Anticancer agents interacting with membrane glucose transporters

The altered metabolism observed in cancer cells generally consists of increased glucose uptake and glycolytic activity. This is associated with an overexpression of glucose transporter proteins (GLUTs), which facilitate glucose uptake across the plasma membrane and play a crucial role in the survival of cancer cells. Therefore, GLUTs are considered as suitable targets for treatment of cancer. Herein we review some of the most relevant GLUT inhibitors that have been recently developed as prospective anticancer agents

Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53 independent pathways

Most cancer cells use aerobic glycolysis to fuel their growth. The enzyme lactate dehydrogenase-A (LDH-A) is key to cancer’s glycolytic phenotype, catalysing the regeneration of nicotinamide adenine dinucleotide (NAD þ ) from reduced nicotinamide adenine dinucleotide (NADH) necessary to sustain glycolysis. As such, LDH-A is a promising target for anticancer therapy. Here we ask if the tumour suppressor p53, a major regulator of cellular metabolism, influences the response of cancer cells to LDH-A suppression. LDH-A knockdown by RNA interference (RNAi) induced cancer cell death in p53 wild-type, mutant and p53-null human cancer cell lines, indicating that endogenous LDH-A promotes cancer cell survival irrespective of cancer cell p53 status. Unexpectedly,however,weuncoveredanovelroleforp53intheregulationofcancercellNADþ anditsreducedformNADH.Thus, LDH-A silencing by RNAi, or its inhibition using a small-molecule inhibitor, resulted in a p53-dependent increase in the cancer cell ratioofNADH:NADþ.Thiseffectwasspecificforp53þ/þ cancercellsandcorrelatedwith(i)reducedactivityofNADþ-dependent deacetylase sirtuin 1 (SIRT1) and (ii) an increase in acetylated p53, a known target of SIRT1 deacetylation activity. In addition, activation of the redox-sensitive anticancer drug EO9 was enhanced selectively in p53 þ / þ cancer cells, attributable to increased activity of NAD(P)H-dependent oxidoreductase NQO1 (NAD(P)H quinone oxidoreductase 1). Suppressing LDH-A increased EO9-inducedDNAdamageinp53þ/þ cancercells,butimportantlyhadnoadditiveeffectinnon-cancercells.Ourresultsidentifya unique strategy by which the NADH/NADþ cellular redox status can be modulated in a cancer-specific, p53-dependent manner and we show that this can impact upon the activity of important NAD(H)-dependent enzymes. To summarise, this work indicates two distinct mechanisms by which suppressing LDH-A could potentially be used to kill cancer cells selectively, (i) through induction of apoptosis, irrespective of cancer cell p53 status and (ii) as a part of a combinatorial approach with redox-sensitive anticancer drugs via a novel p53/NAD(H)-dependent mechanism

Laser cutting of different polymeric plastics (PE, PP and PC) by a CO2 laser beam

Thiswork investigates the application of theCO2 laser cutting process to three thermoplastic polymers, polyethylene (PE), polypropylene (PP), polycarbonate (PC) in different thicknesses ranging from 2 to 10 mm. The process parameters examined were: laser power, range of cutting speed, type of focusing lens, pressure and flow of the covering gas, thickness of the samples. Furthermore, the values of kerf widths on top (Lsup) and bottom (Linf ) thicknesses, the melted transverse area, the melted volume per unit time and surface roughness values (Ra) on cut edges were also measured

On the welding of different materials by diode laser

In technical literature, there are few papers about the use of diode lasers in material processing and particularly in metal welding. In this paper, different materials, according to specific and particular industrial needs and requests, have been tested with a welding process by a diode laser, emitting a 808 nm laser radiation. Beads on plate have been studied. The goal was to evaluate the maximum weldable thickness and define the best process parameters for each material. The experimental evaluation has been carried out considering the following parameters: power level, welding speed (WS), shielding gas, gas nozzle and orientation of the focused elliptical spot as to the welding direction

Influence of Eta-Phase on Wear Behavior of WC-Co Carbides

Cemented carbides, also known as Widia, are hard metals produced by sintering process and widely used in mechanical machining. They show high cutting capacity and good wear resistance; consequently, they result to be excellent materials for manufacturing cutting tools and sandblast nozzles. In this work, the wear resistance of WC-Co carbides containing Eta-phase, a secondary phase present in the hard metals when a carbon content deficiency occurs, is analyzed. Different mixtures of carbide are prepared and sintered, with different weight percentages of carbon, in order to form Eta-phase and then analyze how the carbon content influences the wear resistance of the material. This characterization is carried out by abrasive wear tests. The test parameters are chosen considering the working conditions of sandblast nozzles. Additional information is gathered through microscopic observations and the evaluation of hardness and microhardness of the different mixtures. The analyses highlight that there is a limit of carbon content below which bad sintering occurs. Considering the mixtures without these sintering problems, they show a wear resistance depending on the size and distribution of the Eta-phase; moreover, the one with high carbon content deficiency shows the best performance

Identification and characterization of citrus concave gum-associated virus infecting citrus and apple trees by serological, molecular and high-throughput sequencing approaches

Citrus concave gum-associated virus (CCGaV) is a negative-stranded RNA virus, first reported a few years ago in citrus trees from Italy. It has been reported in apple trees in the USA and in Brazil, suggesting a wider host range and geographic distribution. Here, an anti-CCGaV polyclonal antiserum to specifically detect the virus has been developed and used in a standard double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) that has been validated as a sensitive and reliable method to detect this virus both in citrus and apple trees. In contrast, when the same antiserum was used in direct tissue-blot immunoassay, CCGaV was efficiently detected in citrus but not in apple. Using this antiserum, the first apple trees infected by CCGaV were identified in Italy and the presence of CCGaV in several apple cultivars in southern Italy was confirmed by field surveys. High-throughput sequencing (HTS) allowed for the assembling of the complete genome of one CCGaV Italian apple isolate (CE-c3). Phylogenetic analysis of Italian CCGaV isolates from apple and citrus and those available in the database showed close relationships between the isolates from the same genus (Citrus or Malus), regardless their geographical origin. This finding was further confirmed by the identification of amino acid signatures specific of isolates infecting citrus or apple hosts. Analysis of HTS reads also revealed that the CE-c3 Italian apple tree, besides CCGaV, was simultaneously infected by several viruses and one viroid, including apple rubbery wood virus 2 which is reported for the first time in Italy. The complete or almost complete genomic sequences of the coinfecting agents were determined

Identification, full-length genome sequencing, and field survey of citrus vein enation virus in Italy

Citrus vein enation virus (CVEV) was described in Spain and then it has been reported in several citrus growing areas of Asia, America and Australia. Here, the occurrence of CVEV in Italy has been documented for the first time. The full genome sequence of a CVEV Italian isolate (14Q) was determined by high-throughput sequencing and the presence of the virus was confirmed by RT-PCR and graft-transmission to indicator plants, from which the virus was recovered six-months post-inoculation. Phylogenetic analysis based on the full-length genome of CVEV isolates from different countries showed that they are phylogenetically related to each other based on their geographic origin, rather than on their host and that the Italian isolate is more closely related to the Spanish isolate than to the other ones. A field survey revealed the presence of CVEV in some areas of Campania region (southern Italy), prevalently infecting lemon trees. In the frame of this survey, kumquat was identified for the first time as a host of CVEV. No symptoms were observed in the field so far. The infection of asymptomatic hosts and the transmission by aphid species present in Italy increase the risk that the virus could further spread

Laser Marking of Titanium Coating for Aerospace Applications

Abstract In the aerospace industry, in order to ensure the identification and the traceability of the products, high repeatability, non-invasive and durable marking processes are required. Laser marking is one of the most advanced marking technologies. Compared to traditional marking processes, like punches, microdot, scribing or electric discharge pencil etcher, laser marking offers several advantages, such us: non-contact working, high repeatability, high scanning speed, mark width comparable to the laser spot dimension, high flexibility and high automation of the process itself. In order to assure the mark visibility for the component lifetime, an appropriate depth of the mark is required. In this way, a stable behaviour is ensured also when the component operates in aggressive environments (i.e. in presence of oxidation, corrosion and wear phenomena). The mark depth is strongly affected by the laser source kind and by the process parameters, such us average power, pulse frequency and scanning speed. Moreover, an excessive mark penetration could cause stress concentrations and reduce the fatigue life of the component. Consequently, an appropriate selection of the process parameters is required in order to assure visibility and to avoid excessive damage. Cold Spray Deposition (CSD) is a relative new technology that allows to produce surface coatings without significant substrate temperature increasing. In aeronautics fields this technology is useful to coat materials sensible to temperature, such as solution tempered aluminum alloy, with a titanium layer. Aim of the work is to characterize the laser marking process on CSD Ti coating, in order to study the influence of the laser marking process parameters (pulse power and scanning speed), on the groove geometry of the marking. The experimental marking tests were carried out through a 30 W MOPA Q-Switched Yb:YAG fibre laser; under different process conditions. The groove geometry was measured through a HIROX HK9700 optical microscope. The results showed the effectiveness of the laser process to produce high quality marks on the titanium layer. Moreover, a correlation between the process parameters and the mark's geometry was clearly observed

D(-)lentiginosine-induced apoptosis involves the intrinsic pathway and is p53-independent

We have recently found that D(-)lentiginosine, a synthetic iminosugar exerting glucosidase inhibitory activity, but not its natural enantiomer lentiginosine, is endowed with an unexpected, pro-apoptotic activity. Here, we investigated mechanisms involved in apoptosis induced by D(-)lentiginosine in MOLT-3, HT-29 and SH-SY5Y tumour cell lines. The results showed that D(-)lentiginosine increased caspase 9 expression at 18 h in all the cell lines from 1.5-3.1 folds. Cytochrome c in the cytoplasm was found to be increased from 2.3-2.6 folds in treated cells with respect to control cells. These effects were accompanied by a remarkable collapse of the mitochondrial membrane potential and by the downregulation of anti-apoptotic genes, as well as the upregulation of pro-apoptotic genes of the Bcl-2 family. U937Bcl-2 transfectants, highly expressing Bcl-2, were reluctant to undergo apoptosis even following treatment with 500 μM D(-)lentiginosine, whereas apoptosis by D(-)lentiginosine was induced also in U937 cells, naturally deficient in P53. Thus, our study establishes that the enantiomer of a natural iminosugar is endowed with a possible anti-tumorigenic effect that might be ascribed not only to their capacity to inhibit glycosidases but also to other unknown mechanisms. These data encourage further investigation on similar compounds to make them an interesting platform for the generation of new anticancer drugs