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https://www.readbyqxmd.com/read/28437526/prominin-1-is-a-novel-regulator-of-autophagy-in-the-human-retinal-pigment-epithelium
#1
Sujoy Bhattacharya, Jinggang Yin, Christina S Winborn, Qiuhua Zhang, Junming Yue, Edward Chaum
Purpose: Prominin-1 (Prom1) is a transmembrane glycoprotein, which is expressed in stem cell lineages, and has recently been implicated in cancer stem cell survival. Mutations in the Prom1 gene have been shown to disrupt photoreceptor disk morphogenesis and cause an autosomal dominant form of Stargardt-like macular dystrophy (STGD4). Despite the apparent structural role of Prom1 in photoreceptors, its role in other cells of the retina is unknown. The purpose of this study is to investigate the role of Prom1 in the highly metabolically active cells of the retinal pigment epithelium (RPE)...
April 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28435021/the-mtorc2-pkc-pathway-sustains-compensatory-insulin-secretion-of-pancreatic-%C3%AE-cells-in-response-to-metabolic-stress
#2
Yun Xie, Canqi Cui, Aifang Nie, Yan Wang, Qicheng Ni, Yun Liu, Qinglei Yin, Hongli Zhang, Yong Li, Qidi Wang, Yanyun Gu, Guang Ning
BACKGROUND: Compensation of the pancreatic β cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and β cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced β cell compensation. METHODS: We challenged four-week-old β-cell-specific Rictor (a key component of mTORC2)-knockout mice with a high fat diet (HFD) for 4weeks and measured metabolic and pancreatic morphological parameters...
April 20, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28434143/the-mtor-signaling-pathway-in-myocardial-dysfunction-in-type-2-diabetes-mellitus
#3
REVIEW
Tomohiro Suhara, Yuichi Baba, Briana K Shimada, Jason K Higa, Takashi Matsui
PURPOSE OF REVIEW: T2DM (type 2 diabetes mellitus) is a risk factor for heart failure. The mTOR (mechanistic target of rapamycin) is a key mediator of the insulin signaling pathway. We will discuss the role of mTOR in myocardial dysfunction in T2DM. RECENT FINDINGS: In T2DM, chronically activated mTOR induces multiple pathological events, including a negative feedback loop that suppresses IRS (insulin receptor substrate)-1. While short-term treatment with rapamycin, an mTOR inhibitor, is a promising strategy for cardiac diseases such as acute myocardial infarction and cardiac hypertrophy in T2DM, there are many concerns about chronic usage of rapamycin...
June 2017: Current Diabetes Reports
https://www.readbyqxmd.com/read/28429706/direct-comparison-of-distinct-naive-pluripotent-states-in-human-embryonic-stem-cells
#4
S Warrier, M Van der Jeught, G Duggal, L Tilleman, E Sutherland, J Taelman, M Popovic, S Lierman, S Chuva De Sousa Lopes, A Van Soom, L Peelman, F Van Nieuwerburgh, D I M De Coninck, B Menten, P Mestdagh, J Van de Sompele, D Deforce, P De Sutter, B Heindryckx
Until recently, human embryonic stem cells (hESCs) were shown to exist in a state of primed pluripotency, while mouse embryonic stem cells (mESCs) display a naive or primed pluripotent state. Here we show the rapid conversion of in-house-derived primed hESCs on mouse embryonic feeder layer (MEF) to a naive state within 5-6 days in naive conversion media (NCM-MEF), 6-10 days in naive human stem cell media (NHSM-MEF) and 14-20 days using the reverse-toggle protocol (RT-MEF). We further observe enhanced unbiased lineage-specific differentiation potential of naive hESCs converted in NCM-MEF, however, all naive hESCs fail to differentiate towards functional cell types...
April 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28421341/insufficient-activation-of-akt-upon-reperfusion-because-of-its-novel-modification-by-reduced-pp2a-b55%C3%AE-contributes-to-enlargement-of-infarct-size-by-chronic-kidney-disease
#5
Toshiyuki Tobisawa, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Yukishige Kimura, Satoko Ishikawa, Hidemichi Kouzu, Keitaro Nishizawa, Hideaki Yoshida, Tetsuji Miura
Chronic kidney disease (CKD) increases myocardial infarct size by an unknown mechanism. Here we examined the hypothesis that impairment of protective PI3K-PDK1-Akt and/or mTORC-Akt signaling upon reperfusion contributes to CKD-induced enlargement of infarct size. CKD was induced in rats by 5/6 nephrectomy (SNx group) 4 weeks before myocardial infarction experiments, and sham-operated rats served as controls (Sham group). Infarct size as a percentage of area at risk after ischemia/reperfusion was significantly larger in the SNx group than in the Sham group (56...
May 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28417246/mammalian-target-of-rapamycin-mtor-as-a-potential-therapeutic-target-in-various-diseases
#6
REVIEW
Avileen Kaur, Saurabh Sharma
Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that belongs to Phosphatidylinositol-3-kinase related kinase superfamily. The signaling pathways of mTOR are integrated through the protein complexes of mTORC1 and mTORC2. mTORC1 controls protein synthesis, cell growth, proliferation, autophagy, cell metabolism, and stress responses, whereas mTORC2 seems to regulate cell survival and polarity. Dysregulation of the mTOR pathway has been implicated in the pathophysiology of a number of disease conditions, including cancer, cardiovascular, neurodegenerative, and various renal diseases...
April 17, 2017: Inflammopharmacology
https://www.readbyqxmd.com/read/28410220/reprogramming-induced-by-isoliquiritigenin-diminishes-melanoma-cachexia-through-mtorc2-akt-gsk3%C3%AE-signaling
#7
Xiao-Yu Chen, De-Fang Li, Ji-Chun Han, Bo Wang, Zheng-Ping Dong, Li-Na Yu, Zhao-Hai Pan, Chuan-Jun Qu, Ying Chen, Shi-Guo Sun, Qiu-Sheng Zheng
Isoliquiritigenin (ISL), a member of the flavonoids, is known to have anti-tumor activity in vitro and in vivo. The effect of ISL on reprogramming in cancer cells, however, remains elusive. In this study, we investigated the effect of ISL on reprogramming in human melanoma A375 cells. ISL (15 μg/ml) significantly inhibited A375 cell proliferation, anchorage independent cell proliferation and G2/M cell cycle arrest after ISL exposure for 24 h. However, there were no significant changes in apoptosis rate. Terminal differentiation indicators (melanin content, melanogenesis mRNA expression, tyrosinase (TYR) activity) were all up-regulated by ISL treatment...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404914/the-preclinical-assessment-of-xl388-a-mtor-kinase-inhibitor-as-a-promising-anti-renal-cell-carcinoma-agent
#8
Zuquan Xiong, Yiwen Zang, Shan Zhong, Lujia Zou, Yishuo Wu, Shenghua Liu, Zujun Fang, Zhoujun Shen, Qiang Ding, Shanwen Chen
XL388 is a mammalian target of rapamycin (mTOR) kinase inhibitor. We demonstrated that XL388 inhibited survival and proliferation of renal cell carcinoma (RCC) cell lines (786-0 and A549) and primary human RCC cells. XL388 activated caspase-dependent apoptosis in the RCC cells. XL388 blocked mTOR complex 1 (mTORC1) and mTORC2 activation, and depleted hypoxia-inducible factor 1α (HIF1α) and HIF-2α expression in RCC cells. Yet, XL388 was ineffective in RCC cells with mTOR shRNA knockdown or kinase-dead mutation...
February 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404689/methoxyluteolin-inhibits-neuropeptide-stimulated-tnf-cxcl8-and-vegf-release-via-mtor-activation-from-human-mast-cells
#9
Arti B Patel, Theoharis C Theoharides
Mast cells (MC) are critical for allergic reactions, but are also important in inflammatory processes. Stimulation by neuropeptides, such as substance P (SP) and neurotensin (NT) leads to release of pre-formed molecules stored in numerous MC secretory granules and newly-synthesized pro-inflammatory mediators, including tumor necrosis factor (TNF), interleukin 8 (CXCL8) and vascular endothelial growth factor (VEGF). Here, we investigate the role of mammalian target of rapamycin (mTOR) signaling in the stimulation of cultured human LAD2 MC by NT or SP, and the inhibitory effect of the natural flavonoids 3',4',5,7-tetrahydroxyflavone (luteolin) and its novel structural analog 3 ',4',5,7-tetramethoxyluteolin (methoxyluteolin)...
April 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28402933/pdk1-inhibitor-gsk2334470-exerts-antitumor-activity-in-multiple-myeloma-and-forms-a-novel-multitargeted-combination-with-dual-mtorc1-c2-inhibitor-pp242
#10
Chunmei Yang, Xianbo Huang, Hui Liu, Feng Xiao, Jueying Wei, Liangshun You, Wenbin Qian
A deeper understanding of the complex pathogenesis of multiple myeloma (MM) continues to lead to novel therapeutic approaches. Prior studies suggest that 3-phosphoinositide-dependent kinase 1 (PDK1) is expressed and active, acting as a crucial regulator of molecules that are essential for myelomagenesis. In the present study, we show that GSK2334470 (GSK-470), a novel and highly specific inhibitor of PDK1, induces potent cytotoxicity in MM cell lines including Dexamethasone-resistant cell line, but not in human normal cells...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28400999/mtor-function-and-therapeutic-targeting-in-breast-cancer
#11
REVIEW
Stephen H Hare, Amanda J Harvey
The mTOR pathway was discovered in the late 1970s after the compound and natural inhibitor of mTOR, rapamycin was isolated from the bacterium Streptomyces hygroscopicus. mTOR is serine/threonine kinase belonging to the phosphoinositide 3-kinase related kinase (PIKK) family. It forms two distinct complexes; mTORC1 and mTORC2. mTORC1 has a key role in regulating protein synthesis and autophagy whilst mTORC2 is involved in regulating kinases of the AGC family. mTOR signaling is often over active in multiple cancer types including breast cancer...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28400571/moderate-lifelong-overexpression-of-tuberous-sclerosis-complex-1-tsc1-improves-health-and-survival-in-mice
#12
Hong-Mei Zhang, Vivian Diaz, Michael E Walsh, Yiqiang Zhang
The tuberous sclerosis complex 1/2 (TSC1/2) is an endogenous regulator of the mechanistic target of rapamycin (mTOR). While mTOR has been shown to play an important role in health and aging, the role of TSC1/2 in aging has not been fully investigated. In the current study, a constitutive TSC1 transgenic (Tsc1 (tg) ) mouse model was generated and characterized. mTORC1 signaling was reduced in majority of the tissues, except the brain. In contrast, mTORC2 signaling was enhanced in Tsc1 (tg) mice. Tsc1 (tg) mice are more tolerant to exhaustive exercises and less susceptible to isoproterenol-induced cardiac hypertrophy at both young and advanced ages...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28393852/omega-3-polyunsaturated-fatty-acids-attenuate-fibroblast-activation-and-kidney-fibrosis-involving-mtorc2-signaling-suppression
#13
Zhifeng Zeng, Haiyuan Yang, Ying Wang, Jiafa Ren, Yifan Dai, Chunsun Dai
Epidemiologic studies showed the correlation between the deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs) and the progression of chronic kidney diseases (CKD), however, the role and mechanisms for n-3 PUFAs in protecting against kidney fibrosis remain obscure. In this study, NRK-49F cells, a rat kidney interstitial fibroblast cell line, were stimulated with TGFβ1. A Caenorhabditis elegans fat-1 transgenic mouse model in which n-3 PUFAs are endogenously produced from n-6 PUFAs owing to the expression of n-3 fatty acid desaturase were deployed...
April 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28388573/amsh-prevents-ros-induced-apoptosis-by-inhibiting-foxo1-mtorc2-in-mice-adipose-tissue
#14
Weina Cao, Meihang Li, Tianjiao Wu, Fei Feng, Tongying Feng, Yang Xu, Chao Sun
Alpha-melanocyte stimulating hormone (αMSH) is an important adenohypophysis polypeptide hormone that regulates body metabolic status. To date, it is well known that the disorder of hypothalamic αMSH secretion is related to many metabolic diseases, such as obesity and type II diabetes. However, the underlying mechanisms are poorly understood. In our study, we focused on the reactive oxygen species (ROS)-induced adipocyte apoptosis and tried to unveil the role of αMSH in this process and the signal pathway which αMSH acts through...
March 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28374905/mtor-folate-sensing-links-folate-availability-to-trophoblast-cell-function
#15
Fredrick J Rosario, Theresa L Powell, Thomas Jansson
Folate is a water-soluble B vitamin that is essential for cellular methylation reactions and DNA synthesis and repair. Low maternal folate levels in pregnancy are associated with fetal growth restriction, however the underlying mechanisms are poorly understood. Mechanistic target of rapamycin (mTOR) links nutrient availability to cell growth and function by regulating gene expression and protein translation. Here we show that mTOR functions as a folate sensor in primary human trophoblast (PHT) cells. Folate deficiency in PHT cells caused inhibition of mTOR signalling and decreased the activity of key amino acid transporters...
April 4, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28373901/reperfusion-therapy-with-rapamycin-attenuates-myocardial-infarction-through-activation-of-akt-and-erk
#16
Scott M Filippone, Arun Samidurai, Sean K Roh, Chad K Cain, Jun He, Fadi N Salloum, Rakesh C Kukreja, Anindita Das
Prompt coronary reperfusion is the gold standard for minimizing injury following acute myocardial infarction. Rapamycin, mammalian target of Rapamycin (mTOR) inhibitor, exerts preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. We hypothesized that Rapamycin, given at the onset of reperfusion, reduces myocardial infarct size through modulation of mTOR complexes. Adult C57 male mice were subjected to 30 min of myocardial ischemia followed by reperfusion for 1 hour/24 hours...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28366631/the-anti-hepatocellular-carcinoma-cell-activity-by-a-novel-mtor-kinase-inhibitor-cz415
#17
Wei Zhang, Bingyu Chen, Yu Zhang, Kaiqiang Li, Ke Hao, Luxi Jiang, Xiaozhou Mou, Xiaodong Xu, Zhen Wang
Dysregulation of mammalian target of rapamycin (mTOR) in hepatocellular carcinoma (HCC) represents a valuable treatment target. Recent studies have developed a highly-selective and potent mTOR kinase inhibitor, CZ415. Here, we showed that nM concentrations of CZ415 efficiently inhibited survival and induced apoptosis in HCC cell lines (HepG2 and Huh-7) and primary-cultured human HCC cells. Meanwhile, CZ415 inhibited proliferation of HCC cells, more potently than mTORC1 inhibitors (rapamycin and RAD001). CZ415 was yet non-cytotoxic to the L02 human hepatocytes...
March 30, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28349073/deptor-mtor-signaling-is-critical-for-lipid-metabolism-and-inflammation-homeostasis-of-lymphocytes-in-human-pbmc-culture
#18
Qi-Bing Xie, Yan Liang, Min Yang, Yuan Yang, Xiao-Min Cen, Geng Yin
Abnormal immune response of the body against substances and tissues causes autoimmune diseases, such as polymyositis, dermatomyositis, and rheumatoid arthritis. Irregular lipid metabolism and inflammation may be a significant cause of autoimmune diseases. Although much progress has been made, mechanisms of initiation and proceeding of metabolic and inflammatory regulation in autoimmune disease have not been well-defined. And novel markers for the detection and therapy of autoimmune disease are urgent. mTOR signaling is a central regulator of extracellular metabolic and inflammatory processes, while DEP domain-containing mTOR-interacting protein (DEPTOR) is a natural inhibitor of mTOR...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28343126/pi3k-signaling-in-cancer-beyond-akt
#19
REVIEW
Evan C Lien, Christian C Dibble, Alex Toker
The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer and has a critical role in driving tumor initiation and progression. Although PI3K and its lipid product phosphatidylinositol-3,4,5-trisphosphate (PIP3) have been shown to activate multiple downstream signaling proteins, the vast majority of studies have focused on the protein kinase AKT as the dominant effector of PI3K signaling. However, recent studies have demonstrated many contexts under which other PIP3-dependent signaling proteins critically contribute to cancer progression, illustrating the importance of understanding AKT-independent signaling downstream of PI3K...
March 23, 2017: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/28334043/cc-223-blocks-mtorc1-c2-activation-and-inhibits-human-hepatocellular-carcinoma-cells-in-vitro-and-in-vivo
#20
Zichen Xie, Jiqin Wang, Mei Liu, Deshan Chen, Chao Qiu, Keyu Sun
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related human mortalities. Over-activation of mammalian target of rapamycin (mTOR) is important for HCC tumorigenesis and progression. The current study assessed the potential anti-HCC activity by a novel mTOR kinase inhibitor, CC-223. We demonstrate that CC-223, at nM concentrations, induced profound cytotoxic and anti-proliferative activities against established HCC cell lines (HepG2, KYN-2 and Huh-7) and primary human HCC cells. Meanwhile, CC-223 activated caspase-3/-9 and apoptosis in the above HCC cells...
2017: PloS One
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