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Lactate AND mTOR

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https://www.readbyqxmd.com/read/28317262/hydroxytyrosol-restores-proper-insulin-signaling-in-an-astrocytic-model-of-alzheimer-s-disease
#1
M Carmen Crespo, Joao Tomé-Carneiro, Cristina Pintado, Alberto Dávalos, Francesco Visioli, Emma Burgos-Ramos
Recent epidemiological evidence demonstrated that diabetes is a risk factor for AD onset and development. Indeed, meta-analyses of longitudinal epidemiologic studies show that diabetes increases AD risk by 50-100%, being insulin resistance (IR) the main binding link between diabetes and AD. Astrocytes are the foremost cerebral macroglial cells and are responsible for converting glucose into lactate and transfer it to neurons that use it as fuel, but Aβ(1-42) impairs insulin signaling and glycogen storage. Recent prospective studies showed that the Mediterranean diet is associated with lower incidence of AD...
March 20, 2017: BioFactors
https://www.readbyqxmd.com/read/28315323/increased-serotonin-signaling-contributes-to-the-warburg-effect-in-pancreatic-tumor-cells-under-metabolic-stress-and-promotes-growth-of-pancreatic-tumors-in-mice
#2
Shu-Heng Jiang, Jun Li, Fang-Yuan Dong, Jian-Yu Yang, De-Jun Liu, Xiao-Mei Yang, Ya-Hui Wang, Min-Wei Yang, Xue-Liang Fu, Xiao-Xin Zhang, Qing Li, Xiu-Feng Pang, Yan-Miao Huo, Jiao Li, Jun-Feng Zhang, Ho-Young Lee, Su-Jae Lee, Wen-Xin Qin, Jian-Ren Gu, Yong-Wei Sun, Zhi-Gang Zhang
BACKGROUND & AIMS: The desmoplasia and poor vascularity cause severe metabolic stress in pancreatic ductal adenocarcinomas (PDACs). Serotonin (5-HT) is a neuromodulator with neurotransmitter and neuroendocrine functions that contributes to tumorigenesis. We investigated the role of 5-HT signaling in the growth of pancreatic tumors. METHODS: We measured the levels of proteins that regulate 5-HT synthesis, packaging, and degradation in pancreata from Kras(G12D/+); Trp53(R172H/+); Pdx1-Cre; (KPC) mice, which develop pancreatic tumors, as well as in PDAC cell lines and a tissue microarray containing 81 human PDAC samples...
March 14, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28290700/metabolic-response-to-everolimus-in-patient-derived-triple-negative-breast-cancer-xenografts
#3
Leslie R Euceda, Deborah K Hill, Endre Stokke, Rana Hatem, Rania El Botty, Ivan Bièche, Elisabetta Marangoni, Tone F Bathen, Siver A Moestue
Patients with triple negative breast cancer (TNBC) are unresponsive to endocrine and anti-HER2 pharmacotherapy, limiting their therapeutic options to chemotherapy. TNBC is frequently associated with abnormalities in the PI3K/AKT/mTOR signaling pathway; drugs targeting this pathway are currently being evaluated in these patients. However, response is variable, partly due to heterogeneity within TNBC, conferring a need to identify biomarkers predicting response and resistance to targeted therapy. In this study, we used a metabolomics approach to assess response to the mTOR inhibitor everolimus in a panel of TNBC patient-derived xenografts (PDX) (n=103 animals)...
March 14, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28259993/glycometabolic-adaptation-mediates-the-insensitivity-of-drug-resistant-k562-adm-leukaemia-cells-to-adriamycin-via-the-akt-mtor-c-myc-signalling-pathway
#4
Xueyan Zhang, Ziying Ai, Jing Chen, Juan Yi, Zhuan Liu, Huaishun Zhao, Hulai Wei
In human leukaemia, resistance to chemotherapy leads to treatment ineffectiveness or failure. Previous studies have indicated that cancers with increased levels of aerobic glycolysis are insensitive to numerous forms of chemotherapy and respond poorly to radiotherapy. Whether glycolysis serves a key role in drug resistance of leukaemia cells remains unclear. The present study systematically investigated aerobic glycolytic alterations and regulation in K562/adriamycin (ADM) multidrug‑resistant (MDR) and ADM‑sensitive K562 leukaemia cells in normoxia, and the association between drug resistance and improper glycometabolism...
February 10, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28237591/methionine-leucine-isoleucine-or-threonine-effects-on-mammary-cell-signaling-and-pup-growth-in-lactating-mice
#5
G M Liu, M D Hanigan, X Y Lin, K Zhao, F G Jiang, R R White, Y Wang, Z Y Hu, Z H Wang
Two studies were undertaken to assess the effects of individual essential AA supplementation of a protein-deficient diet on lactational performance in mice using litter growth rates as a response variable. The first study was designed to establish a dietary protein response curve, and the second to determine the effects of Leu, Ile, Met, and Thr supplementation of a protein-deficient diet on lactational performance. In both studies, dams were fed test diets from parturition through d 17 of lactation, when the studies ended...
February 22, 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/28223230/myotoxicity-of-statins-mechanism-of-action
#6
REVIEW
Patrick du Souich, Ghislaine Roederer, Robert Dufour
Statins are effective drugs to reduce cardiovascular events secondary to dyslipidemia; however, they cause frequent undesirable side effects. The incidence of statin-induced myotoxicity (SIM) is presented by 7 to 29% of patients, depending upon the report. SIM may develop in presence of abnormally high concentrations of statins in the myocyte and/or in presence of muscular conditions that may predispose to SIM. High concentrations of statins in the myocyte may occur whenever the activity of liver influx membrane transporters, namely OATP1B1, of drug metabolizing enzymes, and of liver and muscular efflux transporters, MDR1 and BCRP, is reduced...
February 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28219050/synergism-and-mechanism-of-astragaloside-iv-combined-with-ginsenoside-rg1-against-autophagic-injury-of-pc12-cells-induced-by-oxygen-glucose-deprivation-reoxygenation
#7
Xiao-Ping Huang, Huang Ding, Xiao-Qian Yang, Jing-Xian Li, Biao Tang, Xiao-Dan Liu, Ying-Hong Tang, Chang-Qing Deng
The aim of this study was to explore the effect by which the combination of Astragaloside IV (AST IV) and Ginsenoside Rg1 (Rg1) resisted autophagic injury in PC12 cells induced by oxygen glucose deprivation/reoxygenation (OGD/R). We studied the nature of the interaction between AST IV and Rg1 that inhibited autophagy through the Isobologram method, and investigated the synergistic mechanism via the PI3K I/Akt/mTOR and PI3K III/Becline-1/Bcl-2 signaling pathways. Our results showed that, based on the 50% inhibiting concentration (IC50), AST IV combined with Rg1 at a 1:1 ratio resulted in a synergistic effect, whereas the combination of the two had an antagonistic effect on autophagy at ratios of 1:2 and 2:1...
February 17, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28214879/thiamine-deprivation-produces-a-liver-atp-deficit-and-metabolic-and-genomic-effects-in-mice-findings-are-parallel-to-those-of-biotin-deficiency-and-have-implications-for-energy-disorders
#8
Alain de J Hernandez-Vazquez, Josue Andres Garcia-Sanchez, Elizabeth Moreno-Arriola, Ana Salvador-Adriano, Daniel Ortega-Cuellar, Antonio Velazquez-Arellano
Thiamine is one of several essential cofactors for ATP generation. Its deficiency, like in beriberi and in the Wernicke-Korsakoff syndrome, has been studied for many decades. However, its mechanism of action is still not completely understood at the cellular and molecular levels. Since it acts as a coenzyme for dehydrogenases of pyruvate, branched-chain keto acids, and ketoglutarate, its nutritional privation is partly a phenocopy of inborn errors of metabolism, among them maple syrup urine disease. In the present paper, we report metabolic and genomic findings in mice deprived of thiamine...
February 18, 2017: Journal of Nutrigenetics and Nutrigenomics
https://www.readbyqxmd.com/read/28187451/gsk1059615-kills-head-and-neck-squamous-cell-carcinoma-cells-possibly-via-activating-mitochondrial-programmed-necrosis-pathway
#9
Jing Xie, Quan Li, Xi Ding, Yunyun Gao
This study tested the anti-head and neck squamous cell carcinoma (HNSCC) cell activity by GSK1059615, a novel PI3K and mTOR dual inhibitor. GSK1059615 inhibited survival and proliferation of established (SCC-9, SQ20B and A253 lines) and primary human HNSCC cells. GSK1059615 blocked PI3K-AKT-mTOR activation in HNSCC cells. Intriguingly, GSK1059615 treatment in HNSCC cells failed to provoke apoptosis, but induced programmed necrosis. The latter was tested by mitochondria depolarization, ANT-1-cyclophilin-D mitochondrial association and lactate dehydrogenase (LDH) release...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28181145/low-after-high-glucose-down-regulated-cx43-in-h9c2-cells-by-autophagy-activation-via-cross-regulation-by-the-pi3k-akt-mtor-and-mek-erk1-2-signal-pathways
#10
Yaguang Bi, Guangyu Wang, Xiangdong Liu, Meng Wei, Qingyong Zhang
PURPOSE: Hypoglycemia in diabetes is a strong predictor of cardiovascular events. High-glucose have been reported to alter connexin43 expression and to promote autophagy in cardiomyocytes. We investigated whether low-after-high glucose would influence connexin43 expression and autophagy in H9c2 cells. METHODS: H9c2 cells were incubated in 33.3 mM glucose for 24 h followed by 2.5 mM glucose for 2, 4, 6, or 12 h with or without chloroquine (autophagy inhibitor), U0126 (MEK1/2 inhibitor) or LY294002 (PI3K inhibitor)...
February 8, 2017: Endocrine
https://www.readbyqxmd.com/read/28174256/a-time-for-myc-metabolism-and-therapy
#11
Chi V Dang
The MYC oncogene is frequently deregulated in human cancers, whereas the proto-oncogene is exquisitely, tightly regulated in normal cells. Deregulated MYC drives transcriptional imbalance, thereby altering metabolism and disrupting the circadian Bmal1-Clock E-box-dependent transcriptional circuitry. Sustained oncogenic MYC expression drives a constitutive growth program with mammalian target of rapamycin (mTOR) activation that renders cells dependent on nutrients, such that glucose or glutamine deprivation could trigger cell death and key enzymes such as lactate dehydrogenase A (LDHA) and glutaminase (GLS) amenable for targeting in cancers...
February 7, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/28126648/maternal-consumption-of-low-isoflavone-soy-protein-isolate-alters-hepatic-gene-expression-and-liver-development-in-rat-offspring
#12
Sae Bom Won, Anna Han, Young Hye Kwon
In utero environment is known to affect fetal development. Especially, the distinct fetal programming of carcinogenesis was reported in offspring exposed to maternal diets containing soy protein isolate (SPI) or genistein. Therefore, we investigated whether maternal consumption of low-isoflavone SPI or genistein alters hepatic gene expression and liver development in rat offspring. Female Sprague-Dawley rats were fed a casein diet, a low-isoflavone SPI diet or a casein diet supplemented with genistein (250 mg/kg diet) for 2 weeks before mating and throughout pregnancy and lactation...
January 12, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28118663/the-effects-of-nonporous-silica-nanoparticles-on-cultured-human-keratocytes
#13
Bora Yim, Joo-Hee Park, Hyejoong Jeong, Jinkee Hong, Young-Joo Shin, Roy S Chuck, Choul Yong Park
Purpose: Silica nanoparticles (SiNPs) are promising carriers for ophthalmic drug delivery. In this study, we investigated the effect of various sizes of nonporous SiNPs on cultured human keratocytes. Methods: Three different sizes of SiNPs (50, 100, and 150 nm) were manufactured. Primarily cultured human keratocytes were exposed to different concentrations (0, 25, 50, and 100 μg/mL) of three sizes of SiNPs for up to 72 hours. Intracellular reactive oxygen species (ROS) generation, cellular viability, lactate dehydrogenase (LDH) assay, autophagy, vimentin expression, and mammalian target of rapamycin (mTOR) pathway activation were evaluated...
January 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28052008/targeting-p-glycoprotein-function-p53-and-energy-metabolism-combination-of-metformin-and-2-deoxyglucose-reverses-the-multidrug-resistance-of-mcf-7-dox-cells-to-doxorubicin
#14
Chaojun Xue, Changyuan Wang, Yaoting Sun, Qiang Meng, Zhihao Liu, Xiaokui Huo, Pengyuan Sun, Huijun Sun, Xiaodong Ma, Xiaochi Ma, Jinyong Peng, Kexin Liu
Multidrug resistance(MDR) is a major obstacle to efficiency of breast cancer chemotherapy. We investigated whether combination of metformin and 2-deoxyglucose reverses MDR of MCF-7/Dox cells and tried to elucidate the possible mechanisms. The combination of metformin and 2-deoxyglucose selectively enhanced cytotoxicity of doxorubicin against MCF-7/Dox cells. Combination of the two drugs resumed p53 function via inhibiting overexpression of murine doubleminute 2(MDM2) and murine doubleminute 4(MDM4) leading to G2/M arrest and apoptosis in MCF-7/Dox cells...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/27991931/oxidative-stress-downstream-of-mtorc1-but-not-akt-causes-a-proliferative-defect-in-cancer-cells-resistant-to-pi3k-inhibition
#15
M Dermit, P Casado, V Rajeeve, E H Wilkes, D E Foxler, H Campbell, S Critchlow, T V Sharp, J G Gribben, R Unwin, P R Cutillas
Compounds targeting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling are being investigated in multiple clinical settings, but drug resistance may reduce their benefit. Compound rechallenge after drug holidays can overcome such resistance, yet little is known about the impact of drug holidays on cell biochemistry. We found that PI3K inhibitor (PI3Ki)-resistant cells cultured in the absence of PI3Ki developed a proliferative defect, increased oxygen consumption and accumulated reactive oxygen species (ROS), leading to lactate production through hypoxia-inducible factor-1α...
December 19, 2016: Oncogene
https://www.readbyqxmd.com/read/27983688/maternal-food-restriction-during-pregnancy-and-lactation-adversely-affect-hepatic-growth-and-lipid-metabolism-in-three-week-old-rat-offspring
#16
Sangmi Lee, Young-Ah You, Eun Jin Kwon, Sung-Chul Jung, Inho Jo, Young Ju Kim
Maternal malnutrition influences the early development of foetal adaptive changes for survival. We explored the effects of maternal undernutrition during gestation and lactation on hepatic growth and function. Sprague-Dawley rats were fed a normal or a food-restricted (FR) diet during gestation and/or lactation. We performed analyses of covariance (adjusting for the liver weight/body weight ratio) to compare hepatic growth and lipid metabolism among the offspring. Maternal FR during gestation triggered the development of wide spaces between hepatic cells and increased the expression of mammalian target of rapamycin (mTOR) in three-week-old male offspring compared with controls (both p < 0...
December 15, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27908730/mtor-activation-is-critical-for-betulin-treatment-in-renal-cell-carcinoma-cells
#17
Wenlong Cheng, Shiqi Ji, Haijian Zhang, Zhixing Han, Qingjun Liu, Jianwen Wang, Hao Ping
Betulin, a natural product isolated from the bark of the birch trees, exhibits multiple anticancer effects. Activation of mTOR signaling pathway has been found in numerous cancers, including renal cell carcinoma (RCC). Here, we attempted to study whether mTOR signaling was essential for betulin to treat RCC. Based on cell survival and colony formation assays, we found that mTOR hyperactive RCC cell line 786-O cells were more sensitive to betulin treatment compared with mTOR-inactive Caki-2 cells. Knockdown of TSC2 in Caki-2 cells had similar results to 786-O cells, and mTOR silencing in 786-O cells rescued the inhibitory effect of betulin, indicating that betulin inhibited RCC cell proliferation in an mTOR-dependent manner...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27900044/plumbagin-inhibits-cell-proliferation-and-promotes-apoptosis-in-multiple-myeloma-cells-through-inhibition-of-the-pi3k-akt-mtor-pathway
#18
Hongwei Wu, Xiaozhen Dai, Enren Wang
Plumbagin is the primary component of the traditional Chinese medicine Baihua Dan, and possesses anti-infection and anticancer effects with the ability to enhance the sensitivity of tumor cells to radiation therapy. The present study aimed to investigate the potential anticancer effect and mechanism of plumbagin on multiple myeloma (MM) cells. Human MM OPM1 cells were treated with plumbagin, and its impact on cell viability, cytotoxicity, apoptosis and caspase-3 activity was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, lactate dehydrogenase leakage, flow cytometry and colorimetric assays...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27698900/anti-inflammatory-and-antitumor-activity-of-a-triple-therapy-for-a-colitis-related-colorectal-cancer
#19
Gabriela Figueroa-González, Verónica García-Castillo, Jossimar Coronel-Hernández, Eduardo López-Urrutia, Sonia León-Cabrera, Luis E Arias-Romero, L I Terrazas, Miriam Rodríguez-Sosa, Alma Delia Campos-Parra, Eduardo Zúñiga-Calzada, Cesar Lopez-Camarillo, Fermín Morales-González, Nadia J Jacobo-Herrera, Carlos Pérez-Plasencia
Colorectal cancer (CRC) is an important health issue worldwide, accounting for the third place of cancer incidence. Chronic inflammation, as seen in Crohn's disease and ulcerative colitis, is the most important risk factor for developing CRC, as it favours neoplastic transformation by enhancing epithelial cell turnover in the colonic mucosa. Treatments for CRC need to be improved; currently they are not specific and have several secondary effects in patients. The main objective of this work was to evaluate a new therapeutic strategy against a colitis-related colorectal cancer in vivo and in vitro by targeting mTOR-signaling and lactate dehydrogenase A...
2016: Journal of Cancer
https://www.readbyqxmd.com/read/27666003/basal-autophagy-protects-cardiomyocytes-from-doxorubicin-induced-toxicity
#20
Marcela Pizarro, Rodrigo Troncoso, Gonzalo J Martínez, Mario Chiong, Pablo F Castro, Sergio Lavandero
Doxorubicin (Doxo) is one of the most effective anti-neoplastic agents but its cardiotoxicity has been an important clinical limitation. The major mechanism of Doxo-induced cardiotoxicity is associated to its oxidative capacity. However, other processes are also involved with significant consequences for the cardiomyocyte. In recent years, a number of studies have investigated the role of autophagy on Doxo-induced cardiotoxicity but to date it is not clear how Doxo alters that process and its consequence on cardiomyocytes viability...
September 22, 2016: Toxicology
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