Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design

In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug–drug interactions. We recently developed methods for high-speed functional screening and quantitative structure–activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.     

Development of dioxin toxicity evaluation method in human milk by enzyme-linked immunosorbent assay--assay validation for human milk

In this study, the development of a toxicity evaluation method for dioxins in human milk by enzyme-linked immunosorbent assay (ELISA) was reported. A total of 17 human milk samples were tested by ELISA and by gas chromatography/mass spectrometry (GC/MS) to assess whether the ELISA performed on samples obtained from primiparas could be considered as reliable enough for identifying a dioxins contamination in human milk. The concept of toxicity equivalent quantity (TEQ) screening was validated by comparing TEQ values for a set of human milk samples to the ELISA responses predicted for those samples. A fairly good correlation (r=0.920) between immunoassay and GC/MS was achieved for human milk. This ELISA should be useful for biological samples monitoring.     

Modeling the Production and Uses of Biological Resources from the Viewpoint of Energy Flow in a Rural Village in Sichuan,China

This study aimed at clarifying the impact of deforestation and afforestation on the quality of life in a village in Sichuan Province, China. We devised a conceptual model of bioresource production and use based on quantified energy flow. The basic structure of the model has three sectors: production, use, and externals. We developed comprehensive methodology to quantify the model. Bioresource use per person in 1997 was 3.7 GJ for food, 10.2 GJ for fodder, 0.2–0.4 GJ for building material, 12.8 GJ for fuel, and 1.8 GJ for fertilizer, totaling 28.6–28.8 GJ.We used four environmental indicators to evaluate bioresource production and use: a biological productivity indicator, a use-efficiency indicator, a supply–demand balance indicator, and a self-sufficiency indicator. Use of these indicators showed that supply-demand balance of fuel was dramatically improved from 30% to 85% by afforestation, but 99% of bioresource use still depends on domestic products. Thus, it is necessary to improve biological productivity and promote the efficient use of bioresources to achieve sustainable living in the area. Massive deforestation in the 1950s caused a direct shortage of building material and fuel wood. The shortage of wood led to a stagnation in the rebuilding of houses, and fuel wood was substituted with crop residues. Because crop residues had been used for fertilizer and fodder, their use as fuel caused a shortage of fertilizer and fodder. This was an indirect impact of deforestation on peoples quality of life.     

Incorporation of 32PO4 directly taken-up into acid-soluble phosphates of Artemia salina

A study of the direct uptake by Artemia salina of phosphate ion from the medium and its incorporation into acid-soluble organic phosphorous compounds over a range of exposure time from 2 to 30 min, using ³²PO₄ ion, indicated that the phosphate ion was directly taken up and was rapidly incorporated into the energy-rich compounds, such as adenosine triphosphate (ATP), guanosine triphosphate (GTP), and adenosine diphosphate (ADP), which were separated by ion-exchange chromatography using Dowex-1, X2. Even after an exposure of 2 min, the sum of the radioactivity of nucleotide-fractions was 37.4% of that of the whole acid-soluble extract. The most rapid incorporation of ³²P occurred into ATP, followed by GTP and ADP. The amount of ³²P incorporated into each fraction increased with increased exposure, giving straight lines when the radioactivity of each fraction was plotted against the exposure time on a logarithmic scale. Almost no difference, however, was observed in the distribution rate of ³²P into each fraction at 2, 5, 10 and 30 min. These results show that inorganic phosphate absorbed by A. salina is rapidly incorporated into the energy-rich nucleotides, and that a dynamic equilibrium is established among various acid-soluble phosphorous compounds even after very short periods of time.     

Reduction behaviors of permanganate by microbial cells and concomitant accumulation of divalent cations of Mg2+, Zn2+, and Co2+

Permanganate treatment is widely used for disinfection of bacteria in surface-contaminated water. In this paper, the fate of the dissolved permanganate in aqueous solution after contact with cells of Pseudomonas fluorescens was studied. Concomitant accumulation of divalent cations of Mg~(2+), Zn~(2+), and Co~(2+) during precipitation of Mn oxides was also studied. The time course of the Mn concentration in solution showed an abrupt decrease after contact of Mn(VII) with microbial cells, followed by an increase after ～ 24 hr.XRD analysis of the precipitated Mn oxides, called biomass Mn oxides, showed the formation of low-crystalline birnessite. Visible spectroscopy and X-ray absorption near edge structure(XANES) analyses indicated that dissolved Mn(VII) was reduced to form biomass Mn oxides involving Mn(IV) and Mn(III), followed by reduction to soluble Mn(II).The numbers of electron transferred from microbial cells to permanganate and to biomass Mn oxides for 24 hr after the contact indicated that the numbers of electron transfer from microbial cell was approximately 50 times higher to dissolved permanganate than to the biomass Mn oxides in present experimental conditions. The 24 hr accumulation of divalent cations during formation of biomass Mn oxides was in the order of Co~(2+) Zn~(2+) Mg~(2+).XANES analysis of Co showed that oxidation of Co~(2+) to Co~(3+) resulted in higher accumulation of Co than Zn and Mg. Thus, treatment of surface water by KMnO_4 solution is effective not only for disinfection of microorganisms, but also for the elimination of metal cations from surface water.     

Two clinal trends in male-male aggressiveness in a subsocial spider mite (Schizotetranychus miscanthi)

We studied the correlation between male-male aggressive behavior of the spider mite, Schizotetranychus miscanthi and winter coldness, a factor hypothesized to correlate with the degree of relatedness of the interacting males through the frequent occurrence of mother-son mating in the spring. Thirty-one samples from various populations throughout Japan were added to previous data. A cluster analysis revealed two clinal trends for male-male aggression in S. miscanthi in regions of light or no snowfall. The two clines may represent a dimorphism within the species, each having a similar clinal trend within Japan. Further support for the hypothesis that male overwintering survival affects male-male aggressiveness came from a comparison between regions of heavy snowfall and those of light or no snowfall. In regions with heavy snow insulation, overwintering survival may not be as high as in other areas, and there was no correlation between male aggressiveness and the minimum winter temperature. However, there was a significant correlation in regions of light snow. Received: 26 May 1998 / Received in revised form: 16 December 1998 / Accepted: 30 December 1998     

Alkaline hydrolysis of photovoltaic backsheet containing PET and PVDF for the recycling of PVDF

Recovering fluorine from end-of-life products is crucial for the sustainable production and consumption of fluorine-containing compounds because fluorspar, an important natural resource for fluorine, is currently at a supply risk. In this study, we investigated the feasibility of chemically recycling a fluorine-containing photovoltaic (PV) backsheet for fluoropolymer recycling. Herein, a PV backsheet consisting of laminated polyethylene terephthalate (PET) and polyvinylidene fluoride (PVDF) was treated with different concentrations of sodium hydroxide (NaOH) to hydrolyze the PET layer to water-soluble sodium terephthalate (Na₂TP) and to separate pure PVDF layer as a solid material. Optimized alkaline conditions (up to 10 M NaOH at 100 °C for 2 h) were determined, under which 87% of the PET layer could be decomposed without any significant deterioration of the PVDF layer. The hydrolysis kinetics of PET layer in NaOH could be explained by the modified shrinking-core model. Considering that the mass of end-of-life PV panels in Japan is estimated to increase to approximately 280,000 tons per year by 2036, PV backsheets are attractive candidates for fluoropolymer recycling, which can be effectively achieved using chemical recycling approach demonstrated in this study.

     

Bench-scale PVC swelling and rod milling of waste wire harnesses for recovery of Cu,PVC, and plasticizers

Journal of Material Cycles and Waste Management - In this study, we conducted bench-scale investigations for the recovery of Cu wires, PVC coatings, and plasticizers from long non-uniform cables by...     

Characterization and mapping of enset-based home-garden agroforestry for sustainable landscape management of the Gurage socioecological landscape in Ethiopia

Environmental Science and Pollution Research - Developing strategies that counter the ongoing homogenization trends of home-garden agroforestry systems is required to maintain diversity and...     

Effects of heating rate and temperature on product distribution of poly-lactic acid and poly-3-hydroxybutyrate-co-3-hydroxyhexanoate

In this study, poly-lactic acid (PLA) and poly-3-hydroxybutyrate-co-3-hydroxyhexanoate (PHBH) were pyrolyzed at various temperatures (300, 350, 400, 500, 600, and 700 °C) and heating rates (5, 10, 20, 30, and 40 °C min⁻¹) using a pyrolysis–gas chromatograph/mass spectrometer (Py–GC/MS). The results revealed that the main pyrolysis products of PLA were acetaldehyde, lactide (including meso-lactide and d-, l-lactide), and oligomers. Crotonic acid and its oligomers accounted for most of the PHBH pyrolyzates. The pyrolysis temperature significantly correlated with the product distribution, but the heating rate had a small effect on the product distribution. Lactide and crotonic acid were two kinds of high-value chemicals, and their highest yields were obtained at 400 and 600 °C with 29.7 and 72.6 area %, respectively. Secondary reactions could not be neglected at 700 °C, and acetaldehyde and crotonic acid decreased to 65.0 and 69.6 area %, respectively. These results imply that pyrolyzate selectivity can be controlled by temperature management during pyrolysis.