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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 -
Cell Metabolism Jan 2020Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial...
Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2α (HIF-2α) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2α via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.
Topics: Adolescent; Animals; Anti-Bacterial Agents; Basic Helix-Loop-Helix Transcription Factors; Cell Line; Cell Proliferation; Diamines; Dimerization; Duodenum; Feces; Female; Ferritins; Gastrointestinal Microbiome; Glyceraldehyde; Homeostasis; Humans; Iron; Lactobacillus; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Organoids; Probiotics; Propane; Signal Transduction
PubMed: 31708445
DOI: 10.1016/j.cmet.2019.10.005 -
Cogent Biology 2019Acetaldehyde is a physiological species existing in blood. Glyceraldehyde is a commonly-used surrogate for glucose in studies of nonenzymatic glycation. Both species...
New Evidence for the Diversity of Mechanisms and Protonated Schiff Bases Formed in the Non-Enzymatic Covalent Protein Modification (NECPM) of HbA by the Hydrate and Aldehydic Forms of Acetaldehyde and Glyceraldehyde.
Acetaldehyde is a physiological species existing in blood. Glyceraldehyde is a commonly-used surrogate for glucose in studies of nonenzymatic glycation. Both species exist in dynamic equilibrium between two forms, an aldehyde and a hydrate. Nonenzymatic covalent protein modification (NECPM) is a process whereby a protein is covalently modified by a non-glucose species. The purpose here was to elucidate the NECPM mechanism(s) for acetaldehyde and glyceraldehyde with human hemoglobin (HbA). For the first time, both aldehydic and hydrate forms of acetaldehyde and glyceraldehyde were considered. Computations and model reactions followed by H NMR were employed. Results demonstrated that the aldehyde and hydrate forms of acetaldehyde bind and covalently-modify Val1 of HbA via different chemical mechanisms, yet generated an identical protonated Schiff base (PSB). The aldehyde and hydrate of glyceraldehyde also covalently-modified Val1 via mechanisms distinct from one another, yet generated an identical PSB. It is noteworthy that the PSB from acetaldehyde and glyceraldehyde were different structures. The PSB from acetaldehyde is proposed to proceed to covalent adducts that have been implicated in alcohol toxicity. Conversely, the PSB generated from glyceraldehyde can form an Amadori which has been implicated in diabetic complications. Thus, the PSB structure generated from acetaldehyde versus glyceraldehyde may be central to pathophysiological outcomes because it determines the structure of the stable covalent adduct formed.
PubMed: 31440524
DOI: 10.1080/23312025.2019.1584955 -
Acta Crystallographica. Section F,... Sep 2020Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in the glycolytic pathway that catalyzes the conversion of D-glyceraldehyde 3-phosphate to...
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in the glycolytic pathway that catalyzes the conversion of D-glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate. Here, the full-length GAPDH type 1 from Escherichia coli (EcGAPDH1) was cloned and overexpressed, and the protein was purified. Biochemical analyses found that the optimum reaction temperature and pH of EcGAPDH1 were 55°C and 10.0, respectively. The protein has a certain amount of thermostability. Crystals of EcGAPDH1 were obtained using the sitting-drop vapor-diffusion technique and X-ray diffraction data were collected to 1.88 Å resolution. Characterization of the crystals showed that they belonged to space group P422, with unit-cell parameters a = b = 89.651, c = 341.007 Å, α = β = γ = 90°. The structure of EcGAPDH1 contains four subunits, each of which includes an N-terminal NAD-binding domain and a C-terminal catalytic domain. Analysis of the NAD-bound form showed some differences between the structures of EcGAPDH1 and human GAPDH. As EcGAPDH1 shares 100% identity with GAPDH from Shigella sonnei, its structure may help in finding a drug for the treatment of shigellosis.
Topics: Amino Acid Sequence; Catalytic Domain; Cloning, Molecular; Crystallography, X-Ray; Escherichia coli; Escherichia coli Proteins; Gene Expression; Genetic Vectors; Glyceraldehyde 3-Phosphate; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Models, Molecular; NAD; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Subunits; Recombinant Proteins; Shigella sonnei
PubMed: 32880588
DOI: 10.1107/S2053230X20010067 -
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 -
Cells Apr 2021Glyceraldehyde-derived advanced glycation end products (AGEs) play an important role in the pathogenesis of many diseases including cancer. Accumulation of intracellular...
Glyceraldehyde-derived advanced glycation end products (AGEs) play an important role in the pathogenesis of many diseases including cancer. Accumulation of intracellular AGEs could stimulate cancer induction and facilitate cancer progression. We evaluated the toxic effect of glyceraldehyde-derived intracellular AGEs on normal and malignant pancreatic ductal cells by assessing the cell viability, toxicity, and oxidative stress, followed by proteomic analysis. Our functional studies showed that pancreatic cancer cells (PANC-1 and MIA PaCa-2) were more resistant to glyceraldehyde treatment compared to normal pancreatic ductal epithelial cells (HPDE), while cytotoxicity effects were observed in all cell types. Furthermore, using C isotopic labeled glyceraldehyde, the proteomic data revealed a dose-dependent increment of the number of glycation adducts in both these cell types. HPDE cells showed a higher number of intracellular AGEs compared to cancer cells. At a molecular level, the glycations in the lysine residues of proteins showed a concurrent increase with the concentration of the glyceraldehyde treatment, while the arginine glycations appeared to be less affected by the glyceraldehyde doses. Further pathway analysis of these glycated proteins suggested that the glycated proteins participate in important biological processes that are major hallmarks of cancer initiation and progression, including metabolic processes, immune response, oxidative stress, apoptosis, and S100 protein binding.
Topics: Apoptosis; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Survival; Glycation End Products, Advanced; Glyceraldehyde; Glycosylation; Humans; Oxidative Stress; Pancreatic Neoplasms; Proteome; Tumor Cells, Cultured
PubMed: 33923186
DOI: 10.3390/cells10051005 -
Blood Apr 1983Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of... (Comparative Study)
Comparative Study Review
Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of deoxyhemoglobin S or Csat, (2) evaluation of sickling in whole SS blood at various pO2s, (3) measurement of the oxygen affinity of hemoglobin and blood, and (4) examination of red cell indices and morphology. Among the 4 noncovalent agents tested, butylurea was the most potent inhibitor of gelation and sickling in vitro; however, relatively high concentrations were required compared to the covalent agents. In the latter group, bis-(3,5 dibromosalicyl)-fumarate, nitrogen mustard, and dimethyladipimidate were especially effective inhibitors of gelation and/or sickling. All of these compounds require further development before they can be considered for clinical use.
Topics: Anemia, Sickle Cell; Antisickling Agents; Aspirin; Azepines; Carbamyl Phosphate; Cyanates; Cystamine; Dimethyl Adipimidate; Drug Evaluation; Erythrocyte Indices; Glyceraldehyde; Hemoglobins; Humans; Imidoesters; Mechlorethamine; Oxygen Consumption; Phenylalanine; Pyridoxal; Solubility; Urea
PubMed: 6338971
DOI: No ID Found -
Pathogens (Basel, Switzerland) Mar 2020Bast fibers and products derived from them are undergoing a resurgence in demand in the global market. However, fungal diseases have become an important factor limiting... (Review)
Review
Bast fibers and products derived from them are undergoing a resurgence in demand in the global market. However, fungal diseases have become an important factor limiting their yield and quality, causing devastating consequences for the production of bast fiber crops in many parts of the world. Thus, there is a high demand for effective control and prevention strategies against fungal pathogens. Having rapid, specific, sensitive, and cost-effective tests that can be used for early and accurate diagnosis of disease agents is an essential step of such strategies. The objective of this study was to review the current status of research on molecular diagnosis of fungal pathogens on bast fiber crops. Our search of PubMed identified nearly 20 genera of fungal pathogens on bast fiber crops, among which the five most common genera were , , , , and . The gene regions that have been used for molecular identifications of these fungi include internal transcribed spacer (ITS), translation elongation factor 1-α (), ß-tubulin, calmodulin (), histone subunit 3 (), glyceraldehydes-3-phosphate dehydrogenase (), etc. We summarize the molecular assays that have been used to identify these fungi and discuss potential areas of future development for fast, specific, and accurate diagnosis of fungal pathogens on bast fiber crops.
PubMed: 32197350
DOI: 10.3390/pathogens9030223 -
Nature Communications Sep 2022The selective oxidation of glycerol to glyceric acid, an important value-added reaction from polyols, is a typical cascade catalytic process. It is still of great...
The selective oxidation of glycerol to glyceric acid, an important value-added reaction from polyols, is a typical cascade catalytic process. It is still of great challenge to simultaneously achieve high glycerol activity and glyceric acid selectivity, suffering from either deep oxidation and C-C cleavage or poor oxidation efficiency from glyceraldehyde to glyceric acid. Herein, this work, inspired by nature, proposes a cascade synergistic catalysis strategy by atomic and low-coordinated cluster Pt on well-defined Cu-CuZrO, which involves enhanced C-H activation on atomic Pt and O-H activation on cluster Pt in the oxidation of glycerol to glyceraldehyde, and cluster Pt for C=O activation followed by O-H insertion and atomic Pt for C-H activation in the tandem oxidation of glyceraldehyde to glyceric acid. The enhanced C-H activation in the cascade process by atomic Pt is revealed to be essential for the high glycerol activity (90.0±0.1%) and the glyceric acid selectivity (80.2±0.2%).
Topics: Catalysis; Glyceraldehyde; Glyceric Acids; Glycerol
PubMed: 36115832
DOI: 10.1038/s41467-022-33038-w -
Cardiovascular Diabetology Jan 2015We have previously shown that serum levels of glyceraldehyde-derived advanced glycation end products (Gly-AGEs) are elevated under oxidative stress and/or diabetic...
BACKGROUND
We have previously shown that serum levels of glyceraldehyde-derived advanced glycation end products (Gly-AGEs) are elevated under oxidative stress and/or diabetic conditions and associated with insulin resistance, endothelial dysfunction and vascular inflammation in humans. Further, Gly-AGEs not only evoke oxidative and inflammatory reactions in endothelial cells (ECs) through the interaction with a receptor for AGEs (RAGE), but also mimic vasopermeability effects of AGE-rich serum purified from diabetic patients on hemodialysis. These observations suggest that Gly-AGE-RAGE system might be a therapeutic target for vascular complications in diabetes. However, since incubation of glyceraldehyde with proteins will generate a large number of structurally distinct AGEs, it remains unclear what type of AGE structures could mediate the deleterious effects of Gly-AGEs on ECs.
AIMS AND METHODS
Therefore, in this study, we examined (1) whether glyceraldehyde-derived pyridinium (GLAP), one of the Gly-AGEs generated by the incubation of lysine with glyceraldehyde, elicited reactive oxygen species (ROS) generation and inflammatory and thrombogenic gene expression in human umbilical vein ECs (HUVECs) via the interaction with RAGE and (2) if DNA aptamers raised against Gly-AGEs or GLAP (AGE-aptamer or GLAP-aptamer) inhibited the binding of GLAP to RAGE and subsequently suppressed the harmful effects of GLAP on HUVECs.
RESULTS
GLAP stimulated ROS generation in a bell-shaped manner; GLAP at 10 μg/ml increased ROS generation in HUVECs by 40%, which was blocked by the treatment with RAGE-antibody (RAGE-Ab). Ten μg/ml GLAP significantly up-regulated mRNA levels of RAGE, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and plasminogen activator inhibitor-1 in HUVECs, which were also suppressed by RAGE-Ab. AGE-aptamer or GLAP-aptamer significantly blocked these deleterious effects of GLAP on HUVECs. Moreover, quartz crystal microbalance analyses revealed that GLAP actually bound to RAGE and that AGE-aptamer or GLAP-aptamer inhibited the binding of GLAP to RAGE.
CONCLUSIONS
The present study suggests that GLAP might be a main glyceraldehyde-related AGE structure in Gly-AGEs that bound to RAGE and subsequently elicited ROS generation and inflammatory and thrombogenic reactions in HUVECs. Blockade of the GLAP-RAGE interaction by AGE-aptamer or GLAP-aptamer might be a novel therapeutic strategy for preventing vascular injury in diabetes.
Topics: Endothelial Cells; Glyceraldehyde; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Oxidative Stress; Pyridinium Compounds; Reactive Oxygen Species; Receptor for Advanced Glycation End Products; Thrombosis
PubMed: 25582325
DOI: 10.1186/s12933-014-0162-3