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FoxO AND Pyruvate

Wan-Jing Chen, Rwei-Fen S Huang
Low-folate (LF) nutritional status is associated with increased risks of lung cancer. It has unexplored effects on lung cancer malignancy, a cancer stem cell (CSC) disease. We hypothesized that LF may reprogram CSC-like potential and bioenergetics metabolism to increase metastasis potential of lung cancers. Cultivation of human non-small-cell lung cancer cells (H23) in an LF medium enhanced CSC-like properties signified by increased expressions of the CSC surface marker CD44 and pluripotency markers Sox2, Oct4 and ALDH1A1, and promoted self-renewal ability of anchorage-independent oncospheroid formation...
March 2018: Journal of Nutritional Biochemistry
Dimitry A Chistiakov, Alexander N Orekhov, Yuri V Bobryshev
Diabetic heart pathology has a serious social impact due to high prevalence worldwide and significant mortality/invalidation of diabetic patients suffered from cardiomyopathy. The pathogenesis of diabetic and diabetes-related cardiomyopathy is associated with progressive loss and impairment of cardiac function due to adverse effects of metabolic, prooxidant, proinflammatory, and pro-apoptotic stress factors. In the adult heart, the transcriptional factor forkhead box-1 (FOXO-1) is involved in maintaining cardiomyocytes in the homeostatic state and induction of their adaptation to metabolic and pro-oxidant stress stimuli...
August 2, 2017: International Journal of Cardiology
Hannah Crossland, Dumitru Constantin-Teodosiu, Sheila M Gardiner, Paul L Greenhaff
The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi) appears to provide protection against organ dysfunction during endotoxaemia. We examined the potential benefits of Rosi on skeletal muscle protein maintenance and carbohydrate metabolism during lipopolysaccharide (LPS)-induced endotoxaemia. Sprague-Dawley rats were fed either standard chow (control) or standard chow containing Rosi (8.5 ± 0.1 mg·kg(-1)·day(-1)) for 2 weeks before and during 24 h continuous intravenous infusion of LPS (15 μg·kg(-1)·h(-1)) or saline...
July 1, 2017: Clinical Science (1979-)
Richard L Veech, Patrick C Bradshaw, Kieran Clarke, William Curtis, Robert Pawlosky, M Todd King
The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway...
May 2017: IUBMB Life
Hongmei Wu, Chenping Huang, Faten A Taki, Yanqiong Zhang, Dorothy L Dobbins, Lin Li, Hongtao Yan, Xiaoping Pan
In the present study oxidative stress induced by Benzo-α-pyrene (BaP) exposure and the potential involvements of microRNA were investigated. The Caenorhabditis elegans (C. elegans) was applied as model organism. The C. elegans at L1-stage were randomly divided into 4 groups and exposed to 0, 0.2, 2.0, and 20μM BaP for 30h. Expressions of SKiNhead-1 (SKN-1), gamma-glutamine cysteine synthase heavy chain (GCS-1), and their potential regulatory factors in insulin/IGF-1/FOXO signaling pathway and the p38 MAPK pathway were analyzed...
November 2015: Chemosphere
Eumorphia G Konstantakou, Gerassimos E Voutsinas, Athanassios D Velentzas, Aggeliki-Stefania Basogianni, Efthimios Paronis, Evangelos Balafas, Nikolaos Kostomitsopoulos, Konstantinos N Syrigos, Ema Anastasiadou, Dimitrios J Stravopodis
BACKGROUND: Urinary bladder cancer is one of the most fatal and expensive diseases of industrialized world. Despite the strenuous efforts, no seminal advances have been achieved for its clinical management. Given the importance of metabolic reprogramming in cancer cell survival and growth, we have herein employed 3-BrPA, a halogenated derivative of pyruvate and historically considered inhibitor of glycolysis, to eliminate bladder cancer cells with highly oncogenic molecular signatures...
July 22, 2015: Molecular Cancer
Thomas K Sin, Benjamin Y Yung, Parco M Siu
Aging individuals and diabetic patients often exhibit concomitant reductions of skeletal muscle mass/strength and insulin sensitivity, suggesting an intimate link between muscle aging and insulin resistance. Foxo1, a member of the FOXO transcription factor family, is an important player in insulin signaling due to its inhibitory role in glucose uptake and utilization in skeletal muscle. Phosphorylation of Foxo1 is thought to mitigate the transactivation of pyruvate dehydrogenase lipoamide kinase 4 (PDK4), which is a negative regulator of the glycolytic enzyme pyruvate dehydrogenase (PDH)...
2015: Cellular Physiology and Biochemistry
Wilfred Ip, Weijuan Shao, Zhuolun Song, Zonglan Chen, Michael B Wheeler, Tianru Jin
Investigations on the metabolic role of the Wnt signaling pathway and hepatic transcription factor 7-like 2 (TCF7L2) have generated opposing views. While some studies demonstrated a repressive effect of TCF7L2 on hepatic gluconeogenesis, a recent study using liver-specific Tcf7l2(-/-) mice suggested the opposite. As a consequence of redundant and bidirectional actions of transcription factor (TCF) molecules and other complexities of the Wnt pathway, knockout of a single Wnt pathway component may not effectively reveal a complete metabolic picture of this pathway...
June 2015: Diabetes
Jinwei Du, Qiang Li, Fangqiang Tang, Michelle A Puchowitz, Hisashi Fujioka, Sally L Dunwoodie, David Danielpour, Yu-Chung Yang
Mammalian adult hematopoietic stem cells (HSCs) reside in the hypoxic bone marrow microenvironment and display a distinct metabolic phenotype compared with their progenitors. It has been proposed that HSCs generate energy mainly through anaerobic glycolysis in a pyruvate dehydrogenase kinase (Pdk)-dependent manner. Cited2 is an essential regulator for HSC quiescence, apoptosis, and function. Herein, we show that conditional deletion of Cited2 in murine HSCs results in elevated levels of reactive oxygen species, decreased cellular glutathione content, increased mitochondrial activity, and decreased glycolysis...
January 15, 2014: Stem Cells and Development
Xiwen Xiong, Rongya Tao, Ronald A DePinho, X Charlie Dong
Forkhead transcription factors FoxO1/3/4 have pleiotrophic functions including anti-oxidative stress and metabolism. With regard to glucose metabolism, most studies have been focused on FoxO1. To further investigate their hepatic functions, we generated liver-specific FoxO1/3/4 knockout mice (LTKO) and examined their collective impacts on glucose homeostasis under physiological and pathological conditions. As compared to wild-type mice, LTKO mice had lower blood glucose levels under both fasting and non-fasting conditions and they manifested better glucose and pyruvate tolerance on regular chow diet...
2013: PloS One
Niraj K Nirala, Motiur Rahman, Stanley M Walls, Alka Singh, Lihua Julie Zhu, Takeshi Bamba, Eiichiro Fukusaki, Sargur M Srideshikan, Greg L Harris, Y Tony Ip, Rolf Bodmer, Usha R Acharya
The sphingolipid ceramide elicits several stress responses, however, organisms survive despite increased ceramide but how they do so is poorly understood. We demonstrate here that the AKT/FOXO pathway regulates survival in increased ceramide environment by metabolic adaptation involving changes in glycolysis and lipolysis through novel downstream targets. We show that ceramide kinase mutants accumulate ceramide and this leads to reduction in energy levels due to compromised oxidative phosphorylation. Mutants show increased activation of Akt and a consequent decrease in FOXO levels...
June 2013: PLoS Genetics
Ji Yun Jeong, Nam Ho Jeoung, Keun-Gyu Park, In-Kyu Lee
The pyruvate dehydrogenase complex (PDC) activity is crucial to maintains blood glucose and ATP levels, which largely depends on the phosphorylation status by pyruvate dehydrogenase kinase (PDK) isoenzymes. Although it has been reported that PDC is phosphorylated and inactivated by PDK2 and PDK4 in metabolically active tissues including liver, skeletal muscle, heart, and kidney during starvation and diabetes, the precise mechanisms by which expression of PDK2 and PDK4 are transcriptionally regulated still remains unclear...
October 2012: Diabetes & Metabolism Journal
Joanne E Mallinson, Dumitru Constantin-Teodosiu, Philip D Glaves, Elizabeth A Martin, Wendy J Davies, F Russell Westwood, James E Sidaway, Paul L Greenhaff
We previously reported that statin myopathy is associated with impaired carbohydrate (CHO) oxidation in fast-twitch rodent skeletal muscle, which we hypothesised occurred as a result of forkhead box protein O1 (FOXO1) mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) gene transcription. Upregulation of FOXO gene targets known to regulate proteasomal and lysosomal muscle protein breakdown was also evident. We hypothesised that increasing CHO oxidation in vivo, using the pyruvate dehydrogenase complex (PDC) activator, dichloroacetate (DCA), would blunt activation of FOXO gene targets and reduce statin myopathy...
December 15, 2012: Journal of Physiology
Dumitru Constantin-Teodosiu, Despina Constantin, Francis Stephens, David Laithwaite, Paul L Greenhaff
High-fat feeding inhibits pyruvate dehydrogenase complex (PDC)-controlled carbohydrate (CHO) oxidation, which contributes to muscle insulin resistance. We aimed to reveal molecular changes underpinning this process in resting and exercising humans. We also tested whether pharmacological activation of PDC overrides these diet-induced changes. Healthy males consumed a control diet (CD) and on two further occasions an isocaloric high-fat diet (HFD). After each diet, subjects cycled for 60 min after intravenous infusion with saline (CD and HFD) or dichloroacetate (HFD+DCA)...
May 2012: Diabetes
Sri Devi Narasimhan, Kelvin Yen, Ankita Bansal, Eun-Soo Kwon, Srivatsan Padmanabhan, Heidi A Tissenbaum
The insulin/IGF-1 signaling (IIS) pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase), AGE-1 (PI 3-kinase), and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway...
April 2011: PLoS Genetics
Prasanth Puthanveetil, Ying Wang, Fang Wang, Min Suk Kim, Ashraf Abrahani, Brian Rodrigues
Glucocorticoids increase pyruvate dehydrogenase kinase-4 (PDK4) mRNA and protein expression, which phosphorylates pyruvate dehydrogenase, thereby preventing the formed pyruvate from undergoing mitochondrial oxidation. This increase in PDK4 expression is mediated by the mandatory presence of Forkhead box other factors (FoxOs) in the nucleus. In the current study, we examined the importance of the nongenomic effects of dexamethasone (Dx) in determining the compartmentalization of FoxO and hence its transcriptional activity...
May 2010: Endocrinology
Hannah Crossland, Dumitru Constantin-Teodosiu, Paul L Greenhaff, Sheila M Gardiner
We recently provided evidence suggesting a role for cytokine-mediated inhibition of Akt/Forkhead box O 1 (FOXO1) signalling in the induction of muscle atrophy and impairment of muscle carbohydrate oxidation during lipopolysaccharide (LPS)-induced endotoxaemia in rats. We hypothesized that a low-dose dexamethasone (Dex; anti-inflammatory agent) infusion during endotoxaemia would prevent the LPS-induced impairment of Akt/FOXO1 signalling, and therefore prevent the muscle atrophy and impairment of carbohydrate oxidation...
April 15, 2010: Journal of Physiology
Jiaur R Gayen, Maziyar Saberi, Simon Schenk, Nilima Biswas, Sucheta M Vaingankar, Wai W Cheung, Sonia M Najjar, Daniel T O'Connor, Gautam Bandyopadhyay, Sushil K Mahata
Chromogranin A (CHGA/Chga), a proprotein, widely distributed in endocrine and neuroendocrine tissues (not expressed in muscle, liver, and adipose tissues), generates at least four bioactive peptides. One of those peptides, pancreastatin (PST), has been reported to interfere with insulin action. We generated a Chga knock-out (KO) mouse by the targeted deletion of the Chga gene in neuroendocrine tissues. KO mice displayed hypertension, higher plasma catecholamine, and adipokine levels and lower IL-6 and lipid levels compared with wild type mice...
October 16, 2009: Journal of Biological Chemistry
Hannah Crossland, Dumitru Constantin-Teodosiu, Sheila M Gardiner, Despina Constantin, Paul L Greenhaff
Sepsis causes muscle atrophy and insulin resistance, but the underlying mechanisms are unclear. Therefore, the present study examined the effects of lipopolysaccharide (LPS)-induced endotoxaemia on the expression of Akt, Forkhead Box O (FOXO) and its downstream targets, to identify any associations between changes in FOXO-dependent processes influencing muscle atrophy and insulin resistance during sepsis. Chronically instrumented male Sprague-Dawley rats received a continuous intravenous infusion of LPS (15 microg kg(-1) h(-1)) or saline for 24 h at 0...
November 15, 2008: Journal of Physiology
Young I Kim, Felix N Lee, Woo S Choi, Sarah Lee, Jang H Youn
We previously showed that insulin has a profound effect to suppress pyruvate dehydrogenase kinase (PDK) 4 expression in rat skeletal muscle. In the present study, we examined whether insulin's effect on PDK4 expression is impaired in acute insulin-resistant states and, if so, whether this change is accompanied by decreased insulin's effects to stimulate Akt and forkhead box class O (FOXO) 1 phosphorylation. To induce insulin resistance, conscious overnight-fasted rats received a constant infusion of Intralipid or lactate for 5 h, while a control group received saline infusion...
August 2006: Diabetes
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