Comparative In Vivo Effects of Hemoglobin-Based Oxygen Carriers (HBOC) with Varying Prooxidant and Physiological Reactivity

Toma, Vlad-Alexandru; Fărcăş, Anca Daniela; Roman, I; Sevastre, Bogdan; Hathazi, Denisa; Scurtu, Florina; Damian, Grigore; Silaghi-Dumitrescu, Radu

doi:10.1371/journal.pone.0153909

Cited by 16 publications

(29 citation statements)

References 44 publications

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“…Hemoglobins from other sources than bovine (horse, goat, sheep) display longer lag times—with sheep Hb displaying the longest. From these points of view, copolymerization with albumin or replacement of bovine Hb with sheep Hb would appear to be reasonable choices when attempting to design a blood substitute with improved resistance to nitrosative stress [ 6 , 46 , 47 , 48 , 49 ].…”

Section: Resultsmentioning

confidence: 99%

The Reaction of Oxy Hemoglobin with Nitrite: Mechanism, Antioxidant-Modulated Effect, and Implications for Blood Substitute Evaluation

et al. 2018

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The autocatalytic reaction between nitrite and the oxy form of globins involves free radicals. For myoglobin (Mb), an initial binding of nitrite to the iron-coordinated oxygen molecule was proposed; the resulting ferrous-peroxynitrate species was not detected, but its decay product, the high-valent ferryl form, was demonstrated in stopped-flow experiments. Reported here are the stopped flow spectra recorded upon mixing oxy Hb (native, as well as chemically-derivatized in the form of several candidates of blood substitutes) with a supraphysiological concentration of nitrite. The data may be fitted to a simple kinetic model involving a transient met-aqua form, in contrast to the ferryl detected in the case of Mb in a similar reaction sequence. These data are in line with a previous observation of a transient accumulation of ferryl Hb under auto-catalytic conditions at much lower concentrations of nitrite (Grubina, R. et al. J. Biol. Chem. 2007, 282, 12916). The simple model for fitting the stopped-flow data leaves a small part of the absorbance changes unaccounted for, unless a fourth species is invoked displaying features similar to the oxy and tentatively assigned as ferrous-peroxynitrate. Density functional theory (DFT) calculations support this latter assignment. The reaction allows for differentiating between the reactivities of various chemically modified hemoglobins, including candidates for blood substitutes. Polymerization of hemoglobin slows the nitrite-induced oxidation, in sharp contrast to oxidative-stress type reactions which are generally accelerated, not inhibited. Sheep hemoglobin is found to be distinctly more resistant to reaction with nitrite compared to bovine Hb, at large nitrite concentrations (stopped-flow experiments directly observing the oxy + nitrite reaction) as well as under auto-catalytic conditions. Copolymerization of Hb with bovine serum albumin (BSA) using glutaraldehyde leads to a distinct increase of the lag time compared to native Hb as well as to any other form of derivatization examined in the present study. The Hb-BSA copolymer also displays a slower initial reaction with nitrite under stopped-flow conditions, compared to native Hb.

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Section: Resultsmentioning

confidence: 99%

The Reaction of Oxy Hemoglobin with Nitrite: Mechanism, Antioxidant-Modulated Effect, and Implications for Blood Substitute Evaluation

et al. 2018

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“…17 HHb is known as a two-way respiratory transport protein, carrying oxygen and carbon dioxide between the lungs and tissues. 18 In addition, HHb plays an exceptional role in not only a buffering action 18 for oxygen, but also acts as a potential agent in the transport of a number of drugs to their targeted tissues. 19,20 To further investigate the side effects of CNPs in the bloodstream, lymphocyte cell viability was explored to examine the effects of CNPs on the basic immunological functions of human lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Biophysical, docking, and cellular studies on the effects of cerium oxide nanoparticles on blood components: in vitro

Eskandari¹,

Babadaei²,

Nikpur³

et al. 2018

IJN

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IntroductionThe application of nanoparticles (NPs) in medicine and biology has received great interest due to their novel features. However, their adverse effects on the biological system are not well understood.Materials and methodsThis study aims to evaluate the effect of cerium oxide nanoparticles (CNPs) on conformational changes of human hemoglobin (HHb) and lymphocytes by different spectroscopic (intrinsic and synchronous fluorescence spectroscopy and far and near circular dichroism [CD] spectroscopy), docking and cellular (MTT and flow cytometry) investigations.Results and discussionTransmission electron microscopy (TEM) showed that CNP diameter is ~30 nm. The infrared spectrum demonstrated a strong band around 783 cm−1 corresponding to the CNP stretching bond. Fluorescence data revealed that the CNP is able to quench the intrinsic fluorescence of HHb through both dynamic and static quenching mechanisms. The binding constant (Kb), number of binding sites (n), and thermodynamic parameters over three different temperatures indicated that hydrophobic interactions might play a considerable role in the interaction of CNPs with HHb. Synchronous fluorescence spectroscopy indicated that microenvironmental changes around Trp and Tyr residues remain almost unchanged. CD studies displayed that the regular secondary structure of HHb had no significant changes; however, the quaternary structure of protein is subjected to marginal structural changes. Docking studies showed the larger CNP cluster is more oriented toward experimental data, compared with smaller counterparts. Cellular assays revealed that CNP, at high concentrations (>50 µg/mL), initiated an antiproliferative response through apoptosis induction on lymphocytes.ConclusionThe findings may exhibit that, although CNPs did not significantly perturb the native conformation of HHb, they can stimulate some cellular adverse effects at high concentrations that may limit the medicinal and biological application of CNPs. In other words, CNP application in biological systems should be done at low concentrations.

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“…Hemoglobin (Hb) is both an oxygen carrier and pro-oxidant that participates in complex redox processes during conditions of oxidative stress. As a blood substitute, Hb-based oxygen carriers (HBOCs) can exert both inflammatory and toxic effects from oxidative processes involving the reactive group [1][2][3][4], such as the formation of ferric ions (Fe 3þ ), ferryl ions (Fe 4þ ), ferryl heme radicals ( H-Fe 4þ ), ferryl protein radicals ( P-Fe 4þ ), hemichromes, protein radical-induced globin chain cross-links, free heme/iron and non-heme radical species [5][6][7]. Adverse microvascular effects of cell-free Hb have also hindered the development of safe and efficacious HBOCs.…”

Section: Introductionmentioning

confidence: 99%

Glutaraldehyde-polymerized hemoglobin and tempol (PolyHb-tempol) has superoxide dismutase activity that can attenuate oxidative stress on endothelial cells induced by superoxide anion

Feng

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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A Tempol compound with an amine group (4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, NH-Tempol) was cross-linked to hemoglobin in a one-step polymerization reaction to produce a novel hemoglobin-based oxygen carrier (HBOC) designated PolyHb-Tempol. The reaction parameters, including the reaction time, pH, temperature, and ratio of reactants, were optimized, and the physiochemical properties of the resulting product were characterized. PolyHb-Tempol didn't show any toxicity towards endothelial cells. Furthermore, from observations of cell morphology and viability, PolyHb-Tempol showed a significant ability to inhibit or eliminate oxidative stress induced by superoxide free radicals. These results suggest that PolyHb-Tempol may potentially be suitable as an HBOC.

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Comparative In Vivo Effects of Hemoglobin-Based Oxygen Carriers (HBOC) with Varying Prooxidant and Physiological Reactivity

Cited by 16 publications

References 44 publications

The Reaction of Oxy Hemoglobin with Nitrite: Mechanism, Antioxidant-Modulated Effect, and Implications for Blood Substitute Evaluation

The Reaction of Oxy Hemoglobin with Nitrite: Mechanism, Antioxidant-Modulated Effect, and Implications for Blood Substitute Evaluation

Biophysical, docking, and cellular studies on the effects of cerium oxide nanoparticles on blood components: in vitro

Glutaraldehyde-polymerized hemoglobin and tempol (PolyHb-tempol) has superoxide dismutase activity that can attenuate oxidative stress on endothelial cells induced by superoxide anion

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