Small-Molecule Inhibition of Glucose Transporters GLUT-1–4

Glucose addiction is observed in cancer and other diseases that are associated with hyperproliferation. The development of compounds that restrict glucose supply and decrease glycolysis has great potential for the development of new therapeutic approaches. Addressing facilitative glucose transporters (GLUTs), which are often upregulated in glucose-dependent cells, is therefore of particular interest. This article reviews a selection of potent, isoform-selective GLUT inhibitors and their biological characterization. Potential therapeutic applications of GLUT inhibitors in oncology and other diseases that are linked to glucose addiction are discussed.     

Targeting DNA Methylation in Leukemia,Myelodysplastic Syndrome,and Lymphoma: A Potential Diagnostic,Prognostic, and Therapeutic Tool

DNA methylation represents a crucial mechanism of epigenetic regulation in hematologic malignancies. The methylation process is controlled by specific DNA methyl transferases and other regulators, which are often affected by genetic alterations. Global hypomethylation and hypermethylation of tumor suppressor genes are associated with hematologic cancer development and progression. Several epi-drugs have been successfully implicated in the treatment of hematologic malignancies, including the hypomethylating agents (HMAs) decitabine and azacytidine. However, combinations with other treatment modalities and the discovery of new molecules are still the subject of research to increase sensitivity to anti-cancer therapies and improve patient outcomes. In this review, we summarized the main functions of DNA methylation regulators and genetic events leading to changes in methylation landscapes. We provide current knowledge about target genes with aberrant methylation levels in leukemias, myelodysplastic syndromes, and malignant lymphomas. Moreover, we provide an overview of the clinical trials, focused mainly on the combined therapy of HMAs with other treatments and its impact on adverse events, treatment efficacy, and survival rates among hematologic cancer patients. In the era of precision medicine, a transition from genes to their regulation opens up the possibility of an epigenetic-based approach as a diagnostic, prognostic, and therapeutic tool.     

Laccase Mediator Cocktail System as a Sustainable Skin Whitening Agent for Deep Eumelanin Decolorization

The overproduction of eumelanin leads to a panel of unaesthetic hyper-pigmented skin diseases, including melasma and age spots. The treatment of these diseases often requires the use of tyrosinase inhibitors, which act as skin whitening agents by inhibiting the synthesis of eumelanin, with harmful side effects. We report here that laccase from Trametes versicolor in association with a cocktail of natural phenol redox mediators efficiently degraded eumelanin from Sepia officinalis, offering an alternative procedure to traditional whitening agents. Redox mediators showed a synergistic effect with respect to their single-mediator counterpart, highlighting the beneficial role of the cocktail system. The pro-oxidant DHICA sub-units of eumelanin were degraded better than the DHI counterpart, as monitored by the formation of pyrrole-2,3,5-tricarboxylic acid (PTCA) and pyrrole-2,3-dicarboxylic acid (PDCA) degradation products. The most effective laccase-mediated cocktail system was successively applied in a two-component prototype of a topical whitening cream, showing high degradative efficacy against eumelanin.     

Studies on the uptake of glucose derivatives by red blood cells

Erythrocytes express the same glucose transporter (GLUT-1) as is present in the blood-brain barrier. With the aim of testing the viability of using this transport system to deliver glucosyl drug derivatives to the brain, the uptake of several dopamine-glucose conjugates and a few structurally related analogues by erythrocytes was studied with HPLC and (1)H MAS NMR spectroscopy. The results showed that slight structural changes determine the uptake of glycoconjugates by red blood cells. However, experiments in the presence of glucose transport inhibitors showed that none of the conjugates that efficiently crossed the cell membrane were transported by GLUT-1.     

Biochemical,Structural, and Genetic Characterization of Tridecaptin A1, an Antagonist of Campylobacter jejuni

Bacillus circulans NRRL B‐30644 (now Paenibacillus terrae) was previously reported to produce SRCAM 1580, a bacteriocin active against the food pathogen Campylobacter jejuni. We have been unable to isolate SRCAM 1580, and did not find any genetic determinants in the genome of this strain. We now report the reassignment of this activity to the lipopeptide tridecaptin A₁. Structural characterization of tridecaptin A₁ was achieved through NMR, MS/MS and GC‐MS studies. The structure was confirmed through the first chemical synthesis of tridecaptin A₁, which also revealed the stereochemistry of the lipid chain. The impact of this stereochemistry on antimicrobial activity was examined. The biosynthetic machinery responsible for tridecaptin production was identified through bioinformatic analyses. P. terrae NRRL B‐30644 also produces paenicidin B, a novel lantibiotic active against Gram‐positive bacteria. MS/MS analyses indicate that this lantibiotic is structurally similar to paenicidin A.     

微生态制剂在水产养殖中的应用

主要从防治鱼病的发生及减少抗生素滥用、改良水质和防治有害蓝藻等三个方面的作用综述了微生物制剂在水产养殖中的应用现状及研究进展,分析了目前微生物制剂研究及生产中存在的问题,并对微生物制剂在水产养殖中的研究及应用发展趋势作了进一步的展望。     

化学灭火添加剂的灭火有效性实验研究

通过大量的实验及查阅相关的国外文献资料,对化学添加剂的灭火机理及其灭火性能进行了研究,研究的对象分为两类:一类是易溶于水的碱金属盐,主要是研究其作为化学添加剂添加在细水雾中的灭火效果;另一类是含铁、锌、锰等元素的高效化学灭火物质,研究其作为化学添加剂添加到其它气态灭火介质如二氧化碳、氮气中的灭火效果.同时作者通过实验重点论证了灭火添加剂的优化配比、极限性和提高其灭火效能的途径等问题,也讨论了灭火添加剂与其它灭火介质之间的相互作用关系,为研制新型清洁、经济、高效的灭火剂奠定了基础.     

Effects of perfluoroether concentration and curing protocol on morphology and mechanical properties of toughened TGDDM/MNA resin systems

Previous published work has shown that hydroxyl terminated perfluoroether oligomers can be suitably modified and functionalised to make them miscible with epoxy resins in the uncured state. The reaction conditions can adjusted to induce phase separation either through spinodal decomposition to produce an IPN type morphology, or by nucleation and growth if a dispersed-particle microstructure is required.In the present work we examine the relative toughening enhancement efficiency of the two possible heterophase morphologies. Both systems show a sigmoidal increase in fracture toughness, with increasing concentration of the perfluoroether modifier. However, this takes place at much lower modifier concentrations for the systems with a particulate morphology (about 3.5% w/w) than for IPN systems (about 7.5% w/w). The maximum fracture toughness achievable for the two systems, on the other hand, is very similar and coincides with the concentration at which co-continuous phases are formed.These differences in morphology, however, are not reflected in the variation of modulus and compressive yield strength with increasing concentration of perfluoroether modifier, in so far as both systems exhibit a gradual and small reduction in property with increasing concentration. Furthermore, the dynamic mechanical spectra of the two systems are very different, but the changes resulting from increasing the concentration of toughening agent are relatively small in either case.Nanoindentation tests indicate that it is the local plasticity, brought about by the presence of the softer perfluoroether phase, which is responsible for the enhancement of fracture toughness. This is corroborated by AFM examinations, which reveal local plastic deformations in the regions surrounding the softer particles.     

NMR structure of the (+)-CPI-indole/d(GACTAATTGAC)-d(GTCAATTAGTC) covalent complex

We report the NMR solution structure of (+)-CPI-indole (CPI, 1,2,8,8a-tetrahydrocyclopropa[c]pyrrolo[3,2-e]indol-4(5H)-one), an agent belonging to the CC-1065/duocarmycin family of antitumor compounds. This (+)-CPI-indole structure is covalently bound to d(G(1)ACTAATTGTC(11))-d(G(12)TCAATTAGTC(22)), a synthetic DNA duplex containing a high-affinity binding site. The three-dimensional structure has been determined by several cycles of restrained molecular dynamics calculations with a total of 563 NMR-derived constraints, both in vacuo and by using the generalized Born solvent continuum model. In-depth analysis of the structure of this ligand-DNA complex led to a detailed knowledge of the bound state conformation of the CPI-indole, the most simplified agent related to CC-1065 and duocarmycins, the parent members of a family of extremely potent antitumor compounds. Comparison of the CPI-indole bound conformation with those previously found for (+)-duocarmycin SA (DSA), its unnatural enantiomer (-)-DSA, and the demethoxylated analogue (+)-DSI in their DNA complexes provided additional evidence of the tight correlation between the catalytic effect exerted by DNA on the alkylation reaction and the extent of angular twist between the two planar heteroaromatic subunits of these agents. Additionally, comparison of the structural features of the DNA-bound state of a "naked" ligand, such as CPI-indole, with those of various other duocarmycin agents provided useful information for the interpretation of the observed effects on chemical reactivity of the different substitution patterns at the hemispheres of these types of complex.     

Tamoxifen derivatives for delivery of the antitumoral (DACH)Pt group: selective synthesis by McMurry coupling,and biochemical behaviour

The goal of our study was to potentiate the effects of the ((R,R)-trans-1,2-diaminocyclohexane)-platinum(II) fragment [(DACH)Pt], known for its cytotoxic properties, either with tamoxifen (Tam), the most widely used antiestrogen in the treatment of hormone-dependent breast cancers, or with its active metabolite hydroxytamoxifen (hydroxy-Tam). We coupled Tam or hydroxy-Tam derivatives bearing a malonato group at the para position of the beta aromatic ring with the (DACH)Pt fragment. The malonato-Tam and malonato-hydroxy-Tam compounds were prepared through McMurry coupling of the appropriate ketones. The presence of the malonate group resulted in a pronounced stereospecificity in the reaction, since malonato-Tam was obtained only as the Z isomer, while malonato-hydroxy-Tam was obtained as an 80/20 E/Z mixture. Attribution of the isomeric structures was achieved by 2D NMR spectroscopy. The platinum complexes (DACH)Pt-malonato-Tam and (DACH)Pt-malonato-hydroxy-Tam were then prepared by coupling the barium salts derived from the malonato-Tam and malonato-hydroxy-Tam with the nitrate derived from (DACH)PtCl(2). Study of the biochemical properties of these two platinum complexes showed that, while the hydroxy-Tam complex is satisfactorily recognized by the estrogen receptor (relative binding affinity, RBA=6.4 %), the Tam complex is less well recognized (RBA=0.5 %). The effects of these complexes on two hormone-dependent breast cancer cell lines (MCF7 and MVLN) were studied in vitro. Both complexes showed an antiproliferative effect on MCF7 cells, and an antiestrogenic effect on MVLN cells. The observed effects appear to be essentially antihormonal, since incorporation of the (DACH)Pt fragment into the tamoxifen skeleton did not cause an increase in the cytotoxicity of the complexes.