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Journal of Hematology & Oncology Feb 2024Emerging evidences suggest that aberrant metabolites contributes to the immunosuppressive microenvironment that leads to cancer immune evasion. Among tumor...
BACKGROUND
Emerging evidences suggest that aberrant metabolites contributes to the immunosuppressive microenvironment that leads to cancer immune evasion. Among tumor immunosuppressive cells, myeloid-derived suppressor cells (MDSCs) are pathologically activated and extremely immunosuppressive, which are closely associated with poor clinical outcomes of cancer patients. However, the correlation between MDSCs mediated immunosuppression and particular cancer metabolism remained elusive.
METHODS
Spontaneous lung adenocarcinoma and subcutaneous mouse tumor models, gas chromatography-mass spectrometry (GC-MS) and immunofluorescence assay of patient-derived lung adenocarcinoma tissues, and flow cytometry, RNA sequencing and Western blotting of immune cells, were utilized.
RESULTS
Metabolite profiling revealed a significant accumulation of acetic acids in tumor tissues from both patients and mouse model, which contribute to immune suppression and cancer progression significantly through free fatty acid receptor 2 (FFAR2). Furthermore, FFAR2 is highly expressed in the myeloid-derived suppressor cells (MDSCs) from the tumor of lung adenocarcinoma (LUAD) patients which is greatly associated with poor prognosis. Surprisingly, whole or myeloid Ffar2 gene deletion markedly inhibited urethane-induced lung carcinogenesis and syngeneic tumor growth with reduced MDSCs and increased CD8 T cell infiltration. Mechanistically, FFAR2 deficiency in MDSCs significantly reduced the expression of Arg1 through Gαq/Calcium/PPAR-γ axis, which eliminated T cell dysfunction through relieving L-Arginine consumption in tumor microenvironment. Therefore, replenishment of L-Arginine or inhibition to PPAR-γ restored acetic acids/FFAR2 mediated suppression to T cells significantly. Finally, FFAR2 inhibition overcame resistance to immune checkpoint blockade through enhancing the recruitment and cytotoxicity of tumor-infiltrating T cells.
CONCLUSION
Altogether, our results demonstrate that the acetic acids/FFAR2 axis enhances MDSCs mediated immunosuppression through Gαq/calcium/PPAR-γ/Arg1 signaling pathway, thus contributing to cancer progression. Therefore, FFAR2 may serve as a potential new target to eliminate pathologically activated MDSCs and reverse immunosuppressive tumor microenvironment, which has great potential in improving clinical outcomes of cancer immunotherapy.
Topics: Humans; Mice; Animals; Myeloid-Derived Suppressor Cells; Calcium; Peroxisome Proliferator-Activated Receptors; Neoplasms; Adenocarcinoma of Lung; Arginine; Acetates; Tumor Microenvironment
PubMed: 38402237
DOI: 10.1186/s13045-024-01529-6 -
Applied Microbiology and Biotechnology Jun 2022The electrochemical process of microbial electrosynthesis (MES) is used to drive the metabolism of electroactive microorganisms for the production of valuable chemicals... (Review)
Review
The electrochemical process of microbial electrosynthesis (MES) is used to drive the metabolism of electroactive microorganisms for the production of valuable chemicals and fuels. MES combines the advantages of electrochemistry, engineering, and microbiology and offers alternative production processes based on renewable raw materials and regenerative energies. In addition to the reactor concept and electrode design, the biocatalysts used have a significant influence on the performance of MES. Thus, pure and mixed cultures can be used as biocatalysts. By using mixed cultures, interactions between organisms, such as the direct interspecies electron transfer (DIET) or syntrophic interactions, influence the performance in terms of productivity and the product range of MES. This review focuses on the comparison of pure and mixed cultures in microbial electrosynthesis. The performance indicators, such as productivities and coulombic efficiencies (CEs), for both procedural methods are discussed. Typical products in MES are methane and acetate, therefore these processes are the focus of this review. In general, most studies used mixed cultures as biocatalyst, as more advanced performance of mixed cultures has been seen for both products. When comparing pure and mixed cultures in equivalent experimental setups a 3-fold higher methane and a nearly 2-fold higher acetate production rate can be achieved in mixed cultures. However, studies of pure culture MES for methane production have shown some improvement through reactor optimization and operational mode reaching similar performance indicators as mixed culture MES. Overall, the review gives an overview of the advantages and disadvantages of using pure or mixed cultures in MES. KEY POINTS: • Undefined mixed cultures dominate as inoculums for the MES of methane and acetate, which comprise a high potential of improvement • Under similar conditions, mixed cultures outperform pure cultures in MES • Understanding the role of single species in mixed culture MES is essential for future industrial applications.
Topics: Acetates; Carbon Dioxide; Electrochemistry; Electrodes; Methane
PubMed: 35763070
DOI: 10.1007/s00253-022-12031-9 -
Applied and Environmental Microbiology Jun 2023Acetyl-CoA synthetase (ACS) and acetate ligase (ACD) are widespread among microorganisms, including archaea, and play an important role in their carbon metabolism,...
Acetyl-CoA synthetase (ACS) and acetate ligase (ACD) are widespread among microorganisms, including archaea, and play an important role in their carbon metabolism, although only a few of these enzymes have been characterized. Anaerobic methanotrophs (ANMEs) have been reported to convert methane anaerobically into CO, polyhydroxyalkanoate, and acetate. Furthermore, it has been suggested that they might be able to use acetate for anabolism or aceticlastic methanogenesis. To better understand the potential acetate metabolism of ANMEs, we characterized an ACS from ANME-2a as well as an ACS and an ACD from ANME-2d. The conversion of acetate into acetyl-CoA ( of 8.4 μmol mg min and of 0.7 mM acetate) by the monomeric 73.8-kDa ACS enzyme from ANME-2a was more favorable than the formation of acetate from acetyl-CoA ( of 0.4 μmol mg min and of 0.2 mM acetyl-CoA). The monomeric 73.4-kDa ACS enzyme from ANME-2d had similar values for both directions ( of 0.9 μmol mg min versus of 0.3 μmol mg min). The heterotetrameric ACD enzyme from ANME-2d was active solely in the acetate-producing direction. Batch incubations of an enrichment culture dominated by ANME-2d fed with C-labeled acetate produced 3 μmol of [C]methane in 7 days, suggesting that this anaerobic methanotroph might have the potential to reverse its metabolism and perform aceticlastic methanogenesis using ACS to activate acetate albeit at low rates (2 nmol g [dry weight] min). Together, these results show that ANMEs may have the potential to use acetate for assimilation as well as to use part of the surplus acetate for methane production. Acetyl-CoA plays a key role in carbon metabolism and is found at the junction of many anabolic and catabolic reactions. This work describes the biochemical properties of ACS and ACD enzymes from ANME-2 archaea. This adds to our knowledge of archaeal ACS and ACD enzymes, only a few of which have been characterized to date. Furthermore, we validated the activity of ACS in ANME-2d, showing the conversion of acetate into methane by an enrichment culture dominated by ANME-2d.
Topics: Archaea; Acetyl Coenzyme A; Anaerobiosis; Oxidation-Reduction; Acetates; Carbon; Methane
PubMed: 37272802
DOI: 10.1128/aem.00367-23 -
Nutrients Aug 2023Acetate is associated with adipocyte differentiation and lipid deposition. To further develop this scientific point, obese mice on a high-fat diet were given an...
Acetate is associated with adipocyte differentiation and lipid deposition. To further develop this scientific point, obese mice on a high-fat diet were given an intragastric administration of acetate for 8 weeks and mouse adipose mesenchymal stem cells (mAMSCs) were treated with acetate for 24 h. The results showed that the body weight, food intake, Lee's index, adipose tissue coefficient, liver index, blood lipid levels, insulin resistance, pro-inflammatory factors levels and fatty lesions in liver and adipose tissue in obese mice treated with acetate increased markedly, while anti-inflammatory factors levels and liver function decreased significantly ( < 0.05). The mRNA expression levels of PPAR-γ, C/EBP-α, SREBP, AFABP, FAS, ACC-1, SCD-1, LPL, LEPR, GPR41 and GPR43 genes in adipose tissue and mAMSCs were significantly increased, while the mRNA expression levels of HSL, CPT-1, CPT-2, AMPK, AdipoR1 and AdipoR2 genes were significantly reduced ( < 0.05). Except for AMPK-α signaling pathway proteins, the phosphorylation levels of p38 MAPK, ERK1/2, JNK and mTOR were significantly increased ( < 0.05) and these changes were dose-dependent. The findings indicated that acetate played a positive role in regulating adipocyte differentiation and lipid deposition by activating MAPKs and mTOR signaling pathways (the expression up-regulation of genes such as PPAR-γ, C/EBP-α and SREBP-1, etc.) and inhibiting the AMPK signaling pathway (the expression down-regulation of genes such as HSL, CPT-1 and AMPK-α, etc.).
Topics: Animals; Mice; Mice, Obese; AMP-Activated Protein Kinases; Peroxisome Proliferator-Activated Receptors; Sterol Regulatory Element Binding Protein 1; Acetates; Cell Differentiation; CCAAT-Enhancer-Binding Protein-alpha; Carnitine O-Palmitoyltransferase; Adipocytes; RNA, Messenger
PubMed: 37686768
DOI: 10.3390/nu15173736 -
Communications Biology Oct 2023Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Ethanol consumption has been reported to reduce morbidity in RA patients, but the mechanism behind it...
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Ethanol consumption has been reported to reduce morbidity in RA patients, but the mechanism behind it remains unclear. Our results showed that Muribaculaceae was predominant in the gut microbiota of mice after ethanol treatment, and the levels of microbiota metabolite acetate were increased. Acetate reduced arthritis severity in collagen-induced arthritis (CIA) mice, which was associated with a decrease in the articular neutrophils and the myeloperoxidase-deoxyribonucleic acid complex in serum. Meanwhile, in vitro experiments confirmed that acetate affected neutrophil activity by acting on G-protein-coupled receptor 43, which reduced endoplasmic reticulum stress in neutrophils and inhibited neutrophil extracellular traps formation. Furthermore, exogenous acetate reversed CIA mice with exacerbated gut microbial disruption, further confirming that the effect of gut microbial metabolite acetate on neutrophils in vivo is crucial for the immune regulation. Our findings illuminate the metabolic and cellular mechanisms of the gut-joint axis in the regulation of autoimmune arthritis, and may offer alternative avenues to replicate or induce the joint-protective benefits of ethanol without associated detrimental effects.
Topics: Humans; Mice; Animals; Extracellular Traps; Arthritis, Rheumatoid; Neutrophils; Arthritis, Experimental; Acetates
PubMed: 37884797
DOI: 10.1038/s42003-023-05473-y -
The Journal of Biological Chemistry Jun 2023The ability of cells to store and rapidly mobilize energy reserves in response to nutrient availability is essential for survival. Breakdown of carbon stores produces...
The ability of cells to store and rapidly mobilize energy reserves in response to nutrient availability is essential for survival. Breakdown of carbon stores produces acetyl-CoA (AcCoA), which fuels essential metabolic pathways and is also the acyl donor for protein lysine acetylation. Histones are abundant and highly acetylated proteins, accounting for 40% to 75% of cellular protein acetylation. Notably, histone acetylation is sensitive to AcCoA availability, and nutrient replete conditions induce a substantial accumulation of acetylation on histones. Deacetylation releases acetate, which can be recycled to AcCoA, suggesting that deacetylation could be mobilized as an AcCoA source to feed downstream metabolic processes under nutrient depletion. While the notion of histones as a metabolic reservoir has been frequently proposed, experimental evidence has been lacking. Therefore, to test this concept directly, we used acetate-dependent, ATP citrate lyase-deficient mouse embryonic fibroblasts (Acly MEFs), and designed a pulse-chase experimental system to trace deacetylation-derived acetate and its incorporation into AcCoA. We found that dynamic protein deacetylation in Acly MEFs contributed carbons to AcCoA and proximal downstream metabolites. However, deacetylation had no significant effect on acyl-CoA pool sizes, and even at maximal acetylation, deacetylation transiently supplied less than 10% of cellular AcCoA. Together, our data reveal that although histone acetylation is dynamic and nutrient-sensitive, its potential for maintaining cellular AcCoA-dependent metabolic pathways is limited compared to cellular demand.
Topics: Animals; Mice; Acetates; Acetyl Coenzyme A; Acetylation; Carbon; Fibroblasts; Histones; Cells, Cultured
PubMed: 37142219
DOI: 10.1016/j.jbc.2023.104772 -
Cells Mar 2021Pyruvate 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... (Review)
Review
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.
Topics: Acetates; Animals; Biosynthetic Pathways; Embryonic Development; Humans; Neoplasms; Pyruvic Acid; Tumor Microenvironment
PubMed: 33808495
DOI: 10.3390/cells10040762 -
Molecules (Basel, Switzerland) Dec 2020Pinot blanc is a grape variety found in all wine-growing regions of Austria. However, there are only few scientific studies which deal with the aroma of wines of this...
Pinot blanc is a grape variety found in all wine-growing regions of Austria. However, there are only few scientific studies which deal with the aroma of wines of this variety. In the course of this project, the relationship between aroma profile and the typicity of Austrian Pinot blanc wines was studied. The aim was to describe the typicity and to find significant differences in aroma profiles and aroma descriptors of typical and atypical Pinot blanc wines. Since the typicity of a jointly anchored prototype is embedded in the memory, typical attributes for Austrian Pinot blanc wines were first identified by consumers and experts or producers. According to this, 131 flawless commercial Austrian wines of the variety Pinot blanc of the vintages 2015 to 2017 were analysed for more than 100 volatile substances. The wines of the vintages 2015 to 2017 were judged by a panel of producers and experts for their typicity; furthermore, the wines of the vintage 2017 were also evaluated by a consumer panel and a trained descriptive panel. Subsequently, typical and atypical wines were described by the trained descriptive panel. It was found that Pinot blanc wines typical of Austria showed significantly higher concentrations of the ester compounds ethyl hexanoate, ethyl butanoate, ethyl octanoate, ethyl decanoate, methyl hexanoate, hexyl acetate and isoamyl acetate, while atypical wines had higher concentrations of free monoterpenes such as linalool, trans-linalool oxide, nerol oxide, nerol and alpha-terpineol. The sensory description of typical Pinot blanc wines was significantly more pronounced for the attribute "yellow pome fruit", and tended to be more pronounced for the attributes "green pome fruit", "pear", "walnut", "pineapple", "banana" and "vanilla", while the atypical Pinot blanc wines were described more by the attribute "citrus". These findings could help to ensure that, through targeted measures, Austrian Pinot blanc wines become even more typical and distinguish themselves from other origins such as Germany or South Tyrol through a clear concept of typicity.
Topics: Acetates; Austria; Esters; Fruit; Germany; Odorants; Taste; Terpenes; Vitis; Wine
PubMed: 33287238
DOI: 10.3390/molecules25235705 -
Clinics (Sao Paulo, Brazil) 2022Short-Chain Fatty Acids (SCFA) are products of intestinal microbial metabolism that can reach the brain and alter microglia in health and disease contexts. However, data...
INTRODUCTION
Short-Chain Fatty Acids (SCFA) are products of intestinal microbial metabolism that can reach the brain and alter microglia in health and disease contexts. However, data are conflicting on the effect of acetate, the most abundant SCFA in the blood, in these cells.
OBJECTIVE
The authors aimed to investigate acetate as a modulator of the inflammatory response in microglia stimulated with LPS.
METHOD
The authors used an immortalized cell line, C8-B4, and primary cells for in vitro treatments with acetate and LPS. Cell viability was analyzed by MTT, cytokine by RT-PCR, ELISA, and flow cytometry. The authors also performed in vivo and in silico analyses to study the role of acetate and the TNF-α contribution to the development of Experimental Autoimmune Encephalomyelitis (EAE).
RESULTS
Acetate co-administered with LPS was able to exacerbate the production of pro-inflammatory cytokines at gene and protein levels in cell lines and primary culture of microglia. However, the same effects were not observed when acetate was administered alone or as pretreatment, prior to the LPS stimulus. Additionally, pharmacological inhibition of histone deacetylase concomitantly with acetate and LPS led to decreased TNF-α production. In silico analysis showed a crucial role of the TNF-α pathway in EAE development. Moreover, acetate administration in vivo during the initial phase of EAE led to a better disease outcome and reduced TNF-α production.
CONCLUSION
Treatment with acetate was able to promote the production of TNF-α in a concomitant LPS stimulus of microglia. However, the immune modulation of microglia by acetate pretreatment may be a component in the generation of future therapies for neurodegenerative diseases.
Topics: Acetates; Animals; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Lipopolysaccharides; Microglia; Tumor Necrosis Factor-alpha
PubMed: 35779458
DOI: 10.1016/j.clinsp.2022.100062 -
ELife Mar 2021Overflow metabolism refers to the production of seemingly wasteful by-products by cells during growth on glucose even when oxygen is abundant. Two theories have been...
Overflow metabolism refers to the production of seemingly wasteful by-products by cells during growth on glucose even when oxygen is abundant. Two theories have been proposed to explain acetate overflow in - global control of the central metabolism and local control of the acetate pathway - but neither accounts for all observations. Here, we develop a kinetic model of metabolism that quantitatively accounts for observed behaviours and successfully predicts the response of to new perturbations. We reconcile these theories and clarify the origin, control, and regulation of the acetate flux. We also find that, in turns, acetate regulates glucose metabolism by coordinating the expression of glycolytic and TCA genes. Acetate should not be considered a wasteful end-product since it is also a co-substrate and a global regulator of glucose metabolism in . This has broad implications for our understanding of overflow metabolism.
Topics: Acetates; Escherichia coli; Glucose; Kinetics; Models, Biological
PubMed: 33720011
DOI: 10.7554/eLife.63661