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https://www.readbyqxmd.com/read/29656110/targeting-hepatic-pyruvate-dehydrogenase-kinases-restores-insulin-signaling-and-mitigates-chrebp-mediated-lipogenesis-in-diet-induced-obese-mice
#1
Cheng-Yang Wu, Shih-Chia Tso, Jacinta L Chuang, Wen-Jun Gui, Mingliang Lou, Gaurav Sharma, Chalermchai Khemtong, Xiangbing Qi, R Max Wynn, David T Chuang
OBJECTIVE: Mitochondrial pyruvate dehydrogenase kinases 1-4 (PDKs1-4) negatively regulate activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation. PDKs play a pivotal role in maintaining energy homeostasis and contribute to metabolic flexibility by attenuating PDC activity in various mammalian tissues. Cumulative evidence has shown that the up-regulation of PDK4 expression is tightly associated with obesity and diabetes. In this investigation, we test the central hypothesis that PDKs1-4 are a pharmacological target for lowering glucose levels and restoring insulin sensitivity in obesity and type 2 diabetes (T2D)...
March 31, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29653124/doxorubicin-triggers-bioenergetic-failure-and-p53-activation-in-mouse-stem-cell-derived-cardiomyocytes
#2
Teresa Cunha-Oliveira, Luciana L Ferreira, Ana Raquel Coelho, Cláudia M Deus, Paulo J Oliveira
Doxorubicin (DOX) is a widely used anticancer drug that could be even more effective if its clinical dosage was not limited because of delayed cardiotoxicity. Beating stem cell-derived cardiomyocytes are a preferred in vitro model to further uncover the mechanisms of DOX-induced cardiotoxicity. Our objective was to use cultured induced-pluripotent stem cell(iPSC)-derived mouse cardiomyocytes (Cor.At) to investigate the effects of DOX on cell and mitochondrial metabolism, as well as on stress responses. Non-proliferating and beating Cor...
April 10, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29615678/protein-bound-nad-p-h-lifetime-is-sensitive-to-multiple-fates-of-glucose-carbon
#3
Joe T Sharick, Peter F Favreau, Amani A Gillette, Sophia M Sdao, Matthew J Merrins, Melissa C Skala
While NAD(P)H fluorescence lifetime imaging (FLIM) can detect changes in flux through the TCA cycle and electron transport chain (ETC), it remains unclear whether NAD(P)H FLIM is sensitive to other potential fates of glucose. Glucose carbon can be diverted from mitochondria by the pentose phosphate pathway (via glucose 6-phosphate dehydrogenase, G6PDH), lactate production (via lactate dehydrogenase, LDH), and rejection of carbon from the TCA cycle (via pyruvate dehydrogenase kinase, PDK), all of which can be upregulated in cancer cells...
April 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29593636/combined-treatment-with-dichloroacetic-acid-and-pyruvate-reduces-hippocampal-neuronal-death-after-transient-cerebral-ischemia
#4
Dae Ki Hong, A Ra Kho, Bo Young Choi, Song Hee Lee, Jeong Hyun Jeong, Sang Hwon Lee, Kyoung-Ha Park, Jae-Bong Park, Sang Won Suh
Transient cerebral ischemia (TCI) occurs when blood flow to the brain is ceased or dramatically reduced. TCI causes energy depletion and oxidative stress, which leads to neuronal death and cognitive impairment. Dichloroacetic acid (DCA) acts as an inhibitor of pyruvate dehydrogenase kinase (PDK). Additionally, DCA is known to increase mitochondrial pyruvate uptake and promotes glucose oxidation during glycolysis, thus enhancing pyruvate dehydrogenase (PDH) activity. In this study, we investigated whether the inhibition of PDK activity by DCA, which increases the rate of pyruvate conversion to adenosine triphosphate (ATP), prevents ischemia-induced neuronal death...
2018: Frontiers in Neurology
https://www.readbyqxmd.com/read/29535262/skp2-dependent-reactivation-of-akt-drives-resistance-to-pi3k-inhibitors
#5
Emilie Clement, Hiroyuki Inuzuka, Naoe T Nihira, Wenyi Wei, Alex Toker
The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways...
March 13, 2018: Science Signaling
https://www.readbyqxmd.com/read/29527004/microrna-155-positively-regulates-glucose-metabolism-via-pik3r1-foxo3a-cmyc-axis-in-breast-cancer
#6
Sinae Kim, Eunji Lee, Jaeyun Jung, Jong Won Lee, Hee Jung Kim, Jisun Kim, Hyun Ju Yoo, Hee Jin Lee, Sun Young Chae, Sang Min Jeon, Byung Ho Son, Gyungyup Gong, Shyam K Sharan, Suhwan Chang
MicroRNA is an endogenous, small RNA controlling multiple target genes and playing roles in various biological processes including tumorigenesis. Here, we addressed the function of miR-155 using LC-MS/MS-based metabolic profiling of miR-155 deficient breast cancer cells. Our results revealed the loss of miR-155 hampers glucose uptake and glycolysis, via the down-regulation of glucose transporters and metabolic enzymes including HK2, PKM2, and LDHA. We showed this is due to the down-regulation of cMYC, controlled through phosphoinositide-3-kinase regulatory subunit alpha (PIK3R1)-PDK1/AKT-FOXO3a pathway...
March 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29482638/investigation-of-hypoxia-networks-in-ovarian-cancer-via-bioinformatics-analysis
#7
Ke Zhang, Xiangjun Kong, Guangde Feng, Wei Xiang, Long Chen, Fang Yang, Chunyu Cao, Yifei Ding, Hang Chen, Mingxing Chu, Pingqing Wang, Baoyun Zhang
BACKGROUND: Ovarian cancer is a leading cause of the death from gynecologic malignancies. Hypoxia is closely related to the malignant growth of cells. However, the molecular mechanism of hypoxia-regulated ovarian cancer cells remains unclear. Thus, this study was conducted to identify the key genes and pathways implicated in the regulation of hypoxia by bioinformatics analysis. METHODS: Using the datasets of GSE53012 downloaded from the Gene Expression Omnibus (GEO), the differentially expressed genes (DEGs) were screened by comparing the RNA expression from cycling hypoxia group, chronic hypoxia group, and control group...
February 26, 2018: Journal of Ovarian Research
https://www.readbyqxmd.com/read/29471628/activation-of-pyruvate-dehydrogenase-by-sodium-dichloroacetate-shifts-metabolic-consumption-from-amino-acids-to-glucose-in-ipec-j2-cells-and-intestinal-bacteria-in-pigs
#8
Rui An, Zhiru Tang, Yunxia Li, Tiejun Li, Qingqing Xu, Jifu Zhen, Feiru Huang, Jing Yang, Cheng Chen, Zhaoliang Wu, Mao Li, Jiajing Sun, Xiangxin Zhang, Jinchao Chen, Liuting Wu, Shengjun Zhao, Qingyan Jiang, Weiyun Zhu, Yulong Yin, Zhihong Sun
The extensive metabolism of amino acids (AA) as fuel is an important reason for the low use efficiency of protein in pigs. In this study, we investigated whether regulation of the pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase alpha 1 (PDHA1) pathway affected AA consumption by porcine intestinal epithelial (IPEC-J2) cells and intestinal bacteria in pigs. The effects of knockdown of PDHA1 and PDK1 with small interfering RNA (siRNA) on nutrient consumption by IPEC-J2 cells were evaluated. IPEC-J2 cells were then cultured with sodium dichloroacetate (DCA) to quantify AA and glucose consumption and nutrient oxidative metabolism...
February 23, 2018: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29459421/igf-1-protects-sh-sy5y-cells-against-mpp-induced-apoptosis-via-pi3k-pdk-1-akt-pathway
#9
Chanyang Kim, Seungjoon Park
Insulin-like growth factor (IGF)-1 is a well-known anti-apoptotic pro-survival factor and phosphatidylinositol-3-kinase (PI3K)/Akt pathway is linked to cell survival induced by IGF-1. It is also reported that Akt signaling is modulated by 3-phosphoinositide-dependent kinase-1 (PDK1). In the current study, we investigated whether the anti-apoptotic effect of IGF-1 in SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP+) is associated with the activity of PI3K/PDK1/Akt pathway. Treatment of cells with IGF-1 inhibited MPP+-induced apoptotic cell death...
February 19, 2018: Endocrine Connections
https://www.readbyqxmd.com/read/29456710/mechanism-of-apoptosis-induction-associated-with-erk1-2-upregulation-via-goniothalamin-in-melanoma-cells
#10
Suphakorn Tangchirakhaphan, Sukanda Innajak, Sirinun Nilwarangkoon, Nudjaree Tanjapatkul, Wilawan Mahabusrakum, Ramida Watanapokasin
The present study aimed to investigate the effect of goniothalamin on apoptosis induction in the A375 melanoma cell line. Melanoma is a type of skin cancer with increased prevalence and no potential standard treatment. Goniothalamin is a plant, bioactive styrly-lactone, which has various bioactivities including anti-microbial, anti-inflammatory and anti-cancer. Apoptosis induction by goniothalamin has been studied in numerous cancer cell lines, however not in the melanoma cell line A375. The results of the MTT assay demonstrated that goniothalamin induced anti-proliferation in a dose dependent manner...
March 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29406780/acute-activation-of-pyruvate-dehydrogenase-increases-glucose-oxidation-in-muscle-without-changing-glucose-uptake
#11
Lewin Small, Amanda E Brandon, Lake-Ee Quek, James R Krycer, David E James, Nigel Turner, Gregory J Cooney
Pyruvate dehydrogenase (PDH) activity is a key component of the glucose/fatty acid cycle hypothesis for the regulation of glucose uptake and metabolism. We have investigated whether acute activation of PDH in muscle can alleviate the insulin resistance caused by feeding animals a high fat diet. The importance of PDH activity in muscle glucose disposal under insulin-stimulated conditions was determined by infusing the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) into high fat diet-fed (HFD) Wistar rats during a hyperinsulinemic-euglycemic clamp...
February 6, 2018: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29243067/translational-regulation-in-the-anoxic-turtle-trachemys-scripta-elegans
#12
Kama E Szereszewski, Kenneth B Storey
The red-eared slider turtle (Trachemys scripta elegans), has developed remarkable adaptive mechanisms for coping with decreased oxygen availability during winter when lakes and ponds become covered with ice. Strategies for enduring anoxia tolerance include an increase in fermentable fuel reserves to support anaerobic glycolysis, the buffering of end products to minimize acidosis, altered expression in crucial survival genes, and strong metabolic rate suppression to minimize ATP-expensive metabolic processes such as protein synthesis...
December 14, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29191981/impact-of-training-state-on-fasting-induced-regulation-of-adipose-tissue-metabolism-in-humans
#13
Lærke Bertholdt, Anders Gudiksen, Tomasz Stankiewicz, Ida Villesen, Jonas Tybirk, Gerrit van Hall, Jens Bangsbo, Peter Plomgaard, Henriette Pilegaard
Recruitment of fatty acids from adipose tissue is essential during fasting. However, the molecular mechanisms behind fasting-induced metabolic regulation in human adipose tissue and the potential impact of training state in this are unknown. Therefore, the aim of the present study was to investigate 1) fasting-induced regulation of lipolysis and glyceroneogenesis in human adipose tissue as well as 2) the impact of training state on basal oxidative capacity and fasting-induced metabolic regulation in human adipose tissue...
November 30, 2017: Journal of Applied Physiology
https://www.readbyqxmd.com/read/29166598/biological-significance-of-the-suppression-of-oxidative-phosphorylation-in-induced-pluripotent-stem-cells
#14
Cheng Zhang, Maria Skamagki, Zhong Liu, Aparna Ananthanarayanan, Rui Zhao, Hu Li, Kitai Kim
We discovered that induced pluripotent stem cell (iPSC) clones generated from aged tissue donors (A-iPSCs) fail to suppress oxidative phosphorylation. Compared to embryonic stem cells (ESCs) and iPSCs generated from young donors (Y-iPSCs), A-iPSCs show poor expression of the pluripotent stem cell-specific glucose transporter 3 (GLUT3) and impaired glucose uptake, making them unable to support the high glucose demands of glycolysis. Persistent oxidative phosphorylation in A-iPSCs generates higher levels of reactive oxygen species (ROS), which leads to excessive elevation of glutathione (a ROS-scavenging metabolite) and a blunted DNA damage response...
November 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/29128903/impairment-of-thiamine-transport-at-the-gut-bbb-axis-contributes-to-wernicke-s-encephalopathy
#15
P M Abdul-Muneer, Saleena Alikunju, Heather Schuetz, Adam M Szlachetka, Xiaotang Ma, James Haorah
Wernicke's encephalopathy, a common neurological disease, is caused by thiamine (vitamin B1) deficiency. Neuropathy resulting from thiamine deficiency is a hallmark of Wernicke-Korsakoff syndrome in chronic alcohol users. The underlying mechanisms of this deficiency and progression of neuropathy remain to be understood. To uncover the unknown mechanisms of thiamine deficiency in alcohol abuse, we used chronic alcohol consumption or thiamine deficiency diet ingestion in animal models. Observations from animal models were validated in primary human neuronal culture for neurodegenerative process...
November 11, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/29093638/inhibition-of-hif1%C3%AE-and-pdk-induces-cell-death-of-glioblastoma-multiforme
#16
Jiwon Esther Han, Pyung Won Lim, Chul Min Na, You Sik Choi, Joo Young Lee, Yona Kim, Hyung Woo Park, Hyo Eun Moon, Man Seung Heo, Hye Ran Park, Dong Gyu Kim, Sun Ha Paek
Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. GBMs, like other tumors, rely relatively less on mitochondrial oxidative phosphorylation (OXPHOS) and utilize more aerobic glycolysis, and this metabolic shift becomes augmented under hypoxia. In the present study, we investigated the physiological significance of altered glucose metabolism and hypoxic adaptation in the GBM cell line U251 and two newly established primary GBMs (GBM28 and GBM37). We found that these three GBMs exhibited differential growth rates under hypoxia compared to those under normoxia...
October 2017: Experimental Neurobiology
https://www.readbyqxmd.com/read/29090554/-puerariae-lobatae-radix-elevated-expression-levels-of-ob-r-irs2-glut1-and-glut2-to-regulate-glucose-metabolism-in-insulin-resistance-hepg2-cells
#17
Yu Li, Xin-Xin Luo, Feng-Dong Yan, Zhang-Bin Wei, Jun Tu
To observe the anti-hyperglycemic effect of Puerariae Lobatae Radix in hepatocyte insulin resistance(IR) models, and investigate its preliminary molecular mechanism. IR-HepG2 cell model was stably established with 1×10-9 mol•L⁻¹ insulin plus 3.75×10-6 mol•L-1 dexamethasone treatment for 48 h according to optimized protocol in our research group. After IR-HepG2 cells were treated with different concentrations(5%,10% and 15%) of Puerariae Lobatae Radix-containing serum, cell viability was detected by CCK-8 assay; the glucose consumptions in IR-HepG2 cells were separately detected at different time points (12, 15, 18, 21, 24, 30, 36 h) by using glucose oxidase method; intracellular glycogen content was detected by anthrone method; and the protein expression levels of leptin receptor (Ob-R), insulin receptor substrate-2 (IRS2), glucose transporter 1(GLUT1) and GLUT2 were detected by Western blot assay...
May 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/29070699/inhibition-of-pyruvate-dehydrogenase-kinase-improves-pulmonary-arterial-hypertension-in-genetically-susceptible-patients
#18
Evangelos D Michelakis, Vikram Gurtu, Linda Webster, Gareth Barnes, Geoffrey Watson, Luke Howard, John Cupitt, Ian Paterson, Richard B Thompson, Kelvin Chow, Declan P O'Regan, Lan Zhao, John Wharton, David G Kiely, Adam Kinnaird, Aristeidis E Boukouris, Chris White, Jayan Nagendran, Darren H Freed, Stephen J Wort, J Simon R Gibbs, Martin R Wilkins
Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation...
October 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29059435/therapeutic-targeting-of-the-pyruvate-dehydrogenase-complex-pyruvate-dehydrogenase-kinase-pdc-pdk-axis-in-cancer
#19
REVIEW
Peter W Stacpoole
The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. Inhibition of PDC activity by pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation has been associated with the pathobiology of many disorders of metabolic integration, including cancer. Consequently, the PDC/PDK axis has long been a therapeutic target. The most common underlying mechanism accounting for PDC inhibition in these conditions is post-transcriptional upregulation of one or more PDK isoforms, leading to phosphorylation of the E1α subunit of PDC...
November 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28990055/defective-insulin-signaling-and-the-protective-effects-of-dimethyldiguanide-during-follicular-development-in-the-ovaries-of-polycystic-ovary-syndrome
#20
Fan Wang, Shaobing Wang, Zhenghong Zhang, Qingqiang Lin, Yiping Liu, Yijun Xiao, Kaizhuan Xiao, Zhengchao Wang
It is established that the physiological effects of insulin are primarily mediated by the insulin signaling pathway. However, a defective insulin signaling is closely associated with the clinical manifestations of polycystic ovary syndrome (PCOS), which include excess androgen levels, insulin resistance and anovulation, and is involved in the pathophysiology of PCOS at the molecular level. Dimethyldiguanide (DMBG) has been widely employed to alleviate reproduction dysfunction in women with PCOS, however, the exact mechanism of this effect remains unclear...
December 2017: Molecular Medicine Reports
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