1985 …2021
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Research Output 1985 2019

2019
2 Citations (Scopus)

Critical role of C5a in sickle cell disease

Vercellotti, G. M., Dalmasso, A. P., Schaid, T. R., Nguyen, J., Chen, C., Ericson, M. E., Abdulla, F., Killeen, T., Lindorfer, M. A., Taylor, R. P. & Belcher, J. D., Mar 1 2019, In : American Journal of Hematology. 94, 3, p. 327-337 11 p.

Research output: Contribution to journalArticle

Sickle Cell Anemia
Anaphylatoxin C5a Receptor
P-Selectin
Complement Activation
Immunoglobulin G

Heme oxygenase-2 protects against ischemic acute kidney injury: influence of age and sex

Nath, K. A., Garovic, V. D., Grande, J. P., Croatt, A. J., Ackerman, A. W., Farrugia, G., Katusic, Z. S., Belcher, J. D. & Vercellotti, G. M., Sep 1 2019, In : American journal of physiology. Renal physiology. 317, 3, p. F695-F704

Research output: Contribution to journalArticle

Acute Kidney Injury
Ischemia
Heme Oxygenase-1
Heme Oxygenase (Decyclizing)
Kidney
2018
4 Citations (Scopus)

Bivalent ligand MCC22 potently attenuates nociception in a murine model of sickle cell disease

Cataldo, G., Lunzer, M. M., Olson, J., Akgun, E., Belcher, J. D., Vercellotti, G. M., Portoghese, P. S. & Simone, D. A., Jul 1 2018, In : Pain. 159, 7, p. 1382-1391 10 p.

Research output: Contribution to journalArticle

Open Access
Nociception
Sickle Cell Anemia
Ligands
Pain
Morphine
7 Citations (Scopus)

Case series supporting heme detoxification via therapeutic plasma exchange in acute multiorgan failure syndrome resistant to red blood cell exchange in sickle cell disease

Louie, J. E., Anderson, C. J., Fayaz M. Fomani, K., Henry, A., Killeen, T., Mohandas, N., Yazdanbakhsh, K., Belcher, J. D., Vercellotti, G. M. & Shi, P. A., Feb 1 2018, In : Transfusion. 58, 2, p. 470-479 10 p.

Research output: Contribution to journalArticle

Hemopexin
Plasma Exchange
Haptoglobins
Sickle Cell Anemia
Heme
10 Citations (Scopus)

Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: Role of heme oxygenase-1 induction

Belcher, J. D., Chen, C., Nguyen, J., Abdulla, F., Zhang, P., Nguyen, H., Nguyen, P., Killeen, T., Miescher, S. M., Brinkman, N., Nath, K. A., Steer, C. J. & Vercellotti, G. M., Apr 1 2018, In : PloS one. 13, 4, e0196455.

Research output: Contribution to journalArticle

Open Access
heme oxygenase (biliverdin-producing)
Hemopexin
sickle cell anemia
Heme Oxygenase-1
Haptoglobins
5 Citations (Scopus)

Hemoglobin oxidation-dependent reactions promote interactions with band 3 and oxidative changes in sickle cell-derived microparticles

Jana, S., Strader, M. B., Meng, F., Hicks, W., Kassa, T., Tarandovskiy, I., De Paoli, S., Simak, J., Heaven, M. R., Belcher, J. D., Vercellotti, G. M. & Alayash, A. I., Nov 2 2018, In : JCI insight. 3, 21

Research output: Contribution to journalArticle

Open Access
Cell-Derived Microparticles
Hemoglobins
Hydroxyurea
Sickle Cell Anemia
Post Translational Protein Processing
9 Citations (Scopus)

Inflammation in sickle cell disease

Conran, N. & Belcher, J. D., Jan 1 2018, In : Clinical Hemorheology and Microcirculation. 68, 2-3, p. 263-299 37 p.

Research output: Contribution to journalArticle

Open Access
Sickle Cell Anemia
Inflammation
Acute Chest Syndrome
Leg Ulcer
Hydroxyurea
1 Citation (Scopus)

Oral carbon monoxide therapy in murine sickle cell disease: Beneficial effects on vasoocclusion, inflammation and anemia

Belcher, J. D., Gomperts, E., Nguyen, J., Chen, C., Abdulla, F., Kiser, Z. M., Gallo, D., Levy, H., Otterbein, L. E. & Vercellotti, G. M., Oct 1 2018, In : PloS one. 13, 10, e0205194.

Research output: Contribution to journalArticle

Open Access
sickle cell anemia
carbon monoxide
Sickle Cell Anemia
Carbon Monoxide
anemia
7 Citations (Scopus)

Role of TLR4 signaling in the nephrotoxicity of Heme and heme proteins

Nath, K. A., Belcher, J. D., Nath, M. C., Grande, J. P., Croatt, A. J., Ackerman, A. W., Katusic, Z. S. & Vercellotti, G. M., Jan 1 2018, In : American Journal of Physiology - Renal Physiology. 314, 5, p. F906-F914

Research output: Contribution to journalArticle

Hemeproteins
Toll-Like Receptor 4
Heme
Acute Kidney Injury
Kidney
2 Citations (Scopus)

Serum haptoglobin and hemopexin levels are depleted in pediatric sickle cell disease patients

Santiago, R. P., Guarda, C. C., Figueiredo, C. V. B., Fiuza, L. M., Aleluia, M. M., Adanho, C. S. A., Carvalho, M. O. S., Pitanga, T. N., Zanette, D. L., Lyra, I. M., Nascimento, V. M. L., Vercellotti, G. M., Belcher, J. D. & Goncalves, M. S., Sep 1 2018, In : Blood Cells, Molecules, and Diseases. 72, p. 34-36 3 p.

Research output: Contribution to journalLetter

Hemopexin
Haptoglobins
Sickle Cell Anemia
Pediatrics
Serum
2017
8 Citations (Scopus)

A monocyte-TNF-endothelial activation axis in sickle transgenic mice: Therapeutic benefit from TNF blockade

Solovey, A., Somani, A., Belcher, J. D., Milbauer, L., Vincent, L., Pawlinski, R., Nath, K. A., Kelm, R. J., Mackman, N., O'Sullivan, M. G., Gupta, K., Vercellotti, G. M. & Hebbel, R. P., Nov 1 2017, In : American Journal of Hematology. 92, 11, p. 1119-1130 12 p.

Research output: Contribution to journalArticle

Transgenic Mice
Monocytes
Tumor Necrosis Factor-alpha
Sickle Cell Anemia
Blood Cells
19 Citations (Scopus)

Control of Oxidative Stress and Inflammation in Sickle Cell Disease with the Nrf2 Activator Dimethyl Fumarate

Belcher, J. D., Chen, C., Nguyen, J., Zhang, P., Abdulla, F., Nguyen, P., Killeen, T., Xu, P., O'Sullivan, G., Nath, K. A. & Vercellotti, G. M., May 10 2017, In : Antioxidants and Redox Signaling. 26, 14, p. 748-762 15 p.

Research output: Contribution to journalArticle

Open Access
Oxidative stress
Sickle Cell Anemia
Oxidative Stress
Inflammation
Heme
4 Citations (Scopus)

The role of carbon monoxide and heme oxygenase in the prevention of sickle cell disease vaso-occlusive crises

Gomperts, E., Belcher, J. D., Otterbein, L. E., Coates, T. D., Wood, J., Skolnick, B. E., Levy, H. & Vercellotti, G. M., Jun 1 2017, In : American Journal of Hematology. 92, 6, p. 569-582 14 p.

Research output: Contribution to journalReview article

Open Access
Heme Oxygenase (Decyclizing)
Sickle Cell Anemia
Carbon Monoxide
Hemoglobinopathies
beta-Globins
2016
20 Citations (Scopus)
Hemopexin
Sickle Cell Anemia
Blood Vessels
Inflammation
Liver
9 Citations (Scopus)

Sustained treatment of sickle cell mice with haptoglobin increases HO-1 and H-ferritin expression and decreases iron deposition in the kidney without improvement in kidney function

Shi, P. A., Choi, E., Chintagari, N. R., Nguyen, J., Guo, X., Yazdanbakhsh, K., Mohandas, N., Alayash, A. I., Manci, E. A., Belcher, J. D. & Vercellotti, G. M., Nov 1 2016, In : British Journal of Haematology. 175, 4, p. 714-723 10 p.

Research output: Contribution to journalArticle

Apoferritins
Haptoglobins
Sickle Cell Anemia
Iron
Kidney
2015
19 Citations (Scopus)
Proximal Kidney Tubule
Heme Oxygenase-1
Haptoglobins
Sickle Cell Anemia
Hemoglobins
8 Citations (Scopus)

Liver-targeted gene therapy: Approaches and challenges

Aravalli, R. N., Belcher, J. D. & Steer, C. J., Jun 1 2015, In : Liver Transplantation. 21, 6, p. 718-737 20 p.

Research output: Contribution to journalArticle

Genetic Therapy
Liver
Clustered Regularly Interspaced Short Palindromic Repeats
Genes
Integrases
13 Citations (Scopus)

The fucosylation inhibitor, 2-fluorofucose, inhibits vaso-occlusion, leukocyte-endothelium interactions and NF-κB activation in transgenic sickle mice

Belcher, J. D., Chen, C., Nguyen, J., Abdulla, F., Nguyen, P., Nguyen, M., Okeley, N. M., Benjamin, D. R., Senter, P. D. & Vercellotti, G. M., Feb 23 2015, In : PloS one. 10, 2, e0117772.

Research output: Contribution to journalArticle

sickle cell anemia
Sickle Cell Anemia
endothelium
Transgenic Mice
Endothelium
2014
Beauty
beta-Globins
transposons
erythrocytes
Erythrocytes
235 Citations (Scopus)

Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease

Belcher, J. D., Chen, C., Nguyen, J., Milbauer, L., Abdulla, F. R., Alayash, A. I., Smith, A., Nath, K. A., Hebbel, R. P. & Vercellotti, G. M., Jan 16 2014, In : Blood. 123, 3, p. 377-390 14 p.

Research output: Contribution to journalArticle

Endothelial cells
Sickle Cell Anemia
Heme
Endothelial Cells
Chemical activation
21 Citations (Scopus)

H-ferritin ferroxidase induces cytoprotective pathways and inhibits microvascular stasis in transgenic sickle mice

Vercellotti, G. M., Khan, F. B., Nguyen, J., Chen, C., Bruzzone, C. M., Bechtel, H., Brown, G., Nath, K. A., Steer, C. J., Hebbel, R. P. & Belcher, J. D., Jan 1 2014, In : Frontiers in Pharmacology. 5 APR, Article 79.

Research output: Contribution to journalArticle

Apoferritins
Ceruloplasmin
Sickle Cell Anemia
Transgenic Mice
Heme Oxygenase-1
12 Citations (Scopus)

Not simply misshapen red cells: Multimolecular and cellular events in sickle vaso-occlusion

Vercellotti, G. M. & Belcher, J. D., Apr 1 2014, In : Journal of Clinical Investigation. 124, 4, p. 1462-1465 4 p.

Research output: Contribution to journalComment/debate

Blood Platelets
Sickle Cell Anemia
Blood Proteins
Neutrophils
Endothelial Cells
2013
18 Citations (Scopus)

Age sensitizes the kidney to heme protein-induced acute kidney injury

Nath, K. A., Grande, J. P., Farrugia, G., Croatt, A. J., Belcher, J. D., Hebbel, R. P., Vercellotti, G. M. & Katusic, Z. S., Feb 8 2013, In : American Journal of Physiology - Renal Physiology. 304, 3

Research output: Contribution to journalArticle

Hemeproteins
Acute Kidney Injury
Kidney
Hemoglobins
Messenger RNA
118 Citations (Scopus)

Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth

Wegiel, B., Gallo, D., Csizmadia, E., Harris, C., Belcher, J., Vercellotti, G. M., Penacho, N., Seth, P., Sukhatme, V., Ahmed, A., Pandolfi, P. P., Helczynski, L., Bjartell, A., Persson, J. L. & Otterbein, L. E., Dec 1 2013, In : Cancer Research. 73, 23, p. 7009-7021 13 p.

Research output: Contribution to journalArticle

Carbon Monoxide
Heme Oxygenase-1
Growth
Neoplasms
Prostatic Neoplasms
282 Citations (Scopus)

Hemolysis and free hemoglobin revisited: Exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

Schaer, D. J., Buehler, P. W., Alayash, A. I., Belcher, J. D. & Vercellotti, G. M., Feb 21 2013, In : Blood. 121, 8, p. 1276-1284 9 p.

Research output: Contribution to journalReview article

Hemin
Hemolysis
Hemoglobins
Haptoglobins
Hemopexin
46 Citations (Scopus)

MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice

Belcher, J. D., Young, M., Chen, C., Nguyen, J., Burhop, K., Tran, P. & Vercellotti, G. M., Jan 1 2013, In : Blood. 122, 15, p. 2757-2764 8 p.

Research output: Contribution to journalArticle

Heme Oxygenase-1
Carbon Monoxide
Modulators
Transgenic Mice
Hemoglobins
11 Citations (Scopus)

β-globin sleeping beauty transposon reduces red blood cell sickling in a patient-derived CD34+-based in vitro model

Sjeklocha, L. M., Wong, P. Y. P., Belcher, J. D., Vercellotti, G. M. & Steer, C. J., Nov 18 2013, In : PloS one. 8, 11, e80403.

Research output: Contribution to journalArticle

Beauty
Gene therapy
Globins
transposons
Sickle Hemoglobin
2011
13 Citations (Scopus)

Erythroid-specific expression of β-globin from Sleeping Beauty-transduced human hematopoietic progenitor cells

Sjeklocha, L. M., Park, C. W., Wong, P. Y. P., Roney, M. J., Belcher, J. D., Kaufman, D. S., Vercellotti, G. M., Hebbel, R. P. & Steer, C. J., Dec 28 2011, In : PloS one. 6, 12, e29110.

Research output: Contribution to journalArticle

Beauty
Globins
Hematopoietic Stem Cells
transgenes
Transgenes
2010
19 Citations (Scopus)

Acadesine inhibits tissue factor induction and thrombus formation by activating the phosphoinositide 3-kinase/akt signaling pathway

Zhang, W., Wang, J., Wang, H., Tang, R., Belcher, J. D., Viollet, B., Geng, J. G., Zhang, C., Wu, C., Slungaard, A., Zhu, C. & Huo, Y., May 1 2010, In : Arteriosclerosis, thrombosis, and vascular biology. 30, 5, p. 1000-1006 7 p.

Research output: Contribution to journalArticle

1-Phosphatidylinositol 4-Kinase
Thromboplastin
Thrombosis
AMP-Activated Protein Kinases
Lipopolysaccharides
117 Citations (Scopus)

Heme degradation and vascular injury

Belcher, J. D., Beckman, J. D., Balla, G., Balla, J. & Vercellotti, G. M., Jan 15 2010, In : Antioxidants and Redox Signaling. 12, 2, p. 233-248 16 p.

Research output: Contribution to journalReview article

Vascular System Injuries
Heme
Degradation
Hemoglobins
Oxidants
59 Citations (Scopus)
Beauty
Heme Oxygenase-1
Sickle Cell Anemia
Blood Vessels
Genes
44 Citations (Scopus)

The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice

Hebbel, R. P., Vercellotti, G. M., Pace, B. S., Solovey, A., Kollander, R., Abanonu, C. F., Nguyen, J., Vineyard, J. V., Belcher, J. D., Abdulla, F., Osifuye, S., Eaton, J. W., Kelm, R. J. & Slungaard, A., Mar 25 2010, In : Blood. 115, 12, p. 2483-2490 8 p.

Research output: Contribution to journalArticle

trichostatin A
Histone Deacetylase Inhibitors
Transgenic Mice
Blood Vessels
Chemical activation
2009
40 Citations (Scopus)

Adjuvant approaches to enhance cryosurgery

Goel, R., Anderson, K., Slaton, J., Schmidlin, F., Vercellotti, G. M., Belcher, J. D. & Bischof, J. C., Jul 1 2009, In : Journal of Biomechanical Engineering. 131, 7, 740031.

Research output: Contribution to journalReview article

Cryosurgery
Freezing
Tissue
Blood Vessels
Vascular System Injuries
30 Citations (Scopus)

Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease

Beckman, J. D., Belcher, J. D., Vineyard, J. V., Chen, C., Nguyen, J., Nwaneri, M. O., O'Sullivan, G., Gulbahce, E., Hebbel, R. P. & Vercellotti, G. M., Oct 1 2009, In : American Journal of Physiology - Heart and Circulatory Physiology. 297, 4

Research output: Contribution to journalArticle

Leukocytosis
Sickle Cell Anemia
Carbon Monoxide
Anti-Inflammatory Agents
Blood Vessels
2008
3 Citations (Scopus)
Gene therapy
Heme Oxygenase-1
Polymerase chain reaction
Polymorphism
Transgenes
24 Citations (Scopus)

Tumor necrosis factor-α-induced accentuation in cryoinjury: Mechanisms in vitro and in vivo

Jiang, J., Goel, R., Iftekhar, M. A., Visaria, R., Belcher, J. D., Vercellotti, G. M. & Bischof, J. C., Oct 13 2008, In : Molecular Cancer Therapeutics. 7, 8, p. 2547-2555 9 p.

Research output: Contribution to journalArticle

Tumor Necrosis Factor-alpha
Neoplasms
Caspases
Cell Death
Apoptosis
2006
163 Citations (Scopus)

Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice

Belcher, J. D., Mahaseth, H., Welch, T. E., Otterbein, L. E., Hebbel, R. P. & Vercellotti, G. M., Mar 1 2006, In : Journal of Clinical Investigation. 116, 3, p. 808-816 9 p.

Research output: Contribution to journalArticle

Heme Oxygenase-1
Transgenic Mice
Inflammation
Heme Oxygenase (Decyclizing)
Vascular Cell Adhesion Molecule-1
15 Citations (Scopus)

Robust vascular protective effect of hydroxamic acid derivatives in a sickle mouse model of inflammation

Kaul, D. K., Kollander, R., Mahaseth, H., Liu, X. D., Solovey, A., Belcher, J. D., Kelm, R. J., Vercellotti, G. M. & Hebbel, R. P., Sep 1 2006, In : Microcirculation. 13, 6, p. 489-497 9 p.

Research output: Contribution to journalArticle

Hydroxamic Acids
Transgenic Mice
Blood Vessels
3,4-dihydroxybenzohydroxamic acid
Inflammation
2005
102 Citations (Scopus)

Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice

Belcher, J. D., Mahaseth, H., Welch, T. E., Vilback, A. E., Sonbol, K. M., Kalambur, V. S., Bowlin, P. R., Bischof, J. C., Hebbel, R. P. & Vercellotti, G. M., Jun 1 2005, In : American Journal of Physiology - Heart and Circulatory Physiology. 288, 6 57-6

Research output: Contribution to journalArticle

Dexamethasone
Transgenic Mice
Endothelial Cells
Vascular Cell Adhesion Molecule-1
Intercellular Adhesion Molecule-1
32 Citations (Scopus)

Polynitroxyl albumin inhibits inflammation and vasoocclusion in transgenic sickle mice

Mahaseth, H., Vercellotti, G. M., Welch, T. E., Bowlin, P. R., Sonbol, K. M., Hsia, C. J. C., Ma, L., Bischof, J. C., Hebbel, R. P. & Belcher, J. D., Apr 1 2005, In : Journal of Laboratory and Clinical Medicine. 145, 4, p. 204-211 8 p.

Research output: Contribution to journalArticle

Liver
Transgenic Mice
Chemical activation
Inflammation
Adhesion
2004
83 Citations (Scopus)
Transgenic Mice
Leukocytes
Anti-Inflammatory Agents
Oxidants
Sickle Cell Anemia
18 Citations (Scopus)

Endocytosis of Hepatic Lipase and Lipoprotein Lipase into Rat Liver Hepatocytes in Vivo Is Mediated by the Low Density Lipoprotein Receptor-related Protein

Vergés, M., Bensadoun, A., Herz, J., Belcher, J. D. & Havel, R. J., Mar 5 2004, In : Journal of Biological Chemistry. 279, 10, p. 9030-9036 7 p.

Research output: Contribution to journalArticle

LDL-Receptor Related Proteins
Lipoprotein Lipase
LDL Receptors
Lipases
Endocytosis
35 Citations (Scopus)

Human cytomegalovirus causes endothelial injury through the ataxia telangiectasia mutant and p53 DNA damage signaling pathways

Shen, Y. H., Utama, B., Wang, J., Raveendran, M., Senthil, D., Waldman, W. J., Belcher, J. D., Vercellotti, G., Martin, D., Mitchelle, B. M. & Wang, X. L., May 28 2004, In : Circulation research. 94, 10, p. 1310-1317 8 p.

Research output: Contribution to journalArticle

Ataxia Telangiectasia
Cytomegalovirus
DNA Damage
Wounds and Injuries
Apoptosis
51 Citations (Scopus)

Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

Kalambur, V. S., Mahaseth, H., Bischof, J. C., Kielbik, M. C., Welch, T. E., Vilbäck, Å., Swanlund, D. J., Hebbel, R. P., Belcher, J. D. & Vercellotti, G. M., Oct 1 2004, In : American Journal of Hematology. 77, 2, p. 117-125 9 p.

Research output: Contribution to journalArticle

Venules
Transgenic Mice
Skin
Blood Vessels
Leukocyte Rolling
2003
152 Citations (Scopus)

Transgenic sickle mice have vascular inflammation

Belcher, J. D., Bryant, C. J., Nguyen, J., Bowlin, P. R., Kielbik, M. C., Bischof, J. C., Hebbel, R. P. & Vercellotti, G. M., May 15 2003, In : Blood. 101, 10, p. 3953-3959 7 p.

Research output: Contribution to journalArticle

Transgenic Mice
Blood Vessels
Vascular Cell Adhesion Molecule-1
Endothelial cells
Cell Adhesion Molecules
2001
20 Citations (Scopus)

Cytomegalovirus inhibits p53 nuclear localization signal function

Wang, J., Belcher, J. D., Marker, P. H., Wilcken, D. E. L., Vercellotti, G. M. & Wang, X. L., Jan 1 2001, In : Journal of Molecular Medicine. 78, 11, p. 642-647 6 p.

Research output: Contribution to journalArticle

Nuclear Localization Signals
Pyruvate Kinase
Cytomegalovirus
Endothelial Cells
Atherosclerosis
2000
232 Citations (Scopus)

Activated monocytes in sickle cell disease: Potential role in the activation of vascular endothelium and vaso-occlusion

Belcher, J. D., Marker, P. H., Weber, J. P., Hebbel, R. P. & Vercellotti, G. M., Oct 1 2000, In : Blood. 96, 7, p. 2451-2459 9 p.

Research output: Contribution to journalArticle

Endothelial cells
Vascular Endothelium
Sickle Cell Anemia
Monocytes
Chemical activation
30 Citations (Scopus)
Auranofin
Gold Sodium Thiomalate
Gold
Neutrophils
Endothelial Cells
24 Citations (Scopus)

Human cytomegalovirus immediate early proteins upregulate endothelial p53 function

Wang, J., Marker, P. H., Belcher, J. D., Wilcken, D. E. L., Burns, L. J., Vercellotti, G. M. & Wang, X. L., Jun 2 2000, In : FEBS Letters. 474, 2-3, p. 213-216 4 p.

Research output: Contribution to journalArticle

Endothelial cells
Up-Regulation
Endothelial Cells
Plasmids
Apoptosis
157 Citations (Scopus)

Reperfusion injury pathophysiology in sickle transgenic mice

Osarogiagbon, U. R., Choong, S., Belcher, J. D., Vercellotti, G. M., Paller, M. S. & Hebbel, R. P., Jul 1 2000, In : Blood. 96, 1, p. 314-320 7 p.

Research output: Contribution to journalArticle

Ethane
Reperfusion Injury
Transgenic Mice
Tissue
Free Radicals