Structural Basis for Design of New Purine-Based Inhibitors Targeting the Hydrophobic Binding Pocket of Hsp90

Inhibition of the molecular chaperone heat shock protein 90 (Hsp90) represents a promising approach for cancer treatment. BIIB021 is a highly potent Hsp90 inhibitor with remarkable anticancer activity; however, its clinical application is limited by lack of potency and response. In this study, we aimed to investigate the impact of replacing the hydrophobic moiety of BIIB021, 4-methoxy-3,5-dimethylpyridine, with various five-membered ring structures on the binding to Hsp90. A focused array of N⁷/N⁹-substituted purines, featuring aromatic and non-aromatic rings, was designed, considering the size of hydrophobic pocket B in Hsp90 to obtain insights into their binding modes within the ATP binding site of Hsp90 in terms of π–π stacking interactions in pocket B as well as outer α-helix 4 configurations. The target molecules were synthesized and evaluated for their Hsp90α inhibitory activity in cell-free assays. Among the tested compounds, the isoxazole derivatives 6b and 6c, and the sole six-membered derivative 14 showed favorable Hsp90α inhibitory activity, with IC₅₀ values of 1.76 µM, 0.203 µM, and 1.00 µM, respectively. Furthermore, compound 14 elicited promising anticancer activity against MCF-7, SK-BR-3, and HCT116 cell lines. The X-ray structures of compounds 4b, 6b, 6c, 8, and 14 bound to the N-terminal domain of Hsp90 were determined in order to understand the obtained results and to acquire additional structural insights, which might enable further optimization of BIIB021.     

Estimation of exposure dose for decontamination workers from contaminated soil at a nuclear decommissioning site in Korea

Assessment of the exposure dose for workers is crucial to protecting workers from the radiological risk.This preliminary study estimates the potential radiological exposure for a soil remediation worker at a nuclear decommissioning site contaminated with Cs-137 in Korea,and then calculates the maximum workable soil concentration to comply with the occupational dose constraint of 20 mSv per year.The Korean characteristic data,detailed exposure scenarios for workers by the type of work,and relevant exposure pathways were used in the dose estimation.As a result,the most severe exposure-induced work type was identified as the excavator operation with an annual individual dose of 5.92×10^-5 mSv for a unit concentration of soil,from which the derived maximum workable soil concentration was 3.38×10⁵ Bq/kg.Furthermore,dose contribution by each exposure pathway was found to be decreased in the following order:external radiation exposure,soil ingestion,dust inhalation,and skin contamination.The results of this study are expected to be used effectively to optimize radiation protection for workers and establish appropriate work procedures for future site remediation.     

Automatic landing method of a reclaimer on the stockpile

Large excavation reclaimers are used to dig ore and transfer it to the blast furnaces that refine the ore into pure metal form. The reclaiming job consists of two operations: (1) landing a reclaimer bucket on the surface of a pile and (2) slewing its boom with rotating buckets to scoop the ore. An automatic landing method for choosing where to dig in a pile of raw ore is proposed to achieve autonomous reclaiming. The method comprises detecting the shape of a pile, extracting contour lines of the pile, obtaining the joint angles of the reclaimer and determining an optimal landing point. A 3D range finder was developed with laser radar concepts to detect the shape and height of the ore pile. A series of image processing techniques for extracting the contour line from the 3D range data of a pile is suggested. A height map is obtained from the acquired range data for a pile and a contour map is obtained through image processing steps, including interpolation and edge following. The optimal landing point of the bucket on the contour line is determined so that an overload problem does not occur in the slewing operation and the reclaiming efficiency can be maximized. The algorithm for finding the landing point requires an inverse kinematics solution for the reclaimer. The forward kinematics of the reclaimer is first obtained. A constraint equation based on the geometrical relationship is suggested to solve the inverse kinematics of the reclaimer with redundancy. The proposed method was successfully applied to a working reclaimer. An autonomous reclaimer is now being operated in the yards of Kwangyang Steelworks in Korea     

Antioxidant activities of sea buckthorn leaf tea extracts compared with green tea extracts

The polyphenol, flavonoid, and ascorbic acid contents of sea buckthorn leaf tea extracts, along with antioxidant activities, were compared with green tea extracts under different extraction conditions. Sea buckthorn leaf tea and green tea were extracted using water (SW, GW) and ethanol at room temperature (SE, GE), respectively, and at 80°C (SWH, GWH, SEH, and GEH, respectively). GEH, GWH, SE, and SEH contained more antioxidant compounds and higher activities, and SWH, SEH, GWH, and GEH had elevated antioxidant enzyme activity levels in H₂O₂-treated RAW264.7 cells. Cells treated with SWH and SEH showed elevated expression of nuclear factor (erythroid-derived 2)-like 2 and maintained the cell glutathione (GSH)/glutathione disulfide (GSSG) ratio at levels similar to H₂O₂-untreated controls.     

Essential oil of Curcuma longa inhibits Streptococcus mutans biofilm formation

Curcuma longa (C. longa) has been used as a spice in foods and as an antimicrobial in Oriental medicine. In this study, we evaluated the inhibitory effects of an essential oil isolated from C. longa on the cariogenic properties of Streptococcus mutans (S. mutans), which is an important bacterium in dental plaque and dental caries formation. First, the inhibitory effects of C. longa essential oil on the growth and acid production of S. mutans were tested. Next, the effect of C. longa essential oil on adhesion to saliva-coated hydroxyapatite beads (S-HAs) was investigated. C. longa essential oil inhibited the growth and acid production of S. mutans at concentrations from 0.5 to 4 mg/mL. The essential oil also exhibited significant inhibition of S. mutans adherence to S-HAs at concentrations higher than 0.5 mg/mL. S. mutans biofilm formation was determined by scanning electron microscopy (SEM) and safranin staining. The essential oil of C. longa inhibited the formation of S. mutans biofilms at concentrations higher than 0.5 mg/mL. The components of C. longa essential oil were then analyzed by GC and GC-MS, and the major components were α-turmerone (35.59%), germacrone (19.02%), α-zingiberene (8.74%), αr-turmerone (6.31%), trans-β-elemenone (5.65%), curlone (5.45%), and β-sesquiphellandrene (4.73%). These results suggest that C. longa may inhibit the cariogenic properties of S. mutans.     

Approach to non-human species radiation dose assessment in the Republic of Korea

This paper describes the approach to non-human species radiation dose assessment in Korea. As the tentative reference organisms, one plant and seven animals were selected based on the new International Commission on Radiological Protection recommendation issued in 2007, and the size of the selected organisms was determined from the corresponding Korean endemic species. A set of 25 radionuclides was considered as a potential source term of causing radiological damage to organisms. External and internal dose conversion coefficients for the selected organisms and radionuclides were calculated by the uniform isotropic model or Monte Carlo simulation. Concentration ratios of some endemic species are being measured in laboratory experiments, in parallel with the review of existing data.     

Characterisation and food application of curcumin bound to sodium caseinate–polysaccharide electrostatic complexes

Electrostatic complexes between sodium caseinate (NaCas) and high‐methoxyl pectin (HMP) or carboxymethyl cellulose (CMC) were used to stabilise curcumin in this study. Effect of pH on the characteristics of the complex was evaluated, finding pH 4 was optimum. Zeta potential of NaCas‐CMC (?33.59) was larger than that of NaCas‐HMP (?22.19) at pH 4, implying higher colloidal stability. The complexes protected curcumin from heat treatment, and antioxidant activity of curcumin bound to the complexes was similar to that of native curcumin. Incorporation of sucrose partially prevented freeze drying‐induced aggregation of the complex, especially for NaCas‐HMP. In a model beverage, curcumin bound to the complexes showed higher colour stability. In vitro bioaccessibility of curcumin bound to NaCas‐HMP (53.0%) and NaCas‐CMC (51.6%) was higher than the native curcumin (21.4%). This study suggests that curcumin bound to the complexes, especially NaCas‐HMP‐bound curcumin may be used as a potential food colourant where transparency is needed.