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Insulin Signaling Modulates Neuronal Metabolism
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Qian Huang, Jialin Fu, Kelly Anne Borges, Weikang Cai
As discussed earlier, neurons express all essential genes involved in glucose uptake and glycolysis. The glycolytic capacity of neurons, however, is relatively low compared with glial cells in the brain. This is due to the rapid neuronal degradation of 6-phosphofructo-2-kinase /fructose-2,6-bisphosphatase-3 (PFKFB3) (40, 41), which produces fructose-2,6-bisphosphate (F2,6P2), an allosteric activator of phosphofructokinase 1 (PFK1) to potently enhance the glycolytic capacity (40, 42, 43). Therefore, neurons are unable to produce F2,6P2, resulting in a low basal glycolytic rate and the inability to stimulate glycolysis according to substrate abundance (Figure 3.1). From this perspective, as the “execution unit” in the brain controlling neural functions, neurons lack metabolic flexibility.
Metallopharmaceuticals
Published in Varma H. Rambaran, Nalini K. Singh, Alternative Medicines for Diabetes Management, 2023
Varma H. Rambaran, Nalini K. Singh
Under diabetic conditions, there is a consequential increase in L-lactate (Jenei et al. 2019) and CO production (Paredi et al. 1999) and a decrease in glucose-6-phosphate levels (Aiston, Andersen and Agius 2003). Biological studies (using rat hepatocytes) have revealed that like vanadate, tungstate inactivates glycogen synthase (a key enzyme in the conversion of glucose into glycogen) by a mechanism independent of Ca2+ (Mechanism 1). It is also seen to activate glycogen phosphorylase (an enzyme that catalyzes the rate-limiting step in glycogenolysis) by a Ca2+-dependent pathway (Mechanism 2). The actions of the second mechanism consequently increase fructose 2,6-bisphosphate levels and counteract the decrease in this metabolite induced by glucagon. Although these effectors do not directly modify 6-phosphofructo-2-kinase activity, they partially inhibit its inactivation that was influenced by glucagon (Fillat, Rodriguez-Gil and Guinovart 1992) (Figure 4.16).
Chemical Causes of Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Gary M. Williams, Alan M. Jeffrey
In addition to alterations that drive cell proliferation, neoplastic cells acquire a variety of phenotypic alterations that support growth. Important among these is an increased glycolysis for generation of ATP, known as the Warburg effect, which facilitates growth in a hypoxic micro environment. An inducible isozyme of 6-phosphofructo-2 kinase has been implicated in this phenomenon (123). Also, upregulation of glutamine synthetase (124), which catalyzes synthesis of glutamine, and downregulation of 10-formylte-trahydrofolate dehydrogenase (125), which regulates purine biosynthesis through controlling the levels of 10-formyltetrahydrofolate, contribute to tumor cell growth. Additionally, some tumors have diminished biotransformation activities, although not all Phase I and II enzymes are equally affected (126–130) and some enzymes may be increased (126). The basis for most such differences is not known, but it is established that glutathione S-transferase P1 gene, GSTP1, can be silenced by promoter methylation (131).
Role of PFKFB3-driven glycolysis in sepsis
Published in Annals of Medicine, 2023
Min Xiao, Dadong Liu, Yao Xu, Wenjian Mao, Weiqin Li
Recently, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a bifunctional enzyme regulating glycolysis, has been brought to the forefront of immune metabolism research. It can accelerate glycolysis by modulating and maintaining the intracellular concentrations of fructose-2,6-bisphosphate (F-2,6-BP) to allosterically activate 6-phosphofructokinase-1 (PFK-1), the key rate-limiting enzyme of glycolysis (Figure 1) [18]. Recent studies have revealed that PFKFB3 is widely expressed in tissues and plays a vital role in the occurrence and metastasis of tumors, organ damage in diabetes mellitus, and angiogenesis [19–21]. Alterations in the levels of PFKFB3 have been reported in different sepsis-associated cells, such as macrophages [22], neutrophils [22], endothelial cells (ECs) [23] and lung fibroblasts [24]. Furthermore, increased PFKFB3 is associated with an excessive inflammatory response in sepsis. Thus, PFKFB3 has become a novel therapeutic target for inhibiting excessive inflammation in sepsis.
Loss of PFKFB4 induces cell cycle arrest and glucose metabolism inhibition by inactivating MEK/ERK/c-Myc pathway in cervical cancer cells
Published in Journal of Obstetrics and Gynaecology, 2022
Yan Wu, Li Zhang, Yiming Bao, Biao Wan, Dan Shu, Tingting Luo, Zengli He
Recently, studies on cancer metabolism have afforded insight into the adaptive processes of cancer cells, changing their metabolic activity to meet the demands of increased energy and biosynthetic precursors (Yao et al. 2019). Enhanced glycolysis, also called Warburg’s effect, can be observed in numerous cancers, providing a metabolic basis for cancer cell growth (Vander Heiden et al. 2009). 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), as an important mediator of glucose metabolism, guides metabolic pathways needed for macromolecule biosynthesis to sustain rapid growth of cancer cells (Dang 2012). PFKFB4 expression changes glucose consumption, lactate secretion and ROS production of breast cancer cells, which revealing an alternation of the glycolysis pathway (Gao et al. 2018). A recent bioinformatics study constructed a six-gene signature (including PFKFB4) to predict the prognosis of cervical cancer patients, which is also a prognostic factor independent of clinicopathological features (Cai et al. 2020). Another study reported that carbonic anhydrase IX overexpression increased PFKFB4 expression and epithelial–mesenchymal transition, promoting cervical cancer cell migration (Hsin and Hsieh 2021). However, the specific function of PFKFB4 in cervical cancer has not been revealed.
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
Conversion between fructose-6-phosphate(F-6-P) and fructose-2,6-diphosphate (F-2,6-BP) is catalyzed by 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) family. F-2,6-BP is the strongest allosteric activator of PFK1, which mediates the key rate-limiting step of glycolysis. In the PFKFB family, PFKFB3 mainly mediates the synthesis of F-2,6-BP to enhance glycolysis, and the synergistic induction of PFKFB3 is mediated by the transcription factor Sp1 instead of HIF-1α. It has been found that PFKFB3 can affect the phagocytosis and autophagy pathway of macrophages, promoting their defense against virus.54,55 Recent studies have shown that activation of NLRP3 inflammasome can increase the expression of PFKFB3,67 further demonstrating the interaction between glycolysis and NLRP3 inflammasome. Recently, it has been found that the up-regulation of PFKFB3 in human hepatocellular carcinoma infiltrating monocytes increases the expression of programed death ligand 1 (PD-L1) through nuclear factor-kappa B (NF-κB) signaling pathway, and the infiltration level of PFKFB3+ CD68+ cell is negatively correlated with the overall survival rate of patients.56