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Open AccessArticle

Oxidative Stress/Angiotensinogen/Renin-Angiotensin System Axis in Patients with Diabetic Nephropathy

by Masumi Kamiyama, Maki Urushihara, Takashi Morikawa, Yoshio Konishi, Masahito Imanishi, Akira Nishiyama and Hiroyuki Kobori

Int. J. Mol. Sci. 2013, 14(11), 23045-23062; https://doi.org/10.3390/ijms141123045 - 21 Nov 2013

Cited by 59 | Viewed by 7721

Abstract

Although recent studies have proven that renin-angiotensin system (RAS) blockades retard the progression of diabetic nephropathy, the detailed mechanisms of their reno-protective effects on the development of diabetic nephropathy remain uncertain. In rodent models, it has been reported that reactive oxygen species (ROS) [...] Read more.

Although recent studies have proven that renin-angiotensin system (RAS) blockades retard the progression of diabetic nephropathy, the detailed mechanisms of their reno-protective effects on the development of diabetic nephropathy remain uncertain. In rodent models, it has been reported that reactive oxygen species (ROS) are important for intrarenal angiotensinogen (AGT) augmentation in the progression of diabetic nephropathy. However, no direct evidence is available to demonstrate that AGT expression is enhanced in the kidneys of patients with diabetes. To examine whether the expression levels of ROS- and RAS-related factors in kidneys are increased with the progression of diabetic nephropathy, biopsied samples from 8 controls and 27 patients with type 2 diabetes were used. After the biopsy, these patients were diagnosed with minor glomerular abnormality or diabetes mellitus by clinical and pathological findings. The intensities of AGT, angiotensin II (Ang II), 4-hydroxy-2-nonenal (4-HNE), and heme oxygenase-1 (HO-1) were examined by fluorescence in situ hybridization and/or immunohistochemistry. Expression levels were greater in patients with diabetes than in control subjects. Moreover, the augmented intrarenal AGT mRNA expression paralleled renal dysfunction in patients with diabetes. These data suggest the importance of the activated oxidative stress/AGT/RAS axis in the pathogenesis of diabetic nephropathy. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Inhibition of Oxidative Stress by Low-Molecular-Weight Polysaccharides with Various Functional Groups in Skin Fibroblasts

by Szu-Kai Chen, Chu-Hsi Hsu, Min-Lang Tsai, Rong-Huei Chen and Gregor P. C. Drummen

Int. J. Mol. Sci. 2013, 14(10), 19399-19415; https://doi.org/10.3390/ijms141019399 - 25 Sep 2013

Cited by 36 | Viewed by 8040

Abstract

The aim of this study was to evaluate the in cellulo inhibition of hydrogen-peroxide-induced oxidative stress in skin fibroblasts using different low-molecular-weight polysaccharides (LMPS) prepared from agar (LMAG), chitosan (LMCH) and starch (LMST), which contain various different functional groups (i.e., sulfate, [...] Read more.

The aim of this study was to evaluate the in cellulo inhibition of hydrogen-peroxide-induced oxidative stress in skin fibroblasts using different low-molecular-weight polysaccharides (LMPS) prepared from agar (LMAG), chitosan (LMCH) and starch (LMST), which contain various different functional groups (i.e., sulfate, amine, and hydroxyl groups). The following parameters were evaluated: cell viability, intracellular oxidant production, lipid peroxidation, and DNA damage. Trolox was used as a positive control in order to allow comparison of the antioxidant efficacies of the various LMPS. The experimentally determined attenuation of oxidative stress by LMPS in skin fibroblasts was: LMCH > LMAG > LMST. The different protection levels of these LMPS may be due to the physic-chemical properties of the LMPS’ functional groups, including electron transfer ability, metal ion chelating capacities, radical stabilizing capacity, and the hydrophobicity of the constituent sugars. The results suggest that LMCH might constitute a novel and potential dermal therapeutic and sun-protective agent. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Adverse Impact of Diet-Induced Hypercholesterolemia on Cardiovascular Tissue Homeostasis in a Rabbit Model: Time-Dependent Changes in Cardiac Parameters

by Attila Kertész, Mariann Bombicz, Daniel Priksz, Jozsef Balla, Gyorgy Balla, Rudolf Gesztelyi, Balazs Varga, David D. Haines, Arpad Tosaki and Bela Juhasz

Int. J. Mol. Sci. 2013, 14(9), 19086-19108; https://doi.org/10.3390/ijms140919086 - 17 Sep 2013

Cited by 13 | Viewed by 8906

Abstract

The present study evaluates a hypothesis that diet-related hypercholesterolemia increases oxidative stress-related burden to cardiovascular tissue, resulting in progressively increased mortality, along with deterioration of electrophysiological and enzymatic function in rabbit myocardium. New Zealand white rabbits were divided into four groups, defined as [...] Read more.

The present study evaluates a hypothesis that diet-related hypercholesterolemia increases oxidative stress-related burden to cardiovascular tissue, resulting in progressively increased mortality, along with deterioration of electrophysiological and enzymatic function in rabbit myocardium. New Zealand white rabbits were divided into four groups, defined as follows: GROUP I, cholesterol-free rabbit chow for 12 weeks; GROUP II, cholesterol-free chow, 40 weeks; GROUP III, chow supplemented with 2% cholesterol, 12 weeks; GROUP IV, chow supplemented with 2% cholesterol, 40 weeks. At the 12 and 40 weeks time points, animals in each of the aforementioned cohorts were subjected to echocardiographic measurements, followed by sacrifice. Significant deterioration in major outcome variables measured in the present study were observed only in animals maintained for 40 weeks on 2% cholesterol-supplemented chow, with much lesser adverse effects noted in animals fed high cholesterol diets for only 12 weeks. It was observed that rabbits receiving high cholesterol diets for 40 weeks exhibited significantly increased mortality, worsened ejection fraction and general deterioration of cardiac functions, along with increased atherosclerotic plaque formation and infarct size. Additionally, myocardium of GROUP IV animals was observed to contain lower levels of heme oxygenase-1 (HO-1) and cytochrome c oxidase III (COX III) protein relative to the controls. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer’s Disease

by Said AbdAlla, Andreas Langer, Xuebin Fu and Ursula Quitterer

Int. J. Mol. Sci. 2013, 14(8), 16917-16942; https://doi.org/10.3390/ijms140816917 - 16 Aug 2013

Cited by 79 | Viewed by 12059

Abstract

Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The [...] Read more.

Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Serum Oxidant and Antioxidant Status Following an All-Out 21-km Run in Adolescent Runners Undergoing Professional Training—A One-Year Prospective Trial

by Tom K. Tong, Zhaowei Kong, Hua Lin, Giuseppe Lippi, Haifeng Zhang and Jinlei Nie

Int. J. Mol. Sci. 2013, 14(7), 15167-15178; https://doi.org/10.3390/ijms140715167 - 22 Jul 2013

Cited by 12 | Viewed by 6702

Abstract

This study investigated the 1-year longitudinal effect of professional training in adolescent runners on redox balance during intense endurance exercise. Changes in selected serum oxidant and antioxidant status in response to a 21-km running time trial in 10 runners (15.5 ± 1.3 years) [...] Read more.

This study investigated the 1-year longitudinal effect of professional training in adolescent runners on redox balance during intense endurance exercise. Changes in selected serum oxidant and antioxidant status in response to a 21-km running time trial in 10 runners (15.5 ± 1.3 years) undergoing professional training were evaluated twice in 12 months (pre- and post-evaluation). Venous blood samples were collected immediately before and 4-h following the 21-km run for analysis of serum concentrations of thiobarbituric acid-reactive substances (TBARS), xanthine oxidase (XO), catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC). In pre-evaluation trial, serum TBARS and SOD decreased after the 21-km run (p < 0.05) while XO, GSH, CAT and TAOC were unchanged. In post-evaluation trial, serum TBARS and SOD decreased, whereas XO and CAT increased post-exercise (p < 0.05). Furthermore, pre-exercise serum T-AOC, post-exercise serum XO, CAT, T-AOC (p < 0.05), and GSH (p = 0.057) appeared to be higher than the corresponding pre-evaluation values. The current findings suggest that a professional training regime in adolescent runners is not likely to jeopardize the development of their antioxidant defense. However, uncertainties in the maintenance of redox balance in runners facing increased exercise-induced oxidative stress as a consequence of training-induced enhancement of exercise capacity await further elucidation. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Individual and Joint Impacts of Ethanol Use, BMI, Age and Gender on Serum Gamma-Glutamyltransferase Levels in Healthy Volunteers

by Joanna Danielsson, Päivikki Kangastupa, Tiina Laatikainen, Mauri Aalto and Onni Niemelä

Int. J. Mol. Sci. 2013, 14(6), 11929-11941; https://doi.org/10.3390/ijms140611929 - 4 Jun 2013

Cited by 7 | Viewed by 7535

Abstract

Excessive ethanol consumption, obesity and increasing age may all lead to increased serum levels of gamma-glutamyltransferase (GGT) enzyme, which plays a key role in the metabolism of extracellular reduced glutathione. However, as yet, the interactions between the various modulators of GGT activities have [...] Read more.

Excessive ethanol consumption, obesity and increasing age may all lead to increased serum levels of gamma-glutamyltransferase (GGT) enzyme, which plays a key role in the metabolism of extracellular reduced glutathione. However, as yet, the interactions between the various modulators of GGT activities have remained poorly defined. We analyzed data from 15,617 apparently healthy individuals (7254 men and 8363 women, mean age 46 ± 13 years, range 25–74 years) who participated in a national cross-sectional health survey in Finland between 1997 and 2007. All subjects underwent detailed clinical examinations and interviews, including the amount of ethanol use and smoking habits. GGT levels were measured from all participants, and the individual and joint impacts of the different study variables on GGT levels were assessed. Significant individual effects were noted for ethanol use (p < 0.001), body mass index (BMI) (p < 0.001), age (p < 0.001) and smoking (p < 0.001). In men, significant two-factor interactions occurred between ethanol use and age (p < 0.020). Among those over 40 years of age, ethanol consumption was found to be a stronger determinant of increased GGT levels than in men below 40 years, whereas in the latter age group, BMI was found to predominate. In women, a significant two-factor interaction occurred between ethanol and BMI (p = 0.010), whereas it did not with ethanol use and age. The data underscores the role of ethanol consumption and age as major determinants of increased GGT levels in men, whereas in women, a relatively stronger impact was noted for ethanol intake and BMI. In light of the ability of GGT enzyme to modulate crucial redox-sensitive functions, the present findings also support the use of GGT as a biomarker of oxidative stress. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Myricetin-Mediated Lifespan Extension in Caenorhabditis elegans Is Modulated by DAF-16

by Christian Büchter, Daniela Ackermann, Susannah Havermann, Sebastian Honnen, Yvonni Chovolou, Gerhard Fritz, Andreas Kampkötter and Wim Wätjen

Int. J. Mol. Sci. 2013, 14(6), 11895-11914; https://doi.org/10.3390/ijms140611895 - 4 Jun 2013

Cited by 109 | Viewed by 12899

Abstract

Myricetin is a naturally occurring flavonol found in many plant based food sources. It increases the lifespan of Caenorhabditis elegans, but the molecular mechanisms are not yet fully understood. We have investigated the impact of this flavonoid on the transcription factors DAF-16 [...] Read more.

Myricetin is a naturally occurring flavonol found in many plant based food sources. It increases the lifespan of Caenorhabditis elegans, but the molecular mechanisms are not yet fully understood. We have investigated the impact of this flavonoid on the transcription factors DAF-16 (C. elegans FoxO homologue) and SKN-1 (Nrf2 homologue), which have crucial functions in the regulation of ageing. Myricetin is rapidly assimilated by the nematode, causes a nuclear translocation of DAF-16 but not of SKN-1, and finally prolongs the mean adult lifespan of C. elegans by 32.9%. The lifespan prolongation was associated with a decrease in the accumulation of reactive oxygen species (ROS) detected by DCF. Myricetin also decreases the formation of lipofuscin, a pigment consisting of highly oxidized and cross-linked proteins that is considered as a biomarker of ageing in diverse species. The lifespan extension was completely abolished in a daf-16 loss-of-function mutant strain (CF1038). Consistently with this result, myricetin was also not able to diminish stress-induced ROS accumulation in the mutant. These results strongly indicate that the pro-longevity effect of myricetin is dependent on DAF-16 and not on direct anti-oxidative effects of the flavonoid. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Sod1 Loss Induces Intrinsic Superoxide Accumulation Leading to p53-Mediated Growth Arrest and Apoptosis

by Kenji Watanabe, Shuichi Shibuya, Hirofumi Koyama, Yusuke Ozawa, Toshihiko Toda, Koutaro Yokote and Takahiko Shimizu

Int. J. Mol. Sci. 2013, 14(6), 10998-11010; https://doi.org/10.3390/ijms140610998 - 24 May 2013

Cited by 27 | Viewed by 8231

Abstract

Oxidative damages induced by a redox imbalance cause age-related changes in cells and tissues. Superoxide dismutase (SOD) enzymes play a major role in the antioxidant system and they also catalyze superoxide radicals (O₂^·⁻). Since the loss of cytoplasmic SOD [...] Read more.

Oxidative damages induced by a redox imbalance cause age-related changes in cells and tissues. Superoxide dismutase (SOD) enzymes play a major role in the antioxidant system and they also catalyze superoxide radicals (O₂^·⁻). Since the loss of cytoplasmic SOD (SOD1) resulted in aging-like phenotypes in several types of mouse tissue, SOD1 is essential for the maintenance of tissue homeostasis. To clarify the cellular function of SOD1, we investigated the cellular phenotypes of Sod1-deficient fibroblasts. We demonstrated that Sod1 deficiency impaired proliferation and induced apoptosis associated with O₂^·⁻ accumulation in the cytoplasm and mitochondria in fibroblasts. Sod1 loss also decreased the mitochondrial membrane potential and led to DNA damage-mediated p53 activation. Antioxidant treatments effectively improved the cellular phenotypes through suppression of both intracellular O₂^·⁻ accumulation and p53 activation in Sod1-deficient fibroblasts. In vivo experiments revealed that transdermal treatment with a vitamin C derivative significantly reversed the skin thinning commonly associated with the upregulated p53 action in the skin. Our findings revealed that intrinsic O₂^·⁻ accumulation promoted p53-mediated growth arrest and apoptosis as well as mitochondrial disfunction in the fibroblasts. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Structural Alterations of Human Serum Albumin Caused by Glycative and Oxidative Stressors Revealed by Circular Dichroism Analysis

by Fiammetta Monacelli, Daniela Storace, Cristina D'Arrigo, Roberta Sanguineti, Roberta Borghi, Davide Pacini, Anna L. Furfaro, Maria A. Pronzato, Patrizio Odetti and Nicola Traverso

Int. J. Mol. Sci. 2013, 14(6), 10694-10709; https://doi.org/10.3390/ijms140610694 - 23 May 2013

Cited by 29 | Viewed by 7929

Abstract

The aim of this work was to evaluate the ability of oxidative and glycative stressors to modify properties of human serum albumin (HSA) by analyzing markers of glycation (pentosidine) and oxidation (advanced oxidative protein products (AOPPs)) and assessing fluorescence and circular dichroism. HSA [...] Read more.

The aim of this work was to evaluate the ability of oxidative and glycative stressors to modify properties of human serum albumin (HSA) by analyzing markers of glycation (pentosidine) and oxidation (advanced oxidative protein products (AOPPs)) and assessing fluorescence and circular dichroism. HSA was incubated for up to 21 days with ribose, ascorbic acid (AA) and diethylenetriamine pentacetate (DTPA) in various combinations in order to evaluate influences of these substances on the structure of HSA. Ribose was included as a strong glycative molecule, AA as a modulator of oxidative stress, and DTPA as an inhibitor of metal-catalyzed oxidation. Ribose induced a significant increase in pentosidine levels. AA and DTPA prevented the accumulation of pentosidine, especially at later time points. Ribose induced a mild increase in AOPP formation, while AA was a strong inducer of AOPP formation. Ribose, in combination with AA, further increased the formation of AOPP. DTPA prevented the AA-induced generation of AOPP. Ribose was also a potent inducer of fluorescence at 335nm ex/385nm em, which is typical of pentosidine. AA and DTPA prevented this fluorescence. Circular dichroism showed complex results, in which AA and DTPA were strong modifiers of the percentages of the alpha-helical structure of HSA, while ribose affected the structure of HSA only at later time points. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Oxidative Stress Mediates the Disruption of Airway Epithelial Tight Junctions through a TRPM2-PLCγ1-PKCα Signaling Pathway

by Rui Xu, Qi Li, Xiang-Dong Zhou, Juliy M. Perelman and Victor P. Kolosov

Int. J. Mol. Sci. 2013, 14(5), 9475-9486; https://doi.org/10.3390/ijms14059475 - 29 Apr 2013

Cited by 20 | Viewed by 7593

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Soluble Receptor for Advanced Glycation End-Product (sRAGE)/Pentosidine Ratio: A Potential Risk Factor Determinant for Type 2 Diabetic Retinopathy

by Zhi Xiang Ng, Kek Heng Chua, Tajunisah Iqbal and Umah Rani Kuppusamy

Int. J. Mol. Sci. 2013, 14(4), 7480-7491; https://doi.org/10.3390/ijms14047480 - 3 Apr 2013

Cited by 18 | Viewed by 7422

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 [...] Read more.

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 HbA_1c 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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Differential Expression of Genes Associated with the Progression of Renal Disease in the Kidneys of Liver-Specific Glucokinase Gene Knockout Mice

by 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

Int. J. Mol. Sci. 2013, 14(3), 6467-6486; https://doi.org/10.3390/ijms14036467 - 21 Mar 2013

Cited by 9 | Viewed by 8293

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 [...] Read more.

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 (gck^w/−) mice and age-matched normal wild-type control (gck^w/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 gck^w/− and gck^w/w mice at 60 weeks of age. Differential expression of the candidate genes was examined by real-time qPCR in liver-specific gck^w/− and gck^w/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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

LC-MS/MS Determination of Isoprostanes in Plasma Samples Collected from Mice Exposed to Doxorubicin or Tert-Butyl Hydroperoxide

by Monika Janicka, Agata Kot-Wasik, Jolanta Paradziej-Łukowicz, Grażyna Sularz-Peszyńska, Agnieszka Bartoszek and Jacek Namieśnik

Int. J. Mol. Sci. 2013, 14(3), 6157-6169; https://doi.org/10.3390/ijms14036157 - 18 Mar 2013

Cited by 19 | Viewed by 8976

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 F_2α, 8-iso-15(R)-prostaglandin [...] Read more.

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 F_2α, 8-iso-15(R)-prostaglandin F_2α, 11β-prostaglandin F_2α, 15(R)-prostaglandin F_2α) in plasma samples collected from mice. The four plasma isoprostanes are determined by LC–ESI-MS/MS with deuterated 8-iso-PGF_2α-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 F_2α being the exception. The greatest rise was observed in the case of 15(R)-prostaglandin F_2α, by about 50% and 70% in plasma samples derived from mice exposed to DOX and TBHP, respectively. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

A Steroidal Saponin from Ophiopogon japonicus Extends the Lifespan of Yeast via the Pathway Involved in SOD and UTH1

by Kaiyue Sun, Shining Cao, Liang Pei, Akira Matsuura, Lan Xiang and Jianhua Qi

Int. J. Mol. Sci. 2013, 14(3), 4461-4475; https://doi.org/10.3390/ijms14034461 - 25 Feb 2013

Cited by 28 | Viewed by 7535

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Different Forms of Selenoprotein M Differentially Affect Aβ Aggregation and ROS Generation

by Ping Chen, Ruo-Ran Wang, Xiao-Jie Ma, Qiong Liu and Jia-Zuan Ni

Int. J. Mol. Sci. 2013, 14(3), 4385-4399; https://doi.org/10.3390/ijms14034385 - 25 Feb 2013

Cited by 37 | Viewed by 7062

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Effects of Aging and Hypercholesterolemia on Oxidative Stress and DNA Damage in Bone Marrow Mononuclear Cells in Apolipoprotein E-deficient Mice

by Clarissa L. Tonini, Bianca P. Campagnaro, Lis P. S. Louro, Thiago M. C. Pereira, Elisardo C. Vasquez and Silvana S. Meyrelles

Int. J. Mol. Sci. 2013, 14(2), 3325-3342; https://doi.org/10.3390/ijms14023325 - 5 Feb 2013

Cited by 40 | Viewed by 9435

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart

by Haider Raza, Annie John and Frank C. Howarth

Int. J. Mol. Sci. 2012, 13(12), 16241-16254; https://doi.org/10.3390/ijms131216241 - 30 Nov 2012

Cited by 43 | Viewed by 7174

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Microtubule Formation and Activities of Antioxidative Enzymes in PC12 Cells Exposed to Phosphatidylcholine Hydroperoxides

by Yukako Yamanaka, Shumi Yoshida-Yamamoto and Hiroshi Doi

Int. J. Mol. Sci. 2012, 13(12), 15510-15522; https://doi.org/10.3390/ijms131215510 - 22 Nov 2012

Cited by 4 | Viewed by 5892

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Oxidant Stress and Signal Transduction in the Nervous System with the PI 3-K, Akt, and mTOR Cascade

by Kenneth Maiese, Zhao Zhong Chong, Shaohui Wang and Yan Chen Shang

Int. J. Mol. Sci. 2012, 13(11), 13830-13866; https://doi.org/10.3390/ijms131113830 - 26 Oct 2012

Cited by 92 | Viewed by 17584

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Effect of Calcium and Potassium on Antioxidant System of Vicia faba L. Under Cadmium Stress

by Manzer H. Siddiqui, Mohamed H. Al-Whaibi, Ahmed M. Sakran, Mohammed O. Basalah and Hayssam M. Ali

Int. J. Mol. Sci. 2012, 13(6), 6604-6619; https://doi.org/10.3390/ijms13066604 - 29 May 2012

Cited by 156 | Viewed by 11431

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Loss of p16^Ink4a Function Rescues Cellular Senescence Induced by Telomere Dysfunction

by Xiufeng Zhang, Xiaoming Wu, Wenru Tang and Ying Luo

Int. J. Mol. Sci. 2012, 13(5), 5866-5877; https://doi.org/10.3390/ijms13055866 - 16 May 2012

Cited by 17 | Viewed by 8123

Abstract

p16^I^nk4a is a tumor suppressor and a marker for cellular senescence. Previous studies have shown that p16^I^nk4a plays an important role in the response to DNA damage signals caused by telomere dysfunction. In this study, we crossed Wrn^−/− [...] Read more.

p16^I^nk4a is a tumor suppressor and a marker for cellular senescence. Previous studies have shown that p16^I^nk4a plays an important role in the response to DNA damage signals caused by telomere dysfunction. In this study, we crossed Wrn^−/− and p16^I^nk4a−/− mice to knock out the p16^I^nk4a function in a Wrn null background. Growth curves showed that loss of p16^I^nk4a 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 p16^I^nk4a 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 p16^I^nk4a could partially overcome the DNA damage response by disabling p16^I^nk4a 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, p16^I^nk4a−/− and p16^I^nk4a−/−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 p16^I^nk4a function could prevent cells from senescence. These results shed light on the anti-aging strategy through regulation of p16^Ink4a expression. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Review

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404 KiB

Open AccessReview

Oxidative Stress in Aging-Matters of the Heart and Mind

by Krishnan Venkataraman, Sandhya Khurana and T. C. Tai

Int. J. Mol. Sci. 2013, 14(9), 17897-17925; https://doi.org/10.3390/ijms140917897 - 2 Sep 2013

Cited by 108 | Viewed by 10704

Abstract

Oxidative damage is considered to be the primary cause of several aging associated disease pathologies. Cumulative oxidative damage tends to be pervasive among cellular macromolecules, impacting proteins, lipids, RNA and DNA of cells. At a systemic level, events subsequent to oxidative damage induce [...] Read more.

Oxidative damage is considered to be the primary cause of several aging associated disease pathologies. Cumulative oxidative damage tends to be pervasive among cellular macromolecules, impacting proteins, lipids, RNA and DNA of cells. At a systemic level, events subsequent to oxidative damage induce an inflammatory response to sites of oxidative damage, often contributing to additional oxidative stress. At a cellular level, oxidative damage to mitochondria results in acidification of the cytoplasm and release of cytochrome c, causing apoptosis. This review summarizes findings in the literature on oxidative stress and consequent damage on cells and tissues of the cardiovascular system and the central nervous system, with a focus on aging-related diseases that have well-documented evidence of oxidative damage in initiation and/or progression of the disease. The current understanding of the cellular mechanisms with a focus on macromolecular damage, impacted cellular pathways and gross morphological changes associated with oxidative damage is also reviewed. Additionally, the impact of calorific restriction with its profound impact on cardiovascular and neuronal aging is addressed. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Oxidative Stress and Epigenetic Regulation in Ageing and Age-Related Diseases

by Chiara Cencioni, Francesco Spallotta, Fabio Martelli, Sergio Valente, Antonello Mai, Andreas M. Zeiher and Carlo Gaetano

Int. J. Mol. Sci. 2013, 14(9), 17643-17663; https://doi.org/10.3390/ijms140917643 - 28 Aug 2013

Cited by 176 | Viewed by 24307

Abstract

Recent statistics indicate that the human population is ageing rapidly. Healthy, but also diseased, elderly people are increasing. This trend is particularly evident in Western countries, where healthier living conditions and better cures are available. To understand the process leading to age-associated alterations [...] Read more.

Recent statistics indicate that the human population is ageing rapidly. Healthy, but also diseased, elderly people are increasing. This trend is particularly evident in Western countries, where healthier living conditions and better cures are available. To understand the process leading to age-associated alterations is, therefore, of the highest relevance for the development of new treatments for age-associated diseases, such as cancer, diabetes, Alzheimer and cardiovascular accidents. Mechanistically, it is well accepted that the accumulation of intracellular damage determined by reactive oxygen species (ROS) might orchestrate the progressive loss of control over biological homeostasis and the functional impairment typical of aged tissues. Here, we review how epigenetics takes part in the control of stress stimuli and the mechanisms of ageing physiology and physiopathology. Alteration of epigenetic enzyme activity, histone modifications and DNA-methylation is, in fact, typically associated with the ageing process. Specifically, ageing presents peculiar epigenetic markers that, taken altogether, form the still ill-defined “ageing epigenome”. The comprehension of mechanisms and pathways leading to epigenetic modifications associated with ageing may help the development of anti-ageing therapies. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessReview

Preventive or Potential Therapeutic Value of Nutraceuticals against Ionizing Radiation-Induced Oxidative Stress in Exposed Subjects and Frequent Fliers

by Maria Teresa Giardi, Eleftherios Touloupakis, Delfina Bertolotto and Gabriele Mascetti

Int. J. Mol. Sci. 2013, 14(8), 17168-17192; https://doi.org/10.3390/ijms140817168 - 20 Aug 2013

Cited by 26 | Viewed by 8751

Abstract

Humans are constantly exposed to ionizing radiation deriving from outer space sources or activities related to medical care. Absorption of ionizing radiation doses over a prolonged period of time can result in oxidative damage and cellular dysfunction inducing several diseases, especially in ageing [...] Read more.

Humans are constantly exposed to ionizing radiation deriving from outer space sources or activities related to medical care. Absorption of ionizing radiation doses over a prolonged period of time can result in oxidative damage and cellular dysfunction inducing several diseases, especially in ageing subjects. In this report, we analyze the effects of ionizing radiation, particularly at low doses, in relation to a variety of human pathologies, including cancer, and cardiovascular and retinal diseases. We discuss scientific data in support of protection strategies by safe antioxidant formulations that can provide preventive or potential therapeutic value in response to long-term diseases that may develop following exposure. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Exploring the Role of Genetic Variability and Lifestyle in Oxidative Stress Response for Healthy Aging and Longevity

by Serena Dato, Paolina Crocco, Patrizia D'Aquila, Francesco De Rango, Dina Bellizzi, Giuseppina Rose and Giuseppe Passarino

Int. J. Mol. Sci. 2013, 14(8), 16443-16472; https://doi.org/10.3390/ijms140816443 - 8 Aug 2013

Cited by 77 | Viewed by 13299

Abstract

Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to [...] Read more.

Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to have evolved conservative stress response mechanisms, probably derived from a combination of a diet rich in natural antioxidants, an active lifestyle and a favorable genetic background, particularly rich in genetic variants able to counteract the stress overload at the level of both nuclear and mitochondrial DNA. The integration of these factors could allow centenarians to maintain moderate levels of free radicals that exert beneficial signaling and modulator effects on cellular metabolism. Considering the hot debate on the efficacy of antioxidant supplementation in promoting healthy aging, in this review we gathered the existing information regarding genetic variability and lifestyle factors which potentially modulate the stress response at old age. Evidence reported here suggests that the integration of lifestyle factors (moderate physical activity and healthy nutrition) and genetic background could shift the balance in favor of the antioxidant cellular machinery by activating appropriate defense mechanisms in response to exceeding external and internal stress levels, and thus possibly achieving the prospect of living a longer life. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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(Healthy) Ageing: Focus on Iodothyronines

by Pieter De Lange, Federica Cioffi, Elena Silvestri, Maria Moreno, Fernando Goglia and Antonia Lanni

Int. J. Mol. Sci. 2013, 14(7), 13873-13892; https://doi.org/10.3390/ijms140713873 - 4 Jul 2013

Cited by 13 | Viewed by 8279

Abstract

The activity of the thyroid gland diminishes during ageing, but a certain tissue reserve of T3 and its metabolites is maintained. This reserve is thought to play a regulatory role in energy homeostasis during ageing. This review critically assesses this notion. T3 was [...] Read more.

The activity of the thyroid gland diminishes during ageing, but a certain tissue reserve of T3 and its metabolites is maintained. This reserve is thought to play a regulatory role in energy homeostasis during ageing. This review critically assesses this notion. T3 was thought to act predominantly through pathways that require transcriptional regulation by thyroid hormone receptors (TRs). However, in recent years, it has emerged that T3 and its metabolites can also act through non-genomic mechanisms, including cytosolic signaling. Interestingly, differences may exist in the non-genomic pathways utilized by thyroid hormone metabolites and T3. For instance, one particular thyroid hormone metabolite, namely 3,5-diiodo-L-thyronine (T2), increases the activity of the redox-sensitive protein deacetylase SIRT1, which has been associated with improvements in healthy ageing, whereas evidence exists that T3 may have the opposite effect. Findings suggesting that T3, T2, and their signaling pathways, such as those involving SIRT1 and AMP-activated protein kinase (AMPK), are associated with improvements in diet-induced obesity and insulin resistance emphasize the potential importance of the thyroid during ageing and in ageing-associated metabolic diseases. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Hormesis in Aging and Neurodegeneration—A Prodigy Awaiting Dissection

by Lei Mao and Jacqueline Franke

Int. J. Mol. Sci. 2013, 14(7), 13109-13128; https://doi.org/10.3390/ijms140713109 - 25 Jun 2013

Cited by 32 | Viewed by 14552

Abstract

Hormesis describes the drug action of low dose stimulation and high dose inhibition. The hormesis phenomenon has been observed in a wide range of biological systems. Although known in its descriptive context, the underlying mode-of-action of hormesis is largely unexplored. Recently, the hormesis [...] Read more.

Hormesis describes the drug action of low dose stimulation and high dose inhibition. The hormesis phenomenon has been observed in a wide range of biological systems. Although known in its descriptive context, the underlying mode-of-action of hormesis is largely unexplored. Recently, the hormesis concept has been receiving increasing attention in the field of aging research. It has been proposed that within a certain concentration window, reactive oxygen species (ROS) or reactive nitrogen species (RNS) could act as major mediators of anti-aging and neuroprotective processes. Such hormetic phenomena could have potential therapeutic applications, if properly employed. Here, we review the current theories of hormetic phenomena in regard to aging and neurodegeneration, with the focus on its underlying mechanism. Facilitated by a simple mathematical model, we show for the first time that ROS-mediated hormesis can be explained by the addition of different biomolecular reactions including oxidative damage, MAPK signaling and autophagy stimulation. Due to their divergent scales, the optimal hormetic window is sensitive to each kinetic parameter, which may vary between individuals. Therefore, therapeutic utilization of hormesis requires quantitative characterizations in order to access the optimal hormetic window for each individual. This calls for a personalized medicine approach for a longer human healthspan. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Endothelial Aging Associated with Oxidative Stress Can Be Modulated by a Healthy Mediterranean Diet

by Carmen Marín, Elena M Yubero-Serrano, José López-Miranda and Francisco Pérez-Jiménez

Int. J. Mol. Sci. 2013, 14(5), 8869-8889; https://doi.org/10.3390/ijms14058869 - 24 Apr 2013

Cited by 71 | Viewed by 12223

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Nature’s Timepiece—Molecular Coordination of Metabolism and Its Impact on Aging

by Andrea Bednářová, Dalibor Kodrík and Natraj Krishnan

Int. J. Mol. Sci. 2013, 14(2), 3026-3049; https://doi.org/10.3390/ijms14023026 - 31 Jan 2013

Cited by 7 | Viewed by 10157

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. [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Role of Oxidative Stress in Hepatocarcinogenesis Induced by Hepatitis C Virus

by Kyoko Tsukiyama-Kohara

Int. J. Mol. Sci. 2012, 13(11), 15271-15278; https://doi.org/10.3390/ijms131115271 - 19 Nov 2012

Cited by 35 | Viewed by 8033

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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