Rational Design of Potent Inhibitors of a Metallohydrolase Using a Fragment-Based Approach

Metallohydrolases form a large group of enzymes that have fundamental importance in a broad range of biological functions. Among them, the purple acid phosphatases (PAPs) have gained attention due to their crucial role in the acquisition and use of phosphate by plants and also as a promising target for novel treatments of bone-related disorders and cancer. To date, no crystal structure of a mammalian PAP with drug-like molecules bound near the active site is available. Herein, we used a fragment-based design approach using structures of a mammalian PAP in complex with the Maybridge^TM fragment CC063346, the amino acid L-glutamine and the buffer molecule HEPES, as well as various solvent molecules to guide the design of highly potent and efficient mammalian PAP inhibitors. These inhibitors have improved aqueous solubility when compared to the clinically most promising PAP inhibitors available to date. Furthermore, drug-like fragments bound in newly discovered binding sites mapped out additional scaffolds for further inhibitor discovery, as well as scaffolds for the design of inhibitors with novel modes of action.     

Anthocyanin-fortified konjac glucomannan/sodium alginate composite edible boba: characteristics of texture,microstructure, in vitro release behaviour and antioxidant capacity

Konjac glucomannan/sodium alginate composite edible boba (KGM/SA-boba) with good taste is very popular in China, and it is an outstanding carrier for health potential ingredients. In this work, KGM/SA-boba were fortified with 0.25, 0.50, 0.75 and 1.00% purple sweet potato anthocyanin (PSPA), then characterised by the water distribution, texture, microstructure, in vitro release property of PSPA and antioxidant capacity. LF-NMR analysis demonstrated that the free water of KGM/SA-boba could transfer to tightly bound water with the addition of PSPA that made it with better water-binding ability, higher springiness and lower hardness. And the results of SEM and rheology showed that PSPA could stabilise the microstructure of KGM/SA-boba by forming more amorphous regions and hydrogen bonds proved by the results of DSC and FT-IR. Furthermore, 50% of PSPA in PSPA-fortified KGM/SA-boba can be released at the first hour in a simulated gastrointestinal environment. And the scavenging capacity of DPPH and ABTS of the PSPA-fortified KGM/SA-boba after digestion was higher than that of PSPA alone. Generally, PSPA could improve the texture while KGM/SA-boba in turn would make PSPA more stable in the gastrointestinal digestive system.     

TAS-116, a Well-Tolerated Hsp90 Inhibitor,Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells

Chronic inflammation has been associated with several chronic diseases, such as age-related macular degeneration (AMD). The NLRP3 inflammasome is a central proinflammatory signaling complex that triggers caspase-1 activation leading to the maturation of IL-1β. We have previously shown that the inhibition of the chaperone protein, Hsp90, prevents NLRP3 activation in human retinal pigment epithelial (RPE) cells; these are cells which play a central role in the pathogenesis of AMD. In that study, we used a well-known Hsp90 inhibitor geldanamycin, but it cannot be used as a therapy due to its adverse effects, including ocular toxicity. Here, we have tested the effects of a novel Hsp90 inhibitor, TAS-116, on NLRP3 activation using geldanamycin as a reference compound. Using our existing protocol, inflammasome activation was induced in IL-1α-primed ARPE-19 cells with the proteasome and autophagy inhibitors MG-132 and bafilomycin A1, respectively. Intracellular caspase-1 activity was determined using a commercial caspase-1 activity kit and the FLICA assay. The levels of IL-1β were measured from cell culture medium samples by ELISA. Cell viability was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and lactate dehydrogenase (LDH) measurements. Our findings show that TAS-116 could prevent the activation of caspase-1, subsequently reducing the release of mature IL-1β. TAS-116 has a better in vitro therapeutic index than geldanamycin. In summary, TAS-116 appears to be a well-tolerated Hsp90 inhibitor, with the capability to prevent the activation of the NLRP3 inflammasome in human RPE cells.     

Synthesis and characterization of Co5Cr2(P2O7)4 - New pyrophosphate as a colouring substance

A new pyrophosphate(V) of the formula Co₅Cr₂(P₂O₇)₄ was obtained in the system Co₂P₂O₇–Cr₄(P₂O₇)₃ as a result of solid-state reactions taking place between different reactants. The new compound crystallizes in the orthorhombic system and belongs to the family of pyrophosphates of the general formula M₅²⁺M₂³⁺(P₂O₇)₄ and is probably isostructural with Fe₅²⁺Fe₂³⁺(P₂O₇)₄. Powder diffraction pattern, infrared spectrum and SEM image of the new compound were presented. As a new potential inorganic pigment, Co₅Cr₂(P₂O₇)₄ was tested for its thermal stability, particle size distribution and colour properties, which were studied both for powder and after introduction into organic matrix and leadless ceramic glaze. The colour of Co₅Cr₂(P₂O₇)₄ powder was defined as deep grey with the colour coordinates L*/a*/b* = 60.63/-1.42/-3.41 and according to the hue angle (h° = 247.39°) it belongs to the blue region. Co₅Cr₂(P₂O₇)₄, with its relatively high thermal stability (t _m = 1230 ± 10 °C) and appropriate colour properties, is a good candidate to be used as inorganic pigment for colouring of acrylic paints. In the case of leadless glaze, the obtained compound acts as a dye.     

耐腐蚀水性铝颜料的制备及表征

为了提高铝颜料在水性涂料中的耐腐蚀性能，以正硅酸乙酯（ TEOS）为前驱物，通过溶胶-凝胶反应在铝颜料表面形成了一层致密的二氧化硅包覆薄膜，通过优化固含量、溶剂种类及 TEOS的用量，提高铝颜料的耐碱性。利用扫描电镜、刮板试验、接触角测试、析氢实验进行表征，结果表明：以无水乙醇为溶剂，铝金属颜料固含量为 10%，升温至 50 ℃后，逐滴加入 6 g TEOS，再升温至 80 ℃，该条件下制备的 SiO₂膜包覆后的铝颜料具有优异的耐碱性，同时表面性能由疏水性转变成亲水性，对铝颜料起到了很好的保护作用。     

Fucoidans as Potential Therapeutics for Age-Related Macular Degeneration—Current Evidence from In Vitro Research

Age-related macular degeneration (AMD) is the major reason for blindness in the industrialized world with limited treatment options. Important pathogenic pathways in AMD include oxidative stress and vascular endothelial growth factor (VEGF) secretion. Due to their bioactivities, fucoidans have recently been suggested as potential therapeutics. This review gives an overview of the recent developments in this field. Recent studies have characterized several fucoidans from different species, with different molecular characteristics and different extraction methods, in regard to their ability to reduce oxidative stress and inhibit VEGF in AMD-relevant in vitro systems. As shown in these studies, fucoidans exhibit a species dependency in their bioactivity. Additionally, molecular properties such as molecular weight and fucose content are important issues. Fucoidans from Saccharina latissima and Laminaria hyperborea were identified as the most promising candidates for further development. Further research is warranted to establish fucoidans as potential therapeutics for AMD.     

节能减排的颜料印染与助剂(一)

颜料印染对当前印染行业节能减排,降低能耗很有意义,但要做到对纤维没有亲和力的颜料印染,必需制备润湿性、分散性良好的超细颜料粒子。重点阐述利用各种表面活性剂和助剂制备出一种包覆阴离子的超细粒子的稳定分散液,包括各种润湿剂、分散剂、黏合剂和纤维阳离子改性剂,还概述了相关基础理论。     

Retinal Cell Death Caused by Sodium Iodate Involves Multiple Caspase-Dependent and Caspase-Independent Cell-Death Pathways

Herein, we have investigated retinal cell-death pathways in response to the retina toxin sodium iodate (NaIO₃) both in vivo and in vitro. C57/BL6 mice were treated with a single intravenous injection of NaIO₃ (35 mg/kg). Morphological changes in the retina post NaIO₃ injection in comparison to untreated controls were assessed using electron microscopy. Cell death was determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining. The activation of caspases and calpain was measured using immunohistochemistry. Additionally, cytotoxicity and apoptosis in retinal pigment epithelial (RPE) cells, primary retinal cells, and the cone photoreceptor (PRC) cell line 661W were assessed in vitro after NaIO₃ treatment using the ApoToxGlo™ assay. The 7-AAD/Annexin-V staining was performed and necrostatin (Nec-1) was administered to the NaIO₃-treated cells to confirm the results. In vivo, degenerating RPE cells displayed a rounded shape and retracted microvilli, whereas PRCs featured apoptotic nuclei. Caspase and calpain activity was significantly upregulated in retinal sections and protein samples from NaIO₃-treated animals. In vitro, NaIO₃ induced necrosis in RPE cells and apoptosis in PRCs. Furthermore, Nec-1 significantly decreased NaIO₃-induced RPE cell death, but had no rescue effect on treated PRCs. In summary, several different cell-death pathways are activated in retinal cells as a result of NaIO₃.