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PI3K signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Protein kinase B (PKB)/Akt is a serine/threonine-specific kinase and a key class-I PI3K effector, which plays a pivotal role in the regulation of cell survival, cell cycle, glucose metabolism, protein synthesis and migration. There is no direct role of PIP3 in the activation of (PKB)/Akt. It allows recruitment of Akt/PKB to the plasma membrane and its subsequent phosphorylation on Thr308 by the phosphoinositide-dependent kinase-1 (PDK1) (22). Additionally, PDK2 phosphorylates AKT on Ser473, which results in its full activation, followed by its migration to the nucleus and regulation of various cellular functions through phosphorylation of several downstream targets (22) (see Figure 16.2). Activated AKT also leads to the activation of the mTOR complex (21,28–30).
CDK Inhibitors in Leukemia and Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
PI3K/Akt cascade represents a critical signaling pathway in cell survival mediated by many growth factors and cytokines. Phosphorylation at Thr308 of Akt is catalyzed by PDK1 and phosphorylation at Ser473 by PDK2. UCN-01 directly inhibits upstream Akt kinase PDK1 with an IC50 less than 33 nM in vitro and in vivo assays, whereas enforced expression of PDK1 restores Akt kinase activity. Overexpression of active Akt diminishes the cytotoxic effects of UCN-01, indicating inhibition of PDKl-Akt pathway attributes to the antitumor activity of this agent (60).
PDK2 induces cisplatin-resistance in lung adenocarcinoma via transcriptional regulation of CNNM3
Published in Journal of Drug Targeting, 2019
Tinghua Hu, Shuo Yu, Yang Li, Hui Ren, Qian Ning, Jing Wang, Xuan Liang, Manxiang Li
Pyruvate dehydrogenase kinase (PDK) enhances phosphorylation and inactivation of the pyruvate dehydrogenase complex, which occupies a strategic role in the various substrate and hormonal processes [8]. Pyruvate dehydrogenase kinase isoform 2 (PDK2) is one of the 4 PDK isoenzymes identified in mammalian tissues which had considerable regulatory implications for hormonal and nutritional conditions in response to starvation, diabetes and in human muscle cells [9–11]. Moreover, PDK2 is proved to be a key regulator of glycolysis and oxidative phosphorylation, and its expression is increased in a variety of tumours including glioma, colon cancer and lung cancer, etc [12–15]. However, the detailed molecular mechanism, especially the potential downstream targets still remains unclear.
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
Transcriptomic analyses of primed human monocytes further confirmed the prominent decrease in the expression of pro-inflammatory mediators and effectors, including an array of cytokines, chemokines and antimicrobial peptides. Moreover, we observed a differential regulation of genes and pathways involved in metabolism, especially in the transport and use of carbohydrates, amino acids and fatty acids, which could be linked to the decreased metabolic rates and ROS production observed in primed cells. Cellular metabolism is intimately linked to the regulation of immune responses, with metabolic rewiring being described in both acutely stimulated 44 and innate memory cells 45. Notably, priming with live bacteria increased the expression of pyruvate dehydrogenase kinase genes PDK2, PDK3, PDK4. These proteins are involved in cellular metabolism regulation through the inactivation of components of pyruvate dehydrogenase, the enzyme complex converting pyruvate to acetyl-CoA, leading to decreased glucose and lipid metabolism, and aerobic respiration. 46 In addition, ACO1 and ACOD1, coding for aconitase and aconitate decarboxylase, were found downregulated. Itaconate, a metabolite with anti-microbial and immunomodulatory properties, 47 has been associated with the modulation of β-glucan-induced trained immunity, and ACOD1 expression showed decreased levels in memory monocytes compared to acutely stimulated cells. 48 Thus, the observed differential gene expression suggests a reduction in the integrity of the tricarboxylic acid (TCA) cycle and the itaconate pathway that might be relevant for the L. plantarum-induced long-term memory phenotype in monocytes.
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
In 2019, researchers in Japan disclosed the nitrogen-containing heterocyclic amide compounds (2–11) exhibiting PDKs inhibitory activities [67]. In vitro PDK activity inhibitory assay demonstrated that the most potent 2–12 exerted 88% PDK1 inhibition and 81% PDK2 inhibition at 3.0 nM. One year later, researchers in the same institution disclosed the synthetic method for a pyrazole-amide compound that also exhibited PDK inhibitory effect [68]. 2–13 and 2–14 both showed potent PDK1 and PDK2 inhibitory activities with enzyme inhibition IC50 lower than 5.0 nM.