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https://www.readbyqxmd.com/read/27876895/multiple-crosstalk-between-tor-and-the-cell-integrity-mapk-signaling-pathway-in-fission-yeast
#1
Marisa Madrid, Beatriz Vázquez-Marín, Alejandro Franco, Teresa Soto, Jero Vicente-Soler, Mariano Gacto, José Cansado
In eukaryotic cells, the highly conserved Target of Rapamycin (TOR) and the Mitogen Activated Protein Kinase (MAPK) signaling pathways elicit adaptive responses to extra- and intracellular conditions by regulating essential cellular functions. However, the nature of the functional relationships between both pathways is not fully understood. In the fission yeast Schizosaccharomyces pombe the cell integrity MAPK pathway (CIP) regulates morphogenesis, cell wall structure and ionic homeostasis. We show that the Rab GTPase Ryh1, a TORC2 complex activator, cross-activates the CIP and its core member, the MAPK Pmk1, by two distinct mechanisms...
November 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27874079/crosstalk-among-proteome-acetylome-and-succinylome-in-colon-cancer-hct116-cell-treated-with-sodium-dichloroacetate
#2
Danxi Zhu, Lidan Hou, Bin Hu, Hang Zhao, Jie Sun, Jianhua Wang, Xiangjun Meng
Protein lysine acetylation and succinylation play important regulatory roles in cells, both of which or each other has a close relationship. Dichloroacetate (DCA), a well-known pyruvate dehydrogenase kinase (PDK) inhibitor, has the potential to be used as anti-cancer drugs for several tumors including colorectal cancer. However, little is known about the potential mechanism of DCA-based cancer therapy by protein posttranslational modifications (PTM) including global proteome, acetylome and succinylome. Here the combinations with stable isotope labeling (SILAC), antibody affinity enrichment and high resolution LC-MS/MS analysis were performed in human colon cancer HCT116 cells...
November 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27856638/regulation-of-pyruvate-dehydrogenase-kinase-4-in-the-heart-through-degradation-by-the-lon-protease-in-response-to-mitochondrial-substrate-availability
#3
Clair Crewe, Christopher Schafer, Irene Lee, Michael Kinter, Luke I Szweda
Cardiac metabolic inflexibility is driven by robust up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) and phosphorylation-dependent inhibition of pyruvate dehydrogenase (PDH) within a single day of feeding mice a high fat diet. In the current study, we have discovered that PDK4 is a short-lived protein (t1/2 ~1 h) and is specifically degraded by the mitochondrial protease, Lon. Lon does not rapidly degrade PDK1 and 2 indicating specificity toward the PDK isoform that is a potent modulator of metabolic flexibility...
November 17, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27854075/benzimidazole-derivative-m084-extends-the-lifespan-of-caenorhabditis-elegans-in-a-daf-16-foxo-dependent-way
#4
Ai-Jun Ding, Gui-Sheng Wu, Bin Tang, Xuechuan Hong, Michael X Zhu, Huai-Rong Luo
With the growth of aging population, there is increasing demand to develop strategy to improve the aging process and aging-related diseases. Benzimidazole and its derivatives are crucial heterocyclic backbone of many drugs and compounds with diverse therapeutic applications, including alleviation of aging-related diseases. Here, we investigate if the benzimidazole derivative n-butyl-[1H]-benzimidazol-2-amine (M084), a novel inhibitor of TRPC4 and TRPC5 channels and antidepressant, could affect the lifespan of Caenorhabditis elegans (C...
November 16, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27795296/phd2-is-a-regulator-for-glycolytic-reprogramming-in-macrophages
#5
Annemarie Guentsch, Angelika Beneke, Lija Swain, Katja Farhat, Shunmugam Nagarajan, Ben Wielockx, Kaamini Raithatha, Jan Dudek, Peter Rehling, Anke Zieseniss, Aline Jatho, Mei Chong, Celio X C Santos, Ajay M Shah, Dörthe M Katschinski
The prolyl-4-hydroxylase domain (PHD) enzymes are regarded as the molecular oxygen sensors. There is an interplay between oxygen availability and cellular metabolism, which in turn has significant effects on the functionality of innate immune cells like macrophages. If and how PHDs affect macrophage metabolism however is enigmatic. We hypothesized that via manipulation of PHD2 macrophage metabolism and function can be controlled. We characterized the metabolic phenotype of PHD2-deficient RAW cells and primary PHD2 knock out bone marrow derived macrophages (BMDM)...
October 17, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27626688/diisopropylamine-dichloroacetate-enhances-radiosensitization-in-esophageal-squamous-cell-carcinoma-by-increasing-mitochondria-derived-reactive-oxygen-species-levels
#6
Gaochao Dong, Qiang Chen, Feng Jiang, Decai Yu, Qixing Mao, Wenjie Xia, Run Shi, Jie Wang, Lin Xu
Radiotherapy is generally applied in the treatment of esophageal squamous cell carcinoma (ESCC). However, the radioresistance of ESCC still remains an obstacle for the curative effect of this treatment. We hypothesized that diisopropylamine dichloroacetate (DADA), an inhibitor of pyruvate dehydrogenase kinase (PDK), might enhance radiosensitizationin resistant ESCC. The clonogenic survival assay revealed that DADA sensitized ESCC cells to radiotherapy in vitro; furthermore, the combination of DADA and radiotherapy increased the expression of γ-H2AX, which is a hallmark of DNA double-strand breaks...
September 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27626669/kdm4a-coactivates-e2f1-to-regulate-the-pdk-dependent-metabolic-switch-between-mitochondrial-oxidation-and-glycolysis
#7
Ling-Yu Wang, Chiu-Lien Hung, Yun-Ru Chen, Joy C Yang, Junjian Wang, Mel Campbell, Yoshihiro Izumiya, Hong-Wu Chen, Wen-Ching Wang, David K Ann, Hsing-Jien Kung
The histone lysine demethylase KDM4A/JMJD2A has been implicated in prostate carcinogenesis through its role in transcriptional regulation. Here, we describe KDM4A as a E2F1 coactivator and demonstrate a functional role for the E2F1-KDM4A complex in the control of tumor metabolism. KDM4A associates with E2F1 on target gene promoters and enhances E2F1 chromatin binding and transcriptional activity, thereby modulating the transcriptional profile essential for cancer cell proliferation and survival. The pyruvate dehydrogenase kinases (PDKs) PDK1 and PDK3 are direct targets of KDM4A and E2F1 and modulate the switch between glycolytic metabolism and mitochondrial oxidation...
September 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27605385/glucose-dependent-anaplerosis-in-cancer-cells-is-required-for-cellular-redox-balance-in-the-absence-of-glutamine
#8
Naniye Mallı Cetinbas, Jessica Sudderth, Robert C Harris, Aysun Cebeci, Gian L Negri, Ömer H Yılmaz, Ralph J DeBerardinis, Poul H Sorensen
Cancer cells have altered metabolism compared to normal cells, including dependence on glutamine (GLN) for survival, known as GLN addiction. However, some cancer cell lines do not require GLN for survival and the basis for this discrepancy is not well understood. GLN is a precursor for antioxidants such as glutathione (GSH) and NADPH, and GLN deprivation is therefore predicted to deplete antioxidants and increase reactive oxygen species (ROS). Using diverse human cancer cell lines we show that this occurs only in cells that rely on GLN for survival...
September 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27571309/reevaluation-of-two-quantitative-trait-loci-for-type-ii-resistance-to-fusarium-head-blight-in-wheat-germplasm-pi-672538
#9
X Li, Z P Xiang, W Q Chen, Q L Huang, T G Liu, Q Li, S F Zhong, M Zhang, J W Guo, L Lei, P G Luo
Fusarium head blight (FHB), mainly caused by Fusarium graminearum, is a destructive disease in wheat. A population consisting of 229 F2 and F2:3 plants derived from the cross PI 672538 × L661 was used to evaluate the reactions to FHB. The FHB resistance data distribution in the F2 population indicates that some quantitative trait loci (QTLs) were controlling the FHB resistance in PI 672538. We further detected two major QTLs (Qfhs-2B, Qfhs-3B) from analysis of the resistance data and the PCR-amplified results using WinQTLCart 2...
October 18, 2016: Phytopathology
https://www.readbyqxmd.com/read/27569719/expression-and-localization-of-angiopoietin-family-in-corpus-luteum-during-different-stages-of-oestrous-cycle-and-modulatory-role-of-angiopoietins-on-steroidogenesis-angiogenesis-and-survivability-of-cultured-buffalo-luteal-cells
#10
S R Mishra, M S Parmar, V P Yadav, R Reshma, J Bharati, M K Bharti, A Paul, V S Chouhan, G Taru Sharma, G Singh, M Sarkar
The objective of this study was to document the expression and localization of angiopoietin (ANGPT) family members comprising of angiopoietin (ANGPT1 and ANGPT2), and their receptors (Tie1 and Tie2) in buffalo corpus luteum (CL) obtained from different stages of the oestrous cycle, and the modulatory role of ANGPT1 and ANGPT2 alone or in combinations on progesterone (P4 ) secretion and mRNA expression of phosphotidylinositide-3kinase-protein kinase B (PI3K-AKT), phosphoinositide-dependent kinase (PDK), protein kinase B (AKT), Bcl2 associated death promoter (BAD), caspase 3 and von willebrand factor (vWF) in luteal cells obtained from midluteal phase (MLP) of oestrous cycle in buffalo...
December 2016: Reproduction in Domestic Animals, Zuchthygiene
https://www.readbyqxmd.com/read/27514773/anti-cancer-synergy-of-dichloroacetate-and-egfr-tyrosine-kinase-inhibitors-in-nsclc-cell-lines
#11
Zheng Yang, Kin Y Tam
Glycolysis has been observed as a predominant process for most cancer cells to utilize glucose, which was referred to as "Warburg Effect". Targeting critical enzymes, such as pyruvate dehydrogenase kinase (PDK) that inversely regulating the process of glycolysis could be a promising approach to work alone or in combination with other treatments for cancer therapy. EGFR inhibitors for Non-Small-Cell Lung Cancer (NSCLC) treatment have been applied for decades in clinical practices with great success, but also their clinical benefits were somewhat hampered by the rising acquired-resistance...
October 15, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27471054/pyruvate-dehydrogenase-kinase-regulates-hepatitis-c-virus-replication
#12
Gwon-Soo Jung, Jae-Han Jeon, Yeon-Kyung Choi, Se Young Jang, Soo Young Park, Sung-Woo Kim, Jun-Kyu Byun, Mi-Kyung Kim, Sungwoo Lee, Eui-Cheol Shin, In-Kyu Lee, Yu Na Kang, Keun-Gyu Park
During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that promotes aerobic glycolysis, can regulate HCV replication. Levels of c-Myc, hypoxia-inducible factor-1α (HIF-1α), PDK1, PDK3, glucokinase, and serine biosynthetic enzymes were compared between HCV-infected and uninfected human liver and Huh-7...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27462466/the-erk-signaling-target-rnf126-regulates-anoikis-resistance-in-cancer-cells-by-changing-the-mitochondrial-metabolic-flux
#13
Seiko Yoshino, Toshiro Hara, Hiroki J Nakaoka, Akane Kanamori, Yoshinori Murakami, Motoharu Seiki, Takeharu Sakamoto
Loss of anchorage to the extracellular matrix leads to apoptosis (anoikis) in normal cells, but cancerous cells are usually resistant to such stress. Here we report the pivotal role of an E3 ubiquitin ligase, ring-finger protein 126 (RNF126), in the resistance of cancer cells to the stress associated with non-adherent conditions. Non-adherent cancer cells exhibited increased flux through the tricarboxylic acid cycle via increased conversion of pyruvate to acetyl-CoA. RNF126 was found to act as a ubiquitin ligase for pyruvate dehydrogenase kinases (PDKs), resulting in their proteasomal degradation...
2016: Cell Discovery
https://www.readbyqxmd.com/read/27435185/furoates-and-thenoates-inhibit-pyruvate-dehydrogenase-kinase-2-allosterically-by-binding-to-its-pyruvate-regulatory-site
#14
Tiziana Masini, Barbara Birkaya, Simon van Dijk, Milon Mondal, Johan Hekelaar, Manuel Jäger, Anke C Terwisscha van Scheltinga, Mulchand S Patel, Anna K H Hirsch, Edelmiro Moman
The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture...
July 19, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/27432037/time-dependent-ppar%C3%AE-modulation-of-hif-1%C3%AE-signaling-in-hypoxic-pulmonary-artery-smooth-muscle-cells
#15
Justine I Blum, Kaiser M Bijli, Tamara C Murphy, Jennifer M Kleinhenz, C Michael Hart
BACKGROUND: Pathogenesis of pulmonary hypertension is complex and involves activation of the transcription factor, hypoxia-inducible factor-1 (HIF-1) that shifts cellular metabolism from aerobic respiration to glycolysis, in part, by increasing the expression of its downstream target pyruvate dehydrogenase kinase-1 (PDK-1), thereby promoting a proliferative, apoptosis-resistant phenotype in pulmonary vascular cells. Activation of the nuclear hormone transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), attenuates pulmonary hypertension and pulmonary artery smooth muscle cell (PASMC) proliferation...
July 2016: American Journal of the Medical Sciences
https://www.readbyqxmd.com/read/27388934/pathogenic-mechanisms-underlying-x-linked-charcot-marie-tooth-neuropathy-cmtx6-in-patients-with-a-pyruvate-dehydrogenase-kinase-3-mutation
#16
Gonzalo Perez-Siles, Carolyn Ly, Adrienne Grant, Alexander P Drew, Eppie M Yiu, Monique M Ryan, David T Chuang, Shih-Chia Tso, Garth A Nicholson, Marina L Kennerson
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. An X-linked form of CMT (CMTX6) is caused by a missense mutation (R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. PDK3 is one of 4 isoenzymes that negatively regulate the activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation of its first catalytic component pyruvate dehydrogenase (designated as E1). Mitochondrial PDC catalyses the oxidative decarboxylation of pyruvate to acetyl CoA and links glycolysis to the energy-producing Krebs cycle...
October 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27378235/chlorogenic-acid-extends-the-lifespan-of-caenorhabditis-elegans-via-insulin-igf-1-signaling-pathway
#17
Shan-Qing Zheng, Xiao-Bing Huang, Ti-Kun Xing, Ai-Jun Ding, Gui-Sheng Wu, Huai-Rong Luo
Coffee and tea, two of the most popular drinks around the world, share many in common from chemical components to beneficial effects on human health. One of their shared components, the polyphenols, most notably chlorogenic acid (CGA), was supposed to account for many of the beneficial effects on ameliorating diseases occurred accompanying people aging, such as the antioxidant effect and against diabetes and cardiovascular disease. CGA is also present in many traditional Chinese medicines. However, the mechanism of these effects was vague...
July 4, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/27343087/acquired-mitochondrial-abnormalities-including-epigenetic-inhibition-of-superoxide-dismutase-2-in-pulmonary-hypertension-and-cancer-therapeutic-implications
#18
Stephen L Archer
There is no cure for non-small-cell lung cancer (NSCLC) or pulmonary arterial hypertension (PAH). Therapies lack efficacy and/or are toxic, reflecting a failure to target disease abnormalities that are distinct from processes vital to normal cells. NSCLC and PAH share reversible mitochondrial-metabolic abnormalities which may offer selective therapeutic targets. The following mutually reinforcing, mitochondrial abnormalities favor proliferation, impair apoptosis, and are relatively restricted to PAH and cancer cells: (1) Epigenetic silencing of superoxide dismutase-2 (SOD2) by methylation of CpG islands creates a pseudohypoxic redox environment that causes normoxic activation of hypoxia inducible factor (HIF-1α)...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27341107/fusarium-graminearum-pyruvate-dehydrogenase-kinase-1-fgpdk1-is-critical-for-conidiation-mycelium-growth-and-pathogenicity
#19
Tao Gao, Jian Chen, Zhiqi Shi
Pyruvate dehydrogenase kinase (PDK) is an important mitochondrial enzyme that blocks the production of acetyl-CoA by selectively inhibiting the activity of pyruvate dehydrogenase (PDH) through phosphorylation. PDK is an effectively therapeutic target in cancer cells, but the physiological roles of PDK in phytopathogens are largely unknown. To address these gaps, a PDK gene (FgPDK1) was isolated from Fusarium graminearum that is an economically important pathogen infecting cereals. The deletion of FgPDK1 in F...
2016: PloS One
https://www.readbyqxmd.com/read/27323896/pro-haloacetate-nanoparticles-for-efficient-cancer-therapy-via-pyruvate-dehydrogenase-kinase-modulation
#20
Santosh K Misra, Mao Ye, Fatemeh Ostadhossein, Dipanjan Pan
Anticancer agents based on haloacetic acids are developed for inhibition of pyruvate dehydrogenase kinase (PDK), an enzyme responsible for reversing the suppression of mitochondria-dependent apoptosis. Through molecular docking studies mono- and dihaloacetates are identified as potent PDK2 binders and matched their efficiency with dichloroacetic acid. In silico screening directed their conversion to phospholipid prodrugs, which were subsequently self-assembled to pro-haloacetate nanoparticles. Following a thorough physico-chemical characterization, the functional activity of these novel agents was established in wide ranges of human cancer cell lines in vitro and in vivo in rodents...
June 21, 2016: Scientific Reports
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