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Lung cancer (LC) is the leading cause of cancer death worldwide. LC can be classified into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), with the last subtype accounting for approximately 85% of all diagnosed lung cancer cases. Despite the existence of different types of treatment for this disease, the development of resistance to therapies and tumor recurrence in patients have maintained the need to find new therapeutic options to combat this pathology, where natural products stand out as an attractive source for this search. Nordihydroguaiaretic acid (NDGA) is the main metabolite extracted from the Larrea tridentata plant and has been shown to have different biological activities, including anticancer activity. In this study, H1975, H1299, and A549 cell lines were treated with NDGA, and its effect on cell viability, proliferation, and metabolism was evaluated using a resazurin reduction assay, incorporation of BrdU, and ki-67 gene expression and glucose uptake measurement, respectively. In addition, the combination of NDGA with clinical chemotherapeutics was investigated using an MTT assay and Combenefit software (version 2.02). The results showed that NDGA decreases the viability and proliferation of NSCLC cells and differentially modulates the expression of genes associated with different metabolic pathways. For example, the LDH gene expression decreased in all cell lines analyzed. However, GLUT3 gene expression increased after 24 h of treatment. The expression of the HIF-1 gene decreased early in the H1299 and A549 cell lines. In addition, the combination of NDGA with three chemotherapeutics (carboplatin, gemcitabine, and taxol) shows a synergic pattern in the decrease of cell viability on the H1299 cell line. In summary, this research provides new evidence about the role of NDGA in lung cancer. Interestingly, using NDGA to enhance the anticancer activity of antitumoral drugs could be an improved therapeutic resource against lung cancer. [ABSTRACT FROM AUTHOR]

DNA damage induces the activation of many different signals associated with repair or cell death, but it is also connected with physiological events, such as adult neurogenesis and B-cell differentiation. DNA damage induces different signaling pathways, some of them linked to important metabolic changes. The mTORC1 pathway has a central role in the regulation of growth processes and cell division in response to environmental changes and also controls protein synthesis, lipid biogenesis, nucleotide synthesis, and expression of glycolytic genes. Here, we report that double-strand breaks induced with etoposide affect the expression of genes encoding different enzymes associated with specific metabolic pathways in Ramos cells. We also analyzed the role of mTOR signaling, demonstrating that doublestrand breaks induce downregulation of mTOR signaling. Specific inhibition of mTORC1 using rapamycin also induced changes in the expression of metabolic genes. Finally, we demonstrated that DNA damage and rapamycin can regulate glucose uptake. In summary, our findings show that etoposide and rapamycin affect the expression of metabolic genes as well as apoptotic and proliferation markers in Ramos cells, increasing our understanding of cancer metabolism. [ABSTRACT FROM AUTHOR]

Resveratrol is a polyphenolic natural compound produced by a variety of crops. Currently, resveratrol is considered a multi-target anti-cancer agent with pleiotropic activity, including the ability to prevent the proliferation of malignant cells by inhibiting angiogenesis and curtailing invasive and metastatic factors in many cancer models. However, the molecular mechanisms mediating resveratrol-specific effects on lymphoma cells remain unknown. To begin tackling this question, we treated the Burkitt's lymphoma cell line Ramos with resveratrol and assessed cell survival and gene expression. Our results suggest that resveratrol shows a significant anti-proliferative and pro-apoptotic activity on Ramos cells, inducing the DNA damage response, DNA repairing, and modulating the expression of several genes that regulate the apoptotic process and their proliferative activity. [ABSTRACT FROM AUTHOR]

Resveratrol-a polyphenol of natural origin-has been the object of massive research in the past decade because of its potential use in cancer therapy. However, resveratrol has shown an extensive range of cellular targets and effects, which hinders the use of the molecule for medical applications including cancer and type 2 diabetes. Here, we review the latest advances in understanding how resveratrol modulates glucose uptake, regulates cellular metabolism, and how this may be useful to improve current therapies. We discuss challenges and findings regarding the inhibition of glucose uptake by resveratrol and other polyphenols of similar chemical structure. We review alternatives that can be exploited to improve cancer therapies, including the use of other polyphenols, or the combination of resveratrol with other molecules and their impact on glucose homeostasis in cancer and diabetes. [ABSTRACT FROM AUTHOR]

The polyphenol nordihydroguaiaretic acid ( NDGA) has antineoplastic properties, hence it is critical to understand its action at the molecular level. Here, we establish that NDGA inhibits glucose uptake and cell viability in leukemic HL-60 and U-937 cell lines. We monitored hexose uptake using radio-labeled 2-deoxyglucose (2 DG) and found that the inhibition by NDGA followed a noncompetitive mechanism. In addition, NDGA blocked hexose transport in human red blood cells and displaced prebound cytochalasin B from erythrocyte ghosts, suggesting a direct interaction with the glucose transporter GLUT1. We propose a model for the mechanism of action of NDGA on glucose uptake. Our study shows for the first time that NDGA can act as inhibitor of the glucose transporter GLUT1. [ABSTRACT FROM AUTHOR]

Resveratrol acts as a chemopreventive agent for cancer and as a potential antiobesity and antidiabetic compound, by leading to reduced body fat and improved glucose homeostasis. The exact mechanisms involved in improving hyperglycemic state are not known, but most of the glucose uptake into mammalian cells is facilitated by the GLUT hexose transporters. Resveratrol is structurally similar to isoflavones such as genistein, which inhibit the glucose uptake facilitated by the GLUT1 hexose transporter. Here we examined the direct effects of resveratrol on glucose uptake and accumulation in HL-60 and U-937 leukemic cell lines, which express mainly GLUT1, under conditions that discriminate transport from the intracellular substrate phosphorylation/ accumulation. Resveratrol blocks GLUT1-mediated hexose uptake and thereby affects substrate accumulation on these cells. Consequently, we characterized the mechanism involved in inhibition of glucose uptake in human red cells. Resveratrol inhibits glucose exit in human red cells, and the displacement of previously bound cytochalasin B revealed the direct interaction of resveratrol with GLUT1. Resveratrol behaves as a competitive blocker of glucose uptake under zero-trans exit and exchange kinetic assays, but it becomes a mixed noncompetitive blocker when zero-trans entry transport was assayed, suggesting that the binding site for resveratrol lies on the endofacial face of the transporter. We propose that resveratrol interacts directly with the human GLUT1 hexose transporter by binding to an endofacial site and that this interaction inhibits the transport of hexoses across the plasma membrane. This inhibition is distinct from the effect of resveratrol on the intracellular phosphorylation/accumulation of glucose. [ABSTRACT FROM AUTHOR]

Agmatine is a neurotransmitter with anticonvulsant, anti-neurotoxic and antidepressant-like effects, in addition it has hypoglycemic actions. Agmatine is converted to putrescine and urea by agmatinase (AGM) and by an agmatinase-like protein (ALP), a new type of enzyme which is present in human and rodent brain tissues. Recombinant rat brain ALP is the only mammalian protein that exhibits significant agmatinase activity in vitro and generates putrescine under in vivo conditions. ALP, despite differing in amino acid sequence from all members of the ureohydrolase family, is strictly dependent on Mn2+ for catalytic activity. However, the Mn2+ ligands have not yet been identified due to the lack of structural information coupled with the low sequence identity that ALPs display with known ureohydrolases. In this work, we generated a structural model of the Mn2+ binding site of the ALP and we propose new putative Mn2+ ligands. Then, we cloned and expressed a sequence of 210 amino acids, here called the "central-ALP", which include the putative ligands of Mn2+. The results suggest that the central-ALP is catalytically active, as agmatinase, with an unaltered Km for agmatine and a decreased kcat. Similar to wild-type ALP, central-ALP is activated by Mn2+ with a similar affinity. Besides, a simple mutant D217A, a double mutant E288A/K290A, and a triple mutant N213A/Q215A/D217A of these putative Mn2+ ligands result on the loss of ALP agmatinase activity. Our results indicate that the central-ALP contains the active site for agmatine hydrolysis, as well as that the residues identified are relevant for the ALP catalysis. [ABSTRACT FROM AUTHOR]

Exclusive enteral nutrition (EEN) has been shown to be more effective than corticosteroids in achieving mucosal healing in children with Crohn´s disease (CD) without the adverse effects of these drugs. The aims of this study were to determine the efficacy of EEN in terms of inducing clinical remission in children newly diagnosed with CD, to describe the predictive factors of response to EEN and the need for treatment with biological agents during the first 12 months of the disease. We conducted an observational retrospective multicentre study that included paediatric patients newly diagnosed with CD between 2014–2016 who underwent EEN. Two hundred and twenty-two patients (140 males) from 35 paediatric centres were included, with a mean age at diagnosis of 11.6 ± 2.5 years. The median EEN duration was 8 weeks (IQR 6.6–8.5), and 184 of the patients (83%) achieved clinical remission (weighted paediatric Crohn's Disease activity index [wPCDAI] < 12.5). Faecal calprotectin (FC) levels (μg/g) decreased significantly after EEN (830 [IQR 500–1800] to 256 [IQR 120–585] p < 0.0001). Patients with wPCDAI ≤ 57.5, FC < 500 μg/g, CRP >15 mg/L and ileal involvement tended to respond better to EEN. EEN administered for 6–8 weeks is effective for inducing clinical remission. Due to the high response rate in our series, EEN should be used as the first-line therapy in luminal paediatric Crohn's disease regardless of the location of disease and disease activity. [ABSTRACT FROM AUTHOR]

An important hallmark in cancer cells is the increase in glucose uptake. GLUT1 is an important target in cancer treatment because cancer cells upregulate GLUT1, a membrane protein that facilitates the basal uptake of glucose in most cell types, to ensure the flux of sugar into metabolic pathways. The dysregulation of GLUT1 is associated with numerous disorders, including cancer and metabolic diseases. There are natural products emerging as a source for inhibitors of glucose uptake, and resveratrol is a molecule of natural origin with many properties that acts as antioxidant and antiproliferative in malignant cells. In the present review, we discuss how GLUT1 is involved in the general scheme of cancer cell metabolism, the mechanism of glucose transport, and the importance of GLUT1 structure to understand the inhibition process. Then, we review the current state-of-the-art of resveratrol and other natural products as GLUT1 inhibitors, focusing on those directed at treating different types of cancer. Targeting GLUT1 activity is a promising strategy for the development of drugs aimed at treating neoplastic growth. [ABSTRACT FROM AUTHOR]

Tacrolimus is an agent used in clinical immunosuppressive drug therapies. A wide spectrum of adverse effects has been reported in association with this immunosuppressor, including neurotoxic effect. The upper limit of therapeutic blood concentrations of tacrolimus has been described as 30 ng/ml in immunosuppressed patients. We investigated the effect of this therapeutic dose of tacrolimus on the expression and activity of the multidrug resistance protein 1 (MDR1 or Pgp, P-glycoprotein) and ATP-binding cassette transporters A5 (ABCA5) in human brain microvascular endothelial cells (HBMEC), derived from Blood-Brain Barrier (BBB) endothelium, these being the most predominantly expressed transcripts in these cells. The expression and activity of MDR1 transporter decreased with 30 ng/ml tacrolimus. The cell viability was not changed with the therapeutic dose used. By contrast, ABCA5 transcripts, of unknown role as yet, increased their expression at this concentration. We propose that the secondary cytotoxic effects of this immunosuppressor on CSN, besides the functional blockade related to multidrug resistance proteins, such as MDR1, and probably ABCA5, could be linked to variations in the expression levels of these proteins at the BBB.