Evaluating the Capacity to Generate and Preserve Nitric Oxide Bioactivity in Highly Purified Earthworm Erythrocruorin

Roche, Camille J.; Talwar, Abhinav; Palmer, Andre F.; Cabrales, Pedro; Gerfen, Gary J.; Friedman, Joel M.

doi:10.1074/jbc.m114.583260

Cited by 13 publications

(19 citation statements)

References 70 publications

(119 reference statements)

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“…As oxygen binds to the available ferrous heme sites, the equilibrium shifts in a pH and allosteric effector-dependent degree to the R quaternary state conformation (relaxed, high ligand binding affinity). The rate of this NR reaction is sensitive to the redox potential of heme, which accounts for the quaternary structure dependence of the reaction and hence a rate dependence per heme that depends on the degree of heme oxygenation within tetrameric Hb (73,150,151,153), accounting for the quaternary structure dependence of the reaction and hence a rate dependence per heme that depends on the degree of oxygenation within tetrameric Hb (83). The hemes for the R state structure have, relative to the T state structure, a lower redox potential, which favors formation of the ferric heme product.…”

Section: Rbcs Nitric Oxide and Vascular Homeostasismentioning

confidence: 99%

“…This radical can either oxidize ferrous nitrosylheme to yield the ferric NO-heme derivative (Reaction 4a, Table 3) or react directly with the ferrous hemebound nitric oxide radical to produce N 2 O 3 ( Table 3, Reaction 4b) (78). Both ferric NOHb (via production of either NO + or N 2 O 3 ) (Table 3, Reactions 5b, 5c) (78,153,157) and N 2 O 3 generated from NOHb (Table 3, Reaction 4b) are potential Snitrosating agents that could generate SNOHb, GSNO, and CysSNO. These reactions, subsequent to the NR reaction, are still not fully tested and evaluated.…”

Section: Preserving Transporting and Delivering Hb-derived Nox Bioamentioning

confidence: 99%

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HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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Significance: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The b E -globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected. Critical Issues: While HbE by itself presents as a mild anemia and a single gene for b-thalassemia is not serious, it remains unexplained why HbE/b-thalassemia (HbE/b-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/b-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess a-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events. Future Directions: Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26,[794][795][796][797][798][799][800][801][802][803][804][805][806][807][808][809][810][811][812][813]

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Section: Rbcs Nitric Oxide and Vascular Homeostasismentioning

confidence: 99%

Section: Preserving Transporting and Delivering Hb-derived Nox Bioamentioning

confidence: 99%

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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“…[38, 39] The dependence of the nitrite reductase reaction on the quaternary structure of Hb is at least in part due to the difference in the redox potential of the two quaternary state conformations. [40, 41] The R-state conformation has a much lower redox potential, which favors oxidation of a ferrous heme to a ferric heme, as is the case of the nitrite reductase reaction. The intent of the nitrite reductase data presented in Fig 1B is to demonstrate the difference in nitrite reactions between the HbA, LtEc and PEG-LtEc, and to confirm that PEGylation of LtEc preserves the nitrite LtHb reaction, characteristics that can be attributed to the different heme populations of LtEc [42].…”

Section: Discussionmentioning

confidence: 99%

“…[40, 41] The R-state conformation has a much lower redox potential, which favors oxidation of a ferrous heme to a ferric heme, as is the case of the nitrite reductase reaction. The intent of the nitrite reductase data presented in Fig 1B is to demonstrate the difference in nitrite reactions between the HbA, LtEc and PEG-LtEc, and to confirm that PEGylation of LtEc preserves the nitrite LtHb reaction, characteristics that can be attributed to the different heme populations of LtEc [42]. The proposed basis for the absence of vasoactivity is a compensatory mechanism in the form of the nitrite reductase reaction that generates NO from nitrite.…”

Section: Discussionmentioning

confidence: 99%

Polyethylene Glycol Camouflaged Earthworm Hemoglobin

et al. 2017

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Nearly 21 million components of blood and whole blood and transfused annually in the United States, while on average only 13.6 million units of blood are donated. As the demand for Red Blood Cells (RBCs) continues to increase due to the aging population, this deficit will be more significant. Despite decades of research to develop hemoglobin (Hb) based oxygen (O2) carriers (HBOCs) as RBC substitutes, there are no products approved for clinical use. Lumbricus terrestris erythrocruorin (LtEc) is the large acellular O2 carrying protein complex found in the earthworm Lumbricus terrestris. LtEc is an extremely stable protein complex, resistant to autoxidation, and capable of transporting O2 to tissue when transfused into mammals. These characteristics render LtEc a promising candidate for the development of the next generation HBOCs. LtEc has a short half-life in circulation, limiting its application as a bridge over days, until blood became available. Conjugation with polyethylene glycol (PEG-LtEc) can extend LtEc circulation time. This study explores PEG-LtEc pharmacokinetics and pharmacodynamics. To study PEG-LtEc pharmacokinetics, hamsters instrumented with the dorsal window chamber were subjected to a 40% exchange transfusion with 10 g/dL PEG-LtEc or LtEc and followed for 48 hours. To study the vascular response of PEG-LtEc, hamsters instrumented with the dorsal window chamber received multiple infusions of 10 g/dL PEG-LtEc or LtEc solution to increase plasma LtEc concentration to 0.5, then 1.0, and 1.5 g/dL, while monitoring the animals’ systemic and microcirculatory parameters. Results confirm that PEGylation of LtEc increases its circulation time, extending the half-life to 70 hours, 4 times longer than that of unPEGylated LtEc. However, PEGylation increased the rate of LtEc oxidation in vivo. Vascular analysis verified that PEG-LtEc showed the absence of microvascular vasoconstriction or systemic hypertension. The molecular size of PEG-LtEc did not change the colloid osmotic pressure or blood volume expansion capacity compared to LtEc, due to LtEc’s already large molecular size. Taken together, these results further encourage the development of PEG-LtEc as an O2 carrying therapeutic.

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“…The large extracellular hemoglobin protein (erythrocruorin) from the earthworm (Lumbricus terrestris) has shown promise as a potential hemoglobin-based oxygen carrier (HBOC) in vivo studies. Another important factor is the ability for erythrocruorin to either generate or preserve NO bioactivity in response to decreased levels of NO in the blood [35] . The extract of red peony root (Radix Paeoniae Rubra) is also a component of BYHWD and acts an effective natural antioxidant [36][37] .…”

Section: Use Of Natural Antioxidants In the Prevention And Treatment mentioning

confidence: 99%

Free Radicals, the Natural Antioxidant Buyang Huanwu Decoction and Ischemic Stroke

Mao

2015

International Journal of Neurology Research

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INTRODUCTIONOxygen free radicals (OFR) are molecules containing one or more unpaired valence electrons, which makes it highly unstable, and result in the strong reaction and oxidation of DNA and lipids. OFR, including superoxide anion (O2 . -), hydroxyl radical ( . OH), nitric oxide (NO.) and hydrogen peroxide (H2O2) are related to many neurological diseases and brain dysfunction. However, the presence of OFR is also crucial for electron transfer in the mitochondrial respiratory chain, the immune response and cell differentiation and growth. For instance, the NO free radical plays a key role in the relaxation of blood vessels, blood pressure regulation and during learning and memorization. Nevertheless, excessive free radicals can initiate lipid peroxidation and result in protein oxidation and DNA damage in cells, and are often implicated in diseases with high mortality rates, including cardiovascular and cerebrovascular diseases, cancer and neurodegenerative diseases [1][2][3][4] . FREE RADICALS AND ISCHEMIC STROKEStroke can be divided into ischemic and hemorrhagic stroke, with ischemic stroke being far more prevalent. There are generally only two treatments for ischemic stroke: increasing blood flow in order to improve oxygen and glucose uptake in the arteries, or protecting neurons in order to reduce the likelihood of brain ischemia and neuronal excitotoxicity. Neuroprotectants commonly used in clinical treatment include calcium channel blockers, glutamate receptor antagonists and N-methyl-D-aspartic acid receptor (NMDA) antagonists. Research has shown that oxidative stress plays an important role in the pathophysiology of cerebral ischemia and that excessive ROS is produced during cerebral ischemia and ABSTRACTIschemic stroke is a widespread health issue worldwide, and a major cause of death and disability in an aging population. Research shows that reactive oxygen and free radicals generated by oxidative stress play an important role in cell apoptosis and often leads to stroke, one of the main causes of brain damage. Excessive free radicals also cause lipid peroxidation, leading to irreversible damage to cell membranes. The presence of free radical scavengers provides protection to brain tissues and can reduce the risk of stroke. Natural antioxidants have proved to be effective in the prevention and treatment of stroke, while also displaying fewer side effects. Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine prescription is commonly used for the prevention and treatment of ischemic cerebral stroke by inhibiting the formation of reactive oxygen species (ROS). Understanding the role of free radicals and the mechanisms by which natural antioxidants are used for the prevention and treatment of stroke can provide new insight into the research and clinical treatment of ischemic stroke. © 2015 ACT. All rights reserved. International Journal of Neurology Researchreperfusion [1] . Studies have also suggested that oxidative stress and damage caused by free radicals lead are key factors for triggerin...

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Evaluating the Capacity to Generate and Preserve Nitric Oxide Bioactivity in Highly Purified Earthworm Erythrocruorin

Cited by 13 publications

References 70 publications

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Polyethylene Glycol Camouflaged Earthworm Hemoglobin

Free Radicals, the Natural Antioxidant Buyang Huanwu Decoction and Ischemic Stroke

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