China 
Africa 
Explore chapters and articles related to this topic
Organ Cross-Talk Regulates (Brain) Insulin Action
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
The seemingly paradoxical gene expression of Fgf21 caused by fasting (free fatty acids) and feeding signals (fructose, alcohol) suggests that FGF21 is elevated under a nutritional crisis, which includes energy restriction and overfeeding with liver-toxic fructose and alcohol. Since caloric restriction automatically entails a reduction of protein intake, which may be designated as a nutritional crisis as well, it was verified that circulating FGF21 concentrations are robustly induced by dietary protein restriction in rats, mice, and humans – without caloric restriction – which indicates FGF21 as an endocrine signal of dietary protein restriction (104). The general amino acid control pathway is induced by protein restriction and is required for activation of FGF21. The serine/threonine kinase general control nonderepressible 2 (GCN2) is a cellular kinase that phosphorylates the eukaryotic initiation factor 2 alpha (eIF2α) in response to depletion of cellular amino acids (105), with this mechanism coupling amino acid detection to metabolism (106–113). The phosphorylation of eIF2α results in the induction of the activating transcription factor 4 (ATF4), which binds to the FGF21 promoter that contains amino acid response elements (AARE) (114–117).
A Protein-Centric Perspective for Skeletal Muscle Metabolism and Cardiometabolic Health
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Donald K. Layman, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
The protein-centric perspective shifts the focus from a global view of protein as simply a macronutrient similar to carbohydrates and fat to a molecular focus that recognizes the individual roles of each of the 20 amino acids. Each amino acid has at least two important roles, one in protein synthesis as a building block for new proteins and a second in the creation of new biomolecules and/or metabolic signals (Wu, 2013). A few examples of secondary roles of amino acids include tryptophan for synthesis of serotonin, arginine for synthesis of creatine, cysteine for synthesis of glutathione, and lysine for synthesis of carnitine, and signal molecules include histidine for stimulation of GCN2 in the integrated stress response, arginine for nitric oxide and vascular function, and leucine for the activation of the mTORC1 signal cascade for stimulation of muscle protein synthesis (mPS). The leucine signal has received extensive attention because of its role in stimulating mPS and has become a principal factor in defining optimal dietary protein intake (Layman, 2003; Layman et al., 2015).
Profiling of differentially expressed circRNAs and functional prediction in peripheral blood mononuclear cells from patients with rheumatoid arthritis
Published in Annals of Medicine, 2023
Li Xue, Biao Wang, Jianhong Zhu, Qian He, Fang Huang, Wei Wang, Li Tao, Yan Wang, Nan Xu, Ni Yang, Li Jin, Hua Zhang, Ning Gao, Ke Lei, Yanping Zhang, Chaoliang Xiong, Jing Lei, Ting Zhang, Yan Geng, Ming Li
In this study, functional enrichment analyses were also performed to identify the potential roles of DEcircRNAs in the pathogenesis of RA. The GO analysis of the mRNAs targeted by DEcircRNAs showed that CC organization or biogenesis, cellular protein metabolic processes, extracellular matrix component, ATP binding, adenyl ribonucleotide binding, protein binding and protein transport are implicated in the biological and cellular processes related to the pathogenesis of RA. Recently, it has been well recognized that metabolic stress is closely involved in the pathophysiology of systemic autoimmune diseases [23]. For example, glutamine metabolism was demonstrated to have distinct roles in promoting Th17 but constraining Th1 and CTL effector cell differentiation [24]. Another study found that the metabolic stress sensing protein kinase GCN2 played a critical role in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity [25]. Collectively, these aberrantly expressed circRNAs in PBMCs are implicated in many pathophysiological processes of RA, especially those regarding inflammation and immunity, and may be promising biomarkers and therapeutic targets of RA.
Targeting the integrated stress response in ophthalmology
Published in Current Eye Research, 2021
Hsiao-Sang Chu, Cornelia Peterson, Albert Jun, James Foster
Pharmacological inhibition of the ISR can be achieved by inhibition of eIF2α kinases. Three structurally similar compounds indirubin-3ʹ-monoxamie, SP600125 and a SyK inhibitor inactivate GCN2138; amino-pyrazolindine inhibits HRI139; C16 and 2-aminopurine are frequently used for inhibition of PKR140,141; and GSK260614 and its analogue GSK2656157 inactivate PERK.142,143 However, the application of eIF2α kinase inhibitors in ophthalmic researches is scarce. In vitro, GCN2 inhibitors, Indirubin-3ʹ-monoxamie, SP600125, and SyK inhibitor decrease the phosphorylation of eIF2α in mouse embryonic fibroblast cells after UV irradiation.138 Yet, these compounds are poorly specific for GCN2, and additional studies on structure-activity relationship are essential to increase their specificity and potency in treating eye diseases. In vitro, Jiang et al has reported GSK2606414, the highly selective PERK inhibitor, suppressed RPE cell proliferation in a dose-dependent manner. Meanwhile, GSK2606414 treatment reduced the level of peIF2α, CHOP, and VEGF mRNA expression in RPE cells under ER stress.144
The molecular rationale for therapeutic targeting of glutamine metabolism in pulmonary hypertension
Published in Expert Opinion on Therapeutic Targets, 2019
Thomas Bertero, Dror Perk, Stephen Y. Chan
Beyond BMPR2, the direct contribution of other factors genetically associated with PAH has not been fully investigated, but it is tempting to speculate that pathogenic mutations found in genes related to the TGF-β/BMP pathway can also affect glutamine metabolism in the lung vasculature [120–122]. Furthermore, a number of factors genetically linked to PAH may also carry relevance to glutamine biology, independent of BMP signaling. By leveraging advanced computational modeling, it was recently reported that the actions of a network of factors linked to heritable PAH converge upon the matrix stiffening-miR-130/301 molecular circuit (see Section 3.4) in order to remodel the extracellular matrix (ECM) [123]. Given the predominant role of ECM remodeling and stiffening on glutamine metabolism in diverse contexts such as cancer [124] and PH [22], it is reasonable to suspect that these same factors genetically related to PAH could be involved in glutamine metabolism. Moreover, the GCN2 gene has been found to carry the loss of function mutations that are associated with an increased risk of PAH. It encodes for a protein implicated in metabolic-stress sensing and modulating amino acid metabolism in response to nutrient deprivation through its crosstalk with the mTORC1 pathway [125,126]. Considering the importance of the mTORC1 pathway in the regulation of amino acid and notably glutamine metabolism, it is conceivable that mutations in GCN2 that predispose to PAH may also affect glutamine metabolism in the lung vasculature.