bims-oxygme Biomed News
on Oxygen metabolism
Issue of 2024–10–27
twenty-one papers selected by
Onurkan Karabulut, Berkeley City College
  1. Oxygen in the newborn pneriod: Could the oxygen reserve index offer a new perspective?
  2. Mitochondrial Stress as a Central Player in the Pathogenesis of Hypoxia-Related Myocardial Dysfunction: New Insights.
  3. Nitric Oxide-Dependent Regulation of Oxygen-Related Processes in a Rat Model of Lead Neurotoxicity: Influence of the Hypoxia Resistance Factor.
  4. Decreased mitochondrial-related gene expression in adipose tissue after acute sprint exercise in humans: A pilot study.
  5. Metabolic strategies in hypoxic plants.
  6. Advances in myocardial energy metabolism: metabolic remodeling in heart failure and beyond.
  7. Chronic hypoxia for the adaptation of extracellular vesicle phenotype.
  8. Hyperbaric oxygen rapidly produces intracellular bioenergetics dysfunction in human pulmonary cells.
  9. Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry.
  10. Neuroprotective Role of AQP4 Knockdown in Astrocytes After Oxygen-Glucose Deprivation.
  11. Supplemental Oxygen Alters the Pentose Phosphate Pathway in the Developing Mouse Brain Through SIRT Signaling.
  12. Potential mechanisms of metabolic reprogramming induced by ischemia-reperfusion injury in diabetic myocardium.
  13. A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.
  14. Mitochondrial Maintenance in Skeletal Muscle.
  15. Evidence for endogenous hydrogen peroxide production by E. coli fatty acyl-CoA dehydrogenase.
  16. Evidence for Cytotoxicity and Mitochondrial Dysfunction in Human Lung Cells Exposed to Biomass Burning Aerosol Constituents: Levoglucosan and 4-Nitrocatechol.
  17. Environmentally Persistent Free Radicals stimulate CYP2E1-mediated generation of reactive oxygen species at the expense of substrate metabolism.
  18. Pde3a and Pde3b regulation of murine pulmonary artery smooth muscle cell growth and metabolism.
  19. Progesterone increases metabolism via the pentose phosphate pathway in bovine uterine epithelial cells.
  20. Oxidative Processes and Xenobiotic Metabolism in Plants: Mechanisms of Defense and Potential Therapeutic Implications.
  21. L-gulono-γ-lactone Oxidase, the Key Enzyme for L-Ascorbic Acid Biosynthesis.
  1. Pediatr Pulmonol. 2024 Oct 22.
    Oxygen in the newborn pneriod: Could the oxygen reserve index offer a new perspective?
    Catarina Ferraz Liz, Elisa Proença.
      Oxygen therapy has been one of the main challenges in neonatal intensive care units (NICU). The guidelines currently in use try to balance the burden of hypoxia and hyperoxia such as retinopathy of prematurity, bronchopulmonary dysplasia, and death. The goal of this paper is to review neonatal oxygenation and the impact of hyperoxia and hypoxia in neonatal outcomes as well as review the available literature concerning the use of Oxygen Reserve Index (ORiTM) in clinical practice and its potential in Neonatology, particularly in NICU. Pulse oximetry has been used to monitor oxygenation in newborns with the advantage of being a noninvasive and continuous parameter, however it has limitations in detecting hyperoxemic states due to the flattening of the hemoglobin dissociation curve. The ORiTM is a new parameter that has been used to detect moderate hyperoxia and, when used in addiction to spO2, could be helpful in both hypoxia and hyperoxia. Studies using this tool are mainly in the adult population, during anesthetic procedures with only a small number of studies being performed in pediatric context. Oxygen targets remain a major problem for neonatal population and regardless of the efforts made to establish a safe oxygenation range, a more individualized approach seems to be the more appropriate pathway. ORiTM monitoring could help defining how much oxygen is too much for each newborn. Despite its promising potential, ORiTM is still a recent technology that requires more studies to determine its true potential in clinical practice.
    Keywords:  neonatology; oxygenation
    DOI:  https://doi.org/10.1002/ppul.27343
  2. Int J Med Sci. 2024 ;21(13): 2502-2509
    Mitochondrial Stress as a Central Player in the Pathogenesis of Hypoxia-Related Myocardial Dysfunction: New Insights.
    Zhijiang Guo, Yingjie Tian, Nanyang Liu, Ye Chen, Xiaohan Chen, Guoxing Yuan, An Chang, Xing Chang, Jie Wu, Hao Zhou.
      Hypoxic injury is a critical pathological factor in the development of various cardiovascular diseases, such as congenital heart disease, myocardial infarction, and heart failure. Mitochondrial quality control is essential for protecting cardiomyocytes from hypoxic damage. Under hypoxic conditions, disruptions in mitochondrial homeostasis result in excessive reactive oxygen species (ROS) production, imbalances in mitochondrial dynamics, and initiate pathological processes including oxidative stress, inflammatory responses, and apoptosis. Targeted interventions to enhance mitochondrial quality control, such as coenzyme Q10 and statins, have shown promise in mitigating hypoxia-induced mitochondrial dysfunction. These treatments offer potential therapeutic strategies for hypoxia-related cardiovascular diseases by regulating mitochondrial fission and fusion, restoring mitochondrial biogenesis, reducing ROS production, and promoting mitophagy.
    Keywords:  Hypoxia; Mitochondrial Homeostasis; Myocardial Injury
    DOI:  https://doi.org/10.7150/ijms.99359
  3. Cell Physiol Biochem. 2024 Oct 20. 58(5): 597-629
    Nitric Oxide-Dependent Regulation of Oxygen-Related Processes in a Rat Model of Lead Neurotoxicity: Influence of the Hypoxia Resistance Factor.
    Natalia Kurhaluk, Piotr Kamiński, Oleksandr Lukash, Halina Tkaczenko.
       BACKGROUND/AIMS: Lead exposure is known to induce oxidative stress and neurotoxicity. Nitric oxide (NO) plays an important role in modulating oxidative stress, with L-arginine as a precursor of NO and Nω-nitro-L-arginine (L-NNA) as an inhibitor of NO synthase, an enzyme that catalyses the production of nitric oxide (NO) from L-arginine.
    METHODS: This study investigated the differential effects of L-arginine and L-NNA on markers of oxidative stress and biochemical changes in brain tissue from rats with different levels of resistance to hypoxia exposed to lead nitrate. Rats with either low or high resistance to hypoxia were exposed to lead nitrate (oral 3.6 mg lead nitrate/kg b.w. per day for 30 days) and treated with L-arginine (600 mg/kg b.w., i.p., 30 min before and after exposure to lead nitrate) or L-NNA (35 mg/kg b.w., i.p., 30 min before and after exposure to lead nitrate). Brain tissue samples were analysed for lipid peroxidation, oxidative modification of proteins, and activity of antioxidant enzymes, including superoxide dismutase, catalase, glutathione reductase, and peroxidase, and total antioxidant status (TAS). We also examined the biomarkers of biochemical pathways involving the activity of alanine and aspartate aminotransferases, succinate dehydrogenase (SDH), and α-ketoglutarate dehydrogenase (KGDH). In addition, the trend observed was supported by assessments of the acetylcholine levels and acetylcholinesterase activity (ACh-AChE system) in brain tissue.
    RESULTS: In rats with low resistance to hypoxia, the L-arginine treatment significantly reduced lipid peroxidation and oxidative protein modification but increased antioxidant enzyme activity, suggesting a protective effect against lead-induced oxidative stress. Conversely, in rats with high resistance to hypoxia, L-NNA had a protective effect, reducing lead-induced oxidative damage and decreasing lipid peroxidation, whereas L-arginine exacerbated oxidative stress and impaired antioxidant defences. These findings were supported by corresponding changes in the acetylcholine-acetylcholinesterase system, reflecting the observed patterns of lead-induced oxidative stress and neurotoxicity. The study shows that L-arginine exerts a protective effect by reducing lead-induced oxidative damage via an improvement in TAS. Our study shows that lead nitrate exposure significantly increases ala-nine and aspartate aminotransferase activity in brain tissue, with L-arginine exacerbating and L-NNA reversing this effect. The lead nitrate exposure also affected the activities of SDH and KGDH, which are important for cellular energy production and hypoxia resistance, with L-arginine altering SDH activity depending on the level of resistance and L-NNA enhancing both SDH and KGDH activities. These trends were further validated by alterations in the ACh-AChE system, highlighting the differential role of NO-dependent mechanisms in modulating lead-induced neurotoxicity based on hypoxia resistance.
    CONCLUSION: These findings suggest potential targeted therapeutic strategies based on the oxidative stress profile and highlight the potential of nitric oxide system modulators in counteracting lead-induced biochemical alterations and the dynamics of the ACh-AChE system depending on the individual physiological reactivity of organisms.
    Keywords:  Individual physiological reactivity ; Acetylcholine-acetylcholinesterase ; Succinate dehydrogenase ; α-ketoglutarate dehydrogenase ; Oxidative modification of proteins
    DOI:  https://doi.org/10.33594/000000734
  4. Physiol Rep. 2024 Oct;12(20): e70088
    Decreased mitochondrial-related gene expression in adipose tissue after acute sprint exercise in humans: A pilot study.
    Mona Esbjörnsson, Håkan C Rundqvist, Barbara Norman, Ted Österlund, Eric Rullman, Jens Bülow, Eva Jansson.
      The aim was to examine the acute effects of sprint exercise (SIT) on global gene expression in subcutaneous adipose tissue (AT) in healthy subjects, to enhance understanding of how SIT influences body weight regulation. The hypothesis was that SIT upregulates genes involved in mitochondrial function and fat metabolism. A total of 15 subjects performed three 30-s all-out sprints (SIT). Samples were collected from AT, skeletal muscle (SM) and blood (brachial artery and a subcutaneous AT vein) up to 15 min after the last sprint. Results showed that markers of oxidative stress, such as the purines hypoxanthine, xanthine and uric acid, increased markedly by SIT in both the artery and the AT vein. Purines also increased in AT and SM tissue. Differential gene expression analysis indicated a decrease in signaling for mitochondrial-related pathways, including oxidative phosphorylation, electron transport, ATP synthesis, and heat production by uncoupling proteins, as well as mitochondrial fatty acid beta oxidation. This downregulation of genes related to oxidative metabolism suggests an early-stage inhibition of the mitochondria, potentially as a protective mechanism against SIT-induced oxidative stress.
    Keywords:  biopsy; high intensity; microarray analysis; skeletal muscle; sprint interval exercise; subcutaneous white adipose tissue; transcriptome
    DOI:  https://doi.org/10.14814/phy2.70088
  5. Plant Physiol. 2024 Oct 24. pii: kiae564. [Epub ahead of print]
    Metabolic strategies in hypoxic plants.
    Hans van Veen, Paolo Maria Triozzi, Elena Loreti.
      Complex multicellular organisms have evolved in an oxygen-enriched atmosphere. Oxygen is therefore essential for all aerobic organisms including plants, for energy production through cellular respiration. However, plants can experience hypoxia following extreme flooding events and also under aerated conditions in proliferative organs or tissues characterized by high oxygen consumption. When oxygen availability is compromised, plants adopt different strategies to cope with hypoxia and limited aeration. A common feature among different plant species is the activation of an anaerobic fermentative metabolism to provide adenosine triphosphate (ATP) to maintain cellular homeostasis under hypoxia. Fermentation also requires many sugar substrates, which is not always feasible, and alternative metabolic strategies are thus needed. Recent findings have also shown that the hypoxic metabolism is also active in specific organs or tissues of the plant under aerated conditions. Here, we describe the regulatory mechanisms that control the metabolic strategies of plants and how they enable them to thrive despite challenging conditions. A comprehensive mechanistic understanding of the genetic and physiological components underlying hypoxic metabolism should help to provide opportunities to improve plant resilience under the current climate change scenario.
    DOI:  https://doi.org/10.1093/plphys/kiae564
  6. Cardiovasc Res. 2024 Oct 25. pii: cvae231. [Epub ahead of print]
    Advances in myocardial energy metabolism: metabolic remodeling in heart failure and beyond.
    Qiuyu Sun, Qutuba G Karwi, Nathan Wong, Gary D Lopaschuk.
      The very high energy demand of the heart is primarily met by ATP production from mitochondrial oxidative phosphorylation, with glycolysis providing a smaller amount of ATP production. This ATP production is markedly altered in heart failure, primarily due to a decrease in mitochondrial oxidative metabolism. Although an increase in glycolytic ATP production partly compensates for the decrease in mitochondrial ATP production, the failing heart faces an energy deficit, that contributes to the severity of contractile dysfunction. The relative contribution of the different fuels for mitochondrial ATP production dramatically changes in the failing heart, which depends to a large extent on the type of heart failure. A common metabolic defect in all forms of heart failure (including HFrEF, HFpEF, and diabetic cardiomyopathies) is a decrease in mitochondrial oxidation of pyruvate originating from glucose (i.e. glucose oxidation). This decrease in glucose oxidation occurs regardless of whether glycolysis is increased, resulting in an uncoupling of glycolysis from glucose oxidation that can decrease cardiac efficiency. The mitochondrial oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in HFpEF and diabetic cardiomyopathies myocardial fatty acid oxidation increases, while in HFrEF myocardial fatty acid oxidation either decreases or remains unchanged. The oxidation of ketones (which provides the failing heart with an important energy source) also differs depending on the type of heart failure, being increased in HFrEF, and decreased in HFpEF and diabetic cardiomyopathies. The alterations in mitochondrial oxidative metabolism and glycolysis in the failing heart are due to transcriptional changes in key enzymes involved in the metabolic pathways, as well as alterations in redox state, metabolic signaling, and posttranslational epigenetic changes in energy metabolic enzymes. Of importance, targeting the mitochondrial energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac function and cardiac efficiency in the failing heart.
    Keywords:  HFpEF; HFrEF; fatty acid oxidation; glucose oxidation; ketone oxidation
    DOI:  https://doi.org/10.1093/cvr/cvae231
  7. Sci Rep. 2024 Oct 24. 14(1): 25189
    Chronic hypoxia for the adaptation of extracellular vesicle phenotype.
    Chris S Pridgeon, Kerttu Airavaara, Julia Monola, Alisa Jokela, Daniel Palmer, Marjo Yliperttula, Riina Harjumäki.
      Variations in oxygen level affect the phenotype of cells and extracellular vesicles (EVs). Depending on the metabolic oxygen demand of cells, hypoxic cell culture can produce conditions more like those found in vivo, and with appropriate oxygen levels, mimic hypoxic tumours. However, most previous experiments studying both EVs and the effects of hypoxia on cells use periods of 72 h or less of hypoxia. We hypothesised that this was insufficient time for adaptation to hypoxic conditions both for EVs and cells which may skew the results of such studies. In this study, the effects of acute (72 h) and chronic hypoxia (> 2 weeks) on the phenotype of HepG2 and PC3 cells and their EVs were examined. Cells could be cultured normally under chronic hypoxic conditions and cryopreserved and recovered. The effects of hypoxia on EV phenotype are slow to establish and dependent on cell line. In PC3 cells, the greatest change in phenotype and increase in EV production occurred only with chronic hypoxic culture. In HepG2 cells, the number of EVs produced was insensitive to hypoxic culture and the greatest changes in protein expression were observed after acute hypoxic culture. Nonetheless, biphasic changes in EV phenotype were detected in both cell types in response to either acute or chronic hypoxia. These results indicate that for cells which do not induce consumptive oxygen depletion, prolonged hypoxic culture is required for complete adaptation.
    DOI:  https://doi.org/10.1038/s41598-024-73453-1
  8. Chem Biol Interact. 2024 Oct 18. pii: S0009-2797(24)00412-5. [Epub ahead of print]404 111266
    Hyperbaric oxygen rapidly produces intracellular bioenergetics dysfunction in human pulmonary cells.
    Tanvir Hossain, Jackson T Secor, David M Eckmann.
      Hyperoxic exposure lasting days alters mitochondrial bioenergetic and dynamic functions in pulmonary cells as indices of oxygen toxicity. The aim of this study was to examine effects of short duration hyperbaric and hyperoxic exposures to induce oxygen toxicity similarly. Cultured human lung microvascular endothelial cells, human pulmonary artery endothelial cells and A549 cells were exposed to hyperoxia (∼5 % CO2 equivalent, balance O2) under hyperbaric conditions (4.8 ATA) for 1 and 4 h. Measures of mitochondrial dynamics, inner membrane potential, mitochondrial respiration, the intracellular distribution of bioenergetic capacity and respiration complex protein levels were then quantified. Exposures resulted in altered mitochondrial motility, presence of inhomogeneities in respiration parameters, loss of inner membrane potential, and changes in intracellular partitioning of ATP-linked respiration. Changes in the levels of respiration complex protein levels were also found. The combination of hyperoxic exposure with hyperbaric conditions rapidly produced changes in mitochondrial dynamics and bioenergetics in pulmonary cells. These changes are consistent with the onset of pulmonary oxygen toxicity previously known to result from long duration exposure to hyperoxia alone. These findings suggest health caution is warranted in environmental settings in which both hyperoxic and hyperbaric conditions are present. The synergism of hyperoxia and hyperbaria for rapid induction of oxygen toxicity in cellular models has utility for the study of mechanistic determinants of oxygen toxicity, testing of putative therapeutics, and associated investigations of mitochondrial dysfunction.
    Keywords:  Bioenergetics; Hyperbaric; Hyperoxia; Mitochondria; Motility; Respiration
    DOI:  https://doi.org/10.1016/j.cbi.2024.111266
  9. J Vis Exp. 2024 Oct 04.
    Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry.
    Terri A Pietka, Rita T Brookheart.
      Mitochondrial function, a cornerstone of cellular energy production, is critical for maintaining metabolic homeostasis. Its dysfunction in skeletal muscle is linked to prevalent metabolic disorders (e.g., diabetes and obesity), muscular dystrophies, and sarcopenia. While there are many techniques to evaluate mitochondrial content and morphology, the hallmark method to assess mitochondrial function is the measurement of mitochondrial oxidative phosphorylation (OXPHOS) by respirometry. Quantification of mitochondrial OXPHOS provides insight into the efficiency of mitochondrial oxidative energy production and cellular bioenergetics. A high-resolution respirometer provides highly sensitive, robust measurements of mitochondrial OXPHOS in permeabilized muscle fibers by measuring real-time changes in mitochondrial oxygen consumption rate. The use of permeabilized muscle fibers, as opposed to isolated mitochondria, preserves mitochondrial networks, maintains mitochondrial membrane integrity, and ultimately allows for more physiologically relevant measurements. This system also allows for the measurement of fuel preference and metabolic flexibility - dynamic aspects of muscle energy metabolism. Here, we provide a comprehensive guide for mitochondrial OXPHOS measurements in human and mouse skeletal muscle fibers using a high-resolution respirometer. Skeletal muscle groups are composed of different fiber types that vary in their mitochondrial fuel preference and bioenergetics. Using a high-resolution respirometer, we describe methods for evaluating both aerobic glycolytic and fatty acid substrates to assess fuel preference and metabolic flexibility in a fiber-type-dependent manner. The protocol is versatile and applicable to both human and rodent muscle fibers. The goal is to enhance the reproducibility and accuracy of mitochondrial function assessments, which will improve our understanding of an organelle important to muscle health.
    DOI:  https://doi.org/10.3791/66834
  10. Brain Behav. 2024 Oct;14(10): e70107
    Neuroprotective Role of AQP4 Knockdown in Astrocytes After Oxygen-Glucose Deprivation.
    Xin Xing, Shuyan Zhang.
       BACKGROUND: Aquaporin-4 (AQP4), predominantly expressed in astrocytes, has been implicated in the development of brain edema following ischemic events. However, its role in post-stroke neuroinflammation is not fully understood.
    METHODS: Using a middle cerebral artery occlusion (MCAO) mouse model, we assessed AQP4's role in post-stroke inflammation. Brain tissue slices from male C57BL/6 mice were subjected to immunohistochemistry and western blot post-MCAO. Additionally, primary astrocytes were isolated for quantitative real-time PCR and immunofluorescence assays to evaluate the expression of inflammatory markers glial fibrillary acidic protein (GFAP) and AQP4. AQP4 modulation was achieved using viral knockdown and overexpression methods. Neuronal damage was assessed using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) tests in co-culture studies.
    RESULTS: MCAO mice exhibited a significant upregulation in GFAP. This reactive astrogliosis corresponded with an elevation in inflammatory markers. AQP4 expression responded to this inflammatory trend, peaking at 6 h after OGD and returning to baseline levels at 24 and 48 h. Co-culture experiments revealed that AQP4(+) astrocytes exacerbated injury in OGD-treated neurons, as evidenced by increased TUNEL positivity and apoptotic events. Conversely, AQP4(-) astrocytes appeared to have a protective effect. Knockdown of AQP4 resulted in reduced post-OGD inflammatory response, whereas AQP4 overexpression intensified the injury to neurons post-OGD. In vivo experiments also confirmed that AQP4 inhibitor TGN-020 reduced and overexpression of AQP4 increased behavioral abnormalities and brain infarcts.
    CONCLUSION: Our findings underscore AQP4's pivotal role in modulating post-stroke neuroinflammation. Targeting AQP4 may present a novel therapeutic avenue for mitigating ischemia-induced neuronal damage.
    Keywords:  AQP4; MCAO; astrocytes; neuroinflammation
    DOI:  https://doi.org/10.1002/brb3.70107
  11. Neurochem Int. 2024 Oct 20. pii: S0197-0186(24)00213-4. [Epub ahead of print] 105886
    Supplemental Oxygen Alters the Pentose Phosphate Pathway in the Developing Mouse Brain Through SIRT Signaling.
    Defne Engur, Serap Cilaker Micili, Sila Soy, Gökcen Bilici, Kemal Ugur Tufekci, Cagla Kiser, İlkcan Ercan, Abdullah Kumral, Sermin Genc.
      Oxygen support plays a critical role in the management of preterm infants in neonatal intensive care units. On the other hand, the possible effects of oxygen supplementation on cellular functions, specifically glucose metabolism, have been less understood. PURPOSE: of the study is to investigate whether supplemental oxygen alters glucose metabolism and pentose phosphate pathway (PPP) activity in the brain tissue and its relevance with silent information regulator proteins (SIRT) pathway. For this purpose, newborn C57BL/6 pups were exposed to 90% oxygen from birth until postnatal day 7 (PN7) and metabolites of glysolysis and PPP were investigated through metabolomics analysis. SIRT1, glucose-6-phosphate dehydrogenase (G6PD) and transaldolase (TALDO) proteins were examined immunohistochemically and molecularly in the prefrontal and hippocampus regions of the brain. Later on, SIRT1 inhibition was carried out. Our results indicate that supplemental oxygen causes an increase in PPP metabolites as well as activation of G6PD enzyme in the brain tissue, which is reversed by SIRT1 inhibition. Our study underlines a connection between supplemental oxygen, glucose metabolism, PPP pathway and the SIRT signaling. Understanding these intricate relationships not only deepens our knowledge of cellular physiology but also holds promise for therapeutic interventions for creating neuroprotective strategies in preterm brain.
    Keywords:  Hyperoxia; Newborn; Oxygen; Pentose phosphate pathway; SIRT
    DOI:  https://doi.org/10.1016/j.neuint.2024.105886
  12. J Diabetes. 2024 Oct;16(10): e70018
    Potential mechanisms of metabolic reprogramming induced by ischemia-reperfusion injury in diabetic myocardium.
    Haping Ma, Jiyao Zhao, Yan Zheng, Junjie Wang, Yultuz Anwar, Yuxuan He, Jiang Wang.
       OBJECTIVE: This study aimed to explore metabolic reprogramming in diabetic myocardium subjected to ischemia-reperfusion injury (I/RI) and potential mechanisms.
    BACKGROUND: Increased vulnerability after I/RI in diabetic myocardium is a major cause of the high prevalence of perioperative adverse cardiac events, and the specific alterations in energy metabolism after I/RI in diabetic myocardium and the impact on increased vulnerability are not fully understood.
    METHODS: Metabolomic methods were used to explore the differences and characteristics of metabolites in the heart tissues of four groups, and then, single-cell RNA sequencing (ScRNA-seq) was used to explore the potential mechanism of metabolic reprogramming.
    RESULTS: It was found that the fatty acid metabolism of db/db mouse I/RI (DMI) showed a significant upward trend, especially the metabolites of ultra-long and medium-long-chain fatty acids; the metabolic flow analysis found that the U-13C glucose M + 6 was significantly higher in the C57BL mouse sham operation (NM) group than in the db/db mouse sham operation (DM) group, and in the C57BL mouse I/RI (NMI) than in the DMI group. Compared with the NMI group, the intermediate metabolites of glycolysis and tricarboxylic acid (TCA) cycle were significantly reduced in the DMI group; all comparisons were statistically significant (p < 0.05), indicating that the glucose uptake of diabetic myocardetis, the ability of glucose glycolysis after I/RI, and the contribution of glucose to TCA were significantly reduced. The results of ScRNA-seq revealed that the number of Cluster 0 myocardial isoforms was significantly increased in diabetic myocardium, and the differential genes were mainly enriched in fatty acid metabolism, and the PPARA signaling pathway was found to be over-activated and involved in the regulation of metabolic reprogramming of diabetic myocardial I/RI.
    CONCLUSION: Metabolic reprogramming of diabetic myocardial I/RI may be the main cause of increased myocardial vulnerability. The number of myocardial subtype Cluster 0 increased significantly, and PPARA PPARA is a ligand-activated receptor of the nuclear hormone receptor family that plays a central regulatory role in lipid metabolism. signaling pathway activation may be a potential mechanism for reprogramming metabolism in diabetic myocardium.
    Keywords:  diabetic myocardium; energy metabolism; ischemia–reperfusion injury; metabolic reprogramming; vulnerability
    DOI:  https://doi.org/10.1111/1753-0407.70018
  13. Int J Biol Sci. 2024 ;20(13): 5109-5126
    A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.
    Xuan Zhao, Tong Ren, Sijin Li, Xu Wang, Rui Hou, Zhangchun Guan, Dan Liu, Junnian Zheng, Ming Shi.
      Tumor-associated macrophages (TAMs) undergo metabolic reprogramming, encompassing glucose, amino acid, fatty acid metabolism, tricarboxylic acid (TCA) cycle, purine metabolism, and autophagy, within the tumor microenvironment (TME). The metabolic interdependencies between TAMs and tumor cells critically influence macrophage recruitment, differentiation, M2 polarization, and secretion of epithelial-mesenchymal transition (EMT)-related factors, thereby activating intratumoral EMT pathways and enhancing tumor cell invasion and metastasis. Tumor cell metabolic alterations, including hypoxia, metabolite secretion, aerobic metabolism, and autophagy, affect the TME's metabolic landscape, driving macrophage recruitment, differentiation, M2 polarization, and metabolic reprogramming, ultimately facilitating EMT, invasion, and metastasis. Additionally, macrophages can induce tumor cell EMT by reprogramming their aerobic glycolysis. Recent experimental and clinical studies have focused on the metabolic interactions between macrophages and tumor cells to control metastasis and inhibit tumor progression. This review highlights the regulatory role of TAM-tumor cell metabolic codependencies in EMT, offering valuable insights for TAM-targeted therapies in highly metastatic tumors. Modulating the metabolic interplay between tumors and TAMs represents a promising therapeutic strategy for treating patients with metastatic cancers.
    Keywords:  Epithelial-mesenchymal transition; Metabolism; Tumor cells; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.7150/ijbs.99680
  14. Cold Spring Harb Perspect Biol. 2024 Oct 21. pii: a041514. [Epub ahead of print]
    Mitochondrial Maintenance in Skeletal Muscle.
    Laura M de Smalen, Christoph Handschin.
      Skeletal muscle is one of the tissues with the highest range of variability in metabolic rate, which, to a large extent, is critically dependent on tightly controlled and fine-tuned mitochondrial activity. Besides energy production, other mitochondrial processes, including calcium buffering, generation of heat, redox and reactive oxygen species homeostasis, intermediate metabolism, substrate biosynthesis, and anaplerosis, are essential for proper muscle contractility and performance. It is thus not surprising that adequate mitochondrial function is ensured by a plethora of mechanisms, aimed at balancing mitochondrial biogenesis, proteostasis, dynamics, and degradation. The fine-tuning of such maintenance mechanisms ranges from proper folding or degradation of individual proteins to the elimination of whole organelles, and in extremis, apoptosis of cells. In this review, the present knowledge on these processes in the context of skeletal muscle biology is summarized. Moreover, existing gaps in knowledge are highlighted, alluding to potential future studies and therapeutic implications.
    DOI:  https://doi.org/10.1101/cshperspect.a041514
  15. PLoS One. 2024 ;19(10): e0309988
    Evidence for endogenous hydrogen peroxide production by E. coli fatty acyl-CoA dehydrogenase.
    Chaiyos Sirithanakorn, James A Imlay.
      Aerobic organisms continuously generate internal superoxide and hydrogen peroxide, which can damage enzymes and impair growth. To avoid this problem cells maintain high levels of superoxide dismutases, catalases, and peroxidases. Surprisingly, we do not know the primary sources of these reactive oxygen species (ROS) in living cells. However, in vitro studies have shown that flavoenzymes can inadvertently transfer electrons to oxygen. Therefore, it seems plausible that substantial ROS may be generated when large metabolic fluxes flow through flavoproteins. Such a situation may arise during the catabolism of fatty acids. Acyl-CoA dehydrogenase (FadE) is a flavoprotein involved in each turn of the beta-oxidation cycle. In the present study the catabolism of dodecanoic acid specifically impaired the growth of strains that lack enzymes to scavenge hydrogen peroxide. The defect was absent from fadE mutants. Direct measurements confirmed that the beta-oxidation pathway amplified the rate of intracellular hydrogen peroxide formation. Scavenging-proficient cells did not display the FadE-dependent growth defect. Those cells also did not induce the peroxide stress response during dodecanoate catabolism, indicating that the basal defenses are sufficient to cope with moderately elevated peroxide formation. In vitro work still is needed to test whether the ROS evolve specifically from the FadE flavin site and to determine whether superoxide as well as peroxide is released. At present such experiments are challenging because the natural redox partner of FadE has not been identified. This study supports the hypothesis that the degree of internal ROS production can depend upon the type of active metabolism inside cells.
    DOI:  https://doi.org/10.1371/journal.pone.0309988
  16. Environ Pollut. 2024 Oct 21. pii: S0269-7491(24)01890-6. [Epub ahead of print] 125173
    Evidence for Cytotoxicity and Mitochondrial Dysfunction in Human Lung Cells Exposed to Biomass Burning Aerosol Constituents: Levoglucosan and 4-Nitrocatechol.
    Faria Khan, Karina Kwapiszewska, Alicia M Romero, Krzysztof Rudzinski, Domingo Gil-Casanova, Jason D Surratt, Rafal Szmigielski.
      Biomass burning (BB) emissions are one of the largest sources of carbonaceous aerosol, posing a significant risk as an airway irritant. Important BB markers include wood pyrolysis emissions, such as levoglucosan (LG) that is an anhydrous sugar bearing a six-carbon ring structure (i.e., 1,6-anhydro-β-D-glucopyranose). Atmospheric chemical aging of BB-derived aerosol (BBA) in the presence of nitrogen oxides (NOx) can yield nitro-aromatic compounds, including 4-nitrocatechol (4NC). There is building evidence that NOx-mediated chemical aging of BBA poses a more serious exposure effect than primary pyrolysis emissions. This study provides a comparative toxicological assessment following the exposure to important BBA marker compounds in human lung cells (i.e., A549 and BEAS-2B) to determine whether aromatic 4NC is more toxic than BBA-bound anhydrous carbohydrate (i.e., LG). We determined inhibitory concentration-50 (IC50) and examined reactive oxygen species (ROS) changes, mitochondrial dysfunction, and apoptosis induction in the two cell lines following exposure to LG and 4NC in a dose-response manner. In the BEAS-2B cells, estimated IC50 values for 4NC were 33 and 8.8 μg mL-1, and for LG were 2546 and ∼ 3 × 107 μg mL-1 at 24 h and 48 h of exposure, respectively. A549 cells exhibited a much higher IC50 value than BEAS-2B cells. LG exposures resulted in mitochondrial stress with viability inhibition, but cells recovered with increasing exposure time. 4NC exposures at 200 μg mL-1 resulted in the induction of apoptosis at 6 h. Mitochondrial dysfunction and ROS imbalance induced the intrinsic apoptotic pathway induction following 4NC exposures. While increased ROS is caused by LG exposure in lung cells, 4NC is a marker of concern during BB emissions, as we observed apoptosis and high mitochondrial ROS in both lung cells at atmospherically-relevant aerosol concentrations. It may be associated with higher airway or inhalation pathologies in higher BBA emissions, such as wildfires or during wood combustion.
    Keywords:  Biomass burning aerosol; apoptosis; inhibitory concentration-50; nitroaromatics; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.envpol.2024.125173
  17. Drug Metab Dispos. 2024 Oct 21. pii: DMD-AR-2024-001939. [Epub ahead of print]
    Environmentally Persistent Free Radicals stimulate CYP2E1-mediated generation of reactive oxygen species at the expense of substrate metabolism.
    George F Cawley, J Patrick Connick, Marilyn K Eyer, Wayne L Backes.
      Environmentally persistent free radicals (EPFRs) are a recently recognized component of particulate matter that cause respiratory and cardiovascular toxicity. The mechanism of EPFR toxicity appears to be related to their ability to generate reactive oxygen species (ROS), causing oxidative damage. EPFRs were shown to affect P450 function, inducing the expression of some forms through the Ah receptor. However, another characteristic of EPFRs lies in their ability to inhibit P450 activities. CYP2E1 is one of the P450s that is inhibited by EPFR (MCP230) exposure. As CYP2E1 is also known to generate ROS, it is important to understand the ability of EPFRs to influence the function of this enzyme and to identify the mechanisms involved. CYP2E1 was shown to be inhibited by EPFRs, and to a lesser extent by non-EPFR particles. As EPFR-mediated inhibition was more robust at subsaturating NADPH-cytochrome P450 reductase (POR) concentrations, disruption of POR·CYP2E1 complex formation and electron transfer were examined. Surprisingly, neither complex formation nor electron transfer between POR and CYP2E1 were inhibited by EPFRs. Examination of ROS production showed that MCP230 generated a greater amount of ROS than the non-EPFR CuO-Si. When a POR/CYP2E1-containing reconstituted system was added to the pollutant-particle systems there was a synergistic stimulation of ROS production. The results indicate that EPFRs cause inhibition of CYP2E1-mediated substrate metabolism, yet do not alter electron transfer and actually stimulate ROS generation. Taken together, the results are consistent with EPFRs affecting CYP2E1 function by inhibiting substrate metabolism and increasing the generation of ROS. Significance Statement Environmentally persistent free radicals affect CYP2E1 function by inhibition of monooxygenase activity. This inhibition is not due to disruption of the POR·CYP2E1 complex or inhibition of electron transfer, but due to uncoupling of NADPH and oxygen consumption from substrate metabolism to the generation of ROS. These results show that EPFRs block the metabolism of foreign compounds, and also synergistically stimulate the formation of reactive oxygen species that lead to oxidative damage within the organism.
    Keywords:  CYP2E1; Cytochrome P450 (CYP); enzyme inhibitors; enzyme kinetics; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1124/dmd.124.001939
  18. Physiol Rep. 2024 Oct;12(20): e70089
    Pde3a and Pde3b regulation of murine pulmonary artery smooth muscle cell growth and metabolism.
    Paulina N Krause, Gabrielle McGeorge, Jennifer L McPeek, Sidra Khalid, Leif D Nelin, Yusen Liu, Bernadette Chen.
      A role for metabolically active adipose tissue in pulmonary hypertension (PH) pathogenesis is emerging. Alterations in cellular metabolism in metabolic syndrome are triggers of PH-related vascular dysfunction. Metabolic reprogramming in proliferative pulmonary vascular cells causes a metabolic switch from oxidative phosphorylation to glycolysis. PDE3A and PDE3B subtypes in the regulation of metabolism in pulmonary artery smooth muscle cells (PASMC) are poorly understood. We previously found that PDE3A modulates the cellular energy sensor, AMPK, in human PASMC. We demonstrate that global Pde3a knockout mice have right ventricular (RV) hypertrophy, elevated RV systolic pressures, and metabolic dysfunction with elevated serum free fatty acids (FFA). Therefore, we sought to delineate Pde3a/Pde3b regulation of metabolic pathways in PASMC. We found that PASMC Pde3a deficiency, and to a lesser extent Pde3b deficiency, downregulates AMPK, CREB and PPARγ, and upregulates pyruvate kinase dehydrogenase expression, suggesting decreased oxidative phosphorylation. Interestingly, siRNA Pde3a knockdown in adipocytes led to elevated FFA secretion. Furthermore, PASMC exposed to siPDE3A-transfected adipocyte media led to decreased α-SMA, AMPK and CREB phosphorylation, and greater viable cell numbers compared to controls under the same conditions. These data demonstrate that deficiencies of Pde3a and Pde3b alter pathways that affect cell growth and metabolism in PASMC.
    Keywords:  AMPK; CREB; PDK; PGC‐1α; PPARγ; metabolic; pulmonary hypertension; vascular remodeling
    DOI:  https://doi.org/10.14814/phy2.70089
  19. Mol Biol Rep. 2024 Oct 19. 51(1): 1076
    Progesterone increases metabolism via the pentose phosphate pathway in bovine uterine epithelial cells.
    Malia D Berg, Camila U Braz, Matthew Dean.
       BACKGROUND: During early pregnancy, glucose is essential for the uterine epithelium and the developing embryo. In cows, progesterone increases the secretion of glucose into the uterine lumen. The uterine epithelium can convert glucose to fructose, but other fates of glucose in the uterine epithelium have been sparsely investigated. Therefore, our objective was to investigate how progesterone influences glucose metabolism in immortalized bovine uterine epithelial (BUTE) cells.
    METHODS: BUTE cells were grown to 80% confluence and treated with vehicle (DMSO) or 10 µM progesterone for 24 h. Cells were collected and analyzed. Immunohistochemistry was performed on endometrial samples collected from the bovine endometrium on days 1 and 11 of the reproductive cycle.
    RESULTS: Progesterone treatment increased glucose consumption of BUTE cells. RNAseq identified 3,072 genes regulated by progesterone. KEGG analysis indicated that progesterone altered genes associated with metabolic pathways and glutathione metabolism. Manually examining genes unique to specific glucose metabolic pathways identified an increase in the rate-limiting enzyme in the pentose phosphate pathway-glucose-6-phosphate dehydrogenase. Functionally, a major product of the pentose phosphate pathway is NADPH, and progesterone treatment increased NADPH levels in BUTE cells. In cows, immunohistochemistry confirmed that glucose-6-phosphate dehydrogenase levels were higher in the uterine epithelium in the luteal phase when progesterone concentrations are high.
    CONCLUSIONS: Progesterone increased glucose-6-phosphate dehydrogenase expression and metabolism via the pentose phosphate pathway in the bovine uterine epithelium. This metabolism could provide substrates for cell proliferation, molecules to be secreted into the uterine lumen, or maintain reduction/oxidation balance in the uterine epithelium.
    Keywords:  Cow; Glucose-6-phosphate dehydrogenase; Progesterone; Uterus
    DOI:  https://doi.org/10.1007/s11033-024-10001-0
  20. J Xenobiot. 2024 Oct 18. 14(4): 1541-1569
    Oxidative Processes and Xenobiotic Metabolism in Plants: Mechanisms of Defense and Potential Therapeutic Implications.
    Caterina Vicidomini, Rosanna Palumbo, Maria Moccia, Giovanni N Roviello.
      Plants are continuously exposed to environmental challenges, including pollutants, pesticides, and heavy metals, collectively termed xenobiotics. These substances induce oxidative stress by generating reactive oxygen species (ROS), which can damage cellular components such as lipids, proteins, and nucleic acids. To counteract this, plants have evolved complex metabolic pathways to detoxify and process these harmful compounds. Oxidative stress in plants primarily arises from the overproduction of hydrogen peroxide (H2O2), superoxide anions (O2•-), singlet oxygen (1O2), and hydroxyl radicals (•OH), by-products of metabolic activities such as photosynthesis and respiration. The presence of xenobiotics leads to a notable increase in ROS, which can result in cellular damage and metabolic disruption. To combat this, plants have developed a strong antioxidant defense mechanism that includes enzymatic antioxidants that work together to eliminate ROS, thereby reducing their harmful effects. In addition to enzymatic defenses, plants also synthesize various non-enzymatic antioxidants, including flavonoids, phenolic acids, and vitamins. These compounds effectively neutralize ROS and help regenerate other antioxidants, offering extensive protection against oxidative stress. The metabolism of xenobiotic substances in plants occurs in three stages: the first involves modification, which refers to the chemical alteration of xenobiotics to make them less harmful. The second involves conjugation, where the modified xenobiotics are combined with other substances to increase their solubility, facilitating their elimination from the plant. The third stage involves compartmentalization, which is the storage or isolation of conjugated xenobiotics in specific parts of the plant, helping to prevent damage to vital cellular functions. Secondary metabolites found in plants, such as alkaloids, terpenoids, and flavonoids, play a vital role in detoxification and the defense against oxidative stress. Gaining a deeper understanding of the oxidative mechanisms and the pathways of xenobiotic metabolism in plants is essential, as this knowledge can lead to the formulation of plant-derived strategies aimed at alleviating the effects of environmental pollution and enhancing human health by improving detoxification and antioxidant capabilities, as discussed in this review.
    Keywords:  Solanum aethiopicum; bioactive compounds; drug metabolism; human health; metabolomics; plant metabolites; xenobiotic interactions
    DOI:  https://doi.org/10.3390/jox14040084
  21. Curr Issues Mol Biol. 2024 Oct 01. 46(10): 11057-11074
    L-gulono-γ-lactone Oxidase, the Key Enzyme for L-Ascorbic Acid Biosynthesis.
    Abdul Aziz M Gad, Agnieszka Sirko.
      L-ascorbic acid (AsA, vitamin C) plays a vital role in preventing various diseases, particularly scurvy. AsA is known for its antioxidant properties, which help protect against reactive oxygen species generated from metabolic activities; however, at high doses, it may exhibit pro-oxidative effects. The final step in AsA biosynthesis is catalyzed by L-gulono-γ-lactone oxidase (GULO). This enzyme is present in many organisms, but some animals, including humans, guinea pigs, bats, and other primates, are unable to synthesize AsA due to the absence of a functional GULO gene. The GULO enzyme belongs to the family of aldonolactone oxidoreductases (AlORs) and contains two conserved domains, an N-terminal FAD-binding region and a C-terminal HWXK motif capable of binding the flavin cofactor. In this review, we explore AsA production, the biosynthetic pathways of AsA, and the localization of GULO-like enzymes in both animal and plant cells. Additionally, we compare the amino acid sequences of AlORs across different species and summarize the findings related to their enzymatic activity. Interestingly, a recombinant C-terminal rat GULO (the cytoplasmic domain of the rat GULO expressed in Escherichia coli) demonstrated enzymatic activity. This suggests that the binding of the flavin cofactor to the HWXK motif at the C-terminus is sufficient for the formation of the enzyme's active site. Another enzyme, GULLO7 from Arabidopsis thaliana, also lacks the N-terminal FAD-binding domain and is strongly expressed in mature pollen, although its activity has not been specifically measured.
    Keywords:  C-terminal GULO; GULO characterization; HWXK motif; L-gulono-γ-lactone oxidase; ascorbic acid; vitamin C
    DOI:  https://doi.org/10.3390/cimb46100657
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