Carbon Monoxide Signaling in Human Red Blood Cells: Evidence for Pentose Phosphate Pathway Activation and Protein Deglutathionylation

Metere, Alessio; Iorio, Egidio; Scorza, Giuseppe; Camerini, Serena; Casella, Marialuisa; Crescenzi, Marco; Minetti, Maurizio; Pietraforte, Donatella

doi:10.1089/ars.2012.5102

Cited by 28 publications

(22 citation statements)

References 60 publications

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“…Additional studies with HBI-002 are needed to examine potential mechanisms relating to these anti-inflammatory effects and improvement in hemolytic parameters. We speculate that CO may have pleotropic effects on cellular mitochondria [ 31 – 33 ] as well as Hb S polymerization [ 11 , 12 ] and RBC glutathione production [ 34 ].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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Carbon monoxide (CO) at low, non-toxic concentrations has been previously demonstrated to exert anti-inflammatory protection in murine models of sickle cell disease (SCD). However CO delivery by inhalation, CO-hemoglobin infusion or CO-releasing molecules presents problems for daily CO administration. Oral administration of a CO-saturated liquid avoids many of these issues and potentially provides a platform for self-administration to SCD patients. To test if orally-delivered CO could modulate SCD vaso-occlusion and inflammation, a liquid CO formulation (HBI-002) was administered by gavage (10 ml/kg) once-daily to NY1DD and Townes-SS transgenic mouse models of SCD. Baseline CO-hemoglobin (CO-Hb) levels were 1.6% and 1.8% in NY1DD and Townes-SS sickle mice and 0.6% in Townes-AS control mice. CO-Hb levels reached 5.4%, 4.7% and 3.0% within 5 minutes in NY1DD, SS and AS mice respectively after gavage with HBI-002. After ten treatments, each once-daily, hemoglobin levels rose from 5.3g/dL in vehicle-treated Townes-SS mice to 6.3g/dL in HBI-002-treated. Similarly, red blood cell (RBC) counts rose from 2.36 x 106/μL in vehicle-treated SS mice to 2.89 x 106/μL in HBI-002-treated mice. In concordance with these findings, hematocrits rose from 26.3% in vehicle-treated mice to 30.0% in HBI-002-treated mice. Reticulocyte counts were not significantly different between vehicle and HBI-002-treated SS mice implying less hemolysis and not an increase in RBC production. White blood cell counts decreased from 29.1 x 103/μL in vehicle-treated versus 20.3 x 103/μL in HBI-002-treated SS mice. Townes-SS mice treated with HBI-002 had markedly increased Nrf2 and HO-1 expression and decreased NF-κB activation compared to vehicle-treated mice. These anti-inflammatory effects were examined for the ability of HBI-002 (administered orally once-daily for up to 5 days) to inhibit vaso-occlusion induced by hypoxia-reoxygenation. In NY1DD and Townes-SS sickle mice, HBI-002 decreased microvascular stasis in a duration-dependent manner. Collectively, these findings support HBI-002 as a useful anti-inflammatory agent to treat SCD and warrants further development as a therapeutic.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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“…NADPH is a reducing agent required for the reduction of oxidized glutathione (GSSG) by supplying hydrogen to GSSG, thus ensuring high levels of reduced glutathione (GSH) which protects cells from the toxicity of reactive oxygen species (ROS) [53,54]. Therefore, the PPP is extremely important for red blood cells (RBCs) [55]. RBCs are rich in heme iron and oxygen making these cells susceptible to oxidative damage; however, this can be neutralized by the highly efficient GSH anti-oxidative system [56,57].…”

Section: Accepted Articlementioning

confidence: 99%

Beyond energy storage: roles of glycogen metabolism in health and disease

Zhang

Tang

et al. 2020

The FEBS Journal

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Beyond storing and supplying energy in the liver and muscles, glycogen also plays critical roles in cell differentiation, signaling, redox regulation and stemness under various physiological and pathophysiological conditions. Such versatile functions have been revealed by various forms of glycogen storage diseases. Here, we outline the source of carbon flux in glycogen metabolism and discuss how glycogen metabolism guides CD8 + T cell memory formation and maintenance. Likewise, we review how this affects macrophage polarization and inflammatory responses. Furthermore, we dissect how glycogen metabolism supports tumor development by promoting tumor-repopulating cell growth in hypoxic tumor microenvironments. This review highlights the essential role of the gluconeogenesis-glycogenesis-glycogenolysis-PPP metabolic chain in redox homeostasis, thus providing insights into potential therapeutic strategies against major chronic diseases including cancer.

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“…Rat erythrocytes treated with diamide, a thiol oxidizing agent, also presented Hb S-glutathionylation (Kosower et al, 1977). Besides Cys-93, Hb glutathionylation also occurs at Cys-112 in the β-chain (Metere et al, 2014). These authors found that CO treatment of whole blood increases the GSH concentration in red blood cells cytosol, a result of significant Hb deglutathionylation.…”

Section: Hemoglobin (Hb)mentioning

confidence: 93%

Regulation of protein function by S-nitrosation and S-glutathionylation: processes and targets in cardiovascular pathophysiology

Belcastro

Gaucher

Corti

et al. 2017

Biological Chemistry

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Decades of chemical, biochemical and pathophysiological research have established the relevance of post-translational protein modifications induced by processes related to oxidative stress, with critical reflections on cellular signal transduction pathways. A great deal of the so-called 'redox regulation' of cell function is in fact mediated through reactions promoted by reactive oxygen and nitrogen species on more or less specific aminoacid residues in proteins, at various levels within the cell machinery. Modifications involving cysteine residues have received most attention, due to the critical roles they play in determining the structure/function correlates in proteins. The peculiar reactivity of these residues results in two major classes of modifications, with incorporation of NO moieties (S-nitrosation, leading to formation of protein S-nitrosothiols) or binding of low molecular weight thiols (S-thionylation, i.e . in particular S-glutathionylation, S-cysteinylglycinylation and S-cysteinylation).A wide array of proteins have been thus analyzed in detail as far as their susceptibility to either modification or both, and the resulting functional changes have been described in a number of experimental settings. The present review aims to provide an update of available knowledge in the field, with a special focus on the respective (sometimes competing and antagonistic) roles played by protein S-nitrosations and S-thionylations in biochemical and cellular processes specifically pertaining to pathogenesis of cardiovascular diseases.

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Carbon Monoxide Signaling in Human Red Blood Cells: Evidence for Pentose Phosphate Pathway Activation and Protein Deglutathionylation

Cited by 28 publications

References 60 publications

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

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

Beyond energy storage: roles of glycogen metabolism in health and disease

Regulation of protein function by S-nitrosation and S-glutathionylation: processes and targets in cardiovascular pathophysiology

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