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Cancer Cell Feb 2022Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but...
Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but how the metabolites impact CRC is largely unknown. We interrogated fecal metabolites associated with mouse models of colon tumorigenesis with varying mutational load. We find that microbial metabolites from healthy mice or humans are growth-repressive, and this response is attenuated in mice and patients with CRC. Microbial profiling reveals that Lactobacillus reuteri and its metabolite, reuterin, are downregulated in mouse and human CRC. Reuterin alters redox balance, and reduces proliferation and survival in colon cancer cells. Reuterin induces selective protein oxidation and inhibits ribosomal biogenesis and protein translation. Exogenous Lactobacillus reuteri restricts colon tumor growth, increases tumor reactive oxygen species, and decreases protein translation in vivo. Our findings indicate that a healthy microbiome and specifically, Lactobacillus reuteri, is protective against CRC through microbial metabolite exchange.
Topics: Animals; Biomarkers; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Energy Metabolism; Gastrointestinal Microbiome; Glutathione; Glyceraldehyde; Host Microbial Interactions; Humans; Intestinal Mucosa; Metabolomics; Metagenomics; Mice; Models, Biological; Oxidation-Reduction; Oxidative Stress; Propane; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 34951957
DOI: 10.1016/j.ccell.2021.12.001 -
Nature Metabolism Sep 2020The mechanistic target of rapamycin complex 1 (mTORC1) kinase regulates cell growth by setting the balance between anabolic and catabolic processes. To be active, mTORC1...
The mechanistic target of rapamycin complex 1 (mTORC1) kinase regulates cell growth by setting the balance between anabolic and catabolic processes. To be active, mTORC1 requires the environmental presence of amino acids and glucose. While a mechanistic understanding of amino acid sensing by mTORC1 is emerging, how glucose activates mTORC1 remains mysterious. Here, we used metabolically engineered human cells lacking the canonical energy sensor AMP-activated protein kinase to identify glucose-derived metabolites required to activate mTORC1 independent of energetic stress. We show that mTORC1 senses a metabolite downstream of the aldolase and upstream of the GAPDH-catalysed steps of glycolysis and pinpoint dihydroxyacetone phosphate (DHAP) as the key molecule. In cells expressing a triose kinase, the synthesis of DHAP from DHA is sufficient to activate mTORC1 even in the absence of glucose. DHAP is a precursor for lipid synthesis, a process under the control of mTORC1, which provides a potential rationale for the sensing of DHAP by mTORC1.
Topics: AMP-Activated Protein Kinases; Dihydroxyacetone; Dihydroxyacetone Phosphate; Energy Metabolism; Fructose-Bisphosphate Aldolase; Glucose; Glycolysis; HEK293 Cells; Humans; Lipid Metabolism; Phosphotransferases (Alcohol Group Acceptor); TOR Serine-Threonine Kinases
PubMed: 32719541
DOI: 10.1038/s42255-020-0250-5 -
Journal of Experimental Botany Mar 2019During photosynthesis, plants fix CO2 from the atmosphere onto ribulose-bisphosphate, producing 3-phosphoglycerate, which is reduced to triose phosphates (TPs). The TPs... (Review)
Review
During photosynthesis, plants fix CO2 from the atmosphere onto ribulose-bisphosphate, producing 3-phosphoglycerate, which is reduced to triose phosphates (TPs). The TPs are then converted into the end products of photosynthesis. When a plant is photosynthesizing very quickly, it may not be possible to commit photosynthate to end products as fast as it is produced, causing a decrease in available phosphate and limiting the rate of photosynthesis to the rate of triose phosphate utilization (TPU). The occurrence of an observable TPU limitation is highly variable based on species and especially growth conditions, with TPU capacity seemingly regulated to be in slight excess of typical photosynthetic rates the plant might experience. The physiological effects of TPU limitation are discussed with an emphasis on interactions between the Calvin-Benson cycle and the light reactions. Methods for detecting TPU-limited data from gas exchange data are detailed and the impact on modeling of some physiological effects are shown. Special consideration is given to common misconceptions about TPU.
Topics: Phosphates; Photosynthesis; Plant Physiological Phenomena; Trioses
PubMed: 30868155
DOI: 10.1093/jxb/erz058 -
Biochemical Pharmacology Dec 2023Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by progressive neurodegeneration leading to severe cognitive, memory, and behavioral... (Review)
Review
Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by progressive neurodegeneration leading to severe cognitive, memory, and behavioral impairments. The onset of AD involves a complex interplay among various factors, including age, genetics, chronic inflammation, and impaired energy metabolism. Despite significant efforts, there are currently no effective therapies capable of modifying the course of AD, likely owing to an excessive focus on the amyloid hypothesis and a limited consideration of other intracellular pathways. In the present review, we emphasize the emerging concept of AD as a metabolic disease, where alterations in energy metabolism play a critical role in its development and progression. Notably, glucose metabolism impairment is associated with mitochondrial dysfunction, oxidative stress, Ca dyshomeostasis, and protein misfolding, forming interconnected processes that perpetuate a detrimental self-feeding loop sustaining AD progression. Advanced glycation end products (AGEs), neurotoxic compounds that accumulate in AD, are considered an important consequence of glucose metabolism disruption, and glyceraldehyde (GA), a glycolytic intermediate, is a key contributor to AGEs formation in both neurons and astrocytes. Exploring the impact of GA-induced glucose metabolism impairment opens up exciting possibilities for creating an easy-to-handle in vitro model that recapitulates the early stage of the disease. This model holds great potential for advancing the development of novel therapeutics targeting various intracellular pathways implicated in AD pathogenesis. In conclusion, looking beyond the conventional amyloid hypothesis could lead researchers to discover promising targets for intervention, offering the possibility of addressing the existing medical gaps in AD treatment.
Topics: Humans; Alzheimer Disease; Glyceraldehyde; Oxidative Stress; Glycation End Products, Advanced; Glucose; Amyloid beta-Peptides
PubMed: 37871878
DOI: 10.1016/j.bcp.2023.115869 -
Chemical Reviews Feb 2016The utility of metabolic synthons as the building blocks for new biomaterials is based on the early application and success of hydroxy acid based polyesters as... (Review)
Review
The utility of metabolic synthons as the building blocks for new biomaterials is based on the early application and success of hydroxy acid based polyesters as degradable sutures and controlled drug delivery matrices. The sheer number of potential monomers derived from the metabolome (e.g., lactic acid, dihydroxyacetone, glycerol, fumarate) gives rise to almost limitless biomaterial structural possibilities, functionality, and performance characteristics, as well as opportunities for the synthesis of new polymers. This review describes recent advances in new chemistries, as well as the inventive use of traditional chemistries, toward the design and synthesis of new polymers. Specific polymeric biomaterials can be prepared for use in varied medical applications (e.g., drug delivery, tissue engineering, wound repair, etc.) through judicious selection of the monomer and backbone linkage.
Topics: Amino Acids; Biocompatible Materials; Dihydroxyacetone; Glycerol; Hydroxy Acids; Molecular Structure; Polymers
PubMed: 26821863
DOI: 10.1021/acs.chemrev.5b00465 -
Environmental and Molecular Mutagenesis Mar 2021Dihydroxyacetone (DHA) is a three-carbon sugar that is the active ingredient in sunless tanning products and a by-product of electronic cigarette (e-cigarette)... (Review)
Review
Dihydroxyacetone (DHA) is a three-carbon sugar that is the active ingredient in sunless tanning products and a by-product of electronic cigarette (e-cigarette) combustion. Increased use of sunless tanning products and e-cigarettes has elevated exposures to DHA through inhalation and absorption. Studies have confirmed that DHA is rapidly absorbed into cells and can enter into metabolic pathways following phosphorylation to dihydroxyacetone phosphate (DHAP), a product of fructose metabolism. Recent reports have suggested metabolic imbalance and cellular stress results from DHA exposures. However, the impact of elevated exposure to DHA on human health is currently under-investigated. We propose that exogenous exposures to DHA increase DHAP levels in cells and mimic fructose exposures to produce oxidative stress, mitochondrial dysfunction, and gene and protein expression changes. Here, we review cell line and animal model exposures to fructose to highlight similarities in the effects produced by exogenous exposures to DHA. Given the long-term health consequences of fructose exposure, this review emphasizes the pressing need to further examine DHA exposures from sunless tanning products and e-cigarettes.
Topics: Dihydroxyacetone; Dihydroxyacetone Phosphate; Fructose; Humans; Metabolic Networks and Pathways; Mitochondria; Oxidative Stress; Phosphorylation
PubMed: 33496975
DOI: 10.1002/em.22425 -
Microbial Genomics Jan 2022The development of spots or lesions symptomatic of common scab on root and tuber crops is caused by few pathogenic with 87-22 as the model species. Thaxtomin... (Comparative Study)
Comparative Study
The development of spots or lesions symptomatic of common scab on root and tuber crops is caused by few pathogenic with 87-22 as the model species. Thaxtomin phytotoxins are the primary virulence determinants, mainly acting by impairing cellulose synthesis, and their production in is in turn boosted by cello-oligosaccharides released from host plants. In this work we aimed to determine which molecules and which biosynthetic gene clusters (BGCs) of the specialized metabolism of 87-22 show a production and/or a transcriptional response to cello-oligosaccharides. Comparative metabolomic analyses revealed that molecules of the virulome of induced by cellobiose and cellotriose include (i) thaxtomin and concanamycin phytotoxins, (ii) desferrioxamines, scabichelin and turgichelin siderophores in order to acquire iron essential for housekeeping functions, (iii) ectoine for protection against osmotic shock once inside the host, and (iv) bottromycin and concanamycin antimicrobials possibly to prevent other microorganisms from colonizing the same niche. Importantly, both cello-oligosaccharides reduced the production of the spore germination inhibitors germicidins thereby giving the 'green light' to escape dormancy and trigger the onset of the pathogenic lifestyle. For most metabolites - either with induced or reduced production - cellotriose was revealed to be a slightly stronger elicitor compared to cellobiose, supporting an earlier hypothesis which suggested the trisaccharide was the real trigger for virulence released from the plant cell wall through the action of thaxtomins. Interestingly, except for thaxtomins, none of these BGCs' expression seems to be under direct control of the cellulose utilization repressor CebR suggesting the existence of a yet unknown mechanism for switching on the virulome. Finally, a transcriptomic analysis revealed nine additional cryptic BGCs that have their expression awakened by cello-oligosaccharides, suggesting that other and yet to be discovered metabolites could be part of the virulome of .
Topics: Biosynthetic Pathways; Cellobiose; Cellulose; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Macrolides; Metabolomics; Multigene Family; Piperazines; Plant Tubers; RNA-Seq; Streptomyces; Trioses; Virulence Factors
PubMed: 35040428
DOI: 10.1099/mgen.0.000760 -
FEBS Letters Aug 2022Glycolysis is present in nearly all organisms alive today. This article proposes an evolutionary trajectory for the development of glycolysis in the framework of the...
Glycolysis is present in nearly all organisms alive today. This article proposes an evolutionary trajectory for the development of glycolysis in the framework of the chemoautotrophic theory for the origin of life. In the proposal, trioses and triose-phosphates were appointed to starting points. The six-carbon and the three-carbon intermediates developed in the direction of gluconeogenesis and glycolysis, respectively, differing from the from-bottom-to-up development of enzymatic glycolysis. The examination of enzymatic reaction mechanisms revealed that the enzymes incorporated chemical mechanisms of the nonenzymatic stage, making possible to identify kinship between glyoxalases and glyceraldehyde 3-phosphate dehydrogenase as well as methylglyoxal synthase and triose-phosphate isomerase. This developmental trajectory may shed light on how glycolysis might have developed in the nonenzymatic era.
Topics: Carbon; Fossils; Glycolysis; Prebiotics; Triose-Phosphate Isomerase; Trioses
PubMed: 35599367
DOI: 10.1002/1873-3468.14408 -
Dihydroxyacetone suppresses mTOR nutrient signaling and induces mitochondrial stress in liver cells.PloS One 2022Dihydroxyacetone (DHA) is the active ingredient in sunless tanning products and a combustion product from e-juices in electronic cigarettes (e-cigarettes). DHA is...
Dihydroxyacetone (DHA) is the active ingredient in sunless tanning products and a combustion product from e-juices in electronic cigarettes (e-cigarettes). DHA is rapidly absorbed in cells and tissues and incorporated into several metabolic pathways through its conversion to dihydroxyacetone phosphate (DHAP). Previous studies have shown DHA induces cell cycle arrest, reactive oxygen species, and mitochondrial dysfunction, though the extent of these effects is highly cell-type specific. Here, we investigate DHA exposure effects in the metabolically active, HepG3 (C3A) cell line. Metabolic and mitochondrial changes were evaluated by characterizing the effects of DHA in metabolic pathways and nutrient-sensing mechanisms through mTOR-specific signaling. We also examined cytotoxicity and investigated the cell death mechanism induced by DHA exposure in HepG3 cells. Millimolar doses of DHA were cytotoxic and suppressed glycolysis and oxidative phosphorylation pathways. Nutrient sensing through mTOR was altered at both short and long time points. Increased mitochondrial reactive oxygen species (ROS) and mitochondrial-specific injury induced cell cycle arrest and cell death through a non-classical apoptotic mechanism. Despite its carbohydrate nature, millimolar doses of DHA are toxic to liver cells and may pose a significant health risk when higher concentrations are absorbed through e-cigarettes or spray tanning.
Topics: Dihydroxyacetone; Electronic Nicotine Delivery Systems; Reactive Oxygen Species; Mitochondria; Liver
PubMed: 36472985
DOI: 10.1371/journal.pone.0278516 -
Chemical Research in Toxicology Apr 2022Dihydroxyacetone (DHA) is a major byproduct of e-cigarette combustion and is the active ingredient in sunless tanning products. Mounting evidence points to its damaging...
Dihydroxyacetone (DHA) is a major byproduct of e-cigarette combustion and is the active ingredient in sunless tanning products. Mounting evidence points to its damaging effects on cellular functions. While developing a simple synthetic route to monomeric [C]DHA for flux metabolic studies that compared DHA and glyceraldehyde (GA) metabolism, we uncovered that solid DHA ages upon storage and differences in the relative abundance of each of its isomer occur when reconstituted in an aqueous solution. While all three of the dimeric forms of DHA ultimately resolve to the ketone and hydrated forms of monomeric DHA once in water at room temperature, these species require hours rather than minutes to reach an equilibrium favoring the monomeric species. Consequently, when used in bolus or flux experiments, the relative abundance of each isomer and its effects at the time of application is dependent on the initial DHA isomeric composition and concentration, and time of equilibration in solution before use. Here, we make recommendations for the more consistent handling of DHA as we report conditions that ensure that DHA is present in its monomeric form while in solutions, conditions used in an isotopic tracing study that specifically compared monomeric DHA and GA metabolism in cells.
Topics: Dihydroxyacetone; Electronic Nicotine Delivery Systems; Isomerism; Solutions
PubMed: 35324152
DOI: 10.1021/acs.chemrestox.1c00403