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Biomolecules, Volume 5, Issue 3 (September 2015), Pages 1195-2159

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Open AccessReview The Altered Hepatic Tubulin Code in Alcoholic Liver Disease
Biomolecules 2015, 5(3), 2140-2159; https://doi.org/10.3390/biom5032140
Received: 22 July 2015 / Revised: 21 August 2015 / Accepted: 24 August 2015 / Published: 18 September 2015
Cited by 3 | PDF Full-text (514 KB) | HTML Full-text | XML Full-text
Abstract
The molecular mechanisms that lead to the progression of alcoholic liver disease have been actively examined for decades. Because the hepatic microtubule cytoskeleton supports innumerable cellular processes, it has been the focus of many such mechanistic studies. It has long been appreciated that
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The molecular mechanisms that lead to the progression of alcoholic liver disease have been actively examined for decades. Because the hepatic microtubule cytoskeleton supports innumerable cellular processes, it has been the focus of many such mechanistic studies. It has long been appreciated that α-tubulin is a major target for modification by highly reactive ethanol metabolites and reactive oxygen species. It is also now apparent that alcohol exposure induces post-translational modifications that are part of the natural repertoire, mainly acetylation. In this review, the modifications of the “tubulin code” are described as well as those adducts by ethanol metabolites. The potential cellular consequences of microtubule modification are described with a focus on alcohol-induced defects in protein trafficking and enhanced steatosis. Possible mechanisms that can explain hepatic dysfunction are described and how this relates to the onset of liver injury is discussed. Finally, we propose that agents that alter the cellular acetylation state may represent a novel therapeutic strategy for treating liver disease. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
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Open AccessReview Managing Single-Stranded DNA during Replication Stress in Fission Yeast
Biomolecules 2015, 5(3), 2123-2139; https://doi.org/10.3390/biom5032123
Received: 31 July 2015 / Revised: 28 August 2015 / Accepted: 1 September 2015 / Published: 18 September 2015
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Abstract
Replication fork stalling generates a variety of responses, most of which cause an increase in single-stranded DNA. ssDNA is a primary signal of replication distress that activates cellular checkpoints. It is also a potential source of genome instability and a substrate for mutation
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Replication fork stalling generates a variety of responses, most of which cause an increase in single-stranded DNA. ssDNA is a primary signal of replication distress that activates cellular checkpoints. It is also a potential source of genome instability and a substrate for mutation and recombination. Therefore, managing ssDNA levels is crucial to chromosome integrity. Limited ssDNA accumulation occurs in wild-type cells under stress. In contrast, cells lacking the replication checkpoint cannot arrest forks properly and accumulate large amounts of ssDNA. This likely occurs when the replication fork polymerase and helicase units are uncoupled. Some cells with mutations in the replication helicase (mcm-ts) mimic checkpoint-deficient cells, and accumulate extensive areas of ssDNA to trigger the G2-checkpoint. Another category of helicase mutant (mcm4-degron) causes fork stalling in early S-phase due to immediate loss of helicase function. Intriguingly, cells realize that ssDNA is present, but fail to detect that they accumulate ssDNA, and continue to divide. Thus, the cellular response to replication stalling depends on checkpoint activity and the time that replication stress occurs in S-phase. In this review we describe the signs, signals, and symptoms of replication arrest from an ssDNA perspective. We explore the possible mechanisms for these effects. We also advise the need for caution when detecting and interpreting data related to the accumulation of ssDNA. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview The Impact of Non-Enzymatic Reactions and Enzyme Promiscuity on Cellular Metabolism during (Oxidative) Stress Conditions
Biomolecules 2015, 5(3), 2101-2122; https://doi.org/10.3390/biom5032101
Received: 6 May 2015 / Revised: 3 August 2015 / Accepted: 31 August 2015 / Published: 10 September 2015
Cited by 21 | PDF Full-text (1507 KB) | HTML Full-text | XML Full-text
Abstract
Cellular metabolism assembles in a structurally highly conserved, but functionally dynamic system, known as the metabolic network. This network involves highly active, enzyme-catalyzed metabolic pathways that provide the building blocks for cell growth. In parallel, however, chemical reactivity of metabolites and unspecific enzyme
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Cellular metabolism assembles in a structurally highly conserved, but functionally dynamic system, known as the metabolic network. This network involves highly active, enzyme-catalyzed metabolic pathways that provide the building blocks for cell growth. In parallel, however, chemical reactivity of metabolites and unspecific enzyme function give rise to a number of side products that are not part of canonical metabolic pathways. It is increasingly acknowledged that these molecules are important for the evolution of metabolism, affect metabolic efficiency, and that they play a potential role in human disease—age-related disorders and cancer in particular. In this review we discuss the impact of oxidative and other cellular stressors on the formation of metabolic side products, which originate as a consequence of: (i) chemical reactivity or modification of regular metabolites; (ii) through modifications in substrate specificity of damaged enzymes; and (iii) through altered metabolic flux that protects cells in stress conditions. In particular, oxidative and heat stress conditions are causative of metabolite and enzymatic damage and thus promote the non-canonical metabolic activity of the cells through an increased repertoire of side products. On the basis of selected examples, we discuss the consequences of non-canonical metabolic reactivity on evolution, function and repair of the metabolic network. Full article
(This article belongs to the Special Issue Oxidative Stress and Oxygen Radicals) Printed Edition available
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Open AccessReview Splicing Regulation of Pro-Inflammatory Cytokines and Chemokines: At the Interface of the Neuroendocrine and Immune Systems
Biomolecules 2015, 5(3), 2073-2100; https://doi.org/10.3390/biom5032073
Received: 22 April 2015 / Accepted: 28 August 2015 / Published: 7 September 2015
Cited by 7 | PDF Full-text (2299 KB) | HTML Full-text | XML Full-text
Abstract
Alternative splicing plays a key role in posttranscriptional regulation of gene expression, allowing a single gene to encode multiple protein isoforms. As such, alternative splicing amplifies the coding capacity of the genome enormously, generates protein diversity, and alters protein function. More than 90%
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Alternative splicing plays a key role in posttranscriptional regulation of gene expression, allowing a single gene to encode multiple protein isoforms. As such, alternative splicing amplifies the coding capacity of the genome enormously, generates protein diversity, and alters protein function. More than 90% of human genes undergo alternative splicing, and alternative splicing is especially prevalent in the nervous and immune systems, tissues where cells need to react swiftly and adapt to changes in the environment through carefully regulated mechanisms of cell differentiation, migration, targeting, and activation. Given its prevalence and complexity, this highly regulated mode of gene expression is prone to be affected by disease. In the following review, we look at how alternative splicing of signaling molecules—cytokines and their receptors—changes in different pathological conditions, from chronic inflammation to neurologic disorders, providing means of functional interaction between the immune and neuroendocrine systems. Switches in alternative splicing patterns can be very dynamic and can produce signaling molecules with distinct or antagonistic functions and localization to different subcellular compartments. This newly discovered link expands our understanding of the biology of immune and neuroendocrine cells, and has the potential to open new windows of opportunity for treatment of neurodegenerative disorders. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
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Open AccessReview Notable Aspects of Glycan-Protein Interactions
Biomolecules 2015, 5(3), 2056-2072; https://doi.org/10.3390/biom5032056
Received: 5 August 2015 / Revised: 27 August 2015 / Accepted: 27 August 2015 / Published: 1 September 2015
Cited by 10 | PDF Full-text (3056 KB) | HTML Full-text | XML Full-text
Abstract
This mini review highlights several interesting aspects of glycan-mediated interactions that are common between cells, bacteria, and viruses. Glycans are ubiquitously found on all living cells, and in the extracellular milieu of multicellular organisms. They are known to mediate initial binding and recognition
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This mini review highlights several interesting aspects of glycan-mediated interactions that are common between cells, bacteria, and viruses. Glycans are ubiquitously found on all living cells, and in the extracellular milieu of multicellular organisms. They are known to mediate initial binding and recognition events of both immune cells and pathogens with their target cells or tissues. The host target tissues are hidden under a layer of secreted glycosylated decoy targets. In addition, pathogens can utilize and display host glycans to prevent identification as foreign by the host’s immune system (molecular mimicry). Both the host and pathogens continually evolve. The host evolves to prevent infection and the pathogens evolve to evade host defenses. Many pathogens express both glycan-binding proteins and glycosidases. Interestingly, these proteins are often located at the tip of elongated protrusions in bacteria, or in the leading edge of the cell. Glycan-protein interactions have low affinity and, as a result, multivalent interactions are often required to achieve biologically relevant binding. These enable dynamic forms of adhesion mechanisms, reviewed here, and include rolling (cells), stick and roll (bacteria) or surfacing (viruses). Full article
(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)
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Open AccessArticle Histone Deacetylase Inhibitors Activate Tristetraprolin Expression through Induction of Early Growth Response Protein 1 (EGR1) in Colorectal Cancer Cells
Biomolecules 2015, 5(3), 2035-2055; https://doi.org/10.3390/biom5032035
Received: 21 May 2015 / Revised: 30 July 2015 / Accepted: 10 August 2015 / Published: 28 August 2015
Cited by 14 | PDF Full-text (2288 KB) | HTML Full-text | XML Full-text
Abstract
The RNA-binding protein tristetraprolin (TTP) promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE). In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC) inhibitors
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The RNA-binding protein tristetraprolin (TTP) promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE). In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC) inhibitors (Trichostatin A, SAHA and sodium butyrate) promote TTP expression in colorectal cancer cells (HCA-7, HCT-116, Moser and SW480 cells) and cervix carcinoma cells (HeLa). We found that HDAC inhibitors-induced TTP expression, promote the decay of COX-2 mRNA, and inhibit cancer cell proliferation. HDAC inhibitors were found to promote TTP transcription through activation of the transcription factor Early Growth Response protein 1 (EGR1). Altogether, our findings indicate that loss of TTP in tumors occurs through silencing of EGR1 and suggests a therapeutic approach to rescue TTP expression in colorectal cancer. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Open AccessReview Alcoholic Liver Disease: Role of Cytokines
Biomolecules 2015, 5(3), 2023-2034; https://doi.org/10.3390/biom5032023
Received: 3 July 2015 / Revised: 21 August 2015 / Accepted: 24 August 2015 / Published: 28 August 2015
Cited by 11 | PDF Full-text (91 KB) | HTML Full-text | XML Full-text
Abstract
The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor
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The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor that contributes to the pathogenesis of ALD is lipopolysaccharide (LPS), which plays a central role in the induction of steatosis, inflammation, and fibrosis in the liver. LPS derived from the intestinal microbiota enters the portal circulation, and is recognized by macrophages (Kupffer cells) and hepatocytes. In individuals with ALD, excessive levels of LPS in the liver affect immune, parenchymal, and non-immune cells, which in turn release various inflammatory cytokines and recruit neutrophils and other inflammatory cells. In this review, we elucidate the mechanisms by which alcohol contributes to the activation of Kupffer cells and the inflammatory cascade. The role of the stellate cells in fibrogenesis is also discussed. Full article
(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
Open AccessReview Determinants of Glycosaminoglycan (GAG) Structure
Biomolecules 2015, 5(3), 2003-2022; https://doi.org/10.3390/biom5032003
Received: 29 May 2015 / Revised: 17 August 2015 / Accepted: 18 August 2015 / Published: 21 August 2015
Cited by 19 | PDF Full-text (156 KB) | HTML Full-text | XML Full-text
Abstract
Proteoglycans (PGs) are glycosylated proteins of biological importance at cell surfaces, in the extracellular matrix, and in the circulation. PGs are produced and modified by glycosaminoglycan (GAG) chains in the secretory pathway of animal cells. The most common GAG attachment site is a
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Proteoglycans (PGs) are glycosylated proteins of biological importance at cell surfaces, in the extracellular matrix, and in the circulation. PGs are produced and modified by glycosaminoglycan (GAG) chains in the secretory pathway of animal cells. The most common GAG attachment site is a serine residue followed by a glycine (-ser-gly-), from which a linker tetrasaccharide extends and may continue as a heparan sulfate, a heparin, a chondroitin sulfate, or a dermatan sulfate GAG chain. Which type of GAG chain becomes attached to the linker tetrasaccharide is influenced by the structure of the protein core, modifications occurring to the linker tetrasaccharide itself, and the biochemical environment of the Golgi apparatus, where GAG polymerization and modification by sulfation and epimerization take place. The same cell type may produce different GAG chains that vary, depending on the extent of epimerization and sulfation. However, it is not known to what extent these differences are caused by compartmental segregation of protein cores en route through the secretory pathway or by differential recruitment of modifying enzymes during synthesis of different PGs. The topic of this review is how different aspects of protein structure, cellular biochemistry, and compartmentalization may influence GAG synthesis. Full article
(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)
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Open AccessReview Functional Role of NBS1 in Radiation Damage Response and Translesion DNA Synthesis
Biomolecules 2015, 5(3), 1990-2002; https://doi.org/10.3390/biom5031990
Received: 30 June 2015 / Revised: 11 August 2015 / Accepted: 13 August 2015 / Published: 20 August 2015
Cited by 6 | PDF Full-text (630 KB) | HTML Full-text | XML Full-text
Abstract
Nijmegen breakage syndrome (NBS) is a recessive genetic disorder characterized by increased sensitivity to ionizing radiation (IR) and a high frequency of malignancies. NBS1, a product of the mutated gene in NBS, contains several protein interaction domains in the N-terminus and C-terminus. The
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Nijmegen breakage syndrome (NBS) is a recessive genetic disorder characterized by increased sensitivity to ionizing radiation (IR) and a high frequency of malignancies. NBS1, a product of the mutated gene in NBS, contains several protein interaction domains in the N-terminus and C-terminus. The C-terminus of NBS1 is essential for interactions with MRE11, a homologous recombination repair nuclease, and ATM, a key player in signal transduction after the generation of DNA double-strand breaks (DSBs), which is induced by IR. Moreover, NBS1 regulates chromatin remodeling during DSB repair by histone H2B ubiquitination through binding to RNF20 at the C-terminus. Thus, NBS1 is considered as the first protein to be recruited to DSB sites, wherein it acts as a sensor or mediator of DSB damage responses. In addition to DSB response, we showed that NBS1 initiates Polη-dependent translesion DNA synthesis by recruiting RAD18 through its binding at the NBS1 C-terminus after UV exposure, and it also functions after the generation of interstrand crosslink DNA damage. Thus, NBS1 has multifunctional roles in response to DNA damage from a variety of genotoxic agents, including IR. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessArticle Optimized Production of Xylitol from Xylose Using a Hyper-Acidophilic Candida tropicalis
Biomolecules 2015, 5(3), 1979-1989; https://doi.org/10.3390/biom5031979
Received: 6 May 2015 / Revised: 31 July 2015 / Accepted: 3 August 2015 / Published: 19 August 2015
Cited by 4 | PDF Full-text (644 KB) | HTML Full-text | XML Full-text
Abstract
The yeast Candida tropicalis DSM 7524 produces xylitol, a natural, low-calorie sweetener, by fermentation of xylose. In order to increase xylitol production rate during the submerged fermentation process, some parameters-substrate (xylose) concentration, pH, aeration rate, temperature and fermentation strategy-have been optimized. The maximum
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The yeast Candida tropicalis DSM 7524 produces xylitol, a natural, low-calorie sweetener, by fermentation of xylose. In order to increase xylitol production rate during the submerged fermentation process, some parameters-substrate (xylose) concentration, pH, aeration rate, temperature and fermentation strategy-have been optimized. The maximum xylitol yield reached at 60–80 g/L initial xylose concentration, pH 5.5 at 37 °C was 83.66% (w/w) on consumed xylose in microaerophilic conditions (kLa = 2·h−1). Scaling up on 3 L fermenter, with a fed-batch strategy, the best xylitol yield was 86.84% (w/w), against a 90% of theoretical yield. The hyper-acidophilic behaviour of C. tropicalis makes this strain particularly promising for industrial application, due to the possibility to work in non-sterile conditions. Full article
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Open AccessReview Comparative Geometrical Analysis of Leucine-Rich Repeat Structures in the Nod-Like and Toll-Like Receptors in Vertebrate Innate Immunity
Biomolecules 2015, 5(3), 1955-1978; https://doi.org/10.3390/biom5031955
Received: 21 July 2015 / Revised: 10 August 2015 / Accepted: 11 August 2015 / Published: 18 August 2015
Cited by 3 | PDF Full-text (4869 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The NOD-like receptors (NLRs) and Toll-like receptors (TLRs) are pattern recognition receptors that are involved in the innate, pathogen pattern recognition system. The TLR and NLR receptors contain leucine-rich repeats (LRRs) that are responsible for ligand interactions. In LRRs short β-strands stack parallel
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The NOD-like receptors (NLRs) and Toll-like receptors (TLRs) are pattern recognition receptors that are involved in the innate, pathogen pattern recognition system. The TLR and NLR receptors contain leucine-rich repeats (LRRs) that are responsible for ligand interactions. In LRRs short β-strands stack parallel and then the LRRs form a super helical arrangement of repeating structural units (called a coil of solenoids). The structures of the LRR domains of NLRC4, NLRP1, and NLRX1 in NLRs and of TLR1-5, TLR6, TLR8, TLR9 in TLRs have been determined. Here we report nine geometrical parameters that characterize the LRR domains; these include four helical parameters from HELFIT analysis. These nine parameters characterize well the LRR structures in NLRs and TLRs; the LRRs of NLR adopts a right-handed helix. In contrast, the TLR LRRs adopt either a left-handed helix or are nearly flat; RP105 and CD14 also adopt a left-handed helix. This geometrical analysis subdivides TLRs into four groups consisting of TLR3/TLR8/TLR9, TLR1/TLR2/TRR6, TLR4, and TLR5; these correspond to the phylogenetic tree based on amino acid sequences. In the TLRs an ascending lateral surface that consists of loops connecting the β-strand at the C-terminal side is involved in protein, protein/ligand interactions, but not the descending lateral surface on the opposite side. Full article
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Open AccessReview Macrophage Expression of Inflammatory Genes in Response to EMCV Infection
Biomolecules 2015, 5(3), 1938-1954; https://doi.org/10.3390/biom5031938
Received: 16 June 2015 / Revised: 6 August 2015 / Accepted: 8 August 2015 / Published: 18 August 2015
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Abstract
The expression and production of type 1 interferon is the classic cellular response to virus infection. In addition to this antiviral response, virus infection also stimulates the production of proinflammatory mediators. In this review, the pathways controlling the induction of inflammatory genes and
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The expression and production of type 1 interferon is the classic cellular response to virus infection. In addition to this antiviral response, virus infection also stimulates the production of proinflammatory mediators. In this review, the pathways controlling the induction of inflammatory genes and the roles that these inflammatory mediators contribute to host defense against viral pathogens will be discussed. Specific focus will be on the role of the chemokine receptor CCR5, as a signaling receptor controlling the activation of pathways leading to virus-induced inflammatory gene expression. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Pro-Inflammatory Genes)
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Open AccessReview Targeting the Checkpoint to Kill Cancer Cells
Biomolecules 2015, 5(3), 1912-1937; https://doi.org/10.3390/biom5031912
Received: 2 July 2015 / Revised: 7 August 2015 / Accepted: 11 August 2015 / Published: 18 August 2015
Cited by 42 | PDF Full-text (1370 KB) | HTML Full-text | XML Full-text
Abstract
Cancer treatments such as radiotherapy and most of the chemotherapies act by damaging DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Inhibiting the checkpoint allows entry to mitosis despite the
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Cancer treatments such as radiotherapy and most of the chemotherapies act by damaging DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Inhibiting the checkpoint allows entry to mitosis despite the presence of DNA damage and can lead to cell death. Importantly, as cancer cells exhibit increased levels of endogenous DNA damage due to an excessive replication stress, inhibiting the checkpoint kinases alone could act as a directed anti-cancer therapy. Here, we review the current status of inhibitors targeted towards the checkpoint effectors and discuss mechanisms of their actions in killing of cancer cells. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Oxidative Stress and Maxi Calcium-Activated Potassium (BK) Channels
Biomolecules 2015, 5(3), 1870-1911; https://doi.org/10.3390/biom5031870
Received: 8 May 2015 / Revised: 17 July 2015 / Accepted: 20 July 2015 / Published: 17 August 2015
Cited by 13 | PDF Full-text (939 KB) | HTML Full-text | XML Full-text
Abstract
All cells contain ion channels in their outer (plasma) and inner (organelle) membranes. Ion channels, similar to other proteins, are targets of oxidative impact, which modulates ion fluxes across membranes. Subsequently, these ion currents affect electrical excitability, such as action potential discharge (in
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All cells contain ion channels in their outer (plasma) and inner (organelle) membranes. Ion channels, similar to other proteins, are targets of oxidative impact, which modulates ion fluxes across membranes. Subsequently, these ion currents affect electrical excitability, such as action potential discharge (in neurons, muscle, and receptor cells), alteration of the membrane resting potential, synaptic transmission, hormone secretion, muscle contraction or coordination of the cell cycle. In this chapter we summarize effects of oxidative stress and redox mechanisms on some ion channels, in particular on maxi calcium-activated potassium (BK) channels which play an outstanding role in a plethora of physiological and pathophysiological functions in almost all cells and tissues. We first elaborate on some general features of ion channel structure and function and then summarize effects of oxidative alterations of ion channels and their functional consequences. Full article
(This article belongs to the Special Issue Oxidative Stress and Oxygen Radicals) Printed Edition available
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Open AccessReview Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms
Biomolecules 2015, 5(3), 1855-1869; https://doi.org/10.3390/biom5031855
Received: 16 July 2015 / Revised: 6 August 2015 / Accepted: 7 August 2015 / Published: 13 August 2015
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Abstract
DNA damage causally contributes to aging and cancer. Congenital defects in nucleotide excision repair (NER) lead to distinct cancer-prone and premature aging syndromes. The genetics of NER mutations have provided important insights into the distinct consequences of genome instability. Recent work in mice
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DNA damage causally contributes to aging and cancer. Congenital defects in nucleotide excision repair (NER) lead to distinct cancer-prone and premature aging syndromes. The genetics of NER mutations have provided important insights into the distinct consequences of genome instability. Recent work in mice and C. elegans has shed new light on the mechanisms through which developing and aging animals respond to persistent DNA damage. The various NER mouse mutants have served as important disease models for Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD), while the traceable genetics of C. elegans have allowed the mechanistic delineation of the distinct outcomes of genome instability in metazoan development and aging. Intriguingly, highly conserved longevity assurance mechanisms respond to transcription-blocking DNA lesions in mammals as well as in worms and counteract the detrimental consequences of persistent DNA damage. The insulin-like growth factor signaling (IIS) effector transcription factor DAF-16 could indeed overcome DNA damage-driven developmental growth delay and functional deterioration even when DNA damage persists. Longevity assurance mechanisms might thus delay DNA damage-driven aging by raising the threshold when accumulating DNA damage becomes detrimental for physiological tissue functioning. Full article
(This article belongs to the Special Issue DNA Damage Response)
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