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Metabolism consisting of catabolic and anabolic processes encompasses the sum of all chemical conversions in a cell or organism. (a) Anabolism and (b) catabolism.
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Mature human erythrocytes are dependent on anerobic glycolysis, i.e. catabolism (oxidation) of one glucose molecule to produce two ATP and two lactate molecules. Proliferating tumor cells mimick mature human erythrocytes to glycolytically generate two ATP molecules. They deliberately avoid or switch off their respiration, i.e. tricarboxylic acid (T...
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Background: Ribulose 5-phosphate (Ru5P) and guanosine 5'-triphosphate (GTP) are two key precursors of riboflavin, whereby Ru5P is also a precursor of GTP (purine de novo synthesis pathway). As a product of the oxidative pentose phosphate pathway (OPPP), Ru5P can flow back into the Embden-Meyerhof-Parnas pathway (EMP) through the non-oxidative pento...
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... For cells that lack mitochondria, LDH activity represents an index for determining not just the membrane permeability but also as a sensor for energy homeostasis (Miranda et al.,2018). Red blood cells rely exclusively on glycolysis for ATP production, which is crucial for their metabolic processes and maintenance of membrane integrity, as well as providing energy for ATPases (Ghashghaeinia et al., 2019). Although the observed decrease in LDH activity in erythrocytes might suggest damage to these cells, Kose (2020) reported the binding of TiO2-NPs to LDH, which may reduce its activity. ...
The safety of titanium dioxide nanoparticles (TiO2-NPs) remains uncertain due to a scarcity of data regarding its absorption, distribution, elimination, and potential adverse effects following oral exposure. As emerging evidence suggests perturbations in energy metabolism play a pivotal role in the toxicity induced by various toxicants, this investigation aimed to assess the effect of TiO2-NPs on the activities of specific glycolytic enzymes in rats. In this study, seventy-two (72) male Wistar rats (200 ± 20g) were divided into 12 groups, each consisting of 6 animals. The rats were orally exposed to TiO2-NPs (8-12nm) at doses of 50, 150, and 250 mg/kg body weight (BW) for durations of 4, 8, and 12 weeks. The control groups received distilled water. The results showed that, except for the 150 mg/kg BW dose of 12 weeks, TiO2-NPs exposure led to an up-regulation in hexokinase activity in lymphocytes, plasma, erythrocytes, and the liver. Hepatic and lymphocyte aldolase activities were also up-regulated, except at 8 and 12 weeks for the 50 and 150 mg/kg BW doses, where slight decreases were observed. Plasma aldolase increased, except at 12 weeks for 150 mg/kg BW dose, while erythrocyte aldolase increased only during the 4 and 8-week exposure but decreased throughout the 12-week exposure. Notably, compared to erythrocyte lactate dehydrogenase activity, which decreased, a consistent pattern observed in lymphocytes, plasma, and hepatic enzymes was a down-regulation at 8 and 12 weeks for the 50 and 150 mg/kg BW doses of TiO2-NPs. In other instances, and time intervals, lactate dehydrogenase was up-regulated. The data from this study underscores that exposure to TiO2-NPs can disrupt the glycolytic pathway of energy metabolism, particularly during the initial 4 weeks of exposure. These perturbations are characterized by increased glycolytic enzymes activity in the lymphocytes, plasma, and the liver.
... uman red blood cells' (RBCs) that have reached maturity, including hemoglobin (Hb) and protected by a plasma membrane, generate energy through anaerobic glycolysis. 1) RBCs account for 84% of all human cells. They release large quantities of reduced glutathione (GSH) into the blood, contributing to the dynamic interorgan-GSH-metabolism, and they provide a cellular defense mechanism against oxidative stress by connecting the GSH cycle to the NADPH-producing pentose phosphate pathway (PPP). ...
... 5) Nitric oxide synthase (NOS) activation by protein kinase B is a fundamental physiological function of protein kinase B in RBCs, which regulates RBCs abnormalities. Human RBCs are involved in H2S turnover in a significant way, which is a point to be stressed (1) . ...
... Allosteric regulation of oxygen binding efficiency by adenosine triphosphate (ATP) and 2,3-BPG, a glycolytic intermediate unique to RBCs. A close relationship between the O2 binding capacity of Hb and the rate of glycolysis in the RBCs was found by studying the Rapoport-Luebering metabolic pathway, which occurs in mature RBCs and produces high concentrations of 2,3-BPG to facilitate liberation of oxygen from hemoglobin to the tissues through decreasing Hb-oxygen affinity (1) . Consequently, an increase in 2,3-BPG stabilizes the T-form of Hb and, by increasing the binding of 2,3-BPG, lowers the quantity of free 2,3-BPG and ATP, leading to a further acceleration of metabolism and having significant effects on glycolysis (1,2) ; whereas, H + and oxygen can modulate 2,3-BPG level without large variations in glycolytic flux (3) . ...
Early phases of coronavirus disease-2019 (COVID-19) are characterized by hypoxemic arteries that do not result in gasping, clinical deterioration may occur rapidly if hypoxemia is exacerbated by intra-pulmonary forcing, pulmonary vaso-compression fitness is not managed, and intravascular microthrombi are present with impaired lung diffusion. The goal of this hypothesis is to propose that COVID-19 may interfere with the glycolytic pathway by changing the amounts of intracellular metabolites, especially 2,3-bisphosphoglycerate (2,3-BPG), to aid in the release of oxygen from hemoglobin into the tissues, therefore preventing or treating hypoxia. As a conclusion, focusing on hypoxia as the primary cause of severe morbidity in COVID-19 patients is thought to result from an increased stability of the relax (R-form) of hemoglobin at the tissue level due to a decrease in glucose metabolite produced from glycolysis process in RBCs (decrease 2,3-BPG concentration in the blood). This theory proposes raising 2,3-BPG levels, which is to free up more O2 from the R-form of Hb in the tissues. Keywords COVID-19, glucose metabolism, hemoglobin-oxygen binding, 2,3-bisphosphoglycerate Citation AbdulKareem NGh, Mohammad FA. Interference of Coronavirus with glucose metabolism and its effect on affinity of hemoglobin binding to oxygen: A review. List of abbreviations: 2,3-BPG = 2,3-Bisphosphoglycerate, ACE2 = Angiotensin-converting enzyme II, ADP = Adenosine diphosphate, ARDs = Respiratory distress syndrome, ATP = Adenosine triphosphate, CDC = United State centers for disease control and prevention, COVID-19 = Coronavirus disease 2019, ETC = Electron transport chain, Fe 2+ = Ferrous iron, Fe 3+ = Ferric ions, GSH = Glutathione, Hb = hemoglobin, HbA = Adult hemoglobin, HbF = Fetal hemoglobin, HIF-2α = Hypoxia-inducible factor 2-alpha, NAD = Nicotinamide adenine dinucleotide, NADH = reduced form of NAD, NADP+ = Nicotinamide adenine dinucleotide phosphate, NADPH = reduced form of NADP, NFB = Nuclear factor kappa B, NFκB = Nuclear factor kappa B, NOS = Nitric oxide synthase, ODC = Oxygen dissociation curve, PDC = Pyruvate dehydrogenase complex, PHD2 = Prolyl hydroxylase domain 2, PPP = Pentose phosphate pathway, RBCs = Red blood cells, ROS = Reactive oxygen species, RNS = Reactive nitrogen species, R-BHB = (R)-beta-hydroxybutyrate, R-form = Relax-form, S1P = Sphingosine-1-phosphate, SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2, SpO2 = Oxygen saturation, Sphk1 = Sphingosine kinase 1, T-form = Tense form (deoxy-hemoglobin),
... 4,42,43,44 Both proliferating non-cancer cells and cancer cells need the synthesis of building blocks for cell growth which is facilitated by products of glycolysis, such as lactate, 4 and NADPH for biosynthetic reactions. 5,12,13,35,38,45 Fourth, normal quiescent differentiated cell types such as erythrocytes, 46 fibroblasts, 45 ECs, 20 and astrocytes in the central nervous system (CNS) 13,47-49 also use aerobic glycolysis for ATP and lactate synthesis. Excess lactate produced in ECs and astrocytes is exported to the extracellular matrix (ECM) and imported by PCs and neurons, respectively, to either convert it into pyruvate in the cytoplasm via LDHB that is then channeled into mitochondria or to be directly transferred into mitochondria via transporter proteins in their membranes for its use in OXPHOS. ...
Lactate and ATP formation by aerobic glycolysis, the Warburg effect, is considered a hallmark of cancer. During angiogenesis in non-cancerous tissue, proliferating stalk endothelial cells (ECs) also produce lactate and ATP by aerobic glycolysis. In fact, all proliferating cells, both non-cancer and cancer cells, need lactate for the biosynthesis of building blocks for cell growth and tissue expansion. Moreover, both non-proliferating cancer stem cells in tumors and leader tip ECs during angiogenesis rely on glycolysis for pyruvate production, which is used for ATP synthesis in mitochondria through oxidative phosphorylation (OXPHOS). Therefore, aerobic glycolysis is not a specific hallmark of cancer but rather a hallmark of proliferating cells and limits its utility in cancer therapy. However, local treatment of angiogenic eye conditions with inhibitors of glycolysis may be a safe therapeutic option that warrants experimental investigation. Most types of cells in the eye such as photoreceptors and pericytes use OXPHOS for ATP production, whereas proliferating angiogenic stalk ECs rely on glycolysis for lactate and ATP production. (J Histochem Cytochem XX.XXX–XXX, XXXX)
... This underscored that cancer cells experience metabolic changes. Consequently, they rely on the "Warburg" effect's ATP and metabolic intermediates to fuel biological macromolecule synthesis, promoting their survival, growth, and reproduction [29]. Signaling pathways altered in cancer often impact glucose metabolism through various mechanisms. ...
Head and neck cancer ranks as the sixth most prevalent malignancy, constituting 5 % of all cancer cases. Its inconspicuous onset often leads to advanced stage diagnoses, prompting the need for early detection to enhance patient prognosis. Currently, research into early diagnostic markers relies predominantly on genomics, proteomics, transcriptomics, and other methods, which, unfortunately, necessitate tumor tissue homogenization, resulting in the loss of temporal and spatial information. Emerging as a recent addition to the omics toolkit, spatial metabolomics stands out. This method conducts in situ mass spectrometry analyses on fresh tissue specimens while effectively preserving their spatiotemporal information. The utilization of spatial metabolomics in life science research offers distinct advantages. This article comprehensively reviews the progress of spatial metabolomics in head and neck cancer research, encompassing insights into cancer cell metabolic reprogramming. Various mass spectrometry imaging techniques, such as secondary ion mass spectrometry, stroma-assisted laser desorption/ionization, and desorption electrospray ionization, enable in situ metabolite analysis for head and neck cancer. Finally, significant emphasis is placed on the application of presently available techniques for early diagnosis, margin assessment, and prognosis of head and neck cancer.
... G6PD enzyme is in the hub of cellular metabolism (Yang et al., 2021) and products of this enzyme can be used in multiple anabolic pathways including the synthesis of nucleotides, lipogenesis, cellular growth, and oxidative stress (Salati and Amir-Ahmady, 2001). The substrate of the G6PD enzyme, glucose-6phosphate (G6P) can be used in glycolysis, PPP (Ulusu et al., 2003), glucuronic acid pathway, glucose production (Ghashghaeinia et al., 2019), hexosamine pathway (Lam et al., 2021), or in glycogen synthesis also connected with fatty acid metabolism (Adeva-Andany et al., 2016). G6PD is responsible for cellular regulation of all cellular metabolism in health and pathologic conditions (Parnell et al., 2023). ...
... Thus, the growing tumor cell proceeds to slow down the oxygen-dependent generation of ATP in the mitochondria and acquires a metabolism similar to that which has evolved in human erythrocytes, which lack mitochondria and other organelles. Such metabolic mechanisms allow tumor cells to maintain their proliferative autonomy, similar to mature erythrocytes [29]. ...
The tumor microenvironment is an important factor that can determine the success or failure of antitumor therapy. Cells of hematopoietic origin are one of the most important mediators of the tumor–host interaction and, depending on the cell type and functional state, exert pro- or antitumor effects in the tumor microenvironment or in adjacent tissues. Erythroid cells can be full members of the tumor microenvironment and exhibit immunoregulatory properties. Tumor growth is accompanied by the need to obtain growth factors and oxygen, which stimulates the appearance of the foci of extramedullary erythropoiesis. Tumor cells create conditions to maintain the long-term proliferation and viability of erythroid cells. In turn, tumor erythroid cells have a number of mechanisms to suppress the antitumor immune response. This review considers current data on the existence of erythroid cells in the tumor microenvironment, formation of angiogenic clusters, and creation of optimal conditions for tumor growth. Despite being the most important life-support function of the body, erythroid cells support tumor growth and do not work against it. The study of various signaling mechanisms linking tumor growth with the mobilization of erythroid cells and the phenotypic and functional differences between erythroid cells of different origin allows us to identify potential targets for immunotherapy.
... The mitochondrial dysfunction caused by NO may have lots of downstream effects, including the activation of protein kinase signaling with the modulation of sterol regulatory element-binding protein 1, acetyl-CoA carboxylase, medium-chain specific acyl-CoA dehydrogenase, and mitochondrial and peroxisome proliferator-activated receptor-γ coactivator 1α [50]. In several models, including certain types of tumors [51][52][53], healthy brain [54], and lungs with pulmonary hypertension [55], NO-driven metabolic reprogramming towards aerobic glycolysis, or the Warburg effect, showed protective effects. Remarkably, this metabolic reprogramming is quite similar to that observed in the immune system and in endothelium [56]. ...
The search for a clinically affordable substitute of human blood for transfusion is still an unmet need of modern society. More than 50 years of research on acellular hemoglobin (Hb)-based oxygen carriers (HBOC) have not yet produced a single formulation able to carry oxygen to hemorrhage-challenged tissues without compromising the body’s functions. Of the several bottlenecks encountered, the high reactivity of acellular Hb with circulating nitric oxide (NO) is particularly arduous to overcome because of the NO-scavenging effect, which causes life-threatening side effects as vasoconstriction, inflammation, coagulopathies, and redox imbalance. The purpose of this manuscript is not to add a review of candidate HBOC formulations but to focus on the biochemical and physiological events that underly NO scavenging by acellular Hb. To this purpose, we examine the differential chemistry of the reaction of NO with erythrocyte and acellular Hb, the NO signaling paths in physiological and HBOC-challenged situations, and the protein engineering tools that are predicted to modulate the NO-scavenging effect. A better understanding of two mechanisms linked to the NO reactivity of acellular Hb, the nitrosylated Hb and the nitrite reductase hypotheses, may become essential to focus HBOC research toward clinical targets.
... Osteosarcoma is a malignant tumor that arises from mesenchymal tissue and is characterized by the direct production of bone or osteoid tissue by rapidly proliferating tumor cells (Ghashghaeinia et al., 2019;Yang et al., 2023). It is the most common primary malignant bone tumor and exhibits a high degree of malignancy, rapid growth, and early metastasis. ...
In this investigation, we aimed to address the pressing challenge of treating osteosarcoma, a prevalent and difficult-to-treat form of cancer. To achieve this, we developed a quantitative structure-activity relationship (QSAR) model focused on a specific class of compounds called 2-Phenyl-3-(pyridin-2-yl) thiazolidin-4-one derivatives. A set of 39 compounds was thoroughly examined, with 31 compounds assigned to the training set and 8 compounds allocated to the test set randomly. The goal was to predict the IC 50 value of these compounds accurately. To optimize the compounds and construct predictive models, we employed a heuristic method of the CODESSA program. In addition to a linear model using four carefully selected descriptors, we also developed a nonlinear model using the gene expression programming method. The heuristic method resulted in correlation coefficients ( R ² ) of 0.603, 0.482, and 0.107 for R ² cv and S ² , respectively. On the other hand, the gene expression programming method achieved higher R ² and S ² values of 0.839 and 0.037 in the training set, and 0.760 and 0.157 in the test set, respectively. Both methods demonstrated excellent predictive performance, but the gene expression programming method exhibited greater consistency with experimental values. The successful nonlinear model generated through gene expression programming shows promising potential for designing targeted drugs to combat osteosarcoma effectively. This approach offers a valuable tool for optimizing compound selection and guiding future drug discovery efforts in the battle against osteosarcoma.
... The existence of two major metabolic pathways for glucose utilization, namely, glycolysis and pentose phosphate pathway enable human erythrocytes to produce ATP and the reducing agent NADPH. ATP is needed for de novo GSH biosynthesis [97][98][99][100][101] and NADPH for its regeneration [102][103][104] (see also Figure 7 and [105]). Of note, GSH biosynthesis is feedback inhibited by itself [106]. ...
... Mean values of annexin-V-binding erythrocytes (%) of the experiment shown in Figure 6. Linkage of GSH cycle to NADPH producing PPP and NADPH consuming glutathione reductase (GR) -under involvement of glutathione peroxidase -provides cellular defense mechanisms against oxidative stress [105]. γGCS: γ-glutamylcysteine synthetase; GSSG: oxidized form of glutathione. ...
Background: Desipramine a representative of tricyclic antidepressants (TCAs) promotes recovery of depressed patients by inhibition of reuptake of neurotransmitters serotonin (SER) and norepinephrine (NE) in the presynaptic membrane by directly blocking their respective transporters SERT and NET.
Aims: To study the effect of desipramine on programmed erythrocyte death (eryptosis) and explore the underlying mechanisms.
Methods: Phosphatidylserine (PS) exposure on the cell surface as marker of cell death was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry. Hemolysis was determined photometrically, and intracellular glutathione [GSH]i from high performance liquid chromatography.
Results: Desipramine dose-dependently significantly enhanced the percentage of annexin-V-binding cells and didn´t impact glutathione (GSH) synthesis. Desipramine-induced eryptosis was significantly reversed by pre-treatment of erythrocytes with either nitric oxide (NO) donor sodium nitroprusside (SNP) or N-acetyl-L-cysteine (NAC). The highest inhibitory effect was obtained by using both inhibitors together. Calcium (Ca²⁺) depletion aggravated desipramine-induced eryptosis. Changing the order of treatment, i.e. desipramine first followed by inhibitors, could not influence the inhibitory effect of SNP or NAC.
Conclusion: Antidepressants-caused intoxication can be treated by SNP and NAC, respectively. B) Patients with chronic hypocalcemia should not be treated with tricyclic anti-depressants or their dose should be noticeably reduced.
... Serine is a component of glutathione (GSH) and a carbon transfer unit in one-carbon metabolism, which affects redox maintenance and purine synthesis in cancer cells [23][24][25]. The increased mRNA of SHMT1 along with the corresponding peptide levels indicated that the cancer cells highly consumed serine to produce glycine in the one-carbon metabolism. ...
Doxorubicin, a member of the anthracycline family, is a widely prescribed anticancer chemotherapy drug. Unfortunately, cumulative doses of doxorubicin can cause mitochondrial dysfunction, leading to acute or chronic cardiotoxicity. This study demonstrated that Neopetroside-B (NPS-B) protects cardiomyocytes in the presence of doxorubicin. NPS-B improved mitochondrial function in cardiomyocytes by increasing ATP production and oxygen consumption rates. On the other hand, NPS-B negatively influenced cancer cell lines by increasing reactive oxygen species. We analyzed NPS-B-influenced metabolites (VIP > 1.0; AUC>0.7; p < 0.05) and proteins (FC > 2.0) and constructed metabolite-protein enrichment, which showed that NPS-B affected uracil metabolism and NAD-binding proteins (e.g., aldehyde dehydrogenase and glutathione reductase) in cardiomyocytes. However, for the cancer cells, NPS-B decreased the NAD+/NADH balance, impairing cell viability. In a xenograft mouse model treated with doxorubicin, NPS-B reduced cardiac fibrosis and improved cardiac function. NPS-B may be a beneficial intervention to reducing doxorubicin-induced cardiotoxicity with anticancer effects.
