Pulmonary Phosphatidylserine Oxidation in Apoptosis

Summary

Principal Investigator: Valerian Kagan
Affiliation: University of Pittsburgh
Country: USA
Abstract: Although phosphatidylserine (PS) externalization is a well-established early marker of apoptosis and a signal for macrophage-dependent recognition, the functional molecular links between these processes and oxidative stress produced during apoptotic execution are unclear. Our preliminary data suggest a previously unknown signaling role for oxidized PS during Fas-induced apoptosis in Jurkat cells. Since Fas-triggered apoptosis modulates turnover of pulmonary epithelial cells (PUEC) in both healthy and diseased tissue, we propose studying the mechanisms involved in selective PS oxidation and the subsequent PS-dependent signaling events during Fas-mediated apoptosis in PUEC. Our central hypothesis is that PS oxidation is an essential component in the pathway leading to PS externalization during Fas-induced apoptosis in PUEC as well as in efficient recognition and phagocytosis of apoptotic cells by macrophages. As a corollary, inhibition of PS oxidation during Fas-induced apoptosis by antioxidants may affect subsequent externalization/recognition and phagocytosis of apoptotic cells. Our Specific Aims designed to test this hypothesis will: 1) establish a mechanistic link between Fas-induced PS peroxidation and PS-dependent signaling in the PUEC plasma membrane (PS externalization and recognition by macrophages), relationship of PS oxidation to other components of Fas-triggered apoptosis, and extent to which the inhibition of PS oxidation by antioxidants blocks PS-dependent signaling without affecting other major Fas-triggered pathways of apoptosis; 2) establish the catalytic role and mechanisms of cyt c in PS oxidation in plasma membrane; 3) determine the role of PS peroxidation in PS externalization; and 4) reveal the mechanisms for enhanced macrophage recognition and phagocytosis of PUEC expressing oxidized PS. Developmental remodeling of the lung and various acute and chronic lung diseases are characterized by marked apoptosis. Inflammation is limited by effective recognition and phagocytosis of apoptotic cells by macrophages whose critical function is mediated by externalized PS on the surface of apoptotic cells. Our studies will define a new role for site-specific oxidative stress during apoptosis in PUEC, identify oxidized PS as a key signaling molecule that affects macrophage recognition of apoptotic cells and identify antioxidant interventions that can differentially prevent or preserve PS oxidation and downstream signaling events. This will aid in developing new strategies for directed modulation of inflammation in lung disease.
Funding Period: 2002-07-01 - 2007-06-30
more information: NIH RePORT

Top Publications

  1. ncbi LC3 binds externalized cardiolipin on injured mitochondria to signal mitophagy in neurons: implications for Parkinson disease
    Charleen T Chu
    Department of Pathology Division of Neuropathology University of Pittsburgh School of Medicine Pittsburgh, PA USA The McGowan Institute for Regenerative Medicine University of Pittsburgh School of Medicine Pittsburgh, PA USA The Center for Neuroscience University of Pittsburgh School of Medicine Pittsburgh, PA USA
    Autophagy 10:376-8. 2014
  2. pmc Oxidized phospholipids as biomarkers of tissue and cell damage with a focus on cardiolipin
    Alejandro K Samhan-Arias
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA
    Biochim Biophys Acta 1818:2413-23. 2012
  3. pmc Mapping of phospholipids by MALDI imaging (MALDI-MSI): realities and expectations
    Louis J Sparvero
    Center for Free Radical and Antioxidant Health, Pittsburgh, PA 15213, USA
    Chem Phys Lipids 165:545-62. 2012
  4. pmc A natural vanishing act: the enzyme-catalyzed degradation of carbon nanomaterials
    Gregg P Kotchey
    Department of Chemistry, University of Pittsburgh, Pennsylvania, United States
    Acc Chem Res 45:1770-81. 2012
  5. pmc Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury
    Jing Ji
    Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Nat Neurosci 15:1407-13. 2012
  6. pmc Specificity of lipoprotein-associated phospholipase A(2) toward oxidized phosphatidylserines: liquid chromatography-electrospray ionization mass spectrometry characterization of products and computer modeling of interactions
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Biochemistry 51:9736-50. 2012
  7. pmc Dual function of mitochondrial Nm23-H4 protein in phosphotransfer and intermembrane lipid transfer: a cardiolipin-dependent switch
    Uwe Schlattner
    From the Laboratory of Fundamental and Applied Bioenergetics and Federative Research Structure Environmental and Systems Biology, University Joseph Fourier, 38041 Grenoble Cedex 9, France
    J Biol Chem 288:111-21. 2013
  8. pmc Biodegradation of single-walled carbon nanotubes by eosinophil peroxidase
    Fernando T Andón
    Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Nobels vag 13, Stockholm 17177, Sweden
    Small 9:2721-9, 2720. 2013
  9. pmc LC/MS characterization of rotenone induced cardiolipin oxidation in human lymphocytes: implications for mitochondrial dysfunction associated with Parkinson's disease
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    Mol Nutr Food Res 57:1410-22. 2013
  10. pmc Cardiolipin asymmetry, oxidation and signaling
    Valerian E Kagan
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA Electronic address
    Chem Phys Lipids 179:64-9. 2014

Scientific Experts

  • Anna A Shvedova
  • Valerian Kagan
  • Yulia Y Tyurina
  • M Huttemann
  • Donna L Herber
  • B Fadeel
  • Hulya Bayir
  • Ashley R Murray
  • Detcho Stoyanovsky
  • D E Heck
  • Vladimir A Tyurin
  • Naveena Yanamala
  • Natalia A Belikova
  • Jianfei Jiang
  • Zhentai Huang
  • Patrick M Kochanek
  • Jing Ji
  • Judith Klein-Seetharaman
  • Andrew A Amoscato
  • Louis J Sparvero
  • Joel S Greenberger
  • Weihong Feng
  • Alexandr A Kapralov
  • Charleen T Chu
  • Gregg P Kotchey
  • Bruce R Pitt
  • Elena R Kisin
  • Irina I Vlasova
  • Alexander Star
  • Igor V Kurnikov
  • Alejandro K Samhan-Arias
  • Alexander A Kapralov
  • Robert S B Clark
  • Akihiro Maeda
  • Karla J Wasserloos
  • E R Kisin
  • Qing Zhao
  • Jim Peterson
  • V A Tyurin
  • Liana V Basova
  • Michael R Shurin
  • Fernando T Andón
  • Uwe Schlattner
  • Dariush Mohammadyani
  • Y Peter Di
  • Krishnakumar Balasubramanian
  • Amin Cheikhi
  • Kalidasan Thambiayya
  • Rama K Mallampalli
  • Grigory Borisenko
  • Hui Hua Li
  • Vladimir Tyurin
  • Nancy B Ray
  • S Leonard
  • Rajib Sengupta
  • V Castranova
  • Valentyna Kapralova
  • Diane Schwegler-Berry
  • Minke Tang
  • Wenjin Li
  • Daniel E Winnica
  • Arlan H Mintz
  • Ashley Glumac
  • Muhammad A Tungekar
  • Alexandr Kapralov
  • M Ding
  • Erika Witasp
  • Vladimir B Ritov
  • Alexandra Mnuskin
  • G G Borisenko
  • A A Kapralov
  • Anatoly N Osipov
  • B F Serinkan
  • Sacnicte Ramirez
  • Jian Fei Jiang
  • Jianhui Zhu
  • Benedict J Chambers
  • Catherine Baty
  • Raquel F Epand
  • Marie Lise Lacombe
  • Muhammet S Toprak
  • Simon Watkins
  • M Eileen Birch
  • Kent Zhi Qiang Wang
  • Fei Ye
  • Shengli Gao
  • Ruben K Dagda
  • Erin K Steer
  • Mathieu Boissan
  • Dmitriy W Gutkin

Detail Information

Publications76

  1. ncbi LC3 binds externalized cardiolipin on injured mitochondria to signal mitophagy in neurons: implications for Parkinson disease
    Charleen T Chu
    Department of Pathology Division of Neuropathology University of Pittsburgh School of Medicine Pittsburgh, PA USA The McGowan Institute for Regenerative Medicine University of Pittsburgh School of Medicine Pittsburgh, PA USA The Center for Neuroscience University of Pittsburgh School of Medicine Pittsburgh, PA USA
    Autophagy 10:376-8. 2014
    ..Given that a conserved LC3 phosphorylation site is adjacent to key residues involved in CL binding, signaling pathways could potentially modulate this interaction to fine-tune the mitochondrial recycling response. ..
  2. pmc Oxidized phospholipids as biomarkers of tissue and cell damage with a focus on cardiolipin
    Alejandro K Samhan-Arias
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA
    Biochim Biophys Acta 1818:2413-23. 2012
    ..This article is part of a Special Issue entitled: Oxidized phospholipids - their properties and interactions with proteins...
  3. pmc Mapping of phospholipids by MALDI imaging (MALDI-MSI): realities and expectations
    Louis J Sparvero
    Center for Free Radical and Antioxidant Health, Pittsburgh, PA 15213, USA
    Chem Phys Lipids 165:545-62. 2012
    ..This is followed by a review of the current literature, including methodologies that other laboratories have used to overcome these challenges...
  4. pmc A natural vanishing act: the enzyme-catalyzed degradation of carbon nanomaterials
    Gregg P Kotchey
    Department of Chemistry, University of Pittsburgh, Pennsylvania, United States
    Acc Chem Res 45:1770-81. 2012
    ..Finally, the incorporation of CNMs with defect sites in consumer goods could provide a facile mechanism that promotes the degradation of these materials once these products reach landfills...
  5. pmc Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury
    Jing Ji
    Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Nat Neurosci 15:1407-13. 2012
    ..We conclude that cardiolipin oxygenation generates neuronal death signals and that prevention of it by mitochondria-targeted small molecule inhibitors represents a new target for neuro-drug discovery...
  6. pmc Specificity of lipoprotein-associated phospholipase A(2) toward oxidized phosphatidylserines: liquid chromatography-electrospray ionization mass spectrometry characterization of products and computer modeling of interactions
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Biochemistry 51:9736-50. 2012
    ....
  7. pmc Dual function of mitochondrial Nm23-H4 protein in phosphotransfer and intermembrane lipid transfer: a cardiolipin-dependent switch
    Uwe Schlattner
    From the Laboratory of Fundamental and Applied Bioenergetics and Federative Research Structure Environmental and Systems Biology, University Joseph Fourier, 38041 Grenoble Cedex 9, France
    J Biol Chem 288:111-21. 2013
    ....
  8. pmc Biodegradation of single-walled carbon nanotubes by eosinophil peroxidase
    Fernando T Andón
    Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Nobels vag 13, Stockholm 17177, Sweden
    Small 9:2721-9, 2720. 2013
    ..Thus, human EPO (in vitro) and ex vivo activated eosinophils mediate biodegradation of SWCNTs: an observation that is relevant to pulmonary responses to these materials...
  9. pmc LC/MS characterization of rotenone induced cardiolipin oxidation in human lymphocytes: implications for mitochondrial dysfunction associated with Parkinson's disease
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    Mol Nutr Food Res 57:1410-22. 2013
    ..Rotenone is a toxicant believed to contribute to the development of Parkinson's disease...
  10. pmc Cardiolipin asymmetry, oxidation and signaling
    Valerian E Kagan
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA Electronic address
    Chem Phys Lipids 179:64-9. 2014
    ..prokaryotes. This diversity--associated with CL molecular asymmetry--is presented as the basis for mitochondrial communications language...
  11. pmc Long-term effects of carbon containing engineered nanomaterials and asbestos in the lung: one year postexposure comparisons
    Anna A Shvedova
    NIOSH, CDC, 1095 Willowdale Rd, Morgantown, WV 26505
    Am J Physiol Lung Cell Mol Physiol 306:L170-82. 2014
    ..Overall, our data suggest that long-term pulmonary toxicity of SWCNT, CNF, and asbestos is defined, not only by their chemical composition, but also by the specific surface area and type of exposure. ..
  12. pmc Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells
    Charleen T Chu
    Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    Nat Cell Biol 15:1197-205. 2013
    ..These data indicate that redistribution of cardiolipin serves as an 'eat-me' signal for the elimination of damaged mitochondria from neuronal cells. ..
  13. doi Biodiesel versus diesel exposure: enhanced pulmonary inflammation, oxidative stress, and differential morphological changes in the mouse lung
    Naveena Yanamala
    Pathology and Physiology Research Branch NIOSH CDC, Morgantown, WV 26505, USA Electronic address
    Toxicol Appl Pharmacol 272:373-83. 2013
    ..Taken together, these results clearly indicate that BD exhaust particles could exert more toxic effects compared to D. ..
  14. pmc Molecular modeling in structural nano-toxicology: interactions of nano-particles with nano-machinery of cells
    Naveena Yanamala
    Pathology and Physiology Research Branch NIOSH CDC, Morgantown, WV, USA
    Adv Drug Deliv Rev 65:2070-7. 2013
    ..A rationale on how nanoparticles of different sizes, shape, structure and chemical properties can affect the organization and functions of nano-machinery of cells is also presented. ..
  15. pmc Dual acute proinflammatory and antifibrotic pulmonary effects of short palate, lung, and nasal epithelium clone-1 after exposure to carbon nanotubes
    Y Peter Di
    1 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
    Am J Respir Cell Mol Biol 49:759-67. 2013
    ..7 macrophages. Taken together, our data indicate that SPLUNC1 is an important component of mucosal innate immune defense against pulmonary inhaled particles...
  16. pmc LPS-induced decrease in intracellular labile zinc, [Zn]i, contributes to apoptosis in cultured sheep pulmonary artery endothelial cells
    Kalidasan Thambiayya
    Department of Bioengineering, University of Pittsburgh and Universityof Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
    Am J Physiol Lung Cell Mol Physiol 300:L624-32. 2011
    ....
  17. pmc Mass-spectrometry based oxidative lipidomics and lipid imaging: applications in traumatic brain injury
    Louis J Sparvero
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    J Neurochem 115:1322-36. 2010
    ....
  18. doi Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia
    Nancy B Ray
    Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
    Nat Med 16:1120-7. 2010
    ..This discovery opens the door for new therapeutic strategies directed at modulating the abundance or molecular interactions of cardiolipin in pneumonia...
  19. doi Protection of normal brain cells from γ-irradiation-induced apoptosis by a mitochondria-targeted triphenyl-phosphonium-nitroxide: a possible utility in glioblastoma therapy
    Zhentai Huang
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Neurooncol 100:1-8. 2010
    ..Thus, TPEY-Tempo may be a promising adjunct in the treatment of glioblastoma with the potential to not only prolong survival but also to maintain quality of life and reduce treatment toxicity...
  20. doi Unusual peroxidase activity of polynitroxylated pegylated hemoglobin: Elimination of H(2)O(2) coupled with intramolecular oxidation of nitroxides
    Detcho A Stoyanovsky
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    Biochem Biophys Res Commun 399:139-43. 2010
    ....
  21. pmc Lipid accumulation and dendritic cell dysfunction in cancer
    Donna L Herber
    Department of Immunology, H Lee Moffitt Cancer Center, Tampa, Florida, USA
    Nat Med 16:880-6. 2010
    ..These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs...
  22. pmc Programmed cell clearance: molecular regulation of the elimination of apoptotic cell corpses and its role in the resolution of inflammation
    Bengt Fadeel
    Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
    Biochem Biophys Res Commun 396:7-10. 2010
    ..The present review will focus on the molecular regulation of programmed cell clearance, and discuss the role of cell elimination in the resolution of inflammation...
  23. pmc Oxidative lipidomics of hyperoxic acute lung injury: mass spectrometric characterization of cardiolipin and phosphatidylserine peroxidation
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health, Dept of Environmental and Occupational Health, Univ of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, PA 15219, USA
    Am J Physiol Lung Cell Mol Physiol 299:L73-85. 2010
    ....
  24. pmc The multiple functions of cytochrome c and their regulation in life and death decisions of the mammalian cell: From respiration to apoptosis
    Maik Huttemann
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Mitochondrion 11:369-81. 2011
    ..Cytc regulation in respiration and cell death is discussed in a human disease context including neurodegenerative and cardiovascular diseases, cancer, and sepsis...
  25. doi Genotoxicity of carbon nanofibers: are they potentially more or less dangerous than carbon nanotubes or asbestos?
    E R Kisin
    Pathology and Physiology Research Branch, Health Effects Lab Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
    Toxicol Appl Pharmacol 252:1-10. 2011
    ..Further investigations are warranted to elucidate the possible mechanisms involved in CNF-induced genotoxicity...
  26. pmc Oxidative lipidomics of γ-radiation-induced lung injury: mass spectrometric characterization of cardiolipin and phosphatidylserine peroxidation
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, PA, USA
    Radiat Res 175:610-21. 2011
    ....
  27. pmc Impaired clearance and enhanced pulmonary inflammatory/fibrotic response to carbon nanotubes in myeloperoxidase-deficient mice
    Anna A Shvedova
    Pathology and Physiology Research Branch, Health Effects Lab Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, United States of America
    PLoS ONE 7:e30923. 2012
    ....
  28. pmc Adsorption of surfactant lipids by single-walled carbon nanotubes in mouse lung upon pharyngeal aspiration
    Alexander A Kapralov
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    ACS Nano 6:4147-56. 2012
    ..Taken together, this is the first demonstration of the in vivo adsorption of the surfactant lipids and proteins on SWCNTs in a physiologically relevant animal model...
  29. pmc Mitochondria targeting of non-peroxidizable triphenylphosphonium conjugated oleic acid protects mouse embryonic cells against apoptosis: role of cardiolipin remodeling
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    FEBS Lett 586:235-41. 2012
    ..This caused suppression of apoptosis induced by actinomycin D. Triacsin C, an inhibitor of acyl-CoA synthase, blocked integration of oleic acid into cardiolipin and restored cell sensitivity to apoptosis...
  30. pmc Mitochondrial injury after mechanical stretch of cortical neurons in vitro: biomarkers of apoptosis and selective peroxidation of anionic phospholipids
    Jing Ji
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    J Neurotrauma 29:776-88. 2012
    ..The delayed emergence of apoptotic neuronal death after the immediate mechanical damage to mitochondria suggests a possible window of opportunity for targeted therapies...
  31. pmc Mass-spectrometric characterization of peroxidized and hydrolyzed lipids in plasma and dendritic cells of tumor-bearing animals
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219 3130, USA
    Biochem Biophys Res Commun 413:149-53. 2011
    ....
  32. pmc A high-throughput screening assay of ascorbate in brain samples
    Natalia A Belikova
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    J Neurosci Methods 201:185-90. 2011
    ..Assay was validated with high performance liquid chromatography method. The concentration of ascorbate in murine tissue samples, including brain samples after traumatic brain injury and hemorrhagic shock, was measured...
  33. pmc Are mitochondrial reactive oxygen species required for autophagy?
    Jianfei Jiang
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, PA 15219, USA
    Biochem Biophys Res Commun 412:55-60. 2011
    ..2 cells in which both electron transport and ROS generation were completely disrupted. Counter to the widespread view, we conclude that mitochondrial ROS are not required for the induction of autophagy...
  34. pmc Global phospholipidomics analysis reveals selective pulmonary peroxidation profiles upon inhalation of single-walled carbon nanotubes
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    ACS Nano 5:7342-53. 2011
    ....
  35. pmc Topography of tyrosine residues and their involvement in peroxidation of polyunsaturated cardiolipin in cytochrome c/cardiolipin peroxidase complexes
    Alexandr A Kapralov
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA
    Biochim Biophys Acta 1808:2147-55. 2011
    ..Thus, the highly conserved Tyr67 is a likely electron-donor (radical acceptor) in the oxygenase half-reaction of the cyt c/CL peroxidase complex...
  36. doi Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation
    Valerian E Kagan
    Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Nat Nanotechnol 5:354-9. 2010
    ..Our findings suggest that the extent to which carbon nanotubes are biodegraded may be a major determinant of the scale and severity of the associated inflammatory responses in exposed individuals...
  37. pmc The cyclooxygenase site, but not the peroxidase site of cyclooxygenase-2 is required for neurotoxicity in hypoxic and ischemic injury
    Wenjin Li
    Geriatric Research Educational and Clinical Center, VA Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh, Pennsylvania 15205, USA
    J Neurochem 113:965-77. 2010
    ..Taken together, these results indicate that the cyclooxygenase activity of COX-2 is necessary to exacerbate neuronal hypoxia/ischemia injury rather than the peroxidase activity of the enzyme...
  38. pmc Nitric oxide and thioredoxin type 1 modulate the activity of caspase 8 in HepG2 cells
    Rajib Sengupta
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Biochem Biophys Res Commun 391:1127-30. 2010
    ..The data obtained suggest that extrinsic apoptosis can be subjected to redox regulation before induction of proteolytic damage by caspase 3...
  39. pmc Cytoprotective effects of albumin, nitrosated or reduced, in cultured rat pulmonary vascular cells
    Hui Hua Li
    Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Am J Physiol Lung Cell Mol Physiol 300:L526-33. 2011
    ....
  40. doi Oxidative lipidomics of apoptosis: quantitative assessment of phospholipid hydroperoxides in cells and tissues
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA
    Methods Mol Biol 610:353-74. 2010
    ..This has important implications for evaluation of apoptosis in vivo. The anionic phospholipids, cardiolipin (CL) and phosphatidylserine (PS), are the preferred peroxidation substrates...
  41. ncbi The "pro-apoptotic genies" get out of mitochondria: oxidative lipidomics and redox activity of cytochrome c/cardiolipin complexes
    V E Kagan
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, PA 15219, USA
    Chem Biol Interact 163:15-28. 2006
    ....
  42. ncbi Interactions of cardiolipin and lyso-cardiolipins with cytochrome c and tBid: conflict or assistance in apoptosis
    V A Tyurin
    Cell Death Differ 14:872-5. 2007
  43. ncbi Nitrosative stress inhibits the aminophospholipid translocase resulting in phosphatidylserine externalization and macrophage engulfment: implications for the resolution of inflammation
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, and Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
    J Biol Chem 282:8498-509. 2007
    ..scavenger, DAF-2. Thus, macrophage-induced nitrosylation/oxidation plays an important role in cell clearance, and hence in the resolution of inflammation...
  44. pmc Cardiolipin switch in mitochondria: shutting off the reduction of cytochrome c and turning on the peroxidase activity
    Liana V Basova
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    Biochemistry 46:3423-34. 2007
    ..Thus, both redox properties and functions of cyt c change upon interaction with CL in the mitochondrial membrane, diminishing cyt c's electron donor/acceptor role and stimulating its peroxidase activity...
  45. pmc Vitamin E deficiency enhances pulmonary inflammatory response and oxidative stress induced by single-walled carbon nanotubes in C57BL/6 mice
    Anna A Shvedova
    Pathology Physiology Research Branch, HELD, NIOSH, Morgantown, WV, USA
    Toxicol Appl Pharmacol 221:339-48. 2007
    ..Given that pulmonary levels of vitamin E can be manipulated through diet, its effects on SWCNT-induced inflammation may be of practical importance in optimizing protective strategies...
  46. ncbi Single-walled carbon nanotubes: geno- and cytotoxic effects in lung fibroblast V79 cells
    Elena R Kisin
    Pathology Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA
    J Toxicol Environ Health A 70:2071-9. 2007
    ..With two different strains of Salmonella typhimurium, no mutations were found following SWCNT exposure...
  47. pmc Sequential exposure to carbon nanotubes and bacteria enhances pulmonary inflammation and infectivity
    Anna A Shvedova
    Pathology Physiology Research Branch, HELD, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA
    Am J Respir Cell Mol Biol 38:579-90. 2008
    ..In conclusion, enhanced acute inflammation and pulmonary injury with delayed bacterial clearance after SWCNT exposure may lead to increased susceptibility to lung infection in exposed populations...
  48. ncbi Apoptotic interactions of cytochrome c: redox flirting with anionic phospholipids within and outside of mitochondria
    H Bayir
    Center for Free Radical and Antioxidant Health, Pittsburgh, PA 15219, USA
    Biochim Biophys Acta 1757:648-59. 2006
    ..This review is focused on newly discovered redox mechanisms of complexes of cyt c with anionic phospholipids and their role in apoptotic pathways in health and disease...
  49. ncbi Mechanisms of cardiolipin oxidation by cytochrome c: relevance to pro- and antiapoptotic functions of etoposide
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health, Department of EOH, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, PA 15219, USA
    Mol Pharmacol 70:706-17. 2006
    ..Thus, oxidation of cardiolipin by the cytochrome c/cardiolipin peroxidase complex, which is essential for apoptosis, is not inhibited by proapoptotic concentrations of the drug...
  50. pmc Peroxidase activity and structural transitions of cytochrome c bound to cardiolipin-containing membranes
    Natalia A Belikova
    Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219 3130, USA
    Biochemistry 45:4998-5009. 2006
    ....
  51. ncbi Nitric oxide inhibits peroxidase activity of cytochrome c.cardiolipin complex and blocks cardiolipin oxidation
    Irina I Vlasova
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA 15260, USA
    J Biol Chem 281:14554-62. 2006
    ..NO effectively inhibited 1,1'2,2'-tertalinoleoyl cardiolipin oxidation catalyzed by the peroxidase activity of cyt c. Thus, NO can act as a regulator of peroxidase activity of cyt c.CL complexes...
  52. ncbi Direct and indirect effects of single walled carbon nanotubes on RAW 264.7 macrophages: role of iron
    V E Kagan
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, United States
    Toxicol Lett 165:88-100. 2006
    ..Thus, the presence of iron in SWCNT may be important in determining redox-dependent responses of macrophages...
  53. ncbi Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors
    Valerian E Kagan
    Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    Nat Chem Biol 1:223-32. 2005
    ..These results provide insight into the role of reactive oxygen species in triggering the cell-death pathway and describe an early role for cytochrome c before caspase activation...
  54. ncbi Thioredoxin and lipoic acid catalyze the denitrosation of low molecular weight and protein S-nitrosothiols
    Detcho A Stoyanovsky
    Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    J Am Chem Soc 127:15815-23. 2005
    ..We conclude that both thioredoxin and dihydrolipoic acid may be involved in the regulation of cellular S-nitrosothiols...
  55. ncbi Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice
    Anna A Shvedova
    Health Effects Laboratory Div, NIOSH, Morgantown, WV, USA
    Am J Physiol Lung Cell Mol Physiol 289:L698-708. 2005
    ..Equal doses of ultrafine carbon black particles or fine crystalline silica (SiO2) did not induce granulomas or alveolar wall thickening and caused a significantly weaker pulmonary inflammation and damage...
  56. ncbi Apoptotic cells quench reactive oxygen and nitrogen species and modulate TNF-alpha/TGF-beta1 balance in activated macrophages: involvement of phosphatidylserine-dependent and -independent pathways
    B F Serinkan
    Cell Death Differ 12:1141-4. 2005
  57. pmc Cardiolipin deficiency leads to decreased cardiolipin peroxidation and increased resistance of cells to apoptosis
    Zhentai Huang
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    Free Radic Biol Med 44:1935-44. 2008
    ....
  58. ncbi Increased accumulation of neutrophils and decreased fibrosis in the lung of NADPH oxidase-deficient C57BL/6 mice exposed to carbon nanotubes
    A A Shvedova
    Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, West Virginia University, Morgantown, WV, USA
    Toxicol Appl Pharmacol 231:235-40. 2008
    ..These results demonstrate a role for NADPH oxidase-derived reactive oxygen species in determining course of pulmonary response to SWCNT...
  59. pmc A mitochondria-targeted triphenylphosphonium-conjugated nitroxide functions as a radioprotector/mitigator
    Jianfei Jiang
    Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA 15219, USA
    Radiat Res 172:706-17. 2009
    ..We conclude that mitochondrial targeting of TPP-conjugated nitroxides represents a promising approach for the development of novel radioprotectors...
  60. pmc Radioprotection by short-term oxidative preconditioning: role of manganese superoxide dismutase
    Natalia A Belikova
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    FEBS Lett 583:3437-42. 2009
    ..Using MnSOD siRNA, we show that MECs with decreased MnSOD levels displayed a lowered ability to preconditioning. Thus oxidative preconditioning may be used for targeted regulation of MnSOD...
  61. doi Mass-spectrometric characterization of phospholipids and their hydroperoxide derivatives in vivo: effects of total body irradiation
    Yulia Y Tyurina
    Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA
    Methods Mol Biol 580:153-83. 2009
    ..The protocols described may be utilized in studies of signaling functions of oxidized phospholipids in cell physiology and pathology...
  62. doi Size-dependent effects of tungsten carbide-cobalt particles on oxygen radical production and activation of cell signaling pathways in murine epidermal cells
    M Ding
    Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
    Toxicol Appl Pharmacol 241:260-8. 2009
    ....
  63. pmc Peroxidase activity of hemoglobin-haptoglobin complexes: covalent aggregation and oxidative stress in plasma and macrophages
    Alexandr Kapralov
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
    J Biol Chem 284:30395-407. 2009
    ....
  64. ncbi Heterolytic reduction of fatty acid hydroperoxides by cytochrome c/cardiolipin complexes: antioxidant function in mitochondria
    Natalia A Belikova
    Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219 3130, USA
    J Am Chem Soc 131:11288-9. 2009
    ..Regulation of FFA-OOH metabolism may be an important function of cyt c that is associated with elimination of toxic FFA-OOH and synthesis of physiologically active hydroxy-fatty acids in mitochondria...
  65. pmc Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactions
    Valerian E Kagan
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, PA 15219, USA
    Adv Drug Deliv Rev 61:1375-85. 2009
    ..Particular emphasis is placed on the employment of triphenylphosphonium- and hemi-gramicidin S-moieties as two effective vehicles for mitochondrial delivery of antioxidants...
  66. ncbi Single-walled carbon nanotubes impair human macrophage engulfment of apoptotic cell corpses
    Erika Witasp
    Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
    Inhal Toxicol 21:131-6. 2009
    ....
  67. pmc Mitochondria-targeted (2-hydroxyamino-vinyl)-triphenyl-phosphonium releases NO(.) and protects mouse embryonic cells against irradiation-induced apoptosis
    Natalia A Belikova
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
    FEBS Lett 583:1945-50. 2009
    ..We conclude that mitochondria-targeted peroxidase-activatable NO-donors represent a new interesting class of radioprotectors...
  68. pmc Mass-spectrometric analysis of hydroperoxy- and hydroxy-derivatives of cardiolipin and phosphatidylserine in cells and tissues induced by pro-apoptotic and pro-inflammatory stimuli
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219 9361, USA
    J Chromatogr B Analyt Technol Biomed Life Sci 877:2863-72. 2009
    ....
  69. pmc Cytochrome c/cardiolipin relations in mitochondria: a kiss of death
    Valerian E Kagan
    Center for Free Radical and Antioxidant Health, Pittsburgh, PA 15219, USA
    Free Radic Biol Med 46:1439-53. 2009
    ..Finally, new concepts in drug discovery based on the design of mitochondria-targeted inhibitors of cyt c/CL peroxidase and CL peroxidation with antiapoptotic effects are presented...
  70. ncbi Oxidative stress and inflammatory response in dermal toxicity of single-walled carbon nanotubes
    A R Murray
    Health Effects Laboratory Division, Pathology and Physiology Research Branch, NIOSH, M L 2015, 1095 Willowdale Road, Morgantown, WV 26505, United States
    Toxicology 257:161-71. 2009
    ..Altogether, these data indicated that topical exposure to unpurified SWCNT, induced free radical generation, oxidative stress, and inflammation, thus causing dermal toxicity...
  71. ncbi Mechanisms of pulmonary toxicity and medical applications of carbon nanotubes: Two faces of Janus?
    A A Shvedova
    Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, United States
    Pharmacol Ther 121:192-204. 2009
    ....
  72. pmc Molecular design of new inhibitors of peroxidase activity of cytochrome c/cardiolipin complexes: fluorescent oxadiazole-derivatized cardiolipin
    G G Borisenko
    Research Institute of Physico Chemical Medicine, Moscow, Russian Federation
    Biochemistry 47:13699-710. 2008
    ..We conclude that modified CL combining a nonoxidizable monounsaturated trioleoyl CL with a C(12)-NBD fragment undergoes a regiospecific oxidation thereby representing a novel inhibitor of cyt c peroxidase activity...
  73. pmc Mass-spectrometric characterization of phospholipids and their primary peroxidation products in rat cortical neurons during staurosporine-induced apoptosis
    Vladimir A Tyurin
    Center for Free Radical and Antioxidant Health, Pittsburgh, PA, USA
    J Neurochem 107:1614-33. 2008
    ..These oxidation products participate in mitochondrial membrane permeability transition and in PtdSer externalization leading to recognition and uptake of apoptotic cells by professional phagocytes...
  74. pmc Inhalation vs. aspiration of single-walled carbon nanotubes in C57BL/6 mice: inflammation, fibrosis, oxidative stress, and mutagenesis
    A A Shvedova
    Health Effects Laboratory Div, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
    Am J Physiol Lung Cell Mol Physiol 295:L552-65. 2008
    ..SWCNT inhalation was more effective than aspiration in causing inflammatory response, oxidative stress, collagen deposition, and fibrosis as well as mutations of K-ras gene locus in the lung of C57BL/6 mice...
  75. ncbi An epigrammatic (abridged) recounting of the myriad tales of astonishing deeds and dire consequences pertaining to nitric oxide and reactive oxygen species in mitochondria with an ancillary missive concerning the origins of apoptosis
    Diane E Heck
    Departments of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA
    Toxicology 208:259-71. 2005
    ....