2-Deoxyglucose and inflammation.
TL;DR: Evidence is presented which suggests that the anti-oedematous effect of this compound is mediated through this latter mechanism, and it seems that a direct effect on glycolysis is unlikely to be important.
Abstract: Sr~,-2-Deoxyglucose reduces oedema formation produced by injecting dextran into rats (Goth, 1959), and also inhibits the development of erythema in guinea-pigs exposed to ultraviolet irradiation (Gorog & Szporny, 1964). The anti-inflammatory activity of 2-deoxyglucose is generally supposed to be connected with its effects on carbohydrate metabolism. However, 2-deoxyglucose also stimulates the release of catecholamines from the adrenal medulla (Brown & Bachrach, 1959; Hokfelt & Bydgeman, 1961), and evidence is presented which suggests that the anti-oedematous effect of this compound is mediated through this latter mechanism. Groups of six female rats, 140-170 g, received an intraperitoneal injection of saline or 2-deoxyglucose, 250 mg/kg, 30 min before an injection beneath the left hind paw of 0.1 ml of the supernatant fluid from a 5% suspension of Brewers yeast. Foot volumes were recorded plethysmometrically before and 3/4 hr after the injection. Adrenalectomy or adrenal demedullation was performed 1 week before the experiment, and the adrenalectomised rats were maintained on 1% saline instead of tap water. Blood was taken by cardiac puncture at the time of the second foot-volume measurement. The % inhibition of oedema and % increase in blood sugar caused by 2-deoxyglucose were, in normal 58.9 and 81.7, in adrenalectomised 6.2 and 12.2 and in adrenaldemedullated rats 1.1 and 15.7 respectively. In adrenalectomised and demedullated animals this compound has no anti-oedematous effect and its hyperglycaemic activity is reduced but not abolished. Other irritants such as formaldehyde or silver nitrate have been used and the results were similar. Propranolol, 10 mg/kg i.m., given 1 hr before 0.1 ml of the yeast extract, antagonises the anti-oedematous activity of adrenaline, 0.5 mg/kg s.c., and 2-deoxyglucose, 250 mg/kg i.p., given 30 min before the yeast extract. Propranolol, by itself does not affect oedema formation, a % inhibition of 3.1 being obtained, nor does it modify the anti-oedematous effects of cyproheptadine, phenylbutazone or hydrocortisone (Kellett, 1966). 2-Deoxyglucose caused a 62.9% inhibition of oedema, adrenaline 66.3, deoxyglucose + propranolol 27-4 and adrenaline + propranolol29.3% inhibition. There were six rats per group. While the assumption that 2-deoxyglucose inhibits inflammatory reactions by an effect on carbohydrate metabolism may still be correct, it seems that a direct effect on glycolysis is unlikely to be important. It is possible, however, that an indirect effect on carbohydrate metabolism, through catecholamine release from the adrenal medulla, may be involved. Impaired disposition of a glucose load is seen after the injection of 2-deoxyglucose into normal rats, but
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TL;DR: It is found that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF, and its direct regulation of survival and function in the inflammatory microenvironment is demonstrated.
1,773 citations
Cites background or result from "2-Deoxyglucose and inflammation."
...As hen et al., 1967; Kellett, 1966; Kittlick, 1986; Manns, 1967; Weisdorf et al., 1982b), we postulated that theshown in Figure 3A, lactate release is significantly lower in HIF-1 null macrophages, relative to wild-type cells, large decrease in ATP levels caused by decreased glycolysis in myeloid…...
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...Here, we have examined the inflammatory no effect on the inflammatory reponse (Borregaard and response in mice with conditional knockouts of the Herlin, 1982; Kellett, 1966)....
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TL;DR: New insights are providing a deeper understanding of the role of metabolic reprogramming in innate immunity, and another TCA cycle intermediate, succinate, activates HIF-1α and promotes inflammatory gene expression.
Abstract: Activation of macrophages and dendritic cells (DCs) by pro-inflammatory stimuli causes them to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS), similar to the Warburg effect in tumors. However, it is only recently that the mechanisms responsible for this metabolic reprogramming have been elucidated in more detail. The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role under conditions of both hypoxia and normoxia. The withdrawal of citrate from the tricarboxylic acid (TCA) cycle has been shown to be critical for lipid biosynthesis in both macrophages and DCs. Interference with this process actually abolishes the ability of DCs to activate T cells. Another TCA cycle intermediate, succinate, activates HIF-1α and promotes inflammatory gene expression. These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity.
1,128 citations
TL;DR: HIF1α is a key reprogrammer of metabolism in inflammatory cells that promotes inflammatory gene expression and is critically involved in glycolysis and the induction of proinflammatory genes, notably Il1b.
Abstract: HIF1α is a common component of pathways involved in the control of cellular metabolism and has a role in regulating immune cell effector functions. Additionally, HIF1α is critical for the maturation of dendritic cells and for the activation of T cells. HIF1α is induced in LPS-activated macrophages, where it is critically involved in glycolysis and the induction of proinflammatory genes, notably Il1b. The mechanism of LPS-stimulated HIF1α induction involves succinate, which inhibits prolyl hydroxylases (PHDs). Pyruvate kinase M2 (PKM2) is also induced and interacts with and promotes the function of HIF1α. In another critical inflammatory cell type, Th17 cells, HIF1α acts via the retinoic acid-related orphan receptor-γt (RORγt) to drive Th17 differentiation. HIF1α is therefore a key reprogrammer of metabolism in inflammatory cells that promotes inflammatory gene expression.
389 citations
Cites background from "2-Deoxyglucose and inflammation."
...Inhibitors of oxidative phosphorylation have no effect following LPS treatment, indicating that this process is already downregulated by LPS (46)....
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TL;DR: The systematic characterization of caspase-1 substrates identifies the glycolysis pathway as a caspite-1 target and provides new insights into its function during pyroptosis and septic shock.
307 citations
TL;DR: It is demonstrated that the IL-4/STAT6 immune axis, a key pathway in helminth immunity and allergies, controls peripheral nutrient metabolism and insulin sensitivity, and an unexpected molecular link between the immune system and macronutrient metabolism is identified.
Abstract: Immune cells take residence in metabolic tissues, providing a framework for direct regulation of nutrient metabolism. Despite conservation of this anatomic relationship through evolution, the signals and mechanisms by which the immune system regulates nutrient homeostasis and insulin action remain poorly understood. Here, we demonstrate that the IL-4/STAT6 immune axis, a key pathway in helminth immunity and allergies, controls peripheral nutrient metabolism and insulin sensitivity. Disruption of signal transducer and activator of transcription 6 (STAT6) decreases insulin action and enhances a peroxisome proliferator-activated receptor α (PPARα) driven program of oxidative metabolism. Conversely, activation of STAT6 by IL-4 improves insulin action by inhibiting the PPARα-regulated program of nutrient catabolism and attenuating adipose tissue inflammation. These findings have thus identified an unexpected molecular link between the immune system and macronutrient metabolism, suggesting perhaps the coevolution of these pathways occurred to ensure access to glucose during times of helminth infection.
221 citations
Cites background from "2-Deoxyglucose and inflammation."
...Interestingly, the ability of macrophages and neutrophils to support antimicrobial programs is completely dependent on the maintenance of high flux through the glycolytic pathways (3, 4)....
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References
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TL;DR: The inability of 2-DG to cause increased adrenaline secretion after denervation of the adrenal glands points to its action via a centrally located receptor mechanism regulating adrenaline secretion; this center seems not to be sensitive to the blood glucose level as such.
Abstract: Summary2-deoxyglucose(2-DG) causes marked release of adrenaline from the adrenal medulla in the intact rat but not after adrenal denervation. The adrenaline released is to a great extent responsible for the hyperglycemia appearing after 2-DG, but other factors might also be involved. The inability of 2-DG to cause increased adrenaline secretion after denervation of the adrenal glands points to its action via a centrally located receptor mechanism regulating adrenaline secretion; this center seems not to be sensitive to the blood glucose level as such.
90 citations
"2-Deoxyglucose and inflammation." refers background in this paper
...However, 2-deoxyglucose also stimulates the release of catecholamines from the adrenal medulla (Brown & Bachrach, 1959; Hokfelt & Bydgeman, 1961), and evidence is presented which suggests that the anti-oedematous effect of this compound is mediated through this latter mechanism....
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TL;DR: The glucose analogue 2-deoxyglucose was found to inhibit the anaphylactoid reaction of rats to dextran and ovomucoid and this results point to an important role of glucose permeability in certain inflammatory processes.
Abstract: The glucose analogue 2-deoxyglucose was found to inhibit the anaphylactoid reaction of rats to dextran and ovomucoid. A dose of 200 mg/kg of 2-deoxyglucose was sufficient to antagonize the effects of 60 mg/kg of dextran or 10 mg/kg of ovomucoid when these compounds were injected by the intravenous route. The reaction of rats to compound 48/80 was not inhibited. In rats pretreated with insulin larger doses of 2-deoxyglucose were required to obtain the same inhibition of anaphylactoid edema. These results and the previously demonstrated effects of insulin point to an important role of glucose permeability in certain inflammatory processes.
29 citations
"2-Deoxyglucose and inflammation." refers background in this paper
...2-Deoxyglucose and inflammation Sr~,-2-Deoxyglucose reduces oedema formation produced by injecting dextran into rats (Goth, 1959), and also inhibits the development of erythema in guinea-pigs exposed to ultraviolet irradiation (Gorog & Szporny, 1964)....
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TL;DR: There was no impairment of disposition of a glucose load in adrenal-demedullated anesthetized rats pre-treated with large doses of deoxyglucose, suggesting that this glucose analogue is capable of stimulating release of epinephrine from the adrenal medulla.
Abstract: Discussion and SummaryDespite unquestionable evidence from the work of others that 2-deoxyglucose inhibits glucose oxidation in isolated tissues and eviscerated rabbits there was no impairment of disposition of a glucose load in adrenal-demedullated anesthetized rats pre-treated with large doses of deoxyglucose. This suggests that other pathways of glucose disposal must be utilized which compensate for inhibition of oxidation. These avenues of glucose disposal will be explored. Inhibition by DHE of the hyperglycemia which results from injection of deoxyglucose into intact fasted rats suggests that this glucose analogue is capable of stimulating release of epinephrine from the adrenal medulla. The lack of hyperglycemia following deoxyglucose injection in adrenal demedullated rats lends support to this hypothesis.
19 citations
"2-Deoxyglucose and inflammation." refers background in this paper
...Pharmac., 1966, 18, 200 this effect is absent in adrenal demedullated animals (Brown & Bachrach, 1959)....
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...However, 2-deoxyglucose also stimulates the release of catecholamines from the adrenal medulla (Brown & Bachrach, 1959; Hokfelt & Bydgeman, 1961), and evidence is presented which suggests that the anti-oedematous effect of this compound is mediated through this latter mechanism....
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TL;DR: To clarify the role of the major energy producing processes-glycolysis and oxidation-in the development of ultra-violet-induced erythema the authors examined the influence of some enzyme inhibitors, of known biological mechanisms of action, in guinea-pigs.
Abstract: Sm,-Among the methods applied to the measurement of the anti-inflammatory activity of nonsteroid compounds is the inhibition of ultra-violet lightinduced erythema in guinea-pigs. The advantages of the method are its sensitivity and specificity and the close relation between clinical and antierythemic doses. Having subjected more than a hundred compounds to careful analysis, Winder (1958) concluded that only the well known antiphlogistics used clinically have a significant anti-erythemic effect. The existence of a correlation of the antiphlogistic and metabolism-inhibiting (uncoupling) effect of nonsteroid agents is becoming an accepted hypothesis (Whitehouse, 1963). Thus, to clarify the role of the major energy producing processes-glycolysis and oxidation-in the development of ultra-violet-induced erythema we examined the influence of some enzyme inhibitors, of known biological mechanisms of action, in guinea-pigs. The effect of these compounds has not been investigated in this way before. The depilated skin of the guinea-pig's back was irradiated with a lo00 W mercury lamp. Heat rays were filtered by cold water in a quartz tube. Each spot was irradiated for 80 sec. The spots were scored by marks 0, 0.5 and 1, the maximum score for the total of the three spots irradiated being 3 per animal. If the effect scored was below or equal to 1.5 in an animal, this was considered as an inhibition. Table 1 shows that the substances when administered in non-toxic doses, intensely inhibited the appearance of erythema. 2-Deoxyglucose inhibits
6 citations
"2-Deoxyglucose and inflammation." refers background in this paper
...2-Deoxyglucose and inflammation Sr~,-2-Deoxyglucose reduces oedema formation produced by injecting dextran into rats (Goth, 1959), and also inhibits the development of erythema in guinea-pigs exposed to ultraviolet irradiation (Gorog & Szporny, 1964)....
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...…from these experiments about the mode of action of 2-deoxyglucose in the ultraviolet erythema test, but it would be unwise to assume that its effect is due solely to alterations in carbohydrate metabolism (Gorog & Szporny, 1964), since an effect on the adrenal medulla may also be involved....
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