Journal Cover Redox Biology
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   ISSN (Online) 2213-2317
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  • Carnosine attenuates cyclophosphamide-induced bone marrow suppression by
           reducing oxidative DNA damage

    • Authors: Jie Deng; Yi-Fei Zhong; Yan-Ping Wu; Zhuo Luo; Yuan-Ming Sun; Guo-En Wang; Hiroshi Kurihara; Yi-Fang Li; Rong-Rong He
      Pages: 1 - 6
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Jie Deng, Yi-Fei Zhong, Yan-Ping Wu, Zhuo Luo, Yuan-Ming Sun, Guo-En Wang, Hiroshi Kurihara, Yi-Fang Li, Rong-Rong He
      Oxidative DNA damage in bone marrow cells is the main side effect of chemotherapy drugs including cyclophosphamide (CTX). However, not all antioxidants are effective in inhibiting oxidative DNA damage. In this study, we report the beneficial effect of carnosine (β-alanyl-l-histidine), a special antioxidant with acrolein-sequestering ability, on CTX-induced bone marrow cell suppression. Our results show that carnosine treatment (100 and 200mg/kg, i.p.) significantly inhibited the generation of reactive oxygen species (ROS) and 8-hydroxy-2′-deoxyguanosine (8-oxo-dG), and decreased chromosomal abnormalities in the bone marrow cells of mice treated with CTX (20mg/kg, i.v., 24h). Furthermore, carnosine evidently mitigated CTX-induced G2/M arrest in murine bone marrow cells, accompanied by reduced ratios of p-Chk1/Chk1 and p-p53/p53 as well as decreased p21 expression. In addition, cell apoptosis caused by CTX was also suppressed by carnosine treatment, as assessed by decreased TUNEL-positive cell counts, down-regulated expressions of Bax and Cyt c, and reduced ratios of cleaved Caspase-3/Caspase-3. These results together suggest that carnosine can protect murine bone marrow cells from CTX-induced DNA damage via its antioxidant activity.
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      PubDate: 2017-08-18T21:44:36Z
      DOI: 10.1016/j.redox.2017.08.003
      Issue No: Vol. 14 (2017)
       
  • A reciprocal relationship between reactive oxygen species and
           mitochondrial dynamics in neurodegeneration

    • Authors: Clara Hiu-Ling Hung; Sally Shuk-Yee Cheng; Yuen-Ting Cheung; Suthicha Wuwongse; Natalie Qishan Zhang; Yuen-Shan Ho; Simon Ming-Yuen Lee; Raymond Chuen-Chung Chang
      Pages: 7 - 19
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Clara Hiu-Ling Hung, Sally Shuk-Yee Cheng, Yuen-Ting Cheung, Suthicha Wuwongse, Natalie Qishan Zhang, Yuen-Shan Ho, Simon Ming-Yuen Lee, Raymond Chuen-Chung Chang
      Mitochondrial fragmentation due to fission/fusion imbalance has often been linked to mitochondrial dysfunction and apoptosis in neurodegeneration. Conventionally, it is believed that once mitochondrial morphology shifts away from its physiological tubular form, mitochondria become defective and downstream apoptotic signaling pathways are triggered. However, our study shows that beta-amyloid (Aβ) induces morphological changes in mitochondria where they become granular-shaped and are distinct from fragmented mitochondria in terms of both morphology and functions. Accumulation of mitochondrial reactive oxygen species triggers granular mitochondria formation, while mitoTEMPO (a mitochondria-targeted superoxide scavenger) restores tubular mitochondrial morphology within Aβ-treated neurons. Interestingly, modulations of mitochondria fission and fusion by genetic and pharmacological tools attenuated not only the induction of granular mitochondria, but also mitochondrial superoxide levels in Aβ−treated neurons. Our study shows a reciprocal relationship between mitochondrial dynamics and reactive oxygen species and provides a new potential therapeutic target at early stages of neurodegenerative disease pathogenesis.
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      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.010
      Issue No: Vol. 14 (2017)
       
  • Reduced levels of methyltransferase DNMT2 sensitize human fibroblasts to
           oxidative stress and DNA damage that is accompanied by changes in
           proliferation-related miRNA expression

    • Authors: Anna Lewinska; Jagoda Adamczyk-Grochala; Ewa Kwasniewicz; Anna Deregowska; Ewelina Semik; Tomasz Zabek; Maciej Wnuk
      Pages: 20 - 34
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Anna Lewinska, Jagoda Adamczyk-Grochala, Ewa Kwasniewicz, Anna Deregowska, Ewelina Semik, Tomasz Zabek, Maciej Wnuk
      Methyltransferase DNMT2 is suggested to be involved in the regulation of numerous processes, however its biological significance and underlying molecular mechanisms remain elusive. In the present study, we have used WI-38 and BJ human fibroblasts as an in vitro model system to investigate the effects of siRNA-based DNMT2 silencing. DNMT2-depleted cells were found to be sensitive to oxidative stress conditions as judged by increased production of reactive oxygen species and susceptible to DNA damage that resulted in the inhibition of cell proliferation. DNMT2 silencing promoted upregulation of proliferation-related and tumor suppressor miRNAs, namely miR-28-3p, miR-34a-3p, miR-30b-5p, miR-29b-3p, miR-200c-3p, miR-28-5p, miR-379-5p, miR-382-5p, miR-194-5p, miR-193b-3p and miR-409-3p. Moreover, DNMT2 silencing induced cellular senescence and DNMT2 levels were elevated in replicatively senescent cells. Taken together, we found that DNMT2 may take part in the regulation of cell proliferation and longevity in human fibroblasts and speculate that the manipulation of DNMT2 levels that limits cell proliferation may be potentially useful anticancer strategy.

      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.012
      Issue No: Vol. 14 (2017)
       
  • Aging-related decline in the induction of Nrf2-regulated antioxidant genes
           in human bronchial epithelial cells

    • Authors: Lulu Zhou; Hongqiao Zhang; Kelvin J.A. Davies; Henry Jay Forman
      Pages: 35 - 40
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Lulu Zhou, Hongqiao Zhang, Kelvin J.A. Davies, Henry Jay Forman
      Evidence from animal studies suggests that stress-induced increases in Nrf2-regulated antioxidant gene expression, a critical mechanism of cellular protection, declines with aging. This study examined whether this also occurs in humans. We measured the basal and inducible levels of Nrf2-regulated antioxidant genes in human bronchial epithelial (HBE) cells from subjects of young adult (21–29 years) and older (60–69 years) non-smokers, and explored factors affecting expresion. The basal expression of three representative Nrf2-regulated genes, the catalytic and modulator subunits of glutamate cysteine ligase (GCLC and GCLM, respectively), and NAD(P)H quinone oxidoreductase 1 (NQO1), was higher in cells from the older donors compared with cells from the young adult donors. Upon exposure to the Nrf2 activator, sulforaphane (SF), the expression of these antioxidant genes was increased in cells from both the young adults and the older donors; however, the induction by SF in older donor cells was significantly less than that seen in young adult cells. In addition, the activation of an EpRE-driven reporter by SF was lower in cells from older donors compared to cells from young adults. The basal expression of Nrf2 protein was also lower in cells from older donors than cells from young adults. Furthermore, we found that the basal expression of both Bach1 and c-Myc, two Nrf2 suppressors, was higher in cells from older adults than from young adult donors. In summary, our data suggest that, as in other species, basal expression of Nrf2-regulated genes increases with aging, while inducibility declines with aging. The increased expression of Nrf2 suppressors such as Bach1 and c-Myc may contribute to the impaired inducibility of the Nrf2-regulated antioxidant genes with aging in human bronchial epithelial cells.

      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.014
      Issue No: Vol. 14 (2017)
       
  • Peroxiredoxin 6 phospholipid hydroperoxidase activity in the repair of
           peroxidized cell membranes

    • Authors: Aron B. Fisher; Jose P. Vasquez-Medina; Chandra Dodia; Elena M. Sorokina; Jian-Qin Tao; Sheldon I. Feinstein
      Pages: 41 - 46
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Aron B. Fisher, Jose P. Vasquez-Medina, Chandra Dodia, Elena M. Sorokina, Jian-Qin Tao, Sheldon I. Feinstein
      Although lipid peroxidation associated with oxidative stress can result in cellular death, sub-lethal lipid peroxidation can gradually resolve with return to the pre-exposure state. We have shown that resolution of lipid peroxidation is greatly delayed in lungs or cells that are null for peroxiredoxin 6 (Prdx6) and that both the phospholipase A2 and the GSH peroxidase activities of Prdx6 are required for a maximal rate of recovery. Like other peroxiredoxins, Prdx6 can reduce H2O2 and short chain hydroperoxides, but in addition can directly reduce phospholipid hydroperoxides. This study evaluated the relative role of these two different peroxidase activities of Prdx6 in the repair of peroxidized cell membranes. The His26 residue in Prdx6 is an important component of the binding site for phospholipids. Thus, we evaluated the lungs from H26A-Prdx6 expressing mice and generated H26A-Prdx6 expressing pulmonary microvascular endothelial cells (PMVEC) by lentiviral infection of Prdx6 null cells to compare with wild type in the repair of lipid peroxidation. Isolated lungs and PMVEC were exposed to tert-butyl hydroperoxide and mice were exposed to hyperoxia (> 95% O2). Assays for lipid peroxidation in wild type control and mutant lungs and cells showed ~4-fold increase at end-exposure. Control lungs and cells showed gradual resolution during a post-exposure recovery period. However, there was no recovery from lipid peroxidation by H26A-Prdx6 lungs or PMVEC. These studies confirm an important role for Prdx6 in recovery from membrane lipid peroxidation and indicate that reduction of H2O2 or short chain hydroperoxides does not play a role in the recovery process.
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      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.008
      Issue No: Vol. 14 (2017)
       
  • Short overview on metabolomics approach to study pathophysiology of
           oxidative stress in cancer

    • Authors: Luka Andrisic; Danuta Dudzik; Coral Barbas; Lidija Milkovic; Tilman Grune; Neven Zarkovic
      Pages: 47 - 58
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Luka Andrisic, Danuta Dudzik, Coral Barbas, Lidija Milkovic, Tilman Grune, Neven Zarkovic
      Association of oxidative stress with carcinogenesis is well known, but not understood well, as is pathophysiology of oxidative stress generated during different types of anti-cancer treatments. Moreover, recent findings indicate that cancer associated lipid peroxidation might eventually help defending adjacent nonmalignant cells from cancer invasion. Therefore, untargeted metabolomics studies designed for advanced translational and clinical studies are needed to understand the existing paradoxes in oncology, including those related to controversial usage of antioxidants aiming to prevent or treat cancer. In this short review we have tried to put emphasis on the importance of pathophysiology of oxidative stress and lipid peroxidation in cancer development in relation to metabolic adaptation of particular types of cancer allowing us to conclude that adaptation to oxidative stress is one of the main driving forces of cancer pathophysiology. With the help of metabolomics many novel findings are being achieved thus encouraging further scientific breakthroughs. Combined with targeted qualitative and quantitative methods, especially immunochemistry, further research might reveal bio-signatures of individual patients and respective malignant diseases, leading to individualized treatment approach, according to the concepts of modern integrative medicine.

      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.009
      Issue No: Vol. 14 (2017)
       
  • Yap promotes hepatocellular carcinoma metastasis and mobilization via
           governing cofilin/F-actin/lamellipodium axis by regulation of
           JNK/Bnip3/SERCA/CaMKII pathways

    • Authors: Chen Shi; Yong Cai; Yongheng Li; Ye Li; Nan Hu; Sai Ma; Shunying Hu; Pingjun Zhu; Weihu Wang; Hao Zhou
      Pages: 59 - 71
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Chen Shi, Yong Cai, Yongheng Li, Ye Li, Nan Hu, Sai Ma, Shunying Hu, Pingjun Zhu, Weihu Wang, Hao Zhou
      Despite the increasingly important role of Hippo-Yap in hepatocellular carcinoma (HCC) development and progression, little insight is available at the time regarding the specifics interaction of Yap and cancer cells migration. Here, we identified the mechanism by which tumor-intrinsic Yap deletion resulted in HCC migratory inhibition. Yap was greatly upregulated in HCC and its expression promoted the cells migration. Functional studies found that knockdown of Yap induced JNK phosphorylation which closely bound to the Bnip3 promoter and contributed to Bnip3 expression. Higher Bnip3 employed excessive mitophagy leading to mitochondrial dysfunction and ATP shortage. The insufficient ATP inactivated SERCA and consequently triggered intracellular calcium overload. As the consequence of calcium oscillation, Ca/calmodulin-dependent protein kinases II (CaMKII) was signaled and subsequently inhibited cofilin activity via phosphorylated modification. The phosphorylated cofilin failed to manipulate F-actin polymerization and lamellipodium formation, resulting into the impairment of lamellipodium-based migration. Collectively, our results identified Hippo-Yap as the tumor promoter in hepatocellular carcinoma that mediated via activation of cofilin/F-actin/lamellipodium axis by limiting JNK-Bnip3-SERCA-CaMKII pathways, with potential application to HCC therapy involving cancer metastasis.
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      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.013
      Issue No: Vol. 14 (2017)
       
  • PKR activation causes inflammation and MMP-13 secretion in human
           degenerated articular chondrocytes

    • Authors: Ching-Hou Ma; Chin-Hsien Wu; I.-Ming Jou; Yuan-Kun Tu; Ching-Hsia Hung; Pei-Ling Hsieh; Kun-Ling Tsai
      Pages: 72 - 81
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Ching-Hou Ma, Chin-Hsien Wu, I.-Ming Jou, Yuan-Kun Tu, Ching-Hsia Hung, Pei-Ling Hsieh, Kun-Ling Tsai
      Osteoarthritis (OA) is a degenerative joint disease affecting a large population of people. Although the elevated expression of PKR (double stranded RNA-dependent protein kinase) and MMP-13 (collagenase-3) have been indicated to play pivotal roles in the pathogenesis of OA, the exact mechanism underlying the regulation of MMP-13 by PKR following inflammatory stimulation was relatively unknown. The purpose of this study was to determine the signaling pathway involved in the PKR-mediated induction of MMP-13 after TNF-α-stimulation. In this study, cartilages of knee joint were obtained from OA subjects who underwent arthroplastic knee surgery. Cartilages were used for tissue analysis or for chondrocytes isolation. In results, the upregulated expression of PKR was observed in damaged OA cartilages as well as in TNF-α-stimulated chondrocytes. Phosphorylation of PKC (protein kinase C) was found after TNF-α administration or PKR activation using poly(I:C), indicating PKC was regulated by PKR. The subsequent increased activity of NADPH oxidase led to oxidative stress accumulation and antioxidant capacity downregulation followed by an exaggerated inflammatory response with elevated levels of COX-2 and IL-8 via ERK/NF-κB pathway. Activated ERK pathway also impeded the inhibition of MMP-13 by PPAR-γ. These findings demonstrated that TNF-α-induced PKR activation triggered oxidative stress-mediated inflammation and MMP-13 in human chondrocytes. Unraveling these deregulated signaling cascades will deepen our knowledge of OA pathophysiology and provide aid in the development of novel therapies.
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      PubDate: 2017-09-05T23:30:16Z
      DOI: 10.1016/j.redox.2017.08.011
      Issue No: Vol. 14 (2017)
       
  • Augmentation of intracellular iron using iron sucrose enhances the
           toxicity of pharmacological ascorbate in colon cancer cells

    • Authors: Kristin E. Brandt; Kelly C. Falls; Joshua D. Schoenfeld; Samuel N. Rodman; Zhimin Gu; Fenghuang Zhan; Joseph J. Cullen; Brett A. Wagner; Garry R. Buettner; Bryan G. Allen; Daniel J. Berg; Douglas R. Spitz; Melissa A. Fath
      Pages: 82 - 87
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Kristin E. Brandt, Kelly C. Falls, Joshua D. Schoenfeld, Samuel N. Rodman, Zhimin Gu, Fenghuang Zhan, Joseph J. Cullen, Brett A. Wagner, Garry R. Buettner, Bryan G. Allen, Daniel J. Berg, Douglas R. Spitz, Melissa A. Fath
      Pharmacological doses (> 1mM) of ascorbate (a.k.a., vitamin C) have been shown to selectively kill cancer cells through a mechanism that is dependent on the generation of H2O2 at doses that are safely achievable in humans using intravenous administration. The process by which ascorbate oxidizes to form H2O2 is thought to be mediated catalytically by redox active metal ions such as iron (Fe). Because intravenous iron sucrose is often administered to colon cancer patients to help mitigate anemia, the current study assessed the ability of pharmacological ascorbate to kill colon cancer cells in the presence and absence of iron sucrose. In vitro survival assays showed that 10mM ascorbate exposure (2h) clonogenically inactivated 40–80% of exponentially growing colon cancer cell lines (HCT116 and HT29). When the H2O2 scavenging enzyme, catalase, was added to the media, or conditionally over-expressed using a doxycycline inducible vector, the toxicity of pharmacological ascorbate was significantly blunted. When colon cancer cells were treated in the presence or absence of 250µM iron sucrose, then rinsed, and treated with 10mM ascorbate, the cells demonstrated increased levels of labile iron that resulted in significantly increased clonogenic cell killing, compared to pharmacological ascorbate alone. Interestingly, when colon cancer cells were treated with iron sucrose for 1h and then 10mM ascorbate was added to the media in the continued presence of iron sucrose, there was no enhancement of toxicity despite similar increases in intracellular labile iron. The combination of iron chelators, deferoxamine and diethylenetriaminepentaacetic acid, significantly inhibited the toxicity of either ascorbate alone or ascorbate following iron sucrose. These observations support the hypothesis that increasing intracellular labile iron pools, using iron sucrose, can be used to increase the toxicity of pharmacological ascorbate in human colon cancer cells by a mechanism involving increased generation of H2O2.

      PubDate: 2017-09-11T23:57:42Z
      DOI: 10.1016/j.redox.2017.08.017
      Issue No: Vol. 14 (2017)
       
  • Role of glutathione biosynthesis in endothelial dysfunction and fibrosis

    • Authors: Cristina Espinosa-Díez; Verónica Miguel; Susana Vallejo; Francisco J. Sánchez; Elena Sandoval; Eva Blanco; Pablo Cannata; Concepción Peiró; Carlos F. Sánchez-Ferrer; Santiago Lamas
      Pages: 88 - 99
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Cristina Espinosa-Díez, Verónica Miguel, Susana Vallejo, Francisco J. Sánchez, Elena Sandoval, Eva Blanco, Pablo Cannata, Concepción Peiró, Carlos F. Sánchez-Ferrer, Santiago Lamas
      Glutathione (GSH) biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The rate-limiting step requires glutamate-cysteine ligase (GCL), which is composed of the catalytic (GCLc) and the modulatory (GCLm) subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice). In murine lung endothelial cells (MLEC) derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177) and increased eNOS S-glutathionylation, compared to MLEC from wild type (WT) mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+) male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH4. To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+) mice. We observed that obstructed kidneys from Gclc(e/+) mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses.
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      PubDate: 2017-09-11T23:57:42Z
      DOI: 10.1016/j.redox.2017.08.019
      Issue No: Vol. 14 (2017)
       
  • Iron accumulation in senescent cells is coupled with impaired
           ferritinophagy and inhibition of ferroptosis

    • Authors: Shashank Masaldan; Sharnel A.S. Clatworthy; Cristina Gamell; Peter M. Meggyesy; Antonia-Tonia Rigopoulos; Sue Haupt; Ygal Haupt; Delphine Denoyer; Paul A. Adlard; Ashley I. Bush; Michael A. Cater
      Pages: 100 - 115
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Shashank Masaldan, Sharnel A.S. Clatworthy, Cristina Gamell, Peter M. Meggyesy, Antonia-Tonia Rigopoulos, Sue Haupt, Ygal Haupt, Delphine Denoyer, Paul A. Adlard, Ashley I. Bush, Michael A. Cater
      Cellular senescence is characterised by the irreversible arrest of proliferation, a pro-inflammatory secretory phenotype and evasion of programmed cell death mechanisms. We report that senescence alters cellular iron acquisition and storage and also impedes iron-mediated cell death pathways. Senescent cells, regardless of stimuli (irradiation, replicative or oncogenic), accumulate vast amounts of intracellular iron (up to 30-fold) with concomitant changes in the levels of iron homeostasis proteins. For instance, ferritin (iron storage) levels provided a robust biomarker of cellular senescence, for associated iron accumulation and for resistance to iron-induced toxicity. Cellular senescence preceded iron accumulation and was not perturbed by sustained iron chelation (deferiprone). Iron accumulation in senescent cells was driven by impaired ferritinophagy, a lysosomal process that promotes ferritin degradation and ferroptosis. Lysosomal dysfunction in senescent cells was confirmed through several markers, including the build-up of microtubule-associated protein light chain 3 (LC3-II) in autophagosomes. Impaired ferritin degradation explains the iron accumulation phenotype of senescent cells, whereby iron is effectively trapped in ferritin creating a perceived cellular deficiency. Accordingly, senescent cells were highly resistant to ferroptosis. Promoting ferritin degradation by using the autophagy activator rapamycin averted the iron accumulation phenotype of senescent cells, preventing the increase of TfR1, ferritin and intracellular iron, but failed to re-sensitize these cells to ferroptosis. Finally, the enrichment of senescent cells in mouse ageing hepatic tissue was found to accompany iron accumulation, an elevation in ferritin and mirrored our observations using cultured senescent cells.
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      PubDate: 2017-09-11T23:57:42Z
      DOI: 10.1016/j.redox.2017.08.015
      Issue No: Vol. 14 (2017)
       
  • Exercise intervention attenuates hyperhomocysteinemia-induced aortic
           endothelial oxidative injury by regulating SIRT1 through mitigating NADPH
           oxidase/LOX-1 signaling

    • Authors: Shih-Hung Chan; Ching-Hsia Hung; Jhih-Yuan Shih; Pei-Ming Chu; Yung-Hsin Cheng; Huei-Chen Lin; Pei-Ling Hsieh; Kun-Ling Tsai
      Pages: 116 - 125
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Shih-Hung Chan, Ching-Hsia Hung, Jhih-Yuan Shih, Pei-Ming Chu, Yung-Hsin Cheng, Huei-Chen Lin, Pei-Ling Hsieh, Kun-Ling Tsai
      Coronary artery disease (CAD) is a critical cardiovascular disease and a cause of high morbidity and mortality in this world. Hyperhomocysteinemia (HHcy) has been suggested as a risk factor for CAD. In addition, SIRT1 (sirtuin 1) has been reported to play a protective role in a variety of diseases, especially in the cardiovascular system. The main purpose of this study was to investigate the effects of exercise training on apoptosis and inflammation in HHcy animals. We also tested whether exercise protected against Hhcy-induced dysfunction of endothelium through modulation of SIRT1. C57BL mice (8 in each group) were fed with or without 1% L-methionine (w/w) in water for 4 months to induce HHcy. We found that Hhcy repressed SIRT1 and AMPK expression and increased NADPH oxidase activity. Plasma MDA, endothelium LOX-1 and p-p38 were up-regulated by Hhcy induction. NF-κB and it downstream molecules were activated under Hhcy situation, thereby promoting pro-inflammatory responses. Moreover, we also reported that Hhcy caused endothelium apoptosis involving Akt inhibition and mitochondria-dependent apoptotic pathways. Exercise training significantly protected against endothelium from Hhcy caused oxidative injuries. In addition, EX527 (SIRT1 inhibitor) reduced the therapeutic effects by exercise. Our results had indicated that exercise training prevent the development of atherosclerosis through SIRT1 activation and oxidative stress inhibition under Hhcy situation.

      PubDate: 2017-09-11T23:57:42Z
      DOI: 10.1016/j.redox.2017.08.016
      Issue No: Vol. 14 (2017)
       
  • Regulation of platelet activation and thrombus formation by reactive
           oxygen species

    • Authors: Jianlin Qiao; Jane F. Arthur; Elizabeth E. Gardiner; Robert K. Andrews; Lingyu Zeng; Kailin Xu
      Pages: 126 - 130
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Jianlin Qiao, Jane F. Arthur, Elizabeth E. Gardiner, Robert K. Andrews, Lingyu Zeng, Kailin Xu
      Reactive oxygen species (ROS) are generated within activated platelets and play an important role in regulating platelet responses to collagen and collagen-mediated thrombus formation. As a major collagen receptor, platelet-specific glycoprotein (GP)VI is a member of the immunoglobulin (Ig) superfamily, with two extracellular Ig domains, a mucin domain, a transmembrane domain and a cytoplasmic tail. GPVI forms a functional complex with the Fc receptor γ-chain (FcRγ) that, following receptor dimerization, signals via an intracellular immunoreceptor tyrosine-based activation motif (ITAM), leading to rapid activation of Src family kinase signaling pathways. Our previous studies demonstrated that an unpaired thiol in the cytoplasmic tail of GPVI undergoes rapid oxidation to form GPVI homodimers in response to ligand binding, indicating an oxidative submembranous environment in platelets after GPVI stimulation. Using a redox-sensitive fluorescent dye (H2DCF-DA) in a flow cytometric assay to measure changes in intracellular ROS, we showed generation of ROS downstream of GPVI consists of two distinct phases: an initial Syk-independent burst followed by additional Syk-dependent generation. In this review, we will discuss recent findings on the regulation of platelet function by ROS, focusing on GPVI-dependent platelet activation and thrombus formation.
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      PubDate: 2017-09-11T23:57:42Z
      DOI: 10.1016/j.redox.2017.08.021
      Issue No: Vol. 14 (2017)
       
  • Nitric oxide prevents Aft1 activation and metabolic remodeling in
           frataxin-deficient yeast

    • Authors: David Alsina; Joaquim Ros; Jordi Tamarit
      Pages: 131 - 141
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): David Alsina, Joaquim Ros, Jordi Tamarit
      Yeast frataxin homolog (Yfh1) is the orthologue of human frataxin, a mitochondrial protein whose deficiency causes Friedreich Ataxia. Yfh1 deficiency activates Aft1, a transcription factor governing iron homeostasis in yeast cells. Although the mechanisms causing this activation are not completely understood, it is assumed that it may be caused by iron-sulfur deficiency. However, several evidences indicate that activation of Aft1 occurs in the absence of iron-sulfur deficiency. Besides, Yfh1 deficiency also leads to metabolic remodeling (mainly consisting in a shift from respiratory to fermentative metabolism) and to induction of Yhb1, a nitric oxide (NO) detoxifying enzyme. In this work, we have used conditional Yfh1 mutant yeast strains to investigate the relationship between NO, Aft1 activation and metabolic remodeling. We have observed that NO prevents Aft1 activation caused by Yfh1 deficiency. This phenomenon is not observed when Aft1 is activated by iron scarcity or impaired iron-sulfur biogenesis. In addition, analyzing key metabolic proteins by a targeted proteomics approach, we have observed that NO prevents the metabolic remodeling caused by Yfh1 deficiency. We conclude that Aft1 activation in Yfh1-deficient yeasts is not caused by iron-sulfur deficiency or iron scarcity. Our hypothesis is that Yfh1 deficiency leads to the presence of anomalous iron species that can compromise iron bioavailability and activate a signaling cascade that results in Aft1 activation and metabolic remodeling.
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      PubDate: 2017-09-17T15:44:26Z
      DOI: 10.1016/j.redox.2017.09.001
      Issue No: Vol. 14 (2017)
       
  • IDH2 deficiency increases the liver susceptibility to ischemia-reperfusion
           injury via increased mitochondrial oxidative injury

    • Authors: Sang Jun Han; Hong Seok Choi; Jee In Kim; Jeen-Woo Park; Kwon Moo Park
      Pages: 142 - 153
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Sang Jun Han, Hong Seok Choi, Jee In Kim, Jeen-Woo Park, Kwon Moo Park
      Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) is a major producer of mitochondrial NADPH, required for glutathione (GSH)-associated mitochondrial antioxidant systems including glutathione peroxidase (GPx) and glutathione reductase (GR). Here, we investigated the role of IDH2 in hepatic ischemia-reperfusion (HIR)-associated mitochondrial injury using Idh2-knockout (Idh2 -/-) mice and wild-type (Idh2 +/+) littermates. Mice were subjected to either 60min of partial liver ischemia or sham-operation. Some mice were administered with 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (mito-TEMPO, a mitochondria-targeting antioxidant). HIR induced severe histological and functional damages of liver in both Idh2 +/+ mice and Idh2 -/- mice and those damages were more severe in Idh2 -/- mice than in wild-type littermates. HIR induces dysfunction of IDH2, leading to the decreases of NADPH level and mitochondrial GR and GPx functions, consequently resulting in mitochondrial and cellular oxidative injury as reflected by mitochondrial cristae loss, mitochondrial fragmentation, shift in mitochondrial fission, cytochrome c release, and cell death. These HIR-induced changes were greater in Idh2 -/- mice than wild-type mice. The mito-TEMPO supplement significantly attenuated the aforementioned changes, and these attenuations were much greater in Idh2 -/- mice when compared with wild-type littermates. Taken together, results have demonstrated that HIR impairs in the IDH2-NADPH-GSH mitochondrial antioxidant system, resulting in increased mitochondrial oxidative damage and dysfunction, suggesting that IDH2 plays a critical role in mitochondrial redox balance and HIR-induced impairment of IDH2 function is associated with the pathogenesis of ischemia-reperfusion-induced liver failure.
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      PubDate: 2017-09-23T15:04:34Z
      DOI: 10.1016/j.redox.2017.09.003
      Issue No: Vol. 14 (2017)
       
  • Identification of novel Nrf2 activators from Cinnamomum chartophyllum H.W.
           Li and their potential application of preventing oxidative insults in
           human lung epithelial cells

    • Authors: Ming-Xing Zhou; Guo-Hui Li; Bin Sun; You-Wei Xu; Ai-Ling Li; Yan-Ru Li; Dong-Mei Ren; Xiao-Ning Wang; Xue-Sen Wen; Hong-Xiang Lou; Tao Shen
      Pages: 154 - 163
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Ming-Xing Zhou, Guo-Hui Li, Bin Sun, You-Wei Xu, Ai-Ling Li, Yan-Ru Li, Dong-Mei Ren, Xiao-Ning Wang, Xue-Sen Wen, Hong-Xiang Lou, Tao Shen
      Human lung tissue, directly exposed to the environmental oxidants and toxicants, is apt to be harmed to bring about acute or chronic oxidative insults. The nuclear factor erythroid 2-related factor 2 (Nrf2) represents a central cellular defense mechanism, and is a target for developing agents against oxidative insult-induced human lung diseases. Our previous study found that the EtOH extract of Cinnamomum chartophyllum protected human bronchial epithelial cells against oxidative insults via Nrf2 activation. In this study, a systemic phytochemical investigation of the aerial parts of C. chartophyllum led to the isolation of thirty chemical constituents, which were further evaluated for their Nrf2 inducing potential using NAD(P)H: quinone reductase (QR) assay. Among these purified constituents, a sesquiterpenoid bearing α, β-unsaturated ketone group, 3S-(+)-9-oxonerolidol (NLD), and a diphenyl sharing phenolic groups, 3, 3′, 4, 4′-tetrahydroxydiphenyl (THD) significantly activated Nrf2 and its downstream genes, NAD(P)H quinone oxidoreductase 1 (NQO-1), and γ-glutamyl cysteine synthetase (γ-GCS), and enhanced the nuclear translocation and stabilization of Nrf2 in human lung epithelial cells. Importantly, NLD and THD had no toxicities under the Nrf2 inducing doses. THD also demonstrated a potential of interrupting Nrf2-Keap1 protein–protein interaction (PPI). Furthermore, NLD and THD protected human lung epithelial cells against sodium arsenite [As(III)]-induced cytotoxicity. Taken together, we conclude that NLD and THD are two novel Nrf2 activators with potential application of preventing acute and chronic oxidative insults in human lung tissue.
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      PubDate: 2017-09-23T15:04:34Z
      DOI: 10.1016/j.redox.2017.09.004
      Issue No: Vol. 14 (2017)
       
  • The 2-oxoglutarate carrier promotes liver cancer by sustaining
           mitochondrial GSH despite cholesterol loading

    • Authors: Anna Baulies; Joan Montero; Nuria Matías; Naroa Insausti; Oihana Terrones; Gorka Basañez; Carmen Vallejo; Laura Conde de La Rosa; Laura Martinez; David Robles; Albert Morales; Joaquin Abian; Montserrat Carrascal; Keigo Machida; Dinesh B.U. Kumar; Hidekazu Tsukamoto; Neil Kaplowitz; Carmen Garcia-Ruiz; José C. Fernández-Checa
      Pages: 164 - 177
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Anna Baulies, Joan Montero, Nuria Matías, Naroa Insausti, Oihana Terrones, Gorka Basañez, Carmen Vallejo, Laura Conde de La Rosa, Laura Martinez, David Robles, Albert Morales, Joaquin Abian, Montserrat Carrascal, Keigo Machida, Dinesh B.U. Kumar, Hidekazu Tsukamoto, Neil Kaplowitz, Carmen Garcia-Ruiz, José C. Fernández-Checa
      Cancer cells exhibit mitochondrial cholesterol (mt-cholesterol) accumulation, which contributes to cell death resistance by antagonizing mitochondrial outer membrane (MOM) permeabilization. Hepatocellular mt-cholesterol loading, however, promotes steatohepatitis, an advanced stage of chronic liver disease that precedes hepatocellular carcinoma (HCC), by depleting mitochondrial GSH (mGSH) due to a cholesterol-mediated impairment in mGSH transport. Whether and how HCC cells overcome the restriction of mGSH transport imposed by mt-cholesterol loading to support mGSH uptake remains unknown. Although the transport of mGSH is not fully understood, SLC25A10 (dicarboxylate carrier, DIC) and SLC25A11 (2-oxoglutarate carrier, OGC) have been involved in mGSH transport, and therefore we examined their expression and role in HCC. Unexpectedly, HCC cells and liver explants from patients with HCC exhibit divergent expression of these mitochondrial carriers, with selective OGC upregulation, which contributes to mGSH maintenance. OGC but not DIC downregulation by siRNA depleted mGSH levels and sensitized HCC cells to hypoxia-induced ROS generation and cell death as well as impaired cell growth in three-dimensional multicellular HCC spheroids, effects that were reversible upon mGSH replenishment by GSH ethyl ester, a membrane permeable GSH precursor. We also show that OGC regulates mitochondrial respiration and glycolysis. Moreover, OGC silencing promoted hypoxia-induced cardiolipin peroxidation, which reversed the inhibition of cholesterol on the permeabilization of MOM-like liposomes induced by Bax or Bak. Genetic OGC knockdown reduced the ability of tumor-initiating stem-like cells to induce liver cancer. These findings underscore the selective overexpression of OGC as an adaptive mechanism of HCC to provide adequate mGSH levels in the face of mt-cholesterol loading and suggest that OGC may be a novel therapeutic target for HCC treatment.
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      PubDate: 2017-09-30T16:03:23Z
      DOI: 10.1016/j.redox.2017.08.022
      Issue No: Vol. 14 (2017)
       
  • Short overview on metabolomic approach and redox changes in psychiatric
           disorders

    • Authors: Gordana Nedic Erjavec; Marcela Konjevod; Matea Nikolac Perkovic; Dubravka Svob Strac; Lucija Tudor; Coral Barbas; Tilman Grune; Neven Zarkovic; Nela Pivac
      Pages: 178 - 186
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Gordana Nedic Erjavec, Marcela Konjevod, Matea Nikolac Perkovic, Dubravka Svob Strac, Lucija Tudor, Coral Barbas, Tilman Grune, Neven Zarkovic, Nela Pivac
      Schizophrenia, depression and posttraumatic stress disorder (PTSD) are severe mental disorders and complicated diagnostic entities, due to their phenotypic, biological and genetic heterogeneity, unknown etiology, and poorly understood alterations in biological pathways and biological mechanisms. Disturbed homeostasis between overproduction of oxidant species, overcoming redox regulation and a lack of cellular antioxidant defenses, resulting in free radical-mediated pathology and subsequent neurotoxicity contributes to development of depression, schizophrenia and PTSD, their heterogeneous clinical presentation and resistance to treatment. Metabolomics is a discipline that combines different strategies with the aim to extract, detect, identify and quantify all metabolites that are present in a biological sample and might provide mechanistic insights into the etiology of various psychiatric disorders. Therefore, oxidative stress research combined with metabolomics might offer a novel approach in dissecting psychiatric disorders, since these data-driven but not necessarily hypothesis-driven methods might identify new targets, molecules and pathways responsible for development of schizophrenia, depression or PTSD. Findings from the oxidative research in psychiatry together with metabolomics data might facilitate development of specific and validated prognostic, therapeutic and clinical biomarkers. These methods might reveal bio-signatures of individual patients, leading to individualized treatment approach. In reviewing findings related to oxidative stress and metabolomics in selected psychiatric disorders, we have highlighted how these novel approaches might make a unique contribution to deeper understanding of psychopathological alterations underlying schizophrenia, depression and PTSD.
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      PubDate: 2017-09-23T15:04:34Z
      DOI: 10.1016/j.redox.2017.09.002
      Issue No: Vol. 14 (2017)
       
  • Metformin selectively targets redox control of complex I energy
           transduction

    • Authors: Amy R. Cameron; Lisa Logie; Kashyap Patel; Stefan Erhardt; Sandra Bacon; Paul Middleton; Jean Harthill; Calum Forteath; Josh T. Coats; Calum Kerr; Heather Curry; Derek Stewart; Kei Sakamoto; Peter Repiščák; Martin J. Paterson; Ilmo Hassinen; Gordon McDougall; Graham Rena
      Pages: 187 - 197
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Amy R. Cameron, Lisa Logie, Kashyap Patel, Stefan Erhardt, Sandra Bacon, Paul Middleton, Jean Harthill, Calum Forteath, Josh T. Coats, Calum Kerr, Heather Curry, Derek Stewart, Kei Sakamoto, Peter Repiščák, Martin J. Paterson, Ilmo Hassinen, Gordon McDougall, Graham Rena
      Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled.

      PubDate: 2017-09-23T15:04:34Z
      DOI: 10.1016/j.redox.2017.08.018
      Issue No: Vol. 14 (2017)
       
  • Integrated metabolic models for xenobiotic induced mitochondrial toxicity
           in skeletal muscle

    • Authors: William Dott; Jayne Wright; Kelvin Cain; Pratibha Mistry; Karl E. Herbert
      Pages: 198 - 210
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): William Dott, Jayne Wright, Kelvin Cain, Pratibha Mistry, Karl E. Herbert
      There is a need for robust in vitro models to sensitively capture skeletal muscle adverse toxicities early in the research and development of novel xenobiotics. To this end, an in vitro rat skeletal muscle model (L6) was used to study the translation of transcriptomics data generated from an in vivo rat model. Novel sulfonyl isoxazoline herbicides were associated with skeletal muscle toxicity in an in vivo rat model. Gene expression pathway analysis on skeletal muscle tissues taken from in vivo repeat dose studies identified enriched pathways associated with mitochondrial dysfunction, oxidative stress, energy metabolism, protein regulation and cell cycle. Mitochondrial dysfunction and oxidative stress were further explored using in vitro L6 metabolic models. These models demonstrated that the sulfonyl isoxazoline compounds induced mitochondrial dysfunction, mitochondrial superoxide production and apoptosis. These in vitro findings accurately concurred with the in vivo transcriptomics data, thereby confirming the ability of the L6 skeletal muscle models to identify relevant in vivo mechanisms of xenobiotic-induced toxicity. Moreover, these results highlight the sensitivity of the L6 galactose media model to study mitochondrial perturbation associated with skeletal muscle toxicity; this model may be utilised to rank the potency of novel xenobiotics upon further validation.
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      PubDate: 2017-09-23T15:04:34Z
      DOI: 10.1016/j.redox.2017.09.006
      Issue No: Vol. 14 (2017)
       
  • Cytoprotective mechanisms of DJ-1 against oxidative stress through
           modulating ERK1/2 and ASK1 signal transduction

    • Authors: Stephanie E. Oh; M. Maral Mouradian
      Pages: 211 - 217
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Stephanie E. Oh, M. Maral Mouradian
      DJ-1 is a highly conserved multifunctional protein linked to both neurodegeneration and neoplasia. Among its various activities is an antioxidant property leading to cytoprotection under oxidative stress conditions. This is associated with the ability to modulate signal transduction events that determine how the cell regulates normal processes such as growth, senescence, apoptosis, and autophagy in order to adapt to environmental stimuli and stresses. Alterations in DJ-1 expression or function can disrupt homeostatic signaling networks and initiate cascades that play a role in the pathogenesis of conditions such as Parkinson's disease and cancer. DJ-1 plays a major role in various signaling pathways. Related to its anti-oxidant properties, it mediates cell survival and proliferation by activating the extracellular signal-regulated kinase (ERK1/2) pathway and attenuates cell death signaling by inhibiting apoptosis signal-regulating kinase 1 (ASK1) activation. Here, we review the ways through which DJ-1 regulates these pathways, focusing on how its regulation of signal transduction contributes to cellular homeostasis and the pathologic states that result from their dysregulation.

      PubDate: 2017-09-30T16:03:23Z
      DOI: 10.1016/j.redox.2017.09.008
      Issue No: Vol. 14 (2017)
       
  • N-acetylcysteine attenuates systemic platelet activation and cerebral
           vessel thrombosis in diabetes

    • Authors: Bin Wang; Tak Yee Aw; Karen Y. Stokes
      Pages: 218 - 228
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Bin Wang, Tak Yee Aw, Karen Y. Stokes
      Objective We previously demonstrated that diabetes exacerbates stroke-induced brain injury, and that this correlates with brain methylglyoxal (MG)-to-glutathione (GSH) status. Cerebral injury was reversed by N-acetylcysteine (NAC). Here we tested if the pro-thrombotic phenotype seen in the systemic circulation and brain during diabetes was associated with increased MG-glycation of proteins, and if NAC could reverse this. Methods The streptozotocin (STZ)-induced mouse model of type 1 diabetes was used. Thrombus formation in venules and arterioles (pial circulation) was determined by intravital videomicroscopy using the light-dye method. Circulating blood platelet-leukocyte aggregates (PLAs) were analyzed by flow cytometry 1 wk before other measurements. GSH and MG levels in platelets were measured by HPLC. MG-modified proteins, glutathione peroxidase-1 (GPx-1), and superoxide dismutase-1 (SOD1) levels were detected in platelets by western blot at 20 weeks. Proteins involved in coagulation were quantified by ELISA. NAC (2mM) was given in drinking water for 3 weeks before the terminal experiment. Results Thrombus development was accelerated by diabetes in a time-dependent manner. % PLAs were significantly elevated by diabetes. Plasma activated plasminogen activator inhibitor type 1 levels were progressively increased with diabetes duration, with tail bleeding time reduced by 20 wks diabetes. Diabetes lowered platelet GSH levels, GPx-1 and SOD-1 expression. This was associated with higher MG levels, and increased MG-adduct formation in platelets. NAC treatment partly or completely reversed the effects of diabetes. Conclusion Collectively, these results show that the diabetic blood and brain become progressively more susceptible to platelet activation and thrombosis. NAC, given after the establishment of diabetes, may offer protection against the risk for stroke by altering both systemic and vascular prothrombotic responses via enhancing platelet GSH, and GSH-dependent MG elimination, as well as correcting levels of antioxidants such as SOD1 and GPx-1.
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      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.09.005
      Issue No: Vol. 14 (2017)
       
  • Sirt1-Sirt3 axis regulates human blood-brain barrier permeability in
           response to ischemia

    • Authors: Tao Chen; Shu-Hui Dai; Xia Li; Peng Luo; Jie Zhu; Yu-Hai Wang; Zhou Fei; Xiao-Fan Jiang
      Pages: 229 - 236
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Tao Chen, Shu-Hui Dai, Xia Li, Peng Luo, Jie Zhu, Yu-Hai Wang, Zhou Fei, Xiao-Fan Jiang
      Sirtuin1 (Sirt1) and Sirtuin3 (Sirt3) are two well-characterized members of the silent information regulator 2 (Sir2) family of proteins. Both Sirt1 and Sirt3 have been shown to play vital roles in resistance to cellular stress, but the interaction between these two sirtuins has not been fully determined. In this study, we investigated the role of Sirt1-Sirt3 axis in blood-brain barrier (BBB) permeability after ischemia in vitro. Human brain microvascular endothelial cells and astrocytes were co-cultured to model the BBB in vitro and oxygen and glucose deprivation (OGD) was performed to mimic ischemia. The results of transepithelial electrical resistance (TEER) showed that suppression of Sirt1 via siRNA or salermide significantly decreased BBB permeability, whereas Sirt3 knockdown increased BBB permeability. In addition, Sirt1 was shown to regulate Sirt3 expression after OGD through inhibiting the AMPK-PGC1 pathway. Application of the AMPK inhibitor compound C partially prevented the effects of Sirt1-Sirt3 axis on BBB permeability after OGD. The results of flow cytometry and cytochrome c release demonstrated that Sirt1 and Sirt3 exert opposite effects on OGD-induced apoptosis. Furthermore, suppression of Sirt1 was shown to attenuate mitochondrial reactive oxygen species (ROS) generation, which contribute to the Sirt1-Sirt3 axis-induced regulation of BBB permeability and cell damage. In summary, these findings demonstrate that the Sirt1-Sirt3 axis might act as an important modulator in BBB physiology, and could be a therapeutic target for ischemic stroke via regulating mitochondrial ROS generation.

      PubDate: 2017-09-30T16:03:23Z
      DOI: 10.1016/j.redox.2017.09.016
      Issue No: Vol. 14 (2017)
       
  • Butaselen prevents hepatocarcinogenesis and progression through inhibiting
           thioredoxin reductase activity

    • Authors: Xiaoqing Zheng; Weiwei Ma; Ruoxuan Sun; Hanwei Yin; Fei Lin; Yuxi Liu; Wei Xu; Huihui Zeng
      Pages: 237 - 249
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Xiaoqing Zheng, Weiwei Ma, Ruoxuan Sun, Hanwei Yin, Fei Lin, Yuxi Liu, Wei Xu, Huihui Zeng
      Hepatocellular carcinoma (HCC) accounts for most of primary liver cancer, of which five-year survival rate remains low and chemoprevention has become a strategy to reduce disease burden of HCC. We aim to explore the in vivo chemopreventive effect of an organoselenium-containing compound butaselen (BS) against hepatocarcinogenesis and its underlying mechanisms. Pre- and sustained BS treatment (9, 18 and 36mg/Kg BS) could dose-dependently inhibit chronic hepatic inflammation, fibrosis, cirrhosis and HCC on murine models with 24 weeks treatment scheme. The thioredoxin reductase (TrxR), NF-κB pathway and pro-inflammatory factors were activated during hepatocarcinogenesis, while their expression were decreased by BS treatment. BS treatment could also significantly reduce tumor volume in H22-bearing models and remarkably slow tumor growth. HCC cell lines HepG2, Bel7402 and Huh7 were time- and dose-dependently inhibited by BS treatment. G2/M arrest and apoptosis were observed in HepG2 cells after BS treatment, which were mediated by TrxR/Ref-1 and NF-κB pathways inhibition. BS generated reactive oxygen species (ROS), which could be reduced by antioxidant N-acetyl-L-cysteine (NAC) and NADPH oxidase inhibitor DPI. NAC could markedly increase HepG2 cells viability. TrxR activity of HepG2 cells treated with BS were significantly decreased in parallel with proliferative inhibition. The TrxR1-knockdown HepG2 cells also exhibited low TrxR1 activity, high ROS level, relatively low proliferation rate and increased resistance to BS treatment. In conclusion, BS can prevent hepatocarcinogenesis through inhibiting chronic inflammation, cirrhosis and tumor progression. The underlying mechanisms may include TrxR activity inhibition, leading to ROS elevation, G2/M arrest and apoptosis.

      PubDate: 2017-09-30T16:03:23Z
      DOI: 10.1016/j.redox.2017.09.014
      Issue No: Vol. 14 (2017)
       
  • Complement receptor 3 mediates NADPH oxidase activation and dopaminergic
           neurodegeneration through a Src-Erk-dependent pathway

    • Authors: Liyan Hou; Ke Wang; Cong Zhang; Fuqiang Sun; Yuning Che; Xiulan Zhao; Dan Zhang; Huihua Li; Qingshan Wang
      Pages: 250 - 260
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Liyan Hou, Ke Wang, Cong Zhang, Fuqiang Sun, Yuning Che, Xiulan Zhao, Dan Zhang, Huihua Li, Qingshan Wang
      Microglial NADPH oxidase (Nox2) plays a key role in chronic neuroinflammation and related dopaminergic neurodegeneration in Parkinson's disease (PD). However, the mechanisms behind Nox2 activation remain unclear. Here, we revealed the critical role of complement receptor 3 (CR3), a microglia-specific pattern recognition receptor, in Nox2 activation and subsequent dopaminergic neurodegeneration by using paraquat and maneb-induced PD model. Suppression or genetic deletion of CR3 impeded paraquat and maneb-induced activation of microglial Nox2, which was associated with attenuation of dopaminergic neurodegeneration. Mechanistic inquiry revealed that blocking CR3 reduced paraquat and maneb-induced membrane translocation of Nox2 cytosolic subunit p47phox, an essential step for Nox2 activation. Src and Erk (extracellular regulated protein kinases) were subsequently recognized as the downstream signals of CR3. Moreover, inhibition of Src or Erk impaired Nox2 activation in response to paraquat and maneb co-exposure. Finally, we found that CR3-deficient mice were more resistant to paraquat and maneb-induced Nox2 activation and nigral dopaminergic neurodegeneration as well as motor dysfunction than the wild type controls. Taken together, our results showed that CR3 regulated Nox2 activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway in a two pesticide-induced PD model, providing novel insights into the immune pathogenesis of PD.

      PubDate: 2017-10-07T16:28:42Z
      DOI: 10.1016/j.redox.2017.09.017
      Issue No: Vol. 14 (2017)
       
  • Cardiac-specific inactivation of LPP3 in mice leads to myocardial
           dysfunction and heart failure

    • Authors: Mini Chandra; Diana Escalante-Alcalde; Md. Shenuarin Bhuiyan; Anthony Wayne Orr; Christopher Kevil; Andrew J. Morris; Hyung Nam; Paari Dominic; Kevin J. McCarthy; Sumitra Miriyala; Manikandan Panchatcharam
      Pages: 261 - 271
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Mini Chandra, Diana Escalante-Alcalde, Md. Shenuarin Bhuiyan, Anthony Wayne Orr, Christopher Kevil, Andrew J. Morris, Hyung Nam, Paari Dominic, Kevin J. McCarthy, Sumitra Miriyala, Manikandan Panchatcharam
      Lipid Phosphate phosphatase 3 (LPP3), encoded by the Plpp3 gene, is an enzyme that dephosphorylates the bioactive lipid mediator lysophosphatidic acid (LPA). To study the role of LPP3 in the myocardium, we generated a cardiac specific Plpp3 deficient mouse strain. Although these mice were viable at birth in contrast to global Plpp3 knockout mice, they showed increased mortality ~ 8 months. LPP3 deficient mice had enlarged hearts with reduced left ventricular performance as seen by echocardiography. Cardiac specific Plpp3 deficient mice had longer ventricular effective refractory periods compared to their Plpp3 littermates. We observed that lack of Lpp3 enhanced cardiomyocyte hypertrophy based on analysis of cell surface area. We found that lack of Lpp3 signaling was mediated through the activation of Rho and phospho-ERK pathways. There are increased levels of fetal genes Natriuretic Peptide A and B (Nppa and Nppb) expression indicating myocardial dysfunction. These mice also demonstrate mitochondrial dysfunction as evidenced by a significant decrease (P < 0.001) in the basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity as measured through mitochondrial bioenergetics. Histology and transmission electron microscopy of these hearts showed disrupted sarcomere organization and intercalated disc, with a prominent disruption of the cristae and vacuole formation in the mitochondria. Our findings suggest that LPA/LPP3-signaling nexus plays an important role in normal function of cardiomyocytes.
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      PubDate: 2017-10-07T16:28:42Z
      DOI: 10.1016/j.redox.2017.09.015
      Issue No: Vol. 14 (2017)
       
  • Autophagy regulates DUOX1 localization and superoxide production in airway
           epithelial cells during chronic IL-13 stimulation

    • Authors: John D. Dickinson; Jenea M. Sweeter; Kristi J. Warren; Iman M. Ahmad; Xavier De Deken; Matthew C. Zimmerman; Steven L. Brody
      Pages: 272 - 284
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): John D. Dickinson, Jenea M. Sweeter, Kristi J. Warren, Iman M. Ahmad, Xavier De Deken, Matthew C. Zimmerman, Steven L. Brody
      The airway epithelium is a broad interface with the environment, mandating well-orchestrated responses to properly modulate inflammation. Classically, autophagy is a homeostatic pathway triggered in response to external cellular stresses, and is elevated in chronic airway diseases. Recent findings highlight the additional role of autophagy in vesicle trafficking and protein secretion, implicating autophagy pathways in complex cellular responses in disease. Th2 cytokines, IL-13 and IL-4, are increased in asthma and other airway diseases contributing to chronic inflammation. Previously, we observed that IL-13 increases reactive oxygen species (ROS) in airway epithelial cells in an autophagy-dependent fashion. Here, we tested our hypothesis that autophagy is required for IL-13-mediated superoxide production via the NADPH oxidase DUOX1. Using a mouse model of Th2-mediated inflammation induced by OVA-allergen, we observed elevated lung amounts of IL-13 and IL-4 accompanied by increased autophagosome levels, determined by LC3BII protein levels and immunostaining. ROS levels were elevated and DUOX1 expression was increased 70-fold in OVA-challenged lungs. To address the role of autophagy and ROS in the airway epithelium, we treated primary human tracheobronchial epithelial cells with IL-13 or IL-4. Prolonged, 7-day treatment increased autophagosome formation and degradation, while brief activation had no effect. Under parallel culture conditions, IL-13 and IL-4 increased intracellular superoxide levels as determined by electron paramagnetic resonance (EPR) spectroscopy. Prolonged IL-13 activation increased DUOX1, localized at the apical membrane. Silencing DUOX1 by siRNA attenuated IL-13-mediated increases in superoxide, but did not reduce autophagy activities. Notably, depletion of autophagy regulatory protein ATG5 significantly reduced superoxide without diminishing total DUOX1 levels. Depletion of ATG5, however, diminished DUOX1 localization at the apical membrane. The findings suggest non-canonical autophagy activity regulates DUOX1-dependent localization required for intracellular superoxide production during Th2 inflammation. Thus, in chronic Th2 inflammatory airway disease, autophagy proteins may be responsible for persistent intracellular superoxide production.
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      PubDate: 2017-10-07T16:28:42Z
      DOI: 10.1016/j.redox.2017.09.013
      Issue No: Vol. 14 (2017)
       
  • Neuroprotective effect of a new variant of Epo nonhematopoietic against
           oxidative stress

    • Authors: C. Castillo; S. Zaror; M. Gonzalez; A. Hidalgo; C.F. Burgos; O.I. Cabezas; F. Hugues; S.P. Jiménez; E. González-Horta; I. González-Chavarría; J. Gavilán; R. Montesino; O. Sánchez; Manuela G. Lopez; J. Fuentealba; J.R. Toledo
      Pages: 285 - 294
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): C. Castillo, S. Zaror, M. Gonzalez, A. Hidalgo, C.F. Burgos, O.I. Cabezas, F. Hugues, S.P. Jiménez, E. González-Horta, I. González-Chavarría, J. Gavilán, R. Montesino, O. Sánchez, Manuela G. Lopez, J. Fuentealba, J.R. Toledo
      Human erythropoietin is mainly recognized for its hematopoietic function; however, by binding to its receptor (EpoR), it can activate different signaling pathways as STAT, PI3K, MAPK and RAS to increase cellular differentiation or provide neuroprotective effects, among others. A recombinant human erythropoietin variant with low glycosylation and without hematopoietic effect (EpoL) was purified from skimmed goat milk. Recombinant human erythropoietin (Epo) was obtained from CHO cell line and used as control to compare EpoL effects. Neuroprotection studies were performed in PC12 cells and rat hippocampal slices. Cells were pretreated during 1h with EpoL or Epo and exposed to oxidative agents (H2O2 or FCCP); cell viability was assayed at the end of the experiment by the MTT method. Hippocampal slices were exposed to 15min of oxygen and glucose deprivation (OGD) and the neuroprotective drugs EpoL or Epo were incubated for 2h post-OGD in re-oxygenated medium. Cell cultures stressed with oxidative agents, and pretreated with EpoL, showed neuroprotective effects of 30% at a concentration 10 times lower than that of Epo. Moreover, similar differences were observed in OGD ex vivo assays. Neuroprotection elicited by EpoL was lost when an antibody against EpoR was present, indicating that its effect is EpoR-dependent. In conclusion, our results suggest that EpoL has a more potent neuroprotective profile than Epo against oxidative stress, mediated by activation of EpoR, thus EpoL represents an important target to develop a potential biopharmaceutical to treat different central nervous system pathologies related to oxidative stress such as stroke or neurodegenerative diseases.

      PubDate: 2017-10-07T16:28:42Z
      DOI: 10.1016/j.redox.2017.09.010
      Issue No: Vol. 14 (2017)
       
  • Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved
           in chronic ethanol-induced fatty liver

    • Authors: Tao Zeng; Cui-Li Zhang; Ning Zhao; Min-Jie Guan; Mo Xiao; Rui Yang; Xiu-Lan Zhao; Li-Hua Yu; Zhen-Ping Zhu; Ke-Qin Xie
      Pages: 295 - 304
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Tao Zeng, Cui-Li Zhang, Ning Zhao, Min-Jie Guan, Mo Xiao, Rui Yang, Xiu-Lan Zhao, Li-Hua Yu, Zhen-Ping Zhu, Ke-Qin Xie
      Protein kinase B (PKB/Akt) plays important roles in the regulation of lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that cytochrome P4502E1 (CYP2E1) plays causal roles in the pathogenesis of alcoholic fatty liver (AFL). We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic ethanol-induced hepatic steatosis. In this study, we found that chronic ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver. Chronic ethanol exposure had no effects on the protein levels of phosphatidylinositol 3 kinase (PI3K) and phosphatase and tensin homologue deleted on chromosome ten (PTEN), and led to a slight decrease of phosphoinositide-dependent protein kinase 1 (PDK-1) protein level. Ethanol exposure resulted in increased levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)-Akt adducts, which was significantly inhibited by chlormethiazole (CMZ), an efficient CYP2E1 inhibitor. Interestingly, N-acetyl-L-cysteine (NAC) significantly attenuated chronic ethanol-induced hepatic fat accumulation and the decline of Akt phosphorylation at Thr308. In the in vitro studies, Akt phosphorylation was suppressed in CYP2E1-expressing HepG2 (CYP2E1-HepG2) cells compared with the negative control HepG2 (NC-HepG2) cells, and 4-HNE treatment led to significant decrease of Akt phosphorylation at Thr308 in wild type HepG2 cells. Lastly, pharmacological activation of Akt by insulin-like growth factor-1 (IGF-1) significantly alleviated chronic ethanol-induced fatty liver in mice. Collectively, these results indicate that CYP2E1-induced oxidative stress may be responsible for ethanol-induced suppression of Akt phosphorylation and pharmacological modulation of Akt in liver may be an effective strategy for the treatment of ethanol-induced fatty liver.
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      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.09.018
      Issue No: Vol. 14 (2017)
       
  • Epigallocatechin-3-gallate promotes healthy lifespan through mitohormesis
           during early-to-mid adulthood in Caenorhabditis elegans

    • Authors: Li-Gui Xiong; Yi-Jun Chen; Jie-Wen Tong; Yu-Shun Gong; Jian-An Huang; Zhong-Hua Liu
      Pages: 305 - 315
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Li-Gui Xiong, Yi-Jun Chen, Jie-Wen Tong, Yu-Shun Gong, Jian-An Huang, Zhong-Hua Liu
      The green tea polyphenol epigallocatechin-3-gallate (EGCG) is widely consumed as a dietary supplement. Its potential properties include slowing aging and extending lifespan, although how exactly this is achieved remains unclear. Here, we report that EGCG promoted healthy lifespan in Caenorhabditis elegans when administered throughout or only at early-to-mid adulthood. Specifically, EGCG extended lifespan in an inverted U-shaped dose-response manner. The life-extending mechanism was stimulated by EGCG-induced production of reactive oxygen species (ROS). Additionally, EGCG triggered mitochondrial biogenesis to restore mitochondrial function. The EGCG-induced increase in lifespan depends on known energy sensors such as AMPK/AAK-2, as well as SIRT1/SIR-2.1 and FOXO/DAF-16. Interestingly, aging decreased the response to EGCG and progressively neutralized its beneficial effects on longevity. Collectively, our findings link EGCG to the process of mitohormesis and suggest an inducible, AMPK/SIRT1/FOXO-dependent redox signaling module that could be invoked in different contexts to extend healthy lifespan. Its effectiveness is higher in younger adults and declines with age.
      Graphical abstract image

      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.09.019
      Issue No: Vol. 14 (2017)
       
  • A review of the basics of mitochondrial bioenergetics, metabolism, and
           related signaling pathways in cancer cells: Therapeutic targeting of tumor
           mitochondria with lipophilic cationic compounds

    • Authors: Balaraman Kalyanaraman; Gang Cheng; Micael Hardy; Olivier Ouari; Marcos Lopez; Joy Joseph; Jacek Zielonka; Michael B. Dwinell
      Pages: 316 - 327
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Balaraman Kalyanaraman, Gang Cheng, Micael Hardy, Olivier Ouari, Marcos Lopez, Joy Joseph, Jacek Zielonka, Michael B. Dwinell
      The present review is a sequel to the previous review on cancer metabolism published in this journal. This review focuses on the selective antiproliferative and cytotoxic effects of mitochondria-targeted therapeutics (MTTs) in cancer cells. Emerging research reveals a key role of mitochondrial respiration on tumor proliferation. Previously, a mitochondria-targeted nitroxide was shown to selectively inhibit colon cancer cell proliferation at submicromolar levels. This review is centered on the therapeutic use of MTTs and their bioenergetic profiling in cancer cells. Triphenylphosphonium cation conjugated to a parent molecule (e.g., vitamin-E or chromanol, ubiquinone, and metformin) via a linker alkyl chain is considered an MTT. MTTs selectively and potently inhibit proliferation of cancer cells and, in some cases, induce cytotoxicity. MTTs inhibit mitochondrial complex I activity and induce mitochondrial stress in cancer cells through generation of reactive oxygen species. MTTs in combination with glycolytic inhibitors synergistically inhibit tumor cell proliferation. This review discusses how signaling molecules traditionally linked to tumor cell proliferation affect tumor metabolism and bioenergetics (glycolysis, TCA cycle, and glutaminolysis).

      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.09.020
      Issue No: Vol. 14 (2017)
       
  • Identification of a soluble guanylate cyclase in RBCs: preserved activity
           in patients with coronary artery disease

    • Authors: Miriam M. Cortese-Krott; Evanthia Mergia; Christian M. Kramer; Wiebke Lückstädt; Jiangning Yang; Georg Wolff; Christina Panknin; Thilo Bracht; Barbara Sitek; John Pernow; Johannes-Peter Stasch; Martin Feelisch; Doris Koesling; Malte Kelm
      Pages: 328 - 337
      Abstract: Publication date: April 2018
      Source:Redox Biology, Volume 14
      Author(s): Miriam M. Cortese-Krott, Evanthia Mergia, Christian M. Kramer, Wiebke Lückstädt, Jiangning Yang, Georg Wolff, Christina Panknin, Thilo Bracht, Barbara Sitek, John Pernow, Johannes-Peter Stasch, Martin Feelisch, Doris Koesling, Malte Kelm
      Endothelial dysfunction is associated with decreased NO bioavailability and impaired activation of the NO receptor soluble guanylate cyclase (sGC) in the vasculature and in platelets. Red blood cells (RBCs) are known to produce NO under hypoxic and normoxic conditions; however evidence of expression and/or activity of sGC and downstream signaling pathway including phopshodiesterase (PDE)-5 and protein kinase G (PKG) in RBCs is still controversial. In the present study, we aimed to investigate whether RBCs carry a functional sGC signaling pathway and to address whether this pathway is compromised in coronary artery disease (CAD). Using two independent chromatographic procedures, we here demonstrate that human and murine RBCs carry a catalytically active α1β1-sGC (isoform 1), which converts 32P-GTP into 32P-cGMP, as well as PDE5 and PKG. Specific sGC stimulation by NO+BAY 41-2272 increases intracellular cGMP-levels up to 1000-fold with concomitant activation of the canonical PKG/VASP-signaling pathway. This response to NO is blunted in α1-sGC knockout (KO) RBCs, but fully preserved in α2-sGC KO. In patients with stable CAD and endothelial dysfunction red cell eNOS expression is decreased as compared to aged-matched controls; by contrast, red cell sGC expression/activity and responsiveness to NO are fully preserved, although sGC oxidation is increased in both groups. Collectively, our data demonstrate that an intact sGC/PDE5/PKG-dependent signaling pathway exists in RBCs, which remains fully responsive to NO and sGC stimulators/activators in patients with endothelial dysfunction. Targeting this pathway may be helpful in diseases with NO deficiency in the microcirculation like sickle cell anemia, pulmonary hypertension, and heart failure.
      Graphical abstract image

      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.08.020
      Issue No: Vol. 14 (2017)
       
  • Quantitative biology of hydrogen peroxide signaling

    • Authors: Fernando Antunes; Paula Matos Brito
      Pages: 1 - 7
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Fernando Antunes, Paula Matos Brito
      Hydrogen peroxide (H2O2) controls signaling pathways in cells by oxidative modulation of the activity of redox sensitive proteins denominated redox switches. Here, quantitative biology concepts are applied to review how H2O2 fulfills a key role in information transmission. Equations described lay the foundation of H2O2 signaling, give new insights on H2O2 signaling mechanisms, and help to learn new information from common redox signaling experiments. A key characteristic of H2O2 signaling is that the ratio between reduction and oxidation of redox switches determines the range of H2O2 concentrations to which they respond. Thus, a redox switch with low H2O2-dependent oxidability and slow reduction rate responds to the same range of H2O2 concentrations as a redox switch with high H2O2-dependent oxidability, but that is rapidly reduced. Yet, in the first case the response time is slow while in the second case is rapid. H2O2 sensing and transmission of information can be done directly or by complex mechanisms in which oxidation is relayed between proteins before oxidizing the final regulatory redox target. In spite of being a very simple molecule, H2O2 has a key role in cellular signaling, with the reliability of the information transmitted depending on the inherent chemical reactivity of redox switches, on the presence of localized H2O2 pools, and on the molecular recognition between redox switches and their partners.
      Graphical abstract image

      PubDate: 2017-05-25T06:12:03Z
      DOI: 10.1016/j.redox.2017.04.039
      Issue No: Vol. 13 (2017)
       
  • European contribution to the study of ROS: A summary of the findings and
           prospects for the future from the COST action BM1203 (EU-ROS)

    • Authors: Javier Egea; Isabel Fabregat; Yves M. Frapart; Pietro Ghezzi; Agnes Görlach; Thomas Kietzmann; Kateryna Kubaichuk; Ulla G. Knaus; Manuela G. Lopez; Gloria Olaso-Gonzalez; Andreas Petry; Rainer Schulz; Jose Vina; Paul Winyard; Kahina Abbas; Opeyemi S. Ademowo; Catarina B. Afonso; Ioanna Andreadou; Haike Antelmann; Fernando Antunes; Mutay Aslan; Markus M. Bachschmid; Rui M. Barbosa; Vsevolod Belousov; Carsten Berndt; David Bernlohr; Esther Bertrán; Alberto Bindoli; Serge P. Bottari; Paula M. Brito; Guia Carrara; Ana I. Casas; Afroditi Chatzi; Niki Chondrogianni; Marcus Conrad; Marcus S. Cooke; João G. Costa; Antonio Cuadrado; Pham My-Chan Dang; Barbara De Smet; Bilge Debelec–Butuner; Irundika H.K. Dias; Joe Dan Dunn; Amanda J. Edson; Mariam El Assar; Jamel El-Benna; Péter Ferdinandy; Ana S. Fernandes; Kari E. Fladmark; Ulrich Förstermann; Rashid Giniatullin; Zoltán Giricz; Anikó Görbe; Helen Griffiths; Vaclav Hampl; Alina Hanf; Jan Herget; Pablo Hernansanz-Agustín; Melanie Hillion; Jingjing Huang; Serap Ilikay; Pidder Jansen-Dürr; Vincent Jaquet; Jaap A. Joles; Balaraman Kalyanaraman; Danylo Kaminskyy; Mahsa Karbaschi; Marina Kleanthous; Lars-Oliver Klotz; Bato Korac; Kemal Sami Korkmaz; Rafal Koziel; Damir Kračun; Karl-Heinz Krause; Vladimír Křen; Thomas Krieg; João Laranjinha; Antigone Lazou; Huige Li; Antonio Martínez-Ruiz; Reiko Matsui; Gethin J. McBean; Stuart P. Meredith; Joris Messens; Verónica Miguel; Yuliya Mikhed; Irina Milisav; Lidija Milković; Antonio Miranda-Vizuete; Miloš Mojović; María Monsalve; Pierre-Alexis Mouthuy; John Mulvey; Thomas Münzel; Vladimir Muzykantov; Isabel T.N. Nguyen; Matthias Oelze; Nuno G. Oliveira; Carlos M. Palmeira; Nikoletta Papaevgeniou; Aleksandra Pavićević; Brandán Pedre; Fabienne Peyrot; Marios Phylactides; Gratiela G. Pircalabioru; Andrew R. Pitt; Henrik E. Poulsen; Ignacio Prieto; Maria Pia Rigobello; Natalia Robledinos-Antón; Leocadio Rodríguez-Mañas; Anabela P. Rolo; Francis Rousset; Tatjana Ruskovska; Nuno Saraiva; Shlomo Sasson; Katrin Schröder; Khrystyna Semen; Tamara Seredenina; Anastasia Shakirzyanova; Geoffrey L. Smith; Thierry Soldati; Bebiana C. Sousa; Corinne M. Spickett; Ana Stancic; Marie José Stasia; Holger Steinbrenner; Višnja Stepanić; Sebastian Steven; Kostas Tokatlidis; Erkan Tuncay; Belma Turan; Fulvio Ursini; Jan Vacek; Olga Vajnerova; Kateřina Valentová; Frank Van Breusegem; Lokman Varisli; Elizabeth A. Veal; A. Suha Yalçın; Olha Yelisyeyeva; Neven Žarković; Martina Zatloukalová; Jacek Zielonka; Rhian M. Touyz; Andreas Papapetropoulos; Tilman Grune; Santiago Lamas; Harald H.H.W. Schmidt; Fabio Di Lisa; Andreas Daiber
      Pages: 94 - 162
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Javier Egea, Isabel Fabregat, Yves M. Frapart, Pietro Ghezzi, Agnes Görlach, Thomas Kietzmann, Kateryna Kubaichuk, Ulla G. Knaus, Manuela G. Lopez, Gloria Olaso-Gonzalez, Andreas Petry, Rainer Schulz, Jose Vina, Paul Winyard, Kahina Abbas, Opeyemi S. Ademowo, Catarina B. Afonso, Ioanna Andreadou, Haike Antelmann, Fernando Antunes, Mutay Aslan, Markus M. Bachschmid, Rui M. Barbosa, Vsevolod Belousov, Carsten Berndt, David Bernlohr, Esther Bertrán, Alberto Bindoli, Serge P. Bottari, Paula M. Brito, Guia Carrara, Ana I. Casas, Afroditi Chatzi, Niki Chondrogianni, Marcus Conrad, Marcus S. Cooke, João G. Costa, Antonio Cuadrado, Pham My-Chan Dang, Barbara De Smet, Bilge Debelec–Butuner, Irundika H.K. Dias, Joe Dan Dunn, Amanda J. Edson, Mariam El Assar, Jamel El-Benna, Péter Ferdinandy, Ana S. Fernandes, Kari E. Fladmark, Ulrich Förstermann, Rashid Giniatullin, Zoltán Giricz, Anikó Görbe, Helen Griffiths, Vaclav Hampl, Alina Hanf, Jan Herget, Pablo Hernansanz-Agustín, Melanie Hillion, Jingjing Huang, Serap Ilikay, Pidder Jansen-Dürr, Vincent Jaquet, Jaap A. Joles, Balaraman Kalyanaraman, Danylo Kaminskyy, Mahsa Karbaschi, Marina Kleanthous, Lars-Oliver Klotz, Bato Korac, Kemal Sami Korkmaz, Rafal Koziel, Damir Kračun, Karl-Heinz Krause, Vladimír Křen, Thomas Krieg, João Laranjinha, Antigone Lazou, Huige Li, Antonio Martínez-Ruiz, Reiko Matsui, Gethin J. McBean, Stuart P. Meredith, Joris Messens, Verónica Miguel, Yuliya Mikhed, Irina Milisav, Lidija Milković, Antonio Miranda-Vizuete, Miloš Mojović, María Monsalve, Pierre-Alexis Mouthuy, John Mulvey, Thomas Münzel, Vladimir Muzykantov, Isabel T.N. Nguyen, Matthias Oelze, Nuno G. Oliveira, Carlos M. Palmeira, Nikoletta Papaevgeniou, Aleksandra Pavićević, Brandán Pedre, Fabienne Peyrot, Marios Phylactides, Gratiela G. Pircalabioru, Andrew R. Pitt, Henrik E. Poulsen, Ignacio Prieto, Maria Pia Rigobello, Natalia Robledinos-Antón, Leocadio Rodríguez-Mañas, Anabela P. Rolo, Francis Rousset, Tatjana Ruskovska, Nuno Saraiva, Shlomo Sasson, Katrin Schröder, Khrystyna Semen, Tamara Seredenina, Anastasia Shakirzyanova, Geoffrey L. Smith, Thierry Soldati, Bebiana C. Sousa, Corinne M. Spickett, Ana Stancic, Marie José Stasia, Holger Steinbrenner, Višnja Stepanić, Sebastian Steven, Kostas Tokatlidis, Erkan Tuncay, Belma Turan, Fulvio Ursini, Jan Vacek, Olga Vajnerova, Kateřina Valentová, Frank Van Breusegem, Lokman Varisli, Elizabeth A. Veal, A. Suha Yalçın, Olha Yelisyeyeva, Neven Žarković, Martina Zatloukalová, Jacek Zielonka, Rhian M. Touyz, Andreas Papapetropoulos, Tilman Grune, Santiago Lamas, Harald H.H.W. Schmidt, Fabio Di Lisa, Andreas Daiber
      The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.
      Graphical abstract image

      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.05.007
      Issue No: Vol. 13 (2017)
       
  • Mitochondria-meditated pathways of organ failure upon inflammation

    • Authors: Andrey V. Kozlov; Jack R. Lancaster; Andras T. Meszaros; Adelheid Weidinger
      Pages: 170 - 181
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Andrey V. Kozlov, Jack R. Lancaster, Andras T. Meszaros, Adelheid Weidinger
      Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that causative events could be a drop in ATP synthesis, opening of mitochondrial permeability transition pore, specific changes in mitochondrial morphology, impaired Ca2+ uptake, generation of mitochondrial reactive oxygen species (mtROS), turnover of mitochondria and imbalance in electron supply to the respiratory chain. The aim of this review is to critically analyze existing hypotheses, in order to highlight the most promising research lines helping to prevent liver failure induced by SIRS. Evaluation of the literature shows that there is no consistent support that impaired Ca++ metabolism, electron transport chain function and ultrastructure of mitochondria substantially contribute to liver failure. Moreover, our analysis suggests that the drop in ATP levels has protective rather than a deleterious character. Recent data suggest that the most critical mitochondrial event occurring upon SIRS is the release of mtROS in cytoplasm, which can activate two specific intracellular signaling cascades. The first is the mtROS-mediated activation of NADPH-oxidase in liver macrophages and endothelial cells; the second is the acceleration of the expression of inflammatory genes in hepatocytes. The signaling action of mtROS is strictly controlled in mitochondria at three points, (i) at the site of ROS generation at complex I, (ii) the site of mtROS release in cytoplasm via permeability transition pore, and (iii) interaction with specific kinases in cytoplasm. The systems controlling mtROS-signaling include pro- and anti-inflammatory mediators, nitric oxide, Ca2+ and NADPH-oxidase. Analysis of the literature suggests that further research should be focused on the impact of mtROS on organ failure induced by inflammation and simultaneously providing a new theoretical basis for a targeted therapy of overwhelmed inflammatory response.
      Graphical abstract image

      PubDate: 2017-06-04T07:57:30Z
      DOI: 10.1016/j.redox.2017.05.017
      Issue No: Vol. 13 (2017)
       
  • Redox signaling during hypoxia in mammalian cells

    • Authors: Kimberly A. Smith; Gregory B. Waypa; Paul T. Schumacker
      Pages: 228 - 234
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Kimberly A. Smith, Gregory B. Waypa, Paul T. Schumacker
      Hypoxia triggers a wide range of protective responses in mammalian cells, which are mediated through transcriptional and post-translational mechanisms. Redox signaling in cells by reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) occurs through the reversible oxidation of cysteine thiol groups, resulting in structural modifications that can change protein function profoundly. Mitochondria are an important source of ROS generation, and studies reveal that superoxide generation by the electron transport chain increases during hypoxia. Other sources of ROS, such as the NAD(P)H oxidases, may also generate oxidant signals in hypoxia. This review considers the growing body of work indicating that increased ROS signals during hypoxia are responsible for regulating the activation of protective mechanisms in diverse cell types.
      Graphical abstract image

      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.05.020
      Issue No: Vol. 13 (2017)
       
  • Non-linear actions of physiological agents: Finite disarrangements elicit
           fitness benefits

    • Authors: Filip Sedlic; Zdenko Kovac
      Pages: 235 - 243
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Filip Sedlic, Zdenko Kovac
      Finite disarrangements of important (vital) physiological agents and nutrients can induce plethora of beneficial effects, exceeding mere attenuation of the specific stress. Such response to disrupted homeostasis appears to be universally conserved among species. The underlying mechanism of improved fitness and longevity, when physiological agents act outside their normal range is similar to hormesis, a phenomenon whereby toxins elicit beneficial effects at low doses. Due to similarity with such non-linear response to toxins described with J-shaped curve, we have coined a new term “mirror J-shaped curves” for non-linear response to finite disarrangement of physiological agents. Examples from the clinical trials and basic research are provided, along with the unifying mechanisms that tie classical non-linear response to toxins with the non-linear response to physiological agents (glucose, oxygen, osmolarity, thermal energy, calcium, body mass, calorie intake and exercise). Reactive oxygen species and cytosolic calcium seem to be common triggers of signaling pathways that result in these beneficial effects. Awareness of such phenomena and exploring underlying mechanisms can help physicians in their everyday practice. It can also benefit researchers when designing studies and interpreting growing number of scientific data showing non-linear responses to physiological agents.

      PubDate: 2017-06-09T08:42:55Z
      DOI: 10.1016/j.redox.2017.05.008
      Issue No: Vol. 13 (2017)
       
  • Maintenance of redox homeostasis by hypoxia-inducible factors

    • Authors: Debangshu Samanta; Gregg L. Semenza
      Pages: 331 - 335
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Debangshu Samanta, Gregg L. Semenza
      Oxidative phosphorylation enables cells to generate the large amounts of ATP required for development and maintenance of multicellular organisms. However, under conditions of reduced O2 availability, electron transport becomes less efficient, leading to increased generation of superoxide anions. Hypoxia-inducible factors switch cells from oxidative to glycolytic metabolism, to reduce mitochondrial superoxide generation, and increase the synthesis of NADPH and glutathione, in order to maintain redox homeostasis under hypoxic conditions.

      PubDate: 2017-06-18T17:06:38Z
      DOI: 10.1016/j.redox.2017.05.022
      Issue No: Vol. 13 (2017)
       
  • Graphical review: The redox dark side of e-cigarettes; exposure to
           oxidants and public health concerns

    • Authors: Hua Cai; Chen Wang
      Pages: 402 - 406
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Hua Cai, Chen Wang
      Since the initial marketing in 2005, the use of e-cigarettes has increased exponentially. Nonetheless, accumulating evidence has demonstrated the ineffectiveness of e-cigarettes in leading to smoking cessation, and decreasing the adverse health impacts of cigarette smoking. The number of adolescents adapted to e-cigarettes has been increasing substantially each year, and this adaptation has promoted openness to tobacco smoking. The present review discusses controversies regarding the smoking cessation effects of e-cigarettes, recent governmental policies and regulations of e-cigarette use, toxic components and vaporization products of e-cigarettes, and the novel molecular mechanisms underlying the adverse health impacts of e-cigarettes leading to oxidative stress in target tissues, and consequent development of cardiopulmonary diseases (i.e. COPD), neurodegenerative disorders (i.e. Alzheimer's’ disease), and cancer. Health warning signs on the packaging and professional consultation to avoid adaptation in risk groups might be helpful solutions to control negative impacts of e-cigarettes. It is also recommended to further expand basic and clinical investigations to reveal more detailed oxidative stress mechanisms of e-cigarette induced damages, which would ultimately result in more effective protective strategies.
      Graphical abstract image

      PubDate: 2017-07-04T20:32:43Z
      DOI: 10.1016/j.redox.2017.05.013
      Issue No: Vol. 13 (2017)
       
  • Blood-based bioenergetic profiling: A readout of systemic bioenergetic
           capacity that is related to differences in body composition

    • Authors: Anthony J.A. Molina
      Pages: 418 - 420
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Anthony J.A. Molina


      PubDate: 2017-07-13T16:28:00Z
      DOI: 10.1016/j.redox.2017.06.012
      Issue No: Vol. 13 (2017)
       
  • Regulation by S-nitrosylation of the Calvin-Benson cycle
           fructose-1,6-bisphosphatase in Pisum sativum

    • Authors: Antonio Jesús Serrato; María C. Romero-Puertas; Alfonso Lázaro-Payo; Mariam Sahrawy
      Abstract: Publication date: Available online 12 October 2017
      Source:Redox Biology
      Author(s): Antonio Jesús Serrato, María C. Romero-Puertas, Alfonso Lázaro-Payo, Mariam Sahrawy
      Redox regulation is of great importance in chloroplasts. Many chloroplast enzymes, such as those belonging to the Calvin-Benson cycle (CBC), have conserved regulatory cysteines which form inhibitory disulphide bridges when physiological conditions become unfavourable. Amongst these enzymes, cFBP1, the CBC fructose-1,6-bisphosphatase (FBPase) isoform, is well known to be redox activated by thioredoxin f through the reduction of a disulphide bridge involving Cys153 and Cys173. Moreover, data obtained during recent years point to S-nitrosylation as another redox post-translational modification putatively regulating an increasing number of plant enzymes, including cFBP1. In this study we have shown that the Pisum sativum cFBP1 can be efficiently S-nitrosylated by GSNO and SNAP, triggering the formation of the regulatory disulphide. Using in vivo experiments with P. sativum we have established that cFBP1 S-nitrosylation only occurs during the light period and we have elucidated by activity assays with Cys-to-Ser mutants that this enzyme maybe inactivated through the S-nitrosylation of Cys153. Finally, in the light of the new data, we have proposed an extended redox-regulation model by integrating the S-nitrosylation and the TRX f-mediated regulation of cFBP1.

      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.10.008
       
  • Menthol evokes Ca2+ signals and induces oxidative stress independently of
           the presence of TRPM8 (menthol) receptor in cancer cells

    • Authors: Mustafa Nazıroğlu; Walter Blum; Katalin Josvay; Bilal Çiğ; Thomas Henzi; Zoltán Oláh; Csaba Vizler; Beat Schwaller; László Pecze
      Abstract: Publication date: Available online 12 October 2017
      Source:Redox Biology
      Author(s): Mustafa Nazıroğlu, Walter Blum, Katalin Josvay, Bilal Çiğ, Thomas Henzi, Zoltán Oláh, Csaba Vizler, Beat Schwaller, László Pecze
      Menthol is a naturally occurring monoterpene alcohol possessing remarkable biological properties including antipruritic, analgesic, antiseptic, anti-inflammatory and cooling effects. Here, we examined the menthol-evoked Ca2+ signals in breast and prostate cancer cell lines. The effect of menthol (50–500µM) was predicted to be mediated by the transient receptor potential ion channel melastatin subtype 8 (TRPM8). However, the intensity of menthol-evoked Ca2+ signals did not correlate with the expression levels of TRPM8 in breast and prostate cancer cells indicating a TRPM8-independent signaling pathway. Menthol-evoked Ca2+ signals were analyzed in detail in Du 145 prostate cancer cells, as well as in CRISPR/Cas9 TRPM8-knockout Du 145 cells. Menthol (500µM) induced Ca2+ oscillations in both cell lines, thus independent of TRPM8, which were however dependent on the production of inositol trisphosphate. Results based on pharmacological tools point to an involvement of the purinergic pathway in menthol-evoked Ca2+ responses. Finally, menthol (50–500µM) decreased cell viability and induced oxidative stress independently of the presence of TRPM8 channels, despite that temperature-evoked TRPM8-mediated inward currents were significantly decreased in TRPM8-knockout Du 145 cells compared to wild type Du 145 cells.

      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.10.009
       
  • A Novel S-Sulfhydrated Human Serum Albumin Preparation Suppresses Melanin
           Synthesis

    • Authors: Mayumi Ikeda; Yu Ishima; Ryo Kinoshita; Victor T.G. Chuang; Nanami Tasaka; Nana Matsuo; Hiroshi Watanabe; Taro Shimizu; Tatsuhiro Ishida; Masaki Otagiri; Toru Maruyama
      Abstract: Publication date: Available online 11 October 2017
      Source:Redox Biology
      Author(s): Mayumi Ikeda, Yu Ishima, Ryo Kinoshita, Victor T.G. Chuang, Nanami Tasaka, Nana Matsuo, Hiroshi Watanabe, Taro Shimizu, Tatsuhiro Ishida, Masaki Otagiri, Toru Maruyama
      Products of ultraviolet (UV) irradiation such as reactive oxygen species (ROS) and nitric oxide (NO) stimulate melanin synthesis. Reactive sulfur species (RSS) have been shown to have strong ROS and NO scavenging effects. However, the instability and low retention of RSS limit their use as inhibitors of melanin synthesis. The free thiol at Cys34 on human serum albumin (HSA) is highly stable, has a long retention and possess a high reactivity for RSS. We report herein on the development of an HSA based RSS delivery system. Sulfane sulfur derivatives released from sodium polysulfides (Na2Sn) react readily with HSA. An assay for estimating the elimination of sulfide from polysulfide showed that almost all of the sulfur released from Na2Sn bound to HSA. The Na2Sn-treated HSA was found to efficiently scavenge ROS and NO produced from chemical reagents. The Na2Sn-treated HSA was also found to inhibit melanin synthesis in B16 melanoma cells and this inhibition was independent of the number of added sulfur atoms. In B16 melanoma cells, the Na2Sn-treated HSA also inhibited the levels of ROS and NO induced by UV radiation. Finally, the Na2Sn-treated HSA inhibited melanin synthesis from L-DOPA and mushroom tyrosinase and suppressed the extent of aggregation of melanin pigments. These data suggest that Na2Sn-treated HSA inhibits tyrosinase activity for melanin synthesis via two pathways; by directly inhibiting ROS signaling and by scavenging NO. These findings indicate that Na2Sn-treated HSA has potential to be an attractive and effective candidate for use as a skin whitening agent.
      Graphical abstract image

      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.10.007
       
  • Cysteine Perthiosulfenic Acid (Cys-SSOH): A Novel Intermediate in
           Thiol-Based Redox Signaling'

    • Authors: David E. Heppner; Milena Hristova; Tomoaki Ida; Ana Mijuskovic; Christopher M. Dustin; Virág Bogdándi; Jon M. Fukuto; Tobias P. Dick; Péter Nagy; Jianing Li; Takaaki Akaike; Albert van der Vliet
      Abstract: Publication date: Available online 9 October 2017
      Source:Redox Biology
      Author(s): David E. Heppner, Milena Hristova, Tomoaki Ida, Ana Mijuskovic, Christopher M. Dustin, Virág Bogdándi, Jon M. Fukuto, Tobias P. Dick, Péter Nagy, Jianing Li, Takaaki Akaike, Albert van der Vliet
      The reversible oxidation of protein cysteine residues (Cys-SH) is a key reaction in cellular redox signaling involving initial formation of sulfenic acids (Cys-SOH), which are commonly detected using selective dimedone-based probes. Here, we report that significant portions of dimedone-tagged proteins are susceptible to cleavage by DTT reflecting the presence of perthiosulfenic acid species (Cys-SSOH) due to similarly oxidation of hydropersulfides (Cys-SSH), since Cys-S-dimedone adducts are stable toward DTT. Combined studies using molecular modeling, mass spectrometry, and cell-based experiments indicate that Cys-SSH are readily oxidized to Cys-SSOH, which forms stable adducts with dimedone-based probes. We additionally confirm the presence of Cys-SSH within protein tyrosine kinases such as EGFR, and their apparent oxidation to CysSSOH in response NADPH oxidase activation, suggesting that such Cys-SSH oxidation may represent a novel, as yet uncharacterized, event in redox-based signaling.
      Graphical abstract image

      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.10.006
       
  • Angiotensin receptor blockade improves cardiac mitochondrial activity in
           response to an acute glucose load in obese insulin resistant rats

    • Authors: Max Thorwald; Ruben Rodriguez; Andrew Lee; Bridget Martinez; Janos Peti-Peterdi; Daisuke Nakano; Akira Nishiyama; Rudy M. Ortiz
      Abstract: Publication date: Available online 7 October 2017
      Source:Redox Biology
      Author(s): Max Thorwald, Ruben Rodriguez, Andrew Lee, Bridget Martinez, Janos Peti-Peterdi, Daisuke Nakano, Akira Nishiyama, Rudy M. Ortiz
      Hyperglycemia increases the risk of oxidant overproduction in the heart through activation of a multitude of pathways. Oxidation of mitochondrial enzymes may impair their function resulting in accumulation of intermediates and reverse electron transfer, contributing to mitochondrial dysfunction. Furthermore, the renin-angiotensin system (RAS) becomes inappropriately activated during metabolic syndrome, increasing oxidant production. To combat excess oxidant production, the transcription factor, nuclear factor erythriod-2- related factor 2 (Nrf2), induces expression of many antioxidant genes. We hypothesized that angiotensin II receptor type 1 (AT1) blockade improves mitochondrial function in response to an acute glucose load via upregulation of Nrf2. To address this hypothesis, an oral glucose challenge was performed in three groups prior to dissection (n= 5–8 animals/group/time point) of adult male rats: 1) Long Evans Tokushima Otsuka (LETO; lean strain-control), 2) insulin resistant, obese Otsuka Long Evans Tokushima Fatty (OLETF), and 3) OLETF + angiotensin receptor blocker (ARB; 10mg olmesartan/kg/d × 6 weeks). Hearts were collected at T0, T60, and T120 minutes post-glucose infusion. ARB increased Nrf2 binding 32% compared to OLETF at T60. Total superoxide dismutase (SOD) and catalase (CAT) activities were increased 45% and 66% respectively in ARB treated animals compared to OLETF. Mitochondrial enzyme activities of aconitase, complex I, and complex II increased by 135%, 33% and 66%, respectively in ARB compared to OLETF. These data demonstrate the protective effects of AT1 blockade on mitochondrial function during the manifestation of insulin resistance suggesting that the inappropriate activation of AT1 during insulin resistance may impair Nrf2 translocation and subsequent antioxidant activities and mitochondrial function.
      Graphical abstract image

      PubDate: 2017-10-13T17:14:54Z
      DOI: 10.1016/j.redox.2017.10.005
       
  • Acute telomerase components depletion triggers oxidative stress as an
           early event previous to telomeric shortening

    • Authors: Santiago Gisselle; Marta Seco-Cervera Ester Berenguer-Pascual Luis Federico
      Abstract: Publication date: Available online 7 October 2017
      Source:Redox Biology
      Author(s): José Santiago Ibáñez-Cabellos, Gisselle Pérez-Machado, Marta Seco-Cervera, Ester Berenguer-Pascual, José Luis García-Giménez, Federico V. Pallardó
      Loss of function of dyskerin (DKC1), NOP10 and TIN2 are responsible for different inheritance patterns of Dyskeratosis congenita (DC; ORPHA1775). They are key components of telomerase (DKC1 and NOP10) and shelterin (TIN2), and play an important role in telomere homeostasis. They participate in several fundamental cellular processes by contributing to Dyskeratosis congenita through mechanisms that are not fully understood. Presence of oxidative stress was postulated to result from telomerase ablation. However, the resulting disturbed redox status can promote telomere attrition by generating a vicious circle, which promotes cellular senescence. This fact prompted us to study if acute loss of DKC1, NOP10 and TINF2 can promote redox disequilibrium as an early event when telomere shortening has not yet taken place. We generated siRNA-mediated (DKC1, NOP10 and TINF2) cell lines by RNA interference, which was confirmed by mRNA and protein expression analyses. No telomere shortening occurred in any silenced cell line. Depletion of H/ACA ribonucleoproteins DKC1 and NOP10 diminished telomerase activity via TERC down-regulation, and produced alterations in pseudouridylation and ribosomal biogenesis. An increase in the GSSG/GSH ratio, carbonylated proteins and oxidized peroxiredoxin-6 was observed, in addition to MnSOD and TRX1 overexpression in the siRNA DC cells. Likewise, high PARylation levels and high PARP1 protein expression were detected. In contrast, the silenced TINF2 cells did not alter any evaluated oxidative stress marker. Altogether these findings lead us to conclude that loss of DKC1 and NOP10 functions induces oxidative stress in a telomere shortening independent manner.
      Graphical abstract image

      PubDate: 2017-10-07T16:28:42Z
       
  • The dual role of poly (ADP-ribose) polymerase-1 in modulating parthanatos
           and autophagy under oxidative stress in rat cochlear marginal cells of the
           stria vascularis

    • Authors: Hong-Yan Jiang; Yang Yang Yuan-Yuan Zhang Zhen Xie Xue-Yan Zhao
      Abstract: Publication date: Available online 7 October 2017
      Source:Redox Biology
      Author(s): Hong-Yan Jiang, Yang Yang, Yuan-Yuan Zhang, Zhen Xie, Xue-Yan Zhao, Yu Sun, Wei-Jia Kong
      Oxidative stress is reported to regulate several apoptotic and necrotic cell death pathways in auditory tissues. Poly (ADP-ribose) polymerase-1 (PARP-1) can be activated under oxidative stress, which is the hallmark of parthanatos. Autophagy, which serves either a pro-survival or pro-death function, can alsobe stimulated by oxidative stress, but the role of autophagy and its relationship with parthanatos underlying this activation in the inner ear remains unknown. In this study, we established an oxidative stress model in vitro by glucose oxidase/glucose (GO/G), which could continuously generate low concentrations of H2O2 to mimic continuous exposure to H2O2 in physiological conditions, for investigation of oxidative stress-induced cell death mechanisms and the regulatory role of PARP-1 in this process. We observed that GO/G induced stria marginal cells (MCs) death via upregulation of PARP-1 expression, accumulation of poly ADP-ribose (PAR) polymers, decline of mitochondrial membrane potential (MMP) and nuclear translocation of apoptosis-inducing factor (AIF), which all are biochemical features of parthanatos. PARP-1 knockdown rescued GO/G-induced MCs death, as well as abrogated downstream molecular events of PARP-1 activation. In addition, we demonstrated that GO/G stimulated autophagy and PARP-1 knockdown suppressed GO/G-induced autophagy in MCs. Interestingly, autophagy suppression by 3-Methyladenine (3-MA) accelerated GO/G-induced parthanatos, indicating a pro-survival function of autophagy in GO/G-induced MCs death. Taken together, these data suggested that PARP-1 played dual roles by modulating parthanatos and autophagy in oxidative stress-induced MCs death, which may be considered as a promising therapeutic target for ameliorating oxidative stress-related hearing disorders.
      Graphical abstract image

      PubDate: 2017-10-07T16:28:42Z
       
  • Do developmental temperatures affect redox level and lifespan in C.
           elegans through upregulation of peroxiredoxin'

    • Authors: Dylan Henderson; Christian Huebner Moses Markowitz Nicole Taube Zachary Havanek
      Abstract: Publication date: Available online 7 October 2017
      Source:Redox Biology
      Author(s): Dylan Henderson, Christian Huebner, Moses Markowitz, Nicole Taube, Zachary M. Havanek, Ursula Jakob, Daniela Knoefler
      Lifespan in poikilothermic organisms, such as Caenorhabditis elegans, can be substantially increased simply by decreasing growth temperature. To gain insights into the mechanistic underpinnings of this effect, we investigated the effects of temperature in development and adulthood on C. elegans lifespan. We found that worms exposed to 25°C during development and shifted to 15°C in adulthood exhibited an even longer lifespan than animals constantly kept at 15°C. Analysis of the in vivo redox status demonstrated that at 25°C, C. elegans larvae have a more reduced redox state and higher Prdx-2 expression levels than animals raised at 15°C. Worms lacking prdx-2 fail to show the additional lifespan extension upon shift from 25°C to 15°C and reveal a lifespan similar to prdx-2 worms always kept at 15°C. These results suggest that transiently altering the in vivo redox state during development can have highly beneficial long-term consequences for organisms.
      Graphical abstract image

      PubDate: 2017-10-07T16:28:42Z
       
  • Advanced oxidation protein products induce S-phase arrest of hepatocytes
           via the ROS-dependent, β-catenin-CDK2-mediated pathway

    • Authors: Shibo Sun; Fang Xie Xiaoping Qing Cai Qifan Zhang Zhonglin
      Abstract: Publication date: Available online 6 October 2017
      Source:Redox Biology
      Author(s): Shibo Sun, Fang Xie, Xiaoping Xu, Qing Cai, Qifan Zhang, Zhonglin Cui, Yujian Zheng, Jie Zhou
      Liver regeneration has important clinical importance in the setting of partial hepatectomy (PH). Following PH, quiescent hepatocytes can reenter cell cycle to restore liver mass. Hepatocyte cell cycle progression, as the basic motivations of liver regeneration, can be disrupted by multiple pathological factors such as oxidative stress. This study aimed to evaluate the role of advanced oxidation protein products (AOPP) in S-phase arrest in hepatocytes. Serum AOPP level were measured during the perioperative period of PH in 33 patients with hepatocellular carcinoma (HCC). Normal Sprague Dawley rats, human and murine liver cell line (HL-7702 and AML-12) were challenged with AOPP prepared by incubation of rat serum albumin (RSA) with hypochlorous acid, and the effect of AOPP on hepatocytes cell cycle progression and liver regeneration was studied after PH. AOPP levels were increased following partial hepatectomy (PH) in patients with primary liver cancer. AOPP treatment impaired liver regeneration in rats following 70% partial hepatectomy. S-phase arrest was induced by AOPP administration in hepatocytes derived from the remnant liver at controlled times following partial hepatectomy in rats, and in HL-7702 and AML-12 cells. The effect of AOPP on hepatocyte S phase arrest was mainly mediated by a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) generation, downregulation of downstream β-catenin signaling and decreased cyclin-dependent kinase 2 (CDK2) expression, which inhibited S-phase progression in hepatocytes. This study provides preliminary evidence that AOPP can induce S-phase arrest in hepatocytes via the ROS-dependent, β-catenin-CDK2-mediated pathway. These findings suggest a novel pathogenic role of AOPP contributing to the impaired liver regeneration and may provide the basis for developing new strategies to improve liver regeneration in patients undergoing PH.
      Graphical abstract image

      PubDate: 2017-10-07T16:28:42Z
       
  • Direct 1O2 optical excitation: A tool for redox biology

    • Authors: Alfonso
      Abstract: Publication date: October 2017
      Source:Redox Biology, Volume 13
      Author(s): Alfonso Blázquez-Castro
      Molecular oxygen (O2) displays very interesting properties. Its first excited state, commonly known as singlet oxygen (1O2), is one of the so-called Reactive Oxygen Species (ROS). It has been implicated in many redox processes in biological systems. For many decades its role has been that of a deleterious chemical species, although very positive clinical applications in the Photodynamic Therapy of cancer (PDT) have been reported. More recently, many ROS, and also 1O2, are in the spotlight because of their role in physiological signaling, like cell proliferation or tissue regeneration. However, there are methodological shortcomings to properly assess the role of 1O2 in redox biology with classical generation procedures. In this review the direct optical excitation of O2 to produce 1O2 will be introduced, in order to present its main advantages and drawbacks for biological studies. This photonic approach can provide with many interesting possibilities to understand and put to use ROS in redox signaling and in the biomedical field.
      Graphical abstract image

      PubDate: 2017-05-30T07:10:02Z
       
 
 
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