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https://www.readbyqxmd.com/read/29191981/impact-of-training-state-on-fasting-induced-regulation-of-adipose-tissue-metabolism-in-humans
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
https://www.readbyqxmd.com/read/28987868/impairment-of-akt-activity-by-cyp2e1-mediated-oxidative-stress-is-involved-in-chronic-ethanol-induced-fatty-liver
#9
Tao Zeng, Cui-Li Zhang, Ning Zhao, Min-Jie Guan, Mo Xiao, Rui Yang, Xiu-Lan Zhao, Li-Hua Yu, Zhen-Ping Zhu, Ke-Qin Xie
Protein kinase B (PKB/Akt) plays important roles in the regulation of lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that cytochrome P4502E1 (CYP2E1) plays causal roles in the pathogenesis of alcoholic fatty liver (AFL). We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic ethanol-induced hepatic steatosis. In this study, we found that chronic ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver...
September 27, 2017: Redox Biology
https://www.readbyqxmd.com/read/28934276/enhanced-pyruvate-dehydrogenase-activity-improves-cardiac-outcomes-in-a-murine-model-of-cardiac-arrest
#10
Lin Piao, Yong-Hu Fang, Manfred M Kubler, Michael W Donnino, Willard W Sharp
RATIONALE: Post-ischemic changes in cellular metabolism alter myocardial and neurological function. Pyruvate dehydrogenase (PDH), the limiting step in mitochondrial glucose oxidation, is inhibited by increased expression of PDH kinase (PDK) during ischemia/reperfusion injury. This results in decreased utilization of glucose to generate cellular ATP. Post-cardiac arrest (CA) hypothermia improves outcomes and alters metabolism, but its influence on PDH and PDK activity following CA are unknown...
2017: PloS One
https://www.readbyqxmd.com/read/28928113/pdk4-inhibits-cardiac-pyruvate-oxidation-in-late-pregnancy
#11
Laura X Liu, Glenn C Rowe, Steven Yang, Jian Li, Federico Damilano, Mun Chun Chan, Wenyun Lu, Cholsoon Jang, Shogo Wada, Michael Morley, Michael Hesse, Bernd K Fleischmann, Joshua Rabinowitz, Saumya Das, Anthony Rosenzweig, Zoltan Arany
Rationale: Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations are not well understood. Objective: To determine the mechanisms underlying cardiac substrate use during pregnancy. Methods and Results: We use here (13)C-glucose, (13)C-lactate, and (13)C-fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid (TCA) cycle, while reducing glucose and lactate oxidation...
September 19, 2017: Circulation Research
https://www.readbyqxmd.com/read/28904365/rnai-mediated-silencing-of-a-pyruvate-dehydrogenase-kinase-enhances-triacylglycerol-biosynthesis-in-the-oleaginous-marine-alga-nannochloropsis-salina
#12
Xiaonian Ma, Lina Yao, Bo Yang, Yuan Kun Lee, Feng Chen, Jin Liu
Oleaginous microalgae have been emerging as the third-generation feedstocks for biofuel production. Genetic manipulation for improving triacylglycerol (TAG) accumulation represents a promising approach towards the economics of microalgal biofuels. Acetyl-CoA, the essential carbon precursor for de novo fatty acid biosynthesis, can be derived from pyruvate catalyzed by pyruvate dehydrogenase, which is negatively regulated by pyruvate dehydrogenase kinase (PDK). In the present study, we characterized a PDK gene (NsPDK) from Nannochloropsis salina...
September 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28881665/hpv-associated-differential-regulation-of-tumor-metabolism-in-oropharyngeal-head-and-neck-cancer
#13
Young-Suk Jung, Abdo J Najy, Wei Huang, Seema Sethi, Michael Snyder, Wael Sakr, Gregory Dyson, Maik Hüttemann, Icksoo Lee, Rouba Ali-Fehmi, Silvia Franceschi, Linda Struijk, Harold E Kim, Ikuko Kato, Hyeong-Reh Choi Kim
HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV-negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28880546/transcriptomic-and-functional-analyses-on-the-effects-of-dioxin-on-insulin-secretion-of-pancreatic-islets-and-%C3%AE-cells
#14
Keng Po Lai, Hin Ting Wan, Alice Hoi-Man Ng, Jing Woei Li, Ting Fung Chan, Chris Kong-Chu Wong
In this study, transcriptomic and Ingenuity Pathway Analysis (IPA) underlined that an ex-vivo TCDD treatment (0.1 nM) stimulated insulin-release in mouse pancreatic islets via the effect on the Akt-mTOR-p70S6K, AMPK and ERK1/2 pathways. Functional studies using both ex-vivo islets and the mouse β-cell-line (Min-6) validated the stimulatory effects of TCDD (0.1 and 1 nM) on basal-insulin secretion. At 0.1 nM TCDD treatment on Min-6, Western blot analysis showed activation of ERK1/2 and decreased expression of pyruvate dehydrogenase kinase (PDK)...
September 21, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28878225/the-pdk1-inhibitor-dichloroacetate-controls-cholesterol-homeostasis-through-the-erk5-mef2-pathway
#15
Abrar Ul Haq Khan, Nerea Allende-Vega, Delphine Gitenay, Sabine Gerbal-Chaloin, Claire Gondeau, Dang-Nghiem Vo, Sana Belkahla, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Milica Bozic, Jose M Valdivielso, Fabienne Bejjani, Isabelle Jariel, Isabel C Lopez-Mejia, Lluis Fajas, Charles-Henri Lecellier, Javier Hernandez, Martine Daujat, Martin Villalba
Controlling cholesterol levels is a major challenge in human health, since hypercholesterolemia can lead to serious cardiovascular disease. Drugs that target carbohydrate metabolism can also modify lipid metabolism and hence cholesterol plasma levels. In this sense, dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, augments usage of the glycolysis-produced pyruvate in the mitochondria increasing oxidative phosphorylation (OXPHOS). In several animal models, DCA decreases plasma cholesterol and triglycerides...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28870456/pharmacological-synergism-of-2-2-dichloroacetophenone-and-egfr-tki-to-overcome-tki-induced-resistance-in-nsclc-cells
#16
Zheng Yang, Xiaohui Hu, Shaolin Zhang, Wen Zhang, Kin Yip Tam
Combination treatment has been used as one of the therapeutic approaches for patients suffering from lung cancer, either to cope with the issue of acquired drug resistance due to prolong the use of a particular EGFR-TKi treatment, or to decrease the doses of each compound in order to reduce potential toxicity. 2,2-dichloroacetophenone (DAP) was reported as a PDK inhibitor recently, which is much more potent than dichloroacetate (DCA) in anti-cancer therapy. In this study, we applied DAP in combined with EGFR-TKis, erlotinib or gefitinib in NSCLC cell lines and NSCLC xenograft model...
November 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28839175/oxygen-nanobubbles-revert-hypoxia-by-methylation-programming
#17
Pushpak N Bhandari, Yi Cui, Bennett D Elzey, Craig J Goergen, Christopher M Long, Joseph Irudayaraj
Targeting the hypoxic tumor microenvironment has a broad impact in cancer epigenetics and therapeutics. Oxygen encapsulated nanosize carboxymethyl cellulosic nanobubbles were developed for mitigating the hypoxic regions of tumors to weaken the hypoxia-driven pathways and inhibit tumor growth. We show that 5-methylcytosine (5mC) hypomethylation in hypoxic regions of a tumor can be reverted to enhance cancer treatment by epigenetic regulation, using oxygen nanobubbles in the sub-100 nm size range, both, in vitro and in vivo...
August 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28820715/limited-transmission-potential-of-takeda-s-tetravalent-dengue-vaccine-candidate-by-aedes-albopictus
#18
Elizabeth A Dietrich, Yee Tsuey Ong, Janae L Stovall, Hansi Dean, Claire Y-H Huang
Recombinant live-attenuated chimeric tetravalent dengue vaccine viruses, TDV-1, -2, -3, and -4, contain the premembrane and envelope genes of dengue virus serotypes 1-4 in the replicative background of the attenuated dengue virus type-2 (DENV-2) PDK-53 vaccine strain. Previous results have shown that these recombinant vaccine viruses demonstrate limited infection and dissemination in Aedes aegypti and are unlikely to be transmitted by the primary mosquito vector of DENVs. In this report, we expand this analysis by assessing vector competence of all four serotypes of the TDV virus in Aedes albopictus, the secondary mosquito vector of DENVs...
August 14, 2017: American Journal of Tropical Medicine and Hygiene
https://www.readbyqxmd.com/read/28814762/down-regulation-of-pdk4-is-critical-for-the-switch-of-carbohydrate-catabolism-during-syncytialization-of-human-placental-trophoblasts
#19
Xiaohui Liu, Rujuan Zuo, Yirong Bao, Xiaoxian Qu, Kang Sun, Hao Ying
Pyruvate dehydrogenase kinase (PDK) is known as a gatekeeper directing the carbon flux into glycolysis via inhibition of the pyruvate dehydrogenase complex. During syncytialization of placental trophoblasts, both ATP production and oxygen consumption are increased to meet enhanced energetic demands by syntiotrophoblasts. We hypothesized that down-regulation of PDK expression may play a central role in the switch from glycolysis to oxidative phosphorylation (OXPHOS) during syncytialization. By using primary human trophoblasts, we demonstrated that PDK4 was the dominating PDK isoform in human cytotrophoblasts, and its abundance was substantially decreased upon syncytialization, which was accompanied by decreases in lactate production and increases in ATP production...
August 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28799960/critical-contact-lens-oxygen-transmissibility-and-tear-lens-oxygen-tension-to-preclude-corneal-neovascularization
#20
Karen K Yeung, Helen J Yang, Andrew L Nguyen, Barry A Weissman
OBJECTIVE: The purpose of this study is to determine the peripheral oxygen transmissibility (pDk/t) and respective central oxygen transmissibility (cDk/t) in soft contact lenses (SCLs) which might preclude SCL-driven corneal neovascularization (NV) in healthy myopic SCL users. METHODS: Twenty subjectively successful SCL-wearing patients who presented with asymptomatic but active peripheral corneal NV (not ghost vessels) were recruited as study patients. Twenty-one patients who did not have NV were similarly recruited as controls...
August 9, 2017: Eye & Contact Lens
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