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Pyruvate dehydrogenase

Minako Nagatome, Yuki Kondo, Daisuke Kadowaki, Yusuke Saishyo, Mitsuru Irikura, Tetsumi Irie, Yoichi Ishitsuka
Acetaminophen, a common analgesic/antipyretic, is a frequent cause of acute liver failure in Western countries. The development of an effective cure against acetaminophen hepatotoxicity is crucial. Ethyl pyruvate, an ethyl ester derivative of pyruvic acid, has been identified as a possible candidate against acetaminophen hepatotoxicity in animal experiments. However, the mode of the hepatoprotective action of ethyl pyruvate remains unclear. We examined the hepatoprotective effect of ethyl pyruvate against hepatocyte injury and oxidative stress in a mouse model of acetaminophen hepatotoxicity...
February 2018: Heliyon
Keshav Gopal, Malak Almutairi, Rami Al Batran, Farah Eaton, Manoj Gandhi, John Reyes Ussher
Obesity and type 2 diabetes (T2D) increase the risk for cardiomyopathy, which is the presence of ventricular dysfunction in the absence of underlying coronary artery disease and/or hypertension. As myocardial energy metabolism is altered during obesity/T2D (increased fatty acid oxidation and decreased glucose oxidation), we hypothesized that restricting myocardial glucose oxidation in lean mice devoid of the perturbed metabolic milieu observed in obesity/T2D would produce a cardiomyopathy phenotype, characterized via diastolic dysfunction...
2018: Frontiers in Cardiovascular Medicine
Ryan J Mailloux, Adrian Young, Marisa O'Brien, Robert Morris Gill
It has been reported that mitochondria can contain up to 12 enzymatic sources of reactive oxygen species (ROS). A majority of these sites include flavin-dependent respiratory complexes and dehydrogenases that produce a mixture of superoxide (O2●- ) and hydrogen peroxide (H2O2). Accurate quantification of the ROS-producing potential of individual sites in isolated mitochondria can be challenging due to the presence of antioxidant defense systems and side reactions that also form O2●- /H2O2. Use of nonspecific inhibitors that can disrupt mitochondrial bioenergetics can also compromise measurements by altering ROS release from other sites of production...
February 24, 2018: Journal of Visualized Experiments: JoVE
Haohua Wang, Roujun Peng, Xiuxing Chen, Rui Jia, Chunyue Huang, Yuanyuan Huang, Liangping Xia, Guifang Guo
Although hexokinase (HK) 2, pyruvate kinase muscle (PKM) isozyme 2 and lactate dehydrogenase (LDH) A predict the efficacy of medicines in various solid tumors, their ability to predict the efficacy of cetuximab in metastatic colorectal cancer (mCRC) remains unclear. mCRC patients with pathological specimens who received cetuximab and chemotherapy from 2005 to 2015 in the present institution were enrolled. Immunohistochemistry was used to detect HK2, PKM2 and LDHA expression. SPSS20 was used for statistical analysis...
April 2018: Oncology Letters
Hui Di, Xinting Zhang, Yi Guo, Yanfang Shi, Chuan Fang, Yu Yuan, Jiwei Wang, Chao Shang, Wenzhe Guo, Chunhui Li
Glioblastoma multiforme (GBM) is a prevalent and aggressive disease, and the development of a novel therapy to better treat advanced GBM is urgently required. Lactate dehydrogenase A (LDHA), which functions as a key enzyme in transforming pyruvate into lactate, has attracted more attention in recent years due to its critical role in various types of advanced cancer. Previous data derived from the Oncomine database have shown that the expression of LDHA is higher in GBM tissues than that in corresponding normal control tissues...
April 2018: Oncology Letters
B Fang, M Zhang, K S Ge, H Z Xing, F Z Ren
Previous studies have demonstrated that the anti-tumor α-lactalbumin-oleic acid complex (α-LA-OA) may target the glycolysis of tumor cells. However, few data are available regarding the effects of α-LA-OA on energy metabolism. In this study, we measured glycolysis and mitochondrial functions in HeLa cells in response to α-LA-OA using the XF flux analyzer (Seahorse Bioscience, North Billerica, MA). The gene expression of enzymes involved in glycolysis, tricarboxylic acid cycle, electron transfer chain, and ATP synthesis were also evaluated...
March 14, 2018: Journal of Dairy Science
Michael Karsy, Jian Guan, L Eric Huang
OBJECTIVE Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis...
March 16, 2018: Journal of Neurosurgery
Krishna B Singh, Eun-Ryeong Hahm, Lora H Rigatti, Daniel P Normolle, Jian-Min Yuan, Shivendra V Singh
We have shown previously that dietary administration of phenethyl isothiocyanate (PEITC), a small molecule from edible cruciferous vegetables, significantly decreases the incidence of poorly-differentiated prostate cancer in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice without any side effects. In this study, we investigated the role of c-Myc-regulated glycolysis in prostate cancer chemoprevention by PEITC. Exposure of LNCaP (androgen-responsive) and 22Rv1 (castration-resistant) human prostate cancer cells to PEITC resulted in suppression of expression as well as transcriptional activity of c-Myc...
March 15, 2018: Cancer Prevention Research
Jun-Ho Cho, Goo-Young Kim, Brian C Mansfield, Janice Y Chou
Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), a key enzyme in endogenous glucose production. This autosomal recessive disorder is characterized by impaired glucose homeostasis and long-term complications of hepatocellular adenoma/carcinoma (HCA/HCC). We have shown that hepatic G6Pase-α deficiency-mediated steatosis leads to defective autophagy that is frequently associated with carcinogenesis. We now show that hepatic G6Pase-α deficiency also leads to enhancement of hepatic glycolysis and hexose monophosphate shunt (HMS) that can contribute to hepatocarcinogenesis...
March 12, 2018: Biochemical and Biophysical Research Communications
Jian Lu, Min Chen, Sumeng Gao, Jigang Yuan, Zhu Zhu, Xiaoping Zou
The 'Warburg effect' is considered a vital hallmark of cancer cells, characterized by an altered metabolism, in which cells rely on aerobic glycolysis. As a key enzyme of aerobic glycolysis, pyruvate kinase M2 (PKM2) serves a crucial role in tumorigenesis. Accumulating studies have indicated that PKM2 is a potential target for cancer therapy. The aim of the present study was to assess the anticancer effects of LY294002, a specific phosphatidylinositol-3-kinase inhibitor, on gastric cancer (GC) cells and further explore its possible mechanism in vitro ...
April 2018: Oncology Letters
Motoko Sasaki, Yasunori Sato, Yasuni Nakanuma
Dysregulated autophagy may be a central player in trehe pathogenesis of primary biliary cholangitis (PBC) by inducing autoimmune processes via abnormal expression of mitochondrial antigens such as pyruvate dehydrogenase complex, E2 component (PDC-E2) and also by inducing cellular senescence in biliary epithelial cells (BECs) in bile duct lesions in PBC. We examined the association of an impaired "biliary bicarbonate umbrella" due to dysfunction of anion exchanger 2 (AE2) with dysregulated autophagy and cellular senescence in PBC...
March 14, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Christopher Schafer, Zachary T Young, Catherine A Makarewich, Abdallah Elnwasany, Caroline S Kinter, Michael Kinter, Luke I Szweda
Cardiac energy is produced primarily by oxidation of fatty acids and glucose, with the relative contributions of each nutrient being sensitive to changes in substrate availability and energetic demand. A major contributor to cardiac metabolic flexibility is pyruvate dehydrogenase (PDH) which converts glucose-derived pyruvate to acetyl-CoA within the mitochondria. PDH is inhibited by phosphorylation dependent on the competing activities of pyruvate dehydrogenase kinases (PDK1-4) and phosphatases (PDP1-2). A single high-fat meal increases cardiac PDK4 content and subsequently inhibits PDH activity, reducing pyruvate utilization when abundant fatty acids are available...
March 14, 2018: Journal of Biological Chemistry
Jessica N R Peoples, Timmi Maxmillian, Quynh Le, Sergiy M Nadtochiy, Paul S Brookes, George A Porter, Victor L Davidson, Steven N Ebert
Cardiac energy demands during early embryonic periods are sufficiently met through glycolysis, but as development proceeds, oxidative phosphorylation in mitochondria becomes increasingly vital. Adrenergic hormones are known to stimulate metabolism in adult mammals and are essential for embryonic development, but relatively little is known about their effects on metabolism in the embryonic heart.  Here, we show that embryos lacking adrenergic stimulation have approximately 10-fold less cardiac ATP compared to littermate controls...
March 14, 2018: Journal of Biological Chemistry
Mouadh Mihoub, André Pichette, Balla Sylla, Charles Gauthier, Jean Legault
Betulin has a wide range of biological and pharmacological properties with its anticancer activity attracting most of the attention as it offers a possible alternative treatment to chemotherapy. However, betulin's in vivo biological effectiveness is limited by its poor solubility. As such, we synthesized polar glycosylated derivatives to increase its hydrosolubility and enhance its pharmacological properties. Among these synthesized compounds, 28-O-α-l-rhamnopyranosylbetulin 3β-O-α-l-rhamnopyranoside (Bi-L-RhamBet) was assessed for its cytotoxic effects against a suite of lung cancer cell lines...
2018: PloS One
Yuya Nishimura, Terumi Matsui, Jun Ishii, Akihiko Kondo
BACKGROUND: To produce 1-propanol as a potential biofuel, metabolic engineering of microorganisms, such as E. coli, has been studied. However, 1-propanol production using metabolically engineered Saccharomyces cerevisiae, which has an amazing ability to produce ethanol and is thus alcohol-tolerant, has infrequently been reported. Therefore, in this study, we aimed to engineer S. cerevisiae strains capable of producing 1-propanol at high levels. RESULTS: We found that the activity of endogenous 2-keto acid decarboxylase and alcohol/aldehyde dehydrogenase is sufficient to convert 2-ketobutyrate (2 KB) to 500 mg/L 1-propanol in yeast...
March 9, 2018: Microbial Cell Factories
Andreas Schwentner, André Feith, Eugenia Münch, Tobias Busche, Christian Rückert, Jörn Kalinowski, Ralf Takors, Bastian Blombach
Evolutionary approaches are often undirected and mutagen-based yielding numerous mutations, which need elaborate screenings to identify relevant targets. We here apply Metabolic engineering to Guide Evolution (MGE), an evolutionary approach evolving and identifying new targets to improve microbial producer strains. MGE is based on the idea to impair the cell's metabolism by metabolic engineering, thereby generating guided evolutionary pressure. It consists of three distinct phases: (i) metabolic engineering to create the evolutionary pressure on the applied strain followed by (ii) a cultivation phase with growth as straightforward screening indicator for the evolutionary event, and (iii) comparative whole genome sequencing (WGS), to identify mutations in the evolved strains, which are eventually re-engineered for verification...
March 6, 2018: Metabolic Engineering
Theodoros Eleftheriadis, Georgios Pissas, Vassilios Liakopoulos, Ioannis Stefanidis
Indoleamine 2, 3-dioxygenase (IDO) suppresses T-cell function at least in part by altering cell metabolism. Hypoxia-inducible factor-1 (HIF-1) increases upon T-cell activation and alters cell metabolism favoring their differentiation to effector cells. The effect of IDO on HIF-1α expression and activity was evaluated. For this purpose, mixed lymphocyte reaction (MLR) was performed using the IDO inhibitor 1-DL-methyl-tryptophan and the p53 inhibitor pifithrin-α. L-tryptophan degradation and cell proliferation were assessed by enzyme-linked immunosorbent assay, whereas the expression of proteins of interest by western blotting...
February 2018: Iranian Journal of Allergy, Asthma, and Immunology
Alice Jara De Porcellinis, Hanne Nørgaard, Laura Maria Furelos Brey, Simon Matthé Erstad, Patrik R Jones, Joshua L Heazlewood, Yumiko Sakuragi
Cyanobacteria fix atmospheric CO2 to biomass and through metabolic engineering can also act as photosynthetic factories for sustainable productions of fuels and chemicals. The Calvin Benson cycle is the primary pathway for CO2 fixation in cyanobacteria, algae and C3 plants. Previous studies have overexpressed the Calvin Benson cycle enzymes, ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) and bifunctional sedoheptulose-1,7-bisphosphatase/fructose-1,6-bisphosphatase (hereafter BiBPase), in both plants and algae, although their impacts on cyanobacteria have not yet been rigorously studied...
March 3, 2018: Metabolic Engineering
Eduardo H Gilglioni, Jung-Chin Chang, Suzanne Duijst, Simei Go, Aziza A A Adam, Ruurdtje Hoekstra, Arthur J Verhoeven, Emy L Ishii-Iwamoto, Ronald P J Oude Elferink
Primary hepatocyte culture is an important in vitro system for the study of liver functions. In vivo , hepatocytes have high oxidative metabolism. However, oxygen supply by means of diffusion in in vitro static cultures is much less than that by blood circulation in vivo . Therefore, we investigated whether hypoxia contributes to dedifferentiation and deregulated metabolism in cultured hepatocytes. To this end, murine hepatocytes were cultured under static or shaken (60 revolutions per minute) conditions in a collagen sandwich...
March 2018: Hepatology Communications
Peng Zhang, Yarong Song, Yadong Sun, Xuechao Li, Lifeng Chen, Likun Yang, Yifei Xing
Prostate cancer (PCa) represents one of the most common solid neoplasms, and metastasis is the second leading cause of death in adult males. Anoikis is a programmed cell death that is induced upon cell detachment from the extracellular matrix (ECM), which behaves as a critical protective mechanism for anchorage-independent cell growth and metastasis formation. However, in the absence of ECM attachment, shift of metabolic pattern and tolerance to anoikis facilitate the survival of aggressive cancer cells in the circulatory system as well as their metastasis to distant sites...
March 5, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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