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https://www.readbyqxmd.com/read/28638048/maternal-folate-deficiency-causes-inhibition-of-mtor-signaling-down-regulation-of-placental-amino-acid-transporters-and-fetal-growth-restriction-in-mice
#1
Fredrick J Rosario, Peter W Nathanielsz, Theresa L Powell, Thomas Jansson
Maternal folate deficiency is linked to restricted fetal growth, however the underlying mechanisms remain to be established. Here we tested the hypothesis that mTOR functions as a folate sensor in vivo in mice and that maternal folate deficiency inhibits placental mTOR signaling and amino acid transporter activity and causes fetal growth restriction. Folate deficient mice had lower serum folate (-60%). In late pregnancy, fetal weight in the folate deficient group was decreased (-17%, p < 0.05), whereas placental weight, litter size and crown rump length were unaltered...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28611306/erk-inhibition-sensitizes-cz415-induced-anti-osteosarcoma-activity-in-vitro-and-in-vivo
#2
Gang Yin, Jin Fan, Wei Zhou, Qingfeng Ding, Jun Zhang, Xuan Wu, Pengyu Tang, Hao Zhou, Bowen Wan, Guoyong Yin
mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28602697/gsk3-inhibitor-ar-a014418-promotes-osteogenic-differentiation-of-human-adipose-derived-stem-cells-via-erk-and-mtorc2-akt-signaling-pathway
#3
Min Zhang, Ping Zhang, Yunsong Liu, Yongsheng Zhou
Small molecule-based bone tissue engineering is emerging as a promising strategy for bone defects restoration. In this study, we intended to identify the roles and mechanisms of AR-A014418, a highly selective inhibitor of GSK3, on the osteogenic differentiation. We found that AR-A014418 exhibited a dose-dependent effect on osteogenic differentiation of human adipose-derived stem cells (hASCs). hASCs treated with AR-A014418 showed higher activity of ERK and mTORC2/Akt signaling. Administration of ERK inhibitor U0126 or knockdown of RICTOR by siRNA attenuated AR-A014418 induced osteogenic differentiation of hASCs...
June 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28600802/mtorc1-and-mtorc2-as-regulators-of-cell-metabolism-in-immunity
#4
REVIEW
Monika Linke, Stephanie Deborah Fritsch, Nyamdelger Sukhbaatar, Markus Hengstschläger, Thomas Weichhart
The mechanistic target of rapamycin (mTOR) pathway is an evolutionarily conserved signaling pathway that senses intra- and extracellular nutrients, growth factors, and pathogen-associated molecular patterns to regulate the function of innate and adaptive immune cell populations. In this Review, we focus on the role of the mTOR complex 1 (mTORC1) and mTORC2 in the regulation of the cellular energy metabolism of these immune cells to regulate and support immune responses. In this regard, mTORC1 and mTORC2 generally promote an anabolic response by stimulating protein synthesis, glycolysis, mitochondrial functions, and lipid synthesis to influence proliferation and survival, effector and memory responses, innate training and tolerance as well as hematopoietic stem cell maintenance and differentiation...
June 10, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28592519/mtor-is-a-novel-molecular-mechanism-linking-folate-availability-and-cell-function
#5
REVIEW
Elena Silva, Fredrick J Rosario, Theresa L Powell, Thomas Jansson
Folate deficiency has been linked to a wide range of disorders, including cancer, neural tube defects, and fetal growth restriction. Folate regulates cellular function mediated by its involvement in the synthesis of nucleotides, which are needed for DNA synthesis, and its function as a methyl donor, which is critical for DNA methylation. Here we review current data showing that folate sensing by mechanistic target of rapamycin (mTOR) constitutes a novel and distinct pathway by which folate modulates cell functions such as nutrient transport, protein synthesis, and mitochondrial respiration...
June 7, 2017: Journal of Nutrition
https://www.readbyqxmd.com/read/28589878/distinct-akt-phosphorylation-states-are-required-for-insulin-regulated-glut4-and-glut1-mediated-glucose-uptake
#6
Muheeb Beg, Nazish Abdullah, Fathima Shazna Thowfeik, Nasser K Altorki, Timothy E McGraw
Insulin, downstream of Akt activation, promotes glucose uptake into fat and muscle cells to lower postprandial blood glucose, an enforced change in cellular metabolism to maintain glucose homeostasis. This effect is mediated by the Glut4 glucose transporter. Growth factors also enhance glucose uptake to fuel an anabolic metabolism required for tissue growth and repair. This activity is predominantly mediated by the Glut1. Akt is activated by phosphorylation of its kinase and hydrophobic motif (HM) domains. We show that insulin-stimulated Glut4-mediated glucose uptake requires PDPK1 phosphorylation of the kinase domain but not mTORC2 phosphorylation of the HM domain...
June 7, 2017: ELife
https://www.readbyqxmd.com/read/28585698/lycopene-protects-keratinocytes-against-uvb-radiation-induced-carcinogenesis-via-negative-regulation-of-foxo3a-through-the-mtorc2-akt-signaling-pathway
#7
Ping Chen, Shina Xu, Jinlong Qu
Lycopene, one of the most potent anti-oxidants, has been reported to exhibit potent anti-proliferative properties in a wide range of cancer cells through modulation of the cell cycle and apoptosis. Forkhead box O3a (FOXO3a) plays a pivotal role in modulating the expression of genes involved in cell death. Herein, we investigated the role of FOXO3a signaling in the anti-cancer effects of lycopene. Results showed that lycopene pretreatment attenuated UVB-induced cell hyper-proliferation and promoted apoptosis, accompanied by decreased cyclin-dependent kinase 2 (CDK2) and CDK4 complex in both human keratinocytes and SKH-1 hairless mice...
June 6, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28585302/rictor-mtorc2-promotes-macrophage-activation-and-kidney-fibrosis
#8
Jiafa Ren, Jianzhong Li, Ye Feng, Bingyan Shu, Yuan Gui, Wei Wei, Weichun He, Junwei Yang, Chunsun Dai
Mammalian target of rapamycin (mTOR) signaling controls many essential cellular functions. However, the role for Rictor/mTORC2 in regulating macrophage activation and kidney fibrosis remains largely unknown. We report here that Rictor/mTORC2 was activated in macrophages from the fibrotic kidneys of mice. Ablation of Rictor in macrophages diminished kidney fibrosis, inflammatory cell accumulation, macrophage proliferation and polarization after unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI)...
June 6, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28583723/control-of-b-lymphocyte-development-and-functions-by-the-mtor-signaling-pathways
#9
REVIEW
Terri N Iwata, Julita A Ramírez-Komo, Heon Park, Brian M Iritani
Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase originally discovered as the molecular target of the immunosuppressant rapamycin. mTOR forms two compositionally and functionally distinct complexes, mTORC1 and mTORC2, which are crucial for coordinating nutrient, energy, oxygen, and growth factor availability with cellular growth, proliferation, and survival. Recent studies have identified critical, non-redundant roles for mTORC1 and mTORC2 in controlling B cell development, differentiation, and functions, and have highlighted emerging roles of the Folliculin-Fnip protein complex in regulating mTOR and B cell development...
May 22, 2017: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/28576773/distinct-roles-for-the-mtor-pathway-in-postnatal-morphogenesis-maturation-and-function-of-pancreatic-islets
#10
Katie L Sinagoga, William J Stone, Jacqueline V Schiesser, Jamie I Schweitzer, Leesa Sampson, Yi Zheng, James M Wells
While much is known about the molecular pathways that regulate embryonic development and adult homeostasis of the endocrine pancreas, little is known about what regulates early postnatal development and maturation of islets. Given that birth marks the first exposure to enteral nutrition, we investigated how nutrient-regulated signaling pathways influence postnatal islet development. To do this we performed loss-of-function studies of mechanistic target of rapamycin (mTOR), a highly conserved kinase within a nutrient-sensing pathway known to regulate cellular growth, morphogenesis and metabolism...
June 2, 2017: Development
https://www.readbyqxmd.com/read/28569556/guaran%C3%A3-a-highly-caffeinated-food-presents-in-vitro-antitumor-activity-in-colorectal-and-breast-cancer-cell-lines-by-inhibiting-akt-mtor-s6k-and-mapks-pathways
#11
Francine C Cadoná, Jose L Rosa, Taiane Schneider, Monica Cubillos-Rojas, Susana Sánchez-Tena, Verônica F Azzolin, Charles E Assmann, Alencar K Machado, Euler E Ribeiro, Ivana Beatrice M da Cruz
The mammalian target of rapamycin (mTOR) and mitogen-activated protein kinases (MAPKs) pathways are frequently upregulated in cancer. Some authors have reported that some antioxidant molecules could be potential inhibitors of these pathways. Therefore, we investigated the in vitro antitumor effect of guaraná by inhibiting the AKT/mTOR/S6K and MAPKs pathways. Colorectal and breast cancer cell lineages, HT-29 and MCF-7 cells, respectively, were exposed to different guaraná concentrations (0.1, 1, 10, and 100 µg/mL) as well as its main bioactive molecule, caffeine, in proportional concentrations to those found in the extract...
June 1, 2017: Nutrition and Cancer
https://www.readbyqxmd.com/read/28566383/drug-modulators-of-b-cell-signaling-pathways-and-epstein-barr-virus-lytic-activation
#12
John G Kosowicz, Jaeyeun Lee, Brandon Peiffer, Zufeng Guo, Jianmeng Chen, Gangling Liao, S Diane Hayward, Jun O Liu, Richard F Ambinder
Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block BCR signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction...
May 31, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28548926/preclinical-study-of-cc223-as-a-potential-anti-ovarian-cancer-agent
#13
Zhenzhen Jin, Huanfu Niu, Xuenan Wang, Lei Zhang, Qin Wang, Aijun Yang
Aberrant activation of mTOR contributes to ovarian cancer progression. CC223 is a novel and potent mTOR kinase inhibitor. The current study tested its activity against human ovarian cancer cells. We showed that CC223, at nM concentrations, inhibited survival and proliferation of established/primary human ovarian cancer cells. Further, significant apoptosis activation was observed in CC223-treated ovarian cancer cells. CC223 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in SKOV3 cells. Meanwhile, activation of mTORC1 and mTORC2 was almost completely blocked by CC223...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28546423/overexpression-of-kinase-dead-mtor-impairs-glucose-homeostasis-by-regulating-insulin-secretion-and-not-%C3%AE-cell-mass
#14
Emilyn U Alejandro, Nadejda Bozadjieva, Manuel Blandino-Rosano, Michelle Ann Wasan, Lynda Elghazi, Suryakiran Vadrevu, Leslie Satin, Ernesto Bernal-Mizrachi
Regulation of glucose homeostasis by insulin depends on β-cell growth and function. Nutrients and growth factors stimuli converge on the conserved protein kinase mechanistic target of rapamycin (mTOR), existing in two complexes mTORC1 and mTORC2. To understand the functional relevance of mTOR enzymatic activity in β-cell development and in glucose homeostasis, we generated mice overexpressing either one or two copies of a kinase-dead mTOR mutant (KD-mTOR) transgene exclusively in β-cells. We examined glucose homeostasis and β-cell function of these mice in control chow and in high-fat diet (HFD)...
May 25, 2017: Diabetes
https://www.readbyqxmd.com/read/28544747/k-ras-mutation-and-amplification-status-is-predictive-of-resistance-and-high-basal-pakt-is-predictive-of-sensitivity-to-everolimus-in-biliary-tract-cancer-cell-lines
#15
Yvonne Yeung, David K Lau, Fiona Chionh, Hoanh Tran, Janson W T Tse, Andrew J Weickhardt, Mehrdad Nikfarjam, Andrew M Scott, Niall C Tebbutt, John M Mariadason
Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signaling pathway is hyperactivated in a subset of BTCs and clinical activity to the mTOR inhibitor everolimus has been observed in some BTC patients. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways...
May 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28544376/hif-2%C3%AE-regulates-non-canonical-glutamine-metabolism-via-activation-of-pi3k-mtorc2-pathway-in-human-pancreatic-ductal-adenocarcinoma
#16
Wenzhu Li, Changhao Chen, Xiaohui Zhao, Huilin Ye, Yue Zhao, Zhiqiang Fu, Wenwei Pan, Shangyou Zheng, Lusheng Wei, Tianwen Nong, Zhihua Li, Rufu Chen
Hypoxia-inducible factor-2α (HIF-2α) plays an important role in increasing cancer progression and distant metastasis in a variety of tumour types. We aimed to investigate its biological function and clinical significance in human pancreatic ductal adenocarcinoma (PDAC). A total of 283 paired PDAC tissues and adjacent normal tissues were collected from patients who underwent surgery or biopsy at Sun Yat-sen Memorial Hospital between February 2004 and October 2016. In this study, we noted that HIF-2α expression was significantly up-regulated in PDAC, positively associated with disease stage, lymph-node metastasis and patient survival, and identified as an independent prognostic factor of PDAC patients...
May 24, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28492364/na-influx-via-orai1-inhibits-intracellular-atp-induced-mtorc2-signaling-to-disrupt-cd4-t-cell-gene-expression-and-differentiation
#17
Yong Miao, Jaya Bhushan, Adish Dani, Monika Vig
T cell effector functions require sustained calcium influx. However, the signaling and phenotypic consequences of non-specific sodium permeation via calcium channels remain unknown. α-SNAP is a crucial component of Orai1 channels, and its depletion disrupts the functional assembly of Orai1 multimers. Here we show that α-SNAP hypomorph, hydrocephalus with hopping gait, Napa(hyh/hyh) mice harbor significant defects in CD4 T cell gene expression and Foxp3 regulatory T cell (Treg) differentiation. Mechanistically, TCR stimulation induced rapid sodium influx in Napa(hyh/hyh) CD4 T cells, which reduced intracellular ATP, [ATP]i...
May 11, 2017: ELife
https://www.readbyqxmd.com/read/28489822/traf2-and-otud7b-govern-a-ubiquitin-dependent-switch-that-regulates-mtorc2-signalling
#18
Bin Wang, Zuliang Jie, Donghyun Joo, Alban Ordureau, Pengda Liu, Wenjian Gan, Jianping Guo, Jinfang Zhang, Brian J North, Xiangpeng Dai, Xuhong Cheng, Xiuwu Bian, Lingqiang Zhang, J Wade Harper, Shao-Cong Sun, Wenyi Wei
The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways. mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORC1) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer. Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells...
May 10, 2017: Nature
https://www.readbyqxmd.com/read/28475179/mtorc1-independent-autophagy-regulates-receptor-tyrosine-kinase-phosphorylation-in-colorectal-cancer-cells-via-an-mtorc2-mediated-mechanism
#19
Aikaterini Lampada, James O'Prey, Gyorgy Szabadkai, Kevin M Ryan, Daniel Hochhauser, Paolo Salomoni
The intracellular autophagic degradative pathway can have a tumour suppressive or tumour-promoting role depending on the stage of tumour development. Upon starvation or targeting of oncogenic receptor tyrosine kinases (RTKs), autophagy is activated owing to the inhibition of PI3K/AKT/mTORC1 signalling pathway and promotes survival, suggesting that autophagy is a relevant therapeutic target in these settings. However, the role of autophagy in cancer cells where the PI3K/AKT/mTORC1 pathway is constitutively active remains partially understood...
June 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28468668/proteomic-anaysis-of-aged-microglia-shifts-in-transcription-bioenergetics-and-nutrient-response
#20
Antwoine Flowers, Harris Bell-Temin, Ahmad Jalloh, Stanley M Stevens, Paula C Bickford
BACKGROUND: Age is the primary risk factor for many diseases. As such, age is a critical co-factor for examination in order to understand the progression and potential intervention in disease progression. Studies examining both the phenotype and transcriptome of aged microglia demonstrated a propensity for the development of a pro-inflammatory phenotype. Less well studied is the concomitant blunting of anti-inflammatory aspects of microglial function with age which also impact plasticity and repair in the CNS...
May 3, 2017: Journal of Neuroinflammation
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