Hideki Miyataka

Synthesis and biological activities of novel antiallergic agents with 5-lipoxygenase inhibiting action

Novel benzimidazole derivatives were synthesized and their pharmacological activities were examined. These compounds showed a good suppressive action on histamine release from rat peritoneal mast cells produced by antigen-antibody reaction, an antagonistic action on guinea pig ileum contraction caused by histamine, an inhibitory action on 5-lipoxygenase in rat basophilic leukemia-1 (RBL-1) cells, and a preventive action on NADPH dependent lipid peroxidation induced by Fe3+-ADP in rat liver microsomes. In addition, 1-[2-[2-(4-Hydroxy-2,3,5-trimethylphenoxy)ethoxy]-ethyl]-2-(4-meth yl-1-homopiperazino)-1H-benzimidazole difumarate (BOM1006) exhibited a dose dependent suppressive action on 48 h homologous passive cutaneous anaphylaxis (PCA) reaction in rats orally administered the drug.

Increases in Oxidized Low-Density Lipoprotein and Other Inflammatory and Adhesion Molecules With a Concomitant Decrease in High-Density Lipoprotein in the Individuals Exposed to Arsenic in Bangladesh

Elevated exposure to arsenic has been suggested to be associated with atherosclerosis leading to cardiovascular disease (CVD). However, biochemical events underlying the arsenic-induced atherosclerosis have not yet been fully documented. The aim of this study was to investigate the associations of circulating molecules involved in atherosclerosis with arsenic exposure in the individuals exposed to arsenic in Bangladesh. A total of 324 study subjects, 218 from arsenic-endemic areas and 106 from nonendemic areas in Bangladesh, were recruited. Drinking water, hair, nail, and blood samples were collected from the study subjects for analysis. Total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels were lower in arsenic-endemic subjects than those of nonendemic subjects. Oxidized LDL (Ox-LDL), C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) levels were significantly higher in arsenic-endemic subjects than those in nonendemic subjects. All these circulating molecules showed significant correlations with arsenic exposure (water, hair, and nail arsenic concentrations), and all these relations were significant before and after adjusting for relevant covariates. Among the circulating molecules tested in this study, HDL, Ox-LDL, and CRP showed dose-response relationships with arsenic exposure. Ox-LDL/HDL ratios were increased with the increasing concentrations of arsenic in the water, hair, and nails. Furthermore, non-HDL cholesterol and TC/HDL ratios were significantly correlated with arsenic exposure before and after adjusting for relevant covariates. Thus, all the observed associations may be the major features of arsenic exposure-related atherosclerosis leading to CVD.

An Integrative Study of the Genetic, Social and Environmental Determinants of Chronic Kidney Disease Characterized by Tubulointerstitial Damages in the North Central Region of Sri Lanka

An Integrative Study of the Genetic, Social and Environmental Determinants of Chronic Kidney Disease Characterized by Tubulointerstitial Damages in the North Central Region of Sri Lanka: Shanika NANAYAKKARA, et al. Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University—

The role of ZIP8 down-regulation in cadmium-resistant metallothionein-null cells

The mechanisms of cellular cadmium uptake in mammalian cells remain obscure. To solve this problem, we established cadmium‐resistant cells (A7 and B5) from metallothionein‐null mouse cells, and found that cadmium accumulation was markedly suppressed in these cells. DNA microarray and real‐time PCR analyses revealed that expressions of ZIP (Zrt‐, Irt‐related protein) 8 and ZIP14 were down‐regulated in A7 and B5 cells. In particular, both mRNA and protein levels of ZIP8 were markedly suppressed in A7 and B5 cells. Introduction of short hairpin RNA (shRNA) of ZIP8 into parental cells reduced the accumulation of cadmium to about 35% of that of mock‐transfected cells, whereas the introduction of shRNA of divalent metal transporter 1 hardly changed cadmium accumulation. Thus, the cadmium resistance in A7 and B5 cells may be conferred primarily by the down‐regulation of ZIP8. In mouse tissues, high expression of ZIP8 was noted in the liver, kidney, lung and testis. These data suggest that ZIP8 plays an important role in cellular uptake of cadmium. Copyright

Association between arsenic exposure and plasma cholinesterase activity: a population based study in Bangladesh

BackgroundArsenic is a potent pollutant that has caused an environmental catastrophe in certain parts of the world including Bangladesh where millions of people are presently at risk due to drinking water contaminated by arsenic. Chronic arsenic exposure has been scientifically shown as a cause for liver damage, cancers, neurological disorders and several other ailments. The relationship between plasma cholinesterase (PChE) activity and arsenic exposure has not yet been clearly documented. However, decreased PChE activity has been found in patients suffering liver dysfunction, heart attack, cancer metastasis and neurotoxicity. Therefore, in this study, we evaluated the PChE activity in individuals exposed to arsenic via drinking water in Bangladesh.MethodsA total of 141 Bangladeshi residents living in arsenic endemic areas with the mean arsenic exposure of 14.10 ± 3.27 years were selected as study subjects and split into tertile groups based on three water arsenic concentrations: low (< 129 μg/L), medium (130-264 μg/L) and high (> 265 μg/L). Study subjects were further sub-divided into two groups (≤50 μg/L and > 50 μg/L) based on the recommended upper limit of water arsenic concentration (50 μg/L) in Bangladesh. Blood samples were collected from the study subjects by venipuncture and arsenic concentrations in drinking water, hair and nail samples were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). PChE activity was assayed by spectrophotometer.ResultsArsenic concentrations in hair and nails were positively correlated with the arsenic levels in drinking water. Significant decreases in PChE activity were observed with increasing concentrations of arsenic in water, hair and nails. The average levels of PChE activity in low, medium and high arsenic exposure groups were also significantly different between each group. Lower levels of PChE activity were also observed in the > 50 μg/L group compared to the ≤50 μg/L group. Moreover, PChE activity was significantly decreased in the skin (+) symptoms group compared to those without (-).ConclusionsWe found a significant inverse relationship between arsenic exposure and PChE activity in a human population in Bangladesh. This research demonstrates a novel exposure-response relationship between arsenic and PChE activity which may explain one of the biological mechanisms through which arsenic exerts its neuro-and hepatotoxicity in humans.

Interaction between chronic arsenic exposure via drinking water and plasma lactate dehydrogenase activity.

Arsenic is a potent environmental pollutant that has caused one of the largest public health poisonings in the history of human civilization, affecting tens of millions of people worldwide especially in Bangladesh. Lactate dehydrogenase (LDH) in blood plays an important role in predicting cell or organ damage and as an important clue to the diagnosis of a variety of cancers. However, effect of chronic arsenic exposure on the LDH level in blood has not yet been documented. Since the chronic arsenic exposure is associated with organ damages and multi-site cancers, this research aimed at assaying the plasma level of LDH activity in the population who were exposed to arsenic chronically in Bangladesh. A total of 185 individuals living in arsenic-exposed areas and 121 individuals living in non-exposed area in Bangladesh were recruited as study subjects. Arsenic content in drinking water, hair and nails were estimated by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS) and LDH activity was assayed by a spectrophotometer. Significant increase in LDH activity was observed with increasing concentrations of arsenic in water, hair and nails. Further, the study subjects were split into four groups based on the three ways of each exposure metrics (water, hair and nail arsenic concentrations) where the study subjects in the non-exposed area were used as a reference (lowest exposure) group. LDH activity was found to be increased in the higher exposure groups of water and hair arsenic concentrations. LDH activity was also increased at low to medium exposure groups of nail arsenic concentrations.Thus, the elevated plasma LDH activity might be helpful for the early prognosis of organ or tissue damage in the individuals who were exposed to arsenic chronically.

Rat H9c2 cardiac myocytes are sensitive to arsenite due to a modest activation of transcription factor Nrf2

The mechanism underlying the hepatotoxicity induced by arsenic exposure is well investigated. However, little is known about the detailed mechanisms of arsenic-induced cardiotoxicity or cardiac factors involved in high sensitivity to arsenicals in spite of the fact that arsenic trioxide, which is used to treat acute promyelocytic leukemia, causes cardiotoxicity. Here, we show that rat H9c2(2-1) cardiac myocytes exhibit high sensitivity to inorganic arsenite (As(III)) as compared with rat-derived four cell lines (liver epithelial TRL1215 cells, kidney epithelial NRK-52E cells, PC12 phechromocytoma cells and C6 glioma cells). Furthermore, we found a lower steady-state level of glutathione and glutamyl-cysteine ligase (GCL) in H9c2(2-1) cells compared with TRL1215 cells, resulting in an increase in arsenic accumulation. In addition, we detected that the up-regulation of GCL and multi-drug resistance-associated protein (MRP) caused by As(III) was extremely low in H9c2(2-1) cells compared with TRL1215 cells. It is known that Nrf2, which regulates GCL and MRP expression, plays an important role in the protection of cells from arsenicals. We investigated the participation of Nrf2 in the difference of sensitivity to arsenicals between H9c2(2-1) and TRL1215 cells and found that Nrf2 was clearly activated by As(III) exposure in TRL1215 cells but only poorly activated in H9c2(2-1) cells. Considering these results together, we propose that modest activation of Nrf2 during exposure to As(III) in H9c2(2-1) cardiac myocytes leads to reduced ability to metabolize and excrete arsenic.

Anti-allergic and anti-inflammatory actions of 2′-(tetrazole-5-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxanilide 1,1-dioxide

Abstract 2′-(Tetrazole-5-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbox-anilide 1,1-dioxide which was designed by the structural hybridization of tranilast and piroxicam, markedly exhibited the inhibitory effects on the antigen-induced histamine release from rat PEC, 48 h homologous PCA in rats and the carrageenin-induced paw edema in mice.

Associations of total arsenic in drinking water, hair and nails with serum vascular endothelial growth factor in arsenic-endemic individuals in Bangladesh.

Arsenic exposure is associated with cancer and vascular diseases. Angiogenesis is an important step for the pathological development of cancer and vascular diseases. Vascular endothelial growth factor (VEGF) is a specific marker for angiogenesis. However, human study showing the association between arsenic exposure and serum VEGF levels has not yet been documented. This study was aimed to investigate the association between arsenic exposure and serum VEGF levels in the arsenic-endemic individuals in Bangladesh. A total of 260 individuals were recruited for this study. Arsenic exposure levels were measured by ICP-MS and VEGF levels were quantified using VEGF immunoassay kit. The study subjects were stratified into tertile (low, medium and high) groups based on the arsenic in water, hair and nails. Serum VEGF levels were correlated with water (rs = 0.363, p < 0.001), hair (rs = 0.205, p < 0.01) and nail (rs = 0.190, p < 0.01) arsenic. Further, VEGF levels showed dose-response relationships with water, hair and nail arsenic. Mean VEGF levels in ⩽ 10 μg L(-1), 10.1-50 μg L(-1) and > 50 μg L(-1) groups were 91.84, 129.54, and 169.86 pg mL(-1), respectively, however, significant (p < 0.01) difference in VEGF levels was only found in > 50 μg L(-1) versus ⩽ 10 μg L(-1) groups. Significant associations of arsenic exposure with VEGF levels were found even after adjusting with relevant covariates. Therefore, these results provide evidence that arsenic exposure has a pro-angiogenic effect on humans, which may be implicated in arsenic-induced tumorigenesis and vascular diseases.

Elevated levels of plasma Big endothelin-1 and its relation to hypertension and skin lesions in individuals exposed to arsenic

Chronic arsenic (As) exposure affects the endothelial system causing several diseases. Big endothelin-1 (Big ET-1), the biological precursor of endothelin-1 (ET-1) is a more accurate indicator of the degree of activation of the endothelial system. Effect of As exposure on the plasma Big ET-1 levels and its physiological implications have not yet been documented. We evaluated plasma Big ET-1 levels and their relation to hypertension and skin lesions in As exposed individuals in Bangladesh. A total of 304 study subjects from the As-endemic and non-endemic areas in Bangladesh were recruited for this study. As concentrations in water, hair and nails were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The plasma Big ET-1 levels were measured using a one-step sandwich enzyme immunoassay kit. Significant increase in Big ET-1 levels were observed with the increasing concentrations of As in drinking water, hair and nails. Further, before and after adjusting with different covariates, plasma Big ET-1 levels were found to be significantly associated with the water, hair and nail As concentrations of the study subjects. Big ET-1 levels were also higher in the higher exposure groups compared to the lowest (reference) group. Interestingly, we observed that Big ET-1 levels were significantly higher in the hypertensive and skin lesion groups compared to the normotensive and without skin lesion counterpart, respectively of the study subjects in As-endemic areas. Thus, this study demonstrated a novel dose-response relationship between As exposure and plasma Big ET-1 levels indicating the possible involvement of plasma Big ET-1 levels in As-induced hypertension and skin lesions.