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Journal Cover Redox Biology
  [SJR: 2.382]   [H-I: 24]   [1 followers]  Follow
    
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2213-2317
   Published by Elsevier Homepage  [3177 journals]
  • High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate
           mesangial cells and promotes renal inflammatory pathology in nonalcoholic
           fatty liver disease

    • Authors: Firas Alhasson; Ratanesh Kumar Seth; Sutapa Sarkar; Diana A. Kimono; Muayad S. Albadrani; Diptadip Dattaroy; Varun Chandrashekaran; Geoffrey I. Scott; Samir Raychoudhury; Mitzi Nagarkatti; Prakash Nagarkatti; Anna Mae Diehl; Saurabh Chatterjee
      Pages: 1 - 15
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Firas Alhasson, Ratanesh Kumar Seth, Sutapa Sarkar, Diana A. Kimono, Muayad S. Albadrani, Diptadip Dattaroy, Varun Chandrashekaran, Geoffrey I. Scott, Samir Raychoudhury, Mitzi Nagarkatti, Prakash Nagarkatti, Anna Mae Diehl, Saurabh Chatterjee
      High circulatory insulin and leptin followed by underlying inflammation are often ascribed to the ectopic manifestations in non-alcoholic fatty liver disease (NAFLD) but the exact molecular pathways remain unclear. We have shown previously that CYP2E1-mediated oxidative stress and circulating leptin in NAFLD is associated with renal disease severity. Extending the studies, we hypothesized that high circulatory leptin in NAFLD causes renal mesangial cell activation and tubular inflammation via a NOX2 dependent pathway that upregulates proinflammatory miR21. High-fat diet (60% kcal) was used to induce fatty liver phenotype with parallel insulin and leptin resistance. The kidneys were probed for mesangial cell activation and tubular inflammation that showed accelerated NASH phenotype and oxidative stress in the liver. Results showed that NAFLD kidneys had significant increases in α-SMA, a marker of mesangial cell activation, miR21 levels, tyrosine nitration and renal inflammation while they were significantly decreased in leptin and p47 phox knockout mice. Micro RNA21 knockout mice showed decreased tubular immunotoxicity and proinflammatory mediator release. Mechanistically, use of NOX2 siRNA or apocynin,phenyl boronic acid (FBA), DMPO or miR21 antagomir inhibited leptin primed-miR21-mediated mesangial cell activation in vitro suggesting a direct role of leptin-mediated NOX-2 in miR21-mediated mesangial cell activation. Finally, JAK-STAT inhibitor completely abrogated the mesangial cell activation in leptin-primed cells suggesting that leptin signaling in the mesangial cells depended on the JAK-STAT pathway. Taken together the study reports a novel mechanistic pathway of leptin-mediated renal inflammation that is dependent on NOX-2-miR21 axis in ectopic manifestations underlying NAFLD-induced co-morbidities.

      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.04.002
      Issue No: Vol. 17 (2018)
       
  • IDH2 deficiency accelerates skin pigmentation in mice via enhancing
           melanogenesis

    • Authors: Jung Hyun Park; Hyeong Jun Ku; Jin Hyup Lee; Jeen-Woo Park
      Pages: 16 - 24
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Jung Hyun Park, Hyeong Jun Ku, Jin Hyup Lee, Jeen-Woo Park
      Melanogenesis is a complex biosynthetic pathway regulated by multiple agents, which are involved in the production, transport, and release of melanin. Melanin has diverse roles, including determination of visible skin color and photoprotection. Studies indicate that melanin synthesis is tightly linked to the interaction between melanocytes and keratinocytes. α-melanocyte-stimulating hormone (α-MSH) is known as a trigger that enhances melanin biosynthesis in melanocytes through paracrine effects. Accumulated reactive oxygen species (ROS) in skin affects both keratinocytes and melanocytes by causing DNA damage, which eventually leads to the stimulation of α-MSH production. Mitochondria are one of the main sources of ROS in the skin and play a central role in modulating redox-dependent cellular processes such as metabolism and apoptosis. Therefore, mitochondrial dysfunction may serve as a key for the pathogenesis of skin melanogenesis. Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) is a key enzyme that regulates mitochondrial redox balance and reduces oxidative stress-induced cell injury through the generation of NADPH. Downregulation of IDH2 expression resulted in an increase in oxidative DNA damage in mice skin through ROS-dependent ATM-mediated p53 signaling. IDH2 deficiency also promoted pigmentation on the dorsal skin of mice, as evident from the elevated levels of melanin synthesis markers. Furthermore, pretreatment with mitochondria-targeted antioxidant mito-TEMPO alleviated oxidative DNA damage and melanogenesis induced by IDH2 deficiency both in vitro and in vivo. Together, our findings highlight the role of IDH2 in skin melanogenesis in association with mitochondrial ROS and suggest unique therapeutic strategies for the prevention of skin pigmentation.
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      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.04.008
      Issue No: Vol. 17 (2018)
       
  • GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity by
           decreasing cardiomyocyte apoptosis and myocardial oxidative stress

    • Authors: Yue Wang; Tong Lei; Juntao Yuan; Yongguang Wu; Xiyue Shen; Junling Gao; Wei Feng; Zhongbing Lu
      Pages: 25 - 34
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Yue Wang, Tong Lei, Juntao Yuan, Yongguang Wu, Xiyue Shen, Junling Gao, Wei Feng, Zhongbing Lu
      The clinical use of doxorubicin for cancer therapy is limited by its cardiotoxicity, which involves cardiomyocyte apoptosis and oxidative stress. Previously, we showed that general control nonderepressible 2 (GCN2), an eukaryotic initiation factor 2α (eIF2α) kinase, impairs the ventricular adaptation to chronic pressure overload by affecting cardiomyocyte apoptosis. However, the impact of GCN2 on Dox-induced cardiotoxicity has not been investigated. In the present study, we treated wild type (WT) and Gcn2 −/− mice with four intraperitoneal injections (5 mg/kg/week) to induce cardiomyopathy. After Dox treatment, Gcn2 −/− mice developed less contractile dysfunction, myocardial fibrosis, apoptosis, and oxidative stress compared with WT mice. In the hearts of the Dox-treated mice, GCN2 deficiency attenuated eIF2α phosphorylation and induction of its downstream targets, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and preserved the expression of anti-apoptotic factor Bcl-2 and mitochondrial uncoupling protein-2(UCP2). Furthermore, we found that GCN2 knockdown attenuated, whereas GCN2 overexpression exacerbated, Dox-induced cell death, oxidative stress and reduction of Bcl-2 and UCP2 expression through the eIF2α-CHOP-dependent pathway in H9C2 cells. Collectively, our data provide solid evidence that GCN2 has a marked effect on Dox induced myocardial apoptosis and oxidative stress. Our findings suggest that strategies to inhibit GCN2 activity in cardiomyocyte may provide a novel approach to attenuate Dox-related cardiotoxicity.
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      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.04.009
      Issue No: Vol. 17 (2018)
       
  • The phosphorylated redox proteome of Chlamydomonas reinhardtii: Revealing
           novel means for regulation of protein structure and function

    • Authors: Evan W. McConnell; Emily G. Werth; Leslie M. Hicks
      Pages: 35 - 46
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Evan W. McConnell, Emily G. Werth, Leslie M. Hicks
      Post-translational modifications (PTMs) are covalent modifications to protein residues which may alter both conformation and activity, thereby modulating signaling and metabolic processes. While PTMs have been largely investigated independently, examination into how different modification interact, or crosstalk, will reveal a more complete understanding of the reciprocity of signaling cascades across numerous pathways. Combinatorial reversible thiol oxidation and phosphorylation in eukaryotes is largely recognized, but rigorous approaches for experimental discovery are underdeveloped. To begin meaningful interrogation of PTM crosstalk in systems biology research, knowledge of targeted proteins must be advanced. Herein, we demonstrate protein-level enrichment of reversibly oxidized proteoforms in Chlamydomonas reinhardtii with subsequent phosphopeptide analysis to determine the extent of phosphorylation in the redox thiol proteome. Label-free quantification was used to quantify 3353 oxidized Cys-sites on 1457 enriched proteins, where sequential phosphopeptide enrichment measured 1094 sites of phosphorylation on 720 proteins with 23% (172 proteins) also identified as reversibly oxidized. Proteins identified with both reversible oxidation and phosphorylation were involved in signaling transduction, ribosome and translation-related machinery, and metabolic pathways. Several redox-modified Calvin-Benson cycle proteins were found phosphorylated and many kinases/phosphatases involved in phosphorylation-dependent photosynthetic state transition and stress-response pathways had sites of reversible oxidation. Identification of redox proteins serves as a crucial element in understanding stress response in photosynthetic organisms and beyond, whereby knowing the ensemble of modifications co-occurring with oxidation highlights novel mechanisms for cellular control.
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      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.04.003
      Issue No: Vol. 17 (2018)
       
  • Nrf2 deficiency exacerbates age-related contractile dysfunction and loss
           of skeletal muscle mass

    • Authors: Bumsoo Ahn; Gavin Pharaoh; Pavithra Premkumar; Kendra Huseman; Rojina Ranjit; Michael Kinter; Luke Szweda; Tamas Kiss; Gabor Fulop; Stefano Tarantini; Anna Csiszar; Zoltan Ungvari; Holly Van Remmen
      Pages: 47 - 58
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Bumsoo Ahn, Gavin Pharaoh, Pavithra Premkumar, Kendra Huseman, Rojina Ranjit, Michael Kinter, Luke Szweda, Tamas Kiss, Gabor Fulop, Stefano Tarantini, Anna Csiszar, Zoltan Ungvari, Holly Van Remmen
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      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.04.004
      Issue No: Vol. 17 (2018)
       
  • Methods for assessing mitochondrial quality control mechanisms and
           cellular consequences in cell culture

    • Authors: Matthew Redmann; Gloria A. Benavides; Willayat Yousuf Wani; Taylor F. Berryhill; Xiaosen Ouyang; Michelle S. Johnson; Saranya Ravi; Kasturi Mitra; Stephen Barnes; Victor M. Darley-Usmar; Jianhua Zhang
      Pages: 59 - 69
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Matthew Redmann, Gloria A. Benavides, Willayat Yousuf Wani, Taylor F. Berryhill, Xiaosen Ouyang, Michelle S. Johnson, Saranya Ravi, Kasturi Mitra, Stephen Barnes, Victor M. Darley-Usmar, Jianhua Zhang
      Mitochondrial quality is under surveillance by autophagy, the cell recycling process which degrades and removes damaged mitochondria. Inadequate autophagy results in deterioration in mitochondrial quality, bioenergetic dysfunction, and metabolic stress. Here we describe in an integrated work-flow to assess parameters of mitochondrial morphology, function, mtDNA and protein damage, metabolism and autophagy regulation to provide the framework for a practical assessment of mitochondrial quality. This protocol has been tested with cell cultures, is highly reproducible, and is adaptable to studies when cell numbers are limited, and thus will be of interest to researchers studying diverse physiological and pathological phenomena in which decreased mitochondrial quality is a contributory factor.

      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.04.005
      Issue No: Vol. 17 (2018)
       
  • Identification of homocysteine-suppressive mitochondrial ETC complex genes
           and tissue expression profile – Novel hypothesis establishment

    • Authors: Ramon Cueto; Lixiao Zhang; Hui Min Shan; Xiao Huang; Xinyuan Li; Ya-feng Li; Jahaira Lopez; William Y. Yang; Muriel Lavallee; Catherine Yu; Yong Ji; Xiaofeng Yang; Hong Wang
      Pages: 70 - 88
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Ramon Cueto, Lixiao Zhang, Hui Min Shan, Xiao Huang, Xinyuan Li, Ya-feng Li, Jahaira Lopez, William Y. Yang, Muriel Lavallee, Catherine Yu, Yong Ji, Xiaofeng Yang, Hong Wang
      Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD) which has been implicated in matochondrial (Mt) function impairment. In this study, we characterized Hcy metabolism in mouse tissues by using LC-ESI-MS/MS analysis, established tissue expression profiles for 84 nuclear-encoded Mt electron transport chain complex (nMt-ETC-Com) genes in 20 human and 19 mouse tissues by database mining, and modeled the effect of HHcy on Mt-ETC function. Hcy levels were high in mouse kidney/lung/spleen/liver (24–14 nmol/g tissue) but low in brain/heart (~5 nmol/g). S-adenosylhomocysteine (SAH) levels were high in the liver/kidney (59–33 nmol/g), moderate in lung/heart/brain (7–4 nmol/g) and low in spleen (1 nmol/g). S-adenosylmethionine (SAM) was comparable in all tissues (42–18 nmol/g). SAM/SAH ratio was as high as 25.6 in the spleen but much lower in the heart/lung/brain/kidney/liver (7–0.6). The nMt-ETC-Com genes were highly expressed in muscle/pituitary gland/heart/BM in humans and in lymph node/heart/pancreas/brain in mice. We identified 15 Hcy-suppressive nMt-ETC-Com genes whose mRNA levels were negatively correlated with tissue Hcy levels, including 11 complex-I, one complex-IV and two complex-V genes. Among the 11 Hcy-suppressive complex-I genes, 4 are complex-I core subunits. Based on the pattern of tissue expression of these genes, we classified tissues into three tiers (high/mid/low-Hcy responsive), and defined heart/eye/pancreas/brain/kidney/liver/testis/embryonic tissues as tier 1 (high-Hcy responsive) tissues in both human and mice. Furthermore, through extensive literature mining, we found that most of the Hcy-suppressive nMt-ETC-Com genes were suppressed in HHcy conditions and related with Mt complex assembly/activity impairment in human disease and experimental models. We hypothesize that HHcy inhibits Mt complex I gene expression leading to Mt dysfunction.
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      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.03.015
      Issue No: Vol. 17 (2018)
       
  • Nicotinamide riboside attenuates alcohol induced liver injuries via
           activation of SirT1/PGC-1α/mitochondrial biosynthesis pathway

    • Authors: Sufan Wang; Ting Wan; Mingtong Ye; Yun Qiu; Lei Pei; Rui Jiang; Nengzhi Pang; Yuanling Huang; Baoxia Liang; Wenhua Ling; Xiaojun Lin; Zhenfeng Zhang; Lili Yang
      Pages: 89 - 98
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Sufan Wang, Ting Wan, Mingtong Ye, Yun Qiu, Lei Pei, Rui Jiang, Nengzhi Pang, Yuanling Huang, Baoxia Liang, Wenhua Ling, Xiaojun Lin, Zhenfeng Zhang, Lili Yang
      Background Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor which is present in foods such as milk and beer. It was reported that NR can prevent obesity, increase longevity, and promote liver regeneration. However, whether NR can prevent ethanol-induced liver injuries is not known. This study aimed to explore the effect of NR on ethanol induced liver injuries and the underlying mechanisms. Methods We fed C57BL/6 J mice with Lieber-DeCarli ethanol liquid diet with or without 400 mg/kg·bw NR for 16 days. Liver injuries and SirT1-PGC-1α-mitochondrial function were analyzed. In in vitro experiments, HepG2 cells (CYP2E1 over-expressing cells) were incubated with ethanol ± 0.5 mmol/L NR. Lipid accumulation and mitochondrial function were compared. SirT1 knockdown in HepG2 cells were further applied to confirm the role of SirT1 in the protection of NR on lipid accumulation. Results We found that ethanol significantly decreased the expression and activity of hepatic SirT1 and induced abnormal expression of enzymes of lipid metabolism in mice. Both in vivo and in vitro experiments showed that NR activated SirT1 through increasing NAD+ levels, decreased oxidative stress, increased deacetylation of PGC-1α and mitochondrial function. In SirT1 knockdown HepG2 cells, NR lost its ability in enhancing mitochondrial function, and its protection against lipid accumulation induced by ethanol. Conclusions NR can protect against ethanol induced liver injuries via replenishing NAD+, reducing oxidative stress, and activating SirT1-PGC-1α-mitochondrial biosynthesis. Our data indicate that SirT1 plays an important role in the protection of NR against lipid accumulation and mitochondrial dysfunctions induced by ethanol.
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      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.04.006
      Issue No: Vol. 17 (2018)
       
  • Increased oxidative stress mediates the antitumor effect of PARP
           inhibition in ovarian cancer

    • Authors: Dong Hou; Zhaojian Liu; Xiuhua Xu; Qiao Liu; Xiyu Zhang; Beihua Kong; Jian-Jun Wei; Yaoqin Gong; Changshun Shao
      Pages: 99 - 111
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Dong Hou, Zhaojian Liu, Xiuhua Xu, Qiao Liu, Xiyu Zhang, Beihua Kong, Jian-Jun Wei, Yaoqin Gong, Changshun Shao
      PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS). Importantly, antioxidant N-acetylcysteine (NAC) significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells.
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      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.03.016
      Issue No: Vol. 17 (2018)
       
  • GLUT1 protects prostate cancer cells from glucose deprivation-induced
           oxidative stress

    • Authors: Pedro Gonzalez-Menendez; David Hevia; Rebeca Alonso-Arias; Alejandro Alvarez-Artime; Aida Rodriguez-Garcia; Sandrina Kinet; Ivan Gonzalez-Pola; Naomi Taylor; Juan C. Mayo; Rosa M. Sainz
      Pages: 112 - 127
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Pedro Gonzalez-Menendez, David Hevia, Rebeca Alonso-Arias, Alejandro Alvarez-Artime, Aida Rodriguez-Garcia, Sandrina Kinet, Ivan Gonzalez-Pola, Naomi Taylor, Juan C. Mayo, Rosa M. Sainz
      Glucose, chief metabolic support for cancer cell survival and growth, is mainly imported into cells by facilitated glucose transporters (GLUTs). The increase in glucose uptake along with tumor progression is due to an increment of facilitative glucose transporters as GLUT1. GLUT1 prevents cell death of cancer cells caused by growth factors deprivation, but there is scarce information about its role on the damage caused by glucose deprivation, which usually occurs within the core of a growing tumor. In prostate cancer (PCa), GLUT1 is found in the most aggressive tumors, and it is regulated by androgens. To study the response of androgen-sensitive and insensitive PCa cells to glucose deprivation and the role of GLUT1 on survival mechanisms, androgen-sensitive LNCaP and castration-resistant LNCaP-R cells were employed. Results demonstrated that glucose deprivation induced a necrotic type of cell death which is prevented by antioxidants. Androgen-sensitive cells show a higher resistance to cell death triggered by glucose deprivation than castration-resistant cells. Glucose removal causes an increment of H2O2, an activation of androgen receptor (AR) and a stimulation of AMP-activated protein kinase activity. In addition, glucose removal increases GLUT1 production in androgen sensitive PCa cells. GLUT1 ectopic overexpression makes PCa cells more resistant to glucose deprivation and oxidative stress-induced cell death. Under glucose deprivation, GLUT1 overexpressing PCa cells sustains mitochondrial SOD2 activity, compromised after glucose removal, and significantly increases reduced glutathione (GSH). In conclusion, androgen-sensitive PCa cells are more resistant to glucose deprivation-induced cell death by a GLUT1 upregulation through an enhancement of reduced glutathione levels.
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      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.03.017
      Issue No: Vol. 17 (2018)
       
  • Protein and cell wall polysaccharide carbonyl determination by a neutral
           pH 2,4-dinitrophenylhydrazine-based photometric assay

    • Authors: Christos D. Georgiou; Dimitrios Zisimopoulos; Vasiliki Argyropoulou; Electra Kalaitzopoulou; George Salachas; Tilman Grune
      Pages: 128 - 142
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Christos D. Georgiou, Dimitrios Zisimopoulos, Vasiliki Argyropoulou, Electra Kalaitzopoulou, George Salachas, Tilman Grune
      A new 2,4-dinitrophenylhydrazine (DNPH)-based photometric assay is developed for the quantification of carbonyls in protein samples from any biological source by protein carbonyl-DNPH hydrazone formation at acidic pH in the presence of denaturing urea, and subsequent hydrazone solubilization in the presence of SDS and stabilization from acid hydrolysis at pH 7.0. At this neutral (ntr) pH, interfering unreacted DNPH is uncharged and its thus increased hydrophobicity permits its 100% effective removal from the solubilizate with ethyl acetate/hexane wash. The ntrDNPH assay is more reliable and sensitive than the standard (std) DNPH photometric assay because it eliminates its main limitations: (i) interfering unreacted DNPH (pKa 1.55) that is nonspecifically bound to the TCA (pKa 0.7)-protein pellet is not effectively removed after wash with EtOH: ethyl acetate because it is positively charged, (ii) acid (TCA-induced) hydrolysis of the protein carbonyl-DNPH hydrazone, (iii) sample protein concentration re-determination, (iv) loss of sample acid (TCA)-soluble proteins, (v) DNA interference, and (vi) requires high protein quantity samples (≥ 1 mg). Considering ntrDNPH assay’s very low protein limit (1 µg), its cumulative and functional sensitivities are 2600- and 2000-fold higher than those of the stdDNPH assay, respectively. The present study elucidates the DNA interference mechanism on the stdDNPH assay, and also develops a standardized protocol for sample protein treatment and fractionation (into cytoplasmic/aqueous, membrane/lipid-bound, and histone/DNA-bound proteins; see Supplement section V) in order to ensure reproducible carbonyl determination on defined cell protein fractions, and to eliminate assay interference from protein samples containing (i) Cys sulfenic acid groups (via their neutralization with dithiothreitol), and (ii) DNA (via its removal by streptomycin sulfate precipitation). Lastly, the ntrDNPH assay determines carbonyl groups on cell wall polysaccharides, thus paving the way on studies to investigate cell walls acting as antioxidant defense in plants, fungi, bacteria and lichens.
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      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.04.010
      Issue No: Vol. 17 (2018)
       
  • Ameliorating mitochondrial dysfunction restores carbon ion-induced
           cognitive deficits via co-activation of NRF2 and PINK1 signaling pathway

    • Authors: Yang Liu; Jiawei Yan; Cao Sun; Guo Li; Sirui Li; Luwei Zhang; Cuixia Di; Lu Gan; Yupei Wang; Rong Zhou; Jing Si; Hong Zhang
      Pages: 143 - 157
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Yang Liu, Jiawei Yan, Cao Sun, Guo Li, Sirui Li, Luwei Zhang, Cuixia Di, Lu Gan, Yupei Wang, Rong Zhou, Jing Si, Hong Zhang
      Carbon ion therapy is a promising modality in radiotherapy to treat tumors, however, a potential risk of induction of late normal tissue damage should still be investigated and protected. The aim of the present study was to explore the long-term cognitive deficits provoked by a high-linear energy transfer (high-LET) carbon ions in mice by targeting to hippocampus which plays a crucial role in memory and learning. Our data showed that, one month after 4 Gy carbon ion exposure, carbon ion irradiation conspicuously resulted in the impaired cognitive performance, neurodegeneration and neuronal cell death, as well as the reduced mitochondrial integrity, the disrupted activities of tricarboxylic acid cycle flux and electron transport chain, and the depressed antioxidant defense system, consequently leading to a decline of ATP production and persistent oxidative damage in the hippocampus region. Mechanistically, we demonstrated the disruptions of mitochondrial homeostasis and redox balance typically characterized by the disordered mitochondrial dynamics, mitophagy and glutathione redox couple, which is closely associated with the inhibitions of PINK1 and NRF2 signaling pathway as the key regulators of molecular responses in the context of neurotoxicity and neurodegenerative disorders. Most importantly, we found that administration with melatonin as a mitochondria-targeted antioxidant promoted the PINK1 accumulation on the mitochondrial membrane, and augmented the NRF2 accumulation and translocation. Moreover, melatonin pronouncedly enhanced the molecular interplay between NRF2 and PINK1. Furthermore, in the mouse hippocampal neuronal cells, overexpression of NRF2/PINK1 strikingly protected the hippocampal neurons from carbon ion-elicited toxic insults. Thus, these data suggest that alleviation of the sustained mitochondrial dysfunction and oxidative stress through co-modulation of NRF2 and PINK1 may be in charge of restoration of the cognitive impairments in a mouse model of high-LET carbon ion irradiation.

      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.04.012
      Issue No: Vol. 17 (2018)
       
  • Integrative metabolomics and transcriptomics signatures of clinical
           tolerance to Plasmodium vivax reveal activation of innate cell immunity
           and T cell signaling

    • Authors: Luiz G. Gardinassi; Myriam Arévalo-Herrera; Sócrates Herrera; Regina J. Cordy; ViLinh Tran; Matthew R. Smith; Michelle S. Johnson; Balu Chacko; Ken H. Liu; Victor M. Darley-Usmar; Young-Mi Go; Dean P. Jones; Mary R. Galinski; Shuzhao Li
      Pages: 158 - 170
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Luiz G. Gardinassi, Myriam Arévalo-Herrera, Sócrates Herrera, Regina J. Cordy, ViLinh Tran, Matthew R. Smith, Michelle S. Johnson, Balu Chacko, Ken H. Liu, Victor M. Darley-Usmar, Young-Mi Go, Dean P. Jones, Mary R. Galinski, Shuzhao Li
      Almost invariably, humans become ill during primary infections with malaria parasites which is a pathology associated with oxidative stress and perturbations in metabolism. Importantly, repetitive exposure to Plasmodium results in asymptomatic infections, which is a condition defined as clinical tolerance. Integration of transcriptomics and metabolomics data provides a powerful way to investigate complex disease processes involving oxidative stress, energy metabolism and immune cell activation. We used metabolomics and transcriptomics to investigate the different clinical outcomes in a P. vivax controlled human malaria infection trial. At baseline, the naïve and semi-immune subjects differed in the expression of interferon related genes, neutrophil and B cell signatures that progressed with distinct kinetics after infection. Metabolomics data indicated differences in amino acid pathways and lipid metabolism between the two groups. Top pathways during the course of infection included methionine and cysteine metabolism, fatty acid metabolism and urea cycle. There is also evidence for the activation of lipoxygenase, cyclooxygenase and non-specific lipid peroxidation products in the semi-immune group. The integration of transcriptomics and metabolomics revealed concerted molecular events triggered by the infection, notably involving platelet activation, innate immunity and T cell signaling. Additional experiment confirmed that the metabolites associated with platelet activation genes were indeed enriched in the platelet metabolome.
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      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.04.011
      Issue No: Vol. 17 (2018)
       
  • MGST1, a GSH transferase/peroxidase essential for development and
           hematopoietic stem cell differentiation

    • Authors: Lars Bräutigam; Jie Zhang; Kristian Dreij; Linda Spahiu; Arne Holmgren; Hiroshi Abe; Kenneth D. Tew; Danyelle M. Townsend; Michael J. Kelner; Ralf Morgenstern; Katarina Johansson
      Pages: 171 - 179
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Lars Bräutigam, Jie Zhang, Kristian Dreij, Linda Spahiu, Arne Holmgren, Hiroshi Abe, Kenneth D. Tew, Danyelle M. Townsend, Michael J. Kelner, Ralf Morgenstern, Katarina Johansson
      We show for the first time that, in contrast to other glutathione transferases and peroxidases, deletion of microsomal glutathione transferase 1 (MGST1) in mice is embryonic lethal. To elucidate why, we used zebrafish development as a model system and found that knockdown of MGST1 produced impaired hematopoiesis. We show that MGST1 is expressed early during zebrafish development and plays an important role in hematopoiesis. High expression of MGST1 was detected in regions of active hematopoiesis and co-expressed with markers for hematopoietic stem cells. Further, morpholino-mediated knock-down of MGST1 led to a significant reduction of differentiated hematopoietic cells both from the myeloid and the lymphoid lineages. In fact, hemoglobin was virtually absent in the knock-down fish as revealed by diaminofluorene staining. The impact of MGST1 on hematopoiesis was also shown in hematopoietic stem/progenitor cells (HSPC) isolated from mice, where it was expressed at high levels. Upon promoting HSPC differentiation, lentiviral shRNA MGST1 knockdown significantly reduced differentiated, dedicated cells of the hematopoietic system. Further, MGST1 knockdown resulted in a significant lowering of mitochondrial metabolism and an induction of glycolytic enzymes, energetic states closely coupled to HSPC dynamics. Thus, the non-selenium, glutathione dependent redox regulatory enzyme MGST1 is crucial for embryonic development and for hematopoiesis in vertebrates.
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      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.04.013
      Issue No: Vol. 17 (2018)
       
  • Regulation of AMPK-related glycolipid metabolism imbalances redox
           homeostasis and inhibits anchorage independent growth in human breast
           cancer cells

    • Authors: Lin Yang; Zihao He; Jingyue Yao; Renxiang Tan; Yejin Zhu; Zhiyu Li; Qinglong Guo; Libin Wei
      Pages: 180 - 191
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Lin Yang, Zihao He, Jingyue Yao, Renxiang Tan, Yejin Zhu, Zhiyu Li, Qinglong Guo, Libin Wei
      Breast cancer is one of the most lethal tumors in the world, among which 15% are triple-negative breast cancers (TNBCs) with higher metastasis and lower survival rate. Anoikis resistance is a key process during tumor metastasis, which is usually accompanied with metabolism reprogram. In this study, we established an anchorage independent growth model for MDA-MB-231 cells and investigated the changes in metabolism and redox homeostasis. Results showed that during detached-growth, MDA-MB-231 cells tend to generate ATP through fatty acid oxidation (FAO), instead of glycolysis. Amount of glucose was used for pentose phosphate pathway (PPP) to keep redox balance. Moreover, we discovered that a synthesized flavonoid derivative GL-V9, exhibited a potent inhibitory effect on the anchorage independent growth of TNBCs in vitro and anti-metastasis effect in vivo. In terms of the mechanism, GL-V9 could promote the expression and activity of AMPK, leading to the decrease of G6PD and the increase of p-ACC. Thus, the level of PPP was suppressed, whereas FAO was highly enhanced. The reprogram of glycolipid metabolism destroyed the redox balance ultimately and induced cell death. This paper indicated a novel regulating mechanism of redox homeostasis involving with glycolipid metabolism, and provided a potential candidate for the anti-metastatic therapy of TNBCs.

      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.04.016
      Issue No: Vol. 17 (2018)
       
  • Oxygen-dependence of mitochondrial ROS production as detected by Amplex
           Red assay

    • Authors: Vera G. Grivennikova; Alexandra V. Kareyeva; Andrei D. Vinogradov
      Pages: 192 - 199
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Vera G. Grivennikova, Alexandra V. Kareyeva, Andrei D. Vinogradov
      The initial rates of superoxide plus hydrogen peroxide (ROS) generation by intact or permeabilized rat heart mitochondria and coupled inside-out bovine heart submitochondrial particles (SMP) oxidizing NAD-dependent substrates, NADH, and succinate were measured by detecting resorufin formation in the Amplex Red assay at various oxygen concentrations. Linear dependences of the initial rates on oxygen concentration within the range of ~125–750 μM were found for all significant mitochondrial generators, i.e. the respiratory complexes and ammonium-stimulated dihydrolipoamide dehydrogenase. At lower oxygen concentrations upon its decrease from air saturation level to zero, the time-course of resorufin formation by SMP catalyzing coupled oxidation of succinate (the total ROS production by respiratory complexes II and III and by the reverse electron transfer (RET)-mediated by complex I) also corresponds to the linear dependence on oxygen with the same first-order rate constant determined in the initial rate studies. Prolonged incubation of SMP generating succinate-supported complex I-mediated ROS affected neither their NADH oxidase nor ROS generating activity. In contrast to SMP significant deviation from the first-order oxygen dependence in the time-course kinetics during coupled oxidation of succinate by intact mitochondria was evident. Complex I catalyzes the NADH:resorufin oxidoreductase reaction resulting in formation of colorless reduced resorufin. Hydrogen peroxide oxidizes reduced resorufin in the presence of peroxidase, thus showing its dihydroresorufin peroxidase activity. Combined NADH:resorufin reductase and dihydroresorufin peroxidase activities result in underestimation of the amount of hydrogen peroxide generated by mitochondria. We conclude that only initial rates of the mitochondrial ROS production, not the amount of resorufin accumulated, should be taken as the reliable measure of the mitochondrial ROS-generating activity, because of the cycling of the oxidized and reduced resorufin during Amplex Red assays fed by NADH and other possible reductant(s) present in mitochondria.
      Graphical abstract image

      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.04.014
      Issue No: Vol. 17 (2018)
       
  • The mitochondrial oxidoreductase CHCHD4 is present in a semi-oxidized
           state in vivo

    • Authors: Alican J. Erdogan; Muna Ali; Markus Habich; Silja L. Salscheider; Laura Schu; Carmelina Petrungaro; Luke W. Thomas; Margaret Ashcroft; Lars I. Leichert; Leticia Prates Roma; Jan Riemer
      Pages: 200 - 206
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Alican J. Erdogan, Muna Ali, Markus Habich, Silja L. Salscheider, Laura Schu, Carmelina Petrungaro, Luke W. Thomas, Margaret Ashcroft, Lars I. Leichert, Leticia Prates Roma, Jan Riemer
      Disulfide formation in the mitochondrial intermembrane space is an essential process catalyzed by a disulfide relay machinery. In mammalian cells, the key enzyme in this machinery is the oxidoreductase CHCHD4/Mia40. Here, we determined the in vivo CHCHD4 redox state, which is the major determinant of its cellular activity. We found that under basal conditions, endogenous CHCHD4 redox state in cultured cells and mouse tissues was predominantly oxidized, however, degrees of oxidation in different tissues varied from 70% to 90% oxidized. To test whether differences in the ratio between CHCHD4 and ALR might explain tissue-specific differences in the CHCHD4 redox state, we determined the molar ratio of both proteins in different mouse tissues. Surprisingly, ALR is superstoichiometric over CHCHD4 in most tissues. However, the levels of CHCHD4 and the ratio of ALR over CHCHD4 appear to correlate only weakly with the redox state, and although ALR is present in superstoichiometric amounts, it does not lead to fully oxidized CHCHD4.
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      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.03.014
      Issue No: Vol. 17 (2018)
       
  • Respiratory analysis of coupled mitochondria in cryopreserved liver
           biopsies

    • Authors: Mercedes García-Roche; Alberto Casal; Mariana Carriquiry; Rafael Radi; Celia Quijano; Adriana Cassina
      Pages: 207 - 212
      Abstract: Publication date: July 2018
      Source:Redox Biology, Volume 17
      Author(s): Mercedes García-Roche, Alberto Casal, Mariana Carriquiry, Rafael Radi, Celia Quijano, Adriana Cassina
      The aim of this work was to develop a cryopreservation method of small liver biopsies for in situ mitochondrial function assessment. Herein we describe a detailed protocol for tissue collection, cryopreservation, high-resolution respirometry using complex I and II substrates, calculation and interpretation of respiratory parameters. Liver biopsies from cow and rat were sequentially frozen in a medium containing dimethylsulfoxide as cryoprotectant and stored for up to 3 months at −80 °C. Oxygen consumption rate studies of fresh and cryopreserved samples revealed that most respiratory parameters remained unchanged. Additionally, outer mitochondrial membrane integrity was assessed adding cytochrome c, proving that our cryopreservation method does not harm mitochondrial structure. In sum, we present a reliable way to cryopreserve small liver biopsies without affecting mitochondrial function. Our protocol will enable the transport and storage of samples, extending and facilitating mitochondrial function analysis of liver biopsies.
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      PubDate: 2018-04-26T09:21:15Z
      DOI: 10.1016/j.redox.2018.03.008
      Issue No: Vol. 17 (2018)
       
  • Hypoxia enhances H2O2-mediated upregulation of hepcidin: Evidence for
           NOX4-mediated iron regulation

    • Authors: Inês Silva; Vanessa Rausch; Teresa Peccerella; Gunda Millonig; Helmut-Karl Seitz; Sebastian Mueller
      Pages: 1 - 10
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Inês Silva, Vanessa Rausch, Teresa Peccerella, Gunda Millonig, Helmut-Karl Seitz, Sebastian Mueller
      The exact regulation of the liver-secreted peptide hepcidin, the key regulator of systemic iron homeostasis, is still poorly understood. It is potently induced by iron, inflammation, cytokines or H2O2 but conflicting results have been reported on hypoxia. In our current study, we first show that pronounced (1%) and mild (5%) hypoxia strongly induces hepcidin in human Huh7 hepatoma and primary liver cells predominantly at the transcriptional level via STAT3 using two hypoxia systems (hypoxia chamber and enzymatic hypoxia by the GOX/CAT system). SiRNA silencing of JAK1, STAT3 and NOX4 diminished the hypoxia-mediated effect while a role of HIF1α could be clearly ruled out by the response to hypoxia-mimetics and competition experiments with a plasmid harboring the oxygen-dependent degradation domain of HIF1α. Specifically, hypoxia drastically enhances the H2O2-mediated induction of hepcidin strongly pointing towards an oxidase as powerful upstream control of hepcidin. We finally provide evidences for an efficient regulation of hepcidin expression by NADPH-dependent oxidase 4 (NOX4) in liver cells. In summary, our data demonstrate that hypoxia strongly potentiates the peroxide-mediated induction of hepcidin via STAT3 signaling pathway. Moreover, oxidases such as NOX4 or artificially overexpressed urate oxidase (UOX) can induce hepcidin. It remains to be studied whether the peroxide-STAT3-hepcidin axis simply acts to continuously compensate for oxygen fluctuations or is directly involved in iron sensing per se.
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      PubDate: 2018-02-26T00:02:23Z
      DOI: 10.1016/j.redox.2018.02.005
      Issue No: Vol. 16 (2018)
       
  • Hydrogen peroxide production by lactobacilli promotes epithelial
           restitution during colitis

    • Authors: Ashish K. Singh; Rosanne Y. Hertzberger; Ulla G. Knaus
      Pages: 11 - 20
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Ashish K. Singh, Rosanne Y. Hertzberger, Ulla G. Knaus
      Inflammatory bowel disease (IBD) is a multifactorial chronic inflammatory disease of the gastrointestinal tract, characterized by cycles of acute flares, recovery and remission phases. Treatments for accelerating tissue restitution and prolonging remission are scarce, but altering the microbiota composition to promote intestinal homeostasis is considered a safe, economic and promising approach. Although probiotic bacteria have not yet fulfilled fully their promise in clinical trials, understanding the mechanism of how they exert beneficial effects will permit devising improved therapeutic strategies. Here we probe if one of the defining features of lactobacilli, the ability to generate nanomolar H2O2, contributes to their beneficial role in colitis. H2O2 generation by wild type L. johnsonii was modified by either deleting or overexpressing the enzymatic H2O2 source(s) followed by orally administering the bacteria before and during DSS colitis. Boosting luminal H2O2 concentrations within a physiological range accelerated recovery from colitis, while significantly exceeding this H2O2 level triggered bacteraemia. This study supports a role for increasing H2O2 within the physiological range at the epithelial barrier, independently of the enzymatic source and/or delivery mechanism, for inducing recovery and remission in IBD.
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      PubDate: 2018-02-26T00:02:23Z
      DOI: 10.1016/j.redox.2018.02.003
      Issue No: Vol. 16 (2018)
       
  • Differential effects of short chain fatty acids on endothelial Nlrp3
           inflammasome activation and neointima formation: Antioxidant action of
           butyrate

    • Authors: Xinxu Yuan; Lei Wang; Owais M. Bhat; Hannah Lohner; Pin-Lan Li
      Pages: 21 - 31
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Xinxu Yuan, Lei Wang, Owais M. Bhat, Hannah Lohner, Pin-Lan Li
      Short chain fatty acids (SCFAs), a family of gut microbial metabolites, have been reported to promote preservation of endothelial function and thereby exert anti-atherosclerotic action. However, the precise mechanism mediating this protective action of SCFAs remains unknown. The present study investigated the effects of SCFAs (acetate, propionate and butyrate) on the activation of Nod-like receptor pyrin domain 3 (Nlrp3) inflammasome in endothelial cells (ECs) and associated carotid neointima formation. Using a partial ligated carotid artery (PLCA) mouse model fed with the Western diet (WD), we found that butyrate significantly decreased Nlrp3 inflammasome formation and activation in the carotid arterial wall of wild type mice (Asc +/+), which was comparable to the effect of gene deletion of the adaptor protein apoptosis-associated speck-like protein gene (Asc -/-). Nevertheless, both acetate and propionate markedly enhanced the formation and activation of the Nlrp3 inflammasome as well as carotid neointima formation in the carotid arteries with PLCA in Asc +/+, but not Asc -/- mice. In cultured ECs (EOMA cells), butyrate was found to significantly decrease the formation and activation of Nlrp3 inflammasomes induced by 7-ketocholesterol (7-Ket) or cholesterol crystals (CHC), while acetate did not inhibit Nlrp3 inflammasome activation induced by either 7-Ket or CHC, but itself even activated Nlrp3 inflammsomes. Mechanistically, the inhibitory action of butyrate on the Nlrp3 inflammasome was attributed to a blockade of lipid raft redox signaling platforms to produce O2•- upon 7-Ket or CHC stimulations. These results indicate that SCFAs have differential effects on endothelial Nlrp3 inflammasome activation and associated carotid neointima formation.

      PubDate: 2018-02-26T00:02:23Z
      DOI: 10.1016/j.redox.2018.02.007
      Issue No: Vol. 16 (2018)
       
  • Reactive oxygen species promote tubular injury in diabetic nephropathy:
           The role of the mitochondrial ros-txnip-nlrp3 biological axis

    • Authors: Yachun Han; Xiaoxuan Xu; Chengyuan Tang; Peng Gao; Xianghui Chen; Xiaofen Xiong; Ming Yang; Shikun Yang; Xuejing Zhu; Shuguang Yuan; Fuyou Liu; Li Xiao; Yashpal S. Kanwar; Lin Sun
      Pages: 32 - 46
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Yachun Han, Xiaoxuan Xu, Chengyuan Tang, Peng Gao, Xianghui Chen, Xiaofen Xiong, Ming Yang, Shikun Yang, Xuejing Zhu, Shuguang Yuan, Fuyou Liu, Li Xiao, Yashpal S. Kanwar, Lin Sun
      NLRP3/IL-1β activation via thioredoxin (TRX)/thioredoxin-interacting protein (TXNIP) following mitochondria ROS (mtROS) overproduction plays a key role in inflammation. However, the involvement of this process in tubular damage in the kidneys of patients with diabetic nephropathy (DN) is unclear. Here, we demonstrated that mtROS overproduction is accompanied by decreases in TRX expression and TXNIP up-regulation. In addition, we discovered that mtROS overproduction is also associated with increases in NLRP3/IL-1β and TGF-β expression in the kidneys of patients with DN and db/db mice. We reversed these changes in db/db mice by administering a peritoneal injection of MitoQ, an antioxidant targeting mtROS. Similar results were observed in human tubular HK-2 cells subjected to high-glucose (HG) conditions and treated with MitoQ. Treating HK-2 cells with MitoQ suppressed the dissociation of TRX from TXNIP and subsequently blocked the interaction between TXNIP and NLRP3, leading to the inhibition of NLRP3 inflammasome activation and IL-1β maturation. The effects of MitoQ were enhanced by pretreatment with TXNIP siRNA and abolished by pretreatment with monosodium urate (MSU) and TRX siRNA in vitro. These results suggest that mitochondrial ROS-TXNIP/NLRP3/IL-1β axis activation is responsible for tubular oxidative injury, which can be ameliorated by MitoQ via the inhibition of mtROS overproduction.
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      PubDate: 2018-02-26T00:02:23Z
      DOI: 10.1016/j.redox.2018.02.013
      Issue No: Vol. 16 (2018)
       
  • Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against
           MPP+-induced decline of mitochondrial membrane potential and oxidative
           stress

    • Authors: Jiahong Zhong; Hui Yu; Chang Huang; Qiuping Zhong; Yaping Chen; Jinfeng Xie; Zhongzhen Zhou; Jiangping Xu; Haitao Wang
      Pages: 47 - 58
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Jiahong Zhong, Hui Yu, Chang Huang, Qiuping Zhong, Yaping Chen, Jinfeng Xie, Zhongzhen Zhou, Jiangping Xu, Haitao Wang
      Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+) were examined in SH-SY5Y cells. FCPR16 (12.5–50 μM) dose-dependently reduced MPP+-induced loss of cell viability, accompanied by reductions in nuclear condensation and lactate dehydrogenase release. The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells. Furthermore, FCPR16 (25 μM) significantly suppressed the accumulation of reactive oxygen species (ROS), prevented the decline of mitochondrial membrane potential (Δψm) and attenuated the expression of malonaldehyde level. Further studies disclosed that FCPR16 enhanced the levels of cAMP and the exchange protein directly activated by cAMP (Epac) in SH-SY5Y cells. Western blotting analysis revealed that FCPR16 increased the phosphorylation of cAMP response element-binding protein (CREB) and protein kinase B (Akt) down-regulated by MPP+ in SH-SY5Y cells. Moreover, the inhibitory effects of FCPR16 on the production of ROS and Δψm loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401. Collectively, these results suggest that FCPR16 attenuates MPP+-induced dopaminergic degeneration via lowering ROS and preventing the loss of Δψm in SH-SY5Y cells. Mechanistically, cAMP/PKA/CREB and Epac/Akt signaling pathways are involved in these processes. Our findings indicate that FCPR16 is a promising pre-clinical candidate for the treatment of PD and possibly other oxidative stress-related neuronal diseases.
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      PubDate: 2018-02-26T00:02:23Z
      DOI: 10.1016/j.redox.2018.02.008
      Issue No: Vol. 16 (2018)
       
  • Redox control of cancer cell destruction

    • Authors: Csaba Hegedűs; Katalin Kovács; Zsuzsanna Polgár; Zsolt Regdon; Éva Szabó; Agnieszka Robaszkiewicz; Henry Jay Forman; Anna Martner; László Virág
      Pages: 59 - 74
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Csaba Hegedűs, Katalin Kovács, Zsuzsanna Polgár, Zsolt Regdon, Éva Szabó, Agnieszka Robaszkiewicz, Henry Jay Forman, Anna Martner, László Virág
      Redox regulation has been proposed to control various aspects of carcinogenesis, cancer cell growth, metabolism, migration, invasion, metastasis and cancer vascularization. As cancer has many faces, the role of redox control in different cancers and in the numerous cancer-related processes often point in different directions. In this review, we focus on the redox control mechanisms of tumor cell destruction. The review covers the tumor-intrinsic role of oxidants derived from the reduction of oxygen and nitrogen in the control of tumor cell proliferation as well as the roles of oxidants and antioxidant systems in cancer cell death caused by traditional anticancer weapons (chemotherapeutic agents, radiotherapy, photodynamic therapy). Emphasis is also put on the role of oxidants and redox status in the outcome following interactions between cancer cells, cytotoxic lymphocytes and tumor infiltrating macrophages.

      PubDate: 2018-02-26T00:02:23Z
      DOI: 10.1016/j.redox.2018.01.015
      Issue No: Vol. 16 (2018)
       
  • Nature and kinetics of redox imbalance triggered by respiratory and skin
           chemical sensitizers on the human monocytic cell line THP-1

    • Authors: Isabel Ferreira; Ana Silva; João Demétrio Martins; Bruno Miguel Neves; Maria Teresa Cruz
      Pages: 75 - 86
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Isabel Ferreira, Ana Silva, João Demétrio Martins, Bruno Miguel Neves, Maria Teresa Cruz
      Low molecular weight reactive chemicals causing skin and respiratory allergies are known to activate dendritic cells (DC), an event considered to be a key step in both pathologies. Although generation of reactive oxygen species (ROS) is considered a major danger signal responsible for DC maturation, the mechanisms leading to cellular redox imbalance remain poorly understood. Therefore, the aim of this study was to unveil the origin and kinetics of redox imbalance elicited by 1-fluoro-2,4-dinitrobenzene (DNFB) and trimellitic anhydride chloride (TMAC), two golden standards of skin and chemical respiratory allergy, respectively. To track this goal, we addressed the time course modifications of ROS production and cellular antioxidant defenses as well as the modulation of MAPKs signaling pathways and transcription of pathophysiological relevant genes in THP-1 cells. Our data shows that the thiol-reactive sensitizer DNFB directly reacts with cytoplasmic glutathione (GSH) causing its rapid and marked depletion which results in a general increase in ROS accumulation. In turn, TMAC, which preferentially reacts with amine groups, induces a delayed GSH depletion as a consequence of increased mitochondrial ROS production. These divergences in ROS production seem to be correlated with the different extension of intracellular signaling pathways activation and, by consequence, with distinct transcription kinetics of genes such as HMOX, IL8, IL1B and CD86. Ultimately, our observations may help explain the distinct DC phenotype and T-cell polarizing profile triggered by skin and respiratory sensitizers.
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      PubDate: 2018-02-26T00:02:23Z
      DOI: 10.1016/j.redox.2018.02.002
      Issue No: Vol. 16 (2018)
       
  • Fasting exacerbates hepatic growth differentiation factor 15 to promote
           fatty acid β-oxidation and ketogenesis via activating XBP1 signaling in
           liver

    • Authors: Meiyuan Zhang; Weilan Sun; Jin Qian; Yan Tang
      Pages: 87 - 96
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Meiyuan Zhang, Weilan Sun, Jin Qian, Yan Tang
      Liver coordinates a series of metabolic adaptations to maintain systemic energy balance and provide adequate nutrients for critical organs, tissues and cells during starvation. However, the mediator(s) implicated in orchestrating these fasting-induced adaptive responses and the underlying molecular mechanisms are still obscure. Here we show that hepatic growth differentiation factor 15 (GDF15) is regulated by IRE1α-XBP1s branch and promotes hepatic fatty acids β-oxidation and ketogenesis upon fasting. GDF15 expression was exacerbated in liver of mice subjected to long-term fasted or ketogenic diet feeding. Abrogation of hepatic Gdf15 dramatically attenuated hepatic β-oxidation and ketogenesis in fasted mice or mice with STZ-initiated type I diabetes. Further study revealed that XBP1s activated Gdf15 transcription via binding to its promoter. Elevated GDF15 in liver reduced lipid accumulation and impaired NALFD development in obese mice through enhancing fatty acids oxidation in liver. Therefore, our results demonstrate a novel and critical role of hepatic GDF15 activated by IRE1α-XBP1s branch in regulating adaptive responses of liver upon starvation stress.

      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.01.013
      Issue No: Vol. 16 (2018)
       
  • AKT-independent activation of p38 MAP kinase promotes vascular
           calcification

    • Authors: Youfeng Yang; Yong Sun; Jianye Chen; Wayne E. Bradley; Louis J. Dell’Italia; Hui Wu; Yabing Chen
      Pages: 97 - 103
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Youfeng Yang, Yong Sun, Jianye Chen, Wayne E. Bradley, Louis J. Dell’Italia, Hui Wu, Yabing Chen
      Vascular calcification is prevalent in patients with atherosclerosis, and oxidative stress promotes pathogenesis of atherosclerosis. We have previously reported that activation of AKT by oxidative stress induces vascular calcification. Using sodium dichloroacetate (DCA), a previously reported small molecule inhibitor of AKT, the present studies uncovered an AKT-independent mechanism in regulating vascular calcification. We found that DCA dose-dependently induced calcification of vascular smooth muscle cells (VSMC) in vitro and aortic rings ex vivo. Furthermore, DCA markedly enhanced vascular calcification in atherosclerotic ApoE knockout mice in vivo. DCA-induced VSMC calcification was associated with increased Runx2, but not via activation of AKT, a key upstream signal that upregulates Runx2 during VSMC calcification. In contrast, DCA inhibited AKT activation and induced activation of p38 MAPK in calcified atherosclerotic lesions in vivo and calcified VSMC in vitro. Using a pharmacological inhibitor and shRNA for p38 MAPK, we demonstrated that inhibition of p38 MAPK blocked DCA-induced Runx2 upregulation and VSMC calcification. Furthermore, Runx2 deletion attenuated DCA-induced VSMC calcification. Immunoprecipitation analysis revealed association of p38 MAPK with Runx2, which was enhanced by DCA treatment. Knockdown p38 MAPK inhibited DCA-induced Runx2 transactivity, supporting the function of p38 MAPK in regulating Runx2 transactivity. Our studies have uncovered a new function of DCA in regulating vascular calcification, via AKT-independent activation of p38 MAPK. Furthermore, we have identified novel interaction between p38 MAPK and Runx2 enhances Runx2 transactivity, thus promoting VSMC calcification. These results revealed a novel signaling mechanism underlying DCA-induced vascular calcification, and offer opportunities to identify new therapeutic targets.

      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.009
      Issue No: Vol. 16 (2018)
       
  • Astrocytic CCAAT/Enhancer-binding protein delta contributes to reactive
           oxygen species formation in neuroinflammation

    • Authors: Shao-Ming Wang; Sher-Wei Lim; Ya-Han Wang; Hong-Yi Lin; Ming-Derg Lai; Chiung-Yuan Ko; Ju-Ming Wang
      Pages: 104 - 112
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Shao-Ming Wang, Sher-Wei Lim, Ya-Han Wang, Hong-Yi Lin, Ming-Derg Lai, Chiung-Yuan Ko, Ju-Ming Wang
      Excessive reactive oxygen species (ROS) can form an oxidative stress and an associated neuroinflammation. However, the contribution of astrocytes to ROS formation, the cause of the resistance of astrocytes to oxidative stress, and the consequences on neurons remain largely uninvestigated. The transcription factor CCAAT/enhancer-binding protein delta (CEBPD) is highly expressed in astrocytes and has been suggested to contribute to the progress of Alzheimer's disease (AD). In this study, we found that ROS formation and expression of p47phox and p67phox, subunits of NADPH oxidase, were increased in AppTg mice but attenuated in AppTg/Cebpd -/- mice. Cebpd can up-regulate p47 phox and p67 phox transcription via a direct binding on their promoters, which results in an increase in intracellular oxidative stress. In addition, Cebpd also up-regulated Cu/Zn superoxide dismutase (Sod1) in astrocytes. Inactivation of Sod1 increased the sensitization to oxidative stress, which provides a reason for the resistance of astrocytes in an oxidative stress environment. Taken together, the study first revealed and dissected the involvement of astrocytic Cebpd in the promotion of oxidative stress and the contribution of CEBPD to the resistance of astrocytes in an oxidative stress environment.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.011
      Issue No: Vol. 16 (2018)
       
  • Impact of carbonylation on glutathione peroxidase-1 activity in human
           hyperglycemic endothelial cells

    • Authors: Cheryl S. Sultan; Andrea Saackel; Antonia Stank; Thomas Fleming; Maria Fedorova; Ralf Hoffmann; Rebecca C. Wade; Markus Hecker; Andreas H. Wagner
      Pages: 113 - 122
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Cheryl S. Sultan, Andrea Saackel, Antonia Stank, Thomas Fleming, Maria Fedorova, Ralf Hoffmann, Rebecca C. Wade, Markus Hecker, Andreas H. Wagner
      Aims High levels of glucose and reactive carbonyl intermediates of its degradation pathway such as methylglyoxal (MG) may contribute to diabetic complications partly via increased generation of reactive oxygen species (ROS). This study focused on glutathione peroxidase-1 (GPx1) expression and the impact of carbonylation as an oxidative protein modification on GPx1 abundance and activity in human umbilical vein endothelial cells (HUVEC) under conditions of mild to moderate oxidative stress. Results High extracellular glucose and MG enhanced intracellular ROS formation in HUVECs. Protein carbonylation was only transiently augmented pointing to an effective antioxidant defense in these cells. Nitric oxide synthase expression was decreased under hyperglycemic conditions but increased upon exposure to MG, whereas superoxide dismutase expression was not significantly affected. Increased glutathione peroxidase (GPx) activity seemed to compensate for a decrease in GPx1 protein due to enhanced degradation via the proteasome. Mass spectrometry analysis identified Lys-114 as a possible carbonylation target which provides a vestibule for the substrate H2O2 and thus enhances the enzymatic reaction. Innovation Oxidative protein carbonylation has so far been associated with functional inactivation of modified target proteins mainly contributing to aging and age-related diseases. Here, we demonstrate that mild oxidative stress and subsequent carbonylation seem to activate protective cellular redox signaling pathways whereas severe oxidative stress overwhelms the cellular antioxidant defense leading to cell damage. Conclusions This study may contribute to a better understanding of redox homeostasis and its role in the development of diabetes and related vascular complications.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.018
      Issue No: Vol. 16 (2018)
       
  • Early cysteine-dependent inactivation of 26S proteasomes does not involve
           particle disassembly

    • Authors: Martín Hugo; Ioanna Korovila; Markus Köhler; Carlos García-García; J. Daniel Cabrera-García; Anabel Marina; Antonio Martínez-Ruiz; Tilman Grune
      Pages: 123 - 128
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Martín Hugo, Ioanna Korovila, Markus Köhler, Carlos García-García, J. Daniel Cabrera-García, Anabel Marina, Antonio Martínez-Ruiz, Tilman Grune
      Under oxidative stress 26S proteasomes suffer reversible disassembly into its 20S and 19S subunits, a process mediated by HSP70. This inhibits the degradation of polyubiquitinated proteins by the 26S proteasome and allows the degradation of oxidized proteins by a free 20S proteasome. Low fluxes of antimycin A-stimulated ROS production caused dimerization of mitochondrial peroxiredoxin 3 and cytosolic peroxiredoxin 2, but not peroxiredoxin overoxidation and overall oxidation of cellular protein thiols. This moderate redox imbalance was sufficient to inhibit the ATP stimulation of 26S proteasome activity. This process was dependent on reversible cysteine oxidation. Moreover, our results show that this early inhibition of ATP stimulation occurs previous to particle disassembly, indicating an intermediate step during the redox regulation of the 26S proteasome with special relevance under redox signaling rather than oxidative stress conditions.

      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.016
      Issue No: Vol. 16 (2018)
       
  • The immunoproteasome subunit LMP10 mediates angiotensin II-induced
           retinopathy in mice

    • Authors: Shuai Wang; Jing Li; Jie Bai; Jing-Min Li; Yi-Lin Che; Qiu-Yue Lin; Yun-Long Zhang; Hui-Hua Li
      Pages: 129 - 138
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Shuai Wang, Jing Li, Jie Bai, Jing-Min Li, Yi-Lin Che, Qiu-Yue Lin, Yun-Long Zhang, Hui-Hua Li
      Inflammation has been implicated in a variety of retinal diseases. The immunoproteasome plays a critical role in controlling inflammatory responses, but whether activation of immunoproteasome contributes to angiotensin II (Ang II)-induced retinopathy remains unclear. Hypertensive retinopathy (HR) was induced by infusion of Ang II (3000 ng/kg/min) in wild-type (WT) and immunoproteasome subunit LMP10 knockout (KO) mice for 3 weeks. Changes in retinal morphology, vascular permeability, superoxide production and inflammation were examined by pathological staining. Our results showed that immunoproteasome subunit LMP10 expression and its trypsin-like activity were significantly upregulated in the retinas and serum of Ang II-infused mice and in the serum from patients with hypertensive retinopathy. Moreover, Ang II-infused WT mice showed an increase in the central retinal thickness, vascular permeability, reactive oxygen species (ROS) production and inflammation compared with saline controls, and these effects were significantly attenuated in LMP10 KO mice, but were aggravated in mice intravitreally injected with rAAV2-LMP10. Interestingly, administration of IKKβ specific inhibitor IMD-0354 remarkably blocked an Ang II-induced increase in vascular permeability, oxidative stress and inflammation during retinopathy. Mechanistically, Ang II-induced upregulation of LMP10 promoted PTEN degradation and activation of AKT/IKK signaling, which induced IkBα phosphorylation and subsequent degradation ultimately leading to activation of NF-kB target genes in retinopathy. Therefore, this study provided novel evidence demonstrating that LMP10 is a positive regulator of NF-kB signaling, which contributes to Ang II-induced retinopathy. Strategies for inhibiting LMP10 or IKKβ activity in the eye could serve as a novel therapeutic target for treating hypertensive retinopathy.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.022
      Issue No: Vol. 16 (2018)
       
  • Simvastatin reduces circulating oxysterol levels in men with
           hypercholesterolaemia

    • Authors: Irundika H.K. Dias; Ivana Milic; Gregory Y.H. Lip; Andrew Devitt; M. Cristina Polidori; Helen R. Griffiths
      Pages: 139 - 145
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Irundika H.K. Dias, Ivana Milic, Gregory Y.H. Lip, Andrew Devitt, M. Cristina Polidori, Helen R. Griffiths
      Oxysterols (OHC) are biologically active cholesterol metabolites circulating in plasma that may be formed enzymatically (e.g. 24S-OHC, 25-OHC and 27-OHC) or by autoxidative mechanisms (e.g. 7-ketocholesterol, 7β-OHC and 25-OHC). Oxysterols are more soluble than cholesterol and are reported to exert inflammatory, cytoprotective and apoptotic effects according to concentration and species. Esterified oxysterols have been analysed in people with dementia and cardiovascular diseases although there is no consistent relationship between oxysterol esters and disease. However, oxysterol esters are held in lipoprotein core and may not relate to the concentration and activity of plasma free oxysterols. Methodological limitations have challenged the analysis of free oxysterols to date. We have developed a fast, sensitive and specific quantitative LC-MS/MS, multiple reaction monitoring (MRM) method to target five oxysterols in human plasma with analyte recoveries between 72% and 82% and sensitivities between 5 and 135 pg/ml. A novel method was used to investigate the hypothesis that simvastatin may reduce the concentrations of specific plasma free oxysterols in hypercholesterolaemia. Twenty healthy male volunteers were recruited (aged 41–63 years); ten were asymptomatic with high plasma cholesterol > 6.5 mM and ten were healthy with normal plasma cholesterol (< 6.5 mM). Simvastatin (40 mg/day) was prescribed to those with hypercholesterolaemia. Plasma samples were taken from both groups at baseline and after three months. Simvastatin reduced plasma cholesterol by ~35% (p < 0.05) at the end of three months. Oxysterols generated by autoxidation (but not enzymatically) were elevated up to 45 fold in hypercholesterolaemic midlife men. Plasma oxysterols were restored to those of healthy controls after simvastatin intervention suggesting that autoxidation is either prevented by simvastatin directly or that autoxidation is less prevalent when plasma cholesterol concentrations are within the normal range.

      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.014
      Issue No: Vol. 16 (2018)
       
  • Cardiomyocyte hypertrophy induced by Endonuclease G deficiency requires
           reactive oxygen radicals accumulation and is inhibitable by the
           micropeptide humanin

    • Authors: Natividad Blasco; Yolanda Cámara; Estefanía Núñez; Aida Beà; Gisel Barés; Carles Forné; Marisol Ruíz-Meana; Cristina Girón; Ignasi Barba; Elena García-Arumí; David García-Dorado; Jesús Vázquez; Ramon Martí; Marta Llovera; Daniel Sanchis
      Pages: 146 - 156
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Natividad Blasco, Yolanda Cámara, Estefanía Núñez, Aida Beà, Gisel Barés, Carles Forné, Marisol Ruíz-Meana, Cristina Girón, Ignasi Barba, Elena García-Arumí, David García-Dorado, Jesús Vázquez, Ramon Martí, Marta Llovera, Daniel Sanchis
      The endonuclease G gene (Endog), which codes for a mitochondrial nuclease, was identified as a determinant of cardiac hypertrophy. How ENDOG controls cardiomyocyte growth is still unknown. Thus, we aimed at finding the link between ENDOG activity and cardiomyocyte growth. Endog deficiency induced reactive oxygen species (ROS) accumulation and abnormal growth in neonatal rodent cardiomyocytes, altering the AKT-GSK3β and Class-II histone deacethylases (HDAC) signal transduction pathways. These effects were blocked by ROS scavengers. Lack of ENDOG reduced mitochondrial DNA (mtDNA) replication independently of ROS accumulation. Because mtDNA encodes several subunits of the mitochondrial electron transport chain, whose activity is an important source of cellular ROS, we investigated whether Endog deficiency compromised the expression and activity of the respiratory chain complexes but found no changes in these parameters nor in ATP content. MtDNA also codes for humanin, a micropeptide with possible metabolic functions. Nanomolar concentrations of synthetic humanin restored normal ROS levels and cell size in Endog-deficient cardiomyocytes. These results support the involvement of redox signaling in the control of cardiomyocyte growth by ENDOG and suggest a pathway relating mtDNA content to the regulation of cell growth probably involving humanin, which prevents reactive oxygen radicals accumulation and hypertrophy induced by Endog deficiency.

      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.021
      Issue No: Vol. 16 (2018)
       
  • Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: A
           mechanism involving calcium overload/XO/ROS/mPTP pathway

    • Authors: Pingjun Zhu; Shunying Hu; Qinhua Jin; Dandan Li; Feng Tian; Sam Toan; Yang Li; Hao Zhou; Yundai Chen
      Pages: 157 - 168
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Pingjun Zhu, Shunying Hu, Qinhua Jin, Dandan Li, Feng Tian, Sam Toan, Yang Li, Hao Zhou, Yundai Chen
      Receptor-interacting protein 3 (Ripk3)-mediated necroptosis contributes to cardiac ischaemia-reperfusion (IR) injury through poorly defined mechanisms. Our results demonstrated that Ripk3 was strongly upregulated in murine hearts subjected to IR injury and cardiomyocytes treated with LPS and H2O2. The higher level of Ripk3 was positively correlated to the infarction area expansion, cardiac dysfunction and augmented cardiomyocytes necroptosis. Function study further illustrated that upregulated Ripk3 evoked the endoplasmic reticulum (ER) stress, which was accompanied with an increase in intracellular Ca2+ level ([Ca2+]c) and xanthine oxidase (XO) expression. Activated XO raised cellular reactive oxygen species (ROS) that mediated the mitochondrial permeability transition pore (mPTP) opening and cardiomyocytes necroptosis. By comparison, genetic ablation of Ripk3 abrogated the ER stress and thus blocked the [Ca2+]c overload-XO-ROS-mPTP pathways, favouring a pro-survival state that ultimately resulted in the inhibition of cardiomyocytes necroptosis in the setting of cardiac IR injury. In summary, the present study helps to elucidate how necroptosis is mediated by ER stress, via the calcium overload /XO/ROS/mPTP opening axis.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.019
      Issue No: Vol. 16 (2018)
       
  • Selective cytotoxicity of the herbal substance acteoside against tumor
           cells and its mechanistic insights

    • Authors: Christina Cheimonidi; Pinelopi Samara; Panagiotis Polychronopoulos; Eleni N. Tsakiri; Theodora Nikou; Vassilios Myrianthopoulos; Theodore Sakellaropoulos; Vassilis Zoumpourlis; Emmanuel Mikros; Issidora Papassideri; Aikaterini Argyropoulou; Maria Halabalaki; Leonidas G. Alexopoulos; Alexios-Leandros Skaltsounis; Ourania E. Tsitsilonis; Nektarios N. Aligiannis; Ioannis P. Trougakos
      Pages: 169 - 178
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Christina Cheimonidi, Pinelopi Samara, Panagiotis Polychronopoulos, Eleni N. Tsakiri, Theodora Nikou, Vassilios Myrianthopoulos, Theodore Sakellaropoulos, Vassilis Zoumpourlis, Emmanuel Mikros, Issidora Papassideri, Aikaterini Argyropoulou, Maria Halabalaki, Leonidas G. Alexopoulos, Alexios-Leandros Skaltsounis, Ourania E. Tsitsilonis, Nektarios N. Aligiannis, Ioannis P. Trougakos
      Natural products are characterized by extreme structural diversity and thus they offer a unique source for the identification of novel anti-tumor agents. Herein, we report that the herbal substance acteoside being isolated by advanced phytochemical methods from Lippia citriodora leaves showed enhanced cytotoxicity against metastatic tumor cells; acted in synergy with various cytotoxic agents and it sensitized chemoresistant cancer cells. Acteoside was not toxic in physiological cellular contexts, while it increased oxidative load, affected the activity of proteostatic modules and suppressed matrix metalloproteinases in tumor cell lines. Intraperitoneal or oral (via drinking water) administration of acteoside in a melanoma mouse model upregulated antioxidant responses in the tumors; yet, only intraperitoneal delivery suppressed tumor growth and induced anti-tumor-reactive immune responses. Mass-spectrometry identification/quantitation analyses revealed that intraperitoneal delivery of acteoside resulted in significantly higher, vs. oral administration, concentration of the compound in the plasma and tumors of treated mice, suggesting that its in vivo anti-tumor effect depends on the route of administration and the achieved concentration in the tumor. Finally, molecular modeling studies and enzymatic activity assays showed that acteoside inhibits protein kinase C. Conclusively, acteoside holds promise as a chemical scaffold for the development of novel anti-tumor agents.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.015
      Issue No: Vol. 16 (2018)
       
  • Uric acid disrupts hypochlorous acid production and the bactericidal
           activity of HL-60 cells

    • Authors: Larissa A.C. Carvalho; João P.P.B. Lopes; Gilberto H. Kaihami; Railmara P. Silva; Alexandre Bruni-Cardoso; Regina L. Baldini; Flavia C. Meotti
      Pages: 179 - 188
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Larissa A.C. Carvalho, João P.P.B. Lopes, Gilberto H. Kaihami, Railmara P. Silva, Alexandre Bruni-Cardoso, Regina L. Baldini, Flavia C. Meotti
      Uric acid is the end product of purine metabolism in humans and is an alternative physiological substrate for myeloperoxidase. Oxidation of uric acid by this enzyme generates uric acid free radical and urate hydroperoxide, a strong oxidant and potentially bactericide agent. In this study, we investigated whether the oxidation of uric acid and production of urate hydroperoxide would affect the killing activity of HL-60 cells differentiated into neutrophil-like cells (dHL-60) against a highly virulent strain (PA14) of the opportunistic pathogen Pseudomonas aeruginosa. While bacterial cell counts decrease due to dHL-60 killing, incubation with uric acid inhibits this activity, also decreasing the release of the inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF- α). In a myeloperoxidase/Cl-/H2O2 cell-free system, uric acid inhibited the production of HOCl and bacterial killing. Fluorescence microscopy showed that uric acid also decreased the levels of HOCl produced by dHL-60 cells, while significantly increased superoxide production. Uric acid did not alter the overall oxidative status of dHL-60 cells as measured by the ratio of reduced (GSH) and oxidized (GSSG) glutathione. Our data show that uric acid impairs the killing activity of dHL-60 cells likely by competing with chloride by myeloperoxidase catalysis, decreasing HOCl production. Despite diminishing HOCl, uric acid probably stimulates the formation of other oxidants, maintaining the overall oxidative status of the cells. Altogether, our results demonstrated that HOCl is, indeed, the main relevant oxidant against bacteria and deviation of myeloperoxidase activity to produce other oxidants hampers dHL-60 killing activity.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.020
      Issue No: Vol. 16 (2018)
       
  • Protective effect of dioscin against doxorubicin-induced cardiotoxicity
           via adjusting microRNA-140-5p-mediated myocardial oxidative stress

    • Authors: Lisha Zhao; Xufeng Tao; Yan Qi; Lina Xu; Lianhong Yin; Jinyong Peng
      Pages: 189 - 198
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Lisha Zhao, Xufeng Tao, Yan Qi, Lina Xu, Lianhong Yin, Jinyong Peng
      Clinical application of doxorubicin (DOX) is limited because of its cardiotoxicity. Thus, exploration of effective lead compounds against DOX-induced cardiotoxicity is necessary. The aim of the present study was to investigate the effects and possible mechanisms of dioscin against DOX-induced cardiotoxicity. The in vitro model of DOX- treated H9C2 cells and the in vivo models of DOX-treated rats and mice were used in this study. The results showed that discoin markedly increased H9C2 cell viability, decreased the levels of CK, LDH, and improved histopathological and electrocardio- gram changes in rats and mice to protect DOX-induced cardiotoxicity. Furthermore, dioscin significantly inhibited myocardial oxidative insult through adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px in vitro and in vivo. Our data also indicated that dioscin activated Nrf2 and Sirt2 signaling pathways, and thereby affected the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a through decreasing miR-140-5p expression level. In addition, the level of intracellular ROS was significantly increased in H9C2 cells treated by DOX after miR-140-5p mimic transfection, as well as the down-regulated expression levels of Nrf2 and Sirt2, which were markedly reversed by dioscin. In conclusion, our data suggested that dioscin alleviated DOX-induced cardiotoxicity through modulating miR-140-5p-mediated myocardial oxidative stress. This natural product should be developed as a new candidate to alleviate cardiotoxicity caused by DOX in the future.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.026
      Issue No: Vol. 16 (2018)
       
  • Insights into the HyPer biosensor as molecular tool for monitoring
           cellular antioxidant capacity

    • Authors: Helen Hernández; Alejandra Parra; Nicolas Tobar; Jessica Molina; Violeta Kallens; Miltha Hidalgo; Diego Varela; Jorge Martínez; Omar Porras
      Pages: 199 - 208
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Helen Hernández, Alejandra Parra, Nicolas Tobar, Jessica Molina, Violeta Kallens, Miltha Hidalgo, Diego Varela, Jorge Martínez, Omar Porras
      Aerobic metabolism brings inexorably the production of reactive oxygen species (ROS), which are counterbalanced by intrinsic antioxidant defenses avoiding deleterious intracellular effects. Redox balance is the resultant of metabolic functioning under environmental inputs (i.e. diet, pollution) and the activity of intrinsic antioxidant machinery. Monitoring of intracellular hydrogen peroxide has been successfully achieved by redox biosensor advent; however, to track the intrinsic disulfide bond reduction capacity represents a fundamental piece to understand better how redox homeostasis is maintained in living cells. In the present work, we compared the informative value of steady-state measurements and the kinetics of HyPer, a H2O2-sensitive fluorescent biosensor, targeted at the cytosol, mitochondrion and endoplasmic reticulum. From this set of data, biosensor signal recovery from an oxidized state raised as a suitable parameter to discriminate reducing capacity of a close environment. Biosensor recovery was pH-independent, condition demonstrated by experiments on pH-clamped cells, and sensitive to pharmacological perturbations of enzymatic disulfide reduction. Also, ten human cell lines were characterized according their H2O2-pulse responses, including their capacity to reduce disulfide bonds evaluated in terms of their migratory capacity. Finally, cellular migration experiments were conducted to study whether migratory efficiency was associated with the disulfide reduction activity. The migration efficiency of each cell type correlates with the rate of signal recovery measured from the oxidized biosensor. In addition, HyPer-expressing cells treated with N-acetyl-cysteine had accelerated recovery rates and major migratory capacities, both reversible effects upon treatment removal. Our data demonstrate that the HyPer signal recovery offers a novel methodological tool to track the cellular impact of redox active biomolecules.

      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.023
      Issue No: Vol. 16 (2018)
       
  • Regulation of the mechanism of Type-II NADH: Quinone oxidoreductase from
           S. aureus

    • Authors: Filipa V. Sena; Filipe M. Sousa; A. Sofia F. Oliveira; Cláudio M. Soares; Teresa Catarino; Manuela M. Pereira
      Pages: 209 - 214
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Filipa V. Sena, Filipe M. Sousa, A. Sofia F. Oliveira, Cláudio M. Soares, Teresa Catarino, Manuela M. Pereira
      Type-II NADH:quinone oxidoreductases (NDH-2s) are membrane proteins involved in respiratory chains and the only enzymes with NADH:quinone oxidoreductase activity expressed in Staphylococcus aureus (S. aureus), one of the most common causes of clinical infections. NDH-2s are members of the two-Dinucleotide Binding Domains Flavoprotein (tDBDF) superfamily, having a flavin adenine dinucleotide, FAD, as prosthetic group and NAD(P)H as substrate. The establishment of a Charge-Transfer Complex (CTC) between the isoalloxazine ring of the reduced flavin and the nicotinamide ring of NAD+ in NDH-2 was described, and in this work we explored its role in the kinetic mechanism using different electron donors and electron acceptors. We observed that CTC slows down the rate of the second half reaction (quinone reduction) and determines the effect of HQNO, an inhibitor. Also, protonation equilibrium simulations clearly indicate that the protonation probability of an important residue for proton transfer to the active site (D302) is influenced by the presence of the CTC. We propose that CTC is critical for the overall mechanism of NDH-2 and possibly relevant to keep a low quinol/quinone ratio and avoid excessive ROS production in vivo.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.004
      Issue No: Vol. 16 (2018)
       
  • Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular
           relaxation: Role of insufficient hydrogen sulfide

    • Authors: Zhongjian Cheng; Xinggui Shen; Xiaohua Jiang; Huimin Shan; Maria Cimini; Pu Fang; Yong Ji; Joon Young Park; Konstantinos Drosatos; Xiaofeng Yang; Christopher G. Kevil; Raj Kishore; Hong Wang
      Pages: 215 - 225
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Zhongjian Cheng, Xinggui Shen, Xiaohua Jiang, Huimin Shan, Maria Cimini, Pu Fang, Yong Ji, Joon Young Park, Konstantinos Drosatos, Xiaofeng Yang, Christopher G. Kevil, Raj Kishore, Hong Wang
      Insufficient hydrogen sulfide (H2S) has been implicated in Type 2 diabetic mellitus (T2DM) and hyperhomocysteinemia (HHcy)-related cardiovascular complications. We investigated the role of H2S in T2DM and HHcy-induced endothelial dysfunction in small mesenteric artery (SMA) of db/db mice fed a high methionine (HM) diet. HM diet (8 weeks) induced HHcy in both T2DM db/db mice and non-diabetic db/+ mice (total plasma Hcy: 48.4 and 31.3 µM, respectively), and aggravated the impaired endothelium-derived hyperpolarization factor (EDHF)-induced endothelium-dependent relaxation to acetylcholine (ACh), determined by the presence of eNOS inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) and prostacyclin (PGI2) inhibitor indomethacin (INDO), in SMA from db/db mice but not that from db/+ mice. A non-selective Ca2+-active potassium channel (KCa) opener NS309 rescued T2DM/HHcy-impaired EDHF-mediated vascular relaxation to ACh. EDHF-induced relaxation to ACh was inhibited by a non-selective KCa blocker TEA and intermediate-conductance KCa blocker (IKCa) Tram-34, but not by small-conductance KCa (SKCa) blocker Apamin. HHcy potentiated the reduction of free sulfide, H2S and cystathionine γ-lyase protein, which converts L-cysteine to H2S, in SMA of db/db mice. Importantly, a stable H2S donor DATS diminished the enhanced O2 - production in SMAs and lung endothelial cells of T2DM/HHcy mice. Antioxidant PEG-SOD and DATS improved T2DM/HHcy impaired relaxation to ACh. Moreover, HHcy increased hyperglycemia-induced IKCa tyrosine nitration in human micro-vascular endothelial cells. EDHF-induced vascular relaxation to L-cysteine was not altered, whereas such relaxation to NaHS was potentiated by HHcy in SMA of db/db mice which was abolished by ATP-sensitive potassium channel blocker Glycolamide but not by KCa blockers. Conclusions Intermediate HHcy potentiated H2S reduction via CSE-downregulation in microvasculature of T2DM mice. H2S is justified as an EDHF. Insufficient H2S impaired EDHF-induced vascular relaxation via oxidative stress and IKCa inactivation in T2DM/HHcy mice. H2S therapy may be beneficial for prevention and treatment of micro-vascular complications in patients with T2DM and HHcy.

      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.006
      Issue No: Vol. 16 (2018)
       
  • Melatonin suppresses thyroid cancer growth and overcomes radioresistance
           via inhibition of p65 phosphorylation and induction of ROS

    • Authors: Zhen-Wei Zou; Ting Liu; Yong Li; Peng Chen; Xin Peng; Charlie Ma; Wen-Jie Zhang; Pin-Dong Li
      Pages: 226 - 236
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Zhen-Wei Zou, Ting Liu, Yong Li, Peng Chen, Xin Peng, Charlie Ma, Wen-Jie Zhang, Pin-Dong Li
      Thyroid cancer is the most common endocrine carcinoma with increasing incidence worldwide and anaplastic subtypes are frequently associated with cancer related death. Radioresistance of thyroid cancer often leads to therapy failure and cancer-related death. In this study, we found that melatonin showed potent suppressive roles on NF-κB signaling via inhibition of p65 phosphorylation and generated redox stress in thyroid cancer including the anaplastic subtypes. Our data showed that melatonin significantly decreased cell viability, suppressed cell migration and induced apoptosis in thyroid cancer cell lines in vitro and impaired tumor growth in the subcutaneous mouse model in vivo. By contrast, irradiation of thyroid cancer cells resulted in elevated level of phosphorylated p65, which could be reversed by cotreatment with melatonin. Consequently, melatonin synergized with irradiation to induce cytotoxicity to thyroid cancer, especially in the undifferentiated subgroups. Taken together, our results suggest that melatonin may exert anti-tumor activities against thyroid carcinoma by inhibition of p65 phosphorylation and induction of reactive oxygen species. Radio-sensitization by melatonin may have clinical benefits in thyroid cancer.

      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.025
      Issue No: Vol. 16 (2018)
       
  • Astroglial DJ-1 over-expression up-regulates proteins involved in redox
           regulation and is neuroprotective in vivo

    • Authors: Ann Kristin Frøyset; Amanda J. Edson; Naouel Gharbi; Essa A. Khan; Daniel Dondorp; Qing Bai; Ettore Tiraboschi; Maximiliano L. Suster; Joanne B. Connolly; Edward A. Burton; Kari E. Fladmark
      Pages: 237 - 247
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Ann Kristin Frøyset, Amanda J. Edson, Naouel Gharbi, Essa A. Khan, Daniel Dondorp, Qing Bai, Ettore Tiraboschi, Maximiliano L. Suster, Joanne B. Connolly, Edward A. Burton, Kari E. Fladmark
      DJ-1, a Parkinson's disease-associated protein, is strongly up-regulated in reactive astrocytes in Parkinson's disease. This is proposed to represent a neuronal protective response, although the mechanism has not yet been identified. We have generated a transgenic zebrafish line with increased astroglial DJ-1 expression driven by regulatory elements from the zebrafish GFAP gene. Larvae from this transgenic line are protected from oxidative stress-induced injuries as caused by MPP+, a mitochondrial complex I inhibitor shown to induce dopaminergic cells death. In a global label-free proteomics analysis of wild type and transgenic larvae exposed to MPP+, 3418 proteins were identified, in which 366 proteins were differentially regulated. In particular, we identified enzymes belonging to primary metabolism to be among proteins affected by MPP+ in wild type animals, but not affected in the transgenic line. Moreover, by performing protein profiling on isolated astrocytes we showed that an increase in astrocytic DJ-1 expression up-regulated a large group of proteins associated with redox regulation, inflammation and mitochondrial respiration. The majority of these proteins have also been shown to be regulated by Nrf2. These findings provide a mechanistic insight into the protective role of astroglial up-regulation of DJ-1 and show that our transgenic zebrafish line with astrocytic DJ-1 over-expression can serve as a useful animal model to understand astrocyte-regulated neuroprotection associated with oxidative stress-related neurodegenerative disease.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.010
      Issue No: Vol. 16 (2018)
       
  • Lipid peroxidation regulates podocyte migration and cytoskeletal structure
           through redox sensitive RhoA signaling

    • Authors: Claudia Kruger; Susan J. Burke; J. Jason Collier; Trang-Tiffany Nguyen; J. Michael Salbaum; Krisztian Stadler
      Pages: 248 - 254
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Claudia Kruger, Susan J. Burke, J. Jason Collier, Trang-Tiffany Nguyen, J. Michael Salbaum, Krisztian Stadler
      Early podocyte loss is characteristic of chronic kidney diseases (CKD) in obesity and diabetes. Since treatments for hyperglycemia and hypertension do not prevent podocyte loss, there must be additional factors causing podocyte depletion. The role of oxidative stress has been implicated in CKD but it is not known how exactly free radicals affect podocyte physiology. To assess this relationship, we investigated the effects of lipid radicals on podocytes, as lipid peroxidation is a major form of oxidative stress in diabetes. We found that lipid radicals govern changes in podocyte homeostasis through redox sensitive RhoA signaling: lipid radicals inhibit migration and cause loss of F-actin fibers. These effects were prevented by mutating the redox sensitive cysteines of RhoA. We therefore suggest that in diseases associated with increased lipid peroxidation, lipid radicals can determine podocyte function with potentially pathogenic consequences for kidney physiology.

      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.02.024
      Issue No: Vol. 16 (2018)
       
  • MicroRNA-98 regulates foam cell formation and lipid accumulation through
           repression of LOX-1

    • Authors: Yao Dai; Xiaoqin Wu; Dongsheng Dai; Jun Li; Jawahar L. Mehta
      Pages: 255 - 262
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Yao Dai, Xiaoqin Wu, Dongsheng Dai, Jun Li, Jawahar L. Mehta
      Objective Several miR/s that regulate gene/s relevant in atherogenesis are being described. We identified a miR (miR-98) that targets LOX-1, a receptor for ox-LDL, and speculated that it might be relevant in atherogenesis. Approach and results MicroRNA-98 was predicted by bioinformatics tools. The effects of miR-98 (by use of mimics and inhibitors) on LOX-1 expression and foam cell formation in mouse peritoneal macrophages were assessed. ApoE-/- mice fed by high fat diet were administered with mmu-agomiR-98 and mmu-antagomiR-98, and expression of LOX-1 and foam cell formation in aorta were quantified. LOX-1 was established to be a direct target of miR-98 by luciferase reporter assay. Enhancement of miR-98 decreased the expression of LOX-1 and inhibited foam cell formation and lipid accumulation. Inhibition of miR-98 had the opposite effects on all parameters. Conclusions Reduced expression of miR-98 may relate to LOX-1 expression and foam cell formation and lipid accumulation in aortas of ApoE-/- mice. Plasma level of miR-98 may be a biomarker of atherosclerotic disease process and its modulation may offer a therapeutic strategy for atherosclerosis.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.03.003
      Issue No: Vol. 16 (2018)
       
  • Diverse roles of mitochondria in ischemic stroke

    • Authors: Jenq-Lin Yang; Sujira Mukda; Shang-Der Chen
      Pages: 263 - 275
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Jenq-Lin Yang, Sujira Mukda, Shang-Der Chen
      Stroke is the leading cause of adult disability and mortality in most developing and developed countries. The current best practices for patients with acute ischemic stroke include intravenous tissue plasminogen activator and endovascular thrombectomy for large-vessel occlusion to improve clinical outcomes. However, only a limited portion of patients receive thrombolytic therapy or endovascular treatment because the therapeutic time window after ischemic stroke is narrow. To address the current shortage of stroke management approaches, it is critical to identify new potential therapeutic targets. The mitochondrion is an often overlooked target for the clinical treatment of stroke. Early studies of mitochondria focused on their bioenergetic role; however, these organelles are now known to be important in a wide range of cellular functions and signaling events. This review aims to summarize the current knowledge on the mitochondrial molecular mechanisms underlying cerebral ischemia and involved in reactive oxygen species generation and scavenging, electron transport chain dysfunction, apoptosis, mitochondrial dynamics and biogenesis, and inflammation. A better understanding of the roles of mitochondria in ischemia-related neuronal death and protection may provide a rationale for the development of innovative therapeutic regimens for ischemic stroke and other stroke syndromes.
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      PubDate: 2018-03-19T00:42:06Z
      DOI: 10.1016/j.redox.2018.03.002
      Issue No: Vol. 16 (2018)
       
  • Age-dependent regulation of antioxidant genes by p38α MAPK in the
           liver

    • Authors: Salvador Pérez; Sergio Rius-Pérez; Ana M. Tormos; Isabela Finamor; Ángel R. Nebreda; Raquel Taléns-Visconti; Juan Sastre
      Pages: 276 - 284
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Salvador Pérez, Sergio Rius-Pérez, Ana M. Tormos, Isabela Finamor, Ángel R. Nebreda, Raquel Taléns-Visconti, Juan Sastre
      p38α is a redox sensitive MAPK activated by pro-inflammatory cytokines and environmental, genotoxic and endoplasmic reticulum stresses. The aim of this work was to assess whether p38α controls the antioxidant defense in the liver, and if so, to elucidate the mechanism(s) involved and the age-related changes. For this purpose, we used liver-specific p38α-deficient mice at two different ages: young-mice (4 months-old) and old-mice (24 months-old). The liver of young p38α knock-out mice exhibited a decrease in GSH levels and an increase in GSSG/GSH ratio and malondialdehyde levels. However, old mice deficient in p38α had higher hepatic GSH levels and lower GSSG/GSH ratio than young p38α knock-out mice. Liver-specific p38α deficiency triggered a dramatic down-regulation of the mRNAs of the key antioxidant enzymes glutamate cysteine ligase, superoxide dismutase 1, superoxide dismutase 2, and catalase in young mice, which seems mediated by the lack of p65 recruitment to their promoters. Nrf-2 nuclear levels did not change significantly in the liver of young mice upon p38α deficiency, but nuclear levels of phospho-p65 and PGC-1α decreased in these mice. p38α-dependent activation of NF-κB seems to occur through classical IκB Kinase and via ribosomal S6 kinase1 and AKT in young mice. However, unexpectedly the long-term deficiency in p38α triggers a compensatory up-regulation of antioxidant enzymes via NF-κB activation and recruitment of p65 to their promoters. In conclusion, p38α MAPK maintains the expression of antioxidant genes in liver of young animals via NF-κΒ under basal conditions, whereas its long-term deficiency triggers compensatory up-regulation of antioxidant enzymes through NF-κΒ.
      Graphical abstract image

      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.02.017
      Issue No: Vol. 16 (2018)
       
  • N-acetyl cysteine reverts the proinflammatory state induced by cigarette
           smoke extract in lung Calu-3 cells

    • Authors: Ángel G. Valdivieso; Andrea V. Dugour; Verónica Sotomayor; Mariángeles Clauzure; Juan M. Figueroa; Tomás A. Santa-Coloma
      Pages: 294 - 302
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Ángel G. Valdivieso, Andrea V. Dugour, Verónica Sotomayor, Mariángeles Clauzure, Juan M. Figueroa, Tomás A. Santa-Coloma
      Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are lethal pulmonary diseases. Cigarette consumption is the main cause for development of COPD, while CF is produced by mutations in the CFTR gene. Although these diseases have a different etiology, both share a CFTR activity impairment and proinflammatory state even under sterile conditions. The aim of this work was to study the extent of the protective effect of the antioxidant N-acetylcysteine (NAC) over the proinflammatory state (IL-6 and IL-8), oxidative stress (reactive oxygen species, ROS), and CFTR levels, caused by Cigarette Smoke Extract (CSE) in Calu-3 airway epithelial cells. CSE treatment (100 µg/ml during 24 h) decreased CFTR mRNA expression and activity, and increased the release of IL-6 and IL-8. The effect on these cytokines was inhibited by N-acetyl cysteine (NAC, 5 mM) or the NF-kB inhibitor, IKK-2 (10 µM). CSE treatment also increased cellular and mitochondrial ROS levels. The cellular ROS levels were normalized to control values by NAC treatment, although significant effects on mitochondrial ROS levels were observed only at short times (5´) and effects on CFTR levels were not observed. In addition, CSE reduced the mitochondrial NADH-cytochrome c oxidoreductase (mCx I-III) activity, an effect that was not reverted by NAC. The reduced CFTR expression and the mitochondrial damage induced by CSE could not be normalized by NAC treatment, evidencing the need for a more specific reagent. In conclusion, CSE causes a sterile proinflammatory state and mitochondrial damage in Calu-3 cells that was partially recovered by NAC treatment.
      Graphical abstract image

      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.03.006
      Issue No: Vol. 16 (2018)
       
  • The uremic toxin hippurate promotes endothelial dysfunction via the
           activation of Drp1-mediated mitochondrial fission

    • Authors: Mengjie Huang; Ribao Wei; Yang Wang; Tingyu Su; Ping Li; Xiangmei Chen
      Pages: 303 - 313
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Mengjie Huang, Ribao Wei, Yang Wang, Tingyu Su, Ping Li, Xiangmei Chen
      The accumulation of uremic toxins in chronic kidney disease (CKD) induces inflammation, oxidative stress and endothelial dysfunction, which is a key step in atherosclerosis. Accumulating evidence indicates increased mitochondrial fission is a contributing mechanism for impaired endothelial function. Hippurate, a uremic toxin, has been reported to be involved in cardiovascular diseases. Here, we assessed the endothelial toxicity of hippurate and the contribution of altered mitochondrial dynamics to hippurate-induced endothelial dysfunction. Treatment of human aortic endothelial cells with hippurate reduced the expression of endothelial nitric oxide synthase (eNOS) and increased the expression of intercellular cell adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF). The mechanisms of hippurate-induced endothelial dysfunction in vitro depended on the activation of Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and overproduction of mitochondrial reactive oxygen species (mitoROS). In a rat model in which CKD was induced by 5/6 nephrectomy (CKD rat), we observed increased oxidative stress, impaired endothelium-dependent vasodilation, and elevated soluble biomarkers of endothelial dysfunction (ICAM-1 and vWF). Similarly, endothelial dysfunction was identified in healthy rats treated with disease-relevant concentrations of hippurate. In aortas of CKD rats and hippurate-treated rats, we observed an increase in Drp1 protein levels and mitochondrial fission. Inhibition of Drp1 improved endothelial function in both rat models. These results indicate that hippurate, by itself, can cause endothelial dysfunction. Increased mitochondrial fission plays an active role in hippurate-induced endothelial dysfunction via an increase in mitoROS.
      Graphical abstract image

      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.03.010
      Issue No: Vol. 16 (2018)
       
  • Peroxidasin-mediated crosslinking of collagen IV is independent of NADPH
           oxidases

    • Authors: Gábor Sirokmány; Hajnal A. Kovács; Enikő Lázár; Krisztina Kónya; Ágnes Donkó; Balázs Enyedi; Helmut Grasberger; Miklós Geiszt
      Pages: 314 - 321
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Gábor Sirokmány, Hajnal A. Kovács, Enikő Lázár, Krisztina Kónya, Ágnes Donkó, Balázs Enyedi, Helmut Grasberger, Miklós Geiszt
      Collagen IV is a major component of the basement membrane in epithelial tissues. The NC1 domains of collagen IV protomers are covalently linked together through sulfilimine bonds, the formation of which is catalyzed by peroxidasin. Although hydrogen peroxide is essential for this reaction, the exact source of the oxidant remains elusive. Members of the NOX/DUOX NADPH oxidase family are specifically devoted to the production of superoxide and hydrogen peroxide. Our aim in this study was to find out if NADPH oxidases contribute in vivo to the formation of collagen IV sulfilimine crosslinks. We used multiple genetically modified in vivo model systems to provide a detailed assessment of this question. Our data indicate that in various peroxidasin-expressing tissues sulfilimine crosslinks between the NC1 domains of collagen IV can be readily detected in the absence of functioning NADPH oxidases. We also analyzed how subatmospheric oxygen levels influence the collagen IV network in collagen-producing cultured cells with rapid matrix turnover. We showed that collagen IV crosslinks remain intact even under strongly hypoxic conditions. Our hypothesis is that during collagen IV network formation PXDN cooperates with a NOX/DUOX-independent H2O2 source that is functional also at very low ambient oxygen levels.

      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.03.009
      Issue No: Vol. 16 (2018)
       
  • Copper accumulation in senescent cells: Interplay between copper
           transporters and impaired autophagy

    • Authors: Shashank Masaldan; Sharnel A.S. Clatworthy; Cristina Gamell; Zoe M. Smith; Paul S. Francis; Delphine Denoyer; Peter M. Meggyesy; Sharon La Fontaine; Michael A. Cater
      Pages: 322 - 331
      Abstract: Publication date: June 2018
      Source:Redox Biology, Volume 16
      Author(s): Shashank Masaldan, Sharnel A.S. Clatworthy, Cristina Gamell, Zoe M. Smith, Paul S. Francis, Delphine Denoyer, Peter M. Meggyesy, Sharon La Fontaine, Michael A. Cater
      Cellular senescence is characterized by irreversible growth arrest incurred through either replicative exhaustion or by pro-oncogenic cellular stressors (radioactivity, oxidative stress, oncogenic activation). The enrichment of senescent cells in tissues with age has been associated with tissue dyshomeostasis and age-related pathologies including cancers, neurodegenerative disorders (e.g. Alzheimer's, Parkinson's, etc.) and metabolic disorders (e.g. diabetes). We identified copper accumulation as being a universal feature of senescent cells [mouse embryonic fibroblasts (MEF), human prostate epithelial cells and human diploid fibroblasts] in vitro. Elevated copper in senescent MEFs was accompanied by elevated levels of high-affinity copper uptake protein 1 (Ctr1), diminished levels of copper-transporting ATPase 1 (Atp7a) (copper export) and enhanced antioxidant defence reflected by elevated levels of glutathione (GSH), superoxide dismutase 1 (SOD1) and glutaredoxin 1 (Grx1). The levels of intracellular copper were further increased in senescent MEFs cultured in copper supplemented medium and in senescent Mottled Brindled (Mo br ) MEFs lacking functional Atp7a. Finally, we demonstrated that the restoration/preservation of autophagic-lysosomal degradation in senescent MEFs following rapamycin treatment correlated with attenuation of copper accumulation in these cells despite a further decrease in Atp7a levels. This study for the first time establishes a link between Atp7a and the autophagic-lysosomal pathway, and a requirement for both to effect efficient copper export. Such a connection between cellular autophagy and copper homeostasis is significant, as both have emerged as important facets of age-associated degenerative disease.
      Graphical abstract image

      PubDate: 2018-04-18T09:00:18Z
      DOI: 10.1016/j.redox.2018.03.007
      Issue No: Vol. 16 (2018)
       
 
 
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