Cancer cell metabolism in hypoxia: Role of HIF-1 as key regulator and therapeutic target

In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells

Transcriptional Regulation and Function of Malic Enzyme 1 in Human Macrophage Activation

Macrophages represent primary players of the innate immune system. Macrophage activation triggers several signaling pathways and is tightly associated with metabolic changes, which drive different immune subsets. Recent studies unveil the role of various metabolic enzymes in macrophage activation. Here, we show that malic enzyme 1 (ME1) is overexpressed in LPS-induced macrophages. Through chromatin immunoprecipitation, we demonstrate that ME1 transcriptional regulation is under control of NF-κB. Furthermore, ME1 activity is also increased in activated human PBMC-derived macrophages. Notably, ME1 gene silencing decreases nitric oxide as well as reactive oxygen species and prostaglandin E2 inflammatory mediators. Therefore, modulating ME1 provides a potential approach for immunometabolic regulation and in turn macrophage function

A review of sulfoxaflor, a derivative of biological acting substances as a class of insecticides with a broad range of action against many insect pests

Sulfoxaflor is an insecticide used against sap-feeding insects (Aphididae, Aleyrodidae) belonging to the family of sulfoximine; sulfoximine is a chiral nitrogen-containing sulphur (VI) molecule; it is a sub-group of insecticides that act as nicotinic acetylcholine receptor (nAChR) competitive modulators. Sulfoxaflor binds to nAChR in place of acetylcholine and acts as an allosteric activator of nAChR. Thanks to its mode of action resistance phenomena are uncommon, even few cases of resistance were reported. It binds to receptors determining uncontrolled nerve impulses followed by muscle tremors to which paralysis and death follows. Sulfoxaflor acts on the same receptors of neonicotinoids as nicotine and butenolides, but it binds differently. It binds to insects nAChRs more strongly than to mammals’ ones, so it is much less toxic for mammals and man. Sulfoxaflor is supposed to have a low environmental impact and is not much aggressive against non-target species. Unfortunately, it is toxic to impollinator insects, so it must be used only in compliance with a series of legislative norms. At present sulfoxaflor can be considered one of the most interesting products to be used in fighting against agriculture insect pests

Ensemble consensus: An unsupervised algorithm for anomaly detection in network security data

Unsupervised network traffic monitoring is of paramount importance in cyber security. It allows to detect suspicious events that are defined as non-normal and report or block them. In this work the Anomaly Consensus algorithm for unsupervised network analysis is presented. The algorithm aim is to fuse the three most important anomaly detection techniques for unsupervised detection of suspicious events. Tests are performed against the KDD Cup'99 dataset, one of the most famous supervised datasets for automatic intrusion detection created by DARPA. Accuracies reveal that Anomaly Consensus performs on-par with respect to state-of-the-art supervised learning techniques, ensuring high generalization power also in borderline tests when small amount of data (5%) is used for training and the rest is for validation and testing

Mitochondrial Role in Intrinsic Apoptosis Induced by a New Synthesized Chalcone in Hepatocellular Carcinoma Cells

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the fourth cause of cancer-related deaths worldwide. Presently, a few drugs are available for HCC treatment and prevention, including both natural and synthetic compounds. In this study, a new chalcone, (E)-1-(2,4,6-triethoxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (ETTC), was synthesized and its effects and mechanisms of action over human hepatoma cells were investigated. Cytotoxic activity was revealed in HCC cells, while no effects were observed in normal hepatocytes. In HCC cells, ETTC caused subG1 cell cycle arrest and apoptosis, characterized by nuclear fragmentation. The activation of caspases 3/7 and 9, the increase in pro-apoptotic BAX, and the decrease in anti-apoptotic BCL-2 suggest the activation of the intrinsic pathway of apoptosis. ETTC mitochondrial targeting is confirmed by the reduction in mitochondrial membrane potential and Complex I activity together with levels of superoxide anion increasing. Our outcomes prove the potential mitochondria-mediated antitumor effect of newly synthesized chalcone ETTC in HCC

Epidemiological patterns of asbestos exposure and spatial clusters of incident cases of malignant mesothelioma from the Italian national registry

Abstract BACKGROUND: Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM). METHODS: In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster. RESULTS: Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters. CONCLUSIONS: Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs

Immunometabolism Modulation by Extracts from Pistachio Stalks Formulated in Phospholipid Vesicles

Several studies have demonstrated the effectiveness of plant extracts against various diseases, especially skin disorders; namely, they exhibit overall protective effects. The Pistachio (Pistacia vera L.) is known for having bioactive compounds that can effectively contribute to a person’s healthy status. However, these benefits may be limited by the toxicity and low bioavailability often inherent in bioactive compounds. To overcome these problems, delivery systems, such as phospholipid vesicles, can be employed. In this study, an essential oil and a hydrolate were produced from P. vera stalks, which are usually discarded as waste. The extracts were characterized by liquid and gas chromatography coupled with mass spectrometry and formulated in phospholipid vesicles intended for skin application. Liposomes and transfersomes showed small size (<100 nm), negative charge (approximately −15 mV), and a longer storage stability for the latter. The entrapment efficiency was determined via the quantification of the major compounds identified in the extracts and was >80%. The immune-modulating activity of the extracts was assayed in macrophage cell cultures. Most interestingly, the formulation in transfersomes abolished the cytotoxicity of the essential oil while increasing its ability to inhibit inflammatory mediators via the immunometabolic citrate pathway

Mitochondria-mediated apoptosis of hcc cells triggered by knockdown of glutamate dehydrogenase 1: Perspective for its inhibition through quercetin and permethylated anigopreissin a

Metabolic reprogramming is a hallmark of cancer cells required to ensure high energy needs and the maintenance of redox balance. A relevant metabolic change of cancer cell bioenergetics is the increase in glutamine metabolism. Hepatocellular carcinoma (HCC), one of the most lethal cancer and which requires the continuous development of new therapeutic strategies, shows an up-regulation of human glutamate dehydrogenase 1 (hGDH1). GDH1 function may be relevant in cancer cells (or HCC) to drive the glutamine catabolism from L-glutamate towards the synthesis of α-ketoglutarate (α-KG), thus supplying key tricarboxylic acid cycle (TCA cycle) metabolites. Here, the effects of hGLUD1 gene silencing (siGLUD1) and GDH1 inhibition were evaluated. Our results demonstrate that siGLUD1 in HepG2 cells induces a significant reduction in cell proliferation (58.8% ± 10.63%), a decrease in BCL2 expression levels, mitochondrial mass (75% ± 5.89%), mitochondrial membrane potential (30% ± 7.06%), and a significant increase in mitochondrial superoxide anion (25% ± 6.55%) compared to control/untreated cells. The inhibition strategy leads us to identify two possible inhibitors of hGDH1: quercetin and Permethylated Anigopreissin A (PAA). These findings suggest that hGDH1 could be a potential candidate target to impair the metabolic reprogramming of HCC cells

Contributions to a neurophysiology of meaning: The interpretation of written messages could be an automatic stimulus-reaction mechanism before becoming conscious processing of information

Background. Interpretation is the process through which humans attribute meanings to every input they grasp from their natural or social environment. Formulation and exchange of meanings through natural language are basic aspects of human behaviour and important neuroscience subjects; from long ago, they are the object of dedicated scientific research. Two main theoretical positions (cognitivism and embodied cognition) are at present confronting each other; however, available data is not conclusive and scientific knowledge of the interpretation process is still unsatisfactory. Our work proposes some contributions aimed to improve it. Methodology. Our field research involved a random sample of 102 adults. We presented them a real world-like case of written communication using unabridged message texts. We collected data (written accounts by participants about their interpretations) in controlled conditions through a specially designed questionnaire (closed and opened answers). Finally, we carried out qualitative and quantitative analyses through some fundamental statistics. Principal Findings. While readers are expected to concentrate on the text’s content, they rather report focusing on the most varied and unpredictable components: certain physical features of the message (e.g. the message’s period lengths) as well as meta-information like the position of a statement or even the lack of some content. Just about 12% of the participants' indications point directly at the text's content. Our data converge on the hypothesis that the components of a message work at first like physical stimuli, causing readers' automatic (body level) reactions independent of the conscious attribution of meaning. So, interpretation would be a (learned) stimulus-reaction mechanism, before switching to information processing, and the basis of meaning could be perceptual/analogical, before propositional/digital. We carried out a first check of our hypothesis: the employed case contained the emerging of a conflict and two versions (“H” and “S”, same content, different forms) of a reply to be sent at a crucial point. We collected the participants’ (independent) interpretations of the two versions; then, we asked them to choose which one could solve the conflict; finally, we assessed the coherence between interpretations and choice on a 4-level scale. The analysis of the coherence levels' distribution returned that, with regards to our expectations, incoherence levels are over-represented; such imbalance is totally ascribable to “H” choosers. “H” and “S” choosers show significant differences (p&lt;&lt;0.01) in the distributions of coherence levels, what is inconsistent with the traditional hypothesis of a linear information processing resulting in the final choice. In the end, with respect to the currently opposing theories, we found out that our hypothesis has either important convergences or at least one critical divergence, joined with the capacity to encompass they both.</jats:p

ACLY nuclear translocation in human macrophages drives proinflammatory gene expression by NF-κB acetylation

Macrophage stimulation by pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS) or lipoteichoic acid (LTA) drives a proinflammatory phenotype and induces a metabolic reprogramming to sustain the cell’s function. Nevertheless, the relationship between metabolic shifts and gene expression remains poorly explored. In this context, the metabolic enzyme ATP citrate lyase (ACLY), the producer of citrate-derived acetyl-coenzyme A (CoA), plays a critical role in supporting a proinflammatory response. Through immunocytochemistry and cytosol-nucleus fractionation, we found a short-term ACLY nuclear translocation. Protein immunoprecipitation unveiled the role of nuclear ACLY in NF-κB acetylation and in turn its full activation in human PBMC-derived macrophages. Notably, sepsis in the early hyperinflammatory phase triggers ACLY-mediated NF-κB acetylation. The ACLY/NF-κB axis increases the expression levels of proinflammatory genes, including SLC25A1—which encodes the mitochondrial citrate carrier—and ACLY, thus promoting the existence of a proinflammatory loop involving SLC25A1 and ACLY genes