Special Issue "Oxidative Stress and Ageing"
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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular Biology and Biophysics".
Deadline for manuscript submissions: closed (20 May 2013)
Special Issue Editor
Guest Editor
Dr. Gregor Drummen
Guest Editor for MDPI, Switzerland
E-Mail: drummen@mdpi.com
Phone: +49 211 40 51 810
Fax: +49 211 47 45 476
Interests: quantum dots; bionanotechnology; two-photon fluorescence imaging; cellular imaging; fluorescence microscopy; nucleic acids; DNA damage; cancer; cell signaling; radiation biology; oxidative stress; lipids and biomembranes; lipid peroxidation
Special Issue Information
Dear Colleagues,
Molecular oxygen is one of those fundamental and essential elements to ensure life and survival of most organisms on the third rock from the sun. Through this molecule, efficient formation of the energy molecule and genetic building block ATP is possible and thus allows the organism to perform work (the thermodynamical definition thereof). However, it is the same molecular oxygen that threatens aerobic life on this planet, because of its potential for radical formation (it is a biradical, although Pauli restricted). From molecular oxygen derived species, Reactive Oxygen Species (ROS), have long been implicated in a multitude of diseases, but not until the discovery that nitric oxide is an essential signaling molecule has the view of the all destructive ROS changed to include normal biological function. To prevent lasting damage, nature ensures that next to antioxidant enzymes that dismutate reactive species, transition metal ion binding molecules that prevent Fenton reactions, food antioxidants that scavenge reactive species and chain-break radical propagation reactions, and a myriad of repair mechanisms that simply repair the damage done by ROS are in place. This balancing biology was what made aerobic life possible in the first place. However, it is also recognized that once the balance between ROS and anti-ROS/repair is disturbed, pathological conditions, such as cancers, inflammation and other diseases occur. Although not a disease in the classical sense, ROS also play an important role in normal ageing processes.
Since developments in this field are so fast, this special issue calls for contributions, original research, mini and full reviews, commentaries, educational papers, and perspectives that address the progress and current standing in this vast field of biology. These include, but are not limited to
- oxidative stress and diseases
- oxidative stress and aging
- biomarkers and diagnostic methods
- antioxidants
- oxidative biomarkers
- advances in genetics and molecular mechanisms
- methodology and analysis
- pharmacological or dietetic interventions
- oxidative damage, formation, repair and biological consequences
- current strategies to reduce the development of the oxidative stress in neurodegeneration and ageing
Papers relevant to redox signaling, please submit to the separate issue on Redox Signaling in Biology and Patho-Biology in IJMS
Dr. Gregor Drummen
Guest Editor
Submission
Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.
Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs).
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Published Papers (15 papers)
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Received: 11 February 2012; in revised form: 3 May 2012 / Accepted: 10 May 2012 / Published: 16 May 2012
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Abstract: p16Ink4a is a tumor suppressor and a marker for cellular senescence. Previous studies have shown that p16Ink4a plays an important role in the response to DNA damage signals caused by telomere dysfunction. In this study, we crossed Wrn−/− and p16Ink4a−/− mice to knock out the p16Ink4a function in a Wrn null background. Growth curves showed that loss of p16Ink4a could rescue the growth barriers that are observed in Wrn−/− mouse embryonic fibroblasts (MEFs). By challenging the MEFs with the global genotoxin doxorubicin, we showed that loss of p16Ink4a did not dramatically affect the global DNA damage response of Wrn−/− MEFs induced by doxorubicin. However, in response to telomere dysfunction initiated by the telomere damaging protein TRF2∆B∆M, loss of p16Ink4a could partially overcome the DNA damage response by disabling p16Ink4a up-regulation and reducing the accumulation of γ-H2AX that is observed in Wrn−/− MEFs. Furthermore, in response to TRF2∆B∆M overexpression, Wrn−/− MEFs senesced within several passages. In contrast, p16Ink4a−/− and p16Ink4a−/−Wrn−/− MEFs could continuously grow and lose expression of the exogenous TRF2∆B∆M in their late passages. In summary, our data suggest that in the context of telomere dysfunction, loss of p16Ink4a function could prevent cells from senescence. These results shed light on the anti-aging strategy through regulation of p16Ink4a expression.
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Received: 5 April 2012; in revised form: 21 May 2012 / Accepted: 22 May 2012 / Published: 29 May 2012
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Abstract: Cadmium (Cd) in soil poses a major threat to plant growth and productivity. In the present experiment, we studied the effect of calcium (Ca2+) and/or potassium (K+) on the antioxidant system, accumulation of proline (Pro), malondialdehyde (MDA), and content of photosynthetic pigments, cadmium (Cd) and nutrients, i.e., Ca2+ and K+ in leaf of Vicia faba L. (cv. TARA) under Cd stress. Plants grown in the presence of Cd exhibited reduced growth traits [root length (RL) plant−1, shoot length (SL) plant−1, root fresh weight (RFW) plant−1, shoot fresh weight (SFW) plant−1, root dry weight (RDW) plant−1 and shoot dry weight (SDW) plant−1] and concentration of Ca2+, K+, Chlorophyll (Chl) a and Chl b content, except content of MDA, Cd and (Pro). The antioxidant enzymes [peroxidase (POD) and superoxide dismutase (SOD)] slightly increased as compared to control under Cd stress. However, a significant improvement was observed in all growth traits and content of Ca2+, K+, Chl a, Chl b ,Pro and activity of antioxidant enzymes catalase (CAT), POD and SOD in plants subjected to Ca2+ and/or K+. The maximum alleviating effect was recorded in the plants grown in medium containing Ca2+ and K+ together. This study indicates that the application of Ca2+ and/or K+ had a significant and synergistic effect on plant growth. Also, application of Ca2+ and/or K+ was highly effective against the toxicity of Cd by improving activity of antioxidant enzymes and solute that led to the enhanced plant growth of faba bean plants.
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Received: 8 October 2012; in revised form: 19 October 2012 / Accepted: 19 October 2012 / Published: 26 October 2012
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Abstract: Oxidative stress impacts multiple systems of the body and can lead to some of the most devastating consequences in the nervous system especially during aging. Both acute and chronic neurodegenerative disorders such as diabetes mellitus, cerebral ischemia, trauma, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and tuberous sclerosis through programmed cell death pathways of apoptosis and autophagy can be the result of oxidant stress. Novel therapeutic avenues that focus upon the phosphoinositide 3-kinase (PI 3-K), Akt (protein kinase B), and the mammalian target of rapamycin (mTOR) cascade and related pathways offer exciting prospects to address the onset and potential reversal of neurodegenerative disorders. Effective clinical translation of these pathways into robust therapeutic strategies requires intimate knowledge of the complexity of these pathways and the ability of this cascade to influence biological outcome that can vary among disorders of the nervous system.
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Received: 11 September 2012; in revised form: 8 November 2012 / Accepted: 9 November 2012 / Published: 19 November 2012
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Abstract: Hepatitis C virus (HCV) easily establishes chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). During the progression of HCV infections, reactive oxygen species (ROS) are generated, and these ROS then induce significant DNA damage. The role of ROS in the pathogenesis of HCV infection is still not fully understood. Recently, we found that HCV induced the expression of 3β-hydroxysterol ∆24-reductase (DHCR24). We also found that a HCV responsive region is present in the 5'-flanking genomic promoter region of DHCR24 and the HCV responsive region was characterized as (−167/−140). Moreover, the transcription factor Sp1 was found to bind to this region in response to oxidative stress under the regulation of ataxia telangiectasia mutated (ATM) kinase. Overexpression of DHCR24 impaired p53 activity by suppression of acetylation and increased interaction with MDM2. This impairment of p53 suppressed the hydrogen peroxide-induced apoptotic response in hepatocytes. Thus, a target of oxidative stress in HCV infection is DHCR24 through Sp1, which suppresses apoptotic responses and increases tumorigenicity.
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Received: 9 November 2012; in revised form: 19 November 2012 / Accepted: 20 November 2012 / Published: 22 November 2012
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Abstract: Aging increases free radical generation and lipid oxidation and, thereby, mediates neurodegenerative diseases. As the brain is rich in lipids (polyunsaturated fatty acids), the antioxidative system plays an important role in protecting brain tissues from oxidative injury. The changes in microtubule formation and antioxidative enzyme activities have been investigated in rat pheochromocytoma PC12 cells exposed to various concentrations of phosphatidylcholine hydroperoxides (PCOOH). We measured three typical antioxidative enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). The microtubule assembly system was dependent on the antioxidative enzyme system in cells exposed to oxidative stress. The activities of the three enzymes increased in a PCOOH exposure-dependent manner. In particular, the changes in the activity as a result of PCOOH exposure were similar in the three antioxidative enzymes. This is the first report indicating the compatibility between the tubulin-microtubule and antioxidative enzyme systems in cells that deteriorate as a result of phospholipid hydroperoxide administration from an exterior source. The descending order of sensitivity of the three enzymes to PCOOH is also discussed.
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Received: 20 September 2012; in revised form: 31 October 2012 / Accepted: 19 November 2012 / Published: 30 November 2012
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Abstract: The Zucker diabetic fatty (ZDF) rat is a genetic model in which the homozygous (FA/FA) male animals develop obesity and type 2 diabetes. Morbidity and mortality from cardiovascular complications, due to increased oxidative stress and inflammatory signals, are the hallmarks of type 2 diabetes. The precise molecular mechanism of contractile dysfunction and disease progression remains to be clarified. Therefore, we have investigated molecular and metabolic targets in male ZDF (30–34 weeks old) rat heart compared to age matched Zucker lean (ZL) controls. Hyperglycemia was confirmed by a 4-fold elevation in non-fasting blood glucose (478.43 ± 29.22 mg/dL in ZDF vs. 108.22 ± 2.52 mg/dL in ZL rats). An increase in reactive oxygen species production, lipid peroxidation and oxidative protein carbonylation was observed in ZDF rats. A significant increase in CYP4502E1 activity accompanied by increased protein expression was also observed in diabetic rat heart. Increased expression of other oxidative stress marker proteins, HO-1 and iNOS was also observed. GSH concentration and activities of GSH-dependent enzymes, glutathione S-transferase and GSH reductase, were, however, significantly increased in ZDF heart tissue suggesting a compensatory defense mechanism. The activities of mitochondrial respiratory enzymes, Complex I and Complex IV were significantly reduced in the heart ventricle of ZDF rats in comparison to ZL rats. Western blot analysis has also suggested a decreased expression of IκB-α and phosphorylated-JNK in diabetic heart tissue. Our results have suggested that mitochondrial dysfunction and increased oxidative stress in ZDF rats might be associated, at least in part, with altered NF-κB/JNK dependent redox cell signaling. These results might have implications in the elucidation of the mechanism of disease progression and designing strategies for diabetes prevention.
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Received: 13 December 2012; in revised form: 5 January 2013 / Accepted: 16 January 2013 / Published: 31 January 2013
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Abstract: Circadian rhythms are found in almost all organisms from cyanobacteria to humans, where most behavioral and physiological processes occur over a period of approximately 24 h in tandem with the day/night cycles. In general, these rhythmic processes are under regulation of circadian clocks. The role of circadian clocks in regulating metabolism and consequently cellular and metabolic homeostasis is an intensively investigated area of research. However, the links between circadian clocks and aging are correlative and only recently being investigated. A physiological decline in most processes is associated with advancing age, and occurs at the onset of maturity and in some instances is the result of accumulation of cellular damage beyond a critical level. A fully functional circadian clock would be vital to timing events in general metabolism, thus contributing to metabolic health and to ensure an increased “health-span” during the process of aging. Here, we present recent evidence of links between clocks, cellular metabolism, aging and oxidative stress (one of the causative factors of aging). In the light of these data, we arrive at conceptual generalizations of this relationship across the spectrum of model organisms from fruit flies to mammals.
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Received: 26 November 2012; in revised form: 10 January 2013 / Accepted: 29 January 2013 / Published: 5 February 2013
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Abstract: Recent evidence from apolipoprotein E-deficient (apoE−/−) mice shows that aging and atherosclerosis are closely associated with increased oxidative stress and DNA damage in some cells and tissues. However, bone marrow cells, which are physiologically involved in tissue repair have not yet been investigated. In the present study, we evaluated the influence of aging and hypercholesterolemia on oxidative stress, DNA damage and apoptosis in bone marrow cells from young and aged apoE−/− mice compared with age-matched wild-type C57BL/6 (C57) mice, using the comet assay and flow cytometry. The production of both superoxide and hydrogen peroxide in bone marrow cells was higher in young apoE−/− mice than in age-matched C57 mice, and reactive oxygen species were increased in aged C57 and apoE−/− mice. Similar results were observed when we analyzed the DNA damage and apoptosis. Our data showed that both aging and hypercholesterolemia induce the increased production of oxidative stress and consequently DNA damage and apoptosis in bone marrow cells. This study is the first to demonstrate a functionality decrease of the bone marrow, which is a fundamental extra-arterial source of the cells involved in vascular injury repair.
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Received: 31 December 2012; in revised form: 21 January 2013 / Accepted: 22 January 2013 / Published: 25 February 2013
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Abstract: Selenoprotein M (SelM), one of the executants of selenium in vivo, is highly expressed in human brain and most probably involved in antioxidation, neuroprotection, and intracellular calcium regulation, which are the key factors for preventing the onset and progression of Alzheimer’s disease (AD). In this paper, human SelM was successfully overexpressed in human embryonic kidney cells HEK293T. Sodium selenite (Na2SeO3 0.5 μmol/L) increased the expression of full-length SelM and inhibited the expression of truncated SelM. The full-length SelM exhibited higher antioxidant activity than its selenocysteine-to-cysteine mutation form SelM', whereas the truncated SelM had an adverse effect that increased the oxidative stress level of cells. When β-amyloid (Aβ42, an AD relevant peptide) was cotransfected with the empty expression vector, SelM, or SelM' under the induction of 0.5 μmol/L Na2SeO3, the intracellular Aβ42 aggregation rates were detected to be 57.9% ± 5.5%, or 22.3% ± 2.6%, or 26.3% ± 2.1%, respectively, showing the inhibitory effects on Aβ aggregation by the full-length SelM and SelM'. Meanwhile, the intumescentia of mitochondria caused by Aβ42 transfection was significantly mitigated by the cotransfection of SelM or SelM′ with Aβ42 under the induction of 0.5 μmol/L Na2SeO3. On the contrary, cotransfection of SelM and Aβ42 without the induction of Na2SeO3 increased Aβ42 aggregation rate to 65.1% ± 3.2%, and it could not inhibit the Aβ-induced intumescent mitochondria. In conclusion, full-length SelM and SelM¢ might prevent Aβ aggregation by resisting oxidative stress generated during the formation of Aβ oligomers in cells.
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Received: 14 January 2013; in revised form: 16 February 2013 / Accepted: 18 February 2013 / Published: 25 February 2013
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Abstract: Nolinospiroside F is a steroidal saponin isolated from Ophiopogon japonicus (O. japonicus). In this study, we found that nolinospiroside F significantly extends the replicative lifespan of K6001 yeast at doses of 1, 3 and 10 μM, indicating that it has an anti-aging effect. This may be attributed to its anti-oxidative effect, as nolinospiroside F could increase yeast survival under oxidative stress conditions and decrease the level of malondialdehyde (MDA), an oxidative stress biomarker. It could also increase anti-oxidative stress genes, SOD1 and SOD2, expression, and the activity of superoxide dismutase (SOD). It increase the activity of SIRT1, an upstream inducer of SOD2 expression. In sod1 and sod2 mutant yeast strains, nolinospiroside F failed to extend their replicative lifespan. These results indicate that SOD participates in the anti-aging effect of nolinospiroside F. Furthermore, nolinospiroside F inhibited the expression of UTH1, a yeast-aging gene that is involved in the oxidative stress of yeast, and failed to extend the replicative lifespan of uth1 or skn7 mutant yeast cells. SKN7 is the transcriptional activator of UTH1. We also demonstrate that SOD and UTH1 regulate each other’s expression. Together, these results suggest that SOD and UTH1 genes are required for and play interactive roles in nolinospiroside F-mediated yeast lifespan extension.
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Received: 10 January 2013; in revised form: 5 February 2013 / Accepted: 6 March 2013 / Published: 18 March 2013
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Abstract: Isoprostanes are stable products of arachidonic acid peroxidation and are regarded as the most reliable markers of oxidative stress in vivo. Here we describe the LC-MS/MS procedure enabling simultaneous determination of four regioisomers (8-iso prostaglandin F2α, 8-iso-15(R)-prostaglandin F2α, 11β-prostaglandin F2α, 15(R)-prostaglandin F2α) in plasma samples collected from mice. The four plasma isoprostanes are determined by LC–ESI-MS/MS with deuterated 8-iso-PGF2α-d4 as an internal standard (I.S.). For plasma samples spiked with the isoprostanes at a level of 200 pg/mL each, the method imprecision has been below 7.1% and mean inaccuracy equaled 8.7%. The applicability of the proposed approach has been verified by the assessment of changes in isoprostane levels in plasma samples derived from mice exposed to tert-butyl hydroperoxide (TBHP), a model inducer of oxidative stress, or to antitumor drug doxorubicin (DOX) known for potent stimulation of redox cycling. Compared to the control group of mice, both oxidative stress inducers tested increased the levels of three out of four isoprostanes in exposed animals; 11β-prostaglandin F2α being the exception. The greatest rise was observed in the case of 15(R)-prostaglandin F2α, by about 50% and 70% in plasma samples derived from mice exposed to DOX and TBHP, respectively.
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Wei Xu, Hui Li, Rong Wang, Zhen Lei, Yiqing Mao, Xi Wang, Yizhuang Zhang, Tingting Guo, Rongjing Song, Xiaojing Zhang, Ling Jin, Zhixin Li, David M. Irwin, Gang Niu and Huanran Tan
Received: 30 January 2013; in revised form: 18 March 2013 / Accepted: 19 March 2013 / Published: 21 March 2013
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Abstract: Liver glucokinase (GCK) deficient mice possess mild renal complications associated with diabetes. To investigate the progression of kidney disease and identify candidate genes involved in the pathogenesis of renal damage, we examined changes in tissue structure and gene expression in the kidneys of liver-specific GCK knockout (gckw/−) mice and age-matched normal wild-type control (gckw/w) mice as they aged. Suppression subtractive hybridization (SSH) was used to identify candidate genes that showed a pattern of differential expression between kidneys of gckw/− and gckw/w mice at 60 weeks of age. Differential expression of the candidate genes was examined by real-time qPCR in liver-specific gckw/− and gckw/w mice at 16, 26, 40, 60, and 85 weeks of age. Among the candidate genes, only glutathione peroxidase-3 (GPX3) was confirmed to show differential expression by qPCR in the 60-week old mice, however two others genes, MALAT1 and KEG, showed significant changes at other ages. This study shows that liver-specific glucokinase deficient mice display changes in kidney morphology by 40 weeks of age, and that renal complication may be correlated with a reduction in GPX3 levels. Since decreased GPX3 mRNA expression was observed at 26 weeks, which is younger than the age when pathological changes can be seen in kidney biopsies, GPX3 may serve as an early marker for kidney damage.
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Received: 20 February 2013; in revised form: 8 March 2013 / Accepted: 21 March 2013 / Published: 3 April 2013
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Abstract: This study aims to investigate potential diabetic retinopathy (DR) risk factors by evaluating the circulating levels of pentosidine, soluble receptor for advanced glycation end-product (sRAGE), advanced oxidation protein product (AOPP) as well as glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities in DR patients. A total of 235 healthy controls, 171 type 2 diabetic without retinopathy (DNR) and 200 diabetic retinopathy (DR) patients were recruited. Plasma was extracted for the estimation of pentosidine, sRAGE, AOPP levels and GPx activity whereas peripheral blood mononuclear cells were disrupted for SOD activity measurement. DNR and DR patients showed significantly higher levels of plasma pentosidine, sRAGE and AOPP but lower GPx and SOD activities when compared to healthy controls. The sRAGE/pentosidine ratio in DR patients was significantly lower than the ratio detected in DNR patients. Proliferative DR patients had significantly higher levels of plasma pentosidine, sRAGE, AOPP and sRAGE/pentosidine ratio than non-proliferative DR patients. High HbA1c level, long duration of diabetes and low sRAGE/pentosidine ratio were determined as the risk factors for DR. This study suggests that sRAGE/pentosidine ratio could serve as a risk factor determinant for type 2 DR as it has a positive correlation with the severity of DR.
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Received: 5 March 2013; in revised form: 28 March 2013 / Accepted: 2 April 2013 / Published: 24 April 2013
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Abstract: Aging is a condition which favors the development of atherosclerosis, which has been associated with a breakdown in repair processes that occurs in response to cell damage. The dysregulation of the biological systems associated with aging are produced partly through damage which accumulates over time. One major source of this injury is oxidative stress, which can impair biological structures and the mechanisms by which they are repaired. These mechanisms are based on the pathogenesis of endothelial dysfunction, which in turn is associated with cardiovascular disease, carcinogenesis and aging. The dependent dysfunction of aging has been correlated with a reduction in the number and/or functional activity of endothelial progenitor cells, which could hinder the repair and regeneration of the endothelium. In addition, aging, inflammation and oxidative stress are endogenous factors that cause telomere shortening, which is dependent on oxidative cell damage. Moreover, telomere length correlates with lifestyle and the consumption of a healthy diet. Thus, diseases associated with aging and age may be caused by the long-term effects of oxidative damage, which are modified by genetic and environmental factors. Considering that diet is a very important source of antioxidants, in this review we will analyze the relationship between oxidative stress, aging, and the mechanisms which may be involved in a higher survival rate and a lower incidence of the diseases associated with aging in populations which follow a healthy diet.
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Received: 24 January 2013; in revised form: 18 March 2013 / Accepted: 16 April 2013 / Published: 29 April 2013
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Abstract: Oxidative stress has been implicated as an important contributing factor in the pathogenesis of several pulmonary inflammatory diseases. Previous studies have indicated a relationship between oxidative stress and the attenuation of epithelial tight junctions (TJs). In Human Bronchial Epithelial-16 cells (16HBE), we demonstrated the degradation of zonula occludens-1 (ZO-1), and claudin-2 exhibited a great dependence on the activation of the transient receptor potential melastatin (TRPM) 2 channel, phospholipase Cγ1 (PLCγ1) and the protein kinase Cα (PKCα) signaling cascade.
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Planned Papers
The below list represents only planned manuscripts. Some of these
manuscripts have not been received by the Editorial Office yet. Papers
submitted to MDPI journals are subject to peer-review.
Type of Paper: Review
Title: Molecular Mechanism for Pancreatic beta-Cell Glucose Toxicity
Author: Hideaki Kaneto; E-Mail: kaneto@endmet.med.osaka-u.ac.jp
Abstract: Type 2 diabetes is characterized by pancreatic beta-cell dysfunction and insulin resistance, and the number of the patients has markedly increased worldwide. In the diabetic state, hyperglycemia per se and subsequent induction of oxidative stress decrease insulin biosynthesis and secretion, leading to the aggravation of type 2 diabetes. In addition, there is substantial reduction in expression and/or activities of several insulin gene transcription factors. This process is known as beta-cell glucose toxicity which is often observed under diabetic conditions. Taken together, it is likely that oxidative stress explains, at least in part, the molecular mechanism for beta-cell glucose toxicity found in type 2 diabetes.
Title: Oxidative Stress Induced Pathogenesis by Hepatitis C Virus
Author: Kyoko Tsukiyama-Kohara
Affiliation: Department of Animal Hygiene, Transboundary Animal Diseases Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan; E-Mail: kkohara@agri.kagoshima-u.ac.jp
Abstract: Hepatitis C virus (HCV) easily establishes chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCV). For the progression of diseases, inflammation reaction in chronic hepatitis should be significant and generating reactive oxygen species (ROS). ROS implicates in a multitude of diseases including generation of DNA damage in genome, however its detailed role in the pathogenesis of HCV has not been fully understood. Recently, we have found that HCV induced the expression of 3b-hydroxysterol D24-reductase (DHCR24). The 5’-flanking genomic promoter region of DHCR24 was characterized and HCV responsive region was defined (-167/-140). We identified that Sp1 binds to this region in response to oxidative stress under the regulation of ATM kinase. Moreover, overexpression of DHCR24 impaired p53 activity by suppression of acetylation and increment of interaction with MDM2. This impairment of p53 suppressed hydrogen peroxide induced apoptotic response in hepatocytes. Thus, one of the target of oxidative stress in HCV infection is DHCR24 through Sp1 to suppress apoptotic response and increase tumorigenicity.
Title: Crosstalk between oxidative stress and SIRT1 activity: impact on the aging process
Authors: Antero Salminen*, Kai Kaarniranta and Anu Kauppinen
Affiliation: Res. Dir., Univ. Eastern Finland; E- Mail : antero.salminen@uef.fi
Abstract : Increased oxidative stress has been associated with the aging process. However, recent studies have revealed that a low-level oxidative stress can even extend the lifespan of organisms. Reactive oxygen species (ROS) are important signaling molecules and required e.g. for autophagy. SIRT1, a class III protein deacetylase, is a crucial cellular defence protein against oxidative stress insults. SIRT1 can stimulate the expression of antioxidants via FoxO3 pathway. Moreover, SIRT1 inhibits NF-κB signaling which is a major inducer of inflammatory responses. It is known that NF-κB signaling is activated in tissues with aging along with the appearance of a low-level inflammation. Recent studies have demonstrated that increased level of ROS can directly and indirectly inhibit SIRT1 activity. For instance, ROS can inhibit SIRT1 activity by nitration of tyrosine residues and carbonylation of cysteine residues. Moreover, SIRT1 activity is controlled by intracellular thiols since they affect the expression level and activity of SIRT1. Decreased activity of SIRT1 enhances the NF-κB signaling and triggers inflammatory responses with aging. We will review the factors affecting the signaling balance between oxidative stress and SIRT1 activity in respect to the control of the aging process.
Fig. 1. A schematic figure depicting the balance between ROS level and SIRT1 activity in the regulation of the aging process.
Last update: 27 November 2012
