Inhibition of Glutathione Synthesis via Decreased Glucose Metabolism in Stored RBCs

Xiong, Yanlei; Wang, Yueming; Wang, Zhuoya; Zhang, Aiping; Zhao, Nannan; Yu, Zhenhai; Wang, Zhiqiang; Yi, Junzhu; Luan, Xiying

doi:10.1159/000495864

Cited by 19 publications

(11 citation statements)

References 35 publications

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“…The implication of oxidative stress in Cr(VI)‐induced oxidized DNA lesions and reduced GSH was addressed in this study. In accordance with the earlier studies, [ 56,77,78 ] our data indicate that a higher level of oxidative stress in Cr(VI)‐exposed hsp70 ‐KO and ‐KD strain leads to decreased GCLc level and GCL activity, which may further induce the inhibition of GSH de novo synthesis in the midgut cells of exposed Drosophila larvae. Furthermore, our results also suggest that under stress conditions, overexpression of hsp70 accounts for a reduced requirement of novel protein synthesis.…”

Section: Discussionsupporting

confidence: 92%

Cr(VI)‐induced DNA damage is lessened by the modulation of hsp70 via increased GSH de novo synthesis in Drosophila melanogaster

Chaouhan

Jha

Patel

et al. 2021

J Biochem & Molecular Tox

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Hexavalent chromium [Cr(VI)] is a genotoxic chemical, and in the chemical‐exposed organism, oxidative stress is one of the leading causative mechanisms of genotoxicity. Heat shock protein‐70 (Hsp70) is reported to be modulated in environmental chemical exposed organisms. Inadequate information on the protective role of Hsp70 in chemical‐induced DNA lesions prompted us to investigate this possibility in a well‐studied genetically tractable in vivo model Drosophila melanogaster. In the midgut cells of Cr(VI)‐exposed hsp70‐knockout (KO), ‐knockdown (KD), and ‐overexpression Drosophila strains, no significant change in double‐strand breaks generation was observed in comparison to similarly exposed w 1118 and the respective genetic control strain after 48 h. Therefore, the role of hsp70 was investigated on oxidative DNA damage induction in the exposed organisms after 24 h. Oxidized DNA lesions (particularly oxidized purine‐based lesions), 8‐oxo‐dG level, and oxidative stress endpoints were found to be significantly elevated in hsp70‐KO and ‐KD strains in comparison to similarly exposed w 1118 and respective genetic control strain. On the contrary, in ubiquitous hsp70‐overexpression strain exposed to Cr(VI), these endpoints were significantly lowered concurrently with increased GSH level through elevated gclc, and gclm expression, Gclc level, and GCL activity. The study suggests that as a consequence of hsp70 overexpression, the augmented GSH level in cells vis‐a‐vis GSH de novo synthesis can counteract Cr(VI)‐induced oxidized DNA lesions.

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Section: Discussionsupporting

confidence: 92%

Cr(VI)‐induced DNA damage is lessened by the modulation of hsp70 via increased GSH de novo synthesis in Drosophila melanogaster

Chaouhan

Jha

Patel

et al. 2021

J Biochem & Molecular Tox

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“…In prior studies, glutamine supplementation (either unlabeled or 13 C 15 N-glutamine) had been proposed as a strategy to boost glutathione synthesis by feeding glutamine-derived glutamate generation ( Whillier et al, 2011 ; D’alessandro et al, 2017b ). Both prior studies concluded on the lack of efficacy of this strategy, perhaps as a function of decreasing ATP in stored RBCs ( Xiong et al, 2018 ) since de novo glutathione synthesis is an ATP-dependent process. Indeed, hypoxic and hypocapnic storage of RBC was found to prevent ATP consumption in stored units, while fueling GSH synthesis ( Yoshida et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Metabolomics Platform for the Rapid Data-Driven Development of Novel Additive Solutions for Blood Storage

et al. 2022

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Red blood cell transfusion is a life-saving intervention, and storage is a logistic necessity to make ~110 million units available for transfusion every year worldwide. However, storage in the blood bank is associated with a progressive metabolic decline, which correlates with the accumulation of morphological lesions, increased intra- and extra-vascular hemolysis upon transfusion, and altered oxygen binding/off-loading kinetics. Prior to storage, red blood cells are suspended in nutrient formulations known as additive solutions to prolong cellular viability. Despite a thorough expansion of knowledge regarding red blood cell biology over the past few decades, only a single new additive solution has been approved by the Food and Drug Administration this century, owing in part to the limited capacity for development of novel formulations. As a proof of principle, we leveraged a novel high-throughput metabolomics technology as a platform for rapid data-driven development and screening of novel additive solutions for blood storage under both normoxic and hypoxic conditions. To this end, we obtained leukocyte-filtered red blood cells (RBCs) and stored them under normoxic or hypoxic conditions in 96 well plates (containing polyvinylchloride plasticized with diethylhexylphthalate to concentrations comparable to full size storage units) in the presence of an additive solution supplemented with six different compounds. To inform this data-driven strategy, we relied on previously identified metabolic markers of the RBC storage lesion that associates with measures of hemolysis and post-transfusion recovery, which are the FDA gold standards to predict stored blood quality, as well as and metabolic predictors of oxygen binding/off-loading parameters. Direct quantitation of these predictors of RBC storage quality were used here—along with detailed pathway analysis of central energy and redox metabolism—as a decision-making tool to screen novel additive formulations in a multiplexed fashion. Candidate supplements are shown here that boost-specific pathways. These metabolic effects are only in part dependent on the SO2 storage conditions. Through this platform, we anticipate testing thousands of novel additives and combinations thereof in the upcoming months.

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“…In the present study, administration of LC alone and in combination with ART increased erythrocyte GSH levels in mice. Although there is no protein synthesis in erythrocytes, GSH is made from the amino acids glutamate, cysteine, and glycine (Morris et al, 2014; Xiong et al, 2016, 2018). LC induces the expression and activity of enzymes involved in GSH synthesis and thereby increases GSH levels (Q. Wang et al, 2016, 2017; Figure 5).…”

Section: Discussionmentioning

confidence: 99%

Artemisinin and l‐carnitine combination therapy alters the erythrocytes redox status

Basaki

Hashemvand

Tayefi‐Nasrabadi

et al. 2022

Cell Biology International

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Hematopoiesis is a sensitive target of artemisinin (ART) and its derivatives, and hemolysis is one of their commonly reported side effects. L-carnitine (LC), an amino acid derivative involved in lipid metabolism, is beneficial for hematological parameters. Sixty adult laboratory mice were randomly divided into six groups.Group I (control) received saline and corn oil; groups II and III received therapeutic (50 mg/kg) and toxic (250 mg/kg) doses of ART, respectively; groups IV and V received 370 mg/kg LC along with the 50 and 250 mg/kg ART, respectively; and group VI received 370 mg/kg LC. Drugs were administered orally for 7 consecutive days. The erythrocyte glucose 6-phosphate dehydrogenase (G6PD), catalase (CAT), and peroxidase (POX) activity, and the reduced glutathione (GSH) level were assessed by colorimetric methods. ART reduced the G6PD activity both at therapeutic and toxic doses. The therapeutic dose of ART reduced the CAT activity and the GSH level, nonsignificantly. The toxic dose of ART reduced the CAT activity and increased the POX activity. LC reduced the G6PD, CAT, and POX activities and increased GSH level. The therapeutic dose of ART and LC showed synergy in reducing the G6PD activity. LC and ART combination reduced POX activity and increased GSH level without any significant effect on the CAT activity. Inhibition of G6PD may be a potentially new mechanism of ART action. Coadministration of LC with ART or following treatment with ART may have protective effects on erythrocytes.

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Inhibition of Glutathione Synthesis via Decreased Glucose Metabolism in Stored RBCs

Cited by 19 publications

References 35 publications

Cr(VI)‐induced DNA damage is lessened by the modulation of hsp70 via increased GSH de novo synthesis in Drosophila melanogaster

Cr(VI)‐induced DNA damage is lessened by the modulation of hsp70 via increased GSH de novo synthesis in Drosophila melanogaster

High-Throughput Metabolomics Platform for the Rapid Data-Driven Development of Novel Additive Solutions for Blood Storage

Artemisinin and l‐carnitine combination therapy alters the erythrocytes redox status

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