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Biomolecules, Volume 5, Issue 4 (December 2015), Pages 2160-3466

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Research

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Open AccessArticle Two-Dimensional N-Glycan Distribution Mapping of Hepatocellular Carcinoma Tissues by MALDI-Imaging Mass Spectrometry
Biomolecules 2015, 5(4), 2554-2572; doi:10.3390/biom5042554
Received: 16 June 2015 / Revised: 18 September 2015 / Accepted: 28 September 2015 / Published: 15 October 2015
Cited by 13 | PDF Full-text (2315 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A new mass spectrometry imaging approach to simultaneously map the two-dimensional distribution of N-glycans in tissues has been recently developed. The method uses Matrix Assisted Laser Desorption Ionization Imaging Mass Spectrometry (MALDI-IMS) to spatially profile the location and distribution of multiple N
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A new mass spectrometry imaging approach to simultaneously map the two-dimensional distribution of N-glycans in tissues has been recently developed. The method uses Matrix Assisted Laser Desorption Ionization Imaging Mass Spectrometry (MALDI-IMS) to spatially profile the location and distribution of multiple N-linked glycan species released by peptide N-glycosidase F in frozen or formalin-fixed tissues. Multiple formalin-fixed human hepatocellular carcinoma tissues were evaluated with this method, resulting in a panel of over 30 N-glycans detected. An ethylation reaction of extracted N-glycans released from adjacent slides was done to stabilize sialic acid containing glycans, and these structures were compared to N-glycans detected directly from tissue profiling. In addition, the distribution of singly fucosylated N-glycans detected in tumor tissue microarray cores were compared to the histochemistry staining pattern of a core fucose binding lectin. As this MALDI-IMS workflow has the potential to be applied to any formalin-fixed tissue block or tissue microarray, the advantages and limitations of the technique in context with other glycomic methods are also summarized. Full article
(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)
Open AccessArticle Modulation of Intestinal Barrier and Bacterial Endotoxin Production Contributes to the Beneficial Effect of Nicotinic Acid on Alcohol-Induced Endotoxemia and Hepatic Inflammation in Rats
Biomolecules 2015, 5(4), 2643-2658; doi:10.3390/biom5042643
Received: 31 July 2015 / Revised: 21 September 2015 / Accepted: 23 September 2015 / Published: 16 October 2015
Cited by 4 | PDF Full-text (2143 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol consumption causes nicotinic acid deficiency. The present study was undertaken to determine whether dietary nicotinic acid supplementation provides beneficial effects on alcohol-induced endotoxin signaling and the possible mechanisms at the gut-liver axis. Male Sprague-Dawley rats were pair-fed the Lieber-DeCarli liquid diets containing
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Alcohol consumption causes nicotinic acid deficiency. The present study was undertaken to determine whether dietary nicotinic acid supplementation provides beneficial effects on alcohol-induced endotoxin signaling and the possible mechanisms at the gut-liver axis. Male Sprague-Dawley rats were pair-fed the Lieber-DeCarli liquid diets containing ethanol or isocaloric maltose dextrin for eight weeks, with or without dietary supplementation with 750 mg/liter nicotinic acid. Chronic alcohol feeding elevated the plasma endotoxin level and activated hepatic endotoxin signaling cascade, which were attenuated by nicotinic acid supplementation. Alcohol consumption remarkably decreased the mRNA levels of claudin-1, claudin-5, and ZO-1 in the distal intestine, whereas nicotinic acid significantly up-regulated these genes. The concentrations of endotoxin, ethanol, and acetaldehyde in the intestinal contents were increased by alcohol exposure, and niacin supplementation reduced the intestinal endotoxin and acetaldehyde levels. Nicotinic acid supplementation upregulated the intestinal genes involved in aldehyde detoxification via transcriptional regulation. These results demonstrate that modulation of the intestinal barrier function and bacterial endotoxin production accounts for the inhibitory effects of nicotinic acid on alcohol-induced endotoxemia and hepatic inflammation. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessArticle Autophagy Protects against CYP2E1/Chronic Ethanol-Induced Hepatotoxicity
Biomolecules 2015, 5(4), 2659-2674; doi:10.3390/biom5042659
Received: 7 May 2015 / Revised: 9 October 2015 / Accepted: 9 October 2015 / Published: 16 October 2015
Cited by 8 | PDF Full-text (4218 KB) | HTML Full-text | XML Full-text
Abstract
Autophagy is an intracellular pathway by which lysosomes degrade and recycle long-lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to
[...] Read more.
Autophagy is an intracellular pathway by which lysosomes degrade and recycle long-lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to also be protective against CYP2E1-dependent toxicity in vitro in HepG2 cells which express CYP2E1 and in vivo in an acute alcohol/CYPE1-dependent liver injury model. The goal of the current report was to extend the previous in vitro and acute in vivo experiments to a chronic ethanol model to evaluate whether autophagy is also protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. Wild type (WT), CYP2E1 knockout (KO) or CYP2E1 humanized transgenic knockin (KI), mice were fed an ethanol liquid diet or control dextrose diet for four weeks. In the last week, some mice received either saline or 3-methyladenine (3-MA), an inhibitor of autophagy, or rapamycin, which stimulates autophagy. Inhibition of autophagy by 3-MA potentiated the ethanol-induced increases in serum transaminase and triglyceride levels in the WT and KI mice but not KO mice, while rapamycin prevented the ethanol liver injury. Treatment with 3-MA enhanced the ethanol-induced fat accumulation in WT mice and caused necrosis in the KI mice; little or no effect was found in the ethanol-fed KO mice or any of the dextrose-fed mice. 3-MA treatment further lowered the ethanol-decrease in hepatic GSH levels and further increased formation of TBARS in WT and KI mice, whereas rapamycin blunted these effects of ethanol. Neither 3-MA nor rapamycin treatment affected CYP2E1 catalytic activity or content or the induction CYP2E1 by ethanol. The 3-MA treatment decreased levels of Beclin-1 and Atg 7 but increased levels of p62 in the ethanol-fed WT and KI mice whereas rapamycin had the opposite effects, validating inhibition and stimulation of autophagy, respectively. These results suggest that autophagy is protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. We speculate that autophagy-dependent processes such as mitophagy and lipophagy help to minimize ethanol-induced CYP2E1-dependent oxidative stress and therefore the subsequent liver injury and steatosis. Attempts to stimulate autophagy may be helpful in lowering ethanol and CYP2E1-dependent liver toxicity. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessArticle Global N-linked Glycosylation is Not Significantly Impaired in Myoblasts in Congenital Myasthenic Syndromes Caused by Defective Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1)
Biomolecules 2015, 5(4), 2758-2781; doi:10.3390/biom5042758
Received: 16 June 2015 / Revised: 28 August 2015 / Accepted: 13 October 2015 / Published: 16 October 2015
Cited by 5 | PDF Full-text (12301 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the first enzyme of the hexosamine biosynthetic pathway. It transfers an amino group from glutamine to fructose-6-phosphate to yield glucosamine-6-phosphate, thus providing the precursor for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis. UDP-GlcNAc is an essential substrate for all
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Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the first enzyme of the hexosamine biosynthetic pathway. It transfers an amino group from glutamine to fructose-6-phosphate to yield glucosamine-6-phosphate, thus providing the precursor for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis. UDP-GlcNAc is an essential substrate for all mammalian glycosylation biosynthetic pathways and N-glycan branching is especially sensitive to alterations in the concentration of this sugar nucleotide. It has been reported that GFPT1 mutations lead to a distinct sub-class of congenital myasthenic syndromes (CMS) termed “limb-girdle CMS with tubular aggregates”. CMS are hereditary neuromuscular transmission disorders in which neuromuscular junctions are impaired. To investigate whether alterations in protein glycosylation at the neuromuscular junction might be involved in this impairment, we have employed mass spectrometric strategies to study the N-glycomes of myoblasts and myotubes derived from two healthy controls, three GFPT1 patients, and four patients with other muscular diseases, namely CMS caused by mutations in DOK7, myopathy caused by mutations in MTND5, limb girdle muscular dystrophy type 2A (LGMD2A), and Pompe disease. A comparison of the relative abundances of bi-, tri-, and tetra-antennary N-glycans in each of the cell preparations revealed that all samples exhibited broadly similar levels of branching. Moreover, although some differences were observed in the relative abundances of some of the N-glycan constituents, these variations were modest and were not confined to the GFPT1 samples. Therefore, GFPT1 mutations in CMS patients do not appear to compromise global N-glycosylation in muscle cells. Full article
(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)
Open AccessArticle HIV-1 Recruits UPF1 but Excludes UPF2 to Promote Nucleocytoplasmic Export of the Genomic RNA
Biomolecules 2015, 5(4), 2808-2839; doi:10.3390/biom5042808
Received: 7 July 2015 / Revised: 9 September 2015 / Accepted: 16 September 2015 / Published: 20 October 2015
Cited by 6 | PDF Full-text (6665 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Unspliced, genomic HIV-1 RNA (vRNA) is a component of several ribonucleoprotein complexes (RNP) during the viral replication cycle. In earlier work, we demonstrated that the host upframeshift protein 1 (UPF1), a key factor in nonsense-mediated mRNA decay (NMD), colocalized and associated to the
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Unspliced, genomic HIV-1 RNA (vRNA) is a component of several ribonucleoprotein complexes (RNP) during the viral replication cycle. In earlier work, we demonstrated that the host upframeshift protein 1 (UPF1), a key factor in nonsense-mediated mRNA decay (NMD), colocalized and associated to the viral structural protein Gag during viral egress. In this work, we demonstrate a new function for UPF1 in the regulation of vRNA nuclear export. OPEN ACCESS Biomolecules 2015, 5 2809 We establish that the nucleocytoplasmic shuttling of UPF1 is required for this function and demonstrate that UPF1 exists in two essential viral RNPs during the late phase of HIV-1 replication: the first, in a nuclear export RNP that contains Rev, CRM1, DDX3 and the nucleoporin p62, and the second, which excludes these nuclear export markers but contains Gag in the cytoplasm. Interestingly, we observed that both UPF2 and the long isoform of UPF3a, UPF3aL, but not the shorter isoforms UPF3aS and UPF3b, are excluded from the UPF1-Rev-CRM1-DDX3 complex as they are negative regulators of vRNA nuclear export. In silico protein-protein docking analyses suggest that Rev binds UPF1 in a region that overlaps the UPF2 binding site, thus explaining the exclusion of this negative regulatory factor by HIV-1 that is necessary for vRNA trafficking. This work uncovers a novel and unique regulatory circuit involving several UPF proteins that ultimately regulate vRNA nuclear export and trafficking. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
Open AccessArticle Engineering and Characterization of a Fluorescent Native-Like HIV-1 Envelope Glycoprotein Trimer
Biomolecules 2015, 5(4), 2919-2934; doi:10.3390/biom5042919
Received: 31 July 2015 / Revised: 13 October 2015 / Accepted: 15 October 2015 / Published: 23 October 2015
Cited by 2 | PDF Full-text (1880 KB) | HTML Full-text | XML Full-text
Abstract
Generation of a stable, soluble mimic of the HIV-1 envelope glycoprotein (Env) trimer on the virion surface has been considered an important first step for developing a successful HIV-1 vaccine. Recently, a soluble native-like Env trimer (BG505 SOSIP.664) has been described. This protein
[...] Read more.
Generation of a stable, soluble mimic of the HIV-1 envelope glycoprotein (Env) trimer on the virion surface has been considered an important first step for developing a successful HIV-1 vaccine. Recently, a soluble native-like Env trimer (BG505 SOSIP.664) has been described. This protein has facilitated major advances in the HIV-1 vaccine field, since it was the first Env immunogen that induced consistent neutralizing antibodies against a neutralization-resistant (tier 2) virus. Moreover, BG505 SOSIP.664 enabled elucidation of the atomic resolution structure of the Env trimer and facilitated the isolation and characterization of new broadly neutralizing antibodies against HIV-1. Here, we designed and characterized the BG505 SOSIP.664 trimer fused to fluorescent superfolder GFP (sfGFP), a GFP variant that allows efficient folding (BG505 SOSIP.664-sfGFP). Despite the presence of the sfGFP, the Env protein largely retained its morphology, antigenicity, glycan composition, and thermostability. In addition, we show that BG505 SOSIP.664-sfGFP can be used for fluorescence-based assays, such as flow cytometry. Full article
(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)
Open AccessArticle Skin Immunization Obviates Alcohol-Related Immune Dysfunction
Biomolecules 2015, 5(4), 3009-3028; doi:10.3390/biom5043009
Received: 9 July 2015 / Revised: 21 September 2015 / Accepted: 30 September 2015 / Published: 6 November 2015
Cited by 1 | PDF Full-text (1841 KB) | HTML Full-text | XML Full-text
Abstract
Alcoholics suffer from immune dysfunction that can impede vaccine efficacy. If ethanol (EtOH)-induced immune impairment is in part a result of direct exposure of immune cells to EtOH, then reduced levels of exposure could result in less immune dysfunction. As alcohol ingestion results
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Alcoholics suffer from immune dysfunction that can impede vaccine efficacy. If ethanol (EtOH)-induced immune impairment is in part a result of direct exposure of immune cells to EtOH, then reduced levels of exposure could result in less immune dysfunction. As alcohol ingestion results in lower alcohol levels in skin than blood, we hypothesized that the skin immune network may be relatively preserved, enabling skin-targeted immunizations to obviate the immune inhibitory effects of alcohol consumption on conventional vaccines. We employed the two most common chronic EtOH mouse feeding models, the liver-damaging Lieber-DeCarli (LD) and liver-sparing Meadows-Cook (MC) diets, to examine the roles of EtOH and/or EtOH-induced liver dysfunction on alcohol related immunosuppression. Pair-fed mice were immunized against the model antigen ovalbumin (OVA) by DNA immunization or against flu by administering the protein-based influenza vaccine either systemically (IV, IM), directly to liver (hydrodynamic), or cutaneously (biolistic, ID). We measured resulting tissue EtOH levels, liver stress, regulatory T cell (Treg), and myeloid-derived suppressor cell (MDSC) populations. We compared immune responsiveness by measuring delayed-type hypersensitivity (DTH), antigen-specific cytotoxic T lymphocyte (CTL), and antibody induction as a function of delivery route and feeding model. We found that, as expected, and independent of the feeding model, EtOH ingestion inhibits DTH, CTL lysis, and antigen-specific total IgG induced by traditional systemic vaccines. On the other hand, skin-targeted vaccines were equally immunogenic in alcohol-exposed and non-exposed subjects, suggesting that cutaneous immunization may result in more efficacious vaccination in alcohol-ingesting subjects. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
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Open AccessArticle Fluorinated Carbohydrates as Lectin Ligands: 19F-Based Direct STD Monitoring for Detection of Anomeric Selectivity
Biomolecules 2015, 5(4), 3177-3192; doi:10.3390/biom5043177
Received: 9 June 2015 / Revised: 2 November 2015 / Accepted: 4 November 2015 / Published: 13 November 2015
Cited by 4 | PDF Full-text (769 KB) | HTML Full-text | XML Full-text
Abstract
The characterization of the binding of reducing carbohydrates present as mixtures of anomers in solution to a sugar recepor (lectin) poses severe difficulties. In this situation, NMR spectroscopy enables the observation of signals for each anomer in the mixture by applying approaches based
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The characterization of the binding of reducing carbohydrates present as mixtures of anomers in solution to a sugar recepor (lectin) poses severe difficulties. In this situation, NMR spectroscopy enables the observation of signals for each anomer in the mixture by applying approaches based on ligand observation. Saturation transfer difference (STD) NMR allows fast and efficient screening of compound mixtures for reactivity to a receptor. Owing to the exceptionally favorable properties of 19F in NMR spectroscopy and the often complex 1H spectra of carbohydrates, 19F-containing sugars have the potential to be turned into versatile sensors for recognition. Extending the recently established 1H → 1H STDre19F-NMR technique, we here demonstrate its applicability to measure anomeric selectivity of binding in a model system using the plant lectin concanavalin A (ConA) and 2-deoxy-2-fluoro-d-mannose. Indeed, it is also possible to account for the mutual inhibition between the anomers on binding to the lectin by means of a kinetic model. The monitoring of 19F-NMR signal perturbation disclosed the relative activities of the anomers in solution and thus enabled the calculation of their binding affinity towards ConA. The obtained data show a preference for the α anomer that increases with temperature. This experimental approach can be extended to others systems of biomedical interest by testing human lectins with suitably tailored glycan derivatives. Full article
(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)
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Open AccessArticle Alcohol and Apoptosis: Friends or Foes?
Biomolecules 2015, 5(4), 3193-3203; doi:10.3390/biom5043193
Received: 22 September 2015 / Revised: 4 November 2015 / Accepted: 9 November 2015 / Published: 19 November 2015
Cited by 8 | PDF Full-text (1068 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol abuse causes 79,000 deaths stemming from severe organ damage in the United States every year. Clinical manifestations of long-term alcohol abuse on the cardiac muscle include defective contractility with the development of dilated cardiomyopathy and low-output heart failure; which has poor prognosis
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Alcohol abuse causes 79,000 deaths stemming from severe organ damage in the United States every year. Clinical manifestations of long-term alcohol abuse on the cardiac muscle include defective contractility with the development of dilated cardiomyopathy and low-output heart failure; which has poor prognosis with less than 25% survival for more than three years. In contrast, low alcohol consumption has been associated with reduced risk of cardiovascular disease, however the mechanism of this phenomenon remains elusive. The aim of this study was to determine the significance of apoptosis as a mediating factor in cardiac function following chronic high alcohol versus low alcohol exposure. Adult rats were provided 5 mM (low alcohol), 100 mM (high alcohol) or pair-fed non-alcohol controls for 4–5 months. The hearts were dissected, sectioned and stained with cresyl violet or immunohistochemically for caspase-3, a putative marker for apoptosis. Cardiomyocytes were isolated to determine the effects of alcohol exposure on cell contraction and relaxation. High alcohol animals displayed a marked thinning of the left ventricular wall combined with elevated caspase-3 activity and decreased contractility. In contrast, low alcohol was associated with increased contractility and decreased apoptosis suggesting an overall protective mechanism induced by low levels of alcohol exposure. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessArticle In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses
Biomolecules 2015, 5(4), 3280-3294; doi:10.3390/biom5043280
Received: 13 August 2015 / Accepted: 17 November 2015 / Published: 20 November 2015
Cited by 6 | PDF Full-text (2491 KB) | HTML Full-text | XML Full-text
Abstract
Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol
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Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessArticle High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model
Biomolecules 2015, 5(4), 3295-3308; doi:10.3390/biom5043295
Received: 6 September 2015 / Accepted: 10 November 2015 / Published: 20 November 2015
Cited by 3 | PDF Full-text (409 KB) | HTML Full-text | XML Full-text
Abstract
Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that
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Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide “metabolic protection” from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and ß-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessArticle The Hinge Region of Bovine Zona Pellucida Glycoprotein ZP3 Is Involved in the Formation of the Sperm-Binding Active ZP3/ZP4 Complex
Biomolecules 2015, 5(4), 3339-3353; doi:10.3390/biom5043339
Received: 5 September 2015 / Revised: 31 October 2015 / Accepted: 16 November 2015 / Published: 23 November 2015
Cited by 3 | PDF Full-text (2596 KB) | HTML Full-text | XML Full-text
Abstract
The zona pellucida (ZP) surrounds the mammalian oocyte and mediates species-selective sperm-oocyte interactions. Bovine ZP consists of glycoproteins ZP2, ZP3, and ZP4. Neither ZP3 nor ZP4 alone shows inhibitory activity for the binding of sperm to the ZP; however, this activity is seen
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The zona pellucida (ZP) surrounds the mammalian oocyte and mediates species-selective sperm-oocyte interactions. Bovine ZP consists of glycoproteins ZP2, ZP3, and ZP4. Neither ZP3 nor ZP4 alone shows inhibitory activity for the binding of sperm to the ZP; however, this activity is seen with the ZP3/ZP4 heterocomplex. Here, we constructed a series of bovine ZP3 mutants to identify the ZP4-binding site on ZP3. Each ZP3 mutant was co-expressed with ZP4 using a baculovirus-Sf9 cell expression system and examined for interaction with ZP4 as well as inhibitory activity for sperm-ZP binding. N-terminal fragment Arg-32 to Arg-160 of ZP3 interacted with ZP4 and inhibited sperm-ZP binding, whereas fragment Arg-32 to Thr-155 showed much weaker interaction with ZP4. Mutation of N-glycosylated Asn-146 to Asp in the N-terminal fragment Arg-32 to Glu-178 of ZP3 did not interrupt the interaction of this fragment with ZP4, but it did reduce the inhibitory activity of the complex for sperm-ZP binding. In contrast, mutation of N-glycosylated Asn-124 to Asp did not significantly reduce the activity. Taken together, these results suggest that one of the ZP4 binding sites exists in the flexible hinge region of ZP3 and that the N-glycosylation in this region is involved in the sperm binding. Full article
(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)
Open AccessArticle Examination of the Fractalkine and Fractalkine Receptor Expression in Fallopian Adenocarcinoma Reveals Differences When Compared to Ovarian Carcinoma
Biomolecules 2015, 5(4), 3438-3447; doi:10.3390/biom5043438
Received: 20 August 2015 / Revised: 2 November 2015 / Accepted: 30 November 2015 / Published: 3 December 2015
Cited by 1 | PDF Full-text (5214 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Fallopian adenocarcinoma is a rare malignancy arising in the epithelium of the fallopian tube. Fallopian tube epithelium has been proposed as a tissue origin for high-grade serous ovarian carcinoma, the deadliest gynecologic malignancy. Given the commonalities in dissemination and treatment of these malignancies,
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Fallopian adenocarcinoma is a rare malignancy arising in the epithelium of the fallopian tube. Fallopian tube epithelium has been proposed as a tissue origin for high-grade serous ovarian carcinoma, the deadliest gynecologic malignancy. Given the commonalities in dissemination and treatment of these malignancies, we contemplated the possibility of similar patterns of gene expression underlying their progression. To reveal potential similarities or differences in the gene expression of fallopian adenocarcinoma and high-grade serous ovarian carcinoma, we tested expression of the fractalkine receptor (CX3CR1) and its ligand, fractalkine (CX3CL1), in the specimens of normal and pathologic fallopian tube using immunohistochemistry. Our data show that CX3CR1 is expressed in the normal, cancer adjacent normal, inflammatory, and malignant fallopian epithelium. CX3CL1 was expressed only by the normal and cancer adjacent normal fallopian tube epithelium; its expression was largely lost in the inflammatory and malignant fallopian epithelium. In opposite, both CX3CR1 and CX3CL1 are expressed in high-grade serous ovarian carcinoma. These findings are consistent with an idea that fallopian adenocarcinoma and high-grade serous ovarian carcinoma, although currently thought to arise from the same organ, may not share similar molecular characteristics. Full article
(This article belongs to the Special Issue Signal Transduction Pathways in Gynecologic Malignancies)

Review

Jump to: Research

Open AccessReview Uncommon Glycosidases for the Enzymatic Preparation of Glycosides
Biomolecules 2015, 5(4), 2160-2183; doi:10.3390/biom5042160
Received: 20 May 2015 / Revised: 8 September 2015 / Accepted: 9 September 2015 / Published: 24 September 2015
Cited by 4 | PDF Full-text (625 KB) | HTML Full-text | XML Full-text
Abstract
Most of the reports in literature dedicated to the use of glycosyl hydrolases for the preparation of glycosides are about gluco- (α- and β-form) and galacto-sidase (β-form), reflecting the high-availability of both anomers of glucosides and of β-galactosides and their wide-ranging applications. Hence,
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Most of the reports in literature dedicated to the use of glycosyl hydrolases for the preparation of glycosides are about gluco- (α- and β-form) and galacto-sidase (β-form), reflecting the high-availability of both anomers of glucosides and of β-galactosides and their wide-ranging applications. Hence, the idea of this review was to analyze the literature focusing on hardly-mentioned natural and engineered glycosyl hydrolases. Their performances in the synthetic mode and natural hydrolytic potential are examined. Both the choice of articles and their discussion are from a biomolecular and a biotechnological perspective of the biocatalytic process, shedding light on new applicative ideas and on the assortment of biomolecular diversity. The hope is to elicit new interest for the development of biocatalysis and to gather attention of biocatalyst practitioners for glycosynthesis. Full article
Open AccessReview Arsenic Disruption of DNA Damage Responses—Potential Role in Carcinogenesis and Chemotherapy
Biomolecules 2015, 5(4), 2184-2193; doi:10.3390/biom5042184
Received: 14 August 2015 / Revised: 6 September 2015 / Accepted: 9 September 2015 / Published: 24 September 2015
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Abstract
Arsenic is a Class I human carcinogen and is widespread in the environment. Chronic arsenic exposure causes cancer in skin, lung and bladder, as well as in other organs. Paradoxically, arsenic also is a potent chemotherapeutic against acute promyelocytic leukemia and can potentiate
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Arsenic is a Class I human carcinogen and is widespread in the environment. Chronic arsenic exposure causes cancer in skin, lung and bladder, as well as in other organs. Paradoxically, arsenic also is a potent chemotherapeutic against acute promyelocytic leukemia and can potentiate the cytotoxic effects of DNA damaging chemotherapeutics, such as cisplatin, in vitro. Arsenic has long been implicated in DNA repair inhibition, cell cycle disruption, and ubiquitination dysregulation, all negatively impacting the DNA damage response and potentially contributing to both the carcinogenic and chemotherapeutic potential of arsenic. Recent studies have provided mechanistic insights into how arsenic interferes with these processes including disruption of zinc fingers and suppression of gene expression. This review discusses these effects of arsenic with a view toward understanding the impact on the DNA damage response. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Diversity of Endonuclease V: From DNA Repair to RNA Editing
Biomolecules 2015, 5(4), 2194-2206; doi:10.3390/biom5042194
Received: 29 June 2015 / Revised: 9 September 2015 / Accepted: 11 September 2015 / Published: 24 September 2015
Cited by 4 | PDF Full-text (907 KB) | HTML Full-text | XML Full-text
Abstract
Deamination of adenine occurs in DNA, RNA, and their precursors via a hydrolytic reaction and a nitrosative reaction. The generated deaminated products are potentially mutagenic because of their structural similarity to natural bases, which in turn leads to erroneous nucleotide pairing and subsequent
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Deamination of adenine occurs in DNA, RNA, and their precursors via a hydrolytic reaction and a nitrosative reaction. The generated deaminated products are potentially mutagenic because of their structural similarity to natural bases, which in turn leads to erroneous nucleotide pairing and subsequent disruption of cellular metabolism. Incorporation of deaminated precursors into the nucleic acid strand occurs during nucleotide synthesis by DNA and RNA polymerases or base modification by DNA- and/or RNA-editing enzymes during cellular functions. In such cases, removal of deaminated products from DNA and RNA by a nuclease might be required depending on the cellular function. One such enzyme, endonuclease V, recognizes deoxyinosine and cleaves 3' end of the damaged base in double-stranded DNA through an alternative excision repair mechanism in Escherichia coli, whereas in Homo sapiens, it recognizes and cleaves inosine in single-stranded RNA. However, to explore the role of endonuclease V in vivo, a detailed analysis of cell biology is required. Based on recent reports and developments on endonuclease V, we discuss the potential functions of endonuclease V in DNA repair and RNA metabolism. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Combinatorial Control of mRNA Fates by RNA-Binding Proteins and Non-Coding RNAs
Biomolecules 2015, 5(4), 2207-2222; doi:10.3390/biom5042207
Received: 17 July 2015 / Revised: 2 September 2015 / Accepted: 8 September 2015 / Published: 24 September 2015
Cited by 15 | PDF Full-text (249 KB) | HTML Full-text | XML Full-text
Abstract
Post-transcriptional control of gene expression is mediated by RNA-binding proteins (RBPs) and small non-coding RNAs (e.g., microRNAs) that bind to distinct elements in their mRNA targets. Here, we review recent examples describing the synergistic and/or antagonistic effects mediated by RBPs and miRNAs to
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Post-transcriptional control of gene expression is mediated by RNA-binding proteins (RBPs) and small non-coding RNAs (e.g., microRNAs) that bind to distinct elements in their mRNA targets. Here, we review recent examples describing the synergistic and/or antagonistic effects mediated by RBPs and miRNAs to determine the localisation, stability and translation of mRNAs in mammalian cells. From these studies, it is becoming increasingly apparent that dynamic rearrangements of RNA-protein complexes could have profound implications in human cancer, in synaptic plasticity, and in cellular differentiation. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Open AccessReview Impact of Alcohol on Glycemic Control and Insulin Action
Biomolecules 2015, 5(4), 2223-2246; doi:10.3390/biom5042223
Received: 23 May 2015 / Revised: 24 August 2015 / Accepted: 21 September 2015 / Published: 29 September 2015
Cited by 9 | PDF Full-text (645 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol has profound effects on tissue and whole-body fuel metabolism which contribute to the increased morbidity and mortality in individuals with alcohol use disorder. This review focuses on the glucose metabolic effects of alcohol, primarily in the muscle, liver and adipose tissue, under
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Alcohol has profound effects on tissue and whole-body fuel metabolism which contribute to the increased morbidity and mortality in individuals with alcohol use disorder. This review focuses on the glucose metabolic effects of alcohol, primarily in the muscle, liver and adipose tissue, under basal postabsorptive conditions and in response to insulin stimulation. While there is a relatively extensive literature in this area, results are often discordant and extrapolating between models and tissues is fraught with uncertainty. Comparisons between data generated in experimental cell and animals systems will be contrasted with that obtained from human subjects as often times results differ. Further, the nutritional status is also an important component of the sometimes divergent findings pertaining to the effects of alcohol on the regulation of insulin and glucose metabolism. This work is relevant as the contribution of alcohol intake to the development or exacerbation of type 2 diabetes remains ill-defined and a multi-systems approach is likely needed as both alcohol and diabetes affect multiple targets within the body. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessReview 4-Hydroxy-nonenal—A Bioactive Lipid Peroxidation Product
Biomolecules 2015, 5(4), 2247-2337; doi:10.3390/biom5042247
Received: 2 June 2015 / Revised: 24 July 2015 / Accepted: 29 July 2015 / Published: 30 September 2015
Cited by 28 | PDF Full-text (1594 KB) | HTML Full-text | XML Full-text
Abstract
This review on recent research advances of the lipid peroxidation product 4-hydroxy-nonenal (HNE) has four major topics: I. the formation of HNE in various organs and tissues, II. the diverse biochemical reactions with Michael adduct formation as the most prominent one, III. the
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This review on recent research advances of the lipid peroxidation product 4-hydroxy-nonenal (HNE) has four major topics: I. the formation of HNE in various organs and tissues, II. the diverse biochemical reactions with Michael adduct formation as the most prominent one, III. the endogenous targets of HNE, primarily peptides and proteins (here the mechanisms of covalent adduct formation are described and the (patho-) physiological consequences discussed), and IV. the metabolism of HNE leading to a great number of degradation products, some of which are excreted in urine and may serve as non-invasive biomarkers of oxidative stress. Full article
(This article belongs to the Special Issue Oxidative Stress and Oxygen Radicals) Printed Edition available
Open AccessReview New Insights into the Biological Role of Mammalian ADARs; the RNA Editing Proteins
Biomolecules 2015, 5(4), 2338-2362; doi:10.3390/biom5042338
Received: 24 July 2015 / Revised: 9 September 2015 / Accepted: 11 September 2015 / Published: 30 September 2015
Cited by 17 | PDF Full-text (826 KB) | HTML Full-text | XML Full-text
Abstract
The ADAR proteins deaminate adenosine to inosine in double-stranded RNA which is one of the most abundant modifications present in mammalian RNA. Inosine can have a profound effect on the RNAs that are edited, not only changing the base-pairing properties, but can also
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The ADAR proteins deaminate adenosine to inosine in double-stranded RNA which is one of the most abundant modifications present in mammalian RNA. Inosine can have a profound effect on the RNAs that are edited, not only changing the base-pairing properties, but can also result in recoding, as inosine behaves as if it were guanosine. In mammals there are three ADAR proteins and two ADAR-related proteins (ADAD) expressed. All have a very similar modular structure; however, both their expression and biological function differ significantly. Only two of the ADAR proteins have enzymatic activity. However, both ADAR and ADAD proteins possess the ability to bind double-strand RNA. Mutations in ADARs have been associated with many diseases ranging from cancer, innate immunity to neurological disorders. Here, we will discuss in detail the domain structure of mammalian ADARs, the effects of RNA editing, and the role of ADARs in human diseases. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
Open AccessReview RNA-Binding Proteins in the Regulation of miRNA Activity: A Focus on Neuronal Functions
Biomolecules 2015, 5(4), 2363-2387; doi:10.3390/biom5042363
Received: 28 May 2015 / Revised: 16 September 2015 / Accepted: 23 September 2015 / Published: 30 September 2015
PDF Full-text (787 KB) | HTML Full-text | XML Full-text
Abstract
Posttranscriptional modifications of messenger RNAs (mRNAs) are key processes in the fine-tuning of cellular homeostasis. Two major actors in this scenario are RNA binding proteins (RBPs) and microRNAs (miRNAs) that together play important roles in the biogenesis, turnover, translation and localization of mRNAs.
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Posttranscriptional modifications of messenger RNAs (mRNAs) are key processes in the fine-tuning of cellular homeostasis. Two major actors in this scenario are RNA binding proteins (RBPs) and microRNAs (miRNAs) that together play important roles in the biogenesis, turnover, translation and localization of mRNAs. This review will highlight recent advances in the understanding of the role of RBPs in the regulation of the maturation and the function of miRNAs. The interplay between miRNAs and RBPs is discussed specifically in the context of neuronal development and function. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
Open AccessReview The Role of the COP9 Signalosome and Neddylation in DNA Damage Signaling and Repair
Biomolecules 2015, 5(4), 2388-2416; doi:10.3390/biom5042388
Received: 30 June 2015 / Revised: 18 September 2015 / Accepted: 21 September 2015 / Published: 30 September 2015
Cited by 2 | PDF Full-text (1550 KB) | HTML Full-text | XML Full-text
Abstract
The maintenance of genomic integrity is an important process in organisms as failure to sense and repair damaged DNA can result in a variety of diseases. Eukaryotic cells have developed complex DNA repair response (DDR) mechanisms to accurately sense and repair damaged DNA.
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The maintenance of genomic integrity is an important process in organisms as failure to sense and repair damaged DNA can result in a variety of diseases. Eukaryotic cells have developed complex DNA repair response (DDR) mechanisms to accurately sense and repair damaged DNA. Post-translational modifications by ubiquitin and ubiquitin-like proteins, such as SUMO and NEDD8, have roles in coordinating the progression of DDR. Proteins in the neddylation pathway have also been linked to regulating DDR. Of interest is the COP9 signalosome (CSN), a multi-subunit metalloprotease present in eukaryotes that removes NEDD8 from cullins and regulates the activity of cullin-RING ubiquitin ligases (CRLs). This in turn regulates the stability and turnover of a host of CRL-targeted proteins, some of which have established roles in DDR. This review will summarize the current knowledge on the role of the CSN and neddylation in DNA repair. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Rho GTPases: Novel Players in the Regulation of the DNA Damage Response?
Biomolecules 2015, 5(4), 2417-2434; doi:10.3390/biom5042417
Received: 20 August 2015 / Revised: 2 September 2015 / Accepted: 9 September 2015 / Published: 30 September 2015
Cited by 7 | PDF Full-text (971 KB) | HTML Full-text | XML Full-text
Abstract
The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression,
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The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression, mitosis, cell death and gene expression. Rac1 also adjusts cellular responses to genotoxic stress by regulating the activity of stress kinases, including c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 kinases as well as related transcription factors. Apart from being found on the inner side of the outer cell membrane and in the cytosol, Rac1 has also been detected inside the nucleus. Different lines of evidence indicate that genotoxin-induced DNA damage is able to activate nuclear Rac1. The exact mechanisms involved and the biological consequences, however, are unclear. The data available so far indicate that Rac1 might integrate DNA damage independent and DNA damage dependent cellular stress responses following genotoxin treatment, thereby coordinating mechanisms of the DNA damage response (DDR) that are related to DNA repair, survival and cell death. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Physicochemical Properties of Ion Pairs of Biological Macromolecules
Biomolecules 2015, 5(4), 2435-2463; doi:10.3390/biom5042435
Received: 1 July 2015 / Revised: 9 September 2015 / Accepted: 11 September 2015 / Published: 30 September 2015
Cited by 14 | PDF Full-text (1519 KB) | HTML Full-text | XML Full-text
Abstract
Ion pairs (also known as salt bridges) of electrostatically interacting cationic and anionic moieties are important for proteins and nucleic acids to perform their function. Although numerous three-dimensional structures show ion pairs at functionally important sites of biological macromolecules and their complexes, the
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Ion pairs (also known as salt bridges) of electrostatically interacting cationic and anionic moieties are important for proteins and nucleic acids to perform their function. Although numerous three-dimensional structures show ion pairs at functionally important sites of biological macromolecules and their complexes, the physicochemical properties of the ion pairs are not well understood. Crystal structures typically show a single state for each ion pair. However, recent studies have revealed the dynamic nature of the ion pairs of the biological macromolecules. Biomolecular ion pairs undergo dynamic transitions between distinct states in which the charged moieties are either in direct contact or separated by water. This dynamic behavior is reasonable in light of the fundamental concepts that were established for small ions over the last century. In this review, we introduce the physicochemical concepts relevant to the ion pairs and provide an overview of the recent advancement in biophysical research on the ion pairs of biological macromolecules. Full article
Open AccessReview Molecular Process Producing Oncogene Fusion in Lung Cancer Cells by Illegitimate Repair of DNA Double-Strand Breaks
Biomolecules 2015, 5(4), 2464-2476; doi:10.3390/biom5042464
Received: 30 June 2015 / Revised: 10 September 2015 / Accepted: 14 September 2015 / Published: 30 September 2015
Cited by 4 | PDF Full-text (1822 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Constitutive activation of oncogenes by fusion to partner genes, caused by chromosome translocation and inversion, is a critical genetic event driving lung carcinogenesis. Fusions of the tyrosine kinase genes ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) occur
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Constitutive activation of oncogenes by fusion to partner genes, caused by chromosome translocation and inversion, is a critical genetic event driving lung carcinogenesis. Fusions of the tyrosine kinase genes ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) occur in 1%–5% of lung adenocarcinomas (LADCs) and their products constitute therapeutic targets for kinase inhibitory drugs. Interestingly, ALK, RET, and ROS1 fusions occur preferentially in LADCs of never- and light-smokers, suggesting that the molecular mechanisms that cause these rearrangements are smoking-independent. In this study, using previously reported next generation LADC genome sequencing data of the breakpoint junction structures of chromosome rearrangements that cause oncogenic fusions in human cancer cells, we employed the structures of breakpoint junctions of ALK, RET, and ROS1 fusions in 41 LADC cases as “traces” to deduce the molecular processes of chromosome rearrangements caused by DNA double-strand breaks (DSBs) and illegitimate joining. We found that gene fusion was produced by illegitimate repair of DSBs at unspecified sites in genomic regions of a few kb through DNA synthesis-dependent or -independent end-joining pathways, according to DSB type. This information will assist in the understanding of how oncogene fusions are generated and which etiological factors trigger them. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Potential Role of the Gut/Liver/Lung Axis in Alcohol-Induced Tissue Pathology
Biomolecules 2015, 5(4), 2477-2503; doi:10.3390/biom5042477
Received: 31 July 2015 / Revised: 11 September 2015 / Accepted: 21 September 2015 / Published: 30 September 2015
Cited by 5 | PDF Full-text (592 KB) | HTML Full-text | XML Full-text
Abstract
Both Alcoholic Liver Disease (ALD) and alcohol-related susceptibility to acute lung injury are estimated to account for the highest morbidity and mortality related to chronic alcohol abuse and, thus, represent a focus of intense investigation. In general, alcohol-induced derangements to both organs are
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Both Alcoholic Liver Disease (ALD) and alcohol-related susceptibility to acute lung injury are estimated to account for the highest morbidity and mortality related to chronic alcohol abuse and, thus, represent a focus of intense investigation. In general, alcohol-induced derangements to both organs are considered to be independent and are often evaluated separately. However, the liver and lung share many general responses to damage, and specific responses to alcohol exposure. For example, both organs possess resident macrophages that play key roles in mediating the immune/inflammatory response. Additionally, alcohol-induced damage to both organs appears to involve oxidative stress that favors tissue injury. Another mechanism that appears to be shared between the organs is that inflammatory injury to both organs is enhanced by alcohol exposure. Lastly, altered extracellular matrix (ECM) deposition appears to be a key step in disease progression in both organs. Indeed, recent studies suggest that early subtle changes in the ECM may predispose the target organ to an inflammatory insult. The purpose of this chapter is to review the parallel mechanisms of liver and lung injury in response to alcohol consumption. This chapter will also explore the potential that these mechanisms are interdependent, as part of a gut-liver-lung axis. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessReview The Molecular Circadian Clock and Alcohol-Induced Liver Injury
Biomolecules 2015, 5(4), 2504-2537; doi:10.3390/biom5042504
Received: 31 July 2015 / Revised: 2 September 2015 / Accepted: 9 September 2015 / Published: 14 October 2015
Cited by 6 | PDF Full-text (541 KB) | HTML Full-text | XML Full-text
Abstract
Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the
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Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessReview Endoplasmic Reticulum Stress and Ethanol Neurotoxicity
Biomolecules 2015, 5(4), 2538-2553; doi:10.3390/biom5042538
Received: 5 August 2015 / Revised: 2 September 2015 / Accepted: 21 September 2015 / Published: 14 October 2015
Cited by 16 | PDF Full-text (520 KB) | HTML Full-text | XML Full-text
Abstract
Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is
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Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is associated with mental retardation and other behavioral deficits. A number of potential mechanisms have been proposed for ethanol-induced brain damage; these include the promotion of neuroinflammation, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, and thiamine deficiency. The endoplasmic reticulum (ER) regulates posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress and induces unfolded protein response (UPR) which are mediated by three transmembrane ER signaling proteins: pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). UPR is initiated to protect cells from overwhelming ER protein loading. However, sustained ER stress may result in cell death. ER stress has been implied in various CNS injuries, including brain ischemia, traumatic brain injury, and aging-associated neurodegeneration, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). However, effects of ethanol on ER stress in the CNS receive less attention. In this review, we discuss recent progress in the study of ER stress in ethanol-induced neurotoxicity. We also examine the potential mechanisms underlying ethanol-mediated ER stress and the interaction among ER stress, oxidative stress and autophagy in the context of ethanol neurotoxicity. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessReview Alcohol and the Intestine
Biomolecules 2015, 5(4), 2573-2588; doi:10.3390/biom5042573
Received: 1 September 2015 / Revised: 24 September 2015 / Accepted: 5 October 2015 / Published: 15 October 2015
Cited by 6 | PDF Full-text (107 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol abuse is a significant contributor to the global burden of disease and can lead to tissue damage and organ dysfunction in a subset of alcoholics. However, a subset of alcoholics without any of these predisposing factors can develop alcohol-mediated organ injury. The
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Alcohol abuse is a significant contributor to the global burden of disease and can lead to tissue damage and organ dysfunction in a subset of alcoholics. However, a subset of alcoholics without any of these predisposing factors can develop alcohol-mediated organ injury. The gastrointestinal tract (GI) could be an important source of inflammation in alcohol-mediated organ damage. The purpose of review was to evaluate mechanisms of alcohol-induced endotoxemia (including dysbiosis and gut leakiness), and highlight the predisposing factors for alcohol-induced dysbiosis and gut leakiness to endotoxins. Barriers, including immunologic, physical, and biochemical can regulate the passage of toxins into the portal and systemic circulation. In addition, a host of environmental interactions including those influenced by circadian rhythms can impact alcohol-induced organ pathology. There appears to be a role for therapeutic measures to mitigate alcohol-induced organ damage by normalizing intestinal dysbiosis and/or improving intestinal barrier integrity. Ultimately, the inflammatory process that drives progression into organ damage from alcohol appears to be multifactorial. Understanding the role of the intestine in the pathogenesis of alcoholic liver disease can pose further avenues for pathogenic and treatment approaches. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
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Open AccessReview Hsp90: A New Player in DNA Repair?
Biomolecules 2015, 5(4), 2589-2618; doi:10.3390/biom5042589
Received: 14 July 2015 / Revised: 8 September 2015 / Accepted: 10 September 2015 / Published: 16 October 2015
Cited by 13 | PDF Full-text (980 KB) | HTML Full-text | XML Full-text | Correction
Abstract
Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and
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Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and DNA repair. Cells respond to DNA damage by activating complex DNA damage response (DDR) pathways that include: (i) cell cycle arrest; (ii) transcriptional and post-translational activation of a subset of genes, including those associated with DNA repair; and (iii) triggering of programmed cell death. The efficacy of the DDR pathways is influenced by the nuclear levels of DNA repair proteins, which are regulated by balancing between protein synthesis and degradation as well as by nuclear import and export. The inability to respond properly to either DNA damage or to DNA repair leads to genetic instability, which in turn may enhance the rate of cancer development. Multiple components of the DNA double strand breaks repair machinery, including BRCA1, BRCA2, CHK1, DNA-PKcs, FANCA, and the MRE11/RAD50/NBN complex, have been described to be client proteins of Hsp90, which acts as a regulator of the diverse DDR pathways. Inhibition of Hsp90 actions leads to the altered localization and stabilization of DDR proteins after DNA damage and may represent a cell-specific and tumor-selective radiosensibilizer. Here, the role of Hsp90-dependent molecular mechanisms involved in cancer onset and in the maintenance of the genome integrity is discussed and highlighted. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview A Mechanistic Review of Mitophagy and Its Role in Protection against Alcoholic Liver Disease
Biomolecules 2015, 5(4), 2619-2642; doi:10.3390/biom5042619
Received: 11 July 2015 / Revised: 23 September 2015 / Accepted: 25 September 2015 / Published: 16 October 2015
Cited by 12 | PDF Full-text (208 KB) | HTML Full-text | XML Full-text
Abstract
Alcoholic liver disease (ALD) is a major health problem worldwide, and alcohol is well-known to cause mitochondrial damage, which exacerbates alcohol-induced liver injury and steatosis. No successful treatments are currently available for treating ALD. Therefore, a better understanding of mechanisms involved in regulation
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Alcoholic liver disease (ALD) is a major health problem worldwide, and alcohol is well-known to cause mitochondrial damage, which exacerbates alcohol-induced liver injury and steatosis. No successful treatments are currently available for treating ALD. Therefore, a better understanding of mechanisms involved in regulation of mitochondrial homeostasis in the liver and how these mechanisms may protect against alcohol-induced liver disease is needed for future development of better therapeutic options for ALD. Mitophagy is a key mechanism for maintaining mitochondrial homeostasis by removing damaged mitochondria, and mitophagy protects against alcohol-induced liver injury. Parkin, an E3 ubiquitin ligase, is well-known to induce mitophagy in in vitro models although Parkin-independent mechanisms for mitophagy induction also exist. In this review, we discuss the roles of Parkin and mitophagy in protection against alcohol-induced liver injury and steatosis. We also discuss Parkin-independent mechanisms for mitophagy induction, which have not yet been evaluated in the liver but may also potentially have a protective role against ALD. In addition to mitophagy, mitochondrial spheroid formation may also provide a novel mechanism of protection against ALD, but the role of mitochondrial spheroids in protection against ALD progression needs to be further explored. Targeting removal of damaged mitochondria by mitophagy or inducing formation of mitochondrial spheroids may be promising therapeutic options for treatment of ALD. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessReview Αlpha-Synuclein as a Mediator in the Interplay between Aging and Parkinson’s Disease
Biomolecules 2015, 5(4), 2675-2700; doi:10.3390/biom5042675
Received: 13 August 2015 / Revised: 22 September 2015 / Accepted: 13 October 2015 / Published: 16 October 2015
Cited by 8 | PDF Full-text (1498 KB) | HTML Full-text | XML Full-text
Abstract
Accumulation and misfolding of the alpha-synuclein protein are core mechanisms in the pathogenesis of Parkinson’s disease. While the normal function of alpha-synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial
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Accumulation and misfolding of the alpha-synuclein protein are core mechanisms in the pathogenesis of Parkinson’s disease. While the normal function of alpha-synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial activity, as well as proteasome and autophagic degradation of proteins. Remarkably, these functions are also affected when the renewal of macromolecules and organelles becomes impaired during the normal aging process. As aging is considered a major risk factor for Parkinson’s disease, it is critical to explore its molecular and cellular implications in the context of the alpha-synuclein pathology. Here, we discuss similarities and differences between normal brain aging and Parkinson’s disease, with a particular emphasis on the nigral dopaminergic neurons, which appear to be selectively vulnerable to the combined effects of alpha-synuclein and aging. Full article
Open AccessReview The La-Related Proteins, a Family with Connections to Cancer
Biomolecules 2015, 5(4), 2701-2722; doi:10.3390/biom5042701
Received: 6 August 2015 / Revised: 21 September 2015 / Accepted: 7 October 2015 / Published: 16 October 2015
Cited by 18 | PDF Full-text (528 KB) | HTML Full-text | XML Full-text
Abstract
The evolutionarily-conserved La-related protein (LARP) family currently comprises Genuine La, LARP1, LARP1b, LARP4, LARP4b, LARP6 and LARP7. Emerging evidence suggests each LARP has a distinct role in transcription and/or mRNA translation that is attributable to subtle sequence variations within their La modules and
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The evolutionarily-conserved La-related protein (LARP) family currently comprises Genuine La, LARP1, LARP1b, LARP4, LARP4b, LARP6 and LARP7. Emerging evidence suggests each LARP has a distinct role in transcription and/or mRNA translation that is attributable to subtle sequence variations within their La modules and specific C-terminal domains. As emerging research uncovers the function of each LARP, it is evident that La, LARP1, LARP6, LARP7 and possibly LARP4a and 4b are dysregulated in cancer. Of these, LARP1 is the first to be demonstrated to drive oncogenesis. Here, we review the role of each LARP and the evidence linking it to malignancy. We discuss a future strategy of targeting members of this protein family as cancer therapy. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
Open AccessReview The Role of the Transcriptional Regulation of Stromal Cells in Chronic Inflammation
Biomolecules 2015, 5(4), 2723-2757; doi:10.3390/biom5042723
Received: 14 August 2015 / Revised: 23 September 2015 / Accepted: 9 October 2015 / Published: 16 October 2015
Cited by 2 | PDF Full-text (849 KB) | HTML Full-text | XML Full-text
Abstract
Chronic inflammation is a common process connecting pathologies that vary in their etiology and pathogenesis such as cancer, autoimmune diseases, and infections. The response of the immune system to tissue damage involves a carefully choreographed series of cellular interactions between immune and non-immune
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Chronic inflammation is a common process connecting pathologies that vary in their etiology and pathogenesis such as cancer, autoimmune diseases, and infections. The response of the immune system to tissue damage involves a carefully choreographed series of cellular interactions between immune and non-immune cells. In recent years, it has become clear that stromal resident cells have an essential role perpetuating the inflammatory environment and dictating in many cases the outcome of inflammatory based pathologies. Signal transduction pathways remain the main focus of study to understand how stimuli contribute to perpetuating the inflammatory response, mainly due to their potential role as therapeutic targets. However, molecular events orchestrated in the nucleus by transcription factors add additional levels of complexity and may be equally important for understanding the phenotypic differences of activated stromal components during the chronic inflammatory process. In this review, we focus on the contribution of transcription factors to the selective regulation of inducible proinflammatory genes, with special attention given to the regulation of the stromal fibroblastic cell function and response. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Molecular Mechanisms of Transcription Initiation at gal Promoters and their Multi-Level Regulation by GalR, CRP and DNA Loop
Biomolecules 2015, 5(4), 2782-2807; doi:10.3390/biom5042782
Received: 11 May 2015 / Accepted: 25 September 2015 / Published: 16 October 2015
Cited by 1 | PDF Full-text (12931 KB) | HTML Full-text | XML Full-text
Abstract
Studying the regulation of transcription of the gal operon that encodes the amphibolic pathway of d-galactose metabolism in Escherichia coli discerned a plethora of principles that operate in prokaryotic gene regulatory processes. In this chapter, we have reviewed some of the more recent
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Studying the regulation of transcription of the gal operon that encodes the amphibolic pathway of d-galactose metabolism in Escherichia coli discerned a plethora of principles that operate in prokaryotic gene regulatory processes. In this chapter, we have reviewed some of the more recent findings in gal that continues to reveal unexpected but important mechanistic details. Since the operon is transcribed from two overlapping promoters, P1 and P2, regulated by common regulatory factors, each genetic or biochemical experiment allowed simultaneous discernment of two promoters. Recent studies range from genetic, biochemical through biophysical experiments providing explanations at physiological, mechanistic and single molecule levels. The salient observations highlighted here are: the axiom of determining transcription start points, discovery of a new promoter element different from the known ones that influences promoter strength, occurrence of an intrinsic DNA sequence element that overrides the transcription elongation pause created by a DNA-bound protein roadblock, first observation of a DNA loop and determination its trajectory, and piggybacking proteins and delivering to their DNA target. Full article
(This article belongs to the Special Issue Bacterial RNA Polymerase)
Open AccessReview Chronic Ethanol Exposure: Pathogenesis of Pulmonary Disease and Dysfunction
Biomolecules 2015, 5(4), 2840-2853; doi:10.3390/biom5042840
Received: 30 July 2015 / Revised: 4 September 2015 / Accepted: 28 September 2015 / Published: 20 October 2015
Cited by 6 | PDF Full-text (95 KB) | HTML Full-text | XML Full-text
Abstract
Ethanol (EtOH) is the world’s most commonly used drug, and has been widely recognized as a risk factor for developing lung disorders. Chronic EtOH exposure affects all of the organ systems in the body and increases the risk of developing pulmonary diseases such
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Ethanol (EtOH) is the world’s most commonly used drug, and has been widely recognized as a risk factor for developing lung disorders. Chronic EtOH exposure affects all of the organ systems in the body and increases the risk of developing pulmonary diseases such as acute lung injury and pneumonia, while exacerbating the symptoms and resulting in increased mortality in many other lung disorders. EtOH and its metabolites inhibit the immune response of alveolar macrophages (AMs), increase airway leakage, produce damaging reactive oxygen species (ROS), and disrupt the balance of antioxidants/oxidants within the lungs. In this article, we review the role of EtOH exposure in the pathogenesis and progression of pulmonary disease. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
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Open AccessReview Novel Implications of DNA Damage Response in Drug Resistance of Malignant Cancers Obtained from the Functional Interaction between p53 Family and RUNX2
Biomolecules 2015, 5(4), 2854-2876; doi:10.3390/biom5042854
Received: 2 June 2015 / Revised: 17 September 2015 / Accepted: 16 October 2015 / Published: 23 October 2015
Cited by 3 | PDF Full-text (609 KB) | HTML Full-text | XML Full-text
Abstract
During the lifespan of cells, their genomic DNA is continuously exposed to theendogenous and exogenous DNA insults. Thus, the appropriate cellular response to DNAdamage plays a pivotal role in maintaining genomic integrity and also acts as a molecularbarrier towards DNA legion-mediated carcinogenesis. The
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During the lifespan of cells, their genomic DNA is continuously exposed to theendogenous and exogenous DNA insults. Thus, the appropriate cellular response to DNAdamage plays a pivotal role in maintaining genomic integrity and also acts as a molecularbarrier towards DNA legion-mediated carcinogenesis. The tumor suppressor p53 participatesin an integral part of proper regulation of DNA damage response (DDR). p53 is frequentlymutated in a variety of human cancers. Since mutant p53 displays a dominant-negative behavioragainst wild-type p53, cancers expressing mutant p53 sometimes acquire drug-resistantphenotype, suggesting that mutant p53 prohibits the p53-dependent cell death pathwayfollowing DNA damage, and thereby contributing to the acquisition and/or maintenance ofdrug resistance of malignant cancers. Intriguingly, we have recently found that silencing ofpro-oncogenic RUNX2 enhances drug sensitivity of aggressive cancer cells regardless of p53status. Meanwhile, cancer stem cells (CSCs) have stem cell properties such as drug resistance.Therefore, the precise understanding of the biology of CSCs is quite important to overcometheir drug resistance. In this review, we focus on molecular mechanisms behind DDR as wellas the serious drug resistance of malignant cancers and discuss some attractive approachesto improving the outcomes of patients bearing drug-resistant cancers. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview ATM-Dependent Phosphorylation of All Three Members of the MRN Complex: From Sensor to Adaptor
Biomolecules 2015, 5(4), 2877-2902; doi:10.3390/biom5042877
Received: 27 August 2015 / Revised: 14 October 2015 / Accepted: 16 October 2015 / Published: 23 October 2015
Cited by 20 | PDF Full-text (2361 KB) | HTML Full-text | XML Full-text
Abstract
The recognition, signalling and repair of DNA double strand breaks (DSB) involves the participation of a multitude of proteins and post-translational events that ensure maintenance of genome integrity. Amongst the proteins involved are several which when mutated give rise to genetic disorders characterised
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The recognition, signalling and repair of DNA double strand breaks (DSB) involves the participation of a multitude of proteins and post-translational events that ensure maintenance of genome integrity. Amongst the proteins involved are several which when mutated give rise to genetic disorders characterised by chromosomal abnormalities, cancer predisposition, neurodegeneration and other pathologies. ATM (mutated in ataxia-telangiectasia (A-T) and members of the Mre11/Rad50/Nbs1 (MRN complex) play key roles in this process. The MRN complex rapidly recognises and locates to DNA DSB where it acts to recruit and assist in ATM activation. ATM, in the company of several other DNA damage response proteins, in turn phosphorylates all three members of the MRN complex to initiate downstream signalling. While ATM has hundreds of substrates, members of the MRN complex play a pivotal role in mediating the downstream signalling events that give rise to cell cycle control, DNA repair and ultimately cell survival or apoptosis. Here we focus on the interplay between ATM and the MRN complex in initiating signaling of breaks and more specifically on the adaptor role of the MRN complex in mediating ATM signalling to downstream substrates to control different cellular processes. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Competing Interactions of RNA-Binding Proteins, MicroRNAs, and Their Targets Control Neuronal Development and Function
Biomolecules 2015, 5(4), 2903-2918; doi:10.3390/biom5042903
Received: 4 August 2015 / Revised: 15 September 2015 / Accepted: 25 September 2015 / Published: 23 October 2015
Cited by 13 | PDF Full-text (153 KB) | HTML Full-text | XML Full-text
Abstract
Post-transcriptional mechanisms play critical roles in the control of gene expression during neuronal development and maturation as they allow for faster responses to environmental cues and provide spatially-restricted compartments for local control of protein expression. These mechanisms depend on the interaction of cis
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Post-transcriptional mechanisms play critical roles in the control of gene expression during neuronal development and maturation as they allow for faster responses to environmental cues and provide spatially-restricted compartments for local control of protein expression. These mechanisms depend on the interaction of cis-acting elements present in the mRNA sequence and trans-acting factors, such as RNA-binding proteins (RBPs) and microRNAs (miRNAs) that bind to those cis-elements and regulate mRNA stability, subcellular localization, and translation. Recent studies have uncovered an unexpected complexity in these interactions, where coding and non-coding RNAs, termed competing endogenous RNAs (ceRNAs), compete for binding to miRNAs. This competition can, thereby, control a larger number of miRNA target transcripts. However, competing RNA networks also extend to competition between target mRNAs for binding to limited amounts of RBPs. In this review, we present evidence that competitions between target mRNAs for binding to RBPs also occur in neurons, where they affect transcript stability and transport into axons and dendrites as well as translation. In addition, we illustrate the complexity of these mechanisms by demonstrating that RBPs and miRNAs also compete for target binding and regulation. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Open AccessReview The RNA Splicing Response to DNA Damage
Biomolecules 2015, 5(4), 2935-2977; doi:10.3390/biom5042935
Received: 12 August 2015 / Revised: 20 September 2015 / Accepted: 16 October 2015 / Published: 29 October 2015
Cited by 18 | PDF Full-text (2730 KB) | HTML Full-text | XML Full-text
Abstract
The number of factors known to participate in the DNA damage response (DDR) has expanded considerably in recent years to include splicing and alternative splicing factors. While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring
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The number of factors known to participate in the DNA damage response (DDR) has expanded considerably in recent years to include splicing and alternative splicing factors. While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring the formation of RNA/DNA duplexes, splicing factors are also recruited to, or removed from, sites of DNA damage. The first steps of the DDR promote the post-translational modification of splicing factors to affect their localization and activity, while more downstream DDR events alter their expression. Although descriptions of molecular mechanisms remain limited, an emerging trend is that DNA damage disrupts the coupling of constitutive and alternative splicing with the transcription of genes involved in DNA repair, cell-cycle control and apoptosis. A better understanding of how changes in splice site selection are integrated into the DDR may provide new avenues to combat cancer and delay aging. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Update on Alcoholic Hepatitis
Biomolecules 2015, 5(4), 2978-2986; doi:10.3390/biom5042978
Received: 6 September 2015 / Revised: 26 October 2015 / Accepted: 29 October 2015 / Published: 2 November 2015
Cited by 5 | PDF Full-text (78 KB) | HTML Full-text | XML Full-text
Abstract
Alcoholic liver disease is one of the most prevalent liver diseases worldwide, and a major cause of morbidity and mortality. Alcoholic hepatitis is a severe form of liver injury in patients with alcohol abuse, can present as an acute on chronic liver failure
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Alcoholic liver disease is one of the most prevalent liver diseases worldwide, and a major cause of morbidity and mortality. Alcoholic hepatitis is a severe form of liver injury in patients with alcohol abuse, can present as an acute on chronic liver failure associated with a rapid decline in liver synthetic function, and consequent increase in mortality. Despite therapy, about 30%–50% of patients with severe alcoholic hepatitis eventually die. The pathogenic pathways that lead to the development of alcoholic hepatitis are complex and involve oxidative stress, gut dysbiosis, and dysregulation of the innate and adaptive immune system with injury to the parenchymal cells and activation of hepatic stellate cells. As accepted treatment approaches are currently limited, a better understanding of the pathophysiology would be required to generate new approaches that improve outcomes. This review focuses on recent advances in the diagnosis, pathogenesis of alcoholic hepatitis and novel treatment strategies. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessReview Alcohol, Aldehydes, Adducts and Airways
Biomolecules 2015, 5(4), 2987-3008; doi:10.3390/biom5042987
Received: 29 July 2015 / Revised: 13 October 2015 / Accepted: 16 October 2015 / Published: 5 November 2015
Cited by 8 | PDF Full-text (775 KB) | HTML Full-text | XML Full-text
Abstract
Drinking alcohol and smoking cigarettes results in the formation of reactive aldehydes in the lung, which are capable of forming adducts with several proteins and DNA. Acetaldehyde and malondialdehyde are the major aldehydes generated in high levels in the lung of subjects with
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Drinking alcohol and smoking cigarettes results in the formation of reactive aldehydes in the lung, which are capable of forming adducts with several proteins and DNA. Acetaldehyde and malondialdehyde are the major aldehydes generated in high levels in the lung of subjects with alcohol use disorder who smoke cigarettes. In addition to the above aldehydes, several other aldehydes like 4-hydroxynonenal, formaldehyde and acrolein are also detected in the lung due to exposure to toxic gases, vapors and chemicals. These aldehydes react with nucleophilic targets in cells such as DNA, lipids and proteins to form both stable and unstable adducts. This adduction may disturb cellular functions as well as damage proteins, nucleic acids and lipids. Among several adducts formed in the lung, malondialdehyde DNA (MDA-DNA) adduct and hybrid malondialdehyde-acetaldehyde (MAA) protein adducts have been shown to initiate several pathological conditions in the lung. MDA-DNA adducts are pre-mutagenic in mammalian cells and induce frame shift and base-pair substitution mutations, whereas MAA protein adducts have been shown to induce inflammation and inhibit wound healing. This review provides an insight into different reactive aldehyde adducts and their role in the pathogenesis of lung disease. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessReview RNase P-Mediated Sequence-Specific Cleavage of RNA by Engineered External Guide Sequences
Biomolecules 2015, 5(4), 3029-3050; doi:10.3390/biom5043029
Received: 29 July 2015 / Revised: 16 October 2015 / Accepted: 29 October 2015 / Published: 9 November 2015
Cited by 3 | PDF Full-text (439 KB) | HTML Full-text | XML Full-text
Abstract
The RNA cleavage activity of RNase P can be employed to decrease the levels of specific RNAs and to study their function or even to eradicate pathogens. Two different technologies have been developed to use RNase P as a tool for RNA knockdown.
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The RNA cleavage activity of RNase P can be employed to decrease the levels of specific RNAs and to study their function or even to eradicate pathogens. Two different technologies have been developed to use RNase P as a tool for RNA knockdown. In one of these, an external guide sequence, which mimics a tRNA precursor, a well-known natural RNase P substrate, is used to target an RNA molecule for cleavage by endogenous RNase P. Alternatively, a guide sequence can be attached to M1 RNA, the (catalytic) RNase P RNA subunit of Escherichia coli. The guide sequence is specific for an RNA target, which is subsequently cleaved by the bacterial M1 RNA moiety. These approaches are applicable in both bacteria and eukaryotes. In this review, we will discuss the two technologies in which RNase P is used to reduce RNA expression levels. Full article
(This article belongs to the Special Issue Function and Structure of RNase P in Fungi, Bacteria and Human Cells)
Open AccessReview Expression and Function of CD44 in Epithelial Ovarian Carcinoma
Biomolecules 2015, 5(4), 3051-3066; doi:10.3390/biom5043051
Received: 30 September 2015 / Revised: 29 October 2015 / Accepted: 30 October 2015 / Published: 11 November 2015
Cited by 11 | PDF Full-text (265 KB) | HTML Full-text | XML Full-text
Abstract
CD44, a cell surface glycoprotein, has been increasingly implicated in the pathogenesis and progression of epithelial ovarian cancer, the deadliest gynecologic malignancy in women. Here, we review recent reports on the expression and function of CD44 in epithelial ovarian carcinoma. Further functional data
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CD44, a cell surface glycoprotein, has been increasingly implicated in the pathogenesis and progression of epithelial ovarian cancer, the deadliest gynecologic malignancy in women. Here, we review recent reports on the expression and function of CD44 in epithelial ovarian carcinoma. Further functional data for CD44 in peritoneal adhesion and metastatic progression and its association with stem cells is highlighted. Recent studies utilizing CD44 for therapeutic targeting are also discussed. Full article
(This article belongs to the Special Issue Signal Transduction Pathways in Gynecologic Malignancies)
Open AccessReview Computational Studies of Glutamate Transporters
Biomolecules 2015, 5(4), 3067-3086; doi:10.3390/biom5043067
Received: 25 September 2015 / Revised: 29 October 2015 / Accepted: 3 November 2015 / Published: 11 November 2015
Cited by 2 | PDF Full-text (1293 KB) | HTML Full-text | XML Full-text
Abstract
Glutamate is the major excitatory neurotransmitter in the human brain whose binding to receptors on neurons excites them while excess glutamate are removed from synapses via transporter proteins. Determination of the crystal structures of bacterial aspartate transporters has paved the way for computational
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Glutamate is the major excitatory neurotransmitter in the human brain whose binding to receptors on neurons excites them while excess glutamate are removed from synapses via transporter proteins. Determination of the crystal structures of bacterial aspartate transporters has paved the way for computational investigation of their function and dynamics at the molecular level. Here, we review molecular dynamics and free energy calculation methods used in these computational studies and discuss the recent applications to glutamate transporters. The focus of the review is on the insights gained on the transport mechanism through computational methods, which otherwise is not directly accessible by experimental probes. Recent efforts to model the mammalian glutamate and other amino acid transporters, whose crystal structures have not been solved yet, are included in the review. Full article
(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)
Open AccessReview Transcriptional Activation of Inflammatory Genes: Mechanistic Insight into Selectivity and Diversity
Biomolecules 2015, 5(4), 3087-3111; doi:10.3390/biom5043087
Received: 30 July 2015 / Revised: 11 September 2015 / Accepted: 28 October 2015 / Published: 11 November 2015
Cited by 4 | PDF Full-text (263 KB) | HTML Full-text | XML Full-text
Abstract
Acute inflammation, an integral part of host defence and immunity, is a highly conserved cellular response to pathogens and other harmful stimuli. An inflammatory stimulation triggers transcriptional activation of selective pro-inflammatory genes that carry out specific functions such as anti-microbial activity or tissue
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Acute inflammation, an integral part of host defence and immunity, is a highly conserved cellular response to pathogens and other harmful stimuli. An inflammatory stimulation triggers transcriptional activation of selective pro-inflammatory genes that carry out specific functions such as anti-microbial activity or tissue healing. Based on the nature of inflammatory stimuli, an extensive exploitation of selective transcriptional activations of pro-inflammatory genes is performed by the host to ensure a defined inflammatory response. Inflammatory signal transductions are initiated by the recognition of inflammatory stimuli by transmembrane receptors, followed by the transmission of the signals to the nucleus for differential gene activations. The differential transcriptional activation of pro-inflammatory genes is precisely controlled by the selective binding of transcription factors to the promoters of these genes. Among a number of transcription factors identified to date, NF-κB still remains the most prominent and studied factor for its diverse range of selective transcriptional activities. Differential transcriptional activities of NF-κB are dictated by post-translational modifications, specificities in dimer formation, and variability in activation kinetics. Apart from the differential functions of transcription factors, the transcriptional activation of selective pro-inflammatory genes is also governed by chromatin structures, epigenetic markers, and other regulators as the field is continuously expanding. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
Open AccessReview Overview of Glutamatergic Dysregulation in Central Pathologies
Biomolecules 2015, 5(4), 3112-3141; doi:10.3390/biom5043112
Received: 5 October 2015 / Revised: 3 November 2015 / Accepted: 5 November 2015 / Published: 11 November 2015
Cited by 16 | PDF Full-text (989 KB) | HTML Full-text | XML Full-text
Abstract
As the major excitatory neurotransmitter in the mammalian central nervous system, glutamate plays a key role in many central pathologies, including gliomas, psychiatric, neurodevelopmental, and neurodegenerative disorders. Post-mortem and serological studies have implicated glutamatergic dysregulation in these pathologies, and pharmacological modulation of glutamate
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As the major excitatory neurotransmitter in the mammalian central nervous system, glutamate plays a key role in many central pathologies, including gliomas, psychiatric, neurodevelopmental, and neurodegenerative disorders. Post-mortem and serological studies have implicated glutamatergic dysregulation in these pathologies, and pharmacological modulation of glutamate receptors and transporters has provided further validation for the involvement of glutamate. Furthermore, efforts from genetic, in vitro, and animal studies are actively elucidating the specific glutamatergic mechanisms that contribute to the aetiology of central pathologies. However, details regarding specific mechanisms remain sparse and progress in effectively modulating glutamate to alleviate symptoms or inhibit disease states has been relatively slow. In this report, we review what is currently known about glutamate signalling in central pathologies. We also discuss glutamate’s mediating role in comorbidities, specifically cancer-induced bone pain and depression. Full article
(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)
Open AccessReview Immune Mechanisms Linking Obesity and Preeclampsia
Biomolecules 2015, 5(4), 3142-3176; doi:10.3390/biom5043142
Received: 23 July 2015 / Revised: 7 October 2015 / Accepted: 20 October 2015 / Published: 12 November 2015
Cited by 8 | PDF Full-text (2007 KB) | HTML Full-text | XML Full-text
Abstract
Preeclampsia (PE) is characterized by hypertension occurring after the twentieth week of pregnancy. It is a significant contributor to maternal and perinatal morbidity and mortality in developing countries and its pervasiveness is increasing within developed countries including the USA. However, the mechanisms mediating
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Preeclampsia (PE) is characterized by hypertension occurring after the twentieth week of pregnancy. It is a significant contributor to maternal and perinatal morbidity and mortality in developing countries and its pervasiveness is increasing within developed countries including the USA. However, the mechanisms mediating the pathogenesis of this maternal disorder and its rising prevalence are far from clear. A major theory with strong experimental evidence is that placental ischemia, resulting from inappropriate remodeling and widening of the maternal spiral arteries, stimulates the release of soluble factors from the ischemic placenta causing maternal endothelial dysfunction and hypertension. Aberrant maternal immune responses and inflammation have been implicated in each of these stages in the cascade leading to PE. Regarding the increased prevalence of this disease, it is becoming increasingly evident from epidemiological data that obesity, which is a state of chronic inflammation in itself, increases the risk for PE. Although the specific mechanisms whereby obesity increases the rate of PE are unclear, there are strong candidates including activated macrophages and natural killer cells within the uterus and placenta and activation in the periphery of T helper cells producing cytokines including TNF-α, IL-6 and IL-17 and the anti-angiogenic factor sFlt-1 and B cells producing the agonistic autoantibodies to the angiotensin type 1 receptor (AT1-aa). This review will focus on the immune mechanisms that have been implicated in the pathogenesis of hypertension in PE with an emphasis on the potential importance of inflammatory factors in the increased risk of developing PE in obese pregnancies. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
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Open AccessReview DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles’ Heel of Cancer
Biomolecules 2015, 5(4), 3204-3259; doi:10.3390/biom5043204
Received: 7 September 2015 / Accepted: 9 November 2015 / Published: 20 November 2015
Cited by 19 | PDF Full-text (2322 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy.
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For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy. Over the last decade, the discovery of new targeted therapies against DNA damage signalling and repair has offered the possibility of therapeutic improvements in oncology. In this review, we summarize the current knowledge of DNA damage signalling and repair inhibitors, their molecular and cellular effects, and future therapeutic use. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview The Potential Role of the Proteases Cathepsin D and Cathepsin L in the Progression and Metastasis of Epithelial Ovarian Cancer
Biomolecules 2015, 5(4), 3260-3279; doi:10.3390/biom5043260
Received: 7 October 2015 / Accepted: 13 November 2015 / Published: 20 November 2015
Cited by 7 | PDF Full-text (359 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and has a poor prognosis due to relatively unspecific early symptoms, and thus often advanced stage, metastasized cancer at presentation. Metastasis of EOC occurs primarily through the transcoelomic route whereby
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Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and has a poor prognosis due to relatively unspecific early symptoms, and thus often advanced stage, metastasized cancer at presentation. Metastasis of EOC occurs primarily through the transcoelomic route whereby exfoliated tumor cells disseminate within the abdominal cavity, particularly to the omentum. Primary and metastatic tumor growth requires a pool of proangiogenic factors in the microenvironment which propagate new vasculature in the growing cancer. Recent evidence suggests that proangiogenic factors other than the widely known, potent angiogenic factor vascular endothelial growth factor may mediate growth and metastasis of ovarian cancer. In this review we examine the role of some of these alternative factors, specifically cathepsin D and cathepsin L. Full article
(This article belongs to the Special Issue Signal Transduction Pathways in Gynecologic Malignancies)
Open AccessReview Role of microRNAs in Alcohol-Induced Multi-Organ Injury
Biomolecules 2015, 5(4), 3309-3338; doi:10.3390/biom5043309
Received: 29 August 2015 / Accepted: 16 November 2015 / Published: 20 November 2015
Cited by 12 | PDF Full-text (301 KB) | HTML Full-text | XML Full-text
Abstract
Alcohol consumption and its abuse is a major health problem resulting in significant healthcare cost in the United States. Chronic alcoholism results in damage to most of the vital organs in the human body. Among the alcohol-induced injuries, alcoholic liver disease is one
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Alcohol consumption and its abuse is a major health problem resulting in significant healthcare cost in the United States. Chronic alcoholism results in damage to most of the vital organs in the human body. Among the alcohol-induced injuries, alcoholic liver disease is one of the most prevalent in the United States. Remarkably, ethanol alters expression of a wide variety of microRNAs that can regulate alcohol-induced complications or dysfunctions. In this review, we will discuss the role of microRNAs in alcoholic pancreatitis, alcohol-induced liver damage, intestinal epithelial barrier dysfunction, and brain damage including altered hippocampus structure and function, and neuronal loss, alcoholic cardiomyopathy, and muscle damage. Further, we have reviewed the role of altered microRNAs in the circulation, teratogenic effects of alcohol, and during maternal or paternal alcohol consumption. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessReview RNA-Binding Proteins in Trichomonas vaginalis: Atypical Multifunctional Proteins
Biomolecules 2015, 5(4), 3354-3395; doi:10.3390/biom5043354
Received: 21 September 2015 / Revised: 7 November 2015 / Accepted: 12 November 2015 / Published: 26 November 2015
Cited by 2 | PDF Full-text (1897 KB) | HTML Full-text | XML Full-text
Abstract
Iron homeostasis is highly regulated in vertebrates through a regulatory system mediated by RNA-protein interactions between the iron regulatory proteins (IRPs) that interact with an iron responsive element (IRE) located in certain mRNAs, dubbed the IRE-IRP regulatory system. Trichomonas vaginalis, the causal
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Iron homeostasis is highly regulated in vertebrates through a regulatory system mediated by RNA-protein interactions between the iron regulatory proteins (IRPs) that interact with an iron responsive element (IRE) located in certain mRNAs, dubbed the IRE-IRP regulatory system. Trichomonas vaginalis, the causal agent of trichomoniasis, presents high iron dependency to regulate its growth, metabolism, and virulence properties. Although T. vaginalis lacks IRPs or proteins with aconitase activity, possesses gene expression mechanisms of iron regulation at the transcriptional and posttranscriptional levels. However, only one gene with iron regulation at the transcriptional level has been described. Recently, our research group described an iron posttranscriptional regulatory mechanism in the T. vaginalis tvcp4 and tvcp12 cysteine proteinase mRNAs. The tvcp4 and tvcp12 mRNAs have a stem-loop structure in the 5'-coding region or in the 3'-UTR, respectively that interacts with T. vaginalis multifunctional proteins HSP70, α-Actinin, and Actin under iron starvation condition, causing translation inhibition or mRNA stabilization similar to the previously characterized IRE-IRP system in eukaryotes. Herein, we summarize recent progress and shed some light on atypical RNA-binding proteins that may participate in the iron posttranscriptional regulation in T. vaginalis. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Open AccessReview A Novel Aspect of Tumorigenesis—BMI1 Functions in Regulating DNA Damage Response
Biomolecules 2015, 5(4), 3396-3415; doi:10.3390/biom5043396
Received: 7 August 2015 / Revised: 23 October 2015 / Accepted: 26 November 2015 / Published: 1 December 2015
Cited by 3 | PDF Full-text (905 KB) | HTML Full-text | XML Full-text
Abstract
BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs) for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT). Upregulation of BMI1 occurs in multiple
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BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs) for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT). Upregulation of BMI1 occurs in multiple cancer types and is associated with poor prognosis. Mechanistically, BMI1 is a subunit of the Polycomb repressive complex 1 (PRC1), and binds the catalytic RING2/RING1b subunit to form a functional E3 ubiquitin ligase. Through mono-ubiquitination of histone H2A at lysine 119 (H2A-K119Ub), BMI1 represses multiple gene loci; among these, the INK4A/ARF locus has been most thoroughly investigated. The locus encodes the p16INK4A and p14/p19ARF tumor suppressors that function in the pRb and p53 pathways, respectively. Its repression contributes to BMI1-derived tumorigenesis. BMI1 also possesses other oncogenic functions, specifically its regulative role in DNA damage response (DDR). In this process, BMI1 ubiquitinates histone H2A and γH2AX, thereby facilitating the repair of double-stranded DNA breaks (DSBs) through stimulating homologous recombination and non-homologous end joining. Additionally, BMI1 compromises DSB-induced checkpoint activation independent of its-associated E3 ubiquitin ligase activity. We review the emerging role of BMI1 in DDR regulation and discuss its impact on BMI1-derived tumorigenesis. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview VGLUTs and Glutamate Synthesis—Focus on DRG Neurons and Pain
Biomolecules 2015, 5(4), 3416-3437; doi:10.3390/biom5043416
Received: 15 August 2015 / Revised: 13 November 2015 / Accepted: 17 November 2015 / Published: 2 December 2015
Cited by 5 | PDF Full-text (2700 KB) | HTML Full-text | XML Full-text
Abstract
The amino acid glutamate is the principal excitatory transmitter in the nervous system, including in sensory neurons that convey pain sensation from the periphery to the brain. It is now well established that a family of membrane proteins, termed vesicular glutamate transporters (VGLUTs),
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The amino acid glutamate is the principal excitatory transmitter in the nervous system, including in sensory neurons that convey pain sensation from the periphery to the brain. It is now well established that a family of membrane proteins, termed vesicular glutamate transporters (VGLUTs), serve a critical function in these neurons: they incorporate glutamate into synaptic vesicles. VGLUTs have a central role both under normal neurotransmission and pathological conditions, such as neuropathic or inflammatory pain. In the present short review, we will address VGLUTs in the context of primary afferent neurons. We will focus on the role of VGLUTs in pain triggered by noxious stimuli, peripheral nerve injury, and tissue inflammation, as mostly explored in transgenic mice. The possible interplay between glutamate biosynthesis and VGLUT-dependent packaging in synaptic vesicles, and its potential impact in various pain states will be presented. Full article
(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)
Open AccessReview On the Role of Glutamate in Presynaptic Development: Possible Contributions of Presynaptic NMDA Receptors
Biomolecules 2015, 5(4), 3448-3466; doi:10.3390/biom5043448
Received: 28 May 2015 / Revised: 22 October 2015 / Accepted: 26 November 2015 / Published: 14 December 2015
Cited by 5 | PDF Full-text (839 KB) | HTML Full-text | XML Full-text
Abstract
Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is
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Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is a key question in neuroscience. In this review, we focus on the regulation of excitatory presynaptic terminal development by glutamate, the predominant excitatory neurotransmitter in the brain. We discuss the evidence that NMDA receptor activation mediates these effects of glutamate and present the hypothesis that local activation of presynaptic NMDA receptors (preNMDARs) contributes to glutamate-dependent control of presynaptic development. Abnormal glutamate signaling and aberrant synapse development are both thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, epilepsy, anxiety, depression, and schizophrenia. Therefore, understanding how glutamate signaling and synapse development are linked is important for understanding the etiology of these diseases. Full article
(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)
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