Dietary Substances Not Required in Human Metabolism
Luke Bucci in Nutrients as Ergogenic Aids for Sports and Exercise, 2020
Succinic acid is a component of the Krebs cycle, and as such is added to several dietary supplements with accompanying claims of ergogenesis. Only one report of succinate on exercise performance was found.913 Fasted male mice (serving as their own controls) were fed 0,30, or 300 mg/kg sodium succinate, and swim tests to exhaustion started at 30, 60, and 120 min post-feeding. The only group to show improvement in swim times was the 300 mg/kg group 2 h after feeding (455 vs. 389 sec). Retesting of swim times 3 h after initial swim tests revealed no effects of succinate. Chronic feeding (7 d of 20 mg/ml succinate in drinking water) did not affect swim times. Results suggested that large doses of sodium succinate may improve exercise performance in swimming mice under certain conditions, and that extrapolation to humans would indicate that huge doses of succinate need to be studied for a possible ergogenic effect. No guidelines in humans for succinate supplementation exist at this time.
4-Hydroxybutyric aciduria
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
The molecular defect in 4-hydroxybutyric aciduria is in the enzyme succinic semialdehyde hydrogenase (EC 1.2.1.2) (see Figure 13.1) [5, 27, 28]. Succinic semialdehyde is the product of the transamination of GABA and is normally converted to succinic acid. When succinic semialdehyde accumulates, it is alternatively reduced to 4-hydroxybutyric acid. The enzyme is active in lymphocytes freshly isolated from peripheral blood and in cultured lymphoblasts [5, 21, 27, 28]. Accumulation of labeled succinic semialdehyde has been demonstrated in patients’ lymphocytes following incubation with 14C-labeled GABA, and there was no evidence of further metabolism to succinic acid [5]. Direct assay of the enzyme with 14C-labeled succinic semialdehyde yielded activity that approximated 4 percent of the control level in one patient [27] and was undetectable in another. In another [20], it was as high as 21 percent in lymphocytes.
Carbohydrates
S.J. Mulé, Henry Brill in Chemical and Biological Aspects of Drug Dependence, 2019
In 1935 Himwich and Fazekas reported that nicotine (14 mM) reduced the “no substrate” respiration of minced brain of rat, cat and dog and inhibited by 60% the increased oxygen uptake with added lactate, but it had no effect on the increase with added glucose or pyruvate.80,81 It was concluded that lactic dehydrogenase was inhibited. Oxidation of succinate was also inhibited. These observations led Himwich and Fazekas to suggest that glucose oxidation in brain might proceed directly without previous glycolysis, a suggestion based on the assumption that lactate was an intermediate in the oxidation of glucose via the glycolytic pathway of metabolism. The precise role of lactate in carbohydrate metabolism was a matter of debate at that time, and it was not then commonly realized that pyruvate is reduced to lactate in quantity only when there is insufficient oxygen for its complete oxidation. Nor was it always appreciated that an inhibitor of lactic dehydrogenase would inhibit the formation of lactate to the same extent that it inhibits its oxidation. It is however of interest that it was this early work with nicotine that inspired later research leading to the discovery of alternative metabolic pathways for the oxidation of glucose.
Dexmedetomidine enables copper homeostasis in cerebral ischemia/reperfusion via ferredoxin 1
Published in Annals of Medicine, 2023
Qingduo Guo, Meina Ma, Hong Yu, Yuepeng Han, Dong Zhang
Isolation of mitochondria was performed using a tissue mitochondrial isolation kit (Beyotime, Shanghai, China). Fresh brain tissue was homogenized in mitochondrial isolation reagent and centrifuged at 600 × g, 4 °C for 5 min. The obtained supernatant was centrifuged at 11,000 × g, 4° C for 10 min, and the precipitate was the mitochondria, which was then resuspended in storage buffer. Clark electrode instrument was applied to measure dissolved oxygen solubility in a 25 °C water bath. Fresh mitochondria were placed in the chamber until the rate of oxygen consumption stabilized. Supplementation with succinate to test low oxygen consumption rate (R IV) followed by ADP to stimulate high oxygen consumption rate (R III). RCR (R III/R IV) may indicate the mitochondrial capacity for oxidative phosphorylation.
Dysregulated metabolism: A friend-to-foe skewer of macrophages
Published in International Reviews of Immunology, 2023
Keywan Mortezaee, Jamal Majidpoor
Increasing the production of succinate is important for regulation of macrophage polarization. Succinate is a known regulator of pro-inflammatory responses, mediated through HIF-1α stabilization and suppression of anti-inflammatory gene expression profile. Glutamine synthetase is an enzyme related to acid-base homeostasis and nitrogen metabolism. M2 macrophages under starvation induce the activity of glutamine synthase for production of glutamine. Blockade of glutamine synthase causes M2-to-M1 skewing of macrophages and the resultant tumor regression. Incubation of M2 macrophages with the glutamine synthase inhibitor methionine sulfoximine causes succinate accumulation and increased glucose utilization, thereby promoting metabolic rewiring toward attaining M1-like phenotype. Succinate is contributed to HIF-1α stabilization, so it is expected that blockade of glutamine synthase will cause HIF-1α activation, as it is attested [84]. Due to the interference between PKM2 activity with succinate accumulation and glycolysis for M1 polarization, a suggested strategy could be targeting PKM2.
Microbiome therapeutics for the treatment of recurrent Clostridioides difficile infection
Published in Expert Opinion on Biological Therapy, 2023
Patricia P Bloom, Vincent B Young
Alterations in short-chain fatty acid (SCFA) composition can also contribute to rCDI and represent another potential treatment target. SCFA are the main fermentation products of dietary fibers [33,34]. Antibiotic-induced diarrhea is associated with a decrease in succinate-utilizing microbes, and a corresponding increase in succinate availability [35]. On the other hand, rCDI is associated with a loss of butyrate-producing Firmicutes species and low levels of many SCFAs [36]. C. difficile is able to utilize succinate as a carbon source, which can provide a nutrition advantage in an environment deficient in microbial competitors [37]. In one experiment, a defined consortium of 58 bacteria from a healthy donor (DEC58) was treated with ciprofloxacin [37]. The cell-free supernatant of DEC58, containing metabolites, and separately ciprofloxacin-treated DEC58 were applied to bioreactors containing C. difficile. Ciprofloxacin-treated DEC58 supernatant promoted vegetative cell growth of C. difficile, while DEC58 supernatant did not. The main metabolite responsible for this difference was succinate. The ciprofloxacin-treated DEC58 yielded higher concentrations of succinate, which C. difficile was able to utilize. In terms of the potential role of SCFA in recurrent CDI, it has been shown that successful treatment of rCDI with FMT has been associated with restoration of both bile acid profiles and normal levels of SCFAs [38].
Related Knowledge Centers
- Dicarboxylic Acid
- Electron Transport Chain
- Fumaric Acid
- Metabolic Intermediate
- Succinate Dehydrogenase
- Citric Acid Cycle
- Chemical Formula
- Ion
- Adenosine Triphosphate
- Mitochondrion