Acute Increases in Intracellular Zinc Lead to an Increased Lysosomal and Mitochondrial Autophagy and Subsequent Cell Demise in Malignant Melanoma

Changes in zinc content and dysregulated zinc homeostatic mechanisms have been recognized in several solid malignancies such as prostate cancer, breast cancer, or pancreatic cancer. Moreover, it has been shown that zinc serum and/or tissue levels are altered in melanoma with varying effects on melanoma development and biology. This study was conducted to explore the effects of acute increases of intracellular zinc in a set of melanoma tissue explants obtained from clinical samples. Measurements of their zinc content showed an extant heterogeneity in total and free intracellular zinc pools associated with varying biological behavior of individual cells, e.g., autophagy levels and propensity to cell death. Use of zinc pyrithione elevated intracellular zinc in a short time frame which resulted in marked changes in mitochondrial activity and lysosomes. These alterations were accompanied by significantly enhanced autophagy flux and subsequent cell demise in the absence of typical apoptotic cell death markers. The present results show for the first time that acutely increased intracellular zinc in melanoma cells specifically enhances their autophagic activity via mitochondria and lysosomes which leads to autophagic cell death. While biologically relevant, this discovery may contribute to our understanding and exploration of zinc in relation to autophagy as a means of controlling melanoma growth and survival.     

Biological Evaluation and Molecular Docking Studies of Novel 1,3,4-Oxadiazole Derivatives of 4,6-Dimethyl-2-sulfanylpyridine-3-carboxamide

To date, chronic inflammation is involved in most main human pathologies such as cancer, and autoimmune, cardiovascular or neurodegenerative disorders. Studies suggest that different prostanoids, especially prostaglandin E₂, and their own synthase (cyclooxygenase enzyme-COX) can promote tumor growth by activating signaling pathways which control cell proliferation, migration, apoptosis, and angiogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) are used, alongside corticosteroids, to treat inflammatory symptoms particularly in all chronic diseases. However, their toxicity from COX inhibition and the suppression of physiologically important prostaglandins limits their use. Therefore, in continuation of our efforts in the development of potent, safe, non-toxic chemopreventive compounds, we report herein the design, synthesis, biological evaluation of new series of Schiff base-type hybrid compounds containing differently substituted N-acyl hydrazone moieties, 1,3,4-oxadiazole ring, and 4,6-dimethylpyridine core. The anti-COX-1/COX-2, antioxidant and anticancer activities were studied. Schiff base 13, containing 2-bromobenzylidene residue inhibited the activity of both isoenzymes, COX-1 and COX-2 at a lower concentration than standard drugs, and its COX-2/COX-1 selectivity ratio was similar to meloxicam. Furthermore, the results of cytotoxicity assay indicated that all of the tested compounds exhibited potent anti-cancer activity against A549, MCF-7, LoVo, and LoVo/Dx cell lines, compared with piroxicam and meloxicam. Moreover, our experimental study was supported by density functional theory (DFT) and molecular docking to describe the binding mode of new structures to cyclooxygenase.     

Efficient TGF-β1 Delivery to Articular Chondrocytes In Vitro Using Agro-Based Liposomes

The low efficiency in transfecting rat- and human-derived chondrocytes have been hampering developments in the field of cartilage biology. Transforming growth factor (TGF)-β1 has shown positive effects on chondrocytes, but its applications remain limited due to its short half-life, low stability and poor penetration into cartilage. Naturally derived liposomes have been shown to be promising delivery nanosystems due to their similarities with biological membranes. Here, we used agro-based rapeseed liposomes, which contains a high level of mono- and poly-unsaturated fatty acids, to efficiently deliver encapsulated TGF-β1 to rat chondrocytes. Results showed that TGF-β1 encapsulated in nano-sized rapeseed liposomes were safe for chondrocytes and did not induce any alterations of their phenotype. Furthermore, the controlled release of TGF-β1 from liposomes produced an improved response in chondrocytes, even at low doses. Altogether, these outcomes demonstrate that agro-based nanoliposomes are promising drug carriers.     

Selective oxidation of methane with air over silica catalysts

Partial oxidation of methane by oxygen to form formaldehyde, carbon oxides, and C₂ products (ethane and ethene) has been studied over silica catalyst supports (fumed Cabosil and Grace 636 silica gel) in the 630–780 °C temperature range under ambient pressure. The silica catalysts exhibit high space time yields (at low conversions) for methane partial oxidation to formaldehyde, and the C₂ hydrocarbons were found to be parallel products with formaldehyde. Short residence times enhanced both the C₂ hydrocarbons and formaldehyde selectivities over the carbon oxides even within the differential reactor regime at 780 °C. This suggests that the formaldehyde did not originate from methyl radicals, but rather from methoxy complexes formed upon the direct chemisorption of methane at the silica surface at high temperature. Very high formaldehyde space time yields (e.g., 812 g/kg cat h at the gas hourly space velocity = 560 000 (NTP)/kg cat h) could be obtained over the silica gel catalyst at 780 °C with a methane/air mixture of 1.5/1. These yields greatly surpass those reported for silicas earlier, as well as those over many other catalysts. Low CO₂ yields were observed under these reaction conditions, and the selectivities to formaldehyde and C₂ hydrocarbons were 28.0 and 38.8%, respectively, at a methane conversion of 0.7%. A reaction mechanism was proposed for the methane activation over the silica surface based on the present studies, which can explain the product distribution patterns (specifically the parallel formation of formaldehyde and C₂ hydrocarbons).     

Insights into the in vitro Anticancer Effects of Diruthenium‐1

The in vitro anticancer activity of the dinuclear trithiolato‐bridged arene ruthenium complex diruthenium‐1 (DiRu‐1) was evaluated against a panel of human cancer cell lines used as in vitro models for hepatocellular carcinoma (HepG2 cells), estrogen‐responsive breast adenocarcinoma (MCF‐7 cells), and triple‐negative breast adenocarcinoma (MDA‐MB‐231 cells). DiRu‐1 is highly cytotoxic to these cell lines, demonstrating half‐maximal inhibitory concentrations (IC₅₀) in the low‐nanomolar range (77±1.4 to 268.2±4.4 nm ). The main molecular mechanisms responsible for the high cytotoxicity of DiRu‐1 against the most responsive MCF‐7 cell line (IC₅₀=77±1.4 nm) were investigated on the basis of the capacity of DiRu‐1 to induce oxidative stress, apoptosis, and DNA damage, and to inhibit the cell cycle and proliferation. The results show that DiRu‐1 triggers caspase‐dependent apoptosis in MCF‐7 cells on both the intrinsic and extrinsic pathways. Moreover, the Ru complex also causes necrosis, mitotic catastrophe, and autophagy. DiRu‐1 increases the intracellular levels of reactive oxygen species (ROS), which play a significant role in its cytotoxicity and pro‐apoptotic activity. An important mechanism of the anticancer activity of DiRu‐1 appears to be the induction of DNA lesions, mainly due to apoptotic DNA fragmentation and cell‐cycle arrest at the G₂/M checkpoint. These changes are correlated with the concentration of DiRu‐1, the duration of the cell treatment, and the post‐treatment time.     

Preparation of bifunctonal catallysts

Catalyzed reactions are usually a combination of various reaction pathways that require Catalysts to possess more than one chemical function. These reaction types and Catalyst functions are reviewed and bifunctionality of Catalysts is exemplified in the ensemble control effect for oxidation of carbons to CO/CO₂, double redox oxide Catalysts for partial oxidation of methane, base-hydrogenation Catalysts for methanol and higher alcohol synthesis as well as the water gas shift reaction, hydrogenation-CO insertion Catalysts for higher alcohol synthesis, and acid- hydrogenation Catalysts for the synthesis of ethers.     

Serial reversal learning and the evolution of behavioral flexibility in three species of North American corvids (Gymnorhinus cyanocephalus, Nucifraga columbiana, Aphelocoma californica).

In serial reversal learning, subjects learn to respond differentially to 2 stimuli. When the task is fully acquired, reward contingencies are reversed, requiring the subject to relearn the altered associations. This alternation of acquisition and reversal can be repeated many times, and the ability of a species to adapt to this regimen has been considered as an indication of behavioral flexibility. Serial reversal learning of 2-choice discriminations was contrasted in 3 related species of North American corvids: pinyon jays (Gymnorhinus cyanocephalus), which are highly social; Clark's nutcrackers (Nucifraga columbiana), which are relatively solitary but specialized for spatial memory; and western scrub jays (Aphelocoma californica), which are ecological generalists. Pinyon jays displayed significantly lower error rates than did nutcrackers or scrub jays after reversal of reward contingencies for both spatial and color stimuli. The effect was most apparent in the 1st session following each reversal and did not reflect species differences in the rate of initial discrimination learning. All 3 species improved their performance over successive reversals and showed significant transfer between color and spatial tasks, suggesting a generalized learning strategy. The results are consistent with an evolutionary association between behavioral flexibility and social complexity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Towards a Mobile Multimedia Age – Location-Based Services: A Case Study

Japan has been at the leading edge of location-based services (LBS) deployment using wireless assisted GPS technology. These services, which include personal security, navigation, gaming, security and fleet management, have experienced tremendous growth over the last few years. By looking at the factors contributing to this successful growth, LBS can be deployed in Europe with equal success. In addition to success factors, it is important to look at the underlying wireless network technology and its deployment impact, since Japanese deployments are based on synchronous 3G whereas Europe's likely deployments will be based on asynchronous UMTS. Recognizing the implication of both these items in accordance with SnapTrack's vision of UMTS LBS deployment affords a service provider a better opportunity to successfully introduce LBS and drive service revenue. This revised version was published online in August 2006 with corrections to the Cover Date.     

An improved metric for measuring multi-item multi-level schedule instability under rolling schedules

Disruptions in material plans due to unrealistic schedules and frequent plan revisions are common symptoms of a phenomenon generally referred to as nervousness or schedule instability in literature. A number of instability measures had been proposed so far. However, none of them deals with instability measurement comprehensively. An appropriate measurement should be able to reflect the degree of changes under rolling schedules, as well as a tool for analyzing the performance of planning systems and nervousness dampening procedures.The intent of this paper is to present a new metric for measuring multi-item multi-level schedule instability under rolling schedules and to compare it with the previous measures in literature. The new metric composed of linear combination of four sub-instability measures separates quantity and timing changes for both scheduled receipts (SRs) and planned orders (PORs). The new metric is tested by a detailed numerical example taken from literature, and results of simulation studies under various experimental factors are presented at the end of the study.