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Journal of Bone Oncology Feb 2024Metabolic reprogramming is an adaptive response of tumour cells under hypoxia and low nutrition conditions. There is increasing evidence that glucose metabolism... (Review)
Review
Metabolic reprogramming is an adaptive response of tumour cells under hypoxia and low nutrition conditions. There is increasing evidence that glucose metabolism reprogramming can regulate the growth and metastasis of osteosarcoma (OS). Reprogramming in the progress of OS can bring opportunities for early diagnosis and treatment of OS. Previous research mainly focused on the glycolytic pathway of glucose metabolism, often neglecting the tricarboxylic acid cycle and pentose phosphate pathway. However, the tricarboxylic acid cycle and pentose phosphate pathway of glucose metabolism are also involved in the progression of OS and are closely related to this disease. The research on glucose metabolism in OS has not yet been summarized. In this review, we discuss the abnormal expression of key molecules related to glucose metabolism in OS and summarize the glucose metabolism related signaling pathways involved in the occurrence and development of OS. In addition, we discuss some of the targeted drugs that regulate glucose metabolism pathways, which can lead to effective strategies for targeted treatment of OS.
PubMed: 38288377
DOI: 10.1016/j.jbo.2024.100521 -
ELife Nov 2023Compelling evidence has accumulated on the role of oxidative stress on the endothelial cell (EC) dysfunction in acute coronary syndrome. Unveiling the underlying...
Compelling evidence has accumulated on the role of oxidative stress on the endothelial cell (EC) dysfunction in acute coronary syndrome. Unveiling the underlying metabolic determinants has been hampered by the scarcity of appropriate cell models to address cell-autonomous mechanisms of EC dysfunction. We have generated endothelial cells derived from thrombectomy specimens from patients affected with acute myocardial infarction (AMI) and conducted phenotypical and metabolic characterizations. AMI-derived endothelial cells (AMIECs) display impaired growth, migration, and tubulogenesis. Metabolically, AMIECs displayed augmented ROS and glutathione intracellular content, with a diminished glucose consumption coupled to high lactate production. In AMIECs, while PFKFB3 protein levels of were downregulated, PFKFB4 levels were upregulated, suggesting a shunting of glycolysis towards the pentose phosphate pathway, supported by upregulation of G6PD. Furthermore, the glutaminolytic enzyme GLS was upregulated in AMIECs, providing an explanation for the increase in glutathione content. Finally, AMIECs displayed a significantly higher mitochondrial membrane potential than control ECs, which, together with high ROS levels, suggests a coupled mitochondrial activity. We suggest that high mitochondrial proton coupling underlies the high production of ROS, balanced by PPP- and glutaminolysis-driven synthesis of glutathione, as a primary, cell-autonomous abnormality driving EC dysfunction in AMI.
Topics: Humans; Reactive Oxygen Species; Endothelial Cells; Metabolic Reprogramming; Oxidative Stress; Glycolysis; Glutathione; Myocardial Infarction; Phosphofructokinase-2
PubMed: 38014932
DOI: 10.7554/eLife.86260 -
PLoS Pathogens Jul 2023Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In Staphylococcus aureus the role of...
Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In Staphylococcus aureus the role of the pentose phosphate pathway (PPP) remains largely unexplored. Mutation of the 6-phosphogluconolactonase gene pgl, which encodes the only non-essential enzyme in the oxidative phase of the PPP, significantly increased MRSA resistance to β-lactam antibiotics, particularly in chemically defined media with physiologically-relevant concentrations of glucose, and reduced oxacillin (OX)-induced lysis. Expression of the methicillin-resistance penicillin binding protein 2a and peptidoglycan architecture were unaffected. Carbon tracing and metabolomics revealed extensive metabolic reprogramming in the pgl mutant including increased flux to glycolysis, the TCA cycle, and several cell envelope precursors, which was consistent with increased β-lactam resistance. Morphologically, pgl mutant cells were smaller than wild-type with a thicker cell wall and ruffled surface when grown in OX. The pgl mutation reduced resistance to Congo Red, sulfamethoxazole and oxidative stress, and increased resistance to targocil, fosfomycin and vancomycin. Levels of lipoteichoic acids (LTAs) were significantly reduced in pgl, which may limit cell lysis, while the surface charge of pgl cells was significantly more positive. A vraG mutation in pgl reversed the increased OX resistance phenotype, and partially restored wild-type surface charge, but not LTA levels. Mutations in vraF or graRS from the VraFG/GraRS complex that regulates DltABCD-mediated d-alanylation of teichoic acids (which in turn controls β-lactam resistance and surface charge), also restored wild-type OX susceptibility. Collectively these data show that reduced levels of LTAs and OX-induced lysis combined with a VraFG/GraRS-dependent increase in cell surface positive charge are accompanied by significantly increased OX resistance in an MRSA pgl mutant.
Topics: Methicillin-Resistant Staphylococcus aureus; Pentose Phosphate Pathway; Anti-Bacterial Agents; Oxacillin; Cell Wall; Monobactams; beta-Lactam Resistance; Bacterial Proteins; Microbial Sensitivity Tests
PubMed: 37486930
DOI: 10.1371/journal.ppat.1011536 -
Bioengineering (Basel, Switzerland) Nov 2023Microbial cell factories offer an eco-friendly alternative for transforming raw materials into commercially valuable products because of their reduced carbon impact... (Review)
Review
Microbial cell factories offer an eco-friendly alternative for transforming raw materials into commercially valuable products because of their reduced carbon impact compared to conventional industrial procedures. These systems often depend on lignocellulosic feedstocks, mainly pentose and hexose sugars. One major hurdle when utilizing these sugars, especially glucose, is balancing carbon allocation to satisfy energy, cofactor, and other essential component needs for cellular proliferation while maintaining a robust yield. Nearly half or more of this carbon is inevitably lost as CO during the biosynthesis of regular metabolic necessities. This loss lowers the production yield and compromises the benefit of reducing greenhouse gas emissions-a fundamental advantage of biomanufacturing. This review paper posits the perspectives of using CO from the atmosphere, industrial wastes, or the exhausted gases generated in microbial fermentation as a feedstock for biomanufacturing. Achieving the carbon-neutral or -negative goals is addressed under two main strategies. The one-step strategy uses novel metabolic pathway design and engineering approaches to directly fix the CO toward the synthesis of the desired products. Due to the limitation of the yield and efficiency in one-step fixation, the two-step strategy aims to integrate firstly the electrochemical conversion of the exhausted CO into C/C products such as formate, methanol, acetate, and ethanol, and a second fermentation process to utilize the CO-derived C/C chemicals or co-utilize C/C sugars and C/C chemicals for product formation. The potential and challenges of using CO as a feedstock for future biomanufacturing of fuels and chemicals are also discussed.
PubMed: 38135948
DOI: 10.3390/bioengineering10121357 -
Frontiers in Microbiology 2023Metabolic fluxes are at the heart of metabolism and growth in any living system. During tuberculosis (TB) infection, the pathogenic (Mtb) adapts its nutritional...
Metabolic fluxes are at the heart of metabolism and growth in any living system. During tuberculosis (TB) infection, the pathogenic (Mtb) adapts its nutritional behaviour and metabolic fluxes to survive in human macrophages and cause infection. The infected host cells also undergo metabolic changes. However, our knowledge of the infected host metabolism and identification of the reprogrammed metabolic flux nodes remains limited. In this study, we applied systems-based C-metabolic flux analysis (MFA) to measure intracellular carbon metabolic fluxes in Mtb-infected human THP-1 macrophages. We provide a flux map for infected macrophages that quantified significantly increased fluxes through glycolytic fluxes towards pyruvate synthesis and reduced pentose phosphate pathway fluxes when compared to uninfected macrophages. The tri carboxylic acid (TCA) cycle fluxes were relatively low, and amino acid fluxes were reprogrammed upon Mtb infection. The knowledge of host metabolic flux profiles derived from our work expands on how the host cell adapts its carbon metabolism in response to Mtb infection and highlights important nodes that may provide targets for developing new therapeutics to improve TB treatment.
PubMed: 38045029
DOI: 10.3389/fmicb.2023.1289987 -
Frontiers in Immunology 2023In recent years, the central role of cell bioenergetics in regulating immune cell function and fate has been recognized, giving rise to the interest in immunometabolism,...
In recent years, the central role of cell bioenergetics in regulating immune cell function and fate has been recognized, giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Thus, early metabolic changes associated with the polarization of macrophages into pro-inflammatory or pro-resolving cells under different stimuli have been characterized. Tumor-associated macrophages are among the most abundant cells in the tumor microenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, we use a systems biology approach that integrates transcriptomics and metabolomics to unveil the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two DNA-binding agents with proven antitumor activity. Our results show that TRB and LUR activate human macrophages toward a pro-inflammatory phenotype by inducing a specific metabolic rewiring program that includes ROS production, changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, lactate release, tricarboxylic acids (TCA) cycle, serine and methylglyoxal pathways in human macrophages. Glutamine, aspartate, histidine, and proline intracellular levels are also decreased, whereas oxygen consumption is reduced. The observed immunometabolic changes explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer.
Topics: Humans; Trabectedin; Neoplasms; Macrophages; Lactic Acid; Tumor Microenvironment
PubMed: 37675104
DOI: 10.3389/fimmu.2023.1211068 -
PeerJ 2023Prolactin (PRL) has been reported to be associated with oxidative stress, which is an important contributor leading to cell apoptosis. However, little is known about the...
BACKGROUND
Prolactin (PRL) has been reported to be associated with oxidative stress, which is an important contributor leading to cell apoptosis. However, little is known about the mechanisms underlying the effects of PRL on cytotoxicity and oxidative stress in ovine ovarian granulosa cells (GCs).
METHODS
Ovine ovarian GCs were treated with 0, 4, 20, 100 and 500 ng/mL of PRL. Then, the cytotoxicity, cell viability, malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) of GCs were detected. Additionally, 500 ng/mL PRL was chosen as the high PRL concentration (HPC) due to its high cytotoxicity and oxidative stress. Proteomic and metabonomic were performed to examine the overall difference in proteins and metabolic pathways between C (control: 0 ng/mL PRL) and P groups (500 ng/mL PRL).
RESULTS
The results indicated that GCs treated with 4 ng/mL PRL significantly decreased ( < 0.05) the cytotoxicity, ROS and MDA, increased ( < 0.05) the cell viability, SOD and T-AOC, and the GCs treated with 500 ng/mL PRL showed the opposite trend ( < 0.05). Supplementation with 500 ng/mL PRL significantly increased the proteins of MT-ND1, MAPK12, UBA52 and BCL2L1, which were enriched in ROS and mitophagy pathways. Pathway enrichment analysis showed that the pentose phosphate pathway was significantly enriched in the P group.
CONCLUSION
A low concentration of PRL inhibited cytotoxicity and oxidative stress. HPC induced oxidative stress in ovine ovarian GCs via the pentose phosphate pathway by modulating the associated proteins MT-ND1 in ROS pathway and UBA52, MAPK12 and BCL2L1 in mitophagy pathway, resulting in cytotoxicity.
Topics: Female; Sheep; Animals; Reactive Oxygen Species; Prolactin; Proteomics; Oxidative Stress; Granulosa Cells; Antioxidants; Superoxide Dismutase; Sheep, Domestic
PubMed: 37456891
DOI: 10.7717/peerj.15629 -
Redox Biology Nov 2023Pentosidine (PEN) is an advanced glycation end-product (AGEs), where a fluorescent cross-link is formed between lysine and arginine residues in proteins. Accumulation of...
Pentosidine (PEN) is an advanced glycation end-product (AGEs), where a fluorescent cross-link is formed between lysine and arginine residues in proteins. Accumulation of PEN is associated with aging and various diseases. We previously reported that a subpopulation of patients with schizophrenia showed PEN accumulation in the blood, having severe clinical features. PEN is thought to be produced from glucose, fructose, pentoses, or ascorbate. However, patients with schizophrenia with high PEN levels present no elevation of these precursors of PEN in their blood. Therefore, the molecular mechanisms underlying PEN accumulation and the molecular pathogenesis of schizophrenia associated with PEN accumulation remain unclear. Here, we identified glucuronic acid (GlcA) as a novel precursor of PEN from the plasma of subjects with high PEN levels. We demonstrated that PEN can be generated from GlcA, both in vitro and in vivo. Furthermore, we found that GlcA was associated with the diagnosis of schizophrenia. Among patients with high PEN, the proportion of those who also have high GlcA is 25.6%. We also showed that Aldo-keto reductase (AKR) activity to degrade GlcA was decreased in patients with schizophrenia, and its activity was negatively correlated with GlcA levels in the plasma. This is the first report to show that PEN is generated from GlcA. In the future, this finding will contribute to understanding the molecular pathogenesis of not only schizophrenia but also other diseases with PEN accumulation.
Topics: Humans; Lysine; Glycation End Products, Advanced; Glucuronic Acid; Schizophrenia; Arginine
PubMed: 37703666
DOI: 10.1016/j.redox.2023.102876 -
Microbial Cell Factories Aug 2023R. toruloides is an oleaginous yeast, with diverse metabolic capacities and high tolerance for inhibitory compounds abundant in plant biomass hydrolysates. While R....
R. toruloides is an oleaginous yeast, with diverse metabolic capacities and high tolerance for inhibitory compounds abundant in plant biomass hydrolysates. While R. toruloides grows on several pentose sugars and alcohols, further engineering of the native pathway is required for efficient conversion of biomass-derived sugars to higher value bioproducts. A previous high-throughput study inferred that R. toruloides possesses a non-canonical L-arabinose and D-xylose metabolism proceeding through D-arabitol and D-ribulose. In this study, we present a combination of genetic and metabolite data that refine and extend that model. Chiral separations definitively illustrate that D-arabitol is the enantiomer that accumulates under pentose metabolism. Deletion of putative D-arabitol-2-dehydrogenase (RTO4_9990) results in > 75% conversion of D-xylose to D-arabitol, and is growth-complemented on pentoses by heterologous xylulose kinase expression. Deletion of putative D-ribulose kinase (RTO4_14368) arrests all growth on any pentose tested. Analysis of several pentose dehydrogenase mutants elucidates a complex pathway with multiple enzymes mediating multiple different reactions in differing combinations, from which we also inferred a putative L-ribulose utilization pathway. Our results suggest that we have identified enzymes responsible for the majority of pathway flux, with additional unknown enzymes providing accessory activity at multiple steps. Further biochemical characterization of the enzymes described here will enable a more complete and quantitative understanding of R. toruloides pentose metabolism. These findings add to a growing understanding of the diversity and complexity of microbial pentose metabolism.
Topics: Xylose; Arabinose; Pentoses
PubMed: 37537595
DOI: 10.1186/s12934-023-02126-x -
Biochimica Et Biophysica Acta.... Jan 2024Moonlighting proteins have more than one physiologically significant role within one polypeptide chain. The multifunctionality of proteins was first described in 1987 by... (Review)
Review
Moonlighting proteins have more than one physiologically significant role within one polypeptide chain. The multifunctionality of proteins was first described in 1987 by Joram Piatigorsky and Graeme Wistow. Cells can benefit from involvement of these proteins in biological processes in several ways, e.g. at the energy level. Furthermore, cells have developed a number of mechanisms to change these proteins' functions. Moonlighting proteins are found in all types of organisms, including prokaryotes, eukaryotes, and even viruses. These proteins include a variety of enzymes that serve as receptors, secreted cytokines, transcription factors, or proteasome components. Additionally, there are many combinations of functions, e.g. among receptors and transcription factors, chaperones and cytokines, as well as transcription factors within the ribosome. This work describes enzymes involved in several important metabolic processes in cells, namely cellular respiration, gluconeogenesis, the urea cycle, and pentose phosphate metabolism.
Topics: Eukaryota; Molecular Chaperones; Transcription Factors; Cytokines
PubMed: 37774631
DOI: 10.1016/j.bbamcr.2023.119598