the test beverage ingestion periods in either group, and no clinically relevant problems were reported. These findings suggest that 4 weeks of daily ingestion of HHQ-reduced coffee does not reduce or enhance the efficacy of antihypertensive drugs in treated essential hypertensive patients.

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Using chiral liquid chromatography-mass spectrometry (LC/MS), a simple and rapid identification test was developed for aminotadalafil [(6R,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione; RR-ATDF] and its stereoisomers contained in health foods, e.g. herbal products. A sample solution was prepared using methanol extraction. Analysis was performed on a chiral column with the mixture of 0.1% formic acid/acetonitrile (7:3) as mobile phase at 30°C. Each resolution value of four stereoisomers of ATDF was greater than 1.3. A mass spectrometer was used as a detector to enhance specificity by excluding the effects of general components derived from the sample. The four individual stereoisomers of ATDF in the health foods were identified based on their respective retention times. Results showed that structural conversions of RR-ATDF into (6R,12aS)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (RS-ATDF) and (6S,12aS)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (SS-ATDF) into (6S,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione (SR-ATDF) occurred under strongly basic conditions, which indicates that such conditions must be avoided during sample preparation. Using this method, RR-ATDF and SR-ATDF were detected in a health food; this is the first report describing that ATDF diastereomers are present in health foods.

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We compared the effect of dietary intake of isoflavone aglycone-rich fermented soybeans (FS) with that of glucoside-rich non-fermented soybeans (NFS) on bone metabolism, using ovariectomized (OVX) rats. Female Sprague-Dawley rats were given OVX or a sham operation at 8 weeks of age. After a 2-week recovery, sham-operated rats were given a NFS diet for 57 days, while OVX rats were given the NFS or FS diet (Sham-NFS, OVX-NFS, and OVX-FS group, n=10). The two diets had the same level of total isoflavone (228 μmol/100 g). The percentage of isoflavone aglycone to total isoflavone was 100% in the FS diet, and approximately 5% in the NFS diet. Tibial bone calcium and phosphorus contents were significantly lower in the OVX-NFS group than in the Sham-NFS group. This reduction was significantly prevented in the OVX-FS group. Tibial trabecular bone density was also significantly reduced by OVX, but the reduction tended to be prevented in the OVX-FS group (p=0.1). The level of urinary deoxypyridinoline (DPD), a bone resorption marker, was significantly increased by OVX; this increase was significantly prevented in the OVX-FS group. Moreover, urinary total isoflavone levels tended to be higher in the OVX-FS group than in the OVX-NFS group (p=0.1). In conclusion, this study suggested that intake of FS prevented excessive bone resorption and bone loss following OVX in rats. It was also suggested that these beneficial effects on bone resulted from higher absorption of isoflavone aglycone.

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This study investigated the adsorption capacity and adsorption mechanism of phosphate by calcined aluminum oxide (GB) at temperatures of 200 to 1150°C. The results showed that GB and GB calcined at a temperature of 200°C exhibited almost no adsorption capacity, and GB calcined at temperatures of 300 or 400°C exhibited the highest adsorption capacity. After that, adsorption capacity tended to decrease with increasing calcination temperature. The specific surface area and the concentration of surface hydroxyl groups exhibited the highest values in GB calcined at temperatures of 300 and 400°C. From the above facts, it is conjectured that the specific surface area and concentration of surface hydroxyl groups contribute to the adsorption of phosphate in calcined GB. The results of X-ray diffraction showed that the structure of GB changed drastically at temperatures of 200 to 300°C and 900 to 1000°C. Also, it was evident that phosphate was adsorbed selectively even in complex solution systems containing chloride, nitrate, sulfate, hydrogen carbonate and phosphate ions, and that calcined GB is suitable for adsorption of phosphate. For the adsorption of phosphate, it was found that the optimum pH is around 4. When calcined GB is suspended in purified water, it is thought that hydroxyl groups form through dissociative adsorption with water molecules, and that these hydroxyl groups conduct ion exchange with phosphate.

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The fastigial nucleus (FN) plays an important role in regulating cardiovascular, respiratory, and visceral activities. We investigated the effect and mechanism of FN stimulation (FNS) on the prevention of oxidative damage in wistar rats undergoing surgically induced acute myocardial infarction (AMI). The FN lesion (FNL) group was subjected to bilateral FN lesioning before the nucleus was electrically stimulated and AMI was induced. FN of AMI rats were electrically stimulated as the FNS and AMI group. Sham-stimulated and sham-operated rats were randomly selected in one group as control. We measured lactic dehydrogenase (LDH) and creatine phosphokinase (CK) activity, as well as myocardial infarction (MI) size. Malondialdehyde (MDA) content, total anti-oxidative capability (TAOC) and superoxide dismutese (SOD) activity in myocardium were also measured. FNS lowered the activities of LDH and CK in comparison to the AMI group. Infarct size was less in FNS-treated rats. The AMI group had elevated MDA levels compared with sham-treated animals. TAOC and SOD activities were decreased in the AMI group; there was attenuation of MDA and increases of TAOC and SOD activities in the FNS group (p<0.01). We conclude that FNS can reduce damage during MI. The mechanism of the protective effect might be partially related to its antioxidative role.

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Iron, manganese and nickel were analyzed using Atomic Absorption Spectrophotometry (AAS) in 50 beverages sold in Nigeria. Iron levels ranged from 0.020-2.460mg/l for canned and 0.020-2.090mg/l for non-canned beverages. In 95.24% of the canned beverages, iron levels exceeded the maximum contaminant level (MCL) of 0.30mg/l, while 75.86% of the non-canned beverages had iron levels exceeding the MCL. Manganese levels ranged from 0.001-0.730mg/l for canned and 0.001-0.209mg/l for noncanned beverages. 42.86% of the canned beverages had manganese levels that exceeded MCL of 0.05mg/l, while 51.72% of the non-canned beverages had manganese levels exceeding the MCL. Nickel levels ranged from 0.013-0.993mg/l for the canned and 0.009-0.938mg/l for non-canned beverages. 80.95% of the canned beverages had nickel levels that exceeded MCL of 0.10mg/l while 72.41% of the noncanned beverages had nickel levels exceeding the MCL. The sources of these contaminants are unclear and merit further investigation.

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Nitric oxide (NO) enhanced the nuclear localization of metallothionein (MT) in digitonin-permeabilized semi-intact HeLa cells. Although 1-Hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene (NOC5), an NO donor, enhanced the nuclear localization of MT in a manner similar to hydrogen peroxide (H₂O₂), a tenfold higher concentration of NOC5 was required to achieve the same effect as H₂O₂, suggesting that an endogenous NO scavenger existed in the reaction mixture of the nuclear import assay system that we used. We also evaluated the effect of NO on the nuclear localization of MT in intact HeLa cells. Treatment with NOC5 induced the nuclear localization of MT pre-induced with zinc, and its effect was greater than that of H₂O₂. The induced MT was localized in the nucleus and the cytoplasm. The results suggest that MT can scavenge NO using the sulfhydryl groups of cysteines in its molecule to form nitrosothiol, thereby reducing nuclear and cytoplasmic damage by NO.

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