IRAK4 inhibitor mitigates joint inflammation by rebalancing metabolism malfunction in RA macrophages and fibroblasts
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Studies were directed toward defining relationships between brain ion transport, glycolysis, and oxidative phosphorylation. This was done by examining the relative sensitivity to hypoxemia and to iodoacetate (IAA)-induced inhibition of glycolysis in rats anesthetized with pentobarbital. Both insults had minimal effects on K + o baseline. In response to neuronal activation, IAA increased the time required for K + o clearance from maximal values to half-recovery of baseline. Hypoxemia slowed the later phase of K + o clearance, when K + o was approaching “resting” levels. Hypoxemia produced greater declines in high-energy intermediates than did IAA, which indicated that the IAA effect was not due to a greater overall insult to metabolism and suggested a direct link between ATP produced by glycolysis and ion transport activity. These data demonstrate that K + o clearance requires energy from glycolysis and oxidative phosphorylation for different phases of the recovery process and that inhibition specific to glycolysis or oxidative phosphorylation may be temporally resolved within a single stimulus.
Anaerobic glycolysis
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Cellular energy in the form of ATP can be produced through oxidative phosphorylation and through glycolysis. Since oxidative phosphorylation requires oxygen and generates ATP more efficiently than glycolysis, it has been assumed for many years that the presence or absence of oxygen determines that cel ls generate energy through ox idat ive phosphorylation or through glycolysis. Although cells must activate glycolysis in the absence of oxygen to produce ATP, it is now accepted that they can activate both glycolysis and oxidative phosphorylation in the presence of oxygen. In fact, normal proliferating cells and tumor cells are known to have a high glycolytic activity in the presence of adequate oxygen levels, a phenomenon known as aerobic glycolysis or the Warburg effect. Recent observations have demonstrated that the activation of aerobic glycolysis plays a major role in carcinogenesis and tumor growth. Understanding the mechanisms involved in the metabolic switch between oxidative phosphorylation and aerobic glycolysis may therefore be important for the development of potential preventive and therapeutic interventions. In this article, we discuss the role of the intracellular pH in the metabolic switch between oxidative phosphorylation and aerobic glycolysis. We propose that, in the presence of adequate oxygen levels, the intracellular pH may play a key role in determining the way cells obtain energy, an alkaline pH driving aerobic glycolysis and an acidic pH driving oxidative phosphorylation.
Anaerobic glycolysis
Warburg Effect
Metabolic pathway
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Malignant cells are known to enhance glucose metabolism, to increase glucose uptake and to inhibit the process of oxidative phosphorylation. Accelerated glycolysis is one of the biochemical characteristics of cancer cells that allow them to compensate the inefficient extraction of energy from glucose in order to continue their uncontrolled growth and proliferation. Upregulation of glucose transport across the plasma membrane is mediated by a family of facilitated glucose transporter proteins named GLUT. Overexpression of GLUTs, especially the hypoxia-responsive GLUT1, has been frequently observed in various human carcinomas. Many studies have reported a correlation between GLUT1 expression level and the grade of tumor aggressiveness, which suggests that GLUT1 expression may be of prognostic significance. Therefore, GLUT1 is a key rate-limiting factor in the transport and glucose metabolism in cancer cells. This paper presents the current state of knowledge on GLUT1 regulation as well as its utility in the diagnosis and therapy of cancers.
Carbohydrate Metabolism
Hypoxia
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While transformation of normal cells to cancer cells is accompanied with a switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, it is interesting to ask if cancer cells can revert from Warburg effect to OXPHOS. Our previous works suggested that cancer cells reverted to OXPHOS, when they were exposed to lactic acidosis, a common factor in tumor environment. However, the conclusion cannot be drawn unless ATP output from glycolysis and OXPHOS is quantitatively determined. Here we quantitatively measured ATP generation from glycolysis and OXPHOS in 9 randomly selected cancer cell lines. Without lactic acidosis, glycolysis and OXPHOS generated 23.7% - 52.2 % and 47.8% - 76.3% of total ATP, respectively; with lactic acidosis (20 mM lactate with pH 6.7), glycolysis and OXPHOS provided 5.7% - 13.4% and 86.6% - 94.3% of total ATP. We concluded that cancer cells under lactic acidosis reverted from Warburg effect to OXPHOS phenotype.
Lactic acidosis
Warburg Effect
Anaerobic glycolysis
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Warburg Effect
Metabolic pathway
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Abstract The molecular mechanisms by which tumor cells achieve an enhanced glycolytic flux and, presumably, a decreased oxidative phosphorylation are analyzed. As the O 2 concentration in hypoxic regions of tumors seems not limiting for oxidative phosphorylation, the role of this mitochondrial pathway in the ATP supply is re‐evaluated. Drugs that inhibit glycoysis and oxidative phosphorylation are analyzed for their specificity toward tumor cells and effect on proliferation. The energy metabolism mechanisms involved in the use of positron emission tomography are revised and updated. It is proposed that energy metabolism may be an alternative therapeutic target for both hypoxic (glycolytic) and oxidative tumors. © 2009 International Union of Biochemistry and Molecular Biology, Inc.
Bioenergetics
Adenosine triphosphate
Uncoupling Agents
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Glucose uptake has been found to be increased in cancer cells. Previous work has shown increased expression of the human erythrocyte glucose transporter (Glut1) mRNA in some human cancers, indicating that Glut1 may play a significant role in glucose uptake by these tumors. The distribution of Glut1 protein in normal and malignant human tissues is still largely unknown. Using immunohistochemistry, we found that Glut1 is largely undetectable in normal epithelial tissues and benign epithelial tumors but is expressed in a significant proportion of a variety of human carcinomas. We hypothesize that Glut1 expression by human carcinomas indicates an increased glucose uptake, and probably increased utilization of energy, which may correlate with an aggressive behavior. The biological significance of Glut1 expression needs to be determined.
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SUMMARY This paper proposes a mechanism responsible for setting the sustainable level of muscle performance. Our contentions are that the sustainable work rate is determined (i) at the muscle level, (ii) by the ability to maintain ATP supply and (iii) by the products of glycolysis that may inhibit the signal for oxidative phosphorylation. We argue below that no single factor ‘limits’ sustainable performance, but rather that the flux through and the interaction between glycolysis and oxidative phosphorylation set the level of sustainable ATP supply. This argument is based on magnetic resonance spectroscopy measurements of the sources and sinks for energy in vivo in human muscle and rattlesnake tailshaker muscle during sustained contractions. These measurements show that glycolysis provides between 20% (human muscle) and 40% (tailshaker muscle) of the ATP supply during sustained contractions in these muscles. We cite evidence showing that this high glycolytic flux does not reflect an O2 limitation or mitochondria operating at their capacity. Instead, this flux reflects a pathway independent of oxidative phosphorylation for ATP supply during aerobic exercise. The consequence of this high glycolytic flux is accumulation of H+, which we argue inhibits the rise in the signal activating oxidative phosphorylation, thereby restricting oxidative ATP supply to below the oxidative capacity. Thus, both glycolysis and oxidative phosphorylation play important roles in setting the highest steady-state ATP synthesis flux and thereby determine the sustainable level of work by exercising muscle.
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Oligomycin
Deoxyglucose
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