scholarly journals Flavonoid-mediated immunomodulation of human macrophages involves key metabolites and metabolic pathways

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Luís F. Mendes ◽  
Vítor M. Gaspar ◽  
Tiago A. Conde ◽  
João F. Mano ◽  
Iola F. Duarte
Keyword(s):  
Metabolic Pathways ◽  
Tca Cycle ◽  
Immunomodulatory Activity ◽  
Human Macrophages ◽  
Biological Targets ◽  
Glycolytic Activity ◽  
The Tca Cycle ◽  
M1 Phenotype ◽  
Biochemical Level

Abstract The ability of flavonoids to attenuate macrophage pro-inflammatory activity and to promote macrophage-mediated resolution of inflammation is still poorly understood at the biochemical level. In this study, we have employed NMR metabolomics to assess how therapeutically promising flavonoids (quercetin, naringenin and naringin) affect the metabolism of human macrophages, with a view to better understand their biological targets and activity. In vitro-cultured human macrophages were polarized to the pro-inflammatory M1 phenotype, through incubation with LPS + IFN-γ, and subsequently treated with each flavonoid. The metabolic signatures of pro-inflammatory polarization and of flavonoid incubations were then characterized and compared. The results showed that all flavonoids modulated the cells endometabolome with the strongest impact being observed for quercetin. Many of the flavonoid-induced metabolic variations were in the opposite sense to those elicited by pro-inflammatory stimulation. In particular, the metabolic processes proposed to reflect flavonoid-mediated immunomodulation of macrophages included the downregulation of glycolytic activity, observed for all flavonoids, anti-inflammatory reprogramming of the TCA cycle (mainly quercetin), increased antioxidant protection (quercetin), osmoregulation (naringin), and membrane modification (naringenin). This work revealed key metabolites and metabolic pathways involved in macrophage responses to quercetin, naringenin and naringin, providing novel insights into their immunomodulatory activity.

scholarly journals The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 762
Author(s):  
Edward V. Prochownik ◽  
Huabo Wang
Keyword(s):  
Metabolic Pathways ◽  
Redox State ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Vascular Supply ◽  
Extrinsic Factors ◽  
The Tca Cycle ◽  
Initial Substrate ◽  
Numerous Cell ◽  
Bio Synthesis

Pyruvate occupies a central metabolic node by virtue of its position at the crossroads of glycolysis and the tricarboxylic acid (TCA) cycle and its production and fate being governed by numerous cell-intrinsic and extrinsic factors. The former includes the cell’s type, redox state, ATP content, metabolic requirements and the activities of other metabolic pathways. The latter include the extracellular oxygen concentration, pH and nutrient levels, which are in turn governed by the vascular supply. Within this context, we discuss the six pathways that influence pyruvate content and utilization: 1. The lactate dehydrogenase pathway that either converts excess pyruvate to lactate or that regenerates pyruvate from lactate for use as a fuel or biosynthetic substrate; 2. The alanine pathway that generates alanine and other amino acids; 3. The pyruvate dehydrogenase complex pathway that provides acetyl-CoA, the TCA cycle’s initial substrate; 4. The pyruvate carboxylase reaction that anaplerotically supplies oxaloacetate; 5. The malic enzyme pathway that also links glycolysis and the TCA cycle and generates NADPH to support lipid bio-synthesis; and 6. The acetate bio-synthetic pathway that converts pyruvate directly to acetate. The review discusses the mechanisms controlling these pathways, how they cross-talk and how they cooperate and are regulated to maximize growth and achieve metabolic and energetic harmony.

scholarly journals Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2634
Author(s):  
Beatriz Soldevilla ◽  
Angeles López-López ◽  
Alberto Lens-Pardo ◽  
Carlos Carretero-Puche ◽  
Angeles Lopez-Gonzalvez ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Metabolic Networks ◽  
Tca Cycle ◽  
Metabolomic Profile ◽  
Diagnostic Potential ◽  
The Tca Cycle ◽  
Novel Biomarkers ◽  
Potential Methods ◽  
Clinical Potential ◽  
First Time

Purpose: High-throughput “-omic” technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research.

scholarly journals Intracellular Fate of Universally Labelled 13C Isotopic Tracers of Glucose and Xylose in Central Metabolic Pathways of Xanthomonas oryzae

Metabolites ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 66 ◽  
Author(s):  
Manu Shree ◽  
Shyam K. Masakapalli
Keyword(s):  
Amino Acids ◽  
Metabolic Pathways ◽  
Metabolic Networks ◽  
Tca Cycle ◽  
Xanthomonas Oryzae ◽  
Flux Analysis ◽  
Isotopic Tracers ◽  
Feeding Experiments ◽  
The Tca Cycle ◽  
Metabolic Route

The goal of this study is to map the metabolic pathways of poorly understood bacterial phytopathogen, Xanthomonas oryzae (Xoo) BXO43 fed with plant mimicking media XOM2 containing glutamate, methionine and either 40% [13C5] xylose or 40% [13C6] glucose. The metabolic networks mapped using the KEGG mapper and the mass isotopomer fragments of proteinogenic amino acids derived from GC-MS provided insights into the activities of Xoo central metabolic pathways. The average 13C in histidine, aspartate and other amino acids confirmed the activities of PPP, the TCA cycle and amino acid biosynthetic routes, respectively. The similar labelling patterns of amino acids (His, Ala, Ser, Val and Gly) from glucose and xylose feeding experiments suggests that PPP would be the main metabolic route in Xoo. Owing to the lack of annotated gene phosphoglucoisomerase in BXO43, the 13C incorporation in alanine could not be attributed to the competing pathways and hence warrants additional positional labelling experiments. The negligible presence of 13C incorporation in methionine brings into question its potential role in metabolism and pathogenicity. The extent of the average 13C labelling in several amino acids highlighted the contribution of pre-existing pools that need to be accounted for in 13C-flux analysis studies. This study provided the first qualitative insights into central carbon metabolic pathway activities in Xoo.

scholarly journals Metabolic Constants and Plasticity of Cancer Cells in a Limiting Glucose and Glutamine Microenvironment—A Pyruvate Perspective

2020 ◽  
Vol 10 ◽  
Author(s):  
Angela M. Otto
Keyword(s):  
Cancer Cells ◽  
Metabolic Network ◽  
Metabolic Pathways ◽  
Cancer Cell Line ◽  
Tca Cycle ◽  
Reaction Rates ◽  
Diagnostic Methods ◽  
Metabolic Reprogramming ◽  
Amino Acid Synthesis ◽  
The Tca Cycle

The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Understanding tumor metabolism in conditions of nutrient depletion is important for such applications and for interpreting the readouts. To exemplify the metabolic network of tumor cells in a model system, the fate 13C6-glucose was tracked in a breast cancer cell line growing in variable low glucose/low glutamine conditions. 13C-glucose-derived metabolites allowed to deduce the engagement of metabolic pathways, namely glycolysis, the TCA-cycle including glutamine and pyruvate anaplerosis, amino acid synthesis (serine, glycine, aspartate, glutamate), gluconeogenesis, and pyruvate replenishment. While the metabolic program did not change, limiting glucose and glutamine supply reduced cellular metabolite levels and enhanced pyruvate recycling as well as pyruvate carboxylation for entry into the TCA-cycle. Otherwise, the same metabolic pathways, including gluconeogenesis, were similarly engaged with physiologically saturating as with limiting glucose and glutamine. Therefore, the metabolic plasticity in precarious nutritional microenvironment does not require metabolic reprogramming, but is based on dynamic changes in metabolite quantity, reaction rates, and directions of the existing metabolic network.

scholarly journals BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages

2020 ◽  
Vol 133 (22) ◽  
pp. jcs247957
Author(s):  
Jeong-Hun Ko ◽  
Antoni Olona ◽  
Adonia E. Papathanassiu ◽  
Norzawani Buang ◽  
Kwon-Sik Park ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Polarization State ◽  
Tca Cycle ◽  
Metabolic Adaptation ◽  
Human Macrophages ◽  
Relative Contribution ◽  
The Tca Cycle ◽  
Nutrient Consumption ◽  
Anti Oxidant ◽  
Branched Chain

ABSTRACTIn response to environmental stimuli, macrophages change their nutrient consumption and undergo an early metabolic adaptation that progressively shapes their polarization state. During the transient, early phase of pro-inflammatory macrophage activation, an increase in tricarboxylic acid (TCA) cycle activity has been reported, but the relative contribution of branched-chain amino acid (BCAA) leucine remains to be determined. Here, we show that glucose but not glutamine is a major contributor of the increase in TCA cycle metabolites during early macrophage activation in humans. We then show that, although uptake of BCAAs is not altered, their transamination by BCAT1 is increased following 8 h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate into the TCA cycle in basal or stimulated human macrophages. Surprisingly, the pharmacological inhibition of BCAT1 reduced glucose-derived itaconate, α-ketoglutarate and 2-hydroxyglutarate levels without affecting succinate and citrate levels, indicating a partial inhibition of the TCA cycle. This indirect effect is associated with NRF2 (also known as NFE2L2) activation and anti-oxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation.

scholarly journals Host nutrient milieu drives an essential role for aspartate biosynthesis during invasiveStaphylococcus aureusinfection

2020 ◽  
Vol 117 (22) ◽  
pp. 12394-12401 ◽  
Author(s):  
Aimee D. Potter ◽  
Casey E. Butrico ◽  
Caleb A. Ford ◽  
Jacob M. Curry ◽  
Irina A. Trenary ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Aerobic Glycolysis ◽  
Bacterial Pathogen ◽  
Tca Cycle ◽  
Acid Synthesis ◽  
Tricarboxylic Acid ◽  
Staphylococcal Infection ◽  
Amino Acid Synthesis ◽  
The Tca Cycle ◽  
Host Tissues

The bacterial pathogenStaphylococcus aureusis capable of infecting a broad spectrum of host tissues, in part due to flexibility of metabolic programs.S. aureus, like all organisms, requires essential biosynthetic intermediates to synthesize macromolecules. We therefore sought to determine the metabolic pathways contributing to synthesis of essential precursors during invasiveS. aureusinfection. We focused specifically on staphylococcal infection of bone, one of the most common sites of invasiveS. aureusinfection and a unique environment characterized by dynamic substrate accessibility, infection-induced hypoxia, and a metabolic profile skewed toward aerobic glycolysis. Using a murine model of osteomyelitis, we examined survival ofS. aureusmutants deficient in central metabolic pathways, including glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, and amino acid synthesis/catabolism. Despite the high glycolytic demand of skeletal cells, we discovered thatS. aureusrequires glycolysis for survival in bone. Furthermore, the TCA cycle is dispensable for survival during osteomyelitis, andS. aureusinstead has a critical need for anaplerosis. Bacterial synthesis of aspartate in particular is absolutely essential for staphylococcal survival in bone, despite the presence of an aspartate transporter, which we identified as GltT and confirmed biochemically. This dependence on endogenous aspartate synthesis derives from the presence of excess glutamate in infected tissue, which inhibits aspartate acquisition byS. aureus. Together, these data elucidate the metabolic pathways required for staphylococcal infection within bone and demonstrate that the host nutrient milieu can determine essentiality of bacterial nutrient biosynthesis pathways despite the presence of dedicated transporters.

scholarly journals Bovine Oviduct Epithelial Cell-Derived Culture Media and Exosomes Improve Mitochondrial Health by Restoring Metabolic Flux during Pre-Implantation Development

2020 ◽  
Vol 21 (20) ◽  
pp. 7589
Author(s):  
Tabinda Sidrat ◽  
Abdul Aziz Khan ◽  
Myeon-Don Joo ◽  
Yiran Wei ◽  
Kyeong-Lim Lee ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Embryonic Development ◽  
Metabolic Flux ◽  
Culture Media ◽  
Tca Cycle ◽  
Fine Tuning ◽  
The Tca Cycle ◽  
Oviduct Epithelial Cell

Oviduct flushing is enriched by a wide variety of nutrients that guide the 3–4 days journey of pre-implantation embryo through the oviduct as it develops into a competent blastocyst (BL). However, little is known about the specific requirement and role of these nutrients that orchestrate the early stages of embryonic development. In this study, we aimed to characterize the effect of in vitro-derived bovine oviduct epithelial cell (BOECs) secretion that mimics the in vivo oviduct micro-fluid like environment, which allows successful embryonic development. In this study, the addition of an in vitro derived BOECs-condition media (CM) and its isolated exosomes (Exo) significantly enhances the quality and development of BL, while the hatching ability of BLs was found to be high (48.8%) in the BOECs-Exo supplemented group. Surprisingly, BOECs-Exo have a dynamic effect on modulating the embryonic metabolism by restoring the pyruvate flux into TCA-cycle. Our analysis reveals that Exo treatment significantly upregulates the pyruvate dehydrogenase (PDH) and glutamate dehydrogenase (GLUD1) expression, required for metabolic fine-tuning of the TCA-cycle in the developing embryos. Exo treatment increases the influx into TCA-cycle by strongly suppressing the PDH and GLUD1 upstream inhibitors, i.e., PDK4 and SIRT4. Improvement of TCA-cycle function was further accompanied by higher metabolic activity of mitochondria in BOECs-CM and Exo in vitro embryos. Our study uncovered, for the first time, the possible mechanism of BOECs-derived secretion in re-establishing the TCA-cycle flux by the utilization of available nutrients and highlighted the importance of pyruvate in supporting bovine in vitro embryonic development.

scholarly journals Reconstruction of Sugar Metabolic Pathways of Giardia lamblia

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Jian Han ◽  
Lesley J. Collins
Keyword(s):  
Giardia Lamblia ◽  
Metabolic Pathways ◽  
Drug Targets ◽  
Sugar Metabolism ◽  
Tca Cycle ◽  
The Tca Cycle ◽  
Glycolysis Pathway ◽  
Bioinformatic Approaches ◽  
Novel Drug ◽  
Novel Drug Targets

Giardia lamblia is an “important” pathogen of humans, but as a diplomonad excavate it is evolutionarily distant from other eukaryotes and relatively little is known about its core metabolic pathways. KEGG, the widely referenced site for providing information of metabolism, does not yet include many enzymes from Giardia species. Here we identify Giardia’s core sugar metabolism using standard bioinformatic approaches. By comparing Giardia proteomes with known enzymes from other species, we have identified enzymes in the glycolysis pathway, as well as some enzymes involved in the TCA cycle and oxidative phosphorylation. However, the majority of enzymes from the latter two pathways were not identifiable, indicating the likely absence of these functionalities. We have also found enzymes from the Giardia glycolysis pathway that appear more similar to those from bacteria. Because these enzymes are different from those found in mammals, the host organisms for Giardia, we raise the possibility that these bacteria-like enzymes could be novel drug targets for treating Giardia infections.

scholarly journals Serum metabolomic analysis of feline mammary carcinomas based on LC-MS and MRM techniques

2020 ◽  
Vol 64 (4) ◽  
pp. 581-588
Author(s):  
Jia-san Zheng ◽  
Ren-yue Wei ◽  
Zheng Wang ◽  
Jun Song ◽  
Yan-song Ge ◽  
...  
Keyword(s):  
Mammary Carcinoma ◽  
Metabolic Pathways ◽  
Acid Metabolism ◽  
Multiple Reaction Monitoring ◽  
Tca Cycle ◽  
Bioinformatic Analysis ◽  
Multivariate Statistical ◽  
Mammary Carcinomas ◽  
The Tca Cycle ◽  
Feline Mammary Carcinoma

AbstractIntroductionTo date, there have been no panoramic studies of the serum metabolome in feline mammary carcinoma. As the first such study, metabolomics techniques were used to analyse the serum of cats with these tumours. Three important metabolic pathways of screened differential metabolites closely related to feline mammary carcinomas were analysed to lay a theoretical basis for further study of the pathogenesis of these carcinomas.Material and MethodsBlood in a 5–8 mL volume was sampled from twelve cats of the same breed and similar age (close to nine years on average). Six were feline mammary carcinoma patients and six were healthy. L glutamate, L alanine, succinate, adenine, hypoxanthine, and inosine were screened as were alanine, aspartate, and glutamate metabolism, the tricarboxylid acid (TCA) cycle, and purine metabolism. Data were acquired with LC-MS non-target metabolomics, multiple reaction monitoring target metabolomics, and multivariate statistical and bioinformatic analysis.ResultsExpression of five of the metabolites was upregulated and only inosine expression was downregulated. Up- and downregulation of metabolites related to glycometabolism, potentiation of the TCA cycle, greater content of lipid mobilisation metabolites, and abnormality of amino acid metabolism were closely related to the occurrence of the carcinomas.ConclusionThese findings provide a new direction for further study of the mechanisms associated with cat mammary neoplasms.

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