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Biomedicine & Pharmacotherapy =... Dec 2018The role of oxidative stress in the occurrence and development of diabetes mellitus is both critical and pivotal. Several molecular event cascade in different metabolic... (Review)
Review
The role of oxidative stress in the occurrence and development of diabetes mellitus is both critical and pivotal. Several molecular event cascade in different metabolic pathways such as glycolytic, hexosamine, protein kinase C, polyol and advanced glycation end-product (AGE) pathways have been identified as pro-oxidative processes and are usually up-regulated in the diabetics. Inhibition of glyceraldehyde-3-P dehydrogenase by poly-ADP-ribose polymerase 1 and subsequent accumulation of the enzyme substrate (glyceraldehyde-3-P) appears to be central to diabetes-associated oxidative stress. Increased level of glyceraldehyde-3-P activates two major pro-oxidative pathways in diabetes: (i) It activates the AGE pathway, precisely the synthesis of methylglyoxal from non-enzymatic dephosphorylation of the triose phosphates (ii) It activates protein kinase C (PKC) pathway by promoting the synthesis of diacylglycerol. In addition, it causes the accumulation of glycolytic metabolites upstream, and this leads to excessive stimulation of other pro-oxidative pathways such as hexosamine and polyol pathways. This review tends to highlight the main oxidative processes associated with diabetes mellitus.
Topics: Animals; Diabetes Mellitus; Glycolysis; Humans; Metabolic Networks and Pathways; Oxidative Stress
PubMed: 30245465
DOI: 10.1016/j.biopha.2018.09.058 -
The Journal of Physiology Mar 2022After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary...
After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell-cell and intracellular lactate shuttles fulfil purposes of energy substrate production and distribution, as well as cell signalling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signalling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristics such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signalling and shuttling are dysregulated as occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance in 21st century biology.
Topics: Biology; Exercise; Glycolysis; Lactic Acid; Mitochondria
PubMed: 33566386
DOI: 10.1113/JP280955 -
Oncogene Jul 2021Glycolysis plays a crucial role in reprogramming the metastatic tumor microenvironment. A series of lncRNAs have been identified to function as oncogenic molecules by...
Glycolysis plays a crucial role in reprogramming the metastatic tumor microenvironment. A series of lncRNAs have been identified to function as oncogenic molecules by regulating glycolysis. However, the roles of glycolysis-related lncRNAs in regulating colorectal cancer liver metastasis (CRLM) remain poorly understood. In the present study, the expression of the glycolysis-related lncRNA MIR17HG gradually increased from adjacent normal to CRC to the paired liver metastatic tissues, and high MIR17HG expression predicted poor survival, especially in patients with liver metastasis. Functionally, MIR17HG promoted glycolysis in CRC cells and enhanced their invasion and liver metastasis in vitro and in vivo. Mechanistically, MIR17HG functioned as a ceRNA to regulate HK1 expression by sponging miR-138-5p, resulting in glycolysis in CRC cells and leading to their invasion and liver metastasis. More interestingly, lactate accumulated via glycolysis activated the p38/Elk-1 signaling pathway to promote the transcriptional expression of MIR17HG in CRC cells, forming a positive feedback loop, which eventually resulted in persistent glycolysis and the invasion and liver metastasis of CRC cells. In conclusion, the present study indicates that the lactate-responsive lncRNA MIR17HG, acting as a ceRNA, promotes CRLM through a glycolysis-mediated positive feedback circuit and might be a novel biomarker and therapeutic target for CRLM.
Topics: Glycolysis; Liver Neoplasms; RNA, Long Noncoding
PubMed: 34145399
DOI: 10.1038/s41388-021-01859-6 -
ELife Jul 2017Genetic tools help to dissect the relationship between aerobic glycolysis and anabolic metabolism in the retinas of mice.
Genetic tools help to dissect the relationship between aerobic glycolysis and anabolic metabolism in the retinas of mice.
Topics: Animals; Glycolysis; Mice; Neoplasms
PubMed: 28681722
DOI: 10.7554/eLife.29217 -
Molecular Cell Sep 2021Metabolic networks support cancer cell survival, proliferation, and malignant progression. Cancer cells take up large amounts of nutrients such as glucose and glutamine...
Metabolic networks support cancer cell survival, proliferation, and malignant progression. Cancer cells take up large amounts of nutrients such as glucose and glutamine whose metabolism provides the energy, reducing equivalents, and biosynthetic precursors required to meet the biosynthetic demands of proliferation. Intermediates of glycolysis and the tricarboxylic acid (TCA) cycle provide critical building blocks for synthesis of non-essential amino acids, nucleotides, and fatty acids. To view this SnapShot, open or download the PDF.
Topics: Amino Acids; Citric Acid Cycle; Energy Metabolism; Glucose; Glutamine; Glycolysis; Humans; Metabolic Networks and Pathways; Neoplasms; Nucleotides
PubMed: 34547243
DOI: 10.1016/j.molcel.2021.06.021 -
Molecular Neurodegeneration Jan 2019Uncontrolled microglial activation contributes to the pathogenesis of various neurodegenerative diseases. Previous studies have shown that proinflammatory microglia are...
BACKGROUND
Uncontrolled microglial activation contributes to the pathogenesis of various neurodegenerative diseases. Previous studies have shown that proinflammatory microglia are powered by glycolysis, which relays on high levels of glucose uptake. This study aimed to understand how glucose uptake is facilitated in active microglia and whether microglial activation can be controlled by restricting glucose uptake.
METHODS
Primary murine brain microglia, BV2 cells and the newly established microglial cell line B6M7 were treated with LPS (100 ng/ml) + IFNγ (100 ng/ml) or IL-4 (20 ng/ml) for 24 h. The expression of glucose transporters (GLUTs) was examined by PCR and Western blot. Glucose uptake by microglia was inhibited using the GLUT1-specific inhibitor STF31. The metabolic profiles were tested using the Glycolysis Stress Test and Mito Stress Test Kits using the Seahorse XFe96 Analyser. Inflammatory gene expression was examined by real-time RT-PCR and protein secretion by cytokine beads array. The effect of STF31 on microglial activation and neurodegeneraion was further tested in a mouse model of light-induced retinal degeneration.
RESULTS
The mRNA and protein of GLUT1, 3, 4, 5, 6, 8, 9, 10, 12, and 13 were detected in microglia. The expression level of GLUT1 was the highest among all GLUTs detected. LPS + IFNγ treatment further increased GLUT1 expression. STF31 dose-dependently reduced glucose uptake and suppressed Extracellular Acidification Rate (ECAR) in naïve, M(LPS + IFNγ) and M(IL-4) microglia. The treatment also prevented the upregulation of inflammatory cytokines including TNFα, IL-1β, IL-6, and CCL2 in M(LPS + IFNγ) microglia. Interestingly, the Oxygen Consumption Rates (OCR) was increased in M(LPS + IFNγ) microglia but reduced in M(IL-4) microglia by STF31 treatment. Intraperitoneal injection of STF31 reduced light-induced microglial activation and retinal degeneration.
CONCLUSION
Glucose uptake in microglia is facilitated predominately by GLUT1, particularly under inflammatory conditions. Targeting GLUT1 could be an effective approach to control neuroinflammation.
Topics: Animals; Glucose; Glucose Transporter Type 1; Glycolysis; Mice; Mice, Inbred C57BL; Microglia; Retinal Degeneration
PubMed: 30634998
DOI: 10.1186/s13024-019-0305-9 -
Blood Oct 2022Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding...
Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal with limited progress. Here, we show that the enzyme Sphk2 (sphingosine kinase 2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of Sphk2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, Sphk2 deletion globally preserves the young HSC gene expression pattern, improves the function, and sustains the multilineage potential of HSCs during aging. Mechanistically, Sphk2 interacts with prolyl hydroxylase 2 and the Von Hippel-Lindau protein to facilitate HIF1α ubiquitination in the nucleus independent of the Sphk2 catalytic activity. Deletion of Sphk2 increases hypoxic responses by stabilizing the HIF1α protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently enhances the function of HSCs by improving their metabolic fitness; specifically, it enhances anaerobic glycolysis but suppresses mitochondrial oxidative phosphorylation and generation of reactive oxygen species. Overall, targeting Sphk2 to enhance the metabolic fitness of HSCs is a promising strategy to expand and rejuvenate functional HSCs.
Topics: Glycolysis; Hematopoietic Stem Cells; Phosphotransferases (Alcohol Group Acceptor); Prolyl Hydroxylases; Reactive Oxygen Species; Sphingosine
PubMed: 35881840
DOI: 10.1182/blood.2022016112 -
Annual Review of Physiology Feb 2023Information processing imposes urgent metabolic demands on neurons, which have negligible energy stores and restricted access to fuel. Here, we discuss metabolic... (Review)
Review
Information processing imposes urgent metabolic demands on neurons, which have negligible energy stores and restricted access to fuel. Here, we discuss metabolic recruitment, the tissue-level phenomenon whereby active neurons harvest resources from their surroundings. The primary event is the neuronal release of K that mirrors workload. Astrocytes sense K in exquisite fashion thanks to their unique coexpression of NBCe1 and α2β2 Na/K ATPase, and within seconds switch to Crabtree metabolism, involving GLUT1, aerobic glycolysis, transient suppression of mitochondrial respiration, and lactate export. The lactate surge serves as a secondary recruiter by inhibiting glucose consumption in distant cells. Additional recruiters are glutamate, nitric oxide, and ammonium, which signal over different spatiotemporal domains. The net outcome of these events is that more glucose, lactate, and oxygen are made available. Metabolic recruitment works alongside neurovascular coupling and various averaging strategies to support the inordinate dynamic range of individual neurons.
Topics: Humans; Energy Metabolism; Glycolysis; Glucose; Lactic Acid; Brain
PubMed: 36270291
DOI: 10.1146/annurev-physiol-021422-091035 -
Cell Metabolism Jul 2019While the timing of food intake is important, it is unclear whether the effects of exercise on energy metabolism are restricted to unique time windows. As circadian...
While the timing of food intake is important, it is unclear whether the effects of exercise on energy metabolism are restricted to unique time windows. As circadian regulation is key to controlling metabolism, understanding the impact of exercise performed at different times of the day is relevant for physiology and homeostasis. Using high-throughput transcriptomic and metabolomic approaches, we identify distinct responses of metabolic oscillations that characterize exercise in either the early rest phase or the early active phase in mice. Notably, glycolytic activation is specific to exercise at the active phase. At the molecular level, HIF1α, a central regulator of glycolysis during hypoxia, is selectively activated in a time-dependent manner upon exercise, resulting in carbohydrate exhaustion, usage of alternative energy sources, and adaptation of systemic energy expenditure. Our findings demonstrate that the time of day is a critical factor to amplify the beneficial impact of exercise on both metabolic pathways within skeletal muscle and systemic energy homeostasis.
Topics: Animals; Blotting, Western; Calorimetry, Indirect; Circadian Rhythm; Energy Metabolism; Glycolysis; Homeostasis; Hypoxia-Inducible Factor 1, alpha Subunit; Lipid Peroxidation; Male; Mass Spectrometry; Mice; Muscle, Skeletal; Physical Conditioning, Animal; Sequence Analysis, RNA; Software; Transcriptome
PubMed: 31006592
DOI: 10.1016/j.cmet.2019.03.013 -
International Journal of Molecular... May 2022Glycolysis represents the process of breaking down monosaccharides, which involves the energy metabolism, homeostasis, and the linkage of various physiological functions...
Glycolysis represents the process of breaking down monosaccharides, which involves the energy metabolism, homeostasis, and the linkage of various physiological functions such as muscle movement, development, neurotransmission, etc [...].
Topics: Energy Metabolism; Glycolysis; Homeostasis; Monosaccharides; Synaptic Transmission
PubMed: 35563443
DOI: 10.3390/ijms23095052