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Treatment and Pharmacological Interventions in Streptozotocin Diabetes
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Mary L. Battell, Brian Rodrigues, Violet G. Yuen, John H. McNeill
When the carnitine level in tissues is increased, the preexisting acetyl CoA is transformed into acetyl carnitine which can then (1) remain as a storage depot, (2) be converted into fatty acid or cholesterol, or (3) cross the mitochondrial membrane back to the cytosol and from there into the circulation to be eventually excreted in the urine. An important consequence of this effect of carnitine is that it serves as a buffer of the metabolically critical acetyl CoA pool and hence decreases the intramitochondrial acetyl CoA/CoA ratio. As acetyl CoA, by activating pyruvate dehydrogenase kinase, inactivates pyruvate dehydrogenase, a decrease in this ratio results in a subsequent increase in the oxidative utilization of glucose. In addition, as the rate of oxidation of pyruvate is increased, this metabolite is diverted from its reduction to lactate to its oxidation to acetyl CoA.
Glutamine
Published in Elling Kvamme, Glutamine and Glutamate in Mammals, 1988
J. Tyson Tildón, H. Ronald Zielke
The question of why tumor cells, as well as fibroblasts, primarily metabolize glucose to lactate rather than oxidize pyruvate totally to C02 via the TCA cycle is still unresolved. This topic has been extensively reviewed by Pederson.51 However, his suggestion that cultured cells may have reduced capacity to oxidize pyruvate is questionable. The oxidation rate of 100 μΜ[1-14] pyruvate by human fibroblasts was 4.9 compared to 36.0 nmol/hr/ mg protein for 500 μΜ pyruvate.71a Glutamine had no effect on the rate of pyruvate oxidation, nor did pyruvate affect the rate of glutamine oxidation.18 The oxidation rate of pyruvate is greater than that of glucose (see Table 1). The greater oxidation rate with 500 μΜ pyruvate compared to 100 μΜ pyruvate may indicate that pyruvate inactivates the pyruvate dehydrogenase kinase, an inhibitor of pyruvate dehydrogenase.72 The concentration effect of pyruvate is probably not related to the Km (pyruvate) of pyruvate dehydrogenase which is 42 μΜ.73
Targeting glucose metabolism to develop anticancer treatments and therapeutic patents
Published in Expert Opinion on Therapeutic Patents, 2022
Yan Zhou, Yizhen Guo, Kin Yip Tam
It is also worth noting that pyruvate dehydrogenase kinase 4 (PDK4) has emerged to exhibit multiple novel functions in addition to the metabolic role in cancer cells. Recent studies revealed that Pdk4-/- mice exhibited enhanced hepatocyte proliferation and similar phenomena, which were also reflected in PDK4 knockdown hepatocellular carcinoma cells, suggesting PDK4 also plays a potential role in cell cycle regulation [71]. Moreover, another study revealed that PDK4 stood at the checkpoint to determine the hepatocyte extrinsic apoptosis mediated by NF-κB/TNF [72]. Together with other studies related to PDK4 inhibition and apoptosis in breast cancer [73], lung and colorectal cancer [74], PDK4 inhibitors appear to play a pivotal role in triggering cell death in some specific cancers.
The commensal bacterium Lactiplantibacillus plantarum imprints innate memory-like responses in mononuclear phagocytes
Published in Gut Microbes, 2021
Aize Pellon, Diego Barriales, Ainize Peña-Cearra, Janire Castelo-Careaga, Ainhoa Palacios, Nerea Lopez, Estibaliz Atondo, Miguel Angel Pascual-Itoiz, Itziar Martín-Ruiz, Leticia Sampedro, Monika Gonzalez-Lopez, Laura Bárcena, Teresa Martín-Mateos, Jose María Landete, Rafael Prados-Rosales, Laura Plaza-Vinuesa, Rosario Muñoz, Blanca de las Rivas, Juan Miguel Rodríguez, Edurne Berra, Ana M. Aransay, Leticia Abecia, Jose Luis Lavín, Hector Rodríguez, Juan Anguita
Analysis of monocyte transcriptomic profiles also allowed us to identify the impact of priming in several metabolic pathways of monocytes in comparison with cells acutely exposed to L. plantarum, especially in those monocytes pre-stimulated with live bacteria (Figure 4a). Although we did not find great changes in the expression levels within members of central metabolic pathways, we observed that some adjacent metabolic pathways were enriched in our functional study. Indeed, our data showed the upregulation of folic acid metabolism, amino acid and carboxylic acid biosynthesis, and monocarboxylic acid catabolism, and the downregulation of hyaluronan biosynthesis, negative regulation of lipid storage, and glycerol transport (Table S1). Specifically, we observed the upregulation of three pyruvate dehydrogenase kinases genes (PDK2, PDK3, PDK4) in cells primed with live bacteria, as well as a decreased expression of ACO1 and ACOD1, coding for aconitase and aconitate decarboxylase, suggesting a reduction in the integrity of the tricarboxylic acid (TCA) cycle and the itaconate pathway. We also found the differential regulation of several genes coding for metabolite transporters (Figure 3e), including those for glucose (SLC2A1), other hexoses and monocarboxylic compounds (SLC2A6, SLC45A3, SLC16A5), and amino acids (SLC1A2, SLC16A10), which possibly contribute to changes in cellular metabolism.
BCG-induced trained immunity in macrophage: reprograming of glucose metabolism
Published in International Reviews of Immunology, 2020
Yuntong Liu, Shu Liang, Ru Ding, Yuyang Hou, Feier Deng, Xiaohui Ma, Tiantian Song, Dongmei Yan
The pyruvate dehydrogenase complex (PDC) decarboxylates pyruvate into acetyl-CoA for use by the TCA cycle, pyruvate dehydrogenase kinase (PDK) phosphorylates three serine residues of PDH to inhibit its activity.64 One study have shown that HIF-1α-PDK1-mediated metabolic changes in mild hypoxia is essential for the migration of macrophages in the inflammatory areas.63 And the knockdown of PDK1 diminishes macrophage responses to LPS and TLR2 stimulation, but has little effect on LPS activated cytokine production in GM-BMMs(GM-CSF induced macrophages).65 However, another study reveals that although LPS induces HIF-1α, the expression of PDK1 is attenuated. M(LPS) macrophages depend on the PDH flux to induce cytokine expression and synthesis of itaconate, which is explained that an additional regulator specifically prevents PDK1 expression.64 In summary, PDK1 plays a subtle regulatory role in the immune function of macrophages. Inhibiting PDK can switch fatty acid fueling of immune tolerance to glucose fueling of immune resistance.66