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Dive into the research topics where Valerian E. Kagan is active.

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Featured researches published by Valerian E. Kagan.


American Journal of Physiology-lung Cellular and Molecular Physiology | 2008

Inhalation vs. aspiration of single-walled carbon nanotubes in C57BL/6 mice: inflammation, fibrosis, oxidative stress, and mutagenesis

Anna A. Shvedova; Elena R. Kisin; Ashley R. Murray; V. J. Johnson; Olga Gorelik; Sivaram Arepalli; A. F. Hubbs; Robert R. Mercer; Phouthone Keohavong; N. Sussman; J. Jin; J. Yin; S. Stone; B. T. Chen; Gregory J. Deye; Andrew D. Maynard; Vincent Castranova; Paul A. Baron; Valerian E. Kagan

Nanomaterials are frontier technological products used in different manufactured goods. Because of their unique physicochemical, electrical, mechanical, and thermal properties, single-walled carbon nanotubes (SWCNT) are finding numerous applications in electronics, aerospace devices, computers, and chemical, polymer, and pharmaceutical industries. SWCNT are relatively recently discovered members of the carbon allotropes that are similar in structure to fullerenes and graphite. Previously, we (47) have reported that pharyngeal aspiration of purified SWCNT by C57BL/6 mice caused dose-dependent granulomatous pneumonia, oxidative stress, acute inflammatory/cytokine responses, fibrosis, and decrease in pulmonary function. To avoid potential artifactual effects due to instillation/agglomeration associated with SWCNT, we conducted inhalation exposures using stable and uniform SWCNT dispersions obtained by a newly developed aerosolization technique (2). The inhalation of nonpurified SWCNT (iron content of 17.7% by weight) at 5 mg/m(3), 5 h/day for 4 days was compared with pharyngeal aspiration of varying doses (5-20 microg per mouse) of the same SWCNT. The chain of pathological events in both exposure routes was realized through synergized interactions of early inflammatory response and oxidative stress culminating in the development of multifocal granulomatous pneumonia and interstitial fibrosis. 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.


Nature Nanotechnology | 2010

Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation

Valerian E. Kagan; Nagarjun V. Konduru; Weihong Feng; Brett L. Allen; Jennifer Conroy; Yuri Volkov; Irina I. Vlasova; Natalia A. Belikova; Naveena Yanamala; Alexander A. Kapralov; Yulia Y. Tyurina; Jingwen Shi; Elena R. Kisin; Ashley R. Murray; Jonathan Franks; Donna B. Stolz; Pingping Gou; Judith Klein-Seetharaman; Bengt Fadeel; Alexander Star; Anna A. Shvedova

We have shown previously that single-walled carbon nanotubes can be catalytically biodegraded over several weeks by the plant-derived enzyme, horseradish peroxidase. However, whether peroxidase intermediates generated inside human cells or biofluids are involved in the biodegradation of carbon nanotubes has not been explored. Here, we show that hypochlorite and reactive radical intermediates of the human neutrophil enzyme myeloperoxidase catalyse the biodegradation of single-walled carbon nanotubes in vitro, in neutrophils and to a lesser degree in macrophages. Molecular modelling suggests that interactions of basic amino acids of the enzyme with the carboxyls on the carbon nanotubes position the nanotubes near the catalytic site. Importantly, the biodegraded nanotubes do not generate an inflammatory response when aspirated into the lungs of mice. 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.


Biochemical and Biophysical Research Communications | 1990

Antioxidant effects of ubiquinones in microsomes and mitochondria are mediated by tocopherol recycling

Valerian E. Kagan; Elena Serbinova; Lester Packer

Ubiquinones and tocopherols (vitamin E) are intrinsic lipid components which have a stabilizing function in many membranes attributed to their antioxidant activity. The antioxidant effects of tocopherols are due to direct radical scavenging. Although ubiquinones also exert antioxidant properties the specific molecular mechanisms of their antioxidant activity may be due to: (i) direct reaction with lipid radicals or (ii) interaction with chromanoxyl radicals resulting in regeneration of vitamin E. Lipid peroxidation results have now shown that tocopherols are much stronger membrane antioxidants than naturally occurring ubiquinols (ubiquinones). Thus direct radical scavenging effects of ubiquinols (ubiquinones) might be negligible in the presence of comparable or higher concentrations of tocopherols. In support of this our ESR findings show that ubiquinones synergistically enhance enzymic NADH- and NADPH-dependent recycling of tocopherols by electron transport in mitochondria and microsomes. If ubiquinols were direct radical scavengers their consumption would be expected. Further proving our conclusion HPLC measurements demonstrated that ubiquinone-dependent sparing of tocopherols was not accompanied by ubiquinone consumption.


Nature Cell Biology | 2013

Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells

Charleen T. Chu; Jing Ji; Ruben K. Dagda; Jian Fei Jiang; Yulia Y. Tyurina; Alexandr A. Kapralov; Vladimir A. Tyurin; Naveena Yanamala; Indira H. Shrivastava; Dariush Mohammadyani; Kent Zhi Qiang Wang; Jianhui Zhu; Judith Klein-Seetharaman; Krishnakumar Balasubramanian; Andrew A. Amoscato; Grigory G. Borisenko; Zhentai Huang; Aaron M. Gusdon; Amin Cheikhi; Erin Steer; Ruth Wang; Catherine J. Baty; Simon Watkins; Ivet Bahar; Hülya Bayır; Valerian E. Kagan

Recognition of injured mitochondria for degradation by macroautophagy is essential for cellular health, but the mechanisms remain poorly understood. Cardiolipin is an inner mitochondrial membrane phospholipid. We found that rotenone, staurosporine, 6-hydroxydopamine and other pro-mitophagy stimuli caused externalization of cardiolipin to the mitochondrial surface in primary cortical neurons and SH-SY5Y cells. RNAi knockdown of cardiolipin synthase or of phospholipid scramblase-3, which transports cardiolipin to the outer mitochondrial membrane, decreased the delivery of mitochondria to autophagosomes. Furthermore, we found that the autophagy protein microtubule-associated-protein-1 light chain 3 (LC3), which mediates both autophagosome formation and cargo recognition, contains cardiolipin-binding sites important for the engulfment of mitochondria by the autophagic system. Mutation of LC3 residues predicted as cardiolipin-interaction sites by computational modelling inhibited its participation in mitophagy. These data indicate that redistribution of cardiolipin serves as an ‘eat-me’ signal for the elimination of damaged mitochondria from neuronal cells.


Pharmacology & Therapeutics | 2009

Mechanisms of pulmonary toxicity and medical applications of carbon nanotubes: Two faces of Janus? ☆

Anna A. Shvedova; Elena R. Kisin; Dale W. Porter; Paul A. Schulte; Valerian E. Kagan; Bengt Fadeel; Vincent Castranova

Nanotechnology is an emerging science involving manipulation of materials at the nanometer scale. There are several exciting prospects for the application of engineered nanomaterials in medicine. However, concerns over adverse and unanticipated effects on human health have also been raised. In fact, the same properties that make engineered nanomaterials attractive from a technological and biomedical perspective could also make these novel materials harmful to human health and the environment. Carbon nanotubes are cylinders of one or several coaxial graphite layer(s) with a diameter in the order of nanometers, and serve as an instructive example of the Janus-like properties of nanomaterials. Numerous in vitro and in vivo studies have shown that carbon nanotubes and/or associated contaminants or catalytic materials that arise during the production process may induce oxidative stress and prominent pulmonary inflammation. Recent studies also suggest some similarities between the pathogenic properties of multi-walled carbon nanotubes and those of asbestos fibers. On the other hand, carbon nanotubes can be readily functionalized and several studies on the use of carbon nanotubes as versatile excipients for drug delivery and imaging of disease processes have been reported, suggesting that carbon nanotubes may have a place in the armamentarium for treatment and monitoring of cancer, infection, and other disease conditions. Nanomedicine is an emerging field that holds great promise; however, close attention to safety issues is required to ensure that the opportunities that carbon nanotubes and other engineered nanoparticles offer can be translated into feasible and safe constructs for the treatment of human disease.


Free Radical Biology and Medicine | 2009

Cytochrome c/cardiolipin relations in mitochondria: a kiss of death

Valerian E. Kagan; Hülya Bayır; Natalia A. Belikova; Olexandr Kapralov; Yulia Y. Tyurina; Vladimir A. Tyurin; Jianfei Jiang; Detcho A. Stoyanovsky; Peter Wipf; Patrick M. Kochanek; Joel S. Greenberger; Bruce R. Pitt; Anna A. Shvedova; Grigory G. Borisenko

Recently, phospholipid peroxidation products gained a reputation as key regulatory molecules and participants in oxidative signaling pathways. During apoptosis, a mitochondria-specific phospholipid, cardiolipin (CL), interacts with cytochrome c (cyt c) to form a peroxidase complex that catalyzes CL oxidation; this process plays a pivotal role in the mitochondrial stage of the execution of the cell death program. This review is focused on redox mechanisms and essential structural features of cyt cs conversion into a CL-specific peroxidase that represent an interesting and maybe still unique example of a functionally significant ligand change in hemoproteins. Furthermore, specific characteristics of CL in mitochondria--its asymmetric transmembrane distribution and mechanisms of collapse, the regulation of its synthesis, remodeling, and fatty acid composition--are given significant consideration. 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.


Nano Letters | 2008

Biodegradation of single-walled carbon nanotubes through enzymatic catalysis.

Brett L. Allen; Padmakar D. Kichambare; Pingping Gou; Irina I. Vlasova; Alexander A. Kapralov; Nagarjun V. Konduru; Valerian E. Kagan; Alexander Star

We show here the biodegradation of single-walled carbon nanotubes through natural, enzymatic catalysis. By incubating nanotubes with a natural horseradish peroxidase (HRP) and low concentrations of H2O2 (approximately 40 microM) at 4 degrees C over 12 weeks under static conditions, we show the increased degradation of nanotube structure. This reaction was monitored via multiple characterization methods, including transmission electron microscopy (TEM), dynamic light scattering (DLS), gel electrophoresis, mass spectrometry, and ultraviolet-visible-near-infrared (UV-vis-NIR) spectroscopy. These results mark a promising possibility for carbon nanotubes to be degraded by HRP in environmentally relevant settings. This is also tempting for future studies involving biotechnological and natural (plant peroxidases) ways for degradation of carbon nanotubes in the environment.


Toxicology and Applied Pharmacology | 2012

Mechanisms of carbon nanotube-induced toxicity: Focus on oxidative stress

Anna A. Shvedova; Antonio Pietroiusti; Bengt Fadeel; Valerian E. Kagan

Nanotechnologies are emerging as highly promising technologies in many sectors in the society. However, the increasing use of engineered nanomaterials also raises concerns about inadvertent exposure to these materials and the potential for adverse effects on human health and the environment. Despite several years of intensive investigations, a common paradigm for the understanding of nanoparticle-induced toxicity remains to be firmly established. Here, the so-called oxidative stress paradigm is scrutinized. Does oxidative stress represent a secondary event resulting inevitably from disruption of biochemical processes and the demise of the cell, or a specific, non-random event that plays a role in the induction of cellular damage e.g. apoptosis? The answer to this question will have important ramifications for the development of strategies for mitigation of adverse effects of nanoparticles. Recent examples of global lipidomics studies of nanoparticle-induced tissue damage are discussed along with proteomics and transcriptomics approaches to achieve a comprehensive understanding of the complex and interrelated molecular changes in cells and tissues exposed to nanoparticles. We also discuss instances of non-oxidative stress-mediated cellular damage resulting from direct physical interference of nanomaterials with cellular structures.


Nature Cell Biology | 2014

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice

José Pedro Friedmann Angeli; Manuela Schneider; Bettina Proneth; Yulia Y. Tyurina; Vladimir A. Tyurin; Victoria Jayne Hammond; Nadja Herbach; Michaela Aichler; Axel Walch; Elke Eggenhofer; Devaraj Basavarajappa; Olof Rådmark; Sho Kobayashi; Tobias Seibt; Heike Beck; Frauke Neff; Irene Esposito; Rüdiger Wanke; Heidi Förster; Olena Yefremova; Georg W. Bornkamm; Edward K. Geissler; Stephen B. Thomas; Brent R. Stockwell; Valerie B. O’Donnell; Valerian E. Kagan; Joel A. Schick; Marcus Conrad

Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4−/− mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4−/− mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.


Toxicology | 2009

Oxidative stress and inflammatory response in dermal toxicity of single-walled carbon nanotubes

Ashley R. Murray; Elena R. Kisin; Steve Leonard; Shih-Houng Young; Choudari Kommineni; Valerian E. Kagan; Vincent Castranova; Anna A. Shvedova

Single-walled carbon nanotubes (SWCNT) represent a novel material with unique electronic and mechanical properties. The extremely small size ( approximately 1 nm diameter) renders their chemical and physical properties unique. A variety of different techniques are available for the production of SWCNT; however, the most common is via the disproportionation of gaseous carbon molecules supported on catalytic iron particles (high-pressure CO conversion, HiPCO). The physical nature of SWCNT may lead to dermal penetration following deposition on exposed skin. This dermal deposition provides a route of exposure which is important to consider when evaluating SWCNT toxicity. The dermal effects of SWCNT are largely unknown. We hypothesize that SWCNT may be toxic to the skin. We further hypothesize that SWCNT toxicity may be dependent upon the metal (particularly iron) content of SWCNT via the metals ability to interact with the skin, initiate oxidative stress, and induce redox-sensitive transcription factors thereby affecting/leading to inflammation. To test this hypothesis, the effects of SWCNT were assessed both in vitro and in vivo using EpiDerm FT engineered skin, murine epidermal cells (JB6 P+), and immune-competent hairless SKH-1 mice. Engineered skin exposed to SWCNT showed increased epidermal thickness and accumulation and activation of dermal fibroblasts which resulted in increased collagen as well as release of pro-inflammatory cytokines. Exposure of JB6 P+ cells to unpurified SWCNT (30% iron) resulted in the production of ESR detectable hydroxyl radicals and caused a significant dose-dependent activation of AP-1. No significant changes in AP-1 activation were detected when partially purified SWCNT (0.23% iron) were introduced to the cells. However, NFkappaB was activated in a dose-dependent fashion by exposure to both unpurified and partially purified SWCNT. Topical exposure of SKH-1 mice (5 days, with daily doses of 40 microg/mouse, 80 microg/mouse, or 160 microug/mouse) to unpurified SWCNT caused oxidative stress, depletion of glutathione, oxidation of protein thiols and carbonyls, elevated myeloperoxidase activity, an increase of dermal cell numbers, and skin thickening resulting from the accumulation of polymorphonuclear leukocytes (PMNs) and mast cells. Altogether, these data indicated that topical exposure to unpurified SWCNT, induced free radical generation, oxidative stress, and inflammation, thus causing dermal toxicity.

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Hülya Bayır

University of Pittsburgh

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Anna A. Shvedova

National Institute for Occupational Safety and Health

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Jianfei Jiang

University of Pittsburgh

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Elena R. Kisin

National Institute for Occupational Safety and Health

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