A Metabolic Model of Human Erythrocytes: Practical Application of the E-Cell Simulation Environment

Yachie‐Kinoshita, Ayako; Nishino, Taiko; Shimo, Hanae; Suematsu, Makoto; Tomita, Masaru

doi:10.1155/2010/642420

Cited by 24 publications

(25 citation statements)

References 61 publications

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“…Alternatively, Yoshida and colleagues and Zolla and colleagues have independently proposed anaerobic storage of RBCs as a strategy to exploit the above‐mentioned oxygen‐dependent metabolic modulation phenomenon in RBCs to promote energy metabolism, while concomitantly removing a key contributor to pro‐oxidant reactions. Metabolomics studies have been performed to confirm that energy metabolism‐related variables are improved by anaerobic storage at the expense of the pentose phosphate pathway and general antioxidant potential, consistent with previous in vitro studies . More recently, we demonstrated a role for anaerobiosis versus anaerobiosis in presence of CO 2 in modulating metabolic responses upon deoxygenation (Fig.…”

Section: Descriptive Metabolomics In Design and Testing Of Transfusiosupporting

confidence: 88%

Metabolomics in transfusion medicine

et al. 2015

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Biochemical investigations on the regulatory mechanisms of red blood cell (RBC) and platelet (PLT) metabolism have fostered a century of advances in the field of transfusion medicine. Owing to these advances, storage of RBCs and PLT concentrates has become a lifesaving practice in clinical and military settings. There, however, remains room for improvement, especially with regard to the introduction of novel storage and/or rejuvenation solutions, alternative cell processing strategies (e.g., pathogen inactivation technologies), and quality testing (e.g., evaluation of novel containers with alternative plasticizers). Recent advancements in mass spectrometry–based metabolomics and systems biology, the bioinformatics integration of omics data, promise to speed up the design and testing of innovative storage strategies developed to improve the quality, safety, and effectiveness of blood products. Here we review the currently available metabolomics technologies and briefly describe the routine workflow for transfusion medicine–relevant studies. The goal is to provide transfusion medicine experts with adequate tools to navigate through the otherwise overwhelming amount of metabolomics data burgeoning in the field during the past few years. Descriptive metabolomics data have represented the first step omics researchers have taken into the field of transfusion medicine. However, to up the ante, clinical and omics experts will need to merge their expertise to investigate correlative and mechanistic relationships among metabolic variables and transfusion-relevant variables, such as 24-hour in vivo recovery for transfused RBCs. Integration with systems biology models will potentially allow for in silico prediction of metabolic phenotypes, thus streamlining the design and testing of alternative storage strategies and/or solutions.

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Section: Descriptive Metabolomics In Design and Testing Of Transfusiosupporting

confidence: 88%

Metabolomics in transfusion medicine

et al. 2015

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“…26–29 According to this model, 26–29 as much as 92% of glucose is catabolized through the classic Embden-Meyerhoff glycolytic pathway under normoxia, while anoxia triggers consumption of as much as 90% of glucose via the PPP. This model has been supported by in vitro evidence 30 and in silico prediction based on metabolomics data of ex vivo aging RBCs under anaerobic conditions 31,32 . However, evidence of in vivo RBC metabolic adaptations to hypoxia has not been hitherto produced.…”

Section: Introductionmentioning

confidence: 73%

AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia

et al. 2016

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Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia through the so-called oxygen-dependent metabolic regulation, which involves the competitive binding of deoxyhemoglobin and glycolytic enzymes to the N-terminal cytosolic domain of band 3. This mechanism promotes the accumulation of 2,3-DPG, stabilizing the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the Bohr effect. Despite in vitro studies, in vivo adaptations to hypoxia have not yet been completely elucidated. Within the framework of the AltitudeOmics study, erythrocytes were collected from 21 healthy volunteers at sea level, after exposure to high altitude (5260m) for 1, 7 and 16days, and following reascent after 7days at 1525m. UHPLC-MS metabolomics results were correlated to physiological and athletic performance parameters. Immediate metabolic adaptations were noted as early as a few hours from ascending to >5000m, and maintained for 16 days at high altitude. Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide and sulphur/H2S metabolism. Metabolic adaptations were preserved one week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory.

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“…19 Previous metabolomics studies on anaerobically stored RBCs showed limited or no effect of anaerobic storage on glutathione homeostasis, 6 as we confirmed in all arms of this study. At the same time, previous dynamic in silico simulations 20 and actual metabolomics assessment 6 of RBC responses to hypoxia had documented significant beneficial effects of anaerobic storage on energy metabolism. Previously, we observed that anaerobically stored RBC units consistently have significant improvements in ATP and DPG levels as well as an increased 24-hour recovery compared to the control stored under standard aerobic storage conditions.…”

Section: Discussionmentioning

confidence: 95%

CO₂‐dependent metabolic modulation in red blood cells stored under anaerobic conditions

et al. 2015

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Background Anaerobic RBC storage reduces oxidative damage, maintains ATP & 2,3-diphosphoglycerate (DPG) levels and has superior 24hr recovery at 6weeks compared to standard storage. This study will determine if removal of CO2 during O2 depletion by gas exchange may affect RBC during anaerobic storage. Methods This is a matched 3 arm study (n=14): control, O2&CO2 depleted with Ar (AN), O2 depleted with 95%Ar/5%CO2 (AN[CO2]). RBC in additives AS-3 or OFAS3 were evenly divided into 3 bags, and anaerobic conditions were established by gas exchange. Bags were stored 1-6°C in closed chambers under anaerobic conditions or ambient air, sampled weekly for up to 9weeks for a panel of in vitro tests. A full metabolomics screening was conducted for the first 4 weeks of storage. Results Purging with Ar (AN) results in alkalization of the RBC and increased glucose consumption. The addition of 5%CO2 to the purging gas prevented CO2 loss with an equivalent starting and final pH and lactate to control bags (p>0.5, days0-21). ATP levels are higher in AN[CO2] (p<0.0001). DPG was maintained beyond 2 weeks in the AN arm (p<0.0001). Surprisingly, DPG was lost at the same rate in both control and AN[CO2] arms (p=0.6). Conclusion Maintenance of ATP in the AN[CO2] arm demonstrates that ATP production is not solely a function of the pH effect on glycolysis. CO2 in anaerobic storage prevented the maintenance of DPG, and DPG production appears to be pH dependent. CO2 as well as O2 depletion provides metabolic advantage for stored RBC.

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A Metabolic Model of Human Erythrocytes: Practical Application of the E-Cell Simulation Environment

Cited by 24 publications

References 61 publications

Metabolomics in transfusion medicine

Metabolomics in transfusion medicine

AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia

CO₂‐dependent metabolic modulation in red blood cells stored under anaerobic conditions

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A Metabolic Model of Human Erythrocytes: Practical Application of the E-Cell Simulation Environment

Cited by 24 publications

References 61 publications

Metabolomics in transfusion medicine

Metabolomics in transfusion medicine

AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia

CO2‐dependent metabolic modulation in red blood cells stored under anaerobic conditions

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CO₂‐dependent metabolic modulation in red blood cells stored under anaerobic conditions