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Rapamycin

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https://www.readbyqxmd.com/read/28648781/pp2a-controls-genome-integrity-by-integrating-nutrient-sensing-and-metabolic-pathways-with-the-dna-damage-response
#1
Elisa Ferrari, Christopher Bruhn, Marta Peretti, Corinne Cassani, Walter Vincenzo Carotenuto, Mohamed Elgendy, Ghadeer Shubassi, Chiara Lucca, Rodrigo Bermejo, Mario Varasi, Saverio Minucci, Maria Pia Longhese, Marco Foiani
Mec1(ATR) mediates the DNA damage response (DDR), integrating chromosomal signals and mechanical stimuli. We show that the PP2A phosphatases, ceramide-activated enzymes, couple cell metabolism with the DDR. Using genomic screens, metabolic analysis, and genetic and pharmacological studies, we found that PP2A attenuates the DDR and that three metabolic circuits influence the DDR by modulating PP2A activity. Irc21, a putative cytochrome b5 reductase that promotes the condensation reaction generating dihydroceramides (DHCs), and Ppm1, a PP2A methyltransferase, counteract the DDR by activating PP2A; conversely, the nutrient-sensing TORC1-Tap42 axis sustains DDR activation by inhibiting PP2A...
June 12, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28648777/mtorc2-regulates-amino-acid-metabolism-in-cancer-by-phosphorylation-of-the-cystine-glutamate-antiporter-xct
#2
Yuchao Gu, Claudio P Albuquerque, Daniel Braas, Wei Zhang, Genaro R Villa, Junfeng Bi, Shiro Ikegami, Kenta Masui, Beatrice Gini, Huijun Yang, Timothy C Gahman, Andrew K Shiau, Timothy F Cloughesy, Heather R Christofk, Huilin Zhou, Kun-Liang Guan, Paul S Mischel
Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian target of rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation into glutathione, linking growth factor receptor signaling with amino acid uptake and utilization...
June 22, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28647611/autophagy-suppresses-isoprenaline-induced-m2-macrophage-polarization-via-the-ros-erk-and-mtor-signaling-pathway
#3
Meihua Shan, Junfang Qin, Fengjiao Jin, Xiao Han, Haitao Guan, Xiaoge Li, Jiahui Zhang, Hongyao Zhang, Yue Wang
The objective of this study was to examine the effect of autophagy on stress-induced M2 macrophage polarization in the tumor microenvironment of breast cancer and to determine whether the underlying mechanism was related to the reactive oxygen species (ROS)/ERK and mTOR pathway. In vitro, we found that the basal autophagy level in mouse RAW 264.7 macrophages decreased with the incubation of tumor cell culture supernatant. Similarly, the polarization of RAW 264.7 to M2 macrophages was inhibited by the autophagy inducer rapamycin and increased by the autophagy inhibitor 3-MA or by siBeclin1...
June 21, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28647452/differential-roles-of-the-infralimbic-and-prelimbic-areas-of-the-prefrontal-cortex-in-reconsolidation-of-a-traumatic-memory
#4
Natali Levin, Milly Kritman, Mouna Maroun, Irit Akirav
Studies about reconsolidation of conditioned fear memories have shown that pharmacological manipulation at memory reactivation can attenuate or enhance the subsequent expression of the conditioned fear response. Here we examined the effects of a single injection of the mTOR inhibitor rapamycin (Rap) into the infralimbic (IL) and prelimbic (PL) areas [which compose the ventromedial prefrontal cortex (PFC)] on reconsolidation and extinction of a traumatic fear memory. We found opposite effects of Rap infused into the PL and IL on reconsolidation and extinction: intra-PL Rap and systemic Rap impaired reconsolidation and facilitated extinction whereas intra-IL Rap enhanced reconsolidation and impaired extinction...
June 22, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28647341/suppression-of-autophagic-flux-contributes-to-cardiomyocyte-death-by-activation-of-necroptotic-pathways
#5
Makoto Ogasawara, Toshiyuki Yano, Masaya Tanno, Koki Abe, Satoko Ishikawa, Takayuki Miki, Atsushi Kuno, Toshiyuki Tobisawa, Shingo Muratsubaki, Kouhei Ohno, Yuki Tatekoshi, Kei Nakata, Wataru Ohwada, Tetsuji Miura
BACKGROUND: The role of necroptosis in myocardial injury has not been fully characterized. Here we examined roles of mitochondrial permeability transition pore (mPTP) and autophagy in necroptosis of cardiomyocytes. METHODS AND RESULTS: In H9c2 cells, necroptosis was induced by treatment with TNF-α (TNF) and z-VAD-fmk (zVAD) for 24h, and necroptotic death was determined by LDH release (as % of total). TNF/zVAD increased LDH release from 16.6±4.3% to 60.6±2.7%, and the LDH release was suppressed by necrostatin-1 (29...
June 21, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28647331/combination-of-histidine-lysine-methionine-and-leucine-promotes-%C3%AE-casein-synthesis-via-the-mechanistic-target-of-rapamycin-signaling-pathway-in-bovine-mammary-epithelial-cells
#6
H N Gao, S G Zhao, N Zheng, Y D Zhang, S S Wang, X Q Zhou, J Q Wang
The ratio of different AA in the diets of cows is vital to improve milk protein yield. β-Casein is one of the important milk proteins with high nutritive value. However, the suitable ratio of essential amino acids (EAA) for the expression of β-casein in the immortalized bovine mammary epithelial cell line is not fully characterized. This study employed response surface methodology to determine the optimal ratio of His, Lys, Met, and Leu on β-casein expression level in vitro and clarified the effect of the 4 EAA on β-casein via the mechanistic target of rapamycin (mTOR) signaling pathway...
June 21, 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/28647182/preoperative-application-of-combination-of-portal-venous-injection-of-donor-spleen-cells-and-intraperitoneal-injection-of-rapamycin-prolongs-the-survival-of-cardiac-allografts-in-mice
#7
Wen-Lin Gong, Chuang Sha, Gang Du, Zhong-Gui Shan, Zhong-Quan Qi, Su-Fang Zhou, Nuo Yang, Yong-Xiang Zhao
OBJECTIVE: To investigate the effects of preoperative portal venous injection of donor spleen cells (PVIDSC) and intraperitoneal injection of rapamycin in the acute rejection of cardiac allograft in mice and the underlying mechanisms. METHODS: Homogenous female B6 mice and BALB/c mice were used as recipients and donors of heart transplantation. These mice were randomly divided into different groups and received PVIDSC alone, rapamycin alone, or PVIDSC and rapamycin combined therapy...
May 2017: Asian Pacific Journal of Tropical Medicine
https://www.readbyqxmd.com/read/28646236/rapamycin-adjuvant-and-exacerbation-of-severe-influenza-in-an-experimental-mouse-model
#8
Ching-Tai Huang, Chen-Yiu Hung, Tse-Ching Chen, Chun-Yen Lin, Yung-Chang Lin, Chia-Shiang Chang, Yueh-Chia He, Yu-Lin Huang, Avijit Dutta
Influenza virus infection often causes severe disease and acute respiratory distress syndrome. It is a common belief that overwhelming immune response contributes to the severe illness. Physicians and researchers have put forth immune modulation as salvage therapy for better recovery. However, empiric corticosteroid failed in both humans and animal models. Reported success with Rapamycin in humans prompted a comprehensive animal study and mechanistic dissection. Here we report the effect of Rapamycin alone or in combination with Oseltamivir for severe influenza in BALB/c mice...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28646232/inhibition-of-erk1-2-restores-gsk3%C3%AE-activity-and-protein-synthesis-levels-in-a-model-of-tuberous-sclerosis
#9
Rituraj Pal, Vitaliy V Bondar, Carolyn J Adamski, George G Rodney, Marco Sardiello
Tuberous sclerosis (TS) is a multi-organ autosomal dominant disorder that is best characterized by neurodevelopmental deficits and the presence of benign tumors. TS pathology is caused by mutations in tuberous sclerosis complex (TSC) genes and is associated with insulin resistance, decreased glycogen synthase kinase 3β (GSK3β) activity, activation of the mammalian target of rapamycin complex 1 (mTORC1), and subsequent increase in protein synthesis. Here, we show that extracellular signal-regulated kinases (ERK1/2) respond to insulin stimulation and integrate insulin signaling to phosphorylate and thus inactivate GSK3β, resulting in increased protein synthesis that is independent of Akt/mTORC1 activity...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28646031/metabolism-and-acetylation-contribute-to-leucine-mediated-inhibition-of-cardiac-glucose-uptake
#10
Edith Renguet, Audrey Ginion, Roselle Gélinas, Laurent Bultot, Julien Auquier, Isabelle Robillard Frayne, Caroline Daneault, Jean-Louis Vanoverschelde, Christine Des Rosiers, Louis Hue, Sandrine Horman, Christophe Beauloye, Luc Bertrand
High plasma leucine levels strongly correlate with type 2 diabetes. Studies of muscle cells suggest that leucine alters the insulin response for glucose transport by activating an insulin-negative feedback loop driven by the mammalian target of rapamycin/p70 ribosomal S6 kinase (mTOR/p70S6K) pathway. Here, we examined the molecular mechanism involved in leucine's action on cardiac glucose uptake. Leucine was indeed able to curb glucose uptake after insulin stimulation in both cultured cardiomyocytes and perfused hearts...
June 23, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28643873/increased-expression-of-immuno-proteasome-subunits-during-epileptogenesis-is-attenuated-by-inhibition-of-the-mammalian-target-of-rapamycin-pathway
#11
Diede W M Broekaart, Jackelien van Scheppingen, Karlijne W Geijtenbeek, Mark R J Zuidberg, Jasper J Anink, Johannes C Baayen, Angelika Mühlebner, Eleonora Aronica, Jan A Gorter, Erwin A van Vliet
OBJECTIVE: Inhibition of the mammalian target of rapamycin (mTOR) pathway reduces epileptogenesis in various epilepsy models, possibly by inhibition of inflammatory processes, which may include the proteasome system. To study the role of mTOR inhibition in the regulation of the proteasome system, we investigated (immuno)proteasome expression during epileptogenesis, as well as the effects of the mTOR inhibitor rapamycin. METHODS: The expression of constitutive (β1, β5) and immunoproteasome (β1i, β5i) subunits was investigated during epileptogenesis using immunohistochemistry in the electrical post-status epilepticus (SE) rat model for temporal lobe epilepsy (TLE)...
June 23, 2017: Epilepsia
https://www.readbyqxmd.com/read/28641881/peripheral-blood-regulatory-t-cell-counts-as-a-predictive-biomarker-for-the-outcome-of-kidney-transplant-a-systematic-review
#12
Francisco Herrera-Gómez, Mónica Vásquez-Seoane, Waldo Del Aguila, Débora Martín-García, Álvaro Maurtua-Briseño Meiggs, Anunciación González-López, Beatriz Andrés-Martín, Álvaro Nava-Rebollo, Fernando Casquero-Fernández, Pilar Pascual-Núñez, Jesús Grande-Villoria, Jesús Bustamante-Bustamante, Carlos Ochoa-Sangrador, Claude Lambert, Alicia Mendiluce-Herrero
BACKGROUND AND OBJECTIVE: Circulating regulatory T cells could become a suitable biomarker for kidney recipients. The objective of this study was to evaluate the effect of mammalian target of rapamycin (mTOR) inhibitors on regulatory T cell numbers, and the clinical interest of this effect. MATERIAL AND METHODS: Systematic review of published and unpublished studies. Worldwide databases or repositories. Randomised controlled trials and cohort studies comparing regulatory T cell counts and rejection episodes between patients with and without mTOR inhibitors were searched...
June 19, 2017: Medicina Clínica
https://www.readbyqxmd.com/read/28641612/-expression-and-significance-of-hif-1%C3%AE-in-erythropoiesis-of-secondary-iron-overload-disease-after-irradiation-damage
#13
Yi Xing, Ming-Feng Zhao, Xiao-Li Cao, Xin Jin, Jie Chen, Ping Xu, Song-Nan Sui, Yan-Yu Jiang, Xiao-Yuan He
OBJECTIVE: To study the expression of hypoxia inducible factor 1α(HIF-1α) of iron-overloaded in irradiated mice and its effect on erythropoiesis. METHODS: Twenty mice were randomly divided into 4 groups: Ctrl (control group), IR (irradiation group), IO (irradiation + iron overload group), and RAPA (rapamycin treatment group). The iron overload model was verified. The CFU-E (colony forming unit-erythroid) and BFU-E(burst colony forming unit-erythroid) were cultured; flow cytometry was used to detect the ratios of early stage (Ter119(+)CD71(-)) to late stage (Ter119(+)CD71(+)) of primitive erythroblasts; RT-PCR was used to detect the mRNA expression of HIF-1α and its related signal molecules in bone marrow cells...
June 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28641488/uca1-involved-in-the-metformin-regulated-bladder-cancer-cell-proliferation-and-glycolysis
#14
Tian Li, Xiangzhou Sun, Xianhan Jiang
Despite great scientific advances have been achieved in cancer treatment in recent years, the death rate of bladder cancer has been staying at a high level. Metformin, a widely-used and low-cost diabetes medicine, might have the potential of anticancer. The aim of this study was to evaluate the effects of metformin on bladder cancer cells and to identify potential molecular targets and signaling pathways. Bladder cancer 5637 cells transfected with either pcDNA/UCA1 vector or pcDNA3.1 empty vector were treated with various doses of metformin for different periods of time, and then cell proliferation and glycolysis were assessed...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28641136/age-exacerbates-abnormal-protein-expression-in-a-mouse-model-of-down-syndrome
#15
Md Mahiuddin Ahmed, Aaron Block, Suhong Tong, Muriel T Davisson, Katheleen J Gardiner
The Ts65Dn is a popular mouse model of Down syndrome (DS). It displays DS-relevant features of learning/memory deficits and age-related loss of functional markers in basal forebrain cholinergic neurons. Here we describe protein expression abnormalities in brain regions of 12-month-old male Ts65Dn mice. We show that the magnitudes of abnormalities of human chromosome 21 and non-human chromosome 21 orthologous proteins are greater at 12 months than at ∼6 months. Age-related exacerbations involve the number of components affected in the mechanistic target of rapamycin pathway, the levels of components of the mitogen-activated protein kinase pathway, and proteins associated with Alzheimer's disease...
May 10, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28641125/an-altered-redox-environment-assisted-by-over-expression-of-fetal-hemoglobins-protects-from-inflammatory-colitis-and-reduces-inflammatory-cytokine-expression
#16
R M Gorczynski, C Alexander, K Brandenburg, Z Chen, A Heini, D Neumann, J P Mach, E T Rietschel, A Tersikh, A J Ulmer, Kai Yu, U Zahringer, I Khatri
C5BL/6 female mice receiving dextran sodium sulfate in their drinking water develop an acute inflammatory colitis within 7d, with weight loss, histopathologic signs of inflammation, and colonic expression of inflammatory cytokines. In previous studies we have reported that increased inflammatory cytokine expression in aged mice can be attenuated by oral gavage of a crude fetal extract containing glutathione (GSH), MPLA and fetal hemoglobin, or more specifically by injection of a combination of these purified reagents...
June 19, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28639951/metabolic-abnormalities-and-oxidative-stress-in-lupus
#17
Yaima L Lightfoot, Luz P Blanco, Mariana J Kaplan
PURPOSE OF REVIEW: Upon antigen exposure, immune cells rely on cell-specific metabolic pathways to mount an efficient immune response. In autoimmunity, failure in critical metabolic checkpoints may lead to immune cell hyperactivation and tissue damage. Oxidative stress in autoimmune patients can also contribute to immune dysregulation and injury to the host. Recent insights into the immune cell metabolism signatures, specifically associated with systemic lupus erythematosus (SLE) and the consequences of heightened oxidative stress in patients, are discussed herein...
July 20, 2017: Current Opinion in Rheumatology
https://www.readbyqxmd.com/read/28639903/targeting-the-mtor-pathway-in-breast-cancer
#18
Jia Liu, Hui-Qing Li, Fu-Xia Zhou, Jie-Wen Yu, Ling Sun, Zhong-Hou Han
Mechanistic target of rapamycin controls cell growth, metabolism, and aging in response to nutrients, cellular energy stage, and growth factors. In cancers including breast cancer, mechanistic target of rapamycin is frequently upregulated. Blocking mechanistic target of rapamycin with rapamycin, first-generation and second-generation mechanistic target of rapamycin inhibitors, called rapalogs, have shown potent reduction of breast cancer tumor growth in preclinical models and clinical trials. In this review, we summarize the fundamental role of the mechanistic target of rapamycin pathway in driving breast tumors...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28639902/mild-hyperthermia-enhances-sensitivity-of-gastric-cancer-cells-to-chemotherapy-through-reactive-oxygen-species-induced-autophagic-death
#19
Ming-Chen Ba, Hui Long, Shu-Zhong Cui, Yuan-Feng Gong, Zhao-Fei Yan, Shuai Wang, Yin-Bing Wu
Mild hyperthermia enhances anti-cancer effects of chemotherapy, but the precise biochemical mechanisms involved are not clear. This study was carried out to investigate whether mild hyperthermia sensitizes gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death. In total, 20 BABL/c mice of MKN-45 human gastric cancer tumor model were divided into hyperthermia + chemotherapy group, hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group. Reactive oxygen species production and expression of autophagy-related genes Beclin1, LC3B, and mammalian target of rapamycin were determined...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28638821/the-tor-signaling-pathway-in-spatial-and-temporal-control-of-cell-size-and-growth
#20
REVIEW
Suam Gonzalez, Charalampos Rallis
Cell size is amenable by genetic and environmental factors. The highly conserved nutrient-responsive Target of Rapamycin (TOR) signaling pathway regulates cellular metabolic status and growth in response to numerous inputs. Timing and duration of TOR pathway activity is pivotal for both cell mass built up as well as cell cycle progression and is controlled and fine-tuned by the abundance and quality of nutrients, hormonal signals, growth factors, stress, and oxygen. TOR kinases function within two functionally and structurally discrete multiprotein complexes, TORC1 and TORC2, that are implicated in temporal and spatial control of cell size and growth respectively; however, recent data indicate that such functional distinctions are much more complex...
2017: Frontiers in Cell and Developmental Biology
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