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https://www.readbyqxmd.com/read/28100477/inability-to-replete-white-adipose-tissue-during-the-recovery-phase-of-sepsis-is-associated-with-increased-autophagy-apoptosis-and-proteasome-activity
#1
Kristen T Crowell, David I Soybel, Charles H Lang
Adipose tissue is an important energy depot and endocrine organ, and the degree of adiposity impacts the host response to infection. However, little is known regarding the mechanisms by which white adipose tissue (WAT) is lost acutely and then restored after resolution of sepsis. Therefore, signaling pathways governing protein synthesis, autophagy, apoptosis and the ubiquitin-proteasome were investigated to identify potential mechanisms mediating the acute (24 h) loss of WAT after cecal ligation and puncture (CLP) as well as the failure to replenish WAT during recovery (day 10)...
January 18, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28081222/at7867-inhibits-human-colorectal-cancer-cells-via-akt-dependent-and-akt-independent-mechanisms
#2
Shihu Zhang, Zhengming Deng, Chen Yao, Ping Huang, Yi Zhang, Shibing Cao, Xiangcheng Li
AKT is often hyper-activated in human colorectal cancers (CRC). This current study evaluated the potential anti-CRC activity by AT7867, a novel AKT and p70S6K1 (S6K1) dual inhibitor. We showed that AT7867 inhibited survival and proliferation of established (HT-29, HCT116 and DLD-1 lines) and primary human CRC cells. Meanwhile, it provoked caspase-dependent apoptosis in the CRC cells. Molecularly, AT7867 blocked AKT-S6K1 activation in CRC cells. Restoring AKT-S6K1 activation, via expression of a constitutively-active AKT1 ("ca-AKT1"), only partially attenuated AT7867-induced HT-29 cell death...
2017: PloS One
https://www.readbyqxmd.com/read/28078713/the-novel-mtor-complex-1-2-inhibitor-p529-inhibits-human-lung-myofibroblast-differentiation
#3
Keith T Ferguson, Elizabeth E Torr, Ksenija Bernau, Jonathan Leet, Davis Sherris, Nathan Sandbo
Idiopathic pulmonary fibrosis is a progressive and deadly disorder with very few therapeutic options. Palomid 529 (8-(1-hydroxyethyl)-2-methoxy-3-(4-methoxybenzyloxy)-benzo[c]chromen-6-one; P529) is a novel dual inhibitor of mechanistic target of rapamycin complex 1/2 (mTORC1/2). In these studies, we investigated the effect of P529 on TGF-β-dependent signaling and myofibroblast differentiation. TGF-β-induced phosphorylation of the mTORC1 targets, p70 S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), were both dose dependently inhibited by P529 in human lung fibroblasts with maximal inhibition occurring between 10-20 µM...
January 11, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28061838/cryptotanshinone-activates-ampk-tsc2-axis-leading-to-inhibition-of-mtorc1-signaling-in-cancer-cells
#4
Wenxing Chen, Yanhong Pan, Siliang Wang, Yuping Liu, Guangying Chen, Liang Zhou, Wenting Ni, Aiyun Wang, Yin Lu
BACKGROUND: Cryptotanshinone (CPT), a fat-soluble phenanthraquinone from Salvia miltiorrhiza Bunge, has been demonstrated to inhibit phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), a couple of direct downstream effectors of the mammalian target of rapamycin complex 1 (mTORC1), resulting in cancer cell arrested in G0 phase and subsequent inhibition of proliferation. However, its concrete molecular mechanism about how CPT inhibits mTORC1 signaling pathway is unclear...
January 7, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28036295/identification-of-mtor-as-a-primary-resistance-factor-of-the-iap-antagonist-at406-in-hepatocellular-carcinoma-cells
#5
Mao-Chuan Zhen, Fu-Qiang Wang, Shao-Feng Wu, Yi-Lin Zhao, Ping-Guo Liu, Zhen-Yu Yin
Dysregulation of inhibitor of apoptosis (IAP) proteins (IAPs) in hepatocellular carcinoma (HCC) is often associated with poor prognosis. Here we showed that AT406, an IAP antagonist, was cytotoxic and pro-apoptotic to both established (HepG2, SMMC-7721 lines) and primary HCC cells. Activation of mTOR could be a key resistance factor of AT406 in HCC cells. mTOR inhibition (by OSI-027), kinase-dead mutation or knockdown remarkably enhanced AT406-induced lethality in HCC cells. Reversely, forced-activation of mTOR by adding SC79 or exogenous expressing a constitutively active S6K1 (T389E) attenuated AT406-induced cytotoxicity against HCC cells...
December 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/28007963/interaction-of-p190a-rhogap-with-eif3a-and-other-translation-preinitiation-factors-suggests-a-role-in-protein-biosynthesis
#6
Prasanna Parasuraman, Peter Mulligan, James A Walker, Bihua Li, Myriam Boukhali, Wilhelm Haas, Andre Bernards
The negative regulator of Rho family GTPases, p190A RhoGAP, is one of six mammalian proteins harboring so-called FF motifs. To explore the function of these and other p190A segments, we identified interacting proteins by tandem mass spectrometry. Here we report that endogenous human p190A, but not its 50% identical p190B paralog, associates with all 13 eIF3 subunits and several other translational preinitiation factors. The interaction involves the first FF motif of p190A and the winged-helix/PCI domain of eIF3A, is enhanced by serum stimulation and reduced by phosphatase treatment...
December 22, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28004151/reciprocal-regulation-of-mtor-complexes-in-pancreatic-islets-from-humans-with-type-2-diabetes
#7
Ting Yuan, Sahar Rafizadeh, Kanaka Durga Devi Gorrepati, Blaz Lupse, Jose Oberholzer, Kathrin Maedler, Amin Ardestani
AIMS/HYPOTHESIS: Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of nutritional status at the cellular and organismic level. While mTORC1 mediates beta cell growth and expansion, its hyperactivation has been observed in pancreatic islets from animal models of type 2 diabetes and leads to beta cell loss. We sought to determine whether such mTORC1 activation occurs in humans with type 2 diabetes or in metabolically stressed human islets and whether mTORC1 blockade can restore beta cell function of diabetic islets...
December 21, 2016: Diabetologia
https://www.readbyqxmd.com/read/27997905/blocking-mammalian-target-of-rapamycin-mtor-attenuates-hif-1%C3%AE-pathways-engaged-vascular-endothelial-growth-factor-vegf-in-diabetic-retinopathy
#8
Jie Wei, Hua Jiang, Hongrui Gao, Guangjie Wang
BACKGROUND/AIMS: Prior studies demonstrate that hypoxia inducible factor subtype 1α (HIF-1α) in retinal tissues is involved in development of diabetic retinopathy (DR). In this report, we particularly examined the role played by mammalian target of rapamycin (mTOR) in regulating expression of HIF-1α and its downstream pathway, namely vascular endothelial growth factor (VEGF). METHODS: Streptozotocin (STZ) was systemically injected to induce hyperglycemia in rats...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27993818/long-noncoding-rna-malat1-promotes-hepatocellular-carcinoma-development-by-srsf1-up-regulation-and-mtor-activation
#9
Pushkar Malakar, Asaf Shilo, Adi Mogilavsky, Ilan Stein, Eli Pikarsky, Yuval Nevo, Hadar Benyamini, Sharona Elgavish, Xinying Zong, Kannanganattu V Prasanth, Rotem Karni
Several long noncoding RNAs (lncRNA) are abrogated in cancer but their precise contributions to oncogenesis are still emerging. Here we report that the lncRNA MALAT1 is upregulated in hepatocellular carcinoma (HCC) and acts as a proto-oncogene through Wnt pathway activation and induction of the oncogenic splicing factor SRSF1. Induction of SRSF1 by MALAT1 modulates SRSF1 splicing targets, enhancing the production of anti-apoptotic splicing isoforms and activating the mTOR pathway by modulating the alternative splicing of S6K1...
December 19, 2016: Cancer Research
https://www.readbyqxmd.com/read/27993682/trastuzumab-stimulation-of-ribosomal-protein-s6-kinase-1-s6k1-predicts-de-novo-trastuzumab-resistance
#10
Felicia C Huynh, Daniel Nguyen, Frank E Jones
Breast cancer is a complex disease with at least five different molecular subtypes identified. The breast tumor molecular subtypes guide stratification of patients for specific targeted therapy regimens and each subtype is associated with significantly different patient outcomes. For example, patients with the HER2 positive molecular subtype benefit from the HER2 targeted therapy trastuzumab. Unfortunately, women with the HER2 positive molecular subtype have the worst overall prognosis and nearly 70% of women with HER2 positive breast cancer exhibit de novo or acquired resistance to trastuzumab...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27965359/activation-of-the-stress-response-kinase-jnk-attenuates-insulin-action-in-retina-through-a-p70s6k1-dependent-mechanism
#11
William P Miller, Suhana Ravi, Tony D Martin, Scot R Kimball, Michael D Dennis
Despite recent advances in therapeutics, diabetic retinopathy remains a leading cause of vision impairment. Improvement in the treatment of diabetic retinopathy requires a better understanding of the molecular mechanisms that cause neurovascular complications, particularly in type 2 diabetes. The complications of diabetic retinopathy are principally caused by hyperglycemia and reduced insulin-mediated signaling. The purpose of the present study was to evaluate the impact of early type 2 diabetes on retinal insulin signaling and evaluate the mechanism(s) responsible for the changes...
December 13, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27927764/circulating-microrna-are-predictive-of-aging-and-acute-adaptive-response-to-resistance-exercise-in-men
#12
Lee M Margolis, Sarah J Lessard, Yassine Ezzyat, Roger A Fielding, Donato A Rivas
Circulating microRNA (c-miRNA) have the potential to function as novel noninvasive markers of the underlying physiological state of skeletal muscle. This investigation sought to determine the influence of aging on c-miRNA expression at rest and following resistance exercise in male volunteers (Young: n = 9; Older: n = 9). Primary findings were that fasting c-miRNA expression profiles were significantly predictive of aging, with miR-19b-3p, miR-206, and miR-486 distinguishing between age groups. Following resistance exercise, principal component analysis revealed a divergent response in expression of 10 c-miRNA, where expression profiles were upregulated in younger and downregulated in older participants...
December 7, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/27913296/regulation-of-skeletal-muscle-insulin-stimulated-signaling-through-the-mek-redd1-mtor-axis
#13
Cory M Dungan, David L Williamson
Recent findings in adipocytes suggest that mitogen-activated protein kinase (MAPK)/extracellular-regulated signaling kinase (ERK) kinase 1/2 (MEK1/2) signaling regulates regulated in development and DNA damage 1 (REDD1) protein expression. Similarly, our previous work show that a lack of REDD1 protein expression, and associated hyperactive basal mechanistic target of rapamycin (mTOR) signaling, limits skeletal muscle's response to insulin. Therefore, we sought to determine: 1) if MEK1/2 inhibition is sufficient to reduce REDD1 protein expression and subsequently insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation via negative feedback of hyperactive mTOR in REDD1 wild-type (WT) mice and 2) if rapamycin-mediated mTOR inhibition is sufficient to improve IRS-1 tyrosine phosphorylation in REDD1 knockout (KO) mice...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27902464/expression-of-rab1a-is-upregulated-in-human-lung-cancer-and-associated-with-tumor-size-and-t-stage
#14
Xinxin Wang, Feng Liu, Xiaoyu Qin, Tinglei Huang, Bo Huang, Yanjie Zhang, Bin Jiang
Rab1A expression is associated with malignant phenotypes in several human tumors; however, the role of Rab1A in lung cancer is still unclear. In this study, we attempted to establish the role of Rab1A in major human lung cancer subtypes. Rab1A expression in different histological types of human lung cancer was analyzed in lung cancer tissues with paired adjacent noncancerous tissues and a large panel of lung cancer cell lines. The effect of Rab1A expression on multiple cancer-associated signaling pathways was also examined...
November 29, 2016: Aging
https://www.readbyqxmd.com/read/27894091/preclinical-study-of-cinobufagin-as-a-promising-anti-colorectal-cancer-agent
#15
Xing-Sheng Lu, Yin-Biao Qiao, Ya Li, Bo Yang, Min-Bin Chen, Chun-Gen Xing
Here, we assessed the anti-colorectal cancer (CRC) cell activity of cinobufagin (CBG). We found that CBG exerted potent cytotoxic and anti-proliferative activity against CRC lines (HCT-116 and HT-29) and primary human CRC cells. Meanwhile, it activated apoptosis, and disrupted cell-cycle progression in the cells. At the signaling level, CBG treatment in CRC cells provoked endoplasmic reticulum stress (ER stress), the latter was evidenced by caspase-12 activation, CHOP expression, as well as PERK and IRE1 phosphorylations...
November 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27891586/celastrol-attenuates-cadmium-induced-neuronal-apoptosis-via-inhibiting-ca-2-camkii-dependent-akt-mtor-pathway
#16
Ruijie Zhang, Yu Zhu, Xiaoqing Dong, Beibei Liu, Nana Zhang, Xiaoxue Wang, Lei Liu, Chong Xu, Shile Huang, Long Chen
Cadmium (Cd), an environmental and industrial pollutant, affects the nervous system and consequential neurodegenerative disorders. Recently we have shown that celastrol prevents Cd-induced neuronal cell death partially by suppressing Akt/mTOR pathway. However, the underlying mechanism remains to be elucidated. Here we show that celastrol attenuated Cd-elevated intracellular free calcium ([Ca(2+) ]i ) level and apoptosis in neuronal cells. Celastrol prevented Cd-induced neuronal apoptosis by inhibiting Akt-mediated mTOR pathway, as inhibition of Akt with Akt inhibitor X or ectopic expression of dominant negative Akt reinforced celastrol's prevention of Cd-induced phosphorylation of S6K1/4E-BP1 and cell apoptosis...
November 27, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27888418/suppression-of-mtor-signaling-pathway-promotes-bone-marrow-mesenchymal-stem-cells-differentiation-into-osteoblast-in-degenerative-scoliosis-in-vivo-and-in-vitro
#17
Yu Wang, Xiao-Dong Yi, Chun-De Li
To investigate the role of mTOR signaling pathway in bone marrow mesenchymal stem cells (BMSCs) differentiation into osteoblast in degenerative scoliosis (DS). The rat model of DS was established. Thirty-two Sprague-Dawley (SD) rats were selected and divided into the normal control group, the positive control group (normal rats injected with rapamycin), the negative control group (DS rats injected with PBS) and the experiment group (DS rats injected with rapamycin). H&E staining was performed to observe the osteogenesis of scoliosis...
November 25, 2016: Molecular Biology Reports
https://www.readbyqxmd.com/read/27888132/vitamin-e-deficiency-depressed-fish-growth-disease-resistance-and-the-immunity-and-structural-integrity-of-immune-organs-in-grass-carp-ctenopharyngodon-idella-referring-to-nf-%C3%AE%C2%BAb-tor-and-nrf2-signaling
#18
Jia-Hong Pan, Lin Feng, Wei-Dan Jiang, Pei Wu, Sheng-Yao Kuang, Ling Tang, Yong-An Zhang, Xiao-Qiu Zhou, Yang Liu
This study investigated the effects of dietary vitamin E on growth, disease resistance and the immunity and structural integrity of head kidney, spleen and skin in grass carp (Ctenopharyngodon idella). The fish were fed six diets containing graded levels of vitamin E (0, 45, 90, 135, 180 and 225 mg/kg diet) for 10 weeks. Subsequently, a challenge test was conducted by injection of Aeromonas hydrophila. The results showed that compared with optimal vitamin E supplementation, vitamin E deficiency caused depressed growth, poor survival rates and increased skin lesion morbidity in grass carp...
November 22, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27888130/protective-role-of-phenylalanine-on-the-ros-induced-oxidative-damage-apoptosis-and-tight-junction-damage-via-nrf2-tor-and-nf-%C3%AE%C2%BAb-signalling-molecules-in-the-gill-of-fish
#19
Lin Feng, Wen Li, Yang Liu, Wei-Dan Jiang, Sheng-Yao Kuang, Pei Wu, Jun Jiang, Ling Tang, Wu-Neng Tang, Yong-An Zhang, Xiao-Qiu Zhou
This study explored the possible preventive effects of dietary phenylalanine (Phe) on antioxidant responses, apoptosis and tight junction protein transcription in the gills of young grass carp (Ctenopharyngodon idella). Fish were fed six different experimental diets containing graded levels of Phe (3.4-16.8 g kg(-1)) for 8 weeks. The results showed that Phe deficiency induced protein oxidation and lipid peroxidation by decreasing the glutathione content and the activities and mRNA levels of Cu/Zn superoxide dismutase (SOD1), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) in fish gill (P < 0...
November 23, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27879318/inactivation-of-regulatory-associated-protein-of-mtor-raptor-mammalian-target-of-rapamycin-complex-1-mtorc1-signaling-in-osteoclasts-increases-bone-mass-by-inhibiting-osteoclast-differentiation-in-mice
#20
Qinggang Dai, Furong Xie, Yujiao Han, Xuhui Ma, Siru Zhou, Lingyong Jiang, Weiguo Zou, Jun Wang
Mammalian target of rapamycin complex 1 (mTORC1) is involved in anabolic metabolism in both osteoblasts and chondrocytes, but the role of mTORC1 in osteoclast biology in vivo remains to be elucidated. In this study, we showed that deletion of regulatory-associated protein of mTOR (Raptor) in osteoclasts led to an increase in bone mass with decreased bone resorption. Raptor-deficient bone marrow-derived macrophages exhibited lower mTORC1-S6K1 signaling and retarded osteoclast differentiation, as determined by the number of osteoclasts, tartrate-resistant acid phosphatase activity, and expression of osteoclast-specific genes...
January 6, 2017: Journal of Biological Chemistry
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